Asymmetric Sulfa-Michael Addition of α,β-Unsaturated Esters/Amides Using a Chiral N-Heterocyclic Carbene as a Noncovalent Organocatalyst

Article abstract of DOI:10.1055/s-0035-1561843

We report an asymmetric sulfa-Michael reaction of α,β-unsaturated amides and esters using a chiral N-heterocyclic carbene as the HOMO-raising organocatalyst. We discovered an interesting correlation between ¹³C NMR shifts of substrates and ee o

Full text of DOI:10.1055/s-0035-1561843

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© Georg Thieme Verlag Stuttgart · New York
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Asymmetric Sulfa-Michael Addition of α,β-Unsaturated Esters/
Amides Using a Chiral N-Heterocyclic Carbene as a Noncovalent
Organocatalyst
Pengfei Yuan
Sixuan Meng
Jiean Chen*
Yong Huang*
SBn O
O
NHC precursor (10 mol%)
+
BnSH
R
R
LiHMDS (10 mol%), 4 Å MS, –78 °C
Me
O
N
R = OAr, pyrrolidinone, oxazolidinone
NHC as a noncovalent organocatalyst
less reactive esters and amides
no proton shuttle required
N
N
Key Laboratory of Chemical Genomics, School of Chemical
Biology and Biotechnology, Peking University, Shenzhen
Graduate School, Shenzhen, 518055, P. R. of China
chenja@pkusz.edu.cn
Me
BF4 Me
NHC precursor
26 examples, up to 98% yield, 87% ee
huangyong@pkusz.edu.cn
Received: 14.12.2015
Accepted after revision: 26.02.2015
Published online: 08.03.2016
unsaturated esters are not very common and only thiophe-
nols and thioacids were used as the nucleophile.5 Reactions
involving simple alkyl mercaptans are rare.5b As for α,β-un-
saturated amides, only oxazolidinone-derived imides were
successful substrates.6 Herein, we disclose our recent find-
ing of asymmetric sulfa-Michael reactions involving these
less reactive, yet underexplored α,β-unsaturated esters and
amides (Scheme 1).
DOI: 10.1055/s-0035-1561843; Art ID: st-2015-w0969-c
Abstract We report an asymmetric sulfa-Michael reaction of α,β-un-
saturated amides and esters using a chiral N-heterocyclic carbene as
the HOMO-raising organocatalyst. We discovered an interesting cor-
relation between 13C NMR shifts of substrates and ee of their products.
More electron-deficient Michael acceptors afforded higher enantiose-
lectivity.
We initially evaluated the reactivity of benzyl mercap-
tan against various crotonic esters. Simple methyl crotonate
failed to react with BnSH at –78 °C. The more reactive hexa-
fluoroisopropyl ester reacted in high yield (89%) with poor
selectivity (23% ee). In sharp contrast, the corresponding
phenyl ester afforded the sulfa-Michael adduct in good
yield and decent ee. Our previous reports showed that an
acidic proton shuttle (hexafluoroisopropanol) is often re-
quired for noncovalent catalysis by NHC. However, we
found the reaction performed better in the absence of such
a proton shuttle. We reason that ester enolates are quite ba-
sic and BnSH serves as an effective additive by itself. We
next optimized the structure of the catalyst (Table 1). The
Ar group of the aminoindanol-derived triazolium scaffold
was modified. It was very interesting that only those con-
taining a bulky 2,6-disubstituted aryl (4a,b, Table 1, entries
1 and 2) yielded both good reactivity and selectivity. Simple
phenyl or pentafluorophenyl analogues (4c,d, Table 1, en-
tries 3 and 4) failed to promote this reaction. When N-aryl
was changed to N-benzyl (4f, Table 1, entry 6), the product
was obtained with the opposite enantiomer enriched. Oth-
er chiral triazolium and imidazolium NHC precursors were
examined as well. Several commonly used chiral scaffolds
(4g–i, Table 1, entries 7–9) for covalent catalysis returned
very poor selectivity. Solvent was briefly examined. Nonpo-
lar solvents, toluene and diethyl ether in particular, gave
Key words N-heterocyclic carbenes, noncovalent catalysis, sulfa-Mi-
chael, organocatalysis, asymmetric synthesis
Unlike other organocatalysts, N-heterocyclic carbenes
(NHC) possess several unique chemical properties that en-
able them to unlock multiple generic modes of substrate
