Enantioselective cyanoformylation of aldehydes catalyzed by a chiral quaternary ammonium salt and triethylamine

Article abstract of DOI:10.1055/s-2007-986625

An efficient enantioselective cyanoformylation of aldehydes with ethyl cyanoformate, catalyzed by a chiral quaternary ammonium salt and triethylamine, has been developed. The reaction can be carried out in excellent yields (up to 97%) with moderate enanti

Full text of DOI:10.1055/s-2007-986625

2448
LETTER
Enantioselective Cyanoformylation of Aldehydes Catalyzed by a Chiral
Quaternary Ammonium Salt and Triethylamine
Enantioselective
C
a
yanoformy
n
lation of AldehydesPeng,a Hui Zhou,a Xiaohua Liu,a Liwei Wang,a Shikui Chen,a Xiaoming Feng*a,b
a
Key Laboratory of Green Chemistry & Technology (Sichuan University), Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, P. R. of China
b
State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, P. R. of China
Fax +86(28)85418249; E-mail: xmfeng@scu.edu.cn
Received 21 May 2007
entry 7). Therefore Et3N was selected as the Lewis base
for the reaction.
Abstract: An efficient enantioselective cyanoformylation of alde-
hydes with ethyl cyanoformate, catalyzed by a chiral quaternary
ammonium salt and triethylamine, has been developed. The reac-
tion can be carried out in excellent yields (up to 97%) with moderate
enantioselectivity (up to 72% ee).
Key words: cyanation, aldehyde, ethyl cyanoformate, quaternary
ammonium salt, organocatalysis
N+
R2O
X–
R3
R1
Asymmetric cyanation of aldehydes has become a power-
ful tool to synthesize various chiral compounds, which
serve as highly versatile building blocks in biologically
active products.1 During the last two decades, HCN,
K(Na)CN, and TMSCN have been widely used as the
cyanide source to realize this goal.2,3 For their stabiliza-
tion and less toxicity, cyanoformate esters (ROCOCN),
acetyl cyanide, and diethyl cyanophosphonate have been
investigated as the promising candidates in recent years.
Tremendous efforts have been devoted to this field, illus-
trated by Deng,4 Shibasaki,5 Sansano, Nájera and Saá,6
Belokon and North,7 Moberg,8 and our group.9 To date, to
our best knowledge, the majority of chiral catalysts used
in this reaction are chiral ligands in the presence of metal
ions.10 Herein, we wish to report the first organocatalytic
enantioselective cyanation of aldehydes with EtCO2CN
(ethyl cyanoformate).
N
2a: R1 = 4-O2N, R2 = allyl, R3 = H, X = Br
2b: R1 = 4-O2N, R2 = H, R3 = H, X = Br
2c: R1 = 2,3,4-trifluoro, R2 = H, R3 = MeO, X = Br
2d: R1 = 4-CF3, R2 = H, R3 = MeO, X = Br
2e: R1 = 4-O2N, R2 = H, R3 = MeO, X = Br
2f: R1 = 3,4,5-trifluoro, R2 = H, R3 = MeO, X = Br
2g: R1 = 3,5-bis(CF3), R2 = H, R3 = MeO, X = Br
2h: R1 = 3,5-bis(CF3), R2 = H, R3 = MeO, X = MeCOO
Figure 1 Quaternary ammonium salts evaluated for asymmetric
addition of ethyl cyanoformate to benzaldehyde
Table 1 Asymmetric Cyanation of Benzaldehyde Catalyzed by the
Combination of Quaternary Ammonium Salt (Figure 1) and Et3Na
10 mol%
quaternary ammonium salt
10 mol% Et3N
O
O
O
OEt
PhCHO
+
NC
OEt
CH2Cl2
Ph
CN
*
Recently we reported the cyanosilylation of ketones
catalyzed by quaternary ammonium salt combined with
N-oxide.11 Therefore, we speculated that the quaternary
ammonium salt together with a Lewis base may catalyze
the cyanation of aldehydes with NCCO2Et.
1a
3a
Entry
Catalyst
2a
Time (h)
ee (%)b
6
1
2
3
4
5
6
7
8
10
10
10
10
10
10
10
1
2b
13
In a preliminary study, we investigated the addition of
NCCO2Et to benzaldehyde in the presence of chiral
quaternary ammonium salt 2g (10 mol%) and N,N-di-
methylaniline N-oxide (10 mol%). To our delight, the
corresponding product was obtained in 63% yield with
40% ee after 48 hours at –15 °C. It was noted that 2g alone
could not promote this addition reaction. When Et3N was
used in place of N,N-dimethylaniline N-oxide, the reac-
tion was complete in ten hours with 43% ee (Table 1,
2c
13
2d
17
2e
19
2f
24
2g
43
2h
44
a All reactions were performed with benzaldehyde (0.1 mmol) and
NCCO2Et (0.15 mmol) in CH2Cl2 (1 mL) at –15 °C. All reactions gave
quantitative yield.
