Asymmetric synthesis of benzylic quaternary difunctionalized carbons mediated by a remote sulfinyl group

Article abstract of DOI:10.1021/jo2004204

Enantiomerically enriched α-aryl α-cyanoacetates and α-aryl α-acylacetonitriles bearing a benzylic quaternary stereocenter have been readily synthesized by stereoselective reaction of 2-alkyl-2-[2-(p-tolylsulfinyl)phenyl]acetonitriles with different acyla

Full text of DOI:10.1021/jo2004204

NOTE
pubs.acs.org/joc
Asymmetric Synthesis of Benzylic Quaternary Difunctionalized
Carbons Mediated by a Remote Sulfinyl Group
Josꢀe Luis García Ruano,* Esther Torrente, and Ana M. Martín-Castro*
Departamento de Química Orgꢀanica, Universidad Autꢀonoma de Madrid, Cantoblanco, 28049 Madrid, Spain
S Supporting Information
b
ABSTRACT: Enantiomerically enriched R-aryl R-cyanoace-
tates and R-aryl R-acylacetonitriles bearing a benzylic quatern-
ary stereocenter have been readily synthesized by stereo-
selective reaction of 2-alkyl-2-[2-(p-tolylsulfinyl)phenyl]acetonitriles
with different acylating and alkoxycarbonylating reagents under
basic conditions. The stereoselectivity of the reactions proved
closely dependent on the nature of the intermediate carbanionic
species, the evolution of which was effectively controlled by a
sulfinyl group as a remote chiral auxiliary.
Scheme 1. Reported Asymmetric Strategies for R-Aryl
onracemic R-aryl R-cyanoacetates and R-aryl R-acylaceto-
R-Cyanoacetates and R-Aryl R-Acylacetonitriles
N
nitriles have been profusely used as building blocks for the
stereoselective preparation of numerous natural products and
pharmaceuticals containing chiral benzylic all-carbon quaternary
centers, with the cyano group playing an important role in their
biological activities.1 Despite their potential synthetic interest,
the number of methodologies applied for synthesizing them is
rather limited. Over the last years two synthetic strategies have
been reported for the asymmetric synthesis of these structural
frameworks (Scheme 1) based either on the alkylation of R-aryl
R-cyanocarboxylates (route a) or on the carbonyl group incor-
poration on R,R-disubstituted acetonitriles (route b).
Scheme 2. Stereodivergent Quaternization of 2-Alkyl-2-p-
tolylsulfinylacetonitriles Dependent on the Basic Conditions
Route a summarizes most of the procedures used in the
preparation of R,R-disubstituted R-cyanoacetates, which are
based on the use of chiral auxiliaries or, more frequently, catalysts
as the source of chirality in allylation,2 alkylation,3 or conjugate
addition4 reactions of R-cyanocarboxylates. However, these
reactions, which proceed with enantioselectivities ranging from
moderate to good, have been scarcely used for preparing R,
R-disubstituted R-acylacetonitriles, the only reported examples
having been restricted to a number of structurally limited
R-substituted cyclic R-acylacetonitriles.3a
By contrast, the few reported examples involving the carbo-
nylation of R-arylacetonitriles (route b) are based on acylation
processes because the alkoxycarbonylation has proved to be
unsuccessful. In this sense, the nucleophile-catalyzed asymmetric
acylation of silyl ketene imines appears as one of the best
reported methods for preparing enantiomerically enriched R-
aryl R-acylacetonitriles containing all-carbon quaternary benzylic
stereocenters.5
NHMDS).6 Stereochemical results were rationalized by assum-
ing a different structure for the carbanion (planar or pyramidal)
depending on the reaction conditions (Scheme 2), which could
be supported by NMR experiments. Encouraged by these
excellent results as well as by the potential synthetic interest of
R-alkyl R-aryl acetonitriles bearing alkoxycarbonyl or acyl groups
at C-R, we decided to apply our above-mentioned methodology
to the stereoselective preparation of these enantiomerically
enriched building blocks. We report herein the results of the
reactions of the benzyl carbanions, derived from the monoalkylated
We have reported the highly stereoselective generation of
stereogenic quaternary benzylic carbons in their two possible
configurations, by reaction of benzyl carbanions derived from
R-alkyl 2-p-tolylsulfinylphenylacetonitriles with alkyl halides in
the presence of different bases (KHMDS/18-crown-6 ether or
Received: February 24, 2011
Published: March 17, 2011
r
2011 American Chemical Society
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|

The Journal of Organic Chemistry
NOTE
Table 1. Alkoxycarbonylation of 2-[2-(p-Tolylsulfinyl)phenyl]propanenitrile (1) under Different Conditions
entry
electrophile
base (additive)
product
A:B ratio
yield (%)
1
2
ClCO2Me
ClCO2Me
ClCO2Me
ClCO2Me
ClCO2Me
ClCO2Me
ClCO2Me
ClCO2Me
ClCO2i-Pr
ClCO2i-Pr
LHMDS, ꢀ98 °C
2
2
2
2
2
2
2
2
3
3
42:58
44:56
67:33
52:48
87:13
90:10
86:14
46:54
>98:<2
45:55
n.d.
64
LHMDS
3
NHMDS
73
4
KHMDS
62
5
KHMDS (18-crown-6-ether)a
KHMDS, ꢀ98 °C (18-crown-6 ether)a
KHMDS (18-crown-6 ether)b
LHMDSc
76
6
76
7
75
8
n.d.
77
9
KHMDS (18-crown-6 ether)a
10
LHMDS
n.d.
a 1.1 equiv. b 2.4 equiv. c Toluene was used as the solvent.
2-p-tolylsulfinylphenyl acetonitriles,6 with chloroformates (affording
cyanoacetates) and acyl halides (yielding acylacetonitriles), which
provide enantiomerically enriched all-carbon quaternary centers.
