Asymmetric cyanosilylation of aldehydes catalyzed by novel organocatalysts

Article abstract of DOI:10.1055/s-2005-872692

A novel proline-based N,N′-dioxide, which is easily prepared from inexpensive chemicals, serves as an effective catalyst for enantioselective cyanosilylation of aldehydes in up to 73% ee. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-872692

LETTER
2445
Asymmetric Cyanosilylation of Aldehydes Catalyzed by Novel Organo-
catalysts
A
symmetric Cyano
u
silylation of
e
Aldehydeshong Wen, Xiao Huang, Jinglun Huang, Yan Xiong, Bo Qin, Xiaoming Feng*
Key Laboratory of Green Chemistry & Technology (Sichuan University), Ministry of Education, College of Chemistry, Sichuan University,
Chengdu 610064, P. R. of China
Fax +86(28)85418249; E-mail: xmfeng@scu.edu.cn
Received 31 July 2005
catalyze the asymmetric cyanosilylation of aldehydes and
Abstract: A novel proline-based N,N¢-dioxide, which is easily pre-
ketones. Unfortunately, the results were disappointing.17
In order to enhance the activity and enantioselectivity, we
pared from inexpensive chemicals, serves as an effective catalyst
for enantioselective cyanosilylation of aldehydes in up to 73% ee.
designed a new class of proline-based N,N¢-dioxides
Key words: proline-based N,N¢-dioxide, aldehydes, organocata-
(Figure 1) which could be easily prepared from L-proline
lyst, cyanosilylation, enantioselectivity
and amines.18,19 The reactivity was greatly improved
when N,N¢-dioxides were used compared with N-monox-
ides.
Chiral N-oxides have been used in several asymmetric
procedures, such as the allylation of aldehydes,1 the addi-
R2
HN
R2
NH
O
R1
R1
HN
tion of Et2Zn to aldehydes,2 the reduction of ketones,3 the
epoxide openings,4 the aldol reaction5 and the Strecker
reactions.6 Herein, we report on a novel class of organic
catalysts, proline-based N,N¢-dioxide, that efficiently
catalyzes the asymmetric cyanosilylation of aldehydes in
up to 73% ee.
O
O
NH
O
O
N
O
O
N
O
N
N
1
2
2a R2 = CH2Ph 2b R2 = t-Bu
2c R2 = CHPh2
2d R2 = 1-adamantyl
1a R1 = Ph 1b R1 = CH2Ph
1c R1 = t-Bu 1d R1 = CHPh2
1e R1 = cyclohexyl
2e R2
=
1f R1
=
Cyanohydrins have a high synthetic potential in organic
synthesis, which can easily be converted into a wide vari-
ety of important synthetic intermediates including a-hy-
droxy acids, a-amino acids and b-amino alcohols.7 A
number of methods have been reported for the asymmetric
synthesis of cyanohydrins employing enzymes,8 peptides9
and chiral metal complexes.10 In recent years, metal-free
organic molecules have played key roles in asymmetric
synthesis.11 However, there are few examples of the
asymmetric cyanosilylation of aldehydes using organo-
catalysts.12 Hence, it is a very active research effort to-
ward developing new organocatalysts for this addition
reaction.
Ph
Ph
2f R2 = cyclohexyl
Figure 1
In efforts to identify an effective chiral catalyst, we exam-
ined their abilities to promote enantioselective cyano-
silylation of benzaldehyde at –20 °C (Scheme 1). The
results were summarized in Table 1.
O
OTMS
5 mol% N, N'-dioxide
2.0 equiv TMSCN
Ph
H
Ph
H
CN
CH2Cl2, 10 h, –20 °C
In our previous studies, we found that N-oxide played a
role of Lewis base to activate TMSCN. Initially, we de-
veloped a bifunctional catalyst with N-oxide dipolar
moieties13 and a catalytic double activation method
(CDAM)14 for the asymmetric cyanosilylation of ketones.
Then, we observed that quaternary ammonium salt to-
gether with N-oxide15 or phenolic N-oxide alone could
efficiently promote the reaction, too.16 Encouraged by the
researches above, we speculated that chiral N-oxides with
proper structure could catalyze the asymmetric cyanosily-
lation of aldehydes and ketones. L-Proline, a natural
amino acid with a secondary amine functionality, can be
converted into chiral N-oxides easily. In our preliminary
studies, we investigated some proline-based N-oxides to
Scheme 1
As illustrated in Table 1, the amide substituent played an
important role on the enantioselectivity. The cyclohexyl
and (S)-methylphenyl groups afforded better ee values
(Table 1, entries 5, 6). Elongation of the carbon chain of 1
led to catalysts 2 with increased enantioselectivity
(Table 1, entries 7, 8, 11, 12). And 2f was identified as the
most effective catalyst (Table 1, entry 12).