SYNLETT 2007, No. 15, pp 2448–2450
Advanced online publication: 23.08.2007
DOI: 10.1055/s-2007-986625; Art ID: W10007ST
© Georg Thieme Verlag Stuttgart · New York
1
7
.0
9
.2
0
0
7
b Determined by HPLC on a Chiralcel OD-H column. The absolute
configuration was R, determined by comparison with the sign of the
reported optical rotation value.5c

LETTER
Enantioselective Cyanoformylation of Aldehydes
2449
Subsequently, a series of chiral quaternary ammonium Table 3 Asymmetric Cyanoformylation of Aldehydes with Ethyl
Cyanoformate Catalyzed by Combination of 2h and Et3Na
salts derived from quinidine or cinchonine combined with
Et3N was examined. As shown in Table 1, it was note-
worthy that the skeleton of the quinidine has a perceptible
O
10 mol% 2h
20 mol% Et3N
O
O
*
OEt
CN
influence on the enantioselectivity, as compared to cin-
chonine (Table 1, entries 2 and 5). The hydroxyl group
from quinidine (Table 1, entries 1 and 2) and the electron-
withdrawing group on benzyl bromide (Table 1, entries
3–7) were crucial for the chiral induction. Quaternary
ammonium salt derived from quinidine and 3,5-bis(tri-
fluoromethyl)benzyl bromide afforded the best architec-
ture (Table 1, entries 7 vs. 3–6). When the anion Br– was
replaced by MeCOO–,12,13 the rate of the reaction was
enhanced further (Table 1, entries 7 vs. 8).
RCHO
+
NC
OEt
CH2Cl2, –78 °C
R
Entry Aldehyde
Time
(h)
Yield
(%)b
ee (%)c
(config.)d
1
2
3
4
5
6
7
8
9f
benzaldehyde
17
29
96
97
96
85
82
61
70
80
65
57
67 (R)
65
2-methylbenzaldehyde
3-methylbenzaldehyde
4-methylbenzaldehyde
4-fluorobenzaldehyde
4-chlorobenzaldehyde
2-naphthaldehyde
66
65 (R)
67 (R)
63 (R)
61 (R)
72 (95)e
61 (S)
70 (R)
61
93
In order to improve the enantioselectivity, we optimized
the reaction conditions by changing the solvent and reac-
tion temperature (Table 2). Et2O, THF and CH2Cl2
showed a similar level of enantioselectivity at –15 °C
(Table 2, entries 5–7). Relatively lower enantioselectivity
was obtained from toluene, MeCN, hexane (Table 2, en-
tries 2–4). Surprisingly, DMF gave a racemate mixture
(Table 2, entry 1). CH2Cl2 exhibited an excellent toler-
ance to the low temperature employed and the asymmetric
induction was increased as the temperature decreased
(Table 2, entries 7–9). Particularly in CH2Cl2 when the
temperature was decreased to –78 °C, the high reactivity
was maintained and a 67% ee was obtained (Table 2,
entry 10).
48
40
48
1-naphthaldehyde
48
4-methoxybenzaldehyde
heliotropin
160
70
10
a All reactions were performed with aldehyde (0.1 mmol) and
NCCO2Et (0.15 mmol) in CH2Cl2 (2 mL) at –78 °C, unless otherwise
indicated. For typical procedures, see ref. 14.
b Isolated yield.
c Determined by HPLC on a Chiralcel OD-H column.
d The absolute configurations were determined by comparison of
optical rotations with those reported in the literature.5c,7a,9a,
e Yield after a single recrystallization with EtOAc–PE (1:15).
f Et3N (30 mol%) was used.
