Stereoselective addition of α-methylsulfenyl benzyl carbanions to N-sulfinylketimines: Asymmetric synthesis of α,α-dibranched β-sulfanyl amines

Article abstract of DOI:10.1021/jo802200f

(R)- and (S)-Af-sulfinylketimines react with the ort/o-sulfinyl benzyl carbanion derived from (S)-1 affording epimeric mixtures at the benzylic carbon of α,α-dibranched β-sulfanyl amines. The JV-sulfinyl group completely controls the configuration at the

Full text of DOI:10.1021/jo802200f

Stereoselective Addition of r-Methylsulfenyl Benzyl Carbanions to
N-Sulfinylketimines: Asymmetric Synthesis of r,r-Dibranched
ꢀ-Sulfanyl Amines
†
†
,†
‡
´
Yolanda Arroyo, Angela Meana, M. Ascensio´n Sanz-Tejedor,* Ine´s Alonso, and
Jose´ L. Garc´ıa Ruano*,‡
Departamento de Qu´ımica Orga´nica (ETSII), UniVersidad de Valladolid, P del Cauce s/n,
47011 Valladolid, Spain, and Departamento de Qu´ımica Orga´nica (C-I), UniVersidad Auto´noma de
Madrid, Cantoblanco, 28049 Madrid, Spain
atejedor@eis.uVa.es; joseluis.garcia.ruano@uam.es
ReceiVed October 2, 2008
(R)- and (S)-N-sulfinylketimines react with the ortho-sulfinyl benzyl carbanion derived from (S)-1 affording
epimeric mixtures at the benzylic carbon of R,R-dibranched ꢀ-sulfanyl amines. The N-sulfinyl group
completely controls the configuration at the quaternary carbon bonded to the nitrogen, whereas the
C-sulfinyl group is responsible for the level of asymmetric induction. High stereoselectivity can be achieved
when the configuration at the sulfur atoms of the reagents are opposite (matched pair). After a two-step
desulfinylation process, this reaction provides a procedure for synthesizing diastereomerically pure syn-
1,2-sulfanyl amines containing a chiral quaternary carbon adjacent to nitrogen.
SCHEME 1
Introduction
Vic-Sulfanyl amines are valuable building blocks,1 which are
characteristic motifs in bioactive natural products,2 and phar-
macologically important compounds.3 Furthermore, from a
synthetic point of view, they have proven to be efficient
heterobidentate N,S-ligands in asymmetric reactions.4 As a
consequence of their importance, numerous methods for the
synthesis of these compounds have been reported.5 In this field,
we have demonstrated recently that carbanion derived from (S)-1
reacts with (S)-N-sulfinylaldimines with complete control of the
stereoselectivity at the two simultaneously formed chiral centers
(Scheme 1) affording anti-1,2-sulfanyl amines.6
† Universidad de Valladolid.
‡ Universidad Auto´noma de Madrid.
In this context, Vic-sulfanyl amines possessing a quaternary
N-substituted stereocenter potentially might have a major
significance because of the restricted conformational mobility
imposed by the quaternary carbon. However, to the best of our
knowledge, the asymmetric synthesis of these compounds has
never been reported, which prompted us to study the reactions
of N-sulfinylketimines with (S)-1. The use of ketimines as
electrophiles in reactions with organometallic reagents has
always been a major challenge in asymmetric synthesis; their
use suffers many drawbacks derived from their poor electrophilic
(1) (a) Yang, X.-F.; Zhang, M.-J.; Hou, X.-L.; Dai, L.-X. J. Org. Chem.
2002, 67, 8097. (b) Aggarwal, V. K.; Charmant, J. P. H.; Ciampi, C.; Hornby,
J. M.; O’Brien, C. J.; Hynd, G.; Parsons, R. J. Chem. Soc., Perkin Trans. 1
2001, 3159.
(2) (a) Schwartz, A.; Madan, P. B.; Mohacsi, E.; O’Brien, J. P.; Todaro,
L. J.; Coffen, D. L. J. Org. Chem. 1992, 57, 851. (b) Rinehart, K. L. Med. Res.
ReV. 2000, 20, 1. (c) Parveen, S.; Khan, M. O. F.; Austin, S. E.; Croft, S. L.;
Yardley, V.; Rock, P.; Douglas, K. T. J. Med. Chem. 2005, 48, 8087, and
references therein.
(3) (a) Bae, J. H.; Shin, S. H.; Park, C. S.; Lee, W. K. Tetrahedron 1999,
55, 10041. (b) Adams, B.; Beresford, K. J. M.; Whyte, S. M.; Young, D. W.
Chem. Commun. (Cambridge, U.K.) 2000, 619.
764 J. Org. Chem. 2009, 74, 764–772
10.1021/jo802200f CCC: $40.75 2009 American Chemical Society
Published on Web 11/26/2008

Synthesis of R,R-dibranched ꢀ-Sulfanyl Amines
SCHEME 2
TABLE 1. Reaction of (S)-1 with Ketimines 2a
character and propensity for enolization.7 Furthermore, the facile
(E,Z) isomerization decreases the possibility of highly diaste-
reoselective processes.8 The breakthrough in this area came
when Ellman discovered that reactions of N-tert-butanesulfi-
nylketimines with organometallic reagents in the presence of
Me3Al provided a general method to prepare R,R-dibranched
amines.9 More recently, the enantioselective allylation of ketone-
derived imino compounds10 and the radical addition of alkyl
iodides to N-acylhydrazonoesters via Mn-mediated coupling
reactions11 to afford tert-alkyl amines have been reported. In
this field, we also have reported the stereoselective benzylation
of N-sulfinylketimines with 2-(p-tolylsulfinyl) benzyl carbanions
to afford any epimer of R,R-dibranched ꢀ-phenyl ethyl and
propylamines (Scheme 2).12 In these reactions, the N-sulfinyl
group completely controls the configuration of the aminic
carbon, whereas the ortho-sulfinyl group is responsible for the
configuration at the benzylic carbon.
entry
imine (equiv)
yielda (%)
diastereomeric ratiob
de (%)
1
2
3
2′a (1.5)
(S)-2a (1.5)
(R)-2a (1.5)
95
84
89
3a (55):4a (45)
5a (78):6a (22)
7a (94):8a (6)
10
56
88
a Combined yield. b Determined by 1H NMR on the crude reaction
mixture.
4a (Table 1, entry 1). This is evidence that the sulfinyl group
at the nucleophile is not able to control the stereoselectivity of
the process, which contrasts with the results obtained in most
of the reactions so far studied with these benzyl carbanions,
suggesting a decisive role of the SMe group in this change of
behavior. The reaction of (S)-1 with N-sulfinylketimine (S)-2a
affords in a few minutes a 78:22 mixture of two diastereoiso-
mers, 5a and 6a, which are epimers at the newly created
stereogenic center (Table 1, entry 2).13 Under similar conditions,
(R)-2a afforded a 94:6 mixture of 7a and 8a (88% de, Table 1,
entry 3). The major 7a was isolated in 85% yield.
With these precedents, we have studied the behavior of (S)-1
with N-sulfinylketimines. The synthetic results obtained in this
study as well as the transformation of the resulting compounds
into the desired optically pure R,R-dibranched ꢀ-sulfanyl amines
and the theoretical calculations supporting the mechanistic
proposal are reported in this paper.
