Asymmetric synthesis of 1,3-diamines by diastereoselective reduction of enantiopure n-tert-butanesulfinylketimines: unusual directing effects of the ortho-substituent

Article abstract of DOI:10.1021/jo100173f

(Figure Presented) Chiral, nonracemic 1,3-diamines were prepared in a highly diastereoselective reduction of diaryl N-tert-butanesulfinylketimines. Correlation between facial selectivity of the reduction and E or Z geometry of the starting ketimines suggests involvement of a cyclic transition state for the reduction. The ortho-substituent controls the geometry of N-tert- butanesulfinylketimines in the solid state and provides additional stabilization of the cyclic transition state.

Full text of DOI:10.1021/jo100173f

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Asymmetric Synthesis of 1,3-Diamines by Diastereoselective Reduction of
Enantiopure N-tert-Butanesulfinylketimines: Unusual Directing Effects
of the ortho-Substituent
Marina Martjuga, Dmitry Shabashov, Sergey Belyakov, Edvards Liepinsh, and
Edgars Suna*
Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006 Riga, Latvia
edgars@osi.lv
Received February 2, 2010
Chiral, nonracemic 1,3-diamines were prepared in a highly diastereoselective reduction of diaryl
N-tert-butanesulfinylketimines. Correlation between facial selectivity of the reduction and E or Z
geometry of the starting ketimines suggests involvement of a cyclic transition state for the reduction.
The ortho-substituent controls the geometry of N-tert-butanesulfinylketimines in the solid state and
provides additional stabilization of the cyclic transition state.
Introduction
In connection with our research program directed toward
developing new ligands for asymmetric synthesis, we aimed
to prepare chiral diamines 1 and 2 in enantiomerically pure
form (Figure 1).
Chiral, nonracemic 1,3-diamines have been successfully
used in asymmetric synthesis1 as chiral catalysts,2 chiral
reagents,3,4 and chiral ligands.5 Not surprisingly, the deve-
lopment of efficient synthetic methodologies to access
enantiomerically pure 1,3-diamines has been a subject of
intense research.6
(1) For a recent review, see: Kizirian, J.-C. Chem. Rev. 2008, 108, 140.
(2) (a) Pini, D.; Mastantuono, A.; Uccello-Barretta, G.; Iuliano, A.;
Salvadori, P. Tetrahedron 1993, 49, 9613. (b) Vedejs, E.; Kruger, A. W.
J. Org. Chem. 1998, 63, 2792. (c) Yamashita, Y.; Odashima, K.; Koga, K.
Tetrahedron Lett. 1999, 40, 2803. (d) Yamashita, Y.; Emura, Y.; Odashima,
K.; Koga, K. Tetrahedron Lett. 2000, 41, 209. (e) Kano, T.; Maruoka, K.
Chem. Commun. 2008, 5465 and references cited therein. (f ) Kano, T.;
Yamaguchi, Y.; Maruoka, K. Angew. Chem., Int. Ed. 2009, 48, 1838.
(g) Kano, T.; Yamamoto, A.; Shirozu, F.; Maruoka, K. Synthesis 2009, 1557.
(h) Kano, T.; Yamaguchi, Y.; Maruoka, K. Chem.;Eur. J. 2009, 15, 6678.
FIGURE 1. Target diamines 1 and 2.
€
(3) For a recent review on the use of Troger’s base, see: Sergeyev, S. Helv.
Chim. Acta 2009, 92, 415.
(6) For recent selected examples of asymmetric synthesis of chiral 1,3-
diamines, see: (a) Rios-Lombardia, N.; Busto, E.; Garcia-Urdiales, E.;
Gotor-Fernandez, V.; Gotor, V. J. Org. Chem. 2009, 74, 2571. (b) Dagousset,
G.; Drouet, F.; Masson, G.; Zhu, J. Org. Lett. 2009, 11, 5546. (c) Terada, M.;
Machioka, K.; Sorimachi, K. Angew. Chem., Int. Ed. 2009, 48, 2553.
(d) Kurokawa, T.; Kim, M.; Du Bois, J. Angew. Chem., Int. Ed. 2009, 48,
2777. (e) Giampietro, N. C.; Wolfe, J. P. J. Am. Chem. Soc. 2008, 130, 12907.
(4) Application of 1,3-diamines as chiral proton sources: (a) Vedejs, E.;
Lee, N.; Sakata, S. T. J. Am. Chem. Soc. 1994, 116, 2175. (b) Vedejs, E.;
Kruger, A. W.; Suna, E. J. Org. Chem. 1999, 64, 7863. (c) Vedejs, E.; Kruger,
A. W.; Lee, N.; Sakata, S. T.; Stec, M.; Suna, E. J. Am. Chem. Soc. 2000, 122,
4602.
(5) (a) Kammermeier, T.; Wiegrebe, W. Arch. Pharm. 1994, 327, 563.
(b) Grasa, G. A.; Zanotti-Gerosa, A.; Hems, W. P. J. Organomet. Chem.
2006, 691, 2332. (c) Hems, W. P.; Groarke, M.; Zanotti-Gerosa, A.; Grasa,
G. A. Acc. Chem. Res. 2007, 40, 1340.
€
(f ) Braun, W.; Calmuschi-Cula, B.; Englert, U.; Hofener, K.; Alberico, E.;
Salzer, A. Eur. J. Org. Chem. 2008, 2065. (g) Lu, S.-F.; Du, D.-M.; Xu, J.;
Zhang, S.-W. J. Am. Chem. Soc. 2006, 128, 7418.
DOI: 10.1021/jo100173f
r
Published on Web 03/03/2010
J. Org. Chem. 2010, 75, 2357–2368 2357
2010 American Chemical Society

Martjuga et al.
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SCHEME 1. Synthesis of Enantiomerically Pure Diamines 1 and 2
We envisioned that Ellman’s tert-butanesulfinyl group7
could be a suitable chiral auxiliary for the synthesis of the
desired diamines 1 and 2 in enantiomerically pure form via
the corresponding chiral N-sulfinylketimines. Although a
number of literature examples involving the use of ketone-
derived substrates have appeared,8 we anticipated the possi-
bility of unusual directing effects with difunctional sub-
strates as described later. Scheme 1 illustrates the synthesis
of target structures.
angles, Table 1), with the sulfoxide moiety placed in the
trans position. As a consequence, the aryl substituent (phenyl
or naphthyl group) is twisted out of the CdN plane to
minimize nonbonded steric interactions with the bulky tert-
butylsulfinyl group (see C5-C4-C3-N2 torsion angles,
Table 1). Thus, the preferential formation of E-isomers of
imines 4a-d was attributed to the stabilization by the
intramolecular hydrogen bond.11
While imine 4e did not crystallize, single crystals of the
closely related sulfinylimine 4i were obtained. Surprisingly,
X-ray analysis showed that imine 4i exists as the Z-isomer in
the crystalline form (entry 7, Table 1). Because imine (Z)-4i is
unable to form an intramolecular hydrogen bond, we suggest
that, in the absence of stabilizing hydrogen bond interac-
tions, the E geometry for sulfinylimine 4i is unfavorable due
to the electrostatic repulsion between aniline and imine
nitrogen lone pairs and nonbonded steric interactions
between the ortho-substituent and the imine moiety. To
verify the role of the intramolecular hydrogen bond in the
selective formation of E-isomers, additional ortho-substi-
tuted ketimines 4f-h incapable of forming the intramolecu-
lar hydrogen bond were prepared under standard conditions
[(RS)-tert-butanesulfinamide, 90 °C, Ti(OEt)4]. Sulfinyli-
mine 4h was obtained as an oil, but imines 4f,g could be
crystallized. As anticipated, X-ray analysis of single crystals
confirmed that 4f,g exist as the Z-isomers in the crystalline
form (entries 5 and 6, Table 1). In the observed Z geometry,
the large ortho-substituted phenyl moieties of imines 4f,g,i
are turned out of the CdN plane (see C1-C2-C3-N2
torsion angles, Table 1). Consequently, the smaller unsub-
stituted phenyl group in sulfinylimines 4f,g,i is periplanar to
the CdN bond (see C5-C4-C3-N2 torsion angles, Table 1-
). The predominance of the Z-isomers in ketimines 4f,g,i is
noteworthy as it has been traditionally considered that the
most stable isomer has the sulfoxide moiety positioned trans
to the larger C-substituent on the ketimine.12
Results and Discussion
Synthesis and Structural Analysis of Sulfinylimines 4a-i.
Sulfinylimines 4a-d were prepared in crystalline form by
heating ketones 3a-d9 with (RS)-tert-butanesulfinamide at
75 °C in the presence of Ti(OEt)4.8a The X-ray crystal-
lographic analysis helped to establish that sulfinylimines
4a-d were formed as E-isomers. In crystal lattices of sulfi-
nylimines 4a-d, the distance between the nitrogen of the
˚
aniline and that of the sulfinyl group is 2.68-2.72 A,
indicating a hydrogen bond interaction between the aniline
N-H and nitrogen of the imine10 (see N1-N2 distances in
entries 1-4, Table 1).
The intramolecular hydrogen bond enforces a syn-peri-
planar relationship between the aniline ring and the CdN
bond of the imines 4a-d (see C1-C2-C3-N2 torsion
(7) (a) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35,
984. (b) Morton, D.; Stockman, R. Tetrahedron 2006, 62, 8869. (c) Ferreira,
ꢀ
F.; Botuha, C.; Chemla, F.; Perez-Luna, A. Chem. Soc. Rev. 2009, 38, 1162.
(8) (a) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A.
J. Org. Chem. 1999, 64, 1278. (b) Shaw, A. W.; deSolms, S. J. Tetrahedron
Lett. 2001, 42, 7173. (c) Kochi, T.; Tang, T. P.; Ellman, J. A. J. Am. Chem.
Soc. 2003, 125, 11276. (d) Kochi, T.; Ellman, J. A. J. Am. Chem. Soc. 2004,
126, 15652. (e) Chelucci, G.; Baldino, S.; Chessa, S.; Pinna, G. A.; Soccolini,
F. Tetrahedron: Asymmetry 2006, 17, 3163. (f ) Zhao, C.-H.; Liu, L.; Wang,
D.; Chen, Y.-J. Eur. J. Org. Chem. 2006, 2977. (g) Colyer, J. T.; Andersen,
N. G.; Tedrow, J. S.; Soukup, T. S.; Faul, M. M. J. Org. Chem. 2006, 71,
6859. (h) Morton, D.; Pearson, D.; Field, R. A.; Stockman, R. A. Chem.
Commun. 2006, 1833. (i) Denolf, B.; Leemans, E.; De Kimpe, N. J. Org.
Chem. 2007, 72, 3211. ( j) Tanuwidjaja, J.; Peltier, H. M.; Ellman, J. J. Org.
Chem. 2007, 72, 626. (k) Watzke, A.; Wilson, R. M.; O’Malley, S. J.;
Bergman, R. G.; Ellman, J. A. Synlett 2007, 2383. (l) Denolf, B.; Mange-
Facile E/Z isomerization of individual conformers 4a-h in
solutions was observed by NMR spectroscopy (see Table 2),
and the isomer ratio was found to depend on the solvent.13
€
linckx, S.; Tornroos, K. W.; De Kimpe, N. Org. Lett. 2007, 9, 187. (m) Lin,
G.-Q.; Xu, M.-H.; Zhong, Y.-W.; Sun, X.-W. Acc. Chem. Res. 2008, 41, 831.
(n) Guijarro, D.; Pablo, O.; Yus, M. Tetrahedron Lett. 2009, 50, 5386. (o)
Leemans, E.; Mangelinckx, S.; De Kimpe, N. Synlett 2009, 1265.
(9) For preparation of ketones 3a-h, see Supporting Information, pages
S2-S10.
(10) Gilli, G. Molecules and Molecular Crystals. In Fundamentals of
Crystallography; Giacovazzo, C., Ed.; Oxford University Press: New York,
2002; pp 590-595.
(11) Stabilization of the E-isomer in β-hydroxysulfinylketimines by the
intramolecular hydrogen bond between the β-hydroxy group and the oxygen
of sulfinyl imine has been suggested; see ref 8c.
