Enantio- and diastereoselective addition of thioacetic acid to nitroalkenes via N-sulfinyl urea catalysis

Article abstract of DOI:10.1016/j.tet.2012.01.048

The enantioselective addition of thioacetic acid to nitroalkenes was achieved using N-sulfinyl urea catalysis. In this report, the scope of the reaction was extended to the enantio- and diastereoselective thioacetic acid addition to cyclic α,β-disubstitut

Full text of DOI:10.1016/j.tet.2012.01.048

Tetrahedron 68 (2012) 2704e2712
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Enantio- and diastereoselective addition of thioacetic acid to nitroalkenes via
N-sulfinyl urea catalysis
*
Kyle L. Kimmel, MaryAnn T. Robak, Stephen Thomas, Melissa Lee, Jonathan A. Ellman
Department of Chemistry, Yale University, New Haven, CT 06520, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The enantioselective addition of thioacetic acid to nitroalkenes was achieved using N-sulfinyl urea ca-
Received 28 November 2011
Received in revised form 16 January 2012
Accepted 17 January 2012
talysis. In this report, the scope of the reaction was extended to the enantio- and diastereoselective
thioacetic acid addition to cyclic
a,b-disubstituted nitroalkenes. Additionally, the role of the sulfinyl
group was investigated by replacing it with a variety of aryl and sulfonyl groups. Of 15 urea catalysts
synthesized and tested, none displayed comparable selectivity to the sulfinyl catalysts, highlighting the
importance of the sulfinyl group in attaining high enantioselectivity in the thioacetic acid addition.
Ó 2012 Elsevier Ltd. All rights reserved.
Available online 31 January 2012
Keywords:
Sulfinyl urea catalysis
Thioacetic acid
Nitroalkenes
1. Introduction
addition of thioacetic acids to both aryl and alkyl nitroalkene sub-
strates with up to 96% ee and 95% yield.2b Herein, we report the
Asymmetric hydrogen-bonding organocatalysis is a rapidly
expanding field of organic chemistry, spanning a variety of catalytic
systems, including chiral ureas and thioureas, cinchona alkaloids,
squaramides, guanidines, diols, and phosphoric acids.1 N-Sulfinyl
ureas have recently emerged as a successful new class of hydrogen-
bonding organocatalysts,2 in which the sulfinyl group can serve as
an easily tunable, chiral acidifying group.3 The sulfinyl moiety offers
a potential advantage over other acidifying groups in achieving
sufficient steric demand while simultaneously introducing chirality
and good catalyst solubility in nonpolar solvents. The seminal re-
port of N-sulfinyl urea catalysis was a highly enantio- and diaster-
eoselective aza-Henry reaction, utilizing a cis-1,2-aminoindanol-
derived tert-butanesulfinyl urea catalyst and achieving up to 96% ee
and 97:3 diastereoselectivity.2a We then chose to use sulfinyl urea
chemistry to explore asymmetric thioacetic acid additions to
nitroalkenes, where the only previous report gave enantiose-
lectivities ranging from 20 to 70% using Takemoto’s thiourea
organocatalyst 3.4e6 Notably, nitroalkene thioacid addition prod-
ucts are versatile intermediates for the preparation of 1,2-
aminothiol derivatives, which are prevalent in biologically active
compounds, such as penacillamine, penicillin, biotin, and sulco-
nazole, a clinically used azole anti-fungal drug.7
expansion of this work to cyclic nitroalkene substrates in which
both an enantio- and diastereoselective process to set two stereo-
centers is achieved. Moreover, catalyst structureeactivity re-
lationships are defined to show that the sulfinyl moiety is an
essential substituent for achieving a highly selective catalyst.
2. Results and discussion
Under optimized reaction conditions for the addition of thio-
acetic acid to trans-b-nitrostyrene, a variety of sulfinyl catalysts, as
well as Takemoto’s urea and thiourea catalysts, were evaluated for
selectivity and catalytic activity (Table 1). In performing this cata-
lyst screen, cyclopentyl methyl ether (CPME),8 an increasingly
popular industrial solvent, was employed because it provided the
highest selectivity in an initial solvent screen.2b Takemoto’s thio-
urea catalyst 3, though highly active, gave low selectivity (32% ee),
whereas the less acidic Takemoto urea catalyst 4 was less active and
gave improved but still modest (68% ee) enantioselectivity. tert-
Butanesulfinyl ureas 5 and 6 also were only moderately selective,
but switching to the more sterically demanding trisyl sulfinyl ureas
7 and 8 brought the enantioselectivity up to 80 and 90% ee, re-
spectively. Additionally, the more acidic and achiral trisyl sulfonyl
group present in urea 9 gave diminished enantioselectivity as
compared to the sulfinyl catalysts. Urea 8, with a syn relationship
between the sulfinyl and 1,2-diamine stereocenters, was identified
as the optimal catalyst, affording the product in 90% ee and good
conversion within 2 days at ꢀ78 ꢁC.
Using a 1,2-cyclohexanediamine-derived triisopropylphenyl (trisyl)
sulfinyl urea catalyst, we reported the first highly enantioselective
* Corresponding author. Tel.: þ1 203 432 3647; fax: þ1 203 432 3486; e-mail
address: jonathan.ellman@yale.edu (J.A. Ellman).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.01.048

K.L. Kimmel et al. / Tetrahedron 68 (2012) 2704e2712
2705
Table 1
Electronic variation via para substitution shows that more
electron-deficient nitroalkenes (products 2b and 2f) provide
a higher yield, while electron-rich derivatives provide higher
enantioselectivities (products 2cee).9 Ortho substitution also re-
sults in an increase in enantioselectivity (product 2e). Significantly,
Catalyst screen under optimized conditions
o,p-dichloro-trans-b-nitrostyrene, which can be converted to sul-
conazole (vide infra), provides both high yield and enantiose-
lectivity (product 2f). Aliphatic nitroalkenes also undergo the
addition reaction in good yield for both linear (products 2g and 2h)
and branched (product 2i) substrates, although with somewhat
reduced enantioselectivity relative to the aryl substrates. The role
of the configuration of the N-sulfinyl stereocenter in the urea
catalyst is clearly complex because N-sulfinyl catalyst 7 provided
the cyclohexyl product 2i with higher selectivity (84% ee) than N-
sulfinyl catalyst 8 (70% ee), which was the preferred catalyst for all
other substrates (products 2aeh).
Entry
Catalyst
Conva (%)
eeb (%)
1
2
3
4
5
6
7
3
4
5
6
7
8
9
99
65
99
99
89
86
99
32c
68
46
50
80c
90
53
a
Conversion was determined by 1H NMR analysis based upon the ratio of product
to starting material.
In addition to the trans-
above, the enantioselective thioacetic acid addition can also be
applied to the more complex -disubstituted nitroalkenes
b-substituted nitroalkenes discussed
b
Enantiomeric excess was determined by chiral HPLC analysis.
Opposite enantiomer obtained as the major product.
c
a,b
(Scheme 2), in which two stereocenters are set in the addition
reaction. Though the addition of thioacetic acid to nitro-
cyclohexene only proceeded in w70% ee using sulfinyl catalyst 8,
diastereomeric sulfinyl catalyst 7 promoted the reaction in an
impressive 94% ee (product 11a). Additionally, the reaction was
completely diastereoselective, affording exclusively the trans-ad-
dition product in 96% yield. Though variation of the substrate ring
size tended to reduce the diastereoselectivity, both nitro-
cyclopentene (product 11b) and nitrocycloheptene (product 11c)
underwent thioacetic acid addition with high enantioselectivities
(93 and 86% ee, respectively) and good yields (80e82%). The
thioacetic acid addition proceeds with high enantio- and dia-
stereoselectivity for a variety of six-membered substrate analogs,
including electron-deficient, electron-rich and sterically de-
manding 2-nitro-3,4-dihydronaphthalene substrates (85e90% ee,
95:5e97:3 dr, products 11deg). Additionally, the chemical yields
are excellent for the entire range of substrates (96e98%). How-
Though seemingly simple, identifying conditions for the iso-
lation of these compounds proved challenging. After aqueous ex-
traction and purification by silica gel chromatography using
hexanes/ethyl acetate as the eluent, the pure product was analyzed
for enantiomeric excess. Much to our surprise, the observed en-
antiomeric purity after chromatography was <20% ee. Additionally,
the isolated yield was very low (<30% yield). This raised the
question of whether the enantiomeric purity determined on
unpurified material was accurate or whether racemization and
decomposition had in fact occurred during purification. We imag-
ined that instability of the thioacid adducts could be causing the
product to racemize during chromatographic purification. To probe
the stability of the product toward various conditions, we devised
an experiment wherein the crude product was partitioned and
subjected to a 1% solution of mild base, mild acid, and strong acid,
and then analyzed. Acetic acid exposure preserved the enantio-
meric purity (90% ee), hydrochloric acid caused crystallization and
enhanced enantiomeric purity (98% ee), and triethylamine caused
complete racemization (0% ee) and partial decomposition to the
starting nitroalkene. These results suggest that racemization and
decomposition had occurred during chromatography through
a process of base-promoted E2 elimination of thioacetate, followed
by partial nonselective re-addition. Due to the observed acid-
stability of the products, chromatographic purification was modi-
fied through use of acetic acid buffered silica gel to enable
straightforward and reliable isolation of pure product without
racemization.
ever, the acyclic substrate trans-b-methyl-b-nitrostyrene gave
only modest (w2:1) diastereoselectivity, albeit with quite high
enantioselectivity (94% ee, product 11h).