Results and Discussion
We first studied the behavior of (S)-1 with the symmetrical
and nonenolizable N-sulfonyl and N-sulfinyl derivatives of
benzophenone (Table 1). The reaction of (S)-1 with N-
sulfonylketimine 2′a in the presence of LDA leads to an almost
equimolecular mixture of two possible diastereoisomers, 3a and
The configurational assignment of stereoisomers 5a and 7a
was made by chemical correlation (Scheme 3). Both compounds
5a and 7a were transformed into the 1,2-sulfanyl amine 9 by
TFA hydrolysis of their N-sulfinyl moieties, indicating that 5a
and 7a have an identical configuration at the benzyl carbon (they
only differ in the N-sulfinyl configuration), which reveals the
(4) For recent reviews, see: (a) Pellisier, H. Tetrahedron 2007, 63, 1297. (b)
Martin, E.; Die´guez, M. C. R. Chim. 2007, 10, 188. For N,S-ligands in palladium-
catalyzed allylic substitution, see: (c) Adams, H.; Anderson, J. C.; Cubbon, R.;
James, D. S.; Mathias, J. P. J. Org. Chem. 1999, 64, 8256. (d) Rassias, G. A.;
Page, P. C. B.; Reignier, S.; Christie, S. D. R. Synlett 2000, 379. (e) Page,
P. C. B.; Heaney, H.; Reignier, S.; Rassias, G. A. Synlett 2003, 22. (f) Siedlecka,
R.; Wojaczynska, E.; Skarzewski, J. Tetrahedron: Asymmetry 2004, 15, 1437.
(g) Le Fur, N.; Mojovic, L.; Ple´, N.; Turck, A.; Reboul, V.; Metzner, P. J. Org.
Chem. 2006, 71, 2609. For addition of alkyllithium and dialkylzinc reagents to
aldehydes, see. (h) Hof, R. P.; Poelert, M. A.; Peper, N. C. M. W.; Kellog,
R. M. Tetrahedron: Asymmetry 1994, 5, 31. (I) Kang, J.; Lee, J. W.; Kim, J. I.
J. Chem. Soc., Chem. Commun. 1994, 2009. (j) Jin, M. J.; Ahn, S. J.; Lee, K. S.
Tetrahedron Lett. 1996, 37, 8767. (k) Fulton, D. A.; Gibson, C. L. Tetrahedron
Lett. 1997, 38, 2019. (I) Kang, J.; Kim, J. B.; Kim, J. W.; Lee, D. J. Chem.
Soc., Perkin Trans. 2 1997, 189. (m) Anderson, J. C.; Cubbon, R.; Harding, M.;
James, D. S. Tetrahedron: Asymmetry 1998, 9, 3461. (n) Gibson, C. L.
Tetrahedron: Asymmetry 1999, 10, 1551. (o) Kossenjans, M.; Soeberdt, M.;
Wallbaum, S.; Harms, K.; Martens, J.; Aurich, H. G. J. Chem. Soc., Perkin Trans.
1 1999, 2353. (p) Jimeno, C.; Moyano, A.; Perica´s, M. A.; Riera, A. Synlett
2001, 1155. (q) Granander, J.; Sott, R.; Hilmersson, G. Tetrahedron: Asymmetry
2003, 14, 439. (r) Sott, R.; Granander, J.; Dine´r, P.; Hilmersson, G. Tetrahedron:
Asymmetry 2004, 15, 267. (s) Granander, J.; Eriksson, J.; Hilmersson, G.
Tetrahedron: Asymmetry 2006, 17, 2021. For the iridium(I)-catalyzed reduction
of unsymmetrical ketones, see: (t) Petra, D. G. I.; Kamer, P. C. J.; Spek, A. L.;
Schoemaker, H. E.; Van Leeuwen, P. W. N. M. J. Org. Chem. 2000, 65, 3010.
(u) Hage, A.; Petra, D. G. I.; Field, J. A.; Schipper, D.; Wijnberg, J. B. P. A.;
Kamer, P. C. J.; Reek, J. N. H.; van Leeuwen, P. W. N. M.; Wever, R.;
Schoemaker, H. E. Tetrahedron: Asymmetry 2001, 12, 1025. (v) Ekegren, J. K.;
Roth, P.; Ka¨llstro¨m, K.; Tarnai, T.; Andersson, P. G. Org. Biomol. Chem. 2003,
1, 358.
(5) (a) Wu, J.; Hou, X.-L.; Dai, L.-X. J. Chem. Soc., Perkin Trans. 1 2001,
1314. (b) Xiong, C.; Wang, W.; Cai, C.; Hruby, V. J. J. Org. Chem. 2002, 67,
1399. (c) De Paolis, M.; Blankenstein, J.; Bois-Choussy, M.; Zhu, J. Org. Lett.
2002, 4, 1235. (d) Enders, D.; Moll, A.; Schaadt, A.; Raabe, G.; Runsink, J.
Eur. J. Org. Chem. 2003, 3923, and references therein. See also refs 4d, 4e, 4h,
4j-m, 4o, 4p, and 4s.
(6) Arroyo, Y.; Meana, A.; Rodr´ıguez, J. F.; Santos, M.; Sanz-Tejedor, M. A.;
Garc´ıa-Ruano, J. L. J. Org. Chem. 2005, 70, 3914.
(7) (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. C. Tetrahedron: Asymmetry 1995, 6,
349.
(8) (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, D. M.
J. Org. Chem. 1999, 64, 2406. (d) Davis, F. A.; Lee, S.; Zhang, H.; Fanelly,
D. L. J. Org. Chem. 2000, 65, 8704.
(9) (a) Cogan, D. A.; Ellman, J. A. Tetrahedron 1999, 55, 8883. (b) Cogan,
D. A.; Ellman, J. A. J. Am. Chem. Soc. 1999, 121, 268.
(10) (a) Berger, R.; Duff, K.; Leighton, J. L. J. Am. Chem. Soc. 2004, 126,
5686. (b) Wada, R.; Shibuguchi, T.; Makino, S.; Oisaki, K.; Kanai, M.; Shibasaki,
M. J. Am. Chem. Soc. 2006, 128, 7687. (c) Canales, E.; Herna´ndez, E.; Soderquist,
J. A. J. Am. Chem. Soc. 2006, 128, 8712.
(11) Friestad, G. K.; Ji, A. Org. Lett. 2008, 10, 2311.
(12) Garc´ıa-Ruano, J. L.; Alema´n, J.; Parra, A. J. Am. Chem. Soc. 2005,
127, 13048.
(13) Under a substoichiometric amount of (S)-2a, a significant increase in
stereoselectivity was observed with de increasing to more than 98% by adding
0.5 equiv of the electrophile.
J. Org. Chem. Vol. 74, No. 2, 2009 765

Arroyo et al.
SCHEME 3. Chemical Correlation of Compounds 5a and 7a
TABLE 2. Reaction of (S)-1 with N-Sulfinylketimines (S)- and (R)-2b-g
diastereomeric ratioa
entry
R1
imine
anti-10:syn-11
anti-12:syn-13
de (%)
yield (%)b
1
2
3
4
5
6
7
8
9
Ph
(S)-2b
(S)-2c
(S)-2d
(R)-2b
(R)-2c
(R)-2d
(R)-2e
(R)-2f
(R)-2g
65:35
68:32
60:40
30
36
20
90
92
92
84
98
98
83
76
67
87
79
84
70
82
75
p-MeOC6H4
p-BrC6H4
Ph
p-MeC6H4
p-MeOC6H4
p-BrC6H4
p-CNC6H4
i-Pr
5:95
4:96
4:96
8:92
-:>98
-:>98
a
Determined by H NMR on the crude reaction mixture. b Combined yield.
1
configuration is mainly controlled by the ortho-sulfinyl group
at the starting nucleophile (S)-1. Taking into account that all
resulting compounds must be epimers at the carbon joined to
the SMe group.
reactions so far studied of electrophiles with (S)-16,14 or other
γ-sulfinyl benzyl carbanions12,15 have afforded the (S) config-
uration at the benzylic carbon as the major or exclusive
diastereoisomer, we have assumed that amine 9 and their
precursors 5a and 7a also exhibit the (S) configuration at the
benzylic carbon.