(12) See for example: Chelucci, G.; Baldino, S.; Chessa, S. Tetrahedron
2006, 62, 619.
(13) For the influence of solvent on ratio of isomers, see: Stassinopoulou,
C. I.; Zioudrou, C.; Karabatsos, G. J. Tetrahedron 1976, 32, 1147.
2358 J. Org. Chem. Vol. 75, No. 7, 2010

Martjuga et al.
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TABLE 1. Selected Crystallographic Parameters for Sulfinylketimines
4a-d,f,g,i
presence of geometrical isomers. Importantly, both isomers
displayed strongly downfield shifted signals of aniline N-H
(9.94 and 9.89 ppm, both quartets with J = 4.8 Hz),
suggesting that the aniline N-H is involved in hydrogen
bonding in both isomers. Consequently, the two sets of signals
in the NMR spectrum of imine 4c were assigned to two isomers
of (E)-4c with hindered rotation about the naphthylimine axis,
that is, (E)-4cA and (E)-4cB (see Figure 2). The absence of the
(Z)-4c isomer in THF-d8 (within NMR detection limits)
suggests high stability of the E-isomer in solution.
The E/Z ratio in THF-d8 was determined using similar
NMR methods for all of the sulfinylimines 4b,d-h17 (see
Table 2). The major isomers of imines, (E)-4a-d and (Z)-4f,g
in THF-d8 solution, were the same as those in the crystal
lattice. However, the amount of minor E-isomers of imines
4f,g in THF-d8 reached ca. 30%. Furthermore, dissolving the
crystalline (Z)-4e in THF-d8 solution afforded the opposite
isomer (E)-4e as the major component (E/Z = 65:35).
The observed fast equilibration of sulfinylimines 4a-h in
solutions at -15 °C would require relatively low energy barriers
to E/Z isomerization.18 Additional NMR experiments were
therefore performed to determine the free energy of activation
and rate constants for the E/Z isomerization of sulfinylimines
4a-h in THF-d8. These data were calculated from NOESY
spectra comparing the intensities of diagonal and exchange
cross-peaks.19 The (E)-4 to (Z)-4 isomerization barriers in
THF-d8 range from 63.4 to 70.7 kJ/mol (see Table 2), and
hence, they are higher than the activation barrier by 1.7-9 kJ/
mol for the nonsubstituted diarylketimine 7 (61.7 kJ/mol;20 see
Table 2, entry 1).21 The observed difference can be attributed to
the influence of the ortho-substituent. Thus, (E)-4a is more
stable than (Z)-4a by 3.9-5.2 kJ/mol, which is the highest
energy difference in the series (entry 2, Table 2). Similarly, (E)-
4d is more stable than (Z)-4d by2.9kJ/mol(entry5). Thehigher
stability of (E)-4a-d versus (Z)-4a-d can be tentatively attrib-
uted to the stabilizing effect of the hydrogen bond in the E
configuration. A less pronounced preference for the E-isomer
was observed for imines 4e,h (Table 2, entries 6 and 9,
respectively), which are incapable of forming the hydrogen
bond. On the other hand, the Z-conformers have lower ground-
state energy in the case of the structurally related imines 4f,g
(Table 2, entries 7 and 8, respectively). The origin of the small
energetic preferences for 4e-g in THF-d8 solution is not clear.
imine
(RS)-4
N1-N2 C1-C2-C3-N2
torsion angle
C5-C4-C3-N2
torsion angle
˚
(A)
entry
1
2
3
4
5
6
7
(E)-4a
(E)-4ba
(E)-4ca
(E)-4d
(Z)-4f
(Z)-4g
(Z)-4i
2.676
2.721
2.678
2.676
-7.8
15.5
110.8
91.5
88.0
114.3
-8.4
-4.0
3.5
-8.25
-12.1
-64.5
-76.6
-66.6
aAverage values of two molecules crystallized in a unit cell.
Thus, an 80:20 mixture of E/Z-isomers was obtained upon
dissolving (E)-4a in THF-d8 at 10 °C.14 The aniline NH
proton of the major diastereomer was shifted strongly down-
field, appearing as a singlet at δ = 9.63 ppm and suggesting
the involvement of the proton in a hydrogen bond. Lowering
the temperature to -15 °C resulted in a further downfield drift
of the chemical shift to 9.67 ppm. Furthermore, the N-1H
signal changed to a resolved quartet (JMe,H = 4.8 Hz), and
15N-1H splitting (J = 93 Hz) could also be observed. The
temperature coefficient for the chemical shift of the aniline
N-H resonance15 (ΔσHN/ΔT = -1.6 ppb/K) supported the
presence of an intramolecular hydrogen bond. Consequently,
the major isomer of 4a in solution was assigned E geometry.
The minor isomer appeared as two sets of signals in ca. 1:1 ratio
with the aniline N-H resonance at δ = 4.72 and 4.69 ppm
(THF-d8, -15 °C, two quartets, J = 4.8 Hz). On the basis of
two-dimensional NMR experiments,16 the minor isomer was
assigned as a mixture of two rotamers, (Z)-4aA and (Z)-4aB,
with hindered rotation about the arylimine axis (see Figure 2).
Imine (E)-4c displayed two sets of signals in a ratio of 54:44
upon dissolving in THF-d8 at -15 °C, thus pointing to the
The determined ground-state energy differences (ΔΔGq
)
258
correlate well with the equilibrium E/Z ratio in THF-d8
(Table 2). Thus, the lowest barrier was established for imine
(RS)-4h (entry 9), which forms a 2:3 mixture of E- and
Z-isomers. On the other hand, the highest barrier for
(E)-4a translates into an 81:19 ratio of E/Z-isomers.
(14) In CHCl3-d at -15 °C, the amount of major diastereomer of 4a was
96.8%.
(15) Baxter, N. J.; Williamson, M. P. J. Biomol. NMR 1997, 9, 359.
(16) DQF-COSY, ROESY, NOESY, TOCSY, sensitivity-enhanced
13C-H HSQC, and 13C-1H HMBC experiments.
(17) The E- and Z-isomers could be distinguished by comparing chemical
shits of the HA proton in the 1H NMR spectra. Thus, HA protons in
Z-isomers were constantly shifted downfield (Δδ = 0.04-0.25 ppm) com-
pared to those in E-isomers, presumably due to the shielding of the HA by the
phenyl ring. See the Supporting Information (Table S1, page S11) for details.
(18) Related diaryl sulfinylketimines were obtained as a rapidly inter-
converting mixtures of Z- and E-isomers; see ref 8b.
(19) (a) Perrin, C. L. J. Magn. Reson. 1989, 82, 619. (b) Dimitrov, V. S.;
Vassilev, N. G. Magn. Reson. Chem. 1995, 33, 739. (c)Abel, E. W.;Coston, T. P. J.;
Orrell, K. G.; Sik, V.; Stephenson, D. J. Magn. Reson. 1986, 70, 34.
(d) Sandstrom, J. Dynamic NMR Spectroscopy; Academic Press: London, 1982.
(20) E/Z isomerization barrier in CHCl3-d has been determined for
structurally related p-toluenesulfinylketimines. (a) Di-(p-tolyl)methylene-
p-toluenesulfinamide, 15 kcal/mol (62.8 kJ/mol): Annunziata, R.; Cinquini,
M.; Cozzi, F. J. Chem. Soc., Perkin Trans. 1 1982, 339. (b) Diphenylmethy-
lene benzenesulfinamide, 14.1 kcal/mol (59.0 kJ/mol): Davis, F. A.; Kluger,
E. W. J. Am. Chem. Soc. 1976, 98, 302.
(21) The free energy of activation, ΔGq, was determined by 13C NMR at
the coalescence temperature (50 °C) of the diastereotopic ipso-carbon atoms
of diphenylsulfinylketimine 7 using the equation Kc = 2.22Δν and the Eyring
equation (k = 1); see ref 20b.
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TABLE 2. Rate Constants and Free Energy of Activation for E/Z Isomerization of Sulfinylketimines 4a-h in THF-d8
E f Z
ΔGq258 (kJ/mol)
Z f E
ΔGq258 (kJ/mol)
ΔΔGq258 (kJ/mol)
entry
imine
Z/E ratio, %a
k, s-1
k-1, s-1
1
2
(RS)-7
(RS)-4a
61.7
68.3c
70.7
nd
61.7
64.4
65.5
nd
0
19d:81
0.12b
0.04
nd
0.74
0.45
nd
3.9
5.2
nd
nd
2.9
1.3
1.8
1.7
0.9
3
4
5
6
7
8
9
(RS)-4b
(RS)-4c
(RS)-4d
(RS)-4e
(RS)-4f
(RS)-4g
(RS)-4h
23d:77
1:99e
nd
nd
nd
nd
20d:80
35:65
70:30
67:33
39:61
0.20
0.11
0.67
0.39
0.13
66.3
68.5
63.7
65.8
68.2
0.78
0.20
0.30
0.20
0.19
63.4
67.2
65.5
67.5
67.3
aDetermined in THF-d8 at -15 °C by NMR. bRate coefficient values were determined separately for each rotamer (Z)-4aA and (Z)-4aB
258
c
without assignment (see Figure 2). Free energy of activation ΔGq was calculated separately for conversion of (E)-4a to (Z)-4aA and (Z)-4aB.
dRepresents the sum of rotamers of the Z-isomer (see Figure 2). eRepresents the sum of rotamers of (E)-4cA and (E)-4cB which exist in a 56:44 ratio
(see Figure 2).
FIGURE 2. Isomers of imines 4a,c in THF-d8.
Diastereoselective Reduction of Sulfinylimines 4a-h. The
reduction of imines 4a-h was carried out using the two
trivalent hydride reducing agents BH3-THF and DIBAL at
-78 °C in THF (Table 3, conditions A and B, respectively).
of reduction evidently occur heterogeneously on the surface
of the solid NaBH4, but subsequent events may take place
in solution as BH3 THF or similar borane adducts are
3
generated.
22
Additionally, NaBH4-Ti(OEt)4 and NaBH4 were also
Excellent levels of diastereoselectivity were achieved in the
reduction of imines 4a,c-e,g using hydride reducing agents
(Table 3, conditions A and B). Notably, the ratio of diaster-
eomers in all cases exceeded the initial E/Z ratio of the
starting imines (see Table 3), suggesting rapid E/Z intercon-
version at -78 °C on the time scale of the reduction.
In a control experiment, solid (E)-4a was added to precooled
(-78 °C) THF-d8 and an 1H NMR spectrum of the
resulting suspension at -80 °C was acquired. Two sets of
signals in a ratio of 82:18 were observed for the dissolved
fraction, showing that spontaneous E/Z equilibration of
examined (Table 3, conditions C and D, respectively). The
trivalent hydride reducing agents afforded superior diastereo-
selectivities in the reduction, DIBAL being the reducing
agent of choice. Conditions C and D were less efficient, but
the successful use of NaBH4 is noteworthy because the
reducing agent is virtually insoluble in THF. The initial stages
(22) (a) Borg, G.; Cogan, D. A.; Ellman, J. A. Tetrahedron Lett. 1999, 40,
6709. (b) Tanuwidjaja, J.; Peltier, H. M.; Ellman, J. J. Org. Chem. 2007, 72,
626.
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TABLE 3. Diastereoselective Reduction of tert-Butanesulfinylimines 4a-h
aGeometry of the CdN bond in crystalline material was determined by X-ray crystallographic analysis. bThe E/Z ratio in THF-d8 was determined at
c
-15 °C by NOESY experiments. Conditions A: BH3 THF (1.6 equiv), -78 °C, THF, 3 h. Conditions B: DIBAL (3 equiv), -78 °C, THF, 3 h.
3
Conditions C: NaBH4-Ti(OEt)4, -78 °C to room temperature. Conditions D: NaBH4, THF, room temperature, 3 h. dDetermined by 1H NMR and
HPLC assay for the crude reduction mixture. eRelative configuration of the major diastereomer 5 determined by X-ray crystallographic analysis. fYield
of the major diastereomer; in parentheses: conversion of imines 4a-h. gAssignment based on structural analogy with (Z)-(RS)-4i.