activation for catalysis.1 More recently, focus in the field of
NHC catalysis has diverted away from the classical aldehyde
umpolung chemistry.2 Many acyl anion free reactions, espe-
cially those involving less reactive substrates, were report-
ed that have substantially increased the ‘market share’ of
NHC among other organocatalysts. Nevertheless, nearly all
NHC-mediated transformations start from a nucleophilic
attack of NHC to a carbonyl functionality. The newly formed
carbon–carbon bond secures a robust relay of chiral infor-
mation from the catalyst to the substrate. On the other
hand, the well-known Brønsted basicity of NHC received
little success as a potential HOMO-raising activation strate-
gy.3 Recently, we reported the first enantioselective C–C, C–
S, and C–N bond synthesis using NHC as a noncovalent chi-
ral template.4 One key to high asymmetric induction in
these reactions is the use of very reactive Michael accep-
tors, such CF3-containing nitroolefins. The more challeng-
ing α,β-unsaturated esters and amides were not studied.
Enantioselective sulfa-Michael addition reactions of α,β-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

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Classical NHC catalyzed reactions
O
R
OH
R
R
R
O
C
O
aldehyde
acid chloride
anhydride
ester
R
N
N
R
N
or
N
N
N
X
X
N
X
ketene
N
R
X
R
acyl azolium
Breslow
Noncovalent catalysis by NHCs
C–S bond
C–C bond
R1
R1
S
R1OC
R3
COR2
NO2
S
NO2
COR
F3C
R2
R2
NHC
noncovalent
chiral templates
less reactive
R1
HN
R1
R1
S
NO2
F3C
R2
S
and
C–N bond
CO2R
CONR3R4
R2
R2
this work
Scheme 1 NHC are powerful organocatalysts
the highest selectivity, 67% ee and 72% ee, respectively. Due
to the noticeably fast reaction in toluene, it was chosen for
subsequent substrate-scope survey (Scheme 2).
β-carbon similarly by tuning the electronics of the aryloxy
group. We plotted the 13C NMR shift of the β-carbon against
the log (er) of the product (Figure 1). Interestingly, for β-
carbons with 13C NMR ranging from δ = 146.80–148.87
ppm, the selectivity of the sulfa-Michael reaction steadily
increased and plateaued (Table 2). These data clearly show
that more reactive substrates give higher ee, which is in
sharp contrast to nitroolefins. Linear free-energy relation-
ship (LFER) study using substrates in Table 2 revealed a sim-
ilar correlation between Hammett σ and σ+ values of R and
the ee of the product.7 Although we cannot provide an un-
ambiguous answer for this behavior, a weak interaction be-
tween the catalyst and the conjugate system of the Michael
acceptor might be operative.
Various aryl esters of crotonic acid were examined for
the sulfa-Michael addition with BnSH. ortho Substitution
has a negative impact on the selectivity, regardless of the
electronic property of the substituent (3aj,al,an,aq). The
meta and para substituents, on the other hand, have little
effect. However, the electronic nature of the para substitu-
ent does influence the ee of its product. For example, a sub-
strate bearing a strong electron-donating p-methoxy react-
ed with 56% ee, while the corresponding p-nitro analogue
gave 77% ee (3ak vs. 3ac). Interestingly, although Chi and
co-workers reported the activation of p-nitrophenyl esters
(3ac, to the corresponding acyl azolium intermediate) using
similar NHC,2i–l no such reaction was observed due to the
low reaction temperature. No methyl ester was formed
when methanol, a well-known acyl azolium scavenger, was
introduced to the reaction. It is noteworthy that heteroaryls
are well tolerated for this reaction. Those containing a basic
nitrogen – pyridine, and quinoline, for example – did not
interfere with the catalyst (3ao–aq). Decreased selectivity
was observed for large β-alkyl groups (3ar). Due to dimin-
ished reactivity, no sulfa-Michael addition occurred for cin-
namates even at room temperature. Benzyl mercaptan is
the best sulfur source for this reaction. Aromatic substitu-
tion is well tolerated for the benzyl group (3da–ga).
