Improved synthesis of enantiopure sulfinimines (thiooxime S-oxides) from p-toluenesulfinamide and aldehydes and ketones

Full text of DOI:10.1021/jo9820622

J . Org. Chem. 1999, 64, 1403-1406
1403
Sch em e 1
Im p r oved Syn th esis of En a n tiop u r e
Su lfin im in es (Th iooxim e S-Oxid es) fr om
p-Tolu en esu lfin a m id e a n d Ald eh yd es a n d
Keton es
Franklin A. Davis,* Yulian Zhang,
Yemane Andemichael, Tianan Fang,
Dean L. Fanelli, and Huiming Zhang
Department of Chemistry, Temple University,
Philadelphia, Pennsylvania 19122
Received October 13, 1998
Enantiopure sulfinimines (thiooxime S-oxides) 2 are
versatile chiral imine building blocks employed in the
asymmetric synthesis of amines,1 R- and â-amino acids,2,3
R- and â-amino phosphonates,4,5 and heterocycles.6,7 The
N-sulfinyl group is superior to other imine auxiliaries
because it activates the C-N double bond for addition,
is highly stereodirecting, and is easily removed under
mild acid conditions.8 We devised a simple one-pot
procedure for preparing these building blocks from com-
mercially available (1R,2S,5R)-(-)-menthyl (S)-p-tolu-
enesulfinate (1) or (1S,2R,5S)-(+)-menthyl (R)-p-tolu-
enesulfinate (1), lithium bis(trimethylsilyl)amide (Li-
HMDS), and aliphatic and aromatic aldehydes (Scheme
1).9 While this method gave good to excellent yields of 2
from aromatic aldehydes (82-91%), the yields with
aliphatic aldehydes were more modest (60-70%) because
of competing R-deprotonation. Ketones were unreactive
using this procedure.
Ellman and co-workers recently reported the synthesis
of N-tert-butanesulfinimines by condensation of chiral
nonracemic tert-butanesulfinamide (t-BuS(O)NH2), pre-
pared in several steps from tert-butyl disulfide10 with
aldehydes.1a The convenience of (S)-(+)-p-toluenesul-
finamide (3) together with problems of preparing base-
sensitive sulfinimines by the one-pot procedure prompted
this study of the direct condensation of (S)-(+)-p-tolu-
enesulfinamide (3) with aldehydes and ketones. Further-
more, this procedure avoids the sometimes problematic
separation of the menthol byproduct.
(S)-(+)-p-Toluenesulfinamide (3) was readily prepared
in 87-90% yield by treating (-)-1 with 1.3 equiv of
LiHMDS at -78 °C and quenching after 1 h with
saturated NH4Cl solution. Sulfinimines (S)-2 were pre-
pared by reacting equimolar amounts of (+)-3 with
aldehydes in the presence of various additives. These
results are summarized in Table 1.
The relatively weak Lewis acid dehydrating reagents
magnesium sulfate and copper sulfate gave low to
moderate yields (30-40%) of the benzaldehyde-derived
sulfinimine 2 (R ) Ph) (Table 1, entries 2 and 3). With 4
Å molecular sieves, the yield of 2 (R ) Ph) improved to
52%, and similar results were found with other aldehydes
(Table 1).
The condensations were carried out by refluxing equimo-
lar amounts of sulfinamide (+)-3 and the aldehyde in
CH2Cl2 for 24 h in the presence of crushed 4 Å molecular
sieves. Higher boiling solvents such as CHCl3 produced
no increase in efficiency. Although moderate to good
yields (52-80%) of sulfinimines were obtained from
aromatic and heteroaromatic aldehydes (Table 1, entries
5, 10, 12, and 14-16), the yields were generally better
employing the one-pot procedure. On the other hand,
molecular sieves gave better yields of 2 with straight-
chain aliphatic aldehydes (63-93%) than the one-pot
procedure (20-65%) (Table 1, entries 20, 22, 23, and 30).
For example, the acetaldehyde sulfinimine 2 (R ) Me)
was obtained in better than 93% yield under these
conditions (Table 1, entry 20). With sterically hindered
isopropyl and tert-butyl aldehydes, the one-pot procedure
was better (entries 25 and 27). The aldehyde derived
(1) Amines: (a) Liu, G.; Cogan, D. A.; Ellman, J . A. J . Am. Chem.