The initial experiments consisted of the study of the behavior
of 2-[2-(p-tolylsulfinyl)phenyl]propanenitrile (1), as a 50:50
mixture of 2R,(S)S and 2S,(S)S diastereoisomers, in their reac-
tions with alkyl chloroformates. The results obtained in the
presence of different bases under diverse experimental condi-
tions are collected in Table 1.7
reported for the alkylation processes.6 Finally, we investigated
the influence of the steric size of the reagent on the stereo-
selectivity under those two reaction conditions which had afforded
the largest predominance of 2A (entry 5) and 2B (entry 2),
respectively. To this end, isopropyl chloroformate was chosen as
the reagent. Under KHMDS/18-crown-6 ether, the steric influ-
ence was significant and the stereoselectivity was complete,
epimer 3A being the only obtained adduct (3B was not detected
in the reaction mixture, entry 9). By contrast, with LHMDS an
increase in the steric size had little or no influence and the 3B:3A
ratio was 45:55 (entry 10), similar to that of 2A:2B formed with
ClCO2Me under the same basic conditions (entry 2).
We next studied the acylation of the anion generated from 1, a
process which would provide an easy access to R-aryl R-
acylacetonitriles. All these reactions proceeded very rapidly
(10ꢀ15 min were required for completion). The obtained
results are collected in Table 2.7 As was the case of reactions
performed with methyl chloroformate, the highest proportion of
diastereoisomers A was obtained with KHMDS/18-crown-6
ether (conditions a), whereas LHMDS (conditions b) provided
the highest proportion of epimers B. Other conditions were
assayed, but no relevant results were obtained. Reactions with
acetyl chloride at ꢀ78 °C under conditions a afforded an easily
separable 84:16 mixture of diastereoisomers 4A and 4B (entry 1),
whereas an equimolecular mixture of the same compounds was
obtained with LHMDS (entry 6).
We first assayed the quaternization reaction with methyl
chloroformate by using LHMDS, NHMDS, or KHMDS as the
base, in THF at ꢀ78 °C (Table 1, entries 2ꢀ4). Easily separable
mixtures of the two possible diastereoisomers, [2R,(S)S]-2A and
[2S,(S)S]-2B, were obtained in all the cases, with dr values
ranging between 44:56 and 67:33, which evidence a low stereo-
selectivity control, slightly dependent on the metal and concen-
tration of the reagents. Much better results were achieved when
the reaction was conducted under KHMDS in the presence of
18-crown-6 ether (Table 1, entry 5), which provided a 87:13
mixture of 2A and 2B. No improvement in the stereochemical
results was detected on increasing the amount of additive in the
reaction media (entry 7). We next studied the influence of a
decrease in the temperature on those two conditions which had
given the most disparate results. It favored the formation of 2A in
reactions performed under KHMDS/18-crown-6 (2A:2B =
90:10 at ꢀ98 °C, entry 6), but had scarce influence in reactions
with LHMDS (2A:2B = 42:58 at ꢀ98 °C, entry 1). As the use of
toluene as solvent had been reported to improve the stereo-
selectivity in alkylation reactions of phenylacetonitriles with
NHMDS,6 we also explored the influence of this solvent in the
reactions of 1 with ClCO2Me (entry 8). The reactivity signifi-
cantly decreased (2 h were required for completion, as compared
with the 10 min needed in THF) but the stereoselectivity was
scarcely modified. Remarkably, the use of NHMDS did not invert
the sense of the stereoselectivity with respect to that observed
with KHMDS in the presence of 18-crown-6 ether, as had been
The use of bulkier acyl chlorides improved the stereoselectiv-
ity of reactions with KHMDS/18-crown-6, which became almost
complete with t-BuCOCl (5A:5B = 96:4, entry 3). Benzoyl
chloride afforded a 90:10 mixture of 6A:6B (entry 5), as was
expected from the relative size of the R group at electrophile
(Me < Ph < t-Bu). This dependence of dr on the steric size of the
reagent is also observed in reactions conducted under conditions
b (compare entries 6ꢀ8), but the stereoselectivity is not good in
any case. As expected, the stereoselectivity improved as the
temperature decreased (entries 2 and 5).
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The Journal of Organic Chemistry
NOTE
Table 2. Reactions of 2-[2-(p-Tolylsulfinyl)phenyl]propane-
nitrile (1) with Different Acylating Agents under Different
Conditions
Scheme 3. Proposed Planar sp2 Carbanions Accounting
for the Stereoselectivity of the Carbonylation under
KHMDS/18-Crown-6 Ether
entry
electrophile
conditionsa
product
A:B ratio
yield (%)
1
2
3
4
5
6
7
8
MeCOCl
MeCOCl
t-BuCOCl
PhCOCl
PhCOCl
MeCOCl
t-BuCOCl
PhCOCl
a
4
4
5
6
6
4
5
6
84:16
88:12
96:4
72
a (ꢀ98 °C)
a
80
70
a
90:10
93:7
84
a (ꢀ98 °C)
b
b
b
73
49:51
77:23
57:43
n.d.
55b
n.d.
Scheme 4. Proposed Carbanionic Intermediates Accounting
for the Stereoselectivity of the Carbonylation under NHMDS
a Conditions: (a) KHMDS/18-crown-6 ether; (b) LHMDS. b 70% of
conversion with 3 equiv of t-BuCOCl.
Finally, we investigated the dependence of the observed
stereoselectivity on the size of the R group present at the
substrate. In Table 3 are collected the results obtained by using
KHMDS/18-crown-6 ether or NHMDS (the observed effects
under other different conditions are similar but they have been
omitted for being scarcely relevant). The stereoselectivity in-
creased with the size of the R group, both in alkoxycarbonylation
and acylation reactions. Thus, the 87:13 ratio of 2A and 2B
obtained from 1 under KHMDS/18-crown-6 ether (R = Me,
entry 1) increased to 96:4 of 10A and 10B starting from 8 (R =
i-Bu, entry 3) and reached 97:3 of 11A and 11B starting from 9
(R = i-Pr, entry 5). Analogous results were obtained with
NHMDS, although the dr values were lower. A similar tendency
was observed in acylation reactions (entries 7ꢀ11). Isolated
yields of the resulting diastereoisomeric mixtures were good in all
cases, ranging between 70% and 78%, and the major isomers A
were readily purified by flash column chromatography.
