Highly stereoselective hydrocyanation of optically pure α- sulfinylaldehydes

Article abstract of DOI:10.1016/S0957-4166(98)00026-3

Diastereoselective hydrocyanation of enantiomerically pure 2-p-tolyl- sulfinylacetaldehyde and 2-p-tolylsulfinylpropanal with Et₂AlCN catalyzed by ZnBr₂ is described. The sulfur configuration controls the stereochemical course of the reaction. Hydrolysis of the resulting cyanohydrins and further desulfurization yielded the corresponding α-hydroxyamides in high ees (90%).

Full text of DOI:10.1016/S0957-4166(98)00026-3

Pergamon
Tetrahedron: Asymmetry 9 (1998) 859–864
Highly stereoselective hydrocyanation of optically pure
α-sulfinylaldehydes
«
∗
Marta M. Cifuentes García, José Luis García Ruano , Ana M. Martín Castro,
«
†
Jesús H. Rodríguez Ramos and Inmaculada Fernández
Departamento de Química Orgánica, Universidad Autónoma de Madrid, 28049 Madrid, Spain
Received 14 January 1998; accepted 21 January 1998
Abstract
Diastereoselective hydrocyanation of enantiomerically pure 2-p-tolyl-sulfinylacetaldehyde and 2-p-
tolylsulfinylpropanal with Et2AlCN catalyzed by ZnBr2 is described. The sulfur configuration controls the
stereochemical course of the reaction. Hydrolysis of the resulting cyanohydrins and further desulfurization yielded
the corresponding α-hydroxyamides in high ees (90%). © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
Enantiomerically pure cyanohydrins derived from aldehydes are interesting building blocks in asym-
1
metric synthesis. Most of their preparation procedures reported in the literature make use of a homo-
2
chiral catalyst to induce the formation of just one enantiomer of the cyanohydrin. The behavior of
different catalysts has been investigated, including enzymes, polymeric reagents, organometallic species,
and peptides. Under these catalytic conditions, the most frequently used hydrocyanating reagents are
HCN, trimethylsilylcyanide or acetone cyanohydrin, and in many cases only one configuration of the
cyanohydrin is accessible due to the nature of the catalyst. In recent years we have developed a synthetic
method which produces enantiomerically and diastereomerically pure β-sulfinylcyanohydrins in high
3
yields by reaction of enantiomerically pure α-sulfinylketones with Et AlCN. The configuration of the
2
hydroxylic carbon is dependent on that of the sulfoxide. In order to expand the scope of this reaction we
have investigated the hydrocyanation reaction of sulfinyl aldehydes using enantiomerically pure 1 and 2
(
a+b mixture of epimers at C-α; Scheme 1). The obtained cyanohydrins 3 and 4 were hydrolyzed and
further desulfurized into their corresponding hydroxyamides 7 and 8.
∗
†
Corresponding author.
In part.
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00026-3

860
M. M. Cifuentes García et al. / Tetrahedron: Asymmetry 9 (1998) 859–864
Scheme 1.
2. Results and discussion
The synthesis of the starting materials (α-sulfinylacetaldehyde 1 and α-sulfinylpropanal 2) was
accomplished by reaction of (R)-(+)-alkyl (methyl or ethyl) p-tolyl sulfoxide with N-formylpiperidine
4
5
in the presence of LDA following the previously described procedure, slightly modified. Nevertheless,
6
we have not been able to isolate either 1 or 2 due to their instability. Starting from ethyl p-tolyl sulfoxide,
a 60:40 mixture of α-methyl derivatives 2a and 2b was obtained. The major epimer 2a shows a lower δ
value for methyl at the stereogenic carbon than that corresponding to the minor epimer 2b. Both epimers
could not be separated by chromatography. The spectroscopic data of the crude mixtures did not allow
us to assign the configuration of these epimers.
