Novel bifunctional sulfonamides catalyze an enantioselective conjugate addition

Article abstract of DOI:10.1016/j.tet.2008.11.027

A new bifunctional organocatalyst with a novel structural and functional motif has been developed. This bifunctional sulfonamide organocatalyst was used in the conjugate addition of 1,3-dicarbonyl compounds (13) to β-nitrostyrenes (12). Yields up to 91% a

Full text of DOI:10.1016/j.tet.2008.11.027

Tetrahedron 65 (2009) 449–455
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Novel bifunctional sulfonamides catalyze an enantioselective conjugate addition
,
Patrick G. McGarraugh a, Stacey E. Brenner a
*
a Department of Chemistry, Brooklyn College and the City University of New York, 2900 Bedford Avenue, Brooklyn, NY 11210, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 August 2008
Received in revised form 27 October 2008
Accepted 8 November 2008
Available online 13 November 2008
A new bifunctional organocatalyst with a novel structural and functional motif has been developed. This
bifunctional sulfonamide organocatalyst was used in the conjugate addition of 1,3-dicarbonyl com-
pounds (13) to b-nitrostyrenes (12). Yields up to 91% and enantiomeric excesses up to 79% were obtained
in this reaction. This catalyst activates both 13 via its basic moiety and 12 through hydrogen bonding.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Bifunctional organocatalysts
Sulfonamide
Asymmetric catalysis
Michael addition
1. Introduction
reaction were obtained using these organocatalysts.11c Finally, since
there can be a correlation between acidity and hydrogen bond
The use of non-transition metal-based organocatalysts has
gained increasing popularity in recent years due both to a mount-
ing desire to use more environmentally benign catalysts and to the
expanding scope of organocatalytic reactions.1 More specifically,
organocatalysts that act as relatively weak hydrogen bond donors
or as stronger, Brønsted acids have proven effective in a variety of
transformations.2 Within this class of organocatalysts, there are
numerous examples of thioureas3–6 of type 1 (Fig. 1) and several
examples of cinchona alkaloids7 (2) and bis-phenols8 (3). These
organocatalysts each contain two hydrogen bond donors, and act
by coordinating one or both of them to electrophiles. Moreover,
they are considered bifunctional, because they contain a basic ter-
tiary amine and can activate the nucleophilic reaction partner as
well.
donor ability,12 it was postulated that incorporating the more acidic
sulfonamide functional group as a hydrogen bond donor in bi-
functional catalysts of the type illustrated in Figure 1 could be
favorable.
While there is no facile way to modify 5 to incorporate an ap-
propriately situated tertiary amine moiety, the 1,3-benzenedi-
sulfonyl scaffold of 4 would allow for ready incorporation of a broad
structural array of chiral amines. This would enable the de-
velopment of the first bifunctional bissulfonamide organocatalysts,
of type 6, which contain both a tertiary amine and two sulfon-
amides, each capable of forming a discrete hydrogen bond with the
substrate.13
2. Results and discussion
In the search for new structural and functional motifs for
organocatalysts of this type, the strategy of adapting anion recep-
tors that bind anions through the donation of multiple hydrogen
bonds for this purpose was employed. Bissulfonamide 4 (Fig. 2) met
this criterion and was particularly attractive for several reasons.9
First, Crabtree and co-workers demonstrated that 4 could catalyze
an organic reaction (i.e., imine formation) and proposed that dou-
ble hydrogen bond donation of 4 to the electrophile was the mode
of activation.10 Second, it was recently revealed that chiral bissul-
fonamides (5) could act as hydrogen bonding organocatalysts.11
Enantiomeric excesses (ee’s) of up to 87% in a hetero Diels–Alder
It was first necessary to assess the catalytic potential of these
bissulfonamides in organic reactions that generate a chiral center.
Toward this end, compounds 4 and 7 (Fig. 3) were examined in the
conjugate addition of a 1,3-dicarbonyl compound to b-nitrostyrene
(Table 1),14 a transformation in which bifunctional thioureas of type
1 have been successfully employed.3a,4a,5b,6b,c Pleasingly, 4 and 7
produced 2.2- and 2.4-fold rate accelerations, respectively (entries
1–3, Table 1). This suggested that chiral variants of 4 that in-
corporate both acidic bissulfonamide protons and a basic tertiary
amine, could be effective catalysts for an enantioselective conjugate
addition.
Chiral amines that have been successfully employed in bi-
functional thiourea catalysts were selected for incorporation into
* Corresponding author. Tel.: þ1 718 951 5000; fax: þ1 718 951 4607.
E-mail address: sbrenner@brooklyn.cuny.edu (S.E. Brenner).
bissulfonamide catalysts.3–6,15
A variety of catalysts were
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.11.027

450
P.G. McGarraugh, S.E. Brenner / Tetrahedron 65 (2009) 449–455
N
N
CF3
OH
OH
S
OH
OH
F3C
N
H
N
N
H
N
H
N
1
2
3
Figure 1. Bifunctional organocatalysts with two H-bond donors.
synthesized16 to independently test the effect of acidity of the
sulfonamide protons (6b, 6c) and of the chiral moieties (6a, 6b, 6d)
on reaction yield and ee. Additionally, C2-symmetric catalyst 8 was
synthesized from commercially available 1,3-benzenedisulfonyl
chloride. Among the catalysts, the bissulfonamide derived from 1,2-
diphenylethylenediamine generated the product in the highest
yield (entry 4), but lowest ee. The bissulfonamides derived from
1,2-cyclohexanediamine all afforded products in similar, reduced
yields but with improved, yet varying, ee’s (entries 5, 6, and 8). The
bissulfonamide (6d) derived from a sterically demanding, aryl
amine did not catalyze the reaction (entry 7). Tethering the tertiary
amine to the bissulfonamide appears to lower the reaction rate (for
example, entry 6 vs 3; vida infra).17 These initial studies led to the
selection of catalyst 6c for further studies despite the low yield.
