Highly stereoselective benzylation of N-sulfinylketimines

Article abstract of DOI:10.1021/ja0515203

The benzylation of N-sulfinyl ketimines with 2-(p-tolylsulfinyl) ethylbenzene and LDA afford t-alkylamines in good yields. The configuration at each one of the new chiral centers simultaneously created in this reaction is controlled by the configuration o

Full text of DOI:10.1021/ja0515203

Published on Web 08/27/2005
Highly Stereoselective Benzylation of N-Sulfinylketimines
Jose´ Luis Garc´ıa Ruano,* Jose´ Alema´n, and Alejandro Parra
Contribution from the Departamento de Qu´ımica Orga´nica, Facultad de Ciencias,
UniVersidad Auto´noma de Madrid, Cantoblanco, 28049 Madrid, Spain
Received March 9, 2005; E-mail: joseluis.garcia.ruano@uam.es
Abstract: The benzylation of N-sulfinyl ketimines with 2-(p-tolylsulfinyl)ethylbenzene and LDA afford
t-alkylamines in good yields. The configuration at each one of the new chiral centers simultaneously created
in this reaction is controlled by the configuration of the sulfinyl groups at the nucleophile and electrophile,
respectively. Thus, the reactions of the (S)-sulfoxide 6 with the N-(S)-sulfinylketimines 3 only yield the anti
diastereoisomers 18, whereas the syn diastereoisomers 19 are exclusively formed in reactions of (S)-6
with N-(R)-sulfinylketimines 3. After a two-step desulfinylation process ((i) TFA, (ii) Ra-Ni), this reaction
provides a procedure for synthesizing any epimer of R,R-dibranched â-alkylarylamines in optically pure
form by choosing the configuration of the starting materials. A similar behavior is observed for carbanions
derived from the O-protected 2-(p-tolylsulfinyl) benzyl alcohol 7 thus allowing the synthesis of the optically
pure anti- and syn-1,2-amino alcohols containing a chiral quaternary carbon adjacent to the nitrogen.
Scheme 1
Introduction
Nucleophilic addition of organometallics to CdN bonds from
chiral aldimines1 provides one of the most direct and attractive
routes to chiral amino derivatives. The moderate reactivities and
stereoselectivities associated with the use of N-alkyl or aryl
aldimines could be substantially improved by using enantiopure
N-sulfinylimines,2 as it has been evidenced by several authors,
and expecially by the groups of Davis3 and Ellman.4 Conversely,
the reactions of organometallics with ketimines, affording
optically pure R,R-dibranched amines, have been much less
explored, mainly due to the lower reactivity of these electro-
philes and their propensity to enolization.5 Moreover, the facile
E,Z isomerization decreases the possibility of diasteroselective
processes. These problems justified why only some reactions
of limited scope had been reported until 1999,6 when Ellman7
showed that reactions of organometallics with N-tert-butane-
sulfinylketimines in the presence of Me3Al can be considered
a general method to prepare R,R-dibranched amines. One of
the problems to be solved in this field concerns the stereose-
lectivity control in reactions of prochiral carbanions with imines,
resulting in the simultaneous formation of two chiral centers in
a single step. In this regard we discovered that the organolithium
derived from 1, stabilized by R-sulfinyl groups (eq 1, Scheme
1) reacted with aromatic N-sulfinylaldimines 2 with complete
control of the stereoselectivity.8 More recently we reported that
carbanions derived from 5-7, and stabilized by γ-sulfinyl
groups (eq 2, Scheme 2), were also efficient in this task even
in case of the N-sulfinyl derivatives of enolizable aliphatic
aldimines.9 With these γ-sulfinyl carbanions it was also possible
to solve the problem of the stereoselective benzylation of imines,
which had so far proved to be of difficult solution.10
(1) (a) Volkmann, R. A. In ComprehensiVe Organic Synthesis; Schreiber, S.
L., Ed.; Pergamon Press: Oxford, 1991; Vol. 1, Chapter 1.12, p 355. (b)
Risch, N.; Arend, M. In StereoselectiVe Synthesis (Houben-Weyl); Hel-
mechen, G., Hoffmann, R. W., Mulzer, J., Schauman, E., Eds.; Georg
Thieme Verlag: Stutgart, 1995; E21b, D.1.4, p 1833. (c) Enders, D.;
Reinhold, U. Tetrahedron: Asymmetry 1997, 8, 1895.
(2) Davis, F. A.; Reddy, R. E.; Szewczyk, J. M.; Reddy, G. V.; Portonovo, P.
S.; Zhang, H.; Fanelli, D.; Reddy, R. T.; Zhou, P.; Carroll, P. J. J. Org.
Chem. 1997, 62, 2555.
(3) (a) Davis, F. A.; Zhou, P.; Chen, B. C. Chem. Soc. ReV. 1998, 27, 13 and
references therein. (b) Zhou, P.; Chen, B.-C.; Davis, F. A. Tetrahedron
2004, 50, 8003. (c) Davis, F. A.; Nolt, M. B.; Wu, Y.; Prasad, K. R.; Li,
D.; Yang, B.; Bowen, K.; Lee, S. H.; Eardley, J. H. J. Org. Chem. 2005,
70, 2184. (d) Davis, F. A.; Yang, B. J. Am. Chem. Soc. 2005, 127, 8398-
8407.
(4) (a) Cogan, D. A.; Liu, G.; Kim, K.; Backes, B. J.; Ellman, J. A. J. Am.
Chem. Soc. 1998, 120, 8011. (b) Liu, G.; Cogan, D. A.; Owens, T. D.;
Tang, T. P.; Ellman, J. A. J. Org. Chem. 1999, 64, 1278. (c) Ellman, J. A.;
Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984 and references
therein. (d) McMahon, J. P.; Ellman, J. A. Org. Lett. 2004, 6, 1645. (e)
Schenkel, L. B.; Ellman, J. A. Org. Lett. 2004, 6, 3621. (f) Kochi, T.;
Ellman, J. A. J. Am. Chem. Soc. 2004, 126, 15652. (g) Weix, D. J.; Shi,
Y.; Ellman, J. A. J. Am. Chem. Soc. 2005, 127, 1092.
(6) (a) Yamamoto, Y.; Asao, N. Chem. ReV. 1993, 93, 2207. (b) Spero, D.
M.; Kapadia, S. R. J. Org. Chem. 1997, 62, 5537. (c) Steining, A. G.;
Spero, M. D. J. Org. Chem. 1999, 64, 2406.
(7) Cogan, D. A.; Liu, G.; Ellman, J. Tetrahedron 1999, 55, 8883.
(8) (a) Garc´ıa Ruano, J. L.; Alcudia, A.; Prado, M.; Barros, D.; Maestro, M.
C.; Ferna´ndez, I. J. Org. Chem. 2000, 65, 2856.
(9) (a) Garc´ıa Ruano, J. L.; Alema´n, J.; Soriano, J. F. Org. Lett. 2003, 5, 677.
(b) Garc´ıa Ruano, J. L.; Alema´n, J. Org. Lett. 2003, 5, 4513.
(5) (a) Stork, G.; Dowd, S. R. J. Am. Chem. Soc. 1963, 85, 2178. (b) Hua, D.
H.; Miao, S. W.; Chen, J. S.; Iguchi, S. J. Org. Chem. 1991, 56, 4. (c)
Hua, D. H.; Lagneau, N.; Wang, H.; Chen, J. S. Tetrahedron: Asymmetry,
1995, 6, 349.
