4-Trifluoromethanesulfonamidyl prolinol tert-butyldiphenylsilyl ether as a highly efficient bifunctional organocatalyst for Michael addition of ketones and aldehydes to nitroolefins

Article abstract of DOI:10.1016/j.tetlet.2009.02.211

4-Trifluoromethanesulfonamidyl prolinol tert-butyldiphenylsilyl ether bifunctional organocatalyst 3a is a highly efficient catalyst for the asymmetric Michael addition reactions of ketones and aldehydes to nitrostyrenes, leading to syn-selective adducts with excellent yields (>99%), high diastereoselectivities (up to 99:1 dr) and excellent enantioselectivities (up to 99% ee). Control experiments suggested that the trans-configuration relationship between the bulky group (-CH₂OTBDPS) and the sulfonamido group at the 4-position of the pyrrolidine ring was important to achieve high yield and stereoselectivity.

Full text of DOI:10.1016/j.tetlet.2009.02.211

Tetrahedron Letters 50 (2009) 2363–2366
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Tetrahedron Letters
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4-Trifluoromethanesulfonamidyl prolinol tert-butyldiphenylsilyl ether as a
highly efficient bifunctional organocatalyst for Michael addition of ketones
and aldehydes to nitroolefins
*
Chao Wang, Chun Yu, Changlu Liu, Yungui Peng
School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
4-Trifluoromethanesulfonamidyl prolinol tert-butyldiphenylsilyl ether bifunctional organocatalyst 3a is a
highly efficient catalyst for the asymmetric Michael addition reactions of ketones and aldehydes to nitro-
styrenes, leading to syn-selective adducts with excellent yields (>99%), high diastereoselectivities (up to
99:1 dr) and excellent enantioselectivities (up to 99% ee). Control experiments suggested that the trans-
configuration relationship between the bulky group (–CH2OTBDPS) and the sulfonamido group at the 4-
position of the pyrrolidine ring was important to achieve high yield and stereoselectivity.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 24 December 2008
Revised 24 February 2009
Accepted 27 February 2009
Available online 4 March 2009
Asanimportantapproachtosyntheticallyuseful
c
-nitrocarbonyl
improvement of the catalyst performance have also attracted more
and more attention recently since the pioneering work of List.2a
Althoughhighlydiastereo-andenantioselective conjugateadditions
involving ketones were reported by the groups of Kotsuki,7 Tang,9a
Cheng,3a,11c,d and Singh,5g a relatively high catalyst loading, typically
10–20 mol %, was requiredto achieve good results. Therefore, design
and synthesis of highlyefficient and readily tunablecatalysts remain
a challenge for the asymmetric Michael addition of ketones to
nitroolefins.
compounds,1 the asymmetric Michael addition of carbonyl com-
poundstonitroalkeneshasbeenofgreatinterest. In recentyears, tre-
mendous efforts have been focused on the development of an
organocatalytic asymmetric version of the reaction.2–12 Among the
organocatalytic systems, pyrrolidine-based system was found to
be the most useful. Thus, it has been intensively studied and im-
proved, leading to many variations, such as chiral pyrrolidinyl tria-
zole,3 tetrazole,4 aminomethylpyrrolidine,5 2,2-bipyrrolidine,6
pyrrolidine-pyridine,7 pyrrolidine sulfonamide,8 pyrrolidine-thio-
urea,9 diphenylprolinol ethers or their derivatives,10 and others.11
Most of these systems share a common feature: a hydrogen-bond
Interested in developing an efficient chiral organocatalytic sys-
tem to achieve high yield and enantioselectivity in Michael addi-
tion, we developed pyrrolidine-based silyl ether
1 as an
donor substituent at the
a
-position of the pyrrolidine nitrogen atom,
organocatalyst for direct Michael addition reactions,12a in which
the enantioselectivity, controlled primarily by steric interactions.