Encouraged by the result obtained for benzaldehyde, we
investigated a series of aldehydes under the optimized
Table 2 Optimization of the Addition of Ethyl Cyanoformate to
Benzaldehyde in the Presence of 2h and Et3Na
conditions (Table 3). Almost all aromatic aldehydes
tested gave moderate to excellent yields (up to 97%) and
similar enantioselectivities (up to 72% ee) compared to
those obtained from benzaldehyde. The presence of
methyl group on the ortho, para, and meta positions of
benzaldehyde showed a slight influence on the enantio-
selectivity (Table 3, entries 2–4). Halogen-substituted
benzaldehyde, 1-naphthaldehyde and heliotropin gave
similar results (Table 3, entries 5, 6, 8 and 10). p-Meth-
oxybenzaldehyde gave the corresponding product with
increased enantioselectivity, but a loss in reactivity was
noted (Table 3, entry 9). 2-Naphthaldehyde gave the
highest enantioselectivity (72% ee) and the enantiomeric
excess could be increased to 95% after a single recrystal-
lization (Table 2, entry 7). Nevertheless, unsatisfactory
results were obtained for aliphatic aldehydes.15
Entry
Solvent
Temperature Yield
ee
(°C)
–15
–15
–15
–15
–15
–15
–15
–45
–78
–78
(%)b
40
89
97
95
95
96
99
99
96
96
(%)c
1
2
DMF
0
10
29
35
42
45
44
57
65
67
MeCN
hexane
toluene
THF
3
4
5
6
Et2O
7
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
8d
9
10e
At present the mechanistic detail of this conversion re-
mains unknown. We speculate that triethylamine might
function as a Lewis base that activates ethyl cyano-
formate,4,6,8,9b,c and the quaternary ammonium salt might
activate the carbonyl group with the positively charged
nitrogen atom and the free hydroxyl group.11,16
a All reactions were performed with benzaldehyde (0.1 mmol) and
NCCO2Et (0.15 mmol) in solvent (1 mL) with 2h (10 mol%) and Et3N
(10 mol%) for 18 h, unless otherwise indicated.
b Isolated yield.
c Determined by HPLC on a Chiralcel OD-H column. The absolute
configuration was R, determined by comparison with the sign of the
reported optical rotation value.5c,
In summary, we have demonstrated the first enantioselec-
tive catalytic cyanation of aldehydes with NCCO2Et
through a metal-free process. By using chiral quaternary
ammonium salt and triethylamine, the reactions pro-
d Reaction time: 2 h.
e Benzaldehyde (0.1 mmol) and NCCO2Et (0.15 mmol) in CH2Cl2
(2 mL) with Et3N (20 mol%) were employed for 18 h.
Synlett 2007, No. 15, 2448–2450 © Thieme Stuttgart · New York

2450
D. Peng et al.
LETTER
(8) Lundgren, S.; Wingstrand, E.; Penhoat, M.; Moberg, C.
ceeded smoothly with high yields and moderate enantio-
selectivities. Further effort should be devoted to the
optimization of the catalyst to enhance the enantioselec-
tivity.
J. Am. Chem. Soc. 2005, 127, 11592.
(9) (a) Chen, S. K.; Peng, D.; Zhou, H.; Wang, L. W.; Chen, F.
X.; Feng, X. M. Eur. J. Org. Chem. 2007, 639. (b) Gou, S.
H.; Wang, J.; Liu, X. H.; Wang, W. T.; Chen, F. X.; Feng, X.
M. Adv. Synth. Catal. 2007, 349, 343. (c) Gou, S. H.; Chen,
X. H.; Xiong, Y.; Feng, X. M. J. Org. Chem. 2006, 71,
5732. (d) Li, Q. H.; Chang, L.; Liu, X. H.; Feng, X. M.
Synlett 2006, 1675.
(10) For a chemoenzymatic one-pot reaction of ethyl cyano-
formate with benzaldehyde catalyzed by hydroxynitrile
lyase, see: Purkarthofer, T.; Skranc, W.; Weber, H.; Griengl,
H.; Wubbolts, M.; Scholz, G.; Pöchlauer, P. Tetrahedron
2004, 60, 735.
Acknowledgment
The authors thank the National Nature Science Foundation of China
(No. 20602025) for financial support. We also thank Sichuan Uni-
versity Analytical and Testing Center for NMR spectra analysis.
References and Notes
(11) Zhou, H.; Chen, F. X.; Qin, B.; Feng, X. M.; Zhang, G. L.
Synlett 2004, 1077.
(1) For reviews on the synthesis and applications of
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(b) Shibasaki, M.; Kanai, M.; Funabashi, K. Chem.
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A.; Inoue, S. Cyanation of Carbonyl and Amino Groups, In
Comprehensive Asymmetric Synthesis; Jacobsen, E. N.;
Pfaltz, A.; Yamamoto, H., Eds.; Springer-Verlag:
Heidelberg, 1999, 983–992. (g) Effenberger, F. Angew.
Chem., Int. Ed. Engl. 1994, 33, 1555.
(2) For recent reviews on cyanation reactions, see: (a) Chen, F.
X.; Feng, X. M. Curr. Org. Synth. 2006, 3, 77. (b) Thierry,
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Zhang, G. L. J. Org. Chem. 2004, 69, 7910. (h) Tian, S. K.;
Hong, R.; Deng, L. J. Am. Chem. Soc. 2003, 125, 9900.
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(b) Tian, S. K.; Deng, L. Tetrahedron 2006, 62, 11320.
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42, 3143.
