Catalytic asymmetric Mannich-type reactions of α-cyano α-sulfonyl carbanions

Article abstract of DOI:10.1039/c2cc32398b

An efficient asymmetric Mannich-type reaction of α-cyano α-sulfonyl carbanions has been achieved by exploiting the structural modularity and anion-recognition ability of chiral 1,2,3-triazolium ions. This protocol has proven to be applicable to a variety of N-Boc imines and cyanosulfones, affording β-amino α-cyanosulfones in excellent yields with high stereoselectivities.

Full text of DOI:10.1039/c2cc32398b

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COMMUNICATION
Catalytic asymmetric Mannich-type reactions of a-cyano a-sulfonyl
carbanionswz
Kohsuke Ohmatsu, Ayano Goto and Takashi Ooi*
Received 3rd April 2012, Accepted 16th May 2012
DOI: 10.1039/c2cc32398b
An efficient asymmetric Mannich-type reaction of a-cyano
a-sulfonyl carbanions has been achieved by exploiting the structural
modularity and anion-recognition ability of chiral 1,2,3-triazolium
ions. This protocol has proven to be applicable to a variety of
N-Boc imines and cyanosulfones, affording b-amino a-cyanosulfones
in excellent yields with high stereoselectivities.
compounds remain poorly studied, and only a few successful
examples have been reported thus far.8 Herein, we commu-
nicate the efficient asymmetric Mannich-type reaction of
a-cyano a-sulfonyl carbanions based on the exploitation of
the structural diversity and anion-recognition ability of chiral
1,2,3-triazolium ions 1 (see the scheme for Table 1).9
We initially selected 1,2,3-triazolium acetate 1aꢀH(OAc)2
featuring weakly basic acetate ions and evaluated its ability as
a catalyst in the reaction of 2-(phenylsulfonyl)propionitrile, 3a,
Catalytic asymmetric carbon–carbon bond-forming reactions
with carbanions that can be readily generated from the
corresponding pronucleophiles offers a highly effective method
for the assembly of chiral organic molecules. Accordingly,
numerous efforts have been devoted to establish powerful
strategies for the development of catalytic, stereoselective
transformations with a wide variety of carbon nucleophiles,
most of which are categorized into functionalized enolates.1
While a-hetero-substituted carbanions have been generally
under-utilized in this context, probably because of a difficulty
in their catalytic generation, a-sulfonyl carbanions, which are
easily formed from sulfonylmethylene or methine compounds,2
could find potential applications. Enolate ions are well-known
to be predominantly stabilized by the resonance effect, adopting
the planar structure. In contrast, a-sulfonyl carbanions are
mainly stabilized by a negative hyperconjugation (nC–s*SR),3
and those bearing different a-substituents have chirality even
when the substituents on the a-carbon are oriented in a planar
fashion.4 In this respect, sulfonyl carbanions fundamentally
differ from enolates, and thus stereochemical control in the
bond formations from such carbanions constitutes a subject of
significant synthetic and mechanistic implications. In addition,
sulfones have attracted increasing attention in medicinal
chemistry,5 and a-chiral sulfonyl compounds are known to
show interesting biological activities against diseases such as
glaucoma6 or Alzheimer’s.7 However, the catalytic asymmetric
reactions of a-sulfonyl carbanions to construct a-chiral sulfonyl
Table 1 Effect of the structure of 1 and bases on the asymmetric
Mannich-type reaction of cyanosulfone 3aa
Entry
1ꢀX
Base
% Yieldb
anti/sync
% eed
1
2
3
4
5
6
7
1aꢀH(OAc)2
1bꢀH(OAc)2
1cꢀH(OAc)2
1dꢀH(OAc)2
1eꢀH(OAc)2
1fꢀH(OAc)2
1gꢀH(OAc)2
1gꢀH(OAc)2
1gꢀBr
None
None
None
None
None
None
None
None
K2CO3
Cs2CO3
TMG
Cs2CO3
Cs2CO3
98
97
98
99
95
96
88
90
99
99
97
99
99
87 : 13
87 : 13
89 : 11
90 : 10
86 : 14
87 : 13
89 : 11
89 : 11
88 : 12
89 : 11
88 : 12
90 : 10
89 : 11
60/46
71/51
37/12
67/ꢁ4
78/65
83/54
87/70
90/82
90/82
90/83
85/67
90/82
88/79
8e
9e
10e
11e
12e
13e
1gꢀBr
1gꢀBr
1gꢀHSO4
Department of Applied Chemistry, Graduate School of Engineering,
Nagoya University, Nagoya, 464-8603, Japan.
E-mail: tooi@apchem.nagoya-u.ac.jp; Fax: +81 52 789 3338;
Tel: +81 52 789 4501
w This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
z Electronic supplementary information (ESI) available: Experimental
details (including selected NMR spectra) and crystallographic data.
CCDC 867728 and 867729. For ESI and crystallographic data in CIF
or other electronic format see DOI: 10.1039/c2cc32398b
1gꢀBF4
a
Unless otherwise noted, reactions were performed on 0.1 mmol scale
of 3a with 1.2 equiv of 2a, 2 mol% of 1ꢀX and 2 mol% of base in
b
c
500 mL of toluene at 0 1C for 5 h. Isolated yield. Determined by
1H NMR analysis. Determined by HPLC analysis. Carried out at
ꢁ40 1C for 24 h. Relative and absolute stereochemistry of 4a was
established by X-ray crystal structure analysis. See Supplementary
Information for details.
d
e
c
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Chem. Commun.