Although a high level of both enantioselectivity (73–95% ee) and
diastereoselectivity (P20:1 dr) was achieved, the catalytic effi-
ciency was low (up to 20 mol % catalyst loading). In Palomo’s cat-
alytic system,11b the hydrogen-bond donor was a hydroxyl group
and the strength of the hydrogen bond between the hydroxyl pro-
ton and the nitro group was moderate. Inspired by his work, we be-
lieved that introduction of a hydrogen bond into TBDPS protected
prolinol system would enhance the catalytic efficiency and enanti-
oselectivity. We also believed that the selectivity could be further
enhanced by a stronger hydrogen-bond donor at the 4-position
of the catalyst 1. Thus, we designed and synthesized a series of no-
vel catalysts (2–6) that bear diverse proton donors at the 4-posi-
tion and –CH2OTBDPS group at the 2-position of the pyrrolidine
nitrogen atom (Fig. 1). As expected, these molecules were excellent
catalysts in the asymmetric Michael addition reactions of ketones
and aldehydes to nitroolefins. In this Letter, we disclose the preli-
minary results.
which is believed to play a critical role in helping the catalytic reac-
tion to proceed. For example, Wang reported an excellent pyrroli-
dine-sulfonamide system for the asymmetric Michael addition
reactions of aldehydes and ketones. However, the drawback of the
system was high catalyst loading (10–20 mol %).8a–c Palomo made
some improvement, reporting that a hydrogen-bond donor at the
4-position of the pyrrolidine can help the catalytic reaction of alde-
hyde proceed with 5 mol % catalyst loading.11b Most recently, pri-
marily based on the concept of steric control, Ma developed an
even more effective catalytic system, in which the catalyst loading
was lowered to 0.5–2 mol %. Not only was the catalyst capable of
promoting the reaction of aldehydes,10e but also worked well even
for acetaldehyde, the ‘simplest’ nucleophile, as reported by List10f
and Hayashi10g independently. In the case of less reactive donors
such as ketones, development of new catalytic systems and
* Corresponding author. Tel.: +86 23 68254290; fax: +86 23 68254000.
E-mail addresses: pengyungui@hotmail.com, pyg@swu.edu.cn (Y. Peng).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.211

2364
C. Wang et al. / Tetrahedron Letters 50 (2009) 2363–2366
tively. However, the diastereoselectivity in either case remained
S
essentially the same as that of the reaction catalyzed by 2a, while
enantioselectivity decreased slightly from 97% ee (2a) to 93% ee
(2b) and 92% ee (2c) (Table 1, entries 3 and 4). The decrease in
reactivity and enantioselectivity may be caused by the decrease
in the hydrogen bond donating ability of the thiourea hydrogen.
Hydrogen bond donating ability is closely linked to acidity, and is
governed by the electronic nature of the R group. In catalyst 2a,
with two electron-withdrawing groups (–CF3) on the phenyl ring,
both the hydrogen bond donating ability and the acidity of the
thiourea hydrogen were stronger than those in 2b or 2c, and thus
the catalytic reactivity of 2a is superior to that of 2b or 2c. We fur-
ther screened 4-sulfonamido (3, 4, and 6) and 4-hydroxyl (5) pro-
linol ethers (Table 1, entries 5–12) for catalytic performance. To
our delight, the catalytic activity was increased dramatically when
3a was used as the catalyst in comparison with 2a, affording over
99% yield without losing enantioselectivity (97% ee) and diastere-
oselectivity (96% dr) (Table 1, entries 2 and 5). As the acidity and
hydrogen bond donating ability of the sulfonamide proton in 3a
are much higher than those in 3b and 3c, the catalytic performance
of 3a is superior to that of 3b and 3c (Table 1, entries 6 and 7).
However, although the acidity of the sulfonamide proton in 3b is
higher than that in 3c, 3c is a better catalyst. We believe that the
steric hindrance caused by the bulkier toluene group makes the
sulfonamide proton less available in 3b (Table 1, entry 6), thus low-
ering the hydrogen bond donating ability of the proton.
