Synthesis of enantiomerically pure N-tert-butanesulfinyl imines (tert- butanesulfinimines) by the direct condensation of tert-butanesulfinamide with aldehydes and ketones

Article abstract of DOI:10.1021/jo982059i

Experimental details for the first general methods for the one-step preparation of N-tert-butanesulfinyl imines (tert-butanesulfinimines) (2) from aldehydes and ketones is described. To effect the condensations of tert- butanesulfinamide (1) with aldehydes, the Lewis acidic dehydrating agents MgSO₄, CuSO₄, or Ti(OEt)₄ are employed. Aldehyde condensations mediated by MgSO₄ proceed in high yields (84-96%) when an excess of aldehyde is used. In contrast, only a slight excess of aldehyde (1.1 equiv) relative to tert- butanesulfinamide provides sulfinimines in high yields when the more Lewis acidic dehydrating agent CuSO₄ is used. The CuSO₄-mediated procedure is effective for a wide range of aldehydes, including sterically demanding aldehydes, such as isobutyraldehyde (90%), and electron-rich aldehydes, such as p-anisaldehyde (81%). The still more Lewis acidic Ti(OEt)₄ and TI(O-i- Pr)₄ also afford N-tert-butanesulfinyl aldimines from especially unreactive aldehydes, such as pivaldehyde (82%). In addition, Ti(OEt)₄ is effective for the condensation of 1 with ketones to afford a wide range of N-tert- butanesulfinyl ketimines in good yields (77-91%). For sulfinyl ketimines derived from methyl or n-alkyl phenyl ketones and methyl or n-alkyl isopropyl ketones, only the E isomer is detected by ¹H and ¹³C NMR in CDCl₃. For those cases where the difference in steric demand about the imine is very small, such as for 2-hexanone, high E/Z ratios are still observed (5:1).

Full text of DOI:10.1021/jo982059i

1
278
J . Org. Chem. 1999, 64, 1278-1284
Syn th esis of En a n tiom er ica lly P u r e N-ter t-Bu ta n esu lfin yl Im in es
(
ter t-Bu ta n esu lfin im in es) by th e Dir ect Con d en sa tion of
ter t-Bu ta n esu lfin a m id e w ith Ald eh yd es a n d Keton es
†
Guangcheng Liu, Derek A. Cogan, Timothy D. Owens, Tony P. Tang, and
J onathan A. Ellman*
Department of Chemistry, University of California, Berkeley, California 94720
Received October 13, 1998
Experimental details for the first general methods for the one-step preparation of N-tert-
butanesulfinyl imines (tert-butanesulfinimines) (2) from aldehydes and ketones is described. To
effect the condensations of tert-butanesulfinamide (1) with aldehydes, the Lewis acidic dehydrating
agents MgSO , CuSO , or Ti(OEt) are employed. Aldehyde condensations mediated by MgSO
4 4 4 4
proceed in high yields (84-96%) when an excess of aldehyde is used. In contrast, only a slight
excess of aldehyde (1.1 equiv) relative to tert-butanesulfinamide provides sulfinimines in high yields
when the more Lewis acidic dehydrating agent CuSO is used. The CuSO -mediated procedure is
4 4
effective for a wide range of aldehydes, including sterically demanding aldehydes, such as
isobutyraldehyde (90%), and electron-rich aldehydes, such as p-anisaldehyde (81%). The still more
Lewis acidic Ti(OEt)
unreactive aldehydes, such as pivaldehyde (82%). In addition, Ti(OEt)
4
and Ti(O-i-Pr)
4
also afford N-tert-butanesulfinyl aldimines from especially
is effective for the
4
condensation of 1 with ketones to afford a wide range of N-tert-butanesulfinyl ketimines in good
yields (77-91%). For sulfinyl ketimines derived from methyl or n-alkyl phenyl ketones and methyl
1
13
3
or n-alkyl isopropyl ketones, only the E isomer is detected by H and C NMR in CDCl . For those
cases where the difference in steric demand about the imine is very small, such as for 2-hexanone,
high E/ Z ratios are still observed (5:1).
