Reductive nitro-mannich route for the synthesis of 1,2-diamine containing indolines and tetrahydroquinolines

Article abstract of DOI:10.1021/jo3010827

A one-pot, 1,4-hydride addition nitro-Mannich reaction between a set of nitroalkenes 3 and a wide range of N-p-methoxyphenyl-protected aldimines, derived from alkyl, aryl and heteroaryl aldehydes, followed by Zn/HCl reduction leads to stereochemically defined 1,2-diamines. These underwent palladium-catalyzed cyclization and depending upon the presence or not of the trifluoroacetamide protecting group gave either tetrahydroquinolines 18 or indolines 14 in high overall yield and diastereoselectivity (19 examples each). In each case, the more nucleophilic pendant amine cyclizes to give a benzofused saturated heterocyclic 5- or 6-membered ring, with an additional vicinal amino stereocenter in each.

Full text of DOI:10.1021/jo3010827

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Reductive Nitro-Mannich Route for the Synthesis of 1,2-Diamine
Containing Indolines and Tetrahydroquinolines
James C. Anderson,* Adam Noble, and Derek A. Tocher†
Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, U.K.
S
* Supporting Information
ABSTRACT: A one-pot, 1,4-hydride addition nitro-Mannich reaction between a set of nitroalkenes 3 and a wide range of N-p-
methoxyphenyl-protected aldimines, derived from alkyl, aryl and heteroaryl aldehydes, followed by Zn/HCl reduction leads to
stereochemically defined 1,2-diamines. These underwent palladium-catalyzed cyclization and depending upon the presence or
not of the trifluoroacetamide protecting group gave either tetrahydroquinolines 18 or indolines 14 in high overall yield and
diastereoselectivity (19 examples each). In each case, the more nucleophilic pendant amine cyclizes to give a benzofused
saturated heterocyclic 5- or 6-membered ring, with an additional vicinal amino stereocenter in each.
used as a hydride source in the conjugate addition (Scheme
1).10 The use of nitroalkenes (prepared via the Henry reaction)
INTRODUCTION
■
The nitro-Mannich (or aza-Henry) reaction is a powerful
synthetic tool for the construction of C−C bonds. It enables
the formation of β-nitroamines with two contiguous stereo-
centers, often with high levels of enantio- and diastereose-
lectivity.1 These useful synthetic intermediates provide access
to other valuable moieties such as α-amino acids (via Nef
reaction), vicinal diamines (via nitro reduction), and peptides.2
Although first reported by Henry in 1896,3 the nitro-Mannich
reaction received little attention for over a century until the first
acyclic diastereoselective examples.4 There have since been
huge advances in this field with the advent of numerous
asymmetric transition-metal-catalyzed, lanthanide-catalyzed,
and organocatalytic methods.5−7 These now provide easy
access to a range of β-nitroamines with highly selective
procedures available for the formation of both anti- and syn-
diastereomers. The synthetic utility of this reaction has been
further demonstrated through its successful use in the synthesis
of a number of natural products and pharmaceuticals.8
Although there have been considerable advances in the scope
and efficiency of nitro-Mannich protocols, limitations still exist
with respect to the complexity of the nitroalkane used.
Recently, our group disclosed an enantioselective conjugate
addition nitro-Mannich reaction in which addition of
dialkylzincs to nitroalkenes generates zinc nitronates. These
are subsequently trapped with an imine to generate complex β-
nitroamines with excellent diastereocontrol over three con-
tiguous stereocenters.9 Our group also recently published an
achiral reductive nitro-Mannich reaction in which LiHBEt3 is
Scheme 1. Conjugate Addition Nitro-Mannich Reactions
provides easy access to more structurally complex nitro
coupling partners, thereby generating β-nitroamines with
higher levels of functionality which may be further manipulated
to produce a range of useful intermediates.
We envisaged the use of nitroalkenes bearing a pendant o-
halo-aromatic group which could later be utilized in intra-
molecular N-arylation reactions to form a variety of fused
heterocyclic structures (Scheme 2). Synthetic routes to
structurally diverse fused nitrogen heterocycles are of interest
because of their importance in medicinal chemistry and
abundance in biologically active natural products.11,12 Herein,
we report an expedient and highly diastereoselective synthesis
of both 2-aminomethylene indolines 1 and 3-aminotetrahy-
droquinolines 2 by utilizing a diamine derived from a reductive
nitro-Mannich reaction in selective intramolecular N-arylations.
Received: May 25, 2012
© XXXX American Chemical Society
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resulted in a number of complications due to the formation of
dihydroimidazole 11 and both diastereomers of imidazolidine
12 via elimination of water during transacylation and
subsequent reduction of the CN bond (Scheme 4, Table
1). Initial attempts using well-established reduction protocols
gave poor conversions to 7a. Hydrogenation resulted in
complete debromination to form 9 with no observed reduction
of the nitro group, and Raney nickel/N2H4 showed only trace
amounts of hydroxylamine 10 (Table 1, entries 1 and 2).13,14
Nickel boride resulted in complete reduction of 6a but with
debrominated diamine 8 formed as the major product (Table 1,
entry 3).15 Using zinc hydrochloride (Zn/HCl) in EtOH gave a
mixture of the desired diamine 7a, hydroxylamine 10, and two
diastereomers of imidazolidine 12 in a 2:1 dr (Table 1, entry
4).16 Although diamine 7a was formed as the minor product,
the stability of the aromatic bromide under the Zn/HCl
conditions prompted further optimization studies. Increasing
the equivalents of both Zn and HCl increased the amount of
reduction of hydroxylamine 10 but resulted in formation of
imidazolidine 12 (2.5:1 dr) as the major product (Table 1,
entry 5). It was found that using an excess of HCl with respect
to Zn greatly reduced the formation imidazolidine 12, instead
giving rise to larger amounts of dihydroimidazole 11 and the
desired product 7a (Table 1, entries 6−9). Complete reduction
of hydroxylamine 10 was accomplished by addition of the Zn in
two portions, although the additional zinc resulted in the
formation of small amounts of debromination product 8 (Table
1, entry 10). Using a mixture of EtOH and EtOAc aided
solubilization of the reactants and enabled the reactions to be
conducted at higher concentration. Hydrolysis of dihydroimi-
dazole 11, by treating the crude product with 6 M HCl,
provided near-quantitative conversion to diamine 7a and gave a
purified yield of 89% (Table 1, entry 11).
Scheme 2. Synthesis of 1,2-Diamine-Containing Fused
Nitrogen Heterocycles
RESULTS AND DISCUSSION
■
Initial studies began with the LiHBEt3-mediated reductive
nitro-Mannich reaction between 2-bromo-β-nitrostyrene (3)
and N-p-methoxyphenyl (PMP)-phenyl imine (4). Using
conditions previously developed by us, the reaction proceeded
smoothly to provide β-nitroamine 5a with complete conversion
and >95:5 diastereomeric ratio (dr) in favor of the anti-
diastereomer.10 Because of the susceptibility of PMP-protected
β-nitroamines to retro-addition, the product was protected by
treatment with trifluoroacetic anhydride (TFAA) in the
presence of diisopropylethylamine (DIPEA) to provide β-
nitroacetamide 6a in 71% yield over two steps from nitroalkene
3 (Scheme 3).9 The relative stereochemistry of the major
diastereomer was confirmed by single-crystal X-ray crystallog-
raphy (see the Supporting Information).
Scheme 3. Synthesis of β-Nitrotrifluoroacetamide 6a
At this stage, the trifluoroacetyl protecting group could be
removed by treating 7a with KOH in EtOH and H2O,
providing monoprotected diamine 13 in 94% yield (Scheme 5).
With conditions developed that provided ready access to both
bis- and monoprotected diamines 13 and 7a attention was
turned to the intramolecular N-arylation reaction.
To generate the indoline and tetrahydroquinoline structures,
we investigated the use of intramolecular Buchwald−Hartwig
chemistry,17 which has previously been successfully applied to
the formation of 5- and 6-membered ring heterocycles
containing a single amine group.18 Although selective
intermolecular monoarylations of poly- and diamines have
been reported,19 intramolecular examples are far less common
and have mainly been applied to the formation of
polyazamacrocycles in low to moderate yields.20 We began
our investigations by applying catalyst systems that had
The next stage in the synthesis was reduction of the nitro
group to form the 1,2-diamine required for the intramolecular
N-arylation reactions. The reduction of β-nitroacetamide 6a to
form β-aminoacetamide 7a initially proved to be problematic
due to complications caused by the lability of the aromatic
bromide (resulting in the formation of 8 or 9) and the difficulty
in reducing the hydroxylamine intermediate 10. Concomitant
transacylation of the trifluoroacetyl group was observed during
reduction, which is in agreement with previous studies on
similar systems.9,10 This transacylation process, however, also
Scheme 4. Products from Nitro Reduction
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Table 1. Optimization of Nitro Reduction
a
conversion (%)
entry
conditions
7a
8
9
10
11
12
1
2
3
4
5
6
7
8
9
H2, Pd/C, MeOH
Raney Ni/N2H4
0
0
100
0
0
0
0
0
0
0
0
<5
43
0
NiCl2.6H2O, NaBH4, MeOH
35
9
0
21
53
19
28
13
13
8
2
0
Zn (60 equiv), 6 M HCl (30 equiv), EtOH
Zn (80 equiv), 6 M HCl (40 equiv), EtOH
Zn (60 equiv), 6 M HCl (100 equiv), EtOH
Zn (60 equiv), 6 M HCl (200 equiv), EtOH
Zn (60 equiv), 6 M HCl (300 equiv), EtOH
Zn (100 equiv), 6 M HCl (300 equiv), EtOH
Zn (75 equiv), 6 M HCl (300 equiv), EtOH
Zn (75 equiv), 6 M HCl (250 equiv), EtOH, EtOAc
0
0
38
48
1
32
62
74
67
62
78
0
0
1
0
0
9
0
0
13
20
25
16
0
0
0
0
0
5
0
0
b
10
6
0
0
0
b,c
11
95 (89)
5
0
0
0
a
b
c
Determined by 1H NMR. Numbers in parentheses show purified yield. Zinc added in two portions (50 and 25 equiv). Crude product treated with
6 M HCl (20 equiv) in EtOH for 1 h.
Scheme 5. Synthesis of Bis- and Monoprotected Diamines 7a
and 13
Table 2. Optimization of Indoline Formation
a
conversion (%)
4 +
15
entry
1
conditions
14a
16
Pd(PPh3)4 (5 mol %), NaOtBu (1.6 equiv),
K2CO3 (1.6 equiv), toluene, 90 °C
Pd(PPh3)4 (5 mol %), NaOtBu (1.6 equiv),
K2CO3 (1.6 equiv), toluene, 100 °C, 4 h
Pd2(dba)3 (3.3 mol %), P(o-tol)3 (13.3
mol %), CsCO3 (4.0 equiv), toluene,
100 °C
94 (54)
6
<5
<5
0
b
2
>95 (91)
21
0
0
3
previously been used by Buchwald et al. for the formation of
simple indoline and tetrahydroquinoline structures.18a Initial
attempts to affect the cyclization of monoprotected diamine 13
(Scheme 6) were very promising with a 54% yield of indoline
4
5
Pd(dppf)Cl2 (5 mol %), dppf (15 mol %),
NaOtBu (1.6 equiv), toluene, 100 °C, 5 h
Pd2(dba)3 (5 mol %), BINAP (15 mol %),
NaOtBu (1.6 equiv), toluene, 100 °C, 5 h
Pd(OAc)2 (5 mol %), P(o-tol)3 (15 mol %),
NaOtBu (1.6 equiv), toluene, 100 °C, 5 h
70 (65)
73 (51)
27
<5
6
5
9
Scheme 6. Indoline Formation
6
5
0
7
Pd(PPh3)4 (5 mol %), NaOtBu (1.6 equiv),
toluene, 100 °C, 5 h
Pd(PPh3)4 (5 mol %), NaOtBu (2.5 equiv),
toluene, 100 °C, 18 h
Pd(PPh3)4 (5 mol %), K2CO3 (1.6 equiv),
toluene, 100 °C, 5 h
Pd(PPh3)4 (5 mol %), K2CO3 (2.5 equiv),
toluene, 100 °C, 18 h
Pd(PPh3)4 (5 mol %), Cs2CO3 (1.6 equiv),
32
<5
6
0
8
85 (77)
24
6
9
0
<5
17
0
10
11
69 (48)
30
0
0
toluene, 100 °C, 5 h
a
Determined by 1H NMR. Numbers in parentheses show purified
b
yield. Reaction performed with rigorously dried bases and degassed
14a obtained by treatment with Pd(PPh3)4, NaO-t-Bu, and
K2CO3 in toluene at 90 °C (Table 2, entry 1). The product was
accompanied by trace amounts of imine 4 and indole 15,
formed due to the slight instability of 14a to oxidative cleavage
under the reaction conditions (Scheme 6). Rigorous drying of
the bases, degassing of the solvent, and performing the reaction
at 100 °C gratifyingly increased the yield of 14a to 91% (Table
2, entry 2). Various other catalyst systems were also
investigated, but none proved to be as effective as Pd(PPh3)4
(Table 2, entries 2−6). Using conditions employed by the
groups of Jackson and Buchwald for the synthesis of 2-
substituted indolines gave poor conversion to the desired
product (Table 2, entry 3).18b,c Pd(dppf)Cl2/dppf and
Pd2(dba)3/BINAP catalyst systems gave moderate yields of
indoline 14a and also resulted in small amounts of
tetrahydroquinoline 16 (Table 2, entries 3 and 4). It was
found that the cyclization could also be performed with only
NaOtBu as a base, however, the reaction did not proceed as
cleanly as those with two bases resulting in a lower yield of 77%
(Table 2, entry 8). Using only K2CO3 reduced the rate of
solvent.
reaction and resulted in an increased amount of tetrahydro-
quinoline 16 formation (Table 2, entry 10).
Although small amounts of the tetrahydroquinoline 16 were
formed in several reactions (Table 2, entries 4, 5, and 8−10)
further attempts to switch selectivity to favor tetrahydroquino-
line formation were unsuccessful. This was assumed to be due
to the significant difference in rates of formation of the 5- and
6-membered rings. Attention was therefore shifted to the
cyclization of orthogonally protected diamine 7a (Scheme 7,
Table 3). It was postulated that the presence of the
trifluoroacetyl protecting group would enable selective
tetrahydroquinoline formation due to the significantly lower
nucleophilicity of the amide nitrogen. Gratifyingly, complete
reversal of selectivity was observed when 7a was submitted to
the N-arylation conditions, with no formation of the
trifluoroacetyl-protected indoline 17 observed (Table 3, entry
1). Tetrahydroquinoline 18a was formed in 54% yield,
C
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Scheme 7. Tetrahydroquinoline Formation
Scheme 8. Scope of Reductive Nitro-Mannich Route to
Cyclization Precursors 6
nitroacetamide products 6 was achieved by separation of the
two diastereomers during purification by flash column
chromatography. The imines derived from cyclohexyl and
tert-butyl aldehydes performed well in the nitro-Mannich
reaction, with good conversion and diastereoselectivity, but
failed to undergo trifluoroacetyl protection (Table 4, entries 6
and 7). The product derived from 2-trifluoromethylbenzalde-
hyde also suffered from a slower rate in the trifluoroacetyl
protection and required the use of additional TFAA and base to
achieve satisfactory yields (Table 4, entry 15). A number of
substituted 2-bromo-β-nitrostyrenes were also employed in the
reaction and gave uniformly high yields and diastereoselectiv-
ities (Table 4, entries 16−19). Likewise, the nitroalkene derived
from 2-chloro-3-pyridine carboxaldehyde also gave a good yield
of the desired product (Table 4, entry 20).
The successfully synthesized β-nitroacetamides 6a−d,g−t
were then used to investigate the scope of the nitro reduction
(Scheme 9, Table 5). The reduction gave uniformly high yields
in the majority of cases with yields ranging from 79% to 95%
(Table 5, entries 1−6 and 8−15). Problems arising from
debromination occurred when forming compounds 7i, 7r, and
7s (Table 5, entries 7, 16, and 17). Although trace amounts of
the respective debrominated products were formed in the
majority of cases, these could be removed either by column
chromatography or recrystallization. The reductions to form
compounds 7i, 7r, and 7s, however, resulted in significant
amounts of debrominated product which could not be removed
by either column chromatography or recrystallization, thereby
preventing the isolation of these products in pure form. It
should be noted that debromination of dibromo analogue 7i
occurred at the C−Br bond in the R2 substituent, resulting in
the formation of 7a. The reactive C−Cl bond in pyridine
analogue 6t was not stable under the reduction conditions and
complete dechlorination resulted (Table 5, entry 18).
To overcome these dehalogenation problems and resolve the
problem associated with the failure of compounds 5f and 5g to
undergo trifluoroacetyl protection, alternative routes to the
orthogonally protected diamines were investigated (Scheme
10). Previous studies within our group have shown that
unstable β-nitroamines can be cleanly reduced to β-amino-
hydroxylamines by using aluminum amalgam and MeOH.21
The stable β-aminohydroxylamines could then be reduced to
1,2-diamines by either hydrogenation or with LiAlH4. Initial
investigations focused on the reduction of cyclohexyl analogue
5f (Scheme 10, route A). Using slightly modified conditions to
those reported previously,21 the reduction proceeded smoothly
to yield β-aminohydroxylamine 19 in 56% yield and with
excellent dr after separation of the diastereomers by column
chromatography. The anti-configuration of 19 was confirmed
by single-crystal X-ray crystallography (see the Supporting
Information). Further reduction with LiAlH4, followed by
protection of the crude diamine yielded 81% of orthogonally
protected diamine 7f. The use of the Zn/HCl reduction on the
Table 3. Optimization of Tetrahydroquinoline Formation
a
conversion (%)
entry
1
conditions
18a
16
14a
Pd(PPh3)4 (5 mol %), NaOtBu (1.6
equiv), K2CO3 (1.6 equiv), toluene,
90 °C, 18 h
72 (54)
10
12 (7)
2
3
Pd(dppf)Cl2 (5 mol %), dppf (15
mol %), NaOtBu (1.4 equiv),
toluene, 90 °C, 18 h
Pd2(dba)3 (2.5 mol %), BINAP (7.5
mol %), NaOtBu (1.4 equiv),
toluene, 90 °C, 5 h
20
<5
0
0
5
<5
4
5
6
7
Pd(PPh3)4 (5 mol %), NaOtBu (1.6
equiv), toluene, 90 °C, 18 h
Pd(PPh3)4 (5 mol %), K2CO3 (1.6
equiv), toluene, 90 °C, 18 h
Pd(PPh3)4 (5 mol %), LiHMDS (1.6
equiv), toluene, 90 °C, 18 h
Pd(PPh3)4 (5 mol %), K2CO3 (2.5
equiv), toluene, 100 °C, 18 h
71 (54)
90 (76)
<10
19
0
<5
0
0
0
100 (98)
0
0
a
Determined by 1H NMR. Numbers in parentheses show purified
yield.
accompanied by deprotected tetrahydroquinoline 16 and
indoline 14a (Scheme 7). These additional products are
presumably formed via deprotection of the trifluoroacetyl group
by tert-butoxide anions present in the reaction. Deprotection
prior to cyclization results in the formation of monoprotected
diamine 13, which can then undergo cyclization forming
indoline 14a. Various other catalyst systems were investigated
but all failed to compete with the Pd(PPh3)4-catalyzed reaction
(Table 3, entries 2 and 3). By varying the bases used in the
reaction it became clear that the trifluoroacetyl group would
not tolerate NaOtBu, with deprotection occurring both before
and after cyclization to give multiple products (Table 3, entry
4). Using only K2CO3 gave a very clean reaction affording 76%
of 18a (Table 3, entry 5). Increasing the equivalents of K2CO3
and increasing the temperature to 100 °C resulted in complete
conversion to tetrahydroquinoline 18a, which was isolated in
98% yield (Table 3, entry 7).
Following the successful synthesis of both indoline 14a and
tetrahydroquinoline 18a, with excellent levels of diastereose-
lectivity and high yield, attention was then turned to
investigating the scope of the methodology. This began with
the reductive nitro-Mannich reaction, which was applied to a
range of imines and nitroalkenes (Scheme 8, Table 4). The
nitro-Mannich reactions to form 5 proceeded with excellent
diastereoselectivity and the subsequent trifluoroacetamides 6
were formed in good yield for a wide range of imines derived
from aryl, heteroaryl, and alkyl substituents (Table 4, entries 1−
15). Enhancement of the diastereoselectivity of the β-
D
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Table 4. Scope of the Reductive Nitro-Mannich Reaction
a
b
c
d
1
Determined by H NMR. Isolated yields. No reaction occurred. Protection performed with 5.0 equiv TFAA and 5.0 equiv pyridine.
Scheme 9. Scope of Nitro Reduction
Table 5. Scope of Nitro Reduction
crude β-nitroamines was also investigated. It was previously
thought that these compounds would not be stable to acidic
reduction conditions due to their propensity to undergo retro-
addition. However, in the absence of a trifluoroacetyl-
protecting group the reduction becomes much more facile
and can be performed with only 20 equiv of HCl and 10 equiv
of zinc. The rate of reduction is also increased and therefore
minimizes the amount of retro-addition that occurs. These
conditions were used to reduce β-nitroamine 5f which, after
subsequent trifluoroacetyl protection of the diamine, gave a
68% yield of orthogonally protected diamine 7f and with no
observed debromination (Scheme 5, route B). It was found that
separation of the diastereomers of 7f could not be achieved
effectively by column chromatography, but recrystallization
could be used to obtain the major anti-diastereomer with dr >
95:5. The use of Zn/HCl was found to be preferable to
aluminum amalgam as it gave a higher overall yield, required
only a single chromatographic purification, and also avoided the
use of toxic mercury reagents. These conditions enabled the
formation of orthogonally protected 1,2-diamines 7g, 7i, 7r,
and 7s in moderate to good yields (Scheme 6). Because of the
high reactivity of the C−Cl bond in pyridine analogue 5t,
a
b
1
Isolated yields. Determined by H MNR. Numbers in parentheses
c
show conversion to dehalogenated β-aminoacetamide. Debromina-
tion caused inseparable mixture of products.
E
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Scheme 10. Alternative Reduction Strategy
Table 6. Scope of Heterocycle Formation
a
a
entry
R1
R2
18 (%)
98
14 (%, two steps)
b
a
b
c
d
e
f
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
5-F
Ph
86
2-furyl
92
94
91
89
81
61
88
69
66
73
66
80
87
74
3-furyl
2-thienyl
n-pentyl
c
c
cyclohexyl
tert-butyl
2-Me-C6H4
2-Br-C6H4
2-MeO-C6H4
3-MeO-C6H4
4-MeO-C6H4
2-CF3-C6H4
3-CF3-C6H4
4-CF3-C6H4
Ph
g
h
i
d
e
54 (27)
98
83
j
56
66
64
65
59
78
50
48
42
58
k
l
90
98
m
n
o
p
q
r
97
99
99
93
4-MeO, 5-MeO
4-MeO, 5-MeO
Ph
91
2-MeO-C6H4
Ph
88
s
3-OBn, 4-MeO
31
a
b
c
Isolated yields. 5 mol % of Pd(PPh3)4. 10 mol % of Pd(PPh3)4.
d
e
Yield obtained when using 5 mol % of Pd(PPh3)4. NaO-t-Bu (3.2
application of the Zn/HCl reduction protocol again resulted in
dechlorination, with no desired product isolated. This was also
the case when the Al/Hg reduction protocol was used, as the
reduction of the hydroxylamine intermediate with LiAlH4
resulted in dechlorination. The failure to synthesize diamine
7t represents a limitation of the current synthesis and further
investigations into milder reduction protocols are required.
With all of the desired orthogonally protected diamines
formed, the synthesis of the fused heterocycles was surveyed
(Scheme 11, Table 6). The tetrahydroquinolines 18 were
formed in excellent yields in nearly all cases.
equiv) and K2CO3 (3.2 equiv).
Scheme 12. Trifluoroacetyl-Protected Indoline Formation
Scheme 11. Heterocycle Formation
relatively small steric differences between each C−Br bond.
The yield of 18i could be improved to 54% by doubling the
amount of catalyst to 10 mol %. This product was then used to
synthesize tetracycle 22, first by removal of the trifluoroacetyl
group, furnishing primary amine 23 in 87% yield, and
subsequent cyclization, to give 22 in 40% yield (Scheme 13).
Scheme 13. Synthesis of Tetracycle 22
Examples containing bulky alkyl substituents, such as
cyclohexyl and tert-butyl analogues 18f and 18g, were formed
in lower yields due to the unexpected formation of indolines 20
and 21 in 15% and 38% yield, respectively (Scheme 12). The
use of 10 mol % of Pd(PPh3)4 was required to achieve a good
yield of 18f due to the instability of 7f under the reaction
conditions.
When dibromo analogue 7i was submitted to the cyclization
conditions, 18i was formed in only 27% yield because of
competing oxidative addition of the palladium catalyst to both
C−Br bonds. Although the yield was low, the reaction
demonstrates surprisingly high selectivity (ca. 85:15) for the
desired C−Br bond, considering this selectivity arises from
The modest yield of the final cyclization reaction is believed to
be due to the formation of a relatively strained trans-fused ring
system. The cyclization also failed to provide a satisfactory yield
of tetrahydroquinoline 18s, presumably due to the formation of
a sterically crowded product with the PMP and OBn groups in
close proximity to one another (Table 6).
F
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mmol). The mixture was stirred at room temperature for 20 min to
give a white precipitate before being cooled to −78 °C. A solution of
imine (1.10 mmol) in CH2Cl2 (2.8 mL) was added and the mixture
stirred for 10 min before the dropwise addition of trifluoroacetic acid
(1.15 mmol) over 30 s. The reaction was stirred at −78 °C for 90 min
before being removed from the cold bath and allowed to warm for 5
min giving a yellow solution. The reaction was quenched by the
addition of satd aq NaHCO3 and the product extracted into Et2O. The
combined organic phases were washed with brine, dried (MgSO4),
filtered, and concentrated in vacuo to give the crude β-nitroamine
which was used without further purification.
N-((1R*,2S*)-3-(2-Bromophenyl)-2-nitro-1-phenylpropyl)-4-me-
thoxyaniline (5a). Nitroalkene 3 (299 mg, 1.31 mmol) afforded crude
β-nitroamine 5a as a yellow solid (812 mg, >95% conv, >95:5 dr): IR
νmax (neat) 3393, 3058−2833, 1552, 1511, 1243 cm−1; 1H NMR (400
MHz, CDCl3) δ 3.43 (1H, dd, J = 14.7, 10.9), 3.55 (1H, dd, J = 14.7,
2.8), 3.72 (3H, s), 4.26 (1H, d, J = 6.8), 4.93 (1H, t, J = 6.4), 5.19 (1H,
ddd, J = 10.9, 5.9, 2.9), 6.60 (2H, dm, J = 8.9), 6.74 (2H, dm, J = 8.9),
7.10−7.26 (3H, m), 7.32−7.42 (5H, m), 7.53 (1H, dd, J = 7.9, 0.9);
13C NMR (101 MHz, CDCl3) δ 35.7 (CH2), 55.7 (CH3), 62.1 (CH),
91.7 (CH), 114.8 (CH), 115.9 (CH), 124.3 (C), 127.1 (CH), 127.9
(CH), 128.7 (CH), 129.1 (CH), 129.3 (CH), 131.6 (CH), 133.2
(CH), 135.0 (C), 137.4 (C), 139.9 (C), 153.1 (C); MS (ESI+) m/z
441 + 443 (1:1, 42, M + H+), 212 (67, PhCH+NHPMP); HRMS
C22H22(79Br)N2O3 calcd 441.0808, found 441.0798.
N-((1S*,2S*)-3-(2-Bromophenyl)-1-(furan-2-yl)-2-nitropropyl)-4-
methoxyaniline (5b). Nitroalkene 3 (1.01 g, 4.42 mmol) afforded
crude β-nitroamine 5b as a yellow oily solid (2.59 g, >95% conv, 85:15
dr): IR νmax (neat) 3368, 3124−2834, 1551, 1510, 1240, 1034 cm−1;
1H NMRanti (400 MHz, CDCl3) δ 3.47 (1H, dd, J = 14.7, 10.0), 3.64
The final set of cyclizations to be performed were the
indoline syntheses, requiring initial trifluoroacetyl deprotection
of orthogonally protected diamines 7a−s and subsequent
cyclization of the monoprotected diamines (Table 6). Although
the original conditions developed for the synthesis of indoline
14a from diamine 13 used 5 mol % of Pd(PPh3)4, it was found
that the byproduct resulting from the instability of some of the
indoline products 14 caused a decrease in catalyst efficiency and
that more reproducible results could be obtained by increasing
the amount of Pd(PPh3)4 to 10 mol %. This catalyst loading
was then used in the investigation into the scope of indoline
formation. The reactions proceeded with moderate to high
yield over the two steps to furnish indoline products 14a−s.
The yields were consistent for a range of aryl, heteroaryl and
alkyl containing analogues (Table 6). The yields of the
substituted indolines 14p−s were found to be lower as a result
of their lower stabilities, which resulted in difficult purifications
(Table 6). The product formed from the reaction of dibromo
analogue 7i was tetracycle 14i (Table 6 and Scheme 14). This
resulted from a double cyclization reaction which required the
use of additional base for the reaction to reach completion.
Scheme 14. Synthesis of Tetracycle 14i
(1H, dd, J = 14.6, 3.9), 3.75 (3H, s), 4.16 (1H, br d, J = 9.6), 5.02 (1H,
dd, J = 9.9, 6.1), 5.25 (1H, ddd, J = 10.0, 6.1, 4.0), 6.30−6.34 (2H, m),
6.64−6.68 (2H, m), 6.75−6.80 (2H, m), 7.12−7.27 (3H, m), 7.41
1
(1H, m), 7.57 (1H, m); H NMRsyn (400 MHz, CDCl3) δ 3.30 (1H,
dd, J = 14.3, 4.7), 3.41 (1H, dd, J = 14.3, 9.6), 3.74 (3H, s), 4.16 (1H,
br d, J = 9.6), 4.90 (1H, dd, J = 10.7, 7.9), 5.33 (1H, ddd, J = 9.6, 7.9,
4.8), 6.30−6.34 (2H, m), 6.64−6.68 (2H, m), 6.75−6.80 (2H, m),
7.12−7.27 (3H, m), 7.41 (1H, m), 7.55 (1H, m); 13C NMRanti (151
MHz, CDCl3) δ 36.4 (CH2), 55.8 (CH3), 56.5 (CH), 89.3 (CH), 108.9
(CH), 110.7 (CH), 115.0 (CH), 116.4 (CH), 124.5 (C), 128.1 (CH),
129.5 (CH), 131.8 (CH), 133.3 (CH), 135.1 (C), 139.6 (C), 143.0
(CH), 150.1 (C), 153.6 (C); 13C NMRsyn (151 MHz, CDCl3) δ 37.5
(CH2), 55.7 (CH3), 56.4 (CH), 90.0 (CH), the remaining signals
could not be determined; MS (EI) m/z 430 + 432 (1:1, 5, M+), 202
(96, FurylCH+NHPMP); HRMS C20H19(79Br)N2O4 calcd 430.0523,
found 430.0531.
N-((1R*,2S*)-3-(2-Bromophenyl)-1-(furan-3-yl)-2-nitropropyl)-4-
methoxyaniline (5c). Nitroalkene 3 (1.29 g, 5.65 mmol) afforded
crude β-nitroamine 5c as a yellow oily solid (3.20 g, >95% conv, 85:15
dr): IR νmax (neat) 3392, 3131−2834, 1551, 1510, 1241, 1025 cm−1;
1H NMRanti (600 MHz, CDCl3) δ 3.43 (1H, dd, J = 14.6, 10.3), 3.59
(1H, dd, J = 14.6, 3.5), 3.76 (3H, s), 4.00 (1H, br s), 4.91 (1H, d, J =
4.5), 5.16 (1H, ddd, J = 10.2, 6.3, 3.8), 6.41 (1H, m), 6.66 (2H, dm, J
= 8.9), 6.79 (2H, dm, J = 8.9), 7.16 (1H, td, J = 7.6, 1.8), 7.20 (1H, dd,
J = 7.6, 1.7), 7.25 (1H, td, J = 7.5, 1.0), 7.42 (1H, m), 7.47 (1H, s),
7.57 (1H, dd, J = 8.0, 0.9); 1H NMRsyn (600 MHz, CDCl3) δ 0.35 (1H,
dd, J = 14.3, 9.7), 3.39 (1H, dd, J = 14.4, 5.0), 3.75 (3H, s), 4.06 (1H,
br s), 4.81 (1H, br m), 5.22 (1H, ddd, J = 9.6, 7.3, 5.0), the remaining
signals could not be determined;13C NMRanti (151 MHz, CDCl3) δ
36.7 (CH2), 54.7 (CH), 55.8 (CH3), 90.3 (CH), 108.6 (CH), 115.0
(CH), 116.3 (CH), 122.2 (C), 124.5 (C), 128.1 (CH), 129.5 (CH),
131.7 (CH), 133.3 (CH), 135.0 (C), 139.7 (C), 140.8 (CH), 144.1
(CH), 153.5 (C); 13C NMRsyn (151 MHz, CDCl3) δ 37.7 (CH2), 54.3
(CH), 55.7 (CH3), 91.1 (CH), the remaining signals could not be
determined; MS (EI) m/z 432 + 430 (1:1, 25, M+), 202 (98,
FurylCH+NHPMP); HRMS C20H19(79Br)N2O4 calcd 430.0523, found
430.0518.
The yields for the formation of indolines 14a−s were
generally found to be lower than those obtained for the
formation of tetrahydroquinolines 18a−s. This is due to the
lower stability of the indoline products, some of which proved
to be difficult to purify due to degradation during column
chromatography. This was particularly evident for the
substituted indolines 14p−r which could only be isolated in
relatively modest yields (Table 6).
CONCLUSION
■
In conclusion, we have developed an expedient and highly
diastereoselective synthesis of both 3-aminotetrahydroquino-
lines 18a−s and 2-aminomethylene indolines 14a−s that relies
upon a reductive nitro-Mannich reaction and reduction to form
a stereochemically defined 1,2-diamine. A chemoselective
intramolecular N-arylation reaction is dictated by the most
nucleophilic amine which is controlled by the presence or not
of a trifluoroacetamide protecting group. This short and
efficient reaction sequence has allowed access to an array of
fused heterocyclic structures, thereby demonstrating the
synthetic potential of the nitro-Mannich reaction. The
demonstration of carbon and heteroatom nucleophiles in this
process and other cyclization strategies to synthesize hetero-
cycles is currently under investigation, as is the development of
an asymmetric variant and the application of this methodology
to natural product synthesis.