Next, we studied the reactions of (S)-1 with both enantiomers
of nonsymmetrical N-sulfinylketimines 2b derived from ac-
etophenone, where two stereogenic centers (one quaternary)
were simultaneously formed. The reaction of (S)-1 with (S)-2b
afforded a 65:35 mixture of compounds anti-10b and syn-11b,
readily separated by chromatography, with the anti isomer being
the major one ( Table 2, entry 1).16 The reaction of (S)-1 with
(R)-2b is highly diastereoselective, affording a 95:5 mixture of
syn-13b and anti-12b (Table 2, entry 4). As these reactions
produced only two of the four possible diastereoisomeric
ꢀ-sulfanyl amines, it must be concluded that they evolve with
complete control of stereoselectivity in one of the two newly
created chiral centers. On the other hand, the fact that the
stereoselectivity is very similar to that observed in the reactions
of (S)-1 with (R)-2a and (S)-2a (Table 1) suggests that the
To check the scope of these processes, we have studied the
behavior of different N-sulfinylketimines with the carbanion
derived from (S)-1 (Table 2, entries 2, 3, and 5-9). Reactions
carried out with ketimines (S)-2c and (S)-2d, with an aromatic
ring electron-donating group and a weakly electron-withdrawing
group, respectively, afforded diastereoisomeric mixtures of
composition similar to that observed for (S)-2b (36 and 20%
de, respectively; Table 2, entries 2 and 3). This indicates the
limited influence of the electronic factors on the diastereose-
lectivity of these processes. Reactions carried out with (R)-N-
sulfinylketimines showed a similar behavior with a very high
stereoselectivity for (R)-ketimines containing an electron-
donating group [(R)-2c and (R)-2d, Table 2, entries 5 and 6] or
a weakly electron-withdrawing group [(R)-2e, Table 2, entry
7] (de ranges between 84 and 92%). Stereoselectivity becomes
complete (de >98%) for (R)-2f, which contains a strongly
electron-withdrawing group (Table 2, entry 8), and for the
dialkyl ketimine (R)-2g (Table 2, entry 9). These results indicate
that reactions of 2-p-tolylsulfinyl-R-methylsulfenyl benzyl car-
banions with N-sulfinylketimines provide a good alternative for
the asymmetric synthesis of ꢀ-sulfanyl amines. The N-sulfinyl
group completely controls the configuration at the quaternary
chiral carbon joined to the nitrogen. When the configuration at
the sulfinyl groups of both reagents is opposite, the ortho-sulfinyl
group is also highly efficient in controlling the configuration of
its benzylic carbon, thus providing syn-13 in a highly stereo-
selective manner and good yields. When the configuration of
the reagents is the same, the efficiency of the ortho-sulfinyl
group is lower and easily separable mixtures of diastereoisomers
are obtained, with anti ꢀ-sulfanyl amines 10 being the major
ones.
(14) Arroyo, Y.; Rodr´ıguez, J. F.; Santos, M.; Sanz-Tejedor, M. A.; Garc´ıa-
Ruano, J. L. J. Org. Chem. 2007, 72, 1035.
(15) (a) Garc´ıa-Ruano, J. L.; Carren˜o, M. C.; Toledo, M. A.; Aguirre, J. M.;
Aranda, M. T.; Fischer, J. Angew. Chem., Int. Ed. Engl. 2000, 39, 2736. (b)
Garc´ıa-Ruano, J. L.; Alema´n, J.; Soriano, J. F. Org. Lett. 2003, 5, 677. (c) Garc´ıa-
Ruano, J. L.; Alema´n, J.; Soriano, J. F. Org. Lett. 2003, 5, 4513. (d) Garc´ıa-
Ruano, J. L.; Aranda, M. T.; Aguirre, J. M. Tetrahedron 2004, 60, 5383. (e)
Garc´ıa-Ruano, J. L.; Aleman, J.; Cid, M. B. Synthesis 2006, 687.
(16) As occurred with (S)-2a (see ref 13), we observed an increase in de
(80%) when a substoichiometric amount of (S)-2b was added, but total control
of the stereoselectivity was not possible in this case.
766 J. Org. Chem. Vol. 74, No. 2, 2009

Synthesis of R,R-dibranched ꢀ-Sulfanyl Amines
SCHEME 4. Chemical Correlation of Compounds 10b-13b Establishing the Configuration at the Aminic Carbon (C2)
SCHEME 5. Confirmation of the Stereochemical Assignments Indicated in Table 2
Configurational Assignment. The configurational assign-
ment of compounds 10b-13b was made by chemical correlation
(Schemes 4 and 5). Compounds syn-13b (pure) and anti-12b
(80:20 mixture of anti-12b:syn-13b), obtained by chromato-
graphic separation from the reaction mixture resulting in entry
4 of Table 2, were both transformed into 16 by N-desulfinylation
with TFA followed by hydrogenolysis of the two C-S bonds
with Raney nickel (Ra-Ni). This means that the configuration
of carbon bonded to the amine group is identical for syn-13b
and anti-12b. Absolute stereochemistry for 16 was established
as (R) by chemical correlation (C-desulfinylation with Ra-Ni)
with the known (R)-19.12 The optical purity of (R)-16 (>98%
ent-20b, respectively (Scheme 5), which means they differ in
configuration at their two chiral carbons. The configurational
assignment of the different diastereoisomers 10-13 indicated
in Table 2 is based on the assumption that the stereochemical
evolution of the reactions of (S)-1 with (R) and (S) enantiomers
is identical for compounds 2c-g.
The stereochemical model proposed for justifying the results
indicated in Table 2 should explain that the configuration at
the aminic carbon is completely controlled by the sulfinyl group
at the starting ketimine [(R)-2 and (S)-2 yield isomers with (S)
and (R) configuration at the aminic carbon, respectively] and
that the sulfinyl group at the nucleophile is responsible for the
configuration at the benzyl carbon in the major isomers (identical
to that of the starting sulfinyl benzyl carbanion) and the level
of asymmetric induction observed in each reaction (very high
when the configurations at the two sulfinyl reagents are different,
but moderate when they are the same).
Before formulating the mechanistic proposal, we needed to
have some information about the conformational preferences
of sulfinylketimines 2 and the configurational stability of the
R-sulfenylcarbanion 1, acting as the electrophile and nucleophile
in these reactions, respectively. In this sense, information
provided by theoretical calculations is highly valuable.
The conformational stabilities of the different rotamers of the
ketimines around the N-S bond have been studied theoretically
at the DFT (B3LYP)17 level by using the Gaussian03
program.18,19 The (E)-N-phenylsulfinylimine derived from ac-
1
ee) was established by H NMR studies of its (R)- and (S)-
MPTA amides. Compounds syn-14b and anti-15b (Scheme 4)
then will exhibit the same configuration at aminic carbon (R)
and at sulfur (S) (the last one depends only on the starting
N-sulfinylketimine). As they are diastereoisomers (NMR), they
and their precursors syn-13b and anti-12b should exhibit a
different configuration at C3. Similar conclusions could be
established for compounds anti-10b and syn-11b (both obtained
pure by chromatography from the reaction mixture resulting in
entry 1 of Table 2), which were both desulfinylated into the
amine (S)-16, with identical spectroscopic parameters but
specific rotation in the opposite sign of that observed for (R)-
16 (Scheme 4).
Taking into account that the major isomers obtained in the
reactions of (S)-1 with imines (R)-2 and (S)-2 must exhibit an
(S) configuration at the benzylic carbon joined to the SMe group
(see above), we have assigned the absolute configurations
indicated in Table 2 for compounds 10b-13b. In order to
confirm these assignments, compounds syn-13b and syn-11b
were C-desulfinylated with t-BuLi into 20b and its enantiomer
(17) (a) Lee, C.; Yang, W.; Parr, R. G. Phys. ReV. B 1988, 37, 785. (b)
Becke, A. D. J. Chem. Phys. 1993, 98, 1372. (c) Tietze, L. F.; Schuffenhauer,
A.; Schreiner, P. R. J. Am. Chem. Soc. 1998, 120, 7952.
(18) Frisch, M. J.; et al. Gaussian 03, revision E.01; Gaussian, Inc.:
Wallingford, CT, 2004.
J. Org. Chem. Vol. 74, No. 2, 2009 767

Arroyo et al.