The absolute configuration of diastereoisomer 4A, formed as
the major product of the reaction of 2-[2-(p-tolylsulfinyl)phenyl]-
propanenitrile (1) with KHMDS/18-crown-6 ether and acetyl
chloride, was unequivocally determined as 2R,(S)S by X-ray
diffraction studies.8 From this configurational assignment, and
from the assumption that all the herein reported acylation and
alkoxycarbonylation reactions follow the same stereochemical
pathway under the described conditions, the absolute configura-
tion 2R,(S)S has been assigned to all the R-cyanoacetates and
R-acetylacetonitriles obtained as the major products A. Conse-
quently, minor isomers B will be the corresponding epimers at
the benzylic carbon.
course for both processes. The naked carbanion formed with
KHMDS/18-crown-6 ether (Kþ should be sequestered by the
crown ether) will adopt the planar sp2 structures I (major) and I0
(minor) depicted in Scheme 3, with the potassium joined to the
sulfinyl oxygen or to the nitrogen, respectively. The approach of
the electrophile to the upper face of carbanion I, which would
afford diastreoisomers A, is clearly favored because its steric
interactions with the tolyl group are avoided. By contrast, the
evolution of I0 should be less stereoselective because the substit-
uents differentiating both faces of the anion are not too close to
the approaching way of the electrophile. Therefore, the stereo-
selectivity must derive from the shifting of the equilibrium
toward either carbanion. The I:I0 ratio, determined as 4:1 for
2A by NMR studies,6 suggests the formation of a ca. 9:1
diastereoisomeric mixture, which is in good agreement with the
experimental results (entries 1 and 4, Table 3). An increase in the
size of the R group would destabilize I0 increasing the proportion of I
and therefore that of the A diastereoisomers, as can be seen in
Table 3. An increase in the size of the reagent must produce a
decrease in its reactivity and, therefore, enhance the stereoselectivity,
which would explain the changes observed in Table 2.
The stereochemical results reported in this paper should be
explained taking into account the structure of the sulfinylated
benzylcarbanions acting as the nucleophiles, which had been
previously established by NMR studies.6 The results obtained
with KHMDS/18-crown-6 ether, herein described, are quite
similar to those previously reported for the alkylation reactions
of the same carbanions,6 which suggests a similar stereochemical
One of the main differences between the results described in
this paper (acylation) with respect to those reported in ref 6
(alkylation) is the behavior of the benzyl carbanions derived from
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NOTE
Table 3. Influence of the R Group on the Stereoselectivity of Acylation and Alkoxycarbonylation Reactions under Different Basic
Conditions
entry
R
Eþ
base (additive)
substrate
product
time (min)
A:B ratio
yield (%)
1
2
Me
ClCO2Me
ClCO2Me
ClCO2Me
ClCO2Me
ClCO2Me
ClCO2Me
ClCOMe
ClCOMe
ClCOMe
ClCOMe
ClCOMe
KHMDS (18-crown-6 ether)
NHMDS
1
1
7
7
8
8
1
7
7
8
8
2
5
5
87:13
67:33
96:4
76
73
72
69
77
73
72
78
64
70
65
Me
2
3
i-Bu
i-Bu
i-Pr
i-Pr
Me
KHMDS (18-crown-6 ether)
NHMDS
9
15
15
15
20
15
15
15
30
30
4
9
79:21
97:3
5
KHMDS (18-crown-6 ether)
NHMDS
10
10
4
6
80:20
84:16
90:10
78:22
90:10
74:26
7
KHMDS (18-crown-6 ether)
KHMDS (18-crown-6 ether)
NHMDS
8
i-Bu
i-Bu
i-Pr
i-Pr
11
11
12
12
9
10
11
KHMDS (18-crown-6 ether)
NHMDS
2 in the presence of NHMDS. Reactions with alkyl halides mainly
afforded B diastereoisomers6 (a stereodivergent behavior was
therefore detected as compared to that observed with KHMDS/
18-crown-6 ether), whereas chloroformates and acylchlorides
yielded the A isomers predominantly, but the stereoselectivity
was much lower than that observed with KHMDS/18-crown-6
ether (compare entries 2, 4, 6, 9, and 11 with entries 1, 3, 5, 7, 8
and 10, respectively, at Table 3). This can be explained by
assuming that the associated pyramidal sp3 carbanions II, formed
in the absence of a crown ether,6 only exhibit the lower face
accessible to the attack of the electrophile, thus yielding the B
isomers. However, in the presence of the acylating reagent,
anionic species II can easily evolve into the planar sp2 species
III by association of the metal with one of the lone electron pairs
at the carbonylic oxygen, displacing the benzylic carbon (this
does not happen with alkyl halides). The newly formed species
III will be preferently transformed into A isomers by intramo-
lecular acylation (Scheme 4). The evidence that acylation is
much faster when reactions are conducted with NHMDS than
with the system KHMDS/18-crown-6 ether could be a conse-
quence of the proposed intramolecular evolution with NHMDS.
This proposal, based on the intramolecular transfer of the
associated electrophile in the presence of NHMDS, was sup-
ported by the results obtained when an external sodium source
was added to the reaction.9
’ EXPERIMENTAL SECTION
General Procedures. NMR spectra were registered (300 and
75 MHz for 1H and 13C NMR, respectively) in CDCl3 solutions.
Melting points were measured in open capillary tubes. Mass
spectra (MS) were determined by EI, FAB, and ESI, as indicated
in each case. All reactions were carried out in anhydrous solvents
under argon atmosphere. Commercially available anhydrous
tetrahydrofuran (THF) and ethyl ether (Et2O) were dried over
4 Å molecular sieves. Flash column chromatography was per-
formed with use of silica gel (230ꢀ400 mesh).
