Remote stereocontrol by sulfinyl groups: Hydrocyanation of δ-ketosulfoxides

Article abstract of DOI:10.1016/j.tet.2005.10.067

Reactions of (2-p-tolylsulfinyl)benzyl alkyl (and aryl) ketones (δ-ketosulfoxides) with Et₂AlCN in the presence of Yb(OTf) ₃ take place in a completely stereoselective manner, demonstrating the efficiency of the sulfinyl group in the

Full text of DOI:10.1016/j.tet.2005.10.067

Tetrahedron 62 (2006) 1245–1252
Remote stereocontrol by sulfinyl groups:
hydrocyanation of d-ketosulfoxides
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Jose L. Garcıa Ruano, M. Angeles Fernandez-Ibanez, M. Carmen Maestro
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and M. Mercedes Rodrıguez-Fernandez
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Departamento de Quımica Organica, Universidad Autonoma de Madrid, Cantoblanco, 28049 Madrid, Spain
Received 29 June 2005; revised 14 October 2005; accepted 24 October 2005
Available online 17 November 2005
Abstract—Reactions of (2-p-tolylsulfinyl)benzyl alkyl (and aryl) ketones (d-ketosulfoxides) with Et2AlCN in the presence of Yb(OTf)3 take
place in a completely stereoselective manner, demonstrating the efficiency of the sulfinyl group in the control of the stereoselectivity of
1,5-asymmetric hydrocyanation processes as well as the ability of Yb(OTf)3 to form chelated species with ketosulfoxides. The behavior of
their methyl derivatives at the benzylic position is dependent on the configuration at the chiral carbon. The resulting sulfinyl cyanohydrins
were readily transformed into a-hydroxyamides by hydrolysis of the CN group and hydrogenolysis of the C–S bond.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
stability, and also due to a higher steric hindrance around
the carbonyl group precluding the cyanide addition.
Remote stereocontrol (1,n-asymmetric induction with nO3)
is one of the most intriguing challenges to be solved in
asymmetric synthesis.1 The functional groups used to
achieve it are usually able to form chelated species
involving the prochiral centers and appropriate Lewis
acids.2 The sulfinyl oxygen has shown its ability to control
1,4-asymmetric induction processes on both electrophilic3
and nucleophilic4 centers. However, to our knowledge, prior
to our recent paper5 dealing with the reduction of
d-ketosulfoxides 1 (1,5-asymmetric induction) with
DIBAL/Yb(OTf)3 and L-Selectride, no efficient stereo-
controlled reaction with the sulfinyl chiral inductor located
farther away from the reaction centers had been reported.
The sulfinyl group has proved to be a highly efficient
controlling element in the asymmetric hydrocyanation of
a-sulfinyl ketones, with yields and de’s higher than 98%.11
Starting from a-sulfinyl aldehydes, the obtained results were
less satisfactory presumably due to the instability of the
resulting cyanohydrins.12 In order to investigate whether
the ability of the sulfinyl group to efficiently control the
stereoselectivity of the reduction of d-ketosulfoxides5 can
be extended to processes involving C–C bond formation, we
have studied the hydrocyanation reactions of those same
d-ketosulfoxides. In this paper, we report the results
obtained in reactions of 2-(p-tolylsulfinyl)benzyl alkyl
(and aryl) ketones (1a–d), their methyl derivatives at the
benzylic position (6a and 6b), and the aldehyde 1e with
Et2AlCN (all of them 1,5-asymmetric induction processes),
under various conditions as well as the transformation of the
resulting cyanohydrins into hydroxyamides.
Asymmetric hydrocyanation of carbonyl compounds is a
very interesting transformation due to the high value of
the resulting cyanohydrins as synthetic intermediates.6
Consequently, many methods have been reported for their
preparation. Excellent results have been obtained starting
from aldehydes,7 but the applicability of those methods is
much more restricted in the case of ketones,8,9,10 probably
due to the higher tendency of the cyanohydrins to undergo
retrohydrocyanation, as a consequence of their lower
2. Results and discussion
The synthesis of compounds 1a–e was performed following
previously reported procedures.4g The reaction of the
d-ketosulfoxides 1a–c and 1e with Et2AlCN (2.5 equiv) in
THF for 2–3 h at K78 8C yielded mixtures of two
cyanohydrins 2 and 3, which could not be separated
by chromatography (Table 1). The reactivity of 1d was
lower,13 requiring 3 h at 0 8C to reach completion (entry 7).
Keywords: Stereoselective cyanohydrins synthesis; a-Hydroxyamides;
Remote stereocontrol; Sulfinyl group mediated carbonyl hydrocyanation.
*
Corresponding authors. Tel.: C34 914974701; fax: C34 914973966;
e-mail addresses: joseluis.garcia.ruano@uam.es;
carmen.maestro@uam.es
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.10.067

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1246
Table 1. Reaction of 1a–e under different hydrocyanation conditions
Entry
Substrate
Catalyst
2:3 Ratioa
Yield (%)
1
2
3
4
5
6
7
8
9
10
1a
1a
1b
1b
1c
1c
1d
1d
1e
1e
—
Yb(OTf)3
—
Yb(OTf)3
—
Yb(OTf)3
—
Yb(OTf)3
—
Yb(OTf)3
48:52
O98:!2
O98:!2
O98:!2
68:32
O98:!2
58:42b
85:15
98
98
91
98
98
98
97
98
95c
90c
63:37
O98:!2
a Determined by 1H NMR.
b 0 8C.