FIGURE 1. Relative energies of the most stable conformations of
ketimines [kcal ·mol-1, zero-point energy (ZPE) correction included]
and nucleophilic attack preferred for (R)-2 and (S)-2 in their most stable
s-cis rotamers.
FIGURE 2. Molecular structures and energies (kcal ·mol-1) of possible
carbanionic species and favored approaches for E+. The first value
indicates the relative energy, with the ZPE correction included, between
structures C and D, separately. The free energy correction is indicated
in parentheses. For structures D in the second row, relative free energies
with respect to C2 [D + Li(NHMe2)(OMe2)3-C2-OMe2] are indicated
first in vacuo, and second “in THF” (mimicked by IEFPCM).
etophenone was used as a model (Figure 1). Rotamer A, with
the sulfinyl oxygen in s-cis arrangement with respect to the CdN
bond, was 3.0 kcal/mol more stable than rotamer B, with the
lone electron pair in the s-cis arrangement despite the latter being
favored from the steric point of view. The higher stability of
rotamer A may be because of the minimization of the dipolar
moment (3.16 and 4.72 D for A and B, respectively), along
with the significant contribution of a stabilizing hydrogen bond
between the sulfinyl oxygen and the CH3 group (d(SO· · ·HCH2)
) 2.17 Å; θ(O· · ·H-C) ) 136.6°). This energy difference is
enough to shift the conformational equilibrium toward rotamer
A almost completely, which arranges the phenyl group blocking
the upper face of the CdN plane (Figure 1), and therefore
determines that the nucleophilic attack of the benzyl carbanion
to imines (R)-2 and (S)-2 only takes place at the bottom and
upper faces, respectively (Figure 1). It explains the configura-
tions at the aminic carbons of the isomers shown in Table 2.
The formation of mixtures of epimers at benzylic carbon in
reactions of (S)-1 with (R)-2 and (S)-2 indicates that the
approach of the electrophile to the benzyl carbanion takes place
at either of its two diastereotopic faces. It could be due to a
moderately stereoselective evolution of the carbanionic species
generated from (S)-1. However, the complete control of the
configuration observed in reactions of (S)-1 with N-sulfinyla-
ldimines6 questioned this explanation. A second possibility could
be the formation of two carbanionic species evolving into
different diastereoisomers, whose relative reactivity is dependent
on the electrophile. It would indicate that the configurational
stability of the carbanion generated from (S)-1 must be lower
than that of the methyl 2-p-tolylsulfinyl benzyl carbanion
previously studied, which reacted with ketimines and other
electrophiles with complete control of the configuration.12,15 We
have studied the relative stability of the possible structures for
the carbanion derived from (S)-1 by theoretical calculations.20
The most stable structures found for model carbanion-Li+
complexes and free carbanions are shown in Figure 2. Dimethyl
ether and dimethylamine were used as a simplified model for
the solvent and base, respectively, and have been included as
ligands for the lithium atom. The tolyl group also has been
simplified as a phenyl one. The most stable carbanion-Li+
complex is the chelated species C1, with the sulfinyl oxygen
coordinated to the lithium atom and the carbanion stabilized
by a hydrogen bond with the dimethylamine ligand. This type
of complex probably would be the first formed after the de-
protonation step. The boat-like structure C2, with the lone
electron pair on sulfur and the hydrogen arranged toward the
flagpoles of the boat,21 exhibits the Me group joined to the sulfur
atom in an antiperiplanar arrangement with respect to the C-Li
bond, thus contributing to its stabilization by the interaction
σC-Li2f σ*S-Me 22 In these two complexes, the presence of the
.
metal with its ligands precludes the approach of the electrophile
to the upper face of the anion (Figure 2), which will be attacked
only by the bottom face. Taking into account steric effects during
the approach of the electrophile, a higher reactivity for C2 could
be expected. In the case of structures D, in which Li+ is not
stabilizing the carbanion, the upper face will show much less
steric interaction during the approach of the electrophile,
(20) Because of the importance of solvent effects, especially when charged
species are involved, complexes C and D have also been optimized in a dielectric
medium mimicking THF, using the IEF-PCM model: (a) Cance`s, E.; Mennucci,
B.; Tomasi, J. J. Chem. Phys. 1997, 107, 3032. (b) Cossi, M.; Barone, V.;
Mennucci, B.; Tomasi, J. Chem. Phys. Lett. 1998, 286, 253.
(21) A similar structure has been suggested from theoretical calculations as
the most reactive and, therefore, being responsible for the good selectivity
observed in the reactions of methyl 2-p-tolylsulfinyl benzyl carbanions: Garc´ıa
Ruano, J. L.; Alema´n, J.; Alonso, I.; Parra, A.; Marcos, V.; Aguirre, J. Chem.-
Eur. J. 2007, 13, 6179.
(22) (a) Wiberg, K. B.; Castejon, H. J. Am. Chem. Soc. 1994, 116, 10489.
(b) Kaiser, B.; Hoppe, D. Angew. Chem., Int. Ed. Engl. 1995, 34, 323. (c) Dress,
R. K.; Rolle, T.; Hoffmann, R. W. Chem. Ber. 1995, 128, 673. (d) Lehn, J. M.;
Wipff, G.; Demuynck, J. HelV. Chim. Acta 1977, 60, 1239. (e) Brandt, P.;
(19) Geometries have been fully optimized using the standard 6-31G(d) basis
set for all of the atoms: (a) Ditchfield, R.; Hehre, W. J.; Pople, J. A. J. Chem.
Phys. 1971, 54, 724. Frequencies and ZPE were also computed at the same level
of theory. Final energies have been obtained using the more extended 6-311+G**
basis set for all atoms: (b) McLean, A. D.; Chandler, G. S. J. Chem. Phys. 1980,
72, 5639. (c) Krishnan, R.; Binkley, J. S.; Seeger, R.; Pople, J. A. J. Chem.
Phys. 1980, 72, 650. Relative free energies (in kcal · mol-1 were evaluated at
the B3LYP/6-311+G** level with ZPE and entropy corrections evaluated at
298 K using the frequencies previously calculated at the B3LYP/6-31G(d) level.
Haeffner, F. J. Am. Chem. Soc. 2003, 125, 48. Orbital interactions (kcal · mol-1
)
evaluated by means of a second-order perturbational analysis of the Fock
matrix on the NBO basis (natural bond orbital method of Weinhold) indicate
that the charge is mainly delocalized to the aromatic ring (CBnf π*Cipso
-
CorthoSO ) 66.6), but a stabilizing interaction with the S-Me bond is observed
also (CBnf σ*S-Me ) 10.6). (f) Reed, A. E.; Curtiss, L. A.; Weinhold, F.
Chem. ReV. 1988, 88, 899.
768 J. Org. Chem. Vol. 74, No. 2, 2009

Synthesis of R,R-dibranched ꢀ-Sulfanyl Amines
FIGURE 3. Favored approaches of the imines to Li+[(S)-1] adopting the C structure.
especially in D2, which is quite close in energy to D1. These
species are much more unstable in vacuo than the chelated
species C2 (≈79 kcal · mol-1). However, taking into account
solvent effects, the difference in energy dramatically decreases
(≈5 kcal ·mol-1), and the participation of these free carbanion
species during the reaction cannot be underestimated.23 In fact,
they could explain the formation of minor products anti-12 and
syn-11. Because polar solvents stabilize uncoordinated species,
and sulfinylimines are quite polar, a decrease in the degree of
participation of species D could be the cause of the increase in
stereoselectivity observed in the reaction using substoichiometric
amounts of (S)-2a and (S)-2b.13,16
The favored approaches of (R)-2 and (S)-2 to the anion
derived from (S)-1 adopting the C2 structure are depicted in
Figure 3. We also have included the reaction with (S)-N-
FIGURE 4. Favored approaches of the (R) and (S) imines to Li+[(S)-
sulfinylaldimines.6 In the latter case, approach I does not present
serious steric interactions, thus explaining the complete stereo-
selectivity observed, which only results in ꢀ-sulfanyl amines
with the (S) configuration at benzylic carbon. A similar approach
for (S)-ketimines (approach II) must be less stable because of
the steric repulsion between the two methyl groups. It can be
minimized by the SMe bond losing its antiperiplanar arrange-
ment with respect to the C-Li bond, but it would decrease the
stability of the benzyl carbanion, with the possiblity that other
carbanionic species could participate in the reaction (see later).