In tr od u ction
and tert-butanesulfinyl imines are also observed. For the
reaction of Grignard reagents with sulfinyl aldimines,
addition to the sulfur of p-toluenesulfinyl aldimines is
1
N-Sulfinyl imines are versatile intermediates in the
asymmetric synthesis of chiral amines such as R-branched
2
3
4
2c
amines, R,R-dibranched amines, R- and â-amino acids,
competitive with the desired 1,2-addition. The same
5
6
aziridines, and R- and â-aminophosphonic acids (Figure
). While N-p-toluenesulfinyl imines have been the major
reaction with tert-butanesulfinyl aldimines is not only
chemoselective for 1,2-addition but also highly diastereose-
lective.2 More recently, we established that tert-butane-
sulfinyl ketimines are effective substrates for highly
1
e
focus of these synthetic studies, in the few cases where
N-tert-butanesulfinyl imines were compared to their N-p-
toluenesulfinyl counterparts, higher levels of diastereo-
control were attained from the tert-butane derivatives.5b
Due to substantial differences in their steric and elec-
tronic properties, different reactivities between p-toluene-
3
diastereoselective Me Al-mediated 1,2-additions of orga-
8
nolithiums, providing the first general stereoselective
3
route to the quaternary R,R-disubstituted amines. In
addition, we have recently reported the application of tert-
butanesulfinyl imines to the asymmetric synthesis of
â-amino acids including R,â- and â,â-disubstituted â-ami-
no acids that cannot be readily accessed by other
methods.4 In this work the efficacy of the N-sulfinyl
group as a surrogate for the N-Boc protecting group was
also demonstrated.
†
Present address: NTH 2122, GlaxoWellcome Inc., P.O. Box 13398,
RTP, NC 27709-3398.
(
1) We have elected to use the term N-sulfinyl imine instead of
sulfinimine to allow for an easy distinction between N-sulfinyl aldi-
mines and N-sulfinyl ketimines.
c
(
2) (a) Annunziata, R.; Cinquini, M.; Cozzi, F. J . Chem. Soc., Perkin
Trans. 1 1982, 341-343. (b) Hua, D. H.; Miao, S. W.; Chen, J . S.;
Iguchi, S. J . Org. Chem. 1991, 56, 5-6. (c) Moreau, P.; Essiz, M.;
M e´ rour, J .-Y.; Bouzard, D. Tetrahedron: Asymmetry 1997, 8, 591-
The practical preparation of N-sulfinyl imines is cen-
tral to their utility in the asymmetric synthesis of chiral
amines. To this end, sulfinate esters have been promi-
nently used. Menthyl arenesulfinates such as Andersen’s
5
98. (d) Yang, T.-K.; Chen, R.-Y.; Lee, D.-S.; Peng, W.-S.; J iang, Y.-Z.;
Mi, A.-Q.; J ong, T.-T. J . Org. Chem. 1994, 59, 914-921. (e) Liu, G.;
Cogan, D.; Ellman, J . A. J . Am. Chem. Soc. 1997, 119, 9913-9914.
9
(
3) Cogan, D. A.; Ellman, J . A. J . Am. Chem. Soc. 1999, 121, 268-
reagent (3) are easily synthesized and react with imine
2
69.
anions stereospecifically to provide arenesulfinyl imines
(
4) (a) Davis, F. A.; Zhou, P.; Chen, B.-C. Chem. Soc. Rev. 1998, 27,
(Scheme 1).7
b,10
Since the imine anions are generated
1
1
1
3-18. (b) Fujisawa, T.; Kooriyama, Y.; Shimizu, M. Tetrahedron Lett.
996, 37, 3881-3884. (c) Tang, T. P.; Ellman, J . A., J . Org. Chem.
999, 64, 12-13.
from nonenolizable nitriles, only a limited number of
derivatives are available by this method. Similarly, the
DAG tert-butanesulfinate (4) has been applied to the
production of enantiopure tert-butanesulfinyl compounds
(
5) (a) Davis, F. A.; Zhou, P.; Reddy, G. V. J . Org. Chem. 1994, 59,
3
243-3245. (b) Ruano, J . L. G.; Fern a´ ndez, I.; Catalina, M. d.; Cruz,
A. A. Tetrahedron: Asymmetry 1996, 7, 3407-3414. (c) Davis, F. A.;
Zhou, P. Tetrahedron Lett. 1994, 35, 7525-7528. (d) Davis, F. A.;
Reddy, G. V.; Liang, C.-H. Tetrahedron Lett. 1997, 38, 5139-5142.