1
c Crude yield determined by H NMR.
The yields were excellent but the stereoselectivity was very
low except for 1b, which afforded exclusively diastereo-
isomer 2b (entry 3).
assuming that the stereochemical course of the hydro-
cyanation is similar for the whole series of ketosulfoxides.
It is noteworthy that the Yb(OTf)3-promoted hydrocyanation
and the DIBAL/Yb(OTf)3 reduction5 of 1a–d produce similar
stereochemical results, which suggests a similar mechanistic
pathway for both reactions. The approach of the reagent
(DIBAL or Et2AlCN) to the less hindered face of the chelated
species A, formed by association of the catalyst to the sulfinyl
and carbonyl oxygens, would account for the stereochemical
results (Fig. 1). The lower stereoselectivity observed in the
hydrocyanation of phenyl derivative 1d (which also happened
in the DIBAL reduction) can be explained as a consequence of
the lower basicity of its carbonyl oxygen, therefore yielding
less stable chelates. In the absence of Yb(OTf)3, the
stereochemicaloutcome of the reactionof1a–d with Et2AlCN
wasalsosimilartotheDIBALreaction, bothyieldingmixtures
of diastereoisomers, so that a common hypothesis can be
proposed for both reactions.5
Next, we studied the influence of Yb(OTf)3 on the reaction
course (Table 1). Compounds 1a–c and 1e reacted in a
completely stereoselective manner yielding exclusively
diastereoisomers 2a–c and 2e14 (entries 2, 4, 6, and 10). It is
remarkable that the same cyanohydrin 2b15 was also obtained
in the absence of catalyst. However, 1d (RZPh) did not react
with a complete stereoselectivity, and a 85:15 mixture of
2d:3d (70% de, entry 8) was obtained. Yields of 2a–c were
O95% after crystallization, but 2e could not be purified and
decomposed by chromatography. Some trials with TMSCN
gave worse results.
Spectroscopic differences between compounds 2 and 3
allowed their differentiation, though the magnitude of these
differences was not sufficient to assign their relative
configuration. However, their structure and configuration
were unequivocally established by X-ray diffraction studies
for compounds 2a and 2b.15 The configurational assignment
of 2c–e was deduced from their 1H NMR parameters and by
Next, we studied the hydrolysis of the cyanohydrins, which
are prone to dehydrocyanation processes, into the much
more stable carboxamide derivatives. The study of these
Figure 1. Stereochemical model accounting for the observed results.

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J. L. Garcıa Ruano et al. / Tetrahedron 62 (2006) 1245–1252
1247
transformations also aimed to examine whether the ability of
the sulfinyl group to act as an anchimeric assistant in the
hydrolysis of the CN group at b-sulfinyl nitriles12,16 as
conserved for d-sulfinyl nitriles such as 2a–d. The hydrolysis
of the sulfinyl cyanohydrins was performed under very mild
conditions (HBF4 followed by addition of NaI). The sulfinyl
carboxamides 4a–d were obtained as the major products, but
sulfinyl ketonesandsulfinyl cyanohydrinswere alsoformedas
byproducts in most of the cases. A detailed study of the
reaction allowed us to find the experimental conditions
affording compounds 4 in higher yields (Table 2). At
K78 8C, 4a was exclusively obtained from 2a in 95% yield.
Under similar conditions the 85:15 mixture of 2dC3d yielded
4d(70%ee) in71% isolatedyield.Compounds4band 4cwere
obtained in 73 and 50% yields, respectively, after refluxing 2b
and 2c, respectively, in CH2Cl2 with HBF4 and additionof NaI
at room temperature.
stereoselectivity. The synthesis of the above compounds, as
well as their configurational assignment had been pre-
viously reported.4g The best reaction conditions found for
the hydrocyanation of 1a–e (adding the sulfoxide to a THF
solution of Et2AlCN at K78 8C) were applied to 6a and 60a,
yielding the mixtures of cyanohydrins 7a–8a and 70a–80a,
respectively (Table 3).
After 2 h, the hydrocyanation of 6a (entry 1) produced a 1:1
mixture of 7a and 8a. At shorter reaction times, the
conversion was not complete and the stereoselectivity
remained very low. When the hydrocyanation was
performed under Yb(OTf)3 catalysis, it was completely
stereoselective, yielding only 7a in 90% yield (entry 2). The
transformation of 60a, epimer of 6a at C-a, produced a
different result. After 1 h, the reaction of 60a with Et2AlCN
gave a mixture of epimers, 80a being the major one (entry 3),
however, the stereoselectivity increased with the time
(entry 4) and became complete after 2 h, yielding only 80a
(deO98%) in 88% yield (entry 5). Under Yb(OTf)3
catalysis, 60a afforded a 70:30 mixture of 70a and 80a.
Table 2. Hydrolysis of d-sulfinyl nitriles
The configurational assignment of compounds 7a, 70a, 8a,
and 80a was based on the assumption that the configurations
at the sulfur atom and the benzylic carbon must be identical
to those of their respective precursors, which had been
previously assigned. Thus, it was only necessary to
determine the configuration at the hydroxylic carbon. The
absolute configuration of 80a was unequivocally established
as R by X-ray analysis.15 Additionally, the oxidation of
pure cyanohydrins 7a and 80a with MCPBA yielded two
enantiomeric sulfones 9 and ent-9, respectively (Scheme 2)
thus allowing us to assign the configuration of 7a as S at its
hydroxylic carbon. The absolute configuration of the other
two compounds, 70a and 8a, was assigned as indicated in
Table 2 based on the fact that they are epimers at the
hydroxylic carbon of compounds 80a and 7a, respectively.