We also prepared and screened analogues 4, in which the sul-
fonamide group is further away from the pyrrolidine ring by a
methylene group compared with that of 3. The results demon-
strated that catalysts 4a–c are inferior to the corresponding 3a–c
in catalytic performance (Table 1, entries 8–10). When the hydro-
gen-bond donor was a hydroxyl group, similar to the catalytic sys-
tem reported by Palomo,11b catalyst 5 showed very low activity but
high selectivity. Only 10% yield was obtained after 68 h (Table 1,
entry 11). We further investigated the influence of the 4-position
configuration of the catalyst on this reaction. The change of
trans-4-sulfonamido group (3a) to cis-4-sulfonamido group (6)
led to lower yield and decreased diastereoselectivity and enanti-
oselectivity (Table 1, entry 12). This indicated that the trans-4-sul-
fonamido group on the pyrrolidine ring is important not only for
good stereoselectivity, but also for high catalytic activity. In sum-
mary, these studies reveal that a strong hydrogen-bond donor at
the 4-position of pyrrolidine plays an important role toward stere-
oselectivity, and that sulfonamide group is superior to thiourea in
catalytic activity.
R
N
NH
H
OTBDPS
OTBDPS
OTBDPS
N
N
H
1
H
2a: R = 3, 5 -(CF3)2-Ph
2b: R = Ph
2c: R =( p-CH3O)-Ph
RHN
HO
RHNH2C
OTBDPS
N
H
N
H
3a: R = Tf
3b: R = Ts
3c: R = Ms
4a: R = Tf
4b: R = Ts
4c: R = Ms
TfHN
OTBDPS
OTBDPS
N
H
N
H
5
6
Figure 1. Pyrrolidine-based chiral organocatalysts.
We selected the Michael addition reaction of cyclohexanone 7a
and b-nitrostyrene 8a as the model reaction to examine the novel
catalysts (Table 1). Excellent enantioselectivity (97% ee) and dia-
stereoselectivity (96% dr) with a moderate yield (76%) were
achieved when the reaction was catalyzed by 2a (Table 1, entry
2). When 2b or 2c was used as the catalyst, the reactivity decreased
dramatically; giving only 25% or 46% in yield after 36 h, respec-
Table 1
Catalytic asymmetric Michael reaction of cyclohexanone (7a) to nitrostyrene (8a)
under various conditionsa
O
O
Ph
NO2
NO2
cat.
+
hexane/0°C
Ph
8a
7a
9a
Entry
Cat. (%)
Solvent
Time (h)
Yieldb (%)
drc (syn:anti)
eed (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14e
15e
16e
17e
18e
19e
20e
21e
22e
23e
24e
25e,f
1 (20)
2a (20)
2b (20)
2c (20)
3a (20)
3b (20)
3c (20)
4a (20)
4b (20)
4c (20)
5 (20)
6 (20)
3a (5)
3a (5)
3a (5)
3a (5)
3a (5)
3a (5)
3a (5)
3a (5)
3a (5)
3a (5)
3a (5)
3a (5)
3a (5)
Hexane
Hexane
Hexane
Hexane
Hexane
Hexane
Hexane
Hexane
Hexane
Hexane
Hexane
Hexane
Hexane
Hexane
Toluene
Ether
Benzene
CH2Cl2
THF
i-PrOH
CHCl3
CH3CN
DMF
CH3OH
CH3CN
35
36
36
36
36
36
36
36
36
36
68
78
114
47
77
77
77
77
77
100
77
72
77
77
40
34
76
25
41
>99
89
>99
>99
79
92
10
44
18
97
95
95
98
98:2
98:2
98:2
97:3
98:2
96:4
97:3
98:2
98:2
98:2
94:6
92:8
n.d
98:2
96:4
98:2
96:4
95:5
97:3
n.d
93
97
93
92
97
92
95
94
85
85
94
88
92
96
92
95
93
95
87
n.d
90
98
86
n.d
96
We then examined the influence of catalyst loading on the reac-
tion. Although a load of 5 mol % of catalyst 3a alone resulted in dra-
matic decrease in catalytic performance (Table 1, entry 13),
addition of benzoic acid boosted the catalytic performance by
accelerating the formation of the enamine intermediate between
the catalyst and the substrate. In fact, 5 mol % of catalyst 3a along
with 5 mol % of benzoic acid worked just as well as 20% of the same
catalyst used alone (Table 1, entries 5 and 14). A series of solvents
were also screened (Table 1, entries 14–24). Good yields and enan-
tiomeric excesses were obtained in nonpolar or less polar solvents
(Table 1, entries 14–18). The best result was achieved in CH3CN
(Table 1, entry 22). In contrast, the reaction proceeded sluggishly
in polar protic solvents such as iPrOH and CH3OH, only trace
amount of product was observed (Table 1, entries 20 and 24).