Optimization of other reaction conditions ensued using catalyst
6c. A solvent study revealed that non-polar solvents, such as toluene
and Et2O, resulted in higher product yields relative to more polar
solvents, such as THF and CH2Cl2 (entries 2–5, Table 2). The most
polar solvent, acetonitrile, gave the product in the lowest yield
(entry 1). Moderate to good enantiomeric excesses were achieved in
all solvents with the exceptionof THF. The reduced ee obtained using
THF may be related to the enhanced background reaction observed
in this solvent (vida infra). The highest ee’s were attained in non-
coordinating solvents, such as toluene and CH2Cl2. The reaction
could also be run using solvent-free conditions, which generated
products in significantly improved yields, but with only moderate
ee’s (entries 6 and 7). Thus, toluene, being both non-polar and non-
coordinating, was identified as the optimal solvent for this reaction.
Next, several other variables were examined. Tripling the cata-
lyst loading more than doubled the yield, but resulted in a loss of
enantioselectivity (entry 8 vs 2). Alternatively, either doubling the
reaction concentration or doubling the equivalents of 13a increased
the reaction yield to a similar, lesser degree, but resulted in a less
pronounced decrease in ee (entries 9 and 10 vs 5). In longer re-
action times, doubling the equivalents of 13a produced comparable
ee’s and a more dramatic improvement in yield (entry 11 vs 5).
Running the reaction at 0 ꢀC produced a minimal increase in ee, but
halved the yield (entry 12 vs 11). There was no difference in yield
and only slight differences in ee when the equivalents of 13a were
increased further at room temperature (entries 13 and 14 vs 11).
Increasing the reaction time further led to a greater than 4-fold
O2S
NH
SO2
HN
O2S
NH
SO2
HN
F3C
R1
R2
R2
N
CF3
R1
7
6a R1 = H, R2 = C6H5
6b R1 = H, R2 = -(CH2)4-
6c R1 = CF3, R2 = -(CH2)4-
11 R1 = CF3, R2 = H2
O2S
NH
SO2
HN
O2S
NH
SO2
HN
N
N
N
6d
8
O2S
N
SO2
HN
SO2
HN
N
N
9
10
Figure 3. Novel bissulfonamide organocatalysts.
improvement in yield and an insignificant drop in ee relative to
initial reaction conditions (entry 15), as the ee of the reaction in-
creased slightly over time. Finally, running the reaction at elevated
temperatures for extended reaction times led to still greater
product yields, but slightly lower enantioselectivities (entry 16).
Since obtaining useful product yields had been an impediment
with this catalyst, these last conditions were identified as the op-
timal reaction conditions.
O2S
NH
SO2
HN
O2S
NH
SO2
HN
RO2S NH HN SO2R
N
R1
5
6
4
Figure 2. Bissulfonamide organocatalysts with two H-bond donors.

P.G. McGarraugh, S.E. Brenner / Tetrahedron 65 (2009) 449–455
451
Table 1
Optimization of organocatalyst structure
O
O
Table 3
Investigation of substrate scope
NO2
EtO
OEt
NO2
EtO2C
catalyst (10 mol%)
rt
CO2Et
13a
O
O
O
O
R4
R4
NO2
NO2
R4
R4
13
6c (10 mol%)
toluene
12a
(R)-14a
R1
R3
R1
R3
R2
Entry
Catalyst
Solvent
Time (h)
% Yielda
% eeb,c
R2
12
(R)-14
Yielda
69
1
2
3
4
5
6
7
8
Et3N
4þEt3N
7þEt3N
6a
6b
6c
Et2O
Et2O
Et2O
Et2O
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
144
144
144
72
72
72
26
56
62
15
5
d
d
Entry
14
Condition
A
eeb
69c
d
20
50d
72
d
O
O
1
2
3
14b
14b
14c
7
EtO
EtO
OEt
NO2
6d
8
72
72
Trace
8
53
B
60
64
62
Reactions conditions: 12a (1 equiv), 13a (2 equiv), catalyst (0.1 equiv), solvent, rt.
Br
F
a
O
O
Isolated yield.
b
Enantiomeric excess was determined by chiral HPLC analysis.
Absolute configuration was determined by comparison of the specific rotation of
OEt
NO2
c
A
79e
14a with the literature value.18a
d
Similar ee’s for this catalyst were obtained in Et2O.
O
O
These optimized reaction conditions were used in an explora-
EtO
OEt
77d
tion of the substrate scope of this reaction. More reactive b-nitro-
NO2
4
14d
A
75
styrenes (i.e., those substituted with electron-withdrawing groups)
generated reduced yields of the desired product at elevated tem-
peratures (entry 2, Table 3). This was due to the formation of
Cl
Cl
O
byproducts arising from the incorporation of multiple
b-nitro-
O
styrene units. When reactions using these substrates were instead
run at room temperature, byproduct formation was not observed,
and yields up to 75% and ee’s up to 79% were obtained (entries 1, 3,
EtO
OEt
NO2
5
6
7
8
9
14e
14f
14g
14h
14i
A
B
B
B
A
70
51
56
69
91
57d
66c
64c
63c
49c
and 4). While substitution of the b-nitrostyrenes at the meta and
Br
O
O
EtO
OEt
NO2
Table 2
Optimization of reaction conditions
O
O
Me
NO2
EtO
OEt
EtO2C
CO2Et
13a
O
O
NO2
6c (10 mol%)
EtO
O
OEt
NO2
12a
(R)-14a
% Yielda
MeO
Entry
Solvent
Equiv 13a
Time (h)
Temp (ꢀC)
% eeb,c
O
1
2
3
4
5
6
7
8
MeCN
CH2Cl2
THF
Et2O
Toluene
d
2
2
2
2
2
2
2
2
2
4
4
4
6
10
4
2
72
72
72
72
72
72
72
72
72
rt
rt
rt
rt
rt
rt
0
rt
rt
rt
rt
0
4
7
7
47
72
27
65
70
49
53
60d
62e
66
68
70
65
66
69
64
MeO
OMe
NO2
15
13
68
42
16
22
20
45
22
45
45
57
66
O
O
d
CH2Cl2
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
9
NO2
10
11
12
13
14
15
16
72
168
240
168
168
240
168
rt
rt
rt
50
Reactions conditions A: 12 (1 equiv), 13 (4 equiv), 6c (0.1 equiv), toluene, rt, 240 h.
