L -Proline Derived Bifunctional Organocatalysts: Enantioselective Michael Addition of Dithiomalonates to trans-β-Nitroolefins

Article abstract of DOI:10.1021/acs.joc.6b00218

A series of novel l-proline derived tertiary amine bifunctional organocatalysts 9 are reported, which were applied to the asymmetric Michael addition of dithiomalonates 2 to trans-β-nitroolefins 1. The reaction proceeded in high yields (up to 99%) with high enantioselectivities (up to 97% ee). The synthetic utility of this methodology was demonstrated in the short synthesis of (R)-phenibut in high yield.

Full text of DOI:10.1021/acs.joc.6b00218

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Article
L-Proline Derived Bifunctional Organocatalysts: Enantioselective
Michael Addition of Dithiomalonates to trans-beta-Nitroolefins
Hui Jin, Seung Tae Kim, Geum-Sook Hwang, and Do Hyun Ryu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00218 • Publication Date (Web): 18 Mar 2016
Downloaded from http://pubs.acs.org on March 19, 2016
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The Journal of Organic Chemistry
L-Proline Derived Bifunctional Organocatalysts: Enantioselective
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Michael Addition of Dithiomalonates to trans-β-Nitroolefins
†
†
,‡
,†
Hui Jin , Seung Tae Kim , GeumꢀSook Hwang* , and Do Hyun Ryu*
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†
Department of Chemistry, Sungkyunkwan University, Suwon 440ꢀ746, Korea
Western Seoul Center, Korea Basic Science Institute, Seoul 120ꢀ140, Korea
‡
ABSTRACT: A series of novel Lꢀproline derived tertiary amine bifunctional organocatalysts 9 are
reported, which were applied to the asymmetric Michael addition of dithiomalonates 2 to transꢀβꢀ
nitroolefins 1. The reaction proceeded in high yields (up to 99%) with high enantioselectivities (up to
97% ee). The synthetic utility of this methodology was demonstrated in the short synthesis of (R)ꢀ
phenibut in high yield.
INTRODUCTION
The organocatalytic asymmetric Michael addition of various nucleophiles with nitroolefins represents a
1
convenient route to highly functionalized synthetic building blocks in organic synthesis. The nitro
2
a
2b
2c
group can serve as a masked functionality for transformation into an amine, ketone, oxime, nitrile
2d
oxide, etc. after the addition has taken place. Among these reactions, the asymmetric organic catalystꢀ
promoted Michael addition of malonates and their equivalents to nitroolefins were shown to be an
efficient approach to a wide range of synthetically interesting compounds and valuable bioactive chiral
3
compounds.
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After the first report of an enantioselective Michael addition of malonates to nitroolefins catalyzed by
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a
the Takemoto tertiary aminoꢀthiourea catalyst, many kinds of tertiary amine bifunctional
organocatalysts were exploited to promote this type of reaction, including the most widely used
5
4b
4c
cinchona alkaloid , saccharide, and amino acid derived bifunctional organocatalysts. However, most
reported organocatalytic Michael reactions of malonates to nitroolefins require a long reaction time and
high catalyst loadings due to the low reactivity of malonates, except for the very recent report from the
0
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0
5c
Song group in which the reaction was performed “on water” in a short time.
6
Since thioesters are less conjugated than ordinary esters, dithiomalonates are expected to be more
reactive than malonates in Michael additions with nitroolefins. Furthermore, although thioesters possess
7
similar reactivity to esters, they can more easily be transformed into an aldehyde or ketone. Wennemers
8
and coworkers reported the use of mono thiomalonates as a Michael donor. To the best of our
knowledge, the use of dithiomalonates for the Michael addition with nitroolefins is without precedent.
Herein, we disclose the first enantioselective Michael addition of dithiomalonates 2 to transꢀβꢀ
nitroolefins 1 in excellent yields and enantioselectivities catalyzed by a novel Lꢀproline derived urea
organocatalyst 9f.
RESULTS AND DISCUSSION
Initially, the asymmetric Michael addition between S,S’ꢀdiphenyl dithiomalonate 2a and transꢀ
nitrostyrene 1a was examined in the presence of 10 mol% of the widely used quinine derived tertiary
amino thiourea catalyst 3 (Table 1, entry 1). When the reaction was carried out at 25 °C in methyl tꢀ
butyl ether (MTBE), the desired product 11aa was obtained in 83% yield and 60% ee in 2.5 h. Due to
the moderate enantioselectivity with 3, we turned our attention to a new class of chiral bifunctional
organocatalyst based on Lꢀproline. Catalysts 9aꢀ9f were synthesized from commercially available Nꢀ
9
BocꢀLꢀproline methyl ester 4 in 7 steps (Scheme 1). NꢀBocꢀLꢀproline methyl ester 4 was treated with
DIBALꢀH, followed by the addition of the corresponding arylmagnesium bromide to afford the
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0
prolinols 5 diastereoselectively. Then the prolinols 5 were transformed to azides 6 under Mitsunobu
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6
condition with chiral center inverted. Azides 6 were then converted into 7 by NꢀBoc deprotection using
TFA followed by a Nꢀmethylation or Nꢀbenzylation. Finally, azides 7 were reduced with LiAlH to
4
amines which were reacted in situ with 3,5ꢀbis(trifluoromethyl)phenyl isothiocyanate, 3,5ꢀ
bis(trifluoromethyl)phenyl isocyanate or 8 to provide 9a-9f. The absolute configuration of 9a-9f was
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13
confirmed by comparison of the H, C NMR and optical rotation data of 7d with the reported product,
11
of which the stereochemistry was confirmed by Xꢀray diffraction analysis.
Scheme 1. Synthesis of organocatalysts 9a-9f
In order to reveal the effect of the chiral center that bears the urea/thiourea/squaramide moiety in 9a-9f,
1
2
the catalyst 9g was synthesized (Scheme 2). Amino azide 10 was Nꢀmethylated, followed by the azide
reduction to amine, which was treated with 3,5ꢀbis(trifluoromethyl)phenyl isocyanate to afford the
desired organocatalyst 9g.
Scheme 2. Synthesis of organocatalyst 9g
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With several newly synthesized catalysts in hand, catalyst screening was carried out and the results are
outlined in Table 1. Fortunately, compared with quinine derived thiourea 3, Lꢀproline derived thiourea
9a yielded the product with an improved enantioselectivity of 81% ee under identical conditions (Table1,
entry 2). When the phenyl group of 9a on the carbon bearing the thiourea moiety was changed to larger
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,5ꢀdimethylphenyl (9b) or 2ꢀnaphthyl (9c) groups, little change in enantioselectivity was observed
Table 1, entries 3 and 4). The efficiency with 9d decreased significantly compared to 9a (Table 1, entry
), which indicated a small substituent on the pyrrolidine nitrogen is better. Comparing different
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(
5
hydrogen bond donor moieties in the catalyst, we found the urea structure (9f) to be more suitable for
this reaction than thiourea (9a) or squaramide (9e), yielding the product in 96% yield and 90% ee (Table
1
, entries 2, 6, and 7). Diphenyl substituted catalyst 9g with the urea moiety linked to an achiral carbon
showed much lower efficiency than 9f, which determined the requirement of the chiral center in 9f
(Table 1, entry 8). In summary, 9f was identified as the most suitable catalyst for the present reaction.
a
Table 1. Screening of organocatalysts for the enantioselective Michael addition of 2a to 1a
b
c
entry
cat.
3
yield (%)
ee (%)
d
1
2
3
4
5
83
94
92
82
68
60 (+)
9a
9b
9c
9d
81 (ꢀ)
81 (ꢀ)
80 (ꢀ)
64 (ꢀ)
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7
8
9e
9f
67
96
53
10 (ꢀ)
90 (ꢀ)
49 (ꢀ)
1
2
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5
9g
6
a
o
The reaction of 2a (0.17 mmol) and 1a (0.15 mmol) was performed in the presence of cat. (10 mol%) in 1.5 mL of MTBE at 25 C for 2.5
7
8
9
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b
c
d
h. Isolated yield of 11aa. The ee of 11aa was determined by chiral HPLC analysis. Optical rotation.
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Further optimization of the reaction conditions was carried out, after which other dithiomalonates were
investigated (Table 2). Screening the solvents MTBE, CH Cl , and toluene, determined toluene to be the
2
2
best solvent (Table 2, entries 1 and 2). Lowering the catalyst loading to 5 mol% did not affect either the
o
yield or the enantioselectivity. When the reaction was carried out with 5 mol% of 9f at 25 C, 11aa was
obtained in 94% yield and 90% ee, which were identified as the optimized conditions (Table 2, entry 3).
1
3
We then applied these catalytic conditions to other dithiomalonates (Table 2, entries 4ꢀ6). Both
aromatic and aliphatic dithiomalonates provided Michael adducts 11 in high yield and good
enantioselectivity, with aromatic dithiomalonates displaying higher reactivity than aliphatic
dithiomalonates.
Table 2. Reaction condition optimization for the enantioselective Michael addition of 2 to 1a using
a
9
f as a catalyst
b
c
Entry
1
2
R
Ph
11
9f (mol%)
t (h)
1.5
1.5
1.5
1.5
12
yield (%)
ee (%)
2a
2a
2a
2b
2c
2d
11aa
11aa
11aa
11ab
11ac
11ad
10
10
5
98
80
94
92
95
93
90
d
2
Ph
87
3
4
5
6
Ph
90
4ꢀMeOPh
5
92
nꢀpropyl
5
73
ethyl
5
12
89
a
o
Unless otherwise noted, all reactions were carried out between 2 (0.15 mmol) with 1a (0.30 mmol) in 1.5 mL of toluene at 25 C.
b
c
d
Isolated yield of 11. The ee of 11 was determined by chiral HPLC analysis. CH Cl was used instead of toluene.
2
2
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With optimized reaction conditions in hand, a variety of aromatic and heteroaromatic transꢀβꢀ
nitroolefins were investigated (Table 3). Regardless of the electronic properties of substituents on the
aromatic transꢀβꢀnitroolefin, the products 11 were obtained with high enantioselectivities and in
excellent yields, and orthoꢀsubstituted aromatic nitroolefins furnished the desired products with better
enantioselectivities (Table 3, entries 3, 5, and 9).
1
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5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
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2
2
2
2
2
2
2
2
3
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3
3
3
3
4
4
4
4
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4
4
4
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4
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5
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5
5
5
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0
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2
3
4
5
6
7
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9
0
1
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3
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5
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7
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9
0
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0
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0
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7
8
9
0
a
Table 3. Enantioselective Michael addition of 2a to aromatic trans-β-nitroolefins catalyzed by 9f
b
c
d
Entry
1
Ar
11
t (h)
1.5
1.0
0.5
1.0
0.5
1.5
1.0
2.0
1.0
0.5
0.5
0.5
yield (%)
94
ee (%)
ee (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
phenyl
11aa
11ba
11ca
11da
11ea
11fa
11ga
11ha
11ia
11ja
11ka
11la
90
98
4ꢀFꢀC H
92
87
>99
6
4
e
2ꢀFꢀC H
99
91
ꢀ
6
4
4ꢀBrꢀC H
98
90
>99
6
4
e
2ꢀBrꢀC H
98
97
ꢀ
6
4
4ꢀCF ꢀC H
4
88
92
>99
93
3
6
1g
1h
1i
4ꢀMeꢀC H
6
4
94
90
4ꢀMeOꢀC H
98
87
94
6
4
e
2ꢀMeOꢀC H
98
94
ꢀ
6
4
e
1
1
1
0
1
2
1j
2ꢀthienyl
2ꢀfuryl
99
90
ꢀ
e
1k
1l
98
93
ꢀ
2ꢀnaphthyl
92
86
>99
a
All of the reactions were carried out between 2a (0.15 mmol) and 1 (0.30 mmol) in the presence of 9f (5 mol%) in 1.5 mL of toluene at 25
o
b
c
d
e
C. Isolated yield of 11. The ee was determined by chiral HPLC analysis. The ee was determined after recrystallization from ethanol.
Not determined.