While the sulfinyl stereochemistry is of critical importance for
some transformations,2c for the enantioselective catalytic addition
of thioacetic acid to nitroalkenes the impact of sulfinyl stereo-
chemistry is clearly complex. Though catalysts 7 and 8 promote
highly enantioselective additions for a broad variety of nitroalkene
substrates, the role of sulfinyl stereochemistry is perplexing par-
ticularly because the preferred diastereomer of the catalyst seems
to change somewhat randomly across substrates (see Scheme 1,
products 2aeh vs Scheme 1, product 2i and Scheme 2, products 11).
Moreover, in some cases the sulfinyl stereochemistry of the catalyst
seems to have a negligible effect (Table 1, entries 1 and 2). These
The scope of the reaction was then explored for both aromatic
and aliphatic nitroalkenes (Scheme 1). The product of addition
to trans-b-nitrostyrene was isolated in 90% ee and 73% yield.

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K.L. Kimmel et al. / Tetrahedron 68 (2012) 2704e2712
Scheme 1. Catalytic enantioselective addition of thioacetic acid to aromatic and aliphatic
tography. bCatalyst 7 was used.
b
-substituted nitroalkenes. aIsolated yield of analytically pure material after chroma-
results prompted us to pose the questionddoes the catalyst require
sulfinyl chirality at all or can the sulfinyl group be replaced with
a simpler, more inexpensive achiral urea substituent with optimal
steric and electronic properties?
To probe this question, a plethora of catalysts 12 that contain
achiral replacements for the sulfinyl group, derived from readily
available anilines or sulfonamides, were synthesized and tested in
a broad range of urea acidities, from substantially less acidic than
Takemoto’s urea (entry 3) to more acidic (entry 7), but none out-
performed Takemoto’s catalyst. In addition, these catalysts span
a range of steric properties, even up to the incredibly hindered
2,4,6-tri-tert-butylphenyl urea 12b, but even this catalyst only
provided 26% ee (entry 3).
Similarly to the aniline-based catalysts, sulfonamide-based
catalysts spanning a range of acidities, steric profiles and sub-
stitution patterns were tested (Table 2). A range of substituted aryl
sulfonamides with increasing acidity were surveyed, from the p-
dimethylaminophenyl and o,p-dimethoxyphenyl sulfonyl ureas
12h and 12i with highly attenuated acidity (entries 9e10), to the p-
methoxyphenyl sulfonyl urea 12j (entry 11) of comparable acidity
to a sulfinyl urea, to the more acidic sulfonyl ureas 12a, and 12ceg
(entry 12). The electronic effect on catalyst selectivity adhered to
a parabolic pattern rather than a linear trend, with the peak of
selectivity corresponding to an intermediate aciditydthat of the p-
methoxyphenyl sulfonyl urea 12j (68% ee, entry 11). Additionally,
both 2,4,6-trisubstituted and 3,5-disubstituted aryl sulfonyl ureas
of varying steric bulk were evaluated (entries 12e16). Among both
the 2,4,6- and 3,5-substituted series, increasing the steric bulk of
the sulfonamide increased the enantioselectivity, but only up to
a maximum of 66% ee, with the original trisyl sulfonyl urea 9 as the
best candidate (entry 14). Similarly, the tert-butylsulfonyl urea 12o,
with slightly attenuated acidity as compared to the aryl sulfonyl
ureas but with similar steric bulk, did not surpass the benchmark
the enantioselective addition of thioacetic acid to trans-b-nitro-
styrene (Table 2). These catalysts can be easily assembled using the
standard carbonyldiimidazole-mediated coupling of the conserved
1,2-cyclohexanediamine component with a sulfinamide, sulfon-
amide or aniline input. Both aniline and sulfonamide-based cata-
lysts were surveyed with
a range of steric and electronic
properties. It quickly became apparent that although catalytic ef-
ficiency was high for all catalysts surveyed, attaining high enan-
tioselectivity was a more significant challenge. The benchmark for
aniline-based catalysts, Takemoto’s 3,4-bis(trifluoromethyl)phenyl
urea 4 (Table 2, entry 1), afforded the product in 68% ee. The
analogous 3,4-dinitrophenyl urea 12a performed similarly, pro-
viding the adduct in 71% ee (entry 2). A variety of 2,4,6-
trisubstituted aryl ureas 12bee were synthesized and surveyed
and displayed overall mediocre selectivities (entries 3e6). Addi-
tionally, a few other types of highly activated scaffolds, such as the
2,6-dinitrophenyl urea 12f (entry 7) and the pentafluorophenyl
urea 12g (entry 8), were also tested but displayed only moderate
enantioselectivities. It should be noted that these catalysts span

K.L. Kimmel et al. / Tetrahedron 68 (2012) 2704e2712
2707
Scheme 2. Catalytic enantio- and diastereoselective addition of thioacetic acid to a,b
-disubstituted nitroalkenes. aIsolated yield of analytically pure material after chromatography.
bDiastereomeric ratios were determined by 1H NMR and HPLC analysis. cEnantiomeric excess was determined by chiral HPLC analysis. dReaction carried out at 0.4 M [10]. eReaction
performed using 5 equiv of thioacetic acid. fReaction performed at 0.04 M [10] using 3 equiv of thioacetic acid.
68% ee of Takemoto’s catalyst (entry 17). Despite several of these
catalysts exhibiting similar steric bulk and acidity to trisyl sulfinyl
urea 8, none achieved selectivity even remotely close to the enan-
tioselectivity of catalyst 8 (90% ee).
Our studies to date therefore indicate that multiple factors
contribute to asymmetric induction in sulfinyl urea catalysis, in-
cluding the acidity, steric size, electronics, solubility and stereo-
chemistry of the catalyst. Based on mechanistic work by
Takemoto and Jacobsen with similar organocatalytic systems, the
reaction presumably proceeds with bifunctional organocatalysis,
where the urea hydrogens activate the nitroalkene via hydrogen
bonding while the pendant amine deprotonates thioacetic
acid.4,5,10,11
The utility of this process was also demonstrated for pharma-
ceutical applications. Upon examining the structures of a number
of commercial drugs, it occurred to us that the backbone of the
anti-fungal drug sulconazole6 bears a striking resemblance to
our thioacetic acid addition product. Conceptually, sulconazole
appeared to be a derivative of our product in which the thioacid is
converted into a benzyl thioester and the nitro group is converted
into an imidazole moiety. Practically, these manipulations turned
out to be quite feasible, enabling us to achieve the first asymmetric
synthesis of sulconazole from addition product 2b in only four
steps (Scheme 3). Reduction of the 1,2-nitrothiolate was un-
precedented in the literature and is complicated by thiol poisoning
of typical transition metal-catalysts employed in nitro reduction.
However, by using excess tin(II) chloride and anhydrous hydro-
chloric acid, reduction of 2b was achieved with concomitant acyl
transfer to the amine, providing thiol amide 13 in 74% yield. Ad-
ditionally, it should be noted that the nitro reduction was accom-
plished with complete preservation of enantiomeric purity,
a concern that had been raised during initial isolation issues (vide
supra), but was expected to be mitigated by the acid-stability of the
product. Acetyl protection of the amine, which occurred sponta-
neously upon reduction, was a convenient strategy to ensure
complete chemoselectivity in the alkylation of the newly
unmasked thiol. Alkylation with benzyl bromide 14 followed by
quantitative amide hydrolysis gave free amine 15 in 71% overall
yield. Final condensation of amine 15 with glyoxal and formalde-
hyde12 afforded R-sulconazole in 74% yield. The drug was synthe-
sized in 32% overall yield for the five steps and with 96% ee from
nitrostyrene 1b.
b-

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K.L. Kimmel et al. / Tetrahedron 68 (2012) 2704e2712
Table 2
expansive structureeactivity relationship study of urea catalysts,
Catalyst structureeactivity relationship study
we have shown that a sulfinyl group is a key component in the
catalyst that enables high enantioselectivities. Current work is
devoted to the further development of hydrogen-bonding catalysts
that rely on the N-sulfinyl urea motif to attain the optimal elec-
tronic, steric and stereochemical profile for efficient and selective
catalysis.
