Scope of the organocatalysed asymmetric reductive amination of ketones with trichlorosilane

Article abstract of DOI:10.1039/c1ob05965c

A highly active organocatalyst has been shown to affect the asymmetric reductive amination of ketones producing both aromatic and aliphatic amines. At 1 mol% catalyst loading, a series of structurally diverse chiral amines were quickly and economically prepared with good enantioselectivity and generally useful yield. The efficient synthesis of the calcimimetic (+)-NPS R-568 (67%, 89% ee) demonstrated the synthetic applicability of this methodology.

Full text of DOI:10.1039/c1ob05965c

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PAPER
Scope of the organocatalysed asymmetric reductive amination of ketones with
trichlorosilane†
a
a
a
b
Fran c¸ ois-Moana Gautier, Simon Jones,* Xianfu Li and Stephen J. Martin
Received 15th June 2011, Accepted 24th August 2011
DOI: 10.1039/c1ob05965c
A highly active organocatalyst has been shown to affect the asymmetric reductive amination of ketones
producing both aromatic and aliphatic amines. At 1 mol% catalyst loading, a series of structurally
diverse chiral amines were quickly and economically prepared with good enantioselectivity and
generally useful yield. The efficient synthesis of the calcimimetic (+)-NPS R-568 (67%, 89% ee)
demonstrated the synthetic applicability of this methodology.
Introduction
variety of imines in excellent yields and enantioselectivities at
very low catalyst loading. We also found that catalyst 1 did
9
Chiral amines are found in a vast array of natural products and
pharmaceutically active molecules. The asymmetric reduction
not reduce ketones with trichlorosilane, and with this in mind,
envisioned developing a quick and cost effective process for the
asymmetric reductive amination of ketones. Herein, we describe
our efforts towards this goal using an array of ketones employing
trichlorosilane with catalyst 1 at unprecedented low catalyst
loading.
1
of imines has proved to be an efficient route to access such
2,3
compounds, but can be hampered by the sometimes non-trivial
preparation and stability of the imine precursors, resulting in low
overall yields. An alternative strategy using asymmetric reductive
amination provides a convenient alternative that circumvents this
problem. It is not surprising that the development of such a
reaction has been a sought-after goal, and a few groups have
reported breakthroughs using both transition-metal catalysed
Results and discussion
Acetophenone 2 and p-anisidine 3 were used as standard substrates
for optimization of the reaction conditions, starting with previ-
4
hydrogenation and organocatalysed reduction with Hantzsch
3b,5
esters as the hydride source. In contrast, the organocatalysed
asymmetric reduction of imines employing trichlorosilane has
been less studied in this respect. In 2007, Malkov et al. described
a process for the direct synthesis of chiral a-chloroamines from
chloroketones and an aromatic amine, where the ketimine was
prepared in situ before addition of the catalyst and reductant.
More recently, the first example of direct asymmetric reductive
amination using trichlorosilane activated by an organic catalyst at
ously optimized conditions for the direct imine reduction (Scheme
9
1
, Table 1, entry 1). Although the product was obtained in good
6
ee, the yield was significantly reduced. Increasing the equivalents
of acetophenone or p-anisidine increased the yield slightly (Table 1,
entries 2–3), although increasing the equivalents of trichlorosilane
from 2 eq. to 4 eq. gave no benefit (Table 1, entries 4–5). Reaction
in toluene gave the desired amine 4 in a lower yield compared
with that performed in dichloromethane (Table 1, entries 3 and 6).
Although good enantioselectivities were obtained, the yield was
unsatisfactory. Lewis acid catalysts have been successfully used in
7
8
1
0 mol% catalyst loading was reported by Benaglia’s group. They
reported three examples of this process; two benchmark reactions
produced N-phenyl-1-phenylethylamine in 98% yield and 87% ee
after 40 h, and N-4-methoxyphenyl-1-phenylethylamine in 80%
yield and 87% ee after 90 h. Their final example demonstrated the
synthesis of the herbicide metolachlor, providing the product in
86% yield and 70% ee.
We recently reported the development of the imidazole based
organocatalyst 1 that facilitates the asymmetric reduction of a
a
Department of Chemistry, Dainton Building, University of Sheffield, Brook
Hill, Sheffield, UK, S3 7HF. E-mail: simon.jones@sheffield.ac.uk; Fax: +44
(
0)114 222 9346; Tel: +44 (0)114 222 9483
b
Aesica Pharmaceuticals Ltd., Windmill Industrial Estate, Shotton Lane,
Cramlington, Northumberland, NE23 3JL, UK
†
Electronic supplementary information (ESI) available: Copies of
1
13
H and C NMR spectra, and HPLC chromatograms. See DOI:
0.1039/c1ob05965c
1
Scheme 1 Optimisation of reductive amination of ketone 2.
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860 | Org. Biomol. Chem., 2011, 9, 7860–7868

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Table 1 Optimization of reductive amination of ketone 2 according to Scheme 1
Molar ratio
a
Entry
2
3
HSiCl
3
Additive (equiv.)
Solvent (mL)
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
1.2
2
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
2
2
1.5
2
2
2
3
4
2
2
2
2
2
2
2
2
2
2
—
—
—
—
—
—
CH
CH
CH
CH
CH
2
2
2
2
2
Cl
Cl
Cl
Cl
Cl
2
2
2
2
2
(1)
(1)
(1)
(1)
(1)
39
47
53
52
46
39
75
58
52
78
52
40
85
84
84
85
86
84
77
80
76
77
84
71
79
84
84
Toluene (1)
TMSOTf (0.1)
TMSOTf (0.05)
TMSOTf (0.1)
TMSOTf (0.1)
TMSCl (0.1)
TMSCl (1.0)
—
CH
CH
2
Cl
Cl
2
(1)
(1)
2
2
9
Toluene (1)
b
1
1
1
1
1
1
0
1
2
3
4
5
CH
CH
CH
CH
CH
CH
2
2
2
2
2
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
(1)
(1)
(1)
(5)
(0.5)
(0.5)
c
43
66
71
—
—
a
b
c
1
Based on isolated product. 5 mol% of catalyst 1; Refers to conversion calculated from the integrals of appropriate signals in the H NMR spectrum.
the three component Strecker reactions for the preparation of a-
(Table 2, entries 10 and 11). Propiophenone afforded the corre-
sponding amine in high enantioselectivity but low yield (Table 2,
entry 12). This illustrates the limitations of this methodology, since
ketones with further substitution at the aliphatic centre fail to af-
ford the amine and return only the starting materials after workup
(Table 2, entries 13–14). Further elongation of the aliphatic chain,
using benzyl ketones, or conjugated cinnamyl ketones provided
the products in high yields but low enantioselectivities (Table 2,
entries 15–17). Trifluoromethyl ketones did not react, presumably
because the strongly electron withdrawing trifluoromethyl group
stabilizes the tetrahedral hemi-aminal intermediate, disfavoring
imine formation.
10
aminonitriles. It was envisioned that use of these could increase
the rate of imine formation and thus improve the yield of reductive
amination. This was indeed the case; the yield of amine 4 could be
increased to 75% employing 0.1 eq. of TMSOTf as an additive, but
the enantioselectivity decreased (Table 1, entries 7–9) and could
not be recovered by increasing catalyst loading from 1 mol% to
5
mol% (Table 1, entry 10). TMSCl also failed to offer any improve-
ments (Table 1, entries 11 and 12). It was reasoned that increasing
the concentration of the substrate and reagents may also lead to a
similar effect (Table 1, entries 13–15) which gave a much more satis-
factory result, the optimum conditions thus being use of ketone, p-
anisidine and HSiCl
3
in a molar ratio of 1 : 1.5 : 2, providing amine
Various aromatic amines can also be used and afforded
the corresponding products in synthetically useful yield and
good enantioselectivity (Scheme 2, Table 3, entries 1–3). How-
ever, reductive amination employing 3-aminopyridine gave the
product in low enantioselectivity (10% ee), albeit good yield
(Table 3, entry 4).
4
in 71% yield and 84% ee at 1 mol% catalyst loading (Table 1,
entry 15). These conditions offer an order of magnitude difference
in catalyst loading, with considerable time savings (24 h vs. 90 h)
to deliver a product with almost identical yield and ee to the best
8
competitive related catalyst system reported by Benaglia. Indeed,
if one calculates the Asymmetric Catalytic Efficiency (ACE)
11
and Asymmetric Catalytic Efficiency Speed (ACES), catalyst 1
provides amine 4 with an ACE of 37.5 and an ACES of 1.6. These
compare very well next to the competitor catalyst with an ACE
8
of 5.2 and ACES of 0.1, and illustrate the cost and time savings
associated with using the cheap, low molecular weight catalyst 1.
