Dual Lewis acid-Lewis base activation in enantioselective cyanation of aldehydes using acetyl cyanide and cyanoformate as cyanide sources

Article abstract of DOI:10.1021/ja052804q

Dual activation by a chiral Lewis acid and an achiral or chiral Lewis base enabled cyanation of both aromatic and aliphatic aldehydes with acetyl cyanide and ethyl cyanoformate to provide direct access to O-acetylated and O-alkoxycarbonylated cyanohydrins

Full text of DOI:10.1021/ja052804q

Published on Web 07/28/2005
Dual Lewis Acid-Lewis Base Activation in Enantioselective Cyanation of
Aldehydes Using Acetyl Cyanide and Cyanoformate as Cyanide Sources
Stina Lundgren, Erica Wingstrand, Mae¨l Penhoat, and Christina Moberg*
Department of Chemistry, Organic Chemistry, Royal Institute of Technology, SE 100 44 Stockholm, Sweden
Received April 29, 2005; E-mail: kimo@kth.se
Table 1. Cyanation of Benzaldehyde with 3 Catalyzed by 7 in the
Presence of Lewis Bases
Enantiomerically pure cyanohydrins serve as highly versatile
synthetic building blocks.1 Much effort has, therefore, been devoted
to the development of catalytic systems for enantioselective
cyanation of aldehydes and prochiral ketones.2
entry % 7
Lewis base (%)
equiv of 3 T (°
C) time (h) % conva % ee (S)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
5
5
5
5
5
5
5
5
5
5
5
5
5
5
2
2
2
2
2
2
2
1
2
2
2
2
2
2
2
2
2
-40
25
-40
-40
-40
-10
25
-10
-40
-40
-40
-40
-40
-40
-40
-40
-40
24
24
6
6
6
6
4
6
9
8
8
8
9
9
8
9
9
0
30
57
67
76
78
97
63
67
96
97
93
78
80
96
75
73
n.d.
53
94
91
91
89
67
90
92
94
81
65
96
DMAP (10)
DMAP (15)
DMAP (20)
DMAP (10)
DMAP (10)
DMAP (10)
DABCO (10)
Et3N (10)
Trimethylsilyl cyanide (1) has most commonly been used as the
source of cyanide ions. Due to its toxicity and high price, access
to alternative cyanation reagents is desirable. Particularly useful
are reagents providing direct access to O-functionalized derivatives,
which themselves are important synthetic targets.1b Addition of
cyanoformic esters (2) to aldehydes, affording O-alkoxycarbonyl-
functionalized cyanohydrins, has been achieved together with binol-3
and salen-based4 catalysts, as well as in the presence of inorganic
bases5 and Lewis bases,6 although in the latter case, large amounts
of catalyst and prolonged reaction times are often required. Acetyl
cyanide (3), affording O-acetylated cyanohydrins, has so far not
been used for enantioselective cyanation of aldehydes, although
nonselective reactions in the presence of potassium carbonate5 and
using DABCO7 or tributyltin cyanide8 as catalyst9 have been
reported.
DIEA (10)
sparteine (10)
cinchonidine (10)
quinine (10)
92
15 5c sparteine (10)
16 5c cinchonidine (10)
17 5c quinine (10)
-67
-92
-95
a Determined by GC-MS. b Determined by chiral GC. c ent-7 was used.
The activation by different achiral and chiral Lewis bases was
then studied. Activation by DABCO, Et3N, diisopropylethylamine
(DIEA), and sparteine was effective, but the use of DIEA and
sparteine led to decreased selectivities (entries 9-12). Use of chiral
bases had little effect on the enantioselectivity (entries 13 and 14),
and consequently, replacement of 7 with ent-7 had no larger
influence on the reaction outcome (entries 15-17).
Scheme 1
Being interested in having access to enantioenriched O-acetylated
cyanohydrins, we decided to study the reaction of benzaldehyde
and 3 in the presence of 7, known to afford cyanation products of
high enantiomeric purity from both trimethylsilyl cyanide and
cyanoformic esters.10 No reaction occurred between 3 and benzal-
dehyde at -40 °C when 7 alone was used as catalyst, however,
and at room temperature, only a slow unselective reaction took place
(entries 1 and 2, Table 1).
Simultaneous Lewis acid activation of an electrophile and Lewis
base activation of a nucleophile have been achieved in cyanations
employing silyl cyanide and cyanoformic esters3,11 as well as in
other types of catalytic processes.12 We decided to explore whether
dual Lewis acid-Lewis base activation would improve the reactivity
of 3. Gratifyingly, we found that in the presence of DMAP, the
reaction proceeded smoothly to give the product with 94% ee after