Encouraged by the results exhibited in Table 3, we applied these catalytic conditions to reactions
between dithiomalonates 2 and a range of aliphatic transꢀβꢀnitroolefins 1. However, when the optimized
conditions were applied to the reaction between (E)ꢀ1ꢀnitropentꢀ1ꢀene 1m and 2a, the desired product
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o
1
1ma was obtained in 78% ee (Table 4, entry 1). Lowering the temperature to –40 C significantly
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
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5
5
5
5
5
5
5
5
6
improved the enantioselectivity to 90% ee (Table 4, entry 2). When R substituents of 1 were primary
alkyl groups such as nꢀpropyl, isobutyl, 2ꢀphenylethyl, and the longꢀchain nꢀhexyl group, the reactions
proceeded well in high yields and enantioselectivities (Table 4, entries 2ꢀ6), By contrast, this protocol
with secondary substituents, such as a cyclohexyl group, provided the corresponding products 11qa and
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5
6
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8
9
0
1
2
3
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8
9
0
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9
0
1
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9
0
1
2
3
4
5
6
7
8
9
0
o
1
1qb in lower yields and enantioselectivities at 25 C (Table 4, entries 7 and 8).
a
Table 4. Enantioselective Michael addition of 2 to aliphatic trans-β-nitroolefins catalyzed by 9f
b
c
entry
1
R
2
11
t (h)
1
yield (%)
96
ee (%)
d
1
1m
1m
1n
1o
1p
1p
1q
1q
nꢀpropyl
nꢀpropyl
isobutyl
2a
2a
2a
2a
2a
2b
11ma
11ma
11na
11oa
11pa
11pb
11qa
11qb
78
2
3
4
5
6
16
16
14
12
48
72
120
93
90
96
86
2ꢀphenylethyl
95
90
nꢀhexyl
nꢀhexyl
97
86
95
85
d,e
7
cyclohexyl
cyclohexyl
2a
2b
65
81
d,e
8
82
82
a
Unless otherwise noted, all of the reactions were carried out between 2 (0.15 mmol) and 1 (0.30 mmol) in the presence of 9f (5 mol%) in
o
b
c
d
o
e
1
.5 mL of toluene at –40 C. Isolated yield. The ee was determined by chiral HPLC analysis. The reaction was conducted at 25 C. 10
mol% 9f was used.
To demonstrate the synthetic utility of our methodology, further chemical transformations of adduct
11aa were carried out as illustrated in Scheme 3. (R)ꢀPhenibut is a therapeutically useful agonist of γꢀ
1
4
aminobutyric acid (GABA) typeꢀB receptors and is used as a neuropsychotropic drug. Reduction of
the nitro group of 11aa to the amine using zinc/acetic acid and TiCl , followed by intramolecular
3
8c
cyclization to form the lactam 12, and acidic hydrolysis generated the antidepressant (R)ꢀphenibut 13.
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Additionally, adduct 11aa was desymmetrized through a tandem hydrolysisꢀdecarboxylation reaction to
form 14 under mildly basic conditions in 94% yield. Monothioester 14 was converted to 15 by
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
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4
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4
4
4
5
5
5
5
5
5
5
5
5
5
6
7
c
Fukuyama reduction in the presence of activated 4 Å molecular sieves, and 14 was also transformed to
15
the known lactam 16 in 82% yield through the reductionꢀcyclization reaction sequence described
16
above. Comparison of the optical rotation data and chiral HPLC spectrum of 16 with reported data
confirmed the absolute stereochemistry of 11aa as the R enantiomer.
0
1
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7
8
9
0
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9
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8
9
0
Scheme 3. Transformations of adduct 11aa
The observed stereochemistry for the asymmetric Michael addition of dithiomalonates 2 to transꢀβꢀ
nitroolefins 1 using 9f as catalyst can be rationalized by the transitionꢀstate model shown in Figure 1.
There are two generally accepted mechanisms for adduct formation in relevant catalytic Michael
17
addition reactions. Deprotonation of the acidic proton from dithiomalonate 2a by the tertiary amino
group of Nꢀmethylpyrrolidine leads to formation of an ammonium ion. In route A, nitroolefin 1a is
activated through interaction with the protonated amino group of 9f, while simultaneously the enolate of
1
7a, b
2
a interacts with the urea moiety of 9f through hydrogen bonding to form the ternary complex 17.
By contrast, in route B, 1a is activated by the urea moiety of 9f while the enolate of 2a coordinates to
17c
the protonated amino group of 9f to form the ternary complex 18. With either complex 17 or 18,
nucleophilic addition of the enolate of 2a from the re face of 1a leads to the same adduct, Rꢀ11aa, as the
major enantiomer.
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1
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43
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47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 1. Transitionꢀstate model for the asymmetric Michael addition between 2a and 1a catalyzed by 9f.
In conclusion, we have prepared seven novel Lꢀproline derived bifunctional organocatalysts, among
which 9f was successfully applied to the asymmetric Michael reaction of dithiomalonates 2 to transꢀβꢀ
nitroolefins 1 in high yields and enantioselectivities. To the best of our knowledge, this is the first
example of the Michael addition to nitroolefins using dithiomalonates as Michael donors. This
methodology was successfully applied to an efficient synthesis of the neuropsychotropic drug, (R)ꢀ
phenibut. The absolute configuration of 11 was the same as that predicted by the transitionꢀstate model
in Figure 1. Further investigations of the application of these novel catalysts are in progress.
EXPERIMENTAL SECTION
General Information. Unless stated otherwise, reagents were used directly as obtained commercially.
Reactions were monitored by thin layer chromatography. Flash column chromatography was performed
1
13
using silica gel (40ꢀ60 µm particle size). H NMR (500 MHz) and C NMR (125 MHz) spectra were
measured and chemical shifts are reported in ppm using TMS or the residual solvent peak as a reference.
Infrared spectra were recorded on FTꢀIR. HRMS were recorded on an EI/FABꢀMagnetic Sector mass
spectrometer and MS were obtained using an ESIꢀQTOF mass spectrometer. Analytical high
performance liquid chromatography (HPLC) was performed using the indicated chiral column (4.6 mm
×
25 cm). Optical rotations were determined on a polarimeter at 589 nm. Melting points were
determined using a melting point apparatus and are uncorrected.
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1
8
General procedure for the synthesis of dithiomalonates 2. To a stirred solution of malonyl chloride
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
0.19 mL, 2 mmol, 1 equiv) in dry Et O (5 ml), thiol (4.4 mmol, 2.2 equiv) was added and the resulting
2
mixture was stirred for 16 h at room temperature. The mixture was quenched with H O (10 mL) and
2
extracted with Et O (10 mL×3). The combined organic layers were washed with brine, dried over
2
Na SO , and concentrated in vacuo. The crude product was purified by flash column chromatography on
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
4
silica gel.
S,S’ꢀdiphenyl dithiomalonate (2a). Following the general procedure with thiophenol (0.45 ml, 4.4
mmol, 2.2 equiv), 2a was obtained as a white solid (536 mg, 93% yield). Analytical data are consistent
1
8
1
with reported values. Rf : 0.43 (ethyl acetate : hexane = 1:5); H NMR (500 MHz, CDCl ) δ 7.47ꢀ7.41
3
13
(
m, 10H), 3.96 (s, 2H) ppm; C NMR (125 MHz, CDCl ) δ 188.8, 134.5, 129.9, 129.4, 126.7, 56.5 ppm;
3
ꢀ1
IR (neat) 2955, 2916, 1715, 1691, 1477, 1440, 1396, 1307, 1030, 975, 707, 689 cm ; MS (ESIꢀQTOF)
+
m/z: [M + Na] Calcd for C H NaO S 311.018, found 311.011; mp: 95ꢀ96 °C.
15
12
2 2
S,S’ꢀbis(4ꢀmethoxyphenyl) dithiomalonate (2b). Following the general procedure with 4ꢀ
methoxythiophenol (0.54 ml, 4.4 mmol, 2.2 equiv), 2b was obtained as a white solid (488 mg, 70%
1
yield). Rf : 0.23 (ethyl acetate : hexane = 1:5); H NMR (500 MHz, CDCl ) δ 7.36ꢀ7.33 (m, 4H), 6.96ꢀ
3
1
3
6
.93 (m, 4H), 3.91 (s, 2H), 3.83 (s, 6H) ppm; C NMR (125 MHz, CDCl ) δ 190.0, 161.0, 136.2, 117.4,
3
115.1, 56.1, 55.4 ppm; IR (neat) 2941, 2840, 1713, 1689, 1593, 1495, 1291, 1250, 1174, 1028, 976, 827
ꢀ1
+
cm ; HRMS (EIꢀMagnetic Sector) m/z: [M] Calcd for C H O S 348.0490, found 348.0489; mp: 67ꢀ
1
7
16
4 2
7
0 °C.
S,S’ꢀdipropyl dithiomalonate (2c). Following the general procedure with 1ꢀpropanethiol (0.40 ml, 4.4
mmol, 2.2 equiv), 2c was obtained as a colorless oil (278 mg, 63% yield). Rf : 0.63 (ethyl acetate:
1
hexane = 1:5); H NMR (500 MHz, CDCl ) δ 3.77 (s, 2H), 2.91 (t, J = 7.2 Hz, 4H), 1.67ꢀ1.59 (m, 4H),
3
13
0
2
.97 (t, J = 7.4 Hz, 6H) ppm; C NMR (125 MHz, CDCl ) δ 190.7, 57.8, 31.5, 22.6, 13.3 ppm; IR (neat)
3
ꢀ1
965, 2932, 2875, 1701, 1676, 1458, 1408, 1379, 1290, 1242, 1195, 1060, 1041, 990, 910, 785 cm ;
+
HRMS (EIꢀMagnetic Sector) m/z: [M] Calcd for C H O S 220.0592, found 220.0593.
9
16
2 2
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S,S’ꢀdiethyl dithiomalonate (2d). Following the general procedure with ethanethiol (0.32 ml, 4.4
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
mmol, 2.2 equiv), 2d was obtained as a light yellow oil (250 mg, 65% yield). Analytical data are
1
9
1
consistent with reported values. Rf : 0.60 (ethyl acetate: hexane = 1:5); H NMR (500 MHz, CDCl ) δ
3
13
3
1
.77 (s, 2H), 2.94 (q, J = 7.4 Hz, 4H), 1.28 (t, J = 7.4 Hz, 6H) ppm; C NMR (125 MHz, CDCl ) δ
3
ꢀ1
90.7, 57.7, 24.1, 14.4 ppm; IR (neat) 2977, 2865, 1700, 1675, 1454, 1265, 1054, 1033, 1014 cm ; MS
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
(
ESIꢀQTOF) m/z: [M + Na] Calcd for C H NaO S 215.018, found 215.013.
7
12
2 2
10
General procedure for synthesis of 5a, 5b, 5c. DIBALꢀH (1.0 M in hexane, 2.61 mL, 2.61 mmol,
1
.2 equiv) was added to a solution of Nꢀboc proline ethyl ester 4 (500 mg, 2.17 mmol, 1.0 equiv) in
CH Cl (10 mL) at –78 °C. The resulting solution was stirred at –78 °C for 30 min, followed by the
2
2
addition of ArMgBr (1.0 M in THF, 6.52 mL, 6.52 mmol, 3.0 equiv) dropwise at –78 °C. The solution
was then allowed to slowly warm to r.t. overnight. Sat. aq NH Cl (10 mL) was added to quench the
4
reaction. Sat. sodium tartrate solution (10 mL) was added to the resulting gel. The mixture was stirred at
r.t. for 30 min, and then the organic layer was extracted with CH Cl (3 × 15 mL). The combined
2
2
organic layers were dried over anhydrous Na SO and concentrated in vacuo. The crude material was
2
4
purified by flash column chromatography on silica gel to provide the product 5.
S)ꢀtertꢀbutyl 2ꢀ((S)ꢀhydroxy(phenyl)methyl)pyrrolidineꢀ1ꢀcarboxylate (5a). Following the general
procedure with phenyl magnesium bromide (1.0 M in THF, 6.52 mL, 6.52 mmol), 5a was obtained as a
(
2
0
colorless oil (445 mg, 74% yield). Analytical data are consistent with reported values. Rf : 0.23 (ethyl
1
acetate: hexane = 1:5); H NMR (500MHz, CDCl ) δ 7.36ꢀ7.25 (m, 5H), 5.89 (br s, 1H), 4.52 (br d, J =
3
7
.2 Hz, 1H), 4.09 (td, J = 8.4, 3.8Hz, 1H), 3.48ꢀ3.43 (m, 1H), 3.38ꢀ3.34 (m, 1H), 1.80ꢀ1.69 (m, 2H),
1
3
1.64ꢀ1.39 (m, 2H), 1.52 (s, 9H) ppm; C NMR (125 MHz, CDCl ) δ 158.4, 142.7, 128.4, 127.8, 127.3,
3
8
0.8, 79.3, 64.3, 47.8, 28.7, 28.6, 23.9 ppm; IR (neat) 3406 (br signal), 2989, 1692, 1669, 1405, 1254,
ꢀ1
+
1
164, 1117, 1054, 1033, 703 cm ; MS (ESIꢀQTOF) m/z: [M + Na] Calcd for C H NNaO 300.158,
16 23 3
2
0
found 300.151; [α] = ꢀ2.4 (c = 1.0, CHCl3).