Reaction of 1 and 2 (as an epimeric mixture of 2a and 2b) with Et AlCN in toluene–THF (at 0°C for 1
2
and −20°C for 2) in the presence of ZnBr afforded cyanohydrins 3 and 4 (as a mixture of epimers 4a+4b;
2
Scheme 2). The reaction conditions were similar to those previously described for the hydrocyanation of
3
α-sulfinylketones, the order of the addition of the reagents being critical to obtain cyanohydrins in good
yields. Despite the higher reactivity of the aldehydic carbonyl group as compared with the ketonic one, all
the attempts to achieve hydrocyanation of sulfinylaldehydes in the absence of ZnBr were unsuccessful.
2
Scheme 2.
The stereochemical results of the reaction (only the R-configuration at the hydroxylic carbon was
obtained) could be explained by assuming an intermolecular transfer of the cyanide from the reagent
(
Et AlCN) on the most favored face (from steric and stereoelectronic points of view) of a chelated species
2
of both carbonylic and sulfinylic oxygens with the metal, such as had been previously proposed in the
3
case of α-sulfinylketones. The intermolecular attack of the cyanide will give rise to the corresponding
diastereomerically pure β-sulfinylcyanohydrin. As in the case of the reaction of α-sulfinylketones, the
configuration at C-α has no influence on the stereochemical course of the reaction, which is exclusively
controlled by the sulfur configuration.
β-Sulfinylcyanohydrins 3 and 4a+4b were treated under the previously described conditions3e,7 to
give β-sulfenylamides 5 and 6a+6b respectively in high yields (Scheme 3). The reaction consisted of
the treatment of sulfinyl cyanohydrins with HBF in CH Cl , followed by NaI. The reaction means the
4
2
2
transformation of the cyanide group into carboxamide with concomitant reduction of the sulfoxide into
sulfide, such has been proposed to explain the results of the hydrolysis of α-sulfinylcyanohydrins derived
from α-sulfinylketones under the same reaction conditions.

M. M. Cifuentes García et al. / Tetrahedron: Asymmetry 9 (1998) 859–864
861
Scheme 3.
3
Reductive cleavage of 5 and a 6a+6b mixture using Raney nickel in ethanol gave hydroxyamides 7
and 8, respectively (Scheme 3). The sign of the specific rotation of the obtained 7 is the same as that of the
(
R)-(+)-lactamide commercially available from Aldrich Chemical Co and their enantiomeric excess (90%
1
8
ee) was established by H-NMR from their corresponding Mosher (R)-MTPA and (S)-MTPA esters. As
the transfer of cyanide has given rise to only one diastereoisomeric cyanohydrin 3 or a mixture of epimers
at the C-α carbon (4a+4b), the observed slight loss of enantiomeric purity must have taken place either
during the hydrolysis stage of sulfinyl cyanohydrin into sulfenyl carboxamide (partial enolization of the
carbonyl group of the carboxamide moiety under the reaction conditions), or during the desulfinylation
9
stage (secondary alcohols have been reported to suffer epimerization with Raney nickel).
3. Experimental
3.1. General methods
All reactions were carried out in flame dried glassware under an argon atmosphere. Flash chromatog-
raphy was performed with silica gel 60 (230–400 mesh ASTM). Melting points were determined in a
Gallenkamp apparatus in open capillary tubes and are uncorrected. The optical rotations were measured
at room temperature (20–23°C) using a Perkin–Elmer 241 MC polarimeter (concentration in g/100 mL).
1
13
The H and C NMR spectra were recorded at 200 (or 300) and 50 (or 75) MHz respectively in a
1
Bruker AC-200 (or AC-300) spectrometer using CDCl solutions; δ chemical shifts refer to TMS ( H)
3
13
or deuterated chloroform ( C) signals. Elemental analyses were performed with a Perkin–Elmer 2400
CHN analyser.
