Enantioselective conjugate addition of N-heterocycles to α, β-enones mediated by diarylprolinols

Article abstract of DOI:10.2174/157017809788681248

Enantioselective conjugate addition of benzotriazole to α, β-enones catalyzed by prolinol derivatives with moderate yields and enantioselectivities was reported. Studies of stereoelectronic effects of the catalyst showed that the transition state could be

Full text of DOI:10.2174/157017809788681248

Letters in Organic Chemistry, 2009, 6, 397-399
397
Enantioselective Conjugate Addition of N-Heterocycles to ꢀ,ꢁ-Enones
Mediated by Diarylprolinols
Ling Fanga, Aijun Lina, Xuefeng Jiaa, Jie Menga, Yangnian Wanga and Chengjian Zhu*,a,b
aSchool of Chemistry and Chemical Engineering, State Key Laboratory of Coordination Chemistry, Nanjing University,
Nanjing 210093, China
bState Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, Shanghai 200032, China
Received July 08, 2008: Revised April 19, 2009: Accepted April 21, 2009
Abstract: Enantioselective conjugate addition of benzotriazole to ꢀ,ꢁ-enones catalyzed by prolinol derivatives with
moderate yields and enantioselectivities was reported. Studies of stereoelectronic effects of the catalyst showed that the
transition state could be of a hydrogen bonding activation mode, and fine tuning of the substituents on the aryl moiety of
the catalyst is important for the reaction stereoselectivities.
Keywords: Organocatalysis, conjugate addition, diarylprolinols, enones, asymmetric, benzotriazole.
Asymmetric organocatalysis has emerged as an attractive
field in organic synthesis for recent years [1]. More and more
chiral small molecules could be used as the catalysts in
various reactions with excellent results. L-proline and its
derivatives, as the representative one, have been widely
developed in enantioselective construction of C-C [2] and C-
hetero [3] bond. However, optically active C-N bond forming
has always been challenging, and there are only a few reports
with regard to the asymmetric conjugate addition of nitrogen
nucleophiles to ꢀ,ꢁ-unsaturated carbonyl compounds in an
organocatalytic manner [4]. Moreover, compounds con-
taining alkylated benzotriazole exhibit important biological
and pharmaceutical activities [5], whereas reports related to
enantioselective synthesis of these compounds are limited
[6]. Recently, Wang developed chiral thiourea derivatives in
the addition of benzotriazole to ꢀ,ꢁ-enones, with up to 64%
ee, and it was the only example for this organocatalytic
process to our knowledge [7]. Therefore, we were interested
in seeking other alternative catalysts for this transformation.
electronic properties of the catalyst aromatic ring had an
impact on its performance. The catalyst bearing an electron-
donating group on the aromatic ring (1d) exhibited higher
reactivity than one bearing an electron-withdrawing group
(1c), albeit with comparable enantioselectivities (Table 1,
entries 4, 5). The highest enantioselectivity was achieved
with 1d at 0 ºC, giving the product 4a in 53% yield and 42%
ee after 72 h (Table 1, entry 10). However, when the
trimethylsilyl ether 1e was examined (Table 1, entry 6), both
the reactivity and enantioselectivity (40% yield and 20% ee
even after 72h) were even lower than that in the presence of
1a (Table 1, entry 1). This is in contrast with the result of
asymmetric conjugate addition of 2 to the ꢀ,ꢁ-unsaturated
aldehydes: excellent enantioselectivities were obtained when
1e was tested [4c]. Meanwhile, we synthesized a new
prolinol derivative 1g [8], bearing an electron-donating
group at C(4) position of the prolinol backbone.
Disappointedly, 4a was obtained with 11% ee (Table 1, entry
8). This result suggested that the previous enantioselective
attack was partly blocked by the increased steric hindrance
on the prolinol backbone.
We report herein the enantioselective conjugate addition of
benzotriazole to ꢀ,ꢁ-enones catalyzed by diarylprolinols
(Fig. 1). Initially, we studied the reaction of benzotriazole (2)
with chalcone (3a) in the presence of 20 mol%
diphenylprolinol (1a). Solvent screening revealed that
toluene and p-xylene could afford the product 4a with 25%
ee and 29% ee, respectively (Table 1, entries 1, 2).
Meanwhile, the region-isomer 5a also could be isolated in
lower yield, thus its ee value was not detected. Some polar
solvents such as acetonitrile, dichloromethane, THF and
methanol, gave nearly racemic adducts. Several other
prolinol derivative catalysts 1b-1g were then examined using
toluene as the solvent (Table 1, entries 3-8, 11). In general,
Having established the optimal protocol for the reaction,
we then explored the conjugate addition of benzotriazole
with various aromatic ꢀ,ꢁ-enones. The reaction was carried
out with 20 mol% catalyst 1d in toluene at 0 ºC. As shown in
Table 2, for para- and meta- position substituted ꢀ,ꢁ-enones
(3b-3c, 3e-3k), either electron-donating or electron-
withdrawing group on the phenyl rings were found to be
tolerated in this transformation. Products 4b-4c, 4e-4k could
be obtained with moderate yields and enantioselectivities
(Entries 1-2, and 4-10). Unfortunately, probably due to a
steric effect, a sharp drop in enantioselectivity was observed
with the ꢀ,ꢁ-enone bearing substitution at ortho- position of
the Ar1 group (Entries 3, 11). Clearly, compared with
chalcone, most ꢀ,ꢁ-enones regioselectively afforded the N-1
adducts while their N-2 isomers were only in trace amounts.
Additionally, the absolute configuration of the addition
adduct 4g [9] was determined to be R according to the
*Address correspondence to this author at the School of Chemistry and
Chemical Engineering, Nanjing University, Nanjing 210093, China; Tel:
+86 25 83594886; Fax: +86 25 83317761; E-mail: cjzhu@nju.edu.cn
1570-1786/09 $55.00+.00
© 2009 Bentham Science Publishers Ltd.