General Procedure for the Synthesis of 2-Alkyl-2-[2-(p-
tolylsulfinyl)phenyl]acetonitriles (1, 8, and 9). To a solu-
tion of (S)-2-[2-(p-tolylsulfinyl)phenyl]acetonitrile (255.3 mg,
1 mmol) in anhydrous THF (10 mL) at rt under argon was added
LHMDS (1 M in THF) (1.2 mL, 1.2 mmol). The mixture was
stirred at rt for 10 min and then 1.4 mmol of the corresponding
electrophile was added dropwise. The reaction was monitored by
TLC. Upon transformation of the starting material, the reaction
was hydrolyzed with saturated aqueous NH4Cl (5 mL). The
mixture was extracted with Et2O (3 ꢁ 5 mL) and dried
(Na2SO4) and the solvent was evaporated. The diastereoiso-
meric mixture was purified by automated column chromatogra-
phy, using a 5:95 to 100:0 EtOAcꢀhexane gradient as the eluent.
[2S,(S)S]- and [2R,(S)S]-2-[2-(p-Tolylsulfinyl)phenyl]pro-
panenitrile (1): The diastereoisomeric mixture 1 was obtained
by using iodomethane as the electrophile. The reaction mixture
From the above results we can conclude that the experimental
conditions developed for the acylation and alkoxycarbonylation of
2-alkyl-2-[2-(p-tolylsulfinyl)phenyl]acetonitriles are a convenient
synthetic methodology for the stereoselective preparation of a wide
variety of differently substituted chiral R-alkyl R-aryl R-acylacetoni-
triles and R-cyanoacetates. As the sulfinyl group is acting as a remote
chiral auxiliary in these reactions, the suitable choice of the sulfur
configuration at the starting compound makes it possible to obtain
the desired configuration at the quaternary carbon.
1
was stirred at rt for 15 min. Yield 76%; colorless oil; H NMR
[diastereoisomeric mixture (50:50)] δ 7.93ꢀ7.83 (m, 2H),
7.62ꢀ7.49 (m, 6H), 7.46 and 7.29 (AA0BB0 system, 4H), 7.42
and 7.28 (AA0BB0 system, 4H), 4.55 (q, J = 7.1 Hz, 1H), 4.50 (q,
J = 7.1 Hz, 1H), 2.38 (s, 6H), 1.58 (d, J = 7.1 Hz, 3H), 1.37 (d, J =
7.1 Hz, 3H) ppm; 13C NMR [diastereoisomeric mixture
(50:50)] δ 142.1 (3C), 141.6, 140.9, 140.6, 136.6, 135.8,
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NOTE
132.4, 132.3, 130.4 (2C), 130.3 (2C), 129.5, 129.1 (2C), 128.2,
127.1, 126.4, 125.7 (2C), 125.3 (2C), 120.9, 120.7, 26.7, 26.3,
21.4 (2C), 21.3, 21.2 ppm; MS (EIþ) m/z 269 [M]þ (12), 225
(100), 211 (20); HRMS (EIþ) calcd for C16H15NOS [M]þ
269.0874, found 269.0871.
diastereoisomers) 76%. Diastereoisomer [2R,(S)S]-2A: color-
less oil; [R]20 ꢀ123.9 (c 1.9, CHCl3); IR (film) 2954, 2235,
D
1745, 1593, 1252, 1144 cmꢀ1; 1H NMR δ 7.67ꢀ7.62 (m, 2H),
7.57 and 7.27 (AA0BB0 system, 4H), 7.55ꢀ7.49 (m, 2H), 3.88 (s,
3H), 2.38 (s, 3H), 2.24 (s, 3H) ppm; 13C NMR δ 168.8, 145.5,
141.4, 140.2, 135.1, 132.4, 130.9, 129.8 (2C), 126.7, 125.5 (2C),
119.3, 54.6, 47.3, 25.4, 21.3 ppm; MS (ESIþ) m/z 328 [M þ
H]þ (100); HRMS (ESIþ) calcd for C18H18NO3S 328.1003,
found 328.1001. Diastereoisomer [2S,(S)S]-2B: colorless oil;
[R]20D ꢀ80.3 (c 1.2, CHCl3); 1H NMR δ 7.79ꢀ7.76 (m, 1H),
7.58ꢀ7.51 (m, 3H), 7.46 and 7.27 (AA0BB0 system, 4H), 3.88
(s, 3H), 2.38 (s, 3H), 2.07 (s, 3H) ppm; 13C NMR δ 168.6, 144.7,
141.6, 140.8, 135.3, 132.3, 130.7, 129.9 (2C), 129.5, 127.1, 125.8
(2C), 118.9, 54.5, 47.3, 26.2, 21.3 ppm; MS (ESIþ) m/z 328 [M
þ H]þ (100); HRMS (ESIþ) calcd for C18H18NO3S 328.1003,
found 328.1002.
[2S,(S)S]- and [2R,(S)S]-4-Methyl-2-[2-(p-tolylsulfinyl)phe-
nyl]pentanenitrile (7): The diastereoisomeric mixture 7 was
obtained by using 1-iodo-2-methylpropane as the electrophile.
The reaction mixture was stirred at rt for 1 h. Yield 75%; colorless
oil; 1H NMR [diastereoisomeric mixture (50:50)] δ 7.95ꢀ7.82
(m, 2H), 7.61ꢀ7.48 (m, 6H), 7.45 and 7.29 (AA0BB0 system,
4H), 7.42 and 7.29 (AA0BB0 system, 4H), 4.49 (dd, J = 4.9 and
11.0 Hz, 1H), 4.38 (dd, J = 5.0 and 10.1 Hz, 1H), 2.38 (s, 6H),
1.97ꢀ1.57 (m, 4H), 1.35ꢀ1.16 (m, 2H), 1.01 (d, J = 6.5 Hz,
3H), 1.00 (d, J = 6.5 Hz, 3H), 0.93 (d, J = 6.5 Hz, 3H), 0.91 (d, J =
6.5 Hz, 3H) ppm; 13C NMR [diastereoisomeric mixture
(50:50)] δ 142.3, 142.2, 141.9, 141.5, 140.8, 140.7, 136.3,
134.7, 132.3, 132.1, 130.3 (2C), 130.2 (2C), 129.6, 129.4,
128.9, 128.3, 127.6, 125.9, 125.7 (2C), 125.5 (2C), 120.1,
119.8, 44.5, 44.2, 31.0, 30.6, 26.6, 26.4, 22.9, 22.7, 21.3, 21.2,
21.2, 20.9 ppm; MS (FABþ) m/z 312 [M þ H]þ (100), 289
(12), 268 (7), 221 (10); HRMS (FABþ) calcd for C19H22NOS
312.1422, found 312.1425.