Reaction conditions B: 12 (1 equiv), 13 (2 equiv), 6c (0.1 equiv), toluene, 50 ꢀC, 168 h.
a
Isolated yield.
b
Enantiomeric excess was determined by chiral HPLC analysis.
c
Absolute configuration was determined by comparison of the specific rotation of
Reactions conditions: 12a (1 equiv), 13a, 6c (0.1 equiv), solvent, rt.
the products with the literature value.18
a
Isolated yield.
d
Absolute configuration was not determined.
Absolute configuration was S by comparison of the specific rotation of 14c with
b
Enantiomeric excess was determined by chiral HPLC analysis.
Absolute configuration was determined by comparison of the specific rotation of
e
c
the literature value.18a
14a with the literature value.18a
d
Compound 6c (0.3 equiv) was used.
Reaction concentration doubled.
e

452
P.G. McGarraugh, S.E. Brenner / Tetrahedron 65 (2009) 449–455
Table 5
para positions was well tolerated, ortho substitution resulted in
a loss of enantioselectivity (entry 5). Reactions of more electron-
Synthetic mechanistic investigations
O
O
rich b-nitrostyrenes also provided products in good ee, but slightly
reduced yields (entries 6 and 7). The addition of 13a to even less
reactive, alkyl-substituted nitroalkenes, using either reaction con-
dition A or B, led to product formation in up to 58% ee, but in yields
no greater than 12%.19 The conjugate addition of dimethyl malonate
NO2
EtO
EtO2C
catalyst (10 mol%)
rt
CO2Et 13a
OEt
NO2
to b-nitrostyrene afforded the desired product in a good yield and
12a
(R)-14a
ee (entry 8). Analogous to what was observed with more reactive
electrophiles, the more reactive 2,4-pentanedione generated re-
duced yields of the desired product due to the formation of
byproducts at elevated temperatures.19 When this reaction was
instead run at room temperature, the product was obtained in 91%
yield, but only moderate ee (entry 9).
Entry
Catalyst
Solvent
Time (h)
% Yielda
% eeb,c
1
2
3
4
5
6
7
6c
9
10
7
Et3N
Et3Nþ7
11
MeOH
CH2Cl2
CH2Cl2
THF
THF
THF
72
72
72
144
144
144
144
35
<2
<2
nr
48
69
21
5
41
nd
d
d
d
d
Although the design of these organocatalysts was derived from
bissulfonamide 4, the former do not necessarily function like the
latter (i.e., as double hydrogen bond donors). To gain insight into the
role of the catalysts’ sulfonamide protons in this reaction, the in-
teraction of 7 with 12a was examined in titration experiments using
1H NMR. Bissulfonamide 7 was chosen for investigation because it
incorporates a mixed aryl/alkyl sulfonamide systemsimilar tothatof
the optimal catalyst, and its two sulfonamide protons have distinct
chemical shifts. Using rigorously dried deuterated solvent, in the
absence of 12a, the N-aryl sulfonamide proton appeared as a sharp
singlet at 7.50 ppm and the N-alkyl sulfonamide proton appeared as
a sharp doublet at 4.82 ppm (entry 1, Table 4). With an increasing
ratio of 12a to 7, the N-aryl sulfonamide proton gradually shifted
downfield and broadened, while the N-alkyl sulfonamide proton
remained unchanged. When the ratio of 12a to 7 was 4:1, the
THF
Reactions conditions: 12a (1 equiv), 13a (2 equiv), catalyst (0.1 equiv), solvent, rt.
a
Isolated yield.
b
Enantiomeric excess was determined by chiral HPLC analysis.
Absolute configuration was determined by comparison of the specific rotation of
c
14a with the literature value.18a
In addition to the acidic N-aryl sulfonamide, the basic moiety is
also necessary for reaction yield, as hydrogen bonding alone does
not promote this reaction (entry 4, Table 5). Interestingly, how-
ever, catalyst 11 provided the product in reduced yields relative to
both the bissulfonamide that was not tethered to a tertiary amine
as well as to the uncatalyzed reaction (entries 5–7, Table 5). It is
possible that this is the result of sterics, and that tethering the
tertiary amine to the catalyst hinders the association with
N-aryl sulfonamide proton appeared as
a broad singlet at
7.55 ppm (entry 2, Table 4). This subtle shift downfield, in
combination with peak broadening, is consistent with hydrogen
bond donation of the N-aryl sulfonamide moiety and is
comparable to what Takemoto and co-workers observed with
b-nitrostyrene. It is also plausible that there is an intramolecular
hydrogen bond, or a formal proton transfer, between the sulfon-
amides and the tertiary amine. Indeed, there is a pronounced
difference in the chemical shifts and peak shapes of the N-alkyl
and N-aryl sulfonamide protons of catalyst 7, where such intra-
molecular interactions are not possible, and those of catalyst 6c
(entries 1 vs 3, Table 4). Moreover, the fact that both sulfonamide
protons are chemically equivalent in 6c suggests that they are
both tied up in an intramolecular interaction with the tertiary
amine, which may be hampering catalytic activity.