EXPERIMENTAL SECTION
■
General Procedure for the Synthesis of β-Nitroamines 5 by
the Reductive Nitro-Mannich Reaction (Table 4). To a solution
of nitroalkene (1.00 mmol) in CH2Cl2 (5.0 mL) at room temperature
was added dropwise lithium triethylborohydride (1.0 M in THF, 1.05
N-((1S*,2S*)-3-(2-Bromophenyl)-2-nitro-1-(thiophene-2-yl)-
propyl)-4-methoxyaniline (5d). Nitroalkene 3 (85 mg, 0.37 mmol)
afforded crude β-nitroamine 5d as a yellow solid (173 mg, >95% conv,
G
dx.doi.org/10.1021/jo3010827 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
90:10 dr): IR νmax (neat) 3387, 3069−2833, 1551, 1509, 1241, 1026
cm−1; 1H NMRanti (600 MHz, CDCl3) δ 3.48 (1H, m), 3.67 (1H, dd, J
= 14.7, 2.7), 3.74 (3H, s), 4.17 (1H, br d, J = 7.4), 5.18−5.22 (2H, m),
6.66 (2H, dm, J = 8.9), 6.77 (2H, dm, J = 8.9), 6.99 (1H, dd, J = 5.0,
3.6), 7.07 (1H, d, J = 3.5), 7.15 (1H, td, J = 7.6, 1.9), 7.20 (1H, dd, J =
7.6, 1.8), 7.25 (1H, td, J = 7.4, 1.1), 7.27 (1H, m), 7.56 (1H, dd, J =
7.5, 1.3), 7.13 (1H, td, J = 7.7, 1.6), 7.20 (1H, td, J = 7.5, 1.0), 7.55
(1H, dd, J = 7.9, 0.7); 1H NMRsyn (600 MHz, CDCl3) δ 1.04 (9H, s),
3.14 (1H, dd, J = 14.4, 3.7), 3.38 (1H, dd, J = 14.4, 10.3), 3.43 (1H, d,
J = 10.5), 4.51 (1H, d, J = 10.7), 5.38 (1H, m), the remaining signals
could not be determined; 13C NMRanti (151 MHz, CDCl3) δ 26.7
(CH3), 37.5 (C), 38.7 (CH2), 55.9 (CH3), 65.7 (CH), 90.2 (CH),
114.0 (CH), 115.3 (CH), 124.1 (C), 128.0 (CH), 129.3 (CH), 131.7
(CH), 133.1 (CH), 135.5 (C), 142.6 (C), 152.4 (C); 13C NMRsyn (151
MHz, CDCl3) δ 27.1 (CH3), 37.3 (C), 40.4 (CH2), 55.6 (CH3), 65.2
(CH), 87.7 (CH), the remaining signals could not be determined; MS
1
8.0, 1.1); H NMRsyn (600 MHz, CDCl3) δ 3.35 (1H, m), 3.73 (3H,
s), 5.08 (1H, dd, J = 9.7, 7.8), 5.26 (1H, ddd, J = 8.9, 7.8, 5.6), the
remaining signals could not be determined; 13C NMRanti (151 MHz,
CDCl3) δ 36.5 (CH2), 55.7 (CH3), 58.2 (CH), 91.6 (CH), 115.0
(CH), 116.2 (CH), 124.5 (C), 125.7 (CH), 125.9 (CH), 127.5 (CH),
128.1 (CH), 129.6 (CH), 131.7 (CH), 133.3 (CH), 134.9 (C), 139.6
(C), 141.5 (C), 153.6 (C); 13C NMRsyn (151 MHz, CDCl3) δ 38.0
(CH2), 55.7 (CH3), 58.0 (CH), 92.0 (CH), the remaining signals
could not be determined; MS (EI) m/z 448 + 446 (1:1, 20, M+), 217
(96, thiophenylCH+NHPMP); HRMS C20H19(79Br)N2O3S calcd
446.0294, found 446.0310.
(EI) m/z 420 + 422 (1:1, 14, M+), 317 + 319 (1:1, 100, M+
−
(C(CH3)3 + NO2)), 192 (49, PMPNHCH+C(CH3)3); HRMS
C20H25(79Br)N2O3 calcd 420.1043, found 420.1045.
N-((1R*,2S*)-3-(2-Bromophenyl)-2-nitro-1-(o-tolyl)propyl)-4-me-
thoxyaniline (5h). Nitroalkene 3 (64 mg, 0.28 mmol) afforded crude
β-nitroamine 5h as a yellow oily solid (148 mg, >95% conv, 90:10 dr):
1
IR νmax (neat) 3399, 3057−2833, 1549, 1509, 1233, 1026 cm−1; H
NMRanti (600 MHz, CDCl3) δ 2.54 (3H, s), 3.53 (1H, dd, J = 14.7,
11.2), 3.59 (1H, dd, J = 14.7, 2.6), 3.74 (3H, s), 4.19 (1H, br s), 5.22
(1H, ddd, J = 11.1, 5.7, 2.6), 5.29 (1H, d, J = 5.7), 6.62 (2H, dm, J =
8.9), 6.78 (2H, dm, J = 8.9), 7.12 (1H, m), 7.22−7.27 (5H, m), 7.52
(2H, m); 1H NMRsyn (600 MHz, CDCl3) δ 2.62 (3H, s), 3.32 (1H, dd,
J = 14.1, 4.4), 3.72 (3H, s), 5.09 (1H, d, J = 6.7), the remaining signals
could not be determined; 13C NMRanti (151 MHz, CDCl3) δ 19.4
(CH3), 34.9 (CH2), 55.8 (CH3), 58.7 (CH), 90.4 (CH), 115.0 (CH),
115.8 (CH), 124.2 (C), 126.3 (CH), 127.0 (CH), 128.1 (CH), 128.5
(CH), 129.5 (CH), 131.5 (CH), 131.7 (CH), 133.3 (CH), 135.3 (C),
135.9 (C), 136.0 (C), 140.4 (C), 153.2 (C); 13C NMRsyn (151 MHz,
CDCl3) δ 19.6 (CH3), 37.8 (CH2), 55.7 (CH3), 57.3 (CH), 91.9
(CH), the remaining signals could not be determined; MS (EI) m/z
456 + 454 (1:1, 13, M+), 226 (100, ArCH+NHPMP); HRMS
C23H23(79Br)N2O3 calcd 454.0887, found 454.0876.
N-((2S*,3R*)-1-(2-Bromophenyl)-2-nitrooctan-3-yl)-4-methoxya-
niline (5e). Nitroalkene 3 (968 mg, 4.24 mmol) afforded crude β-
nitroamine 5e as a yellow oil (2.73 g, >95% conv, 95:5 dr): IR νmax
(neat) 3379, 3060−2834, 1546, 1509, 1466, 1441, 1234, 1036, 1025
1
cm−1; H NMRanti (600 MHz, CDCl3) δ 0.90 (3H, t, J = 6.9), 1.29−
1.44 (6H, m), 1.61 (1H, m), 1.81 (1H, m), 3.39 (1H, dd, J = 14.5,
5.0), 3.45 (1H, dd, J = 14.4, 9.2), 3.76 (3H, s), 3.78 (1H, m), 4.96
(1H, dt, J = 9.2, 4.7), 6.53 (2H, dm, J = 8.9), 6.77 (2H, dm, J = 8.9),
7.15 (1H, td, J = 7.6, 1.6), 7.21 (1H, dd, J = 7.6, 1.7), 7.25 (1H, td, J =
7.3, 1.0), 7.57 (1H, dd, J = 8.0, 0.9); 1H NMRsyn (600 MHz, CDCl3) δ
3.27 (1H, dd, J = 14.3, 5.1), 3.73 (3H, s), 5.13 (1H, dt, J = 9.9, 4.4),
the remaining signals could not be determined; 13C NMRanti (151
MHz, CDCl3) δ 14.2 (CH3), 22.6 (CH2), 26.1 (CH2), 30.9 (CH2),
31.7 (CH2), 36.4 (CH2), 55.8 (CH3), 57.4 (CH), 89.4 (CH), 115.1
(CH), 115.5 (CH), 124.6 (C), 128.0 (CH), 129.4 (CH), 131.7 (CH),
133.3 (CH), 135.4 (C), 140.4 (C), 152.9 (C); 13C NMRsyn (151 MHz,
CDCl3) δ 55.6 (CH3), 56.9 (CH), 89.7 (CH), the remaining signals
could not be determined; MS (EI) m/z 436 + 434 (1:1, 10, M+), 206
(100, CH3(CH2)4CH+NHPMP); HRMS C21H28(79Br)N2O3 calcd
434.1200, found 434.1204.
N-((1R*,2S*)-1,3-Bis(2-bromophenyl)-2-nitropropyl)-4-methox-
yaniline (5i). Nitroalkene 3 (61 g, 0.27 mmol) afforded crude β-
nitroamine 5i as a yellow solid (196 mg, >95% conv, 90:10 dr). The
anti diastereomer could be obtained in pure form by recrystallization
from Et2O/petroleum ether to give a yellow solid: mp 117−119 °C;
Rfanti 0.25 (20% Et2O/petroleum ether); IR νmax (neat) 3400, 3063−
2834, 1550, 1511, 1244, 1025 cm−1; 1H NMRanti (600 MHz, CDCl3) δ
3.40 (1H, br m), 3.48 (1H, dd, J = 14.6, 11.7), 3.71 (3H, s), 4.52 (1H,
br s), 5.40 (1H, br s), 5.43 (1H, br d, J = 11.4), 6.54 (2H, d, J = 8.9),
6.73 (2H, dm, J = 8.9), 7.11 (1H, m), 7.19−7.23 (3H, m), 7.33 (1H,
m), 7.49 (1H, d, J = 7.9), 7.52 (1H, br d, J = 7.4), 7.64 (1H, dd, J =
N-((1R*,2S*)-3-(2-Bromophenyl)-1-cyclohexyl-2-nitropropyl)-4-
methoxyaniline (5f). Nitroalkene 3 (103 mg, 0.452 mmol) afforded
crude β-nitroamine 5f as a yellow solid (250 mg, >95% conv, 80:20
dr): IR νmax (neat) 3408, 3062−2853, 1547, 1510, 1241, 1027 cm−1;
1H NMRanti (600 MHz, CDCl3) δ 1.08−1.29 (4H, m), 1.33 (1H, qd, J
= 12.3, 3.1), 1.53 (1H, m), 1.64−1.85 (5H, m), 3.25 (1H, dd, J = 14.6,
11.2), 3.42 (1H, d, J = 10.5), 3.55 (1H, dd, J = 14.6, 2.8), 3.76 (3H, s),
3.84 (1H, m), 4.96 (1H, ddd, J = 11.2, 8.4, 2.8), 6.68 (2H, m), 6.80
(2H, m), 7.12 (2H, m), 7.21 (1H, td, J = 7.4, 1.1), 7.54 (1H, d, J =
8.0); 1H NMRsyn (600 MHz, CDCl3) δ 1.04−1.37 (5H, m), 1.52−1.94
(5H, m), 3.32 (1H, dd, J = 14.3, 4.0), 3.41 (1H, dd, J = 14.3, 10.1),
3.61 (1H, m), 3.76 (3H, s), 3.84 (1H, d, J = 10.9), 5.22 (1H, ddd, J =
10.0, 5.6, 4.3), 6.62 (2H, m), 6.78 (2H, m), 7.08 (1H, dd, J = 7.5, 1.7),
7.13−7.20 (2H, m), 7.57 (1H, m); 13C NMRanti (151 MHz, CDCl3) δ
26.0 (CH2), 26.2 (CH2), 26.3 (CH2), 26.4 (CH2), 31.3 (CH2), 37.4
(CH2), 40.2 (CH), 55.9 (CH3), 62.2 (CH), 89.9 (CH), 114.6 (CH),
115.2 (CH), 124.2 (C), 128.1 (CH), 129.3 (CH), 131.5 (CH), 133.2
(CH), 135.5 (C), 142.1 (C), 152.6 (C); 13C NMRsyn (151 MHz,
CDCl3) δ 26.1 (CH2), 26.1 (CH2), 26.2 (CH2), 28.9 (CH2), 30.9
(CH2), 38.5 (CH2), 41.5 (CH), 55.9 (CH3), 61.7 (CH), 89.4 (CH),
114.2 (CH), 115.1 (CH), 124.4 (C), 128.1 (CH), 129.5 (CH), 131.7
(CH), 133.3 (CH), 135.1 (C), 142.4 (C), 152.2 (C); MS (EI) m/z 446
+ 448 (1:1, 11, M+), 317 + 319 (1:1, 31, M-(Cy + NO2)), 218 (100,
CyCH+NHPMP); HRMS C22H27(79Br)N2O3 calcd 446.1200, found
446.1200.
1
8.0, 0.8); H NMRsyn (600 MHz, CDCl3) δ 3.46 (1H, dd, J = 13.7,
4.7), 3.63 (1H, dd, J = 14.0, 9.1), 3.71 (3H, s), 4.95 (1H, d, J = 9.9),
5.23 (1H, dd, J = 9.8, 5.6), 5.35 (1H, dt, J = 9.7, 5.6), 6.52 (2H, dm, J
= 8.9), 6.73 (2H, dm, J = 8.9), 7.14−7.30 (6H, m), 7.57 (1H, dd, J =
2.7, 0.9), 7.58 (1H, dd, J = 2.6, 1.1); 13C NMRanti (151 MHz, CDCl3)
δ 34.1 (CH2), 55.7 (CH3), 61.2 (CH), 88.8 (CH), 114.9 (CH), 115.8
(CH), 123.7 (C), 124.3 (C), 128.0 (CH), 128.2 (CH), 129.5 (CH),
129.7 (CH), 130.3 (CH), 131.7 (CH), 133.3 (CH), 133.9 (CH), 135.0
(C), 136.0 (C), 139.6 (C), 153.3 (C); 13C NMRsyn (151 MHz, CDCl3)
δ 37.8 (CH2), 55.7 (CH3), 58.3 (CH), 90.4 (CH), 114.9 (CH), 115.0
(CH), the remaining signals could not be determined; MS (EI) m/z
522 + 520 + 518 (10:20:10, M+), 292+ 290 (1:1, 100,
ArCH+NHPMP); HRMS C22H20(79Br)2N2O3 calcd 517.9835, found
517.9843. Anal. Calcd for C22H20Br2N2O3: C, 50.79; H, 3.88; N, 5.38;
Found: C, 50.65; H, 3.85; N, 5.28.
N-((1R*,2S*)-3-(2-Bromophenyl)-1-(2-methoxyphenyl)-2-nitro-
propyl)-4-methoxyaniline (5j). Nitroalkene 3 (52 mg, 0.23 mmol)
afforded crude β-nitroamine 5j as a yellow oil (134 mg, >95% conv,
90:10 dr): IR νmax (neat) 3402, 3063−2836, 1549, 1510, 1488, 1464,
1
1439, 1235, 1023 cm−1; H NMRanti (600 MHz, CDCl3) δ 3.40 (1H,
N-((2S*,3R*)-1-(2-Bromophenyl)-4,4-dimethyl-2-nitropentan-3-
yl)-4-methoxyaniline (5g). Nitroalkene 3 (1.03 g, 4.52 mmol)
afforded crude β-nitroamine 5g as a yellow oil (2.20 g, 92% conv,
85:15 dr): IR νmax (neat) 3415, 3060−2833, 1548, 1509, 1471, 1232,
1036, 1024 cm−1; 1H NMRanti (600 MHz, CDCl3) δ 1.07 (9H, s), 3.18
(1H, dd, J = 14.3, 12.0), 3.56 (1H, dd, J = 14.5, 3.0), 3.56 (1H, m),
3.78 (3H, s), 3.90 (1H, dd, J = 8.6, 6.5), 5.12 (1H, ddd, J = 11.6, 6.3,
3.2), 6.78 (2H, dm, J = 8.9), 6.84 (2H, dm, J = 8.9), 7.06 (1H, dd, J =
dd, J = 14.7, 11.5), 3.70 (1H, m), 3.74 (3H, s), 3.96 (3H, s), 4.61 (1H,
br s), 5.13 (1H, d, J = 5.6), 5.54 (1H, ddd, J = 11.5, 7.4, 2.4), 6.70 (2H,
dm, J = 8.9), 6.78 (2H, dm, J = 8.9), 6.92 (1H, td, J = 7.5, 0.7), 6.93
(1H, d, J = 8.2), 7.12 (1H, m), 7.19−7.30 (4H, m), 7.55 (1H, dd, J =
1
8.0, 0.8); H NMRsyn (600 MHz, CDCl3) δ 3.19 (1H, dd, J = 14.0,
3.8), 3.36 (1H, dd, J = 14.2, 10.4), 4.76 (1H, br s), 5.06 (1H, d, J =
6.7), the remaining signals could not be determined; 13C NMRanti (151
H
dx.doi.org/10.1021/jo3010827 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
MHz, CDCl3) δ 36.4 (CH2), 55.7 (CH3), 55.8 (CH3), 60.1 (CH), 90.0
(CH), 111.3 (CH), 114.9 (CH), 115.9 (CH), 121.1 (CH), 124.4 (C),
125.0 (C), 128.0 (CH), 129.3 (CH), 129.7 (CH), 129.8 (CH), 131.6
(CH), 133.2 (CH), 135.7 (C), 140.7 (C), 153.0 (C), 157.3 (C); 13C
NMRsyn (151 MHz, CDCl3) δ 38.4 (CH2), 55.5 (CH3), 55.5 (CH3),
90.6 (CH), the remaining signals could not be determined; MS (EI)
m/z 470 + 472 (1:1, 6, M+), 242 (100, ArCH+NHPMP); HRMS
C23H23(79Br)N2O4 calcd 470.0836, found 470.0820.
(1H, td, J = 7.6, 1.7), 7.18 (1H, dd, J = 7.7, 1.8), 7.23 (1H, td, J = 7.5,
1.1), 7.52 (1H, t, J = 7.7), 7.53 (1H, dd, J = 8.0, 1.1), 7.63 (1H, t, J =
9.4), 7.72 (1H, s); 13C NMR (151 MHz, CDCl3) δ 35.5 (CH2), 55.7
(CH3), 61.8 (CH), 91.4 (CH), 115.0 (CH), 116.0 (CH), 124.1 (1C, q,
J = 272.5, C), 124.2 (1C, q, J = 3.5, CH), 124.3 (C), 125.7 (1C, q, J =
3.5, CH), 128.1 (CH), 129.7 (CH), 129.8 (CH), 130.7 (CH), 131.5
(1C, q, J = 32.4, C), 131.7 (CH), 133.3 (CH), 134.6 (C), 138.8 (C),
139.5 (C), 153.5 (C); 19F NMR (282 MHz, CDCl3) δ −63.0 (3F, s);
MS (EI) m/z 508 + 510 (5, M+), 338 + 340 (5, M+ − (NHPMP +
NO2)), 279 (100, ArCH+NHPMP); HRMS C23H20(79Br)F3N2O3
calcd 508.0604, found 508.0619.
N-((1R*,2S*)-3-(2-Bromophenyl)-2-nitro-1-(4-(trifluoromethyl)-
phenyl)propyl)-4-methoxyaniline (5o). Nitroalkene 3 (211 mg, 0.925
mmol) afforded crude β-nitroamine 5o as a yellow oil (550 mg, >95%
conv, >95:5 dr): IR νmax (neat) 3395, 3057−2835, 1552, 1510, 1323,
1241, 1165, 1121, 1113, 1066, 1035, 1027, 1017 cm−1; 1H NMR (600
MHz, CDCl3) δ 3.46 (1H, dd, J = 14.8, 11.0), 3.55 (1H, dd, J = 14.7,
2.7), 3.73 (3H, s), 4.33 (1H, br s), 5.02 (1H, s), 5.22 (1H, ddd, J =
10.9, 6.0, 2.8), 6.59 (2H, dm, J = 8.9), 6.77 (2H, dm, J = 8.9), 7.14
(1H, td, J = 7.6, 1.7), 7.18 (1H, dd, J = 7.7, 1.7), 7.23 (1H, td, J = 7.4,
1.0), 7.55 (1H, dd, J = 8.1, 1.0), 7.56 (2H, d, J = 8.3), 7.65 (2H, d, J =
8.2); 13C NMR (151 MHz, CDCl3) δ 35.8 (CH2), 55.7 (CH3), 61.7
(CH), 91.4 (CH), 115.0 (CH), 116.0 (CH), 124.0 (1C, q, J = 272.2,
C), 124.3 (C), 126.2 (1C, q, J = 3.5, CH), 127.8 (CH), 128.2 (CH),
129.7 (CH), 131.0 (1C, q, J = 32.5, C), 131.7 (CH), 133.3 (CH),
134.6 (C), 139.4 (C), 141.7 (C), 153.5 (C); 19F NMR (282 MHz,
CDCl3) δ −63.0 (3F, s); MS (EI) m/z 508 + 510 (1:1, 15, M+), 280
(ArCH+NHPMP); HRMS C23H20(79Br)F3N2O3 calcd 508.0604,
found 508.0616.
N-((1R*,2S*)-3-(2-Bromophenyl)-1-(3-methoxyphenyl)-2-nitro-
propyl)-4-methoxyaniline (5k). Nitroalkene 3 (177 mg, 0.776 mmol)
afforded crude β-nitroamine 5k as a yellow oil (486 mg, >95% conv,
>95:5 dr): IR νmax (neat) 3381, 3057−2834, 1551, 1511, 1242, 1037
1
cm−1; H NMR (600 MHz, CDCl3) δ 3.45 (1H, dd, J = 14.8, 11.2),
3.56 (1H, dd, J = 14.8, 2.7), 3.73 (3H, s), 3.80 (3H, s), 4.29 (1H, br s),
4.93 (1H, d, J = 5.9), 5.21 (1H, ddd, J = 11.1, 6.0, 2.7), 6.62 (2H, dm, J
= 8.9), 6.76 (2H, dm, J = 8.9), 6.87 (1H, dd, J = 8.0, 2.3), 6.96 (1H, t, J
= 2.0), 7.02 (1H, d, J = 7.7), 7.12 (1H, td, J = 7.6, 1.8), 7.18 (1H, dd, J
= 7.7, 1.8), 7.22 (1H, td, J = 7.4, 1.0), 7.30 (1H, t, J = 7.9), 7.53 (1H,
dd, J = 8.0, 1.0); 13C NMR (151 MHz, CDCl3) δ 35.8 (CH2), 55.4
(CH3), 55.8 (CH3), 62.1 (CH), 91.7 (CH), 113.2 (CH), 113.9 (CH),
114.9 (CH), 115.9 (CH), 119.5 (CH), 124.4 (C), 128.1 (CH), 129.5
(CH), 130.3 (CH), 131.7 (CH), 133.3 (CH), 135.1 (C), 139.2 (C),
140.1 (C), 153.2 (C), 160.1 (C); MS (EI) m/z 470 + 472 (1:1, 4, M+),
349 + 351 (1:1, 2, M+ − PMPNH), 242 (53, ArCH+NHPMP); HRMS
C23H23(79Br)N2O4 calcd 470.0836, found 470.0845.
N-((1R*,2S*)-3-(2-Bromophenyl)-1-(4-methoxyphenyl)-2-nitro-
propyl)-4-methoxyaniline (5l). Nitroalkene 3 (1.09 g, 4.79 mmol)
afforded crude β-nitroamine 5l as a yellow oily solid (2.70 g, 95% conv,
>95:5 dr): IR νmax (neat) 3401, 3065−2835, 1551, 1510, 1244, 1032
1
cm−1; H NMR (600 MHz, CDCl3) δ 3.44 (1H, dd, J = 14.8, 11.1),
N-((1R*,2S*)-3-(2-Bromo-5-fluorophenyl)-2-nitro-1-phenylprop-
yl)-4-methoxyaniline (5p). 2-Bromo-5-fluoro-β-nitrostyrene (118 mg,
0.480 mmol) afforded crude β-nitroamine 5p as a yellow oil (304 mg,
>95% conv, >95:5 dr): IR νmax (neat) 3401, 3066−2834, 1551, 1510,
1470, 1235, 1030 cm−1; 1H NMR (600 MHz, CDCl3) δ 3.43 (1H, dd,
J = 14.8, 11.0), 3.51 (1H, dd, J = 14.8, 2.7), 3.73 (3H, s), 4.27 (1H, br
s), 4.97 (1H, d, J = 5.6), 5.20 (1H, ddd, J = 11.0, 5.9, 2.7), 6.63 (2H,
dm, J = 8.9), 6.76 (2H, dm, J = 8.9), 6.87 (1H, td, J = 8.3, 3.0), 6.94
(1H, dd, J = 8.9, 3.0), 7.35 (1H, m), 7.38−7.43 (4H, m), 7.48 (1H, dd,
J = 8.8, 5.3); 13C NMR (151 MHz, CDCl3) δ 35.7 (CH2), 55.8 (CH3),
62.2 (CH), 91.4 (CH), 114.9 (CH), 116.0 (CH), 116.7 (1C, d, J =
22.6, CH), 118.5 (1C, d, J = 3.1, C), 118.8 (1C, d, J = 23.2, CH), 127.2
(CH), 128.9 (CH), 129.2 (CH), 134.4 (1C, d, J = 7.9, CH), 137.1 (1C,
d, J = 7.7, C), 137.3 (C), 139.9 (C), 153.3 (C), 161.9 (1C, d, J = 248.5,
C); 19F NMR (126 MHz, CDCl3) δ −114.1 (1F, m); MS (EI) m/z
458 + 460 (5, M+), 290 + 292 (10, M+ − (NHPMP + NO2), 212 (100,
PhCH+NHPMP); HRMS C22H20(79Br)FN2O3 calcd 458.0636, found
458.0635.
N-((1R*,2S*)-3-(2-Bromo-4,5-dimethoxyphenyl)-2-nitro-1-phe-
nylpropyl)-4-methoxyaniline (5q). 2-Bromo-4,5-dimethoxy-β-nitro-
styrene (136 mg, 0.472 mmol) afforded crude β-nitroamine 5q as a
yellow solid (273 mg, >95% conv, >95:5 dr): IR νmax (neat) 3389,
3005−2837, 1551, 1509, 1260, 1243, 1219, 1166 cm−1; 1H NMR (600
MHz, CDCl3) δ 3.35 (1H, dd, J = 14.9, 11.1), 3.44 (1H, dd, J = 14.8,
2.7), 3.72 (3H, s), 3.79 (3H, s), 3.84 (3H, s), 4.28 (1H, br d, J = 4.6),
4.92 (1H, br d, J = 4.9), 5.16 (1H, ddd, J = 11.0, 5.7, 2.7), 6.59 (2H,
dm, J = 8.9), 6.64 (1H, s), 6.74 (2H, dm, J = 8.9), 6.97 (1H, s), 7.33
(1H, m), 7.36−7.41 (4H, m); 13C NMR (151 MHz, CDCl3) δ 35.0
(CH2), 55.3 (CH3), 55.7 (CH3), 55.8 (CH3), 61.7 (CH), 91.6 (CH),
113.6 (CH), 113.8 (C), 114.5 (CH), 115.4 (CH), 115.5 (CH), 126.5
(C), 126.8 (CH), 128.3 (CH), 128.7 (CH), 137.1 (C), 139.6 (C),
148.2 (C), 148.7 (C), 152.7 (C); MS (EI) m/z 500 + 502 (1:1, 2, M+),
289 + 291 (1:1, 16, M+ − PMPNHBn), 242 + 244 (1:1, 46, M+ −
(PMPNHCHPh + NO2)), 211 (91, PhCH+NHPMP); HRMS
C24H25(79Br)N2O5 calcd 500.0941, found 500.0936.
3.57 (1H, dd, J = 14.7, 2.6), 3.72 (3H, s), 3.79 (3H, s), 4.28 (1H, br s),
4.90 (1H, d, J = 5.7), 5.19 (1H, ddd, J = 11.0, 6.1, 2.7), 6.62 (2H, dm, J
= 8.9), 6.76 (2H, dm, J = 8.9), 6.90 (2H, dm, J = 8.7), 7.13 (1H, td, J =
7.6, 1.7), 7.18 (1H, dd, J = 7.6, 1.6), 7.22 (1H, td, J = 7.5, 0.7), 7.33
(2H, dm, J = 8.6), 7.54 (1H, dd, J = 7.9, 0.6); 13C NMR (151 MHz,
CDCl3) δ 36.0 (CH2), 55.4 (CH3), 55.8 (CH3), 61.6 (CH), 91.9
(CH), 114.5 (CH), 114.9 (CH), 115.9 (CH), 124.4 (C), 128.1 (CH),
128.4 (CH), 129.4 (C), 129.5 (CH), 131.7 (CH), 133.3 (CH), 135.2
(C), 140.1 (C), 153.1 (C), 159.8 (C); MS (CI) m/z 472 + 470 (1:1, 7,
M+), 426 + 424 (1:1, 20, M+ − NO2), 242 (100, PMPCH+NHPMP);
HRMS C23H23(79Br)N2O4 calcd 470.0836, found 470.0850.
N-((1R*,2S*)-3-(2-Bromophenyl)-2-nitro-1-(2-(trifluoromethyl)-
phenyl)propyl)-4-methoxyaniline (5m). Nitroalkene 3 (739 mg, 3.24
mmol) afforded crude β-nitroamine 5m as a yellow oil (2.00 g, >95%
conv, 90:10 dr): IR νmax (neat) 3392, 3068−2835, 1552, 1511, 1309,
1243, 1160, 1115, 1034 cm−1; 1H NMRanti (600 MHz, CDCl3) δ 3.45
(1H, dd, J = 14.6, 2.1), 3.55 (1H, dd, J = 14.6, 11.7), 3.72 (3H, s), 4.39
(1H, br s), 5.32 (1H, ddd, J = 11.7, 4.5, 2.3), 5.53 (1H, d, J = 4.3), 6.61
(2H, dm, J = 8.9), 6.75 (2H, dm, J = 8.9), 7.09−7.13 (1H, m), 7.22
(2H, d, J = 4.2), 7.47−7.50 (2H, m), 7.61 (1H, t, J = 7.5), 7.79 (1H, d,
J = 7.7), 7.90 (1H, d, J = 7.9); 1H NMRsyn (600 MHz, CDCl3) δ 3.43−
3.48 (2H, m), 3.71 (3H, s), 4.92 (1H, br s), 5.23 (1H, br s), 5.28−2.31
(1H, m), the remaining signals could not be determined; 13C NMRanti
(151 MHz, CDCl3) δ 33.7 (CH2), 55.7 (CH), 57.9 (CH3), 90.2 (CH),
114.9 (CH), 116.0 (CH), 124.2 (C), 124.4 (1C, q, J = 274.2, C), 127.2
(1C, q, J = 6.0, CH), 128.1 (CH), 129.0 (2 × CH), 129.5 (CH), 131.7
(CH), 132.8 (CH), 133.3 (CH), 134.8 (C), 136.6 (C), 139.5 (C),
153.4 (C); 13C NMRsyn (151 MHz, CDCl3) δ 34.0 (CH2), 55.6 (CH),
55.7 (CH3), 89.7 (CH), the remaining signals could not be
determined; 19F NMRanti (282 MHz, CDCl3) δ −58.3 (3F, s); MS
(EI) m/z 508 + 510 (1:1, 16, M+), 279 (100, ArCH+NHPMP);
HRMS C23H20(79Br)F3N2O3 calcd 508.0604, found 508.0615.
N-((1R*,2S*)-3-(2-Bromophenyl)-2-nitro-1-(3-(trifluoromethyl)-
phenyl)propyl)-4-methoxyaniline (5n). Nitroalkene 3 (142 mg, 0.623
mmol) afforded crude β-nitroamine 5n as a yellow oil (448 mg, >95%
conv, >95:5 dr): IR νmax (neat) 3405, 3061−2836, 1552, 1511, 1327,
1243, 1165, 1123, 1072, 1034, 1026 cm−1; 1H NMR (600 MHz,
CDCl3) δ 3.45 (1H, dd, J = 14.8, 10.5), 3.49 (1H, dd, J = 14.8, 3.3),
3.73 (3H, s), 4.34 (1H, br s), 5.03 (1H, d, J = 5.7), 5.21 (1H, ddd, J =
10.5, 5.6, 3.4), 6.59 (2H, dm, J = 8.9), 6.77 (2H, dm, J = 9.0), 7.14
N-((1R*,2S*)-3-(2-Bromo-4,5-dimethoxyphenyl)-1-(2-methoxy-
phenyl)-2-nitropropyl)-4-methoxyaniline (5r). 2-Bromo-4,5-dime-
thoxy-β-nitrostyrene (775 mg, 2.69 mmol) afforded crude β-
nitroamine 5r as a yellow oil (2.27 g, >95% conv, 85:15 dr): IR νmax
(neat) 3392, 3001−2838, 1550, 1509, 1258, 1237, 1219, 1164, 1025
cm−1; 1H NMRanti (600 MHz, CDCl3) δ 3.29 (1H, dd, J = 14.8, 11.4),
I
dx.doi.org/10.1021/jo3010827 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
3.57 (1H, dd, J = 14.8, 1.9), 3.72 (3H, s), 3.80 (3H, s), 3.83 (3H, s),
3.95 (3H, s), 4.56 (1H, br s), 5.09 (1H, br d, J = 6.1), 5.45 (1H, ddd, J
= 11.4, 7.1, 2.5), 6.65 (2H, dm, J = 8.9), 6.65 (1H, s), 6.75 (2H, dm, J
= 8.9), 6.90−6.93 (2H, m), 6.97 (1H, s), 7.22 (1H, dd, J = 7.5, 1.5),
7.26−7.29 (1H, m); 1H NMRsyn (600 MHz, CDCl3) δ 3.21 (1H, dd, J
= 14.0, 5.9), 4.82 (1H, br s), 4.92 (1H, br s), 5.45 (1H, dt, J = 9.1, 6.5),
6.54 (2H, dm, J = 8.9), 6.62 (1H, s), 6.69 (2H, dm, J = 8.9), 7.00 (1H,
s), 7.18 (1H, dd, J = 7.7, 1.5), the remaining signals could not be
determined; 13C NMRanti (151 MHz, CDCl3) δ 36.0 (CH2), 55.7
(CH3), 55.8 (CH3), 56.1 (CH3), 56.2 (CH3), 59.9 (CH), 90.3 (CH),
111.2 (CH), 114.0 (CH), 114.2 (C), 114.9 (CH), 115.7 (CH), 115.8
(CH), 121.1 (CH), 125.0 (C), 127.5 (C), 129.6 (CH), 129.8 (CH),
140.6 (C), 148.5 (C), 149.0 (C), 153.0 (C), 157.3 (C); 13C NMRsyn
(151 MHz, CDCl3) δ 37.9 (CH2), 55.5 (CH3), 55.6 (CH3), 55.7
(CH3), 55.8 (CH3), 57.2 (CH), 90.0 (CH); the remaining signals
could not be determined; MS (EI) m/z 530 + 532 (1:1, 4, M+), 242
(100, ArCH+NHPMP); HRMS C25H27(79Br)N2O6 calcd 530.1047,
found 530.1055.
petroleum ether); IR νmax (neat) 3062−2841, 1699, 1559, 1512, 1255,
1183, 1169, 1033 cm−1; 1H NMR (600 MHz, CDCl3) δ 3.61 (1H, dd,
J = 14.4, 11.4), 3.79 (1H, dd, J = 14.5, 3.8), 3.82 (3H, s), 5.76 (1H, td,
J = 11.2, 3.6), 6.27 (1H, d, J = 9.0), 6.31 (1H, d, J = 11.3), 6.63 (1H,
dd, J = 8.8, 2.8), 6.92 (1H, dd, J = 8.7, 2.9), 7.08 (2H, d, J = 7.3),
7.16−7.33 (6H, m), 7.41 (1H, dd, J = 8.7, 1.4), 7.61−7.63 (1H, m);
13C NMR (151 MHz, CDCl3) δ 38.7 (CH2), 55.6 (CH3), 64.8 (CH),
87.2 (CH), 113.8 (CH), 114.3 (CH), 116.3 (1C, q, J = 288.7, C),
124.1 (C), 127.6 (C), 128.4 (CH), 128.8 (CH), 129.6 (CH), 129.8
(CH), 129.9 (CH), 130.8 (CH), 131.7 (CH), 132.4 (CH), 132.8 (C),
133.3 (CH), 133.9 (C), 158.3 (1C, q, J = 35.7, C), 160.4 (C); 19F
NMR (282 MHz, CDCl3) δ −67.1 (3F, s); MS (ESI+) m/z 559 + 561
(1:1, 100, M+ + Na); HRMS C24H20(79Br)F3N2O4Na calcd 559.0430,
found 559.0451. Anal. Calcd for C24H20BrF3N2O4: C, 53.65; H, 3.75;
N, 5.21. Found: C, 53.93; H, 3.84; N, 4.95.