[2S,(S)S]- and [2R,(S)S]-3-Methyl-2-[2-(p-tolylsulfinyl)phe-
nyl]butanenitrile (8): The diastereoisomeric mixture 8 was
obtained by using 2-iodopropane as the electrophile. The reac-
tion mixture was stirred at rt for 1 h. Yield 81%; colorless oil; 1H
NMR [diastereoisomeric mixture (60:40)] δ 7.96ꢀ7.93 (m,
1H), 7.81ꢀ7.79 (m, 1H), 7.60ꢀ7.51 (m, 6H), 7.45 and 7.30
(AA0BB0 system, 4H), 7.43 and 7.30 (AA0BB0 system, 4H), 4.44
(d, J = 6.6 Hz, 1H), 4.20 (d, J = 6.6 Hz, 1H), 2.40 (s, 3H), 2.39
(s, 3H), 2.34ꢀ2.22 (m, 1H), 2.06ꢀ1.95 (m, 1H), 1.12 (d, J = 6.8
Hz, 3H), 1.08 (d, J = 6.8 Hz, 3H), 1.07 (d, J = 6.8 Hz, 3H), 0.96
(d, J = 6.8 Hz, 3H) ppm; 13C NMR [diastereoisomeric mixture
(60:40)] δ 143.0, 142.5, 142.2, 141.8, 140.8, 140.7, 135.4, 133.4,
131.9, 131.6, 130.3 (2C), 130.1 (2C), 129.9, 129.5, 129.0, 128.7,
128.0, 125.8, 125.4 (2C), 125.3, 119.0, 118.8, 40.5, 39.7, 33.7,
33.4, 21.3, 21.2, 20.8, 20.7, 18.7, 18.4 ppm; MS (FABþ) m/z 298
[M þ H]þ (100), 289 (9), 253 (11), 229 (7); HRMS (FABþ)
calcd for C18H20NOS 298.1265, found 298.1268.
General Procedure for Carbonylation of 2-Alkyl-2-[2-(p-
tolylsulfinyl)phenyl]acetonitriles. To a solution of corre-
sponding 2-alkyl-2-[2-(p-tolylsulfinyl)phenyl]acetonitrile (1.0
mmol) and 18-crown-6 ether (1.1 mmol) in anhydrous THF
(5 mL) at ꢀ78 °C under argon was added KHMDS (0.5 M in
toluene) (1.1 mmol). The mixture was stirred at ꢀ78 °C for
10 min and then 1.1 mmol of the corresponding electrophile was
added dropwise. The reaction was monitored by TLC. Upon
transformation of the starting material, the reaction was hydro-
lyzed with saturated aqueous NH4Cl (5 mL). The mixture was
extracted with CH2Cl2 (3 ꢁ 5 mL) and dried (Na2SO4) and the
solvent was evaporated. The diastereoisomeric mixture was
purified by flash column chromatography, using as the eluent a
mixture of AcOEt/hexane as indicated in each case.
[2R,(S)S]- and [2S,(S)S]-Methyl 2-cyano-2-[2-(p-tolylsulfi-
nyl)phenyl]propanoate (2A þ 2B): A 50:50 diastereoisomeric
mixture of 2-[2-(p-tolylsulfinyl)phenyl]propanenitrile (1) was
used as the starting material. Methyl chloroformate (1.1 equiv)
was used as the electrophile and the reaction was stirred
at ꢀ98 °C for 15 min to give a 90:10 diastereoisomeric mixture
of 2A þ 2B which were separated and purified by flash column
chromatography (eluent AcOEt/hexane 1:1). Yield (for both
[2R,(S)S]- and [2S,(S)S]-Isopropyl 2-Cyano-2-[2-(p-tolylsul-
finyl)phenyl]propanoate (3A þ 3B): A 50:50 diastereoisomeric
mixture of 2-[2-(p-tolylsulfinyl)phenyl]propanenitrile (1) was
used as the starting material. Isopropyl chloroformate (1.4 equiv)
was used as the electrophile and the reaction was stirred
at ꢀ78 °C for 10 min to give a >98:<2 diastereoisomeric mixture
of 3A þ 3B, from which 3A was isolated and purified by flash
column chromatography (eluent AcOEt/hexane 1:3). Yield 77%.
Diastereoisomer [2R,(S)S]-3A: colorless oil; [R]20 ꢀ134.2
D
(c 0.6, CHCl3); IR (film) 2242, 1727, 1643, 1473, 1082 cmꢀ1
;
1H NMR δ 7.64ꢀ7.56 (m, 4H), 7.54ꢀ7.45 (m, 2H), 7.27 (d, J =
8.4 Hz, 2H), 5.17 (sp, J = 6.3 Hz, 1H), 2.38 (s, 3H), 2.23 (s, 3H),
1.35 (d, J = 6.1 Hz, 3H), 1.34 (d, J = 6.1 Hz, 3H) ppm; 13C NMR
167.9, 145.9, 141.2, 140.5, 135.1, 132.2, 130.8, 129.9, 129.8 (2C),
126.7, 125.5 (2C), 119.6, 72.5, 47.6, 25.3, 21.3, 21.2 (2C) ppm;
MS (FABþ) m/z 356 [M þ H]þ (100); HRMS (FABþ) calcd
for C20H22NO3S 356.1326, found 356.1320.