Entry
Substrate
T (8C)
Product
Yield (%)
1
2
3
4
2a
2b
2c
2dC3d
K78
40
40
4a
4b
4c
95
73
50
K78
4d (70% ee) 71
These conditions are milder than those usually required for
obtaining amides from nitriles,8a,17 which suggests a remote
anchimeric assistance of the sulfinyl group in accordance
with a mechanism similar to that proposed for the hydrolysis
of b-sulfinyl nitriles12,16 (Fig. 2).
The stereochemical outcome of the hydrocyanation of 6a
and 60a under Yb(TfO)3 catalysis is identical to that
observed in the analogous reduction reactions.5 Hence,
only 6a reacted in a completely stereoselective manner.
Therefore, the herein described results can be explained by
using the same models and assuming that the chelated
species formed from 60a is disfavored due to steric
congestion (Fig. 3).19 The stereoselectivity observed for
60a in the absence of Yb(TfO)3 and its changes with the
reaction time must be a consequence of the equilibration
between the two possible cyanohydrins (70a and 80a) and the
higher stability of 80a.
Compounds 4a–d were transformed into amides 5a–d,
which exhibit interesting anticonvulsant properties,18 by
desulfinylation with Raney nickel in refluxing ethanol
(Scheme 1).
Scheme 1.
Finally, we studied the reactions of the a-methyl derivatives
6a and 60a with Et2AlCN. Our aim was to evaluate the
relative influence of both of the substrate’s stereogenic
centers the sulfur atom group and the a-carbon on the
Finally, the hydrolysis of the cyano groups at methylated
sulfinyl cyanohydrins 70a and 80a with HBF4/NaI has been
attempted in order to obtain the corresponding sulfinyl-
amides. However, all attempts were unsuccessful, which
Figure 2. Anchimeric assistance of the SO group in the hydrolysis of the CN into CONH2.

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J. L. Garcıa Ruano et al. / Tetrahedron 62 (2006) 1245–1252
1248
Table 3. Hydrocyanation of 6a and 60a
7:8 or (70:80)a
Entry
Substrate
Reaction time (h)
Isolated yield (%)
86
90
1
2
3
4
5
6
6a
2
2
1
1.5
2
50:50
O98:!2
(20:80)
(11:89)
(!2:O98)
(70:30)
6ab
60a
60a
60a
60ab
c
c
88
92
2
1
a Ratio determined by H NMR.
b In the presence of Yb(OTf)3 (1.1 equiv).
c Not determined.
3. Experimental
3.1. General methods
NMR spectra were obtained in CDCl3 solutions at 300 and
1
75 MHz for H and 13C NMR, respectively (J values are
given in hertz). Melting points were measured in open
capillary tubes and are uncorrected. De’s were evaluated
by integration of well-separated signals of the H NMR
1
spectra. All hydrocyanations were carried out under argon
atmosphere in anhydrous solvents. THF was distilled
from sodium–benzophenone under argon. Flash-column
chromatography was perfomed using silica gel (230–400
mesh).
Scheme 2.
indicates that anchimeric assistance in the hydrolysis is not
available for these substrates. Assuming that the reaction
proceeds as indicated in Figure 2, the failure could be a
consequence of the low stability of the seven membered ring
intermediates (like A in Fig. 1), due to the steric interactions
of the benzylic methyl group with the neighboring
quaternary carbon. In summary, we have described the
stereoselective hydrocyanation of the d-sulfinyl ketones
1a–d as well as that of the two epimers 6a and 60a and
the aldehyde 1e. The results indicate that the sulfinyl group
is an efficient controlling group for of the stereoselectivity
of these C–C bond forming processes, despite the remote
position occupied by the chiral inducer (1,5-asymmetric
induction).
3.2. General procedures for hydrocyanation
Method A. Et2AlCN. A solution of (0.36 mmol) of
ketosulfoxide 1 in 2.7 mL of THF was dropwise added
into a solution of diethyl aluminum cyanide (0.90 mmol) in
4.0 mL of THF at K78 8C (1e needs 0 8C to reach complete
conversion), and the mixture was stirred for 2 h (3 h in the
case of 1e). The reaction mixture was transferred via
cannula (by application of a positive argon pressure to the
reaction flask) into a solution of 1.5 mL of methanol and
1.5 mL of concentrated HCl at K78 8C. The resulting
mixture was vigorously stirred for 1 h at K78 8C, poured
into a solution of 1.2 mL of concentrated HCl and 1.2 mL of
ice-water, and extracted with CH2Cl2. The extracts were
Figure 3. Stereochemical model accounting for 6a and 60a behavior.

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J. L. Garcıa Ruano et al. / Tetrahedron 62 (2006) 1245–1252
1249
washed with water (1.5 mL), dried and the solvent was
evaporated.
A and crystallized from ethyl acetate–hexane. It could not
be isolated diastereomerically pure and was characterized
from a mixture of 2cC3c. White solid; 1H NMR:
(representative parameters) d 5.99 (s, OH), 3.34 and 2.79
(AB system, JZ14.1 Hz, 2H), 2.38 (s, 3H); 13C NMR:
(representative parameters) d 142.2, 141.3, 139.6, 135.7,
134.5, 128.9, 124.5, 120.9, 72.5, 41.02, 21.2, 17.4.