With the optimal conditions in hand, the generality of the pro-
cess was explored. Both electron rich and electron poor aryl methyl
ketones afforded the corresponding amines in good enantioselec-
tivities (70%–84% ee, Table 2, entries 1–7), although slightly lower
yields were observed when using electron poor aryl methyl ketones
as substrates (Table 2, entries 4–5). Surprisingly, the asymmetric
amination of o-methylphenyl methyl ketone afforded the amine in
low yield (12%), but use of o-methoxyphenyl methyl ketone led
to a good yield despite a small drop in enantioselectivity (Table
Scheme 2 Reductive amination of ketone 2 with aryl amines.
Reductive amination of acetophone with aliphatic amines
provided only recovered starting materials, presumably due to
the formation of an initial amino-silane complex that inhibited
subsequent reactions. With this in mind, a two step-one pot
procedure was developed by microwave-assisted imine formation
immediately prior to reduction. Ketone 2 and aliphatic amine
◦
were heated at 150 C for 40 min with 4 A˚ molecular sieves
2
, entries 6 vs. 7). This small change in the steric requirements
using microwave irradiation and the crude product immediately
submitted to standard reduction conditions. Using this process,
several N-alkyl amines were successfully obtained in good yield
and ee (Scheme 3, Table 4, entries 1–7). It was notable that
sterically hindered ketones were also transformed under these
of the substrate adjacent to the reaction site can also been seen
when contrasting the 1-naphthyl substrate with the 2-naphthyl
(
Table 2, entries 8 and 9). 2-Acetyl thiophene is reasonably well
tolerated, while in contrast the furyl analogue is a poor substrate
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a
Table 2 Asymmetric reductive amination with p-anisidine
Table 3 aReductive amination of ketone 2 with aryl amines according to
Scheme 2
b
Entry
1
Ketone
Product
Yield (%)
ee (%)
b
Entry
1
X
R
H
Product
Yield (%)
56
ee (%)
71
84
CH
82
2
3
4
5
76
66
61
46
81
83
83
83
2
3
CH
CH
N
Me
F
64
65
58
84
81
10
c
4
H
a
A mixture of 2 (1 mmol), amine (1.5 mmol), 1 (0.01 mmol) and HSiCl
3
◦
b
(
2 mmol) in CH
2
Cl
2
(0.5 mL) stirred for 24 h at 0 C. Refers to isolated
Cl
c
product. Reaction was performed in 2 mL of CH
2
2
.
6
7
71
12
70
81
8
9
11
63
77
85
Scheme 3 Two-step-one pot reductive amination.
conditions, and that the iso-propyl ketone led to a reversal of
the sense of stereoselectivity (Table 4, entry 7). The origins of this
latter observation are currently being investigated. The two-step
procedure can also be used with aromatic amines, the products
being isolated in approximately the same yield and ee compared
to the one pot procedure (Table 2 entry 1 vs. Table 4, entry 8).
However, the two-step-one pot procedure offers considerable time
savings (4 h 40 min vs. 24 h), increasing the ACES from 1.6 to
1
1
1
0
1
2
61
72
15
79
44
85
7
.6. The synthetic utility of this two-step-one pot procedure was
demonstrated by synthesis of the calcimimetic (R)-(+)-NPS R-568
12
in 67% yield and 89% ee (Scheme 4).
c
1
1
1
3
4
5
—
N.A
N.A
14
c
—
82
Scheme 4 Synthesis of calcimimetic (R)-(+)-NPS R-568.
d
1
1
6
7
81
77
15
0
From the studies outlined in Table 1, it is very likely that the
optimized reaction conditions promote formation of the imine
that then undergoes reduction mediated by the catalyst. The
microwave-assisted reactions for the aliphatic amines are also
likely to act in this manner. What is less clear at the moment
are the mechanistic origins for some of the more surprising results
obtained (for example, Table 2, entries 10 & 11, and Table 4,
entry 7). These may be a result of the optimized reaction conditions
outlined herein, or be a more general feature associated with the
a
A mixture of ketone (1 mmol), p-anisidine 3 (1.5 mmol), catalyst 1 (0.01
(2 mmol) in CH Cl (0.5 mL) were stirred for 24 h
at 0 C. Refers to isolated product. No reaction or < 5% conversion.
mmol) and HSiCl
3
2
2
◦
b
c
d
2 2
Reaction performed in 1 mL of CH Cl .
7
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a
Table 4 Two-step-one pot reductive amination according to Scheme 3
Bruker 400 MHz spectrometer at ambient temperature. Chemical
shifts for H NMR spectra are reported as d in units of parts
1
1
2
b
Entry
1
R
R
Product
Yield (%)
ee (%)
per million (ppm) downfield from SiMe
4
(d 0.0) and relative to
the signal of chloroform-d (d 7.26, singlet). Coupling constants
Me
Me
Me
PhCH
2
63
80
1
3
are reported as a J value in Hz. Data for C NMR are reported
as d in ppm downfield from SiMe (d 0.0) and relative to the
4
c
2
Ph(CH
Ph(CH
2
2
)
)
2
3
65
76
86
84
signal of chloroform-d (d 77.0, triplet). Enantioselectivities were
determined by high performance liquid chromatography (HPLC)
analysis employing a Gilson HPLC chain with an ABI Analytical
Spectroflow 783 UV detector (l 254 nm), using a mixture of
hexane and propan-2-ol as mobile phase and Chiralcel OD-H,
Chiralcel OJ, Kromasil 3-Cellucoat OD or Phenomenex Lux 3u
cellulose-2 column as stationary phase. Mobile phase flow, unless
3
4
5
6
Me
Me
Et
2-methylfuryl
65
64
66
86
83
73
-
1
2-methylthienyl
specified otherwise, was 1.0 mL min . Absolute configuration
of the products was determined by comparison with compounds
previously published.
PhCH
2
2
General procedure A for preparation of amines
7
i-Pr PhCH
62
68
˚
76
84
Ketone (1 mmol), amine (1.5 mmol), catalyst (S)-1 (0.01 mmol)
and dry CH
2
2
Cl (0.5 mL) were introduced into an oven-dried
2
5 mL two-necked flask or an oven-dried carousel tube. The
d
8
Me
p-anisidine
mixture was stirred until complete dissolution, then cooled to
◦
0
C and trichlorosilane (2 mmol, 0.2 mL) was added by
syringe. A suspension was formed immediately upon addition
a
A mixture of ketone (1 mmol), amine (1.5 mmol) and 4 A MS (200 mg)
was irradiated under microwave for 40 min at 150 C, then cooled
of trichlorosilane. The resulting reaction mixture was left to stir
◦
◦
for 24 h at 0 C. The reaction was diluted by CH
2
2
Cl (20 mL),
to RT. Catalyst 1 (0.01 mmol) and CH
2
Cl
2
(0.5 mL) were added, the
(2 mmol) added and left to stir for 8 h;
◦
quenched by water (2 mL) and followed by addition of aqueous
sodium hydroxide (1 M, 20 mL). This mixture was stirred until
the precipitate was completely dissolved and no gas was emitted.
The organic phase was separated and the aqueous phase was
reaction cooled to 0 C, HSiCl
3
b
d
c
Refers to isolated product; Reaction was performed in 2 mL of CH
Conducted for 4 h 40 min.
2 2
Cl .
mechanism of action of catalyst 1 in comparison with related
species. Mechanistic studies which aim to address these issues are
currently in progress and will be reported in due course.
extracted with CH
was wash with brine (20 mL) and dried over MgSO
and concentration gave crude product, which was purified by
chromatography column on silica gel using 2% ~ 10% solution
of diethyl ether in petroleum ether.
2
Cl
2
(2 ¥ 20 mL). The combined organic phase
. Filtration
4
Conclusions
In conclusion, methods for the asymmetric reductive amination
of ketones with aromatic and aliphatic amines were successfully
developed employing organocatalyst 1 at 1 mol% catalyst loading.
Sterically hindered ketones are also transformed in good yield and
ee, highlighted in the asymmetric synthesis of (+)-NPS R-568. For
a number of substrates, this offers quick access to chiral amines of
good enantiomeric purity at a low cost.
General procedure B for preparation of amines
˚
Ketone (1 mmol), amine (1.5 mmol), and 4 A molecular sieves
(
200 mg) was introduced into a microwave tube (10 mL) and
◦
the mixture was heated at 150 C for 40 min under microwave
irradiation. After the reaction mixture was cooled to room
temperature, catalyst (S)-1 (0.01 mmol) and dry CH
2
Cl
2
(0.5 mL
◦
or as mentioned) were added, the vessel cooled to 0 C and
trichlorosilane (2 mmol, 0.2 mL) added by syringe. The resulting
Experimental
◦
reaction mixture was left to stir at 0 C for 8 h. The reaction
General information
was diluted by CH
2
2
Cl (20 mL), quenched by water (2 mL) and
followed by addition of aqueous sodium hydroxide (1 M, 20 mL).