J. Org. Chem. Vol. 75, No. 7, 2010 2361

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imine (E)-4a occurs in THF-d8 solution under the reduction
conditions.23
The reduction of 4b,f,h afforded sulfinamides with lower
diastereomeric ratios. Nevertheless, minor diastereomers of
sulfinylamides 5a-h could be readily separated by flash
column chromatography, thus increasing the purity of the
major diastereomers 5a-h to >99:1 dr.
The relative configuration at the newly created asym-
metric carbon was determined for all reduction products
5a-h by X-ray crystallographic analysis. Sulfinylamides
5a-d were formed with the R absolute configuration at the
newly created asymmetric center, while reduction products
5e-h possessed the S configuration. Intriguingly, the sense
of asymmetric induction is in good correlation with the
favored E or Z configuration of the starting imines 4a-g
in the crystalline form. Thus, the reduction of (E)-4a-d
resulted in the formation of (RS,R)-5a-d, while (Z)-4e-h
afforded sulfinylamides (RS,S)-5e-h. The observed correla-
tion is striking, given the observed isomerization of indivi-
dual E- or Z-conformers of imines 5a-h upon dissolving in
THF-d8.
To better understand the putative relationship between
the sense of asymmetric induction and E/Z configuration of
the starting imines 4a-h, the influence of the intramolecular
hydrogen bond on the diastereoselectivity of the reduction
was evaluated. Thus, NaBH4 reduction of imine (E)-4c was
attempted in protic solvents that may disrupt the hydrogen
bond between the aniline N-H and nitrogen of the imine.
The diastereoselectivity of the reduction of imine (E)-4c was
considerably lower in ethanol (dr = 70:30) and methanol
(dr = 67:33), compared to that in THF (dr = 91:9, condi-
tions D; see Table 3, entry 12), suggesting an involvement of
the intramolecular hydrogen bond in the stabilization of the
transition state for the reduction of imines (E)-4a-d. Con-
sequently, it appears that the hydrogen bonding may be
responsible both for the solid-state geometry and for the
transition-state preferences of imines (E)-4a-d.
For reductions under conditions A and B (see Table 3), a
chelation-controlled reduction mechanism24 is proposed,
where borane forms an “ate” complex with sulfinyl oxygen,25
ensuring the internal sulfoxide-mediated delivery of hydride
from the Si face of the CdN bond to afford sulfinylamides
(RS,R)-5a-d.
In the preferred chairlike conformation of the six-center
transition state for the (E)-sulfinylimines (TS-1, Figure 3),
the bulky t-Bu group and large aniline substituent are placed
equatorially and the smaller phenyl group is in the axial
position. The intramolecular hydrogen bond between the
aniline N-H and nitrogen of the imine stabilizes the favored
E conformation of sulfinylimines 4a-d in the transition state
(TS-1). Assuming that the reduction of sulfinylimines occurs
via a cyclic transition state and internal sulfoxide-mediated
delivery of borane, the isomeric (Z)-sulfinylimines 4e-h
should afford sulfinylamides (RS,S)-5e-h with the opposite,
FIGURE 3. Transition states for the reduction of imines 4a-h.
that is, S absolute configuration. Indeed, (RS,S)-5e-h are
formed as the major diastereomers (Table 3). However, the
observed diastereoselectivity for reduction of 4e-h does not
correlate with the E/Z ratio in solution, and in some cases (for
example, 4e), diastereomeric ratio is much higher than the
E/Z ratio. This outcome means that the diastereoselectivity
for 4e-h is controlled by the relative reactivity of E- and
Z-isomers in the equilibrating E/Z mixture. Notably, the
more reactive conformation of the cyclic transition state
TS-2 implies that the large ortho-substituted aryl moiety is
placed in an axial position to ensure the delivery of hydride
via a six-membered transition state from the Re face of the
sulfinylimines (Z)-4e-h (see Figure 3). On the other hand, a
simple steric explanation is not sufficient to explain the
detailed trends for 4e-h because the actual diastereomeric
ratio varies considerably depending on the reducing agent
and the ortho-substituent. We do not have sufficient evidence
to comment further on the origins of this diastereoselectivity
preference.
An alternative mechanism is also plausible where the
N-H group of anilines 4a-d forms a covalent N-B or
N-Al bond with BH3-THF or DIBAL. Subsequent inter-
nal hydride transfer from the transient amidometallohy-
drides occurs to the less sterically hindered Si face of the
CdN bond, affording (RS,R)-5a-d (see TS-3, Figure 3).26
A
synergistic directing effect of both the sulfinyl oxygen and
aniline nitrogen could also beenvisioned (see TS-4, Figure 3).
We could not rule out these possibilies, although we
regard the mechanism via TS-1 to be sufficiently
plausible and consistent with available data for most
experiments.
The sense of asymmetric induction in the case of Ellman’s
conditions (NaBH4-Ti(OEt)4, -78 °C, THF) as well as by
using NaBH4 (room temperature, THF) matches that ob-
tained in the reduction by BH3-THF complex and DIBAL.
Thus, (E)-4a-d afforded (RS,R)-5a-d, while (Z)-4e-h
(23) An 81:19 mixture of E/Z-isomers was formed in THF-d8 at -15 °C
(see Table 3).
(24) Cyclic six-membered transition state has been proposed in the
reduction of sulfinylketimines with DIBAL: (a) Hose, D. R. J.; Mahon, M.
F.; Molloy, K. C.; Raynham, T.; Wills, M. J. Chem. Soc., Perkin Trans. 1
1996, 691. (b) Ref 12.
(25) Atomic charge calculations have demonstrated considerable nega-
tive charge on oxygen in sulfinylimines: Bharatam, P. V.; Uppal, P.; Kaur, D.
J. Chem. Soc., Perkin Trans. 2 2000, 43.
2362 J. Org. Chem. Vol. 75, No. 7, 2010

Martjuga et al.
JOCArticle
yielded (RS,S)-5e-h (Table 3). The highest diastereoselec-
tivity in reductions with anionic hydride sources was ob-
served for 4e (dr = 99:1, see Table 3). Nevertheless,
rationalization of the reduction stereochemistry in the case
of the NaBH4-Ti(OEt)4 system is a challenging task given
the lack of knowledge about the structure of the “true”
reducing species.27 In the case of NaBH4 reductions, the
cyclic six-membered transition state may not be an appro-
with BH3-THF and DIBAL occurs via the cyclic transition
state and internal sulfoxide-mediated delivery of borane or
via internal hydride transfer from transient amidometallo-
hydrides. In solution, fast E/Z isomerization of sulfinyli-
mines 4a-h was observed and the equilibrium ratio was
found to depend on the solvent. The free energy of activation
for E/Z isomerization in THF-d8 for all sulfinylimines 4a-h
was determined by NMR methods to range from 63.4 to 70.7
kJ/mol. Calculated differences of the ground-state energies
of E- and Z-isomers correspond to the equilibrium ratio of
E/Z-conformers in THF-d8.
-
priate model because the four-coordinated BH4 “ate”
complex cannot interact with oxygen of the sulfinyl group,28
and the reaction may involve additional hydride donors
formed after the initial hydride transfer.
Conversion of Reduction Products 5a-e To Target Di-
amines 1 and 2. The chiral auxiliary was readily cleaved
without racemization of the created chiral center by treat-
ment of sulfinamides (RS,R)-5a-d and (RS,S)-5e with 4 N
HCl in dioxane (see Scheme 1). Introduction of an N-methyl
group at the benzylic nitrogen was performed prior to the
removal of the chiral auxiliary from (RS,R)-5a-d and (RS,
S)-5e. The regioselective alkylation of N-deprotonated sul-
finamide in the presence of aniline N-H was possible by
using LiHMDS as a base.
Experimental Section
General Procedure for the Condensation of Ketones with (RS)-
tert-Butanesulfinamide. To a solution of appropriate ketone 3
(1.0 equiv) and (RS)-tert-butanesulfinamide29 (1.0 equiv) in
anhydrous THF (5 mL/mmol of ketone 3) under an argon
atmosphere in an ACE pressure tube was added neat Ti(OEt)4
(Alfa Aesar, Vertec, 99þ%, 4.0 equiv). The pressure tube was
sealed and heated for 12 h at 75 °C (sulfinylimines 4a-d) or
90 °C (sulfinylimines 4e-i), cooled to ambient temperature, and
poured into a mixture of brine (20 mL/mmol of ketone 3) and
EtOAc (20 mL/mmol of ketone 3). The resulting slurry was
filtered throught a plug of Celite (3 ꢀ 5 cm), and the filter cake
was washed with EtOAc (50 mL/mmol of ketone 3). Organic
layer from the filtrate was washed with brine, dried over
Na2SO4, and concentrated. The residue was purified by column
chromatography on silica gel.
(RS)-N-[(E)-[5-Chloro-2-(methylamino)phenyl](phenyl)methy-
lidene]-2-methyl-2-propanesulfinamide (4a). Following the gene-
ral procedure, ketone 3a (500 mg, 2.0 mmol) was converted into
sulfinylimine 4a. Purification of the crude product by column
chromatography using gradient elution from 6% EtOAc/
petroleum ether to 45% EtOAc/petroleum ether afforded 4a
as a yellow solid (500 mg, 78% yield); analytical TLC on silica
gel, 2:5 EtOAc/petroleum ether, Rf = 0.14. Pure material was
obtained by crystallization from EtOAc/petroleum ether: mp
126-128 °C; IR (film, cm-1) 3213 (NH), 1529 (NdC), 1078
(SdO); 1H NMR (400 MHz, CDCl3, ppm) δ 9.69-9.45 (1H, s),
7.52-7.38 (3H, m), 7.29-7.13 (3H, m), 6.84 (1H, d, J = 2.2 Hz),
6.66 (1H, d, J = 9.0 Hz), 2.98 (3H, d, J = 4.0 Hz), 1.21 (9H, s);
13C NMR (100 MHz, CDCl3, ppm) δ 182.0, 150.8, 136.5, 134.3,
129.3, 128.4, 127.7, 118.6, 117.6, 112.4, 55.4, 29.8, 22.2. Anal.
Calcd for C18H21ClN2OS: C, 61.97; H, 6.07; N, 8.03. Found: C,
61.73; H, 5.98; N, 7.87. Optical rotation [R]20D -157.4 (c 4.45,
EtOH).
Conclusions
The key step in the synthesis of chiral, nonracemic dia-
mines 1 and 2 was the highly diastereoselective reduction of
diaryl tert-butanesulfinylimines. Both the structure of the
starting imines 4a-h and the relative configuration of the
reduction products 5a-h were determined by X-ray crystal-
lographic analysis. The sense of asymmetric induction was
found to be in good correlation with E or Z geometry of the
starting imines 4a-h in the crystalline form. Thus, (E)-imines
4a-d were reduced to (RS,R)-5a-d with R configuration at
the newly created chiral center, while (Z)-4e-h afforded
sulfinylamides (RS,S)-5e-h with S configuration. This cor-
relation could be rationalized assuming that the reduction
(26) A control experiment was performed under conditions where the TS
stabilization by hydrogen bonding is not possible. Thus, (E)-4a was depro-
tonated and the resulting salt (E)-4a-K was reduced with BH3-THF (dr =
82:18, 99% coversion) and DIBAL (dr = 82:18, 50% conversion) under
standard conditions (see Table 3, conditions A and B). The diastereoselec-
tivity of the reduction was lower compared to that of parent imine (E)-4a (see
Table 3, entries 1 and 2), and it correlated well with the E/Z = 81:19 ratio of
starting (E)-4a.
(RS)-N-[(E)-[5-Chloro-2-(methylamino)phenyl](2-naphthyl)meth-
ylidene]-2-methyl-2-propanesulfinamide (4b). Following the gene-
ral procedure, ketone 3b (500 mg, 1.7 mmol) was converted
into sulfinylimine 4b. Purification of the crude product by
column chromatography using gradient elution from 6%
EtOAc/petroleum ether to 100% EtOAc afforded 4b as a
yellow solid (528 mg, 78%); analytical TLC on silica gel,
2:5 EtOAc/petroleum ether, Rf = 0.14. Pure material was
obtained by crystallization from EtOAc/petroleum ether:
mp 129-131 °C; IR (film, cm-1) 3215 (NH), 1565 (NdC),
The atomic charge calculation evidenced that the anionic nitrogen has
stronger negative charge than the sulfinyl oxygen. Consequently, a scenario
where the initial binding of BH3 or DIBAL to the anion to afford an
amidometallohydride prior to the H transfer is conceivable. The observed
correlation with E/Z ratio of starting (E)-4a suggests an increased barrier for
E/Z interconversion for the anion, which slows down the rate of equilibration
on the reduction time scale.