[2R,(S)S]- and [2S,(S)S]-2-Methyl-3-oxo-2-[2-(p-tolylsulfi-
nyl)phenyl]butanenitrile (4A þ 4B): A 50:50 diastereoisomeric
mixture of 2-[2-(p-tolylsulfinyl)phenyl]propanenitrile (1) was
used as the starting material. Acetyl chloride (1.1 equiv) was used
as the electrophile and the reaction was stirred at ꢀ98 °C for 15
min to give a 88:12 diastereoisomeric mixture of 4A þ 4B which
were separated and purified by flash column chromatography
(eluyent AcOEt/hexane 2:1). Yield (for both diastereoisomers)
73%. Diastereoisomer [2R,(S)S]-4A: yellow solid, mp 165ꢀ
167 °C (CH2Cl2ꢀhexane); [R]20D ꢀ145.5 (c 0.8, CHCl3); IR
1
(KBr) 2236, 1727, 1643, 1083 cmꢀ1; H NMR δ 7.71ꢀ7.69
(m, 1H), 7.59 and 7.28 (AA0BB0 system, 4H), 7.58ꢀ7.55 (m,
3H), 2.51 (s, 3H), 2.38 (s, 3H), 2.10 (s, 3H) ppm; 13C NMR
δ 199.6, 145.6, 141.6, 140.2, 134.8, 132.4, 130.9, 129.9 (2C),
129.7, 127.1, 125.7 (2C), 120.4, 52.8, 26.1, 23.7, 21.3 ppm; MS
(ESIþ) m/z 312 [M þ H]þ (100); HRMS (ESIþ) calcd for
C18H18NO2S 312.1037, found 312.1052. Diastereoisomer
[2S,(S)S]-4B: colorless oil; [R]20 ꢀ117.3 (c 1.5, CHCl3); IR
D
(film) 2236, 1727, 1640, 1081 cmꢀ1; 1H NMR δ 7.74ꢀ7.72 (m,
1H), 7.59ꢀ7.45 (m, 3H), 7.41 and 7.27 (AA0BB0 system, 4H),
2.56 (s, 3H), 2.38 (s, 3H), 1.98 (s, 3H) ppm; 13C NMR δ 199.9,
144.8, 141.6, 140.6, 135.4, 132.5, 130.8, 129.9, 129.8 (2C), 127.5,
125.8 (2C), 119.8, 52.8, 26.6, 24.4, 21.3 ppm; MS (ESIþ) m/z
312 [M þ H]þ (100); HRMS (ESIþ) calcd for C18H18NO2S
312.1037, found 312.1014.
[2R,(S)S]- and [2S,(S)S]-2,4,4-Trimethyl-3-oxo-2-[2-(p-to-
lylsulfinyl)phenyl]pentanenitrile (5A þ 5B): A 50:50 diaster-
eoisomeric mixture of 2-[2-(p-tolylsulfinyl)phenyl]propane-
nitrile (1) was used as the starting material. Pivaloyl chloride
3601
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The Journal of Organic Chemistry
NOTE
(1.5 equiv) was used as the electrophile and the reaction was
stirred at ꢀ78 °C for 20 min to give a 96:4 diastereoisomeric
mixture of 5A þ 5B, from which 5A was isolated and purified by
flash column chromatography (eluent AcOEt/hexane 1:3). Yield
73%. Diastereoisomer [2R,(S)S]-5A: colorless oil; [R]20D ꢀ100.2
NMR δ 8.09 (dd, J = 7.8 and 1.5 Hz, 1H), 7.58 and 7.27 (AA0BB0
system, 4H), 7.60ꢀ7.40 (m, 2H), 7.15 (dd, J = 7.9 and 1.3 Hz,
1H), 2.37 (s, 3H), 1.70 (s, 3H), 1.33 (s, 9H) ppm; 13C NMR
205.6, 144.5, 142.1, 141.3, 136.7, 132.4, 131.6, 130.3, 130.1 (2C),
129.9, 128.1, 127.1, 127.0 (2C), 125.6, 120.6, 50.3, 47.1, 29.1,
26.1, 21.4 ppm; MS (FABþ) m/z 354 [M þ H]þ (100); HRMS
(FABþ) calcd for C21H24NO2S 354.1524, found 354.1528.
Diastereoisomer [2S,(S)S]-5B (representative signals from a
96:4 6A þ 6B mixture): 1H NMR δ 7.88ꢀ7.85 (m, 1H), 1.71
(s, 3H), 1.32 (s, 9H) ppm
reaction was stirred at ꢀ78 °C for 15 min to give a 97:3
diastereoisomeric mixture of 10A þ 10B, from which 10A was
isolated and purified by flash column chromatography (eluent
AcOEt/hexane 1:2). Yield 77%. Diastereoisomer [2R,(S)S]-
10A: colorless oil; [R]20 ꢀ151.2 (c 1.1, CHCl3); IR (film)
D
1
(c 0.6, CHCl3); IR (film) 2236, 1727, 1643, 1083 cmꢀ1; H
1
2243, 1747, 1642, 1469, 1396, 1216, 1081 cmꢀ1; H NMR
δ 7.80ꢀ7.74 (m, 2H), 7.54ꢀ7.27 (m, 2H), 7.48 and 7.25
(AA0BB0 system, 4H), 3.71 (s, 3H), 3.42 (sp, J = 6.7 Hz, 1H),
2.37 (s, 3H), 1.30 (d, J = 6.5 Hz, 3H), 1.02 (d, J = 6.5 Hz, 3H)
ppm; 13C NMR 167.7, 146.1, 141.4, 141.1, 133.4, 132.0, 130.6,
130.2, 129.7 (2C), 128.6, 125.8 (2C), 117.2, 59.9, 54.0, 34.5,
21.2, 19.5, 18.6 ppm; MS (FABþ) m/z 356 [M þ H]þ (100);
HRMS (FABþ) calcd for C20H22NO3S 356.1325, found
356.1320. Diastereoisomer [2S,(S)S]-10B (representative sig-
nals from a 97:3 10A þ 10B mixture): 1H NMR δ 7.87ꢀ7.84 (m,
1H), 7.65ꢀ7.62 (m, 1H), 3.75 (s, 3H), 1.30 (d, J = 6.8 Hz, 3H),
0.93 (d, J = 6.8 Hz, 3H) ppm.