4. Experimental section
4.1. General experimental
Entry
Catalyst
R
Conva,b (%)
eec (%)
1
2
3
4
5
6
7
8
4
3,5-(CF3)2Ph
3,5-(NO2)2Ph
2,4,6-t-Bu3Ph
4-NO2ꢀ2,6-Cl2Ph
4-NO2e2,6-Br2Ph
4-CF3ꢀ2,6-Br2Ph
2,6-(NO2)2Ph
C6F5
SO2(4-NMe2Ph)
SO2(2,4-MeO2Ph)
SO2(4-MeOPh)
Ts
SO2Mes
SO2Trisyl
SO2(3,5-Me2Ph)
SO2(3,5-t-Bu2Ph)
SO2tBu
65
54
88
34
92
97
71
49
93
82
88
73
98
97
86
99
94
68
71
26
53
52
46
12
54
59
44
68
48
62
66
44
60
66
12a
12b
12c
12d
12e
12f
12g
12h
12i
12j
12k
12l
9
Unless otherwise noted, all reactions were carried out in flame
dried glassware under inert nitrogen atmosphere. All reagents
were obtained from commercial suppliers and used without further
purification unless otherwise noted. Tetrahydrofuran (THF), ether,
methylene chloride (CH2Cl2) and dioxane were passed though
columns of activated alumina under nitrogen pressure immediately
prior to use. Cyclopentyl methyl ether (CPME) was distilled over
finely cut elemental sodium, re-distilled under inert atmosphere
over benzophenone ketyl into an oven-dried Schlenk tube, then
freeze-pump-thawed and stored in the glove box. All urea catalysts
were dried under high vacuum over fresh P2O5 overnight prior to
use. Thioacetic acid was distilled under inert atmosphere. Dry po-
tassium hydride was stored and weighed under inert atmosphere
in the glove box. Takemoto catalysts 3 and 4,11 diamine S-1,13 trii-
sopropylbenzene sulfonamide,14 and triisopropylbenzene sulfina-
mide2b,15,16 were prepared according to literature procedure.
9
10
11
12
13
14
15
16
17
12m
12n
12o
a
Reactions were performed with 5.0 mol % of catalyst loading at 0.1 M concen-
tration of substrate with 2.0 equiv of thioacetic acid.
b
Conversion was determined by 1H NMR analysis.
Enantiomeric excess was determined by chiral HPLC analysis.
c
Scheme 3. Enantioselective synthesis of (R)-sulconazole.
3. Conclusion
Experimental procedures and full analytical data for compounds 2,
5e9, and 13e15 have been previously reported.2b Reactions were
monitored by thin layer chomatography (TLC) and visualized with
ultraviolet light and ninhydrin or potassium permanganate stains.
Unless otherwise noted, 1H and 13C{1H} NMR chemical shifts are
reported in parts per million relative to either the residual solvent
peak (1H, 13C) or TMS (1H) as an internal standard. IR spectra were
recorded on an FTIR spectrometer equipped with an attenuated
total reflectance accessory as thin films on a KBr beamsplitter, and
only partial data are listed.
In conclusion, we have demonstrated that a sulfinyl urea
organocatalyst promotes the first highly enantioselective addition
of thioacetic acid to aromatic and aliphatic
alkenes as well as a range of cyclic nitroalkenes to introduce two
stereocenters. This reaction can serve as a general method for
preparing chiral 1,2-aminothiols in compounds of pharmaceutical
interest, as demonstrated by the expedient synthesis of R-sulco-
nazole in 96% ee and good overall yield. Furthermore, through an
b-substituted nitro-

K.L. Kimmel et al. / Tetrahedron 68 (2012) 2704e2712
2709
5.66 (s, 1H), 3.49e3.25 (m, 1H), 2.32e2.12 (m, 2H), 2.22 (s, 6H),
1.89e1.78 (m, 1H), 1.78e1.69 (m, 1H), 1.64 (m, 1H), 1.27e1.01 (m,
4H). 13C NMR (126 MHz, MeOD)
d 157.0, 146.8, 142.0, 135.0, 125.1,
68.1, 53.2, 41.1, 35.4, 26.7, 26.4, 24.6. HRMS (ESI) calcd for
C15H20Cl2N4O3 [MH]þ 375.09852; found 375.09817.
4.2.4. Urea 12d (Table 2). The general procedure (B) was followed
using 2,6-dibromo-4-nitroaniline (296 mg, 1.00 mmol), potassium
hydride (120 mg, 3.00 mmol), 1,10-carbonyldiimidazole (162 mg,
1.00 mmol), and (R,R)-diamine S-1 (142 mg, 1.00 mmol). Urea 12d
was purified by silica gel chromatography (90:9:1 CH2Cl2/MeOH/
NH4OH). Product 12d was isolated as a yellow powder (373 mg, 80%
yield), mp 104 ꢁC. IR: 2931, 2858, 2783, 1650,1523,1449,1376,1340,
4.2. General procedure for the preparation of ureas from
sulfinamides, sulfonamides or anilines (Eq. 1)
1233, 738 cmꢀ1. 1H NMR (400 MHz, MeOD)
d 8.49 (s, 2H), 3.70e3.48
A suspension of potassium hydride (3 equiv) in THF (0.6 M) was
cooled in an ice-water bath. A solution of sulfonamide, sulfonamide
or aniline (1.0 equiv) in THF (0.20 M) was added dropwise, and the
suspension was stirred for 15 min. 1,10-Carbonyldiimidazole
(1.0 equiv) was dissolved in 1:1 THF/dioxane (0.20 M) and added
dropwise to the reaction mixture, resulting in the formation of
a white precipitate. The ice-water bath was removed, and the re-
action mixture was allowed to warm to ambient temperature and
was stirred for 2 h. A solution of diamine S-1 (1.0 equiv) in THF
(1.0 M) was added dropwise, and the suspension was stirred at
room temperature for 20 h. The reaction was quenched with a so-
lution of acetic acid (3 equiv) in THF (1.0 M). The crude product was
concentrated in vacuo and purified by silica gel chromatography.
(m,1H), 2.43 (m,1H), 2.38 (s, 6H), 2.23 (m,1H),1.92 (m,1H),1.84 (m,
1H), 1.72 (m, 1H), 1.38e1.22 (m, 4H). 13C NMR (126 MHz, MeOD)
d
157.0, 147.4, 144.5, 128.8, 125.1, 68.0, 53.2, 41.2, 35.5, 26.7, 26.4,
24.9. HRMS (ESI) calcd for C15H20Br2N4O3 [MH]þ 464.99553; found
464.99497.
4.2.5. Urea 12e (Table 2). The general procedure (B) was followed
using 2,6-dibromo-4-(trifluoromethyl)aniline (319 mg, 1.00 mmol),
potassium hydride (120 mg, 3.00 mmol), 1,10-carbonyldiimidazole
(162 mg, 1.00 mmol), and (S,S)-diamine S-1 (156 mg, 1.10 mmol).
Urea 12e was purified by silica gel chromatography (90:9:1 CH2Cl2/
MeOH/NH4OH). Product 12e was isolated as a white powder
(360 mg, 74% yield), mp 180 ꢁC. IR: 2933, 2859, 1645, 1538, 1392,
1312, 1267, 1234, 1163, 1127, 1096, 880, 738 cmꢀ1
.
1H NMR
4.2.1. Urea 12a (Table 2). The general procedure (B) was followed
using 3,5-dinitroaniline (183 mg, 1.00 mmol), potassium hydride
(120 mg, 3.00 mmol), 1,10-carbonyldiimidazole (162 mg,
1.00 mmol), and (S,S)-diamine S-1 (142 mg, 1.00 mmol). Urea 12a
was purified by silica gel chromatography (90:9:1 CH2Cl2/MeOH/
NH4OH). Product 12a was isolated as a yellow powder (265 mg, 75%
yield), mp 109 ꢁC. IR: 2936, 2863, 1674, 1532, 1472, 1335, 1260, 1207,
(500 MHz, MeOD)
d
7.94 (s, 2H), 3.57 (td, J¼10.3, 3.8 Hz, 1H),
2.45e2.37 (m, 1H), 2.34 (s, 6H), 2.27e2.18 (m, 1H), 1.89 (m, 1H), 1.82
(m, 1H), 1.69 (m, 1H), 1.35e1.20 (m, 4H). 13C NMR (126 MHz, MeOD)
d
157.5, 142.1, 131.8 (q, J¼135 Hz), 130.7 (q, J¼15 Hz), 126.4, 124.3 (q,
J¼1085 Hz), 68.02, 53.13, 41.21, 35.60, 26.76, 26.42, 25.12. HRMS
(ESI) calcd for C16H20Br2F3N3O [MH]þ 487.99783; found 487.99633.