Soc. 1997, 119, 9913. (b) Moreau, P.; Essiz, M.; Merour, J .-Y.; Bouzard,
D. Tetrahedron: Asymmetry 1997, 8, 591. (c) Hose, D. R. J .; Mahon,
M. F.; Molloy, K. C.; Raynham, T.; Wills, M. J . Chem. Soc., Perkin
Trans. 1 1996, 691.
(2) R-Amino acids: (a) Davis, F. A.; Fanelli, D. L. J . Org. Chem.
1998, 63, 1981. (b) Davis, F. A.; Portonovo, P. S.; Reddy, R. E.; Chiu,
Y.-H. J . Org. Chem. 1996, 61, 440. (c) Hua, D. H.; Lagneau, N.; Wang,
H.; Chen, J . Tetrahedron: Asymmetry 1995, 6, 349.
(3) â-Amino acids: (a) Davis, F. A.; Szewczyk, J . M. Tetrahedron
Lett. 1998, 39, 5951. (b) Davis, F. A.; Szewczyk, J . M.; Reddy, R. E. J .
Org. Chem. 1996, 61, 2222. (c) Fujisawa, T.; Kooriyama, Y.; Shimizu,
M. Tetrahedron Lett. 1996, 37, 3881. (d) Davis, F. A.; Reddy, R. E.;
Szewczyk, J . M. J . Org. Chem. 1995, 60, 7037. (e) J iang, J .; Schuma-
cher, K. K.; J oullie, M. M.; Davis, F. A.; Reddy, R. E. Tetrahedron Lett.
1994, 35, 2121. (f) Davis, F. A.; Reddy, R. E. Tetrahedron: Asymmetry
1994, 5, 955.
(4) R-Amino phosphonates: (a) Lefebvre I. M.; Evans, S. A., J r. J .
Org. Chem. 1997, 62, 7532. (b) Mikolajczyk, M.; Lyzwa, P.; Drabowicz,
J . Tetrahedron: Asymmetry 1997, 8, 3991.
(5) â-Amino phosophonates: Mikolajczyk, M.; Lyzwa, P.; Drabowicz,
J .; Wieczorek, M. W.; Blaszczyk, J . J . Chem. Soc., Chem. Commun.
1996, 1503.
(6) Aziridines: (a) Davis, F. A.; McCoull, W. Tetrahedron Lett. 1999,
40, 249. (b) Davis, F. A.; Liang, C.-H.; Liu, H. J . Org. Chem. 1997, 62,
3796. (c) Davis, F. A.; Liu, H.; Reddy, G. V. Tetrahedron Lett. 1996,
37, 5473. (d) Davis, F. A.; Reddy, G. V. Tetrahedron Lett. 1996, 37,
4349. (e) Ruano, J . L. G.; Fernandez, I.; Catalina, M. Cruz, A. A.
Tetrahedron: Asymmetry 1996, 7, 3407. (f) Davis, F. A.; Reddy, G. V.;
Liu, H. J . Am. Chem. Soc. 1995, 117, 3651. (g) Davis, F. A.; Zhou, P.;
Liang, C- H.; Reddy, R. E. Tetrahedron: Asymmetry 1995, 6, 1511. (h)
Davis, F. A.; Zhou, P.; Reddy, G. V. J . Org. Chem. 1994, 59, 3243. (i)
Davis, F. A.; Zhou, P. Tetrahedron Lett. 1994, 35, 7525.
(7) Alkaloids: (a) Davis, F. A.; Andemichael, Y. W. Tetrahedron Lett.
1998, 39, 3099. (b) Reference 3a. (c) Balasubramanian, T.; Hassner,
A. Tetrahedron: Asymmetry 1998, 9, 2201. (d) Balasubramanian, T.;
Hassner, A. Tetrahedron Lett. 1996, 37, 5755. (e) Viso, A.; de la
Pradilla, R. F.; Guerrero-Strachan, C.; Alonso, M.; Martinez-Ripoll, M.;
Andre, I. J . Org. Chem. 1997, 62, 2316.