N-((1S*,2S*)-3-(2-Bromophenyl)-1-(furan-2-yl)-2-nitropropyl)-N-
(4-methoxyphenyl)-2,2,2-trifluoroacetamide (6b). Crude β-nitro-
amine 5b (4.42 mmol) afforded crude β-nitroacetamide 6b as a
brown solid. Purification by flash column chromatography (45%
CH2Cl2/petroleum ether) yielded pure β-nitroacetamide 6b as a white
solid (2.03 g, 87%, 95:5 dr). Subsequent recrystallization from
toluene/petroleum ether gave β-nitroacetamide 6b as a single anti
diastereomer (1.63 g, 70%): mp 134−137 °C; Rf 0.44 (45% CH2Cl2/
petroleum ether); IR νmax (neat) 3130−2841, 1701, 1556, 1510, 1253,
N-((1R*,2S*)-3-(3-(Benzyloxy)-2-bromo-4-methoxyphenyl)-2-
nitro-1-phenylpropyl)-4-methoxyaniline (5s). 3-Benzyloxy-2-bromo-
4-methoxy-β-nitrostyrene (426 mg, 1.17 mmol) afforded crude β-
nitroamine 5s as a yellow oily foam (835 mg, >95% conv, >95:5 dr):
IR νmax (neat) 3389, 3065−2836, 1551, 1511, 1485, 1268, 1241, 1032
1
cm−1; H NMR (600 MHz, CDCl3) δ 3.41 (1H, dd, J = 14.9, 11.1),
1
1206, 1180, 1154, 1029 cm−1; H NMR (600 MHz, CDCl3) δ 3.51
3.54 (1H, dd, J = 14.9, 2.6), 3.73 (3H, s), 3.84 (3H, s), 4.32 (1H, s),
4.95 (1H, d, J = 5.9), 5.03 (2H, s), 5.19 (1H, ddd, J = 11.1, 5.9, 2.7),
6.62 (2H, dm, J = 8.9), 6.76 (2H, dm, J = 8.9), 6.79 (1H, d, J = 8.6),
6.93 (1H, d, J = 8.5), 7.33−7.44 (8H, m), 7.55−7.56 (1H, m); 13C
NMR (151 MHz, CDCl3) δ 35.5 (CH2), 55.8 (CH3), 56.2 (CH3), 62.1
(CH), 74.7 (CH2), 92.1 (CH), 111.5 (CH), 114.9 (CH), 115.9 (CH),
120.4 (C), 126.6 (CH), 127.3 (CH), 127.7 (C), 128.3 (CH), 128.5
(CH), 128.6 (CH), 128.7 (CH), 129.2 (CH), 137.2 (C), 137.6 (CH),
140.1 (C), 145.6 (C), 153.1 (C), 153.3 (C); MS (EI) m/z 576 + 578
(1:1, 2, M+), 365 + 367 (1:1, 11, M+ − PhCHNHPMP), 319 + 321
(1H, dd, J = 14.3, 11.7), 3.71 (1H, dd, J = 14.3, 3.8), 3.83 (3H, s), 5.57
(1H, td, J = 11.1, 3.7), 6.26 (1H, dd, J = 3.2, 1.4), 6.27 (1H, d, J = 3.4),
6.45 (1H, d, J = 10.7), 6.49 (1H, d, J = 8.1), 6.71 (1H, dd, J = 8.8, 2.8),
6.93 (1H, dd, J = 8.8, 2.9), 7.14 (1H, dd, J = 7.7, 1.4), 7.19 (1H, td, J =
7.7, 1.6), 7.27 (1H, td, J = 7.5, 0.9), 7.32 (1H, d, J = 1.1), 7.48 (1H, dd,
J = 8.7, 2.1), 7.61 (1H, dd, J = 7.9, 0.8); 13C NMR (151 MHz, CDCl3)
δ 38.3 (CH2), 55.6 (CH3), 58.4 (CH), 86.3 (CH), 111.0 (CH), 112.1
(CH), 113.9 (CH), 114.5 (CH), 116.2 (1C, q, J = 288.6, C), 124.1
(C), 128.0 (C), 128.4 (CH), 130.0 (CH), 130.6 (CH), 131.0 (CH),
131.7 (CH), 133.3 (CH), 133.6 (C), 143.4 (CH), 145.9 (C), 158.2
(1C, q, J = 36.0, C), 160.5 (C); 19F NMR (282 MHz, CDCl3) δ −67.6
(3F, s); MS (CI) m/z 527 + 529 (1:1, 4, M+), 480 + 482 (1:1, 100, M+
− NO2); HRMS C22H18(79Br)F3N2O5 calcd 527.0429, found
527.0438. Anal. Calcd for C22H18BrF3N2O5: C, 50.11; H, 3.44; N,
5.31. Found: C, 50.23; H, 3.50; N, 5.20%.
N-((1R*,2S*)-3-(2-Bromophenyl)-1-(furan-3-yl)-2-nitropropyl)-N-
(4-methoxyphenyl)-2,2,2-trifluoroacetamide (6c). Crude β-nitro-
amine 5c (5.65 mmol) afforded crude β-nitroacetamide 6c as a
brown oily solid. Purification by flash column chromatography (50%
CH2Cl2/petroleum ether followed by 20% Et2O/petroleum ether)
yielded pure β-nitroacetamide 6c as a white solid (2.47 g, 83%, 95:5
dr). Subsequent recrystallization from toluene/petroleum ether gave
β-nitroacetamide 6c as a single anti diastereomer (2.06 g, 69%): mp
120−122 °C; Rf 0.36 (20% Et2O/petroleum ether); IR νmax (neat)
3137−2842, 1697, 1557, 1510, 1253, 1207, 1180, 1155, 1025 cm−1; 1H
NMR (600 MHz, CDCl3) δ 3.49 (1H, dd, J = 14.3, 11.6), 3.71 (1H,
dd, J = 14.3, 3.5), 3.85 (3H, s), 5.67 (1H, m), 5.91 (1H, br m), 6.11
(1H, s), 6.80 (1H, br d, J = 8.8), 6.82 (1H, dd, J = 8.7, 2.6), 6.93 (1H,
dd, J = 8.8, 2.7), 7.14 (1H, dd, J = 7.6, 1.6), 7.18 (1H, td, J = 7.7, 1.7),
7.26 (1H, td, J = 7.5, 1.2), 7.30 (1H, app t, J = 1.1), 7.33 (1H, s), 7.35
(1H, br d, J = 9.1), 7.60 (1H, dd, J = 8.0, 1.2); 13C NMR (151 MHz,
CDCl3) δ 38.3 (CH2), 55.7 (CH3), 58.8 (CH), 88.3 (CH), 110.5
(CH), 114.2 (CH), 114.7 (CH), 116.2 (1C, q, J = 288.6, C), 117.8
(C), 124.2 (C), 128.3 (CH), 128.8 (C), 129.8 (CH), 130.4 (CH),
131.5 (CH), 131.8 (CH), 133.3 (CH), 133.8 (C), 142.9 (CH), 143.6
(CH), 158.2 (1C, q, J = 35.9, C), 160.5 (C); 19F NMR (282 MHz,
CDCl3) δ −67.8 (3F, s); MS (EI) m/z 526 + 528 (1:1, 4, M+), 480 +
482 (1:1, 46, M+ − NO2); HRMS C22H18(79Br)F3N2O5 calcd
526.0346, found 526.0338. Anal. Calcd for C22H18BrF3N2O5: C,
50.11; H, 3.44; N, 5.31. Found: C, 49.96; H, 3.32; N, 5.27.
(1:1, 54, M+
− (PhCHNHPMP + NO2)), 212 (100,
PhCH+NHPMP); HRMS C30H29(79Br)N2O5 calcd 576.1254, found
576.1239.
N-((1R*,2S*)-3-(2-Chloropyridin-3-yl)-2-nitro-1-phenylpropyl)-4-
methoxyaniline (5t). 2-Chloro-3-((E)-2-nitrovinyl)pyridine (41 mg,
0.22 mmol) afforded crude β-nitroamine 5t as a yellow oil (98 mg,
>95% conv, >95:5 dr): IR νmax (neat) 3372, 3059−2834, 1550, 1510,
1
1410, 1238 cm−1; H NMR (600 MHz, CDCl3) δ 3.41 (1H, dd, J =
14.9, 11.2), 3.52 (1H, dd, J = 14.9, 2.4), 3.72 (3H, s), 4.21 (1H, br s),
4.99 (1H, d, J = 5.8), 5.21 (1H, ddd, J = 11.2, 5.9, 2.5), 6.62 (2H, dm, J
= 8.9), 6.75 (2H, dm, J = 8.9), 7.16 (1H, dd, J = 7.6, 4.8), 7.33−7.40
(5H, m), 7.53 (1H, dd, J = 7.6, 1.7), 8.30 (1H, dd, J = 4.7, 1.7); 13C
NMR (151 MHz, CDCl3) δ 33.0 (CH2), 55.8 (CH3), 62.2 (CH), 90.9
(CH), 114.9 (CH), 116.1 (CH), 123.1 (CH), 127.0 (CH), 128.9
(CH), 129.3 (CH), 130.3 (C), 137.1 (C), 139.7 (C), 140.4 (CH),
149.1 (CH), 151.2 (C), 153.3 (C); MS (EI) m/z 397 (3, M+), 212
(31%, M+ − C7H6ClN2O2); HRMS C21H20ClN3O3 calcd 397.1188,
found 397.1196.
General Procedure for the Synthesis of β-Nitroacetamides 6
(Table 4). To a solution of crude β-nitroamine 5 (1.00 mmol) in
CH2Cl2 (10.0 mL) at −78 °C was added DIPEA (2.50 mmol) quickly
followed by the dropwise addition of TFAA (2.50 mmol). The mixture
was stirred at −78 °C for 60 min before being allowed to warm to
room temperature over 30 min. The reaction was quenched by the
addition of 2 M HCl (15 mL). The phases were separated, and the
aqueous portion was further extracted with CH2Cl2. The combined
organic phases were dried (MgSO4), filtered, and concentrated in
vacuo to give the crude β-nitroacetamide 6 which was purified by flash
column chromatography.
N-[(1R*,2S*)-3-(2-Bromophenyl)-2-nitro-1-phenylpropyl]-N-(4-
methoxyphenyl)-2,2,2-trifluoroacetamide (6a). Prepared using gen-
eral procedure H. Crude β-nitroamine 5a (1.31 mmol) afforded crude
β-nitroacetamide 6a as a brown oil. Purification by flash column
chromatography (40% CH2Cl2/petroleum ether followed by 10%
Et2O/petroleum ether) yielded pure β-nitroacetamide 6a as a white
solid (500 mg, 71%, >95:5 dr): mp 118−120 °C; Rf 0.24 (20% Et2O/
N-((1S*,2S*)-3-(2-Bromophenyl)-2-nitro-1-(thiophene-2-yl)-
propyl)-N-(4-methoxyphenyl)-2,2,2-trifluoroacetamide (6d). Crude
β-nitroamine 5d (4.39 mmol) afforded crude β-nitroacetamide 6d as a
brown oil. Purification by flash column chromatography (50%
CH2Cl2/petroleum ether followed by 20% Et2O/petroleum ether)
J
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The Journal of Organic Chemistry
Featured Article
yielded pure β-nitroacetamide 6d as a white solid (1.76 g, 74%, >95:5
dr): mp 126−128 °C; Rf 0.25 (20% Et2O/petroleum ether); IR νmax
(neat) 3082−2841, 1698, 1557, 1510, 1254, 1207, 1180, 1156, 1033
petroleum ether) and subsequent recrystallization from toluene/
petroleum ether yielded pure β-nitroacetamide 6i as a white solid
(2.24 g, 83%, >95:5 dr): mp 197−198 °C; Rf 0.34 (40% CH2Cl2/
petroleum ether); IR νmax (neat) 3067−2840, 1702, 1556, 1511, 1256,
1
cm−1; H NMR (600 MHz, CDCl3) δ 3.54 (1H, dd, J = 14.2, 11.6),
1
1207, 1181, 1167, 1156, 1030 cm−1; H NMR (600 MHz, CDCl3) δ
3.77 (1H, dd, J = 14.3, 3.6), 3.84 (3H, s), 5.81 (1H, br m), 6.23 (1H,
br s), 6.69 (1H, br s), 6.78 (2H, m), 6.86 (1H, dd, J = 5.0, 3.7), 6.93
(1H, dd, J = 8.7, 2.8), 7.15−7.19 (2H, m), 7.26 (1H, td, J = 7.5, 1.1),
7.31 (1H, dd, J = 5.1, 0.9), 7.34 (1H, br d, J = 8.0), 7.61 (1H, dd, J =
8.0, 1.1); 13C NMR (151 MHz, CDCl3) δ 38.5 (CH2), 55.6 (CH3),
61.9 (CH), 88.9 (CH), 114.1 (CH), 114.7 (CH), 116.2 (1C, q, J =
288.5, C), 124.2 (C), 126.9 (CH), 128.0 (CH), 128.4 (CH), 128.8 (C),
129.8 (CH), 129.9 (CH), 130.5 (CH), 131.2 (CH), 131.5 (CH), 133.3
(CH), 133.7 (C), 134.2 (C), 158.1 (1C, q, J = 36.1, C), 160.6 (C); 19F
NMR (282 MHz, CDCl3) δ −67.8 (3F, s); MS (CI) m/z 543 + 545
(1:1, 3, M+ + H), 496 + 498 (1:1, 5, M+ − NO2), 324 + 326 (1:1, 86,
M+ − PMPNTFA); HRMS C22H19(79Br)F3N2O4S calcd 543.0201,
found 543.0185. Anal. Calcd for C22H18BrF3N2O4S: C, 48.63; H, 3.34;
N, 5.16. Found: C, 48.32; H, 3.19; N, 4.95.
N-((2S*,3R*)-1-(2-Bromophenyl)-2-nitrooctan-3-yl)-N-(4-me-
thoxyphenyl)-2,2,2-trifluoroacetamide (6e). Prepared following
general procedure for the synthesis of 6 except using TFAA (5.0
mmol) and pyridine (5.0 mmol). Crude β-nitroamine 5e (4.24 mmol)
afforded crude β-nitroacetamide 6e as a brown oil. Purification by flash
column chromatography (60% CH2Cl2/petroleum ether followed by
20% Et2O/petroleum ether) yielded pure β-nitroacetamide 6e as a
white solid (1.91 g, 85%, >95:5 dr): mp 88−90 °C; Rf 0.33 (20%
Et2O/petroleum ether); IR νmax (neat) 3059−2862, 1698, 1554, 1511,
1255, 1205, 1182, 1171, 1154, 1028 cm−1; 1H NMR (600 MHz,
CDCl3) δ 0.90 (3H, t, J = 7.0), 1.20−1.53 (7H, m), 1.74−1.79 (1H,
m), 3.42 (1H, dd, J = 14.5, 11.4), 3.55 (1H, dd, J = 14.5, 3.7), 3.87
(3H, s), 4.93 (1H, br s), 5.21 (1H, td, J = 10.1, 3.4), 6.96 (2H, dm, J =
9.2), 7.13 (1H, dd, J = 7.6, 1.5), 7.16 (1H, td, J = 7.7, 1.8), 7.21 (1H,
br m), 7.25 (1H, td, J = 7.4, 1.3), 7.38 (1H, br d, J = 7.6), 7.58 (1H,
dd, J = 7.9, 1.2); 13C NMR (151 MHz, CDCl3) δ 14.1 (CH3), 22.5
(CH2), 26.4 (CH2), 28.0 (CH2), 31.3 (CH2), 38.1 (CH2), 55.7 (CH3),
62.5 (CH), 89.2 (CH), 114.6 (CH), 116.3 (1C, q, J = 288.7, C), 124.2
(C), 128.2 (C), 128.2 (CH), 129.7 (CH), 130.6 (CH), 130.8 (CH),
131.5 (CH), 133.3 (CH), 134.1 (C), 158.7 (1C, q, J = 35.2, C), 160.5
(C); 19F NMR (282 MHz, CDCl3) δ −67.4 (3F, s); MS (EI) m/z 530
+ 532 (1:1, 18, M+), 265 + 267 (1:1, M+ − (PMPNTFA + NO2)), 219
(55, PMPN+TFA); HRMS C23H26(79Br)F3N2O4 calcd 530.1023,
found 530.1024. Anal. Calcd for C23H26BrF3N2O4: C, 51.99; H,
4.93; N, 5.27. Found: C, 52.05; H, 4.91; N, 5.21.
3.71 (1H, dd, J = 14.3, 11.6), 3.78 (3H, s), 3.79 (1H, dd, J = 14.3, 3.9),
5.64 (1H, td, J = 11.3, 3.8), 6.22 (1H, d, J = 7.7), 6.50 (1H, dd, J = 8.9,
2.9), 6.71 (1H, d, J = 7.7), 6.90 (1H, dd, J = 8.8, 2.9), 6.97 (1H, m),
7.00 (1H, d, J = 11.0), 7.13 (1H, td, J = 7.7, 1.4), 7.16 (1H, dd, J = 7.5,
1.6), 7.20 (1H, td, J = 7.7, 1.7), 7.28 (1H, td, J = 7.5, 1.1), 7.53 (1H,
dd, J = 8.7, 2.5), 7.63 (2H, dt, J = 8.0, 1.6); 13C NMR (151 MHz,
CDCl3) δ 38.7 (CH2), 55.6 (CH3), 61.9 (CH), 87.2 (CH), 113.6
(CH), 114.4 (CH), 116.4 (1C, q, J = 288.5, C), 123.9 (C), 126.1 (C),
127.0 (C), 127.4 (CH), 128.5 (CH), 129.7 (CH), 130.0 (CH), 130.8
(CH), 130.9 (CH), 131.9 (CH), 132.2 (CH), 132.3 (C), 133.2 (CH),
133.7 (CH), 133.9 (C), 158.1 (1C, q, J = 35.9, C), 160.4 (C); 19F
NMR (282 MHz, CDCl3) δ −67.4 (3F, s); MS (EI) m/z 618 + 616 +
614 (1:2:1, 15, M+), 535 + 537 (1:1, 4, M+ − Br), 353 + 351 + 349
(1:2:1, 45, M+ − (NO2 + PMPNTFA)); HRMS C24H19(79Br)2F3N2O4
calcd 613.9658, found 613.9667. Anal. Calcd for C24H19Br2F3N2O4: C,
46.78; H, 3.11; N, 4.55. Found: C, 47.02; H, 3.00; N, 4.48.
N-((1R*,2S*)-3-(2-Bromophenyl)-1-(2-methoxyphenyl)-2-nitro-
propyl)-N-(4-methoxyphenyl)-2,2,2-trifluoroacetamide (6j). Crude
β-nitroamine 5j (4.80 mmol) afforded crude β-nitroacetamide 6j as a
brown oil. Purification by flash column chromatography (35% Et2O/
petroleum ether followed by 50% CH2Cl2/petroleum ether) yielded
pure β-nitroacetamide 6j as a white solid (2.25 g, 83%, >95:5 dr): mp
130−132 °C; Rf 0.35 (30% Et2O/petroleum ether); IR νmax (neat)
3071−2841, 1699, 1556, 1511, 1252, 1206, 1180, 1166, 1154, 1026
1
cm−1; H NMR (600 MHz, CDCl3) δ 3.65 (1H, dd, J = 14.3, 11.7),
3.79 (3H, s), 3.79 (1H, dd, J = 14.4, 3.9), 3.81 (3H, br s), 5.69 (1H, td,
J = 11.2, 3.1), 6.14 (1H, d, J = 8.2), 6.52 (1H, dd, J = 8.9, 2.9), 6.67
(1H, t, J = 7.5), 6.77 (1H, br d, J = 5.9), 6.86 (1H, d, J = 8.2), 6.89
(1H, dd, J = 8.7, 2.9), 6.96 (1H, br d, J = 11.2), 7.16 (1H, dd, J = 7.5,
1.7), 7.18 (1H, td, J = 7.7, 1.7), 7.24 (1H, m), 7.26 (1H, td, J = 7.4,
1.1), 7.50 (1H, dd, J = 8.7, 2.2), 7.62 (1H, dd, J = 8.0, 1.1); 13C NMR
(151 MHz, CDCl3) δ 38.8 (CH2), 55.5 (CH3), 55.8 (CH3), 57.4
(CH), 86.8 (CH), 110.9 (CH), 113.4 (CH), 114.0 (CH), 116.5 (1C, q,
J = 288.7, C), 120.4 (CH), 121.1 (C), 124.0 (C), 127.5 (C), 128.4
(CH), 129.2 (CH), 129.8 (CH), 130.8 (CH), 130.9 (CH), 131.9
(CH), 132.1 (CH), 133.2 (CH), 134.2 (C), 157.8 (C), 158.1 (1C, q, J
= 35.3, C), 160.2 (C); 19F NMR (282 MHz, CDCl3) δ −67.3 (3F, s,
CF3); MS (EI) m/z 566 + 568 (1:1, 5, M+); HRMS C25H22(79Br)-
F3N2O5 calcd 566.0659, found 566.0642. Anal. Calcd for
C25H22BrF3N2O5: C, 52.92; H, 3.91; N, 4.94. Found: C, 52.81; H,
3.83; N, 4.90.
N-((1R*,2S*)-3-(2-Bromophenyl)-2-nitro-1-(o-tolyl)propyl)-N-(4-
methoxyphenyl)-2,2,2-trifluoroacetamide (6h). Crude β-nitroamine
5h (5.10 mmol) afforded crude β-nitroacetamide 6h as a yellow oil.
Purification by flash column chromatography (35% CH2Cl2/
petroleum ether) yielded β-nitroacetamide 6h as a white solid (2.28
g, 81%, >95:5 dr): mp 154−156 °C; Rf 0.34 (20% Et2O/petroleum
ether); IR νmax (neat) 3067−2841, 1697, 1557, 1511, 1255, 1207,
N-((1R*,2S*)-3-(2-Bromophenyl)-1-(3-methoxyphenyl)-2-nitro-
propyl)-N-(4-methoxyphenyl)-2,2,2-trifluoroacetamide (6k). Crude
β-nitroamine 5k (0.776 mmol) afforded crude β-nitroacetamide 6k as
a dark yellow oil. Purification by flash column chromatography (45%
CH2Cl2/petroleum ether followed by 40% Et2O/petroleum ether)
yielded pure β-nitroacetamide 6k as a white solid (387 mg, 88%, >95:5
dr): mp 132−133 °C; Rf 0.50 (40% Et2O/petroleum ether); IR νmax
(neat) 3056−2839, 1698, 1557, 1511, 1255, 1208, 1181, 1168, 1156,
1
1180, 1167, 1155, 1032 cm−1; H NMR (600 MHz, CDCl3) δ 2.45
(3H, s), 3.67 (1H, dd, J = 14.3, 11.6), 3.80 (3H, s), 3.80 (1H, dd, J =
14.2, 3.9), 5.64 (1H, td, J = 10.8, 2.6), 6.00 (1H, d, J = 6.5), 6.51 (1H,
dd, J = 8.8, 2.8), 6.55 (1H, br s), 6.84 (1H, t, J = 7.4), 6.85 (1H, br m),
6.92 (1H, dd, J = 8.7, 3.0), 7.14−7.21 (4H, m), 7.27 (1H, td, J = 7.4,
1,2), 7.54 (1H, br d, J = 7.9), 7.63 (1H, dd, J = 8.0, 1.0); 13C NMR
(151 MHz, CDCl3) δ 19.8 (CH3), 38.7 (CH2), 55.6 (CH3), 59.0
(CH), 87.2 (CH), 113.5 (CH), 114.2 (CH), 116.4 (1C, q, J = 288.6,
C), 124.0 (C), 125.9 (CH), 126.8 (C), 128.2 (CH), 128.5 (CH), 129.4
(CH), 129.9 (CH), 130.8 (CH), 130.8 (C), 131.1 (CH), 131.9 (CH),
132.7 (CH), 133.2 (CH), 134.0 (C), 138.0 (C), 158.4 (1C, q, J = 35.7,
C), 160.4 (C); 19F NMR (282 MHz, CDCl3) δ −67.3 (3F, s); MS (EI)
m/z 551 + 553 (1:1, 27, M+ + H), 550 + 552 (1:1, 100, M+), 504 +
506 (1:1, 19, M+ − NO2); HRMS C25H22(79Br)F3N2O4 calcd
550.0710, found 550.0714. Anal. Calcd for C25H22BrF3N2O4: C,
54.46; H, 4.02; N, 5.08. Found: C, 54.45; H, 3.93; N, 5.06.
1
1036 cm−1; H NMR (400 MHz, CDCl3) δ 3.59 (1H, dd, J = 14.4,
11.4), 3.70 (3H, s), 3.78 (1H, dd, J = 14.4, 3.7), 3.83 (3H, s), 5.73
(1H, td, J = 11.1, 3.3), 6.26 (1H, br d, J = 10.1), 6.35 (1H, br d, J =
7.8), 6.63−6.68 (3H, m), 6.85 (1H, ddd, J = 8.3, 2.3, 0.9), 6.92 (1H,
dd, J = 8.7, 2.9), 7.13 (1H, t, J = 8.2), 7.17−7.21 (2H, m), 7.27 (1H,
td, J = 7.5), 7.41 (1H, br d, J = 8.0), 7.61−7.63 (1H, m); 13C NMR
(151 MHz, CDCl3) δ 38.7 (CH2), 55.4 (CH3), 55.6 (CH2), 64.7
(CH), 87.2 (CH), 113.8 (CH), 114.4 (CH), 114.9 (CH), 115.6 (CH),
116.3 (1C, q, J = 288.7, C), 121.8 (CH), 124.1 (C), 127.7 (C), 128.4
(CH), 129.8 (CH), 129.9 (CH), 130.8 (CH), 131.6 (CH), 132.4
(CH), 133.3 (CH), 133.9 (C), 134.2 (C), 158.3 (1C, q, J = 35.8, C),
159.7 (C), 160.5 (C); 19F NMR (282 MHz, CDCl3) δ −67.5 (3F, s);
MS (EI) m/z 566 + 568 (1:1, 15, M+), 367 (30, M+ − C8H9BrO), 302
+ 304 (1:1, 52%, M+ − (PMPNTFA + NO2)), 219 (87, PMPN+TFA);
HRMS C25H22(79Br)F3N2O5 calcd 566.0659, found 566.0645. Anal.
N-((1R*,2S*)-1,3-Bis(2-bromophenyl)-2-nitropropyl)-N-(4-me-
thoxyphenyl)-2,2,2-trifluoroacetamide (6i). Crude β-nitroamine 5i
(4.39 mmol) afforded crude β-nitroacetamide 6i as a yellow oil.
Purification by flash column chromatography (40% CH2Cl2/
K
dx.doi.org/10.1021/jo3010827 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
Calcd for C25H22BrF3N2O5: C, 52.92; H, 3.91; N, 4.94. Found: C,
52.95; H, 3.82; N, 4.88.
(1H, d, J = 7.8), 7.42 (1H, d, J = 8.4), 7.59 (1H, d, J = 7.7), 7.63 (1H,
dd, J = 7.9, 1.2); 13C NMR (151 MHz, CDCl3) δ 38.6 (CH2), 55.7
(CH3), 64.3 (CH), 87.2 (CH), 114.4 (CH), 114.5 (CH), 116.2 (1C, q,
J = 288.6, C), 123.5 (1C, q, J = 272.6, C), 124.1 (C), 126.5 (1C, q, J =
3.7, CH), 126.7 (1C, q, J = 3.6, CH), 127.3 (C), 128.5 (CH), 129.5
(CH), 130.0 (CH), 130.8 (CH), 131.2 (1C, q, J = 32.7, C), 131.6
(CH), 132.3 (CH), 133.0 (CH), 133.3 (CH), 133.6 (C), 133.7 (C),
158.4 (1C, q, J = 36.0, C), 160.8 (C); 19F NMR (282 MHz, CDCl3) δ
−67.6 (3F, s), −63.2 (3F, s); MS (EI) m/z 604 + 606 (1:1, 6, M+),
339 + 341 (1:1, 10, M+ − (PMPNTFA + NO2); HRMS
C25H19(79Br)F6N2O4 calcd 604.0427, found 604.0424. Anal. Calcd
for C25H19BrF6N2O4: C, 49.60; H, 3.16; N, 4.63. Found: C, 49.65; H,
3.10; N, 4.55.
N-((1R*,2S*)-3-(2-Bromophenyl)-2-nitro-1-(4-(trifluoromethyl)-
phenyl)propyl)-N-(4-methoxyphenyl)-2,2,2-trifluoroacetamide (6o).
Crude β-nitroamine 5o (0.925 mmol) afforded crude β-nitroacetamide
6o as a brown oil. Purification by flash column chromatography (35%
CH2Cl2/petroleum ether) yielded pure β-nitroacetamide 6o as a white
solid (507 g, 91%, >95:5 dr): mp 126−128 °C; Rf 0.20 (30% CH2Cl2/
petroleum ether); IR νmax (neat) 3060−2843, 1702, 1558, 1511, 1325,
1256, 1211, 1180, 1167, 1124, 1069, 1027 cm−1; 1H NMR (400 MHz,
CDCl3) δ 3.59 (1H, dd, J = 14.3, 11.4), 3.82 (1H, dd, J = 14.4, 3.7),
3.84 (3H, s), 5.82 (1H, td, J = 11.1, 3.4), 6.27 (1H, br d, J = 10.5), 6.36
(1H, br d, J = 7.2), 6.70 (1H, dd, J = 8.8, 2.7), 6.94 (1H, dd, J = 8.7,
2.8), 7.17 (1H, dd, J = 7.5, 1.7), 7.20 (1H, td, J = 7.6, 1.9), 7.24−7.27
(2H, m), 7.28 (1H, td, J = 7.5, 1.3), 7.38 (1H, br d, J = 7.9), 7.52 (2H,
d, J = 8.2), 7.63 (1H, dd, J = 7.9, 1.2); 13C NMR (151 MHz, CDCl3) δ
38.7 (CH2), 55.7 (CH3), 64.8 (CH), 87.1 (CH), 114.2 (CH), 114.6
(CH), 116.2 (1C, q, J = 288.6, C), 123.7 (1C, q, J = 272.5, C), 124.1
(C), 125.9 (1C, q, J = 3.7, CH), 127.7 (C), 128.5 (CH), 130.0 (CH),
130.0 (CH), 130.8 (CH), 131.6 (CH), 131.9 (1C, q, J = 32.8, C),
132.0 (CH), 133.3 (CH), 133.6 (C), 136.7 (C), 158.4 (1C, q, J = 36.1,
C), 160.7 (C); 19F NMR (282 MHz, CDCl3) δ −67.6 (3F, s), −63.3
(3F, s); MS (EI) m/z 604 + 606 (1:1, 13, M+), 339 + 441 (1:1, 12, M+
− (PMPNHTFA + NO2)), 219 (97, M+ − PMPN+TFA); HRMS
C25H19(79Br)F6N2O4 calcd 604.0427, found 604.0424. Anal. Calcd for
C25H19BrF6N2O4: C, 49.60; H, 3.16; N, 4.63. Found: C, 49.80; H,
3.16; N, 4.54.
N-((1R*,2S*)-3-(2-Bromophenyl)-1-(4-methoxyphenyl)-2-nitro-
propyl)-N-(4-methoxyphenyl)-2,2,2-trifluoroacetamide (6l). Crude
β-nitroamine 5l (4.79 mmol) afforded crude β-nitroacetamide 6l as a
brown oil. Purification by flash column chromatography (60%
CH2Cl2/petroleum ether followed by 30% Et2O/petroleum ether)
yielded pure β-nitroacetamide 6l as a white solid (2.23 g, 82%, >95:5
dr): mp 114−116 °C; Rf 0.36 (30% Et2O/petroleum ether); IR νmax
(neat) 3007−2841, 1698, 1557, 1511, 1256, 1207, 1177, 1169, 1156,
1
1031 cm−1; H NMR (400 MHz, CDCl3) δ 3.59 (1H, dd, J = 14.3,
11.6), 3.77 (3H, s), 3.77 (1H, dd, J = 14.3, 3.7), 3.83 (3H, s), 5.70
(1H, br m), 6.26 (1H, br s), 6.31 (1H, br s), 6.67 (1H, dd, J = 8.6,
2.2), 6.74 (2H, d, J = 8.8), 6.92 (1H, dd, J = 8.8, 2.9), 6.98 (2H, br d, J
= 8.0), 7.17−7.19 (2H, m), 7.25−7.28 (1H, m), 7.42 (1H, br d, J =
7.6), 7.61 (1H, d, J = 7.9); 13C NMR (151 MHz, CDCl3) δ 38.6
(CH2), 55.4 (CH3), 55.6 (CH3), 64.5 (CH), 87.5 (CH), 113.8 (CH),
114.1 (CH), 114.4 (CH), 116.4 (1C, q, J = 288.7, C), 124.1 (C), 124.7
(C), 127.7 (C), 128.4 (CH), 129.8 (CH), 130.8 (CH), 130.9 (CH),
131.7 (CH), 132.6 (CH), 133.3 (CH), 134.0 (C), 158.2 (1C, q, J =
35.6, C), 160.4 (C), 160.5 (C); 19F NMR (282 MHz, CDCl3) δ −67.5
(3F, s); MS (EI) m/z 566 + 568 (4, M+), 520 + 522 (12, M+ − NO2),
348 + 350 (M+ − PMPNHTFA), 302 + 304 (M+ − (NO2
+
PMPNHTFA); HRMS C25H22(79Br)F3N2O5 calcd 566.0659, found
566.0638. Anal. Calcd for C25H22BrF3N2O5: C, 52.92; H, 3.91; N,
4.94. Found: C, 53.01; H, 3.84; N, 4.76.
N-((1R*,2S*)-3-(2-Bromophenyl)-2-nitro-1-(2-(trifluoromethyl)-
phenyl)propyl)-N-(4-methoxyphenyl)-2,2,2-trifluoroacetamide
(6m). Prepared following the general procedure for the synthesis of 6
except using TFAA (5.0 mmol) and pyridine (5.0 mmol). Crude β-
nitroamine 5m (3.24 mmol) afforded crude β-nitroacetamide 6m as a
brown oil. Purification by flash column chromatography (40%
CH2Cl2/petroleum ether followed by 30% Et2O/petroleum ether)
yielded pure β-nitroacetamide 6m as a white solid (1.33 g, 68%, 90:10
dr). Subsequent recrystallization from toluene/petroleum ether gave
β-nitroacetamide 6m as a single anti diastereomer (1.18 g, 60%): mp
153−154 °C; Rf 0.33 (30% Et2O/petroleum ether); IR νmax (neat)
3057−2843, 1705, 1557, 1512, 1313, 1257, 1210, 1182, 1159, 1125,
1
1038 cm−1; H NMR (600 MHz, CDCl3) δ 3.71 (1H, dd, J = 14.4,
N-((1R*,2S*)-3-(2-Bromo-5-fluorophenyl)-2-nitro-1-phenylprop-
yl)-N-(4-methoxyphenyl)-2,2,2-trifluoroacetamide (6p). Crude β-
nitroamine 5p (0.480 mmol) afforded crude β-nitroacetamide 6p as
a yellow oil. Purification by flash column chromatography (40%
CH2Cl2/petroleum ether followed by 25% Et2O/petroleum ether)
yielded pure β-nitroacetamide 6p as a white solid (219 mg, 82%, >95:5
dr): mp 118−120 °C; Rf 0.51 (25% Et2O/petroleum ether); IR νmax
(neat) 3069−2842, 1698, 1557, 1511, 1474, 1255, 1208, 1181, 1155,
11.6), 3.79 (3H, s), 3.80 (1H, dd, J = 14.3, 3.8), 5.62 (1H, td, J = 11.1,
3.8), 6.04 (1H, dd, J = 8.8, 2.0), 6.46 (1H, dd, J = 8.8, 2.9), 6.67 (1H,
d, J = 7.9), 6.95 (1H, dd, J = 8.7, 3.0), 7.14 (1H, d, J = 10.5), 7.15 (2H,
dd, J = 7.5, 1.7), 7.20 (1H, td, J = 7.7, 1.6), 7.27 (1H, td, J = 7.5, 1.2),
7.38 (1H, t, J = 7.7), 7.63 (1H, dd, J = 7.9, 1.1), 7.64 (1H, dd, J = 8.7,
2.6), 7.74 (1H, d, J = 7.6); 13C NMR (151 MHz, CDCl3) δ 38.9
(CH2), 55.6 (CH3), 57.5 (CH), 87.7 (CH), 113.7 (CH), 114.3 (CH),
116.3 (1C, q, J = 288.4, C), 123.8 (1C, q, J = 274.1, C), 123.9 (C),
126.6 (C), 126.9 (1C, q, J = 5.9, CH), 128.6 (CH), 129.7 (CH), 130.0
(CH), 130.2 (1C, q, J = 30.4, C), 130.4 (C), 130.4 (CH), 131.2 (CH),
131.4 (CH), 132.0 (CH), 132.6 (CH), 133.2 (CH), 133.8 (C), 158.1
(1C, q, J = 35.9, C), 160.5 (C); 19F NMR (282 MHz, CDCl3) δ −67.6
(3F, s), −60.2 (3F, s); MS (EI) m/z 604 + 606 (1:1, 32, M+), 339 +
1
1032 cm−1; H NMR (600 MHz, CDCl3) δ 3.58 (1H, dd, J = 14.4,
11.4), 3.74 (1H, dd, J = 14.4, 3.7), 3.82 (3H, s), 5.78 (1H, td, J = 11.2,
3.5), 6.24 (1H, br d, J = 10.7), 6.31 (1H, br d, J = 8.2), 6.65 (1H, dd, J
= 8.8, 2.8), 6.93 (2H, td, J = 8.4, 3.1), 6.94 (1H, d, J = 8.2), 7.09 (2H,
d, J = 7.4), 7.24 (2H, t, J = 7.5), 7.30−7.36 (2H, m), 7.56−7.60 (1H,
m); 13C NMR (151 MHz, CDCl3) δ 38.6 (CH2), 55.6 (CH3), 65.1
(CH), 87.0 (CH), 113.9 (CH), 114.4 (CH), 116.3 (1C, q, J = 288.5,
C), 117.2 (1C, d, J = 22.2, CH), 118.3 (1C, d, J = 3.2, C), 118.7 (1C, d,
J = 23.1, CH), 127.7 (C), 128.9 (CH), 129.6 (CH), 129.9 (CH), 130.7
(CH), 132.3 (CH), 132.6 (C), 134.5 (1C, d, J = 7.9, CH), 135.9 (1C,
d, J = 7.6, C), 158.3 (1C, q, J = 35.8, C), 160.5 (C), 162.1 (1C, d, J =
248.8, C); 19F NMR (282 MHz, CDCl3) δ −113.5 (1F, m), −67.5
(3F, s); MS (EI) m/z 554 + 556 (1:1, 7, M+), 335 + 337 (1:1, 9, M+ −
PMPNTFA); HRMS C24H19(79Br)F4N2O4 calcd 554.0459, found
554.0465. Anal. Calcd for C24H19BrF4N2O4: C, 51.91; H, 3.45; N,
5.04. Found: C, 52.04; H, 3.39; N, 5.00.
341 (1:1, 85, M+ − (PMPNHTFA + NO2)), 261 (38, M+
−
(PMPNHTFA + Br + NO2)), 218 (100, PMPN+TFA); HRMS
C25H19(79Br)F6N2O4 calcd 604.0427, found 604.0411. Anal. Calcd for
C25H19BrF6N2O4: C, 49.60; H, 3.16; N, 4.63. Found: C, 49.24; H,
3.03; N, 4.57.
