Stereoselective quaternization of α-amino phenylacetonitriles mediated by a remote sulfinyl group

Article abstract of DOI:10.1021/jo0705519

(Chemical Equation Presented) Enantiomerically pure α-substituted α-amino phenylacetonitriles have been readily prepared from 2-p-tolylsulfinylbenzaldimines following a two-step sequence: a moderately stereoselective hydrocyanation of the imines and a com

Full text of DOI:10.1021/jo0705519

Stereoselective Quaternization of r-Amino Phenylacetonitriles
Mediated by a Remote Sulfinyl Group†
Jose´ Luis Garc´ıa Ruano,* Ana M. Mart´ın-Castro,* Francisco Tato, and Ine´s Alonso
Departamento de Qu´ımica Orga´nica, UniVersidad Auto´noma de Madrid, Cantoblanco,
28049 Madrid, Spain
joseluis.garcia.ruano@uam.es
ReceiVed March 23, 2007
Enantiomerically pure R-substituted R-amino phenylacetonitriles have been readily prepared from 2-p-
tolylsulfinylbenzaldimines following a two-step sequence: a moderately stereoselective hydrocyanation
of the imines and a completely stereoselective quaternization of the resulting diastereoisomeric mixture
of R-amino phenylacetonitriles with different alkylating or acylating reagents in the presence of KHMDS.
Theoretical calculations support a stereoselectivity control exerted by the remote sulfinyl group, as long
as it is responsible for the conformational preferences of the benzyllithium intermediates, which suffer
the attack of the electrophiles to the less hindered diastereotopic face.
Introduction
hydrocyanation of ketimines is considerably smaller,2h probably
due to the easy reversibility of the hydrocyanation process (most
of the reported diastereoselective4 and enantioselective5 hydro-
cyanations having been restricted to cyclic or methyl ketimines).
Hydrocyanation of imines has been extensively studied due
to the large interest in the resulting R-amino nitriles not only
because of their versatility as building blocks in the preparation
of countless organic compounds but also due to their inherent
reactivity.1 Consequently, there have been reported many
hydrocyanating systems for the preparation of aldimine-derived
amino nitriles.2 Moreover, several general methods for the
synthesis of R-amino nitriles making use of a one-pot, three-
component condensation of aldehydes, amines, and cyanide in
the presence of different catalytic systems have also been
described.3 By contrast, the number of reports concerning
(3) (a) Oskooie, H. A.; Heravi, M. M.; Bakhtiari, K.; Zadsirjan, V.;
Bamoharram, F. F. Synlett 2006, 1768. (b) Wang, H.-S.; Zhao, L.-F.; Du,
Z. M. Chin. J. Chem. 2006, 24, 135. (c) De, S. K.; Gibbs, R. A. Tetrahedron
Lett. 2004, 45, 7407. (d) Ranu, B. C.; Dey, S. S.; Hajra, A. Tetrahedron
2002, 58, 2529. (e) Hanafusa, T.; Ichihara, J.; Ashida, T. Chem. Lett. 1987,
687.
(4) (a) Wang, H.; Zhao, X.; Li, Y.; Lu, L. Org. Lett. 2006, 8, 1379. (b)
Garc´ıa Ruano, J. L.; Cifuentes Garc´ıa, M.; Navarro, A. L.; Tato, F.; Mart´ın
Castro, A. M. ARKIVOC 2005 (vi), 33. (c) Avenoza, A.; Busto, J. H.;
Corzana, F.; Peregrina, J. M.; Sucunza, D.; Zurbano, M. M. Synthesis 2005,
575. (d) Badorrey, R.; Cativiela, C.; D´ıaz-de-Villegas, M. D.; D´ıez, R.;
Galbiati, F.; Ga´lvez, J. A. J. Org. Chem. 2005, 70, 10102. (e) Meyer, U.;
Breitling, E.; Bisel, P.; Frahm, A. W. Tetrahedron: Asymmetry 2004, 15,
2029. (f) Li, B.-F.; Yuan, K.; Zhang, M.-J.; Wu, H.; Dai, L.-X.; Wang, Q.
R.; Hou, X.-L. J. Org. Chem. 2003, 68, 6264. (g) Fondekar, K. P. P.; Volk,
F.-J.; Khaliq-uz-Zaman, S. M.; Bisel, P.; Frahm, A. W. Tetrahedron:
Asymmetry 2002, 13, 2241. (h) Warmuth, R.; Munsch, T. E.; Stalker, R.
A.; Li, B.; Beatty, A. Tetrahedron 2001, 57, 6383. (i) Davis, F. A.; Lee,
S.; Zhang, H.; Fanelli, D. J. Org. Chem. 2000, 65, 8704. (j) Wede, J.; Volk,
F.-J.; Frahm, A. W. Tetrahedron: Asymmetry 2000, 11, 3231.
† This article is dedicated to Professor Dr. Vicente Gotor on the occasion of
his 60th birthday.
* To whom correspondence should be addressed. FAX: (Int) +34914973966.
(1) (a) Enders, D.; Shilvock, J. Chem. Soc. ReV. 2000, 29, 359. (b) Gro¨ger,
H. Chem. ReV. 2003, 103, 2795. (c) North, M. In Science of Synthesis
(Houben-Weyl); Murahashi, S.-i., Ed.; Georg Thieme: Stuttgart, 2004; Vol.
19, p 285.
(2) (a) Surendra, K.; Srilakshmi Krishnaveni, N.; Mahesh, A.; Rama Rao,
K. J. Org. Chem. 2006, 71, 2532. (b) Royer, L.; De, S. K.; Gibbs, R. A.
Tetrahedron Lett. 2005, 46, 4595. (c) De, S. K. Synth. Commun. 2005, 35,
1577. (d) De, S. K. J. Mol. Catal. A: Chem. 2005, 225, 169. (e) Yadav, J.
S.; Reddy, B. V. S.; Eshwaraiah, B.; Srinivas, M. Tetrahedron 2004, 60,
1767. (f) Prasad, B. A. B.; Bisai, A.; Singh, V. K. Tetrahedron Lett. 2004,
45, 9565. (g) Yadav, J. S.; Reddy, B. V. S.; Eshwaraiah, B.; Srinivas, M.;
Vishnumurthy, P. New J. Chem. 2003, 27, 462.
(5) (a) Kato, N.; Suzuki, M.; Kanai, M.; Shibasaki, M. Tetrahedron Lett.
2004, 45, 3147. (b) Kato, N.; Suzuki, M.; Kanai, M.; Shibasaki, M.
Tetrahedron Lett. 2004, 45, 3153. (c) Keith, J. M.; Jacobsen, E. N. Org.
Lett. 2004, 6, 153. (d) Masumoto, S.; Usuda, H.; Suzuki, M.; Kanai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 5634. (e) Vachal, P.; Jacobsen,
E. N. J. Am. Chem. Soc. 2002, 124, 10012.
10.1021/jo0705519 CCC: $37.00 © 2007 American Chemical Society
Published on Web 07/13/2007
5994
J. Org. Chem. 2007, 72, 5994-6005

Quaternization of R-Amino Phenylacetonitriles
SCHEME 1
TABLE 1. Synthesis of (S)-2-p-Tolylsulfinyl Benzaldimines 2-10
Additionally, it is well-known that reactions of metalated
R-amino nitriles with the appropriate electrophiles (alkyl or acyl
halides, epoxides, aldehydes, and Michael acceptors) afford
ketimine-derived amino nitriles.6 The racemic version of this
methodology has been applied as an intermediate step in the
synthesis of a number of naturally occurring or pharmacologi-
cally active compounds.7 Nevertheless, a low and not easily
predictable stereocontrol has been found in the few asymmetric
reactions of lithiated R-amino nitriles, containing enantiopure
amine auxiliaries, with Michael acceptors6b-d and aldehydes.6e
Therefore, the search for efficient general methods for synthe-
sizing optically pure R,R-disubstituted R-amino nitriles is
currently an important challenge in asymmetric synthesis.
Recently we have reported a highly stereoselective method
for the hydrocyanation of 2-p-tolylsulfinyl benzaldehyde (1).8
The hydrocyanation of the corresponding ketones was not so
successful, and their optically pure cyanohydrins were prepared
by a highly diastereoconvergent quaternization of the anions
resulting from O-protected cyanohydrins derived from aldehyde
1, with a series of electrophiles (Scheme 1).9 Significant
differences in the stereochemical evolution of CdO and CdN
bonds under hydrocyanation conditions had been previously
evidenced for â-keto-10 and â-iminosulfoxides4b (only the first
ones could be hydrocyanated in a completely stereoselective
way), but there were no precedents describing differences of
behavior between oxygenated and nitrogenated carbanions under
quaternization conditions. Therefore, the results reported in refs
T
t
yield
entry
R
additive
solvent (°C) (h) imine (%)
1
2
3
4
5
6
7
8
9
C6H5
Na2SO4
Na2SO4
Na2SO4
Na2SO4
CH2Cl2
CH2Cl2
toluene 108 96
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
rt 16
rt 16
2
3
4
5
6
7
8
9
91
86
75
87
87
93
90
65
82
4-MeO-C6H4
4-NO2-C6H4
C6H5CH2
4-CF3-C6H4CH2 Na2SO4
4-MeO-C6H4CH2 Na2SO4
i-Bu
MeSO2
p-TolSO2
rt 16
rt 16
rt 16
rt 16
Na2SO4
Et3N, TiCl4 CH2Cl2 40
Et3N, TiCl4 DCE 83
5
4
10
8 and 9 prompted us to investigate the behavior of imines 2
derived from 1 under different hydrocyanating conditions, as
well as the reaction of the resulting mixtures of R-amino-(2-p-
tolylsulfinyl)phenyl acetonitriles under quaternization conditions,
with the aim of developing a ready access to hydrocyanated
phenyl ketimine derivatives. These results are reported in this
paper.
Results
(6) (a) Enders, D.; Kirchhoff, J.; Gerdes, P.; Mannes, D.; Raabe, G.;
Runsink, J.; Boche, G.; Marsch, M.; Ahlbrecht, H.; Sommer, H. Eur. J.
Org. Chem. 1998, 63 and references therein. (b) Enders, D.; Mannes, D.;
Raabe, G. Synlett 1992, 837. (c) Enders, D.; Kirchhoff, J.; Mannes, D.;
Raabe, G. Synthesis 1995, 659. (d) Roux, M.-C.; Wartski, L.; Nierlich, M.;
Lauce, M. Tetrahedron 1996, 52, 10083. (e) Enders, D.; Lotter, H.; Maigrot,
N.; Mazaleyrat, J.-P.; Welvart, Z. NouV. J. Chim. 1984, 8, 747.
(7) For leading references see: (a) Wang, S.; Dong, Y.; Wang, X.; Hu,
X.; Liu, J. O.; Hu, Y. Org. Biomol. Chem. 2005, 3, 911. (b) Haning, H.;
Niewoehner, U.; Schenke, T.; Lampe, T.; Hillisch, A.; Bischoff, E. Biorg.
Med. Chem. Lett. 2005, 15, 3900. (c) Yu, G.; Wang, S.; Wang, K.; Hu, Y.;
Hu, H. Synthesis 2004, 1021. (d) Snider, B. B.; Gu, Y. Org. Lett. 2001, 3,
1761. (e) Paulitz, C.; Steglich, W. J. Org. Chem. 1997, 62, 8474. (f) Silks,
L. A., III; Dunkle, E.; Unkefer, C. J.; Sudmeier, J. L.; Butler, M.;
Bachovchin, W. W. J. Labelled. Compd. Radiopharm. 1995, 36, 947. (g)
Wang, C.; Mosberg, H. I. Tetrahedron Lett. 1995, 36, 3623. (h) Subra-
manyam, C.; Ault, B.; Sawutz; D.; Bacon, E. R.; Singh, B.; Pennock, P.
O.; Kelly, M. D.; Kraynak, M.; Krafte, D.; Treasurywala, A. J. Med. Chem.
1995, 38, 587.
The syntheses of the optically pure sulfinyl imines used as
the starting materials for hydrocyanation reactions were per-
formed following conventional procedures from (S)-2-p-tolyl-
sulfinyl benzaldehyde (1)8 (Table 1). Reactions of 1 with
arylamines (entries 1-3), benzylamines (entries 4-6), and
isobutylamine (entry 7), were accomplished in high yields in
the presence of an excess of Na2SO4. Treatment of 1 with methyl
and p-tolyl sulfonamides (R ) MeSO2, p-TolSO2 in Table 1)
in the presence of Et3N and TiCl4 also afforded the correspond-
ing N-p-tolylsulfinylbenzylidene sulfonamides11 (entries 8 and
9) in good yields.
Hydrocyanation of freshly prepared sulfinylbenzaldimines
2-10 was assayed with Et2AlCN under different experimental
conditions (solvent, temperature, reaction time, amount of
reagent, and addition mode). Diastereoselectivities were lower
at temperatures below 0 °C. Similarly, less polar solvents
(CH2Cl2, toluene) decreased the reactivity (longer reaction times
(8) Garc´ıa Ruano, J. L.; Mart´ın Castro, A. M.; Tato, F.; Ca´rdenas, D. J.
Tetrahedron: Asymmetry 2005, 16, 1963.
(9) Garc´ıa Ruano, J. L.; Mart´ın Castro, A. M.; Tato, F.; Pastor, C. J. J.
Org. Chem. 2005, 70, 7346.
(10) (a) Garc´ıa Ruano, J. L.; Mart´ın Castro, A. M.; Rodr´ıguez, J. H.
Tetrahedron Lett. 1991, 32, 3195. (b) Garc´ıa Ruano, J. L.; Mart´ın Castro,
A. M.; Rodr´ıguez, J. H. J. Org. Chem. 1992, 57, 7235.
(11) Jennings, W. B.; Lovely, C. J. Tetrahedron Lett. 1988, 29, 3725.
J. Org. Chem, Vol. 72, No. 16, 2007 5995

