Asymmetric cyanohydrin synthesis catalyzed by Mn(salen) complex/triphenylphosphine oxide

Article abstract of DOI:10.1081/SCC-200050390

Various aldehydes undergo enantioselective silylcyanation with (CH ₃)₃SiCN trimethylsilylcyanation (TMSCN) employing chiral Mn(salen) and achiral POPh₃ as the catalysts. This is the double activation where Mn(salen) plays

Full text of DOI:10.1081/SCC-200050390

w
Synthetic Communications , 35: 751–759, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200050390
Asymmetric Cyanohydrin Synthesis
Catalyzed by Mn(salen) Complex/
Triphenylphosphine Oxide
Sung Soo Kim and Sang Hyuck Lee
Department of Chemistry, Inha University, Incheon, South Korea
Abstract: Various aldehydes undergo enantioselective silylcyanation with
CH ) SiCN trimethylsilylcyanation (TMSCN) employing chiral Mn(salen) and
3 3
(
achiral POPh
the role of Lewis acid and POPh
3
as the catalysts. This is the double activation where Mn(salen) plays
Lewis base. Numerous aldehydes are subject to
3
the enantioselective addition of TMSCN at 08C. Hydrolysis of the adduct gave
cyanohydrin with up to 96% yield and 62% ee.
3 3 3
Keywords: Aldehydes, (CH ) SiCN, Mn(salen), POPh
INTRODUCTION
Chiral cyanohydrins are useful intermediates because the two functional
groups could be easily transformed into various homochiral ones. These
[
1,2]
[3]
a-hydroxy aldehydes, a-hydroxy ketones,
[3]
include a-hydroxy acids,
[
2,3]
[4]
b-hydroxy amines,
and a-amino acid derivatives.
A number of
[5]
catalysts for the asymmetric addition of cyanide to aldehydes are known
to include synthetic peptides and chiral transition metal complexes.
[
Belokon, Shibasaki, Deng, Hoveyda and Snapper, and Bu
6]
[7]
[8]
[9]
[10]
have
made considerable contributions to development of the catalyst for the
chiral silylcyanation. Achiral silylcyanation of aldehydes and ketones
catalyzed by N-morpholine N-oxide and various alkali fluorides was
Received in Japan 15 October 2004
Address correspondence to Sung Soo Kim, Department of Chemistry, Inha Univer-
sity, Incheon 402-751, South Korea. E-mail: sungsoo@inha.ac.kr

7
52
S. S. Kim and S. H. Lee
[
11]
investigated by us.
numerous metal ions are combined to make effective catalysts. Belokon and
Salen structure was employed as a base into which
[
6]
North et al. reported various Ti(IV) combined salen complexes for
silylcyanation. [Ti(salen)(m-O)]2 proved to be the best catalyst yielding
[6b]
[
6e]
5
2ꢀ92% enantiomeric excess (ee). The same authors
used VO(salen) as
modified the substituents of
[10]
the catalyst to give 68ꢀ95% ee. Bu et al.
the benzene ring of the salen legand (tert-pentyl group) that is combined
with Ti(OPr-i) . The result indicated 84ꢀ94% yield and 92ꢀ97% ee.
4
RESULTS AND DISCUSSION
In this paper we would like to report the chiral silylcyanation of aldehydes
utilizing Mn(salen)/POPh as the catalyst. We have synthesized Mn(salen)
3
[12]
1 according to the known procedure.
with 1 as catalyst under various conditions as shown in Table 1. CH Cl
The silylcyanation was then tried
2
2
proved to be the best solvent for the reaction (entry 1ꢀ3). Addition of
additive POPh can further raise the % ee and shorten the reaction period.
3
The yield and ee are not improved by decrease in amount of catalyst with
longer reaction time (entries 4 and 5). Temperature decrease from rt to 08C
apparently increases the yield (entry 6). However, further temperature
decreases could not obtain the favorable results (entries 7 and 8). Accordingly
the condition of entry 6 is chosen as the optimal condition for the silylcyana-
tion of various aldehydes.
Benzaldehydes with numerous substituents (entries 1ꢀ6) undergo smooth
enantioselective reactions with comparable outcome in terms of % yield and
%
ee. p-Chlorobenzaldehyde shows the best yield (96%) and ee (62%). It
appears that electronic substituents effect may exert only a minor role in the
reactions. trans-Cinnamaldehyde (entry 7) is easily converted into corre-
sponding cyanohydrin for a relatively short reaction time. 2-Furaldehyde
Table 1. Silylcyanation of benzaldehyde under various conditions
Additive
(10 mol%)
Yield
(%)
ee
(%)
Entry
Mn(salen)
Solvent
Temp.
Time
1
2
3
4
5
6
7
8
1, 5 mol%
1, 5 mol%
1, 5 mol%
1, 5 mol%
1, 1 mol%
1, 5 mol%
1, 1 mol%
1, 1 mol%
—
—
—
C
6
H
5
CH
3
r.t
r.t
24 h
24 h
10 h
2 h
60
50
97
95
92
91
90
88
45
50
48
52
53
58
58
59
CH
CH Cl
3
CN
r.t
2
2
2
2
2
2
2
POPh
POPh
3
3
CH
CH
2
Cl
Cl
r.t
2
r.t
15 h
24 h
30 h
5 days
POPh3
CH Cl
2
08C
08C
2108C
POPh
POPh
3
3
CH
CH
2
Cl
Cl
2