Method B. Et2AlCN/Yb(OTf)3. A solution of ketosulfoxide 1
(0.36 mmol) and Yb(OTf)3 (0.40 mmol) in 2.7 mL of THF
was stirred for 30 min at room temperature and then
dropwise added into a solution of of diethyl aluminum
cyanide (0.90 mmol) in 4.0 mL of THF at K78 8C (1e needs
0 8C to reach complete conversion), and the mixture was
stirred for 2 h (3 h in the case of 1e). The work-up was
effected as in method A.
3.2.6. [2R,(S)S]-and-(2S,(S)S)-2-Hydroxy-2-phenyl-3-
[2-(p-tolylsulfinyl)phenyl]propanenitrile (2dC3d). Com-
pound 2dC3d were obtained by method B and crystallized
from ethyl acetate–hexane. Their characterization was
accomplished as a 85:15 mixture of diastereoisomers 2dC
3d. Yield: 98% (diastereoisomeric mixture); white solid; IR
3.2.1. [2S,(S)S]-2-Hydroxy-2-methyl-3-[2-(p-tolylsulfinyl)-
phenyl]propanenitrile (2a). Compound 2a was obtained
by method B and crystallized from ethyl acetate–hexane.
Yield: 98%; white solid; mp: 130–132 8C; [a]2D0 K19.9 (c
0.6, CHCl3); IR (KBr): 3310, 3056, 1021 cmK1; 1H NMR: d
7.62–7.26 (m, 8H), 6.46 (s, OH), 3.68 and 2.84 (AB system,
JZ14.1 Hz, 2H), 2.39 (s, 3H), 1.56 (s, 3H); 13C NMR: d
143.2, 141.5, 139.0, 134.7, 134.3, 132.2, 130.1, 129.3,
128.1, 124.9, 122.8, 66.8, 41.8, 26.6, 21.3; MS (FAB) m/z
300 (MC1)C; HRMS (MC1)C: calcd for C17H18NO2S:
300.1058; found: 300.1044.
(KBr): 3184, 2890, 1082, 1009 cmK1 1H NMR: d
;
7.68–7.18 (m, 16H), 6.34 (s, OH), 6.32 (s, OH), 3.93 and
3.11 (AB system, JZ13.7 Hz, 2H, (2d)), 3.54 and 3.09 (AB
system, JZ14.5 Hz, 2H, (3d)), 2.39 (s, 3H, (2d)), 2.32 (s,
3H, (3d)); 13C NMR: d 142.8, 141.5, 141.3, 139.0, 138.9,
134.7, 133.5, 132.7, 131.7, 130.1, 130.0, 129.5, 129.2,
128.6, 128.2, 127.9, 125.6, 124.8, 124.6, 122.1, 120.5, 74.4,
72.3, 44.8, 44.5, 21.2; MS (FAB) m/z 362 (MC1)C; HRMS
(MC1)C: calcd for C22H20NO2S: 362.1215; found:
362.1224.
3.2.2.
[2R,(S)S]-2-Hydroxy-2-methyl-3-[2-(p-tolyl-
sulfinyl)phenyl]propanenitrile (3a). Compound 3a was
obtained by method A and crystallized from ethyl acetate–
hexane. It could not be isolated diastereomerically pure and
was characterized from a mixture of 2aC3a. White solid;
1H NMR: (representative parameters) d 6.14 (s, OH) 3.35
and 2.91 (AB system, JZ14.1 Hz, 2H), 2.38 (s, 3H), 1.70 (s,
3H); 13C NMR: (representative parameters) d 142.4, 141.3,
139.5, 135.5, 132.8, 129.6, 124.7, 121.5, 68.8, 42.4, 30.1.
3.2.7. [2S,(S)S]-2-Hydroxy-3-[2-(p-tolylsulfinyl)phenyl]-
propanenitrile (2e). Compound 2e was obtained by method
B and could not be purified. Crude yield: 90%; yellow oil;
[a]2D0 K52.7 (c 3.9, CHCl3); IR (CHCl3): 3251, 2870, 1719,
1
1010 cmK1; H NMR: d 7.67–7.64 (m, 1H), 7.43–7.13 (m,
7H), 4.38 (dd, JZ8.8, 5.4 Hz, 1H), 3.29 (dd, JZ13.5,
8.8 Hz, 1H), 2.99 (dd, JZ14.9, 6.1 Hz, 1H), 2.26 (s, 3H);
13C NMR: d 142.8, 141.5, 139.8, 134.8, 132.1, 130.0 (2C),
128.3, 127.5, 125.0, 119.7, 61.2, 36.8, 21.1; MS (FAB) m/z
286 (MC1)C; HRMS (MC1)C: calcd for C16H16NO2S:
286.0902; found 286.0892.
3.2.3.
[2R,(S)S]-2-Hydroxy-3-methyl-2-[2-(p-tolyl-
sulfinyl)benzyl]butanenitrile (2b). Compound 2b was
obtained by method B and crystallized from ethyl acetate–
hexane. Yield: 98%; white solid; mp: 130–131 8C; [a]D20
C32.2 (c 1.0, CHCl3); IR (KBr): 3279, 2973, 1010 cmK1
;
3.2.8. [2R,(S)S]-2-Hydroxy-3-[2-(p-tolylsulfinyl)phenyl]-
propanenitrile (3e). Compound 3e was obtained by method
A. It was characterized from a mixture 2eC3e because it
could not be isolated diastereomerically pure. Yellow oil;
1H NMR: (representative parameters) d 4.51 (t, JZ6.4 Hz,
1H), 3.22 (dd, JZ14.3, 6.2 Hz, 1H), 3.11 (dd, JZ14.5,
6.9 Hz, 1H); 13C NMR: (representative parameters) d 143.1,
141.8, 134.1, 119.5, 61.1, 30.1, 22.4.