C2-symmetric aryl thioureas in the presence of b
-nitrostyrene.4a
Further evidence in support of a role for hydrogen bonding in
this reaction was provided by synthetic experimental data, both
already acquired and new. By comparing entries 5 and 6 in Table 1,
enhancing the acidity of the sulfonamide N–H bond appears to
improve the chiral induction of the catalyst. A correlation between
catalyst acidity and reaction enantioselectivity has been observed
in other hydrogen bonding organocatalysts.12b Additionally, the fact
that the highest yields and ee’s were obtained in non-polar and
non-coordinating solvents, respectively, is consistent with a neu-
trally charged, hydrogen bonding transition state (entries 1–5,
Table 2). Furthermore, when methanol was the reaction solvent,
the products were generated in a 2.7-fold increased yield, but as
a nearly racemic mixture (entry 1, Table 5 vs entry 6, Table 1).
Presumably, methanol accelerated the reaction through hydrogen
3. Conclusion
In conclusion, a novel sulfonamide organocatalyst, 6c, has
been developed. The data suggests this catalyst is indeed bi-
functional, using at least its most acidic proton to activate 12
through hydrogen bonding, and using its basic moiety to activate
13. The data also suggests it might be possible to improve upon
the activity of this catalyst system by altering the tether length, or
type, of the basic moiety. These investigations are presently
underway.
The novel catalyst systems described herein serve to demon-
strate that new structural and functional motifs can be employed in
bifunctional hydrogen bonding catalysts. Ultimately, expanding the
structural and functional motifs used in this class of catalysts may
further enhance their utility in organic synthesis.
bond donation to
b-nitrostyrene; this interfered with the in-
teraction of this substrate with the catalyst that is necessary for the
enantioselectivity of this reaction. Moreover, catalysts 9 and 10,
which lack a second N–H bond, generated products in substantially
diminished yields and reduced enantioselectivies (entries 2 and 3,
Table 5 vs entries 5, 6, and 8, Table 1). Thus, the acidic N-aryl sul-
fonamide appears to be necessary for both reaction yield and
maximum ee’s.
Table 4
1H NMR mechanistic investigations
4. Experimental
Entry
1
Catalyst
1H NMR (CH2Cl2, 0.13 M)
Equiv 12a
4.1. General methods
7
7.50 (s, 1H, NARYL–H)
0
4.82 (d, J¼7.8 Hz, 1H, NAKLYL–H)
1H and 13C NMR data use the following abbreviations: s¼singlet,
d¼doublet, t¼triplet, q¼quartet, m¼multiplet, dd¼doublet of
doublets, td¼triplet of doublets, dt¼doublet of triplets. Enantiomer
2
3
7
7.55 (br s, 1H, NARYL–H)
4
0
4.82 (d, J¼7.8 Hz, 1H, NAKLYL–H)
6.50 (br s, 2H, NARYL–H and NALKYL–H)
6c

P.G. McGarraugh, S.E. Brenner / Tetrahedron 65 (2009) 449–455
453
ratios were determined using an HPLC with Daicel Chemical In-
dustries, LTD. Chiralpak AD-H (0.46ꢁ25 cm) and Chiralpak OD-H
(0.46ꢁ25 cm) columns. Chromatography was carried out with
Merck, grade 9385, 230–400 mesh, 600 Å silica gel and with Merck,
silica 60F254 on glass, 250 um layer TLC plates with fluorescent
indicator. Solvents were dried and kept air free in a solvent puri-
fication unit. Solvents were evaporated using a standard rotovapor
and a high vacuum. All reactions were carried out in oven dried
glassware and conducted under an argon atmosphere.
J¼7.8 Hz, 1H), 6.38 (s, 1H), 6.35 (t, J¼7.8 Hz, 1H), 6.02 (d,
J¼8.8 Hz, 1H), 2.61 (s, 6H) ppm; 13C NMR (100 MHz, CDCl3)
d
148.7, 140.9, 138.9, 135.8, 133.8, 133.7, 132.3, 131.3, 130.8,
130.2, 129.5, 129.5, 129.4, 129.2, 128.8, 128.5, 128.4, 127.9, 127.2,
126.9, 126.7, 125.9, 125.6, 125.1, 124.9, 124.0, 123.6, 122.5, 122.2,
118.0, 43.7 ppm; IR (film)
n 3264, 3060, 2843, 2795, 1589, 1348,
1180, 1156 cmꢂ1; HRMS calcd for C34H29N3O4S2 (Mþ) 607.1600,
obsd 607.1599.
4.2.6. N1-(3,5-Bis(trifluoromethyl)phenyl)-N3-cyclohexylbenzene-
4.2. Preparation of catalysts
1,3-disulfonamide 7
Colorless amorphous; 1H NMR (400 MHz, CDCl3)
d 8.57 (t,
Catalysts were prepared according to a modified procedure.16
J¼1.5 Hz, 1H), 8.12 (dt, J¼1.5, 7.8 Hz, 1H), 7.89 (dt, J¼1.5, 7.8 Hz, 1H),
7.63 (t, J¼7.8 Hz,1H), 7.61 (s, 3H), 5.27 (d, J¼7.6 Hz,1H), 3.17 (m, 1H),
1.74–1.45 (m, 5H), 1.31–1.04 (m, 5H) ppm; 13C NMR (100 MHz,
4.2.1. N1,N3-Diphenylbenzene-1,3-disulfonamide 49
Yellow amorphous solid; 1H NMR (400 MHz, CD3CN)
d
8.13 (m,
CDCl3) d 143.7, 140.1, 138.1, 133.7, 133.3, 133.0, 132.7, 131.7, 131.0,
1H), 8.02 (br s, 2H), 7.86 (dt, J¼2.3, 7.8 Hz, 2H), 7.57 (td, J¼2.4,
130.3, 125.9, 120.9, 119.1, 53.4, 33.9, 25.1, 24.6 ppm; IR (film) n 3277,
7.8 Hz, 1H), 7.27–7.20 (m, 4H), 7.13 (m, 2H), 7.00 (m, 4H) ppm; 13C
2933, 2856, 1377, 1279, 1136 cmꢂ1; HRMS calcd for C20H20F6N2O4S2
(Mþ) 530.0769, obsd 530.0765.