9
13048
J. AM. CHEM. SOC. 2005, 127, 13048-13054
10.1021/ja0515203 CCC: $30.25 © 2005 American Chemical Society

Highly Stereoselective Benzylation of N-Sulfinylketimines
A R T I C L E S
Scheme 2
Table 1. Reactions of (S)-5 with Different N-Thioderivatives of
Benzylideneketimines
The only report concerning reactions of prochiral carbanions
with enolizable N-sulfinylketimines 3 involved the use of
R-sulfinylated ethyl-lithium to afford the R,R-dibranched â-sul-
finylamines11 (eq 1, Scheme 1) in a highly stereoselective
manner. These results suggested that stabilized sulfinyl carban-
ions were able to overcome the problems associated with the
enolization of the N-sulfinylketimines. This prompted us to
investigate the behavior of these electrophiles in their reactions
with ortho-sulfinylbenzylcarbanions, in the search of a general
method for synthesizing â-substituted R,R-dibranched amines.
In this work we describe the reactions of compounds 5-7 with
N-sulfinylketimines (3) as well as the transformation of the
resulting compounds into the desired optically pure amines
(Scheme 2).
products ratio
(yield, %)
conversion
(%)
entry
nucleophile
ketimine
1
2
3
4
5
6
7
8
9
(S)-5
(S)-5
(S)-5
(S)-5
(S)-6
(S)-6
(S)-6
(S)-6
(S)-6
9a
9b
(S)-3a
(R)-3a
9a
10a (0)
10b (89)
67/33; 11a/12a
13a (75)
10/90; 15a/16a
17b (94)
anti-18a (80)
syn-19a (70)
40/60: 20a/anti-18a
-
100
58
100
10-15
100
90
Results and Discussion
9b
(S)-3a
(R)-3a
(S)-3a
A. Optimization Studies for the Addition of γ-Sulfinyl-
carbanions to Ketimines. We first studied the behavior of (S)-5
with different N-sulfinylated benzylideneketimines in the intent
to evaluate viability and stereoselectivity of these reactions, as
well as the problems emerging from the enolization of the
electrophiles. The reactions of (S)-5 with the N-sulfonyl
methylbenzylidenimine 9a12 were completely unfruitful under
different conditions, with the starting materials being recovered
unaltered (entry 1, Table 1). Quick enolization may be respon-
sible for this behavior as it can be inferred from the fact that
diphenylketimine 9b, lacking enolizable protons, reacts com-
pletely under the same conditions and in few minutes, yielding
10b in 89% yield (entry 2). Sulfinyl derivatives are less prone
to enolization, which in turn is dependent on the configuration
at the N-sulfinyl group. Reaction of (S)-5 with (S)-3a in the
presence of LDA leads to a 67:33 mixture of two diastereo-
isomers 11a and 12a (34% de), readily separated by chroma-
tography (entry 3). Both the low stereoselectivity and moderated
conversion observed in this reaction (<60%), which could not
be improved by extending the reaction time, could be a
consequence of the enolization, fortunately less significant with
N-sulfonyl ketimines.13
90
50
results indicate that a completely stereoselective benzylation of
the CdN at ketimines can be achieved by using the matched
pair N-sulfinylketimine/ortho-sulfinylbenzylcarbanion because
of the favorable balance enolization/nucleophilic addition. The
configuration at the chiral carbon of the resulting amine is
determined by the configuration of the starting reagents.
Hydrogenolysis of the N-S bond at compounds 12a and 13a
gave the same compound 14a, thus revealing that they have
identical configuration at the chiral carbon (see Supporting
Information).
We then studied the reactions with the secondary carbanion
derived from 6. In general, the methyl group at the benzylic
position decreases the significance of the enolization and
provides better results. Thus, reactions with the N-sulfonyl-
derivative 9a gives a mixture of diastereoisomers 15a and 16a
in low but significant conversions (ranging from 10 to 15% in
different experiences, entry 5). As in the case of reactions from
(S)-5, (S)-6 reacts with 9b yielding 17b in almost quantitative
yield (entry 6) and with complete stereoselectivity (de g 98%),
indicating that the configuration at the benzylic carbon is
completely controlled by the ortho-sulfinyl group.15 Absolute
configuration of 17b was unequivocally established as R,SS by
X-ray diffraction analysis (see Supporting Information).
We then studied the reaction of 6-Li with each of the
enantiomeric N-p-tolylsulfinyl derivatives of the phenylmeth-
ylketimines (S)-3a and (R)-3a. As in the previous case, the
change in the sulfur function into sulfinyl improves the
conversion, which is now complete with both enantiomeric
To our delight, reaction of (S)-5 with (R)-3a afforded 13a as
the only isomer and in good yield (entry 4, Table 1). This
behavior reveals the existence of a matched and a mismatched
pair of reagents, being the first formed by the sulfoxide and the
imine with different configurations at the sulfur atom.14 These
(10) (a) Moreau, P.; Essiz, M.; Merour, J.-Y.; Bouzard, D. Tetrahedron:
Asymmetry 1997, 8, 591. (b) Barrow, J. C.; Ngo, P. L.; Pellicore, J. M.;
Selnick, H. G.; Nantermet, P. G. Tetrahedron Lett. 2001, 42, 2051. (c)
Davis, F. A.; McCoull, W. J. Org. Chem. 1999, 64, 3396. (d) Davis, F. A.;
Mohanty, P. K.; Burns, D. M.; Andemichael, Y. W. Org. Lett. 2000, 2,
3902. (e) Davis, F. A.; Andemichael, Y. W. Tetrahedron Lett. 1999, 49,
3099. (f) Davis, F. A.; Pradyudmna, K. M. J. Org. Chem. 2002, 67, 1290.
(11) Garc´ıa Ruano, J. L.; Alema´n, J.; Prado, M.; Fernandez, I. J. Org. Chem.
2004, 69, 4454.
(12) Garcia Ruano, J. L.; Alema´n, J.; Cid, M. B.; Parra, A. Org. Lett. 2005, 6,
179.
(13) The obtained results in reaction of (S)-5 and (S)-3 suggest that reaction
rates for enolization and nucleophilic addition processes must be similar.
(14) A similar situation had been found in reactions of (S)-5 with aldimines
(ref 9) but being the reagents with the same configuration at sulphur those
conforming the matched pair.
(15) It suggests that 15a and 16a, formed from 9a, must be epimers at the aminic
carbon.
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J. AM. CHEM. SOC. VOL. 127, NO. 37, 2005 13049

A R T I C L E S
Scheme 3
Garc´ıa Ruano et al.
Table 2. Reactions of (S)-6 with N-Sulfinylketimines (S)- and
(R)-3
ketimines. However the most interesting results concern the
stereoselectivity, since both reactions are completely stereose-
lective. Thus, reaction of (S)-6 with (S)-3a, in the presence of
LDA, progressed completely into only one diastereoisomer anti-
18a, which was isolated in 80% yield (entry 7, Table 1), whereas
(R)-3a was transformed into syn-19a (isolated yield 70%) under
similar conditions (entry 8, Table 1). When the latter reaction
was performed in the presence of HMPA (5 equiv), the
conversion decreased till 50% and a mixture of diastereoisomers,
presumably epimers at the benzylic position,16 was obtained
(entry 9).
Several conclusions can be deduced from these results, and
the first one concerns reactivity. The change of the N-sulfonyl
into the N-sulfinyl group at the imine nitrogen must reduce the
enolization rate at a higher level than the reactivity toward the
nucleophile, thus allowing the reaction to complete before
enolization becomes significant. We were also able to demon-
strate that the reactivity of sulfinyl and sulfonyl derivatives is
not that different by performing a competitive reaction between
N-sulfonylketimine 9b (1 equiv), N-sulfinylketimine (S)-3b (1
equiv), and (S)-6 (1 equiv). As reaction products we could only
identify a 68/32 mixture of sulfonylamine 17b and sulfinylamine
21b (Scheme 3). The same ratio was also observed for (S)-3b/
9b, the unreacted starting materials. This result indicates that
9b is only two times more reactive than (S)-3b. On the other
hand we have also studied the reaction of (S)-6 with racemic
(()-3a (2 equiv). The (R) isomer reacts only slightly faster than
the (S) isomer (a 45/55 mixture of anti-18a/syn-19a was
obtained) which suggests that the difference in the reaction rates
of the N-sulfonyl derivative and the (R) enantiomer of the
N-sulfinyl derivative must be even lower.
