Stereodivergent quaternization of 2-alkyl-2-p-tolylsulfinylacetonitriles: NMR spectroscopic evidence of planar and pyramidal benzylic carbanions

Article abstract of DOI:10.1002/chem.200903521

Enantiomerically enriched α,α-disubstituted phenylacetonitriles have been readily prepared by stereo-selective quaternization of 2-alkyl-2-[2-(p-tolylsulfinyl)phenyl]acetonitriles with different alkylating electrophiles in the presence of bases. The use of potassium hexamethyldisilazane (KHMDS)/[18]crown-6 ether and NHMDS with alkyl halides afforded S,S_S and R,S_S diastereoisomers, respectively, in high enantiomeric purities, thus providing stereodivergent processes for synthesizing both isomers. The dependence of the stereochemical course of the reactions on the experimental conditions (mainly on the counterion) has been rationalized by assuming a planar or pyramidal structure for the benzylic carbanions. This hypothesis has been supported by NMR spectroscopic studies, which permit one to assign a chelated pyramidal structure to the sodium benzylic carbanions and an almost planar naked carbanionic structure to the potassium benzylic carbanions generated in the presence of [18]crown-6 ether.

Full text of DOI:10.1002/chem.200903521

FULL PAPER
DOI: 10.1002/chem.200903521
Stereodivergent Quaternization of 2-Alkyl-2-p-tolylsulfinylacetonitriles:
NMR Spectroscopic Evidence of Planar and Pyramidal Benzylic Carbanions
Josꢀ Luis Garcꢁa Ruano,*[a] Ana M. Martꢁn-Castro,*[a] Francisco Tato,[a]
Esther Torrente,[a] and Ana M. Poveda[b]
Dedicated to Professor Antonio Garcꢀa Martinez on the occasion of his 70th birthday
Abstract: Enantiomerically enriched
a,a-disubstituted phenylacetonitriles
have been readily prepared by stereo-
selective quaternization of 2-alkyl-2-[2-
(p-tolylsulfinyl)phenyl]acetonitriles
tively, in high enantiomeric purities,
thus providing stereodivergent process-
es for synthesizing both isomers. The
dependence of the stereochemical
course of the reactions on the experi-
mental conditions (mainly on the coun-
terion) has been rationalized by assum-
ing a planar or pyramidal structure for
the benzylic carbanions. This hypothe-
sis has been supported by NMR spec-
troscopic studies, which permit one to
assign a chelated pyramidal structure
to the sodium benzylic carbanions and
an almost planar naked carbanionic
structure to the potassium benzylic car-
banions generated in the presence of
[18]crown-6 ether.
with different alkylating electrophiles
in the presence of bases. The use of po-
tassium
(KHMDS)/[18]crown-6
hexamethyldisilazane
ether and
Keywords: asymmetric synthesis ·
carbanions · chirality · diastereo-
selectivity · NMR spectroscopy
NHMDS with alkyl halides afforded
S,SS and R,SS diastereoisomers, respec-
Introduction
chiral centers, especially those bearing only carbon substitu-
ents, has been an attractive though difficult challenge to or-
ganic chemists in recent years.[1] Both the stoichiometric use
of chiral auxiliaries and enantioselective catalytic methods
have been investigated for the asymmetric synthesis of mol-
ecules containing a quaternary carbon center, which in
many cases occupies a benzylic position.[2] In this context,
the chiral a,a-dialkyl phenylacetonitrile fragment has been
found present in highly active molecules of the azole family
of fungicides and herbicides,[3] such as fenbuconazole or my-
clobutanyl, and calcium channel blockers,[4,5] (verapamil,
norverapamil, gallopamil, emopamil, or E2050), which have
emerged as important and useful agents for treating hyper-
tension, angina pectoris, migraines, and arrhythmias.
À
The stereoselective construction of C C bonds has been
profusely studied in recent decades due to its frequent appli-
cation to the synthesis of many natural and biologically
active products. Among them, compounds bearing chiral
quaternary carbon centers are numerous. The development
of synthetic strategies for the asymmetric formation of such
[a] Prof. J. L. Garcꢀa Ruano, Prof. A. M. Martꢀn-Castro, Dr. F. Tato,
E. Torrente
Departamento Quimica Orgꢁnica
Cantoblanco, 28049 Madrid (Spain)
Fax : (+34)914973966
E-mail: joseluis.garcia.ruano@uam.es
martin.castro@uam.es
2-p-Tolylsulfinyl benzyl carbanions[6] (derived from 1 by
treatment with lithium diisopropylamide (LDA)) have
shown a very high stereoselective nucleophilic behavior in
their reactions with different electrophiles such as alkyl hal-
ides,[7] carbonyl compounds,[8] N-sulfinyl imines,[9] and N-aryl
imines.[10] In all these reactions, chelated structures, with the
counterion (Li+) joined to the benzylic carbon and stabi-
lized by the sulfinyl oxygen, have been postulated to ac-
count for the stereoselectivity [Scheme 1, Eq. (1)]. Addition-
ally, carbanions formed from O-protected cyanohydrins[11]
(2, Y=OP) and their corresponding N-protected a-aminoni-
[b] Dr. A. M. Poveda
Servicio Interdepartamental de Investigaciꢂn
Universidad Autꢂnoma de Madrid
Cantoblanco, 28049 Madrid (Spain)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200903521. It includes H and
1
13C NMR spectra for starting materials 5–6, tertiary a-alkylphenylace-
tonitriles 3a–g, quaternary a,a-dialkylphenylacetonitriles 7–10, chem-
ical correlation products 11–13, and subproducts 14–16 (ref. [21]), as
well as the 2D NMR spectra of anions derived from 3a.