(
Scheme 1).11 Unfortunately, diastereomeric mixtures of
(
6) (a) Mikolajczyk, M.; Lyzwa, P.; Drabowicz, J . Tetrahedron:
high molecular weight DAG sulfinates must be chro-
matographically separated.
Researchers in Davis’ labs have recently described the
first synthesis of N-sulfinyl aldimines from aldehydes.
Asymmetry 1997, 8, 3991-3994. (b) Lefebvre, I. M.; Evans, S. A., J r.
J . Org. Chem. 1997, 62, 7532-7533. (c) Mikolajczyk, M.; Lyzwa, P.;
Drabowicz, J .; Wieczorek, M. W.; Blaszczyk, J . J . Chem. Soc., Chem.
Commun. 1996, 1503-1504.
1
0.1021/jo982059i CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/04/1999

Enantiomerically Pure N-tert-Butanesulfinyl Imines
J . Org. Chem., Vol. 64, No. 4, 1999 1279
F igu r e 1. Reactions of N-sulfinyl imines to provide chiral intermediates for the synthesis of important amine derivatives.
Treatment with acid releases the corresponding amine products.
Sch em e 1
Sch em e 2
to DAG-tert-butanesulfinate (Scheme 1), but this method
is again limited by the unwieldy chromatographic puri-
fication to provide diastereomerically pure DAG-tert-
butanesulfinate precursor.12 Davis and co-workers have
also demonstrated that stoichiometric oxidations of sulfen-
imines derived from aromatic aldehydes or acetophenone
with chiral oxaziridines can proceed with good enantio-
control.7 However, this method requires stoichiometric
amounts of the high molecular weight chiral oxidants.
We previously reported the large scale preparation of
tert-butanesulfinamide 1 in enantiopure form in two
steps and in 71% overall yield from the very inexpensive
b,13
Treatment of N,N-bis(trimethylsilyl)-p-toluenesulfinam-
ide with aldehydes affords N-p-toluenesulfinyl aldimines.
Although yields are high for nonenolizable aldehydes,
yields are much lower when the aldehydes are enolizable.7b
These conditions also do not deliver N-sulfinyl ketimines
from ketones. In addition, because N,N-bis(trimethyl-
silyl)-p-toluenesulfinamide is obtained in situ by addition
of LHMDS to sulfinate 3 (Scheme 1), separation of the
sulfinyl imine product from menthol is required.
Other chiral intermediates have been described for the
in situ preparaton of N,N-bis(trimethylsilyl)-p-toluene-
sulfinamide but are limited by the high costs of the chiral
reagents.12 N,N-Bis(trimethylsilyl)-tert-butanesulfina-
mide has also been prepared by the addition of LHMDS
14
starting material tert-butyl disulfide (Scheme 2). Herein
we provide the full experimental details for the straight-
(8) For the synthesis of racemic or achiral R,R-disubstituted amines,
see: (a) Barbot, F.; Miginiac, L. Synth. Commun. 1997, 27, 2601-2614.
(b) Calderwood, D. J .; Davies, R. V.; Rafferty, P.; Twigger, H. L.;
Whelan, H. M. Tetrahedron Lett. 1997, 38, 1241-1244. (c) Ciganek,
E. J . Org. Chem. 1992, 57, 4521-4527. (d) Charette, A. B.; Gagnon,
A.; J anes, M.; Mellon, C. Tetrahedron Lett. 1998, 39, 5147-5150.
(9) (a) Andersen, K. K. In The Chemistry of Sulfones and Sulfoxides;
Patai, S., Rappoport, Z., Stirling, C. J . M., Ed.; J ohn Wiley & Sons:
New York, 1988; Chapter 3, pp 56-94. (b) Kagan, H. B.; Rebiere, F.