D
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(
S)ꢀtertꢀbutyl 2ꢀ((S)ꢀ(3,5ꢀdimethylphenyl)(hydroxy)methyl)pyrrolidineꢀ1ꢀcarboxylate (5b). Following
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
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3
3
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4
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4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
the general procedure with 3,5ꢀdimethylphenyl magnesium bromide (1.0 M in THF, 6.52 mL, 6.52
mmol), 5b was obtained as a colorless oil (464 mg, 70% yield). Rf : 0.29 (ethyl acetate: hexane = 1:5);
1
H NMR (500MHz, CDCl ) δ 6.96ꢀ6.88 (m, 3H), 5.76 (br s, 1H), 4.42 (br d, J = 6.9 Hz, 1H), 4.08 (td, J
3
=
8.6, 3.5 Hz, 1H), 3.48ꢀ3.42 (m, 1H), 3.39ꢀ3.34 (m, 1H), 2.30 (s, 6H), 1.85ꢀ1.69 (m, 2H), 1.64ꢀ1.38 (m,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
2
6
H), 1.51 (s, 9H) ppm; C NMR (125 MHz, CDCl ) δ 158.3, 142.6, 137.8, 129.4, 125.1, 80.7, 79.3,
3
4.1, 47.6, 28.6, 28.5, 23.8, 21.3 ppm; IR (neat) 3401 (br signal), 2974, 1664, 1402, 1366, 1265, 1166,
ꢀ1
+
1120, 849 cm ; HRMS (FABꢀMagnetic Sector) m/z: [M + H] Calcd for C H NO 306.2069, found
1
8
28
3
20
3
06.2071; [α] = +6.0 (c = 1.0, CHCl3).
D
(S)ꢀtertꢀbutyl 2ꢀ((S)ꢀhydroxy(naphthalenꢀ2ꢀyl)methyl)pyrrolidineꢀ1ꢀcarboxylate (5c). Following the
general procedure with naphthyl magnesium bromide (1.0 M in THF, 6.52 mL, 6.52 mmol), 5c was
1
obtained as a light yellow oil (547 mg, 77% yield). Rf : 0.25 (ethyl acetate: hexane = 1:5); H NMR
(
500MHz, CDCl ) δ) 7.83ꢀ7.77 (m, 4H), 7.54ꢀ7.43 (m, 3H), 6.00 (br s, 1H), 4.69 (br d, J = 7.5 Hz, 1H),
3
4
2
1
.19 (td, J = 8.4, 4.3 Hz, 1H), 3.49ꢀ3.44 (m, 1H), 3.39ꢀ3.31 (m, 1H), 1.76ꢀ1.66 (m, 2H), 1.62ꢀ1.40 (m,
1
3
H), 1.53 (s, 9H) ppm; C NMR (125 MHz, CDCl ) δ 158.4, 140.1, 133.22, 133.19, 128.2, 128.0, 127.7,
3
26.4, 126.0, 125.8, 125.1, 80.9, 79.5, 64.2, 47.8, 28.8, 28.5, 23.9 ppm; IR (neat) 3400 (br signal), 3057,
ꢀ1
2975, 2881, 1690, 1665, 1402, 1367, 1256, 1169, 1124, 1062, 901, 858, 821, 775, 750 cm ; HRMS (EIꢀ
+
20
Magnetic Sector) m/z: [M] Calcd for C H NO 327.1834, found 327.1837; [α] = ꢀ6.8 (c = 1.0,
D
2
0
25
3
CHCl3).
General procedure for synthesis of 6a, 6b, 6c. A 25 mL flameꢀdried flask was charged with
compound 5 (1.5 mmol, 1 equiv) and PPh (0.787 g, 3.0 mmol, 2 equiv). The reaction vessel was
3
evacuated and backfilled with argon and this process repeated three times. Anhydrous THF (7 mL) was
added and the mixture was cooled to 0 °C whereupon diethyl azodicarboxylate (0.47 mL, 3.0 mmol, 2
equiv) was added dropwise. Then diphenyl phosphoryl azide (0.39 mL, 1.8 mmol, 1.2 equiv) was added
by a similar way. The reaction vessel was slowly warmed to 25 °C and stirred overnight. The reaction
mixture was concentrated in vacuo, after which water (10 mL) was added. The mixture was extracted
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with EtOAc three times (10 mL×3). The combined organic layers were dried over anhydrous Na SO ,
2
4
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel to
afford the product 6.
(S)ꢀtertꢀbutyl 2ꢀ((R)ꢀazido(phenyl)methyl)pyrrolidineꢀ1ꢀcarboxylate (6a). Following the general
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
procedure with compound 5a (416 mg, 1.5 mmol), the desired product was obtained as a colorless oil
1
(354 mg, 78% yield). Rf : 0.55 (ethyl acetate: hexane = 1:5); H NMR (500MHz, CDCl ) (60:40 mixture
3
of rotamers) δ 7.35ꢀ7.26 (m, 5H), 5.54 (br s, 0.57H), 5.20 (br s, 0.39H), 4.06 (br s, 0.61H), 3.98 (br s,
0
.40H), 3.63ꢀ3.59 (m, 0.42H), 3.53ꢀ3.48 (m, 0.61H), 3.45ꢀ3.40 (m, 1H), 2.04ꢀ1.96 (m, 1H), 1.91ꢀ1.80
13
(m, 1H), 1.73ꢀ1.68 (m, 1H), 1.62ꢀ1.57 (m, 1H), 1.54 (s, 3.62H), 1.51 (s, 5.43H) ppm; C NMR (125
MHz, CDCl ) (mixture of rotamers) δ 154.8, 154.2, 137.8, 128.7, 128.5, 127.8, 127.5, 126.5, 126.4,
3
8
0.1, 79.8, 67.4, 65.6, 62.9, 62.8, 47.7, 47.2, 28.6, 26.0, 25.1, 24.3, 23.6 ppm; IR (neat) 2979, 2103,
ꢀ1
+
1691, 1393, 1259, 1172, 1120, 700 cm ; HRMS (FABꢀMagnetic Sector) m/z: [M + H] Calcd for
20
C H N O 303.1821, found 303.1818; [α] = ꢀ93.5 (c = 1.0, CHCl3).
16
23
4
2
D
(S)ꢀtertꢀbutyl 2ꢀ((R)ꢀazido(3,5ꢀdimethylphenyl)methyl)pyrrolidineꢀ1ꢀcarboxylate (6b). Following the
general procedure with compound 5b (458 mg, 1.5 mmol), the desired product was obtained as a
1
colorless oil (322 mg, 65% yield). Rf : 0.60 (ethyl acetate: hexane = 1:5); H NMR (500MHz, CDCl )
3
(60:40 mixture of rotamers) δ 6.97ꢀ6.90 (m, 3H), 5.47 (br s, 0.59H), 5.12 (br s, 0.36H), 4.04 (br s,
0.60H), 3.96 (br s, 0.40H), 3.65ꢀ3.57 (m, 0.40H), 3.52ꢀ3.47 (m, 0.60H), 3.45ꢀ3.41 (m, 1H), 2.30 (s, 6H),
2
5
.05ꢀ1.97 (m, 1H), 1.94ꢀ1.83 (m, 1H), 1.73ꢀ1.69 (m, 1H), 1.68ꢀ1.58 (m, 1H), 1.54 (s, 3.61H), 1.51 (s,
1
3
.43H) ppm; C NMR (125 MHz) (mixture of rotamers) δ 154.9, 154.2, 138.2, 138.1, 137.7, 129.4,
129.2, 124.23, 124.16, 80.1, 79.7, 67.5, 65.8, 62.9, 62.7, 47.7, 47.2, 28.6, 26.1, 25.0, 24.3, 23.6, 21.3
ꢀ1
ppm; IR (neat) 2978, 2882, 2101, 1689, 1603, 1391, 1366, 1273, 1257, 1165, 1118, 852, 775, 700 cm ;
+
20
HRMS (FABꢀMagnetic Sector) m/z: [M + H] Calcd for C H N O 331.2134, found 331.2137; [α]
D
18 27
4
2
=
ꢀ97.0 (c = 1.0, CHCl3).
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(
S)ꢀtertꢀbutyl 2ꢀ((R)ꢀazido(naphthalenꢀ2ꢀyl)methyl)pyrrolidineꢀ1ꢀcarboxylate (6c). Following the
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
general procedure with compound 5c (491 mg, 1.5 mmol), the desired product 6c was obtained as a
1
colorless oil (264 mg, 50% yield). Rf : 0.40 (ethyl acetate: hexane = 1:5); H NMR (500MHz, CDCl )
3
(
60:40 mixture of rotamers) δ 7.83ꢀ7.78 (m, 4H), 7.49ꢀ7.37 (m, 3H), 5.71 (br s, 0.61H), 5.36 (br s,
0
1
.37H), 4.18 (br s, 0.60H), 4.09 (br s, 0.40H), 3.65ꢀ3.61 (m, 0.40H), 3.55ꢀ3.50 (m, 0.62H), 3.49ꢀ3.44 (m,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
H), 2.07ꢀ2.00 (m, 1H), 1.99ꢀ1.90 (m, 1H), 1.74ꢀ1.69 (m, 1H), 1.67ꢀ1.58 (m, 1H), 1.55 (s, 3.64H), 1.52
13
(
s, 5.47H) ppm; C NMR (125 MHz, CDCl ) (mixture of rotamers) δ 154.9, 154.2, 135.3, 133.2, 132.8,
3
128.5, 128.2, 128.0, 127.7, 126.5, 126.3, 126.0, 125.3, 124.5, 124.3, 80.2, 79.8, 67.6, 65.8, 62.8, 62.6,
7.7, 47.3, 28.6, 26.1, 25.1, 24.3, 23.6 ppm; IR (neat) 3060, 2974, 2102, 1688, 1392, 1367, 1258, 1168,
4
ꢀ1
+
1
120, 928, 900, 861, 815, 775, 744 cm ; HRMS (FABꢀMagnetic Sector) m/z: [M + H] Calcd for
2
0
C H N O 353.1978, found 353.1976; [α] = ꢀ122 (c = 1.0, CHCl3).
2
0
25
4
2
D
General procedure for synthesis of 7a, 7b, 7c. TFA (3 mL) was added to a stirred solution of 6 (1
o
mmol, 1 equiv.) in CH Cl (3 mL) at 0 C under an argon atmosphere. The resulting solution was
2
2
warmed to 25 °C and stirred overnight. The reaction mixture was concentrated in vacuo, the residue was
dissolved in 5mL of CH Cl and then treated with saturated aqueous NaHCO solution for 1 h at 25 °C.
2
2
3
The resulting mixture was extracted with CHCl three times (5 mL×3). The combined organic layers
3
were dried over anhydrous Na SO , and concentrated in vacuo. Then H O (1 mL), HCOOH (98%, 0.5
2
4
2
mL) and HCHO (37% aqueous solution, 0.75 mL) were added to the residue. The resulting mixture was
refluxed for 5 h. The reaction mixture was then cooled to room temperature, basified with saturated
aqueous NaOH solution, and extracted with CH Cl (3 mL×3). The combined organic layers were dried
2
2
over anhydrous Na SO4 and concentrated in vacuo. The residue was purified by column
2
chromatography on silica gel to afford the product 7.
(S)ꢀ2ꢀ((R)ꢀazido(phenyl)methyl)ꢀ1ꢀmethylpyrrolidine (7a). Following the general procedure with
compound 6a (302 mg, 1 mmol), the desired product was obtained as a yellow oil (188 mg, 87% yield).
1
Rf : 0.33 (ethyl acetate: hexane = 1:5); H NMR (500MHz, CDCl ) δ 7.38ꢀ7.35 (m, 2H), 7.32ꢀ7.28 (m,
3
3
H), 4.70 (d, J = 3.9 Hz, 1H), 3.14ꢀ3.11 (m, 1H), 2.51ꢀ2.47 (m, 1H), 2.34 (s, 3H), 2.26ꢀ2.20 (m, 1H),
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The Journal of Organic Chemistry
1
3
1
.94ꢀ1.88 (m, 1H), 1.83ꢀ1.74 (m, 1H), 1.68ꢀ1.63 (m, 1H), 1.62ꢀ1.54 (m, 1H) ppm; C NMR (125 MHz,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
CDCl ) δ 138.4, 128.6, 127.8, 127.0, 71.0, 66.6, 57.5, 41.0, 25.9, 22.8 ppm; IR (neat) 2791, 2101, 1451,
3
ꢀ1
+
1353, 1288, 1253, 700 cm ; HRMS (FABꢀMagnetic Sector) m/z: [M + H] Calcd for C H N
4
1
2
17
20
2
17.1453, found 217.1455; [α] = ꢀ161.5 (c = 1.0, CHCl3).
D
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(S)ꢀ2ꢀ((R)ꢀazido(3,5ꢀdimethylphenyl)methyl)ꢀ1ꢀmethylpyrrolidine (7b). Following the general
procedure with compound 6b (330 mg, 1 mmol), the desired product was obtained as a yellow solid
1
(
215 mg, 88% yield). Rf : 0.33 (ethyl acetate: hexane = 1:5); H NMR (500MHz, CDCl ) δ 6.92ꢀ6.90 (m,
3
3
H), 4.63 (d, J = 3.8 Hz, 1H), 3.14ꢀ3.11 (m, 1H), 2.48ꢀ2.44 (m, 1H), 2.35 (s, 3H), 2.32 (s, 6H), 2.24ꢀ
13
2.17 (m, 1H), 1.94ꢀ1.88 (m, 1H), 1.84ꢀ1.74 (m, 1H), 1.67ꢀ1.62 (m, 1H), 1.61ꢀ1.55 (m, 1H) ppm; C
NMR (125 MHz, CDCl ) δ 138.3, 138.1, 129.5, 124.7, 71.0, 66.6, 57.5, 40.9, 25.8, 22.8, 21.4 ppm; IR
3
ꢀ1
(
neat) 2959, 2786, 2100, 1604, 1457, 1352, 1275, 848, 701 cm ; HRMS (FABꢀMagnetic Sector) m/z:
+
20
[M + H] Calcd for C H N 245.1766, found 245.1768; [α]
= ꢀ187.3 (c = 1.0, CHCl ); mp: 50ꢀ
3
1
4
21
4
D
5
5 °C.