Garc´ıa Ruano et al.
TABLE 2. Hydrocyanation of Sulfinylimines 4-10
TABLE 3. δ Values for the Benzylic Protons of Amino Nitriles
11-17 and 11′-17′
11-17:11′-17′
ratio
(yield [%])b
t
Lewis
acid
amino
nitriles
entry imine
R
(h)
amino
1H δ
amino
1H δ
R
nitrile (CH-CN) nitrile (CH-CN)
∆δ
1
4
4-NO2-C6H4
4-NO2-C6H4
C6H5CH2
C6H5CH2
4-CF3-C6H4CH2
4-CF3-C6H4CH2
2
2
2
2
16
16
-
11 + 11′
39:61 (75)
28:72
48:52 (90)
29:71
41:59 (86)
36:64
40:60 (88)
49:51 (74)
58:42 (86)
61:39
2
4
Yb(OTf)3 11 + 11′
12 + 12′
Yb(OTf)3 12 + 12′
4-NO2-C6H4
C6H5CH2
4-CF3-C6H4CH2
4-MeO-C6H4CH2
i-Bu
11
12
13
14
15
16
17
6.56
4.85
4.95
4.81
4.84
5.89
5.72
11′
12′
13′
14′
15′
16′
17′
6.80
5.45
5.46
5.41
5.42
6.07
6.07
0.34
0.60
0.51
0.60
0.58
0.18
0.35
3
5
-
4
5
5
6
7
6
6a
7
-
-
-
-
-
13 + 13′
13 + 13′
14 + 14′
15 + 15′
16 + 16′
4-MeO-C6H4CH2 16
MeSO2
8
8
i-Bu
16
2
2
2
2
p-TolSO2
9
9
MeSO2
MeSO2
p-TolSO2
p-TolSO2
10
11
12
13
14
9
10
10
Yb(OTf)3 16 + 16′
17 + 17′
-
90:10 (90)
89:11
85:15
Yb(OTf)3 17 + 17′
Yb(OTf)3 17 + 17′
-
10a p-TolSO2
10a p-TolSO2
2
1
17 + 17′
91:9
a Inverse addition. b Combined yield of both diastereoisomers
being needed) and did not improve the diastereoselectivity. In
some cases, TMSCN was also used as the cyanide source. The
best results were obtained in THF using an excess (4 equiv) of
Et2AlCN (TMSCN gave poorer results). Under these optimized
conditions the reactions with different imines are summarized
in Table 2.
N-Phenylimine 1 and N-p-methoxyphenylimine 2 did not react
with an excess of Et2AlCN under any of the studied conditions.
Imines 4-9 provided diastereoisomeric mixtures with low
stereoselectivities (Table 2). When the reactions evolved under
Yb(OTf)3 catalysis, slight changes in the epimeric ratio were
observed in some cases, but they were not so large as to provide
highly stereoselective transformations. We have also investigated
the role of the temperature in the reactions catalyzed by
Yb(OTf)3. The best results were detected at 0 °C, which suggests
that lower temperatures must hinder the association of the
catalyst to the basic centers of the substrates. Finally, in some
cases, the addition mode of the reagent also had a small
influence on the stereoselectivity. Only imine 10 evolved with
high levels of stereoselectivity (de’s ranged between 70 and
80%), which were scarcely modified by the above-mentioned
factors (entries 11-14).
The combined yields obtained in these reactions are usually
higher than 74%, but the isolation of each diastereoisomer was
rather difficult due to the easy retrohydrocyanation observed
during chromatographic purifications. From the stereochemical
point of view, the main conclusion deduced from the results
collected at Table 2 is that the control exerted by the sulfinyl
group on the stereoselectivity of the hydrocyanation reactions
of imines 4-9 was only moderate, much lower than that
observed in similar processes catalyzed by Yb(OTf)3 from the
corresponding aldehyde.8 By contrast, 10 reacted with high
stereoselectivity (70-80% de) regardless the experimental
conditions. These results suggest that the composition of the
mixtures obtained from reactions of 4-9 is the consequence of
a thermodynamic equilibration of the resulting amino nitriles
with the starting imines. Only those mixtures obtained from 10
correspond to kinetic control processes, probably due to the
FIGURE 1. Presumably most stable conformations for [2S,(S)S] and
[2R,(S)S] epimers (11-17 and 11′-17′).
higher stability of the amide anion derived from 17 and 17′,
which makes difficult the retrohydrocyanation.
Configurational assignment of epimers 11-17 and 11′-17′
was initially based on their 1H NMR spectra. The main
difference between both epimers is the chemical shift of their
benzylic protons, which is clearly lower for isomers 11-17 (∆δ
≈ 0.5-0.6 ppm for N-alkylderivatives and ∼0.18-0.35 ppm
for N-aryl and N-sulfonylderivatives, Table 3). In Figure 1 are
depicted presumably the most stable conformations for both
epimers, taking into account the fact that the strong dipolar
repulsion between the CtN and SfO bonds will arrange them
as far as possible unless it involves strong steric interactions.
Thus, a significant population can be expected for rotamers A
and B, respectively stabilized by dipolar and steric factors, at
the (S,S)-epimers (Figure 1), the first one presumably being
favored. By contrast, the sterically favored D rotamers must be
clearly predominant for the (R,S)-epimers as a result of the
strong steric restrictions of the electrostatically stabilized C
conformations. The spatial arrangement of the benzylic proton
at A rotamers suggests that it will be shielded by the aromatic
ring at the (S,S) epimers (see Table 3 graphic), whereas it is
not the case for such a proton in the most populated D
conformation for the (R,S) isomers. Therefore, the chemical
shifts of the benzylic protons at (S,S) epimers should be lower
than those of the (R,S) isomers. This criteria allowed us to assign
the (S,S) configuration to epimers 11-17. This assignment was
unequivocally confirmed by X-ray diffraction analysis of
5996 J. Org. Chem., Vol. 72, No. 16, 2007

Quaternization of R-Amino Phenylacetonitriles
SCHEME 2
SCHEME 3
TABLE 4. Reactions of Amino Nitriles 12 + 12′ with Different
Electrophiles
compounds 13′ and 17, which exhibit the absolute configurations
[2R,(S)S] and [2S,(S)S],12 respectively.
In order to corroborate this configurational assignment, a 12
+ 12′ mixture (38:62) was hydrolyzed (HCl(g)/HCO2H, 0 °C,
10 h) into the corresponding sulfenyl R-amino amide (18),13
which was subsequently desulfenylated (Raney Ni, THF/EtOH).
The resulting R-amino amide 19 exhibits an [R]20 value of
D
-16.6 (c 0.5, CHCl3), of the sign opposite to that reported for
enantiomerically pure (S)-(2-benzylamino)-2-phenylacetamide
entry
electrophile
MeI
MeI (18-crown-6)
EtOTf
PhCH2Br
CH2dCH-CH2Br
ClCO2Me
MeOH
t (h)
product
dra (yield,b %)
(19) {[R]20 +71 (c 1.0, CHCl3)}.14 This result confirms that
D
1
2
3
4
5
6
7
8
9
1
2
2
2
22
22
23
24
25
26
12 + 12′
12 + 12′
12 + 12′
>98:<2 (81)
>98:<2
>98:<2 (79)
>98:<2 (77)
>98:<2 (82)
>98:<2 (84)
3:97 (78)
the starting 12 + 12′ mixture was enriched in the epimer with
R configuration at carbon, which means that the major epimer
12′ has [2R,(S)S] configuration (Scheme 2).
2
All attempts to achieve the hydrocyanation of ketimines were
unsuccessful, since they were recovered unaltered after several
hours under hydrocyanating conditions. This prompted us to
explore the use of the mixtures of amino nitriles obtained from
o-sulfinylbenzaldimines as starting materials for quaternization
processes. Initially, we used mixtures 17 + 17′ as the starting
material. Treatment of these mixtures with 1-4 equiv of base
(LHMDS, KHMDS, LDA, n-BuLi) followed by addition of 1-8
equiv of MeI, allowing the reaction to evolve at different
temperatures (from -78 °C up to rt), invariably led to complex
mixtures where only N-[2-(p-tolylsulfinyl)phenylethylidene]-p-
toluenesulfonamide (20) and methyl 2-[p-(tolylsulfinyl)phenyl]-
ketone (21) could be detected in ∼10% yield determined by
1H NMR (Scheme 3). The low proportion of these compounds,
which would result from quaternization of 17 + 17′ followed
by elimination of HCN and hydrolysis of the resulting ketimine,
suggests that they must be formed in secondary processes.
Next we explored the behavior of N-benzylamino nitriles 12
+ 12′ as the starting materials for quaternization processes,
because the CH acidity of R-amino nitriles derived from
aromatic aldehydes is known to be larger than their NH acidity,15
and therefore, it should be expected that benzylic carbanion
0.5
0.5
0.5
0.5
HCl(g)
HBF4
20:80
20:80
a Determined by H NMR from the crude reaction. b Isolated yields.
1
would be exclusively formed by using 1 equiv of base, thus
precluding the undesired base-induced elimination of HCN
(retro-Strecker reaction) from the substrate and/or from the
quaternization product. Thus, when diastereomeric 12 + 12′
mixtures were treated with KHMDS (Table 4) and the resulting
anion reacted with MeI, compound 22 was obtained as a single
diastereoisomer in an 81% isolated yield (entry 1, Table 4).
Similar results were obtained in the presence of 18-crown-6
ether (entry 2, Table 4), which suggests that the role of the cation
is not crucial for the stereochemical course of the reaction. We
also studied the reactions of mixtures 12 + 12′ with other
alkylating reagents such as ethyl triflate, benzyl bromide, and
allyl bromide, which yielded compounds 23, 24, and 25,
respectively, as single diastereoisomers (entries 6-8). Analo-
gously, reaction of 12 + 12′ with ClCO2Me afforded 26 as the
exclusive acylation product (entry 9). All these reactions are
extraordinarily clean and proceed in high yields with a complete
control of the stereoselectivity, giving compounds 23 (R ) Et,
entry 6), 24 (R ) Bn, entry 7), 25 (R ) allyl, entry 8), and 26
(R ) CO2Me, entry 9) respectively, as single diastereoisomers
(determined by NMR analysis of the crude reactions). The use
of other bases such as LHMDS and NHMDS did not produce
any change in the yields or stereoselectivities of these reactions.
The results indicated in Table 4 suggested a scarce influence
of the nature of the electrophile on the stereoselectivity control,
which therefore seems to be exclusively related to the structure
(12) Crystallographic data (excluding structure factors) for 13′, 17, and
23 have been deposited with the Cambridge Crystallographic Data Centre
as supplementary publication numbers 638581, 638582, and 638583,
respectively. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, U.K. [fax:
+44(0)-1223-366033 or e-mail: deposit@ccdc.cam.uk].
(13) The reduction of the sulfinyl into the sulfenyl group takes place
under conditions used for the hydrolysis of the CN group.
(14) Hassan, N. A.; Bayer, E.; Jochims, J. C. J. Chem. Soc., Perkin Trans.
1 1998, 22, 3747.
(15) Kison, C.; Meyer, N.; Opatz, T. Angew. Chem., Int. Ed. 2005, 44,
5662.
J. Org. Chem, Vol. 72, No. 16, 2007 5997