The second conclusion concerns stereoselectivity. The fact
that (R)-3a only gives the syn diastereoisomer syn-19a, whereas
(S)-3a affords anti-18a, evidences that the configuration at the
quaternary carbon adjacent to nitrogen is mainly controlled by
the N-sulfinyl group, whereas the configuration at the tertiary
benzylic carbon is only dependent on the configuration at
carbanion. This behavior allows the synthesis of the four
possible diastereoisomers of the R,R′-dibranched â-phenyl
propylamines by choosing the configuration of the starting
reagents.
Finally, the third conclusion concerns the influence of the
Li+ metal on the stereochemical course of the reaction. The
results on entry 9 suggest some kind of association between
the metal and the reagents that must be determinant for the high
stereoselectivity observed.
reagent
(config)
product
entry
R1
(yield %)
% de
1
2
3
4
5
Ph
(S)-3a
(S)-3c
(S)-3d
(S)-3e
(S)-3f
(S)-3g
(S)-3′gb
(R)-3c
(R)-3d
(R)-3a
(R)-3e
(R)-3f
(R)-3g
(R)-3′gb
anti-18a (80)
anti-18b (66)
anti-18d (69)
anti-18e (64)
anti-18f (41)
anti-18g (-)
anti-18′g (58)
syn-19c (67)
syn-19d (73)
syn-19a (70)
syn-19e (61)
syn-19f (40)
syn-19g (-)
syn-19′g (58)
g98
g98
g98
g98
50
p-MeOC6H4
p-MeC6H4
p-BrC6H4
p-CNC6H4
i-Pr
6
-
7a
8
i-Pr
g98
g98
g98
g98
g98
55
p-MeOC6H4
p-MeC6H4
Ph
p-BrC6H4
p-CNC6H4
i-Pr
9
10
11
12
13
14a
-
i-Pr
g98
a In the presence of Me3Al. b N-tert-Butanesulfinylketimine was used.
with other (S)-ketimines containing electron-donating (S)-3d or
weakly electron-withdrawing groups, (S)-3e, which allowed us
to synthesize the amines anti-18d and anti-18e in a completely
stereoselective manner (entries 3 and 4, Table 2). The behavior
of the corresponding (R)-N-sulfinyl ketimines, (R)-3c-e, was
analogous to that of the (S) enantiomers in their reactions with
(S)-6, but now yielding syn-19c-e amines (entries 8-11, Table
2). The yields obtained in all these reactions ranged from 60 to
80%, and the optical purity of the amines is complete (g98%
de). Starting from (S)- and (R)-3f ketimines, which contain a
strongly electron-withdrawing group in the aromatic ring, the
favored diastereoisomers are the expected anti-18f and syn-19f,
respectively, but the yield and the stereoselectivity decrease
significantly (entries 5 and 12). In these cases the conversion
was only 50%. We also studied the behavior of the N-p-
tolylsulfinyldialkylketimines (S)-3g and (R)-3g and their cor-
responding tert-butanesulfinylketimines, (S)-3′g and (R)-3′g.
These compounds do not undergo addition under the reaction
conditions used for benzylideneimines (entries 6 and 12).
However, the addition of Me3Al to the reaction mixture7
determine the transformation of the (S)- and (R)-tert-butane-
sulfinyl derivatives into anti-18′g and syn-19′g, respectively,
in a completely stereoselective manner (entries 7 and 14, Table
2).17
These results indicate that ortho-sulfinylbenzylcarbanions are
able to perform the stereoselective benzylation of dialkyl and
arylalkyl N-sulfinylketimines with complete control of the
configuration at the two chiral centers formed in the reaction.
This allows the synthesis of all possible amine diastereoisomers
B. Reaction Scope for the Addition of γ-Sulfinylcarbanion
to N-Sulfinylketimines. We have studied the behavior of
different N-sulfinylketimines with (S)-6 in order to check the
scope of the reaction. The results are indicated in Table 2. The
reaction of (S)-6 with (S)-3c at -78 °C affords anti-18c as the
only product (entry 2, Table 2). Similar results were obtained
(17) These reactions were performed on the racemic (()-3′g leading to a 1:1
mixture of the expected anti-18′g and syn-19′g, easily separated by
chromatography. Imine (()-3g is not stable enough in the presence of Me3-
Al and decomposes into the corresponding ketone and N-sulfinamide.
(16) This result it was obtained in the case of the carbanion with ketones. See
ref 19.
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Highly Stereoselective Benzylation of N-Sulfinylketimines
A R T I C L E S
Scheme 4. Conversion of Some anti-18 and syn-19 into Free Amines
by choosing the adequate configurations at the sulfoxide (which
controls the benzyl center) and at the N-sulfinylketimine
(controls the aminic carbon). The configurational assignments
of 18 and 19 were based on their NMR parameters, chemical
correlations, and X-ray diffraction studies (see Supporting
Information).
reason could be responsible of the low conversion observed for
(S)-3f. On the other hand, by comparing the transition states in
reactions starting from (S)-5 and (S)-6, we can conclude that
the change of Me by H leads to the relative stabilization of BR
and BS with respect to AR and AS, respectively {[(Ar/Me) -
(Ar/H)] > [(Me/Me) - (Me/H)]}. As a consequence ∆E(BR -
AR) must be higher and ∆E(AS - BS) must be lower for (S)-5
than for (S)-6. This would also explain why the reaction between
(S)-5 and (R)-3a, evolving through TSs BR and AR, is
completely stereoselective, whereas that of (S)-5 with (S)-3a,
evolving through TSs BS and AS, is only moderately stereose-
lective.
The last step of this methodology involves the synthesis of
the free amines by sequential desulfinylation of compounds anti-
18 and syn-19, which can be performed by subsequent reaction
of compounds anti-18 and syn-19 with TFA (hydrogenolysis
of the N-S bonds) and Ra-Ni (hydrogenolysis of the C-S
bond). We have illustrated these desulfinylation processes with
the compounds indicated in Scheme 2. Reactions of anti-18 and
syn-19 with TFA (MeOH, 0 °C) yielded the amino sulfoxides
anti-22 and syn-22, respectively, in excellent yield (80-97%).