This mixture was stirred until the precipitate was completely
dissolved and no gas was emitted. The organic phase was separated
Unless stated otherwise, all solvents were obtained from a Grubbs
dry solvent system and glassware was flame dried and cooled
under vacuum before use. All chemicals were used as received
without further purification unless otherwise stated. Analytical
thin layer chromatography (TLC) was performed using Merck
and the aqueous phase was extracted with CH
combined organic phase was wash with brine (20 mL) and dried
over MgSO . Filtration and concentration gave crude product,
which was purified by chromatography column on silica gel using
% ~ 20% solution of diethyl ether in petroleum ether.
2
Cl
2
(2 ¥ 20 mL). The
4
6
0 F254 precoated silica gel plate. Subsequent to elution, plates
were visualized using UV radiation (254 nm); further visualiza-
tion was possible by staining with basic solution of potassium
permanganate. Flash chromatography was performed using silica
2
Analytical data of amines
˚
gel 40–63 m 60 A (Fluorochem Limited). Columns were typically
packed as slurry and equilibrated with the appropriate solvent
system prior to use. H and C NMR spectra were recorded on
For ease of identification, a numbering system for these com-
pounds has been devised relating to the ketone and amine that
1
13
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Table 5 Numbering system for condensation of ketones and amines.
H, m, ArH) and 7.26–7.29 (2 H, m, ArH); d (63 MHz; CDCl )
C
3
2
1.2 (CH
3
), 25.2 (CH
3
), 54.0 (NCH), 55.8 (OCH
3
), 114.7 (ArCH),
Ketone
Amine
114.9 (ArCH), 125.9 (ArCH), 129.4 (ArCH), 136.4 (ArC), 141.8
(
ArC), 142.6 (ArC) and 152.0 (ArC); Enantiomeric excess was
a Acetophenone
a p-Methoxyaniline
b Aniline
b 4-Methoxyacetophenone
c 4-Methylacetophenone
d 4-Chloroacetophenone
e 4-Nitroacetophenone
f 2-Methoxyacetophenone
g 2-Methylacetophenone
h 1-Acetylnaphthalene
i 2-Acetylnaphthalene
j 2-Acetylthiophene
determined by chiral phase HPLC (Chiralcel OD-H) 5% ipa in
hexane @ 1 mL min , t
Data was in accordance with the literature.
c p-Methylaniline
-1
R
= 7.5 min (minor), t
R
= 8.6 min (major).
d p-Fluoroaniline
e 3-Aminopyridine
f Benzylamine
g 2-Phenylethylamine
h 3-Phenylpropylamine
i 2-(Aminomethyl)furan
j 2-(Aminomethyl)thiophene
14
(
S)-N-[1-(4¢-Chlorophenyl)ethyl]-4-methoxyaniline (da)
Obtained using general procedure A as a yellow oil (61% yield);
14
[
a]
97% ee, R isomer); d
CH ), 3.73 (3 H, s, OCH ), 3.81 (1 H, br s, NH), 4.41 (1 H,
D
-10.9 (c 1.1 in CHCl
3
, 83% ee, lit. +8.9, c 1.16 in CHCl
3
,
k 2-Acetylfuran
l Propiophenone
m 4-Phenyl-2-butanone
n 3¢,4¢-Dimethoxyphenyl-propanone
o (E)-4-Phenyl-3-buten-2-one
p Isobutyrophenone
H
(400 MHz; CDCl
3
) 1.50 (3 H, d, J 6.6,
3
3
q, J 6.6, NCH), 6.47 [2 H, (AX)
ArCH] and 7.28–7.35 (4 H, m, ArH); d
CH ), 53.8 (NCH), 55.8 (OCH ), 114.6 (ArCH), 114.9 (ArCH),
27.4 (ArCH), 128.8 (ArCH), 132.4 (ArC), 141.4 (ArC), 144.2
ArC) and 152.1 (ArC); Enantiomeric excess was determined by
chiral phase HPLC (Phenomenex Lux 3 mm Cellulose-1) 8% ipa
2
, ArCH], 6.73 [2 H, (AX)
2
,
C
(100 MHz; CDCl ) 25.2
3
(
1
(
3
3
have been condensed (see Table 5). Thus product aa comes from
the imine formed by condensing ketone a with amine a.
-
1
in hexane @ 1 mL min , t
(
R
= 10.6 min (minor), t = 12.6 min
R
9
(
S)-N-(1-Phenylethyl)-4-methoxyaniline 4 (aa)
major); Data was in accordance with the literature.
Obtained using general procedure A as a brown oil (71% yield);
9
9
[
a]
CHCl
.72 (3 H, s, OCH
NCH), 6.49 [2 H, (AX)
D
-2.5 (c 3.0 in CHCl
, 87% ee); d (400 MHz; CDCl
), 3.81 (1 H, br, NH), 4.43 (1 H, q, J 6.8,
, ArCH], 6.71 [2 H, (AX) , ArCH] and
.23–7.40 (5 H, m, ArCH); d (100 MHz; CDCl ) 25.2 (CH ),
4.3 (NCH), 55.8 (CH O), 114.6 (ArCH), 114.8 (ArCH), 125.9
3
, 84% ee; Lit. [a]
D
-5.6, c 0.54 in
(S)-N-[1-(4¢-Nitrophenyl)ethyl]-4-methoxyaniline (ea)
3
H
3
) 1.52 (3 H, d, J 6.8, CH
3
),
Obtained using general procedure A as a brown oil (46% yield);
3
3
9
[
a]
6% ee); d
H, s, OCH
2 H, (AX)
ArCH] and 8.20 [2 H, (AX)
CH ), 54.0 (NCH), 55.7 (OCH
124.1 (ArCH), 126.8 (ArCH), 140.7 (ArC), 147.0 (ArC), 152.3
ArC) and 153.6 (ArC); Enantiomeric excess was determined by
chiral phase HPLC (Phenomenex Lux 3 mm Cellulose-1) 10% ipa
D
-30.8 (c 1.0 in CHCl
(400 MHz; CDCl
), 3.93 (1 H, br s, NH), 4.53 (1 H, q, J 6.8, NCH), 6.43
, ArCH], 6.72 [2 H, (AX) , ArCH], 7.57 [2 H, (AX)
, ArCH]; d (100 MHz; CDCl ) 25.0
), 114.5 (ArCH), 114.8 (ArCH),
3
, 83% ee, lit. -25.9, c 0.54 in CHCl
3
,
2
2
8
H
3
) 1.55 (3 H, d, J 6.8, CH ), 3.72 (3
3
7
5
C
3
3
3
3
[
2
2
2
,
(
ArCH), 126.9 (ArCH), 128.7 (ArCH), 141.6 (ArC), 145.5 (ArC)
2
C
3
and 151.9 (ArC); Enantiomeric excess was determined by chiral
(
3
3
phase HPLC (Phenomenex Lux 3 mm Cellulose-1) 2% ipa in
-
1
hexane @ 1 mL min , t
R
= 16.5 min (minor), 19.2 min (major).
(
Data was in accordance with the literature.
-
1
9
in hexane @ 1 mL min , t
R
= 28.3 min (minor), t
R
= 34.8 min
(
S)-N-[1-(4¢-Methoxyphenyl)ethyl]-4-methoxyaniline (ba)
(major); Data was in accordance with the literature.
Obtained using general procedure A as a white solid (76% yield);
◦
mp 93–95 C (not reported in literature); [a]
D
-14.5 (c 0.96 in
, 85% ee); d (250
), 3.72 (3 H, s, OCH ),
.76 (1 H, br s, NH), 3.80 (3 H, s, OCH ), 4.39 (1 H, q, J 6.6,
NCH), 6.49 [2 H, (AX) , ArCH], 6.71 [2 H, (AX) , ArCH], 6.87 [2
H, (AX) , ArCH] and 7.29 [2 H, (AX) , ArCH]; d (63 MHz;
CDCl ) 25.1 (CH ), 53.7 (NCH), 55.3 (OCH ), 55.8 (OCH ),
14.0 (ArCH), 114.6 (ArCH), 114.8 (ArCH), 127.0 (ArCH), 137.6
ArC), 141.7 (ArC), 151.9 (ArC) and 158.5 (ArC); Enantiomeric
excess was determined by chiral phase HPLC (Phenomenex Lux
15
(
S)-N-[1-(2¢-Methoxyphenyl)ethyl]-4-methoxyaniline (fa)
9
CHCl
3
, 81% ee, lit. -15.5, c 1.1 in CHCl
MHz; CDCl
3
H
Obtained using general procedure A as a light yellow solid (71%
3
) 1.49 (3 H, d, J 6.6, CH
3
3
◦
yield), mp 56–58 C (not reported in literature); [a]
D
+11.8 (c 1.5
, 90% ee, absolute
(250 MHz; CDCl ) 1.58 (3 H,
), 3.96 (3 H, s, OCH ), 4.04 (1 H,
br s, NH), 4.90 (1 H, q, J 6.6, NCH), 6.59 [2 H, (AX) , ArH], 6.80
2 H, (AX) , ArH], 6.99 (2 H, t, J 7.4, ArH), 7.29 (1 H, td, J 7.4
and 1.6, ArH) and 7.42 (1 H, dd, J 7.4 and 1.6, ArH); d (63 MHz;
CDCl ) 23.0 (CH ), 49.0 (NCH), 55.4 (OCH ), 55.8 (OCH ),
10.6 (ArCH), 114.7 (ArCH), 114.9 (ArCH), 120.9 (ArCH), 126.6
ArCH), 127.7 (ArCH), 133.1 (ArC), 141.9 (ArC), 151.9 (ArC)
and 156.9 (ArC); Enantiomeric excess was determined by chiral
phase HPLC (Chiralcel OD-H) 5% ipa in hexane @ 1 mL min ,
3
3
15
in CHCl
configuration assumed to be S); d
d, J 6.6, CH ), 3.77 (3 H, s, OCH
3
, 70% ee, lit. +14.0 c 0.25 in CDCl
3
2
2
H
3
2
2
C
3
3
3
3
3
3
3
1
(
2
[
2
C
-
1
3
mm Cellulose-1) 10% ipa in hexane @ 1 mL min , t
minor), t = 10.1 min (major). Data was in accordance with the
R
= 9.1 min
3
3
3
3
1
(
(
R
literature.