Garc´ıa Ruano et al.
SCHEME 4
must be benzylic carbanions with the negative charge delocal-
ized at both the ring and the nitrogen of the CN group.
Conformational preferences of the anion can be governed by
electrostatic and/or steric grounds. The strong dipolar repulsion
between the S-O and CN bonds should favor conformations
A (Figure 2), exhibiting both dipoles arranged in the opposite
direction. By contrast, steric effects would determine the
predominance of B rotamers, due to the larger size of the NHBn
group with respect to the CN one. In turn, the formation of a
hydrogen bond between the NH and the sulfinyl oxygen would
explain a significant population of C rotamer (Figure 2).
In order to clarify this point we have performed some
theoretical calculations. The structures of possible conformations
(Figures 3, 4 and 5) have been studied at DFT (B3LYP)16 level
by using the Gaussian03 program.17 The standard 6-31G(d) basis
set was used for all the atoms except iodine, for which the
LANL2DZ basis set supplemented with a d function of exponent
0.289 was used.18 Harmonic frequencies were calculated at the
same level of theory to characterize the stationary points and
to determine the zero-point energies (ZPE). In the model
structures I, II, and III19 (analogous to A, B, and C) the methyl
group in the p-tolyl ring has been eliminated, and the benzyl
group at nitrogen has been changed by a methyl one (Figure
3). For I and II we have also calculated the influence of the
orientation of the substituents at nitrogen on the energy,
maintaining the lone electron pair oriented toward the sulfur.
Other structures with the N-H bond directed toward the sulfur
atom (I′′) or to the oxygen atom (III) were also studied.
According to these calculations, rotamers I and I′ are the most
stable ones, which allow us to conclude that dipolar repulsion
is the main factor controlling the conformational preferences
of the carbanion. On the other hand, according to the distances
between N1 and S20 and based on the NBO21 analysis, there is
a stabilizing interaction between N1 and the sulfinyl group
(n2fπ*0) which also contributes to stabilize these conformations.
It is in agreement with the higher stability of I with respect to
that of I′′ where such an interaction is much smaller. Thus,
intermediate I′′ is quite less stable despite the presence of a
small hydrogen bond, S‚‚‚H-N. In the case of intermediate III,
of the metalated carbanion. It prompted us to investigate whether
protonation of the carbanion derived from the mixture 12 +
12′ would be able to provide one diastereoisomer with high de,
which had not been achieved by direct hydrocyanation from 5.
The reaction of a diastereoisomeric 60:40 mixture of 12 and
12′ with KHMDS and further quenching with MeOH provided
a 3:97 mixture of 12 + 12′ epimers (entry 7, Table 4), which
indicated that protonation also was highly stereoselective. The
epimer obtained as predominant is [2R,(S)S]-12′, as it could be
unequivocally determined by X-ray analysis (vide infra).
Surprisingly, it exhibits the configuration (R) at R-carbon, which
is the opposite one to that observed for the quaternization
products 22-26. These results indicate different stereochemical
pathways for protonation and quaternization reactions that are
not easy to explain. The use of other sources of protonation,
such as HCl(g) and HBF4 (entries 8-9, Table 3) provided 20:
80 mixtures of 12 + 12′, indicating a lower stereoselectivity
but maintaining the preference for the epimer 12′.
The absolute configuration of the only diastereoisomer, 23,
obtained from the reaction of 12 + 12′ with EtOTf, was
unequivocally determined as [2S,(S)S] by X-ray diffraction
studies.12 We have assigned the same stereochemistry to isomers
22 and 24-26, 28, and 30, obtained as the exclusive products
from reactions of (S)-sulfoxides (Table 4 and Scheme 3).
In order to check the possible influence of intramolecular
π-stacking interactions between the aryl rings at the N-benzyl
moiety and the benzylic carbanion on the observed diastereo-
selectivity, we studied the behavior of other amino nitriles (13-
14) bearing substituents of different electronic character at the
benzyl ring. We also studied the N-isobutyl derivative 15, with
no benzyl group at the structure. The results are indicated in
Scheme 4. Amino nitriles 13 and 14 evolved with complete
stereoselectivity into 28 and 30, respectively, under the same
methylation conditions optimized for 12. Only one quaterniza-
tion product (32) was also detected by 1H NMR and MS starting
from amino nitrile 15, but it could not be isolated because its
chromatographic purification only afforded imine 33, resulting
from the retrohydrocyanation process from 32. As we can see
from Scheme 4, imines 27, 29, and 31 were also obtained in all
these reactions as a consequence of the instability of the
quaternary amino nitriles under the conditions used for their
chromatographic purification, which decreased the isolated
yields of the amino nitriles. These results suggest that the
influence of the substituent at the benzylic position is not
relevant in the stereoselectivity control, which must be exclu-
sively dependent on the sulfinyl configuration.
(16) (a) Lee, C.; Yang, W.; Parr, R. G. Phys. ReV. B 1988, 37, 785. (b)
Becke, A. D. J. Chem. Phys. 1993, 98, 1372.
(17) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K.
N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li,
X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich,
S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A.
D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A.
G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham,
M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian
03, Revision B.03; Gaussian, Inc.: Wallingford, CT, 2004.
(18) (a) Ditchfield, R.; Hehre, W. J.; Pople, J. A. J. Chem. Phys. 1971,
54, 724. (b) Hehre, W. J.; Ditchfield, R.; Pople, J. A. J. Chem. Phys. 1972,
56, 2257. (c) Hariharan, P. C.; Pople, J. A. Theor. Chim. Acta 1973, 28,
213. (d) Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 299.
(19) Other structures varying the conformation around S-Ph or C-NHMe
bonds turned out to be less stable.
(20) Bondi, A. J. Phys. Chem. 1964, 68, 441 (van der Waals radii values
in Å: H ) 1.20; N ) 1.55; S ) 1.80; O ) 1.52).
(21) Natural bond orbital method of Weinhold: Reed, A. E.; Curtiss, L.
A.; Weinhold, F. Chem. ReV. 1988, 88, 899.
The high levels of diastereoselectivity observed in these
reactions can be explained by assuming a stereoconvergent
course involving the formation of a common intermediate for
both epimeric starting nitriles 12 and 12′. These intermediates
5998 J. Org. Chem., Vol. 72, No. 16, 2007

Quaternization of R-Amino Phenylacetonitriles
FIGURE 2. Plausible conformations for benzylic carbanion.
FIGURE 3. Structures and relative energies (kcal‚mol-1) of the presumably most stable conformations of benzylic carbanion. ZPE correction
included. Selected bond distances (Å) and orbital interactions (kcal‚mol-1) evaluated by means of a second-order perturbational analysis of the
Fock matrix on the NBO basis are also indicated.
due to the orientation of the groups, an effective hydrogen bond
SO‚‚‚H-N cannot be formed to compensate dipolar repulsion,
and only a small interaction N-S (n2fd0) is possible. As a
result, III is quite less stable than I. Finally, the orientation of
the substituents at nitrogen are not significant for B conforma-
tions (II and II′ have a similar energy content), but it is
significant for the A ones (I is 1.1 kcal‚mol-1 more stable than
I′) as a consequence of the steric repulsions between Ph and
Me groups.
Another interesting point concerns the distribution of the
negative charge on the different atoms at the anion, because it
must be related to the preferred places for the association of
the metal. For species I and I′, the negative charge of the
carbanion is delocalized, and the nitrogen supports a larger
negative charge (-0.48 au) than the benzylic carbon (-0.17 to
-0.18 au). It suggests the preference of the metal to be
associated to the nitrogen. Additionally, the sulfinyl oxygen has
also a high density of negative charge as a consequence of the
nature of the S-O bond (-0.99 au). We have calculated the
energy associated to species IVC, IVO, and IVN (Figure 4) with
the metal respectively associated to such atoms at rotamer I,
the most stable one of the previous calculations. We have also
evaluated the stability of species VC with the metal joined to
the carbon but stabilized by the sulfinyl oxygen, because it has
been found as the most stable species for other less delocalized
benzylic carbanions.22 Taking into account that the stereo-
selectivity is not dependent on the cation present during the
reaction, in the model structures Li+ has been used due to its
simpler coordination mode. Dimethylamine, that comes from
the simplified base, and dimethylether, as the simplified model
solvent, were used as the rest of the ligands. According to the
higher electron density on sulfinyl oxygen, these calculations
reveal that IVO is the most stable species; quite close is VC,
followed by IVN, that has also been proposed by other authors
from NMR studies for similar benzylic carbanions lacking the
sulfinyl group.1,23 Finally IVC is the least stable due to its higher
steric interactions.
Looking at these structures,24 IVO and VC would afford the
same diastereoselectivity since their lower faces show less steric
(22) Garc´ıa Ruano, J. L.; Alema´n, J.; Alonso, I.; Parra, A.; Marcos, V.;
Aguirre, J. Chem. Eur. J. 2007, 13, 6179.
(23) Enders, D.; Kirchhoff, J.; Gerdes, P.; Mannes, D.; Raabe, G.;
Runsink, J.; Boche, G.; Marsch, M.; Ahlbrecht, H.; Sommer H. Eur. J.
Org. Chem. 1998, 63.
J. Org. Chem, Vol. 72, No. 16, 2007 5999