1H NMR: d 7.53–7.24 (m, 8H), 6.14 (s, OH), 3.39 and 3.33
(AB system, JZ14.5 Hz, 2H), 2.39 (s, 3H). 2.01 (sp, JZ
6.4 Hz, 1H), 1.20 (d, JZ6.3 Hz, 3H), 1.16 (d, JZ6.3 Hz,
3H); 13C NMR: d 143.4, 142.0, 138.3, 135.2, 133.6, 131.9,
130.1, 128.3, 128.0, 125.7, 120.6, 75.6, 38.1, 36.0, 21.3,
17.8, 17.2; MS (FAB) m/z 328 (MC1)C; HRMS (MC1)C:
calcd for C19H22NO2S: 328.1371; found: 328.1356.
3.2.4. [2S,(S)S]-2-Hydroxy-2-[2-(p-tolylsulfinyl)benzyl]-
pentanenitrile (2c). Compound 2c was obtained by method
B and crystallized from ethyl acetate–hexane. Yield: 98%;
white solid; mp: 136–138 8C; [a]2D0 C12.9 (c 0.8, CHCl3);
3.2.9. [2S,3R,(S)S]-2-Hydroxy-2-methyl-3-[2-(p-tolyl-
sulfinyl)phenyl]butanenitrile (7a). Hydrocyanation of
ketosulfoxide 6a following method B afforded 7a as a
white solid. It was crystallized from ethyl acetate–hexane;
IR (KBr): 3421, 3251, 2959, 1010 cmK1 1H NMR: d
;
1
mp 174–176 8C; [a]D20 K38.3 (c 2.6, CHCl3); H NMR d
7.56–7.25 (m, 8H), 6.35 (s, OH), 3.56 and 3.04 (AB system,
JZ14.1 Hz, 2H), 2.39 (s, 3H). 1.76–1.66 (m, 4H), 0.98 (m,
3H); 13C NMR: d 143.3, 141.7, 138.8, 134.7, 134.3, 132.1,
130.1, 129.0, 128.1, 125.1, 121.9, 70.8, 41.4, 40.8, 21.3,
17.7, 13.8; MS (FAB) m/z 328 (MC1)C; HRMS (MC1)C:
calcd for C19H22NO2S: 328.1371; found: 328.1368. Anal.
Calcd for C19H21NO2S: C, 69.69; H, 6.46; N, 4.28; S, 9.79.
Found: C, 69.10; H, 6.46; N, 4.29; S, 9.71.
7.72–7.69 (m, 1H), 7.57–7.29 (m, 7H), 4.30 (m, OH, 1H),
3.67 (q, JZ6.7 Hz, 1H), 2.39 (s, 3H), 1.67 (s, 3H), 1.35 (d,
JZ6.7 Hz, 3H); 13C NMR d 143.8, 142.6, 139.3, 139.2,
131.7, 130.3, 128.6, 128.3, 126.3, 125.3, 120.9, 72.3, 43.4,
27.9, 21.5, 17.1; MS (FAB) m/z 314.1 [MC1]C, 287.1
(MCKCN); HRMS [MC1]C: calcd for C18H20NO2S:
314.1215; found: 314.1200.
Hydrocyanation of ketosulfoxide 6a following method A
afforded a 50:50 mixture of 7a and 8a. 1H NMR:
(representative parameters of 8a) d 4.70 (m, OH, 1H),
3.2.5. [2R,(S)S]-2-Hydroxy-2-[2-(p-tolylsulfinyl)benzyl]-
pentanenitrile (3c). Compound 3c was obtained by method

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1250
3.62 (q, JZ6.7 Hz, 1H), 1.42 (s, 3H), 1.35 (d, JZ6.7 Hz,
3H).
(s, 3H), 2.18 (sp, JZ6.8 Hz, 1H), 1.04 (d, JZ6.8 Hz, 3H),
0.95 (d, JZ6.8 Hz, 3H); 13C NMR: d 176.7, 137.8, 137.4,
134.8, 132.5, 132.0, 130.4, 130.2, 128.0, 127.7, 82.7, 39.3,
35.6, 21.0, 17.5, 15.8; MS (FAB) m/z 330 (MC1)C; HRMS
(MC1)C: calcd for C19H24NO2S: 330.1528; found:
330.1509.
3.2.10. [2S,3S,(S)S]-2-Hydroxy-2-methyl-3-[2-(p-tolyl-
sulfinyl)phenyl]butanenitrile (70a). Hydrocyanation of
compound 60a following method B afforded a mixture
70:30 of diastereoisomers 70a and 80a, as a white solid.