Chem. Eur. J. 2010, 16, 6317 – 6325
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6317

Scheme 2. Synthesis of the starting materials.
bromide as the electrophile. The effect of different bases
(LHMDS, NHMDS, KHMDS), additives, solvents, and tem-
peratures was investigated (Table 1). When LHMDS was
Scheme 1.
Table 1. Stereodivergent behavior of 3a with benzyl bromide under dif-
ferent conditions.
triles[12] (2, Y=NHBn) and potassium hexamethyldisilazane
(KHMDS) also evolved in a highly stereoselective way
[Scheme 1, Eq. (2)] allowing the creation of chiral benzylic
quaternary centers with high optical purities. In these cases,
planar nonchelated carbanions stabilized by the CN group,
in which the counterion (K+, less prone to the association)
is not joined to the benzylic carbon, have been proposed as
the intermediates.
These results suggested the possibility of achieving both
types of intermediates starting from the same substrate,
simply by choosing the reaction conditions, mainly the base
containing the appropriate metal. To verify the viability of
such a proposal, we decided to study the alkylation of 2-
alkyl-2-[(2-p-tolylsulfinyl)phenyl]acetonitriles 3 (Scheme 1)
under different conditions, which would provide a ready
access to the a,a-dialkylphenylacetonitrile fragment, present
in biologically active molecules, in either of its two possible
configurations. Compounds 3, with intermediate structures
between those of 1 and 2, were chosen for this study be-
cause marked conformational constrains of differently meta-
lated nitriles have been reported recently as responsible for
their stereodivergent evolution in intramolecular[13] and in-
termolecular[14] alkylation processes. Results obtained in this
study are herein reported.
Entry
Base (additive)
Solvent
T
[8C]
7aA/
Yield
[%][b]
7aB[a]
1
2
3
4
5
6
7
8
LHMDS
LHMDS
THF
CH2Cl2
THF
THF
THF
THF
THF
THF
À78
À78
À78
À78
À78
À98
À78
À78
74:26
64:36
80:20
57:43
87:13
89:11
10:90
68:32
77
[c]
LHMDS ([12]crown-4)
KHMDS
KHMDS ([18]crown-6)
KHMDS ([18]crown-6)
NHMDS
79
84
86
86
84
[c,d]
NHMDS ([15]crown-5)
[a] Determined by integration of well-separated signals in the 1H NMR
spectra of the crude reaction. [b] Combined yield for both diastereoiso-
mers. [c] Not determined. [d] 30% conversion.
used as the base in THF at À788C, the reaction evolved
with moderate stereoselectivity yielding a 74:26 diastereo-
isomeric mixture of 7aA and 7aB (Table 1, entry 1).[16] The
use of CH2Cl2 as the solvent determined a decrease in the
stereoselectivity (Table 1, entry 2), whereas the addition of
[12]crown-4 ether had scarce influence on the diastereoiso-
meric ratio (d.r.) (Table 1, entry 3). More interesting results
were obtained when KHMDS was employed as the base
(Table 1, entries 4–6), mainly in the presence of [18]crown-6
ether, which provided a very high proportion of compound
7aA (entries 5 and 6). As expected, the d.r. improved when
the temperature was lowered (compare entries 5 and 6), al-
though such an improvement was rather low and it did not
compensate for the higher experimental difficulties and the
decrease in the yield. Interestingly, the use of NHMDS af-
forded a 10:90 mixture of 7aA and 7aB (Table 1, entry 7),
with the stereoselectivity being opposite to that detected
with KHMDS and LHMDS. The addition of [15]crown-5
ether substantially decreased the stereoselectivity (Table 1,
entry 8) and the conversion (30%).
Results and Discussion
The synthesis of the starting sulfinyl phenylacetonitriles 3a–
d was performed by quantitative NaBH4 reduction of (S)-
4,[15] substitution of the OH at the resulting alcohol (S)-5 by
CN, and final alkylation of nitrile (S)-6 (Scheme 2). Com-
pounds 3a–g were obtained as inseparable mixtures of dia-
stereoisomers (<36% de) under all the assayed conditions
(different bases, solvents, and temperatures).
Quaternization reactions were initially assayed on a dia-
stereoisomeric 1:1 mixture of 3a by treatment with benzyl
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Tolylsulfinylacetonitriles
FULL PAPER
From these results we can conclude that quaternization of
3a with benzyl bromide proceeds with good yields and dia-
stereomeric excess (de) values in a completely stereodiver-
gent process closely dependent on the experimental basic
conditions; 7aB is favored with NHMDS and 7aA with
KHMDS/[18]crown-6 ether.
Then we investigated the benzylation reactions of sub-
strates 3b–3d, 3 f, and 3g, which differ in the R group,
under the experimental conditions of entries 5 and 7 of
Table 1 (Table 2). Regardless the nature of R, reactions con-
conditions the reactivity was higher (shorter reaction times
were needed for the reaction to reach completion). As ex-
pected, the use of alkyl iodides instead of alkyl bromides de-
creased the reaction times and sometimes provided slightly
better yields, but the stereoselectivity remained almost iden-
tical (only one example has been included in Table 3). These
results confirm the stereodivergent behavior of the carban-
ions derived from 3 depending on the counterion and indi-
cate that the synthesis of any of the epimers can be per-
formed by tuning the experimental conditions, in particular,
the base used in the reaction.