(27) It has been demonstrated that the reaction between TiCl4 and LiBH4
afforded two potent reducing agents;Ti(BH4)3 and diborane: (a) Hoekstra,
H. R.; Katz, J. J. J. Am. Chem. Soc. 1949, 71, 2488. See also: (b) Jensen, J. A.;
Wilson, S. R.; Girolami, G. S. J. Am. Chem. Soc. 1988, 110, 4977.
(28) Nevertheless, involvement of the cyclic transition state has been
suggested for reductions with anionic hydride sources: (a) with LiAlH4 (ref
20a). (b) with NaBH4 (refs 8g and 8i).
1
1077 (SdO); H NMR (400 MHz, CDCl3, ppm) δ 9.71-9.58
(1H, br s), 8.02-7.84 (3H, m), 7.76 (1H, s), 7.63-7.53 (2H, m),
7.38-7.27 (2H, m), 6.89 (1H, d, J = 2.0 Hz), 6.72 (1H, d,
J = 9.0 Hz), 3.04 (3H, s), 1.26 (9H, s); 13C NMR (100 MHz,
CDCl3, ppm) δ 180.0, 149.0, 132.3, 132.0, 131.3, 130.5, 126.7,
126.4, 126.0, 125.3, 125.1, 123.2, 116.9, 115.6, 110.5, 53.7,
27.9, 20.3. Anal. Calcd for C22H23ClN2OS: C, 66.23; H, 5.81;
(29) Synthesized according to the reported procedure: Cogan, D. A.; Liu,
G.; Kim, K.; Backes, B. J.; Ellman, J. A. J. Am. Chem. Soc. 1998, 120, 8011.
J. Org. Chem. Vol. 75, No. 7, 2010 2363

Martjuga et al.
JOCArticle
N, 7.02. Found: C, 66.09; H, 5.76; N, 6.99. Optical rotation
CDCl3, ppm) δ 7.73 (2H, d, J = 7.2 Hz), 7.52-7.42 (2H, m),
7.40-7.36 (2H, m), 7.22 (1H, br s), 7.07-6.95 (2H, m), 3.80 (3H,
s), 1.30 (9H, s); 13C NMR (100 MHz, CDCl3, ppm) δ 175.3,
155.8, 138.2, 131.9, 130.9, 129.4, 129.1, 128.3, 125.2, 120.1,
111.1, 110.6, 56.7, 55.4, 22.5. Anal. Calcd for C18H21ClNO2S:
C, 68.54; H, 6.71; N, 4.44. Found: C, 68.42; H, 6.63; N, 4.38.
Optical rotation [R]20D -126.3 (c 4.81, EtOH).
[R]20D -121.1 (c 4.09, EtOH).
(RS)-N-[(E)-[5-Chloro-2-(methylamino)phenyl](1-naphthyl)meth-
ylidene]-2-methyl-2-propanesulfinamide (4c). Following the gen-
eral procedure, ketone 3c (500 mg, 1.7 mmol) was converted into
sulfinylimine 4c. Purification of the crude product by column
chromatography using gradient elution from 6% EtOAc/petro-
leum ether to 100% EtOAc afforded 4c as a yellow solid
(251 mg, 37% yield); analytical TLC on silica gel, 2:5 EtOAc/
petroleum ether, Rf = 0.12. Pure material was obtained by
crystallization from EtOAc/petroleum ether: mp 162-164 °C; IR
(RS)-N-[(Z)-(2-Bromophenyl)(phenyl)methylidene]-2-methyl-
2-propanesulfinamide (4g). Following the general procedure,
ketone 3g (500 mg, 1.92 mmol) was converted into sulfinylimine
4g. Purification of the crude product by column chromatogra-
phy using gradient elution from 6% EtOAc/petroleum ether to
20% EtOAc/petroleum ether afforded 4g as a yellow solid
(414 mg, 60%); analytical TLC on silica gel, 2:5 EtOAc/
petroleum ether, Rf = 0.32. Pure material was obtained by
crystallization from EtOAc/petroleum ether: mp 72-74 °C; IR
(film, cm-1) 1563 (NdC), 1086 (SO); 1H NMR (400 MHz,
CDCl3, ppm) δ 7.72-7.62 (3H, m), 7.56-7.47 (1H, m),
7.47-7.16 (5H, m), 1.33 (9H, s); 13C NMR (100 MHz, CDCl3,
ppm; a mixture of Z- and E-isomers) δ 175.9, 137.5, 136.9, 132.6,
132.4, 132.3, 132.2, 130.6, 130.1, 128.9, 128.6, 128.2, 127.1,
126.8, 125.5, 119.8, 58.7, 57.0, 22.8, 22.5. Anal. Calcd for
C17H18BrNOS: C, 56.05; H, 4.98; N, 3.84. Found: C, 56.09;
H, 4.87; N, 3.87. Optical rotation [R]20D -123.4 (c 0.99, EtOH).
(RS)-N-[(Z)-(2-Isopropylphenyl)(phenyl)methylidene]-2-meth-
yl-2-propanesulfinamide (4h). Following the general procedure,
ketone 3h (340 mg, 1.51 mmol) was converted into sulfinylimine
4h. Purification of the crude product by column chromatogra-
phy using gradient elution from 6% EtOAc/petroleum ether to
20% EtOAc/petroleum ether afforded 4h as an yellow oil (331 mg,
67%); analytical TLC on silica gel, 4:10 EtOAc/petroleum ether,
Rf = 0.44: IR (film, cm-1) 1560 (NdC), 1073 (SdO); 1H NMR
(400 MHz, CDCl3, ppm; a mixture of Z- and E-isomers) δ 7.78-
7.68 (2H, m), 7.53-7.35 (5H, m), 7.33-7.23 (1.5H, m), 7.03-6.97
(0.5H, m), 2.79-2.55 (1H, m), 1.36-1.26 (11H, m), 1.25-1.20
(1H, m), 1.02-0.95 (3H, m); 13C NMR (100 MHz, CDCl3, ppm; a
mixture of Z- and E-isomers) δ 180.8, 179.5, 146.0, 144.8, 138.3,
137.9, 135.5, 134.6, 132.4, 129.7, 129.6, 129.4, 128.7, 128.4, 126.9,
126.1, 125.6, 125.4, 56.6, 56.3, 31.6, 31.2, 24.1, 24.0, 23.9, 23.5, 22.6,
22.3; HRMS-ESI (m/z) calcd for C20H26NOS [M þ H]þ 328.1735,
found 328.1717. Optical rotation [R]20D -69.7 (c 4.73, EtOH).
(RS)-N-[(Z)-[2-(Dimethylamino)phenyl](phenyl)methylidene]-
2-methyl-2-propanesulfinamide (4i). Following the general pro-
cedure, ketone 3i (342 mg, 1.52 mmol) was converted into
sulfinylimine 4i. Purification of the crude product by column
chromatography using gradient elution from 6% EtOAc/petro-
leum ether to 40% EtOAc/petroleum ether afforded 4i as a
yellow solid (250 mg, 51%); analytical TLC on silica gel, 4:10
EtOAc/petroleum ether, Rf = 0.28. Pure material was obtained
by crystallization from EtOAc/petroleum ether: mp 76-78 °C;
IR (film, cm-1) 1533 (NdC), 1083 (SdO); 1H NMR (400 MHz,
CDCl3, ppm; a mixture of Z- and E-isomers) δ 7.88-7.75 (2H,
m), 7.54-7.46 (1H, m), 7.44-7.34 (3H, m), 7.21-7.14 (0.5H, m),
7.09-6.88 (2.5H, m), 2.81-2.65 (6H, m), 1.40-1.14 (9H, m);
13C NMR (100 MHz, CDCl3, ppm; a mixture of Z- and E-
isomers) δ 177.7, 175.4, 151.8, 150.9, 139.2, 138.0, 132.0, 131.6,
130.9, 130.8, 130.5, 129.7, 129.6, 129.3, 128.2, 127.3, 120.0,
119.3, 117.6, 117.4, 56.9, 43.3, 42.9, 23.0, 22.2. Anal. Calcd for
C19H24N2OS: C, 69.48; H, 7.36; N, 8.53. Found: C, 69.21; H,
7.38; N, 8.47. Optical rotation [R]20D -88.1 (c 1.78, EtOH).
General Procedure A for the Reduction of N-tert-Butanesulfi-
nylimines 4a-h with BH3-THF. Sulfinylimine 4 (1.0 equiv) was
dissolved in anhydrous THF (10 mL/mmol of imine 4) and
cooled to -78 οC under argon atmosphere. Borane-THF
complex (1.0 M solution in THF, 1.6 equiv) was added drop-
wise, and the resulting solution was stirred at -78 °C for 3 h,
whereupon it was quenched at -78 °C with brine (50 mL/mmol
of imine 4). After warming to room temperature, EtOAc
1
(film, cm-1) 3210 (NH), 1535 (NdC), 1080 (SdO); H NMR
(400 MHz, CDCl3, ppm) δ 9.79-9.56 (1H, m), 7.97-7.75 (2H,
m), 7.63-7.50 (1H, m), 7.49-7.40 (2H, m), 7.37-7.28 (1H, m),
7.21-7.07 (2H, m), 6.73-6.59 (2H, m), 2.99 (3H, d, J = 5.0 Hz),
1.18-1.07 (9H, m); 13C NMR (100 MHz, CDCl3, ppm; a
mixture of two rotamers (Z)-4cA and (Z)-4cB) δ 182.7, 180.4,
150.8, 150.8, 134.8, 134.4, 134.3, 134.1, 133.8, 133.7, 133.2,
133.1, 130.2, 130.0, 129.6, 129.6, 128.7, 128.2, 127.6, 127.0,
126.4, 126.3, 125.7, 125.6, 125.3, 125.2, 124.3, 119.0, 118.8,
117.6, 117.4, 112.5, 55.9, 54.5, 29.9, 29.9, 22.3. Anal. Calcd for
C22H23ClN2OS: C, 66.23; H, 5.81; N, 7.02. Found: C, 66.01; H,
5.75; N, 6.94. Optical rotation [R]20D -110.2 (c 3.80, EtOH).
(RS)-N-[(E)-(2-Amino-5-chlorophenyl)(phenyl)methylidene]-2-
methyl-2-propanesulfinamide (4d). Following the general proce-
dure, ketone 3d (500 mg, 2.16 mmol) was converted into
sulfinylimine 4d. Purification of the crude product by column
chromatography using gradient elution from 6% EtOAc/petro-
leum ether to 60% EtOAc/petroleum ether afforded 4d as a
yellow solid (555 mg, 78%); analytical TLC on silica gel, 1:1
EtOAc/petroleum ether, Rf = 0.24. Pure material was obtained
by crystallization from EtOAc/petroleum ether: mp 142-143 °C;
IR (film, cm-1) 3367 (NH2), 1461 (NdC), 1049 (SdO); 1H
NMR (400 MHz, CDCl3, ppm) δ 7.60-7.38 (3H, m), 7.34-7.08
(2H, m), 7.01-6.78 (2H, m), 6.69 (1H, d, J = 8.6 Hz), 3.99-3.51
(2H, br s), 1.26 (9H, s); 13C NMR (100 MHz, CDCl3, ppm) δ
181.9, 149.28, 136.5, 133.5, 129.4, 128.4, 127.6, 118.3, 55.7, 22.3.
Anal. Calcd for C17H19ClN2OS: C, 60.98; H, 5.72; N, 8.37.
Found: C, 61.12; H, 5.63; N, 8.18. Optical rotation [R]20
-105.3 (c 1.95, EtOH).