(8) For a review on the chemistry of sulfinimines, see: Davis, F. A.;
Zhou, P.; Chen, B.-C. Chem. Soc. Rev. 1998, 27, 13.
(9) Davis, F. A.; Reddy, R. E.; Szewczyk, J . M.; Reddy. G. V.;
Portonovo, P. S.; Zhang, H.; Fanelli, D.; Thimma Reddy, R.; Zhou, P.;
Carroll, P. J . J . Org. Chem. 1997, 62, 2555.
(10) Cogan, D. A.; Liu, G.; Kim, K.; Backes, B. J .; Ellman, J . A. J .
Am. Chem. Soc. 1998, 120, 8011.
10.1021/jo9820622 CCC: $18.00 © 1999 American Chemical Society
Published on Web 01/22/1999

1404 J . Org. Chem., Vol. 64, No. 4, 1999
Ta ble 1. Syn th esis of Su lfin im in es (S)-2, (S)-6, a n d (S)-7 fr om Ald eh yd es a n d Keton es
Notes
(S)-2 % yield
entry
R
R′
conditions
CH2Cl2, reflux, 24 h
(one-pot % yield)a
1
2
Ph
H
no reaction
40 (76)
CH2Cl2, reflux, 24 h, MgSO4
3
CH2Cl2, reflux, 24 h, CuSO4
30
4
CH2Cl2, reflux, 8 h, 4 Å MS
40
5
CH2Cl2, reflux, 24 h, 4 Å MS
52
6
7
8
9
CH2Cl2, reflux, 24 h, ZnCl2, 4 Å MS
CH2Cl2, reflux, 24 h, 1 equiv of Ti(OEt)4
CH2Cl2, reflux, 24 h, 1 equiv of Ti(OEt)4, 4 Å MS
CH2Cl2, reflux, 4 h, 5 equiv of Ti(OEt)4
CH2Cl2, reflux, 24 h, 4 Å MS
CH2Cl2, reflux, 4 h, 5 equiv of Ti(OEt)4
CH2Cl2, reflux, 24 h, 4 Å MS
CH2Cl2, reflux, 4 h, 5 equiv of Ti(OEt)4
CH2Cl2, reflux, 8 h, 4 Å MS
CH2Cl2, reflux, 24 h, 4 Å MS
CH2Cl2, reflux, 24 h, 4 Å MS
CH2Cl2, reflux, 4 h, 5 equiv of Ti(OEt)4
CH2Cl2, reflux, 24 h, 4 Å MS
CH2Cl2, reflux, 4 h, 5 equiv of Ti(OEt)4
CH2Cl2, rt, 24 h, 4 Å MS
CH2Cl2, rt, 8 h, 4 Å MS
CH2Cl2, rt, 24 h, 4 Å MS
CH2Cl2, reflux, 24 h, 4 Å MS
CH2Cl2, reflux, 4 h, 5 equiv of Ti(OEt)4
CH2Cl2, rt, 24 h, 4 Å MS
CH2Cl2, reflux, 0.5 h, 5 equiv of Ti(OEt)4
CH2Cl2, reflux, 24 h, 4 Å MS
CH2Cl2, reflux, 4 h, 5 equiv of Ti(OEt)4
CH2Cl2, rt, 12 h, 4 Å MS
MeCN, rt, 2 h, 4 Å MS
CH2Cl2, reflux, 0.5 h, 5 equiv of Ti(OEt)4
CH2Cl2, rt, 48 h, 4 Å MS
52
50
50
99
54
92
63 (89)
92
80 (74)
80 (64)
66 (68)
95
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
m-MeOPh
p-MeOPh
H
H
p-NO2Ph
3-pyridyl
2-furyl
H
H
H
MeCHdCH-
H
H
20 (60)
92
Mec
93 (20)b
82
n-Pr
Ph(CH2)4-
H
H
87 (65)
63 (40)b
90
no reaction (60)
90
i-Pr
H
H
H
t-Bu
30 (60)
89
Cl(CH2)5-
Cl(CH2)5-
52 (77)b
72
88
MeC(O)(CH2)2-
H
40 (20)b
50
CH2Cl2, reflux, 4 h, 5 equiv of Ti(OEt)4
CH2Cl2, rt, 48 h, 4 Å MS
CH2Cl2, reflux, 17 h, 5 equiv of Ti(OEt)4
CHCl3, reflux 17 h, 5 equiv of Ti(OEt)4
CH2Cl2, reflux, 20 h, 5 equiv of Ti(OEt)4
Ph
Me
no reaction (no reaction)
62 (6)
60
n-Bu
Me
40d (7)
a
b
d
Reference 9 unless otherwise noted. This work. c 3.0 equiv of acetaldehyde used. 3:1 mixture of E/Z isomers.