Compound 70a was crystallized from AcOEt–hexane and
characterized from a mixture 91:9 of diasteroisomers, mp
3.3.3. (2S)-2-Hydroxy-2-[2-(p-tolylthio)benzyl]pentan-
amide (4c). Reaction temperature: 40 8C. Yield: 50%;
yellow oil; [a]2D0 K46.4 (c 0.8, CHCl3); IR (film): 3396,
2873, 1564, 809 cmK1; 1H NMR: d 7.35–7.10 (m, 8H), 6.58
(s, NH), 5.39 (s, NH), 3.30 (s, OH), 3.28 (s, 2H), 2.33 (s, 3H),
2.01–1.91 (m, 1H), 1.74–1.25 (m, 3H), 0.92 (t, JZ7.2 Hz,
3H); 13C NMR: d 177.0, 137.2, 135.3, 132.5, 132.0, 130.6,
130.2, 129.9, 127.9, 127.8, 126.1, 80.1, 42.5, 41.9, 21.0, 16.7,
14.2; MS (FAB) m/z 252 (MCNa)C; HRMS (MCNa)C:
calcd for C19H23NO2NaS: 352.1347; found: 352.1341.
1
175–177 8C; [a]2D0 K15.5 (c 2.2, CHCl3); H NMR d 7.78
(dd, JZ7.6, 1.2 Hz, 1H), 7.58 (dd, JZ7.6, 1.2 Hz, 1H),
7.48–7.41 (m, 2H), 7.29–7.23 (m, 4H), 6.33 (br s, OH, 1H),
3.95 (q, JZ7.1 Hz, 1H), 2.37 (s, 3H), 1.38 (s, 3H), 1.02 (d,
JZ7.1 Hz, 3H). 13C NMR d 142.6, 141.0, 140.3, 140.1,
132.6, 131.1, 129.9, 127.8, 124.4, 122.9, 70.9, 41.1,
21.2, 20.9, 15.9; MS (FAB) m/z 314.1 [MC1]C, 287.1
(MCKCN); HRMS [MC1]C: calcd for C18H20NO2S:
314.1215; found: 314.1204.
3.3.4. 2-Hydroxy-2-phenyl 3-[2-(p-tolylthio)phenyl]-
propanamide (4d). Reaction temperature: K78 8C.
Compound 4d was characterized from an enantiomeric
85:15 mixture. Yield: 71%; white solid; [a]2D0 K4.3 (c 1.0,
CHCl3); IR (film): 3472, 2923, 1680, 1492 cmK1; 1H NMR:
d 7.72–7.69 (m, 2H), 7.39–7.10 (m, 11H), 6.70 (s, NH), 5.48
(s, NH), 3.98 (s, OH), 3.90 and 3.54 (AB system, JZ
14.1 Hz, 2H), 2.33 (s, 3H); 13C NMR: d 175.7, 142.4, 137.4,
136.8, 135.6, 132.3, 132.0, 130.8, 130.7, 130.2, 128.2,
128.0, 127.7, 125.3, 80.3, 42.3, 21.0; MS (FAB) m/z 319
(MKCONH2)C; HRMS MC: calcd for C22H21NO2S:
363.1293; found: 363.1279. Anal. Calcd for C22H21NO2S:
C, 72.70; H, 5.82; N, 3.85; S, 8.82. Found: C, 72.70; H, 5.81;
N, 3.98; S, 8.76.
3.2.11. [2R,3S,(S)S]-2-Hydroxy-2-methyl-3-[2-(p-tolyl-
sulfinyl)phenyl]butanenitrile (80a). Hydrocyanation of
ketosulfoxide 60a following method A afforded 80a as a
white solid. It was crystallized from ethyl acetate–hexane;
1
mp 157–159 8C; [a]D20 K66.7 (c 1.8, CHCl3); H NMR d
7.82–7.75 (m, 2H), 7.64 (t, JZ5.9 Hz, 1H), 7.46 (t, JZ
7.6 Hz, 1H), 7.29–7.24 (m, 4H), 5.39 (m, OH, 1H), 3.60 (q,
JZ7.3 Hz, 1H), 2.38 (s, 3H), 1.65 (s, 3H), 1.06 (dd, JZ
7.3 Hz, 1H). 13C NMR d 142.3, 141.7, 140.9, 140.6, 133.4,
130.1, 130.0, 129.9, 127.7, 124.4, 120.3, 72.9, 42.5, 28.8,
21.2, 16.4; MS (FAB) m/z 314.1 [MC1]C; HRMS [MC
1]C: calcd for C18H20NO2S: 314.1215, found: 314.1216.
3.3. Hydrolysis of cyanohydrins into sulfinyl hydroxy
amides. General procedure with HBF4
3.4. C–S bond cleavage. General procedure
To a solution of cyanohydrin (0.24 mmol) in 1.7 mL of
anhydrous CH2Cl2 were added 0.32 mL of fluoboric acid at
the indicated temperature. The mixture was stirred for 6 h
and then 96 mg (0.64 mmol) of NaI were added at room
temperature. It was stirred for 15 h and the resulting mixture
was treated with 1.6 mL of water and extracted with
CH2Cl2. The extracts were washed with aqueous NaHSO3,
dried (Na2SO4) and evaporated. The residue was purified by
flash chromatography (ethyl acetate–hexane 1:1).
An excess of activated Raney nickel was added onto a
solution of thioether 4 in a minimal amount of absolute
EtOH. The reaction was refluxed for 12 h, filtered through a
Celite pad and the solvent was evaporated.
3.4.1. (S)-2-Hydroxy-2-methyl-3-phenylpropanamide
(5a). The residue was purified by flash chromatography
(ethyl acetate–hexane 1:1). Yield: 80%; colorless oil; [a]D20
K51.2 (c 1.1, CHCl3); IR (film): 3347, 2924, 1667 cmK1
;
1H NMR: d 7.39–7.26 (m, 5H), 6.57 (s, NH), 5.56 (s, NH),
3.33 and 2.88 (AB system, JZ13.4 Hz, 2H), 2.39 (s, OH),
1.51 (s, 3H); 13C NMR: d 178.2, 135.6, 130.3, 128.6, 127.2,
75.9, 45.4, 26.3; MS (EI) m/z 179 MC; HRMS MC: calcd
for C10H13NO2: 179.0946; found: 179.0941.