S)ꢀ2ꢀ((R)ꢀazido(naphthalenꢀ2ꢀyl)methyl)ꢀ1ꢀmethylpyrrolidine (7c). Following the general procedure
(
with compound 6c (352 mg, 1 mmol), the desired product was obtained as a yellow oil (242 mg, 91%
1
yield). Rf : 0.23 (ethyl acetate: hexane = 1:5); H NMR (500MHz, CDCl ) δ 7.85ꢀ7.79 (m, 4H), 7.51ꢀ
3
7
.41 (m, 3H), 4.86 (d, J = 4.0 Hz, 1H), 3.15ꢀ3.12 (m, 1H), 2.61ꢀ2.57 (m, 1H), 2.35 (s, 3H), 2.26ꢀ2.21 (m,
1
3
1H), 2.00ꢀ1.93 (m, 1H), 1.85ꢀ1.76 (m, 1H), 1.67ꢀ1.62 (m, 1H), 1.61ꢀ1.54 (m, 1H) ppm; C NMR (125
MHz, CDCl ) δ 135.9, 133.2, 132.9, 128.4, 128.0, 127.7, 126.4, 126.2, 126.1, 124.8, 70.9, 66.8, 57.6,
3
4
1.1, 26.1, 22.9 ppm; IR (neat) 3058, 2966, 2844, 2783, 2100, 1602, 1509, 1454, 1364, 1271, 1046, 897,
ꢀ1
+
857, 818, 746 cm ; HRMS (FABꢀMagnetic Sector) m/z: [M + H] Calcd for C H N 267.1610, found
1
6
19
4
20
2
67.1611; [α] = ꢀ215.7 (c = 1.0, CHCl3).
D
(S)ꢀ2ꢀ((R)ꢀazido(phenyl)methyl)ꢀ1ꢀbenzylpyrrolidine (7d). TFA (3 mL) was added to a stirred solution
o
of 6a (302 mg, 1 mmol, 1 equiv.) in CH Cl (3 mL) at 0 C under an argon atmosphere. The resulting
2
2
solution was warmed to 25 °C and stirred overnight. The reaction mixture was concentrated in vacuo,
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Page 16 of 37
the residue was dissolved in 5mL of CH Cl and then treated with a saturated aqueous NaHCO solution
2
2
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
for 1 h at 25 °C. The aqueous layer was extracted with CHCl three times (5 mL×3). The combined
3
organic layers were dried over anhydrous Na SO , and concentrated in vacuo. Without purification, the
2
4
residue was dissolved in dry DMF (2.4 mL), whereupon K CO (166 mg, 1.2 mmol, 1.2 equiv) was
2
3
added and stirred for 10 minutes. Then benzyl bromide (0.14 mL, 1.2 mmol, 1.2 equiv) was added and
the resulting mixture was stirred for additional 10 h at room temperature. The reaction mixture was
diluted with water (8 mL) and extracted with CH Cl (5 mL×3). The extract was washed three times
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
2
with water (10 mL×3), dried over anhydrous Na SO and concentrated in vacuo. The residue was
2
4,
purified by column chromatography on silica gel to afford the product 7d as a light yellow oil (278 mg,
11
1
9
5%). Analytical data are consistent with reported values . Rf : 0.70 (ethyl acetate: hexane = 1:5); H
NMR (500MHz, CDCl ) δ 7.35ꢀ7.29 (m, 6H), 7.26ꢀ7.20 (m, 4H), 4.57 (d, J = 3.7 Hz, 1H), 3.92 (d, J =
3
1
1
2.9 Hz, 1H), 3.47 (d, J = 12.9 Hz, 1H), 3.04ꢀ3.00 (m, 1H), 2.94ꢀ2.90 (m, 1H), 2.27ꢀ2.22 (m, 1H), 1.94ꢀ
1
3
.88 (m, 1H), 1.82ꢀ1.74 (m, 1H), 1.68ꢀ1.58 (m, 2H) ppm; C NMR (125 MHz, CDCl ) δ 139.5, 138.6,
3
128.9, 128.5, 128.4, 127.7, 127.1, 127.0, 69.8, 67.4, 59.8, 55.0, 26.1, 23.7 ppm; IR (neat) 3068, 2970,
ꢀ1
+
2
794, 2100, 1495, 1452, 1351, 1293, 698 cm ; MS (ESIꢀQTOF) m/z: [M + H] Calcd for C H N
18 21 4
2
0
11
20
2
93.177, found 293.171; [α] = ꢀ100.4 (c = 1.0, CHCl ), [lit. [α] = ꢀ97 (c = 1.0, CHCl )].
D
3
D
3
General procedure for synthesis of 9a, 9b, 9c, 9d. To a stirred suspension of LiAlH (30 mg, 0.8
4
mmol, 1 equiv) in 0.8 mL of dry THF, a solution of compound 7 (0.8 mmol, 1 equiv) in 1.6 mL of dry
o
THF was added dropwise at 0 C under an argon atmosphere. The reaction mixture was stirred at room
temperature for 1.5 h and then quenched by a 5% aqueous sodium potassium tartarate solution. The
resulting mixture was filtered through a pad of Celite, dried over anhydrous Na SO , and concentrated
2
4
in vacuo. The residue was dissolved in dry CH Cl (2.4 mL), then 3,5ꢀbis(trifluoromethyl)phenyl
2
2
isothiocyanate (0.18 mL, 0.96 mmol, 1.2 equiv) was added and stirred overnight at room temperature.
The reaction mixture was concentrated in vacuo and purified by column chromatography on silica gel to
afford the desired product.
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The Journal of Organic Chemistry
1
ꢀ(3,5ꢀbis(trifluoromethyl)phenyl)ꢀ3ꢀ((R)ꢀ((S)ꢀ1ꢀmethylpyrrolidinꢀ2ꢀyl)(phenyl)methyl)thiourea (9a).
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Following the general procedure with compound 7a (173 mg, 0.8 mmol), the desired product was
1
obtained as a white solid (288 mg, 78% yield). Rf : 0.69 (methylene chloride: methanol = 10:1); H
NMR (500MHz, CD OD) δ 8.23 (s, 2H), 7.59 (s, 1H), 7.33ꢀ7.27 (m, 4H), 7.24ꢀ7.19 (m, 1H), 5.78 (br s,
3
13
1
H), 3.07 (t, J = 7.2 Hz, 1H), 2.66 (br s, 1H), 2.37 (s, 3H), 2.26 (br s, 1H), 1.72ꢀ1.46 (m, 4H) ppm; C
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
NMR (125 MHz, CD OD) δ 183.0, 143.4, 141.7, 132.6 (q, J = 33.2 Hz), 129.5, 128.2, 127.8, 124.7 (q, J
3
=
271.3 Hz), 123.2, 117.6, 71.6, 58.6, 58.1, 41.1, 26.9, 22.8 ppm; IR (neat) 1612, 1473, 1384, 1276,
ꢀ1
+
1176, 1131, 883, 699, 682cm ; HRMS (FABꢀMagnetic Sector) m/z: [M + H] Calcd for C H F N S
2
1
22
6
3
20
4
62.1439, found 462.1437; [α] = ꢀ52.4 (c = 1.0, CHCl ); mp: 49ꢀ51 °C.
D 3
1
ꢀ(3,5ꢀbis(trifluoromethyl)phenyl)ꢀ3ꢀ((R)ꢀ(3,5ꢀdimethylphenyl)((S)ꢀ1ꢀmethylpyrrolidinꢀ2ꢀ
yl)methyl)thiourea (9b). Following the general procedure with compound 7b (195 mg, 0.8 mmol), the
desired product was obtained as a light yellow foam (313 mg, 80% yield). Rf : 0.48 (methylene chloride:
1
methanol = 10:1); H NMR (500MHz, CDCl ) δ 13.80 (br s, 1H), 8.09 (s, 2H), 7.59 (s, 1H), 6.98 (s, 1H),
3
6
.90 (s, 2H), 6.45 (s, 1H), 4.92 (s, 1H), 3.19 (br s, 1H), 2.84 (br s, 1H), 2.61 (s, 3H), 2.52ꢀ2.43 (m, 1H),
13
2
.32 (s, 6H), 2.29ꢀ2.25 (m, 1H), 2.09ꢀ2.04 (m, 1H), 1.93ꢀ1.85 (m, 2H) ppm; C NMR (125 MHz,
CDCl ) δ 182.7, 142.3, 139.2, 138.8, 131.8 (q, J = 33.4 Hz), 130.3, 124.6, 123.3 (q, J = 272.7 Hz),
3
122.5, 117.6, 71.5, 62.1, 56.1, 40.8, 25.6, 24.4, 21.4 ppm; IR (neat) 1610, 1474, 1385, 1276, 1178, 1132,
ꢀ1
+
8
83, 699, 685 cm ; HRMS (EIꢀMagnetic Sector) m/z: [M] Calcd for C H F N S 489.1673, found
23 25 6 3
20
4
89.1675; [α] = ꢀ61.9 (c = 1.0, CHCl ); mp: 55ꢀ59 °C.
D
3
1
ꢀ(3,5ꢀbis(trifluoromethyl)phenyl)ꢀ3ꢀ((R)ꢀ((S)ꢀ1ꢀmethylpyrrolidinꢀ2ꢀyl)(naphthalenꢀ2ꢀ
yl)methyl)thiourea (9c). Following the general procedure with compound 7c (213 mg, 0.8 mmol), the
desired product was obtained as a light yellow foam (307 mg, 75% yield). Rf : 0.53 (methylene chloride:
1
methanol = 10:1); H NMR (500MHz, CDCl ) δ 13.85 (br s, 1H), 8.09 (s, 2H), 7.87ꢀ7.81 (m, 3H), 7.75
3
(
s, 1H), 7.61 (s, 1H), 7.53ꢀ7.52 (m, 2H), 7.38 (dd, J = 8.5, 1.7 Hz, 1H), 6.58 (br s, 1H), 5.18 (br s, 1H),
3
1
.23ꢀ3.20 (m, 1H), 2.95ꢀ2.89 (m, 1H), 2.63 (s, 3H), 2.51ꢀ2.46 (m, 1H), 2.39ꢀ2.30 (m, 1H), 2.15ꢀ2.04 (m,
1
3
H), 1.98ꢀ1.85 (m, 2H) ppm; C NMR (125 MHz, CDCl ) δ 182.8, 142.1, 136.1, 133.3, 133.0, 131.9 (q,
3
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Page 18 of 37
J = 32.5 Hz), 129.5, 128.0, 127.8, 127.0, 126.8, 125.7, 124.4, 123.2 (q, J = 272.8 Hz), 122.5, 117.6, 71.4,
2.0, 56.1, 40.7, 25.6, 24.4 ppm; IR (neat) 1610, 1473, 1385, 1277, 1177, 1132, 1038, 1002, 964, 883,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
ꢀ1
+
819, 700, 681 cm ; HRMS (EIꢀMagnetic Sector) m/z: [M] Calcd for C H F N S 511.1517, found
2
5
23
6
3
20
5
11.1514; [α] = ꢀ83.6 (c = 1.0, CHCl ); mp: 56ꢀ59 °C.
D 3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
ꢀ((R)ꢀ((S)ꢀ1ꢀbenzylpyrrolidinꢀ2ꢀyl)(phenyl)methyl)ꢀ3ꢀ(3,5ꢀbis(trifluoromethyl)phenyl)thiourea (9d).
Following the general procedure with compound 7d (234 mg, 0.8 mmol), the desired product was
obtained as a light yellow foam (357 mg, 83% yield). Rf : 0.83 (methylene chloride: methanol = 10:1);
1
H NMR (500MHz, CDCl ) δ 13.16 (br s, 1H), 7.72 (s, 2H), 7.60 (s, 1H), 7.39ꢀ7.34 (m, 3H), 7.25ꢀ7.18
3
(m, 3H), 7.15 (s, 4H), 6.51 (br s, 1H), 4.88 (br s, 1H), 4.01 (d, J = 12.4 Hz, 1H), 3.66 (d, J = 12.1 Hz,
1
3
1
H), 3.19ꢀ3.14 (m, 2H), 2.59ꢀ2.54 (m, 1H), 2.30 (br s, 1H), 2.03ꢀ1.84 (m, 3H) ppm; C NMR (125
MHz, CDCl ) δ 183.1, 141.4, 138.9, 136.2, 131.7 (q, J = 32.5 Hz), 129.7, 129.5, 128.8 (x2), 128.3,
3
126.9, 124.4, 123.1 (q, J = 272.8 Hz), 118.4, 69.7, 63.2, 60.7, 54.1, 25.7, 24.5 ppm; IR (neat) 1608,
ꢀ1
+
1
473, 1383, 1276, 1175, 1133, 886, 699, 681 cm ; HRMS (EIꢀMagnetic Sector) m/z: [M] Calcd for
2
0
C H F N S 537.1673, found 537.1670; [α] = ꢀ117.0 (c = 1.0, CHCl ); mp: 47ꢀ49 °C.