D
(RS)-N-[(Z)-[5-Chloro-2-(dimethylamino)phenyl](phenyl)met-
hylidene]-2-methyl-2-propanesulfinamide (4e). Following the
general procedure, ketone 3e (300 mg, 1.16 mmol) was con-
verted into sulfinylimine 4e. Purification of the crude product by
column chromatography using gradient elution from, 6%
EtOAc/petroleum ether to 40% EtOAc/petroleum ether af-
forded the desired product as a yellow foam (250 mg, 60%
yield); analytical TLC on silica gel, 2:5 EtOAc/petroleum ether,
Rf = 0.31: IR (film, cm-1) 1558 (NdC), 1081 (SdO); 1H NMR
(400 MHz, CDCl3, ppm; a mixture of Z- and E-isomers) δ
7.85-7.73 (2H, m), 7.55-7.48 (1H, m), 7.45-7.38 (2H, m), 7.32
(1H, d, J = 8.0 Hz), 7.10-6.90 (2H, m), 2.72 (6H, s), 1.40-1.17
(9H, m); 13C NMR (100 MHz, CDCl3, ppm; a mixture of Z- and
E-isomers) δ 171.8, 150.5, 149.6, 138.9, 137.3, 132.3, 131.7,
130.6, 130.3, 130.2, 129.5, 129.3, 128.8, 128.4, 124.9, 124.4,
118.8, 118.6, 57.6, 57.2, 43.2, 42.8, 23.2, 22.2; HRMS-ESI (m/z)
calcd for C19H24N2OS35Cl [M þ H]þ 363.1298, found 363.1326.
Optical rotation [R]20D -134.9 (c 1.61, EtOH).
(RS)-N-[(Z)-(2-Methoxyphenyl)(phenyl)methylidene]-2-meth-
yl-2-propanesulfinamide (4f). Following the general procedure,
ketone 3f (336 mg, 1.59 mmol) was converted into sulfinylimine
4f. Purification of the crude product by column chromatogra-
phy using gradient elution from 6% EtOAc/petroleum ether to
40% EtOAc/petroleum ether afforded 4f as a yellow solid
(394 mg, 79% yield); analytical TLC on silica gel, 2:5 EtOAc/
petroleum ether, Rf = 0.20. Pure material was obtained by
crystallization from EtOAc/petroleum ether: mp 99-101 °C; IR
1
(film, cm-1) 1560 (NdC), 1084 (SdO); H NMR (400 MHz,
2364 J. Org. Chem. Vol. 75, No. 7, 2010

Martjuga et al.
JOCArticle
C18H23ClN2OS: C, 61.54; H, 6.68; N, 7.93. Found: C, 61.59; H,
(50 mL/mmol of imine 4) was added and layers were separated.
The organic phase was washed with brine, dried over Na2SO4,
and concentrated. An aliquot of the crude product was sub-
mitted to 1H NMR and HPLC analysis to determine the
diastereoselectivity of the reduction. Diastereomerically pure
product was obtained after purification by column chromato-
graphy on silica gel.
General Procedure B for the Reduction of N-tert-Butanesulfi-
nylimines 4a-h with DIBAL. Sulfinylimine 4 (1.0 equiv) was
dissolved in anhydrous THF (5.0 mL/mmol of imine 4) and
cooled to -78 οC under argon atmosphere. Diisobutylalumi-
num hydride (1.0 M solution in hexanes, 3.0 equiv) was added
dropwise, and the resulting solution was stirred at -78 °C for 3
h, whereupon it was quenched at -78 °C with brine (12 mL/
mmol of imine 4). After warming to room temperature, EtOAc
(15 mL/mmol of imine 4) was added and layers were separated.
The organic phase was washed with brine, dried over Na2SO4,
and concentrated. An aliquot of the crude product was sub-
mitted to 1H NMR and HPLC analysis to determine the
diastereoselectivity of the reduction. Diastereomerically pure
product was obtained after purification by column chromato-
graphy on silica gel.
General Procedure C for the Reduction of N-tert-Butanesulfi-
nylimines 4a-h with NaBH4 in the Presence of Ti(OEt)4. NaBH4
(5.0 equiv) was added to a solution of Ti(OEt)4 (2.0 equiv) in
anhydrous THF (3 mL/mmol of imine 4), and the resulting
suspension was cooled to -78 °C under argon atmosphere. A
solution of sulfinylimine 4 (1.0 equiv) in anhydrous THF (3 mL/
mmol of imine 4) was added dropwise at -78 °C, and the
mixture was gradually warmed to room temperature and left
to stir for 12 h, whereupon it was poured into a mixture of brine
(20 mL/mmol of imine 4) and EtOAc (20 mL/mmol of imine 4).
The resulting slurry was filtered throught a plug of Celite (3 ꢀ
5 cm), and the filter cake was washed with EtOAc (50 mL/mmol
of imine 4). Organic layer from the filtrate was washed with
brine, dried over Na2SO4, and concentrated. An aliquot of the
crude product was submitted to 1H NMR and HPLC analysis to
determine the diastereoselectivity of the reduction. Diastereo-
merically pure product was obtained after purification by
column chromatography on silica gel.
General Procedure D for the Reduction of N-tert-Butanesulfi-
nylimines 4a-h with NaBH4. Sodium borohydride (NaBH4)
(5.0 equiv) was added portionwise to a solution of the imine
(1.0 equiv) in anhydrous THF (5 mL/mmol of imine 4) at room
temperature. After stirring for 3 h, the suspension was poured
into a mixture of brine (30 mL/mmol of imine 4) and EtOAc (30
mL/mmol of imine 4). Layers were separated, and the organic
phase was dried over anhydrous Na2SO4 and concentrated. An
6.55; N, 7.93. Optical rotation (99% de, HPLC/csp) [R]20
D
-65.8 (c 3.65, EtOH). HPLC/csp assay: Daicel CHIRALPAK
IA, 25 cm ꢀ 4.6 mm i.d., mobile phase 6% IPA/94% Hex, flow
rate 0.9 mL/min, detector UV 254 nm, retention time 7.5 min
((R,RS)-5a) major and 10.7 min ((S,RS)-5a) minor.
(RS)-N-[(R)-[5-Chloro-2-(methylamino)phenyl](2-naphthyl)met-
hyl]-2-methyl-2-propanesulfinamide (5b). Following the general
procedure B for the reduction, sulfinylimine 4b (528 mg, 1.32 mmol)
was converted into 5b. Purification of the crude product by column
chromatography using gradient elution from 6% EtOAc/petro-
leum ether to 20% EtOAc/petroleum ether afforded 5b as a white
solid (386 mg, 73% yield); analytical TLC on silica gel, 2:5 EtOAc/
petroleum ether, Rf = 0.20. Pure material was obtained by crystal-
lization from EtOAc/petroleum ether: mp 179-181 °C; IR (film,
cm-1) 3366 (NH), 1049 (SdO); 1H NMR (400 MHz, CDCl3, ppm)
δ 7.97 (1H, s), 7.92-7.83 (3H, m), 7.57-7.50 (2H, m), 7.44 (1H, d,
J=8.6Hz), 7.19(1H, dd,J= 8.6, 2.4 Hz), 6.67-6.63 (2H, m), 5.76
(1H, s), 5.13 (1H, br s), 3.68 (1H, s), 2.93 (3H, s), 1.30 (9H, s); 13
C
NMR (100 MHz, CDCl3, ppm) δ 145.0, 137.3 133.2, 133.0, 129.2,
128.7, 128.5, 128.1, 127.8, 127.1, 126.7, 126.3, 126.3, 126.2, 121.0,
111.8, 56.7, 55.8, 30.5, 22.6. Anal. Calcd for C22H25ClN2OS: C,
65.90; H, 6.28; N, 6.99. Found: C, 65.95; H, 6.19; N, 6.90. Optical
rotation (99% de, HPLC/csp) [R]20D -58.2 (c 1.94, EtOH). HPLC/
csp assay: Daicel CHIRALPAK IA, 25 cm ꢀ 4.6 mm i.d., mobile
phase 7% IPA/93% Hex, flow rate 0.9 mL/min, detector UV
254 nm, retention time 10.2 min ((R,RS)-5b) major and 12.4 min
((S,RS)-5b) minor.
(RS)-N-[(R)-[5-Chloro-2-(methylamino)phenyl](1-naphthyl)me-
thyl]-2-methyl-2-propanesulfinamide (5c). Following the general
procedure B for the reduction, sulfinylimine 4c (848 mg, 2.13 mmol)
was converted into 5c. Purification of the crude product by column
chromatography using gradient elution from 6% EtOAc/
petroleum ether to 50% EtOAc/petroleum ether afforded 5c as a
white solid (801 mg, 94% yield); analytical TLC on silica gel, 2:5
EtOAc/petroleum ether, Rf = 0.30. Pure material was obtained by
crystallization from Et2O: mp 153-155 °C; IR (film, cm-1) 3350
(NH), 1058 (SdO); 1H NMR (400 MHz, CDCl3, ppm) δ
7.92-7.84 (3H, m), 7.61-7.55 (1H, m), 7.52-7.49 (1H, m),
7.48-7.43 (1H, m), 7.40-7.35 (1H, m), 7.15 (1H, dd, J = 8.6,
2.4 Hz), 6.70 (1H, d, J = 8.6 Hz), 6.47 (1H, d, J = 2.4 Hz), 6.23
(1H, d, J = 1.4 Hz), 5.51 (1H, d, J = 4.0 Hz), 3.50 (1H, d, J = 1.4
Hz), 3.01 (3H, d, J = 4.0 Hz), 1.31 (9H, s); 13C NMR (100 MHz,
CDCl3, ppm) δ 144.9,135.7, 133.8, 131.0, 129.4, 128.7, 128.5, 128.3,
126.5, 126.5, 125.8, 125.4, 125.0, 123.4, 120.9, 112.0, 55.8, 53.2, 30.6,
22.6. Anal. Calcd for C22H25ClN2OS: C, 65.90; H, 6.28; N, 6.99.
Found: C, 65.70; H, 6.29; N, 6.74. Optical rotation (99% de,
HPLC/csp) [R]20D þ6.4 (c 1.24, EtOH). HPLC/csp assay: Daicel
CHIRALPAK IA, 25 cm ꢀ 4.6 mm i.d., mobile phase 7% IPA/
93% Hex, flow rate 0.9 mL/min, detector UV 254 nm, retention
time 7.5 min ((R,RS)-5c) major and 10.9 min ((S,RS)-5c) minor.
(RS)-N-[(R)-(2-Amino-5-chlorophenyl)(phenyl)methyl]-2-methyl-
2-propanesulfinamide (5d). Following the general procedure B
for the reduction, sulfinylimine 4d (555 mg, 1.66 mmol) was
converted into 5d. Purification of the crude product by column
chromatography using gradient elution from 6% EtOAc/
petroleum ether to 60% EtOAc/petroleum ether afforded 5d
as a white solid (428 mg, 77% yield); analytical TLC on silica gel,
1:1 EtOAc/petroleum ether, Rf = 0.26. Pure material was
obtained by crystallization from Et2O: mp 156-158 °C; IR
1
aliquot of the crude product was submitted to H NMR and
HPLC analysis to determine the diastereoselectivity of the
reduction. Diastereomerically pure product was obtained after
purification by column chromatography on silica gel.