Two facts are noteworthy from Table 3. The first one is
the marked differences in stereoselectivity observed for the
methylation reaction, which exhibits the lowest de values
with KHMDS but the highest ones with NHMDS. The other
remarkable data is the higher de values observed for allyla-
tions (84%) with KHMDS/[18]crown-6 ether as compared
with those observed with other alkylating reagents. These
results induced us to study these two reactions thoroughly.
The results obtained from the allylation reactions are col-
lected in Table 4.
Table 2. Stereodivergent benzylation of substrates 3a–3d, 3 f, and 3g.
Compound
(de [%])
Yield
[%]
Compound
(R)
Yield
[%]
Compound
ACHTUNGTRNE(NUNG de [%])
U
7aB (80)[a]
7bB (70)
7cB (76)
7dB (78)
7 fB (52)[b]
7gB (80)
84
79
78
81
85
77
7a (Me)
7b (Et)
7c (Pr)
7d (CH2Bn)
7 f (iBu)
7g (iPr)
86
82
83
90
91
79
7aA (74)
7bA (76)
7cA (76)
7dA (80)
7 fA (76)[b]
7gA (74)
Table 4. Stereodivergent evolution of allylation reactions.
[a] In toluene, de>98%, yield=71%. [b] In toluene, de=80%, yield=
10%.
ducted with KHMDS/[18]crown-6 ether yielded diastereo-
isomers A as the major ones with 74–80% de, whereas epi-
mers B were mainly obtained in those reactions performed
with NHMDS, with 70–80% de, except for 7 fB (52% de).
Reaction times under the former conditions were shorter
than under the latter ones, thus providing evidence of the
higher reactivity of potassium carbanions. All the reactions
proceeded in high yields.
Compound Yield de
U
R
Yield Compound
[%]
[%]
ACHTUNGTRENNUNG(de [%])
10aB
10bB
10cB
10dB
10eB
10 fB
10gB
78
79
81
84
71
81
81
80
74
58
66
34
Me (3a)
Et (3b)
Pr (3c)
82
83
77
10aA (86)
10bA (88)
10cA (84)
10dA (88)
10eA (90)
10 fA (96)
10gA (90)
BnCH2 (3d) 83
Bn (3e)
iBu (3 f)
iPr (3g)
77
76
74
À24
78
Next we investigated the behavior of other alkylating re-
agents under the optimum conditions favoring the stereodi-
vergence. The study was performed on 3c and furnished
similar results (Table 3) to those obtained for benzylation
reactions (Table 2). Thus, stereodivergence was observed for
all the alkylation reactions with isomers A being predomi-
nant with KHMDS/[18]crown-6 ether, whereas isomers B
were preferentially formed with NHMDS. Under the former
[a] Toluene was used as the solvent.
The observed stereoselectivity with KHMDS/[18]crown-6
ether was very high with all the assayed electrophiles (84–
90% de). By contrast, reactions conducted in the presence
of NHMDS, which once again evolved with the opposite se-
lectivity, exhibited a stereoselectivity dependent on the
nature of the R group present in the starting material, rang-
ing between 34% for 10eB (R=Bn) and 80% for 10aB
(R=Me). This behavior seems to be related to the steric
size of the R group (the selectivity decreases as the size in-
creases), which would explain the completely unexpected
result obtained from 3 f, which yielded 10 fA as the major
diastereoisomer in the presence of NHMDS. However, the
high stereoselectivity observed in the reaction of 3g (R=
iPr) with NHMDS, which is not compatible with this ten-
dency, suggests a more complex dependence. Most of these
reactions were performed starting from allyl bromides and
iodides. The reactivity of the iodides was higher (shorter re-
Table 3. Stereodivergent behavior of 3c with different electrophiles.
À
R X
Compound
(de [%])
Yield
[%]
Time
[h]
Time
[h]
Yield
[%]
Compound
ACHTUNGTRNE(NUNG de [%])
U
8cB (86)
9cB (70)
7cB (76)
10cB (54)
10cB (58)
79
56
78
74
81
1
8
3
3
MeI
EtI
BnBr
allyl-Br
allyl-I
0.5
2.5
0.5
0.5
–
83
71
83
79
–
8cA (46)
9cA (66)
7cA (76)
10cA (84)
–
0.2
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J. L. Garcꢀa Ruano, A. M. Martꢀn-Castro et al.
action times were necessary) in all cases but the stereoselec-
tivity remained almost unaltered.
Results obtained in the methylation reactions of different
substrates are collected in Table 5. As we can see, the ste-
reoselectivity of the reactions conducted with KHMDS/
and opposite sign to that previously reported for (S)-2-
methyl-2-phenylbutanoic acid (94% ee).[17] Consequently,
the R configuration could be assigned to our 2-methyl-2-
phenylbutanoic acid and, therefore, to the benzylic carbon
atom at the major diastereoisomeric nitrile 8bB.