[2R,(S)S]- and [2S,(S)S]-4-Methyl-2-(1-oxoethyl)-2-[2-(p-
tolylsulfinyl)phenyl]pentanitrile (11A þ 11B): A 50:50 dia-
stereoisomeric mixture of 4-methyl-2-[2-(p-tolylsulfinyl)phe-
nyl]pentanitrile (7) was used as the starting material. Acetyl
chloride (1.1 equiv) was used as the electrophile and the reaction
was stirred at ꢀ78 °C for 15 min to give a 90:10 diastereoiso-
meric mixture of 11A þ 11B, from which 11A was isolated and
purified by flash column chromatography (eluent AcOEt/hexane
1:2). Yield 78%. Diastereoisomer [2R,(S)S]-11A: colorless oil;
[R]20D ꢀ125,4 (c 1.0, CHCl3); IR (film) 2246, 1747, 1645, 1470,
1083 cmꢀ1; 1H NMR: δ 7.80 (dd, J 7.8 and 1.4 Hz, 1H), 7.72
(dd, J = 7.5 and 1.5 Hz, 2H), 7.60ꢀ7.46 (m, 2H), 7.48 and 7.27
(AA0BB0 system, 4H), 2.70 (dd, J = 14.3 and 4.8 Hz, 1H), 2.38
(s, 3H), 2.36 (dd, J = 14.3 and 4.8 Hz, 1H), 1.63 (sp, J = 6.5 Hz,
1H), 1.03 (d, J = 6.6 Hz, 3H), 0.88 (d, J = 6.6 Hz, 3H) ppm; 13C
NMR 198.9, 145.4, 141.6, 140.1, 133.5, 133.2, 130.6, 129.9, 129.8
(2C), 129.0, 125.9 (2C), 119.4, 59.6, 44.2, 26.4, 26.0, 23.5, 22.7,
21.3 ppm; MS (FABþ) m/z 354 [M þ H]þ (100); HRMS
(FABþ) calcd for C21H24NO2S 354.1534, found 354.1528.
Diastereoisomer [2S,(S)S]-11B (representative signals from a
90:10 11A þ 11B mixture): 1H NMR δ 7.86ꢀ7.83 (m, 1H),
2.40 (s, 3H), 1.01 (d, J = 6.6 Hz, 3H), 0.64 (d, J = 6.6 Hz,
3H) ppm.
[2R,(S)S]- and [2S,(S)S]-2-Benzoyl-2-[2-(p-tolylsulfinyl)-
phenyl]propanenitrile (6A þ 6B): A 50:50 diastereoisomeric
mixture of 2-[2-(p-tolylsulfinyl)phenyl]propanenitrile (1) was
used as the starting material and benzoyl chloride (1.1 equiv) was
used as the electrophile. The reaction was stirred at ꢀ98 °C for
15 min to give a 93:7 diastereoisomeric mixture of 6A þ 6B, from
which 6A was isolated and purified by flash column chromatog-
raphy (eluent AcOEt/hexane 1:2). Yield 73%. Diastereoisomer
[2R,(S)S]-6A: colorless oil; [R]20D ꢀ139.2 (c 0.8, CHCl3); IR
1
(film) 2320, 1727, 1643, 1083 cmꢀ1; H NMR δ 7.91ꢀ7.85
(m, 3H), 7.65ꢀ7.50 (m, 6H), 7.48ꢀ7.45 (m, 2H), 7.09 and 7.05
(m, 2H), 6.90ꢀ6.88 (m, 2H), 2.38 (s, 3H), 2.20 (s, 3H) ppm;
13C NMR 190.5, 143.8, 141.4, 139.5, 137.8, 133.7, 133.1, 132.9,
130.7 (2C), 130.5, 130.0, 129.6 (2C), 128.7 (2C), 127.3, 125.7
(2C), 119.9, 51.6, 27.0, 21.3 ppm; MS (FABþ) m/z 374 [M þ
H]þ (100); HRMS (FABþ) calcd for C23H20NO2S 374.1208,
found 374.1215. Diastereoisomer [2S,(S)S]-6B (representative
signals from a 93:7 6A þ 6B mixture): 1H NMR δ 8.01ꢀ7.99 (m,
1H), 7.75ꢀ7.73 (m, 1H), 2.39 (s, 3H), 1.95 (s, 3H) ppm.
[2R,(S)S]- and [2S,(S)S]-Methyl 2-Cyano-4-methyl-2-[2-(p-
tolylsulfinyl)phenyl]pentanoate (9A þ 9B): A 50:50 diaster-
eoisomeric mixture of 4-methyl-2-[2-(p-tolylsulfinyl)phenyl]pe-
ntanenitrile (7) was used as the starting material. Methyl
chloroformate (1.1 equiv) was used as the electrophile and
the reaction was stirred at ꢀ78 °C for 15 min to give a 96:4 dias-
tereoisomeric mixture of 9A þ 9B, from which 9A was isolated
and purified by flash column chromatography (eluent AcOEt/
hexane 1:2). Yield 72%. Diastereoisomer [2R,(S)S]-9A: colorless
oil; [R]20D ꢀ108,2 (c 1.0, CHCl3); IR (film) 2242, 2092, 1747,
1727, 1643, 1470, 1083 cmꢀ1; 1H NMR δ 7.81 (dd, J = 7.8 and
1.3 Hz, 1H), 7.62ꢀ7.42 (m, 3H), 7.47 and 7.26 (AA0BB0 system,
4H), 3.80 (s, 3H), 2.67 (dd, J = 14.4 and 5.2 Hz, 1H), 2.55 (dd,
J = 14.4 and 5.2 Hz, 1H), 2.38 (s, 3H), 1.69 (sp, J = 6.6 Hz, 1H),
1.04 (d, J = 6.7 Hz, 3H), 0.87 (d, J = 6.7 Hz, 3H) ppm; 13C NMR
δ 168.5, 145.2, 141.3, 140.5, 134.5, 132.1, 130.6, 130.2, 129.8
(2C), 128.2, 125.6 (2C), 118.6, 54.4, 52.6, 45.8, 25.7, 23.4, 22.8,
21.3 ppm; MS (FABþ) m/z 370 [M þ H]þ (100); HRMS
(FABþ) calcd for C21H24NO3S 370.1488, found 370.1477.