Garc´ıa Ruano et al.
FIGURE 4. Structures and relative energies (kcal‚mol-1) of species with the metal associated to different atoms of benzylic carbanion. The energy
corresponding to VC has been evaluated as VC + dimethylether - IVO. ZPE correction included.
the energy content between transition states with structures quite
similar to those indicated in Figure 5 as TSI and TSI′. These
structures result from the approximation of the electrophile (MeI
has been used as a model) to the less hindered face of the most
stable A conformation of the benzylic carbanion (we have
considered the attack to rotamers I and I′ because they are not
too different in energy, see Figure 3). As it can be seen in Figure
5, TSI, yielding compounds with [2S,(S)S] configuration, is
more stable than TSI′, yielding compounds with [2R,(S)S]
configuration, for 1.4 kcal‚mol-1. This difference in energy
content at -78 °C predicts a dr of 97:3, which is in excellent
agreement with the experimental results. Steric interactions
between the groups located at the lower face must be higher in
TSI′ than in TSI according to the distances between the carbon
atoms of CH3NH or CH3I and the nearest carbon atom of the
Ph group. This fact forces the Ph group to adopt a different
FIGURE 5. Structures and relative energies (kcal‚mol-1) of plausible
transition states involved in the reaction of benzylic carbanions with
conformation in TSI′ with respect to that in TSI (compare
dihedral angles) with the loss of a weak stabilizing hydrogen
bond between H4 and N1.19 It can be expected that the presence
of the benzyl group instead of the methyl one at the nitrogen
used in the calculations will predict that energetic differences
MeI. ZPE correction is included. Free energy correction calculated at
-78 °C is indicated in brackets. Selected bond distances (Å), dihedral
angles (deg) and orbital interactions (kcal‚mol-1) evaluated by means
of a second-order perturbational analysis of the Fock matrix on the
NBO basis are also indicated.
between TSI and TSI′ will be even larger than 1.4 kcal‚mol-1
.
hindrance for the approximation of an electrophile. However,
the fact that the stereoselectivity is not dependent on the presence
of a crown ether during the reaction suggests that the coordina-
tion to the metal would take place far from the reaction center,
which is in agreement with the evolution of the reaction through
species such as IVO. Thus, in order to understand the origin of
the stereoselectivity, an additional simplification can be made.
The stereoselectivity could be determined by the difference in
From a steric point of view, these results suggest that the
(24) It is interesting to note that the distances between N1 and S in all
these structures are smaller than the sum of their van der Waals radii19 (it
is also the case for intermediates I, II, and III, Figure 3), which could be a
consequence of the stabilizing electronic interactions that have been found
between the coplanar sulfur and nitrogen functions [IVN: d(N-S): 2.86,
N1fp*(S-O): 3.20; IVO: d(N-S): 2.91, N1f2p*(S-O): 2.82; VC:
d(N-S): 2.71, N1fs*(S-CTol): 5.93].
6000 J. Org. Chem., Vol. 72, No. 16, 2007

Quaternization of R-Amino Phenylacetonitriles
used without further purification. Yield: 87%; white solid; [R]20
orientation of the benzyl group at nitrogen, which is dependent
on that of the p-tolyl group at sulfur, is mainly responsible for
stereoselectivity control.
D
-228.4 (c 1.0, CHCl3); mp 116-118 °C (CH2Cl2/hexane); IR
1
(KBr): 1326, 1216, 756 cm-1; H NMR: δ 8.55 (s, 1H), 8.45 (d,
J ) 7.7 Hz, 1H), 7.79-7.67 (m, 2H), 7.64-7.58 (m, 1H), 7.59
and 7.37 (AA′BB′ system, 4H), 7.41 and 7.09 (AA′BB′ system,
4H), 4.86 and 4.78 (AB system, J ) 14.5 Hz, 2H), 2.32 (s, 3H);
13C NMR: δ 159.5, 144.9, 143.2, 142.5, 142.4, 140.6, 133.2, 131.0,
As a conclusion, we have demonstrated that reactions of
compounds 2 with hydrocyanating reagents yielding mixtures
of R-amino phenylacetonitrile derivatives are moderately stereo-
selective, whereas the reaction of the hydrocyanated mixtures
with alkylating or acylating reagents in the presence of KHMDS
takes place in a completely stereoselective way, only yielding
compounds with configuration S at benzylic carbon, thus
allowing the synthesis of enantiomerically pure R-substituted
R-amino phenylacetonitriles. DFT calculations support that the
efficient stereoselectivity control exerted by the sulfinyl group
is mainly related to its electrostatic interactions with the cyano
group governing the conformational preferences of the benzylic
anion intermediate.
2
130.9, 130.4, 129.3 (2C), 128.8 (q, J ) 32.3 Hz, C-CF3), 127.8
(2C), 126.1 (2C), 125.1, 125.0 [q, 3J ) 3.9 Hz, (CH)2C-CF3], 124.0
(q, 1J ) 272.2 Hz, CF3), 63.7, 20.9; MS (EI+) m/z 401 (M+); HRMS
(EI+) calcd for C22H18F3NOS (M+): 401.1061; found: 401.1045.
N-((E,S)-{2-[(4-Methylphenyl)sulfinyl]phenyl}methylene)-1-
(4-methoxyphenyl)methanamine (7). p-Methoxybenzylamine was
used as the starting amine, and the product was used without further
purification. Yield: 93%; white solid; [R]20D -259.2 (c 1.0, CHCl3);
mp 120-122 °C (CH2Cl2/hexane); IR (KBr): 1512, 1248, 1058,
1
755 cm-1; H NMR: δ 8.41 (s, 1H), 8.37 (d, J ) 6.9 Hz, 1H),
7.73-7.64 (m, 2H), 7.54 (t, J ) 6.9 Hz, 1H), 7.41 and 7.09
(AA′BB′ system, 4H), 7.17 and 6.88 (AA′BB′ system, 4H), 4.77
and 4.66 (AB system, J ) 14.1 Hz, 2H), 3.82 (s, 3H), 2.31 (s,
3H); 13C NMR: δ 158.6, 158.2, 145.2, 143.4, 140.7, 133.6, 130.9,
130.5, 130.4, 130.3, 129.4 (2C), 129.1 (2C), 126.2 (2C), 125.0,
113.8 (2C), 63.8, 55.2, 21.2; MS (FAB+) m/z 364 (M + H)+;
HRMS (FAB+) calcd for C22H22NO2S (M + H)+: 364.1371;