3.2. Synthesis of α-sulfinylaldehydes
Compounds 1 and 2 were obtained from methyl or ethyl p-tolyl sulfoxide (1.0 eq), respectively,
4,5
HMDSL (1.1 eq) and N-formylpiperidine (0.5 eq) following the method described in the literature.
These compounds were used directly after workup without further purification.5,6
3.3. 2-(p-Tolylsulfinyl)propanal 2
Compound 2 was obtained as a 60:40 mixture of 2a+2b, epimers at C-2: δ (CDCl ) of a 2a+2b
H
3
0
0
mixture: 9.70 (d, 1H, J 2.1 Hz, CHO (2a)), 9.51 (d, 1H, J 2.2 Hz, CHO (2b)), 7.42 and 7.38 (AA BB
system, 8H, C H (2a) and C H (2b)), 3.65 (dq, 4H, J 7.0 and 9.0 Hz, CHSO (2a) and CHSO (2b)),
6
4
6
4
2
.38 (s, 6H, CH Ar (2a) and CH Ar (2b)), 1.35 (d, 3H, J 7.0 Hz, CH (2b)), 1.20 (d, 3H, J 7.0 Hz, CH
3 3 3 3
(2a)).

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M. M. Cifuentes García et al. / Tetrahedron: Asymmetry 9 (1998) 859–864
3.4. Hydrocyanation of α-sulfinylaldehydes
To a solution of 337 mg (1.5 mmol) of ZnBr in 12 mL of anhydrous THF, a solution of 1 mmol
2
of α-sulfinylaldehyde in 6 mL of anhydrous THF was added. The reaction mixture was stirred at room
temperature for 30 min and then added to a cold (0°C for 1 and −20°C for 2a+2b) 1 M solution of 4
mL (4 mmol) of Et AlCN in toluene, diluted in 12 mL of anhydrous THF. The mixture was stirred for 5
2
min at the corresponding temperature and then transferred by cannula under argon into a cold (−78°C)
solution of 5 mL of concentrated HCl in 5 mL of methanol. The mixture was stirred for 1 h, poured into
5
mL of concentrated HCl in 5 mL of ice water, and then extracted with CH Cl (3×6 mL). The extracts
2
2
were washed with water (2×4 mL) and the solvent was evaporated under reduced pressure.
3.5. (2R,(S)S)-2-Hydroxy-3-(p-tolylsulfinyl)propanenitrile 3
Compound 3 (de >96%) was obtained from 1 in 78% yield after chromatography (eluent ethyl
acetate:hexane=1:1) and further crystallization (ethyl acetate), mp 162–164°C (white solid); [α] +309.6
D
0
0
(
1
c 0.5, chloroform); δ (CDCl ) 7.54 and 7.39 (AA BB system, 4H, C H ), 5.60 (bs, 1H, OH), 5.03 (m,
H, CH), 3.32 (dd, 1H, J 9.6 and 13.3 Hz, CH ), 3.04 (dd, 1H, J 2.4 and 13.3 Hz, CH ), 2.45 (s, 3H,
CH ); δ (CDCl ) 142.9 (C-4 Tol), 138.5 (C-1 Tol), 130.5 (C-3 and C-3 Tol), 124.0 (C-2 and C-2 Tol),
18.3 (CN), 59.8 (CH), 56.4 (CH ), 21.5 (CH ); anal. calcd for C H NO S: C 57.30, H 5.30, N 6.69,
H
3
6
4
2
2
0
0
3
C
3
1
2 3 10 11 2
S 15.32. Found: C 57.30, H 5.41, N 6.30, S 15.15.