We also optimized the reaction temperature and found that reac-
tion ran at 0 °C to afford the highest yield and the best enantiose-
lectivity (Table 1, entries 22 and 25).
94
73
Trace
92
95:5
95:5
94:6
n.d
>99
63
Trace
>99
94:6
a
Unless specified, reactions conducted on a 0.25 mmol scale nitroolefin in sol-
vent (1 mL) with cyclohexanone (2.5 mmol) in the presence of catalyst.
b
Isolated yield.
With the optimal conditions in hand, the scope of the reaction
was examined (Table 2).13 The results showed that the reaction
has broad applicabilities. In general, b-nitrostyrenes possessing
electron-withdrawing, electron-donating groups on their aromatic
Determined by 1H NMR spectroscopy.
Determined by chiral HPLC analysis.
5 mol % of benzoic acid was added.
c
d
e
f
Reaction at 10 °C.

C. Wang et al. / Tetrahedron Letters 50 (2009) 2363–2366
2365
Table 2
substitution patterns of b-nitrostyrenes had certain influences on
reactivity, diastereoselectivity, and enantioselectivity in some sub-
strates. For example, when the methyl group position of b-nitrosty-
rene was changed from para- to ortho-, the reaction time was
prolonged from 67 h to 137 h, the yield decreased from 99% to
90%, and the diastereoselectivity and enantioselectivity increased
from 92% de to 98% de and 95% ee to 98% ee, respectively (Table
2, entries 13 and 14). When the aliphatic trans-nitroolefin
CH3(CH2)3CH@CHNO2 was employed as substrate for the process,
good results (81% yield, 90% ee, and 96% dr) were obtained (Table
2, entry 21).
Aldehyde and other ketone substrates were investigated as well
(Table 3). The ring size of cyclic ketones strongly affects the reac-
tion rate (Table 3, entries 2 and 3). Cyclopentanone and cyclohep-
tanone were less reactive; however, good yields and moderate
selectivities were achieved with catalyst 3a. The results were much
better than those reported previously.8c,9a,14 With unsymmetrical
ketone substrates, the reaction took place at the more substituted
sites, presumably because the enamine intermediates formed un-
der thermodynamic control (Table 3, entries 5–7).