NMR (100 MHz, CD3CN)
126.6, 122.7 ppm.
d 141.5, 137.6, 132.2, 131.3, 130.4, 126.7,
4.2.7. N1,N3-Bis((1R,2R)-2-(dimethylamino)cyclohexyl)benzene-
4.2.2. N1-((1R,2R)-2-(Dimethylamino)-1,2-diphenylethyl)-N3-
phenylbenzene-1,3-disulfonamide 6a
1,3-disulfonamide 8
27
White crystals; mp 167–170 ꢀC; [
a
]
ꢂ144.0 (c 1.00, CHCl3); 1H
D
28
Colorless amorphous; [
a
]
þ128.5 (c 1.03, CH2Cl2); 1H NMR
NMR (400 MHz, CDCl3)
d
8.30 (t, J¼1.8 Hz, 1H), 7.99 (dd, J¼1.8,
D
(400 MHz, CDCl3)
d
8.09 (t, J¼1.8 Hz, 1H), 7.61 (d, J¼7.8 Hz, 1H), 7.49
7.8 Hz, 2H), 7.58 (t, J¼7.8 Hz, 1H), 6.03 (br s, 2H), 2.59 (m, 2H), 2.23
(m, 2H), 2.05 (td, J¼3.0, 11.9 Hz, 2H), 1.97 (s, 12H), 1.66 (m, 4H), 1.54
(m, 2H), 1.18–0.98 (m, 6H), 0.97–0.83 (m, 2H) ppm; 13C NMR
(d, J¼7.8 Hz, 1H), 7.31–7.23 (m, 2H), 7.23–7.12 (m, 5H), 7.08–7.03 (m,
2H), 7.00–6.94 (m, 2H), 6.89–6.76 (m, 5H), 4.76 (d, J¼11.1 Hz, 1H),
3.57 (d, J¼11.1 Hz, 1H), 2.16 (s, 6H) ppm; 13C NMR (100 MHz, CDCl3)
(100 MHz, CDCl3)
d 141.9, 130.9, 129.7, 126.1, 66.3, 54.3, 39.7, 32.6,
d
142.4, 139.9, 137.0, 136.1, 131.3, 130.9, 130.3, 129.9, 129.6, 129.1,
25.0, 24.2, 21.1 ppm; IR (film) n 3191, 2993, 2860, 2782, 1454, 1344,
128.7, 128.0, 128.0, 127.6, 126.3, 126.1, 122.2, 73.1, 57.6, 40.3 ppm; IR
1180, 1157, 1086, 1042 cmꢂ1; HRMS calcd for C22H38N4O4S2 (Mþ)
486.2335, obsd 486.2342.
(film) n
3256, 2933, 2790, 1593, 1348, 1176, 1148 cmꢂ1; HRMS calcd
for C28H29N3O4S2 (Mþ) 535.1600, obsd 535.1608.
4.2.8. N-((1R,2R)-2-(Dimethylamino)cyclohexyl)-
4.2.3. N1-((1R,2R)-2-(Dimethylamino)cyclohexyl)-N3-
phenylbenzene-1,3-disulfonamide 6b
benzenesulfonamide 9
27
White crystals; mp 77–82 ꢀC; [
a
]
ꢂ118.4 (c 1.00, CHCl3); 1H
D
28
Colorless amorphous; [
(400 MHz, CDCl3)
a
]
ꢂ61.6 (c 1.03, CH2Cl2); 1H NMR
NMR (400 MHz, CDCl3) d 7.84 (m, 2H), 7.56–7.42 (m, 3H), 5.99 (br s,
D
d
8.33 (s, 1H), 7.95 (d, J¼7.1 Hz, 1H), 7.83 (s,
1H), 2.56 (td, J¼4.0, 10.6 Hz, 1H), 2.35 (m, 1H), 2.09 (td, J¼3.8,
J¼7.1 Hz, 1H), 7.47 (t, J¼7.3 Hz, 1H), 7.19–6.95 (m, 5H), 6.52 (s,
2H), 2.53 (m, 1H), 2.11 (m, 1H), 2.03 (t, J¼11.1 Hz, 1H), 1.77 (s, 6H),
1.63 (m, 2H), 1.50 (m, 1H), 1.02 (m, 3H), 0.84 (m, 1H) ppm; 13C
10.4 Hz, 1H), 1.85 (s, 6H), 1.68 (m, 2H), 1.58 (m, 1H), 1.30–1.01 (m,
3H), 0.93 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3)
d 140.1, 132.5,
129.0, 127.4, 66.4, 54.2, 39.7, 32.8, 25.2, 24.3, 21.1 ppm; IR (film)
n
NMR (100 MHz, CDCl3)
d
142.1, 140.6, 136.1, 131.4, 131.0, 129.9,
3199, 2933, 2860, 2786, 1720, 1446, 1340, 1164, 1091 cmꢂ1; HRMS
calcd for C14H22N2O2S (Mþ) 282.1402, obsd 282.1407.
129.6, 126.3, 126.0, 122.1, 66.4, 54.4, 39.7, 32.7, 25.0, 24.3,
21.2 ppm; IR (film)
n 2925, 2852, 1597, 1454, 1344, 1180, 1152,
1111, 1082 cmꢂ1; HRMS calcd for C20H27N3O4S2 (Mþ) 437.1443,
obsd 437.1450.