Amides were examined as well. Although simple alkyl
amides did not react with thiols under the standard reac-
tion conditions, more reactive imides were good substrates.
Both pyrrolidinone- and oxazolidinone-derived imides
were good substrates for asymmetric sulfa-Michael reac-
Our previous studies using β-aryl-β-trifluoromethylni-
troolefins showed that the electronic density of the β-aryl
group directly correlates to the ee of the product. We won-
dered whether we could affect the electronic density of the
Figure 1
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

C
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Table 1 Optimization of Conditionsa
O
SR1
O
4a (10 mol%), LiHMDS (10 mol%)
R1SH
+
R2
R3
4 Å MS, toluene, –78 °C
R2
R3
SBn
O
O
NHC precursor 4 (10 mol%)
LiHMDS (10 mol%), 4 Å MS, –78 °C
1
2
3
+
BnSH
OPh
OPh
CF3
NO2
SBn
O
SBn
O
SBn O
1a
2a
3aa
O
O
O
NHC precursors (4):
3aa, 96% (67% ee)
3ab, 71% (79% ee)
SBn
3ac, 72% (77% ee)
O
CO2Et
F
Cl
N
BF4
O
SBn
O
O
SBn O
N
N
N
N
BF4
BF4
R
N
N
N
N
O
O
O
Mes
Mes
i-Bu
Bn
3ad, 78% (72% ee)
SBn
3ae, 75% (68% ee)
3af, 74% (74% ee)
SBn
4g
4h
Br
4a: R = 2,4,6-Me3C6H2
4b: R = 2,6-Et2C6H3
4c: R = Ph
O
O
SBn
O
BF4
O
Cl
O
N
N
O
4d: R = C6F5
4e: R = 3,5-(CF3)2C6H3
4f: R = Bn
Me
Me
4i
3ag, 62% (72% ee)
SBn
3ah, 88% (75% ee)
3ai, 91% (73% ee)
SBn
O
O
OMe
SBn
O
O
O
Entry
NHC precursor 4 Solvent
Yield (%)b
ee (%)c
O
OMe
3al, 98% (35% ee)
3aj, 86% (47% ee)
1
2
4a
4b
4c
4d
4e
4f
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
MeCN
96
78
<5
<5
<5
56
84
63
92
42
65
50
48
67
65
3ak, 95% (56% ee)
SBn
O
SBn
O
SBn
O
d
3
–
O
N
O
O
d
4
–
d
5
–
3am, 65% (66% ee)
3an, 89% (38% ee)
SBn
3ao, 87% (78% ee)
6
–20
–36
–4
O
N
SBn
O
SBn
O
7
4g
4h
4i
O
Et
O
8
O
N
9
–11
54
3ap, 86% (62% ee)
3aq, 80% (54% ee)
3ar, 73% (50% ee)
10
11
12
13
4a
4a
4a
4a
Ph
23
S
O
O
S
O
THF
42
O
Et2O
72
3ba, 81% (0% ee)
3ca, 77% (29% ee)
a Reaction conditions: 1a (0.2 mmol), 2c (0.1 mmol), NHC precursor (10
mol%), LiHMDS (10 mol%), 4 Å MS (100 mg), solvent (1.2 mL), –78 °C, 36 h.
b Isolated yield.
3da: R = 4-ClC6H4, 53% (73% ee)
3ea: R = 4-MeC6H4, 67% (70% ee)
3fa: R = 3-FC6H4, 66% (65% ee)
3ga: R = 2-MeC6H4, 80% (66% ee)
R
S
O
c Determined by chiral HPLC.
d Not determined.