27 25
6
3
D
3
3ꢀ(3,5ꢀbis(trifluoromethyl)phenylamino)ꢀ4ꢀ((R)ꢀ((S)ꢀ1ꢀmethylpyrrolidinꢀ2ꢀ
yl)(phenyl)methylamino)cyclobutꢀ3ꢀeneꢀ1,2ꢀdione (9e). To a stirred suspension of LiAlH (30 mg, 0.8
4
mmol, 1 equiv) in 0.8 mL of dry THF, a solution of compound 7a (173 mg, 0.8 mmol, 1 equiv) in 1.6
o
mL of dry THF was added dropwise at 0 C under an argon atmosphere. The reaction mixture was
stirred at room temperature for 1.5 h and then quenched by a 5% aqueous sodium potassium tartarate
solution. The resulting mixture was filtered through a pad of Celite, dried over anhydrous Na SO , and
2
4
concentrated in vacuo. The residue was dissolved in dry CH Cl (2.4 mL), then 8 (273 mg, 0.8 mmol, 1
2
2
equiv) was added and stirred overnight at room temperature. The reaction mixture was concentrated in
vacuo and purified by column chromatography on silica gel to obtain the desired product as a yellow
1
solid (326 mg, 82% yield). Rf : 0.57 (methylene chloride: methanol = 10:1); H NMR (500MHz,
CD OD) δ 8.10 (br s, 2H), 7.55 (s, 1H), 7.39ꢀ7.35 (m, 4H), 7.30ꢀ7.26 (m, 1H), 5.59 (br s, 1H), 3.12ꢀ3.10
3
13
(
m, 1H), 2.75 (br s, 1H), 2.41 (s, 3H), 2.38ꢀ2.31 (m, 1H), 1.81ꢀ1.70 (m, 4H) ppm; C NMR (125 MHz,
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The Journal of Organic Chemistry
CD OD) δ 185.6, 182.4, 171.5, 164.4, 142.5, 141.1, 133.9 (q, J = 33.5 Hz), 129.9, 128.8, 127.5, 124.6
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(q, J = 272.1 Hz), 119.2, 116.5, 71.5, 59.2, 58.3, 41.0, 26.1, 23.1 ppm; IR (neat) 1792, 1680, 1594, 1558,
ꢀ1
+
1448, 1380, 1278, 1182, 1133, 751, 699 cm ; HRMS (FABꢀMagnetic Sector) m/z: [M + H] Calcd for
20
C H F N O 498.1616, found 498.1619; [α] = ꢀ60.4 (c = 0.5, CHCl ); mp: 150ꢀ160 °C decomposed.
24
22
6
3
2
D
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
ꢀ(3,5ꢀbis(trifluoromethyl)phenyl)ꢀ3ꢀ((R)ꢀ((S)ꢀ1ꢀmethylpyrrolidinꢀ2ꢀyl)(phenyl)methyl)urea (9f). To a
stirred suspension of LiAlH (30 mg, 0.8 mmol, 1 equiv) in 0.8 mL of dry THF, a solution of compound
4
o
7
a (173 mg, 0.8 mmol, 1 equiv) in 1.6 mL of dry THF was added dropwise at 0 C under an argon
atmosphere. The reaction mixture was stirred at room temperature for 1.5 h and then quenched by 5%
aqueous sodium potassium tartarate solution. The resulting mixture was filtered through a short Celite
pad, dried over anhydrous Na SO , and concentrated in vacuo. The residue was dissolved in dry CH Cl
2
2
4
2
(2.4 mL), then 3,5ꢀbis(trifluoromethyl)phenyl isocyanate (0.14 mL, 0.8 mmol, 1 equiv) was added and
stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and purified by
column chromatography on silica gel to obtain the desired product as a white solid (285 mg, 80% yield).
1
Rf : 0.52 (methylene chloride: methanol = 10:1); H NMR (500MHz, CDCl ) δ 7.75 (s, 2H), 7.35 (s,
3
1
H), 7.26ꢀ7.23 (m, 2H), 7.19ꢀ7.18 (m, 3H), 5.70 (br s, 1H), 4.81 (s, 1H), 3.07ꢀ3.04 (m, 1H), 2.66ꢀ2.64
13
(
m, 1H), 2.43 (s, 3H), 2.32ꢀ2.27 (m, 1H), 2.00ꢀ1.97 (m, 1H), 1.68 (br s, 3H) ppm; C NMR (125 MHz,
CDCl ) δ 156.7, 141.6, 140.1, 132.1 (q, J=33.1Hz), 129.0, 127.9, 126.4, 123.3 (q, J = 272.7 Hz), 118.1,
3
115.2, 71.0, 56.6 (x2), 40.3, 25.1, 23.2 ppm; IR (neat) 1660, 1574, 1507, 1476, 1390, 1277, 1193, 1131,
ꢀ1
+
7
01, 649 cm ; HRMS (FABꢀMagnetic Sector) m/z: [M + H] Calcd for C H F N O 446.1667, found
2
1
22
6
3
20
446.1669; [α] = ꢀ43.6 (c = 1.0, CHCl ); mp: 188ꢀ190 °C.
D
3
(S)ꢀ1ꢀ(3,5ꢀbis(trifluoromethyl)phenyl)ꢀ3ꢀ((1ꢀmethylpyrrolidinꢀ2ꢀyl)diphenylmethyl)urea (9g). A 10
12
mL round bottom flask was charged with amino azide 10 (415 mg, 1.49 mmol, 1 equiv), then H O (1.7
2
mL), HCOOH (98%, 0.85 mL) and HCHO (37% aqueous solution, 1.25 mL) were added. The resulting
mixture was refluxed for 5 h. The reaction mixture was then cooled to room temperature, basified with
saturated aqueous NaOH solution, and extracted with CH Cl (5 mL×3). The combined organic layers
2
2
were dried over anhydrous Na SO and concentrated in vacuo. The residue was dissolved in 2 mL of dry
2
4
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THF and was slowly added to a suspension of LiAlH (57 mg, 1.49 mmol, 1 equiv) in 1 mL of dry THF
4
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
o
at 0 C under an argon atmosphere. The reaction mixture was stirred at room temperature for 1.5 h, and
then quenched using a 5% aqueous sodium potassium tartarate solution. The resulting mixture was
filtered through a pad of Celite, dried over anhydrous Na SO , and concentrated in vacuo. The residue
2
4
was dissolved in dry CH Cl (4 mL), then 3,5ꢀbis(trifluoromethyl)phenyl isocyanate (0.26 mL, 1.49
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
2
mmol, 1 equiv) was added and stirred overnight at room temperature. The reaction mixture was
concentrated in vacuo and purified by column chromatography on silica gel to obtain the desired
1
product 9g as a white solid (427 mg, 55% yield). Rf : 0.32 (methylene chloride: methanol = 10:1); H
NMR (500MHz, CDCl ) δ 12.34 (br s, 1H), 7.70 (s, 2H), 7.44ꢀ7.36 (m, 5H), 7.29ꢀ7.24 (m, 4H), 7.21ꢀ
3
7
.16 (m, 2H), 5.59 (br s, 1H), 4.17 (dd, J = 9.6, 3.4 Hz, 1H), 3.06ꢀ3.02 (m, 1H), 2.57ꢀ2.52 (m, 1H),
1
3
2.31ꢀ2.22 (m, 1H), 2.26 (s, 3H), 2.08ꢀ2.04 (m, 1H), 1.76ꢀ1.75 (m, 1H), 1.63 (br s, 1H) ppm; C NMR
(
125 MHz, CDCl ) δ 156.6, 146.0, 142.8, 141.6, 132.0 (q, J = 33.1 Hz), 128.8, 128.3, 127.7, 127.4,
3
1
27.1, 126.7, 123.3 (q, J = 272.6 Hz), 118.1, 115.1, 71.8, 69.8, 58.5, 44.3, 30.7, 24.4 ppm; IR (neat)
ꢀ1
+
1658, 1564, 1389, 1278, 1169, 1136, 885, 668 cm ; HRMS (EIꢀMagnetic Sector) m/z: [M] Calcd for
20
C H F N O 521.1902, found 521.1898; [α] = +193.6 (c = 1.0, CHCl ); mp: 158ꢀ159 °C.
27
25
6
3
D
3
General procedure for asymmetric Michael addition reaction. To a stirred solution of catalyst 9f
(3.3 mg, 0.0075 mmol, 5%) and βꢀnitroolefin 1 (0.3 mmol), dithiomalonate 2 (0.15 mmol) was added
o
under an argon atmosphere. The reaction mixture was stirred at room temperature or ꢀ40 C. After the
reaction was completed (monitored by TLC), the reaction mixture was concentrated under reduced
pressure and the residue was purified through column chromatography on silica gel.
(R)ꢀ2ꢀ(2ꢀnitroꢀ1ꢀphenylethyl)ꢀmalonic acid diphenyl dithioester (11aa). Following the general
procedure with nitroolefin 1a (45 mg, 0.30 mmol), S,S’ꢀdiphenyl dithiomalonate 2a (43 mg, 0.15 mmol)
and catalyst 9f (3.3 mg, 5 mol%), the desired product was obtained as a white solid (62 mg, 94% yield,
1
9
7
8
0% ee). Rf : 0.33 (ethyl acetate: hexane = 1:5); H NMR (500 MHz, CDCl ) δ 7.48ꢀ7.33 (m, 11H),
3
.30ꢀ7.27 (m, 2H), 7.17ꢀ7.15 (m, 2H), 4.90ꢀ4.82 (m, 2H), 4.49 (d, J = 9.6 Hz, 1H), 4.40 (ddd, J = 9.6,
1
3
.8, 4.8 Hz, 1H) ppm; C NMR (125 MHz, CDCl ) δ 190.4, 189.6, 135.2, 134.3, 134.2, 130.3, 130.1,
3
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The Journal of Organic Chemistry
1
1
29.6, 129.4, 129.1, 128.6, 128.4, 126.11, 126.08, 77.1, 69.4, 44.4 ppm; IR (neat) 1703, 1550, 1478,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
ꢀ1
+
442, 1380, 1268, 944, 748 cm ; HRMS (FABꢀMagnetic Sector) m/z: [M + H] Calcd for C H NO S
4 2
2
3
20
438.0834, found 438.0837; HPLC Chiracel ODꢀH column, iꢀPrOH/nꢀhexane = 20/80, 25 °C, 1.0 ml/min,
20
λ= 254 nm, t = 16.92 min (minor), t = 22.90 min (major); [α] = ꢀ102.0 (c = 1.0, CHCl ; 98% ee); mp:
R
R
D
3
1
60ꢀ162 °C.
(R)ꢀ2ꢀ(2ꢀnitroꢀ1ꢀphenylethyl)ꢀmalonic acid bisꢀ4ꢀmethoxyphenyl dithioester (11ab). Following the
general procedure with nitroolefin 1a (45 mg, 0.30 mmol), S,S’ꢀbis(4ꢀmethoxyphenyl) dithiomalonate
b (52 mg, 0.15 mmol) and catalyst 9f (3.3 mg, 5 mol%), the reaction was completed in 1.5 h at r.t..
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
After column chromatography, the desired product was obtained as a white solid (69 mg, 92% yield,
1
9
2% ee). Rf : 0.30 (ethyl acetate: hexane = 1:3); H NMR (500 MHz, CDCl ) δ 7.39ꢀ7.31 (m, 5H), 7.27ꢀ
3
7
.26 (m, 2H), 7.06ꢀ7.03 (m, 2H), 6.99ꢀ6.96 (m, 2H), 6.89ꢀ6.86 (m, 2H), 4.89ꢀ4.81 (m, 2H), 4.44 (d, J =
1
3
9.5 Hz, 1H), 4.40ꢀ4.35 (m, 1H), 3.84 (s, 3H), 3.80 (s, 3H) ppm; C NMR (125 MHz, CDCl ) δ 191.5,
3
1
4
90.7, 161.2, 161.1, 136.0, 135.9, 135.3, 129.1, 128.6, 128.4 (x2), 116.7, 115.2, 115.0, 68.8, 55.5, 55.4,
ꢀ1
4.3 ppm; IR (neat) 1700, 1593, 1550, 1496, 1457, 1378, 1292, 1254, 1174, 971, 824, 654 cm ; HRMS
+
(EIꢀMagnetic Sector) m/z: [M] Calcd for C H NO S 497.0967, found 497.0968; HPLC Chiracel
2
5
23
6 2
ODꢀH column, iꢀPrOH/nꢀhexane = 30/70, 40 °C, 1.0 ml/min, λ= 254 nm, t = 21.92 min (minor), t =
R
R
20
23.91 min (major); [α] = ꢀ100.5 (c = 1.0, CHCl ; 92% ee); mp: 110ꢀ135 °C decomposed.