3.3.1.
(2S)-2-Hydroxy-2-methyl-3-[2-(p-tolylthio)-
phenyl]propanamide (4a). Reaction temperature:
K78 8C. Yield: 95%; white solid; mp: 120–122 8C; [a]D20
K58.9 (c 0.4, CHCl3); IR (KBr): 3417, 2919, 1629,
1
803 cmK1; H NMR: d 7.35–7.10 (m, 8H), 6.64 (s, NH),
5.35 (s, NH), 3.38 (s, OH), 3.34 and 3.28 (AB system, JZ
14.1 Hz, 2H), 2.33 (s, 3H), 1.50 (s, 3H); 13C NMR: d 177.8,
137.4, 137.2, 135.4, 132.5, 132.0, 131.1, 130.7, 130.1,
127.9, 127.7, 77.4, 42.4, 27.1, 21.0; MS (FAB) m/z 302
(MC1)C; HRMS (MC1)C: calcd for C17H20NO2S:
302.1215; found: 302.1220.
3.4.2. (R)-2-Benzyl-2-hydroxy-3-methylbutanamide (5b).
The residue was purified by washing with hexane. Yield:
71%; white solid; mp: 116–118 8C; [a]2D0 K15.4 (c 0.9,
1
CHCl3); IR (film): 3493, 2965, 1679 cmK1; H NMR: d
7.33–7.22 (m, 5H), 6.31 (s, NH), 5.34 (s, NH), 3.32 and 2.82
(AB system, JZ13.2 Hz, 2H), 2.3 (sp, JZ6.6 Hz, 1H), 1.07
(d, JZ6.6 Hz, 3H), 1.01 (d, JZ6.6 Hz, 3H); 13C NMR: d
177.0, 135.7, 130.2, 128.6, 127.1, 81.0, 42.4, 35.5, 17.6,
16.3; MS (EI) m/z 207 MC; HRMS MC: calcd for
C12H17NO2: 207.1259; found: 207.1250.
3.3.2. (2R)-2-Hydroxy-3-methyl-2-[2-(p-tolylthio)-
benzyl]butanamide (4b). Reaction temperature: 40 8C.
Yield: 73%; white solid; mp: 125–127 8C; [a]2D0 K46.3 (c
1
0.3, CHCl3); IR (film): 3447, 2884, 1539, 773 cmK1; H
NMR: d 7.37–7.09 (m, 8H), 6.54 (s, NH), 5.26 (s, NH), 3.39
(s, OH), 3.37 and 3.13 (AB system, JZ14.1 Hz, 2H), 2.33
3.4.3. (S)-2-Benzyl-2-hydroxypentanamide (5c). The
residue was purified by washing with hexane. Yield: 93%;

´
J. L. Garcıa Ruano et al. / Tetrahedron 62 (2006) 1245–1252
1251
white solid; mp: 116–118 8C; [a]2D0 K15.8 (c 1.4, CHCl3);
IR (film): 3472, 3306, 2935, 1659 cmK1; 1H NMR: d 7.27–
7.15 (m, 5H), 6.40 (s, NH), 5.47 (s, NH), 3.21 and 2.75 (AB
system, JZ13.3 Hz, 2H), 2.16 (s, OH),1.87 (ddd, JZ13.7,
11.9, 4.4 Hz, 1H), 1.52–1.58 (m, 3H), 0.85 (t, JZ7.3 Hz,
3H); 13C NMR: d 177.0, 135.7, 130.2, 128.6, 127.1, 81.0,
42.4, 35.5, 17.6, 16.3; MS (EI) m/z 207 MC; HRMS MC:
calcd for C12H17NO2: 207.1259; found: 207.1251.
Nakamura, S.; Kuroyanagi, M.; Watanabe, Y.; Toru, T.
´
J. Chem Soc., Perkin Trans. 1 2000, 3143. (e) Solladie, G.;
Colobert, F.; Somny, F. Tetrahedron Lett. 1999, 40, 1227. (f)
Girodier, L. D.; Rouessac, F. P. Tetrahedron: Asymmetry 1994,
5, 1203. (g) Arai, Y.; Masuda, T.; Masaki, Y. Synlett 1997,
´
1459. (h) Almorın, A.; Carren˜o, M. C.; Somoza, A.; Urbano,
´
A. Tetrahedron Lett. 2003, 44, 5597. (i) Garcıa Ruano, J. L.;
´ ´
Cardenas, D.; Martın Castro, A. M.; Tato, F. Tetrahedron:
Asymmetry 2005, 16, 1963.
´
4. (a) Garcıa Ruano, J. L.; Carren˜o, M. C.; Toledo, M. A.;
Aguirre, J. M.; Aranda, M. T.; Fischer, J. Angew. Chem., Int.
3.4.4. 2-Hydroxy-2,3-diphenylpropanamide (5d). The
residue was purified by flash chromatography (ethyl
acetate/hexane 1:1) and washed with hexane to afford 5d,
that was characterized from an enantiomeric 85:15 mixture.