Sch em e 2
sulfinimine of 4-oxopentanal was regioselectively formed
in 40% yield with sieves and in only 20% yield by the
one-pot method (Table 1, entry 32). Acetophenone failed
to react under these conditions (Table 1, entry 34).
Titanium(IV) ethoxide is a weak Lewis acid that has
been employed as a catalyst in transesterfication11 and
lactamization12 reactions. With a catalytic amount of
titanium(IV) ethoxide, the condensation of (+)-3 with
benzaldehyde produced little, if any, of the desired
sulfinimine after 24 h. With an equivalent amount of the
titanium reagent, sulfinimine (+)-2 (R ) Ph) was ob-
tained in 50% yield after 24 h at reflux (Table 1, entry
7). Significantly, with 5 equiv of Ti(OEt)4, the condensa-
tion was complete within 4 h, affording the benzaldehyde
sulfinimine in almost quantitative yield (Table 1, entry
9). Similar results with comparable yields of 88 to >90%
were observed with other aromatic, alkenyl, and steri-
cally hindered aliphatic aldehydes (Table 1, entries 11,
13, 17, 19, 24, 26, 28, and 31). After the reaction mixture
was quenched with H2O at 0 °C, the slightly turbid
solution was passed through Celite, and the solvent was
removed to give in most cases the sulfinimine in high
purity as determined by mp and optical rotation. Chro-
matographic purification of the product was generally not
necessary. Importantly, there was no detectable race-
mization of the sulfinimines 2 prepared under both these
conditions as determined by comparison of optical rota-
tions with literature values9 and chiral shift reagent
experiments with Eu(hfc)3.
With bis-aldehydes, it was possible to selectively
prepare the mono- and bis-sulfinimines. Thus, treatment
of terephthaldicarboxaldehyde with 1.0 equiv of sulfina-
mide (+)-3 and 10 equiv of Ti(OEt)4 afforded a 68% yield
of (S)-(+)-4 after 24 h following isolation by preparative
TLC. With lesser amounts of the titanium reagent the
reaction was incomplete. With 2 equiv of (+)-3 and 25
equiv of Ti(OEt)4, the bis-sulfinimine (S,S)-(+)-5 was
obtained in 91% yield (Scheme 2).
N-Alkylidine-p-toluenesulfinamides such as 6 have
only been available via the method of Cinquini where a
metal ketimine (Ar(R)CdNM), prepared by reacting
aromatic nitriles with lithium and Grignard reagents, is
treated with the Andersen reagent 1.13 Significantly,
heating acetophenone with (+)-3 and Ti(OEt)4 for 17 h
(11) Seebach, D.; Hungerbuhler, E.; Naef, R.; Schnurrenberger, P.;
Weidmann, B.; Zuger, M. Synthesis 1982, 138.
(12) Mander, M.; Helquist, P. Tetrahedron Lett. 1988, 29, 3049.

Notes
J . Org. Chem., Vol. 64, No. 4, 1999 1405
to give 2.27 g (86%) of (+)-3: mp 113 °C (lit.9 mp 113 °C); [R]20
afforded a 62% yield of [S-(E)]-(+)-N-R-methylbenzylidene-
p-toluenesulfinamide (6) (Table 1, entry 35). In a similar
manner, (S)-7 was obtained in 60% yield as 3:1 insepa-
rable mixture of E/Z isomers.14 In the course of these
studies, Ellman and co-workers also described the syn-
thesis of ketone-derived sulfinimines from tert-butane-
sulfinamide and Ti(OEt)4.15
The effectiveness of the titanium(IV) ethoxide reagent
in these condensation reactions is likely due to a combi-
nation of two factors. First, it acts as a Lewis acid,
activating the carbonyl group for condensation with the
sulfinamide. Second, titanium(IV) ethoxide undoubtedly
acts as a dehydrating reagent ultimately producing TiO2,
although there was no apparent improvement in yield
on addition of 4 Å molecular sieves (Table 1, compare
entries 7 and 8). An excess of the reagent is presumably
necessary because it complexes with the carbonyl oxygen
and the sulfinyl oxygens in 3 and in the product 2, in
addition to functioning as a dehydrating agent.