SYNLETT 1990, 643-649. (c) Solladi e´ , G. Synthesis 1981, 185-196.
(10) (a) Cinquini, M.; Cozzi, F. J . Chem. Soc., Chem. Commun. 1977,
5
02-503. (b) Davis, F. A.; Szewczyk, J . M.; Portonovo, P. S. Tetrahe-
(
7) For additional applications of N-sulfinyl imines and leading
dron Lett. 1993, 34, 6229-6232.
references, see: (a) Davis, F. A.; Portonovo, P. S.; Reddy, R. E.; Reddy,
G. V.; Zhou, P. Phosphorus, Sulfur, Silicon Relat. Elem. 1997, 120/
21, 291-303. (b) Davis, F. A.; Reddy, R. E.; Szewczyk, J . M.; Reddy,
G. V.; Portonovo, P. S.; Zhang, H.; Fanelli, D.; Reddy, R. T.; Zhou, P.;
(11) (a) Khiar, N.; Fern a´ ndez, I.; Alcudia, F. Tetrahedron Lett. 1994,
35, 5719-5722. (b) Fern a´ ndez, I.; Khiar, N.; Llera, J . M.; Alcudia, F.
J . Org. Chem. 1992, 57, 6789-6796.
1
(12) Oppolzer, W.; Froelich, O.; Wiaux-Zamar, C.; Bernardinelli, G.
Tetrahedron Lett. 1997, 38, 2825-2828 and references therein.
Carroll, P. J . J . Org. Chem. 1997, 62, 2555-2563.

1
280 J . Org. Chem., Vol. 64, No. 4, 1999
Liu et al.
Ta ble 1. Con d en sa tion s of 1 w ith Ald eh yd es Med ia ted
Ta ble 2. Con d en sa tion s of 1 w ith Ald eh yd es Med ia ted
by Cu SO4
a
by MgSO4 a n d P P TS
entry
product
R1
yield (%)
entry
product
R1
yield (%)
b
1
2
3
4
2a
2b
2c
2c
2d
i-Pr
Et
Bn
Bn
Ph
90
96
86
84
90
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
i-Pr
Et
Bn
Ph
4-MeOPh
CO2Me
2-pyridyl
3-pyridyl
2-furyl
90
96
79
91
81
65
95
trace
40
b
b
c
d
5
a
All reactions were performed using 5 equiv of MgSO4 and 0.05
equiv of PPTS in CH2Cl2 at room temperature. Reactions were
performed with 2 equiv of aldehyde. Reaction was performed with
.5 equiv of aldehyde. Reaction was performed with 3 equiv of
b
c
d
1
1
0
2j
t-Bu
trace
aldehyde.
a
All reactions were carried out using 2.0 equiv of CuSO4 and
forward and high-yielding methods for the one-step
preparation of a wide range of tert-butanesulfinyl imines
by the condensation of tert-butanesulfinamide 1 with
aldehydes and ketones. This route provides a rapid entry
to a wider range of sulfinyl imines than previously avail-
able and can be performed easily on multigram scales.
1
.1 equiv of aldehyde in CH2Cl2 at room temperature.
Cop p er (II) Su lfa te Med ia ted Con d en sa tion s. To
enhance the synthetic utility of the condensation ap-
proach to imines 2, a number of alternative conditions
were investigated. Although trimethoxyorthoformate was
found to be an effective solvent for the condensation of 1
with aldehydes, it was not more efficient than the initial
Resu lts a n d Discu ssion
MgSO
Lewis acidic CuSO
Indeed, CuSO is such an efficient drying agent and
Lewis acid catalyst that the protic acid catalyst PPTS
was not necessary to effect the desired condensation
4
and PPTS conditions. We reasoned that the more
Ma gn esiu m Su lfa te Med ia ted Con d en sa tion s. We
began our efforts to prepare tert-butanesulfinyl imines
by investigating the direct condensation of 1 with alde-
hydes (eq 1). Neither molecular sieves nor sodium sulfate
was effective in providing N-tert-butanesulfinyl aldimines
in high yield, even in the presence of a protic acid
catalyst. Attempts to drive the reaction to completion by
azeotropic removal of water using a Dean-Stark ap-
paratus and either benzene or toluene solvents were also
unsuccessful due to competitive decomposition of the tert-
butanesulfinyl imine products.