Finally, reactions of (R)-2 with the anion C2, according to
approach III (Figure 3), which would yield compounds syn-13,
would be sterically more favorable than II (the size of the planar
nitrogen is lower than the Me group) and significantly stabilized
by the hydrogen bond between the nitrogen (negatively charged
in the transition state) and the Me joined to sulfur.
1] adopting the D2 structure.
approach IV] and anti-12 [from (R)-2, approach V] obtained in
the reactions of Table 2. The fact that the stereoselectivity of
the reactions of (S)-1 with (R)-2 is higher than that with (S)-2
can be explained by taking into account that the energy
difference between the transition state corresponding to ap-
proaches III (Figure 3) and V (Figure 4) must be higher than
that existing for approaches II and IV, mainly because of the
expected higher stability of TS(III) with respect to TS(II) by
steric grounds and hydrogen bond considerations (see before).
Compounds 10-13 were easily transformed into their cor-
responding R,R-dibranched ꢀ-sulfanyl amines syn-21 and anti-
23 by subsequent C-desulfinylation (with t-BuLi) and N-des-
ulfinylation (with TFA). These processes were investigated
starting with anti-10b, syn-13b, syn-13c, and syn-13d (Scheme
6). In all cases, very high yields were obtained for both steps.
The minor components of the reaction mixtures [anti-12 with
(R)-2 and syn-11 with (S)-1], with (R) configuration at the
benzylic carbon, could come from the planar nonchelated species
D2, in which the sulfinyl oxygen is arranged in the position
minimizing the electrostatic repulsion with the carbanionic
center (Figure 4). The evolution of D2 would explain the
formation of the minor diastereoisomers syn-11 [from (S)-2,
Conclusion
In summary, we have demonstrated that the reactions of the
lithium carbanion derived from (S)-1 with N-sulfinylketimines,
followed by consecutive C- and N-desulfinylations of the
resulting isomers, constitute a good alternative for the asym-
metric synthesis of R,R-dibranched ꢀ-sulfanyl amines. When
the configurations at the sulfinyl groups of the reagents are
opposite, compounds with syn stereochemistry are obtained in
a highly stereoselective manner and good yields, whereas for
reagents with the same configuration, easily separable mixtures
(23) In the case of the methyl 2-phenylsulfinyl benzyl carbanion model, this
difference is greater (13 kcal · mol-1). This fact along with the lack of any steric
hindrance at the bottom face of the equivalent C2 complex could explain the
complete control of the configuration in the reactions of methyl 2-p-tolylsulfinyl
benzyl carbanions with ketimines and other electrophiles (refs 12 and 15). These
results confirm the lower configurational stability of the sulfenylated benzyl
carbanion with respect to the methyl 2-p-tolylsulfinyl benzyl carbanion.
J. Org. Chem. Vol. 74, No. 2, 2009 769

Arroyo et al.
SCHEME 6. Conversion of syn-13b, syn-13c, syn-13d, and anti-10b into Corresponding Free Wic-Sulfanyl Amines
[2R,3S,S(S)]-N-{2-(4-Methoxyphenyl)-3-[(S)-2-(p-toluenesulfi-
nyl)phenyl]-3-(methylsulfenyl)propyl}-p-toluenesulfinamide (anti-
10c). N-Sulfinylketimine (S)-2c was used as electrophile: eluent
for chromatography hexane/Et2O 1:15; yield 52%; white solid; mp
of diastereoisomers are obtained, with the anti ꢀ-sulfanyl amines
being the major ones. Theoretical calculations suggest that the
presence of the SMe group at the benzylic position reduces the
configurational stability of the carbanions generated at this
position and supports the stereochemical proposal that explains
the experimental results.
20
1
129-130 °C (hexane/Et2O); [R]D ) -33.5 (c 0.5, CHCl3); H
NMR (300 MHz, CDCl3) δ 7.65 (t, 1H, J ) 8.6 Hz), 7.55-7.48
(m, 2H), 7.44, 7.31, 7.30, 7.19, 7.08, and 6.79 (three AA′BB′
systems, 12H), 7.36-7.30 (m, 1H), 6.38 (bs, 1H), 4.88 (s, 1H),
3.78 (s, 3H), 2.42 and 2.35 (2s, 6H), 2.20 (s, 3H), 1.26 (s, 3H); 13
C
Experimental Section
NMR (75 MHz, CDCl3) δ 159.0, 143.7, 143.6, 140.9, 140.7, 131.8,
132.5, 131.6, 130.3, 129.6, 129.4, 128.2, 128.0, 125.3, 125.1, 112.7,
64.5, 57.3, 55.0, 28.2, 21.3, 21.2, 14.5; HRMS calcd for
C31H34NO3S3 (M+ + 1) 564.1695, found 564.1690.
General Procedure for the Reactions Summarized in Tables
1 and 2. A solution of n-BuLi (2.5 M in hexane, 1.5 mL, 0.6 mmol,
1.2 equiv) was added over i-Pr2NH (0.12 mL, 0.9 mmol, 1.8 equiv)
in THF (3 mL) at 0 °C. After 30 min of stirring, the mixture was
cooled to -78 °C, and then a solution of (S)-R-(methylsulfenyl)-
2-(p-tolylsulfinyl)toluene6 (138 mg, 0.5 mmol, 1 equiv) in THF (2
mL) was added. After 5 min of stirring, the electrophile [ketimine12,8d
(2′, (S)-2a-d or (R)-2a-g), 1.0 mmol, 2 equiv] dissolved in THF
(4 mL) was added at -78 °C. When the reaction was completed
(3-5 min), the mixture was hydrolyzed at that temperature with
saturated aqueous NH4Cl solution (2 mL) and extracted with CH2Cl2
(3 × 10 mL). The combined organic layers were dried over MgSO4,
and the solvent was removed under reduced pressure. The residue
was purified by flash column chromatography.
[2R,3S,S(S)]-N-{2-(4-Bromophenyl)-3-[(S)-2-(p-toluenesulfi-
nyl)phenyl]-3-(methylsulfenyl)propyl}-p-toluenesulfinamide (anti-
10d). N-Sulfinylketimine (S)-2d was used as electrophile: eluent
for chromatography hexane/Et2O 1:15; yield 39%; white solid; mp
20
1
113-114 °C (hexane/Et2O); [R]D ) -36.6 (c 0.5, CHCl3); H
NMR (300 MHz, CDCl3) δ 7.53-7.50 (m, 2H), 7.44, 7.41, 7.29,
7.28, 7.27, 7.24, and 7.08 (three AA′BB′ systems, 6H), 7.40-7.38
(m, 2H), 6.47 (bs, 1H), 4.87 (s, 1H), 2.43 and 2.37 (2s, 6H), 2.19
(s, 3H), 1.21 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 143.5, 143.4,
142.7, 142.6, 141.0, 139.5, 139.4, 122.2, 132.5, 131.8, 130.9, 130.6,
129.8, 129.5, 128.4, 128.2, 125.3, 125.0, 64.7, 56.8, 28.0, 21.4,
21.2, 15.0; HRMS calcd for C30H31BrNO2S3 612.0694, found
612.0722.