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with N-Boc imine 2a in toluene at 0 1C (Table 1, entry 1). The
bond formation reached completion in 5 h, and the desired
Mannich-adduct 4a was obtained almost quantitatively with
moderate diastereo- and enantioselectivity (anti/syn = 87 : 13,
60% ee for the major anti isomer and 46% ee for the syn
isomer). In our previous study, we recognized two important
factors that govern the stereocontrolling ability of triazolium
ions 1 in the reactions of nucleophilic counterions: (1) the
anion-binding affinities of triazolium C(5) protons and amide
protons are crucial for asymmetric induction; and (2) the
substituents at C-4 of the triazolium (2-R-C6H4) and at the
amide carbonyl (Ar2) are located in the vicinity of the counter-
ions and have a major influence on the stereoselectivity.
Therefore, we switched the substituent at N-3 of the triazolium
core (Ar1) to the electron-withdrawing group, expecting a
beneficial impact of the enhanced acidity of C(5) protons on
the selectivity. Indeed, a higher level of enantiocontrol was
attained when 1bꢀH(OAc)2 with a p-trifluoromethylbenzyl
appendage was used as a catalyst (entry 2). With a little
surprise, however, the introduction of electron-withdrawing
functionality into the amide substituent (Ar2) resulted in
diminished enantioselectivity (entries 3 and 4), and further
screening revealed that the 3,5-dimethylphenyl group was the
most appropriate choice of amide substituent (entry 5). The
final structural modification made by installing o-trifluoro-
methylphenyl (R = CF3) or o-isopropylphenyl (R = i-Pr)
substituents onto the triazolium C(4) delivered a critical
improvement in the enantioselectivity (entries 6 and 7), and
the triazolium ion 1g was identified to be optimal for this
Mannich-type reaction. We then tuned the reaction condi-
tions, and as expected, lowering the reaction temperature to
ꢁ40 1C led to the formation of 4a with a synthetically
satisfactory level of enantiomeric purity (entry 8). In addition,
the catalyst system consisting of bromide salt 1gꢀBr and
external bases exhibited a slightly higher efficiency than that
of 1gꢀH(OAc)2 (entries 9–11). It should be noted that changes
in the counterions of 1g subtly affected the selectivity profile
(entries 12 and 13).
Table 3 Substrate scopea
Entry
2
R2
3
4
% Yieldb anti/sync % eed
1
2
2b o-Me-C6H4 3a 4g 99
2c o-MeO-C6H4 3a 4h 96
93 : 7
96/78
95/76
87/80
93/80
97/84
90/88
95/nd
84/76
96/82
97/85
92/57
95/49
82 : 18
76 : 24
76 : 24
82 : 18
75 : 25
495 : 5
92 : 8
70 : 30
43 : 57
91 : 9
3
4
2d o-Cl-C6H4
2e o-Br-C6H4
3a 4i
3a 4j
99
99
5
2f p-MeO-C6H4 3a 4k 99
6
7
8
9
10
11
12
2g p-Br-C6H4
2h 1-Naph
2i 2-Naph
2j 2-Furyl
2k c-Hex
2a Ph
3a 4l
99
3a 4m 99
3a 4n 99
3a 4o 99
3a 4p 99
3g 4q 99
2a Ph
3h 4r
99
83 : 17
a
Reactions were performed on 0.1 mmol scale of 3 with 1.2 equiv of
2a, 2 mol% of 1gꢀBr and 2 mol% of Cs2CO3 in 500 mL of toluene at
ꢁ40 1C for 24 h. Isolated yield. Determined by 1H NMR analysis.
b
c
d
Determined by HPLC analysis; nd = not determined.
substituents having differing electronic properties were