Optimization of other reaction parameters resulted in fur-
ther improvements in enantioselectivity with catalyst 2f
(Table 2). Solvent effects showed that CH2Cl2 was the
most favorable solvent (Table 2, entries 1–4). Tempera-
ture clearly affected the yield and the enantioselectivity.
Lowering the temperature caused a drop in reactivity and
an increase in enantioselectivity (Table 2, entries 4–6).
The yield was dramatically influenced by catalyst loading
SYNLETT 2005, No. 16, pp 2445–2448
0
4
.1
0
.2
0
0
5
Advanced online publication: 21.09.2005
DOI: 10.1055/s-2005-872692; Art ID: U25905ST
© Georg Thieme Verlag Stuttgart · New York

2446
Y. Wen et al.
LETTER
Table 1 Asymmetric Cyanosilylation of Benzaldehyde Catalyzed
by 1, 2a
Under the optimized conditions, a range of aldehydes was
investigated (Scheme 2). The results were listed in
Table 3.20 Aromatic aldehydes gave better results, with
good yields and up to 73% ee. In general, alkyl, alkoxy
and halogen groups at the meta-position of aromatic ring
were tolerated well (Table 3, entries 3, 5, 6, 9), whereas
substituents at the para-position gave slightly lower ee
(Table 3, entries 2, 4, 10). 2-Naphthaldehyde afforded a
higher ee value than 1-naphthaldehyde (Table 3, entries
12, 11). The heterocyclic and aliphatic aldehydes gave
moderate enantioselectivities (Table 3, entries 13, 14).
Entry
1
Catalyst
1a
Yield (%)b
ee (%)c
5
93
96
98
94
94
98
96
98
95
96
98
98
2
1b
1c
17
3
36
4
1d
1e
36
5
40
6
1f
42
OTMS
O
2.5 mol% 2f
7
2a
30
1.3 equiv TMSCN
R
H
R
H
CN
4
CH2Cl2, 80 h, –78 °C
3
8
2b
2c
48
Scheme 2
9
30
10
11
12
2d
2e
54
In summary, we have developed a novel proline-based
N,N¢-dioxide that catalyzed the enantioselective addition
of TMSCN to aldehydes with reasonable yields and enan-
tioselectivities. Attractive features of the method include
the ease of catalyst preparation and the low catalyst load-
ing. To improve enantioselectivity, modification of the
N,N¢-dioxide structure can be rationally based and study
on the mechanism of the reaction is underway.
48
2f
55
a Reactions were carried out on a 0.2-mmol scale of benzaldehyde in
1.0 mL of CH2Cl2
b Isolated yield of the TMS ether.
c The ee values were determined by HPLC on Chiralcel OD column
after conversion to the corresponding acetate. The absolute configu-
ration was R by comparison of the reported optical rotation.
Acknowledgment
The authors thank the National Natural Science Foundation of
China (No. 20225206, 20390055 and 20472056) and the Ministry
of Education, China (No. 104209, 20030610021 and others) for
financial support.
and concentration of substrate as well. When the amount
of catalyst was reduced, the chemical yield decreased
stepwise. Fortunately, it was recovered by increasing the
concentration of the reaction components without any loss
of enantioselectivities (Table 2, entries 6–9).
Table 2 Optimization of the Cyanosilylation of Benzaldehyde in the Presence of 2fa
Entry
2f (mol%)
Solvent
THF
Temp (°C)
–20
Time (h)
11
Yield (%)b
ee (%)c
34
1
2
3
4
5
6
7
8
9
5
97
98
96
98
93
51
76
93
92
5
Toluene
Et2O
–20
12
42
5
–20
12
30
5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
–20
10
55
5
–45
36
61
5d
10d
5e
2.5f
–78
84
73
–78
84
72
–78
80
73
–78
80
73
a Unless otherwise specified, the reaction was carried out on a 0.2-mmol scale of benzaldehyde in 1.0 mL of CH2Cl2, TMSCN (2.0 equiv).
b Isolated yield of the TMS ether.
c Determined by HPLC on Chiralcel OD column, after conversion to the corresponding acetate.
d 1.3 Equiv of TMSCN, [benzaldehyde] = 0.2 M.
e 1.3 Equiv of TMSCN, [benzaldehyde] = 0.4 M.
f 1.3 Equiv of TMSCN, [benzaldehyde] = 1.0 M.