[2S,S(S)]-N-{1,1-Diphenyl-2-[(S)-2-(p-toluenesulfinyl)phenyl]-
2-(methylsulfenyl)ethyl}-p-toluenesulfinamide (5a). N-Sulfi-
nylketimine (S)-2a was used as electrophile: eluent for chroma-
tography hexane/Et2O 1:5; yield 67%; white solid; mp 91-92 °C
[2S,S(R)]-N-{1,1-Diphenyl-2-[(S)-2-(p-toluenesulfinyl)phenyl]-
2-(methylsulfenyl)ethyl}-p-toluenesulfinamide (7a). N-Sulfi-
nylketimine (R)-2a was used as electrophile: eluent for chroma-
tography hexane/Et2O 1:5; yield 85%; white solid; mp 100-101
20
1
(hexane/Et2O); [R]D ) -130.6 (c 0.5, CHCl3); H NMR (300
MHz, CDCl3) δ 7.94 and 7.81 (2d, 3H, J ) 7.1 Hz), 7.61-7.40
(m, 4H), 7.57, 7.50, 7.34, and 7.23 (two AA′BB′ systems, 8H),
7.40-7.16 (m, 6H), 7.01 (dd, 1H, J ) 7.7, 4.9 Hz), 5.49 (bs, 1H),
5.14 (s, 1H), 2.43, 2.34 (2s, 6H), 0.89 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 145.2, 143.4, 142.7, 141.3, 140.4, 138.5, 135.7, 131.7,
130.3, 130.2, 130.1, 129.6, 129.0, 128.6, 128.0, 127.7, 127.5, 127.2,
125.0, 123.5, 73.2, 56.1, 21.4, 14.5; HRMS calcd for C35H34NO2S3
(M+ + 1) 596.1746, found 596.1740.
20
°C (hexane/Et2O); [R]D ) -95.5 (c 0.5, CHCl3); FT IR(KBr)
1
3427, 1594, 1492, 1443, 1395, 1087 cm-1; H NMR (300 MHz,
CDCl3) δ 7.81 (dd, 1H, J ) 7.9, 1.1 Hz), 7.58-7.23 (m, 18H),
7.50 (part of AA′BB′ system, 2H), 6.98 (d, 1H, J ) 7.0 Hz), 5.41
(bs, 1H), 5.31 (s, 1H), 2.40 and 2.38 (2s, 6H), 1.05 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 144.7, 143.7, 142.7, 141.6, 141.0, 140.5,
136.0, 131.9, 130.5, 130.2, 129.6, 128.6, 128.1, 127.7, 127.5, 127.2,
125.4, 123.5, 71.8, 54.8, 21.5, 21.3, 13.9; HRMS calcd for
C35H34NO2S3 (M+ + 1) 596.1746, found 596.1751.
[2R,3S,S(S)]-N-{2-Phenyl-3-[(S)-2-(p-toluenesulfinyl)phenyl]-
3-(methylsulfenyl)propyl}-p-toluenesulfinamide (anti-10b). N-
Sulfinylketimine (S)-2b was used as electrophile: eluent for
chromatography hexane/Et2O 1:4; yield 55%; white solid; mp
[2S,3S,S(R)]-N-{2-Phenyl-3-[(S)-2-(p-toluenesulfinyl)phenyl]-
3-(methylsulfenyl)propyl}-p-toluenesulfinamide (syn-13b). N-
Sulfinylketimine (R)-2b was used as electrophile: eluent for
chromatography hexane/Et2O 1:4; yield 84%; white solid; mp
20
68-69 °C (hexane/Et2O); [R]D ) -36.7 (c 2.1, CHCl3); FT
IR(KBr) 3421, 1595, 1492, 1445, 1083 cm-1; 1H NMR (300 MHz,
CDCl3) δ 7.55 (d, J ) 8.7 Hz, 1H), 7.48, 7.38, 7.20, and 7.08 (two
AA′BB′ systems, 8H), 7.41 (dd, J ) 3.9, 2.3 Hz, 2H), 7.40-7.22
(m, 6H), 6.39 (bs, 1H), 4.91 (s, 1H), 2.43 and 2.35 (2s, 6H), 2.21
(s, 3H), 1.23 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 143.6, 143.5,
140.9, 140.8, 140.5, 140.3, 139.5, 132.5, 131.7, 129.7, 129.4, 128.9,
128.2, 128.1, 127.8, 127.5, 125.3, 125.2, 64.9, 57.0, 29.4, 21.3,
21.2, 14.6; HRMS calcd for C30H32NO2S3 (M+ + 1) 534.1589,
found 534.1585.
20
132-133 °C (hexane/Et2O); [R]D ) -14.0 (c 0.5, CHCl3); FT
IR(KBr) 3417, 1601, 1491, 1402, 1126 cm-1; 1H NMR (300 MHz,
CDCl3) δ 7.71 and 7.67 (2dd, 3H, J ) 10.5 Hz), 7.53 (td, J ) 8.7,
4.4 Hz), 7.40, 7.22, 7.16, and 7.12 (two AA′BB′ systems, 8H),
7.45-7.28 (m, 5H), 6.15 (bs, 1H), 5.01 (s, 1H), 2.36 and 2.32 (2s,
6H), 2.10 (s, 3H), 1.10 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 144.9,
143.7, 143.1, 140.9, 140.8, 140.3, 139.2, 132.2, 129.7, 129.4, 128.6,
770 J. Org. Chem. Vol. 74, No. 2, 2009

Synthesis of R,R-dibranched ꢀ-Sulfanyl Amines
128.4, 128.0, 127.4, 125.2, 125.0, 64.4, 57.0, 22.4, 21.3, 21.2, 14.9;
HRMS calcd for C30H32NO2S3 (M+ + 1) 534.1589, found 534.1583.
[2S,3S,S(R)]-N-{2-(4-Methylphenyl)-3-[(S)-2-(p-toluenesulfi-
nyl)phenyl]-3-(methylsulfenyl)propyl}-p-toluenesulfinamide (syn-
13c). N-Sulfinylketimine (R)-2c was used as electrophile: eluent
for chromatography hexane/Et2O 1:15; yield 77%; white solid; mp
98-99 °C (hexane/Et2O); [R]D20 ) -27.5° (c 0.5, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 7.73 (d, 1H, J ) 8.2 Hz), 7.54, 7.47, 7.23,
7.22, 7.16, and 7.10 (three AA′BB′ systems, 12H), 7.40-7.31 (m,
3H), 5.85 (bs, 1H), 5.07 (s, 1H), 2.40, 2.38 and 2.35 (3s, 9H), 2.09
(s, 3H) and 1.23 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 144.2,
143.2, 141.4, 140.9, 140.8, 140.2, 139.1, 137.2, 132.0, 129.6, 129.4,
128.7, 128.4, 128.3, 127.4, 125.2, 125.0, 64.3, 57.1, 23.0, 21.3,
21.2, 21.1, 14.9; HRMS calcd for C31H34NO2S3 (M+ + 1) 548.1746,
found 548.1752.
mmol) in THF (2 mL) was added t-BuLi (0.15 mL, 0.22 mmol,
1.5 M in hexane, 1.8 equiv) When the reaction was completed (5
min), the mixture was hydrolyzed with saturated aqueous NH4Cl
solution (1 mL) and extracted with CH2Cl2 (3 × 3 mL). The
combined organic layers were dried over MgSO4, and the solvent
was removed under reduced pressure. The residue was purified by
flash column chromatography.
[2S,3S,S(R)]-N-[2,3-Diphenyl-3-(methylsulfenyl)propyl]-p-
toluenesulfinamide (syn-20b). This product was obtained from syn-
13b: eluent for chromatography hexane/Et2O 1:5; yield 81%; white
syrup; [R]D20 ) -30.3 (c 0.9, CHCl3); 1H NMR (300 MHz, CDCl3)
δ 7.58 and 7.30 (AA′BB′ system, 4H), 7.49 (dd, 2H, J ) 8.1, 1.6
Hz), 7.41-7.33 (m, 3H), 7.24-7.11 (m, 5H), 4.59 (bs, 1H), 4.12
(s, 1H), 2.42 (s, 3H), 1.99 (s, 3H), 1.69 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 141.8, 141.1, 137.3, 130.5, 129.6, 129.5, 128.0,
127.9, 125.4, 125.3, 66.1, 64.1, 24.9, 21.3, 15.6.