4.2.9. N1-((1R,2R)-2-(Dimethylamino)cyclohexyl)-N3-methyl-N3-
phenylbenzene-1,3-disulfonamide 10
27
Colorless amorphous; [
(400 MHz, CDCl3)
a]
ꢂ79.4 (c 1.00, CHCl3); 1H NMR
D
4.2.4. N1-(3,5-Bis(trifluoromethyl)phenyl)-N3-((1R,2R)-2-
(dimethylamino)cyclohexyl)benzene-1,3-disulfonamide 6c
d
8.13 (t, J¼1.5 Hz, 1H), 8.09 (dt, J¼1.5, 7.6 Hz, 1H),
7.64 (dt, J¼1.5, 7.6 Hz, 1H), 7.58 (t, J¼7.6 Hz, 1H), 7.38–7.27 (m, 3H),
7.07 (m, 2H), 3.21 (s, 3H), 2.66 (td, J¼4.0, 10.4 Hz, 1H), 2.26 (m, 1H),
2.13 (td, J¼4.0, 10.4 Hz, 1H), 1.95 (s, 6H), 1.74 (m, 2H), 1.62 (m, 1H),
27
Colorless amorphous; [
a
]
ꢂ32.4 (c 1.00, CHCl3); 1H NMR
D
(400 MHz, CDCl3)
d
8.76 (s, 1H), 8.07 (d, J¼7.8 Hz, 1H), 7.97 (d,
J¼7.8 Hz, 1H), 7.58 (t, J¼7.8 Hz, 1H), 7.55 (s, 2H), 7.35 (s, 1H), 7.32 (br
s, 2H), 3.04 (m, 1H), 2.74 (m, 1H), 2.32 (s, 6H), 1.81 (m, 1H), 1.69 (m,
2H), 1.37 (m, 1H), 1.18–0.85 (m, 4H) ppm; 13C NMR (100 MHz,
1.39–0.75 (m, 4H) ppm; 13C NMR (100 MHz, CDCl3)
d 142.1, 141.0,
138.3, 131.4, 131.2, 129.6, 129.3, 127.9, 126.8, 126.6, 66.4, 54.4, 39.7,
38.6, 32.6, 25.1, 24.3, 21.1 ppm; IR (film)
n 2933, 2860, 2782, 1491,
CDCl3)
d
145.9, 145.4, 135.4, 135.1, 134.7, 134.4, 133.7, 132.2, 132.1,
1450, 1356, 1185, 1152, 1074 cmꢂ1; HRMS calcd for C21H29N3O4S2
(Mþ) 451.1600, obsd 451.1609.
128.8, 126.8, 124.0, 122.5, 117.1, 66.6, 52.8, 38.1, 30.4, 21.9, 21.7,
19.4 ppm; IR (film)
n 2921, 2852, 1609, 1466, 1381, 1176, 1131,
1012 cmꢂ1; HRMS calcd for C22H25F6N3O4S2 (Mþ) 573.1191, obsd
573.1202.
4.2.10. N1-(3,5-Bis(trifluoromethyl)phenyl)-N3-(2-
(dimethylamino)ethyl)benzene-1,3-disulfonamide 11
White crystals; mp 158–162 ꢀC; 1H NMR (400 MHz, CDCl3)
4.2.5. (R)-N1-(20-(Dimethylamino)-1,10-binaphthyl-2-yl)-N3-
d
8.60 (m, 1H), 8.04 (d, J¼7.8 Hz, 1H), 7.94 (d, J¼7.8 Hz, 1H), 7.63 (s,
phenylbenzene-1,3-disulfonamide 6d
2H), 7.60 (t, J¼7.8 Hz, 1H), 7.52 (s, 1H), 5.83 (br s, 2H), 3.06 (t,
27
White crystals; mp 194–197 ꢀC; [
a
]
ꢂ207.2 (c 1.00, CHCl3);
J¼5.8 Hz, 2H), 2.62 (t, J¼5.8 Hz, 2H), 2.32 (s, 6H) ppm; 13C NMR
D
1H NMR (400 MHz, CDCl3)
d
8.67 (s, 1H), 7.99 (s, 2H), 7.91 (m,
(100 MHz, CD3CN) d 144.4, 143.4, 142.3, 133.3, 133.0, 132.7, 132.3,
2H), 7.74 (m, 1H), 7.66 (d, J¼8.1 Hz, 1H), 7.47 (d, J¼9.1 Hz, 1H),
7.43 (t, J¼7.6 Hz, 1H), 7.18 (t, J¼7.8 Hz, 1H), 7.13 (t, J¼7.3 Hz, 1H),
7.07–6.94 (m, 5H), 6.88 (d, J¼7.8 Hz, 1H), 6.82 (m, 2H), 6.63 (t,
131.8, 131.6, 131.4, 126.4, 122.2, 116.8, 58.2, 44.8, 40.6 ppm; IR (film)
1610, 1642, 1373, 1274, 1168, 1127, 1021 cmꢂ1; HRMS calcd for
C18H19F6N3O4S2 (Mþ) 519.0721, obsd 519.0723.
n

454
P.G. McGarraugh, S.E. Brenner / Tetrahedron 65 (2009) 449–455
4.3. General procedure for enantioselective catalysis of
Michael addition of 1,3-dicarbonyl compounds to nitroolefins
and characterization
4.3.7. Diethyl 2-(1-(2-bromophenyl)-2-nitroethyl)malonate 14e4a
28
Orange oil; [
CDCl3)
a
]
ꢂ5.5 (c 1.00, CHCl3, 57% ee); 1H NMR (400 MHz,
D
d
7.60 (d, J¼7.8 Hz, 1H), 7.28–7.12 (m, 3H), 5.12 (m, 1H), 4.94
(dd, J¼4.3, 13.6 Hz, 1H), 4.75 (m, 1H), 4.32–4.01 (m, 5H), 1.24 (t,
4.3.1. Condition A
J¼7.1 Hz, 3H), 1.13 (t, J¼7.3 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3)
To an oven dried flask under an argon atmosphere were added
d 167.5, 166.9, 135.7, 134.0, 129.8, 128.7, 128.0, 125.0, 75.9, 62.2, 62.2,
dicarbonyl 13 (2.0 mmol), toluene (1.0 mL), and
b
-nitrostyrene 12
53.5, 41.7, 14.1, 13.9 ppm; HPLC [Chiralcel OD-H, hexane/2-prop-
anol¼95:5, 1.0 mL/min, ¼254 nm, retention times: (minor)
15.4 min, (major) 21.8 min].