Catalytic asymmetric Michael reaction of cyclohexanone with various trans-b-
nitrostyrenesa
O
O
R
3a (5 mol %)
PhCOOH (5mol %)
NO2
NO2
+
CH3CN/0°C
R
Entry
R
Time (h)
72
Yieldb (%)
drc (syn:anti)
eed (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21e
Ph
>99
>99
>99
>99
98
95:5
92:8
96:4
97:3
96:4
97:3
99:1
99:1
94:6
93:7
95:5
97:3
96:4
99:1
99:1
97:3
99:1
96:4
93:7
91:9
98:2
98
98
98
99
99
95
97
99
98
99
97
98
95
98
94
96
98
99
99
91
90
4-NO2Ph
4-FPh
4-ClPh
4-BrPh
2-NO2Ph
2-FPh
2-ClPh
2-BrPh
3-NO2Ph
3-BrPh
2,4-Cl2Ph
4-MePh
2-MePh
2-MeOPh
3-MePh
1-Naphthyl
2-Naphthyl
2-Thienyl
2-Furyl
n-Bu
47
96
66
72
53
48
47
53
72
72
29
67
137
71
97
>99
>99
96
>99
99
94
>99
90
>99
>99
87
95
>99
99
TBDMS protected
a-hydroxyl acetone gave the product in 91%
95
yield, 94% ee, and 85:15 dr (Table 3, entry 6), while 2-butanone
gave 88% yield, 86% ee, and 94% dr (Table 3, entry 7). 3-Pentanone
afforded syn adduct with excellent enantio- (93% ee) and diastere-
oselectivity (Table 3, entry 8). To the best of our knowledge only
two reports detailing syn-selective catalytic systems have thus
far been found for the analogous transformation of more challeng-
ing acyclic ketone such as 3-pentanone with >90% ee.2k,8c Finally,
good enantioselectivity (75–80% ee) and diastereoselectivity (78–
90% dr) were obtained when aldehydes were used as donors (Table
3, entries 9–11).
The achievement of high stereoselectivity may be explained by
acyclic synclinal transition state model originally proposed by See-
bach and Golinski.15 As shown in Figure 2, for cyclohexanone, the
bulky group (–CH2OTBDPS) should effectively shield the si-face of
an enamine double bond, which would make nitrostyrene accep-
tors approach from the nonshielded side to give the observed ma-
jor enantiomer. The hydrogen bond between the sulfonamide
161
177
107
67
43
81
a
Unless specified, reactions conducted on a 0.25 mmol scale nitroolefin in CH3CN
(1 mL) with cyclohexanone (2.5 mmol) in the presence of 5 mol % 3a and benzoic
acid.
b
Isolated yield.
c
Determined by 1H NMR spectroscopy.
d
Determined by chiral HPLC analysis.
20 mol % catalyst loading and reaction performed at room temperature.
e
ring and heteroaromatic substituents reacted efficiently (>99%
yield) with high diastereoselectivity (up to 98% de) and enantiose-
lectivity (up to 99% ee) for syn adduct (Table 2, entries 1–20). The
Table 3
Enantioselective addition of various ketones and aldehydes to nitroolefina
O
Ph
3a
PhCOOH
CH3CN/0°C or rt
O
NO2
NO2
∗
∗
R1
R2
+
Ph
R1
R2
Entry
1e,f
R1
R2
Time
15 h
Yieldb (%)
drc (syn:anti)
eed (%)
71
98
99:1
R1
O
O
R2
2e,f
3e,f
4e,f
5e
–(C3H6)–
–(C5H10)–
10 d
8 d
42 h
5.5 d
5 d
4.8 d
9 d
66 h
66 h
60 h
88
80
>99
56
91
88
93
98
>99
>99
57:43
90:10
-
69:31
85:15
97:3
93:7
89:11
90:10
95:5
80 (87)
49
50
69 (0)
94
86
93
75
80
79
CH3
CH3
CH3
CH3
Et
H
H
H
H
OH
OTBS
CH3
CH3
Et
6
7e,f
8e,f
9
10
11
Pr
C6H13
a
Unless specified, reactions conducted on a 0.25 mmol scale nitroolefin in CH3CN (1 mL) with ketone (2.5 mmol) in the presence of 5 mol % 3a and benzoic acid; absolute
configuration was demonstrated in supporting information.
b
Isolated yield.
c
Determined by 1H NMR spectroscopy.
d
Determined by chiral HPLC analysis.
20 mol % catalyst loading.
Reaction performed at room temperature.
e
f

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Figure 2. Proposed transition state model.
proton and the nitro group could activate the nitrostyrene
effectively.