398 Letters in Organic Chemistry, 2009, Vol. 6, No. 5
1a, Ar=Ph,R=H
Fang et al.
RO
Ar
1b, Ar=3,5-(CH3)2C6H3, R=H
1c, Ar=3,5-(CF3)2C6H3, R=H
1d, Ar=4-CH3OC6H4, R=H
1e, Ar=Ph,R=TMS
OH
Ar
1f, Ar=Ph, R=H
1g, Ar=4-CH3OC6H4,
R=Bn
Ar
N
N
Ar
N
H
H
H
OR
1h
OH
Fig. (1). Prolinol derivative catalysts.
Table 1. Screening of Reaction Conditions for the Conjugate Addition of Benzotriazole (2) to Chalcone (3a)a
N
N
N
O
N
N
N
O
20 mol% Cat*
Toluene
N
O
N
+
+
N
H
Ph
Ph
Ph
Ph
Ph
Ph
4a
3a
2
5a
Entry
Cat.
T/oC
Time/h
Yield/%b of 4a
Yield/%b of 5a
Ee/%c of 4a
1
2d
3
1a
1a
1b
1c
1d
1e
1f
rt
15
rt
48
48
48
72
48
72
72
72
48
72
48
54
52
14
15
25
29
24
33
34
20
27
11
36
42
0
68(82 e)
11
4
rt
48
18
5
rt
55
13
6
rt
40
n.d.f
7
rt
50
15
8
1g
1d
1d
1h
15
15
0
45
10
9d
10
11
52
n.d.f
n.d.f
n.d.f
53
rt
46
aThe reaction was carried out with 1.3 equiv of 2. bIsolated yields. cDetermined by Daicel Chiralpak AD-H column. dp-xylene was used as the solvent. eIsolated yield after 5 days. fNot
determined.
Table 2. Scope of the Conjugate Addition Reactiona
N
H
N
O
N
Cat* 1d (20 mol%)
N
N
O
+
Ar1
Ar2
N
Toluene, 0oC, 72h
Ar1
Ar2
2
3b-l
4b-l
Entry
Ar1
Ar2
4
Yield/%b
Ee/%c
1
2
4-ClC6H4
4-MeC6H4
2-ClC6H4
4-ClC6H4
4-ClC6H4
4-MeOC6H4
C6H5
4b
4c
4d
4e
4f
55
60
45
35
4
3
C6H5
43
4
4-MeC6H4
C6H5
62
50
46
50
44
45
34
32
4
5
59
54(72 d)
6
4-NO2C6H4
3-BrC6H4
C6H5
4g
4h
4i
7
C6H5
61
8
3-NO2C6H4
4-MeOC6H4
4-BrC6H4
C6H5
58
9
C6H5
4j
55
10
11
C6H5
4k
4l
62
2-BrC6H4
C6H5
55
aThe reaction was carried out with 1.3 equiv of 2, products 5 were not determined. bIsolated yields. cDetermined by Daicel Chiralpak AD-H or AS-H column. dIsolated yield after 5
days.