1067, 892, 726 cmꢀ1. 1H NMR (500 MHz, MeOD)
2H), 8.53 (t, J¼2.0 Hz, 1H), 3.61 (td, J¼10.7, 4.0 Hz, 1H), 2.53e2.40
(m, 1H), 2.34 (s, 6H), 2.26 (m, 1H), 1.96 (m, 1H), 1.87 (m, 1H),
1.79e1.71 (m, 1H), 1.41e1.24 (m, 4H). 13C NMR (126 MHz, MeOD)
d
8.70 (d, J¼2.0 Hz,
4.2.6. Urea 12f (Table 2). The general procedure (B) was followed
using 2,6-dinitroaniline (183 mg, 1.00 mmol), potassium hydride
(120 mg, 3.00 mmol), 1,10-carbonyldiimidazole (162 mg,
1.00 mmol), and (R,R)-diamine S-1 (142 mg, 1.00 mmol). Urea 12f
was purified by silica gel chromatography (90:9:1 CH2Cl2/MeOH/
NH4OH). Product 12f was isolated as an orange powder (257 mg,
81% yield), mp 110 ꢁC. IR: 2934, 2860, 2787, 1668, 1532, 1478, 1344,
d
157.2, 150.6, 144.6, 118.7, 111.9, 68.2, 52.7, 40.9, 35.2, 26.6, 26.4,
23.7. HRMS (ESI) calcd for C15H21N5O5 [MH]þ 352.16155; found
352.16150.
1298, 1236, 728 cmꢀ1. 1H NMR (400 MHz, CDCl3)
d
8.11 (d, J¼8.2 Hz,
4.2.2. Urea 12b (Table 2). The general procedure (B) was followed
using 2,4,6-tri-tert-butylaniline (120 mg, 0.460 mmol), potassium
hydride (56 mg, 1.4 mmol), 1,10-carbonyldiimidazole (74 mg,
0.46 mmol), and (R,R)-diamine S-1 (65 mg, 0.46 mmol). Urea 12b
was purified by silica gel chromatography (90:9:1 CH2Cl2/MeOH/
NH4OH). Product 12b was isolated as a white powder (47 mg, 24%
yield), mp 190 ꢁC. IR: 3178, 2930, 2863, 2781, 1661, 1510, 1477, 1362,
2H), 7.10 (t, J¼8.3 Hz, 1H), 6.08 (br s, 1H), 3.25 (td, J¼10.5, 3.0 Hz,
1H), 2.33e2.17 (m, 2H), 2.14 (s, 6H), 1.78e1.61 (m, 2H), 1.51 (m, 1H),
1.07 (m, 4H). 13C NMR (126 MHz, MeOD)
d 156.0, 145.6, 131.4, 130.1,
124.3, 68.1, 52.9, 41.1, 35.6, 26.6, 26.5, 24.4. HRMS (ESI) calcd for
C15H21N5O5 [MH]þ 352.16155; found 352.16147.2
1341, 1267, 1241, 811, 731 cmꢀ1. 1H NMR (400 MHz, CDCl3)
d 7.40 (s,
2H), 5.60 (br s, 1H), 4.67 (br s, 1H), 3.19 (m, 1H), 2.71 (m, 1H),
2.05e1.79 (s, 6H), 1.78e1.65 (m, 2H), 1.59 (m, 1H), 1.44 (s, 9H), 1.43
(s, 9H), 1.34 (s, 9H), 1.25 (m, 2H), 1.16e1.03 (m, 2H), 0.94 (m, 1H). 13C
4.2.7. Urea 12g (Table 2). The general procedure (B) was followed
using pentafluoroaniline (147 mg, 0.803 mmol), potassium hydride
(97 mg, 2.4 mmol), 1,10-carbonyldiimidazole (131 mg, 0.808 mmol),
and (R,R)-diamine S-1 (115 mg, 0.810 mmol). Urea 12g was purified
by silica gel chromatography (90:9:1 CH2Cl2/MeOH/NH4OH).
Product 12g was isolated as a yellow powder (229 mg, 65% yield),
mp 147 ꢁC. IR: 2935, 2862, 1648, 1551, 1518, 1267, 1233, 1003, 975,
NMR (101 MHz, CDCl3)
d 158.6, 149.5, 131.0, 123.3, 122.9, 66.7, 51.3,
40.1, 36.8, 36.6, 35.0, 32.7, 32.2, 32.0, 31.9, 31.5, 25.4, 24.4, 21.3.
HRMS (ESI) calcd for C27H47N3O [MH]þ 430.37919; found
430.37780.
874, 734 cmꢀ1. 1H NMR (400 MHz, CDCl3)
d 5.95 (br s, 1H), 3.43 (m,
1H), 2.39 (td, J¼10.9, 3.3 Hz,1H), 2.28 (s, 6H), 2.18e2.16 (m,1H),1.84
(m, 1H), 1.81e1.70 (m, 1H), 1.65 (m, 1H), 1.27e1.03 (m, 4H). 13C NMR
4.2.3. Urea 12c (Table 2). The general procedure (B) was followed
using 2,6-dichloro-4-nitroaniline (140 mg, 0.676 mmol), potassium
hydride (79 mg, 2.0 mmol), 1,10-carbonyldiimidazole (110 mg,
0.679 mmol), and (R,R)-diamine S-1 (96 mg, 0.676 mmol). Urea 12c
was purified by silica gel chromatography (90:9:1 CH2Cl2/MeOH/
NH4OH). Product 12c was isolated as a yellow powder (180 mg, 73%
yield), mp 160 ꢁC. IR: 2932, 2859, 2784, 1651,1530,1456,1386,1340,
(126 MHz, MeOD)
d
162.9 (m), 157.8, 145.3 (dm, J¼1000 Hz), 141.1
(dm, J¼1000 Hz), 139.5 (dm, J¼1000 Hz), 117.3 (m), 115.3 (m), 69.9,
51.4, 43.1, 38.1, 34.5, 25.9, 25.5, 24.6. HRMS (ESI) calcd for
C15H18F5N3O [MH]þ 352.14428; found 352.14410.
4.2.8. Urea 12h (Table 2). The general procedure (B) was followed
using 4-(N,N-dimethyl)benzenesulfonamide (46 mg, 0.23 mmol),
1253, 1232, 811, 740 cmꢀ1. 1H NMR (400 MHz, CDCl3)
d 8.12 (s, 2H),

2710
K.L. Kimmel et al. / Tetrahedron 68 (2012) 2704e2712
potassium hydride (28 mg, 0.69 mmol), 1,10-carbonyldiimidazole
(37 mg, 0.23 mmol), and (S,S)-diamine S-1 (33 mg, 0.23 mmol).
Urea 12h was purified by silica gel chromatography (90:9:1 CH2Cl2/
MeOH/NH4OH). Product 12h was isolated as a white powder
(22 mg, 26% yield), mp 134 ꢁC. IR: 2936, 2860, 1596, 1512, 1446,
1319, 1235, 1115, 1086, 867, 652 cmꢀ1. 1H NMR (500 MHz, MeOD)
yield), mp 108 ꢁC. IR: 2936, 2861, 1702, 1601, 1450, 1379, 1339,
1236, 1112, 851, 658 cmꢀ1 1H NMR (400 MHz, MeOD)
6.92 (s,
.
d
2H), 3.62 (m, 1H), 3.00 (td, J¼11.7, 2.8 Hz, 1H), 2.78 (s, 6H), 2.69 (s,
6H), 2.27 (s, 3H), 2.05 (m, 1H), 1.90 (m, 2H), 1.73 (m, 1H),
1.49e1.25 (m, 4H). 13C NMR (101 MHz, MeOD)
d 162.9, 141.6, 141.6,
139.8, 132.2, 71.6, 70.5, 50.9, 40.4, 34.1, 25.6, 25.2, 24.0, 23.3, 20.9.