(0.5 mmol) at room temperature. The disulfonamide catalyst
(0.05 mmol, 28.7 mg) was added and reaction was allowed to stir at
room temperature for 240 h. The reaction mixture was purified via
column chromatography on silica gel (petroleum ether/EtOAc 9:1
as eluent) to give the desired product 14.
l
4.3.8. (R)-Diethyl 2-(2-nitro-1-p-tolylethyl)malonate 14f18c
28
Colorless oil; [
(400 MHz, CDCl3)
a
d
]
ꢂ3.3 (c 1.00, CHCl3, 66% ee); 1H NMR
D
7.11 (s, 4H), 4.86 (m, 2H), 4.21 (m, 3H), 4.02 (q,
4.3.2. Condition B
To an oven dried flask under an argon atmosphere were added
dicarbonyl 13 (1.0 mmol), toluene (1.0 mL), and
J¼7.1 Hz, 2H), 3.80 (d, J¼9.4 Hz, 1H), 2.30 (s, 3H), 1.26 (t, J¼7.6 Hz,
3H), 1.07 (t, J¼7.1 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3)
d 167.6,
b
-nitrostyrene 12
167.0, 138.1, 133.4, 129.7, 128.0, 77.9, 62.1, 61.9, 55.2, 42.8, 21.12, 14.1,
(0.5 mmol) at room temperature. The disulfonamide catalyst
(0.05 mmol, 28.7 mg) was added and reaction was allowed to stir in
anoilbathat50 ꢀC for168 h. Thereactionmixturewascooledtoroom
temperature and purified via column chromatography on silica gel
(petroleum ether/EtOAc 9:1 as eluent) to give the desired product 14.
13.8 ppm; HPLC [Chiralcel AD-H, hexane/2-propanol¼95:5, 1.0 mL/
min,
l
¼254 nm, retention times: (R) (major) 20.8 min, (S) (minor)
53.1 min].
4.3.9. (R)-Diethyl 2-(1-(4-methoxyphenyl)-2-nitroethyl)-
malonate 14g18c
18a
28
4.3.3. (R)-Diethyl 2-(2-nitro-1-phenylethyl)malonate 14a
Yellow oil; [
a
]
ꢂ4.9 (c 1.00, CHCl3, 64% ee); 1H NMR (400 MHz,
D
27
Colorless oil; [
(400 MHz, CDCl3)
a]
ꢂ4.6 (c 1.00, CHCl3, 69% ee); 1H NMR
CDCl3)
d
7.16 (d, J¼8.6 Hz, 2H), 6.83 (d, J¼8.6 Hz, 2H), 4.85 (m, 2H),
D
d
7.38–7.21 (m, 5H), 4.90 (m, 2H), 4.23 (m, 3H),
4.20 (m, 3H), 4.02 (q, J¼7.1 Hz, 2H), 3.77 (m, 4H), 1.27 (t, J¼7.1 Hz,
4.01 (q, J¼7.1 Hz, 2H), 3.83 (d, J¼9.4 Hz, 1H), 1.27 (t, J¼7.1 Hz, 3H),
3H), 1.08 (t, J¼7.1 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3)
d 167.6,
1.05 (t, J¼7.1 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3)
d
167.6, 166.9,
167.0, 159.6, 129.3, 128.2, 114.4, 78.0, 62.2, 61.9, 55.3, 55.3, 42.5, 14.1,
136.5, 129.1, 128.5, 128.2, 77.8, 62.2, 62.0, 55.2, 43.1, 14.1, 13.8 ppm;
13.9 ppm; HPLC [Chiralcel AD-H, hexane/ethanol¼90:10, 1.0 mL/
HPLC [Chiralcel AD-H, hexane/ethanol¼95:5, 1.0 mL/min,
min,
34.0 min].
l
¼254 nm, retention times: (R) (major) 21.8 min, (S) (minor)
l
¼254 nm, retention times: (R) (major) 14.4 min, (S) (minor)
18.8 min].
4.3.10. (R)-Dimethyl 2-(2-nitro-1-phenylethyl)malonate 14h18a
28
4.3.4. (R)-Diethyl 2-(1-(4-bromophenyl)-2-nitroethyl)-
White solid; mp 53–54 ꢀC; [
a]
ꢂ4.6 (c 1.00, CHCl3, 63% ee); 1H
D
malonate 14b18c
NMR (400 MHz, CDCl3) d 7.34–7.2 (m, 5H), 4.91 (m, 2H), 4.25 (td,
28
White solid; mp 56–57 ꢀC; [
a
]
ꢂ6.8 (c 1.00, CHCl3, 69% ee); 1H
J¼5.3, 8.8 Hz, 1H), 3.87 (d, J¼9.1 Hz, 1H), 3.76 (s, 3H), 3.56 (s,
3H) ppm; 13C NMR (100 MHz, CDCl3)
167.9, 167.3, 136.3, 129.1,
128.5, 128.0, 77.5, 54.9, 53.0, 52.8, 43.0 ppm; HPLC [Chiralcel AD-H,
D
NMR (400 MHz, CDCl3)
d
7.45 (d, J¼8.6 Hz, 2H), 7.13 (d, J¼8.6 Hz,
d
2H), 4.86 (m, 2H), 4.22 (m, 3H), 4.04 (q, J¼7.1 Hz, 2H), 3.77 (d,
J¼9.4 Hz, 1H), 1.27 (t, J¼7.1 Hz, 3H), 1.09 (t, J¼7.1 Hz, 3H) ppm; 13C
hexane/2-propanol¼95:5, 1.0 mL/min, ¼254 nm, retention times:
l
NMR (100 MHz, CDCl3)
d
167.3, 166.7, 135.5, 132.2, 129.9, 122.5, 77.4,
(R) (major) 26.2 min, (S) (minor) 40.8 min].