These, in turn, react with Ra-Ni (THF, rt) also in high yields
(80-91%), affording diastereomeric free amines anti-23 and
syn-23 without appreciable epimerization (Scheme 4).18
C. Stereochemical Models. The stereochemical model
proposed to explain the reactions of (S)-5 and (S)-6 with
N-sulfinyl aldimines9 also accounts for the results obtained with
ketimines and for the differences observed between both types
of electrophiles. The association of the lone electron pair at the
imine nitrogen to the benzyllithium, whose presumably most
stable conformation is the one depicted in Figure 1,19 must be
previous to the nucleophilic attack. The four most stable
transition states (the sub index denotes the configuration of the
N-sulfinylimine) must display the lone electron pair at the sulfur
atom oriented toward the nucleophile thus minimizing steric
repulsions (Figure 1). As BS and AR exhibit the strongly
destabilizing (Tol/Me)1,3-p interaction,20 only AS (yielding syn-
19) and BR (yielding anti-18) must be considered to explain
the observed results. The fact that the reactivity of the N-sulfonyl
derivatives is lower than expected (it is only similar to that of
the N-sulfinyl derivatives) can be due to the low electronic
availability of the imine nitrogen, making difficult its association
to the lithium and allowing that the competition with the
enolization processes to decrease the conversion level. A similar
D. Synthesis of Syn and Anti r,a-Dibranched â-Phenyl
Ethanolamines. The good results obtained in these reactions
prompted us to explore the applicability of the method in the
synthesis of â-amino alcohols in both syn and anti configura-
tions, starting from the protected benzyl alcohol (S)-7. Amino
alcohols are structural subunits with an overspread use as
stationary phases in HPLC,21 as key synthetic intermediates for
synthesizing biologically active compounds22 and as chiral
ligands or auxiliaries in asymmetric reactions.23 In this latter
field triorganyl substituted amino ethanol compounds may
potentially have a major significance because of their restricted
conformational mobility imposed by the quaternary carbon.
(18) Epimerization at chiral centers in the hydrogenolysis of the C-S bonds
with Ra-Ni has been observed in some cases. See: Garc´ıa Ruano, J. L.;
Paredes, C. G.; Hamdouchi, C. Tetrahedron: Asymmetry 1999, 10, 2935
and references therein.
(19) Garc´ıa Ruano, J. L.; Carren˜o, M. C.; Toledo, M. A.; Aguirre, J. M.; Aranda,
M.; Fischer, J. Angew. Chem., Int. Ed. 2000, 39, 2736.
(20) These transition states would not be negligible for N-sulfinylaldimines and
would explain the differences in their behaviour with respect to the
N-sulfinylketimines.
Figure 1. Transition states for reactions of (S)-5 and (S)-6 with (R)-3 (AR
and BR) and (S)-3 (AS and BS).
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J. AM. CHEM. SOC. VOL. 127, NO. 37, 2005 13051

A R T I C L E S
Garc´ıa Ruano et al.
Scheme 5. Synthesis of Syn and Anti â-Amino Alcohols
79 were previously synthesized. All N-sulfinylketimines 3a-g were
synthesized using Davis’ methodology. N-Sulfinylketimine 3b was
described by Annunziata;25 3c (R ) p-MeOC6H4), 3d (R ) p-MeC6H4),
and 3a (R ) Ph) were described by Davis;26 3f (R ) p-CNC6H4) was
described by Garc´ıa Ruano;12 and 3e (R ) p-Br-C6H4) is described in
the Supporting Information. The N-tert-butylsulfinylketimine 3g′ was
synthesized following Ellman’ procedure.7
General Procedure for Benzylation of N-Sulfinylketimines. A
solution of n-BuLi (0.6 mmol, 2.3 M in hexane) was added to iPr2NH
(0.9 mmol) in THF (3 mL) at 0 °C. After stirring for 20 min the mixture
was cooled to -78 °C. A solution of sulfoxide (S)-6 (0.5 mmol) in
THF (2 mL) was added. After stirring for 30 min, the corresponding
sulfinylketimine 3a-g (0.5 mmol) was added at -78 °C. When the
reaction completed (20-30 min), the mixture was hydrolyzed (saturated
NH4Cl), extracted (3 × 10 mL Et2O), washed (2 × 10 mL sat NH4Cl),
and dried (MgSO4) and the solvent was removed under reduced
pressure. Compounds were purified by flash silica gel column (eluent
is indicated in each case).
However, to our knowledge, few examples concerning the
asymmetric synthesis of these compounds have been reported.24
The reaction of (S)-7 with LDA at -78 °C and subsequent
treatment with compound (S)-3a for 15 min yielded the amino
alcohol anti-24 (55% yield) as the only diastereoisomer. The
cleavage of the N-S and C-S bonds with TFA and Ra-Ni,
respectively, afforded the enantiomerically pure 2-aminoethanol
derivative (1S,2S)-anti-25 (Scheme 5). Likewise, the reaction
of (S)-7 with (R)-3a afforded exclusively the syn-24 isomer
(77% yield), easily transformed into (1S,2R)-syn-25 (Scheme
5). Starting from (S)-7 it would be possible to synthesize the
other two diastereoisomeric â-amino alcohols.
Conclusion
In summary, we have developed a general and highly
stereoselective method to obtain R,R-dibranched â-phenyl
propylamines and ethanolamines, in any of their possible
configurations, through the reaction of the ortho-sulfinylben-
zylcarbanions derived from 5-7 with the N-sulfinylketimines
3. Configuration at each of the newly formed chiral centers is
controlled by the configuration of the sulfinyl groups at the
reagents.
N-{1,2-Diphenyl-[(S)-3-(p-toluenesulfinyl)phenyl]ethyl}-p-tolu-
enesulfonamide (10b): N-Sulfonylketimine 9b was used as electro-
phile. Chromatography: n-hexane-AcOEt 2:1; yield: 89%; white solid;
mp: 92-94 °C; [R]D20 -43.5 (c 0.3, CHCl3); IR (NaCl): 3110, 1493,
1
1331, 1158, 1055, 1032 cm-1; H NMR (300 MHz, CDCl3): δ 7.53
(dd, J ) 6.4, 1.2 Hz, 1H), 7.25-6.82 (m, 20H), 6.39 (d, J ) 7.7 Hz,
1H), 7.09 (d, J ) 13.6 Hz, 1H), 4.15 (d, J ) 13.5 Hz, 1H), 3.30 (d,
J ) 13.5 Hz, 1H), 2.29 (s, 3H), 2.25 (s, 3H); 13C NMR (75 MHz,
CDCl3): δ 143.9, 141.9, 141.4, 141.2 (2C), 141.1, 139.5, 135.3, 133.7,
131.0, 129.9(2C), 129.5, 129.1, 128.6, 127.6, 127.4(2C), 127.3, 127.2,
126.4, 125.0, 67.6, 42.9, 30.9, 21.4. Anal. Calcd for C32H27NO2S2: C,
73.67; H, 5.22; N, 2.68; S, 12.29. Found: C, 73.51; H, 5.13; N, 2.68;
S, 12.67.
Experimental Section
General Procedures. All flasks were flame-dried under a stream
of argon and cooled before use. Solvents and solutions were transferred
with syringes and cannulas using standard inert atmosphere techniques.
1H NMR spectra were acquired at either 200 or 300 MHz, and 13C
NMR were acquired at 50 or 75 MHz (unless otherwise indicated).
Chemical shifts (δ) are reported in ppm relative to CDCl3 (7.26 and
77.0 ppm). Mass spectra (MS) were determined by FAB. All reactions
were carried out in anhydrous solvents and under argon atmosphere.
THF and Et2O were distilled from sodium-benzophenone under argon.