N-((1R*,2S*)-3-(2-Bromophenyl)-2-nitro-1-(3-(trifluoromethyl)-
phenyl)propyl)-N-(4-methoxyphenyl)-2,2,2-trifluoroacetamide (6n).
Crude β-nitroamine 5n (0.623 mmol) afforded crude β-nitroacetamide
6n as a brown oil. Purification by flash column chromatography (40%
CH2Cl2/petroleum ether followed by 30% Et2O/petroleum ether)
yielded pure β-nitroacetamide 6n as an off-white solid (344 mg, 91%,
>95:5 dr): mp 57−60 °C; Rf 0.53 (30% Et2O/petroleum ether); IR
νmax (neat) 3061−2841, 1700, 1557, 1511, 1328, 1257, 1209, 1180,
N-((1R*,2S*)-3-(2-Bromo-4,5-dimethoxyphenyl)-2-nitro-1-phe-
nylpropyl)-N-(4-methoxyphenyl)-2,2,2-trifluoroacetamide (6q).
Crude β-nitroamine 5q (0.472 mmol) afforded crude β-nitroacetamide
6q as a yellow foam. Purification by flash column chromatography
(50% Et2O/petroleum ether) yielded pure β-nitroacetamide 6q as an
off-white solid (248 mg, 88%, >95:5 dr): mp 72−75 °C; Rf 0.48 (50%
Et2O/petroleum ether); IR νmax (neat) 3008−2842, 1697, 1556, 1509,
1
1164, 1127, 1076, 1026 cm−1; H NMR (400 MHz, CDCl3) δ 3.61
(1H, dd, J = 14.4, 11.4), 3.81 (1H, dd, J = 14.2, 3.6), 3.82 (3H, s), 5.75
(1H, td, J = 11.1, 3.4), 6.26 (1H, d, J = 8.0), 6.36 (1H, d, J = 10.7),
6.66 (1H, dd, J = 8.8, 2.8), 6.96 (1H, dd, J = 8.8, 2.9), 7.16−7.22 (2H,
m), 7.23 (1H, s), 7.28 (1H, td, J = 7.5, 1.3), 7.33 (1H, d, J = 7.9), 7.39
1
1258, 1206, 1180, 1155, 1032 cm−1; H NMR (400 MHz, CDCl3) δ
L
dx.doi.org/10.1021/jo3010827 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
3.52 (1H, dd, J = 14.4, 11.4), 3.72 (1H, dd, J = 14.4, 3.8), 3.82 (3H, s),
3.82 (3H, s), 3.87 (3H, s), 5.71 (1H, td, J = 11.1, 3.5), 6.26 (1H, br d, J
= 8.0), 6.31 (1H, br d, J = 11.0), 6.63 (1H, m), 6.64 (1H, s), 6.92 (1H,
dd, J = 8.7, 2.8), 7.05 (1H, s), 7.06 (2H, m), 7.23 (2H, t, J = 7.5),
7.27−7.33 (1H, m), 7.42 (1H, br d, J = 7.3); 13C NMR (151 MHz,
CDCl3) δ 38.4 (CH2), 55.6 (CH3), 56.2 (CH3), 56.3 (CH3), 64.7
(CH), 87.4 (CH), 113.8 (CH), 113.9 (CH), 114.0 (C), 114.3 (CH),
115.6 (CH), 116.3 (1C, q, J = 288.7, C), 125.6 (C), 127.6 (C), 128.8
(CH), 129.5 (CH), 129.8 (CH), 130.8 (CH), 132.5 (CH), 132.8 (C),
148.8 (CO), 149.4 (CO), 158.3 (1C, q, J = 35.7, C), 160.5 (CO); 19F
NMR (282 MHz, CDCl3) δ −67.5 (3F, s); MS (ES+) m/z 619 + 621
(1:1, 43%, M+ + Na), 550 + 552 (86, M+ − NO2), 331 + 333 (1:1,
18%, M+ − PMPNTFA), 228 + 230 (75, M+ − C17H14F3N2O4);
HRMS C26H24(79Br)F3N2O6Na calcd 619.0668, found 619.0672.
N-((1R,2S)-3-(2-Bromo-4,5-dimethoxyphenyl)-1-(2-methoxy-
phenyl)-2-nitropropyl)-N-(4-methoxyphenyl)-2,2,2-trifluoroaceta-
mide (6r). Crude β-nitroamine 5r (2.69 mmol) afforded crude β-
nitroacetamide 6r as a brown oil. Purification by flash column
chromatography (70% CH2Cl2/petroleum ether followed by 60%
Et2O/petroleum ether) yielded pure β-nitroacetamide 6r as a white
solid (1.22 g, 72%, >95:5 dr): mp 81−83 °C; Rf 0.32 (50% Et2O/
petroleum ether); IR νmax (neat) 3005−2842, 1700, 1556, 1511, 1496,
(290 mg, 59%, >95:5 dr): mp 53−55 °C; Rf 0.32 (25% EtOAc/
petroleum ether); IR νmax (neat) 3039−2851, 1697, 1557, 1510, 1411,
1
1254, 1207, 1180, 1155 cm−1; H NMR (400 MHz, CDCl3) δ 3.56
(1H, dd, J = 14.5, 11.6), 3.79 (1H, dd, J = 14.5, 3.6), 3.82 (3H, s), 5.70
(1H, td, J = 11.3, 3.5), 6.20 (1H, d, J = 8.1), 6.39 (1H, d, J = 10.0),
6.62 (1H, dd, J = 8.8, 2.9), 6.95 (1H, dd, J = 8.7, 2.9), 7.05 (2H, d, J =
7.4), 7.20−7.25 (3H, m), 7.32 (1H, m), 7.38 (1H, br dd, J = 8.7, 1.9),
7.52 (1H, dd, J = 7.6, 1.9), 8.37 (1H, dd, J = 4.7, 1.9); 13C NMR (151
MHz, CDCl3) δ 36.0 (CH2), 55.5 (CH3), 64.0 (CH), 86.6 (CH), 113.7
(CH), 114.4 (CH), 116.2 (1C, q, J = 288.6, C), 123.3 (CH), 127.0
(C), 128.8 (CH), 129.0 (C), 129.4 (CH), 129.8 (CH), 130.4 (CH),
132.3 (C), 132.5 (CH), 140.3 (CH), 149.5 (CH), 150.8 (C), 158.4
(1C, q, J = 35.9, C), 160.5 (C); 19F NMR (282 MHz, CDCl3) δ −67.5
(3F, s); MS (ES+) m/z 494 (80, M+), 447 (100, M+ − NO2), 230 (50,
C14H12ClN); HRMS C23H20ClF3N3O4 calcd 494.1094, found
494.1103.
General Procedure for the Synthesis of β-Aminoacetamides
7 (Table 5). To a solution of β-nitroacetamide (1.00 mmol) in EtOAc
(30.0 mL) and EtOH (40.0 mL) at 0 °C was added 6 M aq HCl (250
mmol). The colorless solution was vigorously stirred, and zinc dust
(50.0 mmol) was added in three portions over 10 min. The gray
suspension was removed from the cold bath and allowed to warm to rt
over 2 h to give a colorless solution. Zinc dust (25.0 mmol) was added
in one portion, and the resultant gray suspension stirred at room
temperature for a further 1 h. The EtOH and EtOAc were removed in
vacuo, and the resultant aqueous solution was neutralized by the
addition of NaHCO3(s) and extracted with EtOAc. The combined
organic phases were washed with 2 M HCl and brine, dried (MgSO4),
filtered, and concentrated in vacuo. The residue was dissolved in
EtOH (40.0 mL), 6 M HCl(aq) (20.0 mmol) was added and the
mixture stirred at rt for 1 h before removal of the EtOH in vacuo. To
the residue was added H2O, and the product was extracted into
EtOAc. The combined organic phases were washed with brine, dried
(MgSO4), filtered, and concentrated in vacuo to give crude β-
aminoacetamide which was purified by column chromatography.
N-((1R*,2S*)-3-(2-Bromophenyl)-1-((4-methoxyphenyl)amino)-1-
phenylpropan-2-yl)-2,2,2-trifluoroacetamide (7a). β-Nitroacetamide
6a (893 mg, 1.66 mmol) afforded crude β-aminoacetamide 7a as a
brown solid. Purification by flash column chromatography (20%
EtOAc/petroleum ether) yielded pure β-aminoacetamide 7a as a white
solid (751 mg, 89%): mp 166−169 °C; Rf 0.33 (20% EtOAc/
petroleum ether); IR νmax (neat) 3303, 3065−2834, 1702, 1512, 1180
1
1255, 1207, 1181, 1167, 1033 cm−1; H NMR (600 MHz, CDCl3) δ
3.56 (1H, dd, J = 14.4, 11.5), 3.73 (1H, dd, J = 14.4, 4.0), 3.79 (3H, s),
3.81 (6H, s), 3.88 (3H, s), 5.65 (1H, td, J = 11.3, 3.8), 6.14 (1H, d, J =
8.0), 6.52 (1H, dd, J = 8.8, 2.9), 6.63 (1H, s), 6.67 (1H, t, J = 7.4), 6.76
(1H, d, J = 7.2), 6.86 (1H, d, J = 8.9), 6.89 (1H, dd, J = 8.8, 2.9), 6.95
(1H, d, J = 11.3), 7.05 (1H, s), 7.23−7.27 (1H, m), 7.50 (1H, dd, J =
8.7, 2.2); 13C NMR (151 MHz, CDCl3) δ 38.6 (CH2), 55.5 (CH3),
55.8 (CH3), 56.1 (CH3), 56.3 (CH3), 57.2 (CH), 86.9 (CH), 110.9
(CH), 113.4 (CH), 113.9 (C), 113.9 (CH), 114.1 (CH), 115.5 (CH),
116.5 (1C, q, J = 288.6, C), 120.4 (CH), 121.1 (C), 125.9 (C), 127.5
(C), 129.3 (CH), 130.8 (CH), 130.9 (CH), 132.2 (CH), 148.8 (C),
149.3 (C), 157.8 (C), 158.1 (1C, q, J = 35.3, C), 160.2 (C); 19F NMR
(282 MHz, CDCl3) δ −67.3 (3F, s); MS (EI) m/z 626 + 628 (1:1, 20,
M+), 361 + 363 (1:1, 100, M+ − (PMPNHTFA + NO2)), 229 + 231
(1:1, 98, M+ − C18H17F3N2O5); HRMS C27H26(79Br)F3N2O7 calcd
626.0870, found 626.0847. Anal. Calcd for C27H26BrF3N2O7: C, 51.69;
H, 4.18; N, 4.46. Found: C, 51.95; H, 4.14; N, 4.45.
N-((1R*,2S*)-3-(3-(Benzyloxy)-2-bromo-4-methoxyphenyl)-2-
nitro-1-phenylpropyl)-N-(4-methoxyphenyl)-2,2,2-trifluoroaceta-
mide (6s). Crude β-nitroamine 5s (1.17 mmol) afforded crude β-
nitroacetamide 6s as a brown oil. Purification by flash column
chromatography (60% CH2Cl2/petroleum ether) and subsequent
recrystallization from Et2O/petroleum ether yielded pure β-nitro-
acetamide 6s as a white solid (550 mg, 82%, >95:5 dr): mp 168−169
°C; Rf 0.33 (60% CH2Cl2/petroleum ether); IR νmax (neat) 3064−
2840, 1699, 1557, 1511, 1487, 1300, 1270, 1256, 1208, 1181, 1170,
1
cm−1; H NMR (600 MHz, CDCl3) δ 2.84 (1H, dd, J = 14.1, 11.1),
3.15 (1H, dd, J = 14.1, 3.7), 3.71 (3H, s), 4.33 (1H, br s), 4.70 (1H, d,
J = 3.7), 4.75 (1H, m), 6.39 (1H, br d, J = 9.4), 6.56 (2H, dm, J = 8.9),
6.72 (2H, dm, J = 8.9), 7.10 (2H, m), 7.22 (1H, td, J = 7.5, 0.9), 7.35
(1H, m), 7.40- 7.43 (4H, m), 7.52 (1H, m); 13C NMR (151 MHz,
CDCl3) δ 36.7 (CH2), 55.4 (CH), 55.8 (OCH3), 62.2 (CH), 114.9
(CH), 115.5 (CH), 115.7 (1C, q, J = 288.0, C), 124.9 (C), 127.3
(CH), 127.9 (CH), 128.3 (CH), 129.0 (CH), 129.1 (CH), 131.0
(CH), 133.1 (CH), 136.1 (C), 138.3 (C), 140.6 (C), 152.8 (C), 157.4
(1C, q, J = 37.2, C); 19F NMR (282 MHz, CDCl3) δ −76.4 (3F, s);
MS (ESI+) m/z 507 + 509 (26, M+ + H), 429 (100, M+ − Br); HRMS
C24H23(79Br)F3N2O2 calcd 507.0890, found 507.0879. Anal. Calcd for
C24H22BrF3N2O2: C, 56.82; H, 4.37; N, 5.52. Found: C, 56.63; H,
4.31; N, 5.29.
N-((1S*,2S*)-3-(2-Bromophenyl)-1-(furan-2-yl)-1-((4-
methoxyphenyl)amino)propan-2-yl)-2,2,2-trifluoroacetamide (7b).
β-Nitroacetamide 6b (586 mg, 1.11 mmol) afforded crude β-
aminoacetamide 7b as a brown solid. Purification by flash column
chromatography (20% EtOAc/petroleum ether) and subsequent
recrystallization from toluene/petroleum ether yielded pure β-
aminoacetamide 7b as a white solid (501 mg, 91%): mp 131−133
°C; Rf 0.24 (30% Et2O/petroleum ether); IR νmax (neat) 3306, 3113−
2834, 1703, 1511, 1244, 1232, 1207, 1167 cm−1; 1H NMR (600 MHz,
CDCl3) δ 2.94 (1H, dd, J = 14.0, 10.2), 3.13 (1H, dd, J = 14.0, 4.8),
3.74 (3H, s), 3.98 (1H, br s), 4.71 (1H, d, J = 4.0), 4.80 (1H, ddd, J =
14.4, 9.7, 4.6), 6.32 (1H, d, J = 3.3), 6.37 (1H, dd, J = 3.3, 1.9), 6.62
(2H, dm, J = 8.9), 6.67 (1H, br d, J = 9.4), 6.76 (2H, dm, J = 8.9), 7.12
(1H, td, J = 7.6, 1.6), 7.21 (1H, dd, J = 7.7, 1.7), 7.25 (1H, td, J = 7.5,
1
1156, 1033 cm−1; H NMR (600 MHz, CDCl3) δ 3.56 (1H, dd, J =
14.4, 11.4), 3.78 (1H, dd, J = 14.4, 3.8), 3.82 (3H, s), 3.86 (3H, s),
5.06 (2H, s), 5.71 (1H, td, J = 11.2, 3.5), 6.22 (1H, d, J = 8.1), 6.36
(1H, d, J = 10.5), 6.61 (1H, dd, J = 8.8), 6.83 (1H, d, J = 8.6), 6.91
(1H, d, J = 8.5), 6.92 (1H, dd, J = 8.8, 2.9), 7.06 (2H, d, J = 7.3), 7.23
(2H, t, J = 7.5), 7.29−7.44 (4H, m), 7.46 (1H, d, J = 8.7), 7.56−7.58
(2H, m); 13C NMR (151 MHz, CDCl3) δ 38.6 (CH2), 55.6 (CH3),
56.1 (CH3), 64.5 (CH), 74.8 (CH2), 87.3 (CH), 111.7 (CH), 113.7
(CH), 114.3 (CH), 116.4 (1C, q, J = 289.0, C), 120.2 (C), 126.5 (C),
126.7 (CH), 127.5 (C), 128.3 (CH), 128.5 (CH), 128.6 (CH), 128.8
(CH), 129.6 (CH), 129.7 (CH), 130.9 (CH), 132.5 (CH), 132.9 (C),
137.1 (C), 145.5 (C), 153.6 (C), 158.3 (1C, q, J = 35.8, C), 160.4 (C);
19F NMR (282 MHz, CDCl3) δ −67.4 (3F, s); MS (FAB+) m/z 695 +
697 (1:1, 8, M+ + Na), 549 + 551 (1:1, 5, M+ − C8H10O); HRMS
C32H28(79Br)F3N2O6Na calcd 695.0981, found 695.0968. Anal. Calcd
for C32H28BrF3N2O6: C, 57.07; H, 4.19; N, 4.16. Found: C, 57.40; H,
4.20; N, 4.05.
N-((1R*,2S*)-3-(2-Chloropyridin-3-yl)-2-nitro-1-phenylpropyl)-N-
(4-methoxyphenyl)-2,2,2-trifluoroacetamide (6t). Crude β-nitro-
amine 5t (0.99 mmol) afforded crude β-nitroacetamide 6t as a
brown oil. Purification by flash column chromatography (25% EtOAc/
petroleum ether) yielded pure β-nitroacetamide 6t as a white solid
M
dx.doi.org/10.1021/jo3010827 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
1.2), 7.45 (1H, dd, J = 1.7, 0.7), 7.55 (1H, dd, J = 8.0, 1.0); 13C NMR
(151 MHz, CDCl3) δ 37.0 (CH2), 54.0 (CH), 55.8 (CH3), 56.5 (CH),
108.8 (CH), 110.8 (CH), 114.9 (CH), 115.8 (1C, q, J = 288.3, C),
116.1 (CH), 125.0 (C), 127.8 (CH), 129.0 (CH), 131.3 (CH), 133.2
(CH), 136.2 (C), 140.3 (C), 142.8 (CH), 152.0 (C), 153.4 (C), 157.2
(1C, q, J = 37.0, C); 19F NMR (282 MHz, CDCl3) δ −76.3 (3F, s);
MS (EI) m/z 496 + 498 (4, M+), 202 (100, M+ − C10H8BrF3NO);
HRMS C22H20(79Br)F3N2O3 calcd 496.0604, found 496.0614. Anal.
Calcd for C22H20BrF3N2O3: C, 53.13; H, 4.05; N, 5.63. Found: C,
53.44; H, 4.16; N, 5.89.
N-((1R*,2S*)-3-(2-Bromophenyl)-1-(furan-3-yl)-1-((4-
methoxyphenyl)amino)propan-2-yl)-2,2,2-trifluoroacetamide (7c).
β-Nitroacetamide 6c (511 mg, 0.969 mmol) afforded crude β-
aminoacetamide 7c as a brown solid. Purification by flash column
chromatography (20% EtOAc/petroleum ether) and subsequent
recrystallization from toluene/petroleum ether yielded pure β-
aminoacetamide 7c as a white solid (448 mg, 93%): mp 131−133
°C; Rf 0.46 (20% EtOAc/petroleum ether); IR νmax (neat) 3398, 3312,
3111−2835, 1705, 1511, 1244, 1230, 1209, 1164, 1027 cm−1; 1H
NMR (600 MHz, CDCl3) δ 2.91 (1H, dd, J = 13.9, 10.9), 3.17 (1H,
dd, J = 14.0, 4.0), 3.74 (1H, s), 3.90 (1H, br s), 4.65 (1H, d, J = 3.2),
4.72 (1H, m), 6.45 (1H, s), 6.52 (1H, d, J = 9.3), 6.63 (2H, dm, J =
8.9), 6.77 (2H, dm, J = 8.9), 7.12 (1H, td, J = 7.7, 1.5), 7.17 (1H, dd, J
= 7.6, 1.4), 7.25 (1H, t, J = 7.4), 7.45−7.47 (2H, m), 7.55 (1H, d, J =
8.0); 13C NMR (151 MHz, CDCl3) δ 36.6 (CH2), 54.5 (CH), 55.4
(CH), 55.8 (CH3), 109.3 (CH), 115.0 (CH), 115.7 (1C, q, J = 288.2,
C), 115.8 (CH), 123.8 (C), 124.9 (C), 127.9 (CH), 129.1 (CH), 131.2
(CH), 133.2 (CH), 136.1 (C), 140.5 (CH), 140.6 (C), 144.2 (CH),
153.2 (C), 157.3 (1C, q, J = 37.2, C); 19F NMR (282 MHz, CDCl3) δ
−76.3 (3F, s); MS (EI) m/z 496 + 498 (1:1, 2, M+), 202 (100, M+ −
C10H8BrF3NO); HRMS C22H20(79Br)F3N2O3 calcd 496.0604, found
496.0598. Anal. Calcd for C22H20BrF3N2O3: C, 53.13; H, 4.05; N,
5.63. Found: C, 53.27; H, 4.02; N, 5.52.
N-((1S*,2S*)-3-(2-Bromophenyl)-1-((4-methoxyphenyl)amino)-1-
(thiophene-2-yl)propan-2-yl)-2,2,2-trifluoroacetamide (7d). β-Nitro-
acetamide 6d (516 mg, 0.950 mmol) afforded crude β-aminoacetamide
7d as a brown solid. Purification by flash column chromatography
(20% EtOAc/petroleum ether) and subsequent recrystallization from
toluene/petroleum ether yielded pure β-aminoacetamide 7d as a white
solid (402 mg, 82%): mp 131−133 °C; Rf 0.46 (20% EtOAc/
petroleum ether); IR νmax (neat) 3298, 3104−2834, 1700, 1512, 1244,
1233, 1207, 1178 cm−1; 1H NMR (600 MHz, CDCl3) δ 2.93 (1H, dd,
J = 14.0, 10.8), 3.20 (1H, dd, J = 14.1, 4.1), 3.73 (3H, s), 4.23 (1H, d, J
= 6.7), 4.79 (1H, m), 4.93 (1H, dd, J = 6.6, 3.5), 6.49 (1H, br d, J =
9.4), 6.61 (2H, dm, J = 8.9), 6.75 (2H, dm, J = 8.9), 7.07 (1H, dd, J =
5.0, 3.5), 7.11−7.14 (2H, m), 7.18 (1H, dd, J = 7.7, 1.7), 7.26 (1H, td,
J = 7.5, 1.4), 7.31 (1H, dd, J = 5.1, 1.1), 7.55 (1H, dd, J = 8.0, 1.1); 13C
NMR (151 MHz, CDCl3) δ 37.0 (CH2), 55.2 (CH), 55.8 (CH3), 59.0
(CH), 114.9 (CH), 115.7 (CH), 115.7 (1C, q, J = 288.3, C), 125.0
(C), 125.5 (CH), 125.6 (CH), 127.5 (CH), 127.9 (CH), 129.1 (CH),
131.1 (CH), 133.2 (CH), 136.0 (C), 140.4 (C), 143.0 (C), 153.2 (C),
157.6 (1C, q, J = 37.3, C); 19F NMR (282 MHz, CDCl3) δ −76.3 (3F,
s); MS (EI) m/z 514 + 512 (3, M+), 218 (100, M+ − C10H8BrF3NO);
HRMS C22H20(79Br)F3N2O2S calcd 512.0376, found 512.0374. Anal.
Calcd for C22H20BrF3N2O2S: C, 51.47; H, 3.93; N, 5.46. Found: C,
51.62; H, 3.86; N, 5.41.
22.6 (CH2), 26.3 (CH2), 31.8 (CH2), 33.5 (CH2), 35.1 (CH2), 53.6
(CH), 55.8 (CH3), 59.0 (CH), 115.2 (CH), 115.6 (CH), 115.8 (1C, q,
J = 288.2, C), 125.0 (C), 127.7 (CH), 128.9 (CH), 131.3 (CH), 133.1
(CH), 136.5 (C), 142.0 (C), 153.0 (C), 156.6 (1C, q, J = 36.9, C); 19F
NMR (282 MHz, CDCl3) δ −76.4 (3F, s); MS (EI) m/z 500 + 502
(4, M+), 206 (100, M+ − C10H8BrF3NO); HRMS C23H28(79Br)-
F3N2O2 calcd 500.1281, found 500.1289. Anal. Calcd for
C23H28BrF3N2O2: C, 55.10; H, 5.63; N, 5.59. Found: C, 55.33; H,
5.65; N, 5.61.
N-((1R*,2S*)-3-(2-Bromophenyl)-1-((4-methoxyphenyl)amino)-1-
(o-tolyl)propan-2-yl)-2,2,2-trifluoroacetamide (7h). β-Nitroaceta-
mide 6h (159 mg, 0.288 mmol) afforded crude β-aminoacetamide
7h as a brown oil. Purification by flash column chromatography (20%
EtOAc/petroleum ether) yielded pure β-aminoacetamide 7h as a white
solid (138 mg, 91%): mp 190−192 °C; Rf 0.51 (20% EtOAc/
petroleum ether); IR νmax (neat) 3409, 3327, 3063−2834, 1703, 1511,
1
1243, 1232, 1211, 1169, 1034 cm−1; H NMR (600 MHz, CDCl3) δ
2.55 (3H, s), 2.88 (1H, dd, J = 13.7, 11.9), 3.14 (1H, dd, J = 13.8, 3.0),
3.71 (3H, s), 4.24 (1H, br s), 4.65 (1H, m), 4.96 (1H, d, J = 3.8), 6.58
(2H, dm, J = 8.9), 6.70 (1H, br d, J = 9.2), 6.74 (2H, dm, J = 8.9), 7.06
(1H, dd, J = 7.6, 1.0), 7.08 (1H, dd, J = 7.7, 1.4), 7.19−7.26 (4H, m),
7.31−7.33 (1H, m), 7.50 (1H, d, J = 7.9); 13C NMR (151 MHz,
CDCl3) δ 19.6 (CH3), 35.1 (CH2), 54.2 (CH), 55.8 (CH3), 58.5
(CH), 115.0 (CH), 115.7 (1C, q, J = 288.2, C), 115.9 (CH), 124.8
(C), 125.9 (CH), 126.5 (CH), 127.8 (CH), 127.9 (CH), 129.0 (CH),
131.0 (CH), 131.5 (CH), 133.1 (CH), 136.2 (C), 136.3 (C), 136.4
(C), 140.5 (C), 153.1 (C), 157.1 (1C, q, J = 37.1, C); 19F NMR (282
MHz, CDCl3) δ −76.3 (3F, s); MS (EI) m/z 520 + 522 (10, M+), 226
(100, M+ − C10H8BrF3NO); HRMS C25H24(79Br)F3N2O2 calcd
520.0968, found 520.0974. Anal. Calcd for C25H24BrF3N2O2: C,
57.59; H, 4.64; N, 5.37. Found: C, 57.88; H, 4.63; N, 5.29.
N-((1R*,2S*)-3-(2-Bromophenyl)-1-(2-methoxyphenyl)-1-((4-
methoxyphenyl)amino)propan-2-yl)-2,2,2-trifluoroacetamide (7j).
β-Nitroacetamide 6j (154 mg, 0.271 mmol) afforded crude β-
aminoacetamide 7j as a brown oil. Purification by flash column
chromatography (20% EtOAc/petroleum ether) yielded pure β-
aminoacetamide 7j as a white solid (136 mg, 94%): mp 137−138
°C; Rf 0.41 (20% EtOAc/petroleum ether); IR νmax (neat) 3373,
3062−2836, 1710, 1511, 1235, 1208, 1163, 1027 cm−1; 1H NMR (600
MHz, CDCl3) δ 2.87 (1H, dd, J = 14.2, 10.7), 3.36 (1H, dd, J = 14.2,
3.7), 3.71 (3H, s), 3.94 (3H, s), 4.39 (1H, br s), 4.71 (1H, qdd, J =
10.0, 6.2, 3.8), 4.96 (1H, d, J = 6.1), 6.57 (2H, dm, J = 8.9), 6.70 (1H,
d, J = 9.3), 6.72 (2H, dm, J = 8.9), 6.92−6.94 (2H, m), 7.09 (1H, td, J
= 7.6, 1.6), 7.16 (1H, dd, J = 7.7, 1.7), 7.22 (1H, td, J = 7.4, 1.2), 7.24−
7.28 (2H, m), 7.52 (1H, dd, J = 8.0, 1.1); 13C NMR (151 MHz,
CDCl3) δ 37.6 (CH2), 54.5 (CH), 55.6 (CH3), 55.8 (CH3), 57.5
(CH), 110.8 (CH), 114.9 (CH), 115.4 (CH), 115.8 (1C, q, J = 288.3,
C), 121.3 (CH), 125.0 (C), 126.5 (C), 127.7 (CH), 128.2 (CH), 128.7
(CH), 129.2 (CH), 131.2 (CH), 133.0 (CH), 136.8 (C), 140.7 (C),
152.7 (C), 156.8 (1C, q, J = 36.8, C), 157.1 (C); 19F NMR (282 MHz,
CDCl3) δ −76.6 (3F, s); MS (CI) m/z 537 + 539 (1:1, 12, M+ + H),
414 + 416 (1:1, 15, M+ − NHPMP), 301 + 303 (5%, M+
−
C9H9F3N2O2), 242 (25, M+ − C10H8BrF3NO); HRMS C25H25(79Br)-
F3N2O3 calcd 537.1001, found 537.1013. Anal. Calcd for
C25H24BrF3N2O3: C, 55.88; H, 4.50; N, 5.21. Found: C, 55.58; H,
4.40; N, 5.25.
N-((2S*,3R*)-1-(2-Bromophenyl)-3-((4-methoxyphenyl)amino)-
octan-2-yl)-2,2,2-trifluoroacetamide (7e). β-Nitroacetamide 6e (999
mg, 1.88 mmol) afforded crude β-aminoacetamide 7e as a pale brown
oil. Purification by flash column chromatography (10% EtOAc/
petroleum ether) yielded pure β-aminoacetamide 7e as an off-white
solid (899 mg, 95%): mp 51−53 °C; Rf 0.23 (10% EtOAc/petroleum
ether); IR νmax (neat) 3391, 3297, 3105−2834, 1702, 1510, 1232,
N-((1R*,2S*)-3-(2-Bromophenyl)-1-(3-methoxyphenyl)-1-((4-
methoxyphenyl)amino)propan-2-yl)-2,2,2-trifluoroacetamide (7k).
β-Nitroacetamide 6k (177 mg, 0.312 mmol) afforded crude β-
aminoacetamide 7k as a brown oil. Purification by flash column
chromatography (20% EtOAc/petroleum ether) followed by recrystal-
lization from toluene/petroleum ether yielded pure β-aminoacetamide
7k as a white solid (137 mg, 82%): mp 130−131 °C; Rf 0.31 (20%
EtOAc/petroleum ether); IR νmax (neat) 3389, 3306, 3107−2836,
1701, 1511, 1242, 1232, 1208, 1158, 1037 cm−1; 1H NMR (600 MHz,
CDCl3) δ 2.84 (1H, dd, J = 13.9, 11.3), 3.15 (1H, dd, J = 14.1, 3.6),
3.71 (3H, s), 3.81 (3H, s), 4.29 (1H, br s), 4.66 (1H, br s), 4.75 (1H,
m), 6.42 (1H, d, J = 9.4), 6.56 (2H, d, J = 6.2), 6.72 (2H, d, J = 8.9),
6.87 (1H, dd, J = 8.2, 2.1), 6.95 (1H, s), 7.00 (1H, d, J = 7.6), 7.09−
7.12 (2H, m), 7.22 (1H, td, J = 7.4, 0.7), 7.33 (1H, t, J = 7.9), 7.53
1
1208, 1178, 1163, 1039 cm−1; H NMR (600 MHz, CDCl3) δ 0.87
(3H, t, J = 6.9), 1.24−1.32 (4H, m), 1.37−1.47 (2H, m), 1.55−1.61
(1H, m), 1.65−1.71 (1H, m), 2.84 (1H, dd, J = 13,7, 11.3), 3.13 (1H,
br s), 3.20 (1H, dd, J = 13.7, 3.9), 3.55 (1H, m), 3.77 (3H, s), 4.49
(1H, m), 6.61−6.65 (3H, m), 6.79 (2H, dm, J = 8.9), 7.12 (1H, td, J =
7.7, 1.5), 7.19 (1H, dd, J = 7.6, 1.5), 7.25 (1H, td, J = 7.4, 0.8), 7.55
(1H, dd, J = 8.0, 0.7); 13C NMR (151 MHz, CDCl3) δ 14.1 (CH3),
N
dx.doi.org/10.1021/jo3010827 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
(1H, d, J = 8.1); 13C NMR (151 MHz, CDCl3) δ 36.8 (CH2), 55.2
(CH), 55.4 (CH3), 55.8 (CH3), 62.3 (CH), 112.9 (CH), 113.6 (CH),
114.9 (CH), 115.5 (CH), 115.7 (1C, q, J = 288.1, C), 119.6 (CH),
124.9 (C), 127.9 (CH), 129.0 (CH), 130.2 (CH), 131.0 (CH), 133.1
(CH), 136.1 (C), 140.0 (C), 140.6 (C), 152.8 (C), 157.4 (1C, q, J =
37.3, C), 160.2 (C); 19F NMR (282 MHz, CDCl3) δ −76.3 (3F, s);
MS (ES−) m/z 536 + 538 (1:1, 25, M−), 535 + 537 (1:1, 100, M −
H+), 457 (18, M− − Br); HRMS C25H23(79Br)F3N2O3 calcd 535.0844,
found 535.0837. Anal. Calcd for C25H24BrF3N2O3: C, 55.88; H, 4.50;
N, 5.21. Found: C, 55.60; H, 4.40; N, 5.16.
N-((1R*,2S*)-3-(2-Bromophenyl)-1-(4-methoxyphenyl)-1-((4-
methoxyphenyl)amino)propan-2-yl)-2,2,2-trifluoroacetamide (7l).
β-Nitroacetamide 6l (169 mg, 0.298 mmol) afforded crude β-
aminoacetamide 7l as a pale brown solid. Purification by flash column
chromatography (20% EtOAc/petroleum ether) yielded pure β-
aminoacetamide 7l as a white solid (146 mg, 91%): mp 173−175
°C; Rf 0.35 (20% EtOAc/petroleum ether); IR νmax (neat) 3399, 3302,
3107−2836, 1702, 1510, 1243, 1209, 1175, 1033 cm−1; 1H NMR (600
MHz, CDCl3) δ 2.81 (1H, dd, J = 14.0, 11.2), 3.15 (1H, dd, J = 14.1,
3.8), 3.71 (3H, s), 3.83 (3H, s), 4.28 (1H, br s), 4.64 (1H, br s), 4.73
(1H, m), 6.33 (1H, d, J = 9.4), 6.54 (2H, d, J = 8.6), 6.71 (2H, d, J =
8.9), 6.94 (2H, dm, J = 8.7), 7.09−7.10 (1H, m), 7.11 (1H, d, J = 7.4),
7.22 (1H, td, J = 7.5, 1.1), 7.32 (2H, dm, J = 8.6), 7.53 (1H, dd, J =
8.3, 1.1); 13C NMR (151 MHz, CDCl3) δ 36.9 (CH2), 55.4 (CH3 +
CH), 55.8 (CH3), 61.7 (CH), 114.5 (CH), 114.9 (CH), 115.5 (CH),
115.7 (1C, q, J = 288.2, C), 124.9 (C), 127.9 (CH), 128.4 (CH), 129.0
(CH), 130.0 (C), 131.0 (CH), 133.1 (CH), 136.1 (C), 140.6 (C),
152.7 (C), 157.5 (1C, q, J = 37.2, C), 159.5 (C); 19F NMR (282 MHz,
CDCl3) δ −76.3 (3F, s); MS (CI) m/z 537 + 539 (1:1, 100, M+ + H),
536 + 538 (1:1, 23, M+), 242 (44, M+ − C10H8BrF3NO); HRMS
C25H25(79Br)F3N2O3 calcd 537.1001, found 537.1008. Anal. Calcd for
C25H24BrF3N2O3: C, 55.88; H, 4.50; N, 5.21. Found: C, 56.03; H,
4.48; N, 5.16.