HRMS (ESI) calcd for C18H29N3O3S [MH]þ 368.20024; found
368.20020.
d
7.63 (d, J¼8.8 Hz, 2H), 6.63 (d, J¼9.0 Hz, 2H), 3.53 (m, 1H), 2.90 (s,
6H), 2.89 (m, 1H), 2.61 (s, 6H), 1.92 (m, 1H), 1.81 (m, 1H), 1.77 (m,
1H), 1.61 (m, 1H), 1.33 (m, 1H), 1.20 (m, 3H). 13C NMR (126 MHz,
MeOD)
d
152.7, 130.7, 128.3, 128.3, 110.7, 69.3, 39.3, 33.0, 29.7, 29.6,
4.2.13. Urea 12m (Table 2). The general procedure (B) was followed
using 3,5-dimethylbenzenesulfonamide (93 mg, 0.50 mmol), po-
tassium hydride (60 mg, 1.5 mmol), 1,10-carbonyldiimidazole
(81 mg, 0.50 mmol), and (S,S)-diamine S-1 (85 mg, 0.60 mmol).
Urea 12m was purified by reverse phase chromatography using
a 43 g C18 column (95:5 H2O/MeCN to 100% MeCN, 40 mL/min,
24.5, 24.2, 22.9. HRMS (ESI) calcd for C17H28N4O3S [MH]þ
369.19549; found 369.19533.
4.2.9. Urea 12i (Table 2). The general procedure (B) was followed
using 2,4-dimethoxybenzenesulfonamide (217 mg, 1.00 mmol),
potassium hydride (120 mg, 3.00 mmol), 1,10-carbonyldiimidazole
(162 mg, 1.00 mmol), and (S,S)-diamine S-1 (142 mg, 1.00 mmol).
Urea 12i was purified by silica gel chromatography (90:9:1 CH2Cl2/
MeOH/NH4OH). Product 12i was isolated as a white solid (165 mg,
43% yield), mp 113 ꢁC. IR: 3053, 2939, 2861, 1702, 1593, 1578, 1466,
l
¼254, 210 nm). Product 12m was isolated as a white powder
(144 mg, 81% yield), mp 114e115 ꢁC. IR: 3047, 2937, 2862, 1602,
1513, 1468, 1450, 1381, 1321, 1274, 1243, 1126, 1096, 886, 786 cmꢀ1
1H NMR (500 MHz, MeOD)
7.54 (s, 2H), 7.14 (s, 1H), 3.67 (m, 1H),
.
d
3.19 (td, J¼12.0, 3.5 Hz, 1H), 2.78 (s, 6H), 2.36 (s, 6H), 2.09e2.01 (m,
1314, 1254, 1212, 1163, 1076, 1026, 732 cmꢀ1
.
1H NMR (400 MHz,
1H), 1.88 (m, 2H), 1.72 (m, 1H), 1.54e1.26 (m, 4H). 13C NMR
MeOD)
d
7.86 (d, J¼8.7 Hz, 1H), 6.65 (d, J¼2.1 Hz, 1H), 6.61 (dd,
(126 MHz, MeOD) d 163.7, 146.6, 139.7, 133.8, 125.8, 70.3, 51.2, 40.7,
J¼8.8, 2.2 Hz, 1H), 3.91 (s, 3H), 3.88 (s, 3H), 3.73 (s, 1H), 3.11 (td,
J¼11.8, 3.5 Hz, 1H), 2.78 (s, 6H), 2.06 (m, 1H), 1.90 (m, 2H), 1.74 (m,
34.6, 26.1, 25.6, 24.5, 21.8. HRMS (ESI) calcd for C17H27O3N3S [MH]þ
354.18459; found 354.18397.
1H), 1.46 (m, 1H), 1.35 (m, 3H). 13C NMR (126 MHz, MeOD)
d 165.8,
160.1, 159.7, 132.8, 124.0, 105.4, 100.2, 69.9, 56.7, 56.2, 54.8, 40.3,
34.1, 25.5, 25.2, 24.0. HRMS (ESI) calcd for C17H27N3O5S [MH]þ
386.17442; found 386.17427.
4.2.14. Urea 12n (Table 2). The general procedure (B) was followed
using 3,5-di(tert-butyl)benzenesulfonamide (135 mg, 0.500 mmol),
potassium hydride (60 mg, 1.5 mmol), 1,10-carbonyldiimidazole
(81 mg, 0.50 mmol), and (S,S)-diamine S-1 (78 mg, 0.55 mmol).
Urea 12n was purified by silica gel chromatography (90:9:1
CH2Cl2/MeOH/NH4OH). Product 12n was isolated as a white solid
(106 mg, 48% yield), mp 132 ꢁC. IR: 2955, 2865, 1702, 1595, 1517,
4.2.10. Urea 12j (Table 2). The general procedure (B) was followed
using 4-methoxybenzenesulfonamide (207 mg, 1.00 mmol), po-
tassium hydride (120 mg, 3.00 mmol), 1,10-carbonyldiimidazole
(162 mg, 1.00 mmol), and (R,R)-diamine S-1 (142 mg, 1.00 mmol).
Urea 12j was purified by silica gel chromatography (90:9:1 CH2Cl2/
MeOH/NH4OH). Product 12j was isolated as a white solid (220 mg,
58% yield), mp 114 ꢁC. IR: 2941, 2863, 1595, 1497, 1383, 1242, 1123,
1476, 1394, 1364, 1322, 1245, 1097, 882, 734 cmꢀ1
.
1H NMR
(400 MHz, MeOD) 7.82 (s, 2H), 7.60 (s, 1H), 3.71 (m, 1H), 3.19 (td,
d
J¼11.9, 3.4 Hz, 1H), 2.80 (s, 6H), 2.06 (m, 1H), 1.89 (m, 2H), 1.73 (m,
1H), 1.48e1.28 (m, 4H), 1.42 (s, 18H). 13C NMR (126 MHz, MeOD)
1082, 1025, 729, 666 cmꢀ1
.
1H NMR (500 MHz, MeOD)
d
7.82 (d,
d 163.3, 152.3, 145.6, 126.1, 121.9, 69.9, 50.8, 40.2, 36.0, 34.2, 31.8,
J¼8.7 Hz, 2H), 6.95 (d, J¼8.8 Hz, 2H), 3.80 (s, 3H), 3.63 (m, 1H), 3.12
25.6, 25.2, 24.0. HRMS (ESI) calcd for C23H39N3O3S [MH]þ
438.27849; found 438.27807.
(td, J¼11.9, 3.4 Hz, 1H), 2.72 (s, 6H), 1.99 (m, 1H), 1.81 (m, 2H), 1.65
(m, 1H), 1.45e1.21 (m, 4H). 13C NMR (126 MHz, MeOD)
d 163.2,
138.2, 129.8, 129.7, 114.5, 69.8, 56.1, 50.8, 40.3, 34.1, 25.6, 25.2, 24.1.
HRMS (ESI) calcd for C16H25N3O4S [MH]þ 356.16385; found
356.16400.
4.2.15. Urea 12o (Table 2). The general procedure (B) was followed
using tert-butanesulfonamide (126 mg, 0.920 mmol), potassium
hydride (110 mg, 2.80 mmol), 1,10-carbonyldiimidazole (149 mg,
0.920 mmol), and (R,R)-diamine S-1 (131 mg, 0.923 mmol). Urea
12o was purified by silica gel chromatography (90:9:1 CH2Cl2/
MeOH/NH4OH). Product 12o was isolated as a white solid (211 mg,
75% yield), mp 189 ꢁC. IR: 2933, 2862, 1705, 1585, 1514, 1478, 1450,
4.2.11. Urea 12k (Table 2). The general procedure (B) was fol-
lowed using p-toluenesulfonamide (187 mg, 1.00 mmol), potas-
sium hydride (120 mg, 3.00 mmol), 1,10-carbonyldiimidazole
(162 mg, 1.00 mmol), and (R,R)-diamine S-1 (142 mg, 1.00 mmol).
Urea 12k was purified by silica gel chromatography (90:9:1
CH2Cl2/MeOH/NH4OH). Product 12k was isolated as a white solid
1388, 1324, 1282, 1216, 1132, 1091, 1066, 864 cmꢀ1
(400 MHz, MeOD) 3.85e3.66 (m, 1H), 3.05 (m, 1H), 2.80 (s, 6H),
2.07 (m, 2H), 1.92 (m, 1H), 1.78 (m, 1H), 1.55e1.45 (m, 1H), 1.44e1.39
(s, 9H), 1.33 (m, 3H). 13C NMR (126 MHz, MeOD)
162.3, 70.6, 60.2,
.
1H NMR
d
ꢁ
(107 mg, 30% yield), mp 81 C. IR: 2939, 2864, 1597, 1437, 1249,
d
1119, 1070, 869, 813, 729 cmꢀ1. 1H NMR (500 MHz, MeOD)
d
7.89
51.8, 40.7, 34.5, 26.1, 25.7, 25.5, 24.4. HRMS (ESI) calcd for
C13H27N3O3S [MH]þ 306.18459; found 306.18450.
