Synthesis of optically pure vic-sulfanyl amines mediated by a remote sulfinyl group

Article abstract of DOI:10.1021/ol201696y

Enantiomerically pure syn-1,2-diaryl-1,2-sulfanylamine derivatives can be obtained in a completely stereoselective manner by reaction of the benzylcarbanion Li-(S)-1 with N-phenyl (or PMP)-arylidene aldimines and further desulfinylation with t-BuLi. Theoretical studies at the DFT (mPW1PW91) level with the CPCM model, by using the Gaussian09 program, provide a good explanation for the stereochemical results.

Full text of DOI:10.1021/ol201696y

ORGANIC
LETTERS
2011
Vol. 13, No. 17
4534–4537
Synthesis of Optically Pure vic-Sulfanyl
Amines Mediated by a Remote
Sulfinyl Group
,†
Yolanda Arroyo,* M. Ascension Sanz-Tejedor, Ines Alonso, and
†
‡
ꢀ
ꢀ
,‡
ꢀ
Jose L. Garcıa-Ruano*
´
o
Departamento de Quımica Organica (EII), Universidad de Valladolid, P del Cauce 59,
´
47011 Valladolid, Spain, and Departamento de Quımica Organica (C-I),
ꢀ
´
Universidad Autonoma de Madrid, Cantoblanco, 28049 Madrid, Spain
ꢀ
ꢀ
yarroyo@eis.uva.es; joseluis.garcia.ruano@uam.es
Received June 24, 2011
ABSTRACT
Enantiomerically pure syn-1,2-diaryl-1,2-sulfanylamine derivatives can be obtained in a completely stereoselective manner by reaction of the
benzylcarbanion Li-(S)-1 with N-phenyl (or PMP)-arylidene aldimines and further desulfinylation with t-BuLi. Theoretical studies at the DFT
(mPW1PW91) level with the CPCM model, by using the Gaussian09 program, provide a good explanation for the stereochemical results.
vic-Sulfanyl amines are efficient heterobidentate
N,S-ligands in asymmetric reactions1 and valuable build-
ings blocks,2 which are characteristic motifs in bioactive
natural products,3 and pharmacologically important
compounds.4 Despite this interest, only two general routes
have been reported for synthesizing optically pure
1,2-sulfanylamines containing two chiral centers. The
Enders’ approach5 involves the sequential formation of
the two chiral centers by R-alkylation of optically pure
R-sulfanylated acetaldehyde-SAMP-hydrazones followed
by 1,2-addition to a CdN bond (Scheme 1, upper). Our
approach6 involves the reactions of the R-methylsulfenyl-
benzyl carbanion Li-(S)-1 with (S)-N-sulfinylaldimines,
affording anti-1,2-sulfanylamines (Scheme 1, lower), which
takes place with simultaneous formation of the two chiral
centers according to a completely stereoselective double
asymmetric induction process. Both approaches allow
the preparation of the enantiomerically pure anti diaster-
eoisomers in high de (g96% de), but none of them is
suitable for obtaining the syn ones. Consequently, the
† Universidad de Valladolid.
‡
ꢀ
Universidad Autonoma de Madrid.
(1) For recent reviews, see: (a) Pellisier, H. Tetrahedron 2007, 63,
ꢀ
1297. (b) Martin, E.; Dieguez, M. C. R. Chim. 2007, 10, 188. For other
ꢀ
references, see:(c) Le Fur, N.; Mojovic, L.; Ple, N.; Turck, A.; Reboul,
V.; Metzner, P. J. Org. Chem. 2006, 71, 2609. (d) Granander, J.;
Eriksson, J.; Hilmersson, G. Tetrahedron: Asymmetry 2006, 17, 2021.
€
€
(e) Ekegren, J. K.; Roth, P.; Kallstrom, K.; Tarnai, T.; Andersson, P. G.
Org. Biomol. Chem. 2003, 1, 358. (f) 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. (g) 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.
(4) (a) Boge, T. C.; Georg, G. I. In Enantioselective Synthesis of β-
Amino Acids; Juaristi, E., Ed.; Wiley-VCH: NewYork, 1996; p 1. (b) Bae,
J. H.; Shin, S. H.; Park, C. S.; Lee, W. K. Tetrahedron 1999, 55, 10041. (c)
Adams, B.; Beresford, K. J. M.; Whyte, S. M.; Young, D. W. Chem.
Commun. (Cambridge, U.K.) 2000, 619.