13
-1
(
S)-N-[1-(4¢-Methylphenyl)ethyl]-4-methoxyaniline (ca)
t
R
= 7.9 min (minor), t
R
= 9.2 min (major); Data was in accordance
Obtained using general procedure A as a yellow solid (66% yield);
with the literature.
◦
mp 50–52 C (not reported in literature); [a]
D
-17.8 (c 1.05 in
, 79% ee); d (250 MHz;
), 2.34 (3 H, s, CH ), 3.72 (3
), 3.78 (1 H, br s, NH), 4.41 (1 H, q, J 6.6, NCH),
.49 [2 H, (AX) , ArCH], 6.71 [2 H, (AX) , ArCH], 7.13–7.16 (2
13
CHCl
3
, 83% ee, lit. +13.3, c 2 in CHCl
3
H
3a
(
S)-N-[1-(2¢-Methylphenyl)ethyl]-4-methoxyaniline (ga)
CDCl
3
) 1.50 (3 H, d, J 6.6, CH
3
3
H, s, OCH
3
Obtained using general procedure A as a yellow oil (12% yield);
3a
6
2
2
[a]
D
+35.4 (c 0.48 in MeOH, 81% ee, lit. -33.5, c 2.2 in MeOH,
7
864 | Org. Biomol. Chem., 2011, 9, 7860–7868
This journal is © The Royal Society of Chemistry 2011

View Article Online
-
1
7
8% ee, R isomer); d
CH ), 2.49 (3 H, s, CH
NCH), 6.45 [2 H, (AX)
H
(250 MHz; CDCl
), 3.74 (3 H, s, OCH
, ArH], 6.74 [2 H, (AX)
3 H, m, ArH) and 7.46–7.50 (1 H, m, ArH); d
3
) 1.50 (3 H, d, J 6.6,
), 4.65 (1 H, q, J 6.6,
, ArH], 7.17–7.25
(63 MHz; CDCl
), 50.5 (NCH), 55.8 (OCH ), 114.3 (ArCH),
14.9 (ArCH), 124.7 (ArCH), 126.6 (ArCH), 130.6 (ArCH), 134.6
in hexane @ 1 mL min , t
R
= 15.1 min (minor), t = 17.3 min
R
3
3
3
(major); Data was in accordance with literature.
2
2
17
(
C
3
)
(S)-N-[1-(Furan-2-yl)ethyl]-4-methoxyaniline (ka)
19.0 (CH
3
), 23.2 (CH
3
3
Obtained using general procedure A as a yellow oil (72% yield);
1
16
[
a]
D
-46 (c 1.0 in CHCl
(250 MHz; CDCl
3
, 44% ee, lit. -48, c 1.0 in CHCl
) 1.57 (3 H, d, J 6.6, CH ), 3.63 (1 H, br
3
, 62%
(
ArC), 141.7 (ArC), 143.1 (ArC) and 151.9 (ArC); Enantiomeric
ee); d
H
3
3
excess was determined by chiral phase HPLC (Phenomenex Lux
3
-
1
s, NH), 3.76 (3 H, s, OCH ), 4.58 (1 H, q, J 6.6, NCH), 6.18 (1
H, app. d, J 3.2, ArH), 6.32 (1 H, dd, J 3.2 and 1.8, ArH), 6.63
3
mm Cellulose-1) 10% ipa in hexane @ 1 mL min , t
R
= 6.3 min
(
minor), t = 7.7 min (major); Data was in accordance with the
R
[
2 H, (AX)
ArH); d (63 MHz; CDCl
05.1 (ArCH), 110.1 (ArCH), 114.8 (ArCH), 115.2 (ArCH), 141.2
ArC), 141.4 (ArCH), 152.5 (ArC) and 157.6 (ArC); Enantiomeric
excess was determined by chiral phase HPLC (Chiralcel OJ) 10%
2
, ArH], 6.79 [2 H, (AX)
2
, ArH] and 7.36 (1 H, app. s,
literature.
C
3
) 21.0 (CH
3
), 48.4 (NCH), 55.7 (OCH ),
3
1
(
9
(
S)-N-[1-(Naphthalen-1-yl)ethyl]-4-methoxyaniline (ha)
Obtained using general procedure A as a yellow solid (11% yield),
-
1
◦
9
◦
9
ipa in hexane @ 1 mL min , t = 45.1 min (major), t = 56.4 min
minor); Data was in accordance with literature.
R
R
mp 88–89 C (lit. 61 C); [a]
123.8, c 0.44 in CHCl , 74% ee); d
H, d, J 6.6, CH ), 3.73 (3 H, s, OCH
1 H, q, J 6.6, NCH), 6.50 [2 H, (AX)
D
+135 (c 0.4 in CHCl
3
, 77% ee, lit.
(
+
3
H
(400 MHz; CDCl ) 1.70 (3
3
3
3
), 4.00 (1 H, br s, NH), 5.28
, ArH], 6.73 [2 H, (AX)
9
(
S)-N-(1-Phenylpropyl)-4-methoxyaniline (la)
(
2
2
,
ArH], 7.48 (1 H, t, J 7.6, ArH), 7.56–7.65 (2 H, m, ArH), 7.73 (1
H, d, J 7.1, ArH), 7.81 (1 H, d, J 8.1, ArH), 7.97 (1 H, d, J 8.1,
Obtained using general procedure A as a yellow oil (15% yield);
9
[
d
a]
H
D
-22 (c 1.0 in CHCl
(250 MHz; CDCl
m, CH ), 3.71 (3 H, s, OCH
J 6.6, NCH), 6.58 [2 H, (AX)
3
, 85% ee, lit. -26.9, c 1.0, CHCl
3
, 84% ee);
), 1.74–1.90 (2 H,
), 3.85 (1 H, br s, NH), 4.17 (1 H, t,
, ArH], 6.72 [2 H, (AX) , ArH] and
(63 MHz; CDCl ) 11.0 (CH CH ),
), 60.7 (NCH), 114.6 (ArCH), 114.9
ArH) and 8.24 (1 H, d, J 8.3, ArH); d
CH ), 50.2 (NCH), 55.8 (OCH ), 114.4 (ArCH), 114.9 (ArCH),
22.4 (ArCH), 122.7 (ArCH), 125.5 (ArCH), 126.0 (ArCH), 126.1
ArCH), 127.5 (ArCH), 129.2 (ArCH), 130.9 (ArC), 134.2 (ArC),
40.3 (ArC), 141.5 (ArC) and 151.9 (ArC); Enantiomeric excess
was determined by chiral phase HPLC (Phenomenex Lux 3 mm
C
(100 MHz; CDCl
3
) 23.9
3
) 0.96 (3 H, t, J 7.2, CH
3
(
3
3
2
3
1
(
1
2
2
7
3
.20–7.37 (5 H, m, ArH); d
1.8 (CH CH ), 55.8 (OCH
C
3
2
3
2
3
3
(
(
ArCH), 126.7 (ArCH), 127.0 (ArCH), 128.6 (ArCH), 142.0
ArC), 144.3 (ArC) and 152.0 (ArC); Enantiomeric excess was
-
1
Cellulose-1) 5% ipa in hexane @ 1 mL min , t
R
= 12.9 min (minor),
t
R
= 19.0 min (major); Data was in accordance with literature.
determined by chiral phase HPLC (Chiralcel OD-H) 5% ipa in
-
1
hexane @ 1 mL min , t
R
= 7.0 min (minor), t = 7.7 min (major);
R
9
(
S)-N-[1-(Naphthalen-2-yl)ethyl]-4-methoxyaniline (ia)
Data was in accordance with literature.