Dichloromethane was distilled with calcium hydride. i-Pr2NH was
distilled with KOH. Flash silica gel column chromatography was
performed using silica gel Merk-60 (230-400 mesh). n-BuLi (2.5 M
solution in hexane) was purchased from Aldrich. Compounds 5, 6, and
[1R,(S)R]-N-(1-Methyl-1-phenyl-2-{2-[(S)-p-tolylsulfinyl]phenyl}-
ethyl)-p-toluensulfinamide (13a): (R)-N-Sulfinylketimine 3a was used
as electrophile. Chromatography: n-hexane-AcOEt 2:1; yield: 75%;
20
white solid; [R]D -84.4 (c 0.45, acetone); IR (NaCl): 3181, 1493,
1470, 1118, 1085 cm-1; 1H NMR (300 MHz, CDCl3): δ 7.57 (dd, J )
6.2, 1.5 Hz, 1H), 7.51 (d, J ) 8.1 Hz, 2H), 7.43 (dd, J ) 7.0, 1.1 Hz,
2H), 7.34-7.14 (m, 9H), 7.07 (d, J ) 8.1 Hz, 2H), 6.84 (dd, J ) 6.4,
1.1 Hz, 1H), 4.80 (bs, 1H), 3.40 (d, J ) 13.9 Hz, 1H), 3.20 (dd, J )
13.9 Hz, 1H), 2.31 (s, 3H), 2.24 (s, 3H), 1.88 (s, 3H); 13C NMR (75
MHz, CDCl3): δ 145.2, 144.1, 143.4, 141.3, 141.2, 140.9, 135.3, 132.3,
130.8, 129.9, 129.6, 128.5, 128.3, 127.7, 127.2, 126.6, 125.5, 125.4,
62.2, 53.5, 46.6, 27.5, 21.4. Anal. Calcd for C29H29NO2S2: C, 71.42;
H, 5.99; N, 2.87; S, 13.15. Found: C, 71.50; H, 6.01; N, 2.90; S, 13.40.
[1S,(S)R]-N-(1-Methyl-1-phenyl-2-{2-[(S)-p-tolylsulfinyl]phenyl}-
ethyl)-p-toluensulfinamide (11a). (S)-N-Sulfinylketimine 3a was used
as electrophile. This compound was obtained as a major diastereoisomer.
Chromatography: n-hexane-AcOEt 3:1; yield: 34%; white solid;
(21) Yuki, Y.; Saigo, K.; Tachibana, K.; Hasegava, M. Chem. Lett. 1986, 1347.
(22) Relevant bioactive naturally occurring amino alcohols: (a) Nikolau, K.
C.; Mitchel, H. J.; van Delft, F. L.; Rubsam, F.; Rodr´ıguez, R. M. Angew.
Chem., Int. Ed. 1998, 37, 1871. (b) Heightman, T. D.; Vasella, A. T. Angew.
Chem., Int. Ed. 1998, 38, 750. (c) Kolter, T.; Sandhoff, K. Angew. Chem.,
Int. Ed. 1998, 38, 1532. (d) Bergmeier, S. C. Tetrahedron 2000, 56, 2561.
(23) Recent reviews: (a) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. ReV.
1996, 96, 835. (b) Bloch, R. Chem. ReV. 1998, 98, 1407. (c) Reetz, M. T.
Chem. ReV. 1999, 99, 1121. (d) ComprehensiVe Asymmetric Catalyst;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag: Berlin,
1999. (e) Ojima, I. Catalytic Asymmetric Synthesis, 2nd ed.; VCH: New
York, 2000. (f) Bergmeier, S. C. Tetrahedron 2000, 56, 2561. (g) Bonini,
C.; Righi, G. Tetrahedron 2002, 58, 4981. (h) Tang, Z.; Jiang, F.; Yu,
L.-T.; Xin, C.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z.; Wu, Y.-D. J. Am.
Chem. Soc. 2003, 125, 5262.
(25) Annunziata, R.; Cinquini, M.; Cozzi, F. J. Chem. Soc., Perkin Trans. 1
1982, 2, 339.
(26) Davis, F. A.; Seung, L.; Zhang, H.; Fanelli, D. L. J. Org. Chem. 2000, 65,
(24) Fuller, A. A.; Chen, B.; Minter, A.; Mapp. A. Synlett 2004, 8, 1409.
8704.
9
13052 J. AM. CHEM. SOC. VOL. 127, NO. 37, 2005

Highly Stereoselective Benzylation of N-Sulfinylketimines
A R T I C L E S
20
mp: 75-77 °C; [R]D -115.9 (c 0.71, acetone); IR (NaCl): 3186,
[2S,3S,(S)S]-N-{2-(4-Methylphenyl)-3-[(S)-2-(p-toluenesulfinyl)-
phenyl]butyl}-p-toluenesulfinamide (anti-18d): (S)-N-Sulfinylketimine
3d was used as electrophile. In this case 2 equiv of the carbanion
derivate from 6 were used. Chromatography: n-hexane-AcOEt 3:2;
1493, 1472, 1086, 1085, 1058, 1038 cm-1 1H NMR (300 MHz,
;
CDCl3): δ 7.75 (dd, J ) 6.2, 1.5 Hz, 1H), 7.49 (dd, J ) 7.3, 1.3 Hz,
2H), 7.36-7.31 (m, 6H), 7.21-7.15 (m, 6H), 7.07 (d, J ) 8.1 Hz,
2H), 5.02 (bs, 1H), 3.46 (d, J ) 13.7, 1H), 3.29 (d, J ) 13.7 Hz, 1H),
2.32 (s, 3H), 2.24 (s, 3H), 1.75 (s, 3H); 13C NMR (75 MHz, CDCl3):
δ 145.7, 144.9, 143.3, 141.5, 141.4, 141.1, 135.7, 132.6, 130.8, 129.9,
129.5, 128.5, 127.9, 127.5, 126.4, 126.2, 125.5, 125.4, 61.9, 43.8, 27.6,
21.4 (2C). Anal. Calcd for C29H29NO2S2: C, 71.42; H, 5.99; N, 2.87;
S, 13.15. Found: C, 71.65; H, 6.11; N, 2.73; S, 12.67.
20
yield: 69%; white solid; mp: 172-175 °C; [R]D +67.6 (c 2.0,
CHCl3); IR (NaCl): 3423, 3243, 2950, 1638, 1440, 1064, 810, 753
cm-1; 1H NMR (300 MHz, CDCl3): δ 7.74 (dd, J ) 7.6, 1.1 Hz, 1H),
7.65 (t, J ) 7.5 Hz, 1H), 7.60 (d, J ) 8.3 Hz, 1H), 7.56-7.52 (m,
1H), 7.53-7.51 (m, 2H), 7.21 (d, J ) 6.9 Hz, 4H), 7.14 (d, J ) 6.8
Hz, 4H), 7.01 (d, J ) 8.2 Hz, 2H), 6.92 (bs, 1H), 3.90 (q, J ) 7.1 Hz,
1H), 2.40 (s, 3H), 2.37 (s, 3H), 2.30 (s, 3H), 1.90 (s, 3H), 0.57 (d, J )
7.1 Hz, 3H);13C NMR (75 MHz, CDCl3): δ 145.0, 144.1, 143.5, 142.7,
140.8, 140.1, 139.9, 136.1, 131.9, 130.4, 129.8, 129.4, 128.8, 128.5,
126.3 (2C), 125.5, 124.2, 62.8, 47.7, 21.1, 21.0, 20.8, 18.7, 14.8; MS
(FAB+) m/z 516 (M + 1, 28), 504 (28), 503 (100), 497 (10), 481 (18);
Anal. Calcd for C31H33NO2S2: C, 72.19; H, 6.45; N, 2.72; S, 12.44.
Found: C, 72.10; H, 6.45; N, 2.61; S, 12.42.
[1R,(S)R]-N-(1-Methyl-1-phenyl-2-{2-[(S)-p-tolylsulfinyl]phenyl}-
ethyl)-p-toluensulfinamide (12a): (S)-N-Sulfinylketimine 3a was used
as electrophile. This compound was obtained as minor diastereoisomer.