(5) Enders, D.; Moll, A.; Schaadt, A.; Raabe, G.; Runsink, J. Eur. J.
Org. Chem. 2003, 3923 and references therein.
(2) (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.
(3) (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) Tamariz, J.
In Enantioselective Synthesis of β-Amino Acids; Juaristi, E., Ed.; Wiley-
VCH: New York, 1996; p 45. (c) Rinehart, K. L. Med. Res. Rev. 2000, 20,
1. (d) 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.
(6) (a) Arroyo, Y.; Meana, A.; Rodrı
Tejedor, M. A.; Garcıa-Ruano, J. L. J. Org. Chem. 2005, 70, 3914. (b)
Arroyo, Y.; Meana, A.; Sanz-Tejedor, M. A.; Alonso, I.; Garcıa-Ruano,
J. L. J. Org. Chem. 2009, 74, 764.
´
guez, J. F.; Santos, M.; Sanz-
´
´
r
10.1021/ol201696y
Published on Web 08/11/2011
2011 American Chemical Society

search for methods to obtain enantiomerically pure vic-
sulfanyl amines remains a challenging task.
entries 2ꢀ6). The NMR spectra of the reaction crudes
are very clean and reveal a complete conversion and the
almost exclusive formation of the syn stereoisomers.
Signals corresponding to another product can be de-
tected in reaction crudes obtained from 2c and 2f
(entries 3 and 6), but their low proportion (e2%)
precludes their characterization. The behaviors of
the N-p-methoxyphenyl and N-2,4,6-trimethoxyphenyl
arylidene imines are identical, allowing optically pure
syn-1,2-sulfanylamine derivatives to be obtained (3gꢀ3o,
entries 7ꢀ15, Table 1), which indicates that the influ-
ence of EDG enhancing the electron density on the
aniline ring does not produce any significant change,
regardless of the substituent at the arylidene ring. The
isolated yields for compounds 3aꢀ3o ranged between
65 and 80%.
Scheme 1. Approaches for Synthesizing anti 1,2-Sulfanyl
Amines
We have reported that the stereoselectivity of the reac-
tions of alkyl 2-(p-tolylsulfinyl)benzyl carbanions with
N-arylarylideneamines depends on the electronic density
of the rings at the imine, with electron-donating (EDG)
and electron-withdrawing groups (EWG), respectively,
favoring the formation of the syn and anti stereoisomers7
(Scheme 2). This behavior prompted us to study the
reactions of (S)-1 with N-arylimines, with the hope to find
the appropriate substituents allowing the preparation of
the optically pure syn-1,2-sulfanyl amines. The results
obtained in this study are reported herein.
Table 1. Reactions of (S)-1 with N-Arylarylideneamines 2aꢀo
Using a Single Asymmetric Induction Procedure
de
(%)a
yield,
b
entry
Ar
Ph
R
product
3a
%
1
H
>98
>98
g96d
>98
>98
g96d
>98
>98
>98
>98
>98
>98
>98
>98
>98
75
80
65
77
70
80
70
75
65
2
Ph
4-CH3
4-CH3O
3-Cl
3b
3
Ph
3cc þ 30c
4
Ph
3d
Scheme 2. Reactions of 2-(p-Tolylsulfinyl)benzylcarbanions
with N-Arylarylideneimines7
5
Ph
4-CF3
4-CN
H
3e
6
Ph
3f þ 30f
7
PMP
PMP
PMP
PMP
PMP
PMP
PMP
TMP
TMP
3g
8
4-CH3
4-CH3O
2-Br
3h
9
3i
e
10
11
12
13
14
15
3j
ꢀ
3-Cl
3k
75
65
75
75
75
4-CF3
4-CN
4-CH3
4-CN
3l
3m
3n
Optically pure (S)-1 was easily synthesized in two steps
starting from commercially available o-bromotoluene.6a
N-Arylarylideneamines 2aꢀu were prepared from ani-
lines and benzaldehydes in the presence of molecular
sieves.7
3o
a Determined by 1H NMR of the crude reaction mixture. b Isolated
yield. c The ORTEP structure of 3c can be found in the Supporting
Information. d See text. e Compound 3j was completely decomposed
during chromatographic purification.
We first studied the reactions of the benzylcarbanion
derived from (S)-1 with N-phenylbenzylideneamine 2a.