Obtained using general procedure A as a light yellow solid (63%
1
8
◦
9
◦
(S)-N-[2-(4¢-Phenylbutyl)]-4-methoxyaniline (ma)
yield), mp 96–98 C (lit. 95–96 C); [a]
D
-24 (c 1.0 in CHCl
(250 MHz; CDCl
), 3.70 (3 H, s, OCH
3
,
)
9
85% ee, lit. -26.0, c 1.0 in CHCl
3
, 86% ee); d
H
3
Obtained using general procedure A as a light yellow oil (82%
1
.59 (3 H, d, J 6.9, CH
3
3
), 3.90 (1 H, br s,
, ArH], 6.71 [2
, ArH], 7.42–7.55 (3 H, m, ArH) and 7.80–7.86 (4 H, m,
(63 MHz, CDCl ) 25.2 (CH ), 54.6 (NCH), 55.8 (OCH ),
14.7 (ArCH), 114.8 (ArCH), 124.4 (ArCH), 124.5 (ArCH),
25.5 (ArCH), 126.0 (ArCH), 127.7 (ArCH), 127.9 (ArCH), 128.5
18
yield); [a]
CHCl , 91% ee, R isomer); d
J 6.3, CH ), 1.72–2.00 (2 H, m, CH
.17 (1 H, br s, NH), 3.46 (1 H, m, NCH), 3.80 (3 H, s, OCH
.57 [2 H, (AX) , ArH], 6.83 [2 H, (AX)
(63 MHz; CDCl ) 20.9 (CH
), 49.0 (NCH), 55.9 (OCH ), 114.8 (ArCH), 115.0 (ArCH),
25.9 (ArCH), 128.4 (ArCH), 128.5 (ArCH), 141.9 (ArC), 142.2
ArC) and 151.9 (ArC); Enantiomeric excess was determined by
D
+0.7 (c 5.1 in CHCl
3
, 14% ee, lit. -4.0, c 2.06 in
NH), 4.59 (1 H, q, J 6.9, NCH), 6.53 [2 H, (AX)
H, (AX)
ArH); d
1
1
2
3
H
(250 MHz; CDCl
3
) 1.25 (3 H, d,
2
3
2
), 2.78 (2 H, t, J 7.8, CH
2
),
),
C
3
3
3
3
6
3
2
2
, ArH] and 7.22–7.37 (5
), 32.6 (CH ), 38.9
H, m, ArH); d
CH
C
3
3
2
(
1
ArCH), 132.8 (ArC), 133.7 (ArC), 141.7 (ArC), 143.1 (ArC) and
52.0 (ArC); Enantiomeric excess was determined by chiral phase
HPLC (Phenomenex Lux 3 mm Cellulose-1) 10% ipa in hexane @
(
2
3
1
(
-
1
1
mL min , t
R
= 10.1 min (minor), t = 12.0 min (major); Data
R
chiral phase HPLC (Chiralcel OD-H) 5% ipa in hexane @ 1 mL
was in accordance with literature.
-1
min , t
R
= 10.7 min (minor), t = 11.8 min (major); Data was in
R
accordance with literature.
16
(
S)-N-[1-(Thiophen-2-yl)ethyl]-4-methoxyaniline (ja)
1
9
(
S)-N-[2-(3¢,4¢-Dimethoxyphenylpropyl)]-4-methoxyaniline (na)
Obtained using general procedure A as a yellow oil (61% yield);
1
6
[
a]
9% ee); d
3 H, s, OCH
ArH], 6.75 [2 H, (AX)
.18 (1 H, dd, J 4.7 and 1.6, ArH); d
CH ), 50.6 (NCH), 55.8 (OCH ), 114.9 (ArCH), 115.2 (ArCH),
23.0 (ArCH), 123.6 (ArCH), 126.7 (ArCH), 141.2 (ArC), 150.6
D
-8.0 (c 1.0 in CHCl
(250 MHz; CDCl
), 4.76 (1 H, q, J 6.6, NCH), 6.62 [2 H, (AX)
3
, 79% ee, lit. -9.0, c 1.0 in CHCl
3
,
Obtained using general procedure A as a light yellow oil (81%
19
8
(
H
3
) 1.63 (3 H, d, J 6.6, CH
3
), 3.75
yield); [a]
CHCl , 66% ee R isomer); d
6.3, CH ), 2.70 (1 H, dd, J 13.5 and 6.9, 1 ¥ CH
J 13.5 and 4.7, 1 ¥ CH ), 3.27 (1 H, br s, NH), 3.62–3.72 (1 H,
m, NCH), 3.72 (3 H, s, OCH ), 3.86 (3 H, s, OCH ), 3.88 (3 H, s,
) and 6.60–6.84 (7 H, m, ArH); d (63 MHz; CDCl ) 20.3
), 50.3 (NCH), 55.9 (2 ¥ OCH ), 111.3 (ArCH),
D
+4.5 (c 1.0 in CHCl
3
, 15% ee, lit. -3.5, c 0.3 in
) 1.15 (3 H, d, J
), 2.84 (1 H, dd,
3
2
,
3
H
(250 MHz; CDCl
3
2
, ArH], 6.94–6.98 (2 H, m, ArH) and
(63 MHz; CDCl ) 24.8
3
2
7
(
1
C
3
2
3
3
3
3
OCH
(CH
3
C
3
(
ArC) and 152.5 (ArC); Enantiomeric excess was determined by
3
), 41.7 (CH
2
3
chiral phase HPLC (Phenomenex Lux 3 mm Cellullose-1) 2% ipa
113.0 (ArCH), 115.0 (ArCH), 121.6 (ArCH), 131.2 (ArC), 141.6
This journal is © The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 7860–7868 | 7865

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(
ArC), 147.6 (ArC), 148.8 (ArC) and 152.1 (ArC); Enantiomeric
(1 H, m, ArH) and 7.32–7.38 (4 H, m, ArH); d
C
(100 MHz;
3
excess was determined by chiral phase HPLC (Phenomenex Lux
CDCl
3
) 25.1 (CH
3
), 54.1 (NCH), 114.1 (d, JC-F 6.9, ArCH),
-
1
2
Cellulose-2) 5% ipa in hexane @ 1 mL min , t
minor), t = 34.9 min (major); Data was in accordance with
literature.
R
= 29.4 min
115.5 (d, JC-F 22.2, ArCH), 125.9 (ArCH), 127.0 (ArCH), 128.8
(ArCH), 143.7(ArC), 145.1 (ArC) and 155.5 ( JC-F 234.6, ArC); d
1
(
R
F
(235 MHz; CDCl ) -128.4; Enantiomeric excess was determined
3
by chiral phase HPLC (Kromasil 3-Cellucoat OD-H) 2% ipa in
20
-1
(
±)-(E)-N-(4-Phenylbut-3-en-2-yl)-4-methoxyaniline (oa)
hexane @ 1 mL min , t
R
= 5.5 min (minor), 6.1 min (major); Data
was in accordance with literature.
Obtained using general procedure A as a yellow oil (77% yield);
0
% ee; d (250 MHz; CDCl ) 1.41 (3 H, d, J 7.6, CH ), 3.45 (1 H,
br s, NH), 3.76 (3 H, s, OCH ), 4.04–4.14 (1 H, m, NCH), 6.24
1 H, dd, J 16.0 and 6.0, CH CH), 6.55–6.68 (3 H, m, 2 ¥ ArH
and CH CH), 6.76–6.81 (2 H, m, ArH) and 7.20–7.40 (5 H, m,
ArH); d (63 MHz; CDCl ) 22.2 (CH ), 51.9 (NCH), 55.8 (OCH ),
15.0 (ArCH), 115.1 (ArCH), 126.5 (ArCH), 127.4 (ArCH), 128.6
ArCH), 129.4 (CH), 133.7 (CH), 137.2 (ArC), 141.8 (ArC) and
52.2 (ArC); Enantiomeric excess was determined by chiral phase
HPLC (Kromasil 3-Cellucoat OD-H) 5% ipa in hexane @ 1 mL
H
3
3
2
3
3
(
S)-N-(1-Phenylethyl)-3-aminopyridine (ae)
(
Obtained using general procedure A as a white solid, except 2 mL
◦
of CH
in literature); [a]
reported); d (400 MHz; CDCl
2
Cl
2
was used (58% yield), mp 88–90 C (not reported
C
3
3
3
1
(
1
D
0 (c 1 in CHCl
3
, 10% ee, no literature data
), 4.33
H
3
) 1.55 (3 H, d, J 6.6, CH
3
(1 H, br s, NH), 4.49 (1 H, q, J 6.6, NCH), 6.72 (1 H, ddd, J
8.3, 2.7 and 1.2, ArH), 6.97 (1 H, dd, J 8.3 and 4.7, ArH), 7.23–
7.38 (5 H, m, ArH), 7.91 (1 H, d, J 4.2, ArH) and 8.02 (1 H,
-
1
min , t
literature.