In conclusion, we have designed and synthesized novel pyrrol-
idine-sulfonamide and -thiourea silylether based bifunctional
organocatalysts, and we have successfully applied these catalysts
to the asymmetric Michael addition reactions of ketones and alde-
hydes to nitroolefins. When 3a was used as the catalyst, 5 mol %
catalyst loading afforded not only quantitative yields (>99%) but
also exceptional stereoselectivities (up to 98% dr and 99% ee). We
have demonstrated that fine tuning of the strength of the hydrogen
bond could result in high performance catalysts, a strategy to de-
sign more effective organocatalysts for direct asymmetric Michael
reactions. Further investigation on the application of this organo-
catalyst is in progress.
Acknowledgments
We thank the Natural Science Foundation of China (NSFC
20572087 and 20872120), the Ministry of Education, PR China
(No. 106141) and the Program for New Century Excellent Talents
(NCET-06-0772) in University for generous financial support.
11. (a) Martin, H. J.; List, B. Synlett 2003, 1901; (b) Palomo, C.; Vera, S.; Mielgo, A.;
Gómez-Bengoa, E. Angew. Chem., Int. Ed. 2006, 45, 5984; (c) Luo, S. Z.; Mi, X. L.;
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D.; Alonso, D. A.; Nájera, C. Tetrahedron: Asymmetry 2006, 17, 2064; (f) Reyes,
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.02.211.
12. (a) Liu, F. Y.; Wang, S. W.; Wang, N.; Peng, Y. G. Synlett 2007, 15, 2415; The
catalyst 1 has also been used in catalytic epoxidation reactions: (b) Zhao, G. L.;
Ibrahem, I.; Sunden, H.; Cordova, A. Adv. Synth. Catal. 2007, 349, 1210.
13. General procedure for asymmetric Michael addition of ketones or aldehydes to
References and notes
1. (a) Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH: New York, 2001;
(b) Calderari, G.; Seebach, D. Helv. Chim. Acta 1995, 58, 1592; (c) Czekelius, C.;
Carreira, E. M. Angew. Chem., Int. Ed. 2005, 44, 612.
nitroolefins catalyzed by 3a.
A mixture of catalyst 3a (5 mol %), PhCOOH
(5 mol %), and ketone or aldehyde (2.5 mol) in 1 mL of CH3CN were stirred at
room temperature for 20 min, and then cooled to 0 °C. Nitroolefin (0.25 mmol)
was added. The mixture was stirred at 0 °C until the completion of the reaction
monitored by TLC. The product was purified by silica gel column
chromatography (petroleum ether and ethyl acetate as eluent). (S)-2-((R)-2-
nitro-1-phenylethyl)cyclohexanone (Table 2, entry 1): >99% yield. mp 125–
2. (a) List, B.; Pojarliev, P.; Martin, H. J. Org. Lett. 2001, 3, 2423; (b) Dalko, P. I.;
Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138; (c) Seayad, J.; List, B. Org.
Biomol. Chem. 2005, 3, 719; (d) Berkessel, A.; Groger, H. Asymmetric
Organocatalysis: From Biomimmetic Concepts to Applications in Asymmetric
Synthesis; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2005;
(e) Tsogoeva, S. B.; Wei, S. W. Chem. Commun. 2006, 1451; (f) Huang, H. B.;
Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128, 7170; (g) Lalonde, M. P.; Chen, Y. G.;
Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 6366; (h) Xu, Y. M.; Córdova, A.
Chem. Commun. 2006, 460; (i) Xu, Y. M.; Zou, W. B.; Sundén, H.; Ibrahem, I.;
Córdova, A. Adv. Synth. Catal. 2006, 348, 418; (j) Tsogoeva, S. B. Eur. J. Org. Chem.
126 °C; ½a rDt
ꢀ
ꢁ26.1 (c 1.42, CHCl3). HPLC condition: chirlpak AD-H, 254 nm,
0.5 mL/min,
hexane/i-PrOH = 90/10, (major) = 25.90 min,
t
t
(minor) = 21.61 min, ee = 98%, dr = 95:5.
14. Gu, L.; Wu, Y.; Zhang, Y.; Zhao, G. J. Mol. Catal. A: Chem. 2007, 263, 186.
15. Seebach, D.; Golinski, J. Helv. Chim. Acta 1981, 64, 1413.