(RS)-N-[(R)-[5-Chloro-2-(methylamino)phenyl](phenyl)methyl]-
2-methyl-2-propanesulfinamide (5a). Following the general pro-
cedure B for the reduction, sulfinylimine 4a (555 mg, 1.59 mmol)
was converted into 5a. Purification of the crude product by
column chromatography using gradient elution from 6%
EtOAc/petroleum ether to 50% EtOAc/petroleum ether af-
forded 5a as a white solid (526 mg, 95% yield); analytical TLC
on silica gel, 2:5 EtOAc/petroleum ether, Rf = 0.19. Pure
material was obtained by crystallization from EtOAc/petroleum
ether: mp 144-146 °C; IR (film, cm-1) 3368 (NH), 1052 (SdO);
1H NMR (400 MHz, CDCl3, ppm) δ 7.42-7.32 (5H, m), 7.17
(1H, dd, J = 8.6, 2.6 Hz), 6.62 (1H, d, J = 9.0 Hz), 6.60 (1H, d,
J = 2.6 Hz), 5.58 (1H, d, J = 2.6 Hz), 5.14-4.99 (1H, br s), 3.56
(1H, d, J = 1.6 Hz), 2.90 (3H, s), 1.27 (9H, s); 13C NMR (100
MHz, CDCl3, ppm) δ 144.9, 139.8, 129.0, 128.6, 128.6, 128.2,
128.0, 126.9, 120.9, 111.8, 56.6, 55.8, 30.4, 22.5. Anal. Calcd for
1
(film, cm-1) 3350 (NH2), 3234 (NH), 1043 (SdO); H NMR
(400 MHz, CDCl3, ppm) δ 7.46-7.30 (5H, m), 7.06 (1H, dd, J =
8.6, 2.4 Hz), 6.67 (1H, d, J = 2.5 Hz), 6.65 (1H, d, J = 8.6 Hz),
5.61 (1H, d, J =2.5Hz), 4.58-4.18 (2H, br s),3.67 (1H, d, J = 2.0
Hz), 1.27 (9H, s); 13C NMR (100 MHz, CDCl3, ppm) δ 142.8,
139.7, 129.0, 128.6, 128.6, 128.1, 127.9, 127.5, 122.6, 117.9, 57.0,
55.8, 22.6. Anal. Calcd for C17H21ClN2OS: C, 60.61; H, 6.28;
N, 8.32. Found: C, 60.49; H, 6.35; N, 8.08. Optical rotation
J. Org. Chem. Vol. 75, No. 7, 2010 2365

Martjuga et al.
JOCArticle
(99% de, HPLC/csp) [R]20 -72.9 (c 2.85, EtOH). HPLC/csp
rate 0.9 mL/min, detector UV 210 nm, retention time 14.6 min
((R,RS)-5g) minor and 11.2 min ((S,RS)-5g) major.
D
assay: Daicel CHIRALPAK IA, 25 cm ꢀ 4.6 mm i.d., mobile
phase 20% IPA/80% Hex/0.1% DEA, flow rate 0.9 mL/min,
detector UV 254 nm, retention time 9.1 min ((S,RS)-5d) minor and
10.3 min ((R,RS)-5d) major.
(RS)-N-[(S)-(2-Isopropylphenyl)(phenyl)methyl]-2-methyl-2-pro-
panesulfinamide (5h). Following the general procedure C for the
reduction, sulfinylimine 4h (328 mg, 1.0 mmol) was converted
into 5h. Purification of the crude product by column chroma-
tography using gradient elution from 6% EtOAc/petroleum
ether to 40% EtOAc/petroleum ether afforded 5h as a white
solid (247 mg, 75%); analytical TLC on silica gel, 2:5 EtOAc/
petroleum ether, Rf = 0.28. Pure material was obtained by
crystallization from Et2O: mp 109-111 °C; IR (film, cm-1) 3210
(RS)-N-[(S)-[5-Chloro-2-(dimethylamino)phenyl](phenyl)met-
hyl]-2-methyl-2-propanesulfinamide (5e). Following the general
procedure C for the reduction, sulfinylimine 4e (150 mg, 0.41 mmol)
was converted into 5e. Purification of the crude product by column
chromatography using gradient elution from 6% EtOAc/
petroleum ether to 55% EtOAc/petroleum ether afforded 5e as a
white solid (127 mg, 84% yield yield); analytical TLC on silica
gel, 4:10 EtOAc/petroleum ether, Rf = 0.22. Pure material was
obtained by crystallization from petroleum ether: mp: 117-119 °C;
1
(NH), 1062 (SdO); H NMR (400 MHz, CDCl3, ppm) δ 7.53
(1H, dd, J = 7.8, 1.2 Hz), 7.36-7.05 (8H, m), 6.02 (1H, d, J =
3.0 Hz), 3.63 (1H, d, J = 3.0 Hz), 3.23 (1H, septet, J = 7.0 Hz),
1.25 (3H, d, J = 7.0 Hz), 1.23 (9H, s), 1.0 (3H, d, 7.0 Hz); 13C
NMR (100 MHz, CDCl3, ppm) δ 146.8, 142.6, 137.5, 128.8,
127.9, 127.79, 127.81, 127.6, 125.7, 57.7, 55.8, 28.4, 24.2, 23.4,
22.7. Anal. Calcd for C20H27NOS: C, 72.90; H, 8.26; N, 4.25.
Found: C, 72.84; H, 8.37; N, 4.18. Optical rotation (99% de,
IR (film, cm-1) 3166 (NH), 1045 (SdO); H NMR (400 MHz,
1
CDCl3, ppm) δ 7.47 (1H, d, J = 2.6 Hz), 7.43-7.34 (2H, m),
7.35-7.26 (2H, m), 7.25-7.15 (2H, m), 7.11 (1H, d, J = 8.6 Hz),
6.24 (1H, d, J = 3.0 Hz), 3.87 (1H, d, J = 3.0 Hz), 2.53 (6H, s), 1.23
(9H, s); 13C NMR (100 MHz, CDCl3, ppm) δ 151.7, 142.4, 139.4,
129.7, 128.8, 128.7, 128.2, 127.6, 127.4, 123.0, 56.4, 55.9, 45.7, 22.6.
Anal. Calcd for C19H25ClN2OS: C, 62.53; H, 6.91; N, 7.68. Found:
C, 62.21; H, 6.89; N, 7.57. Optical rotation (99% de, HPLC/csp)
[R]20D -24.2 (c 1.34, EtOH). HPLC/csp assay: Daicel CHIRAL-
PAK IC, 25 cm ꢀ 4.6 mm i.d., mobile phase 3% IPA/97% Hex,
flow rate 0.9 mL/min, detector UV 210 nm, retention time 13.6 min
((S,RS)-5e) major and 21.3 min ((R,RS)-5e) minor.
HPLC/csp) [R]20 -57.1 (c 0.85, EtOH). HPLC/csp assay:
D
Daicel CHIRALPAK IC, 25 cm ꢀ 4.6 mm i.d., mobile phase
2% IPA/98% Hex, flow rate 0.9 mL/min, detector UV 210 nm,
retention time 17.9 min ((S,RS)-5h) major and 18.9 min ((R,RS)-
5h) minor.
General Procedure for the Alkylation of N-tert-Butanesulfiny-
lamides 5a-e. Sulfinylamide 5 (1.0 equiv) was dissolved in
anhydrous DMF (3 mL/mmol of amide 5) and cooled to -20 °C
under argon atmosphere. A solution of LiHMDS in THF (1 M
solution in THF, 1.0 equiv) was added dropwise, and the yellow
solution was stirred at -20 °C for 1 h, whereupon neat MeI (2.0
equiv) was added. After warming to room temperature and stirring
for 2 h, the mixture was diluted with water (30 mL/mmol of amide
5) and extracted with MeOtBu. Combined organic extracts were
dried (Na2SO4) and concentrated, and the residue was purified by
column chromatography on silica gel.
(RS)-N-[(R)-[5-Chloro-2-(methylamino)phenyl](phenyl)methyl-
N,2-dimethyl-2-propanesulfinamide (6a). Following the general
procedure for the alkylation, sulfinylamide 5a (543 mg, 1.55 mmol)
was converted into 6a. Purification of the crude product by column
chromatography using gradient elution from 6% EtOAc/
petroleum ether to 20% EtOAc/petroleum ether afforded 6a as a
white solid (527 mg, 93% yield); analytical TLC on silica gel, 2:5
EtOAc/petroleum ether, Rf = 0.20. Pure material was obtained by
crystallization from EtOAc/petroleum ether: mp 95-97 °C; IR
(film, cm-1) 3393 (NH), 1060 (SdO); 1H NMR (400 MHz, CDCl3
ppm) δ 7.38-7.27 (5H, m), 7.20 (1H, dd, J = 8.7, 2.5 Hz), 7.08
(1H, d, J = 2.6 Hz), 6.59 (1H, d, J = 8.7 Hz), 5.68 (1H, s), 3.73
(1H, d, J = 4.7 Hz), 2.74 (3H, d, J = 5.2 Hz), 2.61 (3H, s), 1.12
(9H, s); 13C NMR (100 MHz, CDCl3 ppm) δ 145.3, 138.0, 129.4,
128.7, 128.6, 128.3, 128.0, 126.3, 121.7, 111.7, 62.0, 58.6, 33.5, 30.7,
23.3. Anal. Calcd for C19H25ClN2OS: C, 62.53; H, 6.91; N, 7.68.
Found: C, 62.57; H, 6.77; N, 7.53. Optical rotation [R]20D -42.4 (c
3.08, EtOH).
(RS)-N-[(R)-[5-Chloro-2-(methylamino)phenyl](2-naphthyl)met-
hyl]-N,2-dimethyl-2-propanesulfinamide (6b). Following the gen-
eral procedure for the alkylation, sulfinylamide 5b (1.0 g, 2.49 mmol
was converted into 6b. Purification of the crude product by column
chromatography using gradient elution from 6% EtOAc/
petroleum ether to 50% EtOAc/petroleum ether afforded 6b as a
white solid (800 mg, 77% yield); analytical TLC on silica gel, 2:5
EtOAc/petroleum ether, Rf = 0.20 Pure material was obtained by
crystallization from EtOAc/petroleum ether: mp 88-90 °C; IR
(film, cm-1) 3412 (NH), 1060 (SdO); 1H NMR (400 MHz, CDCl3
ppm) δ 7.86-7.78 (3H, m), 7.76 (1H, s), 7.55-7.44 (3H, m), 7.23
(1H, dd J = 8.6, 2.6 Hz), 7.16 (1H, d, J = 2.6 Hz), 6.61 (1H, d, J =
8.6 Hz), 5.87 (1H, s), 3.80-3.65 (1H, br s), 2.73 (3H, s), 2.67 (3H, s),
1.15 (9H, s); 13C NMR (100 MHz, CDCl3, ppm) δ 145.3, 135.4,
133.2, 132.9, 128.7, 128.6, 128.3, 128.3, 128.2, 127.6, 127.2, 126.4,
(RS)-N-[(S)-(2-Methoxyphenyl)(phenyl)methyl]-2-methyl-2-
propanesulfinamide (5f). Following the general procedure A for
the reduction, sulfinylimine 4f (188 mg, 0.60 mmol) was con-
verted into 5f. Purification of the crude product by column
chromatography using gradient elution from 3% i-PrOH/
petroleum ether to 15% i-PrOH/petroleum ether afforded 5f
as a white solid (151 mg, 80% yield); analytical TLC on silica gel,
2:5 EtOAc/petroleum ether, Rf = 0.19. Pure material was
obtained by crystallization from 5% i-PrOH/hexane: mp
133-135 °C; IR (film, cm-1) 3228 (NH), 1029 (SdO); 1H
NMR (400 MHz, CDCl3, ppm) δ 7.44 (1H, dd, J = 7.6, 1.8
Hz), 7.39-7.32 (2H, m), 7.31-7.17 (4H, m), 6.97-6.93 (1H, m),
6.84 (1H, dd, J = 8.2, 1.0 Hz), 6.01 (1H, d, J = 3.8 Hz), 3.80 (1H,
d, J = 3.8 Hz), 3.75 (3H, s), 1.22 (9H, s); 13C NMR (100 MHz,
CDCl3, ppm) δ 157.0, 142.5, 128.5, 128.5, 128.2, 127.4, 127.3,
120.4, 110.9, 56.6, 55.9, 55.4, 22.7. Anal. Calcd for C18H23NO2S:
C, 68.10; H, 7.30; N, 4.41. Found: C, 67.66; H, 7.23; N, 4.28.
HRMS-ESI (m/z) calcd for C18H24NO2S35 [M þ H]þ 318.1528,
found 318.1558. Optical rotation (99% de, HPLC/csp) [R]20
D
-51.9 (c 2.25, EtOH). HPLC/csp assay: Daicel CHIRALPAK
IA, 25 cm ꢀ 4.6 mm i.d., mobile phase 5% IPA/95% Hex/ flow
rate 0.9 mL/min, detector UV 254 nm, retention time 5.8 min
((S,RS)-5f) major and 7.1 min ((R,RS)-5f) minor.