Asymmetric Cyanohydrin Synthesis
753
(entry 8) requires the shortest time for the reaction. 3-Phenylpropanal (entry 9)
reacts smoothly to give the cyanohydrin. Trimethylsilyl cyanide is readily
added to citral for the silylcyanation in order to produce the cyanohydrin
(Table 2).
In the absence of POPh , reaction time is much longer and % ee is lower
3
(compare entries 3 and 4 of Table 1). This may indicate the double activation
process occurring through the catalysis of chiral Lewis acid and achiral Lewis
base. Mn(salen) complex functions as a Lewis acid to activate the oxygen
atom of aldehyde while POPh works as a base for activation of TMSCN.
3
The attack of N;C would prefer si face of the aldehyde carbonyl to afford
an R-cyanohydrin because re face is blocked by the bonding between
carbonyl oxygen and the Mn atom of chiral Mn(salen) (Fig. 1).
CONCULSION
A double activation catalysis was developed for the enantioselective silylcya-
nation of various aldehydes. The Mn atom of chiral Mn(salen) is used to
activate carbonyl oxygen for formation of the Si–O bond. POPh functions
3
for N;C group to be transferred to the carbon atom of the carbonyl. The
chirality of Mn(salen) controls the direction of approach of both groups to
give the more R form of cyanohydrin.
EXPERIMENTAL
0
Synthesis of (S,S)-N,N -Bis(3,5-di-tert-butylsalicylidene)-1,
2
-diphenyl-ethylenediamine
(
S,S)-1,2-Diphenylethylenediamine (0.25 g, 1.18 mmol) and 3,5-di-tert-butyl-
-hydroxybenzaldehyde (0.55 g, 2.35 mmol) were refluxed in absolute ethanol
10 mL) for 3 h. A small amount of water was added to the reaction mixture,
2
(
then it was allowed cool to 28C and kept at that temperature for 2 h. The
product was collected by suction filtration to afford a yellow powder, yield
0
.53 g (70%) mp 197–1988C.
IR (KBr): 3087, 3062, 3030, 2958, 2909, 2869, 1626, 1598, 1469, 1454,
21
1
442, 1362, 1250, 1174, 876, 776, 700 cm
.

7
54
S. S. Kim and S. H. Lee
a
Table 2. Silylcyanation of aldehydes catalyzed by Mn(salen) and POPh3
c
% ee
(R or S)
b
Substrate
Temp.
Time
24 h
% Yield
91
1
2
08C
58 (R)
08C
08C
24 h
48 h
96
87
62 (R)
54 (R)
3
4
5
08C
08C
20 h
35 h
93
92
52 (R)
48 (R)
6
08C
20 h
82
54 (R)
7
8
08C
08C
20 h
18 h
93
91
55 (R)
47 (R)
9
0
08C
08C
20 h
24 h
90
86
52 (R)
44 (R)
1
a
b
c
5
mol% of Mn(salen) and 10 mol% of POPh
Isolated yield by weight.
ee determined by chiral HPLC column.
3
were used.
%

Asymmetric Cyanohydrin Synthesis
755
Figure 1. Transition state involved in the enantioselective cyanosilylation of
aldehydes by double-activation catalysis.
1
H NMR: d 1.22(18H, s, t-Bu), 1.42(18H, s, t-Bu), 4.72(2H, s, CH-N),
6
Ar-H), 8.40(2H, s, CH 55 N), 13.59(2H, s, OH).
.98(2H, d, J ¼ 2.4 Hz, Ar-H), 7.18(10H, s, Ph), 7.31(2H, d, J ¼ 2.4 Hz,
1
3
C NMR: d 29.4, 31.4, 34.0, 34.9, 80.0, 117.7, 126.2, 127.0, 127.3,
27.9, 128.1, 136.2, 139.7, 139.9, 157.8, 167.1.
1
High resolution mass spectrometry (HRMS) (EI) m/z: calcd. for
C H N O 644.4342, found 644.4329.
4
4 56 2 2
0
Synthesis of [(S,S)-N,N -Bis(3,5-di-tert-butylsalicylidene)-1,
-diphenyl-ethylenediamine] chloromanganese(III)
2
.
Solid Mn(OAc)2 4H O (0.40 g, 1.63 mmol) was added to a solution of (S,S)-
2
0
N,N -bis(3,5-di-tert-butyl-salicylidene)-1,2-diphenylethylenediamine (0.51 g,
0
.79 mmol) in absolute ethanol (10 mL), and the dark brown mixture was
refluxed for 2 h under air. Solid LiCl (0.11 g, 2.60 mmol) was then added
and the mixture was refluxed for an additional 2 h and then stirred at 708C
overnight. The reaction mixture was cooled, and then water was added
resulting in the precipitation of a brown powder that was collected by