3.6. (2R,3R,(S)S) and (2R,3R,(S)S)-2-Hydroxy-3-(p-tolylsulfinyl)butanenitrile 4a+4b
A 2:1 mixture of 4a+4b was obtained from 2a+2b (88% yield after treatment identical to 3) as a white
0
0
solid. [α] +172.8 (c 0.5, chloroform); δ (CDCl ) (4a) 7.43 and 7.40 (AA BB system, 4H, C H ),
D
H
3
6
4
6
.78 (bs, 1H, OH), 4.75 (dd, 1H, J 5.0 and 9.1 Hz, CHCN), 3.10 (dc, 1H, J 7.1 and 9.1 Hz, CHSO), 2.44
0
0
(
s, CH Ar), 1.06 (d, 3H, J 7.1 Hz, CH ); δ (CHCl ) (4b) 7.59 and 7.47 (AA BB system, 4H, C H ),
3
3
H
3
6
4
5
3
(
.78 (bs, 1H, OH), 5.13 (m, 1H, CH), 2.99 (dc, 1H, J 7.1 and 9.1 Hz, CHCN), 2.44 (CH Ar), 1.32 (d,
3
0
H, J 7.0 Hz, CH ); δ (CDCl ) (4a) 142.3 (C-4 Tol), 134.7 (C-1 Tol), 130.4 (C-3 and C-3 Tol), 125.0
C-2 and C-2 Tol), 118.1 (CN), 62.2 (C-OH), 61.2 (CHSO), 21.4 (CH Ar), 6.5 (CH ); anal. calcd for
3
C
3
0
3
3
C H NO S: C 59.17, H 5.87, N 6.27, S 14.33. Found for a 4a+4b mixture: C 59.17, H 5.43, N 6.67, S
11
13
2
14.04.
3.7. Hydrolysis of sulfinylcyanohydrins into sulfenylhydroxyamides
To a cold (0°C) solution of 1 mmol of β-sulfinylcyanohydrin in 30 mL of anhydrous CH Cl , 1 mL
2
2
of freshly distilled HBF was added. The mixture was stirred at 0°C for 3 h, and then 1.6 g (11 mmol)
4
of NaI was added. The resulting mixture was vigorously stirred at room temperature for 15 h. Water (15
mL) was added and the aqueous layer was extracted with CH Cl (3×5 mL). The extracts were washed
2
2
with aqueous Na S O (2×5 mL) and concentrated under reduced pressure.
2
2
5
3.8. (R)-2-Hydroxy-3-(p-tolylsulfenyl)propanamide 5
Compound 5 was obtained from 3 in 81% yield, after chromatography (eluent acetone:hexane=1:2)
and crystallization (ethyl acetate), mp 115–116°C (white solid); [α] +45.5 (c 1.0, acetone); δ (CDCl )
D
H
3
0 0
.33 and 7.12 (AA BB system, 4H, C H ), 6.68 (bs, 1H, NH), 5.42 (bs, 1H, NH), 4.04 (dd, 1H, J 4.0
6 4
7

M. M. Cifuentes García et al. / Tetrahedron: Asymmetry 9 (1998) 859–864
863
and 8.9 Hz, CH), 3.48 (dd, 1H, J 4.0 and 14.4 Hz, CHS), 3.29 (bs, 1H, OH), 3.01 (dd, 1H, J 8.9 and
1
4.4 Hz, CHS), 2.33 (s, 3H, CH ); δ (methanol-d ) 178.4 (CONH ), 138.2 (C-4 Tol), 132.3 (C-1 Tol),
3
C
4
2
0
0
131.6 (C-3 and C-3 Tol), 130.7 (C-2 and C-2 Tol), 71.8 (COH), 40.7 (CH S), 21.1 (CH ); anal. calcd
2
3
for C H NO S: C 56.85, H 6.20, N 6.63, S 15.17. Found: C 57.08, H 5.74, N 5.83, S 14.54.