(d, J¼8.3 Hz, 2H), 7.42 (d, J¼8.0 Hz, 2H), 3.81 (td, J¼11.1, 4.3 Hz,
1H), 3.29e3.23 (m, 1H), 2.88 (s, 3H), 2.78 (s, 3H), 2.46 (s, 3H), 2.11
(m, 1H), 1.91 (m, 1H), 1.85e1.78 (m, 1H), 1.75 (m, 1H), 1.56e1.47
4.3. Representative procedure for racemic addition
(m, 1H), 1.37 (m, 3H). 13C NMR (126 MHz, MeOD)
d
154.5, 146.4,
of thioacetic acid to trans-
b-nitrostyrene
139.0, 131.1, 129.2, 69.7, 50.9, 43.3, 38.2, 34.3, 25.8, 25.4, 24.4,
21.9. HRMS (ESI) calcd for C16H25N3O3S [MH]þ 340.16894; found
340.16900.
To a solution of trans- -nitrostyrene (30 mg, 0.20 mmol) in
b
diethyl ether (1.0 mL) was added one drop of triethylamine. The
solution was cooled to ꢀ15 ꢁC. Thioacetic acid (0.029 mL,
0.40 mmol) was added. The reaction mixture was stirred at ꢀ15 ꢁC
for 4 h, then quenched at that temperature by addition of saturated
NaHCO3(aq) (1 mL). The mixture was then diluted with ether (2 mL)
and washed with saturated NaHCO3(aq) (2ꢂ2 mL). The crude
product was purified by silica gel chomatography (9:1 hexanes/
EtOAc).
4.2.12. Urea 12l (Table 2). The general procedure (B) was followed
using mesitylenesulfonamide (199 mg, 1.00 mmol), potassium
hydride (120 mg, 3.00 mmol), 1,10-carbonyldiimidazole (162 mg,
1.00 mmol), and (R,R)-diamine S-1 (142 mg, 1.00 mmol). Urea 12l
was purified by silica gel chromatography (90:9:1 CH2Cl2/MeOH/
NH4OH). Product 12l was isolated as a white solid (92 mg, 25%

K.L. Kimmel et al. / Tetrahedron 68 (2012) 2704e2712
2711
4.4. Representative procedure for enantioselective addition
of thioacetic acid to trans- -nitrostyrenes
28.3, 27.1, 26.6, 26.4, 23.5, 23.1. HRMS-ESI (m/z): [MþH]þ calcd for
C9H15NO3S, 218.08454; found, 218.08447. The ee of the major di-
astereomer was determined to be 86% by chiral HPLC analysis
b
A mixture of trans-
b
-nitrostyrene (30 mg, 0.20 mmol) and sul-
(Chiralcel IA, hexane/isopropanol 99/1, 1.0 mL/min,
(11c major)¼17.3 min, tR (11c minor)¼10.5 min.
l
¼210 nm): tR
finyl urea catalyst (0.010 mmol) in cyclopentyl methyl ether
(2.0 mL) was cooled to ꢀ78 ꢁC. Thioacetic acid (0.029 mL,
0.40 mmol) was added. The reaction mixture was stirred at ꢀ78 ꢁC
for 48 h, then quenched at that temperature by addition of satu-
rated NaHCO3(aq) (1 mL). The mixture was then diluted with diethyl
ether (1 mL) and allowed to warm with shaking until the aqueous
layer was thawed. The layers were separated and the organic layer
was washed quickly with saturated NaHCO3(aq) (3ꢂ1 mL). The crude
ether solution was eluted immediately through a silica gel plug
with diethyl ether. The resulting solution was concentrated in
vacuo. The crude product was purified by silica gel chromatography
(90:9:1 hexanes/EtOAc/AcOH). Enantiomeric excess was de-
termined by chiral HPLC analysis.
4.4.4. trans-1-Thioacetyl-2-nitro-3,4-dihydronaphthalene 11d (Scheme
2). The general procedure was followed using trans-2-nitro-3,4-
dihydronaphthalene (18 mg, 0.10 mmol), catalyst 7 (2.2 mg,
0.0050 mmol), and thioacetic acid (14 mL, 0.20 mmol) in cyclopentyl
methyl ether (0.25 mL) to afford a 96:4 diastereomeric mixture of
product 11d (24 mg, 96% yield) as a colorless oil. IR: 2934, 2333,1697,
1548, 1489, 1453, 1436, 1374, 1355, 1265, 1127, 952, 909, 729,
626 cmꢀ1 1H NMR (500 MHz, CDCl3)
. d 7.38e7.31 (m, 1H), 7.23 (t,
J¼3.5 Hz, 2H), 7.16e7.07 (m, 1H), 5.66 (d, J¼4.3 Hz, 1H), 5.50 (t,
J¼5.8 Hz, 1H), 5.04 (ddd, J¼10.7, 4.6, 3.2 Hz, 1H), 4.98e4.89 (m, 1H),
3.14e3.01 (m,1H), 3.01e2.91 (m,1H), 2.61e2.50 (m,1H), 2.40 (s, 3H),
2.40e2.37 (m, 1H). 13C NMR (126 MHz, CDCl3)
d 193.3, 134.4, 134.3,
4.4.1. trans-1-Thioacetyl-2-nitro-cyclohexane 11a (Scheme 2). The
general procedure was followed using trans-1-nitrocyclohexene
(13 mg, 0.10 mmol), catalyst 7 (2.2 mg, 0.0050 mmol), and thio-
129.7, 129.2, 128.5, 127.6, 84.2, 44.9, 30.7, 27.2, 25.1. HRMS-ESI (m/z):
[MþH]þ calcd for C12H13NO3S, 252.06889; found, 252.06870. The ee
of the major diastereomer was determined to be 90% by chiral HPLC
analysis (Chiralcel AS-H, hexane/isopropanol 95/5, 1.0 mL/min,
acetic acid (14 mL, 0.20 mmol) in cyclopentyl methyl ether (1 mL) to
afford product 11a (19 mg, 95% yield) with >99% diastereomeric
purity as a colorless oil. IR: 2943, 2862,1693, 1543, 1448,1373, 1353,
1301, 1269, 1244, 1112, 999, 953, 911, 859, 758, 625 cmꢀ1. 1H NMR
l
¼210 nm): tR (11d major)¼25.4 min, tR (11d minor)¼17.6 min.
4.4.5. trans-1-Thioacetyl-2-nitro-3,4-dihydro-7-bromonaphthalene
11e (Scheme 2). The general procedure was followed using trans-2-
nitro-3,4-dihydro-7-bromonaphthalene (51 mg, 0.20 mmol), cata-
(500 MHz, CDCl3)
d
4.66 (dt, J¼7.9, 4.1 Hz, 1H), 4.25 (s, 1H), 2.33 (s,
3H), 2.09 (dd, J¼8.4, 5.1 Hz, 3H), 1.88e1.79 (m, 1H), 1.74e1.56 (m,
3H), 1.52e1.42 (m, 1H). 13C NMR (126 MHz, CDCl3)
d
193.9, 85.2,
lyst 7 (4.4 mg, 0.010 mmol), and thioacetic acid (29 mL, 0.40 mmol)
42.9, 30.6, 29.9, 28.8, 23.3, 21.6. HRMS-ESI (m/z): [MþNa]þ calcd for
in cyclopentyl methyl ether (0.5 mL) to afford a 95:5 diastereomeric
mixture of product 11e (64 mg, 98% yield) as a colorless oil. IR:
2939, 2326, 2084, 1695, 1591, 1546, 1480, 1435, 1373, 1354, 1265,
C8H13NO3S, 226.05084; found, 226.05033. ½a D20
ꢀ52.2 (c 1.0, CHCl3).