D
3
(R)ꢀ2ꢀ(2ꢀnitroꢀ1ꢀphenylethyl)ꢀmalonic acid dipropyl dithioester (11ac). Following the general
procedure with nitroolefin 1a (45 mg, 0.30 mmol), S,S’ꢀdipropyl dithiomalonate 2c (33 mg, 0.15 mmol)
and catalyst 9f (3.3 mg, 5 mol%), the desired product was obtained as a white solid (53 mg, 95% yield,
1
73% ee). Rf : 0.48 (ethyl acetate: hexane = 1:5); H NMR (500 MHz, CDCl ) δ 7.32ꢀ7.24 (m, 3H), 7.22ꢀ
3
7
2
0
7
.19 (m, 2H), 4.78ꢀ4.71 (m, 2H), 4.39ꢀ4.34 (m, 1H), 4.27 (d, J = 10.1 Hz, 1H), 2.95 (t, J = 7.2 Hz, 2H),
.79ꢀ2.74 (m, 1H), 2.71ꢀ2.66 (m, 1H), 1.67ꢀ1.60 (m, 2H), 1.43ꢀ1.31 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H),
1
3
.77 (t, J = 7.4 Hz, 3H) ppm; C NMR (125 MHz, CDCl ) δ 192.3, 191.3, 135.5, 129.1, 128.5, 128.3,
3
ꢀ1
7.6, 70.6, 44.3, 32.0, 31.8, 22.7, 22.5, 13.4, 13.1 ppm; IR (neat) 1697, 1559, 1381, 977, 663 cm ;
+
HRMS (EIꢀMagnetic Sector) m/z: [M] Calcd for C H NO S 369.1069, found 369.1071; HPLC
1
7
23
4 2
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Chiracel ODꢀH column, iꢀPrOH/nꢀhexane = 20/80, 25 °C, 1.0 ml/min, λ= 254 nm, t = 6.93 min (major),
R
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
0
tR= 7.76 min (minor); [α] = ꢀ27.4 (c = 1.0, CHCl ; 73% ee); mp: 66ꢀ69 °C.
D
3
(R)ꢀ2ꢀ(2ꢀnitroꢀ1ꢀphenylethyl)ꢀmalonic acid diethyl dithioester (11ad). Following the general
procedure with nitroolefin 1a (45 mg, 0.30 mmol), S,S’ꢀdiethyl dithiomalonate 2d (29 mg, 0.15 mmol)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
and catalyst 9f (3.3 mg, 5 mol%), the desired product was obtained as a white solid (48 mg, 93% yield,
1
89% ee). Rf : 0.41 (ethyl acetate: hexane = 1:5); H NMR (500 MHz, CDCl ) δ 7.32ꢀ7.25 (m, 3H), 7.22ꢀ
3
7
.20 (m, 2H), 4.79ꢀ4.72 (m, 2H), 4.40ꢀ4.35 (m, 1H), 4.25 (d, J = 10.1 Hz, 1H), 2.98 (qd, J = 7.4, 1.1 Hz,
13
2
H), 2.81ꢀ2.74 (m, 1H), 2.74ꢀ2.67 (m, 1H), 1.29 (t, J = 7.4 Hz, 3H), 1.02 (t, J = 7.4 Hz, 3H) ppm; C
NMR (125 MHz, CDCl ) δ 192.1, 191.1, 135.3, 128.9, 128.4, 128.2, 77.4, 70.3, 44.2, 24.5, 24.3, 14.2,
3
ꢀ1
1
4.1 ppm; IR (neat) 2929, 1692, 1560, 1457, 1379, 1261, 1090, 967, 701, 640 cm ; HRMS (EIꢀ
+
Magnetic Sector) m/z: [M] Calcd for C H NO S 341.0756, found 341.0756; HPLC Chiracel ODꢀH
1
5
19
4 2
column, iꢀPrOH/nꢀhexane = 5/95, 25 °C, 1.0 ml/min, λ= 254 nm, t = 13.85 min (major), t = 15.02 min
R
R
20
(
minor); [α] = ꢀ34.3 (c = 1.0, CHCl ; 89% ee); mp: 72ꢀ75 °C.
D 3
(R)ꢀ2ꢀ(1ꢀ(4ꢀfluoroꢀphenyl)ꢀ2ꢀnitroꢀethyl)ꢀmalonic acid diphenyl dithioester (11ba). Following the
general procedure with nitroolefin 1b (50 mg, 0.30 mmol), S,S’ꢀdiphenyl dithiomalonate 2a (43 mg,
0
.15 mmol) and catalyst 9f (3.3 mg, 5 mol%), the desired product was obtained as a white solid (63 mg,
1
9
2% yield, 87% ee). Rf : 0.33 (ethyl acetate: hexane = 1:5); H NMR (500 MHz, CDCl ) δ 7.48ꢀ7.36 (m,
3
8H), 7.27ꢀ7.25 (m, 2H), 7.18ꢀ7.16 (m, 2H), 7.09ꢀ7.04 (m, 2H), 4.81 (d, J = 6.7 Hz, 2H), 4.45 (d, J = 9.7
1
3
Hz, 1H), 4.42–4.37 (m, 1H) ppm; C NMR (125 MHz, CDCl ) δ 190.3, 189.5, 162.7 (d, J = 248.2 Hz),
3
1
34.3, 134.2, 131.0 (d, J = 3.3 Hz), 130.3, 130.2, 130.1, 129.6, 129.5, 125.9 (d, J = 6.6 Hz), 116.2, 116.1,
ꢀ1
77.1, 69.3, 43.6 ppm; IR (neat) 1709, 1558, 1512, 1478, 1442, 1375, 1231, 1163, 968, 838, 668 cm ;
+
HRMS (EIꢀMagnetic Sector) m/z: [M] Calcd for C H FNO S 455.0661, found 455.0664; HPLC
23
18
4 2
Chiracel ODꢀH column, iꢀPrOH/nꢀhexane = 20/80, 25 °C, 1.0 ml/min, λ= 254 nm, t = 16.83 min
R
2
0
(
minor), t = 24.81 min (major); [α] = ꢀ92.8 (c =1.0, CHCl ; >99% ee); mp: 141ꢀ145 °C.
R D 3
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The Journal of Organic Chemistry
(
R)ꢀ2ꢀ(1ꢀ(2ꢀfluoroꢀphenyl)ꢀ2ꢀnitroꢀethyl)ꢀmalonic acid diphenyl dithioester (11ca). Following the
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
general procedure with nitroolefin 1c (50 mg, 0.30 mmol), S,S’ꢀdiphenyl dithiomalonate 1a (43 mg,
0.15 mmol) and catalyst 9f (3.3 mg, 5 mol%), the desired product was obtained as a white solid (68 mg,
1
9
5
9% yield, 91% ee). Rf : 0.40 (ethyl acetate: hexane = 1:5); H NMR (500 MHz, CDCl ) δ 7.46ꢀ7.42 (m,
3
H), 7.38ꢀ7.33 (m, 4H), 7.25ꢀ7.22 (m, 1H), 7.14ꢀ7.10 (m, 4H), 4.94 (dd, J = 13.2, 9.7 Hz, 1H), 4.80 (dd,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
J = 13.2, 4.0 Hz, 1H), 4.65 (d, J = 10.1 Hz, 1H), 4.59 (ddd, J = 10.1, 9.7, 4.0 Hz, 1H) ppm; C NMR
125 MHz, CDCl ) δ 190.1, 189.4, 161.3 (d, J = 246.6 Hz), 134.3, 134.2, 131.6 (d, J = 4.2 Hz), 130.6 (d,
(
3
J = 8.8 Hz), 130.3, 130.1, 129.6, 129.4, 126.0 (d, J = 2.6 Hz), 124.8 (d, J = 3.3 Hz), 122.1 (d, J = 12.7
Hz), 116.4, 116.2, 75.7 (d, J = 2.9 Hz), 67.2 (d, J = 2.2 Hz), 40.5 ppm; IR (neat) 2974, 2927, 1708, 1556,
ꢀ1
+
1
494, 1441, 1377, 1052, 1033, 1006, 969, 650 cm ; HRMS (EIꢀMagnetic Sector) m/z: [M] Calcd for
C H FNO S 455.0661, found 455.0664; HPLC Chiracel ODꢀH column, iꢀPrOH/nꢀhexane = 20/80,
2
3
18
4 2
20
2
5 °C, 1.0 ml/min, λ= 254 nm, t = 11.00 min (minor), t = 18.32 min (major); [α] = ꢀ85.5 (c = 1.0,
R R D
CHCl ; 91% ee); mp: 88ꢀ92 °C.
3
(R)ꢀ2ꢀ(1ꢀ(4ꢀbromoꢀphenyl)ꢀ2ꢀnitroꢀethyl)ꢀmalonic acid diphenyl dithioester (11da). Following the
general procedure with nitroolefin 1d (68 mg, 0.30 mmol), S,S’ꢀdiphenyl dithiomalonate 2a (43 mg,
0
.15 mmol) and catalyst 9f (3.3 mg, 5 mol%), the desired product was obtained as a white solid (76 mg,
1
98% yield, 90% ee). Rf : 0.43 (ethyl acetate: hexane = 1:5); H NMR (500 MHz, CDCl ) δ 7.52ꢀ7.45 (m,
3
5
1
H), 7.44ꢀ7.36 (m, 5H), 7.20ꢀ7.14 (m, 4H), 4.85ꢀ4.79 (m, 2H), 4.44 (d, J = 9.6 Hz, 1H), 4.39ꢀ4.34 (m,
1
3
H) ppm; C NMR (125 MHz, CDCl ) δ 190.2, 189.4, 134.34, 134.26, 134.2, 132.3, 130.3, 130.2,
3
130.0, 129.6, 129.5, 125.93, 125.86, 122.8, 76.8, 69.0, 43.7 ppm; IR (neat) 2923, 2850, 1701, 1555,
ꢀ1
+
1
478, 1441, 1377, 1059, 1033, 1012, 967, 752, 655 cm ; HRMS (EIꢀMagnetic Sector) m/z: [M] Calcd
for C H BrNO S 514.9861, found 514.9863; HPLC Chiracel ODꢀH column, iꢀPrOH/nꢀhexane =
2
3
18
4 2
20
20/80, 25 °C, 1.0 ml/min, λ= 254 nm, t = 19.86 min (minor), t = 31.74 min (major); [α] = ꢀ100.2 (c
R
R
D
=
1.0, CHCl ; >99% ee); mp: 147ꢀ149 °C.
3
(R)ꢀ2ꢀ(1ꢀ(2ꢀbromoꢀphenyl)ꢀ2ꢀnitroꢀethyl)ꢀmalonic acid diphenyl dithioester (11ea). Following the
general procedure with nitroolefin 1e (68 mg, 0.30 mmol), S,S’ꢀdiphenyl dithiomalonate 2a (43 mg,
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0
.15 mmol) and catalyst 9f (3.3 mg, 5 mol%), the desired product was obtained as a light yellow oil (76
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
mg, 98% yield, 97% ee). Rf : 0.42 (ethyl acetate: hexane = 1:5); H NMR (500 MHz, CDCl ) δ 7.64 (dd,
3
J = 8.0, 1.0 Hz, 1H), 7.47ꢀ7.35 (m, 8H), 7.33ꢀ7.27 (m, 3H), 7.26ꢀ7.18 (m, 2H), 5.13ꢀ5.08 (m, 1H), 4.97ꢀ
13
4
1
1
.78 (m, 3H) ppm; C NMR (125 MHz, CDCl ) δ 190.8, 189.8, 134.4, 134.32, 134.29, 134.1, 130.3,
3
30.2, 130.1, 129.6, 129.5, 128.0 (x2), 126.2, 126.0, 124.9, 75.1, 67.0, 43.0 ppm; IR (neat) 2919, 1706,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ꢀ1
+
558, 1478, 1442, 1377, 1058, 1033, 747, 668 cm ; HRMS (EIꢀMagnetic Sector) m/z: [M] Calcd for
C H BrNO S 514.9861, found 514.9857; HPLC Chiracel ODꢀH column, iꢀPrOH/nꢀhexane = 20/80,
23
18
4 2
2
0
25 °C, 1.0 ml/min, λ= 254 nm, t = 11.31 min (minor), t = 21.30 min (major); [α] = ꢀ21.5 (c = 1.0,
R
R
D
CHCl ; 97% ee).
3
(R)ꢀ2ꢀ(1ꢀ(4ꢀtrifluoromethylꢀphenyl)ꢀ2ꢀnitroꢀethyl)ꢀmalonic acid diphenyl dithioester (11fa).