Branchaud has reported that sulfenamides can be
condensed with aldehydes in near quantitative yields
using magnesium sulfate as a drying agent and PPTS
as a catalyst.15 When these conditions were employed for
the direct condensation of optically pure 1 with several
types of aldehydes, the desired sulfinyl aldimines 2 were
isolated in high yields (eq 1 in Table 1). No racemization
was observed during the condensation reaction as deter-
mined by chiral HPLC analysis of the imine product 2d .
The condensations were complete after 12-24 h at room
temperature. Even phenylacetaldehyde readily con-
densed to afford 2c in high yield without formation of
the enamine, which is a significant side product during
the formation of the corresponding N-p-toluenesulfinyl
imine.7b It is, however, necessary to use aldehydes in
excess to drive these condensation reactions to comple-
tion. To obtain aliphatic aldimine derivatives, usually 2
equiv of aldehyde in excess of 1 are required, although
as little as 1.5 equiv of aldehyde is nearly as effective
4
would be more effective than MgSO .
4
4
reaction (eq 2 in Table 2). Thus, with CH
and 2 equiv of CuSO , good yields of sulfinyl aldimines
were obtained when 1 was condensed with only 1.1
2 2
Cl as solvent
4
2
equiv of aldehydes of several structural types (Table 2).
Even the condensation of the unreactive electron rich
aldehyde, p-anisaldehyde, provided sulfinyl aldimine 2e
in high yield (81%; entry 5). Once again, phenylacetal-
dehyde was condensed without enamine formation (entry
3). As was previously observed for the MgSO
conditions, no racemization was observed in the presence
of CuSO . Yields were poor for the electron deficient
4
/PPTS
4
heteroaromatic aldehyde furfural (entry 9) and the
extremely sterically demanding pivaldehyde (entry 10).
Ketones did not afford sulfinyl ketimines in the presence
4
of CuSO .
Interestingly, the condensation of 1 with 2-pyridine-
carboxaldehyde afforded 2g in high yield (entry 7), while
the condensation of 1 with 3-pyridinecarboxaldehyde did
not proceed (entry 8). A deep-blue color was observed
immediately upon addition of 3-pyridinecarboxaldehyde
to CuSO
4
, suggesting the formation of a pyridine-Cu
complex. Interestingly, even the use of 4 equiv of CuSO
4
did not effect the desired condensation. The success of
the condensation of 1 with 2-pyridinecarboxaldehyde may
be attributed to the proximity of the aldehyde to the basic
nitrogen, which may result in the formation of a five-
membered chelate that activates the aldehyde for 1,2-
attack by 1.
(entry 4). In contrast, for condensations with less reactive
aromatic aldehydes, such as benzaldehyde, at least 3
equiv of aldehyde was necessary to obtain high yields
(entry 5).
Tita n iu m (IV)-Med ia ted Con d en sa tion s. Titanium-
(
IV) salts were next investigated, primarily to effect the
(
13) Davis, F. A.; Reddy, R. T.; Reddy, R. E. J . Org. Chem. 1992,
5
7, 6387-6389. Also, for the diasteroselective oxidation of chiral
condensation of sulfinamide 1 with ketones. Due to their
sulfenimines see ref 2d.
14) Cogan, D. A.; Liu, G.; Kim, K.; Backes, B. J .; Ellman, J . A. J .
Am. Chem. Soc. 1998, 120, 8011-8019.
15) Branchaud, B. P. J . Org. Chem. 1983, 48, 3531-3538.
Lewis acidity and excellent water-scavenging ability, Ti-
(
(
4 4
IV) salts such as TiCl and Ti(O-i-Pr) have been used
1
6
17
(
to condense amines and even ureas with ketones.