Yield: 92%; white solid; [a]2D0 C21.8 (c 0.5, CHCl3); IR
(film): 3497, 3381, 2923, 1668 cmK1; 1H NMR: d 7.71–7.68
(m, 2H), 7.41–7.19 (m, 8H), 6.54 (s, NH), 5.35 (s, NH), 3.85
and 3.15 (AB system, JZ13.5 Hz, 2H), 2.75 (s, OH); 13C
NMR: d 175.8, 141.8, 134.9, 130.5, 128.7, 128.3, 127.8,
127.5, 125.2, 78.9, 45.5; MS (EI) m/z 207 (MC1)C; HRMS
(MC1)C: calcd for C15H16NO2: 242.1181; found: 242.1178.
´
Ed. 2000, 39, 2736. (b) Garcıa Ruano, J. L.; Aleman, J.;
´
´
Soriano, J. F. Org. Lett. 2003, 5, 677. (c) Garcıa Ruano, J. L.;
´
´
Aleman, J. Org. Lett. 2003, 5, 4513. (d) Garcıa Ruano, J. L.;
´
´
Aleman, J.; Padwa, A. Org. Lett. 2004, 6, 1757. (e) Garcıa
´ ´
Ruano, J. L.; Aleman, J.; Aranda, M. T.; Arevalo, M. J.;
´
Padwa, A. Org. Lett. 2005, 7, 19. (f) Garcıa Ruano, J. L.;
Aranda, M. T.; Aguirre, J. M. Tetrahedron 2004, 60, 5383. (g)
´ ´ ´
Garcıa Ruano, J. L.; Aleman, J.; Aranda, M. T.; Fernandez-
´ ´
Iban˜ez, M. A.; Rodriguez-Fernandez, M. M.; Maestro, M. C.
Tetrahedron 2004, 60, 10067.
´
´
5. Garcıa Ruano, J. L.; Fernandez-Iban˜ez, M. A.; Maestro, M. C.;
3.5. Oxidation of the sulfinyl group. General procedure
´
´
Rodrıguez-Fernandez, M. M. J. Org. Chem. 2005, 70, 1796.
6. For reviews on the preparation and applications of cyano-
hydrins see: (a) Brunel, J.-M.; Holmes, I. P. Angew. Chem.,
Int. Ed. 2004, 43, 2752. (b) North, M. Tetrahedron: Asymmetry
2003, 14, 147. (c) Gregory, R. J. H. Chem. Rev. 1999, 99, 3649.
(d) Effenberger, F. Angew. Chem., Int. Ed. Engl. 1994, 33,
1555. (e) North, M. Synlett 1993, 807.
A solution of the corresponding hydroxysulfoxides 7a and
80a in CDCl3 was added to a NMR tube containing an excess
of previously dried (MgSO4) MCPBA solution in the same
solvent. The NMR signals were obtained from the crude
mixtures.
7. For recent asymmetric cyanation of aldehydes using chemical
catalysts see: (a) Yamagiwa, N.; Tian, J.; Matsunaga, S.;
Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 3413. (b) He, K.;
Zhou, Z.; Wang, L.; Li, K.; Zhao, G.; Zhou, Q.; Tang, C.
3.5.1. (2S,3R)-2-Hydroxy-2-methyl-3-[2-(p-tolyl-
sulfonyl)phenyl]butanenitrile (9) and (2R,3S)-2-hydroxy-
2-methyl-3-[2-(p-tolylsulfonyl)phenyl]butanenitrile
(ent-9). 1H NMR d 8.03–7.75 (m), 3.89 (q, JZ6.9 Hz, 1H),
2.37 (s, 3H), 1.56 (s, 3H), 1.16 (d, JZ6.9 Hz, 3H).
´
Tetrahedron 2004, 60, 10505. (c) Casas, J.; Najera, C.;
´
Sansano, J. M.; Saa, J. M. Tetrahedron 2004, 60, 10487. (d)
Belokon, Y. N.; Blacker, A. J.; Carta, P.; Clutterbuck, L. A.;
North, M. Tetrahedron 2004, 60, 10433. (e) Rowlands, G. J.
Synlett 2003, 236.
Acknowledgements
We thank the CICYT (Grant BQU2003-04012) for financial
´
support. M.A.F.-I. thanks the Comunidad Autonoma de
Madrid for a predoctoral fellowship.
8. For indirect methodologies using chiral auxiliaries see: (a)
Schrader, T.; Kirsten, C.; Herm, M. Phosphorus, Sulfur and
Silicon 1999, 161, 144–146. (b) Schrader, T. Angew. Chem.
Int., Ed. Engl. 1995, 34, 917. (c) Cativiela, C.; Diaz de
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Villegas, M. D.; Galvez, J. A. Tetrahedron 1996, 52, 687. (d)
´ ´
Pareja, C.; Martın-Zamora, E.; Fernandez, R.; Lassaletta, J. M.
References and notes
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14. Reactions of 1e with TMSCN in the presence of Yb(OTf)3
gave 80:20 mixtures of the two possible diastereoisomers.
15. Crystallographic data for structures of 2a, 2b and 80a have been
deposited with the Cambridge Crystallographic Data Center.
Deposition No CCDC 271118 (2a). Deposition No. 271119 (2b).
Deposition No. 271120 (80a). Copies of the data can be obtained
free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax C44 1223 336033; e-mail:
deposit@ccdc.cam.ac.uk].
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Pichel, J.; Vinuesa, S.; Garcıa-Lopez, M. T. J. Org. Chem.
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19. For a detailed discussion see Ref. 5.