10
13
2
3.9. (2R,3R) and (2R,3S)-2-Hydroxy-3-(p-tolylsulfenyl)butanamide 6a+6b
A 2:1 mixture of 6a+6b was obtained from a 2:1 mixture of 4a+4b. After chromatography (eluent
acetone:hexane=1:2) of the crude reaction only the major diastereoisomer (6a) was isolated. It was
crystallized from ethyl acetate (yield 87%), mp 121–122°C (white solid); [α] −7.5 (c 0.3, acetone);
D
0
0
δ (methanol-d ) 7.35 and 7.10 (AA BB system, 4H, C H ), 4.16 (dd, 1H, J 3.0 Hz, CHOH), 3.60 (dc,
H, J 3.0 and 7.0 Hz, CHS), 3.01 (dd, 1H, J 8.9 and 14.4 Hz, CHS), 2.29 (s, 3H, CH Ar), 1.41 (d, 3H, J
.0 Hz, CH ); δ (methanol-d ) 178.0 (CONH ), 138.2 (C-4 Tol), 133.7 (C-3 and C-3 Tol), 132.7 (C-1
Tol), 130.6 (C-2 and C-2 Tol), 76.1 (CHOH), 49.6 (CHS), 21.1 (CH Ar), 19.8 (CH ); anal. calcd for
H
4
6
4
1
7
3
0
3
C
4
2
0
3
3
C H NO S: C 58.64, H 6.72, N 6.22, S 14.20. Found: C 58.15, H 6.39, N 6.02, S 14.11.
11
15
2
3.10. Desulfurization of sulfenylhydroxyamides
3
This was carried out with Raney nickel following the previously described procedure. (R)-(+)-
Lactamide 7 was prepared from 5 in 72% yield; [α] +10.7 (c 0.25, methanol:ethanol=1:1). Spectro-
D
scopic data were identical to those obtained from a sample from Aldrich: δ (methanol-d ) 4.10 (c, 1H, J
H
4
6
.2 Hz, CH), 1.37 (d, 3H, J 6.2 Hz, CH ); δ (methanol-d ) 181.1 (CONH ), 68.9 (CHOH), 18.4 (CH ).
3
C
4
2
3
3.11. (R)-(+)-2-Hydroxybutanamide 8
Compound 8 was prepared in 70% yield from the mixture of 6a+6b; [α] +5.14 (c 1.3, acetone); δ
D
H
(
methanol-d ) 4.00 (dd, 1H, J 4.0 and 7.1 Hz, CH), 1.95–1.55 (m, 2H, CH ), 1.00 (t, 3H, J 7.1 Hz, CH );
4
2
3
δ (methanol-d ) 180.1 (CONH ), 73.7 (CHOH), 28.6 (CH ), 9.6 (CH ).
C
4
2
2
3
Acknowledgements
We thank the Dirección General de Investigación Científica y Tecnica (DGICYT, Grant PB95-210)
and the Centro de Investigación Justesa Imagen S.A. for financial support.
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M. M. Cifuentes García et al. / Tetrahedron: Asymmetry 9 (1998) 859–864
5
. The previously described procedure (Ref. 4) for the synthesis of 1 uses a 1.0:1.1:1.1 sulfoxide:base:N-formylpiperidine
ratio. We have used a 1.0:1.1:0.5 ratio in order to avoid the presence of N-formylpiperidine which contaminates the reaction
product, since it was not possible to eliminate it either in this step or in a further one. Under these conditions a mixture of
the corresponding aldehyde 1 or 2 and the unchanged alkyl (methyl or ethyl) p-tolyl sulfoxide was obtained. All attempts
to isolate pure aldehyde by chromatography (either with silica gel or alumina) were unsuccessful. Hence, these mixtures
were used as the starting material in further reactions. The resulting excess of unchanged sulfoxide can be easily removed
in the following step. Difficulties in the purification of α-sulfinylaldehydes may be responsible for the fact that despite the
synthesis of compound 1 described in 1988 (Ref. 4), to our knowledge this work is the first application of this compound in
asymmetric synthesis so far reported in the literature.
6
. Previously it had been reported that α-sulfinylacetaldehyde 1 could not be prepared due to its instability (Banfi, L.;
Colombo, L.; Gennari, C. Synthesis 1982, 829).
7
8
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9