Chromatography: n-hexane-AcOEt 3:1; yield: 17%; white solid;
20
mp: 80-82 °C; [R]D -135.9 (c 0.64, acetone); IR (NaCl): 3175,
3057, 2984, 2924, 1493, 1471,1085, 1058, 1031, 809, 754 cm-1; H
1
NMR (300 MHz, CDCl3): δ 7.75 (dd, J ) 6.6, 1.2 Hz, 1H), 7.52 (d,
J ) 8.2 Hz, 2H), 7.38-7.19 (m, 10H), 7.12-7.04 (m, 3H), 6.40 (d,
J ) 7.7 Hz, 1H), 4.69 (bs, 1H), 3.33 (d, J ) 13.6 Hz, 1H), 3.15 (d,
J ) 13.6 Hz, 1H), 2.33 (s, 3H), 2.26 (s, 3H), 1.95 (s, 3H);13C NMR
(75 MHz, CDCl3): δ 145.2, 143.3, 143.2, 141.7, 141.5, 141.2, 134.3,
131.9, 130.6, 129.9, 129.6, 128.4, 128.2, 127.8, 127.5, 125.5, 125.4,
125.3, 62.5, 46.9, 27.7, 21.4 (2C). Anal. Calcd for C29H29NO2S2: C,
71.42; H, 5.99; N, 2.87; S, 13.15. Found: C, 71.36; H, 6.28; N, 2.77;
S, 13.05.
[2S,3S,(S)S]-N-{2-(4-Bromophenyl)-3-[(S)-2-(p-toluenesulfinyl)-
phenyl]butyl}-p-toluenesulfinamide (anti-18e): (S)-N-Sulfinylketimine
3e was used as electrophile. Chromatography: n-hexane-AcOEt 5:2;
20
yield: 64%; white solid; mp: 141-143 °C; [R]D +103.8 (c 2.0,
CHCl3); IR (NaCl): 3168, 1590, 1491, 1083 cm-1; 1H NMR (200 MHz,
CDCl3): δ 7.72-7.43 (m, 8H), 7.17-7.06 (m, 6H), 6.90 (d, J ) 8.1
Hz, 2H), 3.73 (q, J ) 7.1 Hz, 1H), 2.34 (s, 3H), 2.25 (s, 3H), 1.83 (s,
3H), 0.42 (d, J ) 7.1 Hz, 3H); 13C NMR (50 MHz, CDCl3): δ 146.5,
144.6, 143.0, 142.3, 140.7, 140.2, 132.2, 131.4, 130.9, 130.5, 130.2,
129.5, 128.8, 128.4, 126.6, 125.5, 123.9, 120.7, 62.6, 43.5, 21.1, 20.9,
17.9, 14.3; Anal. Calcd for C30H30BrNO2S2: C, 62.06; H, 5.21; N, 2.41;
S, 11.05. Found: C, 62.08; H, 5.26; N, 2.34; S, 10.51.
[3S,(S)S]-N-{2,2-Diphenyl-[(S)-3-(p-toluenesulfinyl)phenyl]butyl}-
p-toluenesulfinamide (21b): (S)-N-Sulfinylketimine 3b was used as
electrophile. Chromatography: n-hexane-AcOEt 1:1; yield: 73%;
white solid; mp: 171-173 °C; [R]D20 -4.4 (c 1.0, CHCl3); IR (NaCl):
[2S,3S,(S)S]-N-{2-(4-Nitrilephenyl)-3-[(S)-2-(p-toluenesulfinyl)-
phenyl]butyl}-p-toluenesulfinamide (anti-18f): (S)-N-Sulfinylketimine
3f was used as electrophile. Chromatography: n-hexane-AcOEt 1:1;
3134, 1656, 1599, 1085 cm-1; H NMR (300 MHz, CDCl3): δ 7.70
1
(dd, J ) 7.7, 1.3 Hz, 1H), 7.58 (d, J ) 8.5 Hz, 1H), 7.50-7.25 (m,
17H), 7.18 (d, J ) 8.5 Hz, 2H), 7.08 (bs, 1H), 5.86 (d, J ) 6.9 Hz,
1H), 4.82 (q, J ) 7.0 Hz, 1H), 2.42 (s, 3H), 2.41 (s, 3H), 0.68 (d, J )
7.0 Hz, 3H);13C NMR (75 MHz, CD3OD): δ 147.2, 143.8, 131.4, 130.0,
129.9 (2C), 128.9 (2C), 128.8 (2C), 128.1 (2C), 61.0, 52.9, 31.7, 25.1,
17.1; MS (FAB+) m/z 564 (M + 1, 95), 409 (100), 320 (33), 182 (76).
20
yield: 31%; yellow solid; mp: 200-201 °C; [R]D +54.6 (c 1.0,
1
acetone); IR (NaCl): 3442, 3127, 2980, 2230, 1607, 732 cm-1; H
NMR (300 MHz, CDCl3): δ 7.81 (d, J ) 8.6 Hz, 2H), 7.75-7.72 (m,
2H), 7.65 (d, J ) 8.6 Hz, 2H), 7.54-7.49 (m, 2H), 7.64 (bs, 1H), 7.10
(s, 4H), 7.09 (d, J ) 7.8 Hz, 2H), 6.89 (d, J ) 8.3 Hz, 2H), 3.79 (q,
J ) 7.2 Hz, 1H), 2.41 (s, 3H), 2.31 (s, 3H), 1.92 (s, 3H), 0.43 (d, J )
7.2 Hz, 3H);13C NMR (75 MHz, CDCl3): δ 153.1, 144.4, 142.9, 142.5,
140.8, 140.7, 140.3, 132.4, 131.8, 130.7, 130.4, 129.6, 129.0, 127.5,
126.8, 125.6, 124.0, 118.9, 110.7, 62.9, 43.4, 21.2, 21.0, 17.7, 14.2;
MS (FAB+) m/z 527 (M + 1, 11), 504 (24), 503 (100), 481 (5); HRMS
calcd for C31H30N2O2S2 527.1846, found 527.1827.
[2S,3S,(S)S]-N-{2-Phenyl-3-[(S)-2-(p-toluenesulfinyl)phenyl]bu-
tyl}-p-toluenesulfinamide (anti-18a): (S)-N-Sulfinylketimine 3a was
used as electrophile Chromatography: n-hexane-AcOEt 1:1; yield:
80%; white solid; mp: 197-199 °C; [R]D20 +25.7 (c 0.56, CHCl3); IR
(NaCl): 3417, 3194, 1492, 1450, 1438 cm-1; H NMR (300 MHz,
1
CDCl3): δ 7.70 (dd, J ) 6.4 Hz, 2.0 Hz, 1H), 7.65-7.58 (m, 4H),
7.49-7.44 (m, 2H), 7.38-7.33 (m, 2H), 7.24 (d, J ) 8.3 Hz, 1H),
7.17-7.14 (m, 1H), 7.09 (d, J ) 7.0 Hz, 4H), 6.95 (d, J ) 8.3 Hz,
2H), 3.86 (q, J ) 7.1 Hz, 1H), 2.36 (s, 3H), 2.26 (s, 3H), 1.87 (s, 3H),
0.49 (d, J ) 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 147.0, 145.0,
143.6, 142.8, 140.9, 140.3, 140.0, 132.0, 130.5, 129.9, 129.7, 129.4,
128.9, 127.9, 126.7, 126.6, 125.6, 124.3, 63.1, 43.8, 21.2, 21.0, 18.7,
14.8; MS (FAB+) m/z 502 (M + 1, 100), 495 (7), 473 (28), 429 (25);
HRMS calcd for C30H31NO2S2 [M + 1] 502.1874, found 502.1874.