O
Scheme 2 Substrate scopea
O
O
O
O
SBn
O
O
4a (10 mol%), LiHMDS (10 mol%)
tion with benzyl mercaptan. For the reaction using 4a, 89%
yield and 87% ee were obtained. Slightly lower ee was ob-
tained for substrate 4b. Again, more reactive substrate af-
forded higher enantioselectivity (Scheme 3).
We propose the following transition state that explains
the observed absolute stereochemistry (Scheme 4). Up on
hydrogen bonding to the NHC catalyst, the thiol is pushed
above the flat NHC heterocycle due to severe crowding in
the lower space. The Michael acceptor approaches from the
top, with the large aryl ester oriented away from the bulky
mesyl group. The α-carbon of the ester is in close proximity
to the thiol hydrogen for intramolecular proton transfer.4b,c
The newly formed chiral center was determined to be S
+
+
BnSH
N
N
4 Å MS, toluene, –78 °C
1a
4a
5aa
89%, 87% ee
SBn
O
O
4a (10 mol%), LiHMDS (10 mol%)
BnSH
N
O
N
4 Å MS, toluene, –78 °C
O
1a
4b
5ab
95%, 76% ee
Scheme 3 Asymmetric sulfa-Michael addition reactions of imides
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

D
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Table 2 Correlation of Electron Density of the β-Carbon with the Se-
lectivity
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561843.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
R
R
4a (10 mol%)
SBn
O
O
LiHMDS (10 mol%)
+
O
BnSH
O
4 Å MS, toluene, –78 °C
References and Notes
1a
2
3
(1) For comprehensive overviews on NHC-catalyzed reactions, see:
(a) Enders, D.; Niemeier, O.; Henseler, A. Chem. Rev. 2007, 107,
5606. (b) Nair, V.; Menon, R. S.; Biju, A. T.; Sinu, C. R.; Paul, R. R.;
Jose, A.; Sreekumar, V. Chem. Soc. Rev. 2011, 40, 5336.
(c) Bugaut, X.; Glorius, F. Chem. Soc. Rev. 2012, 41, 3511.
(d) Grossmann, A.; Enders, D. Angew. Chem. Int. Ed. 2012, 51,
314. (e) Izquierdo, J.; Hutson, G. E.; Cohen, D. T.; Scheidt, K. A.
Angew. Chem. Int. Ed. 2012, 51, 11686. (f) Vora, H. U.; Wheeler,
P.; Rovis, T. Adv. Synth. Catal. 2012, 354, 1617. (g) Sarkar, S. D.;
Biswas, A.; Samanta, R. C.; Studer, A. Chem. Eur. J. 2013, 19,
4664. (h) Flanigan, D. M.; Romanov-Michailidis, F.; White, N. A.;
Rovis, T. Chem. Rev. 2015, 115, 9307.
(2) For a recent review on acyl anion free reactions, see: (a) Ryan, S.
J.; Candish, L.; Lupton, D. W. Chem. Soc. Rev. 2013, 42, 4906. For
representative examples, see: (b) Sun, X.; Ye, S.; Wu, J. Eur. J.
Org. Chem. 2006, 4787. Selected examples for halide: (c) Ryan, S.
J.; Candish, L.; Lupton, D. W. J. Am. Chem. Soc. 2011, 133, 4694.
(d) Ryan, S. J.; Stasch, A.; Paddon-Row, M. N.; Lupton, D. W.
J. Org. Chem. 2012, 77, 1113. (e) Candish, L.; Lupton, D. W.
J. Am. Chem. Soc. 2013, 135, 58. (f) Zhang, Y. R.; He, L.; Wu, X.;
Shao, P. L.; Ye, S. Org. Lett. 2008, 10, 277. (g) Huang, X. L.; He, L.;
Shao, P. L.; Ye, S. Angew. Chem. Int. Ed. 2009, 48, 192. (h) Zhang,
H. M.; Gao, Z. H.; Ye, S. Org. Lett. 2014, 16, 3079. (i) Hao, L.; Du,
Y.; Lv, H.; Chen, X.; Jiang, H.; Shao, Y.; Chi, Y. R. Org. Lett. 2012,
14, 2154. (j) Cheng, J.; Huang, Z.; Chi, Y. R. Angew. Chem. Int. Ed.