found: 364.1381.
Experimental Section
General Procedure for the Synthesis of 2-(S)-Sulfinylbenz-
aldimines 2, 3, 5-8. To a solution of aldehyde 1 (244.3 mg, 1
mmol) in anhydrous CH2Cl2 (5 mL), in the presence of an excess
amount of Na2SO4,was added the corresponding amine (1 mmol),
and the reaction was stirred for 16 h at rt. The reaction mixture
was filtered through a Celite pad, and the solvent was evaporated.
The products were purified by crystallization.
2-Methyl-N-((E,S)-{2-[(4-methylphenyl)sulfinyl]phenyl}-
methylene)propan-1-amine (8). Isobutylamine was used as the
starting amine, and the product was used without further purifica-
tion. Yield: 90%; pale yellow oil; [R]20 -208.4 (c 1.0, CHCl3);
D
IR (film): 1650, 1028, 764 cm-1; 1H NMR: δ 8.35 (m, 1H), 8.31
(dd, J ) 1.2 and 7.5 Hz, 1H), 7.68-7.59 (m, 2H), 7.52 (dd, J )
1.2 and 7.5 Hz, 1H), 7.46 and 7.14 (AA′BB′ system, 4H), 3.46
(ddd, J ) 1.4, 6.6, and 11.3 Hz, 1H), 3.27 (ddd, J ) 0.9, 6.6, and
11.3 Hz, 1H), 1.93 (sept, J ) 6.6 Hz, 1H), 0.91 (d, J ) 6.6 Hz,
3H), 0.87 (d, J ) 6.6 Hz, 3H); 13C NMR: δ 157.5, 145.1, 143.7,
140.6, 133.9, 130.7, 130.4, 130.3, 129.5 (2C), 126.1 (2C), 125.1,
69.4, 29.5, 21.2, 20.6, 20.5; MS (ESI+) m/z 300 (M + H)+; HRMS
(ESI+) calcd for C18H22NOS (M + H)+: 300.1416; found:
300.1427.
(()-N-((E)-{2-[(4-Methylphenyl)sulfinyl]phenyl}methylene)-
aniline (2). Aniline was used as the starting amine, and the product
was purified by crystallization from CH2Cl2/hexane. Yield: 91%;
1
white solid; mp 92-94 °C; IR (KBr): 1628, 1026, 767 cm-1; H
NMR: δ 8.56 (s, 1H), 8.39 (dd, J ) 1.4 and 7.8 Hz, 1H), 7.82
(dd, J ) 1.6 and 7.5 Hz, 1H), 7.69 (td, J ) 1.6 and 7.5 Hz, 1H),
7.57 (dd, J ) 1.6 and 7.2 Hz, 1H), 7.50 and 7.12 (AA′BB′ system,
4H), 7.40-7.30 (m, 2H), 7.27-7.18 (m, 1H), 7.08-7.02 (m, 2H),
2.28 (s, 3H); 13C NMR: δ 156.5, 150.4, 146.0, 143.4, 140.9, 133.7,
131.5, 131.1, 130.5, 129.5 (2C), 129.1, 126.5, 126.3 (2C), 125.3,
120.7, 21.2; MS (FAB+) m/z 320 (M + H)+; HRMS (FAB+) calcd
for C20H18NOS (M + H)+: 320.1103; found: 320.1094.
N-((E,S)-{2-[(4-Methylphenyl)sulfinyl]phenyl}methylene)-4-
nitroaniline (4). A solution of aldehyde 1 (244.3 mg, 1 mmol)
and nitroaniline (145 mg, 1.05 mmol) in toluene (25 mL), in the
presence of an excess amount of Na2SO4, was heated at reflux in
a Dean-Stark apparatus for 96 h. The reaction was cooled at rt,
filtered through a Celite pad, and the solvent was evaporated. The
product was purified by crystallization from CH2Cl2/hexane.
(()-(E)-4-Methoxy-N-[2-(p-tolylsulfinyl)benzylidene]aniline
(3). p-Anisidine was used as the starting amine, and the product
was purified by crystallization from CH2Cl2/hexane. Yield: 86%;
white solid; mp 80-82 °C; IR (KBr): 1626, 1247, 1029, 754 cm-1
;
1H NMR: δ 8.62 (s, 1H), 8.43 (dd, J ) 1.2 and 7.5 Hz, 1H), 7.83
(dd, J ) 1.5 and 7.5 Hz, 1H), 7.70 (td, J ) 1.5 and 7.5 Hz, 1H),
7.58-7.48 (m, 1H), 7.50 and 7.21 (AA′BB′ system, 4H), 7.16 and
6.94 (AA′BB′ system, 4H), 3.83 (s, 3H), 2.32 (s, 3H); 13C NMR:
δ 158.7, 154.1, 145.5, 143.4, 143.1, 140.7, 134.0, 131.0, 130.7,
130.4, 129.4 (2C), 126.1 (2C), 125.2, 122.1 (2C), 114.3 (2C), 55.3,
21.2; MS (ESI+) m/z 350 (M + H)+; HRMS (ESI+) calcd for
C21H20NO2S (M + H)+: 350.1209; found: 350.1199.
Yield: 75%; yellow solid; mp 68-70 °C; [R]20 -375.6 (c 1.0,
D
1
CHCl3); IR (KBr): 1701, 1587, 1310, 1028, 726 cm-1; H NMR:
δ 8.58 (s, 1H), 8.41 (dd, J ) 1.1 and 7.9 Hz, 1H), 8.27 and 7.07
(AA′BB′ system, 4H), 7.90 (dd, J ) 1.1 and 7.9 Hz, 1H), 7.80 (td,
J ) 1.1 and 7.9 Hz, 1H), 7.64 (td, J ) 1.1 and 7.9 Hz, 1H), 7.43
and 7.17 (AA′BB′ system, 4H), 2.33 (s, 3H); 13C NMR: δ 159.2,
156.1, 146.4, 145.8, 142.9, 141.4, 132.9, 132.6, 131.9, 130.9, 129.8
(2C), 126.4 (2C), 125.9, 125.1 (2C), 121.1 (2C), 21.3; MS (FAB+)
m/z 365 (M + H)+; HRMS (FAB+) calcd for C20H17N2O3S (M +
H)+: 365.0954; found: 365.0958.
N-((E,S)-{2-[(4-Methylphenyl)sulfinyl]phenyl}methylene)-1-
phenylmethanamine (5). Benzylamine was used as the starting
amine, and the product was purified by crystallization from CH2Cl2/
hexane. Yield: 87%; white solid; [R]20 -257.3 (c 1.0, CHCl3);
General Procedure for the Synthesis of (S)-2-Sulfinylbenz-
aldimines 9-10. To a solution of aldehyde 1 (244.3 mg, 1 mmol)
and sulfonamide (1 mmol) in CH2Cl2 or DCE (6 mL) at rt under
argon was added Et3N (202 mg, 0.279 mL, 2 mmol) and TiCl4 (95
mg, 0.055 mL, 0.5 mmol). The resulting mixture was heated at
reflux for 5 h. The reaction was hydrolyzed with 1 M HCl (2 mL),
and the organic layer was washed with saturated aqueous NaHCO3
(2 mL) and dried (Na2SO4), and the solvent was evaporated.
N-((E,S){2-[(4-Methylphenyl)sulfinyl]phenyl}methylene)-
methanesulfonamide (9). Methanesulfonamide (95.1 mg, 1 mmol)
was used as the starting amine, and CH2Cl2 (6 mL) was used as
the solvent. The product was purified by crystallization from
D
mp 84-86 °C; IR (KBr): 1626, 1061, 753 cm-1; 1H NMR: δ 8.52
(s, 1H), 8.37 (dd, J ) 1.1 and 7.5 Hz, 1H), 7.75-7.65 (m, 2H),
7.55 (td, J ) 1.1 and 7.5 Hz, 1H), 7.39 and 7.09 (AA′BB′ system,
4H), 7.34-7.20 (m, 5H), 4.84 and 4.73 (AB system, J ) 14.1 Hz,
2H), 2.31 (s, 3H); 13C NMR: δ 158.7, 145.4, 143.4, 140.7, 138.4,
133.7, 131.1, 130.6, 130.4, 129.6 (2C), 128.5 (2C), 127.9 (2C),
127.0, 126.3 (2C), 125.2, 64.5, 21.2; MS (EI+) m/z 334 (M + H)+;
HRMS (EI+) calcd for C21H20NOS (M + H)+: 334.1260; found:
334.1271.
N-((E,S)-{2-[(4-Methylphenyl)sulfinyl]phenyl}methylene)-1-
[4-(trifluoromethyl)phenyl] methanamine (6). p-Trifluoromethyl-
benzylamine was used as the starting amine, and the product was
CH2Cl2/hexane. Yield: 65%; white solid; mp 74-76 °C; [R]20
D
J. Org. Chem, Vol. 72, No. 16, 2007 6001