7.52−7.54 (2H, m), 7.61 (2H, t, J = 8.5), 7.67 (1H, s); 13C NMR (151
MHz, CDCl3) δ 36.3 (CH2), 55.5 (CH), 55.8 (CH3), 62.1 (CH), 115.0
(CH), 115.6 (CH), 115.6 (1C, q, J = 288.0, C), 124.0 (1C, q, J =
272.5, C), 124.2 (1C, q, J = 3.6, CH), 124.8 (C), 125.2 (1C, q, J = 3.5,
CH), 128.0 (CH), 129.2 (CH), 129.6 (CH), 130.6 (CH), 131.0 (CH),
131.4 (1C, q, J = 32.4, C), 133.2 (CH), 135.7 (C), 139.9 (C), 140.0
(C), 153.1 (C), 157.6 (1C, q, J = 37.4, C); 19F NMR (282 MHz,
CDCl3) δ −76.4 (3F, s), −63.0 (3F, s); MS (CI) m/z 575 + 577 (5,
M+ + H), 280 (100, M+ − C8H10BrF3NO); HRMS C25H22(79Br)-
F6N2O2 calcd 575.0769, found 575.0778. Anal. Calcd for
C25H21BrF6N2O2: C, 52.19; H, 3.68; N, 4.87. Found: C, 52.27; H,
3.57; N, 4.85.
N-((1R*,2S*)-3-(2-Bromophenyl)-1-((4-methoxyphenyl)amino)-1-
(4-(trifluoromethyl)phenyl)propan-2-yl)-2,2,2-trifluoroacetamide
(7o). β-Nitroacetamide 6o (176 mg, 0.291 mmol) afforded crude β-
aminoacetamide 7o as a pale brown solid. Purification by flash column
chromatography (20% EtOAc/petroleum ether) yielded pure β-
aminoacetamide 7o as a white solid (147 mg, 88%): mp 154−156
°C; Rf 0.45 (20% EtOAc/petroleum ether); IR νmax (neat) 3402, 3293,
3106−2836, 1701, 1512, 1326, 1243, 1211, 1166, 1125, 1068 cm−1; 1H
NMR (600 MHz, CDCl3) δ 2.88 (1H, dd, J = 14.1, 10.8), 3.15 (1H,
dd, J = 14.1, 3.8), 3.71 (3H, s), 4.40 (1H, d, J = 5.5), 4.73−4.78 (2H,
m), 6.41 (1H, d, J = 8.9), 6.53 (2H, dm, J = 8.9), 6.73 (2H, dm, J =
8.9), 7.10−7.13 (2H, m), 7.23 (1H, td, J = 7.5, 1.1), 7.52−7.53 (1H,
m), 7.54 (2H, d, J = 8.1), 7.66 (2H, d, J = 8.2); 13C NMR (151 MHz,
CDCl3) δ 36.3 (CH2), 55.4 (CH), 55.8 (CH3), 62.0 (CH), 115.0
(CH), 115.5 (CH), 115.6 (1C, q, J = 288.2, C), 124.0 (1C, q, J =
272.2, C), 124.8 (C), 126.0 (1C, q, J = 3.4, CH), 127.7 (CH), 128.0
(CH), 129.2 (CH), 130.5 (1C, q, J = 32.5, C), 131.0 (CH), 133.2
(CH), 135.6 (C), 140.0 (C), 142.8 (C), 153.1 (C), 157.6 (1C, q, J =
37.4, C); 19F NMR (282 MHz, CDCl3) δ −76.3 (3F, s), −63.0 (3F, s);
MS (CI) m/z 575 + 577 (1:1, 100, M+ + H), 574 + 576 (1:1, 7, M+);
HRMS C25H22(79Br)F6N2O2 calcd 575.0769, found 575.0771. Anal.
Calcd for C25H21BrF6N2O2: C, 52.19; H, 3.68; N, 4.87. Found: C,
52.06; H, 3.60; N, 4.85.
N-((1R*,2S*)-3-(2-Bromo-5-fluorophenyl)-1-((4-methoxyphenyl)-
amino)-1-phenylpropan-2-yl)-2,2,2-trifluoroacetamide (7p). β-Ni-
troacetamide 6p (649 mg, 1.17 mmol) afforded crude β-amino-
acetamide 7p as a brown oil. Purification by flash column
chromatography (10% EtOAc/petroleum ether) yielded pure β-
aminoacetamide 7p as a white solid (546 mg, 89%): mp 148−150
°C; Rf 0.26 (10% EtOAc/petroleum ether); IR νmax (neat) 3397, 3301,
3107−2835, 1700, 1512, 1471, 1236, 1210, 1179, 1033 cm−1; 1H
NMR (600 MHz, CDCl3) δ 2.80 (1H, dd, J = 14.0, 11.2), 3.13 (1H,
dd, J = 14.0, 3.5), 3.71 (3H, s), 4.27 (1H, br s), 4.70 (1H, s), 4.74 (1H,
m), 6.47 (1H, d, J = 9.4), 6.57 (2H, d, J = 8.5), 6.72 (2H, dm, J = 8.9),
6.83−6.86 (2H, m), 7.33−7.36 (1H, m), 7.39−7.43 (4H, m), 7.47
(1H, dd, J = 9.6, 5.3); 13C NMR (151 MHz, CDCl3) δ 36.8 (CH2),
55.1 (CH), 55.8 (CH3), 62.2 (CH), 114.9 (CH), 115.7 (CH), 115.7
(1C, q, J = 288.2, C), 116.3 (1C, d, J = 22.3, CH), 118.0 (1C, d, J =
22.8, CH), 118.9 (1C, d, J = 3.2, C), 127.2 (CH), 128.4 (CH), 129.2
(CH), 134.3 (1C, d, J = 8.1, CH), 138.1 (C), 138.3 (1C, d, J = 7.4, C),
140.4 (C), 153.0 (C), 157.4 (1C, q, J = 37.3, C), 161.9 (1C, d, J =
248.2, C); 19F NMR (282 MHz, CDCl3) δ −114.6 (1F, m), −76.3
(3F, s); MS (EI) m/z 524 + 526 (1:1, 5, M+), 446 (3, M+ − Br), 212
(100, M+ − C10H7BrF4NO); HRMS C24H21(79Br)F4N2O2 calcd
524.0717, found 524.0704. Anal. Calcd for C24H21BrF4N2O2: C,
54.87; H, 4.03; N, 5.33. Found: C, 54.91; H, 3.97; N, 5.28.
N-((1R*,2S*)-3-(2-Bromophenyl)-1-((4-methoxyphenyl)amino)-1-
(2-(trifluoromethyl)phenyl)propan-2-yl)-2,2,2-trifluoroacetamide
(7m). β-Nitroacetamide 6m (824 mg, 1.36 mmol) afforded crude β-
aminoacetamide 7m as a brown oil. Purification by flash column
chromatography (20% EtOAc/petroleum ether) and subsequent
recrystallization from toluene/petroleum ether yielded pure β-
aminoacetamide 7m as a white solid (642 mg, 82%): mp 140−142
°C; Rf 0.38 (20% EtOAc/petroleum ether); IR νmax (neat) 3362,
3066−2836, 1712, 1512, 1310, 1243, 1234, 1212, 1161, 1118, 1035
1
cm−1; H NMR (600 MHz, CDCl3) δ 3.06 (1H, dd, J = 14.1, 10.1),
3.55 (1H, dd, J = 14.1, 3.4), 3.71 (3H, s), 4.30 (1H, br s), 4.55 (1H,
m), 4.98 (1H, d, J = 6.6), 6.40 (1H, d, J = 8.8), 6.63 (2H, d, J = 8.8),
6.74 (2H, d, J = 8.8), 7.11 (1H, td, J = 7.6, 1.4), 7.19 (1H, dd, J = 7.5,
1.4), 7.24 (1H, t, J = 7.4), 7.38 (1H, t, J = 7.7), 7.52−7.55 (2H, m),
7.68 (2H, d, J = 8.0); 13C NMR (151 MHz, CDCl3) δ 37.7 (CH2),
55.5 (CH), 55.7 (CH3), 58.7 (CH), 114.9 (CH), 115.5 (1C, q, J =
288.2, C), 115.9 (CH), 124.7 (1C, q, J = 273.9, C), 124.8 (C), 126.2
(1C, q, J = 5.9, CH), 127.8 (CH), 127.9 (CH), 128.2 (1C, q, J = 29.4,
C), 128.3 (CH), 129.1 (CH), 131.3 (CH), 132.8 (CH), 133.2 (CH),
136.1 (C), 138.9 (C), 139.8 (C), 153.2 (C), 156.4 (1C, q, J = 37.2, C);
19F NMR (282 MHz, CDCl3) δ −76.8 (3F, s), −57.2 (3F, s); MS (EI)
m/z 574 + 576 (1:1, 3, M+), 280 (100, M+ − C8H10BrF3NO); HRMS
C25H21(79Br)F6N2O2 calcd 574.0685, found 574.0696. Anal. Calcd for
C25H21BrF6N2O2: C, 52.19; H, 3.68; N, 4.87. Found: C, 51.92; H,
3.45; N, 4.94.
N-((1R*,2S*)-3-(2-Bromo-4,5-dimethoxyphenyl)-1-((4-
methoxyphenyl)amino)-1-phenylpropan-2-yl)-2,2,2-trifluoroaceta-
mide (7q). β-Nitroacetamide 6q (89 mg, 0.15 mmol) afforded crude
β-aminoacetamide 7q as a pale brown oil. Purification by flash column
chromatography (60% Et2O/petroleum ether) yielded pure β-
aminoacetamide 7q as a white solid (67 mg, 79%): mp 167−169
°C; Rf 0.27 (60% Et2O/petroleum ether); IR νmax (neat) 3410, 3296,
3113−2837, 1695, 1509, 1259, 1241, 1217, 1178, 1166, 1034 cm−1; 1H
NMR (600 MHz, CDCl3) δ 2.81 (1H, dd, J = 14.3, 10.7), 3.10 (1H,
dd, J = 14.3, 3.6), 3.70 (3H, s), 3.77 (3H, s), 3.84 (3H, s), 4.33 (1H, d,
J = 6.1), 4.68 (1H, d, J = 5.2), 4.70 (1H, m), 6.37 (1H, br d, J = 9.0),
6.55 (2H, dm, J = 8.9), 6.57 (1H, s), 6.71 (2H, dm, J = 8.9), 6.96 (1H,
N-((1R*,2S*)-3-(2-Bromophenyl)-1-((4-methoxyphenyl)amino)-1-
(3-(trifluoromethyl)phenyl)propan-2-yl)-2,2,2-trifluoroacetamide
(7n). β-Nitroacetamide 6n (688 mg, 1.14 mmol) afforded crude β-
aminoacetamide 7n as a brown oil. Purification by flash column
chromatography (20% EtOAc/petroleum ether) yielded pure β-
aminoacetamide 7n as a white solid (579 mg, 89%): mp 133−134
°C; Rf 0.24 (20% EtOAc/petroleum ether); IR νmax (neat) 3408, 3292,
3108−2836, 1699, 1511, 1327, 1242, 1233, 1210, 1162, 1124, 1072,
1
1033 cm−1; H NMR (600 MHz, CDCl3) δ 2.88 (1H, dd, J = 14.0,
11.0), 3.16 (1H, dd, J = 14.1, 3.8), 3.72 (3H, s), 4.40 (1H, br s), 4.72
(1H, m), 4.77 (1H, d, J = 3.8), 6.41 (1H, d, J = 9.1), 6.55 (2H, dm, J =
8.9), 6.74 (2H, dm, J = 8.9), 7.10−7.12 (2H, m), 7.23 (1H, t, J = 7.5),
O
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s), 7.33 (1H, m), 7.40 (4H, m); 13C NMR (151 MHz, CDCl3) δ 36.3
(CH2), 55.6 (CH), 55.8 (CH3), 56.1 (CH3), 56.2 (CH3), 62.3 (CH),
113.1 (CH), 114.7 (C), 114.9 (CH), 115.5 (CH), 115.5 (CH), 115.7
(1C, q, J = 288.2, C), 127.3 (CH), 127.8 (C), 128.3 (CH), 129.1
(CH), 138.4 (C), 140.5 (C), 148.7 (C), 148.8 (C), 152.8 (C), 157.5
(1C, q, J = 37.2, C); 19F NMR (282 MHz, CDCl3) δ −76.3 (3F, s);
MS (FAB+) m/z 591 + 589 (12, M + Na+), 212 (100,
C12H12BrF3NO3); HRMS C26H26(79Br)F3N2O4Na calcd 589.0926,
found 589.0912. Anal. Calcd for C26H26BrF3N2O4: C, 55.04; H, 4.62;
N, 4.94. Found: C, 55.38; H, 4.53; N, 4.75.
6.62 (2H, dm, J = 8.9), 6.67 (1H, d, J = 9.5), 6.78 (2H, dm, J = 8.9),
7.10 (1H, td, J = 7.7, 1.6), 7.19 (1H, dd, J = 7.6, 1.7), 7.24 (1H, td, J =
7.5, 1.0), 7.54 (1H, dd, J = 8.1, 1.0); 13C NMR (151 MHz, CDCl3) δ
26.0 (CH2), 26.0 (CH2), 26.2 (CH2), 30.5 (CH2), 30.5 (CH2), 34.6
(CH2), 42.2 (CH), 51.8 (CH), 55.8 (CH3), 63.9 (CH), 114.6 (CH),
115.2 (CH), 115.8 (1C, q, J = 288.2, C), 125.1 (C), 127.7 (CH), 128.8
(CH), 131.4 (CH), 133.0 (CH), 136.5 (C), 143.3 (C), 152.7 (C),
156.4 (1C, q, J = 36.8, C); 19F NMR (282 MHz, CDCl3) δ −76.4 (3F,
s); MS (EI) m/z 512 + 514 (1:1, 5, M+), 218 (100, M+
−
C10H8BrF3NO); HRMS C24H28(79Br)F3N2O2 calcd 512.1281, found
512.1276. Anal. Calcd for C24H28BrF3N2O2: C, 56.15; H, 5.50; N,
5.46. Found: C, 55.92; H, 5.48; N, 5.42.
N-((1R*,2S*)-3-(2-Bromophenyl)-1-cyclohexyl-2-(hydroxyamino)-
propyl)-4-methoxyaniline (19). To a solution of crude β-nitroamine
5f (0.452 mmol) in THF (2.5 mL) at 0 °C was added MeOH (274 μL,
6.78 mmol) followed by the portionwise addition of freshly
amalgamated Al foil (61.0 mg, 2.26 mmol) [coils of Al foil (∼1.00
mmol) were soaked in Et2O to remove machining oils and individually
immersed in sat. HgCl2(aq) solution for 30 s, washed in H2O for 5 s,
roughly dried on tissue, and added to the reaction mixture]. The
mixture was allowed to warm to rt and rigorously stirred for 2 h to give
a dark gray suspension. The mixture was filtered through Celite and
washed with Et2O (2 × 15 mL) and MeOH (15 mL) and the solvents
removed in vacuo to give crude β-aminohydroxylamine 19 as a yellow
oil. Purification by flash column chromatography (30% EtOAc/
petroleum ether) yielded pure β-aminohydroxylamine 19 as a colorless
solid (109 mg, 56%, >95:5 dr): mp 139−141 °C; Rf 0.60 (30%
EtOAc/petroleum ether); IR νmax (neat) 3356, 3242, 3056−2850,
General Procedure for the Synthesis of β-Aminoacetamides
7 (Scheme 10). To a solution of β-nitroamine 5 (1.00 mmol) in
EtOH (20.0 mL) and EtOAc (20.0 mL) at rt was added 6 M HCl
(20.0 mmol) followed by Zn dust (10.0 mmol) in one portion. The
gray suspension was stirred vigorously rt for 1 h before removal of the
solvents in vacuo. The residue was neutralized by the addition of
NaHCO3(s) and the product extracted into EtOAc. The combined
organic extracts were washed with water, brine, dried (MgSO4),
filtered and the solvents removed in vacuo to give crude 1,2-diamine.
To a solution of the crude 1,2-diamine in CH2Cl2 (10.0 mL) at −78
°C was added DIPEA (1.50 mmol) quickly followed by the dropwise
addition of TFAA (1.50 mmol). The reaction was stirred at −78 °C for
30 min before being allowed to warm to rt over 30 min. The reaction
was quenched by the addition of 2 M HCl, the layers were separated
and the aqueous layer further extracted with CH2Cl2. The combined
organic extracts were dried (MgSO4), filtered and the solvents
removed in vacuo to give crude β-aminoacetamide, which was purified
by flash column chromatography.
7g N-((2S*,3R*)-1-(2-Bromophenyl)-3-((4-methoxyphenyl)-
amino)-4,4-dimethylpentan-2-yl)-2,2,2-trifluoroacetamide. Crude
β-nitroamine 5g (4.52 mmol) afforded crude β-aminoacetamide 7g
as a brown oil. Purification by flash column chromatography (10%
EtOAc/petroleum ether) yielded pure β-aminoacetamide 7g as a white
solid (1.42 g, 65%, 85:15 dr): mp 82−84 °C; Rf 0.51 (20% EtOAc/
petroleum ether); IR νmax (neat) 3399, 3311, 3062−2833, 1706, 1509,
1243, 1231, 1207, 1159, 1038, 1023 cm−1; 1H NMR (600 MHz,
CDCl3) δ 1.14 (9H, s), 2.91 (1H, dd, J = 13.6, 12.1), 3.23 (1H, dd, J =
13.7, 3.6), 3.45 (1H, br s), 3.54 (1H, br s), 3.76 (3H, s), 4.74 (1H, m),
6.55 (1H, br d, J = 9.2), 6.66 (2H, dm, J = 9.0), 6.79 (2H, dm, J = 9.0),
7.10 (1H, td, J = 7.6, 1.7), 7.14 (1H, dd, J = 7.7, 1.7), 7.23 (1H, td, J =
7.5, 1.2), 7.53 (1H, dd, J = 8.0, 1.1); 13C NMR (151 MHz, CDCl3) δ
28.1 (CH3), 36.2 (CH2), 36.4 (C), 52.3 (CH), 55.9 (CH3), 67.0 (CH),
114.7 (CH), 115.3 (CH), 115.7 (1C, q, J = 288.4, C), 125.0 (C), 127.7
(CH), 128.8 (CH), 131.4 (CH), 133.0 (CH), 136.5 (C), 143.3 (C),
152.6 (C), 156.0 (1C, q, J = 36.9, C); 19F NMR (282 MHz, CDCl3) δ
−76.5 (3F, s); MS (EI) m/z 486 + 488 (1:1, 13%, M+), 429 + 431
(1:1, 22%, M+-C(CH3)3), 192 (100%, PMPNHCH+C(CH3)3);
HRMS C22H26(79Br)F3N2O2 calcd 486.1124, found 486.1134; Anal.
Calcd for C22H26BrF3N2O2: C, 54.22; H, 5.38; N, 5.75; found: C,
54.11; H, 5.32; N, 5.72%.
1
1509, 1233, 1037, 1024 cm−1; H NMR (600 MHz, CDCl3) δ 0.99
(1H, qd, J = 12.3, 3.1), 1.10−1.28 (4H, m), 1.62−1.68 (2H, m), 1.71−
1.76 (2H, m), 1.86 (2H, m), 2.66 (1H, dd, J = 14.0, 11.0), 2.99 (1H,
dd, J = 14.0, 3.2), 3.17 (1H, br d, J = 7.1), 3.31 (1H, ddd, J = 11.0, 4.3,
3.5), 3.63 (1H, br s), 3.76 (3H, s), 6.72 (2H, dm, J = 9.0), 6.77 (2H,
dm, J = 9.1), 7.10 (1H, ddd, J = 8.0, 6.8, 2.2), 7.24−7.28 (2H, m), 7.55
(1H, dd, J = 8.0, 0.8); 13C NMR (151 MHz, CDCl3) δ 26.3 (2 ×
CH2), 26.5 (CH2), 29.8 (CH2), 31.2 (CH2), 33.2 (CH2), 41.4 (CH),
55.9 (CH3), 59.8 (CH), 63.0 (CH), 114.4 (CH), 115.1 (CH), 124.8
(C), 127.5 (CH), 128.1 (CH), 131.9 (CH), 133.0 (CH), 139.0 (C),
144.6 (C), 151.8 (C); MS (CI) m/z 433 + 435 (1:1, 25, M+ + H), 432
+ 434 (1:1, 18, M+), 418 + 420 (1:1, 42, M+ − CH2), 415 + 417 (1:1,
35, M+−OH), 218 (28, M+ − C8H9BrNO); HRMS C22H30(79Br)N2O2
calcd 433.1491, found 433.1487. Anal. Calcd for C22H29BrN2O2: C,
60.97; H, 6.74; N, 6.46. Found: C, 61.07; H, 6.79; N, 6.30.
N-((1R*,2S*)-3-(2-Bromophenyl)-1-cyclohexyl-1-((4-
methoxyphenyl)amino)propan-2-yl)-2,2,2-trifluoroacetamide (7f).
To a solution of β-aminohydroxylamine 19 (146 mg, 0.337 mmol)
in toluene (6.7 mL) at 0 °C was added dropwise LiAlH4 (2 M in THF,
843 μL, 1.69 mmol). The reaction was stirred at 0 °C for 1 h before
being allowed to warm to rt and stirred until the reaction was complete
by TLC analysis (3 h). The mixture was cooled to 0 °C before being
i
quenched by the careful dropwise addition of PrOH (0.35 mL per
mmol LiAlH4 = 0.61 mL) and brine (0.10 mL per mmol LiAlH4 = 0.17
mL). The mixture was dried (MgSO4) and filtered through Celite, and
the solvents were removed in vacuo to give the crude 1,2-diamine. To
a solution of the crude 1,2-diamine in CH2Cl2 (3.4 mL) at −78 °C was
added DIPEA (88.1 μL, 0.506 mmol) quickly followed by the
dropwise addition of TFAA (70.3 μL, 0.506 mmol). The reaction was
stirred at −78 °C for 30 min before being allowed to warm to rt over
30 min. The reaction was quenched by the addition of 2 M HCl (5
mL), the layers were separated and the aqueous layer further extracted
with CH2Cl2 (2 × 5 mL). The combined organic extracts were dried
(MgSO4) and filtered and the solvents removed in vacuo to give crude
β-aminoacetamide 7f as a yellow oil. Purification by flash column
chromatography (10% EtOAc/petroleum ether) yielded pure β-
aminoacetamide 7f as a white solid (141 mg, 81%): mp 60−63 °C;
Rf 0.52 (20% EtOAc/petroleum ether); IR νmax (neat) 3360, 3305,
3105−2853, 1703, 1509, 1243, 1232, 1207, 1162, 1039, 1027 cm−1; 1H
NMR (600 MHz, CDCl3) δ 0.90 (1H, qd, J = 12.6, 2.9), 1.11−1.30
(4H, m), 1.50−1.56 (1H, m), 1.67 (1H, d, J = 10.9), 1.71 (1H, d, J =
11.5), 1.80−1.82 (1H, m), 1.91 (1H, d, J = 13.2), 2.04 (1H, d, J =
12.4), 2.87 (1H, dd, J = 13.7, 11.6), 3.14 (1H, dd, J = 13.8, 3.7), 3.24
(1H, d, J = 9.2), 3.32 (1H, td, J = 9.0, 3.5), 3.76 (3H, s), 4.66 (1H, m),
7i N-((1R*,2S*)-1,3-Bis(2-bromophenyl)-1-((4-methoxyphenyl)-
amino)propan-2-yl)-2,2,2-trifluoroacetamide. Crude β-nitroamine
5i (4.15 mmol) afforded crude β-aminoacetamide 7i as a brown oil.
Purification by flash column chromatography (15% EtOAc/petroleum
ether) yielded pure β-aminoacetamide 7i as a white solid (1.50 g, 62%,
95:5 dr): mp 176−178 °C; Rf 0.27 (15% EtOAc/petroleum ether); IR
νmax (neat) 3409, 3268, 3106−2832, 1702, 1510, 1240, 1232, 1208,
1
1182, 1157, 1033, 1017 cm−1; H NMR (600 MHz, CDCl3) δ 3.30
(1H, dd, J = 14.1, 11.0), 3.43 (1H, dd, J = 14.2, 3.5), 3.71 (3H, s), 4.47
(1H, br s), 4.69 (1H, m), 5.09 (1H, br s), 6.54 (2H, br d, J = 7.5), 6.56
(1H, br d, J = 10.3), 6.73 (2H, d, J = 8.8), 7.11 (1H, td, J = 7.7, 1.6),
7.16 (1H, td, J = 7.7, 1.4), 7.17 (1H, dd, J = 7.6, 1.5), 7.23 (1H, td, J =
7.4, 0.9), 7.29 (1H, td, J = 7.6, 0.7), 7.40 (1H, dd, J = 7.8, 1.4), 7.53
(1H, dd, J = 8.0, 0.8), 7.59 (1H, dd, J = 8.0, 0.8); 13C NMR (151 MHz,
CDCl3) δ 37.2 (CH2), 54.8 (CH), 55.8 (CH3), 60.9 (CH), 115.0
(CH), 115.3 (CH), 115.6 (1C, q, J = 287.9, C), 124.6 (C), 124.9 (C),
127.9 (CH), 128.2 (CH), 128.4 (CH), 129.1 (CH), 129.8 (CH), 131.2
(CH), 133.2 (CH), 133.3 (CH), 136.1 (C), 137.8 (C), 139.9 (C),
P
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152.9 (C), 156.9 (1C, q, J = 37.2, C); 19F NMR (282 MHz, CDCl3) δ
−76.5 (3F, s); MS (EI) m/z 584 + 586 + 588 (1:2:1, 97%, M+), 290 +
292 (1:1, 100%, M+-C10H8BrF3NO); HRMS C24H21(79Br)2F3N2O2
calcd 583.9916, found 583.9924; Anal. Calcd for C24H21Br2F3N2O2: C,
49.17; H, 3.61; N, 4.78; found: C, 49.43; H, 3.34; N, 4.97%.
(1H, m), 4.89 (1H, s), 6.66 (1H, br d, J = 7.3), 6.69 (1H, d, J = 8.3),
6.77 (1H, t, J = 7.3), 6.87 (2H, dm, J = 8.7), 7.05−7.11 (4H, m),
7.28−7.36 (5H, m); 13C NMR (151 MHz, CDCl3) δ 27.7 (CH2), 47.6
(CH), 55.5 (CH3), 66.2 (CH), 113.7 (CH), 115.2 (CH), 115.7 (1C, q,
J = 288.0, C), 115.8 (C), 118.0 (CH), 126.4 (CH), 127.7 (CH), 127.9
(CH), 128.1 (CH), 128.9 (CH), 130.7 (CH), 139.1 (C), 141.0 (C),
143.7 (C), 156.9 (1C, q, J = 37.2, C), 157.6 (C); 19F NMR (282 MHz,
CDCl3) δ −76.2 (3F, s); MS (EI) m/z 427 (22, M + H+), 426 (100,
M+); HRMS C24H21F3N2O2 calcd 426.1550, found 426.1539. Anal.
Calcd for C24H21F3N2O2: C, 67.60; H, 4.96; N, 6.57. Found: C, 67.62;
H, 4.95; N, 6.57.
7r N-((1R*,2S*)-3-(2-Bromo-4,5-dimethoxyphenyl)-1-(2-methox-
yphenyl)-1-((4-methoxyphenyl)amino)propan-2-yl)-2,2,2-trifluoroa-
cetamide. Crude β-nitroamine 5r (3.30 mmol) afforded crude β-
aminoacetamide 7r as a brown oil. Purification by flash column
chromatography (30% EtOAc/petroleum ether) yielded pure β-
aminoacetamide 7r as a white solid (793 mg, 40%, 90:10 dr): mp
73−75 °C; Rf 0.38 (30% EtOAc/petroleum ether); IR νmax (neat)
3365, 3069−2840, 1714, 1508, 1463, 1439, 1258, 1234, 1214, 1161,
2,2,2-Trifluoro-N-[(2S*,3S*)-2-(furan-2-yl)-1-(4-methoxyphenyl)-
1,2,3,4-tetrahydroquinolin-3-yl]acetamide (18b). β-Aminoacetamide
7b (107 mg, 0.215 mmol) afforded crude tetrahydroquinoline 18b as a
brown oil. Purification by flash column chromatography (20% EtOAc/
petroleum ether) yielded pure tetrahydroquinoline 18b as a white
solid (84 mg, 92%): mp 127−130 °C; Rf 0.32 (20% EtOAc/petroleum
ether); IR νmax (neat) 3414, 3300, 3073−2838, 1710, 1509, 1492,
1
1028 cm−1; H NMR (600 MHz, CDCl3) δ 2.90 (1H, dd, J = 14.3,
9.9), 3.31 (1H, dd, J = 14.4, 3.0), 3.69 (3H, s), 3.71 (3H, s), 3.84 (3H,
s), 3.92 (3H, s), 4.65 (1H, dtd, J = 7.9, 7.9, 3.4), 4.92 (1H, d, J = 6.5),
6.56 (2H, d, J = 8.3), 6.69 (1H, s), 6.71 (2H, dm, J = 8.9), 6.83 (1H, br
s), 6.91−6.93 (2H, m), 6.98 (1H, s), 7.25 (2H, t, J = 7.1); 13C NMR
(151 MHz, CDCl3) δ 37.0 (CH2), 54.8 (CH), 55.6 (CH3), 55.8
(CH3), 55.9 (CH3), 56.2 (CH3), 57.0 (CH), 110.8 (CH), 113.5 (CH),
114.8 (C), 114.9 (CH), 115.5 (CH), 115.5 (CH), 115.8 (1C, q, J =
288.4, C), 121.3 (CH), 126.6 (C), 128.1 (CH), 128.4 (C), 129.2 (CH),
140.5 (C), 148.5 (C), 148.6 (C), 152.8 (C), 156.8 (1C, q, J = 36.7, C),
157.1 (C); 19F NMR (282 MHz, CDCl3) δ −76.5 (3F, s); MS (ES−)
m/z 596 + 598 (30%, M−), 595 + 597 (100%, M-H+); Accurate
HRMS could not be obtained.
1
1457, 1243, 1207, 1180 cm−1; H NMR (600 MHz, CDCl3) δ 2.79
(1H, d, J = 17.2), 3.12 (1H, dd, J = 17.1, 4.7), 3.82 (3H, s), 4.77 (1H,
ddd, J = 10.4, 5.1, 2.7), 4.83 (1H, m), 6.19 (1H, dd, J = 2.5, 0.7), 6.30
(1H, dd, J = 3.3, 1.8), 6.59 (1H, d, J = 8.2), 6.65 (1H, br d, J = 7.7),
6.76 (1H, td, J = 7.4, 1.0), 6.89 (2H, dm, J = 8.9), 7.02−7.06 (2H, m),
7.07 (2H, dm, J = 8.9), 7.38 (1H, dd, J = 1.7, 0.7); 13C NMR (151
MHz, CDCl3) δ 29.2 (CH2), 45.8 (CH), 55.6 (CH3), 60.8 (CH), 108.4
(CH), 110.5 (CH), 114.5 (CH), 115.2 (CH), 115.8 (1C, q, J = 288.0,
C), 116.7 (C), 118.6 (CH), 127.8 (CH), 128.0 (CH), 130.6 (CH),
138.6 (C), 142.5 (CH), 143.1 (C), 153.0 (C), 156.9 (1C, q, J = 37.3,
C), 157.8 (C); 19F NMR (282 MHz, CDCl3) δ −76.2 (3F, s); MS (EI)
m/z 417 (28%, M++H), 416 (100, M+), 303 (26, M+ − NHTFA), 196
(48, M+ − C22H19F3N2O3); HRMS C22H19F3N2O3 calcd 416.1342,
found 416.1334. Anal. Calcd for C22H19F3N2O3: C, 63.46; H, 4.60; N,
6.73. Found: C, 63.44; H, 4.52; N, 6.55.
7s N-((1R*,2S*)-3-(3-(Benzyloxy)-2-bromo-4-methoxyphenyl)-1-
((4-methoxyphenyl)amino)-1-phenylpropan-2-yl)-2,2,2-trifluoroa-
cetamide. Crude β-nitroamine 5s (1.15 mmol) afforded crude β-
aminoacetamide 7s as a pale brown solid. Purification by flash column
chromatography (30% EtOAc/petroleum ether) yielded pure β-
aminoacetamide 7s as a white solid (882 mg, 43%, >95:5 dr): mp
68−70 °C; Rf 0.34 (30% EtOAc/petroleum ether); IR νmax (neat)
3393, 3303, 3089−2838, 1702, 1511, 1485, 1454, 1440, 1296, 1271,
2,2,2-Trifluoro-N-[(2R*,3S*)-2-(furan-2-yl)-1-(4-methoxyphenyl)-
1,2,3,4-tetrahydroquinolin-3-yl]acetamide (18c). β-Aminoacetamide
7c (104 mg, 0.209 mmol) afforded crude tetrahydroquinoline 18c as a
brown oil. Purification by flash column chromatography (20% EtOAc/
petroleum ether) yielded pure tetrahydroquinoline 18c as a yellow
solid (82 mg, 94%): mp 139−141 °C; Rf 0.70 (20% EtOAc/petroleum
ether); IR νmax (neat) 3413, 3302, 3143−2838, 1713, 1508, 1492,
1457, 1242, 1207, 1160, 1036, 1023 cm−1; 1H NMR (400 MHz,
CDCl3) δ 2.78 (1H, d, J = 17.3), 3.14 (1H, dd, J = 17.2, 4.8), 3.81
(3H, s), 4.53 (1H, ddd, J = 10.4, 5.0, 2.7), 4.73 (1H, t, J = 1.4), 6.32
(1H, dd, J = 1.6, 0.8), 6.64 (1H, d, J = 8.1), 6.64 (1H, br m), 6.76 (1H,
td, J = 7.4, 1.0), 6.88 (2H, dm, J = 9.0), 7.02−7.06 (2H, m), 7.09 (2H,
dm, J = 9.0), 7.30 (1H, m), 7.38 (1H, t, J = 1.7); 13C NMR (151 MHz,
CDCl3) δ 28.5 (CH2), 47.2 (CH), 55.6 (CH3), 59.1 (CH), 108.9
(CH), 114.6 (CH), 115.2 (CH), 115.8 (1C, q, J = 288.1, C), 116.7
(C), 118.6 (CH), 125.5 (C), 127.5 (CH), 127.9 (CH), 130.7 (CH),
139.0 (C), 140.6 (CH), 143.0 (C), 143.8 (CH), 156.9 (1C, q, J = 37.2,
C), 157.6 (C); 19F NMR (282 MHz, CDCl3) δ −76.2 (3F, s); MS (EI)
1
1241, 1210, 1163, 1033 cm−1; H NMR (600 MHz, CDCl3) δ 2.83
(1H, dd, J = 14.0, 11.1), 3.13 (1H, dd, J = 14.2, 3.5), 3.71 (3H, s), 3.83
(3H, s), 4.36 (1H, br s), 4.69−4.74 (2H, m), 4.96 (1H, d, J = 10.5),
5.00 (1H, d, J = 10.6), 6.39 (1H, d, J = 9.2), 6.55 (2H, d, J = 7.3), 6.72
(2H, d, J = 8.8), 6.80 (1H, d, J = 8.5), 6.85 (1H, d, J = 8.5), 7.33−7.41
(8H, m), 7.54 (2H, d, J = 7.3); 13C NMR (151 MHz, CDCl3) δ 36.3
(CH2), 55.7 (CH3), 55.8 (CH), 56.2 (CH3), 62.2 (CH), 74.7 (CH2),
111.5 (CH), 114.9 (CH), 115.5 (CH), 115.8 (1C, q, J = 288.2, C),
121.1 (C), 125.8 (CH), 127.4 (CH), 128.2 (CH), 128.3 (CH), 128.4
(CH), 128.6 (CH), 128.9 (C), 129.1 (CH), 137.2 (C), 138.4 (C),
140.6 (C), 145.5 (C), 152.7 (C), 152.9 (C), 157.5 (1C, q, J = 37.2, C);
19F NMR (282 MHz, CDCl3) δ −76.2 (3F, s); MS (ES−) m/z 642 +
644 (1:1, 32%, M−), 641 + 643 (1:1, 97%, M-H+); HRMS
C32H29(79Br)F3N2O4 calcd 641.1263, found 641.1230; Anal. Calcd
for C32H30BrF3N2O4: C, 59.73; H, 4.35; N, 4.87; found: C, 59.79; H,
4.70; N, 4.35%.