R
= 10.2 min, t
R
= 11.9 min; Data was in accordance with
d, J 2.2, ArH); d
19.0 (ArCH), 123.6 (ArCH), 125.8 (ArCH), 127.2 (ArCH), 128.8
(ArCH), 136.6 (ArCH), 138.5 (ArCH), 143.3 (ArC) and 144.3
C
(100 MHz; CDCl
3
) 24.9 (CH ), 53.3 (NCH),
3
1
9
(
S)-N-(1-Phenylethyl)-aniline (ab)
(
(
ArC); Enantiomeric excess was determined by chiral phase HPLC
Phenomenex Lux 3 mm Cellulose-1), 15% ipa in hexane @ 1 mL
Obtained using general procedure A as a yellow oil (56% yield);
9
[
a]
6% ee); d
1 H, br s, NH), 4.51 (1 H, q, J 6.6, CH), 6.51–6.55 (2 H,
m, ArH), 6.63–6.70 (1 H, m, ArH), 7.08–7.14 (2 H, m, ArH)
and 7.21–7.42 (5 H, m, ArH); d (CDCl ; 63 MHz) 25.1 (CH ),
3.5 (NCH), 113.4 (ArCH), 117.4 (ArCH), 126.0 (ArCH), 127.0
D
+13 (c 1.0 in MeOH, 82% ee, lit. [a]
D
+13.9, c 1.0 in MeOH,
-1
min , t
accordance with literature.
R
= 12.2 min (major), 23.7 min (minor); Data was in
8
(
H
(250 MHz; CDCl
3
) 1.55 (3 H, d, J 6.6, CH
3
), 4.05
24
C
3
3
(
S)-N-Benzyl-1-phenylethylamine (af)
5
Obtained using general procedure B as a colorless oil (63% yield);
a] -44.3 (c 0.7 in EtOH, 80% ee, Lit. -41.1, c 0.6 in EtOH,
91% ee) dH (250 MHz; CDCl ) 1.39 (3 H, d, J 6.6, CH ), 1.59
1 H, br s, NH), 3.60 (1 H, d, J 13.1, 1 ¥ CH
(
(
(
t
ArCH), 128.8 (ArCH), 129.2 (ArCH), 145.4 (ArC) and 147.4
ArC); Enantiomeric excess was determined by chiral phase HPLC
Kromasil 3-Cellucoat OD-H), 5% ipa in hexane @ 1 mL min ,
24
[
D
-
1
3
3
(
2
), 3.68 (1 H, d,
R
= 4.8 min (major), 5.7 min (minor); Data was in accordance
J 13.1, 1 ¥ CH
H, m, ArH); d
57.6 (NCH), 126.8 (ArCH), 126.9 (ArCH), 127.0 (ArCH), 128.2
ArCH), 128.4 (ArCH), 128.5 (ArCH), 140.7 (ArC) and 145.7
2
), 3.84 (1 H, q, J 6.6, NCH) and 7.23–7.41 (10
with literature.
C
(63 MHz; CDCl ) 24.5 (CH ), 51.7 (NCH ),
3
3
2
21
(
S)-N-(1-Phenylethyl)-4-methylaniline (ac)
(
Obtained using general procedure A as a yellow solid (64% yield),
(ArC); Enantiomeric excess was determined by comparison of the
◦
21
◦
1
mp 75–76 C (lit. 70 C); [a]
D
+27 (c 1.0 in ethyl acetate,
+27.3, c 0.7 in ethyl acetate, 91% ee); d
) 1.54 (3 H, d, J 6.6, CH ), 2.22 (3 H, s,
), 3.95 (1 H, br s, NH), 4.49 (1 H, q, J 6.6, NCH),
, ArH], 6.94 [2 H, (AX) , ArH] and 7.24–7.42
m, 5H, ArH); d (100 MHz; CDCl ) 20.5 (CH ), 25.2 (CH ),
3.8 (NCH), 113.5 (ArCH), 126.0 (ArCH), 126.4 (ArC), 126.9
integrals in the H NMR spectrum in CDCl of the diastereomeric
3
21
84% ee, lit. [a]
D
H
salts formed by addition of excess L-mandelic acid; Data was in
accordance with literature.
(400 MHz; CDCl
3
3
ArCH
3
6
.47 [2 H, (AX)
2
2
25
(
C
3
3
3
(S)-N-(2-Phenylethyl)-1-phenylethylamine (ag)
5
Obtained using general procedure B as a light yellow oil, except
mL of CH Cl was used (65% yield); [a] -47.8 (c 1.1 in
CHCl , 86% ee, Lit. +54.2, c 2.84 in CHCl , 97% ee R-
isomer); dH (250 MHz; CDCl ) 1.34 (3 H, d, J 6.6, CH ),
(
(
(
ArCH), 128.7 (ArCH), 129.7 (ArCH), 145.1 (ArC) and 145.6
ArC); Enantiomeric excess was determined by chiral phase HPLC
Phenomenex Lux 3 mm Cellulose-1) 2% ipa in hexane @ 1 mL
2
2
2
D
25
3
3
-
1
3
3
min , t = 10.0 min (minor), 11.7 min (major); Data was in ac-
cordance with literature–the signal at d 2.22 ppm is missing from
reference 21
R
2
7
3
.70–2.84 (4 H, m, CH
.16–7.36 (10 H, m, ArH); d
6.5 (CH Ph), 48.9 (NCH ), 58.2 (NCH), 126.1 (ArCH), 126.6
2
CH
2
), 3.81 (1 H, q, J 6.6, NCH) and
H
C
(63 MHz; CDCl ) 24.3 (CH ),
3
3
2
2
2
2
(ArCH), 126.9 (ArCH), 128.4 (ArCH), 128.7 (ArCH), 140.1
ArC) and 145.7 (ArC); Enantiomeric excess was determined by
(
S)-N-(1-Phenylethyl)-4-fluoroaniline (ad)
(
1
Obtained using general procedure A as a yellow oil (65% yield);
comparison of the integrals in the H NMR spectrum in CDCl of
3
2
2
[
a]
CHCl
J 6.6, CH
D
+20 (c 1.05 in CHCl
, 84% ee R isomer); d
), 3.95 (1 H, br s, NH), 4.44 (1 H, q, J 6.6, NCH),
.43–6.47 (2 H, m, ArH), 6.79–6.84 (2 H, m, ArH), 7.23–7.28
3
, 81% ee, lit. [a]
D
-16.8, c 1.0 in
the diastereomeric salts formed by addition of excess L-mandelic
acid; Data was in general accordance with literature–the signal
3
H
(400 MHz; CDCl
3
) 1.53 (3 H, d,
1
3
3
at d
C
145.7 ppm is missing in the reported C NMR data in
6
reference 25
7
866 | Org. Biomol. Chem., 2011, 9, 7860–7868
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2
6
(
S)-N-(3-Phenylpropyl)-1-phenylethylamine (ah)
(ArC); Enantiomeric excess was determined by comparison of the
1
integrals in the H NMR spectrum in CDCl
3
of the diastereomeric
Obtained using general procedure B as a brown oil (76% yield);
salts formed by addition of excess L-mandelic acid; Data was in
accordance with literature.
[
d
a] -40 (c 1.1 in CHCl , 84% ee, [a] not reported in literature);
(250 MHz; CDCl ) 1.30 (1 H, br s, NH), 1.37 (3 H, d, J 6.6,
CH ), 1.75–1.87 (2 H, m, CH ), 2.45–2.74 (4 H, m, NCH and
PhCH ), 3.77 (1 H, q, J 6.6, NCH) and 7.16–7.39 (10 H, m,
ArH); d (63 MHz; CDCl ) 24.4 (CH ), 32.0 (CH ), 33.8 (CH ),
7.4 (NCH ), 58.4 (NCH), 125.8 (ArCH), 126.6 (ArCH), 126.9
ArCH), 128.36 (ArCH), 128.44 (ArCH), 128.5 (ArCH), 142.3
ArC) and 146.0 (ArC); Enantiomeric excess was determined by
comparison of the integrals in the H NMR spectrum in CDCl
the diastereomeric salts formed by addition of excess L-mandelic
D
3
D
H
3
3
2
2
28
(
R)-N-Benzyl-2-methyl-1-phenylpropylamine (pf)
2
C
3
3
2
2
Obtained using general procedure B as a colorless oil (62% yield);
28
4
(
(
2
[a]D +56 (c 1.05 in CHCl , 76% ee, Lit. +63.1, c 1.4 in CHCl3
3
94% ee); dH (400 MHz; CDCl ) 0.77 (3 H, d, J 6.8, CH ), 1.00 (3
3
3
H, d, J 6.6, CH ), 1.61 (1 H, br s, NH), 1.86–1.92 (1 H, m, CH),
3
1
3
of
3.37 (1 H, d, J 9.0, NCH), 3.49 (1 H, d, J 13.3, 1 ¥ NCH ), 3.67
2
(1 H, d, J 13.3, 1 ¥ NCH ) and 7.24–7.38 (10 H, m, ArH); d (100
2
C
1
3
acid; C NMR data in accordance with literature, while two
methylene signals have been omitted in the literature H NMR
MHz, CDCl ) 19.5 (CH ), 19.7 (CH ), 34.5 (CH), 51.8 (NCH ),
3
3
3
2
1
68.8 (NCH), 126.8 (2 ¥ ArCH), 128.0 (ArCH), 128.2 (ArCH),
128.3 (ArCH), 141.0 (ArC) and 142.9 (ArC); Enantiomeric excess
data.