[2R,3S,(S)S]-N-{2-(4-Nitrilephenyl)-3-[(S)-2-(p-toluenesulfinyl)-
phenyl]butyl}-p-toluenesulfinamide (syn-18f): (S)-N-Sulfinylketimine
3f was used as electrophile. This compound was obtained as a minority
diastereoisomer. Chromatography: n-hexane-AcOEt 1:1; yield: 10%;
20
yellow solid; mp: 205-206 °C; [R]D -175.0 (c 1.0, CHCl3); IR
(NaCl): 3441, 3157, 2974, 2925, 2855, 1497, 1084, 1044, 731 cm-1
;
1H NMR (300 MHz, CDCl3): δ 7.67 (dd, J ) 7.6, 2.0 Hz, 1H), 7.60
(d, J ) 8.0 Hz, 2H), 7.41-7.17 (m, 12H), 6.66 (bs, 1H), 6.47 (dd, J )
7.3, 1.4 Hz, 1H), 3.82 (q, J ) 7.1 Hz, 1H), 2.41 (s, 3H), 2.34 (s, 3H),
2.03 (s, 3H), 0.57 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 146.1, 140.8,
131.6, 131.3, 131.0, 130.1, 129.7, 129.6, 129.4 (2C), 127.2 (2C), 125.4,
125.3 (2C), 124.4 (2C), 118.7, 111.3, 64.9, 43.6, 29.3, 21.4, 21.2, 15.5;
MS (FAB) m/z 527 (M + 1, 33), 497 (20), 459 (100), 453 (17); HRMS
calcd for C31H30N2O2S2 527.1826, found 527.1845.
[2S,3S,(S)S]-N-{2-(4-Methoxyphenyl)-3-[(S)-2-(p-toluenesulfinyl)-
phenyl]butyl}-p-toluenesulfinamide (anti-18b): (S)-N-Sulfinylketimine
3b was used as electrophile. Chromatography: n-hexane-AcOEt 2:1;
20
yield: 66%; white solid; mp: 172-175 °C; [R]D +106.0 (c 1.0,
acetone); IR (NaCl): 3424, 3196, 2970, 1612, 1514 cm-1; H NMR
1
(300 MHz, CDCl3): δ 7.69 (d, J ) 7.7 Hz, 1H), 7.61-7.53 (m, 3H),
7.47-7.42 (m, 2H), 7.16 (d, J ) 8.4 Hz, 4H), 7.10 (d, J ) 6.8 Hz,
2H), 6.96 (d, J ) 8.2 Hz, 2H), 6.88 (d, J ) 8.9 Hz, 2H), 6.83 (bs, 1H),
3.88 (q, J ) 7.1 Hz, 1H), 3.79 (s, 3H), 2.35 (s, 3H), 2.26 (s, 3H), 1.83
(s, 3H), 0.50 (d, J ) 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ
158.2, 145.1, 143.6, 142.7, 140.9, 140.2, 139.9, 139.2, 131.9, 130.4,
129.9, 129.4, 128.8, 127.7, 126.5, 125.6, 124.3, 113.2, 62.7, 55.0, 43.9,
21.2, 21.1, 18.9, 14.8; MS (FAB+) m/z 532 (M + 1, 100), 504 (18),
503 (81), 481 (6); Anal. Calcd for C31H33NO3S2: C, 70.02; H, 6.26;
N, 2.63; S, 12.06. Found: C, 69.94; H, 6.45; N, 2.45; S, 11.95.
[2S,3S,(S)S]-N-{2-(Isopropyl)-3-[(S)-2-(p-toluenesulfinyl)phenyl]-
butyl}-tert-butanesulfinamide (anti-18′g): In this case the ortho-
sulfinylcarbanion derivate from (S)-6 using the standard procedure was
added over a solution of the N-tert-butanesulfinylketimine 3′g and 110
mol % of AlMe3 (2 M, toluene) in 1 mL of toluene at -78 °C.
Chromatography: n-hexane-AcOEt 1:1; yield: 58%; colorless oil;
[R]D20 +58.2 (c 1.0, acetone); IR (NaCl): 3343, 1494, 1471, 1378 cm-1
;
1H NMR (200 MHz, CDCl3): δ 7.82 (d, J ) 8.2 Hz, 2H), 7.60-7.10
(m, 6H), 3.80 (q, J ) 7.0 Hz, 1H), 3.33 (bs, 1H), 2.37 (s, 3H), 2.33-
9
J. AM. CHEM. SOC. VOL. 127, NO. 37, 2005 13053

A R T I C L E S
Garc´ıa Ruano et al.
2.19 (m, 1H), 1.24 (s, 9H), 1.17 (d, J ) 7.0 Hz, 3H), 1.03 (d, J ) 6.8
Hz, 3H), 0.92 (d, J ) 7.1 Hz, 3H), 0.82 (s, 3H); 13C NMR (50 MHz,
CDCl3): δ 145.1, 143.9, 141.0, 131.5, 130.8, 129.9, 129.7, 128.2, 127.3,
125.5, 65.0, 63.7, 39.7, 32.6, 23.4, 23.1, 21.3, 20.6, 17.9, 17.7.
[2R,3S,(S)S]-N-{2-Phenyl-3-[(S)-2-(p-toluenesulfinyl)phenyl]bu-
tyl}-p-toluenesulfinamide (syn-19a): (R)-N-Sulfinylketimine 3a was
used as electrophile. Chromatography: n-hexane-AcOEt 1:1; yield:
70%; white solid; mp: 135-138 °C; [R]D20 -60.1 (c 1.0, CHCl3); IR
15.8; Anal. Calcd for C30H30BrNO2S2: C, 62.06; H, 5.21; N, 2.41; S,
11.05. Found: C, 61.82; H, 5.26; N, 2.34; S, 10.51.
[2R2S,3S,(S)S]-N-{2-(4-Nitrilephenyl)-3-[(S)-2-(p-toluenesulfinyl)-
phenyl]butyl}-p-toluenesulfinamide (syn-19f/anti-19f): These com-
pounds were obtained as an unseparated mixture of diastereoisomers.
Chromatography: n-hexane-AcOEt 1:1; combined yield: 40%; yellow
oil; Major isomer syn-4′e: 1H NMR (300 MHz, CDCl3): δ 7.91 (d,
J ) 8.6 Hz, 2H), 7.75-7.22 (m, 14H), 3.94 (q, J ) 7.0 Hz, 1H), 2.30
(s, 6H), 2.05 (s, 3H), 0.48 (d, J ) 7.2 Hz, 3H). Minor isomer anti-4′e:
1H NMR (300 MHz, CDCl3): δ 7.93 (d, J ) 8.7 Hz, 2H), 7.75-7.22
(m, 14H), 4.03 (q, J ) 7.2 Hz, 1H), 2.28 (s, 6H), 2.02 (s, 3H), 0.32 (d,
J ) 7.2 Hz, 3H).
1
(NaCl): 3186, 3088, 1492, 1469, 1085 cm-1; H NMR (300 MHz,
CDCl3): δ 7.67 (d, J ) 8.6 Hz, 2H), 7.45-7.14 (m, 12H), 7.06 (s,
4H), 5.38 (bs, 1H), 4.22 (q, J ) 7.3 Hz, 1H), 2.32 (s, 3H), 2.30 (s,
3H), 1.94 (s, 3H), 0.76 (t, J ) 7.3 Hz, 3H); 13C NMR (75 MHz,
CDCl3): δ 145.2, 144.3, 143.2, 140.6, 140.3, 139.8, 135.2, 131.9, 130.4
(2C), 129.3, 129.1, 128.4, 127.8, 127.5, 127.2, 125.2, 124.8, 64.3, 44.7,
21.7, 21.3, 21.2 16.3; Anal. Calcd for C30H31NO2S2: C, 71.82; H, 6.23;
N, 2.79; S, 12.78. Found: C, 71.79; H, 6.26; N, 2.70; S, 12.82.