2013, 52, 8592. (k) Fu, Z.; Xu, J.; Zhu, T.; Leong, W. W.; Chi, Y. R.
Nat. Chem. 2013, 5, 835. (l) Chauhan, P.; Enders, D. Angew. Chem.
Int. Ed. 2014, 53, 1485.
Entry
R
13C NMR δ of the β-carbon er
(ppm)
log (er)
1
2
3
4
5
6
7
8
2k OMe
2a H
146.80
147.04
147.36
147.62
147.65
147.83
148.10
148.87
78:22
0.550
0.771
0.720
0.807
0.841
0.792
0.931
0.886
85.5:14.5
84:16
2e F
2f Cl
86.5:13.5
87.5:12.5
86:14
2h Br
2d CO2Et
2b CF3
89.5:10.5
88.5:11.5
2c NO2
ArO2C
H
R2
S
Me
R1
H
N
N
N
O
Me
Me
SR1
O
(S)
R2
OAr
Scheme 4 Proposed transition state
(3) (a) Kim, Y.-J.; Streitwieser, A. J. Am. Chem. Soc. 2002, 124, 5757.
(b) Amyes, T. L.; Diver, S. T.; Richard, J. P.; Rivas, F. M.; Toth, K.
J. Am. Chem. Soc. 2004, 126, 4366. (c) Massey, R. S.; Collett, C. J.;
Lindsay, A. G.; Smith, A. D.; O’Donoghue, A. C. J. Am. Chem. Soc.
2012, 134, 20421. Selected examples for utilizing NHC as
chiral Brønsted base: (d) Phillips, E. M.; Riedrich, M.; Scheidt,
K. A. J. Am. Chem. Soc. 2010, 132, 13179. (e) Boddaert, T.;
Coquerel, Y.; Rodriguez, J. Chem. Eur. J. 2011, 17, 2266.
(4) (a) Chen, J.; Huang, Y. Nat. Commun. 2014, 5, 3437. (b) Chen, J.;
Meng, S.; Wang, L.; Tang, H.; Huang, Y. Chem. Sci. 2015, 6, 4184.
(c) Wang, L.; Chen, J.; Huang, Y. Angew. Chem. Int. Ed. 2015, 54,
15414.
(5) (a) Nishimura, K.; Ono, M.; Nagaoka, Y.; Tomioka, K. J. Am. Chem.
Soc. 1997, 119, 12974. (b) Emori, E.; Arai, T.; Sasai, H.; Shibasaki,
M. J. Am. Chem. Soc. 1998, 120, 4043. (c) Leow, D.; Lin, S.;
Chittimalla, S. K.; Fu, X.; Tan, C. H. Angew. Chem. Int. Ed. 2008,
47, 5641. (d) Wang, R.; Liu, J.; Xu, J. Adv. Synth. Catal. 2015, 357,
159.
configuration by comparing to literature reported optical
rotation values.6b,d
In summary, the recently unlocked noncovalent cataly-
sis mode for chiral NHC was investigated in asymmetric sul-
fa-Michael addition reactions using less reactive α,β-unsat-
urated esters and amides.8 β-Benzylthio esters were syn-
thesized in good yield and moderate to good
enantioselectivity. In contrast to nitroolefins, more reactive
ester/amide substrates yielded higher selectivity and no ex-
ternal proton shuttle is required for catalyst turnover. We
expect NHC will be more intensively studied as a powerful
noncovalent organocatalysts in the near future.
Acknowledgment
(6) Selected papers for sulfa-Michael reactions of oxazolidinone
derivatives: (a) Kanemasa, S.; Oderaotoshi, Y.; Wada, E. J. Am.