7
56
S. S. Kim and S. H. Lee
suction filtration. The powder was redissolved in CH Cl and extracted with
2
2
water and brine. The organic phase was dried over anhydrous Na SO , and
2
4
the solvent was evaporated to afford a brown powder, yield 0.54 g (93%),
mp .3008C.
IR (KBr): 3063, 3027, 2956, 2904, 2867, 1610, 1534, 1455, 1429, 1317,
2
1
1
2
252, 1174, 857, 700, 579 cm
.
þ
.
2 2
MS(FAB) m/z 697.6 (M-Cl) . Anal. Calcd. for C H ClMnN O 1/
H2O: C, 71.19; H, 7.47; N, 3.77. Found: C, 71.36; H, 7.47; N, 3.66.
4
4
54
Silylcyanation of the Aldehydes Catalyzed by Mn(salen) and POPh3
Aldehyde (2 mmol), TMSCN (3 mmol), Mn(salen) (5 mol%), and POPh3
(
10 mol%) were mixed and reacted at 08C for 18ꢀ48 h. The solvent was
evaporated. 1N HCl (30 mL) and ethyl acetate (30 mL) were added to the
residue that underwent reaction for 4 h. The organic layer was extracted
with ethyl acetate (2 ꢀ 20 mL) that was washed with brine and dried on
anhydrous Na SO . The product was purified on Silica gel chromatography
2
4
with petroleum ether/ethyl acetate (5:1) eluent. The sample was identified
1
13
by H, C-NMR, HRMS; and ee % was determined by chiral high pressure
liquid chromatography (HPLC) column (DAICEL CHIRALCEL OD and
DAICEL CHIRALCEL AS).
2
-Hydroxy-2-phenylacetonitrile
1
H NMR (CDCl ) d 7.44 (m, 5H), 6.15 (s, 1H), 4.22 (m, 2H), 1.27
3
1
3
(t, J ¼ 7.0 Hz, 3H). C NMR (CDCl ) d 153.6, 131.3, 130.8, 129.4, 127.9,
3
þ
1
2
1
15.6, 66.3, 65.6, 14.3. HRMS(M ) cacld. for C H NO 205.0739 found
3
1
1
11
05.0753. R enantiomer in 58% ee. HPLC (DAICEL CHIRALCEL OD)
1.5 min and 14.0 min. (The enantiomeric excess was determined by HPLC
after conversion to ethylcarbonate.)
2-Hydroxy-2-(4-chlorophenyl)acetonitrile
1
H NMR (CDCl ) d 3.13 (s, 1H), 5.46 (s, 1H), 7.38 (d, 2H), 7.36 (d, 2H).
3
1
3
C NMR (CDCl ) d 63.35, 118.87, 128.46, 129.84, 134.08, 136.37.
3
þ
HRMS(M ) cacld. for C H ClNO 167.0138 found 167.0143. R enantiomer
8
6
in 62% ee. HPLC (DAICEL CHIRALCEL OD) 16.4 min and 19.9 min.
2-Hydroxy-2-(4-methoxyphenyl)acetonitrile
1
H NMR (CDCl ) d 2.8 (brs, 1H), 3.86 (s, 3H), 5.48 (s, 1H), 6.95
3
1
3
(d, J ¼ 8.5 Hz, 2H), 7.46 (d, J ¼ 8.5 Hz, 2H). C NMR (CDCl ) d 55.40,
3
6
3.27, 114.52, 118.93, 127.50, 128.29, 160.70. R enantiomer in 54% ee.