Synlett 2005, No. 16, 2445–2448 © Thieme Stuttgart · New York

LETTER
Asymmetric Cyanosilylation of Aldehydes
2447
Table 3 Asymmetric Cyanosilylation of Aldehydes Catalyzed by 2fa
(8) (a) Kanerva, L. T. Acta Chem. Scand. 1996, 50, 234.
(b) Effenberger, B. F.; Ziegler, T.; Förster, S. Angew. Chem.,
Int. Ed. Engl. 1987, 26, 458. (c) Niedermeyer, U.; Kula, M.-
R. Angew. Chem., Int. Ed. Engl. 1990, 29, 386. (d) Han, S.;
Chen, P.; Lin, G.; Huang, H.; Li, Z. Tetrahedron: Asymmetry
2001, 12, 843. (e) Brussee, J.; Ross, E. C.; Vander, A. G.
Tetrahedron Lett. 1988, 29, 4485.
Entry
1
Aldehyde
Yield (%)b ee (%)c
Benzaldehyde(3a)
92
69
80
57
78
74
70
83
90
63
92
79
59
68
73d
69
71
64
69
71
69
67
66
65
59
71
53
62
2
4-Methylbenzaldehyde (3b)
3-Methylbenzaldehyde (3c)
4-Methoxybenzaldehyde (3d)
3-Methoxybenzaldehyde (3e)
3-Phenoxybenzaldehyde (3f)
4-Fluorobenzaldehyde (3g)
2-Chlorobenzaldehyde (3h)
3-Chlorobenzaldehyde (3i)
4-Chlorobenzaldehyde (3j)
1-Naphthaldehyde (3k)
2-Naphthaldehyde (3l)
(9) (a) Danda, H. Bull. Chem. Soc. Jpn. 1991, 64, 3743.
(b) Hogg, D. J. P.; North, M. Tetrahedron 1993, 49, 1079.
(c) Callant, D.; Coussens, B.; v. d. Maten, T.; Vries, J. G.;
Vries, N. K. Tetrahedron: Asymmetry 1992, 3, 401.
(d) Nitta, H.; Yu, D.; Kudo, M.; Mori, A.; Inoie, S. J. Am.
Chem. Soc. 1992, 114, 7969.
3
4
5
6
(10) (a) Bolm, C.; Müller, P. Tetrahedron Lett. 1995, 36, 1625.
(b) Brunel, J.-M.; Legrand, O.; Buono, G. Tetrahedron:
Asymmetry 1999, 10, 1979. (c) Tian, J.; Yamagiwa, N.;
Matsunaga, S.; Shibasaki, M. Angew. Chem. Int. Ed. 2002,
41, 3636. (d) Casas, J.; Najera, C.; Sansano, J. M.; Saa, J. M.
Org. Lett. 2002, 4, 2589. (e) Ooi, T.; Miura, T.; Takaya, K.;
Ichikawa, H.; Maruoka, K. Tetrahedron 2001, 57, 867.
(f) Ryu, D. H.; Corey, E. J. J. Am. Chem. Soc. 2004, 126,
8106. (g) Hayashi, M.; Miyamoto, Y.; Inoue, T.; Oguni, N.
J. Org. Chem. 1993, 58, 1515. (h) Hayashi, M.; Inoue, T.;
Miyamoto, Y.; Oguni, N. Tetrahedron 1994, 50, 4385.
(i) Belokon, Y. N.; Gutnov, A. V.; Moskalenko, M. A.;
Yashkina, L. V.; Lesovoy, D. E.; Ikonnikov, N. S.; Larichev,
V. S.; North, M. Chem. Commun. 2002, 244. (j) Hatano,
M.; Ikeno, T.; Miyamoto, T.; Ishihara, K. J. Am. Chem. Soc.
2005, 127, 10776. (k) Li, Y.; He, B.; Qin, B.; Feng, X.-M.;
Zhang, G.-L. J. Org. Chem. 2004, 69, 7910. (l) Trost, B.
M.; Martínez-Sánchez, S. Synlett 2005, 627.