In summary, efficient methodology is reported for the
synthesis of sulfinimines by condensing (S)-(+)-p-tolu-
enesulfinamide (3) with aldehydes and ketones in the
presence of 4 Å molecular sieves or titanium(IV) ethoxide
reagent. This procedure avoids the problem of removing
the menthol byproduct, produced in the one-pot method.
Importantly, ketone-derived sulfinimines are also avail-
able by this methodology, as are the selective formation
of mono- and bis-sulfinimines.
D
+80.2 (c 1.2, CHCl3) [lit.9 [R]20 +79.2 (c 1.0 CHCl3)].
D
Typ ica l P r oced u r e for th e Syn th esis of Su lfin im in es
fr om Ald eh yd es Usin g 4 Å Molecu la r Sieves: (S)-(+)-N-
(Ben zylid en e)-p-tolu en esu lfin a m id e. In a 25 mL one-neck
round-bottomed flask fitted with a condenser, septum, argon
inlet, and magnetic stirring bar were placed 0.1 g (0.65 mmol)
of (S)-(+)-3 in CH2Cl2 (5 mL), 2 g of crushed 4 Å molecular sieves
(4-8 mesh, Aldrich), and 0.65 mL (0.65 mmol) of benzaldehyde.
The reaction mixture was refluxed for 24 h and filtered, and
the sieves were washed with EtOAc (2 × 10 mL). The organic
phase was concentrated, and the resulting solid was purified
by flash chromatography (10% ethyl acetate in n-hexane) to
afford 0.85 g (53%) of 2 (R ) Ph): mp 77 °C [lit.9 mp 77-78 °C];
[R]20 117.8 (c 1.6, CHCl3), [lit.9 [R]20 119.3 (c 1.77, CHCl3)].
D
D
Typ ica l P r oced u r e for th e Syn th esis of Su lfin im in es
fr om Ald eh yd es Usin g Tita n iu m (IV) Eth oxid e: (S)-(+)-N-
(Ben zylid en e)-p-tolu en esu lfin a m id e. In a 50 mL round-
bottom flask equipped with condenser, stirring bar, and argon
balloon was placed 0.10 g (0. 645 mmol) of (+)-3, 0.066 mL (0.645
mmol) of benzaldehyde, and 0.68 mL (3.23 mmol) of titanium-
(IV) ethoxide (Aldrich) in 10 mL of CH2Cl2. After being refluxed
for 4 h and monitored by TLC, the reaction mixture was
quenched at 0 °C by addition of H2O (10 mL). The turbid solution
was filtered through Celite, and the filter cake was washed with
CH2Cl2 (2 × 10 mL). The phases were separated, the aqueous
phase was washed with 10 mL of CH2Cl2, and the combined
organic portions were dried (Na2SO4) and concentrated to give
0.156 g (99%) of (S)-(+)-N-(benzylidene)-p-toluenesulfinamide:
mp 77-8 °C (lit.9 mp 77-78 °C); [R]20D 117.5 (c 1.6, CHCl3) [lit.9
[R]20 119.3 (c 1.77, CHCl3)].
D
(S )-(+)-N -(m -Me t h oxyb e n zylid e n e )-p -t olu e n e su lfin a -
m id e. An analytically pure sample was obtained by preparative
TLC (10% ethyl acetate/n-hexane): mp 66-67 °C; [R]20 94.3 (c
D
1.06, CHCl3); IR (KBr) 1659, 1072 cm-1; 1H NMR (CDCl3) δ 2.37
(s, 3H), 3.80 (s, 3H), 7.02-7.64 (m, 9H), 8.72 (s, 1H); 13C NMR
(CDCl3) δ 161.3, 160.6, 142.4, 135.8, 130.6, 130.5, 125.5, 123.5,
119.9, 113.7, 56.1, 22.1. Anal. Calcd for C15H15NO2S: C, 65.61;
H, 5.53; N, 5.12 Found: C, 66.00, H; 5,51; N, 4.71.