To our surprise, a completely stereoselective reaction,
only yielding the syn-1,2-sulfanylamine 3a in 75%
isolated yield (entry 1, Table 1), was observed. This
result contrasts with the 91:9 mixture of anti/syn amines
obtained from 2-p-tolylsulfinyl ethylbenzene.7a We
then studied the reactions with other N-phenylarylide-
neamines 2bꢀf, bearing EDG and EWG (Table 1,
By assuming a similar behavior for all reactions shown
in Table 1, the absolute configuration for compounds syn-
3 was established as (SS, 1S, 2S) once it was unequivocally
assigned by X-ray analysis for syn-3c and for the sulfone
derived from syn-3p (see Supporting Information (SI)
and Table 2).
Desulfinylation of 3 into the N-aryl-1,2-sulfanylamines
syn-4 can be achieved with t-BuLi. These reactions were
investigated with syn-3m, syn-3o, and syn-3r (Scheme 3),
respectively yielding syn-4m, syn-4o, and syn-4r in quanti-
tative yields, without affecting the benzylic CꢀS bond or
the configurational integrity at C(1) and C(2).
ꢀ
(7) (a) Garcıa-Ruano, J. L.; Aleman, J.; Alonso, I.; Parra, A.;
´
ꢀ
Marcos, V.; Aguirre, J. Chem.;Eur. J. 2007, 13, 6179. (b) Aleman, J.
ꢀ
PhD Thesis, Universidad Autonoma de Madrid, Spain. (c) Jiao, L.;
Liang, Y.; Xu, J. J. Am. Chem. Soc. 2006, 128, 6060. (d) Liang, Y.; Jiao,
L.; Zhang, S.; Yu, Z.-X.; Xu, J. J. Am. Chem. Soc. 2009, 131, 1542.
Org. Lett., Vol. 13, No. 17, 2011
4535

at the benzylidene moiety of p-cyanophenyl imines
2pꢀ2u, are identical to that previosly observed for
N-aryl imines in the Scheme 2. The anti-stereochemistry
assigned to compounds 5 was based on their NMR data,
and their absolute configuration was unequivocally
established by chemical correlation (see SI). It is remark-
able that the absolute configuration at the chiral carbons
for compounds anti-5 is different from that of the anti
compounds at Scheme 2.
Scheme 3. Desulfinylation of Compounds 3mꢀ3r
To understand the stereochemical results we must take
into account that both diastereomeric amines show the
same (S) configuration at the aminic carbon. It suggests
that reactions take place through the approach of the
nucleophile to the re face of imines 2. By contrast, the
configuration at carbon bonded to sulfur is S for syn-3
and R for anti-5, indicating the imine’s approach occurs
at the re and si faces of carbanion (S)-1, respectively
(Figure 1).
Once our synthetic objective was achieved, some
mechanistic explanation to the substantial changes
observed in the stereochemical results shown in Table 1
(only affording syn isomers) with respect to those of the
Scheme 2 (affording mixtures of syn and anti isomers
with the same imines) deserved investigation. As the
presence of the EWG at the iminic rings would favor the
formation of the anti isomers in Scheme 2, we studied
the reactions of (S)-1 with N-p-cyanophenylarylidene-
amines 2pꢀu. The results are collected in Table 2.
Table 2. Reactions of (S)-1 with N-p-Cyanophenylarylidene
Amines 2pꢀu
Figure 1. Approaches of the imines 2 to Liþ[(S)-1] explaining the
stereochemical results.
dr (%)a
Additionally, since syn-3 amines are the only products
obtained in reactions from imines derived from activated
anilines (Table 1) whereas the anti-5 ones become impor-
tant only when highly activated imines are employed (EWG
in both aromatic rings, Table 2), the energy of the resulting
transition states should depend on the nature of the groups
(EDG or EWG) present in imine aromatic rings. The
stability of the possible structures of the carbanion and
transition states, in the solvent phase, were studied theore-
tically at the DFT (mPW1PW91)8 level, with the CPCM
model,9 by using the Gaussian09 program10 (Figure 2).
Carbanion model I11 results from the stereoselective depro-
tonation of the species generated by association of the
sulfinyl oxygen with the lithium at the base. It is stabilized
by a hydrogen bond between benzylic carbon and the NꢀH
entry
R
imine
syn-3/anti-5
yield, %b
1
2
3
4
5
6
CH3O
CH3
H
2p
2q
2r
2s
2t
>98c:ꢀ
64:36
63:37
17:83
15:85
ꢀ:>98
75
70
99
55
70
75
3-Cl
CF3
CN
2u
a Determined by 1H NMR of the crude reaction mixture. b Combined
yield. The ORTEP structure of sulfone 30p obtained from 3p can be
found in the Supporting Information.
c
Imine 2p, bearing a strong EDG at the arylidene ring,
evolves with a complete syn-stereoselectivity, only af-
fording syn-3p in 75% isolated yield (entry 1; Table 2).