General Procedure for the Synthesis of 3-Aminotetrahy-
droquinolines 18 (Table 6). A flame-dried Schenk tube was charged
with β-aminoacetamide (1.00 mmol), Pd(PPh3)4 (5.00 mol %) and
K2CO3 (2.50 mmol). The tube was triple evacuated/N2 filled before
the addition of toluene (10.0 mL). The resulting mixture was stirred
while N2 was bubbled through it, using a needle, for 15 min. The N2
needle was removed and the reaction was heated to 100 °C for 18 h to
give a dark brown mixture. The reaction was allowed to cool to rt
before being filtered through Celite and washed with EtOAc, and the
solvents were removed in vacuo to give crude tetrahydroquinoline,
which was purified by flash column chromatography.
m/z 416 (6, M+), 220 (18, M+ − C7H7F3O3), 205 (39, M+
−
C7H7F3NO3); HRMS C22H19F3N2O3 calcd 416.1342, found 416.1354.
Anal. Calcd for C22H19F3N2O3: C, 63.46; H, 4.60; N, 6.73. Found: C,
63.33; H, 4.54; N, 6.64.
2,2,2-Trifluoro-N-((2S*,3S*)-1-(4-methoxyphenyl)-2-(thiophene-
2-yl)-1,2,3,4-tetrahydroquinolin-3-yl)acetamide (18d). β-Aminoace-
tamide 7d (102 mg, 0.199 mmol) afforded crude tetrahydroquinoline
18d as a brown oil. Purification by flash column chromatography (20%
Et2O/petroleum ether) yielded pure tetrahydroquinoline 18d as an
off- white solid (79 mg, 91%): mp 134−136 °C; Rf 0.41 (20% Et2O/
petroleum ether); IR νmax (neat) 3413, 3295, 3075−2838, 1709, 1508,
1491, 1456, 1242, 1206, 1168, 1036 cm−1; 1H NMR (600 MHz,
CDCl3) δ 2.78 (1H, d, J = 17.3), 3.18 (1H, dd, J = 17.2, 4.7), 3.81
(3H, s), 4.63 (1H, m), 5.06 (1H, m), 6.64 (1H, br d, J = 7.6), 6.67
(1H, d, J = 7.9), 6.79 (1H, td, J = 7.4, 1.0), 6.88 (2H, dm, J = 8.9),
6.95−6.97 (2H, m), 7.07 (2H, m), 7.12 (2H, dm, J = 9.0), 7.22 (1H,
dd, J = 4.8, 1.4); 13C NMR (151 MHz, CDCl3) δ 28.3 (CH2), 48.1
(CH), 55.6 (CH3), 62.5 (CH), 114.9 (CH), 115.2 (CH), 115.8 (1C, q,
J = 288.1, C), 116.5 (C), 118.8 (CH), 125.0 (CH), 125.1 (CH), 127.3
2,2,2-Trifluoro-N-[(2R*,3S*)-1-(4-methoxyphenyl)-2-phenyl-
1,2,3,4-tetrahydroquinolin-3-yl]acetamide (18a). β-Aminoacetamide
7a (100 mg, 0.197 mmol) afforded crude tetrahydroquinoline 18a as a
brown solid. Purification by flash column chromatography (10%
EtOAc/petroleum ether) yielded pure tetrahydroquinoline 18a as a
white solid (82 mg, 98%): mp 162−164 °C; Rf 0.31 (10% EtOAc/
petroleum ether); IR νmax (neat) 3418, 3284, 3065−2838, 1709, 1508,
1
1491, 1456, 1240, 1205, 1167 cm−1; H NMR (600 MHz, CDCl3) δ
2.71 (1H, d, J = 17.0), 2.96 (1H, dd, J = 17.0, 4.2), 3.80 (3H, s), 4.58
Q
dx.doi.org/10.1021/jo3010827 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
(CH), 127.6 (CH), 128.0 (CH), 130.7 (CH), 139.0 (C), 142.8 (CH),
144.3 (C), 157.0 (1C, q, J = 37.4, C), 157.7 (C); 19F NMR (282 MHz,
CDCl3) δ −76.2 (3F, s); MS (EI) m/z 432 (18%, M+); HRMS
C22H19F3N2O2S calcd 432.1114, found 432.1116. Anal. Calcd for
C22H19F3N2O2S: C, 61.10; H, 4.43; N, 6.48. Found: C, 61.15; H, 4.38;
N, 6.42.
C22H26F3N2O2 calcd 407.1946, found 407.1953. Anal. Calcd for
C22H25F3N2O2: C, 65.01; H, 6.20; N, 6.89. Found: C, 64.75; H, 6.23;
N, 6.61.
2,2,2-Trifluoro-N-((2R*,3S*)-1-(4-methoxyphenyl)-2-(o-tolyl)-
1,2,3,4-tetrahydroquinolin-3-yl)acetamide (18h). β-Aminoacetamide
7h (114 mg, 0.219 mmol) afforded crude tetrahydroquinoline 18h as a
brown oil. Purification by flash column chromatography (15% EtOAc/
petroleum ether) yielded pure tetrahydroquinoline 18h as an orange
solid (85 mg, 88%): mp 62−65 °C; Rf 0.67 (15% EtOAc/petroleum
ether); IR νmax (neat) 3418, 3285, 3063−2838, 1719, 1601, 1528,
1508, 1491, 1456, 1280, 1239, 1206, 1166, 1035 cm−1; 1H NMR (600
MHz, CDCl3) δ 2.48 (3H, s), 2.71 (1H, d, J = 16.9), 3.07 (1H, dd, J =
16.9, 3.4), 3.80 (3H, s), 4.51 (1H, m), 5.03 (1H, d, J = 1.3), 6.61 (1H,
d, J = 8.4), 6.65 (1H, br d, J = 6.4), 6.77 (1H, t, J = 7.4), 6.87 (2H, br
d, J = 7.8), 7.04 (2H, br d, J = 8.1), 7.08−7.10 (2H, m), 7.15 (1H, t, J
= 7.3), 7.19−7.23 (2H, m), 7.35 (1H, d, J = 7.7); 13C NMR (151
MHz, CDCl3) δ 19.0 (CH3), 27.9 (CH2), 45.6 (CH), 55.5 (CH3), 64.1
(CH), 113.2 (CH), 114.9 (C), 115.3 (CH), 115.9 (1C, q, J = 288.1,
C), 117.7 (CH), 126.4 (CH), 126.8 (CH), 127.8 (CH), 128.3 (CH),
128.6 (CH), 130.8 (CH), 131.2 (CH), 135.1 (C), 139.1 (C), 139.1
(C), 144.5 (C), 157.2 (1C, q, J = 37.2, C), 157.9 (C); 19F NMR (282
MHz, CDCl3) δ −76.1 (3F, s); MS (EI) m/z 441 (27, M+ + H), 440
(100, M+); HRMS C25H23F3N2O2 calcd 440.1706, found 440.1712;
Anal. Calcd for C25H23F3N2O2: C, 68.17; H, 5.26; N, 6.36. Found: C,
67.84; H, 5.23; N, 6.36.
N-((2R*,3S*)-2-(2-Bromophenyl)-1-(4-methoxyphenyl)-1,2,3,4-
tetrahydroquinolin-3-yl)-2,2,2-trifluoroacetamide (18i). Prepared
using the general for the synthesis of 3-aminotetrahydroquinolines
except with 10 mol % Pd(PPh3)4. β-Aminoacetamide 7i (90 mg, 0.15
mmol) afforded crude tetrahydroquinoline 18i as a brown oil.
Purification by flash column chromatography (20% Et2O/petroleum
ether) yielded pure tetrahydroquinoline 18i as a white solid (42 mg,
54%): mp 145−146 °C; Rf 0.36 (10% Et2O/petroleum ether); IR νmax
(neat) 3421, 3311, 3065−2838, 1725, 1508, 1491, 1457, 1240, 1205,
1167, 1036, 1023 cm−1; 1H NMR (600 MHz, CDCl3) δ 2.77 (1H, d, J
= 17.0), 2.91 (1H, dd, J = 17.0, 4.1), 3.80 (3H, s), 4.84 (1H, dt, J =
11.3, 3.4), 5.09 (1H, s), 6.59 (1H, br d, J = 8.0), 6.65 (1H, d, J = 8.2),
6.79 (1H, td, J = 7.3, 0.5), 6.87 (2H, d, J = 8.9), 7.03 (2H, d, J = 8.6),
7.07 (1H, d, J = 7.4), 7.08 (1H, t, J = 7.8), 7.17 (1H, td, J = 7.7, 1.6),
7.25 (1H, td, J = 7.6, 0.8), 7.41 (1H, dd, J = 7.8, 1.4), 7.57 (1H, dd, J =
7.9, 1.0); 13C NMR (151 MHz, CDCl3) δ 28.4 (CH2), 44.9 (CH), 55.6
(CH3), 66.7 (CH), 113.6 (CH), 115.4 (CH), 115.8 (C), 115.9 (1C, q,
J = 288.3, C), 118.5 (CH), 122.0 (C), 127.9 (CH), 128.2 (CH), 128.3
(CH), 128.6 (CH), 129.7 (CH), 130.9 (CH), 133.7 (CH), 138.6 (C),
139.4 (C), 143.8 (C), 156.7 (1C, q, J = 37.1, C), 157.9 (C); 19F NMR
(282 MHz, CDCl3) δ −76.1 (3F, s); MS (CI) m/z 506 + 508 (1:1, 29,
M+ + H2), 505 + 507 (1:1, 100, M+ + H), 504 + 506 (1:1, 8, M+);
HRMS C24H21(79Br)F3N2O2 calcd 505.0739, found 505.0746. Anal.
Calcd for C24H20BrF3N2O2: C, 57.04; H, 3.99; N, 5.54. Found: C,
57.17; H, 3.84; N, 5.73.
2,2,2-Trifluoro-N-((2R*,3S*)-2-(2-methoxyphenyl)-1-(4-methoxy-
phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)acetamide (18j). β-Amino-
acetamide 7j (113 mg, 0.210 mmol) afforded crude tetrahydroquino-
line 18j as a brown solid. Purification by flash column chromatography
(20% EtOAc/petroleum ether) yielded pure tetrahydroquinoline 18j
as an orange solid (94 mg, 98%): mp 168−170 °C; Rf 0.63 (20%
EtOAc/petroleum ether); IR νmax (neat) 3417, 3313, 3069−2838,
1722, 1600, 1508, 1488, 1456, 1283, 1238, 1202, 1160, 1097, 1031
cm−1; 1H NMR (600 MHz, CDCl3) δ 2.72 (1H, d, J = 17.0), 2.87 (1H,
dd, J = 16.9, 4.2), 3.79 (3H, s), 3.87 (3H, s), 4.79 (1H, m), 5.09 (1H,
s), 6.65 (1H, d, J = 7.9), 6.69 (1H, d, J = 8.3), 6.76 (1H, t, J = 7.3),
6.85−6.89 (3H, m), 6.90 (1H, d, J = 8.1), 7.03 (1H, d, J = 7.4), 7.06−
7.10 (3H, m), 7.26−7.29 (2H, m); 13C NMR (151 MHz, CDCl3) δ
28.8 (CH2), 44.9 (CH), 55.4 (CH3), 55.6 (CH3), 62.2 (CH), 110.6
(CH), 113.6 (CH), 115.2 (CH), 115.9 (1C, q, J = 288.2, C), 116.3
(C), 118.1 (CH), 120.6 (CH), 127.6 (CH), 127.9 (2 × CH), 128.4
(C), 129.0 (CH), 130.8 (CH), 139.3 (C), 144.0 (C), 155.9 (C), 156.7
(1C, q, J = 36.8, C), 157.6 (C); 19F NMR (282 MHz, CDCl3) δ −76.2
(3F, s); MS (EI) m/z 457 (27, M+ ), 456 (100, M+), 342 (37, M+ −
3H5F3O); HRMS C25H23F3N2O3 calcd 456.1655, found
2,2,2-Trifluoro-N-((2R*,3S*)-1-(4-methoxyphenyl)-2-pentyl-
1,2,3,4-tetrahydroquinolin-3-yl)acetamide (18e). β-Aminoacetamide
7e (187 mg, 0.373 mmol) afforded crude tetrahydroquinoline 18e as a
brown oil. Purification by flash column chromatography (10% EtOAc/
petroleum ether) yielded pure tetrahydroquinoline 18e as a white solid
(137 mg, 87%): mp 93−94 °C; Rf 0.50 (10% EtOAc/petroleum
ether); IR νmax (neat) 3415, 3292, 3066−2860, 1712, 1507, 1492,
1
1456, 1242, 1204, 1157, 1037 cm−1; H NMR (600 MHz, CDCl3) δ
0.87 (3H, t, J = 6.8), 1.22−1.45 (6H, m), 1.52 (1H, dddd, J = 19.3,
14.3, 10.0, 5.1), 1.75 (1H, dddd, J = 16.4, 13.9, 11.0, 5.5), 2.82 (1H, d,
J = 17.3), 3.23 (1H, dd, J = 17.3, 4.7), 3.56 (1H, m), 3.84 (3H, s), 4.50
(1H, m), 6.57 (1H, d, J = 8.3), 6.64 (1H, br d, J = 7.3), 6.74 (1H, t, J =
7.3), 6.94 (2H, dm, J = 8.6), 6.99 (1H, t, J = 7.7), 7.07 (1H, d, J = 7.4),
7.11 (2H, dm, J = 8.7); 13C NMR (151 MHz, CDCl3) δ 14.1 (CH3),
22.6 (CH2), 25.2 (CH2), 28.2 (CH2), 31.7 (CH2), 31.8 (CH2), 44.8
(C), 55.6 (CH3), 62.7 (CH), 115.3 (CH), 115.5 (CH), 115.8 (1C, q, J
= 288.0, C), 117.0 (C), 118.4 (CH), 127.6 (CH), 128.2 (CH), 130.6
(CH), 139.3 (C), 142.6 (C), 156.7 (1C, q, J = 37.1, C), 157.4 (C); 19F
NMR (282 MHz, CDCl3) δ −76.3 (3F, s); MS (EI) m/z 420 (10,
M+), 349 (100, M+ − npentyl); HRMS C23H27F3N2O2 calcd 420.2019,
found 420.2002. Anal. Calcd for C23H27F3N2O2: C, 65.70; H, 6.47; N,
6.66. Found: C, 65.93; H, 6.51; N, 6.67.
N-((2R*,3S*)-2-Cyclohexyl-1-(4-methoxyphenyl)-1,2,3,4-tetrahy-
droquinolin-3-yl)-2,2,2-trifluoroacetamide (18f). Prepared using the
general for the synthesis of 3-aminotetrahydroquinolines except with
10 mol % Pd(PPh3)4. β-Aminoacetamide 7f (63 mg, 0.12 mmol)
afforded crude tetrahydroquinoline 18f as a pale brown oil. Purification
by flash column chromatography (20% Et2O/petroleum ether) yielded
pure tetrahydroquinoline 18f as an off-white solid (43 mg, 81%): mp
95−97 °C; Rf 0.46 (20% Et2O/petroleum ether); IR νmax (neat) 3410,
3304, 3067−2852, 1721, 1506, 1491, 1456, 1272, 1244, 1229, 1203,
1174, 1037 cm−1; 1H NMR (600 MHz, CDCl3) δ 1.10−1.26 (5H, m),
1.39−1.46 (1H, m), 1.69 (1H, m), 1.78−1.86 (3H, m), 2.10 (1H, d, J
= 12.1), 2.86 (1H, d, J = 17.8), 3.16 (1H, dd, J = 17.8, 5.5), 3.48 (1H,
dd, J = 10.0, 2.2), 3.80 (3H, s), 4.62 (1H, m), 6.53 (1H, br d, J = 7.0),
6.83 (2H, dm, J = 9.0), 6.86 (1H, td, J = 7.4, 0.9), 6.94 (1H, d, J = 8.1),
7.06 (1H, td, J = 7.7, 0.9), 7.11−7.13 (3H, m); 13C NMR (151 MHz,
CDCl3) δ 26.3 (CH2), 26.3 (CH2), 26.5 (CH2), 28.7 (CH2), 29.5
(CH2), 31.7 (CH2), 39.0 (CH), 45.5 (CH), 55.7 (CH3), 67.2 (CH),
115.1 (CH), 115.6 (1C, q, J = 288.2, C), 120.4 (CH), 120.5 (CH),
120.9 (C), 123.5 (CH), 127.3 (CH), 130.6 (CH), 141.5 (C), 143.3
(C), 155.5 (C), 156.5 (1C, q, J = 37.0, C); 19F NMR (282 MHz,
CDCl3) δ −76.4 (3F, s); MS (CI) m/z 433 (100, M+ + H), 432 (44,
M+), 349 (32, M+ − Cy); HRMS C24H28F3N2O2 calcd 433.2103,
found 433.2115. Anal. Calcd for C24H27F3N2O2: C, 66.65; H, 6.29; N,
6.48. Ffound: C, 66.64; H, 6.49; N, 6.16.
N-((2R*,3S*)-2-tert-Butyl-1-(4-methoxyphenyl)-1,2,3,4-tetrahy-
droquinolin-3-yl)-2,2,2-trifluoroacetamide (18g). β-Aminoacetamide
7g (94 mg, 0.19 mmol) afforded crude tetrahydroquinoline 18g as a
dark brown oil. Purification by flash column chromatography (20%
Et2O/petroleum ether) yielded pure tetrahydroquinoline 18g as a
white solid (48 mg, 61%): mp 119−121 °C; Rf 0.46 (20% Et2O/
petroleum ether); IR νmax (neat) 3418, 3291, 3080−2838, 1712, 1507,
1491, 1456, 1243, 1205, 1157, 1038 cm−1; 1H NMR (600 MHz,
CDCl3) δ 1.00 (9H, s), 2.83 (1H, d, J = 7.6), 3.27 (1H, dd, J = 17.5,
5.2), 3.57 (1H, t, J = 1.8), 3.81 (3H, s), 4.75 (1H, td, J = 5.4, 2.5), 6.46
(1H, br d, J = 7.0), 6.78−6.80 (2H, m), 6.88 (2H, dm, J = 8.9), 7.02
(1H, t, J = 7.7), 7.07 (1H, d, J = 7.6), 7.12 (2H, dm, J = 8.9); 13C
NMR (151 MHz, CDCl3) δ 28.6 (CH3), 30.0 (CH2), 36.9 (C), 45.0
(CH), 55.6 (CH3), 71.2 (CH), 115.0 (CH), 115.7 (1C, q, J = 288.1,
C), 117.4 (CH), 118.4 (C), 119.3 (CH), 126.8 (CH), 127.7 (CH),
130.6 (CH), 142.7 (C), 143.8 (C), 156.4 (1C, q, J = 37.1, C), 156.5
(C); 19F NMR (282 MHz, CDCl3) δ −76.3 (3F, s); MS (CI) m/z 407
(100, M++ H), 407 (12, M+), 349 (17, M+ − C(CH3)3); HRMS
R
dx.doi.org/10.1021/jo3010827 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
456.1659.Anal. Calcd for C25H23F3N2O3: C, 65.78; H, 5.08; N, 6.14.
Found; C, 65.55; H, 5.01; N, 6.03.
2,2,2-Trifluoro-N-((2R*,3S*)-1-(4-methoxyphenyl)-2-(3-
trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)acetamide
(18n). β-Aminoacetamide 7n (119 mg, 0.207 mmol) afforded crude
tetrahydroquinoline 18n as a brown oil. Purification by flash column
chromatography (10% EtOAc/petroleum ether) yielded pure
tetrahydroquinoline 18n as a white solid (101 mg, 99%): mp 169−
171 °C; Rf 0.32 (10% EtOAc/petroleum ether); IR νmax (neat) 3419,
3301, 3072−2840, 1710, 1508, 1492, 1458, 1328, 1316, 1242, 1205,
2,2,2-Trifluoro-N-((2R*,3S*)-2-(3-methoxyphenyl)-1-(4-methoxy-
phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)acetamide (18k). β-Amino-
acetamide 7k (130 mg, 0.242 mmol) afforded crude tetrahydroquino-
line 18k as a brown oil. Purification by flash column chromatography
(30% Et2O/petroleum ether) yielded pure tetrahydroquinoline 18k as
a white solid (99 mg, 90%): mp 114−116 °C; Rf 0.38 (30% Et2O/
petroleum ether); IR νmax (neat) 3418, 3306, 3069−2837, 1712, 1601,
1508, 1489, 1456, 1278, 1238, 1205, 1151, 1037 cm−1; 1H NMR (600
MHz, CDCl3) δ 2.70 (1H, d, J = 17.0), 2.97 (1H, dd, J = 17.0, 4.2),
3.75 (3H, s), 3.80 (3H, s), 4.59 (1H, m), 4.85 (1H, s), 6.66−6.68 (1H,
br m), 6.68 (1H, d, J = 8.3), 6.75 (1H, t, J = 7.4), 6.83 (1H, dd, J = 8.2,
2.2), 6.86−6.88 (3H, m), 6.95 (1H, d, J = 7.6), 7.06 (2H, t, J = 8.3),
7.09 (2H, d, J = 8.2), 7.26 (1H, t, J = 7.9); 13C NMR (151 MHz,
CDCl3) δ 27.9 (CH2), 47.7 (CH), 55.3 (CH3), 55.6 (CH3), 66.2
(CH), 112.3 (CH), 113.0 (CH), 113.9 (CH), 115.3 (CH), 115.8 (1C,
q, J = 288.0, C), 116.0 (C), 118.1 (CH), 118.7 (CH), 127.9 (CH),
128.1 (CH), 130.1 (CH), 130.8 (CH), 139.2 (C), 142.8 (C), 143.7
(C), 157.0 (1C, q, J = 37.2, C), 157.6 (C), 160.0 (C); 19F NMR (282
MHz, CDCl3) δ −76.2 (3F, s); MS (EI) m/z 457 (28, M+ + H), 456
(100, M+), 342 (68, M+ − C3H5F3O), 236 (47, M+ − C9H9F3NO2);
HRMS C25H23F3N2O3 calcd 456.1655, found 456.1652. Anal. Calcd
for C25H23F3N2O3: C, 65.78; H, 5.08; N, 6.14. Found: C, 65.98; H,
5.23; N, 5.96.
1
1163, 1125, 1074, 1038 cm−1; H NMR (600 MHz, CDCl3) δ 2.72
(1H, d, J = 17.1), 2.91 (1H, dd, J = 17.0, 4.3), 3.80 (3H, s), 4.57 (1H,
m), 4.96 (1H, s), 6.60 (1H, br d, J = 7.4), 6.67 (1H, d, J = 8.2), 6.79
(1H, td, J = 7.4, 0.9), 6.87 (2H, dm, J = 8.9), 7.02 (2H, dm, J = 8.8),
7.07 (1H, d, J = 7.5), 7.10 (1H, t, J = 8.3), 7.47 (1H, t, J = 7.7), 7.56−
7.57 (2H, m), 7.60 (1H, s); 13C NMR (151 MHz, CDCl3) δ 27.6
(CH2), 47.6 (CH), 55.6 (CH3), 66.0 (CH), 114.1 (CH), 115.4 (CH),
115.5 (C), 115.7 (1C, q, J = 287.9, C), 118.5 (CH), 123.4 (1C, q, J =
3.5, CH), 124.0 (1C, q, J = 272.5, C), 124.9 (1C, q, J = 3.7, CH), 128.1
(CH), 128.4 (CH), 129.6 (CH), 130.0 (CH), 130.8 (CH), 131.4 (1C,
q, J = 32.5, C), 138.8 (C), 142.2 (C), 143.5 (C), 157.1 (1C, q, J = 37.5,
C), 157.9 (C); 19F NMR (282 MHz, CDCl3) δ −76.2 (3F, s), −63.0
(3F, s); MS (CI) m/z 496 (23, M+ + H2), 495 (100, M+ + H), 494
(45, M+); HRMS C25H21F6N2O2 calcd 495.1507, found 495.1490.
Anal. Calcd for C25H20F6N2O2: C, 60.73; H, 4.08; N, 5.67. Found: C,
60.62; H, 4.08; N, 5.57.
2,2,2-Trifluoro-N-((2R*,3S*)-1-(4-methoxyphenyl)-2-(4-
trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)acetamide
(18o). β-Aminoacetamide 7o (139 mg, 0.242 mmol) afforded crude
tetrahydroquinoline 18o as a brown oil. Purification by flash column
chromatography (20% Et2O/petroleum ether) yielded pure tetrahy-
droquinoline 18o as an off-white solid (118 mg, 99%): mp 162−164
°C; Rf 0.41 (20% Et2O/petroleum ether); IR νmax (neat) 3417, 3281,
3069−2848, 1710, 1509, 1492, 1457, 1323, 1244, 1208, 1164, 1124,
1106, 1067, 1037 cm−1; 1H NMR (600 MHz, CDCl3) δ 2.72 (1H, d, J
= 17.2), 2.90 (1H, dd, J = 17.1, 4.1), 3.80 (3H, s), 4.56 (1H, m), 4.95
(1H, s), 6.62 (1H, br d, J = 6.6), 6.68 (1H, d, J = 8.3), 6.79 (1H, t, J =
7.4), 6.87 (2H, d, J = 8.8), 7.03 (2H, d, J = 8.5), 7.07 (1H, d, J = 7.4),
7.10 (1H, t, J = 7.9), 7.49 (2H, d, J = 8.0), 7.61 (2H, d, J = 8.1); 13C
NMR (151 MHz, CDCl3) δ 27.6 (CH2), 47.5 (CH), 55.6 (CH3), 66.0
(CH), 114.1 (CH), 115.4 (CH), 115.5 (C), 115.7 (1C, q, J = 287.8,
C), 118.5 (CH), 124.1 (1C, q, J = 272.1, C), 126.0 (1C, q, J = 3.6,
CH), 127.0 (CH), 128.0 (CH), 128.4 (CH), 130.2 (1C, q, J = 32.6, C),
130.8 (CH), 138.8 (C), 143.5 (C), 145.1 (C), 157.1 (1C, q, J = 37.5,
C), 157.9 (C); 19F NMR (282 MHz, CDCl3) δ −76.2 (3F, s), −63.0
(3F, s); MS (CI) m/z 496 (28%, M+ + H2), 495 (100, M+ + H), 494
(17, M+), 406 (52), 280 (32); HRMS C25H21F6N2O2 calcd 495.1507,
found 495.1512. Anal. Calcd for C25H20F6N2O2: C, 60.73; H, 4.08; N,
5.67. Found: C, 60.68; H, 3.98; N, 5.63.
2,2,2-Trifluoro-N-((2R*,3S*)-2-(4-methoxyphenyl)-1-(4-methoxy-
phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)acetamide (18l). β-Amino-
acetamide 7l (123 mg, 0.229 mmol) afforded crude tetrahydroquino-
line 18l as a brown oil. Purification by flash column chromatography
(15% EtOAc/petroleum ether) yielded pure tetrahydroquinoline 18l
as an orange solid (102 mg, 98%): mp 118−120 °C; Rf 0.51 (15%
EtOAc/petroleum ether); IR νmax (neat) 3418, 3300, 3067−2837,
1709, 1608, 1508, 1491, 1456, 1240, 1206, 1170, 1105, 1032 cm−1; 1H
NMR (600 MHz, CDCl3) δ 2.69 (1H, d, J = 17.0), 2.97 (1H, dd, J =
17.0, 4.4), 3.79 (3H, s), 3.79 (3H, s), 4.52 (1H, m), 4.80 (1H, s), 6.62
(1H, br d, J = 7.7), 6.66 (1H, d, J = 8.3), 6.75 (1H, t, J = 7.4), 6.85−
6.87 (4H, m), 7.04−7.08 (4H, m), 7.24 (2H, dm, J = 8.7); 13C NMR
(151 MHz, CDCl3) δ 27.7 (CH2), 47.8 (CH), 55.4 (CH3), 55.6
(CH3), 65.8 (CH), 113.8 (CH), 114.3 (CH), 115.2 (CH), 115.8 (1C,
q, J = 288.0, C), 116.0 (C), 118.0 (CH), 127.6 (CH), 128.0 (CH),
128.1 (CH), 130.8 (CH), 133.0 (C), 139.1 (C), 143.8 (C), 157.0 (1C,
q, J = 37.2, C), 157.6 (C), 159.2 (C); 19F NMR (282 MHz, CDCl3) δ
−76.2 (3F, s); MS (EI) m/z 457 (27, M+ + H), 456 (100, M+), 342
(42, M+ − C3H5F3O); HRMS C25H23F3N2O3 calcd 456.1655, found
456.1662. Anal. Calcd for C25H23F3N2O3: C, 65.78; H, 5.08; N, 6.14.
Found: C, 65.88; H, 5.04; N, 6.14.
2,2,2-Trifluoro-N-((2R*,3S*)-1-(4-methoxyphenyl)-2-(2-
trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)acetamide
(18m). β-Aminoacetamide 7m (85 mg, 0.15 mmol) afforded crude
tetrahydroquinoline 18m as a pale brown oil. Purification by flash
column chromatography (10% EtOAc/petroleum ether) yielded pure
tetrahydroquinoline 18m as a white solid (71 mg, 97%): mp 176−178
°C; Rf 0.31 (10% EtOAc/petroleum ether); IR νmax (neat) 3418, 3312,
3075−2855, 1726, 1509, 1492, 1457, 1311, 1280, 1245, 1209, 1157,
1122, 1105, 1037 cm−1; 1H NMR (600 MHz, CDCl3) δ 2.85 (1H, dd,
J = 16.9, 2.3), 3.10 (1H, dd, J = 16.9, 4.0), 3.78 (3H, s), 4.69 (1H, app
dt, J = 12.0, 3.6), 5.15 (1H, d, J = 2.0), 6.57 (2H, d, J = 8.3), 6.80 (1H,
td, J = 7.4, 0.7), 6.84 (2H, d, J = 8.8), 6.96 (2H, d, J = 8.2), 7.08 (1H, t,
J = 7.8), 7.11 (1H, d, J = 7.4), 7.41 (1H, t, J = 7.6), 7.51 (1H, t, J =
7.6), 7.64 (1H, d, J = 7.9), 7.66 (1H, d, J = 7.8); 13C NMR (151 MHz,
CDCl3) δ 28.5 (CH2), 46.6 (CH), 55.5 (CH3), 63.4 (CH), 113.7
(CH), 115.3 (CH), 115.8 (1C, q, J = 288.2, C), 116.0 (C), 118.5
(CH), 124.2 (1C, q, J = 274.3, C), 126.6 (1C, q, J = 5.9, CH), 127.8
(1C, q, J = 30.3, C), 128.3 (CH), 128.4 (CH), 128.8 (CH), 129.0
(CH), 130.9 (CH), 132.3 (CH), 138.0 (C), 139.9 (C), 144.3 (C),
156.4 (1C, q, J = 37.2, C), 158.0 (C); 19F NMR (282 MHz, CDCl3) δ
−76.2 (3F, s), −58.6 (3F, s); MS (EI) m/z 494 (30, M+), 380 (100,
M+ − C3H5F3O), 236 (62, M+ − C9H6F6NO); HRMS C25H20F6N2O2
calcd 494.1424, found 494.1428. Anal. Calcd for C25H20F6N2O2: C,
60.73; H, 4.08; N, 5.67. Found: C, 60.58; H, 3.76; N, 5.58.
2,2,2-Trifluoro-N-[(2R*,3S*)-6-fluoro-1-(4-methoxyphenyl)-2-
phenyl-1,2,3,4-tetrahydroquinolin-3-yl]acetamide (18p). β-Amino-
acetamide 7p (115 mg, 0.219 mmol) afforded crude tetrahydroquino-
line 18p as a brown oil. Purification by flash column chromatography
(10% EtOAc/petroleum ether) yielded pure tetrahydroquinoline 18p
as a white solid (91 mg, 93%): mp 112−124 °C; Rf 0.35 (10% EtOAc/
petroleum ether); IR νmax (neat) 3416, 3291, 3066−2838, 1709, 1508,
1
1497, 1243, 1209, 1178, 1034 cm−1; H NMR (600 MHz, CDCl3) δ
2.68 (1H, d, J = 17.3), 2.90 (1H, dd, J = 17.2, 4.2), 3.79 (3H, s), 4.58
(1H, m), 4.85 (1H, s), 6.61 (1H, br d, J = 7.5), 6.65 (1H, dd, J = 9.0,
4.8), 6.77−6.82 (2H, m), 6.85 (2H, dm, J = 8.9), 7.05 (2H, dm, J =
8.8), 7.28−7.36 (5H, m); 13C NMR (151 MHz, CDCl3) δ 28.1 (CH2),
47.6 (CH), 55.6 (CH3), 66.1 (CH), 115.0 (1C, d, J = 22.2, CH), 115.0
(1C, d, J = 7.3, CH), 115.3 (CH), 115.8 (1C, q, J = 288.0, C), 116.7
(1C, d, J = 22.3, CH), 117.5 (1C, d, J = 7.0, C), 126.3 (CH), 127.5
(CH), 127.9 (CH), 129.0 (CH), 139.4 (C), 139.9 (1C, d, J = 1.6, C),
140.7 (C), 155.8 (1C, d, J = 237.3, C), 157.0 (1C, q, J = 37.3, C), 157.6
(C); 19F NMR (282 MHz, CDCl3) δ −127.4 (1H, m), −76.2 (3F, s);
MS (EI) m/z 445 (23, M+ + H), 444 (100, M+), 330 (53, M+
−
C3H5F3O), 254 (33, M+ − C8H7F3NO); HRMS C24H20F4N2O2 calcd
444.1455, found 444.1459. Anal. Calcd for C24H20F4N2O2: C, 64.86;
H, 4.54; N, 6.30. Found: C, 64.94; H, 4.57; N, 6.15.
S
dx.doi.org/10.1021/jo3010827 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
N-[(2R*,3S*)-6,7-Dimethoxy-1-(4-methoxyphenyl)-2-phenyl-
1,2,3,4-tetrahydroquinolin-3-yl]-2,2,2-trifluoroacetamide (18q). β-
Aminoacetamide 7q (49 mg, 86 μmol) afforded crude tetrahydroqui-
noline 18q as a brown oil. Purification by flash column
chromatography (50% Et2O/petroleum ether) yielded pure tetrahy-
droquinoline 18q as a white solid (38 mg, 91%): mp 136−138 °C; Rf
0.40 (50% Et2O/petroleum ether); IR νmax (neat) 3416, 3292, 3064−
2836, 1709, 1507, 1465, 1451, 1443, 1241, 1209, 1176, 1143, 1032
cm−1; 1H NMR (600 MHz, CDCl3) δ 2.60 (1H, d, J = 16.9), 2.81 (1H,
dd, J = 16.8, 4.4), 3.69 (3H, s), 3.79 (3H, s), 3.83 (3H, s), 4.58 (1H,
m), 4.84 (1H, s), 6.38 (1H, s), 6.54 (1H, s), 6.66 (1H, br d, J = 7.9),
6.84 (2H, d, J = 8.9), 7.07 (2H, d, J = 8.5), 7.28−7.35 (5H, m); 13C
NMR (151 MHz, CDCl3) δ 27.6 (CH2), 48.0 (CH), 55.6 (CH3), 55.9
(CH3), 56.5 (CH3), 65.8 (CH), 99.5 (CH), 107.7 (C), 113.9 (CH),
115.1 (CH), 115.8 (1C, q, J = 288.0, C), 126.4 (CH), 126.6 (CH),
127.7 (CH), 129.0 (CH), 137.0 (C), 140.1 (C), 140.8 (C), 142.2 (C),
148.9 (C), 156.9 (1C, q, J = 37.1, C), 157.0 (C); 19F NMR (282 MHz,
CDCl3) δ −76.3 (3F, s); MS (EI) m/z 487 (28, M+ + H), 486 (100,
M+), 471 (26, M+ − CH3), 372 (14, M+ − C3H5F3O); HRMS
C26H25F3N2O4 calcd 486.1761, found 486.1746. Anal. Calcd for
C26H25F3N2O4: C, 64.19; H, 5.18; N, 5.76. Found: C, 64.32; H, 5.17;
N, 5.63.