Exp er im en ta l Section
Gen er a l P r oced u r e. Column chromatography was per-
formed on silica gel, Merck grade 60 (230-400 mesh). Analytical
and preparative thin-layer chromatography was performed on
precoated silica gel plates (250 and 1000 microns) purchased
from Analtech, Inc. TLC plates were visualized with UV, in an
iodine chamber, or with phosphomolybdic acid unless noted
otherwise. THF was freshly distilled under nitrogen from a
purple solution of sodium and benzophenone.
Unless stated otherwise, all reagents were purchased from
commercial sources and used without additional purification.
4-Oxopentanal was prepared as previously described,16 and
6-chlorohexanal was prepared in 72% yield by Swern oxidation
of 6-chloro-1-hexanol.17 Sulfinimines were prepared by the one-
pot procedure as previously described.9
(S)-(+)-p-Tolu en esu lfin a m id e (3). In a 100 mL one-neck,
round-bottomed flask equipped with a magnetic stirring bar,
rubber septum, and argon inlet was placed 5.0 g (17.0 mmol) of
(-)-118 (Aldrich) in THF (40 mL). The reaction mixture was
cooled to -78 °C, and 23.0 mL of LiHMDS (1.0 M solution in
THF, 23.0 mmol) was added dropwise via syringe. The reaction
was warmed to room temperature, stirred for 1 h, and monitored
for the disappearance of 1 by TLC. The reaction mixture was
quenched with saturated NH4Cl (30 mL), an additional 10 mL
of water was added, and the mixture was extracted with ethyl
acetate (3 × 15 mL). The organic phase was dried (MgSO4) and
concentrated to give a solid that was crystallized with n-hexane
(S )-(+)-N -(5-P h e n y lp e n t y lid e n e )-p -t o lu e n e s u lfin a -
m id e. Purified by flash chromatography using 10% EtOAc/n-
hexane to give a yellow oil: [R]20D 243.2 (c 1.06, CHCl3); IR (neat)
1621, 1506, 1094 cm-1; 1H NMR (CDCl3) δ 1.65 (m, 4H), 2.40 (s,
3H), 2.51 (m, 2H), 2.60 (t, 2H), 7.19 (m, 5H), 7.27 (d, 2H, J )
7.4 Hz), 7.54 (d, 2H, J ) 2 Hz), 8.21(t, 1H, J ) 5 Hz); 13C NMR
(CDCl3) δ 147.6, 142.6, 142.3, 130.4, 129.0, 128.9. 126.4, 125.2,
36.3, 36.2, 31.4, 25.6, 22.1. Anal. Calcd for C18H21NSO: C, 72.24,
H, 7.02, N, 4.68. Found: C, 72.33, H, 7.14, N, 4.95.
(S)-(+)-N-(4-Oxop en t a n ylid en e)-p -t olu en esu lfin a m id e:
colorless oil, purified by flash chromatography (20% EtOAc/n-
pentane); [R]20D 243.3 (c 1.5, CHCl3); IR (neat) 1712, 1621, 1097
cm-1; 1H NMR (CDCl3) δ 8.28 (t, 1H, J ) 2.6 Hz), 7.52 (t, 2H, J
) 6.2 Hz), 7.29 (t, 2H, J ) 7.3 Hz), 2.77 (m, 4H), 2.40 (s, 3H),
2.15 (s, 3H); 13C NMR (CDCl3) δ 207.2, 166.2, 142.4, 142.3, 130.5,
125.3, 38.7, 30.7, 30.4, 22.1. Anal. Calcd for C12H15NO2S: C,
60.73; H, 6.37; N, 5.90. Found: C, 60.44; H, 6.49; N, 5.64.