Garc´ıa Ruano et al.
-106.6 (c 0.5, CHCl3); IR (KBr): 1612, 1322, 1149, 805, 753
CHCl3/hexane gave [2R,(S)S]-12′ as a pure diastereoisomer.
1
cm-1; H NMR: δ 9.25 (s, 1H), 8.40 (dd, J ) 1.4 and 7.8 Hz,
Yield: 44%; white solid; mp 116-118 °C; [R]20 -90.7 (c 1.0,
D
1H), 7.97 (dd, J ) 1.4 and 7.8 Hz, 1H), 7.88 (td, J ) 1.4 and 7.8
Hz, 1H), 7.64 (td, J ) 1.4 and 7.8 Hz, 1H), 7.50 and 7.20 (AA′BB′
system, 4H), 3.04 (s, 3H), 2.31 (s, 3H); 13C NMR: δ 168.1, 149.2,
142.0, 141.9, 135.3, 133.5, 131.0 (2C), 130.1, 129.3, 126.2 (2C),
125.7, 40.4, 21.3; MS (ESI+) m/z 322 (M + H)+; HRMS (ESI+)
calcd for C15H16NO3S2 (M + H)+: 322.0566; found: 322.0553.
4-Methyl-N-((E,S)-{2-[(4-methylphenyl)sulfinyl]phenyl}-
methylene)benzenesulfonamide (10). p-Toluenesulfonamide (171.2
mg, 1 mmol) was used as the starting amine, and DCE (6 mL) was
used as the solvent. The product was purified by flash column
chromatography (EtOAc/hexane, 1:1). Yield: 82%; white solid;
CHCl3); IR (KBr): 2230, 1216, 1031, 755 cm-1; 1H NMR: δ 7.83-
7.79 (m, 1H), 7.77-7.71 (m, 1H), 7.58-7.49 (m, 4H), 7.31-7.16
(m, 7H), 5.45 (s, 1H), 4.02 and 3.93 (AB system, J ) 11.8 Hz,
2H), 2.36 (s, 3H), 1.84 (bs, 1H); 13C NMR: δ 144.9, 141.6, 141.3,
137.2, 133.6, 131.8, 130.7, 129.9 (2C), 128.7 (2C), 128.6 (2C),
128.1, 127.8, 127.6, 125.3 (2C), 117.7, 51.9, 50.7, 21.3; MS (FAB+)
m/z 361 (M + H)+; HRMS (FAB+) calcd for C22H21N2OS (M +
H)+: 361.1374; found: 361.1366. Diastereoisomer [2S,(S)S]-12 was
1
characterized from a 12 + 12′ mixture; H NMR: δ 8.13-8.07
(m, 1H), 7.76-7.13 (m, 12H), 4.85 (s, 1H), 4.05-3.78 (m, 2H),
2.35 (s, 3H), 2.06 (bs, 2H); 13C NMR: δ 144.7, 141.3, 141.0, 137.0,
133.3, 131.5, 130.5, 129.6 (2C), 128.5 (2C), 128.3 (2C), 127.7,
127.4, 125.1 (2C), 117.4, 51.0, 50.5, 21.2.
mp 171-173 °C; [R]20 -248.0 (c 1.0, CHCl3); IR (KBr): 1610,
D
1330, 1207, 815, 786 cm-1; 1H NMR: δ 9.23 (s, 1H), 8.37 (dd, J
) 1.2 and 7.9 Hz, 1H), 7.92 (dd, J ) 1.2 and 7.9 Hz, 1H), 7.84
(td, J ) 1.2 and 7.9 Hz, 1H), 7.81 and 7.34 (AA′BB′ system, 4H),
7.59 (td, J ) 1.2 and 7.9 Hz, 1H), 7.43 and 7.12 (AA′BB′ system,
4H), 2.45 (s, 3H), 2.30 (s, 3H); 13C NMR: δ 166.4, 149.2, 145.0,
141.9, 141.7, 135.0, 134.6, 133.6, 130.9, 129.9 (2C), 129.8 (2C),
129.5, 128.2 (2C), 126.2 (2C), 125.3, 21.7, 21.3; MS (FAB+) m/z
398 (M + H)+; HRMS (FAB+) calcd for C21H20NO3S2 (M + H)+:
398.0884; found: 398.0887.
[2S,(S)S]- and [2R,(S)S]-{2-[(4-Methylphenyl)sulfinyl]phenyl}-
{[4-(trifluoromethyl)benzyl]amino}acetonitrile (13 + 13′). It was
prepared as a diastereoisomeric 41:59 mixture from imine 6
following method A using 4 equiv of Et2AlCN (reaction time: 2
h). It was used in further transformations without any purification.
Crystallization from CHCl3/hexane gave [2R,(S)S]-13′ as a pure
diastereoisomer. Yield: 38%; yellow solid; mp 142-144 °C; [R]20
D
-53.1 (c 1.0, CHCl3); IR (KBr): 2229, 1325, 1133, 1063, 774
cm-1; 1H NMR: δ 7.83-7.79 (m, 1H), 7.78-7.72 (m, 1H), 7.58-
7.44 (m, 2H), 7.52 and 7.20 (AA′BB′ system, 4H), 7.47 and 7.31
(AA′BB′ system, 4H), 5.46 (s, 1H), 4.07 and 3.97 (AB system, J
) 12.4 Hz, 2H), 2.37 (s, 3H), 1.94 (bs, 1H); 13C NMR: δ 144.4,
141.6, 141.3, 133.5, 132.0, 130.8, 130.0 (q, 2J ) 32.3 Hz, C-CF3),
129.9 (2C), 128.8 (2C), 128.4, 127.9, 125.5 [q, 3J ) 3.7 Hz,
General Procedures for the Synthesis of r-Amino Nitriles
11-17/11′-17′. Method A. To a solution of imine (0.1 mmol) in
THF (1 mL) under argon was added 1 M toluene solution of
Et2AlCN. The resulting mixture was stirred at rt for 2-16 h. The
reaction was slowly hydrolyzed with saturated aqueous potassium
sodium tartrate‚4H2O (1 mL) and stirred for 30 min. The organic
layer was separated, washed with saturated aqueous NaCl (1 mL),
and dried (Na2SO4), and the solvent was evaporated.
Method B. A solution of imine (0.1 mmol) in THF (1 mL) under
argon was added dropwise to a 1 M toluene solution of Et2AlCN
(0.4 mmol) in THF (4 mL). The resulting mixture was stirred at 0
°C for 2-16 h. The reaction was slowly hydrolyzed with saturated
aqueous potassium sodium tartrate‚4H2O (1 mL) and stirred for
30 min. The organic layer was separated, washed with saturated
aqueous NaCl (1 mL) and dried (Na2SO4), and the solvent was
evaporated.
1
(CH)2C-CF3], 125.4 (2C), 124.0 (q, J ) 271.9 Hz, CF3), 117.5,
51.2, 50.7, 21.3; MS (ESI+) m/z 429 (M + H)+; HRMS (ESI+)
calcd for C23H20F3N2OS (M + H)+: 429.1242; found: 429.1249.
Diastereoisomer [2R,(S)S]-13 was characterized from a 13 + 13′
1
mixture; H NMR: δ 7.81 (dd, J ) 3.3 and 5.8, 1H), 7.75-7.65
(m, 2H), 7.50-7.35 (m, 4H), 7.27-7.05 (m, 4H), 6.96 (d, J ) 7.1
Hz, 1H), 4.87 (s, 1H), 4.03-3.85 (m, 2H), 2.37 (s, 3H), 1.95 (bs,
1H); 13C NMR (representative parameters): δ 143.4, 141.0, 140.7,
137.2, 133.3, 131.2, 130.5, 129.6 (2C), 128.4 (2C), 128.1, 127.5,
127.2, 125.1 (2C), 117.4, 51.0, 50.1, 21.1.
Method C. A solution of imine (0.1 mmol) and Yb(OTf)3 (0.1
mmol) in THF (1 mL) under argon was added dropwise to a 1 M
toluene solution of Et2AlCN (0.4 mmol) in THF (4 mL). The
resulting mixture was stirred at 0 °C for 2-16 h. The reaction was
slowly hydrolyzed with saturated aqueous potassium sodium
tartrate‚4H2O (1 mL) and stirred for 30 min. The organic layer
was separated, washed with saturated aqueous NaCl (1 mL) and
dried (Na2SO4), and the solvent was evaporated.
[2S,(S)S]- and [2R,(S)S]-{2-[(4-Methylphenyl)sulfinyl]phenyl}-
[(4-nitrophenyl)amino]acetonitrile (11 + 11′). It was prepared
as a diastereoisomeric 39:61 mixture from imine 4 following
method A using 2 equiv of Et2AlCN (reaction time: 8 h). It was
crystallized from CHCl3/hexane. Yield: 75%; yellow solid; 1H
NMR (11 + 11′ mixture, d6-DMSO): δ 8.25 (d, J ) 8.1 Hz, 1H),
8.18 and 6.94 (AA′BB′ system, 4H), 8.17 and 6.93 (AA′BB′ system,
4H), 8.02-7.95 (m, 3H), 7.89-7.82 (m, 3H), 7.81-7.73 (m, 3H),
7.54 and 7.34 (AA′BB′ system, 4H), 7.39 and 7.24 (AA′BB′ system,
4H), 6.80 (d, J ) 9.0 Hz, 1H), 6.56 (d, J ) 7.9 Hz, 1H), 2.35 (s,
3H), 2.30 (s, 3H); 13C NMR (11 + 11′ mixture, d6-DMSO): δ
152.0, 151.6, 145.8, 145.2, 142.5, 142.3, 142.2, 141.9, 139.7, 139.6,
133.3, 133.1, 132.6, 132.5, 132.1 (2C), 130.9 (2C), 130.7 (2C),
129.5, 129.3, 128.1, 127.4, 126.9 (2C), 126.8 (2C), 126.0 (2C),
125.8 (2C), 118.7, 118.5, 113.6 (2C), 46.3, 46.2, 21.8, 21.7; MS
(FAB+) m/z 392 (M + H)+; HRMS (FAB+) calcd for C21H18N3O3S
(M + H)+: 392.1068; found: 392.1062.
[2S,(S)S]- and [2R,(S)S]-[(4-Methoxybenzyl)amino]{2-[(4-
methylphenyl)sulfinyl]phenyl} acetonitrile (14 + 14′). It was
prepared as a diastereoisomeric 40:60 mixture from imine 7
following method A using 4 equiv of Et2AlCN (reaction time: 2
h). It was used in further reactions without any purification.
Crystallization from CHCl3/hexane gave [2R,(S)S]-14′ as a pure
diastereoisomer. Yield: 42%; yellow solid; mp 123-125 °C; [R]20
D
-87.3 (c 1.0, CHCl3); IR (KBr): 2224, 1247, 1018, 1007, 810
cm-1; 1H NMR: δ 7.80 (dd, J ) 3.4 and 5.9 Hz, 1H), 7.74 (dd, J
) 3.4 and 5.8 Hz, 1H), 7.56 and 7.21 (AA′BB′ system, 4H), 7.53-
7.48 (m, 2H), 7.15 and 6.81 (AA′BB′ system, 4H), 5.42 (s, 1H),
3.97 and 3.88 (AB system, J ) 12.0 Hz, 2H), 3.79 (s, 3H), 2.37 (s,
3H), 1.78 (bs, 1H); 13C NMR: δ 159.2, 145.0, 141.6, 141.2, 133.6,
131.7, 130.7, 130.0 (2C), 129.9 (2C), 129.2, 127.9, 127.6, 125.3
(2C), 117.7, 113.9 (2C), 55.3, 51.3, 50.6, 21.3; MS (FAB+) m/z
391 (M + H)+; HRMS (FAB+) calcd for C23H23N2O2S (M + H)+:
391.1480; found: 391.1481. Diastereoisomer [2R,(S)S]-14 was
1
characterized from a 14 + 14′ mixture; H NMR: δ 8.09-8.06
(m, 1H), 7.75-7.68 (m, 2H), 7.65-7.11 (m, 8H), 6.95-6.88 (m,
2H), 4.81 (s, 1H), 4.00-3.73 (m, 2H), 3.81 (s, 3H), 2.35 (s, 3H),
1.88 (bs, 1H); 13C NMR: δ 159.3, 143.7, 142.3, 141.0, 132.4, 131.4,
130.3, 130.2 (2C), 130.1 (2C), 129.4, 127.9, 126.3, 126.2 (2C),
117.6, 114.0 (2C), 55.2, 50.7, 50.2, 21.4.
[2S,(S)S]- and [2R,(S)S]-(Isobutylamino){2-[(4-methylphenyl)-
sulfinyl]phenyl}acetonitrile (15 + 15′). It was prepared as a
diastereoisomeric 49:51 mixture from imine 8 following method
A using 4 equiv of Et2AlCN (reaction time: 16 h). It was used in
further reactions without any purification. Yield: 74%; white oil;
1H NMR (15 + 15′ mixture): δ 8.06 (dd, J ) 1.4 and 7.8 Hz,
1H), 7.82-7.76 (m, 1H), 7.74-7.68 (m, 2H), 7.61-7.54 (m, 1H),
[2S,(S)S]- and [2R,(S)S]-(Benzylamino){2-[(4-methylphenyl)-
sulfinyl]phenyl}acetonitrile (12 + 12′). It was prepared as a
diastereoisomeric 48:52 mixture from imine 5 following method
A using 2 equiv of Et2AlCN (reaction time: 8 h). It was used in
further reactions without any purification. Crystallization from
6002 J. Org. Chem., Vol. 72, No. 16, 2007