ꢃ
The ee was determined to be 94% by chiral HPLC analysis (Chiralcel
IA, hexane/isopropanol 97/3, 1.0 mL/min,
major)¼11.1 min, tR (11a minor)¼8.0 min.
l¼210 nm): tR (11a
1149, 1125, 951, 733, 625 cmꢀ1. 1H NMR (500 MHz, CDCl3)
d 7.43 (s,
1H), 7.30 (d, J¼8.2 Hz, 1H), 6.95 (d, J¼8.3 Hz, 1H), 5.51 (d, J¼4.2 Hz,
1H), 5.05e4.89 (m, 1H), 2.94 (dt, J¼17.3, 5.6 Hz, 1H), 2.88e2.77 (m,
1H), 2.49 (s, 1H), 2.41e2.28 (m, 1H), 2.38 (s, 3H). 13C NMR (126 MHz,
4.4.2. 1-Thioacetyl-2-nitro-cyclopentane 2l (Scheme 2). The general
procedure was followed using trans-1-nitrocyclopentene (11 mg,
0.10 mmol), catalyst 7 (2.2 mg, 0.0050 mmol), and thioacetic acid
(21 mL, 0.30 mmol) in cyclopentyl methyl ether (2.5 mL) to afford
a 65:35 diastereomeric mixture of product 11b (15 mg, 80% yield) as
CDCl3) d 193.2, 136.4, 133.5, 132.2, 131.5, 130.8, 121.0, 84.0, 44.1, 30.8,
26.5, 25.2. HRMS-ESI (m/z): [MþH]þ calcd for C12H12BrNO3S,
329.97940; found, 329.97937. The ee of the major diastereomer was
determined to be 89% by chiral HPLC analysis (Chiralcel IA, hexane/
a colorless oil. IR: 2960, 1694, 1548, 1449, 1369, 1355, 1324, 1272,
isopropanol 95/5, 1.0 mL/min,
tR (11e minor)¼11.1 min.
l
¼210 nm): tR (11e major)¼14.8 min,
1128, 955, 628 cmꢀ1. 1H NMR (500 MHz, CDCl3)
d
(only peaks cor-
responding the the major isomer are listed) 5.12 (dd, J¼9.0, 4.5 Hz,
1H), 4.81e4.77 (m, 1H), 4.28 (dd, J¼12.5, 7.5 Hz, 1H), 3.90 (dt,
J¼14.0, 7.1 Hz, 1H), 2.41e2.22 (m, 6H), 2.13e2.06 (m, 1H), 2.01 (d,
J¼11.9 Hz, 1H), 1.84e1.68 (m, 1H). 13C NMR (126 MHz, CDCl3)
4.4.6. trans-1-Thioacetyl-2-nitro-3,4-dihydro-6-methoxynaphthalene
11f (Scheme 2). The general procedure was followed using trans-2-
nitro-3,4-dihydro-6-methoxynaphthalene (21 mg, 0.10 mmol),
d
(peaks corresponding to both the major and minor diastereomers
catalyst 7 (2.2 mg, 0.0050 mmol), and thioacetic acid (36 mL,
are listed) 195.1, 194.6, 91.6, 89.3, 46.6, 45.1, 32.5, 31.8, 31.3, 30.4,
30.4, 29.6, 24.2, 22.8. HRMS-ESI (m/z): [MþNa]þ calcd for
C7H11NO3S, 212.03519; found, 212.03510. The ee for the major di-
astereomer was determined to be 93% by chiral HPLC analysis
0.50 mmol) in cyclopentyl methyl ether (1 mL) to afford a 97:3 di-
astereomeric mixture of product 11f (27 mg, 97% yield) as a yellow
oil. IR: 2944, 2838, 2341, 1696, 1607, 1549, 1500, 1463, 1432, 1374,
1318,1272,1244, 1159,1127, 1035, 951, 625 cmꢀ1. 1H NMR (500 MHz,
(Chiralcel AD-H, hexane/isopropanol 97/3, 1.0 mL/min,
tR (11b major)¼16.3 min, tR (11b minor)¼9.8 min.
l
¼210 nm):
CDCl3)
d
7.23 (d, J¼8.6 Hz, 1H), 6.78 (d, J¼8.4 Hz, 1H), 6.61 (s, 1H),
5.63 (d, J¼4.1 Hz, 1H), 5.45 (m, 1H), 5.00 (dd, J¼7.4, 3.7 Hz, 1H), 4.91
(s, 1H), 3.79 (s, 3H), 3.09e2.98 (m, 1H), 2.98e2.81 (m, 1H), 2.52 (dd,
J¼21.4, 15.3 Hz, 1H), 2.41e2.29 (m, 1H), 2.39 (s, 3H). 13C NMR
4.4.3. 1-Thioacetyl-2-nitro-cycloheptane 11c (Scheme 2). The gen-
eral procedure was followed using trans-1-nitrocycloheptene
(14 mg, 0.10 mmol), catalyst 7 (2.2 mg, 0.0050 mmol), and thio-
acetic acid (14 mL, 0.20 mmol) in cyclopentyl methyl ether (1 mL) to
afford a 80:20 diastereomeric mixture of product 11c (18 mg, 82%
(126 MHz, CDCl3) d 193.1, 159.2, 135.4, 130.6, 126.0, 113.8, 113.0, 83.9,
55.3, 44.3, 30.4, 27.2, 24.5. HRMS-ESI (m/z): [MþNa]þ calcd for
C13H15NO3S, 304.06140; found, 304.06163. The ee of the major di-
astereomer was determined to be 85% by chiral HPLC analysis
yield) as a colorless oil. IR: 2933, 2862, 1691, 1545, 1457, 1374, 1354,
(Chiralcel IA, hexane/isopropanol 95/5, 1.0 mL/min,
(11f major)¼17.9 min, tR (11f minor)¼13.9 min.
l¼210 nm): tR
1297, 1107, 953, 854, 771, 628 cmꢀ1
.
1H NMR (500 MHz, CDCl3)
d
(only peaks corresponding the the major isomer are listed)
4.89e4.78 (m, 1H), 4.72 (dd, J¼11.8, 7.7 Hz, 1H), 4.25 (t, J¼12.5 Hz,
1H), 2.36 (s, 3H), 2.26e2.15 (m, 2H), 1.92 (dd, J¼16.3, 6.7 Hz, 1H),
1.82e1.68 (m, 3H), 1.67e1.56 (m, 3H). 13C NMR (126 MHz, CDCl3)
4.4.7. trans-1-Thioacetyl-2-nitro-3,4-dihydro-5,7-dimethylnaphthalene
11g (Scheme 2). The general procedure was followed using trans-2-
nitro-3,4-dihydro-5,7-dimethylnaphthalene (41 mg, 0.20 mmol),
d
(peaks corresponding to both the major and minor diastereomers
catalyst 7 (4.4 mg, 0.010 mmol), and thioacetic acid (29
mL,
are listed) 194.2, 91.2, 89.1, 46.3, 45.3, 32.7, 32.5, 31.6, 30.9, 30.5,
0.40 mmol) in cyclopentyl methyl ether (0.5 mL) to afford a 96:4

2712
K.L. Kimmel et al. / Tetrahedron 68 (2012) 2704e2712
Ellman, J. A. J. Am. Chem. Soc. 2009, 131, 8754; (c) Kimmel, K. L.; Weaver, J. W.;
Ellman, J. A. Chem. Sci. 2012, 3, 121.
diastereomeric mixture of product 11g (50 mg, 90% yield) as a color-
less oil. IR: 1698, 1549, 1482, 1432, 1375, 1355, 1265, 1125, 953, 908,
3. For other examples of organocatalysts containing sulfinamide, see: (a) Beck, E.
M.; Hyde, A. M.; Jacobsen, E. N. Org. Lett. 2011, 13, 4260; (b) Tan, K. L.; Jacobsen,
E. N. Angew. Chem., Int. Ed. 2007, 46, 1315; (c) Pei, D.; Wang, Z.; Wei, S.; Zhang,
Y.; Sun, J. Org. Lett. 2006, 8, 5913; (d) Wang, C.; Wu, X.; Zhou, L.; Sun, J. Chem.
dEur. J. 2008, 14, 8789; (e) Pei, D.; Zhang, Y.; Wei, S.; Wang, M.; Sun, J. Adv.
Synth. Catal. 2008, 350, 619.
731, 702, 655, 624 cmꢀ1. 1H NMR (500 MHz, CDCl3)
d 6.94 (s, 1H), 6.90
(s, 1H), 5.60 (d, J¼2.7 Hz, 1H), 5.03e4.88 (m, 1H), 4 2.87 (m, 1H),
2.73e2.60 (m, 1H), 2.60e2.52 (m, 1H), 2.34 (s, 3H), 2.30e2.24 (m, 1H),
2.24 (s, 3H), 2.16 (s, 3H). 13C NMR (126 MHz, CDCl3)
d 193.2, 137.1,
136.8, 134.3, 131.1, 129.9, 127.8, 83.9, 45.4, 30.8, 25.0, 24.8, 21.2, 19.9.
HRMS-ESI (m/z): [MþH]þ calcd for C14H17NO3S, 280.10019; found,
280.10010. The ee of the major diastereomer was determined to be
90% by chiral HPLC analysis (Chiralcel IA, hexane/isopropanol 97/3,
4. For a review on asymmetric Michael additions of thiols, see: Enders, D.;
Luettgen, K.; Narine, A. A. Synthesis 2007, 7, 959. For organocatalytic enan-
tioselective Michael additions of sulfur nucleophiles to a,b-unsaturated car-
bonyl compounds, see: (a) Liu, Y.; Sun, B.; Wang, B.; Wakem, M.; Deng, L. J. Am.