(RS)-N-[(S)-(2-Bromophenyl)(phenyl)methyl]-2-methyl-2-pro-
panesulfinamide (5g). Following the general procedure B for the
reduction, sulfinylimine 4g (500 mg, 1.37 mmol) was converted
into 5g. Purification of the crude product by column chroma-
tography using gradient elution from 6% EtOAc/petroleum
ether to 45% EtOAc/petroleum ether afforded 5g as a white
solid (466 mg, 93% yield); analytical TLC on silica gel, 2:5
EtOAc/petroleum ether, Rf = 0.23. Pure material was obtained
by crystallization from EtOAc/petroleum ether: mp 131-
133 °C; IR (film, cm-1) 3217 (NH), 1039(SdO); 1H NMR
(400 MHz, CDCl3, ppm) δ 7.53 (1H, d, J = 8.0 Hz), 7.47 (1H,
d, J = 8.0 Hz), 7.36-7.13 (6H, m), 7.10-7.04 (1H, m), 6.04 (1H,
d, J = 3.0 Hz), 3.68 (1H, d, J = 3.0 Hz), 1.18 (9H, s); 13C NMR
(100 MHz, CDCl3, ppm) δ 141.0 140.4, 133.3, 129.5, 129.0,
128.8, 127.9, 127.8, 127.4, 124.0, 61.2, 56.1, 22.7. Anal. Calcd for
C17H20BrNOS: C, 55.74; H, 5.50; N, 3.82. Found: C, 55.74; H,
5.37; N, 3.96. Optical rotation (99% de, HPLC/csp) [R]20
-35.1 (c 0.97, EtOH). HPLC/csp assay: Daicel CHIRALPAK
IA, 25 cm ꢀ 4.6 mm i.d., mobile phase 3% IPA/97% Hex/, flow
D
2366 J. Org. Chem. Vol. 75, No. 7, 2010

Martjuga et al.
JOCArticle
126.3, 126.3, 121.8, 117.8, 61.3, 58.7, 34.1, 30.7, 23.3. Anal. Calcd
for C23H27ClN2OS: C, 66.57; H, 6.56; N, 6.75. Found: C, 66.37; H,
6.60; N, 6.57. Optical rotation [R]20D -35.6 (c 1.36, EtOH).
(RS)-N-[(R)-[5-Chloro-2-(methylamino)phenyl](1-naphthyl)met-
hyl]-N,2-dimethyl-2-propanesulfinamide (6c). Following the gen-
eral procedure for the alkylation, sulfinylamide 5c (640 mg,
1.60 mmol was converted into 6c. Purification of the crude
product by column chromatography using gradient elution
from 6% EtOAc/petroleum ether to 20% EtOAc/petroleum
ether afforded 6c as a white solid (533 mg, 80% yield); analytical
TLC on silica gel, 2:5 EtOAc/petroleum ether, Rf = 0.20. Pure
material was obtained by crystallization from EtOAc/petroleum
ether: mp 168-170 °C; IR (film, cm-1) 3392 (NH), 1040 (SdO);
1H NMR (400 MHz, CDCl3 ppm) δ 7.86 (2H, dd, J = 8.6, 8.6
Hz), 7.76 (1H, d, J = 7.4 Hz), 7.60 (1H, d, J = 8.6 Hz), 7.54 (1H,
dd, J = 7.4 Hz), 7.48-7.38 (2H, m), 7.16 (1H, dd, J = 8.5, 2.4
Hz), 6.68 (1H, d, J = 6.6 Hz), 6.67 (1H, s), 6.31 (1H, s), 4.41 (1H,
q, J = 5.0 Hz), 2.91 (3H, d, J = 5.0 Hz), 2.68 (3H, s), 1.18 (9H,
s); 13C NMR (100 MHz, CDCl3 ppm) δ 145.8, 135.1, 133.9,
131.0, 129.9, 128.9, 128.8, 128.6, 126.6, 125.9, 125.8, 125.1,
123.3, 121.9, 112.1, 64.7, 58.8, 30.9, 30.5, 24.1. Anal. Calcd for
C23H27ClN2OS: C, 66.57; H, 6.56; N, 6.75. Found: C, 66.48; H,
6.54; N, 6.70. Optical rotation [R]20D þ97.9 (c 1.89, EtOH).
(RS)-N-[(R)-(2-Amino-5-chlorophenyl)(phenyl)methyl]-N,2-dim-
ethyl-2-propanesulfinamide (6d). Following the general proce-
dure for the alkylation, sulfinylamide 5d (206 mg, 0.61 mmol)
was converted into 6d. Purification of the crude product by
column chromatography using gradient elution from 6%
EtOAc/petroleum ether to 58% EtOAc/petroleum ether af-
forded 6d as a white solid (180 mg, 80% yield); analytical TLC
on silica gel, 1:1 EtOAc/petroleum ether, Rf = 0.30. Pure
material was obtained by crystallization from Et2O/petroleum
ether: mp 88-90 °C; IR (film, cm-1) 3341 (NH2), 1056 (SdO);
1H NMR (400 MHz, CDCl3, ppm) δ 7.39-7.27 (5H, m), 7.13
(1H, d, J = 2.4 Hz), 7.09 (1H, dd, J = 8.4, 2.4 Hz), 6.61 (1H, d,
J = 8.4 Hz), 5.75 (1H, s), 3.61 (2H, s), 2.63 (3H, s), 1.15 (9H, s);
13C NMR (100 MHz, CDCl3 ppm) δ 142.9, 137.9, 129.4, 128.8,
128.7, 128.2, 128.0, 127.0, 123.3, 117.9, 61.8, 58.7, 33.6, 23.3;
HRMS-ESI (m/z) calcd for C18H24N2OS35Cl [M þ H]þ
over Na2SO4, and concentrated (rotary evaporator) to afford the
1,3-diamine.
2-[(R)-Amino(phenyl)methyl]-4-chloro-N-methylaniline (1a). Fol-
lowing the general procedure, cleavage of the chiral auxiliary in
sulfinylamide 5a (500 mg, 1.43 mmol) afforded 1,3-diamine 1a as a
white solid (353 mg, 99% yield); analytical TLC on silica gel, 1:1
EtOAc/petroleum ether, Rf = 0.48. Pure material was obtained by
crystallization from petroleum ether: mp 57-59 °C; IR (film, cm-1);
1
3374 (NH), 3307 (NH); H NMR (400 MHz, CDCl3, ppm) δ
7.39-7.24 (5H, m), 7.12 (1H, dd, J = 8.8, 2.6 Hz), 6.85 (1H, d, J =
2.6Hz), 6.52(1H, d,J=8.8Hz), 5.11(1H, s), 2.78(3H, s), 1.76(2H,
br s); 13C NMR (100 MHz, CDCl3, ppm) δ 0.8, 143.3, 129.6, 128.7,
128.0, 127.9, 127.4, 126.9, 120.9, 111.3, 57.6, 30.4. Anal. Calcd for
C14H15ClN2: C, 68.15; H, 6.13; N, 11.35. Found: C, 68.21; H, 6.09;
N, 11.36. Optical rotation (99% ee, HPLC/csp) [R]20D -31.1 (c3.30,
EtOH). HPLC/csp assay: Daicel CHIRALPAK IB, 25 cm ꢀ 4.6
mm i.d., mobile phase 1% IPA/99% Hex/0.1% DEA, flow rate 0.9
mL/min, detector UV 254 nm, retention time 13.3 min ((R)-1a)
major and 14.6 min ((S)-1a) minor.
2-[(R)-Amino(2-naphthyl)methyl]-4-chloro-N-methylaniline (1b).
Following the general procedure, cleavage of the chiral auxiliary
in sulfinylamide 5b (250 mg, 0.62 mmol) afforded 1,3-diamine 1b
as a white solid (184 mg, 99% yield); analytical TLC on silica gel,
1:1 EtOAc/petroleum ether, Rf = 0.56. Pure material was
obtained by crystallization from Et2O/petroleum ether: mp
118-120 °C; IR (film, cm-1) 3301 (NH); 1H NMR (400 MHz,
CDCl3, ppm) δ 7.89-7.81 (4H, m), 7.56-7.47 (2H, m), 7.42 (1H,
dd, J = 8.6, 1.4 Hz), 7.44-7.39 (1H, m), 7.19-7.14 (1H, m),
6.95-6.91 (1H, m), 6.57 (1H, d, J = 8.6 Hz), 5.29 (1H, s), 2.80
(3H, s), 1.91 (2H, br s); 13C NMR (100 MHz, CDCl3, ppm) δ
146.8, 140.7, 133.3, 132.8, 129.4, 128.4, 128.1, 128.0, 127.9,
127.7, 126.2, 125.9, 125.5, 125.0, 121.0, 111.4, 57.6, 30.5. Anal.
Calcd for C18H17ClN2: C, 72.84; H, 5.77; N, 9.44. Found:
C,72.55; H, 5.82; N, 9.22. Optical rotation [R]20D þ8.1 (c 1.88,
EtOH).
2-[(R)-Amino(1-naphthyl)methyl]-4-chloro-N-methylaniline (1c).
Following the general procedure, cleavage of the chiral auxiliary
in sulfinylamide 5c (226 mg, 0.56 mmol) afforded 1,3-diamine 1c
as a white solid (166 mg, 99% yield); analytical TLC on silica gel,
1:1 EtOAc/petroleum ether, Rf = 0.60. Pure material was
obtained by crystallization from petroleum ether: mp 141-
142 °C; IR (film, cm-1) 3384 (NH), 3309 (NH); 1H NMR (400
MHz, CDCl3, ppm) δ 7.93-7.89 (1H, m), 7.87-7.82 (2H, m),
7.58-7.41 (4H, m), 7.14 (1H, dd, J = 8.6, 2.4 Hz), 6.67 (1H, d,
J = 2.4 Hz), 6.64 (1H, d, J = 8.6 Hz), 5.84 (1H, s), 5.49 (1H, br
s), 2.87 (3H, s), 1.82 (2H, br s); 13C NMR (100 MHz, CDCl3) δ
146.7, 139.4, 133.8, 131.0, 129.9, 128.9, 128.2, 128.0, 127.6,
126.4, 125.8, 125.4, 123.7, 123.4, 121.4, 111.4, 52.6, 30.6. Anal.
Calcd for C18H17ClN2: C, 72.84; H, 5.77; N, 9.44. Found: C,
351.1298, found 351.1277. Optical rotation [R]20 -44.9
D
(c 1.33, EtOH).
(RS)-N-[(S)-[5-Chloro-2-(dimethylamino)phenyl](phenyl)methyl]-
N,2-dimethyl-2-propanesulfinamide (6e). Following the general
procedure for the alkylation, sulfinylamide 5e (300 mg, 0.82 mmol
was converted into 6e. Purification of the crude product by column
chromatography using gradient elution from 6% EtOAc/petro-
leum ether to 36% EtOAc/petroleum ether afforded 6e as a white
solid (249 mg, 80% yield); analytical TLC on silica gel, 1:1 EtOAc/
petroleum ether, Rf = 0.48. Pure material was obtained by crystal-
lization from Et2O/petroleum ether: mp 116-117 °C; IR (film,
cm-1) 1073 (SdO); 1HNMR(400MHz, CDCl3 ppm) δ7.35-7.17
(7H, m), 7.12 (1H, d, J = 8.6 Hz), 6.32 (1H, s), 2.55 (6H, s), 2.52
(3H, s), 1.09 (9H, s); 13C NMR (100 MHz, CDCl3 ppm) δ 151.6,
139.7, 137.9, 129.6, 129.2, 128.5, 128.5, 128.3, 127.3, 122.2, 65.7,
65.7, 58.6, 45.6, 28.2, 23.9. Anal. Calcd for C20H27ClN2OS: C,
63.39; H, 7.18; N, 7.39. Found: C, 63.37; H, 7.18; N, 7.26. Optical
rotation [R]20D þ41.8 (c 2.79, EtOH).
72.88; H, 5.78; N, 9.38. Optical rotation [R]20 -28.7 (c 1.86,
D
EtOH).