(5.0 mL) and H2O (1.0 mL) was heated to 85 °C to give a
homogeneous solution. The reaction was heated until complete by
TLC analysis (4 h) and allowed to cool to rt, H2O was added, and the
product was extracted into EtOAc. The combined organic extracts
were washed with water, brine, dried (MgSO4), and filtered and the
solvents removed in vacuo to give crude 1,2-diamine 13 as a pale
brown oil. Purification by passing through a short plug of silica and
eluting with EtOAc yielded pure 1,2-diamine 13 as a pale yellow oil
(124 mg, 94%): Rf 0.31 (50% EtOAc/petroleum ether); IR νmax (neat)
3382, 3059−2830, 1511, 1240, 1037 cm−1; 1H NMR (600 MHz,
CDCl3) δ 2.42 (1H, dd, J = 13.5, 10.5), 3.17 (1H, dd, J = 13.5, 2.7),
3.47 (1H, ddd, J = 10.4, 4.7, 2.9), 3.70 (3H, s), 4.41 (1H, d, J = 4.7),
6.54 (2H, dm, J = 8.9), 6.69 (2H, dm, J = 8.9), 7.10 (1H, td, J = 7.6,
1.4), 7.16 (1H, dd, J = 7.5, 1.4), 7.23 (1H, t, J = 7.2), 7.28 (1H, t, J =
7.3), 7.36 (2H, t, J = 7.6), 7.42 (2H, d, J = 7.4), 7.55 (1H, d, J = 7.9);
13C NMR (151 MHz, CDCl3) δ 41.7 (CH2), 55.6 (CH), 55.8 (CH3),
63.0 (CH), 114.8 (CH), 114.9 (CH), 125.0 (C), 127.5 (CH), 127.5
(CH), 127.9 (CH), 128.3 (CH), 128.6 (CH), 131.7 (CH), 133.2
(CH), 138.7 (C), 140.1 (C), 141.6 (C), 151.9 (C); MS (ESI+) m/z
411 + 413 (1:1, 100, M+ + H), 290 + 288 (1:1, 33, M+ − NHPMP);
HRMS C22H24(79Br)N2O calcd 411.1064, found 411.1067.
N-((R*)-((S*)-Indolin-2-yl)(phenyl)methyl)-4-methoxyaniline
(14a). A flame-dried Schenk tube was charged with Pd(PPh3)4 (28.0
mg, 24.3 μmol, NaOtBu (74.7, 0.778 mmol) and K2CO3 (107 mg,
0.778 mmol). The tube was triple evacuated/N2 filled before the
addition of a solution of 1,2-diamine 13 (200 mg, 0.486 mmol) in
toluene (9.7 mL). The resulting mixture was stirred while N2 was
bubbled through it, using a needle, for 15 min. The N2 needle was
removed and the reaction was heated to 100 °C for 4 h to give a dark
brown mixture. The reaction was allowed to cool to rt before being
filtered through Celite, washed with EtOAc and the solvents removed
in vacuo to give crude indoline 14a as a brown solid. Purification by
flash column chromatography (30% Et2O/petroleum ether) yielded
pure indoline 14a as a pale yellow solid (148 mg, 91%): mp 51−55
°C; Rf 0.27 (30% Et2O/petroleum ether); IR νmax (neat) 3359, 3027−
2832, 1609, 1509, 1483, 1466, 1454, 1237, 1035 cm−1; 1H NMR (600
MHz, CDCl3) δ 2.91 (1H, dd, J = 15.9, 8.8), 3.18 (1H, dd, J = 15.9,
8.7), 3.70 (3H, s), 4.16 (1H, dt, J = 8.3, 7.1), 4.37 (1H, d, J = 6.4), 6.49
(2H, dm, J = 8.9), 6.61 (1H, d, J = 7.7), 6.68 (2H, d, J = 8.7), 6.73
(1H, t, J = 7.4), 7.05 (1H, t, J = 7.7), 7.07 (1H, d, J = 7.3), 7.30 (1H, t,
J = 7.2), 7.37 (2H, t, J = 7.4), 7.42 (2H, d, J = 7.4); 13C NMR (151
MHz, CDCl3) δ 32.3 (CH2), 55.8 (CH3), 62.2 (CH), 65.3 (CH), 109.2
(CH), 114.8 (CH), 115.4 (CH), 119.1 (CH), 125.0 (CH), 127.1
(CH), 127.5 (CH), 127.6 (CH), 128.2 (C), 128.9 (CH), 141.3 (C),
141.7 (C), 150.5 (C), 152.4 (C); MS (EI) m/z 330 (3, M+), 213 (93,
M+ − C8H7N), 212 (99, M+ − C8H8N), 118 (100, M+ − C14H14NO);
HRMS C22H22N2O calcd 330.1727, found 330.1735. Anal. Calcd for
C22H22N2O: C, 79.97; H, 6.71; N, 8.48. Found: C, 79.79; H, 6.69; N,
8.24.
General Procedure for the Synthesis of Indolines 14 (Table
6). A stirred suspension of β-nitroacetamide 7 (1.00 mmol) and KOH
(15.0 mmol) in EtOH (15.0 mL) and H2O (3.0 mL) was heated to 85
°C to give a homogeneous solution. The reaction was heated until
complete by TLC analysis (2−6 h), allowed to cool to rt, H2O was
added and the product extracted into EtOAc. The combined organic
extracts were washed with water, brine, dried (MgSO4), filtered and
the solvents removed in vacuo to give crude 1,2-diamine, which was
purified by passing through a short plug of silica. A flame-dried Schenk
tube was charged with Pd(PPh3)4 (10.0 mol %), NaO-t-Bu (1.60
mmol), and K2CO3 (1.60 mmol). The tube was triple evacuated/N2
filled before the addition of a solution of 1,2-diamine (1.00 mmol) in
toluene (20.0 mL). The resulting mixture was stirred while N2 was
bubbled through it, using a needle, for 15 min. The N2 needle was
removed, and the reaction was heated to 100 °C for 4 h to give a dark
brown mixture. The reaction was allowed to cool to rt before being
filtered through Celite, washed with EtOAc and the solvents removed
in vacuo to give crude indoline 14, which was purified by flash column
chromatography.
N-((2R*,3S*)-6,7-Dimethoxy-2-(2-methoxyphenyl)-1-(4-methoxy-
phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)-2,2,2-trifluoroacetamide
(18r). β-Aminoacetamide 7r (112 mg, 0.187 mmol) afforded crude
tetrahydroquinoline 18r as a brown oil. Purification by flash column
chromatography (30% EtOAc/petroleum ether) yielded pure
tetrahydroquinoline 18r as a white solid (85 mg, 88%): mp 159−
161 °C; Rf 0.44 (30% EtOAc/petroleum ether); IR νmax (neat) 3416,
3311, 3066−2837, 1720, 1508, 1489, 1464, 1452, 1441, 1284, 1240,
1
1211, 1178, 1147, 1031 cm−1; H NMR (600 MHz, CDCl3) δ 2.64
(1H, d, J = 16.7), 2.74 (1H, dd, J = 16.7, 4.5), 3.69 (3H, s), 3.79 (3H,
s), 3.83 (3H, s), 3.87 (3H, s), 4.80 (1H, m), 5.05 (1H, s), 6.39 (1H, s),
6.53 (1H, s), 6.69 (1H, br d, J = 8.0), 6.84 (2H, d, J = 8.8), 6.86 (1H, t,
J = 7.5), 6.90 (1H, d, J = 8.1), 7.09 (2H, d, J = 8.5), 7.25−7.29 (2H,
m); 13C NMR (151 MHz, CDCl3) δ 28.5 (CH2), 45.4 (CH), 55.4
(CH3), 55.6 (CH3), 55.9 (CH3), 56.5 (CH3), 61.9 (CH), 99.3 (CH),
108.1 (C), 110.5 (CH), 114.0 (CH), 115.1 (CH), 115.9 (1C, q, J =
288.3, C), 120.7 (CH), 126.6 (CH), 127.6 (CH), 128.3 (C), 129.0
(CH), 137.3 (C), 140.2 (C), 142.1 (C), 148.8 (C), 155.9 (C), 156.7
(1C, q, J = 36.8, C), 157.0 (C); 19F NMR (282 MHz, CDCl3) δ −76.3
(3F, s); MS (EI) m/z 517 (29, M+ + H), 516 (100, M+), 501 (17, M+
− CH3), 402 (15, M+ − C3H5F3O); HRMS C27H27F3N2O5 calcd
516.1867, found 516.1870. Anal. Calcd for C27H27F3N2O5: C, 62.78;
H, 5.27; N, 5.42. Found: C, 63.11; H, 5.31; N, 5.38.
N-((2R*,3S*)-8-(Benzyloxy)-7-methoxy-1-(4-methoxyphenyl)-2-
phenyl-1,2,3,4-tetrahydroquinolin-3-yl)-2,2,2-trifluoroacetamide
(18s). β-Aminoacetamide 7s (88 mg, 0.14 mmol) afforded crude
tetrahydroquinoline 18s as a brown oil. Purification by flash column
chromatography (20% EtOAc/petroleum ether) yielded pure
tetrahydroquinoline 18s as a white solid (24 mg, 31%): mp 126−
128 °C; Rf 0.38 (20% EtOAc/petroleum ether); IR νmax (neat) 3411,
3302, 3066−2853, 1709, 1506, 1490, 1448, 1288, 1241, 1206, 1162,
1136, 1099, 1033 cm−1; 1H NMR (600 MHz, CDCl3) δ 2.76 (1H, dd,
J = 17.2, 2.2), 2.81 (1H, dd, J = 17.3, 4.5), 3.74 (3H, s), 3.84 (3H, s),
4.66 (1H, m), 4.71 (1H, d, J = 10.7), 4.82 (1H, d, J = 10.6), 5.08 (1H,
d, J = 3.9), 6.61 (1H, d, J = 8.5), 6.62 (1H, br m), 6.72 (2H, dm, J =
8.9), 6.81 (1H, d, J = 8.5), 6.90−6.94 (4H, m), 7.16−7.19 (3H, m),
7.27−7.35 (5H, m); 13C NMR (151 MHz, CDCl3) δ 27.7 (CH2), 48.7
(CH), 55.8 (CH3), 55.9 (CH3), 67.3 (CH), 73.4 (CH2), 105.5 (CH),
114.5 (CH), 114.8 (C), 115.6 (1C, q, J = 288.2, C), 122.2 (CH), 125.6
(CH), 126.0 (CH), 127.5 (CH), 127.7 (CH), 127.8 (CH), 128.0
(CH), 129.0 (CH), 135.8 (C), 137.5 (C), 138.1 (C), 140.4 (C), 144.7
(C), 153.2 (C), 155.7 (C), 156.9 (1C, q, J = 37.2, C); 19F NMR (282
MHz, CDCl3) δ −76.4 (3F, s); MS (ES+) m/z 564 (20, M+ + H2), 563
(65, M+ + H), 472 (100, M+ − PhCH2), 433 (55, M+ − C3H4F3O2);
HRMS C32H30F3N2O4 calcd 563.2158, found 563.2131.
(1R*,2S*)-3-(2-Bromophenyl)-N1-(4-methoxyphenyl)-1-phenyl-
propane-1,2-diamine (13). A stirred suspension of β-aminoacetamide
7a (164 mg, 0.323 mmol) and KOH (272 mg, 4.85 mmol) in EtOH
N-((S*)-Furan-2-yl((S*)-indolin-2-yl)methyl)-4-methoxyaniline
(14b). β-Aminoacetamide 7b (92 mg, 0.18 mmol) afforded crude
T
dx.doi.org/10.1021/jo3010827 | J. Org. Chem. XXXX, XXX, XXX−XXX

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Featured Article
indoline 14b as a brown oil. Purification by flash column
chromatography (30% Et2O/petroleum ether) yielded pure indoline
14b as an off-white semisolid (41 mg, 69%): Rf 0.55 (30% Et2O/
petroleum ether); IR νmax (neat) 3365, 3112−2833, 1609, 1509, 1484,
1465, 1234, 1035 cm−1; 1H NMR (600 MHz, CDCl3) δ 3.18 (2H, d, J
= 8.0), 3.73 (3H, s), 4.24 (1H, q, J = 7.9), 4.41 (1H, d, J = 7.6), 6.27
(1H, d, J = 3.2), 6.33 (1H, dd, J = 3.2, 1.9), 6.59 (2H, dm, J = 8.9),
6.62 (1H, d, J = 7.7), 6.73−6.76 (3H, m), 7.05 (1H, t, J = 7.6), 7.10
(1H, d, J = 7.3), 7.39 (1H, dd, J = 1.7, 0.5); 13C NMR (151 MHz,
CDCl3) δ 33.3 (CH2), 55.8 (CH3), 57.1 (CH), 62.5 (CH), 107.9
(CH), 109.4 (CH), 110.4 (CH), 114.8 (CH), 115.6 (CH), 119.0
(CH), 125.0 (CH), 127.5 (CH), 128.1 (C), 141.3 (C), 142.2 (CH),
150.4 (C), 152.8 (C), 154.3 (C); MS (CI) m/z 321 (5, M+ + H), 320
(2, M+), 202 (17, M+ − C8H8N), 118 (100, M+ − C12H12NO2);
HRMS C20H21N2O2 calcd 321.1603, found 321.1607.
N-((R*)-Cyclohexyl((S*)-indolin-2-yl)methyl)-4-methoxyaniline
(14f). β-Aminoacetamide 7f (65 mg, 0.13 mmol) afforded crude
indoline 14f as a brown oil. Purification by flash column
chromatography (10% EtOAc/petroleum ether) yielded pure indoline
14f as an off-white solid (34 mg, 80%): mp 85−88 °C; Rf 0.39 (10%
EtOAc/petroleum ether); IR νmax (neat) 3384, 3051−2851, 1609,
1
1509, 1485, 1465, 1236, 1039 cm−1; H NMR (600 MHz, CDCl3) δ
1.12−1.32 (5H, m), 1.65−1.83 (6H, m), 2.88 (1H, dd, J = 16.0, 8.5),
3.14 (1H, dd, J = 16.0, 8.9), 3.34 (1H, dd, J = 8.1, 3.9), 3.75 (3H, s),
3.98 (1H, q, J = 8.6), 6.56 (2H, dm, J = 8.9), 6.61 (1H, d, J = 7.7), 6.71
(1H, t, J = 7.4), 6.75 (2H, dm, J = 8.6), 7.02 (1H, t, J = 7.7), 7.05 (1H,
d, J = 7.3); 13C NMR (151 MHz, CDCl3) δ 26.5 (CH2), 26.6 (CH2),
26.6 (CH2), 27.1 (CH2), 31.2 (CH2), 34.1 (CH2), 40.9 (CH), 55.9
(CH3), 61.9 (CH), 63.7 (CH), 109.5 (CH), 114.1 (CH), 115.0 (CH),
119.0 (CH), 124.8 (CH), 127.4 (CH), 128.9 (C), 143.6 (C), 150.7
(C), 151.7 (C); MS (ES+) m/z 337 (19, M+ + H), 214 (100, M+ −
NHPMP); HRMS C22H29N2O calcd 337.2280, found 337.2285. Anal.
Calcd for C22H28N2O: C, 78.53; H, 8.39; N, 8.33. Found: C, 78.07; H,
8.59; N, 7.75.
N-((R*)-Furan-3-yl((S*)-indolin-2-yl)methyl)-4-methoxyaniline
(14c). β-Aminoacetamide 7c (54 mg, 0.11 mmol) afforded crude
indoline 14c as a brown oil. Purification by flash column
chromatography (30% Et2O/petroleum ether) yielded pure indoline
14c as a pale brown semisolid (23 mg, 66%): Rf 0.30 (30% Et2O/
petroleum ether); IR νmax (neat) 3359, 3138−2832, 1609, 1510, 1485,
N-((R*)-1-((S*)-Indolin-2-yl)-2,2-dimethylpropyl)-4-methoxyani-
line (14g). β-Aminoacetamide 7g (58 mg, 0.12 mmol) afforded crude
indoline 14g as a brown oil. Purification by flash column
chromatography (10% EtOAc/petroleum ether) yielded pure indoline
14g as a colorless oil (32 mg, 87%): Rf 0.34 (10% EtOAc/petroleum
ether); IR νmax (neat) 3375, 3053−2832, 1610, 1509, 1486, 1466,
1
1466, 1239, 1035, 1020 cm−1; H NMR (600 MHz, CDCl3) δ 3.09
(1H, dd, J = 16.0, 8.8), 3.13 (1H, dd, J = 16.0, 8.0), 3.73 (3H, s), 4.14
(1H, q, J = 7.9), 4.33 (1H, d, J = 6.7), 6.42 (1H, d, J = 0.7), 6.58 (2H,
dm, J = 8.9), 6.61 (1H, d, J = 7.7), 6.72−6.75 (3H, m), 7.04 (1H, t, J =
7.6), 7.08 (1H, d, J = 7.3), 7.41 (1H, t, J = 1.5), 7.42 (1H, s); 13C
NMR (151 MHz, CDCl3) δ 32.8 (CH2), 55.0 (CH), 55.8 (CH3), 63.8
(CH), 109.1 (CH), 109.3 (CH), 114.8 (CH), 115.6 (CH), 119.1
(CH), 125.0 (CH), 125.7 (C), 127.5 (CH), 128.3 (C), 140.4 (CH),
141.6 (C), 143.7 (CH), 150.5 (C), 152.6 (C); MS (ESI+) m/z 320 (4,
M+), 202 (100, M+ − C8H8N), 118 (92, M+ − C12H12NO2); HRMS
C20H20N2O2 calcd 320.1519, found 320.1526.
1
1232, 1038 cm−1; H NMR (600 MHz, CDCl3) δ 1.06 (9H, s), 3.00
(1H, dd, J = 15.8, 9.9), 3.05 (1H, dd, J = 15.8, 8.9), 3.32 (1H, d, J =
4.9), 3.74 (3H, s), 4.23 (1H, td, J = 9.4, 4.8), 6.53−6.57 (3H, m), 6.69
(1H, t, J = 7.3), 6.73 (2H, dm, J = 8.9), 6.99 (1H, t, J = 7.6), 7.05 (1H,
d, J = 7.3); 13C NMR (151 MHz, CDCl3) δ 27.9 (CH3), 33.3 (CH2),
36.2 (C), 55.9 (CH3), 62.2 (CH), 66.9 (CH), 109.6 (CH), 114.2
(CH), 114.9 (CH), 118.9 (CH), 124.5 (CH), 127.3 (CH), 129.0 (C),
144.3 (C), 150.9 (C), 151.6 (C); MS (ES+) m/z 311 (43, M+ + H),
280 (92, M+ − OCH3), 192 (18, M+ − C8H8N), 188 (100, M+ −
NHPMP); HRMS C20H27N2O calcd 311.2123, found 311.2130.
N-((R*)-((S*)-Indolin-2-yl)(o-tolyl)methyl)-4-methoxyaniline
(14h). β-Aminoacetamide 7h (65 mg, 0.13 mmol) afforded crude
indoline 14h as a brown oil. Purification by flash column
chromatography (30% Et2O/petroleum ether) yielded pure indoline
14h as an off-white solid (32 mg, 74%): mp 47−50 °C; Rf 0.34 (30%
Et2O/petroleum ether); IR νmax (neat) 3355, 3053−2832, 1610, 1510,
N-((S*)-((S*)-Indolin-2-yl)(thiophene-2-yl)methyl)-4-methoxyani-
line (14d). β-Aminoacetamide 7d (165 mg, 0.322 mmol) afforded
crude indoline 14d as a brown oil. Purification by flash column
chromatography (30% Et2O/petroleum ether) yielded pure indoline
14d as an pale yellow solid (79 mg, 73%): mp 46−49 °C; Rf 0.33 (30%
Et2O/petroleum ether); IR νmax (neat) 3360, 3051−2832, 1609, 1508,
1
1483, 1465, 1233, 1035 cm−1; H NMR (600 MHz, CDCl3) δ 3.12
(1H, dd, J = 16.1, 9.0), 3.18 (1H, dd, J = 16.1, 7.9), 3.73 (3H, s), 4.00
(2H, br s), 4.18 (1H, q, J = 7.9), 4.63 (1H, d, J = 6.8), 6.59 (2H, dm, J
= 9.0), 6.63 (1H, d, J = 7.7), 6.73−6.76 (3H, m), 7.01 (1H, dd, J = 5.0,
3.5), 7.06 (2H, m), 7.10 (1H, d, J = 7.3), 7.24 (1H, dd, J = 5.0, 1.1);
13C NMR (151 MHz, CDCl3) δ 33.0 (CH2), 55.8 (CH3), 59.1 (CH),
64.9 (CH), 109.3 (CH), 114.8 (CH), 115.6 (CH), 119.1 (CH), 124.7
(CH), 124.8 (CH), 125.0 (CH), 127.1 (CH), 127.6 (CH), 128.1 (C),
141.3 (C), 146.3 (C), 150.3 (C), 152.8 (C); MS (CI) m/z 337 (30, M+
+ H), 253 (5, M+ − C4H3S), 218 (95, M+ − C8H8N), 123 (100, M+ −
C13H11NS), 118 (19, M+ − C12H12NOS); HRMS C20H21N2OS calcd
337.1375, found 337.1386. Anal. Calcd for C20H20N2OS: C, 71.40; H,
5.99; N, 8.33. Found: C, 71.46; H, 6.02; N, 8.10.
N-((R*)-1-((S*)-Indolin-2-yl)hexyl)-4-methoxyaniline (14e). β-
Aminoacetamide 7e (164 mg, 0.327 mmol) afforded crude indoline
14e as a brown oil. Purification by flash column chromatography (30%
Et2O/petroleum ether) yielded pure indoline 14e as an pale brown oil
(70 mg, 66%): Rf 0.48 (30% Et2O/petroleum ether); IR νmax (neat)
3370, 3052−2855, 1609, 1509, 1485, 1465, 1232, 1038 cm−1; 1H
NMR (600 MHz, CDCl3) δ 0.90 (3H, t, J = 5.7), 1.26−1.53 (7H, m),
1.66−1.71 (1H, m), 2.95 (1H, dd, J = 16.0, 8.5), 3.17 (1H, dd, J =
16.0, 9.3), 3.39 (1H, dt, J = 6.9, 5.0), 3.77 (3H, s), 4.05 (1H, td, J =
8.9, 5.8), 6.60 (2H, d, J = 8.8), 6.61 (1H, d, J = 7.9), 6.72 (1H, t, J =
7.4), 6.79 (2H, dm, J = 8.8), 7.04 (1H, t, J = 7.6), 7.09 (1H, d, J = 7.3);
13C NMR (151 MHz, CDCl3) δ 14.2 (CH3), 22.8 (CH2), 25.8 (CH2),
31.7 (CH2), 32.2 (CH2), 32.9 (CH2), 55.9 (CH3), 58.4 (CH), 62.5
(CH), 109.4 (CH), 114.6 (CH), 115.1 (CH), 118.8 (CH), 124.8
(CH), 127.5 (CH), 128.8 (C), 142.5 (C), 151.1 (C), 152.0 (C); MS
(CI) m/z 326 (23, M+ + H2), 325 (100, M+ + H), 324 (6, M+), 118
(15, M+ − C13H20NO); HRMS C21H29N2O calcd 325.2280, found
325.2282. Anal. Calcd for C21H28N2O: C, 77.74; H, 8.70; N, 8.63.
Found: C, 77.54; H, 8.73; N, 8.65.
1
1484, 1466, 1236, 1036 cm−1; H NMR (600 MHz, CDCl3) δ 2.45
(3H, s), 2.90 (1H, dd, J = 15.9, 8.8), 3.24 (1H, dd, J = 15.9, 8.8), 3.70
(3H, s), 3.75 (1H, br s), 4.18 (1H, q, J = 8.0), 4.20 (1H, br s), 4.64
(1H, d, J = 6.3), 6.43 (2H, dm, J = 8.9), 6.60 (1H, d, J = 7.7), 6.68
(2H, dm, J = 8.9), 6.73 (1H, t, J = 7.4), 7.04 (1H, t, J = 7.6), 7.09 (1H,
d, J = 7.3), 7.19−7.22 (3H, m), 7.52−7.54 (1H, m); 13C NMR (151
MHz, CDCl3) δ 19.7 (CH3), 32.3 (CH2), 55.8 (CH3), 58.0 (CH), 64.0
(CH), 109.2 (CH), 114.8 (CH), 115.1 (CH), 119.0 (CH), 125.0
(CH), 126.4 (CH), 126.8 (CH), 127.2 (CH), 127.5 (CH), 128.3 (C),
130.8 (CH), 135.6 (C), 139.2 (C), 142.0 (C), 150.7 (C), 152.3 (C);
MS (CI) m/z 345 (18, M+ + H), 226 (17, M+ − C8H8N), 220 (100,
M+ − C16H15NO); HRMS C23H25N2O calcd 345.1967, found
345.1950.
(10R*,10aS*)-N-(4-Methoxyphenyl)-10a,11-dihydro-10H-indolo-
[1,2-a]indol-10-amine (14i). Prepared using general procedure for the
synthesis of indolines except with 3.2 equiv NaOtBu and 3.2 equiv
K2CO3. β-Aminoacetamide 7i (73 mg, 0.12 mmol) afforded crude
indoline 14i as a brown oil. Purification by flash column
chromatography (20% EtOAc/petroleum ether) yielded pure indoline
14i as a yellow solid (34 mg, 83%): mp 47−50 °C; Rf 0.17 (20%
EtOAc/petroleum ether); IR νmax (neat) 3367, 3028−2832, 1592,
1
1509, 1478, 1456, 1233, 1036 cm−1; H NMR (600 MHz, CDCl3) δ
3.28 (1H, dd, J = 15.9, 8.6), 3.41 (1H, dd, J = 15.9, 9.5), 3.80 (3H, s),
4.58 (1H, td, J = 9.1, 5.5), 5.15 (1H, d, J = 5.3), 6.70 (2H, dm, J = 8.8),
6.86 (2H, dm, J = 8.8), 6.95−6.98 (2H, m), 7.19−7.23 (4H, m), 7.29
(1H, t, J = 7.8), 7.31 (1H, d, J = 7.4); 13C NMR (151 MHz, CDCl3) δ
35.7 (CH2), 55.9 (CH3), 63.8 (CH), 73.4 (CH), 113.2 (CH), 113.7
(CH), 115.2 (CH), 115.2 (CH), 122.1 (CH), 122.4 (CH), 125.2
(CH), 125.5 (CH), 127.8 (CH), 129.7 (CH), 132.5 (C), 133.4 (C),
U
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141.3 (C), 148.2 (C), 149.2 (C), 152.7 (C); MS (CI) m/z 329 (39, M+
(2H, d, J = 8.8), 6.66−6.68 (3H, m), 6.74 (1H, t, J = 7.4), 7.05−7.07
(2H, m), 7.41 (1H, t, J = 7.5), 7.54 (1H, t, J = 7.7), 7.75 (1H, d, J =
7.9), 7.99 (1H, d, J = 7.8); 13C NMR (151 MHz, CDCl3) δ 30.2
(CH2), 55.8 (CH3), 56.9 (CH), 64.3 (CH), 109.6 (CH), 114.7 (CH),
115.8 (CH), 119.4 (CH), 124.8 (1C, q, J = 274.3, C), 124.9 (CH),
126.7 (1C, q, J = 6.0, CH), 127.6 (CH), 127.7 (CH), 127.7 (1C, q, J =
29.5, C), 128.2 (C), 128.8 (CH), 132.6 (CH), 140.0 (C), 141.3 (C),
150.6 (C), 152.8 (C); 19F NMR (282 MHz, CDCl3) δ −58.1 (3F, s);
MS (CI) m/z 399 (100%, M+ + H), 398 (10, M+), 274 (19, M+ −
C7H10NO); HRMS C23H22F3N2O calcd 399.1679, found 399.1684.
N-((R*)-((S*)-Indolin-2-yl)(3-(trifluoromethyl)phenyl)methyl)-4-
methoxyaniline (14n). β-Aminoacetamide 7n (64 mg, 0.11 mmol)
afforded crude indoline 14n as a brown oil. Purification by flash
column chromatography (25% Et2O/petroleum ether) yielded pure
indoline 14n as a pale brown oil (26 mg, 59%): Rf 0.27 (25% Et2O/
petroleum ether); IR νmax (neat) 3359, 3053−2834, 1610, 1509, 1484,
1467, 1436, 1326, 1237, 1195, 1164, 1121, 1071, 1036 cm−1; 1H NMR
(600 MHz, CDCl3) δ 2.85 (1H, dd, J = 15.9, 8.9), 3.14 (1H, dd, J =
15.9, 9.2), 3.70 (3H, s), 4.21 (1H, m), 4.44 (1H, d, J = 6.0), 6.47 (2H,
d, J = 8.8), 6.63 (1H, d, J = 7.7), 6.70 (2H, d, J = 8.8), 6.74 (1H, t, J =
7.4), 7.04−7.07 (2H, m), 7.49 (1H, t, J = 7.7), 7.56 (1H, d, J = 7.6),
7.65 (1H, d, J = 7.7), 7.70 (1H, s); 13C NMR (151 MHz, CDCl3) δ
31.9 (CH2), 55.8 (CH3), 62.1 (CH), 65.1 (CH), 109.4 (CH), 114.8
(CH), 115.6 (CH), 119.4 (CH), 123.8 (1C, q, J = 3.6, CH), 124.6 (1C,
q, J = 272.3, C), 124.6 (1C, q, J = 3.6, CH), 125.0 (CH), 127.7 (CH),
127.9 (C), 129.4 (CH), 130.6 (CH), 131.2 (1C, q, J = 32.2, C), 141.2
(C), 142.5 (C), 150.3 (C), 152.7 (C); 19F NMR (282 MHz, CDCl3) δ
−62.8 (3F, s); MS (CI) m/z 399 (52, M+ + H), 398 (10, M+), 280
(84, M+ − C8H8N); HRMS C23H22F3N2O calcd 399.1679, found
399.1681.
+ H), 328 (14, M+), 220 (42, M+ − PMPH), 206 (46, M+
−
NHPMP); HRMS C22H21N2O calcd 329.1654, found 329.1649. Anal.
Calcd for C22H20N2O: C, 80.46; H, 6.14; N, 8.53. Found: C, 80.13; H,
6.13; N, 8.65.
N-((R*)-((S*)-Indolin-2-yl)(2-methoxyphenyl)methyl)-4-methox-
yaniline (14j). β-Aminoacetamide 7j (152 mg, 0.282 mmol) afforded
crude indoline 14j as a brown oil. Purification by flash column
chromatography (30% Et2O/petroleum ether) yielded pure indoline
14j as an off-white oily foam (57 mg, 56%): Rf 0.24 (30% Et2O/
petroleum ether); IR νmax (neat) 3361, 3030−2834, 1601, 1509, 1485,
1
1463, 1439, 1233, 1026 cm−1; H NMR (600 MHz, CDCl3) δ 2.89
(1H, dd, J = 15.9, 8.9), 3.18 (1H, dd, J = 16.0, 8.2), 3.70 (3H, s), 3.89
(3H, s), 4.39 (1H, q, J = 7.9), 4.68 (1H, s), 6.50 (2H, dm, J = 8.8),
6.59 (1H, d, J = 7.9), 6.69 (2H, dm, J = 8.9), 6.73 (1H, t, J = 7.0),
6.93−6.95 (2H, m), 7.04 (1H, t, J = 7.6), 7.08 (1H, d, J = 7.3), 7.25−
7.28 (1H, m), 7.40 (1H, d, J = 7.3); 13C NMR (151 MHz, CDCl3) δ
32.3 (CH2), 55.5 (CH3), 55.8 (CH3), 57.7 (CH), 62.4 (CH), 109.2
(CH), 110.8 (CH), 114.7 (CH), 115.3 (CH), 118.9 (CH), 121.0
(CH), 125.0 (CH), 127.4 (CH), 128.5 (CH), 128.5 (C), 128.6 (C),
128.9 (CH), 142.2 (C), 150.9 (C), 152.2 (C), 157.1 (C); MS (CI) m/z
361 (30, M+ + H), 342 (31, M+ − C8H8N), 123 (100, M+
−
C16H15NO), 118 (35, M+ − C15H16NO2); HRMS C23H25N2O2 calcd
361.1911, found 361.1916.
N-((R*)-((S*)-Indolin-2-yl)(3-methoxyphenyl)methyl)-4-methox-
yaniline (14k). β-Aminoacetamide 7k (140 mg, 0.261 mmol) afforded
crude indoline 14k as a brown oil. Purification by flash column
chromatography (30% Et2O/petroleum ether) yielded pure indoline
14k as an off-white solid (62 mg, 66%): mp 53−56 °C; Rf 0.29 (30%
Et2O/petroleum ether); IR νmax (neat) 3360, 3052−2833, 1608, 1585,
1509, 1483, 1465, 1436, 1233, 1036 cm−1; 1H NMR (600 MHz,
CDCl3) δ 2.93 (1H, dd, J = 16.0, 8.8), 3.18 (1H, dd, J = 16.0, 8.6),
3.71 (3H, s), 3.82 (3H, s), 4.14 (1H, q, J = 7.9), 4.20 (1H, br s), 4.33
(1H, d, J = 6.5), 6.51 (2H, dm, J = 8.9), 6.61 (1H, d, J = 7.7), 6.70
(2H, dm, J = 8.9), 6.74 (1H, t, J = 7.4), 6.85 (1H, dd, J = 8.2, 2.3), 7.00
(1H, s), 7.03 (1H, d, J = 7.5), 7.06 (1H, t, J = 7.6), 7.09 (1H, d, J =
7.2), 7.30 (1H, t, J = 7.9); 13C NMR (151 MHz, CDCl3) δ 32.4
(CH2), 55.3 (CH3), 55.8 (CH3), 62.2 (CH), 65.2 (CH), 109.2 (CH),
112.7 (CH), 112.8 (CH), 114.8 (CH), 115.4 (CH), 119.1 (CH), 119.4
(CH), 125.0 (CH), 127.5 (CH), 128.2 (C), 129.9 (CH), 141.8 (C),
143.3 (C), 150.5 (C), 152.4 (C), 160.1 (C); MS (EI) m/z 361 (5%,
M+ + H), 360 (8, M+); HRMS C23H24N2O2 calcd 360.1832, found
360.1835. Anal. Calcd for C23H24N2O2: C, 76.64; H, 6.71; N, 7.77.
Found: C, 76.42; H, 6.91; N, 7.81.
N-((R*)-((S*)-Indolin-2-yl)(4-methoxyphenyl)methyl)-4-methox-
yaniline (14l). β-Aminoacetamide 7l (54 mg, 0.10 mmol) afforded
crude indoline 14l as a brown oil. Purification by flash column
chromatography (15% EtOAc/petroleum ether) yielded pure indoline
14l as a pale brown oil (23 mg, 64%): Rf 0.23 (15% EtOAc/petroleum
ether); IR νmax (neat) 3363, 3052−2833, 1609, 1509, 1484, 1465,
1238, 1174, 1034 cm−1; 1H NMR (600 MHz, CDCl3) δ 2.93 (1H, dd,
J = 15.9, 8.8), 3.16 (1H, dd, J = 15.9, 8.6), 3.70 (3H, s), 3.82 (3H, s),
4.11 (1H, q, J = 8.0), 4.31 (1H, d, J = 6.5), 6.49 (2H, d, J = 8.9), 6.60
(1H, d, J = 7.7), 6.69 (2H, d, J = 8.8), 6.73 (1H, t, J = 7.4), 6.91 (2H,
d, J = 8.6), 7.04 (1H, t, J = 7.6), 7.08 (1H, d, J = 7.2), 7.33 (2H, d, J =
8.5); 13C NMR (151 MHz, CDCl3) δ 32.4 (CH2), 55.4 (CH3), 55.8
(CH3), 61.6 (CH), 65.4 (CH), 109.2 (CH), 114.3 (CH), 114.8 (CH),
115.4 (CH), 119.0 (CH), 125.0 (CH), 127.5 (CH), 128.1 (CH), 128.3
(C), 133.3 (C), 141.8 (C), 150.5 (C), 152.3 (C), 159.0 (C); MS (CI)
m/z 361 (4, M+ + H), 242 (100, M+ − C8H8N); HRMS C23H25N2O2
calcd 361.1911, found 361.1907.