However, the reaction of (S)-1 with imine 2q, supporting
a weaker EDG, provides a mixture of two diasterei-
somers, syn-3q and anti-5q (entry 2, Table 2), with the
syn isomer as the major one still. A similar result was
obtained from 2r (entry 3, Table 2). In contrast, reac-
tions with imines 2s and 2t, bearing weakly EWG at
the arylidene ring, provide mixtures with a larger pro-
portion of the isomer anti-5 (entries 4 and 5, Table 2),
whereas reaction with N-4-cyanophenyl imine 2u af-
forded anti-5u as the only isomer (entry 6, Table 2).
These results, showing the dependence between stereose-
lectivity and the electronic character of the substituents
(8) (a) Perdew, J. P.; Chevary, S. H.; Vosko, K. A.; Jackson, K. A.;
Pederson, M. R.; Singh, D. J.; Fiolhais, C. Phys. Rev. B 1992, 46, 6671.
(b) Perdew, J. P.; Chevary, S. H.; Vosko, K. A.; Jackson, K. A.;
Pederson, M. R.; Singh, D. J.; Fiolhais, C. Phys. Rev. B 1993, 48,
4978. (c) Perdew, J. P.; Burke, K.; Wang, Y. Phys. Rev. B 1996, 54,
16533. (d) Adamo, C.; Barone, V. J. Chem. Phys. 1998, 108, 664. (e) It is
proposed that the mPW1PW91 can account for the likely long-range
dispersive interactions as well as hydrogen bonding (see: Patil, M. P.;
Sunoj, R. B. Chem. Asian L. 2009, 4, 714 and references therein).
(9) (a) Barone, V.; Cossi, M. J. Phys. Chem. A 1998, 102, 1995. (b)
Cossi, M.; Rega, N.; Scalmani, G.; Barone, V. J. Comput. Chem. 2003,
24, 669.
(10) Frisch, M. J. et al. Gaussian 09, revision A.02; Gaussian, Inc.:
Wallingford CT, 2009 (see SI).
(11) Other structures for the carbanion have been studied and
compared with I at the B3LYP level (see SI).
4536
Org. Lett., Vol. 13, No. 17, 2011

of the amine bonded to the lithium atom. Conformation II,
with the Me of the SMe group oriented toward the upper
face, is 1.4 kcal/mol less stable than I probably due to steric
effects. We then calculated the TSs of the approaches of
imines 2a, 2p, 2r, and 2u (Tables 1 and 2) to the carbanions I
and II by the opposite face to that occupied by the Me of the
SMe group. Results are also depicted in Figure 2. TS-syn
corresponds to the approach of the re face of the imine to
the less hindered re face of the carbanion II. It is stabilized
by a hydrogen bond between the iminic nitrogen and the
ortho hydrogen atom of the sulfinylated aromatic ring,
which could be responsible for the preferred approach of
the imine by its re face (Figure 2).12 TS-anti results from the
approach of the re face of the imine to the upper face of the
carbanion I. It is also stabilized by a hydrogen bond
between the sulfinyl sulfur and the ortho hydrogen of the
aromatic ring joined to the iminic nitrogen.
In agreement with the de indicated in Tables 1 and 2,
TS-syn is clearly favored with respect to TS-anti for 2a
and 2p (ΔGrelat. = 2.7 and 2.3 kcal/mol respectively). The
model predicts a 60:40 ratio of syn-3r/anti-5r (ΔGrelat. =
0.2 kcal/mol), comparable with experimental results
(Table 2, entry 3). Finally, with imine 2u only TS-anti
Figure 2. CPCM(THF)/mPW1PW91/6-311G(d,p)//6-31G(d) op-
timized carbanion and transition states for the reaction of the
imines 2 with Liþ[(S)-1].16 ΔG (kcal/mol) and representative
distance (d in A) and torsion angles (τ in deg) are indicated.
indicate that decreases the strength of these bonds. Also,
according to these analyses, the negative charge of the
carbanion moiety in TSs in which X = CN (more
reactive) is mainly polarized toward the benzylic posi-
tion, whereas in the case of X = H (less reactive) it is
mainly located at CR which allows its stabilization by the
sulfinyl group (being higher for the TS-syn15) which
could be found, thus precluding establishing the ΔGrelat.