Diastereoisomer [2S,(S)S]-9B (representative signals from a
96:4 9A þ 9B mixture): 1H NMR δ 7.87ꢀ7.84 (m, 3H), 3.90
(s, 3H), 2.37 (s, 3H) ppm.
[2R,(S)S]- and [2S,(S)S]-3-Methyl-2-(1-oxoethyl)-2-[2-(p-
tolylsulfinyl)phenyl]butanenitrile (12A þ 12B): A 50:50 dia-
stereoisomeric mixture of 3-methyl-2-[2-(p-tolylsulfinyl)phe-
nyl]butanenitrile (8) was used as the starting material. Acetyl
chloride (1.1 equiv) was used as the electrophile and the reaction
was stirred at ꢀ78 °C for 30 min to give a 90:10 diastereoiso-
meric mixture of 12A þ 12B, which was purified by flash column
chromatography (eluent AcOEt/hexane 1:1). Yield 70%. Dia-
stereoisomer [2R,(S)S]-12A (from a 90:10 mixture of 12A þ
12B): IR (film) 2243, 1749, 1632, 1470, 1081 cmꢀ1; 1H NMR
δ 7.93ꢀ7.90 (m, 1H), 7.83ꢀ7.80 (m, 1H), 7.63ꢀ7.46 (m, 2H),
7.47 and 7.26 (AA0BB0 system, 4H), 3.44 (sp, J = 6.6 Hz, 1H),
2.37 (s, 3H), 2.28 (s, 3H), 1.26 (d, J = 6.4 Hz, 3H), 0.94 (d, J = 6.4
Hz, 3H) ppm; 13C NMR 198.6, 146.3, 141.5, 141.2, 132.5, 131.4,
130.6, 130.4, 129.9 (2C), 129.8, 126.0 (2C), 118.4, 66.5, 33.2,
28.2, 21.3, 19.5, 18.6 ppm; MS (FABþ) m/z 340 [M þ H]þ
(100); HRMS (FABþ) calcd for C20H22NO2S 340.1190, found
340.1188. Diastereoisomer [2S,(S)S]-12B (representative sig-
[2R,(S)S]- and [2S,(S)S]-Methyl 2-Cyano-3-methyl-2-[2-(p-
tolylsulfinyl)phenyl]butanoate (10A þ 10B): A 50:50 diaster-
eoisomeric mixture of 3-methyl-2-[2-(p-tolylsulfinyl)phenyl]bu-
tanenitrile (8) was used as the starting material. Methyl chlor-
oformate (1.1 equiv) was used as the electrophile and the
1
nals from a 90:10 12A þ 12B mixture): H NMR δ 2.99 (m,
1H), 2.05 (s, 3H), 1.33 (d, J = 6.5 Hz, 3H), 1.05 (d, J = 6.5 Hz,
3H) ppm; 13C NMR 21.2. 18.9, 18.8 ppm.
3602
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The Journal of Organic Chemistry
NOTE
’ ASSOCIATED CONTENT
(6) García Ruano, J. L.; Martín-Castro, A. M.; Tato, F.; Torrente, E.;
Poveda, A. M. Chem.—Eur. J. 2010, 16, 6317.
Supporting Information. 1H and 13C NMR for quatern-
(7) Despite the well-known ability of acylating and alkoxycarbony-
lating reagents to reduce sulfoxides, the reactions proved to be highly
chemoselective and no sulfenyl byproduct was detected in the crude
mixtures. See: (a) Drabowicz, J.; Numata, T.; Oae, S. Org. Prep. Proced.
Int. 1977, 9, 63. (b) Drabowicz, J.; Togo, H.; Mikozajczyk, M.; Oae, S.
Org. Prep. Proced. Int. 1984, 16, 171.
S
b
ary difunctionalized compounds 2ꢀ6 and 9ꢀ12, and X-ray
ORTEP and crystallographic data for compound 4A (CIF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
(8) Crystallographic data (excluding structure factors) for com-
pound 4A have been deposited with the Cambridge Crystallographic
Data Centre; deposition no. CCDC 812033. These data can be
obtained, free of charge, from the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, U.K. [fax þ44(0)-
1223ꢀ366033; e-mail deposit@ccdc.cam.ac.uk; www.ccdc.cam.ac.uk/
conts/retrieving.html].
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: joseluis.garcia.ruano@uam.es (J.L.G.R.) and martin.castro@
uam.es (A.M.M.-C.).
(9) Thus, when NaI or sodium tetrakis[3,5-bis(trifluoromethyl)ph-
enyl]borate (NaBARF)] was added to the reaction, the stereoselectivity
was much lower as a consequence of an increase in the proportion of
diastereoisomer B, presumably resulting from the evolution of the boat-
like species II, as was the case for reactions with alkyl halides.
Unfortunately, this experimental modification, although clarifying from
a mechanistic viewpoint, did not allow us to invert the stereoselectivity.
’ ACKNOWLEDGMENT
Financial support of this work by the Ministerio de Ciencia
y Tecnología (CTQ2009-12168), UAM-Comunidad de
Madrid (CCG08UAM/PPQ-4235), and Comunidad de Madrid
(AVANCAT, S-2009-PPQ-1634) is gratefully acknowledged.
E.T. thanks Ministerio de Educaciꢀon y Ciencia for a predoctoral
fellowship.
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