Asymmetric Cyanohydrin Synthesis
757
HPLC (DAICEL CHIRALCEL OD) 12.7 min and 14.8 min. (The enantio-
meric excess was determined by HPLC after conversion to acetyl ester.)
2
-Hydroxy-2-(4-methylphenyl)acetonitrile
1
H NMR (CDCl ) d 7.44 (d, J ¼ 8.25 Hz, 2H), 7.25 (d, J ¼ 8.25 Hz, 2H), 6.22
3
1
3
(s, 1H), 4.28 (m, 2H), 2.39 (s, 3H), 1.35 (t, J ¼ 7.3 Hz. 3H). C NMR (CDCl )
3
þ
d 153.5, 140.7, 129.9, 128.6, 127.9, 115.9, 66.2, 65.3, 21.4, 14.1. HRMS(M )
cacld. for C H NO 219.0895 found 219.0889. R entiomer in 52% ee. HPLC
1
2
13
3
(DAICEL CHIRALCEL OD) 17.4 min and 19.5 min. (The enantiomeric
excess was determined by HPLC after conversion to ethylcarbonate.)
2
-Hydroxy-2-(4-tert-butylphenyl)acetonitrile
1
13
H NMR (CDCl ) d 1.25 (s, 9H), 2.88 (s, 1H), 5.43 (s, 1H), 7.37 (m, 4H).
C
NMR (CDCl ) d 31.64, 35.18, 63.77, 119.46, 126.56, 126.94, 132.79, 153.56.
3
3
þ
HRMS(M ) cacld. for C H NO 189.1154 found 189.1143. R enantiomer in
1
2 15
4
8% ee. HPLC (DAICEL CHIRALCEL OD) 21.5 min and 24.0 min.
2
-Hydroxy-4-phenyl-3-butenenitrile
1
H NMR (CDCl ) d 7.43 (m, 5H), 6.98 (d, J ¼ 15.9 Hz, 1H), 6.19 (dd,
3
1
3
J ¼ 15.9, 6.7 Hz. 1H), 6.03 (dd, J ¼ 6.7, 0.9 Hz), 2.15 (s, 3H). C NMR
(CDCl ) d 168.9, 137.9, 134.6, 129.6, 128.9, 127.1, 118.4, 115.7, 61.5,
3
þ
2
0.5 HRMS(M ) cacld. for C H NO 201.0790 found 201.0782. R
2
1
11
2
entiomer in 55% ee. HPLC (DAICEL CHIRALCEL OD) 18.1 min and
2.3 min. (The enantiomeric excess was determined by HPLC after conver-
sion to acetylester.)
2
2
-Hydroxy-2-(3-phenoxyphenyl)acetonitrile
1
13
H NMR (CDCl ) d 3.5 (brs, 1H), 5.46 (s, 1H), 7.5 (m, 9H). C NMR (CDCl3)
3
d 63.17, 116.63, 118.59, 119.65, 120.94, 123.94, 129.93, 130.52, 137.05,
1
3
56.34, 158.12. R entiomer in 54% ee. HPLC (DAICEL CHIRALCEL OD)
6.1 min and 40.7 min. (The enantiomeric excess was determined by HPLC
after conversion to acetylester.)
2
-(2-Furyl)-2-hydroxyethanenitrile
1
H NMR (CDCl ) d 7.50 (dt, J ¼ 1.8 Hz, 1H), 6.65 (d, J ¼ 3.4 Hz, 1H), 6.44
3
(s, 1H), 6.47 (dd, J ¼ 3.4, 1.8 Hz, 1H), 2.15 (s, 3H). R entiomer in 47% ee.
HPLC (DAICEL CHIRALCEL AS) 8.7 min and 9.7 min. (The enantiomeric
excess was determined by HPLC after conversion to acetylester.)

7
58
S. S. Kim and S. H. Lee
2-Hydroxy-4-phenylbutanenitrile
1
H NMR (CDCl ) d 7.31 (m, 2H), 7.22 (m, 3H), 4.44 (t, J ¼ 6.4 Hz, 1H), 2.80
3
1
m, 2H), 2.15 (m, 2H), 0.92 (s, 9H), 0.18 (s, 3H), 0.12 (s, 3H). C NMR
3
(
(
CDCl ) d 140.0, 128.5, 128.4, 126.2, 119.9, 61.3, 37.9, 25.8, 18.1, 20.51,
3
25.3. R entiomer in 52% ee. HPLC (DAICEL CHIRALCEL OD) 8.7 min
and 10.9 min. (The enantiomeric excess was determined by HPLC after
conversion to TBDMSether.)
2-Hydroxy-4,8-dimethyl-nona-3,7-dienenitrile
1
H NMR (CDCl ) d 1.63 (s, 3H), 1.71 (s, 3H), 1.76 (s, 3H), 2.14 (m, 5H), 5.04
3
(
t, J ¼ 7 Hz, 1H), 5.13 (dd, J ¼ 7 Hz, 6.5Hz, 1H), 5.44 (dd, J ¼ 6.5 Hz, 7Hz,
1
H). C NMR (CDCl ) d 16.83, 17.63, 25.88, 26.25, 39.17, 57.88, 118.83,
3
1
1
3
19.16, 122.91, 132.45, 145.11. R enantiomer in 44% ee. HPLC (DAICEL
CHIRALCEL OD) 12.1 min and 14.0 min.
ACKNOWLEDGMENT
The authors warmly thank the Inha University for the financial support in
2005.
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759
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1