-
value.13 Three main parameters can be used to under-
stand the relative stability of these TSs. d1 is the distance
separating the reactive centers. It is inversely propor-
tional to the imine’s reactivity (increases in the order
2u > 2r > 2p > 2a, Figure 2), and it is longer for TS-syn
because the hydrogen bond N HC increases the posi-
3 3 3
could be an important factor in determining the ΔGrelat.
-
tive charge at the iminic carbon and therefore its reactiv-
ity. d2 indicates the formation of the hydrogen bonds
CꢀH N and CꢀH S for TS-syn and TS-anti res-
value. These orbital interactions may be mainly related
to the value of the third parameter τ, the torsion angle
OꢀSꢀCRꢀCβ, which is very different in both TSs. It is
3 3 3
3 3 3
pectively. Although the presence of EWG at the rings
scarcely changes d2 values in Figure 2, NBO analyses14
larger (maybe due to the hydrogen bond CꢀH N)
3 3 3
and almost constant for TS-syn, whereas it is lower and
variable for TS-anti. In this latter case, τ is also related
to the steric repulsions of the imine with the sulfinyl
associated to the base, becoming lower when τ de-
creases. Thus, steric destabilization of the TS-anti is
minimized for the most reactive imines (those sup-
porting EWG) giving rise to changes in the syn/anti
selectivity.
(12) CꢀH...X interactions in TSs are crucial for the diastereoselec-
tivity (for example, see Washington, I.; Houk, K. N. Angew. Chem., Int.
Ed. 2001, 40, 4485). The approach of imine 2a by its si-face that would
yield the diastereomeric anti product shown in Scheme 2, mainly formed
in the case of R = Me (ref 7), was also studied. However, the
corresponding TS (see structure TS-anti0-2a in the SI) was much less
stable (ΔGrelat. = 3.9 kcal/mol) which would explain the absence of this
product in the present case. The different behaviour of carbanions with
R = Me, in which the CꢀH N bond could have also been formed and
3 3 3
R=SMe must be due to the different distribution of the charge,
delocalized through the aromatic ring and was stabilized by the sulfinyl
group or partially stabilized by the SMe group in the latter case.
(13) TS-syn and the remaining TSs were also studied with the B3LYP
level (see SI). However, despite the relative stabilities of these structures
showing the tendency experimentally observed, they correlate worse
with experimental results.
In summary, we have demonstrated that the synthesis of
enantiomerically pure syn-1,2-sulfanylamine derivatives 3,
(S,S)-1-aryl-2-(methylsulfenyl)-2-(phenyl)ethylamines, can
be performed by reaction of (S)-R-(methylsulfenyl)-2-
(p-tolylsulfinyl)toluene, (S)-1, with N-arylarylideneamines
and LDA and further desulfinylation with t-BuLi.
(14) Reed, A. E.; Curtiss, L. A.; Weinhold, F. Chem. Rev. 1988, 88,
899. The stabilizing interactions (kcal molꢀ1), evaluated by means of a
3
second-order perturbational analysis of the Fock matrix, between the
lone pair of a nitrogen atom in TS-syn and the CꢀH antibonding orbital,
decreases with the presence of EWG: 2.86, 2.62, and 2.36 from 2a to 2r.
Acknowledgment. Financial support from the Spanish
Government (CTQ-2009-12168) and CAM (programa
AVANCAT CS2009/PPQ-1634) and computational time
ꢀ
´
provided by the Centro de Computacion Cientıfica at the
UAM (CCC-UAM) are gratefully acknowledged.
The strength of the hydrogen bond CꢀH S in TS-anti also decreases
3 3 3
(1.50, 1.25, 1.21, and 1.21 from 2a to 2u). Another very weak CꢀH
S
3 3 3
bond in TS-syn between the sulfur atom of SMe and the iminic hydrogen
could be proposed according to its length (2.81ꢀ2.85 A); however,
taking into account the same criteria regarding its strength (less than
0.23) it was considered negligible.
(15) Stabilizing interactions (kcal molꢀ1) between a lone pair at CR
3
and the SꢀO and SꢀPh bonds have been found for I (14.5), II (14.8), TS-
Supporting Information Available. Additional experi-
mental details. This material is available free of charge via
Internet at http://pubs.acs.org.
syn-2a (12.2), or TS-anti-2a (10.7).
(16) Me2O, Me2NH, and Ph were used as simplified models for a
solvent, base, and Tol group respectively.
Org. Lett., Vol. 13, No. 17, 2011
4537