Enantioselective Conjugate Addition
Letters in Organic Chemistry, 2009, Vol. 6, No. 5
399
Commun., 2005, 4821; (d) Marigo, M.; Wabnitz, T.C.; Fielenbach,
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K.A. Angew. Chem. Int. Ed. Engl., 2007, 46, 1983; (d) Ibrahem, I.;
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literature [6, 7]. Although the reaction mechanism is not
clear, the catalyst screening results shown above suggested
that the ꢀ,ꢁ-enone substrate and benzotriazole were activated
by the catalyst 1d via hydrogen bonding [10].
[4]
[5]
In summary, we have presented the diarylprolinol-
catalyzed enantioselective conjugate addition between
benzotriazole and ꢀ,ꢁ-enones with moderate enantioselec-
tivity. Studies suggested that the transition state could be
hydrogen bonding activation mode. Further investigations on
the optimization of the catalyst structure to improve the
stereoselectivity as well as the development of the scope of
various substrates are currently underway.
[6]
ACKNOWLEDGEMENTS
[7]
[8]
Wang, J.; Zu, L.; Li, H.; Xie, H.; Wang, W. Synthesis, 2007, 2576.
Compound 1g, 1H NMR (300 MHz, CDCl3) ꢃ 7.48 (d, J = 9.0 Hz,
2H), 7.38-7.31 (m, 7H), 6.86-6.80 (m, 4H), 4.50 (dd, J = 6.9, 9.9
Hz, 1H), 4.45 (s, 2H), 4.09-4.04 (m, 1H), 3.77 (s, 6H), 3.15-3.14
(m, 2H), 1.80 (ddd, J = 5.4, 9.6, 13.5 Hz, 1H), 1.68 (ddd, J = 1.2,
6.6, 13.5 Hz, 1H), 13C NMR (75 MHz, CDCl3) ꢃ 158.2, 158.0,
140.3, 138.4, 137.8, 128.5, 127.7, 127.1, 126.6, 113.6, 113.4, 79.6,
76.5, 70.8, 63.6, 55.3, 55.2, 52.0, 33.0
We gratefully acknowledge the National Natural Science
Foundation of China (20672053, 20832001) and the National
Basic Research Program of China (2007CB925103) for their
financial support. The Program for New Century Excellent
Talents in the University of China (NCET-06-0425) is also
acknowledged.
[9]
General procedure for the asymmetric conjugate addition of ꢀ,ꢁ-
enones: to a stirred solution of catalyst 1d (6.3 mg, 0.02 mmol) and
ꢀ,ꢁ-enone 3 (0.1 mmol) in toluene (1 ml) at 0 oC was added
benzotriazole 2 (15 mg, 0.13 mmol), and the resulting mixture was
stirred for the specified time (Table 2). The crude reaction mixture
was directly purified by flash chromatography on silica gel to
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1
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