2-[(R)-Amino(phenyl)methyl]-4-chloroaniline (1d). Following
the general procedure, cleavage of the chiral auxiliary in sulfi-
nylamide 5d (376 mg, 1.09 mmol) afforded 1,3-diamine 1d as a
yellow oil (253 mg, 99% yield); analytical TLC on silica gel, 1:1
EtOAc/petroleum ether, Rf = 0.40: IR (film, cm-1) 3436 (NH),
3309 (NH); 1H NMR (400 MHz, CDCl3, ppm) δ 7.41-7.27 (5H,
m), 7.03 (1H, dd, J = 8.4, 2.4 Hz), 7.01 (1H, d, J = 2.4 Hz), 6.58
(1H, d, J = 8.4 Hz), 5.16 (1H, s), 4.35 (2H, br s), 1.86 (2H, br s);
13C NMR (100 MHz, CDCl3, ppm) δ 143.7, 142.2, 129.7, 128.8,
128.0, 127.6, 126.9, 123.1, 118.0, 57.1; HRMS-ESI (m/z) calcd
for C13H14N235Cl [M þ H]þ 233.0846, found 233.0785. Optical
rotation [R]20D -15.6 (c 2.35, EtOH).
2-[(S)-Amino(phenyl)methyl]-4-chloro-N,N-dimethylaniline (1e).
Following the general procedure, cleavage of the chiral auxi-
liary in sulfinylamide 5e (159 mg, 0.44 mmol) afforded 1,
3-diamine 1e as a yellow oil (115 mg, 99% yield); analytical
TLC on silica gel, 1:1 EtOAc/petroleum ether, Rf = 0.48: IR
General Procedure for Cleavage of N-tert-Butanesulfinyl Chir-
al Auxiliary. Sulfinylamide 6 (1.0 equiv) was dissolved in a 1:1
mixture of anhydrous 1,4-dioxane and anhydrous MeOH (6 mL/
mmol of amide 6), and anhydrous HCl in dioxane (4 M solution in
dioxane, 4.0 equiv) was added. After stirring at room temperature
for 1 h, all volatiles were removed in vacuo, and the residue was
dissolved in water (20 mL/mmol of amide 6) and extracted with
EtOAc (10 mL/mmol of amide 6). Water layer was basified to
pH = 8 with aqueous concentrated NH4OH and extracted with
EtOAc. Combined organic extracts were washed with brine, dried
J. Org. Chem. Vol. 75, No. 7, 2010 2367

Martjuga et al.
JOCArticle
(film, cm-1) 3374 (NH), 3299 (NH); 1H NMR (400 MHz, CDCl3,
ppm) δ 7.41-7.38 (2H, m), 7.35-7.30 (3H, m), 7.25-7.21 (1H,
m), 7.18 (1H, dd, J = 8.6, 2.4 Hz), 7.12 (1H, d, J = 8.6 Hz), 5.72
(1H, s), 2.60 (6H, s), 1.88 (2H, br s); 13C NMR (100 MHz, CDCl3,
ppm) δ 150.9, 144.9, 143.5, 129.8, 128.3, 128.1, 127.6, 127.5,
127.0, 126.7, 122.4, 53.6, 45.8; HRMS-ESI (m/z) calcd for
C15H18N235Cl [M þ H]þ 261.1159, found 261.1171. Optical
rotation [R]20D þ2.1 (c 2.33, EtOH).
petroleum ether: mp 97-99 °C; IR (film, cm-1) 3273 (NH), 3059
(NH); 1H NMR (400 MHz, CDCl3, ppm) δ 7.96-7.88 (2H, m),
7.83 (1H, J = 8.0 Hz), 7.55-7.45 (3H, m), 7.41-7.38 (1H, m),
7.16 (1H, dd, J = 8.6, 2.6 Hz), 6.85 (1H, d, J = 2.6 Hz), 6.64 (1H,
d, J = 8.6 Hz), 6.00-5.85 (1H, br s), 5.46 (1H, s), 2.85 (3H, s),
2.50 (3H, s), 1.78-1.53 (1H, br s); 13C NMR (100 MHz, CDCl3,
ppm) δ 147.5, 135.6, 134.2, 131.6, 129.1, 128.6, 128.2, 127.9,
127.4, 126.5, 125.6, 125.5, 125.0, 122.8, 121.2, 111.3, 62.4, 34.9,
30.6. Anal. Calcd for C19H19ClN2: C, 73.42; H, 6.16; N, 9.01.
Found: C, 73.35; H, 6.12; N, 9.01. Optical rotation (99% ee,
4-Chloro-N-methyl-2-[(R)-(methylamino)(phenyl)methyl]aniline
(2a). Following the general procedure, cleavage of the chiral
auxiliary in sulfinylamide 6a (1.2 g, 3.27 mmol) afforded 1,3-
diamine 2a as a white solid (853 mg, 99% yield); analytical TLC
on silica gel, 1:1 EtOAc/petroleum ether, Rf = 0.52. Pure
material was obtained by crystallization from petroleum ether:
mp 93-95 °C; IR (film, cm-1) 3274 (NH); 1H NMR (400 MHz,
CDCl3, ppm) δ 7.37-7.29 (4H, m), 7.29-7.21 (1H, m), 7.09 (1H,
dd, J = 8.8, 2.6 Hz), 6.92 (1H, d, J = 2.6 Hz), 6.49 (1H, d, J =
8.8 Hz), 6.21-6.03 (1H, br s), 4.66 (1H, s), 2.77 (3H, s), 2.38 (3H,
s), 1.65-1.36 (1H, br s); 13C NMR (100 MHz, CDCl3, ppm) δ
147.2, 141.3, 128.7, 128.6, 127.9, 127.4, 127.4, 127.3, 120.3,
111.2, 68.0, 34.7, 30.4. Anal. Calcd for C15H17ClN2: C, 69.09;
H, 6.57; N, 10.74. Found: C, 69.10; H, 6.58; N, 10.74. Optical
HPLC/csp) [R]20 -95.7 (c 2.78, EtOH). HPLC/csp assay:
D
Daicel CHIRALPAK IA, 25 cm ꢀ 4.6 mm i.d., mobile phase
1% IPA/99% Hex, flow rate 0.9 mL/min, detector UV 254 nm,
retention time 8.5 min ((R)-2c) major and 12.8 min ((S)-2c)
minor.
4-Chloro-2-[(R)-(methylamino)(phenyl)methyl]aniline (2d). Fol-
lowing the general procedure, cleavage of the chiral auxiliary in
sulfinylamide 6d (140 mg, 0.31 mmol) afforded 1,3-diamine 2d as a
yellow oil (75 mg, 99% yield); analytical TLC on silica gel, 1:1
EtOAc/petroleum ether, Rf = 0.42: IR (film, cm-1) 3436 (NH),
3309 (NH); 1H NMR (400 MHz, CDCl3, ppm) δ 7.30-7.16 (5H,
m), 6.96 (1H, d, J = 2.6 Hz), 6.92 (1H, dd, J = 8.6, 2.6 Hz), 6.45
(1H, d, J = 8.6 Hz), 4.60 (1H, s), 4.48 (2H, br s), 2.34 (3H, s), 1.20
(1H, br s); 13C NMR (100 MHz, CDCl3) δ 144.4, 141.1, 128.9,
128.6, 127.9, 127.7, 127.4, 122.4, 117.5, 67.7, 34.8; HRMS-ESI
(m/z) calcd for C14H16N235Cl [M þ H]þ 247.1002, found
247.0941. Optical rotation [R]20D -31.2 (c 1.72 EtOH).
rotation (99% ee, HPLC/csp) [R]20 -46.0 (c 2.84, EtOH).
D
HPLC/csp assay: Daicel CHIRALPAK IA, 25 cm ꢀ 4.6 mm
i.d., mobile phase 1% IPA/99% Hex, flow rate 0.9 mL/min,
detector UV 254 nm, retention time 6.7 min ((R)-2a) major and
7.4 min ((S)-2a) minor.
4-Chloro-N-methyl-2-[(R)-(methylamino)(2-naphthyl)methyl]-
aniline (2b). Following the general procedure, cleavage of the
chiral auxiliary in sulfinylamide 6b (750 mg, 1.81 mmol) af-
forded 1,3-diamine 2b as a white solid (537 mg, 99% yield);
analytical TLC on silica gel, 1:1 EtOAc/petroleum ether, Rf =
0.48. Pure material was obtained by crystallization from EtOAc/
petroleum ether: mp 146-147 °C; IR (film, cm-1) 3248 (NH),
2853 (NH); 1H NMR (400 MHz, CDCl3, ppm) δ 7.86-7.80 (3H,
m), 7.53-7.47 (2H, m), 7.45 (1H, dd, J = 8.6, 1.8 Hz), 7.27 (1H,
s), 7.13 (1H, dd, J = 8.6, 2.6 Hz), 7.01 (1H, d, J = 2.6 Hz), 6.53
(1H, d, J = 8.6 Hz), 6.20-5.95 (1H, br s), 4.85 (1H, s), 2.80 (3H,
s), 2.45 (3H, s), 1.77-1.46 (1H, br s); 13C NMR (100 MHz,
CDCl3, ppm) δ 147.2, 138.335 133.3, 132.8, 128.8, 128.4, 128.0,
127.9, 127.6, 127.3, 126.1, 126.0, 125.9, 125.7, 120.8, 111.3, 67.8,
34.7, 30.4. Anal. Calcd for C19H19ClN2: C, 73.42; H, 6.16; N, 9.01.
Found: C, 73.32; H, 6.11; N, 9.03. Optical rotation (99% ee,
HPLC/csp) [R]20D þ17.2 (c 1.13, EtOH). HPLC/csp assay: Daicel
CHIRALPAK IA, 25 cm ꢀ 4.6 mm i.d., mobile phase 7% IPA/
93% Hex, flow rate 0.9 mL/min, detector UV 254 nm, retention
time 7.0 min ((R)-2b) major and 8.2 min ((S)-2b) minor.
4-Chloro-N,N-dimethyl-2-[(S)-(methylamino)(phenyl)methyl]-
aniline (2e). Following the general procedure, cleavage of the
chiral auxiliary in sulfinylamide 6e (123 mg, 0.32 mmol) af-
forded 1,3-diamine 2e as a yellow oil (88 mg, 99% yield);
analytical TLC on silica gel, 1:1 EtOAc/petroleum ether, Rf =
0.56: IR (film, cm-1) 3327 (NH); 1H NMR (400 MHz, CDCl3,
ppm) δ 7.48 (1H, d, J = 2.6 Hz), 7.42-7.40 (2H, m), 7.33-7.28
(2H, m), 7.24-7.18 (1H, m), 7.17 (1H, dd, J = 8.6, 2.6 Hz), 7.11
(1H, d, J = 8.6 Hz), 5.30 (1H, s), 2.57 (6H, s), 2.40 (3H, s), 1.76
(1H, br s); 13C NMR (100 MHz, CDCl3, ppm) δ 151.4, 143.5,
141.5, 129.9, 128.3, 128.0, 127.5, 126.8, 122.5, 62.4, 62.4, 45.7,
35.0; HRMS-ESI (m/z) calcd for C16H20N235Cl [M þ H]þ
275.1315, found 275.1219. Optical rotation [R]20 þ22.2 (c
D
1.48, EtOH).
Acknowledgment. This work was supported by European
Social Fund (No. 2009/0203/1DP/1.1.1.2.0/09/APIA/VIAA/
023). Authors thank Prof. E. Vedejs for helpful discussions.
Supporting Information Available: Experimental proce-
dures and characterization data for ketones 3; copies of 1H
and 13C NMR spectra for all compounds; X-ray crystallo-
graphic data for imines 4a-d,f,g,i and 5a-h (CIF files). This
material is available free of charge via the Internet at http://
pubs.acs.org.
4-Chloro-N-methyl-2-[(R)-(methylamino)(1-naphthyl)methyl]-
aniline (2c). Following the general procedure, cleavage of the
chiral auxiliary in sulfinylamide 6c (601 mg, 1.45 mmol) af-
forded 1,3-diamine 2c as a white solid (451 mg, 99% yield);
anaytical TLC on silica gel, 1:1 EtOAc/petroleum ether,
Rf = 0.46. Pure material was obtained by crystallization from
2368 J. Org. Chem. Vol. 75, No. 7, 2010