[2S,3S,S(R)]-N-[2-(4-Methylphenyl)-3-(phenyl)-3-(methylsulfe-
nyl)propyl]-p-toluenesulfinamide (syn-20c). This product was
obtained from syn-13c: eluent for chromatography hexane/Et2O 1:6;
quantitative yield; white syrup; [R]D20 ) -18.5 (c 0.6, CHCl3); 1H
NMR (300 MHz, CDCl3) δ 7.50, 7.32, 7.21, and 7.15 (two AA′BB′
systems, 8H), 7.18-7.11 (m, 5H), 4.44 (bs, 1H), 4.05 (s, 1H), 2.34
and 2.30 (2s, 6H), 1.89 (s, 3H), 1.59 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 143.4, 141.1, 138.8, 137.6, 137.3, 130.5, 129.6, 128.7,
128.0, 125.5, 125.4, 66.0, 63.9, 24.8, 21.3, 21.1, 15.6; HRMS calcd
for C24H27NOS2Na (M+ + Na) 432.1432, found 432.1430.
[2S,3S,S(R)]-N-[2-(4-Methoxyphenyl)-3-(phenyl)-3-(methyl-
sulfenyl)propyl]-p-toluenesulfinamide (syn-20d). This product was
obtained from syn-13d: eluent for chromatography hexane/Et2O 1:5;
yield 88%; white syrup; [R]D20 ) +60.0 (c 0.4, CHCl3); FT IR(KBr)
3414, 1609, 1513, 1455, 1252 cm-1; 1H NMR (300 MHz, CDCl3)
δ 7.50, 7.35, 7.22, and 6.84 (two AA′BB′ systems, 8H), 7.18-7.11
(m, 5H), 4.43 (bs, 1H), 4.03 (s, 1H), 3.76 (s, 3H), 2.34 (s, 3H),
1.88 (s, 3H), 1.60 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 159.0,
147.1, 143.4, 141.1, 135.2, 137.3, 133.7, 130.5, 129.6, 129.5, 129.3,
129.2, 128.0, 125.4, 113.2, 66.1, 63.7, 55.2, 25.0, 21.3, 15.6.
[2S,3S,S(R)]-N-{2-(4-Methoxyphenyl)-3-[(S)-2-(p-toluenesulfi-
nyl)phenyl]-3-(methylsulfenyl)propyl}-p-toluenesulfinamide (syn-
13d). N-Sulfinylketimine (R)-2d was used as electrophile: eluent
for chromatography hexane/Et2O 1:15; yield 80%; white solid; mp
95-96 °C; [R]D20 ) -8.2 (c 1.4, CHCl3); FT IR(KBr) 3449,1606,
1512, 1460, 1379, 1088 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.69
(d, 1H, J ) 8.0 Hz), 7.56, 7.46, 7.22, 7.15, 7.09, and 6.92 (three
AA′BB′ systems, 12H), 7.36-7.31 (m, 3H), 5.83 (bs, 1H), 5.04
(s, 1H), 3.84 (s, 3H), 2.37 and 2.34 (2s, 6H), 2.07 (s, 3H), 1.23 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 158.7, 143.9, 143.0, 141.8,
140.7, 140.1, 138.9, 136.2, 131.9, 130.0, 129.3, 128.7, 128.3, 128.2,
125.1, 124.9, 113.1, 64.0, 57.1, 55.0, 23.1, 21.2 21.1, 14.8; HRMS
calcd for C31H34NO3S3 (M+ + 1) 564.1695, found 564.1690.
[2S,3S,S(R)]-N-{2-(4-Bromophenyl)-3-[(S)-2-(p-toluenesulfi-
nyl)phenyl]-3-(methylsulfenyl)propyl}-p-toluenesulfinamide (syn-
13e). N-Sulfinylketimine (R)-2e was used as electrophile: eluent
for chromatography hexane/Et2O 1:12; yield 65%; white solid; mp
20
1
100-101 °C (hexane/Et2O); [R]D ) +18.3 (c 0.5, CHCl3); H
NMR (300 MHz, CDCl3) δ 7.73 (d, 1H, J ) 8.0 Hz), 7.63-7.42
(m, 7H), 7.38, 7.22, 7.18, and 7.12 (two AA′BB′ systems, 8H),
6.41 (bs, 1H), 4.88 (s, 1H), 2.38 and 2.33 (2s, 6H), 2.05 (s, 3H),
1.02 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 144.5, 143.3, 143.1,
141.0, 140.8, 140.2 139.3, 121.6, 132.3, 131.0, 129.8, 129.4, 129.1,
128.8, 128.4, 125.1, 124.8, 64.1, 56.5, 21.9, 21.3, 21.2, 14.7; HRMS
calcd for C30H31BrNO2S3 (M+ + 1) 612.0694, found 612.0709.
[2S,3S,S(R)]-N-{2-(4-Cyanophenyl)-3-[(S)-2-(p-toluenesulfi-
nyl)phenyl]-3-(methylsulfenyl)propyl}-p-toluenesulfinamide (syn-
13f). N-Sulfinylketimine (R)-2f was used as electrophile: eluent for
chromatography hexane/Et2O 1:5; yield 82%; yellow solid; mp
[2R,3S,S(S)]-N-[2,3-Diphenyl-3-(methylsulfenyl)propyl]-p-
toluenesulfinamide (anti-22b). This product was obtained from
anti-10b: eluent for chromatography hexane/Et2O 1:4; yield 80%;
20
1
white syrup; [R]D ) +4.0 (c 1.8, CHCl3); H NMR (300 MHz,
CDCl3) δ 7.67 and 7.34 (AA′BB’system, 4H), 7.35-7.31 (m, 3H),
7.30-7.23 (m, 3H), 7.15-7.00 (m, 3H), 6.91 (dd, 1H, J ) 8.0, 1.6
Hz), 5.42 (bs, 1H), 4.06 (s, 1H), 2.43 (s, 3H), 1.98 (s, 3H), 1.86 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 143.7, 142.1, 141.1, 137.6,
130.0, 129.6, 127.9, 127.6, 127.4, 127.2, 125.3, 125.2, 66.7, 65.0,
23.4, 21.4, 16.0.
20
81-82 °C (hexane/Et2O); [R]D ) -81.0 (c 0.4, CHCl3); FT
IR(KBr) 3423, 2227, 1600, 1490, 1461, 1403, 1083 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.74, 7.62, 7.19, and 7.09 (two AA′BB′
systems, 8H), 7.66 (dd, 1H, J ) 7.6, 1.1 Hz), 7.58-7.20 (m, 2H),
7.10-7.05 (m, 5H), 6.93 (bs, 1H), 4.71 (s, 1H), 2.30 and 2.25 (2s,
6H), 1.94 (s, 3H), 0.70 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 152.0,
143.1, 142.6, 141.2, 140.9, 140.1, 139.7, 111.1, 132.7, 132.6, 131.8,
129.9, 129.5, 129.4, 128.4, 127.8, 125.0, 124.6, 119.0, 64.2, 55.9,
21.4, 21.2, 20.1, 14.4; HRMS calcd for C31H31N2O2S3 (M+ + 1)
559.1542, found 559.1556.
Representative Procedure for N- and S-Desulfinylation. To
a stirred solution of 5a, 7a, anti-10b, syn-11b, anti-12b, syn-13b,
syn-20b-d, or anti-22b (0.05 mmol) in methanol (1 mL) was added
TFA (12.5 µL, 0.15 mmol, 3 equiv). After the mixture was stirred
for 3 h at 0 °C, the solvent was evaporated, and the residue was
purified by SCX column chromatography (ammonia solution 7 M
in methanol) to afford the corresponding amine.
[2S,3S,S(R)]-N-{2-Isopropyl-3-[(S)-2-(p-toluenesulfinyl)phe-
nyl]-3-(methylsulfenyl)propyl}-p-toluenesulfinamide (syn-13g).