The stereodivergent behavior of benzylic carbanions de-
rived from 3a–g can be explained by assuming that they
adopt a different structure dependent on the nature of the
base (NHMDS or KHMDS) used in their generation. Two
types of carbanionic species can be conceived. Carbanions
3-I and 3-I’ have the metal detached from the planar sp2
benzylic carbanion[18]—the charge will delocalize throughout
the ring and the CN group—and stabilized by association to
the sulfinyl oxygen (3-I) or to the nitrogen (3-I’), as well as
by molecules of coordinating solvents (THF). The higher
electronic density at the sulfinyl oxygen as compared with
that at the nitrogen atom suggests that the association
O···M+ must be stronger and, therefore, 3-I would be pre-
dominant in its equilibrium with 3-I’ (steric factors also sup-
port this preference, Scheme 4). Chelated species 3-II and 3-
Table 5. Stereodivergent evolution of methylation reactions.
Compound Yield de
G
R
Yield Compound
[%]
[%]
ACHTUNGTRNE(NUNG de [%])
8bB
8cB
8dB
8eB
8 fB
8gB
86
79
81
78
76
83
86
86
86
82
62
84
–
Et (3b)
Pr (3c)
BnCH2 (3d) 86
Bn (3e)
iBu (3 f)
iPr (3g)
84
83
8bA (46)
8cA (46)
8dA (56)
8eA (44)
8 fB (50)
8gA (46)
AHCTUNGTRENGN(UN 98, 65)
–
–
AHCTUNGTRENGN(UN 84, 20)
–
86
79
84
[a] Toluene was used as the solvent.
[18]crown-6 ether (ca. 50% de) is scarcely dependent on the
size of R in the starting material and lower than that ob-
served for other alkylation reactions (for example, compare
Tables 4 and 5). On the contrary, reactions with NHMDS
are highly stereoselective (78–86% de), with the exception
of 3 f (R=iBu), which afforded a 19:81 mixture of 8 fA and
8 fB.
Chromatographic purification and separation of the dia-
stereoisomeric mixtures obtained in most of these reactions
afforded the major diastereoisomers. All the attempts to
achieve good crystals of the nitriles proved unsuccessful and
therefore chemical correlation with configurational assign-
ment was necessary.
Thus, 8bB (R=Me, R’=Et) was chemically correlated
with (R)-2-methyl 2-ethyl phenyl acetic acid (Scheme 3).
Hydrolysis of a 93:7 mixture of nitriles 8bB and 8bA fol-
lowed by desulfinylation of the major diastereoisomeric sul-
finyl carboxamide 11 and additional hydrolysis of the result-
ing amide 13 produced nonracemic 2-methyl-2-phenylbuta-
noic acid, the [a] value of which was of a similar magnitude
Scheme 4. Proposed carbanions accounting for the stereodivergence of
quaternization reactions.
II’, with the metal joined to both the sulfinyl oxygen and the
sp3 benzylic carbon and additionally stabilized by solvent
molecules (THF), are also plausible. These species will
adopt a boatlike conformation (it allows for a significant
charge delocalization throughout the ring) with the lone
electron pair at sulfur orientated towards one of the flagpole
positions of the boat.[19] The second flagpole position could
be occupied either by the CN (3-II) or by the R group (3-
II’) at the benzylic carbon (Scheme 4), but the latter situa-
tion must be less stable since the size of the alkyl groups
hinders them from adopting the flagpole position in a boat-
like structure.
Scheme 3. Chemical correlation of compound 8bB.
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Tolylsulfinylacetonitriles
FULL PAPER
In the presence of NHMDS, a mixture of carbanionic spe-
cies will be formed, chelated 3-II being the major one and,
therefore, responsible for the observed stereoselectivity. By
contrast, the larger K+ will not adapt well in chelated 3-II
and 3-II’ structures. Hence the addition of [18]crown-6 ether
would determine the easy capture of the cation, which
would increase its relative size. As a consequence, its pres-
ence in a chelated species will be practically forbidden on
steric grounds and the equilibrium will be completely shifted
towards the singly associated species. Thus, the stereoselec-
tivity of the reactions with KHMDS/[18]crown-6 ether must
be rationalized by taking into account the evolution of spe-
cies 3-I (presumably more stable than 3-I’,[20] see above).
The electrophiles can approach only the opposite face to
that occupied by the metal at species II (Scheme 4). Accord-
ingly, the evolution of carbanion 3-II (predominant when
the reaction was conducted under NHMDS) will mainly
afford diastereoisomers B. By contrast, carbanion 3-I (gener-
ated as the major one with KHMDS/[18]crown-6-ether) will
mainly evolve into diastereoisomers A due to the steric re-
pulsion of the tolyl group with the electrophile approaching
the bottom face (Scheme 4). This would justify the stereodi-
vergence observed with the change of the base. Another
point to be explained concerns the reactivity, which is signif-
icantly higher (shorter reaction times were needed for the
reaction to reach completion) for reactions performed with
KHMDS. The smaller steric hindrance and the higher elec-
tronic density associated to the nonassociated carbanions II
could account for their higher reactivity.
Scheme 5. Influence of the steric size on the stereoselectivity.
species are involved, evolution through 3-I will be clearly fa-
vored due to the large size of the K-coordinated CN group
in 3-I’. However, in these reactions the small size of R’ at
the electrophile may permit the approach of the reagent to
3-I from the anion face that exhibits the p-tolyl group, thus
affording the minor isomer B.