62.3, 62.1, 54.8, 42.5, 14.0, 13.8 ppm; HPLC [Chiralcel AD-H, hexane/
2-propanol¼90:10, 1.0 mL/min,
l
¼254 nm, retention times: (R)
4.3.11. (R)-3-(2-Nitro-1-phenylethyl)pentane-2,4-dione 14i18b
28
(major) 21.7 min, (S) (minor) 57.3 min].
White solid; mp 110–111 ꢀC; [
a
]
ꢂ95.4 (c 1.00, CHCl3, 49% ee);
D
1H NMR (400 MHz, CDCl3)
(m, 2H), 4.37 (d, J¼10.9 Hz, 1H), 4.24 (m, 1H), 2.30 (s, 3H), 1.94 (s,
3H) ppm; 13C NMR (100 MHz, CDCl3)
201.8, 201.1, 136.3, 129.5,
128.7, 128.1, 78.3, 70.9, 43.0, 30.5, 29.7 ppm; HPLC [Chiralcel AD-H,
d 7.34–7.27 (m, 3H), 7.19 (m, 2H), 4.63
4.3.5. (S)-Diethyl 2-(1-(4-fluorophenyl)-2-nitroethyl)-
malonate 14c18a
Colorless oil; [
(400 MHz, CDCl3)
d
28
a
d
]
D
ꢂ4.9 (c 1.00, CHCl3, 79% ee); 1H NMR
7.23 (m, 2H), 7.01 (t, J¼8.6 Hz, 2H), 4.87 (m, 2H),
hexane/2-propanol¼95:5, 1.0 mL/min, ¼254 nm, retention times:
l
4.23 (m, 3H), 4.03 (q, J¼7.1 Hz, 2H), 3.78 (d, J¼9.3 Hz, 1H), 1.27 (t,
(S) (minor) 18.2 min, (R) (major) 25.6 min].
J¼7.3 Hz, 3H), 1.08 (t, J¼7.1 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3)
d
167.4, 166.8, 130.0, 129.9, 116.1, 115.9, 77.8, 62.3, 62.1, 55.1, 42.5,
4.4. NMR experiments
14.1, 13.9 ppm; HPLC [Chiralcel AD-H, hexane/ethanol¼95:5,
1.0 mL/min,
(minor) 31.8 min].
l
¼254 nm, retention times: (S) (major) 21.0 min, (R)
Measurements were carried out using a Bruker 400 MHz NMR
Spectrometer. CD2Cl2 99.9% D was dried over molecular sieves,
4 Å, 1.6 mm pellets in a glove box for 4–5 days. Samples were
prepared in a glove box with both vacuum dried catalyst and b-
nitrostyrene using oven dried glassware and needles. NMR sam-
ples (0.5 mL) were prepared from a 13.4 mM catalyst stock
4.3.6. Diethyl 2-(1-(3,4-dichlorophenyl)-2-nitroethyl)malonate 14d
28
White solid; mp 59–60 ꢀC; [
a]
1.1 (c 1.00, CHCl3, 77% ee); 1H
D
NMR (400 MHz, CDCl3)
d
7.40 (d, J¼8.3 Hz, 1H), 7.36 (d, J¼2.0 Hz,
1H), 7.11 (dd, J¼2.0, 8.3 Hz, 1H), 4.87 (m, 2H), 4.22 (m, 3H), 4.08 (q,
solution to which were added a proportionate amount of
b-
J¼7.3 Hz, 2H), 3.76 (d, J¼8.8 Hz, 1H), 1.27 (t, J¼7.1 Hz, 3H), 1.13 (t,
nitrostyrene.4a
J¼7.1 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3)
d 167.2, 166.6, 136.8,
133.3, 132.9, 131.0, 130.4, 127.6, 77.2, 62.5, 62.3, 54.8, 42.2, 14.1,
13.9 ppm; IR (film)
n
3412, 2983, 2929, 1728, 1552, 1471, 1176, 1152,
Acknowledgements
1033 cmꢂ1; HRMS calcd for C15H17Cl2NO6 (Mþ) 377.0433, obsd
377.0441; HPLC [Chiralcel AD-H, hexane/2-propanol¼90:10,
This work was supported by a grant from the National Institutes
of Health (1SC2GM082360-01). The authors gratefully acknowl-
edge Dr. Cliff Soll for his assistance with high-resolution mass
1.0 mL/min,
27.9 min].
l
¼254 nm, retention times: (major) 20.8 min, (minor)

P.G. McGarraugh, S.E. Brenner / Tetrahedron 65 (2009) 449–455
455
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Pettersen, D.; Piana, F.; Bernardi, L.; Fini, F.; Fochi, M.; Sgarzani, V.; Ricci, A.
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Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.11.027.
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´
nitroalkenes see: (a) Almas¸i, D.; Alonso, D. A.; Najera, C. Tetrahedron: Asymmetry
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15. A bissulfonamide of type 6 which incorporated a cinchona alkaloid could not be
isolated as a pure compound, possibly due to racemization at the benzylic
position during sulfonamide bond formation.
16. Using a modified protocol from: Bubert, C.; Blacker, J.; Brown, S. M.; Crosby, J.;
Fitzjohn, S.; Muxworthy, J. P.; Thorpe, T.; Williams, J. M. J. Tetrahedron Lett. 2001,
42, 4037–4039.
17. An equilibrium state is not being achieved; the retro reaction was not observed.
18. (a) Ji, J.; Barnes, D. M.; Zhang, J.; King, S. A.; Wittenberger, S. J.; Morton, H. E.
J. Am. Chem. Soc. 1999, 121, 10215–10216; (b) Terada, M.; Ube, H.; Yaguchi, Y. J.
Am. Chem. Soc. 2006, 128, 1454–1455; (c) Evans, D. A.; Mito, S.; Seidel, D. J. Am.
Chem. Soc. 2007, 129, 11583–11592.
19. Data not shown.