(12) Procedure for Preparation of 2h: To a solution of 2g
(0.100 g, 0.158 mmol) in CH2Cl2 (10 mL) at r.t. was added
MeCOOAg (0.0277 g, 0.166 mmol, 1.05 equiv), and the
mixture was stirred in the dark at r.t. for one week. The
residue was centrifuged for half an hour. Then the precipitate
was filtered off and the filtrate was concentrated under
reduced pressure to afford a yellow solid; mp 142–143 °C;
[a]D25 121 (c = 0.108, CHCl3). IR (KBr): 3411, 2931, 2361,
1622, 1509, 1374, 1280, 1178, 1136, 905, 683 cm–1. 1H
NMR (300 MHz, CDCl3): d = 8.57 (d, J = 4.5 Hz, 1 H), 8.02
(s, 1 H), 7.66–7.81 (m, 4 H), 7.24–7.25 (m, 1 H), 6.94–6.98
(dd, J = 2.3, 9.2 Hz, 1 H), 6.49 (d, J = 12.5 Hz, 1 H), 6.37 (s,
1 H), 5.82–5.94 (sept, 1 H), 5.41 (d, J = 13.1 Hz, 1 H), 5.17–
5.25 (m, 1 H), 4.70 (t, J = 10.5 Hz, 1 H), 4.52 (t, J = 10.1 Hz,
1 H), 4.15 (t, J = 8.9 Hz, 1 H), 3.72 (s, 3 H), 3.05 (t, J = 11.3
Hz, 1 H), 2.51–2.61 (q, 1 H), 2.30–2.39 (q, 1 H), 2.14 (t, J =
12.1 Hz, 1 H), 2.03 (s, 3 H), 1.70–1.87 (m, 3 H), 0.70–0.76
(m, 1 H). 13C NMR (100 MHz, DMSO-d6): d = 175.1, 157.9,
147.9, 145.1, 144.2, 137.9, 135.1, 132.2, 131.9, 131.8,
131.4, 131.1, 130.8, 126.1, 125.0, 124.3, 122.3, 121.3,
121.0, 117.4, 102.9, 68.9, 64.2, 61.2, 56.1, 54.0, 37.6, 27.1,
24.9, 23.8, 21.2. HRMS (ESI): m/z [M+ – MeCOO] calcd for
C29H29F6N2O2: 551.2128; found: 551.2020.
(13) Ohshima, T.; Shibuguchi, T.; Fukuta, Y.; Shibasaki, M.
Tetrahedron 2004, 60, 7743.
(14) Typical Procedure: To a mixture of benzaldehyde (0.1
mmol), quaternary ammonium salt 2h (0.01 mmol, 10
mol%) and Et3N (0.01 mmol) in CH2Cl2 (2 mL) under a N2
atmosphere, was added ethyl cyanoformate (0.15 mmol, 1.5
equiv) at –78 °C. The reaction was monitored by TLC, and
after the reaction time indicated in Table 3, the residue was
directly purified by silica gel column chromatography (PE–
Et2O, 10:1) to afford the title compound as a colorless oil in
96% yield with 67% ee as determined by HPLC analysis
with a Chiralcel OD-H column [l = 254 nm, hexane–2-
propanol = 99:1, 1.0 mL/min, tR(major) = 9.2 min,
tR(minor) = 10.9 min]; [a]D25 = 6.49 (c = 0.154, CHCl3).
1H NMR (300 MHz, CDCl3): d = 7.53–7.56 (m, 2 H, ArH),
7.45–7.49 (m, 3 H, ArH), 6.27 (s, 1 H, OCHCN), 4.26–4.32
(m, 2 H, OCH2), 1.34 (t, J = 7.1 Hz, 3 H, OCH2CH3).
(15) Only 50% ee was obtained for the corresponding product of
cyclohexanal and isopropanal.
(16) (a) Perrard, T.; Plaquevent, J.; Desmurs, J.; Hébrault, D.
Org. Lett. 2000, 2, 2959. (b) Palomo, C.; Oiarbide, M.;
Laso, A.; López, R. J. Am. Chem. Soc. 2005, 127, 17622.
(c) Nerinckx, W.; Vandewalle, M. Tetrahedron: Asymmetry
1990, 1, 265. (d) Ooi, T.; Ohara, D.; Tamura, M.; Maruoka,
K. J. Am. Chem. Soc. 2004, 126, 6844. (e) Ooi, T.; Ohara,
D.; Fukumoto, K.; Maruoka, K. Org. Lett. 2005, 7, 3195.
(7) (a) Belokon, Y. N.; Blacker, A. J.; Carta, P.; Clutterbuck, L.
A.; North, M. Tetrahedron 2004, 60, 10433. (b) Belokon,
Y. N.; Blacker, A. J.; Clutterbuck, L. A.; North, M. Org.
Lett. 2003, 5, 4505.
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