To confirm this hypothesis, we reasoned that the use of
toluene as the solvent, less polar than THF and, therefore,
unable to stabilize the metal, would increase the proportion
of chelated 3-II with respect to singly associated 3-I, thus fa-
voring the formation of diastereoisomers B and improving
the stereoselectivity of the reactions performed with
NHMDS. As the reactions in toluene were much slower,
probably due to solubility problems, these conditions were
mainly assayed in allylation processes. The results of reac-
tions conducted in toluene are collected in Table 4. The ste-
reoselectivity substantially increased in all the cases and
became almost complete in allylations of 3a and 3b. Im-
provements were noteworthy starting from 3c and 3e, which
is synthetically relevant because the yields obtained in tolu-
ene were similar to those of reactions conducted in THF.
Methylation of 3c in toluene also evolved with higher ste-
reoselectivity than in THF (Table 5). We have also studied
different alkylation reactions in toluene starting from 3 f,
which is the substrate that provides the poorest stereoselec-
tivities in reactions with NHMDS in THF. In all the cases,
the stereoselectivity substantially increased, thus reinforcing
our mechanistic proposal, but these reactions are not syn-
thetically useful because of the low conversions detected in
all of them: allylation, 8% (Table 4); methylation, 20%
(Table 5), and benzylation, 10% (Table 2).[21]
Other significant changes in the stereoselectivity, deduced
from Tables 2–5, are the following:
1) The increase in the size of the electrophile seemingly im-
proves the stereoselectivity of reactions performed with
KHMDS/[18]crown-6-ether (methylation is the less ste-
reoselective process), whereas the opposite tendency is
observed with NHMDS (methylation is the most stereo-
selective process).
2) The increase in the size of the R group at the substrate
decreases the stereoselectivity in reactions with
NHMDS, whereas it has a scarce influence in reactions
with KHMDS/[18]crown-6 ether.
The equilibrium between species 3-II (major) and 3-I for
reactions with NHMDS, and between 3-I (major) and 3-I’
for reactions with KHMDS/[18]crown-6 ether, permit an ex-
planation of the above observations. As can be deduced
from Scheme 5, the steric repulsion (R/R’) in the evolution
of tetracoordinated 3-II is higher than that of tricoordinated
3-I due to the smaller steric hindrance of the nucleophilic
center in 3-I. Consequently, an increase in the size of the R
or R’ will cause a decrease in the stereoselectivity in reac-
tions conducted with NHMDS. Therefore, methylation will
produce the highest proportion of diastereoisomers B and
the increase in the size of R will afford larger amounts of
diastereoisomers A. By contrast, in reactions conducted
with KHMDS/[18]crown-6 ether, in which only 3-I and 3-I’
NMR spectroscopic studies of carbanion intermediates: To
support the mechanistic proposal depicted in Scheme 4, it
would be highly interesting to find some experimental evi-
dence that supports the different structures of the proposed
carbanions. We reasoned that a detailed analysis of the carb-
anion NMR spectroscopic data could be suitable for this
purpose because chemical shifts are highly sensitive to the
electronic delocalization, which in turn must be dependent
on the structure of the carbanion. Thus, we performed an
NMR spectroscopic study of the carbanions generated by re-
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J. L. Garcꢀa Ruano, A. M. Martꢀn-Castro et al.
action of 3a (as a diastereoisomeric mixture) with NHDMS
and KHDMS/[18]crown-6 ether, respectively, under experi-
mental conditions similar to those previously used in the
synthetic work, that is, À508C in [D8]THF (see the Support-
ing Information).
We started our study generating the sodium carbanion by
treating the diastereoisomeric mixture 3a with NHMDS. A
new species 3a-II was detected, with total conversion of the
starting material at the previously described experimental
conditions. On the other hand, when the anion was formed
by treating 3a with KHMDS in the presence of [18]crown-6
ether, a complex mixture was obtained. In fact, an equilibri-
um of four species in chemical exchange was detected by
NMR spectroscopy (see Figure 1), which corresponds to the
two diastereoisomeric starting materials 3a (21 and 24%)
and another two anionic species, 3a-I (44%) and 3a-I’
(11%), the NMR spectroscopic data of which are different
to those of 3a-II (see Table 6).
1
The analysis of the H and 13C NMR spectroscopic reso-
nances of the new species generated from 3a and bases, by
using 2D-COSY, HSQC, HMBC, and NOESY (mixing
time: 300 ms) experiments, permitted us to demonstrate that
a strong shielding in the signals that corresponds to the
ortho-disubstituted aromatic ring, with respect to those of
3a, was taking place. It can be satisfactorily explained by as-
suming the formation of three different benzylic carbanionic
species able to delocalize the charge onto the p-aromatic
system. This delocalization is particularly significant on the
aromatic NMR-spectroscopy-sensitive nuclei at ortho (6’
and 2’) and para (4’) positions, with respect to the benzylic
fragment. Indeed, it is even more evident for the 13C NMR
spectroscopic resonances, as deduced from the HSQC and
HMBC experiments. Hence, the carbanionic species show
important variations of the chemical shifts of the nuclei at
Figure 1. Section of the 2D-NOESY/EXSY spectrum of the compound
3a treated with KHMDS/[18]crown-6 ether at À508C in [D8]THF, show-
ing the chemical exchange among the starting products and the two
anions in the aromatic rings zone. Some NOE cross peaks are observed.