7
8
9
10
11
12
13
14
2-Furaldehyde (3m)
2-Phenylacetaldehyde (3n)
a Concentration of aldehydes = 1.0 M.
b Isolated yield of the TMS ether.
c The ee values were determined by HPLC or GC after conversion to
the corresponding acetates.
(11) (a) Dalko, P. I.; Moisan, L. Angew. Chem. Int. Ed. 2004, 43,
5138. (b) Schreiner, P. R. Chem. Soc. Rev. 2003, 32, 289.
(12) (a) Fuerst, E. D.; Jacobsen, N. E. J. Am. Chem. Soc. 2005,
127, 8964. (b) Ishikawa, T.; Isobe, T. Chem.–Eur. J. 2002, 8,
553.
d The configuration was R by comparison of the reported optical
rotation.
(13) (a) Shen, Y.-C.; Feng, X.-M.; Li, Y.; Zhang, G.-L.; Jiang,
Y.-Z. Synlett 2002, 793. (b) Shen, Y.-C.; Feng, X.-M.;
Zhang, G.-L.; Jiang, Y.-Z. Synlett 2002, 1353. (c) Shen, Y.-
C.; Feng, X.-M.; Li, Y.; Zhang, G.-L.; Jiang, Y.-Z.
Tetrahedron 2003, 59, 5667. (d) Shen, Y.-C.; Feng, X.-M.;
Li, Y.; Zhang, G.-L.; Jiang, Y.-Z. Eur. J. Org. Chem. 2004,
129.
(14) (a) Chen, F.-X.; Feng, X.-M.; Qin, B.; Zhang, G.-L.; Jiang,
Y.-Z. Org. Lett. 2003, 5, 949. (b) Chen, F.-X.; Feng, X.-M.;
Qin, B.; Zhang, G.-L.; Jiang, Y.-Z. Synlett 2003, 558.
(c) Chen, F.-X.; Zhou, H.; Liu, X.-H.; Qin, B.; Feng, X.-M.;
Zhang, G.-L.; Jiang, Y.-Z. Chem.–Eur. J. 2004, 10, 4790.
(15) Zhou, H.; Chen, F.-X.; Qin, B.; Feng, X.-M.; Zhang, G.-L.
Synlett 2004, 1077.
(16) (a) Li, Y.; He, B.; Feng, X.-M.; Zhang, G.-L. Synlett 2004,
1598. (b) Chen, F.-X.; Feng, X.-M. Synlett 2005, 892.
(17) Only 10% to 30% ee was obtained using the N-monoxide.
(18) General Procedure for the Preparation of N,N¢-Dioxides.
To a solution of (S)-1-(tert-butoxycarbonyl) pyrrolidine-2-
carboxylic acid (1.183 g, 5.5 mmol) in CH2Cl2 was added
Et3N (2 mL), isobutyl carbonochloridate (0.72 mL, 5.5
mmol) at 0 °C under stirring. After 15 min,
References
(1) (a) Nakajima, M.; Saito, M.; Shiro, M.; Hashimoto, S. I. J.
Am. Chem. Soc. 1998, 120, 6419. (b) Shimada, T.; Kina, A.;
Hayashi, T. J. Org. Chem. 2003, 68, 6329. (c) Malkov, A.
V.; Bell, M.; Orsini, M.; Pernazza, D.; Massa, A.; Herrmann,
P.; Meghani, P.; Kočovský, P. J. Org. Chem. 2003, 68,
9659. (d) Traverse, J. F.; Zhao, Y.; Hoveyda, A. H.;
Snapper, M. L. Org. Lett. 2005, 7, 3151. (e) Malkov, A. V.;
Bell, M.; Castelluzzo, F.; Kočovský, P. Org. Lett. 2005, 7,
3219.
(2) Derdau, V.; Laschat, S.; Hupe, E.; Konig, W. A.; Dix, I.;
Jones, P. G. Eur. J. Inorg. Chem. 1999, 1001.
(3) O’Neil, I. A.; Turner, C. D.; Kalindjian, S. B. Synlett 1997,
777.
(4) Tao, B.; Lo, M. M.-C.; Fu, G. C. J. Am. Chem. Soc. 2001,
123, 353.
(5) Denmark, S. E.; Fan, Y. J. Am. Chem. Soc. 2002, 124, 4233.