Quaternization of R-Amino Phenylacetonitriles
7.56 and 7.23 (AA′BB′ system, 4H), 7.53-7.49 (m, 3H), 7.43 and
7.26 (AA′BB′ system, 4H), 5.42 (s, 1H), 4.84 (s, 1H), 2.69-2.61
(m, 1H), 2.60-2.50 (m, 2H), 2.45-2.37 (m, 1H), 2.35 (s, 3H),
2.34 (s, 3H), 1.75 (sept, J ) 6.5 Hz, 1H), 1.64 (sept, J ) 6.5 Hz,
1H), 1.63 (bs, 2H), 0.96 (d, J ) 6.5 Hz, 3H), 0.94 (d, J ) 6.5 Hz,
3H), 0.86 (d, J ) 6.5 Hz, 3H), 0.84 (d, J ) 6.5 Hz, 3H); 13C NMR
(15 + 15′ mixture): δ 144.8, 143.6, 142.2, 141.6, 141.2, 140.9,
133.9, 132.7, 131.7, 131.3, 130.6, 130.2 (2C), 130.1, 129.8 (2C),
128.1, 127.9, 127.5, 126.6, 126.2 (2C), 125.2 (2C), 118.0, 117.9,
55.4, 54.9, 51.6, 51.5, 28.3, 28.2, 21.4, 21.2, 20.7, 20.6, 20.5, 20.4;
MS (ESI+) m/z 327 (M + H)+; HRMS (ESI+) calcd for C19H23N2OS
(M + H)+: 327.1535; found: 327.1525.
2-Benzylamino-2-phenylacetamide (19). A solution of 30 mg
(0.083 mmol) of 2-benzylamino-2-(p-tolylsulfenyl)phenylacetamide
(18) in THF (1 mL) was added onto a suspension of Raney-Ni
(∼0.5 g) in EtOH (5 mL). The mixture was stirred at rt for 4 h.
Then, the supernatant liquid was decanted, and the Raney-Ni was
treated with 5 mL of NH3 (7 M in methanol). The mixture was
boiled for 20 min, and the supernatant liquid was filtered throught
a small Celite pad. The Raney-Ni was extracted two more times.
The organic layers were combined, and the solvent was evaporated
al reduced pressure. The residue was purified by flash column
chromatography (eluent EtOAc/hexane, 3:1); Yield: 89%; white
solid; [R]20D -16.6 (c 0.5, CHCl3) [for 19 obtained from 12 + 12′
(24% de) in two steps] [lit.13 [R]20 +71 (c 1.0, CHCl3) for (S)-
D
[2S,(S)S]- and [2R,(S)S]-N-(Cyano{2-[(4-methylphenyl)sulfinyl]-
phenyl}methyl) methanesulfonamide (16 + 16′). It was prepared
as a diastereoisomeric 58:42 mixture from imine 9 following
method A using 2 equiv of Et2AlCN (reaction time: 2 h). It was
used in further reactions without any purification. Yield: 86%;
enantiomer]; 1H NMR: δ 7.43-7.27 (m, 9H), 6.96 (bs, 1H), 5.70
(bs, 1H), 4.24 (s, 1H), 3.80 (s, 2H).
General Procedure for Quaternization of Benzylic Carbons.
To a solution of amino nitrile 12-15 (0.5 mmol) in THF (5 mL)
at -78 °C under argon was added 1.1 mmol of KHMDS (0.5 M in
toluene). The mixture was stirred at -78 °C for 10 min, and then
1.5 mmol of the corresponding electrophile was added dropwise.
The reaction was monitored by TLC. Upon transformation of the
starting material, the reaction was hydrolyzed with saturated
aqueous NH4Cl (2.5 mL). The mixture was extracted with Et2O (3
× 2.5 mL) and dried (Na2SO4), and the solvent was evaporated.
The product was purified by flash column chromatography or
Redisep normal phase column in an automated flash chromatog-
raphy.
1
white solid; H NMR (16 + 16′ mixture): δ 7.91-7.75 (m, 1H),
7.77-7.71 (m, 2H), 7.67-7.62 (m, 1H), 7.61-7.47 (m, 8H), 7.34-
7.25 (m, 3H), 7.21-7.15 (m, 2H), 6.71 (bs, 2H), 6.07 (s, 1H), 5.89
(s, 1H), 3.05 (s, 3H), 3.04 (s, 3H), 2.38 (s, 3H), 2.36 (s, 3H); 13C
NMR (16 + 16′ mixture): δ 143.0, 142.9, 142.7, 142.3, 139.6,
139.5, 132.6, 132.1, 131.2, 131.0, 130.6, 130.5 (2C), 130.4 (3C),
130.2, 129.6, 128.2, 126.6, 126.1 (2C), 125.3 (2C), 116.7, 116.5,
44.8 (2C), 41.9, 41.7, 21.4, 21.3; MS (ESI+) m/z 349 (M + H)+;
HRMS (ESI+) calcd for C16H17N2O3S2 (M + H)+: 349.0675;
found: 349.0673.
[2S,(S)S]-2-(Benzylamino)-2-{2-[(4-methylphenyl)sulfinyl]-
phenyl}propanenitrile (22). Amino nitriles 12 + 12′ were used
as the starting material. Iodomethane was used as the electrophile,
and the reaction was stirred at -78 °C for 1 h to give compound
[2S,(S)S]-22, which was purified in an automated flash chroma-
tography (5:95 to 100:0 EtOAc/hexane gradient). Yield: 81%; white
solid; mp 48-50 °C; [R]20D +134.7 (c 1.0, CHCl3); IR (KBr): 2223,
1494, 1013, 755 cm-1; 1H NMR: δ 8.28 (dd, J ) 1.5 and 7.4 Hz,
1H), 7.79 (dd, J ) 1.5 and 7.4 Hz, 1H), 7.65-7.51 (m, 4H), 7.43-
7.34 (m, 3H), 7.37 and 7.17 (AA′BB′ system, 4H), 3.98-3.78 (m,
2H), 2.33 (s, 3H), 1.80 (dd, J ) 2.8 and 9.6 Hz, 1H), 1.33 (s, 3H);
13C NMR: δ 143.3, 142.8, 141.5, 137.8, 137.2, 131.3, 129.9, 129.8
(2C), 128.9 (2C), 128.8 (2C), 127.9, 127.8, 127.7, 127.0 (2C), 121.0,
62.4, 50.4, 29.9, 21.4; MS (FAB+) m/z 375 (M + H)+; HRMS
(FAB+) calcd for C23H23N2OS (M + H)+: 375.1531; found:
375.1537.
[2S,(S)S]- and [2R,(S)S]-N-(Cyano{2-[(4-methylphenyl)sulfinyl]-
phenyl}methyl)-4-methylbenzenesulfonamide (17 + 17′). It was
prepared as a diastereoisomeric 90:10 mixture from imine 10
following method A using 2 equiv of Et2AlCN (reaction time: 2
h). It was used in further reactions without any purification.
Crystallization from CHCl3/hexane gave [2S,(S)S]-17 as a pure
diastereoisomer. Yield: 76%; white solid; mp 186-188 °C; [R]20
D
-43.8 (c 1.0, CHCl3); IR (KBr): 2401, 1341, 1216, 1063, 755
1
cm-1; H NMR: δ 7.79 (dd, J ) 1.5 and 7.8 Hz, 1H), 7.76 and
7.30 (AA′BB′ system, 4H), 7.60-7.50 (m, 3H), 7.47 and 7.27
(AA′BB′ system, 4H), 6.20 (bs, 1H), 5.72 (s, 1H), 2.42 (s, 3H),
2.38 (s, 3H); 13C NMR: δ 144.5, 143.0, 142.9, 140.2, 136.2, 131.9,
130.9, 130.7, 130.5 (2C), 129.9 (2C), 127.4 (2C), 126.7, 126.2 (2C),
125.7, 115.6, 45.0, 21.6, 21.4; MS (FAB+) m/z 425 (M + H)+;
HRMS (FAB+) calcd for C22H21N2O3S2 (M + H)+: 425.0993;
found: 425.0977. Diastereoisomer [2R,(S)S]-17′ was characterized
from a 17 + 17′ mixture; 1H NMR: δ 7.91-7.84 (m, 1H), 7.79-
7.20 (m, 11H), 6.67 (bs, 2H), 6.07 (s, 1H), 2.39 (s, 3H), 2.36 (s,
3H); 13C NMR: δ 144.1, 143.2, 142.4, 141.9, 139.6, 139.2, 132.2,
131.7, 129.6 (2C), 129.5, 129.2, 127.5, 127.2 (2C), 126.1 (2C),
125.2 (2C), 115.8, 44.3, 21.5, 21.3.
[2S,(S)S]-2-(Benzylamino)-2-{2-[(4-methylphenyl)sulfinyl]-
phenyl}butanenitrile (23). Amino nitriles 12 + 12′ were used as
the starting material. Ethyl trifluoromethanesulfonate was used as
the electrophile, and the reaction was stirred at -78 °C for 1 h to
give compound [2S,(S)S]-23, which was purified in an automated
flash chromatography (5:95 to 100:0 EtOAc/hexane gradient).
Yield: 79%; white solid; mp 49-50 °C; [R]20 -113.0 (c 1.0,
2-Benzylamino-2-{2-[(4-methylphenyl)sulfinyl]phenyl}-
acetamide (18). To 40 mg (0.11 mmol) of a 38:62 diastereoisomeric
mixture 12 + 12′ cooled at 0 °C was added a saturated solution of
HCl(g) in HCO2H (2 mL). The resulting mixture was stirred at 0
°C for 10 h. The solvent was evaporated at reduced pressure, and
the residue was treated with a saturated aqueous solution of
NaHCO3 (2 mL) for 30 min at room temperature. The product was
extracted with CHCl3 (3 × 5 mL), and the organic layers were
combined and dried (Na2SO4). The solvent was evaporated at
reduced pressure, and the product was purified by flash column
chromatography (eluent EtOAc/hexane, 2:1). Yield: 76%; white
solid; mp 129-131 °C (EtOAc/hexane); IR (KBr): 3318, 3179,
1659 cm-1; 1H NMR: δ 7.44 (d, J ) 7.2 Hz, 1H), 7.34-7.20 (m,
8H), 7.16 and 7.09 (AA′BB′ system, 4H), 6.92 (bs, 1H), 5.83 (bs,
1H), 4.85 (s, 1H), 3.72 and 3.66 (AB system, J ) 13.1 Hz, 2H),
2.50 (bs, 1H), 2.31 (s, 3H); 13C NMR: δ 174.6, 139.8, 139.2, 137.2,
135.2, 133.5, 132.1, 130.7 (2C), 130.1 (2C), 128.8, 128.6, 128.4
(2C), 128.2 (2C), 128.1, 127.2, 63.6, 52.3, 21.0; MS (ESI+) m/z
363 [M + H]+ (40), 318 (11), 211 (21); HRMS (ESI+) calcd for
C22H23N2OS: 363.1525; found: 363.1541.
D
CHCl3); IR (KBr): 2224, 1494, 1014, 754 cm-1; 1H NMR: δ 8.16
(dd, J ) 1.5 and 7.5, 1H), 7.77 (dd, J ) 1.5 and 7.5 Hz, 1H),
7.60-7.48 (m, 4H), 7.42-7.31 (m, 3H), 7.39 and 7.20 (AA′BB′
system, 4H), 3.98-3.75 (m, 2H), 2.35 (s, 3H), 1.85 (dd, J ) 2.4
and 10.1 Hz, 1H), 1.70-1.59 (m, 2H), 0.86 (t, J ) 7.1 Hz, 3H);
13C NMR: δ 143.2, 143.1, 141.3, 137.9, 136.0, 130.9, 130.0, 129.7
(2C), 128.9 (2C), 128.8, 128.7 (2C), 128.5, 127.7, 126.4 (2C), 119.9,
67.8, 50.3, 34.9, 21.3, 9.0; MS (FAB+) m/z 389 (M + H)+; HRMS
(FAB+) calcd for C24H25N2OS (M + H)+: 389.1688; found:
389.1694.
[2S,(S)S]-2-(Benzylamino)-2-{2-[(4-methylphenyl)sulfinyl]-
phenyl}-3-phenylpropanenitrile (24). Amino nitriles 12 + 12′
were used as the starting material. Benzyl bromide was used as
the electrophile, and the reaction was stirred at -78 °C for 1 h to
give compound [2S,(S)S]-24, which was purified in an automated
flash chromatography (5:95 to 100:0 EtOAc/hexane gradient).
Yield: 77%; white solid; mp 76-78 °C; [R]20 -136.9 (c 1.0,
D
CHCl3); IR (KBr): 2402, 1215, 1009, 773 cm-1; 1H NMR: δ 8.45
(d, J ) 7.7, 1H), 7.63-7.55 (m, 1H), 7.55-7.24 (m, 9H), 7.19-
J. Org. Chem, Vol. 72, No. 16, 2007 6003