6 h at -40 °C (entry 3). Increasing the amount of DMAP (entries
4 and 5) or the temperature (entries 6 and 7) resulted in increased
rates, but in the latter case in a decrease in enantioselectivity.
Lowering the amount of 3 resulted in a slower reaction (entry 8).
Reaction with only base as catalyst resulted in low conversion
and for the chiral bases low enantioselectivity, demonstrating that
dual activation is required for the reaction to proceed efficiently
(Table 2).
With these results in hand, we decided to study the effect of
Lewis bases in the reaction of ethyl cyanoformate with benzalde-
hyde catalyzed by 7, which is normally a quite sluggish reaction
requiring 18 h reaction time at -42 °C.4 In the presence of 10 mol
% of DMAP, the reaction of benzaldehyde with 2 equiv of 2
catalyzed by 5 mol % of dimer 7 occurred smoothly within 4 h at
-40 °C, with only a minor loss in selectivity (from 95 to 93% ee,
entries 1 and 3, Table 3). Increasing the amount of DMAP allowed
the reaction time to be further reduced, at the expense of a slight
loss in enantiomeric excess (entries 4 and 5). The presence of
9
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J. AM. CHEM. SOC. 2005, 127, 11592-11593
10.1021/ja052804q CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Cyanation of Benzaldehyde with 3 Catalyzed by Lewis
Table 4. Cyanation of Aldehydes with 2 and 3 Catalyzed by 7 in
the Presence of Et3N
Basesa
entry
Lewis base (%)
equiv of 3
time (h)
% convb
% ee (S)c
1
2
3
4
5
6
7
DMAP (10)
DABCO (10)
Et3N (10)
2
2
2
2
2
2
2
8
8
8
8
8
8
8
<1
<1
13
16
23
9
DIEA (10)
sparteine (10)
cinchonidine (10)
quinine (10)
0
40
15
entry
aldehyde (R)
2/3
product
time (h)
% yielda
% eeb
2
1
2
3
4
5
6
7
8
9
10
11
12
13
14
4a
4a
Ph
Ph
2
3
2
3
2
3
2
3
2
3
2
3
2
3
5a
6a
5b
6b
5c
6c
5d
6d
5e
6e
5f
4
10
6
10
6
12
4
8
7
12
5
6
5
95
89
88
90
79
72
90
89
97
64
81
84
83
89
92
94
94
96
94
94
93
95
93
93
73
76
89
90
a All reactions were run at -40 °C. b Determined by GC-MS. c Deter-
mined by chiral GC.
4b 4-CH3-C6H4
4b 4-CH3-C6H4
Table 3. Cyanation of Benzaldehyde with 2 Catalyzed by 7 in the
Presence of Lewis Bases at -40 °C
4c
4c
4-CH3O-C6H4
4-CH3O-C6H4
4d 4-Cl-C6H4
4d 4-Cl-C6H4
4e
4e
4f
4f
4g
4g
entry
% 7
Lewis base (%)
equiv of 2
time (h)
% convb
% ee (S)c
1a
2a
3
4
5
6
7
8
9
10
11
12
13
14
15
16
5
1
5
5
5
1
5
5
5
5
5
5
2
2
2
2
2
2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
18
19
4
3
2
8
8
7
3
3
3
4
4
3
7
7
100
100
99
96
93
78
95
90
97
96
98
98
93
98
93
97
95
83
93
91
86
95
94
90
92
89
78
94
93
-79
-94
-94
(E)-PhCHdCH
(E)-PhCHdCH
(CH3)3C
(CH3)3C
CH3(CH2)4
CH3(CH2)4
DMAP (10)
DMAP (15)
DMAP (20)
DMAP (2)
DMAP (10)
DABCO (10)
Et3N (10)
6f
5g
6g
6
a
Isolated yield. b Determined by chiral GC.
DIEA (10)
residing in different molecules, allows facile structural variations
and, thereby, tuning of the catalytic properties. The scope and
mechanism of this new dual Lewis acid-Lewis base activation are
under investigation.
sparteine (10)
cinchonidine (10)
quinine (10)
sparteine (10)
cinchonidine (10)
quinine (10)
5
5d
5d
5d
Acknowledgment. This work was financed by the Swedish
Foundation for Strategic Research.
a Reactions were run at -42 °C. b Determined by GC-MS. c Determined
by chiral GC. d ent-7 was used.
Supporting Information Available: Experimental procedures and
analytical data. This material is available free of charge via the Internet
at http://pubs.acs.org.
DMAP (2 mol %) in reactions using 1 mol % of 7 resulted in a
product with higher enantiomeric excess (entries 2 and 6). Use of
5 mol % of catalyst, 10 mol % of DMAP, and a smaller excess,
1.2 equiv, of cyanoformate afforded 95% conversion and 94% ee
within 7 h (entry 7).
Et3N and DIEA were found to give essentially quantitative
reactions within 3 h, with only minor decrease in selectivity (entries
9 and 10), whereas sparteine exhibited high reactivity but lower
enantioselectivity (entry 11). The use of other chiral bases did not
offer any major advantages (entries 12 and 13). Replacement of 7
by ent-7 had only a marginal effect on the selectivity but resulted
in slower reactions in the case of cinchonidine and quinine (entries
15 and 16).
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