The key aromatic exchange peaks are shown within boxes.
40.0–46.6 ppm) than the equivalent signal for 3a (d=26.8–
27.1 ppm), and the strong deshielding of the CN group (Dd
ranging between +12.3 and +17.3 ppm) and the ipso carbon
C-1’ (Dd ranging between +8.0 and +12.0 ppm). Taking
into account the above-mentioned precedents, these varia-
tions allow us to conclude that species 3a-II, 3a-I, and 3a-I’
have a carbanionic structure.
the para position (Dd
À24.9 ppm and Dd(H-4) rang-
ing between and
À1.8
G
ACHTUNGTRENNUNG
(Dd
between À6.6 and À20 ppm and
Dd
(Hortho-6) between À0.8 and
ACHTUNGTRENNUNG(C-6) and DdACHTUNGTRENNUNG(C-2) range
ACHTUNGTRENNUNG
À1.8 ppm) with respect to the
starting product (Table 6). The
larger range observed for nuclei
at the ortho position is due to
the influence of the substituents
(vide infra). In addition to
these variations, there are other
ones that are clearly indicative
of the formation of benzylic
carbanions. This is the case of
the 13C NMR spectroscopic
signal of the benzylic carbon
atoms (Figure 2), which reso-
3a
3a
3a-I
3a-I
3a-I’
3a-I’
3a-II
3a-II
1H
13C[a]
1H
13C[a]
1H
13C[a]
1H
13C[a]
1-CN
2 (anion)
3-Me
Ar-1’
Ar-2’
Ar-3’
Ar-4’
Ar-5’
Ar-6’
–
121.7
–
–
1.66
–
–
7.35
5.8
6.6
5.9
7.84
7.13
2.22
137
–
–
1.99
–
–
6.9
5.6
6.4
6.9
7.4
7.17
2.16
134
–
–
1.69
–
–
6.38
5.71
6.61
6.16
7.37
7.16
2.25
139
40
16.9
149
124
129.9
109.7
130
117
125.4
129
4.6/4.9
1.1/1.4
–
26.8/27.1
21.1/21.3
137
40.6
18.4
145
46.6
21.2
149
–
144
129
125
8.1/7.9
7.6/7.5
7.6/7.5
7.7/7.5
7.6
126/126.5
129.7/130
132.6
129.6/129.7
125/126
131
124.2
108.4
129.3
116
128.3
108.1
128.7
123
125.5
130.7
21.16
Tol-2’’/6’’
Tol-3’’/5’’
Me-Tol
126.5
129
7.3
2.24
21.1/21.3
n.d.[b]
20.2
nate at much lower field (d= [a] 13C data from HSQC and HMBC experiments. [b] n.d.=not detected.
6322
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Chem. Eur. J. 2010, 16, 6317 – 6325

Tolylsulfinylacetonitriles
FULL PAPER
chemical exchange. When cross peak intensities are calculat-
ed relative to their corresponding diagonal peaks, the cross
peak with the largest relative intensity always corresponds
to the H6’ (any of the species in solution) and Me (3a-I,
major anion) interaction (see the Supporting Information).
This indicates that the H6’/Me moieties are close in space in
the 3a-I anionic compound and that this is the primary
NOE contact, thereby supporting the structural assignment
of these carbanionic species.
To confirm this assignment, the following differences in
chemical shifts are worth mentioning:
1) In 3a-I’, the electronic density of the anion must be delo-
calized through the cyano group more efficiently than in
3a-I, because the electron-demanding character of the
CN in the former one must be enhanced by its associa-
tion to K+. It agrees with the higher 13C d value of the
carbanionic carbon observed for 3a-I’ (d=46.6 ppm)
than for 3a-I (d=40.6 ppm). In turn, the observed 13C d
value for the cyano carbon signal of 3a-I’ resonates at
higher field (d=134.0 ppm) than that of 3a-I (d=
137.0 ppm), as expected by the electron-withdrawing
effect of the K+ on the electronic cloud of the cyano
moiety.
Figure 2. HSQC (solid lines)/HMBC (broken lines) superimposition of
the aliphatic region showing the correspondence between the methyl
moieties (dotted circles) and the related anionic nonprotonated carbons
(dotted squares) for A) the product obtained by reaction of 3a with
NHDMS and B) the reaction mixture obtained by reaction of 3a with
KHDMS/[18]crown-6 ether. C) HSQC spectrum of the corresponding
region for the diastereoisomeric mixture 3a (500 MHz, À508C,
[D8]THF).
2) The observed relative low-field chemical shift for the
ortho proton H-6’ in 3a-Iꢂ (d=6.9 ppm) with respect to
that observed in 3a-I (d=5.9 ppm) can be explained by
the anisotropic effect of the quasi-ketenimine moiety
that results from charge delocalization of the anion
To get the charge delocalized through the aromatic ring,
benzyl carbanions must be able to arrange their lone elec-
tron pairs in an orientation parallel to that of the aromatic p
system. The three species depicted in Scheme 4 fulfill this
requirement: benzylmetals II (3a-II when generated from
3a) with the sp3 orbital that contain the lone electron pair
adopting an almost parallel arrangement to the p cloud be-
cause of the boatlike structure, and free carbanions I and I’
(3a-I and 3a-I’ when they derive from 3a) with sp2 hybridi-
zation, in which the conjugation of the p orbital with the p
orbital of the aromatic ring could be slightly distorted by
steric interactions of either the R or CN groups with the sul-
finyl group. Delocalization must be similarly effective in the
three species, maybe slightly higher for the planar carban-
ions 3a-I and 3a-I’, which is in agreement with the values of
Dd for the nuclei at the para position (Table 6), at which no
additional electronic influence of the substituents is present.