Garc´ıa Ruano et al.
1
7.12 (m, 5H), 6.78 (dd, J ) 1.4 and 7.7 Hz, 2H), 3.91-3.82 (m,
2H), 2.67 and 2.52 (AB system, J ) 13.2 Hz, 2H), 2.33 (s, 3H),
1.85 (dd, J ) 2.7 and 9.9 Hz, 1H); 13C NMR: δ 143.6, 142.3,
141.9, 137.8, 135.7, 132.8, 130.9, 130.5 (2C), 130.0 (2C), 129.9,
129.2, 128.8 (2C), 128.6 (2C), 128.5 (2C), 128.1, 127.7, 127.5 (2C),
127.4, 119.5, 67.4, 50.2, 47.2, 21.4; MS (FAB+) m/z 451 (M +
H)+; HRMS (FAB+) calcd for C29H27N2OS (M + H)+: 451.1844;
found: 451.1843.
760 cm-1; H NMR: δ 8.28 (dd, J ) 1.6 and 7.8 Hz, 1H), 7.79
(dd, J ) 1.5 and 7.7 Hz, 1H), 7.62 (td, J ) 1.4 and 7.4 Hz, 1H),
7.54 (td, J ) 1.5 and 7.5 Hz, 1H), 7.49 and 7.17 (AA′BB′ system,
4H), 7.37 and 6.93 (AA′BB′ system, 4H), 3.93-3.86 (m, 1H), 3.82
(s, 3H), 3.81-3.72 (m, 1H), 2,34 (s, 3H), 1.80 (d, J ) 9.6 Hz,
1H), 1.32 (s, 3H); 13C NMR: δ 159.2, 143.4, 142.8, 141.5, 137.3,
131.3, 130.2 (2C), 130.0, 129.9, 129.8 (2C), 127.9, 127.7, 127.0
(2C), 121.0, 114.2 (2C), 62.4, 55.3, 49.9, 30.0, 21.4; MS (FAB+)
m/z 405 (M + H)+; HRMS (FAB+) calcd for C24H25N2O2S (M +
H)+: 405.1643; found: 405.1636.
[2S,(S)S]-2-(Benzylamino)-2-{2-[(4-methylphenyl)sulfinyl]-
phenyl}pent-4-enenitrile (25). Amino nitriles 12 + 12′ were used
as the starting material. Allyl bromide was used as the electrophile,
and the reaction was stirred at -78 °C for 1 h to give compound
[2S,(S)S]-25, which was purified in an automated flash chroma-
tography (5:95 to 100:0 EtOAc/hexane gradient). Yield: 82%; white
solid; mp 51-53 °C; [R]20D -117.2 (c 1.0, CHCl3); IR (KBr): 2225,
N-((E,S)-1-{2-[(4-Methylphenyl)sulfinyl]phenyl}ethylidene)-
1-phenylmethanamine (27). Amino nitriles 12 + 12′ were used
as the starting material. Iodomethane was used as the electrophile,
and the reaction was stirred at -78 °C for 1 h to give compound
27 as a byproduct. It was purified in an automated flash chroma-
tography (5:95 to 100:0 EtOAc/hexane gradient). Yield: 15%; white
solid; mp 86-88 °C; [R]20D -113.6 (c 1.0, CHCl3); IR (KBr): 2401,
1
1216, 1014, 773 cm-1; H NMR: δ 8.41 (dd, J ) 1.4 and 7.8,
1H), 7.77 (dd, J ) 1.4 and 7.8 Hz, 1H), 7.67 (td, J ) 1.4 and 7.8
Hz, 1H), 7.61-7.49 (m, 3H), 7.47-7.31 (m, 3H), 7.35 and 7.18
(AA′BB′ system, 4H), 5.82-5.65 (m, 1H), 5.16 (d, J ) 10.1 Hz,
1H), 4.70 (d, J ) 16.8 Hz, 1H), 2.97-2.78 (m, 2H), 2.37-2.23
(m, 1H), 2.34 (s, 3H), 1.83 (dd, J ) 1.7 and 10.8 Hz, 1H), 1.77-
1.61 (m, 1H); 13C NMR: δ 143.8, 142.4, 141.6, 137.7, 136.0, 131.1,
130.3, 129.9 (2C), 128.9 (2C), 128.8 (2C), 128.7, 127.8, 127.4 (2C),
122.8, 119.5, 65.8, 50.3, 45.9, 21.4; MS (FAB+) m/z 401 (M +
H)+; HRMS (FAB+) calcd for C25H25N2OS (M + H)+: 401.1687;
found: 401.1696.
1642, 1494, 1216, 1020, 770 cm-1; H NMR: δ 8.35 (d, J ) 7.4
1
Hz, 1H), 7.70-7.62 (m, 2H), 7.59-7.50 (m, 1H), 7.34-7.17 (m,
5H), 7.28 and 7.04 (AA′BB′ system, 4H), 4.70 and 4.60 (AB
system, J ) 7.4 Hz, 2H), 2.28 (s, 3H), 2.23 (s, 3H); 13C NMR: δ
164.3, 145.3, 144.9, 140.0, 139.4, 138.9, 130.1, 130.0, 129.3 (2C),
128.3 (2C), 128.0 (2C), 127.6, 126.7, 126.4, 126.1 (2C), 55.5, 21.2,
16.5; MS (FAB+) m/z 348 (M + H)+; HRMS (FAB+) calcd for
C22H22NOS (M + H)+: 348.1422; found: 348.1419.
N-((E,S)-1-{2-[(4-Methylphenyl)sulfinyl]phenyl}ethylidene)-
1-[4-(trifluoromethyl)phenyl]methanamine (29). Amino nitriles
13 + 13′ were used as the starting material. Iodomethane was used
as the electrophile, and the reaction was stirred at -78 °C for 1 h
to give compound 29 as a byproduct, which was purified by flash
column chromatography (EtOAc/hexane, 1:3). Yield: 10%; yellow
[2S,(S)S]-Methyl (benzylamino)(cyano){2-[(4-methylphenyl)-
sulfinyl]phenyl}acetate (26). Amino nitriles 12 + 12′ were used
as the starting material. Methyl chloroformate was used as the
electrophile, and the reaction was stirred at -78 °C for 1 h to give
compound [2S,(S)S]-26, which was purified in an automated flash
chromatography (5:95 to 100:0 EtOAc/hexane gradient). Yield:
84%; white solid; mp 50-52 °C; [R]20D -91.1 (c 1.0, CHCl3); IR
(KBr): 2401, 1755, 1216, 1015, 757 cm-1; 1H NMR: δ 8.14 (dd,
J ) 1.3 and 7.7, 1H), 7.87 (dd, J ) 1.3 and 7.7 Hz, 1H), 7.67 (td,
J ) 1.3 and 7.7 Hz, 1H), 7.58 (td, J ) 1.3 and 7.7 Hz, 1H), 7.45
and 7.07 (AA′BB′ system, 4H), 7.25-7.17 (m, 3H), 6.84-6.78
(m, 2H), 3.97 (s, 3H), 3.84 (dd, J ) 2.9 and 12.1 Hz, 1H), 3.15-
2.89 (m, 2H), 2.32 (s, 3H); 13C NMR: δ 166.6, 144.5, 141.7, 141.3,
136.7, 133.2, 131.2, 131.1, 129.8 (2C), 128.9, 128.4 (2C), 128.3,
128.0 (2C), 127.5, 126.2 (2C), 115.6, 67.2, 55.1, 48.5, 21.3; MS
(FAB+) m/z 419 (M + H)+; HRMS (FAB+) calcd for C24H23N2O3S
(M + H)+: 419.1429; found: 419.1419.
oil; [R]20 -93.7 (c 0.8, CHCl3); IR (KBr): 1679, 1325, 1126,
D
1019, 759 cm-1; H NMR: δ 8.33 (d, J ) 7.44 Hz, 1H), 7.96-
1
7.83 (m, 2H), 7.65 and 6.99 (AA′BB′ system, 4H), 7.60-7.51 (m,
2H), 7.47 and 6.21 (AA′BB′ system, 4H), 4.72 and 4.60 (AB
system, J ) 16.3 Hz, 2H), 2.27 (s, 3H), 2.26 (s, 3H); 13C NMR:
2
δ 165.0, 145.2, 144.7, 140.1, 139.3, 130.4, 130.2, 129.3 (q, J )
31.3 Hz, C-CF3), 129.2 (2C), 128.2 (2C), 127.7, 126.7, 126.1 (2C),
125.2 [q, J ) 3.3 Hz, (CH)2C-CF3], 124.5 (q, J ) 271.1 Hz,
CF3), 55.1, 21.1, 16.7; MS (FAB+) m/z 416 (M + H)+; HRMS
(FAB+) calcd for C23H21NOF3S (M + H)+: 416.1295; found:
416.1311.
3
1
1-(4-Methoxyphenyl)-N-((E,S)-1-{2-[(4-methylphenyl)sulfinyl]-
phenyl}ethylidene)methanamine (31). Amino nitriles 14 + 14′
were used as the starting material. Iodomethane was used as the
electrophile, and the reaction was stirred at -78 °C for 1 h to give
compound 31 as a byproduct, which was purified by flash column
chromatography (EtOAc/hexane, 1:3). Yield: 27%; yellow oil;
[2S,(S)S]-2-{2-[(4-Methylphenyl)sulfinyl]phenyl}-2-{[4-
(trifluoromethyl)benzyl]amino}propanenitrile (28). Amino ni-
triles 13 + 13′ were used as the starting material. Iodomethane
was used as the electrophile, and the reaction was stirred at -78
°C for 30 min to give compound [2S,(S)S]-28, which was purified
by flash column chromatography (EtOAc/hexane, 1:3). Yield: 57%;
[R]20 -137.1 (c 0.7, CHCl3); IR (film): 1511, 1248, 1027, 760
D
yellow oil; [R]20 -87.5 (c 1.0, CHCl3); IR (KBr): 2224, 1326,
cm-1; 1H NMR: δ 8.37-8.32 (m, 1H), 7.68-7.58 (m, 2H), 7.56-
7.47 (m, 1H), 7.29 and 7.02 (AA′BB′ system, 4H), 7.11 and 6.79
(AA′BB′ system, 4H), 4.64 and 4.53 (AB system, J ) 14.8 Hz,
2H), 3.79 (s, 3H), 2.28 (s, 3H), 2.20 (s, 3H); 13C NMR: δ 163.8,
158.4, 145.2, 144.9, 139.9, 139.4, 131.1, 130.0, 129.9, 129.2 (2C),
129.1 (2C), 127.6, 126.3, 126.1 (2C), 113.7 (2C), 55.2, 54.8, 21.2,
16.3; MS (FAB+) m/z 378 (M + H)+; HRMS (FAB+) calcd for
C23H24NO2S (M + H)+: 378.1528; found: 378.1544.
D
1
1125, 758 cm-1; H NMR: δ 8.11 (dd, J ) 1.5 and 6.9 Hz, 1H),
7.83 (dd, J ) 1.5 and 6.9 Hz, 1H), 7.70 and 7.65 (AA′BB′ system,
4H), 7.62-7.50 (m, 2H), 7.39 and 7.22 (AA′BB′ system, 4H), 4.04
(dd, J ) 3.1 and 11.8 Hz, 1H), 3.93-3.81 (m, 1H), 2.39 (s, 3H),
1.90 (dd, J ) 3.1 and 9.8 Hz, 1H), 1.58 (s, 3H); 13C NMR: δ
143.3, 142.7, 141.7, 141.5, 137.3, 131.6, 130.2, 129.9 (2C), 129.8
(q, 2J ) 32.3 Hz, C-CF3), 129.1 (2C), 128.7, 127.8, 127.2 (q, 1J )
272.0 Hz, CF3), 126.5 (2C), 125.7 [q, 3J ) 3.9 Hz, (CH)2C-CF3],
120.7, 62.5, 49.9, 30.2, 21.4; MS (FAB+) m/z 443 (M + H)+;
HRMS (FAB+) calcd for C24H22F3N2OS (M + H)+: 443.1405;
found: 443.1397.
2-Methyl-N-((E,S)-1-{2-[(4-methylphenyl)sulfinyl]phenyl}-
ethylidene)propan-1-amine (33). Amino nitriles 15 + 15′ were
used as the starting material. Iodomethane was used as the
electrophile, and the reaction was stirred at -78 °C for 1 h to give
compound 33 as a byproduct, which was purified by flash column
chromatography (EtOAc/hexane, 1:2). Yield: 56%; yellow oil;
[R]20D -89.9 (c 1.4, CHCl3); IR (film): 1640, 1026, 763 cm-1; 1H
NMR: δ 8.21 (dd, J ) 1.7 and 6.8 Hz, 1H), 7.62-7.51 (m, 3H),
7.48 and 7.14 (AA′BB′ system, 4H), 3.23 (m, 2H), 2.32 (s, 3H),
2.16 (s, 3H), 1.92 (m, 1H), 0.90 (d, J ) 6.8 Hz, 3H), 0.88 (d, J )
6.8 Hz, 3H); 13C NMR: δ 162.8, 145.3, 145.1, 140.0, 139.9, 130.0,
[2S,(S)S]-2-[(4-Methoxybenzyl)amino]-2-{2-[(4-methylphenyl)-
sulfinyl]phenyl}propanenitrile (30). Amino nitriles 14 + 14′ were
used as the starting material. Iodomethane was used as the
electrophile, and the reaction was stirred at -78 °C for 1 h to give
compound [2S,(S)S]-30, which was purified by flash column
chromatography (EtOAc/hexane, 1:3). Yield: 56%; yellow oil;
[R]20 -74.5 (c 1.5, CHCl3); IR (film): 2228, 1514, 1303, 1014,
D
6004 J. Org. Chem., Vol. 72, No. 16, 2007

Quaternization of R-Amino Phenylacetonitriles
129.9, 129.2 (2C), 127.3, 126.3, 126.0 (2C), 60.2, 29.6, 21.2, 21.1,
21.0, 16.3; MS (FAB+) m/z 314 (M + H)+; HRMS (FAB+) calcd
for C19H24NOS (M + H)+: 314.1528; found: 314.1563.
Computacio´n Cient´ıfica (UAM) for computation time and Dr.
M. Alcam´ı (UAM) for helpful discussions.
Supporting Information Available: 1H and 13C NMR spectra
for imines 2-10, R-amino nitriles 11-17 + 11′-17′, quaternization
products 22-26, 28 and 30 and retrohydrocyanation ketimines 27,
29, 31, and 33. X-Ray crystal structures for 13′, 17, and 23. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We thank CAICYT (Grant BQU2003-
04012) and UAM-CM (Grant CCG06-UAM/PPQ-0275) for
financial support. F.T. thanks Comunidad Auto´noma de Madrid
for a predoctoral fellowship. We also thank the Centro de
JO0705519
J. Org. Chem, Vol. 72, No. 16, 2007 6005