N-Sulfinylketimine (R)-2g was used as electrophile: eluent for
(2S)-1,1-Diphenyl-2-[(S)-2-(p-toluenesulfinyl)phenyl]-2-
(methylsulfenyl)ethyl}ethylamine (9). This product was obtained
20
from 5a and 7a: yield 93%; white syrup; [R]D ) -90.0° (c 1.8,
20
chromatography hexane/Et2O 1:6; yield 75%; white syrup; [R]D
CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.84 and 7.74 (2dd, 2H, J
) 7.1, 1.8 Hz), 7.58-7.50 (m, 4H), 7.48-7.31 (m, 3H), 7.39 and
7.27 (AA′BB′ system, 4H), 7.21-7.08 (m, 5H), 5.19 (s, 1H), 2.40
(bs, 2H), 2.38 (s, 3H), 1.10 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
145.4, 145.2, 144.9, 142.4, 141.8, 136.6, 131.6, 130.2, 128.4, 128.1,
127.7, 127.6, 127.4, 127.1, 123.4, 65.5, 53.8, 21.4, 14.1.
) -122.2 (c 0.5, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.98 and
7.89 (2d, 2H, J ) 7.6 Hz), 7.65 (t, 1H, J ) 7.5 Hz), 7.54, 7.24,
7.20, and 7.18 (two AA′BB′ systems, 8H), 7.49 (t, 1H, J ) 7.5
Hz), 7.04 (bs, 1H), 4.64 (s, 1H), 2.36 and 2.32 (2s, 6H), 2.26-2.20
(m, 1H), 1.56 (s, 3H), 1.04 and 0.98 (2d, 6H, J ) 6.7 Hz), 0.70 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 144.1, 142.9, 140.8, 140.6,
140.1, 133.9, 132.3, 130.1, 129.7, 129.2, 127.6, 125.1, 124.4, 64.3,
51.4, 36.2, 21.3, 21.1, 17.8, 17.2, 17.0, 12.9; HRMS calcd for
C27H34NO2S3 (M+ + 1) 500.1746, found 500.1735.
(2S,3S)-3-(Methylsulfenyl)-2,3-diphenylpropylamine (syn-
21b). This product was obtained from syn-20b: yield 90%; colorless
oil; [R]D20 ) +280.0° (c 0.6, CHCl3); 1H NMR (300 MHz, CDCl3)
δ 7.31 (bs, 6H), 7.20 (d, 2H, J ) 6.7 Hz), 7.09 (d, 2H, J ) 5.8
Hz), 4.22 (s, 1H), 1.80 and 1.73 (2s, 6H); 13C NMR (75 MHz,
General Procedure for C- and S-Desulfinylation. To a stirred
solution of anti-10b, syn-11b, syn-13b, syn-13c, or syn-13d (0.12
J. Org. Chem. Vol. 74, No. 2, 2009 771

Arroyo et al.
CDCl3) δ 139.9, 137.1, 130.2, 27.9, 127.8, 126.5, 63.2, 60.7, 24.9,
15.6; HRMS calcd for C15H16NS (M+ - CH3) 242.1003, found
242.0996.
reaction mixture was stirred for 3 h and filtered, and the residue
was purified by SCX column affording the pure free amine.
(1R)-1-Methyl-1,2-diphenylethylamine [(R)-16]. This product
was obtained from syn-14b, a mixture of compounds anti-15b/syn-
14b (80:20) or (R)-19:12 yield 86% from syn-14b, 77% from anti-
(2S,3S)-2-(p-Methylphenyl)-3-(methylsulfenyl)-3-phenylpro-
pylamine (syn-21c). This product was obtained from syn-20c: yield
79%; colorless oil; [R]D20 ) +62.9 (c 0.7, CHCl3); 1H NMR (300
MHz, CDCl3) δ 7.25-7.13 (m, 7H), 7.07 (part of one AA′BB′
system, 2H), 4.05 (s, 1H), 2.40 (bs, 2H), 2.31 (s, 3H), 1.75 (s, 3H),
1.62 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 138.4, 136.4, 130.1,
128.4, 127.6, 127.2, 126.1, 65.4, 58.5, 27.7, 21.0, 15.6; HRMS calcd
for C17H18S (M+ - NH3) 254.1129, found 254.1126.
20
15b/syn-14b, and 80% from (R)-19; white syrup; [R]D ) +76.4
1
(c 0.9, CHCl3); H NMR (300 MHz, CDCl3) δ 7.42 (dd, 2H, J )
7.9, 1.5 Hz), 7.32 and 7.23 (2dd, 3H, J ) 7.4, 1.6 Hz), 7.16 (dd,
3H, J ) 4.9, 1.7 Hz), 6.88 (dd, 2H, J ) 6.5, 2.9 Hz), 3.04 (AB
system, 2H, J ) 17.5 Hz), 1.86 (bs, 2H), 1.55 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 148.3, 137.5, 130.2, 128.2, 127.9, 126.9, 126.7,
125.2, 57.8, 50.1, 29.8; HRMS calcd for C14H14N (M+ - CH3)
196.1126, found 196.1129.
(2S,3S)-2-(p-Methoxyphenyl)-3-(methylsulfenyl)-3-phenylpro-
pylamine (syn-21d). This product was obtained from syn-20d: yield
20
1
88%; yellow oil; [R]D ) +48.3 (c 0.6, CHCl3); H NMR (300
MHz, CDCl3) δ 7.26 and 6.81 (AA′BB′ system, 4H), 7.23-7.13
(m, 5H), 4.04 (s, 1H), 3.80 (s, 3H), 2.40 (bs, 2H), 1.78 (s, 3H),
1.64 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 158.3, 141.1, 138.4,
138.0, 136.9, 130.0, 127.6, 127.3, 127.1, 112.9, 65.6, 58.3, 55.1,
28.0, 15.6; HRMS calcd for C17H18OS (M+ - NH3) 270.1072,
found 270.1078.
(2R,3S)-3-(Methylsulfenyl)-2,3-diphenylpropylamine (anti-
23b). This product was obtained from anti-22b: yield 92%; white
syrup; [R]D20 ) +60.0 (c 0.8, CHCl3); 1H NMR (300 MHz, CDCl3)
δ 7.46 (d, 2H, J ) 7.5 Hz), 7.34-7.29 (m, 2H), 7.26-7.24 (m,
6H), 4.14 (s, 1H), 2.68 (bs, 2H), 1.71 (s, 3H), 1.41 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 146.2, 138.6, 129.9, 127.9, 127.8, 127.3,
126.8, 125.8, 65.3, 58.9, 28.6, 15.6.
Acknowledgment. We thank the Spanish Government (Grant
CTQ2006-06741) and JCYL (VA-085A08) for financial support.
A generous allocation of computer time at the Centro de
Computacio´n Cient´ıfico de la UAM is also acknowledged.
Supporting Information Available: General experimental
methods. Characterization data for 3a, 4a, 6a, 8a, syn-11b-d,
anti-12b-e, syn-14b, anti-15b, (S)-16, anti-17b, syn-18b, and
ent-20b. 1H NMR and 13C NMR spectra of compounds 3a, 4a,
5a, 7a, 8a, 9, anti-10b-d, syn-11b-d, anti-12c, anti-12e, syn-
13b-g, syn-14b, (R)- and (S)-16, anti-17b, syn-18b, 20b, ent-
20b, syn-20c,d, anti-22b, syn-21b-d, and anti-23b. Full citation
for ref 18 and Cartesian coordinates for all optimized structures,
their electronic energies, and ZPVEs. This material is available
free of charge via the Internet at http://pubs.acs.org.
Representative Procedure for C- and S-Desulfinylation with
Ra-Ni. To a solution of the corresponding compound syn-14b, anti-
15b, anti-17b, and syn-18b or (R)-1912(0.09 mmol) in THF (1 mL)
was added activated Raney nickel (0.6 g) in THF (2 mL). The
JO802200F
772 J. Org. Chem. Vol. 74, No. 2, 2009