1
was determined by comparison of the integrals in the H NMR
26
(
S)-N-(Furan-2-ylmethyl)-1-phenylethylamine (ai)
spectrum in CDCl
3
of the diastereomeric salts formed by addition
of excess L-mandelic acid; Data was in accordance with literature.
Obtained using general procedure B as a colorless oil (65% yield);
[
d
a] -78 (c 0.4 in CHCl , 86% ee, [a] not reported in literature);
(250 MHz; CDCl ) 1.38 (3 H, d, J 6.6, CH ), 1.66 (1 H, br
s, NH), 3.59 (1 H, d, J 14.4, 1 ¥ CH ), 3.69 (1 H, d, J 14.4, 1 ¥
CH ), 3.80 (1 H, q, J 6.6, NCH), 6.12 (1 H, dd, J 0.4 and 3.1,
ArH), 6.32 (1 H, dd, J 1.8 and 3.1, ArH), 7.23–7.40 (6 H, m,
D
3
D
(
S)-N-(1-Phenylethyl)-4-methoxyaniline 4 (aa)
H
3
3
Obtained using general procedure B but for 4 h instead of
8 h as a brown oil (68% yield, 84% ee); Data as previously
reported.
2
2
1
3
ArH); C NMR (63 MHz; CDCl
5
3
) d
C
24.3 (CH
3
), 44.0 (NCH
2
),
7.1 (NCH), 106.8 (ArCH), 110.1 (ArCH), 126.8 (ArCH), 127.0
3-(2-Chlorophenyl)-propylamine 5
(
(
ArCH), 128.5 (ArCH), 141.7 (ArCH), 145.1 (ArC) and 154.1
KOH powder (2 g, 36.1 mmol) and 2-chlorobenzaldehyde (5.07 g,
ArC); Enantiomeric excess was determined by comparison of the
3
6.1 mmol) were stirred in acetonitrile (300 mL) at room temper-
ature for 24 h and then poured into a 1 : 1 mixture of ice-water
300 g). The mixture was extracted with dichloromethane (3 ¥
50 mL), the combined extracts washed with brine (50 mL) and
dried over MgSO . After filtration, the filtrate was concentrated
and the residue was purified by chromatography on silica gel
1
integrals in the H NMR spectrum in CDCl
salts formed by addition of excess L-mandelic acid; Data was in
accordance with literature.
3
of the diastereomeric
(
1
4
(
S)-N-(Thiophen-2-ylmethyl)-1-phenylethylamine (aj)
(
petroleum ether–ethyl acetate = 20 : 1 to 5 : 1) to give 1.57 g 2-
Obtained using general procedure B as a yellow oil (64% yield);
◦
-
1
chloro-cinnamonitrile as white solid; mp 35–37 C (not reported
in literature), d
7
7
(
1
while reported H NMR data is at much lower resolution.
A suspension of 2-chloro-cinnamonitrile (1.57 g, 9.6 mmol)
and CoCl (2.42 g, 18.6 mmol) in MeOH (60 mL) was cooled
[
1
1
a]
D
-42.5 (c 0.8 in CHCl
492, 1451; d (400 MHz; CDCl
.65 (1 H, br s, NH), 3.81–3.89 (2 H, m, CH
3
, 83% ee); vmax (ATR)/cm 2963,
) 1.40 (3 H, d, J 6.6, CH ),
), 3.88 (1 H, q,
H
(250 MHz; CDCl
.28–7.48 (3 H, m, ArH), 7.56 (1 H, dd, J 1.9 and 7.5, ArH) and
.51 (1 H, d, J 16.6, CH); d (63 MHz; CDCl ) 99.0 (CH), 117.8
3
) 5.92 (1 H, d, J 16.6, CH),
H
3
3
2
J 6.6, NCH), 6.88–6.89 (1 H, m, ArH), 6.96 (1 H, dd, J 3.4
and 5.1, ArH), 7.23 (1 H, dd, J 1.2 and 5.1, ArH), 7.26–7.31
C
3
C), 127.0 (CH), 127.4 (CH), 130.3 (CH), 131.6 (C), 132.1 (CH),
1
3
34.4 (C) and 146.3 (CH); C NMR not reported in the literature,
(
1 H, m, ArH) and 7.35–7.39 (4 H, m, ArH); d
MHz) 24.4 (CH ), 46.1 (NCH ), 57.1 (NCH), 124.3 (ArCH),
24.7 (ArCH), 126.6 (ArCH), 126.8 (ArCH), 127.1 (ArCH), 128.5
C
(CDCl
3
; 100
1
29
3
2
1
(
+
ArCH), 144.5 (ArC) and 145.2 (ArC); m/z (EI ) 217.0923 (4%,
2
◦
+
to 0 C under N atmosphere. NaBH (3.5 g, 93 mmol) was added
M , C13
H
15NS requires 217.0925), 202 (60), 97 (100); Enantiomeric
2
4
1
portionwise over 30 min. The resulting mixture was allowed to
warm to room temperature and stirred overnight. 6N HCl (20 mL)
was added, and the reaction carefully basified with 2N aqueous
NaOH to pH 11. The resulting mixture was extracted with diethyl
ether (3 ¥ 150 mL), the combined organic phases washed with
brine (50 mL) and dried over MgSO
was evaporated under reduced pressure to afford the desire amine
(1.2 g) as light brown oil; d (250 MHz; CDCl ) 1.14 (2 H, br s,
NH ), 1.73–1.85 (2 H, m, CH ), 2.70–2.82 (4 H, m, CH CH ) and
7.11–7.37 (4 H, m, ArH); d (63 MHz, CDCl ) 30.9 (CH ), 33.9
(CH ), 41.9 (CH ), 126.7 (ArCH), 127.3 (ArCH), 129.5 (ArCH),
130.3 (ArCH) and 139.7 (ArCH); Data was in general accordance
excess was determined by comparison of the integrals in the H
NMR spectrum in CDCl
3
of the diastereomeric salts formed by
addition of excess L-mandelic acid.
27
(
S)-N-Benzyl-1-phenylpropylamine (lf)
4
. After filtration, the solvent
Obtained using general procedure B as a colorless oil (66% yield);
2
7
[
8
a]
9% ee for R-isomer); d
CH ), 1.65–1.87 (3 H, m, CH
and 1 ¥ NCH ), 3.71 (1 H, d, J 13.2, 1 ¥ NCH
10 H, m, ArH); d (100 MHz, CDCl ) 10.8 (CH
1.6 (NCH ), 64.2 (NCH), 126.8 (ArCH), 126.9 (ArCH), 127.5
ArCH), 128.2 (ArCH), 128.3 (ArCH), 140.8 (ArC) and 144.1
D
-37 (c 1.0 in CHCl
3
, 73% ee, Lit. +32, c 0.2 in CHCl
(400 MHz; CDCl ) 0.86 (3 H, t, J 7.4,
and NH), 3.57–3.61 (2 H, m, NCH
) and 7.27–7.42
), 31.2 (CH ),
3
,
H
3
H
3
2
2
2
2
3
2
C
3
2
2
2
2
2
(
5
(
C
3
3
2
1
3
2
with literature, although 1 signal in the C NMR was ambiguous
due to the low concentration of the sample.
30
This journal is © The Royal Society of Chemistry 2011
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(
1
R)-3-(2-Chlorophenyl)-N-(1-(3-methoxyphenyl)ethyl)propan-
-amine 6 [(+)-NPS R-568]
5 (a) R. I. Storer, D. E. Carrera, Y. Ni and D. W. C. MacMillan, J. Am.
Chem. Soc., 2006, 128, 84; (b) S. Hoffmann, M. Nicoletti and B. List, J.
Am. Chem. Soc., 2006, 128, 13074; (c) G. Li, Y. Liang and J. C. Antilla,
J. Am. Chem. Soc., 2007, 129, 5830; (d) V. N. Wakchaure, J. Zhou, S.
Hoffmann and B. List, Angew. Chem., Int. Ed., 2010, 49, 4612; (e) V. N.
Wakchaure, M. Nicoletti, L. Ratjen and B. List, Synlett, 2010, 2708.