(S)-(+)-N-(Acetylid en e)-p-tolu en esu lfin a m id e: flash filter
(CH2Cl2) oil; [R]20 418.2 (c 1.20, CHCl3); IR (neat) 1640, 1095,
D
cm-1; 1H NMR (CDCl3) δ 8.23 (q, J ) 5 Hz, 1 H), 7.55 (d, J ) 8
Hz, 2H), 7.29 (d, J ) 8 Hz, 2 H), 2.38 (s, 3H), 2.19 (d, J ) 5 Hz,
3H); 13C NMR (CDCl3) δ 163.56, 141.67, 129.743, 125.28, 124.40,
22.27, 21.34. 8.23 (q, J ) 5 Hz, 1H), 7.55 (d, J ) 8 Hz, 1H), 7.29
(d, J ) 8 Hz, 1H), 2.38 (s, 3H), 2.19 (d, J ) 5 Hz, 3H). Anal.
Calcd for C9H11NOS: C, 59.61; H, 6.12; N, 7.73. Found: C, 59.22;
H, 6.37; N, 7.52.
(13) (a) Annunziata, R.; Cinquini, M.; Cozzi, F. J . Chem. Soc., Perkin
Trans. 1 1982, 1, 339. (b) Hua, D. H.; Miao, S. W.; Chen, J . S.; Iguchi,
S. J . Org. Chem. 1991, 56, 4.
(14) The E/Z isomerization barriers for arenesulfinyl ketimines are
13-14 and 17 kcal/mol. (a) Davis, F. A.; Friedman, A. J .; Kluger, E.
W. J . Am. Chem. Soc. 1974, 96, 5000. (b) Davis, F. A.; Kluger, E. W.
J . Am. Chem. Soc. 1976, 98, 302.
(15) Cogan, D. A.; Liu, G.; Ellman, J . A. Abstracts, 216th ACS
National Meeting, Boston, MA, ORGN 246.
(16) Molander, G. A.; Cameron, K. O. J . Am. Chem. Soc. 1993, 115,
830.
(S)-(+)-N-(6-Ch lor oh exylid en e)-p -t olu en esu lfin a m id e:
flash chromatography (CH2Cl2) oil; [R]20 270.7 (c 1.40, CHCl3);
D
IR (neat) 1621, 1093.6 cm-1; H NMR (CDCl3) δ 8.23 (t, J ) 5
1
Hz, 1 H), 7.56 (d, J ) 8 Hz, 2H), 7.31 (d, J ) 8 Hz, 2 H), 3.50 (t,
J ) 6.5 Hz, 2H), 2.51 (m, 2H), 2.41 (s, 3H), 1.77 (quintet, J ) 7
Hz, 2H), 1.65 (quintet, J ) 7.5 Hz, 2H), 1.46 (m, 2H); 13C NMR
(CDCl3) δ 166.67, 164.70, 129.80, 129.77, 124.50, 44.71, 35.61,
32.18, 26.30, 24.55, 21.41; HRMS calcd for C13H18NOSCl (M +
H) 272.0871, found 272.0851.
(17) Le Borgne, J .-F. J . Organomet. Chem. 1976, 122, 123.
(18) (a) Hulce, M.; Mallamo, J . P.; Frye, L. L.; Kogan, T. P.; Posner,
G. H. Organic Syntheses; Wiley: New York, 1990; Collect. Vol. VII, p
495. (b) Solladie, G. Synthesis 1981, 185.
(S)-(+)-N-(4-Ca r b oxya ld eh yd eb en zylid en e)-p -t olu en e-
su lfin a m id e (4). Prepared from 0.017 g (0.013 mmol) of
terephthaldicarboxaldehyde, 0.27 mL (1.3 mmol) of Ti(OEt)4, and

1406 J . Org. Chem., Vol. 64, No. 4, 1999
Notes
0.02 g (0.13 mmol) of (+)-3 for 24 h at room temperature in CH2-
Cl2 (8 mL). The solution was filtered through Celite, concen-
trated, and purified by preparative TLC (30% EtOAc/hexanes)
142.6, 138.8, 132.6, 130.5, 129.1, 128.2, 125.9, 125.8, 125.7, 22.1,
20.9.