[2R,3S,(S)S]-N-{2-(4-Methoxyphenyl)-3-[(S)-2-(p-toluenesulfinyl)-
phenyl]butyl}-p-toluenesulfinamide (syn-19c): (R)-N-Sulfinylketimine
3b was used as electrophile. Chromatography: n-hexane-AcOEt 1:2;
[2R,3S,(S)S]-N-{2-(Isopropyl)-3-[(S)-2-(p-toluenesulfinyl)phenyl]-
butyl}-tert-butanesulfinamide (syn-19′g): In this case the ortho-
sulfinylcarbanion derivate from (S)-6 using the stardard procedure was
added to a solution of the N-tert-butanesulfinylketimine 3′g and 110
mol % of AlMe3 (2 M, toluene) in 1 mL of toluene at -78 °C.
Chromatography: n-hexane-AcOEt 1:1; yield: 58%; colorless oil;
[R]D20 +12.5 (c 1.0, acetone); IR (NaCl): 3348, 1493, 1472, 1378 cm-1
;
20
1H NMR (200 MHz, CDCl3): δ 7.83 (d, J ) 8.6 Hz, 2H), 7.55-7.20
(m, 6H), 3.89 (q, J ) 7.0 Hz, 1H), 3.45 (bs, 1H), 2.39 (s, 3H), 1.93
(pent, J ) 7.1 Hz, 1H), 1.28-1.24 (m, 12H), 1.06 (s, 3H), 0.93 (d,
J ) 7.1 Hz, 6H); 13C NMR (50 MHz, CDCl3): δ 145.0, 143.4, 141.2,
140.6, 131.9, 130.0, 129.7, 127.9, 127.6, 125.9, 63.5, 56.9, 40.4, 37.3,
23.1, 21.3, 20.5, 18.5, 18.0, 17.4.
yield: 67%; white solid; mp: 180-182 °C; [R]D -51.6 (c 1.0,
CHCl3); IR (NaCl): 3188, 1609, 1512, 1464 cm-1; 1H NMR (200 MHz,
CDCl3): δ 7.60 (d, J ) 8.9 Hz, 2H), 7.48 (d, J ) 8.1 Hz, 2H), 7.37-
7.05 (m, 10H), 6.97 (d, J ) 8.9 Hz, 2H), 5.01 (bs, 1H), 4.24 (q, J )
6.9 Hz, 1H), 3.86 (s, 3H), 2.35 (s, 6H), 1.92 (s, 3H), 0.85 (d, J ) 6.9
Hz, 3H); 13C NMR (50 MHz, CDCl3): δ 144.3, 143.2, 140.6, 140.3,
139.7, 136.7, 136.6, 131.7, 130.2, 129.3 (2C), 128.7 (2C), 127.6, 125.1
(2C), 124.8 (2C), 113.3, 63.9, 54.9, 44.8, 22.3, 21.1, 16.4, 13.9. MS
(FAB+) m/z 532 (M + 1, 22), 503 (21), 377 (100); HRMS (FAB+)
calcd for C31H34N1O3S2 [M + 1] 532.1980, found 532.1997.
(2S)-N-{1,1-Diphenyl-[(S)-3-(p-toluenesulfinyl)phenyl]propyl}-p-
toluenesulfonamide (17b): In this case N-sulfonylketimine 9b was
used as electrophile. Chromatography: n-hexane-AcOEt 1:1; yield:
94%; white solid; mp: 247-248 °C; [R]D20 +23.8 (c 1.0, CHCl3); IR
1
(NaCl): 3529, 3509, 1493, 1378 cm-1; H NMR (300 MHz, CDCl3):
[2R,3S,(S)S]-N-{2-(4-Methylphenyl)-3-[(S)-2-(p-toluenesulfinyl)-
phenyl]butyl}-p-toluenesulfinamide (syn-19d): (R)-N-Sulfinylketimine
3c was used as electrophile. In this case 2 equiv of the carbanion
derivate from 5 were used. Chromatography: n-hexane-AcOEt 5:2;
δ 8.29 (bs, 1H), 7.81 (dd, J ) 6.8, 1.3 Hz, 1H), 7.39-7.23 (m, 13H),
7.13-7.10 (m, 1H), 7.00-6.90 (m, 6H), 5.47 (d, J ) 8.1 Hz, 1H),
5.51 (q, J ) 7.0 Hz, 1H), 2.40 (s, 3H), 2.37 (s, 3H), 0.39 (d, J ) 7.0
Hz, 3H);13C NMR (75 MHz, CDCl3): δ 142.2, 141.7, 141.2, 140.6,
139.9, 138.7, 137.7, 133.5, 131.7, 130.3, 129.8, 129.7, 128.3, 127.6,
127.1, 126.9, 126.1, 123.9, 70.9, 42.3, 21.3, 21.2, 16.9. MS (FAB+)
m/z 564 (M + 1, 94), 409 (100), 182 (76).
20
yield: 73%; white solid; mp: 179-181 °C; [R]D +105.6 (c 1.0,
CHCl3); IR (NaCl): 3187, 1595, 1513, 1442 cm-1; 1H NMR (200 MHz,
CDCl3): δ 7.54 (d, J ) 7.6 Hz, 2H), 7.44 (d, J ) 8.3 Hz, 1H), 7.38-
7.00 (m, 13H), 5.09 (bs, 1H), 4.23 (q, J ) 6.9 Hz, 1H), 2.38 (s, 3H),
2.32 (s, 3H), 1.92 (s, 3H), 0.82 (d, J ) 6.9 Hz, 3H); 13C NMR (50
MHz, CDCl3): δ 144.6, 143.3, 141.9, 140.7, 140.4, 139.7, 136.9, 131.9,
130.3, 129.4, 129.3, 128.9, 128.8, 127.8, 127.5, 125.3, 124.9, 124.8,
64.2, 44.8, 22.2, 21.2, 21.1, 20.9, 16.5. Anal. Calcd for C31H33NO2S2:
C, 72.19; H, 6.45; N, 2.72; S, 12.44. Found: C, 72.24; H, 6.60; N,
2.48; S, 12.51.
Acknowledgment. We thank the Spanish Government for
financial support (Grant BQU2003-4012). J.A and A.P. thank
the Ministerio de Ciencia y Tecnolog´ıa and Universidad
Auto´noma de Madrid, respectively, for the predoctoral fellow-
ships.
[2S,3S,(S)S]-N-{2-(4-Bromophenyl)-3-[(S)-2-(p-toluenesulfinyl)-
phenyl]butyl}-p-toluenesulfinamide (syn-19e): (R)-N-Sulfinylketimine
3e was used as electrophile. Chromatography: n-hexane-AcOEt 5:2;
yield: 61%; white solid; mp: 131-133 °C; [R]D20 -4.6 (c 1.0, CHCl3);
IR (NaCl): 3180, 1711, 1589, 1589, 1490, 1083 cm-1; 1H NMR (200
MHz, CDCl3): δ 7.52 (s, 4H), 7.46-7.05 (m, 12H), 5.75 (bs, 1H),
4.08 (q, J ) 7.0 Hz, 1H), 2.34 (s, 3H), 2.30 (s, 3H), 1.89 (s, 3H), 0.67
(d, J ) 7.0 Hz, 3H); 13C NMR (50 MHz, CDCl3): δ 144.9, 143.7,
143.1, 143.0, 140.6, 140.4, 139.8, 132.0, 131.0, 130.4, 129.4, 129.3,
129.2, 129.1, 127.6, 125.0, 124.5, 121.2, 63.8, 44.3, 29.5, 21.2, 21.1,
Supporting Information Available: Experimental procedures
and spectroscopic data for all new additional compounds, X-ray
data for 17b and anti-18b, and the NMR spectra of all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
JA0515203
9
13054 J. AM. CHEM. SOC. VOL. 127, NO. 37, 2005