6 For a comprehensive review of the asymmetric reduction of imines
by organocatalyzed trichlorosilane reduction see S. Guizzetti and M.
Benaglia, Eur. J. Org. Chem., 2010, 5529.
31
Obtained using general procedure B as a light brown oil, except
mL of CH Cl was used with 1 mol% of (R)-1 as catalyst
67% yield); [a]
2
2
2
31
(
D
+41.2 (c 0.8 in CHCl
assumed to be 100% ee); d
.37 (3 H, d, J 6.6, CH ), 1.74–1.89 (2 H, m, CH
), 2.68–2.86 (2 H, m, CH ), 3.77 (1 H, q, J 6.6,
NCH), 3.84 (3 H, s, OCH ), 6.80 (1 H, ddd, J 1.0, 2.4 and
.3, ArH), 6.91–6.93 (2 H, m, ArH), 7.09–7.35 (5 H, m, ArH);
(63 MHz; CDCl ) 24.3 (CH ), 30.2 (CH ), 31.3 (CH ), 47.3
), 55.2 (OCH ), 58.3 (NCH), 112.1 (ArCH), 112.2 (ArCH),
19.0 (ArCH), 126.7 (ArCH), 127.2 (ArCH), 129.4 (2 ¥ ArCH),
30.3 (ArCH), 133.9 (ArC), 139.8 (ArC), 147.7 (ArC) and 159.8
3
, 89% ee, Lit. +41.9, c
(250 MHz; CDCl
), 2.47–2.65
1
1
(
.1 in CHCl
3
H
3
)
3
2
7
A. V. Malkov, S. Stoncius and P. Kocovsky, Angew. Chem., Int. Ed.,
007, 46, 3722.
8 S. Guizzetti, M. Benaglia, F. Cozzi and R. Annunziata, Tetrahedron,
009, 65, 6354.
F.-M. Gautier, S. Jones and S. J. Martin, Org. Biomol. Chem., 2009, 7,
29.
2 H, m, CH
2
2
2
3
2
8
d
(
1
1
9
C
3
3
2
2
2
CH
2
3
10 (a) G. K. S. Prakash, T. Mathew, C. Panja, S. Alconcel, H. Vaghoo, C.
Do and G. A. Olah, Proc. Natl. Acad. Sci. U. S. A., 2007, 104, 3703;
(
b) G. K. S. Prakash, C. Panja, C. Do, T. Mathew and G. A. Olah,
Synlett, 2007, 2395.
(
ArC); Enantiomeric excess was determined by comparison of the
1
1 A recently proposed formulaic method to compare efficiency of
asymmetric transformations See: S. El-Fayyoumy, M. H. Todd and
C. J. Richards, Beilstein J. Org. Chem., 2009, 5, 67.
1
integrals in the H NMR spectrum in CDCl
salts formed by addition of excess L-mandelic acid; Data in
general agreement with the literature, although C NMR data
in reference 31 has an additional signal and data has been mis-
assigned.
3
of the diastereomeric
1
3
12 For alternative approaches see K. Han, Y. Kim, J. Park and M.-J. Kim,
Tetrahedron Lett., 2010, 51, 3536 and references therein.
1
1
3 A. Kumar, S. Sharma and R. A. Maurya, Adv. Synth. Catal., 2010, 352,
2227.
4 S.-F. Zhu, J.-B. Xie, Y.-Z. Zhang, S. Li and Q.-L. Zhou, J. Am. Chem.
Soc., 2006, 128, 12886.
Acknowledgements
15 C. Moessner and C. Bolm, Angew. Chem., Int. Ed., 2005, 44, 7564.
1
6 A. V. Malkov, K. Vrankov a´ , S. Ston a´ ius and P. Ko cˇ ovsk y´ , J. Org. Chem.,
2009, 74, 5839.
We thank Aesica (FMG) and University of Sheffield for support.
1
7 D. Menche, J. Hassfeld, J. Li, G. Menche, A. Ritter and S. Rudolph,
Org. Lett., 2006, 8, 741.
18 S. E. Denmark, N. Nakajima, C. M. Stiff,O. J. C. Nicaise and M. Kranz,
Notes and references
Adv. Synth. Catal., 2008, 350, 1023.
1
(a) T. Henkel, R. M. Brunne, H. M u¨ ller and F. Reichel, Angew. Chem.,
Int. Ed., 1999, 38, 643; (b) A. K. Ghose, V. N. Viswanadhan and J. J.
Wendoloski, J. Comb. Chem., 1999, 1, 55.
1
2
9 S. Arrasate, E. Lete and N. Sotomayor, Tetrahedron: Asymmetry, 2001,
1
2, 2077.
0 A. V. Malkov, M. Figlus, S. Ston cˇ ius and P. Ko cˇ ovsk y´ , J. Org. Chem.,
007, 72, 1315.
2
Selected examples of transition-metal catalyzed imine hydrogenation:
2
(
a) G. Hou, R. Tao, Y. Sun, X. Zhang and F. Gosselin, J. Am. Chem.
2
2
2
1 D. Pei, Z. Wang, Y. Zhang, S. Wei and J. Sun, Org. Lett., 2006, 8, 5913.
2 T. Imamoto, N. Iwadate and K. Yoshida, Org. Lett., 2006, 8, 2289.
3 Q. Shen, T. Ogata and J. F. Hartwig, J. Am. Chem. Soc., 2008, 130,
Soc., 2010, 132, 2124; (b) N. Mr sˇ i c´ , A. J. Minnaard, B. L. Feringa and J.
G. de Vries, J. Am. Chem. Soc., 2009, 131, 8358; (c) C. Li and J. Xiao, J.
Am. Chem. Soc., 2008, 130, 13208; (d) C. Li, C. Wang, B. Villa-Marcos
and J. Xiao, J. Am. Chem. Soc., 2008, 130, 14450.
Selected examples of chiral phosphoric acid catalyzed transfer hydro-
genation of imines:(a) M. Rueping, E. Sugiono, C. Azap, T. Theissmann
and M. Bolte, Org. Lett., 2005, 7, 3781; (b) S. Hoffmann, A. M. Seayad
and B. List, Angew. Chem., Int. Ed., 2005, 44, 7424.
6
586.
2
2
4 Z. Han, Z. Wang, X. Zhang and K. Ding, Angew. Chem., Int. Ed., 2009,
3
4
4
8, 5345.
5 M. S. A. Hamid, C. L. Allen, G. W. Lamb, A. C. Maxwell, H. C.
Maytum, A. J. A. Watson and J. M. J. Williams, J. Am. Chem. Soc.,
2
009, 131, 1766.
(a) H.-U. Blaser, H.-P. Buser, H.-P. Jalett, B. Pugin and F. Spindler,
Synlett, 1999, 867; (b) R. Kadyrov, T. H. Riermeier, U. Dingerdissen,
V. Ta r a rov a n d A . B o¨ rner, J. Org. Chem., 2003, 68, 4067; (c) Y. Chi, Y.-
G. Zhou and X. Zhang, J. Org. Chem., 2003, 68, 4120; (d) R. Kadyrov
and T. H. Riermeier, Angew. Chem., Int. Ed., 2003, 42, 5472; (e) V. I.
Tararov, R. Kadyrov, T. H. Riermeier and A. B o¨ rner, Chem. Commun.,
2
6 O. Saidi, A. J. Blacker, S. P. Marsden and J. M. J. Williams, Chem.
Commun., 2010, 46, 1541.
2
2
7 C. Wang, X. Wu, L. Zhou and J. Zhou, Chem.–Eur. J., 2008, 14, 8789.
8 J. L. Stymiest, G. Dutheuil, A. Mahmood and V. K. Aggarwal, Angew.
Chem., Int. Ed., 2007, 46, 7491.
9 S. A. Dibiase, B. A. Lipisko, A. Haag, R. A. Wolak and G. W. Gokel,
J. Org. Chem., 1979, 44, 4640.
2
3
3
2
000, 1867; (f) L. Rubio-P e´ rez, F. J. P e´ rez-Flores, P. Sharma, L. Velasco
and A. Cabrera, Org. Lett., 2008, 11, 265; (g) C. Li, B. Villa-Marcos
and J. Xiao, J. Am. Chem. Soc., 2009, 131, 6967; (h) D. Steinhuebel, Y.
Sun, K. Matsumura, N. Sayo and T. Saito, J. Am. Chem. Soc., 2009,
0 D. I. B. Kerr, J. Ong, M. V. Perkins, R. H. Prager and N. M. Puspawati,
Aust. J. Chem., 2006, 59, 445.
1 M. Atobe, N. Yamazaki and C. Kibayashi, J. Org. Chem., 2004, 69,
1
31, 11316.
5
595.
7
868 | Org. Biomol. Chem., 2011, 9, 7860–7868
This journal is © The Royal Society of Chemistry 2011