[S-(E/Z)]-(+)-N-r-Met h ylp en t ylid en e-p -t olu en esu lfin a -
to give 0.023 g (68%) of 4: mp 126-128 °C; [R]20 22.0 (c 0.16,
m id e (7): 40%; purified by flash chromatography (20% EtOAc/
D
CHCl3); IR (KBr) 1697, 1531, 1049 cm-1; 1H NMR δ 10.1 (s, 1H),
8.81 (s, 1H), 7.81-8.08 (m, 4H), 7.64 (d, 2H, J ) 8.1 Hz), 7.33
(d, 2H, J ) 8.1 Hz), 2.41 (s, 3H); 13C NMR δ 191.4, 159.3, 142.7,
141.6, 138.6, 138.5, 130.7, 130.6, 129.9, 124.6, 21.4. Anal. Calcd
for C15H13NO2S: C, 66.39; H, 4.83; N, 5.15. Found: C, 66.28; H,
4.77; N, 5.04.
n-hexane); colorless oil; [R]20 2.70 (c 0.44, CHCl3); IR (neat)
D
1611, 1093 cm-1; H NMR (CDCl3) E isomer, δ 0.88 (t, 3H, J )
1
7.5 Hz), 1.29 (m, 2H), 1.56 (m, 2H), 2.34 (s, 3H), 2.37 (m, 2H),
2.39 (s, 3H), 7.31 (d, 2H, J ) 8 Hz), 7.64 (d, 2H, J ) 8 Hz); Z
isomer, δ 0.95 (t, 3H, J ) 7 Hz), 1.40 (m, 2H), 1.73 (s, 3H), 2.16
(s, 3H), 2.74 (m, 2H), 7.31 (d, 2H, J ) 8 Hz), 7.64 (d, 2H, J ) 8
Hz); 13C NMR (CDCl3) E isomer, δ 14.4, 22.0, 22.8, 23.3, 28.5,
43.5, 125.7, 130.3, 142.3, 144.1, 183.6; Z isomer, δ 14.4, 21.9,
23.4, 28.3, 30.0, 37.9, 126.0, 130.3, 142.0, 144.0, 185.0. Anal.
Calcd for C13H19NOS: C, 65.78; H, 8.07; N, 5.90. Found: C,
65.77; H, 8.27; N, 5.69.
(S,S)-(-)-N ,N ′-(1,4-Be n zylid e n e )b is(p -t olu e n e su lfin a -
m id e) (5). Prepared from 1.56 mL (7.5 mmol) of Ti(OEt)4, 0.04
g (0.3 mmol) of terephthaldicarboxaldehyde, and 0.093 g (0.6
mmol) of (+)-3 for 24 h at room temperature in CH2Cl2 (10 mL).
Filtration through Celite, concentration, and purification by
preparative TLC (50% EtOAc/hexanes) gave 0.11 g (91%) of 5:
mp 152-154 °C dec; [R]20 -137.5 (c 0.032, CHCl3); IR (KBr)
Ack n ow led gm en t. This work was supported by
grants from the National Institutes of Health (GM
51982) and the National Science Foundation. We thank
Professor David R. Dalton for helpful discussions and
J oanna Szewczyk for preliminary studies.
D
1606, 1087 cm-1; H NMR δ 8.76 (s, 2H), 7.91 (s, 8H), 7.63 (d,
1
2H, J ) 8.4 Hz), 7.31 (d, 2H, J ) 8.4 Hz), 2.39 (s, 6H); 13C NMR
δ 160.3, 142.6, 141.9, 137.6, 130.8, 130.6, 125.4, 22.1. Anal. Calcd
for C22H20N2O2S2: C, 64.67; H, 4.94; N, 6.85. Found: C, 64.50;
H, 4.89; N, 6.72.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
and IR spectra of (S)-(+)-N-(6-chlorohexylidene)-p-toluene-
sulfinamide. This material is available free of charge via the
Internet at http://pubs.acs.org.
[S -(E )]-(+)-N -r-Me t h ylb e n zylid e n e -p -t olu e n e su lfin a -
m id e (6): 62%; purified by flash chromatography (10% EtOAc/
n-hexane); mp 99-100 °C (lit.13 mp 99-100 °C); [R]20 118.0 (c
D
1.06, CHCl3) (lit.13 [R]20D 98.0 (c 1.0, CHCl3); 1H NMR (CDCl3) δ
7.88 (d, 2H, J ) 7 Hz), 7.73 (d, 2H, J ) 7 Hz), 7.26-7.7.48 (m,
5H), 2.79 (s, 3H), 2.41 (s, 3H); 13C NMR (CDCl3) δ 175.1, 144.0,
J O9820622