Enantiomerically Pure N-tert-Butanesulfinyl Imines
J . Org. Chem., Vol. 64, No. 4, 1999 1281
Ta ble 3. Con d en sa tion s of 1 w ith Acetop h en on e
Ta ble 4. Con d en sa tion of Keton es w ith 1 Med ia ted by
Ti(OEt)4a
a
Med ia ted by Ti(IV) Com p ou n d s
temp time yield
entry
Lewis acid
solvent
temp (°C)
yield (%)
product
R1
R2
(°C)
(h)
(%)
(E/ Z)b
1
2
3
4
5
6
7
8
9
Ti(O-i-Pr)4
Ti(O-i-Pr)4
TiCl4
TiCl2(O-i-Pr)2
TiCl2(O-i-Pr)2
TiCl(O-i-Pr)3
TiCl(O-i-Pr)3
Ti(OEt)4
Ti(OEt)4
toluene
toluene
toluene
THF
toluene
THF
toluene
toluene
THF
110
22
0 f 22
0 f 22
0 f 22
60
110
110
75
60
34
40
51
65
84
60
87
89
2
2
2
2
2
2
2
2
2
k
l
Ph
-(CH2)5-
i-Pr
Me
75c
60
15
4
7
24
5
15
10
10
24
89
91
84
77
77
73
88
77
82
one isomer
b
m
n
o
p
q
r
Me
Bu
Bu
Me
Me
Me
Me
60
75
75
75
one isomer
one isomer
one isomer
one isomer
6:1
c
c
c
i-Pr
c
Ph
d
2-Npthd
i-Bu
c
d
60
60
75
Bu
t-Bu
5:1
one isomer
c
s
a
Reactions were run at 0.5 M. 4 equiv of Et3N was added. c
equiv of Et3N was added. 1 equiv of Et3N was added.
b
2
a
Reactions were performed with 1.1 equiv of ketone with 2.0
d
b
1
equiv of Ti(OEt)4 in THF. Ratios were determined by H NMR.
c
The reflux temperature of the reaction mixture. d 2-naphthyl.
Titanium(IV) reagents are inexpensive and, upon addi-
tion of water, provide solid titanium oxide byproducts
that can be rapidly filtered away. The initial experiments
focused on the condensation of sulfinamide 1 with aceto-
phenone to afford sulfinyl imine 2k (eq 3 in Table 3).
Acetophenone is less electrophilic and more prone to
enolization and competitive aldol condensation reactions
than aliphatic ketones. Therefore, conditions developed
for the synthesis of 2k should be applicable to a variety
of N-tert-butanesulfinyl ketimines.
Ta ble 5. Con d en sa tion s of 1 w ith Ald eh yd es Med ia ted
by Ti(IV) Sa ltsa
product
R1
Ti(IV) salt
time (h)
yield (%)
2
2b
2
2
2
2
b
Et
Et
Ti(OEt)4
Ti(O-i-Pr)4
Ti(OEt)4
Ti(O-i-Pr)4
Ti(OEt)4
Ti(OEt)4
Ti(OEt)4
3
7
6
14
6
4
quant.
83
84
77
quant.
82
At elevated temperatures, Ti(O-i-Pr)
effective (entries 1 and 2). The stronger Lewis acid, TiCl
rapidly provided the imine product in the presence of
Et N as acid scavenger, but aldol condensation was
competitive under these conditions (entry 3). Mixtures
of Ti(O-i-Pr) and TiCl were used to form condensing
4
was moderately
c
c
h
i
Bn
Bn
3-pyridyl
2-furyl
t-Bu
4
,
3
2j
5
82
4
4
a
Reactions were performed at room temperature with 1.1 equiv
reagents with attenuated reactivity (entries 4-7). Al-
though these less Lewis acidic compounds reduced the
amount of aldol condensation product observed with
concomitant improvements in the chemical yield of 2k ,
aldol condensation was not eliminated. Fortunately, Ti-
of aldehyde and 2 equiv of Ti(IV) salt in THF.
a variety of ketones, including the exceptionally sterically
hindered pinacolone to afford sulfinyl ketimine 2s. Al-
though this sterically hindered ketone required more
forcing conditions to deliver 2s, the product sulfinyl
ketimine was stable to the higher temperatures. The
standard procedure is to begin the condensation reaction
at 60 °C. If the reaction is sluggish, the temperature is
elevated to effect the condensation at a more reasonable
rate. The thermal stability of the sulfinyl ketimine
products appears to be related to the steric demand about
the carbonyl, and ketones that require more forcing
conditions to condense deliver imine products that do not
decompose noticeably under these conditions.