employable without any detrimental effects on the reactivity
or stereoselectivity (entries 1–4). The alkylsulfonyl-substituted
cyanosulfone was also amenable to the present system, and
a similar degree of diastereo- and enantioselectivity was
observed (entry 5).
The generality of the 1gꢀBr-catalyzed, asymmetric Mannich-
type reaction of a-cyano a-sulfonyl carbanions was further
explored under optimized conditions, and the representative
results are summarized in Table 3. Generally, 2 mol% of 1gꢀBr
was sufficient for a smooth reaction in toluene at ꢁ40 1C,
giving 4 in an almost quantitative yield. With respect to
aromatic N-Boc imines, this protocol tolerated the incorpo-
ration of both electron-donating and electron-withdrawing
substituents (entries 1–6). Slightly lower enantioselectivity
was observed in the reaction with imine prepared from
2-naphthaldehyde (entry 8), whereas a virtually complete
stereochemical control was realized with 1-naphthaldehyde-
derived imine (entry 7). Moreover, heteroaromatic and
aliphatic aldehyde-derived imines appeared to be good
Mannich acceptors, although a certain decrease in diastereo-
selectivity was detected (entries 9 and 10). As is evident from
the results of the reactions with cyanosulfones having different
a-substituents, other cyanosulfones could also be employed as
pronucleophiles (entries 11 and 12).
With the combination of chiral 1,2,3-triazolium salt 1gꢀBr
and Cs2CO3 in hand, we next examined the reactions of imine
2a with cyanosulfones possessing various sulfonyl compo-
nents. As shown in Table 2, cyanosulfones with arylsulfonyl
Table 2 Variability in the sulfonyl substituent of 3a
In conclusion, we developed an asymmetric Mannich-
type reaction of a-cyano a-sulfonyl carbanions using chiral
1,2,3-triazolium salts as catalysts. The judicious use of the
structural modularity and anion-recognition ability of the
chiral triazolium ions allowed for rigorous enantiocontrol.
We believe that the present study expands the versatility of
sulfonyl nucleophiles for the construction of synthetically
valuable a-chiral sulfonyl compounds.
Entry
3
R1
4
% Yieldb
anti/sync
% eed
1
2
3
4
5
3b
3c
3d
3e
3f
p-t-Bu-C6H4
p-MeO-C6H4
p-CF3-C6H4
p-NO2-C6H4
i-Pr
4b
4c
4d
4e
4f
99
99
99
99
99
88 : 12
84 : 16
88 : 12
89 : 11
85 : 15
91/87
88/81
92/74
91/80
91/83
a
Reactions were performed on 0.1 mmol scale of 3 with 1.2 equiv of
2a, 2 mol% of 1gꢀBr and 2 mol% of Cs2CO3 in 500 mL of toluene at
b
c
ꢁ40 1C for 24 h. Isolated yield. Determined by 1H NMR analysis.
This work was financially supported by the Funding Program
for Next Generation World-Leading Researchers from JSPS,
d
Determined by HPLC analysis.
c
Chem. Commun.
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Grant-in-Aid for Young Scientists (B), the Daiko Foundation,
Tokuyama Science Foundation, the Global COE Program in
Chemistry of Nagoya University and Program for Leading
Graduate Schools ‘‘Integrative Graduate Education and Research
Program in Green Natural Sciences’’ in Nagoya University.
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c
This journal is The Royal Society of Chemistry 2012
Chem. Commun.