Following the general procedure with nitroolefin 1f (65 mg, 0.30 mmol), S,S’ꢀdiphenyl dithiomalonate
2a (43 mg, 0.15 mmol) and catalyst 9f (3.3 mg, 5 mol%), the desired product was obtained as a white
1
solid (67 mg, 88% yield, 92% ee). Rf : 0.45 (ethyl acetate: hexane = 1:5); H NMR (500 MHz, CDCl ) δ
3
7
.64 (d, J = 8.1 Hz, 2H), 7.50–7.35 (m, 10H), 7.15– 7.12 (m, 2H), 4.90–4.82 (m, 2H), 4.50–4.45 (m, 2H)
13
ppm; C NMR (125 MHz, CDCl ) δ 190.1, 189.4, 139.4, 134.3, 134.2, 130.9 (q, J = 33.0 Hz), 130.4,
3
1
30.3, 129.6, 129.5, 129.0, 126.1 (q, J = 3.7 Hz), 125.8, 125.7, 123.8 (q, J = 272.3 Hz), 76.7, 68.8, 43.9
ppm; IR (neat) 2919, 1738, 1696, 1558, 1479, 1442, 1377, 1327, 1167, 1124, 1070, 966, 852, 747, 658
ꢀ1
+
cm ; HRMS (EIꢀMagnetic Sector) m/z: [M] Calcd for C H F NO S 505.0629, found 505.0632;
2
4
18
3
4 2
HPLC Chiracel ODꢀH column, iꢀPrOH/nꢀhexane = 20/80, 25 °C, 1.0 ml/min, λ= 254 nm, t = 15.00 min
R
20
(minor), t = 28.76 min (major); [α] = ꢀ95.0 (c = 1.0, CHCl ; >99% ee); mp: 110ꢀ120 °C.
R
D
3
(R)ꢀ2ꢀ(1ꢀ(4ꢀmethylꢀphenyl)ꢀ2ꢀnitroꢀethyl)ꢀmalonic acid diphenyl dithioester (11ga). Following the
general procedure with nitroolefin 1g (49 mg, 0.30 mmol), S,S’ꢀdiphenyl dithiomalonate 2a (43 mg,
0
9
5
9
.15 mmol) and catalyst 9f (3.3 mg, 5 mol%), the desired product was obtained as a white solid (64 mg,
1
4% yield, 90% ee). Rf : 0.36 (ethyl acetate: hexane = 1:5); H NMR (500 MHz, CDCl ) δ 7.47ꢀ7.40 (m,
3
H), 7.40ꢀ7.34 (m, 3H), 7.19ꢀ7.13 (m, 6H), 4.87ꢀ4.79 (m, 2H), 4.46 (d, J = 9.5 Hz, 1H), 4.36 (ddd, J =
1
3
.5, 8.7, 5.0 Hz, 1H), 2.34(s,1H) ppm; C NMR (125 MHz, CDCl ) δ 190.5, 189.6, 138.4, 134.3, 134.2,
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1
1
32.1, 130.2, 130.0, 129.8, 129.5, 129.4, 128.2, 126.18, 126.16 77.2, 69.5, 44.1, 21.2ppm; IR (neat)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
ꢀ1
+
708, 1555, 1478, 1441, 1376, 1257, 954 cm ; HRMS (FABꢀMagnetic Sector) m/z: [M + H] Calcd for
C H NO S 452.0990, found 452.0993; HPLC Chiracel ODꢀH column, iꢀPrOH/nꢀhexane = 20/80,
24
22
4 2
20
2
5 °C, 1.0 ml/min, λ= 254 nm, t = 14.31 min (minor), t = 20.09 min (major); [α] = ꢀ88.5 (c = 1.0,
R R D
CHCl ; 93% ee); mp: 150ꢀ155 °C.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
(R)ꢀ2ꢀ(1ꢀ(4ꢀmethoxyꢀphenyl)ꢀ2ꢀnitroꢀethyl)ꢀmalonic acid diphenyl dithioester (11ha). Following the
general procedure with nitroolefin 1h (54 mg, 0.30 mmol), S,S’ꢀdiphenyl dithiomalonate 2a (43 mg,
0
.15 mmol) and catalyst 9f (3.3 mg, 5 mol%), the desired product was obtained as a white solid (69 mg,
1
98% yield, 87% ee). Rf : 0.32 (ethyl acetate: hexane = 1:5); H NMR (500 MHz, CDCl ) δ 7.46ꢀ7.42 (m,
3
5
H), 7.39ꢀ7.34 (m, 3H), 7.20ꢀ7.17 (m, 4H), 6.90ꢀ6.86 (m, 2H), 4.84ꢀ4.77 (m, 2H), 4.45 (d, J = 9.7 Hz,
1
3
1
H), 4.37ꢀ4.33 (m, 1H), 3.80 (s, 3H) ppm; C NMR (125 MHz, CDCl ) δ 190.5, 189.6, 159.7, 134.3,
3
134.2, 130.2, 130.1, 129.6, 129.5, 129.4, 127.0, 126.17, 126.16, 114.5, 77.3, 69.6, 55.3, 43.8 ppm; IR
ꢀ1
(neat) 2984, 1703, 1559, 1515, 1442, 1376, 1255, 1181, 1057, 1033, 968, 831, 751, 646 cm ; HRMS
+
(EIꢀMagnetic Sector) m/z: [M] Calcd for C H NO S 467.0861, found 467.0864; HPLC Chiracel
24 21
5 2
ODꢀH column, iꢀPrOH/nꢀhexane = 30/70, 25 °C, 1.0 ml/min, λ= 254 nm, t = 14.62 min (minor), t =
R
R
20
1
9.86 min (major); [α] = ꢀ105.6 (c = 1.0, CHCl ; 94% ee); mp: 130ꢀ135 °C.
D 3
(R)ꢀ2ꢀ(1ꢀ(2ꢀmethoxyꢀphenyl)ꢀ2ꢀnitroꢀethyl)ꢀmalonic acid diphenyl dithioester (11ia). Following the
general procedure with nitroolefin 1i (54 mg, 0.30 mmol), S,S’ꢀdiphenyl dithiomalonate 2a (43 mg, 0.15
mmol) and catalyst 9f (3.3 mg, 5 mol%), the desired product was obtained as a white solid (69 mg, 98%
1
yield, 94% ee). Rf : 0.37 (ethyl acetate: hexane = 1:5); H NMR (500 MHz, CDCl ) δ 7.44ꢀ7.41 (m, 5H),
3
7.37ꢀ7.29 (m, 4H), 7.15ꢀ7.13 (m, 1H), 7.06ꢀ7.04 (m, 2H), 6.93ꢀ6.89 (m, 2H), 5.08 (dd, J = 12.9, 9.8 Hz,
1
3
1
1
H), 4.86 (d, J = 10.2 Hz, 1H), 4.73 (dd, J = 12.9, 4.2 Hz, 1H), 4.53 (ddd, J = 10.2, 9.8, 4.2 Hz, 1H),
1
3
.94 (s, 3H) ppm; C NMR (125 MHz, CDCl ) δ 190.6, 189.8, 157.7, 134.34, 134.25, 131.9, 130.1,
3
30.0, 129.9, 129.5, 129.3, 126.3 (x2), 122.5, 121.0, 111.2, 75.6, 66.6, 55.5, 42.6 ppm; IR (neat) 3059,
ꢀ1
+
711, 1555, 1495, 1441, 1378, 1247, 973, 745, 652 cm ; HRMS (EIꢀMagnetic Sector) m/z: [M] Calcd
for C H NO S 467.0861, found 467.0858; HPLC Chiracel ODꢀH column, iꢀPrOH/nꢀhexane = 30/70,
2
4
21
5 2
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2
0
2
5 °C, 1.0 ml/min, λ= 254 nm, t = 8.11 min (minor), t = 10.29 min (major); [α] = ꢀ128.8 (c = 1.0,
R R D
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
CHCl ; 94% ee); mp: 110ꢀ113 °C.
3
(S)ꢀ2ꢀ(1ꢀ(2ꢀthiophenyl)ꢀ2ꢀnitroꢀethyl)ꢀmalonic acid diphenyl dithioester (11ja). Following the general
procedure with nitroolefin 1j (47 mg, 0.30 mmol), S,S’ꢀdiphenyl dithiomalonate 2a (43 mg, 0.15 mmol)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
and catalyst 9f (3.3 mg, 5 mol%), the desired product was obtained as a white solid (66 mg, 99% yield,
1
90% ee). Rf : 0.40 (ethyl acetate: hexane = 1:5); H NMR (500 MHz, CDCl ) δ 7.46ꢀ7.36 (m, 8H), 7.29ꢀ
3
7
.24 (m, 3H), 6.99ꢀ6.96 (m, 2H), 4.88ꢀ4.81 (m, 2H), 4.69 (ddd, J = 7.8, 8.9, 5.1 Hz, 1H), 4.55 (d, J = 8.9
1
3
Hz, 1H) ppm; C NMR (125 MHz, CDCl ) δ 190.3, 189.6, 137.7, 134.3, 130.3, 130.2, 129.6, 129.5,
3
127.6, 127.2, 126.09, 126.06, 125.9, 77.7, 69.8, 39.8 ppm; IR (neat) 1700, 1556, 1478, 1441, 1378,
ꢀ1
+
1
264, 1059, 963, 747, 673 cm ; HRMS (EIꢀMagnetic Sector) m/z: [M] Calcd for C H NO S
21 17 4 3
4
43.0320, found 443.0322; HPLC Chiracel ODꢀH column, iꢀPrOH/nꢀhexane = 20/80, 25 °C, 1.0 ml/min,
2
0
λ= 254 nm, t = 15.72 min (minor), t = 23.07 min (major); [α] = ꢀ45.6 (c = 1.0, CHCl ; 90% ee); mp:
R
R
D
3
1
33ꢀ137 °C.
S)ꢀ2ꢀ(1ꢀ(2ꢀfuryl)ꢀ2ꢀnitroꢀethyl)ꢀmalonic acid diphenyl dithioester (11ka). Following the general
(
procedure with nitroolefin 1k (42 mg, 0.30 mmol), S,S’ꢀdiphenyl dithiomalonate 2a (43 mg, 0.15 mmol)
and catalyst 9f (3.3 mg, 5 mol%), the desired product was obtained as a white solid (63 mg, 98% yield,
1
9
3% ee). Rf : 0.40 (ethyl acetate: hexane = 1:5); H NMR (500 MHz, CDCl ) δ 7.46ꢀ7.39 (m, 9H), 7.32ꢀ
3
7.31 (m, 2H), 6.35 (dd, J = 3.2, 1.9 Hz, 1H), 6.27 (d, J = 3.3 Hz, 1H), 4.88ꢀ4.79 (m, 2H), 4.62 (d, J = 8.9
13
Hz, 1H), 4.51 (ddd, J = 8.9, 8.6, 4.2 Hz, 1H) ppm; C NMR (125 MHz, CDCl ) δ 190.1, 189.7, 148.5,
3
1
43.2, 134.32, 134.29, 130.3, 130.2, 129.6, 129.5, 126.08, 126.06, 110.7, 109.5, 75.1, 66.9, 38.1 ppm;
ꢀ
1
IR (neat) 2930, 1708, 1555, 1478, 1442, 1376, 1257, 982 cm ; HRMS (FABꢀMagnetic Sector) m/z: [M
+
+
H] Calcd for C H NO S 428.0626, found 428.0624; HPLC Chiracel ODꢀH column, iꢀPrOH/nꢀ
21
18
5 2
20
D
hexane = 30/70, 25 °C, 1.0 ml/min, λ= 254 nm, t = 10.81 min (minor), t = 17.04 min (major); [α] = ꢀ
R
R
6
4.9 (c = 1.0, CHCl ; 93% ee); mp: 114ꢀ122 °C decomposed.
3
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(
R)ꢀ2ꢀ(1ꢀ(2ꢀnaphthyl)ꢀ2ꢀnitroꢀethyl)ꢀmalonic acid diphenyl dithioester (11la). Following the general
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
procedure with nitroolefin 1l (60 mg, 0.30 mmol), S,S’ꢀdiphenyl dithiomalonate 2a (43 mg, 0.15 mmol)
and catalyst 9f (3.3 mg, 5 mol%), the desired product was obtained as a white solid (67 mg, 92% yield,
1
8
7
2
1
6% ee). Rf : 0.37 (ethyl acetate: hexane = 1:5); H NMR (500 MHz, CDCl ) δ 7.88ꢀ7.81 (m, 3H), 7.74ꢀ
3
.71 (m, 1H), 7.53ꢀ7.49 (m, 2H), 7.48ꢀ7.33 (m, 7H), 7.30ꢀ7.25 (m, 2H), 7.07ꢀ7.05 (m, 2H), 5.02ꢀ4.91 (m,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
H), 4.60ꢀ4.55 (m, 2H) ppm; C NMR (125 MHz, CDCl ) δ 190.5, 189.6, 134.3, 134.2, 133.3, 133.1,
3
32.6, 130.3, 130.0, 129.6, 129.4, 129.1, 128.04, 127.96, 127.8, 126.7, 126.1, 126.0, 125.3, 77.0, 69.3,
44.5 ppm; IR (neat) 3064, 2926, 1710, 1684, 1561, 1478, 1441, 1425, 1379, 1251, 1069, 1023, 962, 911,
ꢀ1
+
8
59, 828, 746, 668 cm ; HRMS (EIꢀMagnetic Sector) m/z: [M] Calcd for C H NO S 487.0912,
27 21 4 2
found 487.0910; HPLC Chiracel ODꢀH column, iꢀPrOH/nꢀhexane = 30/70, 25 °C, 1.0 ml/min, λ= 254
2
0
nm, t = 26.03 min (major), t = 33.66 min (minor); [α] = ꢀ81.5 (c = 1.0, CHCl ; >99% ee); mp: 165ꢀ
R
R
D
3
1
75 °C decomposed.