Chem. Soc. 1999, 121, 8675. (b) Abe, A. M.; Sauerland, S. J.;
Koskinen, A. M. J. Org. Chem. 2007, 72, 5411. (c) Zu, L.; Wang, J.;
Li, H.; Xie, H.; Jiang, W.; Wang, W. J. Am. Chem. Soc. 2007, 129,
1036. (d) Liu, Y.; Sun, B.; Wang, B.; Wakem, M.; Deng, L. J. Am.
Chem. Soc. 2009, 131, 418. (e) Dai, L.; Yang, H.; Chen, F. Eur. J.
Org. Chem. 2011, 5071. (f) Chen, W.; Jing, Z.; Chin, K. F.; Qiao, B.;
Zhao, Y.; Yan, L.; Tan, C.-H.; Jiang, Z. Adv. Synth. Catal. 2014, 356,
This work is financially supported by the National Natural Science
Foundation of China (21372013, 21572004), the Shenzhen Peacock
Program (KQTD201103) and the Disciplinary Development Program
for Chemical Biology by the Shenzhen Municipal Development and
Reform Commission.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

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1292. (g) Breman, A. C.; Telderman, S. E.; van Santen, R. P.; Scott,
J. I.; van Maarseveen, J. H.; Ingemann, S.; Hiemstra, H. J. Org.
Chem. 2015, 80, 10561.
–78 °C. A solution of substrate 2 (0.1 mmol) in toluene (0.6
mL) was slowly added over 30 min. The reaction was stirred
at –78 °C for 48 h. The reaction was quickly filtered through a
plug of silica gel and concentrated. The residue was purified by
silica gel flash column chromatography (eluent: hexane–
EtOAc = 50:1) to give product 3.
(7) (a) Hammett, L. P. J. Am. Chem. Soc. 1937, 59, 96. (b) Hansch, C.;
Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165. (c) Jensen, K. H.;
Sigman, M. S. Angew. Chem. Int. Ed. 2007, 46, 4748. (d) Sigman,
M. S.; Miller, J. J. J. Org. Chem. 2009, 74, 7633. (e) Gustafson, J. L.;
Sigman, M. S.; Miller, S. J. Org. Lett. 2010, 12, 2794.
Compound 3aa: 27 mg; 96% yield; colorless oil. 1H NMR (400
MHz, CDCl3): δ = 7.51–7.19 (m, 8 H), 7.10 (d, J = 7.7 Hz, 2 H),
3.97–3.77 (m, 2 H), 3.36–3.18 (m, 1 H), 2.87 (dd, J = 15.4, 6.5 Hz,
(8) General Procedure for the NHC-Catalyzed Sulfa-Michael
Addition Reaction
1 H), 2.73 (dd, J = 15.4, 7.9 Hz, 1 H), 1.43 (d, J = 6.8 Hz, 3 H). 13
C
NHC precursor 4a (4.2 mg, 0.01 mmol) and oven-dried 4 Å MS
(100 mg) were mixed in dry toluene (0.6 mL) in a 10 mL test
tube. The reaction vessel was degassed and back-filled with
argon three times before LiHMDS (1 M in THF–ethylbenzene, 10
μL, 0.01 mmol) was slowly added. The mixture was stirred at r.t.
for 30 min and another 30 min at –78 °C. Thiol 1 (0.2 mmol)
was slowly added, and the mixture was stirred for 30 min at
NMR (100 MHz, CDCl3): δ = 169.87 (s), 150.58 (s), 138.08 (s),
129.43 (s), 128.87 (s), 128.58 (s), 127.10 (s), 125.90 (s), 121.54
(s), 42.09 (s), 36.05 (s), 35.38 (s), 21.34 (s). Chiral HPLC (AD-H,
5% EtOH in hexanes, 1.0 mL/min, 210 nm): tR (major) = 7.4 min,
tR (minor) = 6.4 min, 67% ee. HRMS (ESI+): m/z calcd for
C
17H18O2NaS+ [M + Na]+: 309.0925; found: 309.0920.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E