To elucidate the structures of the different carbanions it is
necessary to take into account other factors. The new spe-
cies obtained with NHMDS (3a-II) is characterized by the
existence of NOE cross peaks between the methyl group
bonded to the anionic carbon and the ortho proton (H-6’),
as well as additional contacts between the tolyl ring and the
ortho proton with respect to the sulfur function (H-3’).
These facts suggest that these groups are located very close
each other, which agrees with the proposed structure (and
geometry) for the boatlike 3a-II (Figure 1).
through the cyano group. Additionally, as far as 13C d
ACHTUNGTRENNUNG(C-
6’) values for 3a-I and 3a-II are concerned, their high-
field chemical shifts, relative to that for 3a-I’, may be a
consequence of their 1,3-parallel interaction with the
methyl group in their presumably proposed more stable
conformation[22] (see Figure 1).
3) The relatively low-field chemical shift of H-3’ (d=
7.35 ppm) in 3a-I, relative to that of 3a-I’ (d=6.90 ppm),
can also be accounted for by the anisotropic effect of the
À
S O bond, which is coplanar to the aromatic ring in 3a-
I. In the same sense, the low d value observed for H-3’ in
3a-II (d=6.38 ppm) is consistent with the anisotropic
shielding effect of the tolyl group in this compound (see
Scheme 6).
4) Finally, the higher value of the chemical shift of the CH3
1
group (13C: d=21.2 ppm; H: d=1.99 ppm) for 3a-I’, rel-
ative to those for 3a-I (13C: d=18.4 ppm; 1H: d=
1.66 ppm) could be a consequence of the association of
the potassium to the nitrogen in 3a-I’, thereby increasing
the electron-withdrawing power of the cyano group, al-
though the formation of a weak intramolecular hydrogen
bond of the CH3 with the lone electron pair at sulfur
could also play some role in these differences.
On the other hand, the NOE cross peaks between the
tolyl ring and H-3’ are absent in 3a-I and 3a-I’, whereas
those of Me group and H-6’ are involved in a complex
system due to the dynamics of the system and the existing
Therefore, as a conclusion from the NMR spectroscopic
analysis, two different types of geometries for the herein re-
ported carbanionic species can be claimed. The first one is a
cyclic geometry, closer to a pyramidal state, with involve-
Chem. Eur. J. 2010, 16, 6317 – 6325
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6323

J. L. Garcꢀa Ruano, A. M. Martꢀn-Castro et al.
Experimental Section
General procedure for the synthesis of compounds 7–10
Method A: KHMDS (0.5m in toluene; 0.24 mL, 1.2 mmol) was added to
a solution of the corresponding (S)-2-[2-(p-tolylsulfinyl)phenyl]acetoni-
trile (0.1 mmol) (3a–g) and [18]crown-6 ether (31.7 mg, 0.12 mmol) in an-
hydrous THF (1 mL) cooled to À788C under argon. The reaction mixture
was stirred at À788C for 10 min and then the electrophile was added.
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 (3ꢄ5 mL), dried (Na2SO4),
and the solvent was evaporated. The resulting diastereoisomeric mixture
was purified by flash column chromatography.
Method B: NHMDS (0.5m in toluene; 0.24 mL, 1.2 mmol) was added to
a solution of the corresponding (S)-2-[2-(p-tolylsulfinyl)phenyl]acetoni-
trile (0.1 mmol) (3a–g) in anhydrous THF (1 mL) cooled to À788C
under argon. The reaction mixture was stirred at À788C for 10 min and
then the electrophile was added. 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 Et2O (3ꢄ5 mL), dried (Na2SO4), and the solvent was evaporated.
The resulting diastereoisomeric mixture was purified by flash column
chromatography.
Compounds (2R,(S)S)-7aA and (2S,(S)S)-7bB:
A diastereoisomeric
50:50 mixture of (2R,(S)S)- and (2S,(S)S)-3a was used as the starting ma-
terial. Benzyl bromide (1.4 equiv) was used as the electrophile, and the
reaction was stirred at À788C for 30 min to give a diastereoisomeric
87:13 mixture of 7aA+7bB, which were separated and purified by flash
column chromatography (eluent CH2Cl2/Et2O/hexane 20:1:5). Combined
yield (for both diastereoisomers): 86%. Diastereoisomer (2R,(S)S)-7aA:
colorless oil: [a]2D0 =À206.3 (c=1.9, CHCl3); 1H NMR: d=7.74 (dd, J=
1.6, 7.5 Hz, 1H), 7.67 and 7.30 (AA’BB’ system, 4H), 7.47–7.35 (m, 2H),
7.26–7.22 (m, 4H), 7.16–7.12 (m, 2H), 3.70 and 3.44 (AB system, J=
13.4 Hz, 2H), 2.39 (s, 3H), 1.89 ppm (s, 3H); 13C NMR: d=146.2, 141.1,
140.8, 138.5, 134.1, 131.8, 130.6 (2C), 130.3, 130.2, 129.9 (2C), 128.2 (2C),
127.6, 126.0, 125.5 (2C), 124.2, 47.9, 40.7, 25.0, 21.3 ppm; IR (film): 2234,
1027 cmÀ1; MS (FAB+): m/z (%): 360 (100) [M+H]+, 225 (8); HRMS
(FAB+): m/z calcd for C23H22NOS [M+H]+: 360.1422; found: 360.1407.