(S)ꢀ2ꢀ(1ꢀ(nꢀpropyl)ꢀ2ꢀnitroꢀethyl)ꢀmalonic acid diphenyl dithioester (11ma). Following the general
procedure with nitroolefin 1m (35 µL, 0.30 mmol), S,S’ꢀdiphenyl dithiomalonate 2a (43 mg, 0.15 mmol)
and catalyst 9f (3.3 mg, 5 mol%), the desired product was obtained as a yellow solid (56 mg, 93% yield,
1
9
0% ee). Rf : 0.45 (ethyl acetate: hexane = 1:5); H NMR (500 MHz, CDCl ) δ 7.45 (s, 5H), 7.44 (s,
3
5H), 4.73 (dd, J = 13.6, 4.090 Hz, 1H), 4.49 (dd, J = 13.6, 6.4 Hz, 1H), 4.34 (d, J = 7.2 Hz, 1H), 3.07ꢀ
1
3
3
.01 (m, 1H), 1.57ꢀ1.40 (m, 4H), 0.95 (t, J = 7.1 Hz, 3H) ppm; C NMR (125 MHz, CDCl ) δ 190.98,
3
1
90.96, 134.37, 134.32, 130.19, 130.16, 129.55, 129.52, 126.37, 126.32, 76.0, 67.6, 38.4, 32.0, 19.9,
ꢀ1
13.8 ppm; IR (neat) 2960, 2930, 1707, 1552, 1478, 1441, 1381, 1266, 997, 971, 688 cm ; HRMS (FABꢀ
+
Magnetic Sector) m/z: [M + H] Calcd for C H NO S 404.0990, found 404.0988; HPLC Chiracel
20
22
4 2
ODꢀH column, iꢀPrOH/nꢀhexane = 20/80, 25 °C, 1.0 ml/min, λ= 254 nm, t = 6.57 min (minor), t = 9.44
R
R
20
min (major); [α] = ꢀ46.6 (c = 1.0, CHCl ; 90% ee); mp: 63ꢀ67 °C.
D
3
(S)ꢀ2ꢀ(1ꢀisobutylꢀ2ꢀnitroꢀethyl)ꢀmalonic acid diphenyl dithioester (11na). Following the general
procedure with nitroolefin 1n (40 µL, 0.30 mmol), S,S’ꢀdiphenyl dithiomalonate 2a (43 mg, 0.15 mmol)
and catalyst 9f (3.3 mg, 5 mol%), the desired product was obtained as a colorless oil (60 mg, 96% yield,
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1
8
5
6% ee). Rf : 0.48 (ethyl acetate: hexane = 1:5); H NMR (500 MHz, CDCl ) δ 7.45 (s, 5H), 7.44 (s,
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
H), 4.74 (dd, J = 13.7, 4.1 Hz, 1H), 4.49 (dd, J = 13.7, 6.1 Hz, 1H), 4.34 (d, J = 6.8 Hz, 1H), 3.11ꢀ3.05
(m, 1H), 1.78ꢀ1.70 (m, 1H), 1.40 (t, J = 7.1 Hz, 2H), 0.95 (d, J = 6.7 Hz, 3H), 0.94 (d, J = 6.7 Hz, 3H)
13
ppm; C NMR (125 MHz, CDCl ) δ 191.05, 191.02, 134.4, 134.3, 130.18, 130.15, 129.55, 129.51,
3
1
26.4, 126.3, 76.3, 67.5, 38.8, 36.6, 25.2, 22.6, 22.0 ppm; IR (neat) 2962, 2918, 1708, 1552, 1478, 1441,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ꢀ1
+
1
382, 1270, 1208, 979, 744, 669, 640 cm ; HRMS (EIꢀMagnetic Sector) m/z: [M] Calcd for
C H NO S 417.1069, found 417.1066; HPLC Chiracel ODꢀH column, iꢀPrOH/nꢀhexane = 20/80,
21
23
4 2
2
0
25 °C, 1.0 ml/min, λ= 254 nm, t = 5.64 min (minor), t = 8.25 min (major); [α] = ꢀ48.6 (c = 1.0,
D
R
R
CHCl ; 86% ee).
3
(S)ꢀ2ꢀ(1ꢀ(2ꢀphenylethyl)ꢀ2ꢀnitroꢀethyl)ꢀmalonic acid diphenyl dithioester (11oa). Following the
general procedure with nitroolefin 1o (48 µL, 0.30 mmol), S,S’ꢀdiphenyl dithiomalonate 2a (43 mg,
0.15 mmol) and catalyst 9f (3.3 mg, 5 mol%), the desired product was obtained as a white solid (66 mg,
1
9
1
1
5% yield, 90% ee). Rf : 0.47 (ethyl acetate: hexane = 1:5); H NMR (500 MHz, CDCl ) δ 7.46ꢀ7.43 (m,
3
0H), 7.32ꢀ7.29 (m, 2H), 7.24ꢀ7.17 (m, 3H), 4.76 (dd, J = 13.7, 4.1 Hz, 1H), 4.52 (dd, J = 13.7, 6.4 Hz,
1
3
H), 4.37 (d, J = 7.2 Hz, 1H), 3.10ꢀ3.04 (m, 1H), 2.81ꢀ2.69 (m, 2H), 1.94ꢀ1.80 (m, 2H) ppm; C NMR
(
125 MHz, CDCl ) δ 190.93, 190.86, 140.1, 134.4, 134.3, 130.22, 130.21, 129.56, 129.55, 128.8, 128.3,
3
126.5, 126.3, 126.2, 75.9, 67.4, 38.2, 33.0, 31.6 ppm; IR (neat) 2919, 1704, 1551, 1478, 1442, 1382,
ꢀ1
+
1
271, 970, 746, 688 cm ; HRMS (FABꢀMagnetic Sector) m/z: [M + H] Calcd for C H NO S
25 24 4 2
4
66.1147, found 466.1146; HPLC Chiracel ODꢀH column, iꢀPrOH/nꢀhexane = 20/80, 25 °C, 1.0 ml/min,
20
λ= 254 nm, t = 13.27 min (minor), t = 17.46 min (major); [α] = ꢀ40.9 (c = 1.0, CHCl ; 90% ee); mp:
R
R
D
3
9
4ꢀ98 °C.
S)ꢀ2ꢀ(1ꢀ(nꢀhexyl)ꢀ2ꢀnitroꢀethyl)ꢀmalonic acid diphenyl dithioester (11pa). Following the general
(
procedure with nitroolefin 1p (47 µL, 0.30 mmol), S,S’ꢀdiphenyl dithiomalonate 2a (43 mg, 0.15 mmol)
and catalyst 9f (3.3 mg, 5 mol%), the desired product was obtained as a white solid (65 mg, 97% yield,
1
8
6% ee). Rf : 0.60 (ethyl acetate: hexane = 1:5); H NMR (500 MHz, CDCl ) δ 7.47ꢀ7.43 (m, 10H), 4.74
3
(
dd, J = 13.6, 4.0 Hz, 1H), 4.50 (dd, J = 13.6, 6.5 Hz, 1H), 4.35 (d, J = 7.3 Hz, 1H), 3.05ꢀ2.99 (m, 1H),
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The Journal of Organic Chemistry
1
3
1
.59ꢀ1.48 (m, 2H), 1.47ꢀ1.37 (m, 2H), 1.35ꢀ1.25 (m, 6H), 0.89 (t, J = 6.9 Hz, 3H) ppm; C NMR (125
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
MHz, CDCl ) δ 191.00, 190.98, 134.4, 134.3, 130.20, 130.17, 129.55, 129.52, 126.34, 126.28, 76.0,
3
67.5, 38.6, 31.5, 29.8, 29.0, 26.5, 22.5, 14.1 ppm; IR (neat) 2957, 2932, 2856, 1707, 1551, 1478, 1441,
ꢀ1
+
1
380, 967, 746, 688, 668 cm ; HRMS (EIꢀMagnetic Sector) m/z: [M] Calcd for C H NO S
23 27 4 2
4
45.1382, found 445.1383; HPLC Chiracel ODꢀH column, iꢀPrOH/nꢀhexane = 20/80, 25 °C, 1.0 ml/min,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
20
λ= 254 nm, t = 5.79 min (minor), t = 7.90 min (major); [α] = ꢀ41.5 (c = 1.0, CHCl ; 86% ee); mp:
R
R
D
3
6
8ꢀ73 °C.
S)ꢀ2ꢀ(1ꢀ(nꢀhexyl)ꢀ2ꢀnitroꢀethyl)ꢀmalonic acid bis(4ꢀmethoxyphenyl) dithioester (11pb). Following
the general procedure with nitroolefin 1p (47 µL, 0.30 mmol), S,S’ꢀbisꢀ4ꢀmethoxyphenyl dithiomalonate
(
2
b (52 mg, 0.15 mmol), and catalyst 9f (3.3 mg, 5 mol%), the desired product was obtained as a
1
colorless oil (72 mg, 95% yield, 85% ee). Rf : 0.34 (ethyl acetate: hexane = 1:5); H NMR (500 MHz,
CDCl ) δ 7.38ꢀ7.33 (m, 4H), 6.99ꢀ6.95 (m, 4H), 4.73 (dd, J = 13.6, 4.0 Hz, 1H), 4.48 (dd, J = 13.6, 6.6
3
Hz, 1H), 4.32 (d, J = 7.1 Hz, 1H), 3.835 (s, 3H), 3.832 (s, 3H), 3.03ꢀ2.97 (m, 1H), 1.58ꢀ1.48 (m, 2H),
1
3
1
1
3
.44ꢀ1.36 (m, 2H), 1.33ꢀ1.26 (m, 6H), 0.90 (t, J = 6.9 Hz, 3H). ppm; C NMR (125 MHz, CDCl ) δ
3
92.10, 192.06, 161.19, 161.16, 136.06, 136.00, 116.96, 116.90, 115.17, 115.14, 76.1, 66.9, 55.4, 38.6,
1.5, 29.9, 29.0, 26.5, 22.5, 14.1 ppm; IR (neat) 2932, 2857, 1707, 1593, 1552, 1496, 1440, 1380, 1291,
ꢀ1
+
1251, 1174, 1029, 968, 826, 668 cm ; HRMS (EIꢀMagnetic Sector) m/z: [M] Calcd for C H NO S
6 2
2
5
31
5
05.1593, found 505.1597; HPLC Chiracel ODꢀH column, iꢀPrOH/nꢀhexane = 30/70, 25 °C, 1.0 ml/min,
20
λ= 254 nm, t = 10.10 min (minor), t = 12.56 min (major); [α] = ꢀ43.2 (c = 1.0, CHCl ; 85% ee).
R
R
D
3
(S)ꢀ2ꢀ(1ꢀcyclohexylꢀ2ꢀnitroꢀethyl)ꢀmalonic acid diphenyl dithioester (11qa). Following the general
procedure with nitroolefin 1q (21 µL, 0.15 mmol), S,S’ꢀdiphenyl dithiomalonate 2a (22 mg, 0.075 mmol)
and catalyst 9f (3.3 mg, 10 mol%), the desired product was obtained as a white solid (22 mg, 65% yield,
1
8
1% ee). Rf : 0.47 (ethyl acetate: hexane = 1:5); H NMR (500 MHz, CDCl ) δ 7.47ꢀ7.41 (m, 10H), 4.82
3
(dd, J = 14.8, 3.2 Hz, 1H), 4.60 (dd, J = 14.8, 7.1 Hz, 1H), 4.42 (d, J = 5.4 Hz, 1H), 3.04ꢀ3.00 (m, 1H),
13
1
.83ꢀ1.69 (m, 5H), 1.57ꢀ1.50 (m, 1H), 1.31ꢀ1.26 (m, 1H), 1.23ꢀ1.03 (m, 4H) ppm; C NMR (125 MHz,
CDCl ) δ 191.5, 191.1, 134.5, 134.3, 130.2, 130.1, 129.6, 129.5, 126.4, 126.3, 74.9, 65.7, 44.3, 40.0,
3
ACS Paragon Plus Environment