(6) (a) Liu, B.; Feng, X.-M.; Chen, F.-X.; Zhang, G.-L.; Jiang,
Y.-Z. Synlett 2001, 1551. (b) Jiao, Z.-G.; Feng, X.-M.; Liu,
B.; Chen, F.-X.; Zhang, G.-L.; Jiang, Y.-Z. Eur. J. Org.
Chem. 2003, 3818.
(7) (a) Gaucher, A.; Ollivier, J.; Salaün, J. Synlett 1991, 151.
(b) Schwindt, M. A.; Belmont, D. T.; Carlson, M.; Franklin,
L. C.; Hendrickson, V. S.; Karrick, G. L.; Poe, R. W.;
Sobieray, D. M.; Van de Vusse, J. J. Org. Chem. 1996, 61,
9564. (c) Effenberger, F.; Jäger, J. J. J. Org. Chem. 1997, 62,
3867.
cyclohexanamine (0.57 mL, 5 mmol) was added. It was
allowed to warm to r.t. and stirred for 3 h. The mixture was
washed with 1 M KHSO4, sat. NaHCO3, brine, dried over
anhyd Na2SO4 and concentrated. The residue in CH2Cl2 (20
mL) was added TFA (5 mL) and stirred for 1 h. Then, the
solvent was evaporated, and H2O was added (10 mL). The
pH of the mixture was brought into the range of 8–10 by the
addition of 2 M NaOH. The aqueous phase was extracted
with CH2Cl2. The CH2Cl2 extracts were pooled, washed with
Synlett 2005, No. 16, 2445–2448 © Thieme Stuttgart · New York

2448
Y. Wen et al.
LETTER
(20) Typical Procedure for the Trimethylsilylcyanation of
brine, dried over anhyd Na2SO4 and evaporated in vacuo.
The residue was used for next step directly.
Aldehydes.
To a solution of N-cyclohexylpyrrolidine-2-carboxamide
(980 mg, 5 mmol) in MeCN was added K2CO3 (691 mg, 5
mmol) and 1, 3-dibromopropane (0.26 mL, 2.5 mmol) under
stirring. It was kept at 80 °C, and monitored by TLC after 10
h. Then, K2CO3 was removed by filtration. The residue was
purified by silica gel column chromatography (EtOAc) to
give 1,1¢-(propane-1,3-diyl)bis(N-cyclohexylpyrrolidine-2-
carboxamide) (974 mg, 90%) as a white solid.
To a solution of 2f (4.7 mg, 0.01 mmol) in CH2Cl2 (0.4 mL)
was added freshly distilled benzaldehyde (42 mL, 0.4 mmol)
under N2 atmosphere, then TMSCN (68 mL, 0.52 mmol) was
added at –78 °C. After stirring for 80 h at this temperature,
the reaction was quenched. Further purification was
performed by silica gel column chromatography to give the
product (76 mg, 92%) as a colorless oil. To the product was
added a mixture of 1 M HCl (5 mL) and EtOAc (10 mL) and
stirred for 3 h at r.t., the organic layer was washed with
distilled H2O, and dried over anhyd Na2SO4. The
cyanohydrin was converted into the corresponding acetate
by reaction with two equiv of Ac2O and pyridine in CH2Cl2
(5 mL) at r.t. for 1 h. The organic layer was washed with
distilled H2O, dried over anhyd Na2SO4 and concentrated.
The crude was purified by flash chromatography on silica
gel (PE–EtOAc, 10:1) to yield the corresponding acetylated
cyanohydrin for further analysis.
For the oxidation step and stereochemistry of the N-oxide,
see: O’Neil, I. A.; Miller, N. D.; Peake, J.; Barkley, J. V.;
Low, C. M. R.; Kalindjian, S. B. Synlett 1993, 515.
(19) The following are the NMR data of 2f: 1H NMR (400 MHz,
CDCl3): d = 10.59 (2 H, d, J = 6.8 Hz, NH), 3.77 (2 H, m),
3.62 (2 H, m), 3.32–3.60 (8 H, m), 2.39–2.64 (8 H, m), 1.57–
2.03 (12 H, m), 1.27–1.35 (10 H, m) ppm. 13C NMR (100
MHz, CDCl3): d = 19.73, 24.39, 25.32, 27.42, 32.26, 32.73,
47.26, 64.72, 67.55, 76.45, 166.28 ppm. HRMS (ESI): m/z
calcd for C25H44N4O4: 465.3435 [M + H]+; found: 465.3428
[M + H]+.
Synlett 2005, No. 16, 2445–2448 © Thieme Stuttgart · New York