Diastereoisomer (2S,(S)S)-7bB: colorless oil; [a]2D0 =À136.4 (c=0.4,
CHCl3); 1H NMR: d=7.84 (dd, J=1.4 and 7.7 Hz, 1H), 7.75 (dd, J=1.4
and 7.7 Hz, 1H), 7.70–7.64 (m, 2H), 7.53–7.33 (m, 6H), 7.33–7.08 (m,
16H), 3.67 and 3.42 (AB system, J=13.6 Hz, 2H), 2.38 (s, 3H), 2.02 ppm
(s, 3H); 13C NMR: d=146.2, 144.4, 141.4, 141.3, 141.0, 140.9, 138.6, 138.5,
134.5, 134.1, 131.9, 131.8, 130.5 (2C), 130.3, 130.2, 130.1, 130.0 (2C),
129.9, 129.8, 128.2 (3C), 127.6, 127.5, 126.0, 125.7 (2C), 125.5 (2C), 124.2,
122.7, 47.9, 46.9, 45.0, 40.7, 29.0, 25.0, 21.3 ppm; IR (film): 2234,
1027 cmÀ1; MS (ESI+): m/z (%): 360 (51) [M+H]+, 225 (9); HRMS
(ESI+): m/z calcd for C23H22NOS: 360.1422; found: 360.1416.
Scheme 6. 1H and 13C NMR spectroscopic chemical shifts relevant for
structural assignments of sulfinyl benzylic carbanions.
ment of the Na+ ion as contact ion pair, for 3a-II. The
second one is an almost planar and open geometry, exhibit-
ed by the species 3a-I and 3a-I’. In these cases, the smaller
degree of coordination to the anion expected for the K+/
crown ether complexes, as well as their large size, would
prevent the formation of the cyclic intermediate, and these
systems behave as solvated-like ion pairs, thereby differing
in the position at which the metal is associated to the anion
(oxygen in 3a-I and nitrogen in 3a-I’). As the restrictions
imposed by the cyclic geometry are no longer present, inter-
conversion between the trigonal sp2 and the pyramidal sp3
states, with the result of an averaged planar structure, is
probably taking place for the extended 3a-I and 3a-Iꢂ struc-
tures.[23]
Conclusion
In summary, we have demonstrated that benzylic carbanions
derived from 2-alkyl-2-p-tolylsulfinylphenylacetonitriles
show a stereodivergent behavior in their reactions with alkyl
halides in the presence of KHMDS/[18]crown-6 ether or
NHMDS. This stereodivergence allows the highly stereose-
lective generation of chiral quaternary benzylic carbon cen-
ters in their two possible configurations. This behavior
seems to be associated with the planar or pyramidal struc-
ture adopted by the carbanion, which in turn is related to
the conditions (solvent, additive, and mainly counterion)
used in the reaction. NMR spectroscopy has proved to be a
valuable instrument for determining structural differences in
the carbanionic intermediates.
Acknowledgements
Financial support of this work by the Ministerio de Ciencia y Tecnologꢀa
(CTQ2009-12168), UAM-Comunidad de Madrid (CCG08-UAM/PPQ-
4235), and CAM (S-2009-PPQ-1634) are gratefully acknowledged. E.T.
thanks Ministerio de Educaciꢂn y Ciencia for a predoctoral fellowship.
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ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 6317 – 6325

Tolylsulfinylacetonitriles
FULL PAPER
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À
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for ethylation, and 10 for allylation. The lower-case letter refers the
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[18] To clarify the discussion, an sp2 hybridization has been assigned to
carbanionic centers of species I and I’. However, the rather small
energetic difference between the two plausible pyramidal (sp3) or
trigonal (sp2) states for free carbanions suggests that species I and I’
should be more accurately described as flattened pyramidal struc-
tures with intermediate hybridization between sp3 and sp2.
[19] This structure has also been suggested for some lithium 2-p-tolylsul-
finyl benzyl carbanions on the basis of theoretical calculations (see
ref. [10]).
[20] Structures similar to 3a-I’ have been suggested for other benzylic
carbanions stabilized by cyano groups and generated in the presence
of [18]crown-6 ether (see ref. [11] and references therein).
[21] Reactions were considerably slower in toluene than in THF and the
formation of alkyl (Et, Pr, or Bn) 2-p-tolylsulfinylphenyl ketones
(14–16) was detected.
[22] This effect is quite analogous to the well-known influence reported
for an axial methyl group on C3 and C5 positions of a cyclohexane
ring.
[23] In fact, the existence of a rather small energy difference between
the two possible pyramidal (sp3) or trigonal (sp2) states precludes
the presence of a unique geometry (see: G. Vanermen, S. Toppet,
M. Van Beylen, P. Geerlings, J. Chem. Soc. Perkin. Trans. 2 1986,
707).
Received: December 22, 2009
Published online: April 21, 2010
Chem. Eur. J. 2010, 16, 6317 – 6325
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6325