Chem. Soc. 2009, 131, 418; (b) Marigo, M.; Schulte, T.; Franzen, J.; Jorgensen, K.
J. Am. Chem. Soc. 2005, 127, 15710; (c) Hiemstra, H.; Wynberg, H. J. Am. Chem.
Soc. 1981, 103, 417; (d) Ricci, P.; Carlone, A.; Bartoli, G.; Bosco, M.; Sambri, L.;
Melchiorre, P. Adv. Synth. Catal. 2008, 350, 49 For metal-catalyzed enantio-
1.0 mL/min,
8.9 min.
l¼210 nm): tR (11g major)¼12.1 min, tR (11g minor)¼
selective Michael additions of sulfur nucleophiles to a,b-unsaturated carbonyl
compounds, see; (e) Abe, A. M.; Sauerland, S. J.; Koskinen, A. M. J. Org. Chem.
2007, 72, 5411; (f) Nishamura, K.; Tomioka, K. J. Org. Chem. 2002, 67, 431; (g)
Saito, M.; Nakajima, M.; Hashimoto, S. Tetrahedron 2000, 56, 9589; (h) Ka-
nemasa, S.; Oderaotoshi, Y.; Wada, E. J. Am. Chem. Soc. 1999, 121, 8675; (i)
Emori, E.; Arai, T.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1998, 120, 4043; (j)
Dong, X.-Q.; Fang, X.; Wang, C.-J. Org. Lett. 2011, 13, 4426; (k) Rana, N. K.;
Selvakumar, S.; Singh, V. K. J. Org. Chem. 2010, 75, 2089; (l) Hui, Y.-H.; Jiang, J.;
Wang, W.-T.; Chen, W.-L.; Cai, Y.-F.; Lin, L.-L.; Liu, X.-H.; Feng, X.-M. Angew.
Chem., Int. Ed. 2010, 49, 4290; (m) Tian, X.; Cassani, C.; Lium, Y.; Moran, A.;
Urakawa, A.; Galzerano, P.; Arceo, E.; Melchiorre, P. J. Am. Chem. Soc. 2011, 133,
17934.
5. For Michael additions of sulfur nucleophiles to nitroalkenes, see: (a) See Ref. 2b
(b) Li, H.; Wang, J.; Zu, L.; Wang, W. Tetrahedron Lett. 2006, 47, 2585; (c) Ko-
bayashi, N.; Iwai, K. J. Org. Chem. 1981, 46, 1823 To obtain a reasonable ee (58%),
stoichiometric cinchona alkaloid catalyst was required.
6. (a) Takemoto, Y. J. Am. Chem. Soc. 2005, 127, 119; (b) Hoashi, Y.; Okino, T.;
Takemoto, Y. Angew. Chem., Int. Ed. 2005, 44, 4032; (c) Xu, X.; Yabuta, T.; Yuan,
P.; Takemoto, Y. Synlett 2006, 1, 137.
7. Fromtling, R. A. Clin. Microbiol. Rev. 1988, 1, 187 Azole antifungals, such as sul-
conazole are known to act by inhibition of the fungal cell CYP51 lanosterol
demethylase. Though inhibitory activity data for the enantiomers of sulcona-
zole is not available, in vitro studies of very similar azole antifungals have
demonstrated that the R-enantiomer can be up to 60-fold more active than the
S-enantiomer. For biological data on azole enantiomers, see; (a) Quaglia, M. G.;
Donati, E.; Desideri, N.; Fanali, S.; D’Auria, F. D.; Tecca, M. Chirality 2002, 14, 449;
(b) Lamb, D. C.; Kelly, D. E.; Baldwin, B. C.; Gozzo, F.; Boscott, P.; Richards, W. G.;
Kelly, S. L. FEMS Microbiol. Lett. 1997, 149, 25; (c) Foguet, R.; Ramentol, J.; Gu-
glietta, A.; Palacin, C.; Anglada, L. (Ferrer Internacional S.A., Spain) PCT Appl.
WO 03/068770, February 4, 2003. Berkessel, A.; Cleemann, F.; Mukherjee, S.;
Mueller, T. N.; Lex, J. Angew. Chem., Int. Ed. 2005, 44, 807.
4.4.8. 1-Thioacetyl-1-phenyl-2-nitropropane 11h (Scheme 2). The
general procedure was followed using trans- -methyl- -nitro-
styrene (16 mg, 0.10 mmol), catalyst 7 (2.2 mg, 0.0050 mmol), and
thioacetic acid (21 L, 0.30 mmol) in cyclopentyl methyl ether
(2.5 mL) to afford a 67:33 diastereomeric mixture of product 11h
(23 mg, 96% yield) as a colorless oil. IR: 2941, 1696, 1549, 1492, 1451,
1386, 1356, 1293, 1124, 1094, 953, 864, 747, 698, 624 cmꢀ1. 1H NMR
b
b
m
(500 MHz, CDCl3)
d (peaks listed for both diastereomers) 7.34 (m,
5H), 5.17 (d, J¼9.2 Hz, 0.67H), 5.14 (d, J¼9.1 Hz, 0.33H), 5.05e4.95
(m, 1H), 2.40 (s, 2H), 2.35 (s, 1H), 1.71 (d, J¼6.7 Hz, 2H), 1.51 (d,
J¼6.7 Hz, 1H). 13C NMR (126 MHz, CDCl3)
d (peaks listed for both
diastereomers) 192.4, 137.0, 129.1, 129.0, 128.6, 128.3, 128.0, 86.6,
86.1, 50.4, 50.3, 30.5, 30.5, 18.0, 17.6. HRMS-ESI (m/z): [MþNa]þ
calcd for C11H13NO3S, 262.05084; found, 262.05073. The ee of the
major diastereomer was determined to be 94% by chiral HPLC
analysis (Chiralcel AS-H, hexane/ethanol 98/2, 1.0 mL/min,
l¼210 nm): tR (11h major)¼9.6 min, tR (11h minor)¼10.4 min.
Acknowledgements
This work was supported by the NSF (CHE-1049571).
Supplementary data
8. For leading references on CPME, see: (a) Antonucci, V.; Coleman, J.; Ferry, J.
B.; Johnson, N.; Mathe, M.; Scott, J. P.; Xu, J. Org. Process Res. Dev. 2011, 15,
939; (b) Watanabe, K.; Yamagiwa, N.; Torisawa, Y. Org. Process Res. Dev. 2007,
11, 251.
Complete experimental procedures, product characterization,
and HPLC traces. This material is available free of charge via the
Internet at http://pubs.acs.org. Supplementary data related to this
article can be found online at doi:10.1016/j.tet.2012.01.048.
9. The reduced enantioselectivity of electron-deficient b-substituted nitroalkenes
is believed to be a result of an inverse reactivity-selectivity correlation, rather
than epimerization of the product. It is known that racemization does not occur
under the reaction conditions because the enantioselectivity was observed to
be constant over time
References and notes
10. For relevant mechanistic studies of H-bonding organocatalysis, see: Vachal, P.;
Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 10012.
11. Matsuoka, Y.; Ishida, Y.; Sasaki, D.; Saigo, K. Tetrahedron 2006, 62, 8199.
12. Takemoto, Y. Org. Biomol. Chem. 2005, 127, 119.
13. Mitchell, J. M.; Finney, N. S. Tetrahedron Lett. 2000, 41, 8431.
14. Hayashi, T.; Kawai, M.; Tokunaga, N. Angew. Chem., Int. Ed. 2004, 43, 6125.
15. Han, Z.; Krishnamurthy, D.; Grover, P.; Fang, Q. K.; Senanayake, C. H. J. Am. Chem.
Soc. 2002, 124, 7880.
1. For reviews of H-bonding organocatalysis, see: (a) Taylor, M. S.; Jacobsen, E. N.
Angew. Chem., Int. Ed. 2006, 45, 1520; (b) Takemoto, Y. Org. Biomol. Chem. 2005,
3, 4299; (c) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713; (d) Akiyama,
T. Chem. Rev. 2007, 107, 5744; (e) Yu, X.; Wang, W. Chem.dAsian J. 2008, 3, 516;
(f) Terada, M. Synthesis 2010, 12, 1929; (g) Rueping, M.; Koenigs, R. M.; Ato-
diresei, I. Chem.dEur. J. 2010, 16, 9350.
16. Senanayake, C. H.; Krishnamurthy, D.; Lu, Z.-H.; Han, Z.; Gallou, I. Aldrichimica
2. For examples of N-sulfinyl urea catalysis, see: (a) Robak, M. T.; Trincado, M.;
Acta 2005, 38, 93.
Ellman, J. A. J. Am. Chem. Soc. 2007, 129, 15110; (b) Kimmel, K. L.; Robak, M. T.;