N-((R*)-((S*)-Indolin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-4-
methoxyaniline (14o). β-Aminoacetamide 7o (178 mg, 0.309 mmol)
afforded crude indoline 14o as a brown oil. Purification by flash
column chromatography (30% Et2O/petroleum ether) yielded pure
indoline 14o as a pale brown solid (96 mg, 78%): mp 57−60 °C; Rf
0.37 (30% Et2O/petroleum ether); IR νmax (neat) 3358, 3054−2835,
1610, 1511, 1484, 1467, 1324, 1238, 1163, 1122, 1066, 1036, 1017
1
cm−1; H NMR (600 MHz, CDCl3) δ 2.85 (1H, dd, J = 16.0, 8.9),
3.16 (1H, dd, J = 15.9, 9.3), 3.72 (3H, s), 4.20 (1H, td, J = 9.0, 6.2),
4.46 (1H, d, J = 6.0), 6.46 (2H, dm, J = 8.9), 6.64 (1H, d, J = 7.6), 6.71
(2H, dm, J = 8.8), 6.76 (1H, t, J = 7.4), 7.06−7.09 (2H, m), 7.58 (2H,
d, J = 8.0), 7.65 (2H, d, J = 7.8); 13C NMR (151 MHz, CDCl3) δ 32.0
(CH2), 55.8 (CH3), 61.9 (CH), 65.1 (CH), 109.4 (CH), 114.8 (CH),
115.5 (CH), 119.4 (CH), 124.3 (1C, q, J = 272.0, C), 125.0 (CH),
125.9 (1C, q, J = 3.7, CH), 127.5 (CH), 127.7 (CH), 128.0 (C), 129.9
(1C, q, J = 32.4, C), 141.3 (C), 145.6 (C), 150.4 (C), 152.7 (C); 19F
NMR (282 MHz, CDCl3) δ −62.8 (3F, s); MS (CI) m/z 399 (13,
M+), 280 (100, M+ − C8H8N); HRMS C23H22F3N2O calcd 399.1679,
found 399.1671. Anal. Calcd for C23H21F3N2O: C, 69.34; H, 5.31; N,
7.03. Found: C, 68.95; H, 5.29; N, 6.81.
N-((R*)-((S*)-5-Fluoroindolin-2-yl)(phenyl)methyl)-4-methoxya-
niline (14p). β-Aminoacetamide 7p (57 mg, 0.11 mmol) afforded
crude indoline 14p as a brown oil. Purification by flash column
chromatography (10% EtOAc/petroleum ether) yielded pure indoline
14p as a pale yellow oily solid (19 mg, 50%): Rf 0.18 (10% EtOAc/
petroleum ether); IR νmax (neat) 3354, 3060−2833, 1511, 1488, 1451,
1
1236, 1036 cm−1; H NMR (600 MHz, CDCl3) δ 2.89 (1H, dd, J =
16.2, 8.8), 3.15 (1H, dd, J = 16.2, 8.8), 3.69 (3H, s), 4.18 (1H, dd, J =
15.3, 8.6), 4.36 (1H, d, J = 6.5), 6.48−6.51 (3H, m), 6.68 (2H, dm, J =
8.8), 6.73 (1H, td, J = 8.9, 2.1), 6.78 (1H, d, J = 8.3), 7.29 (1H, t, J =
7.2), 7.36 (2H, t, J = 7.5), 7.41 (2H, d, J = 7.4); 13C NMR (151 MHz,
CDCl3) δ 32.6 (CH2), 55.8 (CH3), 62.1 (CH), 65.9 (CH), 109.4 (1C,
d, J = 8.3, CH), 112.4 (1C, d, J = 23.9, CH), 113.4 (1C, d, J = 23.2,
CH), 114.8 (CH), 115.5 (CH), 127.1 (CH), 127.7 (CH), 128.9 (CH),
129.9 (1C, d, J = 8.1, C), 141.0 (C), 141.5 (C), 146.5 (C), 152.5 (C),
157.2 (1C, d, J = 235.5, C); 19F NMR (282 MHz, CDCl3) δ −126.4
(1F, m); MS (EI) m/z 348 (11, M+), 212 (100, M+ − C8H7FN), 136
(92, M+ − C14H14NO); HRMS C22H21FN2O calcd 348.1632, found
348.1624.
N-((R*)-((S*)-Indolin-2-yl)(2-(trifluoromethyl)phenyl)methyl)-4-
methoxyaniline (14m). β-Aminoacetamide 7m (29 mg, 50 μmol)
afforded crude indoline 14m as a brown oil. Purification by flash
column chromatography (10% EtOAc/petroleum ether) yielded pure
indoline 14m as a pale brown oil (13 mg, 65%): Rf 0.36 (10% EtOAc/
petroleum ether); IR νmax (neat) 3357, 3031−2834, 1609, 1511, 1484,
1467, 1308, 1246, 1238, 1162, 1116, 1035 cm−1; 1H NMR (600 MHz,
CDCl3) δ 2.60 (1H, dd, J = 15.8, 8.9), 3.29 (1H, dd, J = 15.3, 11.1),
3.69 (3H, s), 4.41 (1H, td, J = 9.5, 3.6), 4.91 (1H, d, J = 3.8), 6.48
V
dx.doi.org/10.1021/jo3010827 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
N-((R*)-((S*)-5,6-Dimethoxyindolin-2-yl)(phenyl)methyl)-4-me-
thoxyaniline (14q). β-Aminoacetamide 7q (136 mg, 0.240 mmol)
afforded crude indoline 14q as a brown oil. Purification by flash
column chromatography (80% Et2O/petroleum ether) yielded pure
indoline 14q as a pale yellow solid (45 mg, 48%): mp 58−61 °C; Rf
0.38 (70% Et2O/petroleum ether); IR νmax (neat) 3351, 3061−2833,
1509, 1481, 1464, 1237, 1195, 1175, 1109, 1034 cm−1; 1H NMR (600
MHz, CDCl3) δ 2.85 (1H, dd, J = 15.6, 8.9), 3.11 (1H, dd, J = 15.5,
8.7), 3.69 (3H, s), 3.81 (3H, s), 3.82 (3H, s), 4.14 (1H, q, J = 7.9),
4.37 (1H, d, J = 6.4), 6.30 (1H, s), 6.49 (2H, dm, J = 8.9), 6.68 (2H,
dm, J = 8.9), 6.70 (1H, s), 7.27−7.30 (1H, m), 7.36 (2H, t, J = 7.6),
7.42 (2H, d, J = 7.4); 13C NMR (151 MHz, CDCl3) δ 32.4 (CH2),
55.8 (CH3), 56.2 (CH3), 57.1 (CH3), 62.3 (CH), 66.0 (CH), 95.6
(CH), 110.2 (CH), 114.7 (CH), 115.4 (CH), 118.9 (C), 127.1 (CH),
127.6 (CH), 128.9 (CH), 141.4 (C), 141.8 (C), 142.7 (C), 144.3 (C),
dm, J = 9.0), 6.83−6.89 (3H, m), 7.61 (1H, br s); 1H NMRrotamerA (600
MHz, C6D6, 25 °C, 65:35 ratio of rotamers A:B) δ 0.71−1.65 (10H,
m), 1.83 (1H, d, J = 12.5), 2.28 (1H, d, J = 16.0), 2.57 (1H, dd, J =
16.0, 9.1), 3.31 (3H, s), 3.51 (1H, d, J = 8.0), 4.69 (1H, d, J = 8.6),
5.99 (2H, d, J = 8.4), 6.61 (2H, d, J = 8.8), 6.70−6.87 (3H, m), 8.01
(1H, d, J = 7.2); 1H NMRrotamerB (600 MHz, C6D6, 25 °C) δ 0.71−1.65
(10H, m), 1.87 (1H, br m), 2.25−2.27 (1H, m), 2.46−2.51 (1H, m),
3.35 (3H, s), 3.92 (1H, br s), 4.82 (1H, br s), 6.10 (2H, br s), 6.61
(2H, m), 6.70−6.87 (3H, m), 6.98−7.00 (1H, m); 13C NMRrotamerA
(151 MHz, C6D6, 25 °C) δ 26.3 (CH2), 26.4 (CH2), 26.5 (CH2), 29.3
(CH2), 30.1 (CH2), 30.6 (CH2), 41.1 (CH), 55.2 (CH3), 61.7 (CH),
63.7 (CH), 113.8 (CH), 115.0 (CH), 117.2 (1C, q, J = 288.4, C),
119.4 (CH), 123.1 (CH), 125.5 (CH), 127.5 (CH), 131.9 (C), 142.5
(C), 143.2 (C), 152.5 (C), 154.0 (1C, q, J = 36.6, C); 13C NMRrotamerB
(151 MHz, C6D6, 25 °C) δ 26.3 (CH2), 26.4 (CH2), 26.5 (CH2), 27.7
(CH2), 30.0 (CH2), 30.2 (CH2), 40.6 (CH), 55.3 (CH3), 58.9 (CH),
65.1 (CH), 113.8 (CH), 115.0 (CH), 115.8 (CH), 124.7 (CH), 125.1
(CH), 127.3 (CH), 133.6 (C), 140.0 (C), 152.5 (C), the remaining
signals could not be determined; 19F NMRrotamerA (282 MHz, C6D6, 25
°C) δ −69.5 (3F, s); 19F NMRrotamerB (282 MHz, C6D6, 25 °C) δ
−70.6 (3F, s); MS (CI) m/z 434 (26, M+ + H2), 433 (100, M+ + H),
432 (16, M+), 218 (15, M+ − C10H7F3NO); HRMS C24H28F3N2O2
calcd 433.2103, found 433.2106.
2,2,2-Trifluoro-1-((S*)-2-((R*)-1-((4-methoxyphenyl)amino)-2,2-
dimethylpropyl)indolin-1-yl)ethanone (21). Formed as a byproduct
during the synthesis of tetrahydroquinoline 18g. β-Aminoacetamide 7g
(94 mg, 0.19 mmol) afforded crude indoline 21 as a dark brown oil.
Purification by flash column chromatography (10% EtOAc/petroleum
ether) yielded pure indoline 21 as a pale brown oil (30 mg, 38%): Rf
0.38 (10% EtOAc/petroleum ether); IR νmax (neat) 3410, 2957−2833,
1672, 1510, 1230, 1199, 1170, 1143 cm−1; 1H NMR (400 MHz, C6D6,
90 °C) δ 0.92 (9H, s), 2.69 (1H, dd, J = 16.2, 1.5), 2.81 (1H, dd, J =
16.2, 9.0), 3.38 (3H, s), 3.77 (1H, s), 4.99 (1H, d, J = 8.5), 6.05 (2H,
br s), 6.53 (2H, dm, J = 9.0), 6.76−6.85 (3H, m), 7.45 (1H, br s); 1H
NMRrotamerA (600 MHz, C6D6, 25 °C, 55:45 ratio of rotamers A:B) δ
0.80 (9H, s), 2.59 (1H, d, J = 15.7), 2.66 (1H, dd, J = 16.1, 8.6), 3.30
(3H, s), 3.58 (1H, s), 4.82 (1H, d, J = 7.7), 5.99 (2H, d, J = 6.5), 6.55
(2H, d, J = 8.9), 6.66−6.81 (3H, m), 8.01 (1H, d, J = 6.5); 1H
NMRrotamerB (600 MHz, C6D6, 25 °C) δ 0.93 (9H, s), 2.46 (1H, d, J =
16.2), 2.56 (1H, dd, J = 16.4, 9.4), 3.32 (3H, s), 3.94 (1H, s), 4.94
(1H, d, J = 6.8), 6.03 (2H, br s), 6.55 (2H, d, J = 8.9), 6.66−6.81 (3H,
m), 6.95 (1H, d, J = 7.7); 13C NMRrotamerA (151 MHz, C6D6, 25 °C) δ
27.9 (CH3), 30.9 (CH2), 35.7 (C), 55.2 (CH3), 61.5 (CH), 67.5 (CH),
114.0 (CH), 114.9 (CH), 117.1 (1C, q, J = 288.3, C), 119.5 (CH),
122.9 (CH), 125.6 (CH), 127.5 (CH), 132.0 (C), 139.6 (C), 142.9
(C), 152.7 (C), 154.1 (1C, q, J = 36.6, C); 13C NMRrotamerB (151 MHz,
C6D6, 25 °C) δ 27.8 (CH3), 28.9 (CH2), 35.7 (C), 55.3 (CH3), 63.5
(CH), 64.4 (CH), 114.1 (CH), 114.9 (CH), 115.4 (CH), 116.9 (1C, q,
J = 286.2, C), 124.5 (CH), 125.1 (CH), 127.3 (CH), 133.7 (C), 139.6
(C), 143.4 (C), 152.7 (C), 153.7 (1C, q, J = 39.1, C); 19F NMRrotamerA
(282 MHz, C6D6, 25 °C) δ −69.2 (3F, s); 19F NMRrotamerB (282 MHz,
C6D6, 25 °C) δ −70.8 (3F, s); MS (CI) m/z 407 (55, M+ + H), 192
(100, M+ − C10H7F3NO); HRMS C22H26F3N2O2 calcd 407.1946,
found 407.1949.
149.0 (C), 152.3 (C); MS (EI) m/z 390 (4, M+), 213 (37, M+
C10H11NO2), 212 (47, M+ − C10H12NO2), 178 (100, M+
−
−
C14H14NO); HRMS C24H26N2O3 calcd 390.1938, found 390.1942.
Anal. Calcd for C24H26N2O3: C, 73.82; H, 6.71; N, 7.17. Found: C,
73.46; H, 6.73; N, 6.94.
N-((R*)-((S*)-5,6-Dimethoxyindolin-2-yl)(2-methoxyphenyl)-
methyl)-4-methoxyaniline (14r). β-Aminoacetamide 7r (61 mg, 0.10
mmol) afforded crude indoline 14r as a brown oil. Purification by flash
column chromatography (70% Et2O/petroleum ether) yielded pure
indoline 14r as an off-white solid (18 mg, 42%): mp 65−68 °C; Rf 0.52
(70% Et2O/petroleum ether); IR νmax (neat) 3357, 2997−2834, 1509,
1
1489, 1463, 1236, 1195, 1029 cm−1; H NMR (600 MHz, CDCl3) δ
2.83 (1H, dd, J = 15.6, 9.0), 3.10 (1H, dd, J = 15.7, 8.1), 3.69 (3H, s),
3.81 (3H, s), 3.82 (3H, s), 3.88 (3H, s), 4.36 (1H, td, J = 8.3, 6.7), 4.67
(1H, d, J = 6.1), 6.28 (1H, s), 6.49 (2H, dm, J = 8.9), 6.68 (2H, dm, J
= 8.9), 6.71 (1H, s), 6.91−6.93 (2H, m), 7.25 (1H, td, J = 7.8, 1.6),
7.38 (1H, d, J = 7.4); 13C NMR (151 MHz, CDCl3) δ 32.5 (CH2),
55.5 (CH3), 55.8 (CH3), 56.2 (CH3), 57.1 (CH3), 57.9 (CH), 63.0
(CH), 95.7 (CH), 110.3 (CH), 110.8 (CH), 114.7 (CH), 115.3 (CH),
119.3 (C), 120.9 (CH), 128.4 (CH), 128.6 (C), 128.9 (CH), 142.2
(C), 142.6 (C), 144.7 (C), 148.9 (C), 152.2 (C), 157.1 (C); MS (EI)
m/z 420 (10, M+), 243 (51, M+ − C10H11NO2), 242 (100, M+
−
C10H12NO2), 178 (31, M+ − C15H16NO2); HRMS C25H28N2O4 calcd
420.2044, found 420.2041.
N-((R*)-((S*)-7-(Benzyloxy)-6-methoxyindolin-2-yl)(phenyl)-
methyl)-4-methoxyaniline (14s). β-Aminoacetamide 7s (67 mg, 0.10
mmol) afforded crude indoline 14s as a brown oil. Purification by flash
column chromatography (10% EtOAc/petroleum ether) yielded pure
indoline 14s as a pale yellow oily solid (28 mg, 58%): Rf 0.17 (10%
EtOAc/petroleum ether); IR νmax (neat) 3365, 3064−2835, 1622,
1511, 1495, 1465, 1454, 1266, 1237, 1090, 1038 cm−1; 1H NMR (600
MHz, CDCl3) δ 2.79 (1H, dd, J = 15.4, 8.6), 3.10 (1H, dd, J = 15.4,
9.1), 3.70 (3H, s), 3.86 (3H, s), 3.98 (1H, m), 4.29 (1H, d, J = 6.1),
4.99 (2H, q, J = 10.4), 6.30 (1H, d, J = 7.9), 6.48 (2H, d, J = 8.6), 6.69
(2H, d, J = 8.2), 6.73 (1H, d, J = 7.9), 7.29−7.39 (10H, m); 13C NMR
(151 MHz, CDCl3) δ 32.1 (CH2), 55.8 (CH3), 56.2 (CH3), 62.2
(CH), 66.3 (CH), 74.6 (CH2), 102.7 (CH), 114.7 (CH), 115.6 (CH),
119.7 (CH), 122.2 (C), 127.1 (CH), 127.6 (CH), 128.2 (CH), 128.5
(CH), 128.6 (CH), 128.8 (CH), 132.1 (C), 138.1 (C), 141.1 (C),
141.5 (C), 144.8 (C), 152.4 (C), 152.5 (C); MS (ES+) m/z 467 (5, M+
+ H), 344 (100, M+ − NHPMP), 253 (33%, M+ − C14H15NO);
HRMS C30H31N2O3 calcd 467.2315, found 467.2335.
1-((S*)-2-((R*)-Cyclohexyl((4-methoxyphenyl)amino)methyl)-
indolin-1-yl)-2,2,2-trifluoroethanone (20). Formed as a byproduct
during the synthesis of tetrahydroquinoline 18f. Prepared using the
general procedure for the preparation of 3-aminotetrahydroquinolines
except with 10 mol % Pd(PPh3)4. β-Aminoacetamide 7f (63 mg, 0.12
mmol) afforded crude indoline 20 as a pale brown oil. Purification by
flash column chromatography (10% Et2O/petroleum ether) yielded
pure indoline 20 as a pale brown oil (10 mg, 15%): Rf 0.31 (10%
EtOAc/petroleum ether); IR νmax (neat) 3393, 3035−2853, 1677,
1509, 1249, 1229, 1200, 1179, 1144 cm−1; 1H NMR (400 MHz, C6D6,
90 °C) δ 1.10−1.37 (6H, m), 1.57−1.66 (4H, m), 1.87 (1H, d, J =
13.0), 2.52 (1H, d, J = 16.1), 2.76 (1H, dd, J = 16.1, 9.2), 3.40 (3H, s),
3.69 (1H, br s), 4.83 (1H, d, J = 8.6), 6.06 (2H, d, J = 8.4), 6.58 (2H,
(2R*,3S*)-2-(2-Bromophenyl)-1-(4-methoxyphenyl)-1,2,3,4-tetra-
hydroquinolin-3-amine (23). Prepared using the same procedure that
was used for the preparation of 1,2-diamine 13. Tetrahydroquinoline
18i (82 mg, 0.16 mmol) afforded crude primary amine 23 as a pale
brown solid. Purification by passing through a short plug of silica and
eluting with EtOAc yielded pure primary amine 23 as an off-white
solid (57 mg, 87%): Rf 0.19 (50% EtOAc/petroleum ether); IR νmax
(neat) 3363, 3062−2836, 1600, 1507, 1491, 1456, 1439, 1241, 1034,
1
1021 cm−1; H NMR (600 MHz, CDCl3) δ 2.62 (1H, d, J = 16.3),
2.86 (1H, dd, J = 16.3, 3.8), 3.57 (1H, d, J = 2.3), 3.79 (3H, s), 4.92
(1H, s), 6.55 (1H, d, J = 8.3), 6.72 (1H, t, J = 7.3), 6.86 (2H, d, J =
8.8), 7.01 (1H, t, J = 7.6), 7.07 (1H, d, J = 7.3), 7.11 (1H, td, J = 7.4,
1.3), 7.13 (2H, d, J = 8.5), 7.25 (1H, t, J = 7.4), 7.45 (1H, dd, J = 7.8,
1.0), 7.51 (1H, d, J = 7.7); 13C NMR (151 MHz, CDCl3) δ 31.5
(CH2), 46.7 (CH), 55.5 (CH3), 71.2 (CH), 112.8 (CH), 115.1 (CH),
117.6 (CH), 117.7 (C), 122.4 (C), 127.4 (CH), 127.7 (CH), 128.7
W
dx.doi.org/10.1021/jo3010827 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
(CH), 128.9 (CH), 129.0 (CH), 130.9 (CH), 133.2 (CH), 139.5 (C),
141.7 (C), 144.4 (C), 157.5 (C); MS (EI) m/z 409 + 411 (1:1, 25, M+
+ H), 408 + 410 (1:1, 100, M+); HRMS C22H21(79Br)N2O calcd
408.0832, found 408.0836.
Shibasaki, M. J. Am. Chem. Soc. 2007, 129, 4900. (c) Handa, S.;
Gnanadesikan, V.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2010,
132, 4925.
(7) For asymmetric organocatalytic examples, see: (a) Okino, T.;
Nakamura, S.; Furukawa, T.; Takemoto, Y. Org. Lett. 2004, 6, 625.
(b) Nugent, B. M.; Yoder, R. A.; Johnston, J. N. J. Am. Chem. Soc.
2004, 126, 3418. (c) Yoon, T. P.; Jacobsen, E. N. Angew. Chem., Int.
Ed. 2005, 44, 466. (d) Fini, F.; Sgarzani, V.; Petterson, D.; Herrera, R.
P.; Bernardi, L.; Ricci, A. Angew. Chem., Int. Ed. 2005, 44, 7975.
(5aR*,10aS*)-5-(4-Methoxyphenyl)-5a,10,10a,11-tetrahydro-5H-
indolo[3,2-b]quinoline (22). Prepared using the same procedure that
was used for the preparation of indoline 14a. Primary amine 23 (52
mg, 0.13 mmol) afforded crude tetrahydroindoloquinoline 22 as a
black oil. Purification by flash column chromatography (15% EtOAc/
petroleum ether) yielded pure tetrahydroindoloquinoline 22 as an off-
white solid (17 mg, 40%): mp 175−180 °C dec; Rf 0.49 (15% EtOAc/
petroleum ether); IR νmax (neat) 3351, 3052−2774, 1607, 1508, 1485,
1461, 1453, 1324, 1241, 1220, 1033 cm−1; 1H NMR (600 MHz,
CDCl3) δ 3.21 (1H, dd, J = 14.8, 4.9), 3.44 (1H, t, J = 13.4), 3.92 (3H,
s), 4.05 (1H, td, J = 11.7, 4.9), 4.66 (1H, d, J = 11.2), 5.93 (1H, d, J =
7.6), 6.36 (1H, d, J = 8.3), 6.55 (1H, t, J = 7.5), 6.77 (1H, t, J = 7.3),
6.79 (1H, d, J = 8.5), 6.98 (1H, t, J = 7.7), 7.04−7.06 (3H, m), 7.15
(1H, d, J = 7.4), 7.30 (2H, d, J = 8.8); 13C NMR (151 MHz, CDCl3) δ
35.5 (CH2), 55.6 (CH3), 63.7 (CH), 66.3 (CH), 111.1 (CH), 115.1
(CH), 115.8 (CH), 118.7 (CH), 119.6 (CH), 121.3 (C), 124.7 (CH),
127.2 (CH), 128.0 (CH), 129.0 (C), 130.7 (CH), 131.3 (CH), 138.6
(C), 148.4 (C), 150.8 (C), 158.7 (C); MS (EI) m/z 329 (18, M+ + H),
328 (100, M+), 327 (34, M+ − H); HRMS C22H20N2O calcd
328.1570, found 328.1568.
́
(e) Palomo, C.; Oiarbibe, M.; Laso, A.; Lopez, R. J. Am. Chem. Soc.
2005, 127, 17622. (f) Xu, X.; Furukawa, T.; Okino, T.; Miyabe, H.;
Takemoto, Y. Chem.Eur. J. 2006, 12, 466. (g) Robak, M. T.;
Trincado, M.; Ellman, J. A. J. Am. Chem. Soc. 2007, 129, 15110.
(h) Wang, C.-J.; Dong, X.-Q.; Zhang, Z.-H.; Xue, Z.-Y.; Teng, H.-L. J.
Am. Chem. Soc. 2008, 130, 8606.
(8) (a) Tsuritani, N.; Tamada, K.-I.; Yoshikawa, N.; Sibasaki, M.
Chem. Lett. 2002, 276. (b) Jakubec, P.; Cockfield, D. M.; Dixon, D. J.
Am. Chem. Soc. 2009, 131, 16632. (c) Weng, J.; Li, Y.-B.; Wang, R.-B.;
Li, F.-Q.; Liu, C.; Chan, A. S. C.; Lu, Gui. J. Org. Chem. 2010, 75, 3125.
(d) Xie, H.; Zhang, Y.; Zhang, S.; Chen, X.; Wang, W. Angew. Chem.,
Int. Ed. 2011, 50, 11773. (e) Davis, T. A.; Johnston, J. N. Chem. Sci.
2011, 2, 1076.
(9) Anderson, J. C.; Stepney, G. J.; Mills, M. R.; Horsfall, L. R.; Blake,
A. J.; Lewis, W. J. Org. Chem. 2011, 76, 1961.
(10) Anderson, J. C.; Blake, A. J.; Koovits, P. J.; Stepney, G. J. J. Org.
Chem. 2012, 77, 4711.
ASSOCIATED CONTENT
■
S
* Supporting Information
(11) For examples of tetrahydroquinolines, see: (a) Katritzky, A. R.;
Rachwal, S.; Rachwal, B. Tetrahedron 1996, 52, 15031. (b) Fabio, R.
D.; Tranquillini, E.; Bertani, B.; Alvaro, G.; Micheli, F.; Sabbatini, F.;
Pizzi, M. D.; Pentassuglia, G.; Pasquarello, A.; Messeri, T.; Donati, D.;
Ratti, E.; Arban, R.; Forno, G. D.; Reggiani, A.; Barnaby, R. J. Bioorg.
Med. Chem. Lett. 2003, 13, 3863. (c) Wallace, O. B.; Lauwers, S. A.;
Jones, S. A.; Dodge, J. A. Bioorg. Med. Chem. Lett. 2003, 13, 1907.
(d) Rano, T. A.; Sieber-McMaster, E.; Pelton, P. D.; Yang, M.;
Demarest, K. T.; Kuo, G.-H. Bioorg. Med. Chem. Lett. 2009, 19, 2456.
(e) Nallan, L.; Bauer, K. D.; Bendale, P.; Rivas, K.; Yokoyama, K.;
General experimental details, X-ray representations, and copies
of H and 13C NMR spectra. This material is available free of
1
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: j.c.anderson@ucl.ac.uk.
†Corresponding author for crystallographic results.
■
́
Horney, C. P.; Pendyala, P. R.; Floyd, D.; Lombardo, L. J.; Williams,
D. K.; Hamilton, A.; Sebti, S.; Windsor, W. T.; Weber, P. C.; Buckner,
F. S.; Chakrabarti, D.; Gelb, M. H.; Van Voorhis, W. C. J. Med. Chem.
2005, 48, 3704. (f) Wang, T.; Zhuo, L.-G.; Li, Z.; Chen, F.; Ding, Z.;
He, Y.; Fan, Q.-H.; Xiang, J.; Yu, Z.-X.; Chan, A. S. C. J. Am. Chem. Soc.
ACKNOWLEDGMENTS
■
We thank Dr. Ian Campbell and Mr. Sebastien Campos for
discussions, the EPSRC and GSK for funding, Dr. L. Harris for
mass spectra, and Ms. J. Maxwell for microanalytical data.
2011, 133, 9878. (g) Sridharan, V.; Suryavanshi, P. A.; Menen
Chem. Rev. 2011, 111, 7157. (h) Sridharan, V.; Suryavanshi, P. A.;
Menendez, J. C. Chem. Rev. 2011, 111, 7157.
́
dez, J. C.
REFERENCES
́
■
(12) For examples of indolines, see: (a) Boger, D. L.; Boyce, C. W.;
Garbaccio, R. M.; Goldberg, J. A. Chem. Rev. 1997, 97, 787.
(b) Sunazuka, T.; Hirose, T.; Shirahata, T.; Harigaya, Y.; Hayashi,
M.; Komiyama, K.; Omura, S. J. Am. Chem. Soc. 2000, 122, 2122.
(c) Gan, Z.; Reddy, P. T.; Quevillon, S.; Couve-Bonnaire, S.; Arya, P.
Angew. Chem., Int. Ed. 2005, 44, 1366. (d) Dounay, A. B.; Overman, L.
E.; Wrobleski, A. D. J. Am. Chem. Soc. 2005, 127, 10186. (e) Nicolaou,
K. C.; Rao, P. B.; Hao, J.; Reddy, M. V.; Rassias, G.; Huang, X.; Chen,
D. Y.-K.; Snyder, S. A. Angew. Chem., Int. Ed. 2003, 42, 1753.
(f) Bermudez, J.; Dabbs, S.; Joiner, K. A.; King, F. D. J. Med. Chem.
1990, 33, 1929. (g) Bromidge, S. M.; Duckworth, M.; Forbes, I. T.;
Ham, P.; King, F. D.; Thewlis, K. M.; Blaney, F. E.; Naylor, C. B.;
Blackburn, T. P.; Kennett, G. A.; Wood, M. D.; Clarke, S. E. J. Med.
Chem. 1997, 40, 3494. (h) Hobson, L. A.; Nugent, W. A.; Anderson, S.
R.; Deshmukh, S. S.; Haley, J. J., III; Liu, P.; Magnus, N. A.; Sheeran,
P.; Sherbine, J. P.; Stone, B. R. P.; Zhu, J. Org. Process Res. Dev. 2007,
11, 985.
(1) For a review, see: Marques
́
-Lop
́
ez, E.; Merino, P.; Tejero, T.;
Herrera, R. P. Eur. J. Org. Chem. 2009, 2401.
(2) For α-aminocarbonyl compounds, see: (a) Ballini, R.; Petrini, M.
Tetrahedron 2004, 60, 1017. (b) Palomo, C.; Oiarbibe, M.; Halder, R.;
Laso, A.; Lopez, R. Angew. Chem., Int. Ed. 2006, 45, 117. For the
́
synthesis of 1,2-diamines, see: (c) Adams, H.; Anderson, J. C.; Peace,
S.; Pennell, A. M. K. J. Org. Chem. 1998, 63, 9932. (d) Bernardi, L.;
̀
Bonini, B. F.; Capito, E.; Dessole, G.; Comes-Franchini, M.; Fochi, M.;
Ricci, A. J. Org. Chem. 2004, 69, 8168. (e) Sturgess, A. M.; Yarberry, D.
J. Tetrahedron Lett. 1993, 34, 4743. For peptide synthesis, see:
(f) Shen, B.; Makley, D. M.; Johnston, J. N. Nature 2010, 465, 1027.
(3) Henry, L. Bull. Acad. R. Belg. 1896, 32, 33.
(4) See ref 2c and: Anderson, J. C.; Peace, S.; Pih, S. Synlett 2000,
850.
(5) For asymmetric transition-metal-catalyzed examples, see ref 2b
and: (a) Yamada, K.-I.; Shibasaki, M. Synlett 2001, 980. (b) Knudsen,
K. R.; Risgaard, T.; Nishiwaki, N.; Gothelf, K. V.; Jørgensen, K. A. J.
Am. Chem. Soc. 2001, 123, 5843. (c) Anderson, J. C.; Howell, G. P.;
Lawrence, R. M.; Wilson, C. S. J. Org. Chem. 2005, 70, 5665. (d) Trost,
B. M.; Lupton, D. W. Org. Lett. 2007, 9, 2023. (e) Chen, Z.;
Morimoto, H.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2008,
130, 2170.
(13) Hanessian, S.; Seida, M.; Nilssona, I. Tetrahedron Lett. 2002, 43,
1991.
(14) Gowda, S.; Gowda, D. C. Tetrahedron 2002, 58, 2211.
(15) Sohtome, Y.; Kato, Y.; Handa, S.; Aoyama, N.; Nagawa, K.;
Matsunaga, S.; Shibasaki, M. Org. Lett. 2008, 10, 2231.
(16) (a) Yasuhara, T.; Nishimura, K.; Yamashita, M.; Fukuyama, N.;
Yamada, K.-I.; Muraoka, O.; Tomioka, K. Org. Lett. 2003, 5, 1123.
(b) Wurz, R. P.; Charette, A. B. J. Org. Chem. 2004, 69, 1262.
(6) For asymmetric lanthanide-catalyzed examples, see: (a) Yamada,
K.-I.; Harwood, S. J.; Groger, H.; Shibasaki, M. Angew. Chem., Int. Ed.
̈
1999, 38, 3504. (b) Handa, S.; Gnanadesikan, V.; Matsunaga, S.;
X
dx.doi.org/10.1021/jo3010827 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
(17) (a) Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew. Chem.,
Int. Ed. 1995, 34, 1348. (b) Louie, J.; Hartwig, J. F. Tetrahedron Lett.
1995, 36, 3609.
(18) For selected examples, see ref 17a and: (a) Wolfe, J. P.; Rennels,
R. A.; Buchwald, S. L. Tetrahedron 1996, 52, 7525. (b) Deboves, H. J.
C.; Hunter, C.; Jackson, R. F. W. J. Chem. Soc., Perkin Trans. 1 2002,
733. (c) Wagaw, S.; Rennels, R. A.; Buchwald, S. L. J. Am. Chem. Soc.
1997, 119, 8451. (d) Peat, A. J.; Buchwald, S. L. J. Am. Chem. Soc.
1996, 118, 1028. (e) Coleman, R. S.; Chen, W. Org. Lett. 2001, 3,
1141. (f) Luo, X.; Chenard, E.; Martens, P.; Cheng, Y.-X.;
Tomaszewshi, M. J. Org. Lett. 2010, 12, 3574. (g) Lemen, G. S.;
Wolfe, J. P. Org. Lett. 2011, 13, 3218.
(19) For selective intermolecular N-arylations of poly- and diamines,
see: (a) Beletskaya, I. P; Bessmertnykh, A. G.; Guilard, R. Tetrahedron
Lett. 1997, 38, 2287. (b) Hong, Y.; Tanoury, G. J.; Wilkinson, H. S.;
Bakale, R. P.; Wald, S. A.; Senanayake, C. H. Tetrahedron Lett. 1997,
38, 5607. (c) Hong, Y.; Senanayake, C. H.; Xiang, T.; Vandenbossche,
C. P.; Tanoury, G. J.; Bakale, R. P.; Wald, S. A. Tetrahedron Lett. 1998,
39, 3121. (d) Beletskaya, I. P; Bessmertnykh, A. G.; Guilard, R. Synlett
1999, 1459. (e) Parrot, I.; Ritter, G.; Wermuth, C. G.; Hibert, M.
Synlett 2002, 1123. (f) Beletskaya, I. P.; Bessmertnykh, A. G.; Averin,
A. D.; Denat, F.; Guilard, R. Eur. J. Org. Chem. 2005, 261. (g) Cabello-
Sanchez, N.; Jean, L.; Maddaluno, J.; Lasne, M.-C.; Rouden, J. J. Org.
Chem. 2007, 72, 2030.
(20) (a) Beletskaya, I. P.; Averin, A. D.; Borisenko, A. A.; Denat, F.;
Guilard, R. Tetrahedron Lett. 2003, 44, 1433. (b) Beletskaya, I. P.;
Averin, A. D. Pure Appl. Chem. 2004, 76, 1605. (c) Alexei, D.; Averin,
A. D.; Ranyuk, E. R.; Lukashev, N. V.; Beletskaya, I. P. Chem.Eur. J.
2005, 11, 7030. (d) Beletskaya, I. P.; Averin, A. D.; Pleshkova, N. A.;
Borisenko, A. A.; Serebryakova, M. V.; Denat, F.; Guilard, R. Synlett
2005, 87. (e) Beletskaya, I. P.; Bessmertnykh, A. G.; Averin, A. D.;
Denat, F.; Guilard, R. Eur. J. Org. Chem. 2005, 281.
(21) Anderson, J. C.; Chapman, H. A. Synthesis 2006, 3309.
Y
dx.doi.org/10.1021/jo3010827 | J. Org. Chem. XXXX, XXX, XXX−XXX