(
OEt)
without promotion of the aldol condensation side reaction.
An 89% yield of 2k was obtained when Ti(OEt) was used
in THF. Unlike the chlorotitanium complexes (entries
-7), there was not a significant difference between
toluene and THF as solvent (entries 8 and 9). Technical
grade Ti(OEt) is effective for the condensation reaction.
4 4
was found to be more effective than Ti(O-i-Pr)
4
3
4
These conditions were also effective for aliphatic ketones.
For example, with careful monitoring at 60 °C in THF,
cyclohexanone gave the product 2l in 91% yield and
3
-methyl-2-butanone gave the sulfinyl ketimine product
2
m in 84% yield (Table 4). The same condensation
4
The Ti(OEt) conditions were also investigated for the
synthesis of N-tert-butanesulfinyl aldimines, including
those few that were not formed in synthetically useful
reactions performed at reflux temperature afforded sulfi-
nyl ketimines in less desirable yields (60-70%) due to
thermal decomposition.
yields by the CuSO
Sulfinamide 1 condensed smoothly with propionaldehyde
in the presence of either Ti(OEt) or Ti(O-i-Pr) without
4
-mediated methodology (Table 2).
4
To establish the generality of this procedure, Ti(OEt) -
mediated condensations were performed with a number
of other ketones with varying steric demand about the
carbonyl (eq 4 in Table 4). This straighforward procedure
affords sulfinyl ketimines cleanly and in high yields from
4
4
competitive aldol condensation or Meerwein-Pondorff-
Verley reduction to afford sulfinyl aldimines 2 (eq 5 in
Table 5). The less active aldehydes, furfural and pival-
dehyde, were also effectively converted to their corre-
sponding tert-butanesulfinyl aldimines 2i and 2j. Sulfinyl
imine 2h , whose 3-pyridyl functionality was incompatible
(
16) Selva, M.; Tundo, P.; Marques, C. A. Synth. Commun. 1995,
3, 369-378.
17) Armstrong, I., J . D.; Wolfe, C. N.; Keller, J . L.; Lynch, J .;
Bhupathy, L. M.; Volante, R. P. Tetrahedron Lett. 1997, 38, 1531-
532.
2
(
with the CuSO
4
methodology, was also prepared by the
1
Ti(OEt) -mediated methodology.
4

1
282 J . Org. Chem., Vol. 64, No. 4, 1999
Liu et al.
Sta bility a n d Isola tion of Su lfin im in es. Although
tical access to numerous important chiral amines. The
some tert-butanesulfinyl imines hydrolyze very slowly in
air, they can be stored dry at low temperatures (-5 °C)
for extended periods of time. The sulfinyl aldimines are
the more robust derivatives and have shown no sign of
either hydrolysis or oligomerization. Other undetermined
decomposition pathways do result in minor contamina-
tion of the sulfinyl aldimines after a period of weeks or
months if stored in air at room temperature. The sulfinyl
ketimine derivatives show varying rates of hydrolysis in
air depending on substitution about the imine. For
example, R-aryl ketimines such as 2k , 2o, and 2p
hydrolyze very slowly while sulfinyl imines 2l (derived
from cyclohexanone) and 2r (derived from 2-hexanone)
will fully hydrolyze over the course of 2 days in air.
Nonetheless, all the sulfinyl imines can be handled in
air, and even 2l and 2r have been stored dry for months
at -5 °C with no sign of decomposition. Although sulfinyl
imines rearrange at high temperatures,18 the lower
boiling derivatives have been distilled at low temperature
4
CuSO -mediated synthesis of tert-butanesulfinyl aldi-
mines from 1 and aldehydes proceeds in high yields, is
operationally straightforward, and requires only a slight
excess of aldehyde (1.1 equiv). For the few aldehydes
where the CuSO
in high yields, Ti(IV) salts are effective. Moreover, Ti-
(OEt) effects the condensation of ketones to afford N-tert-
4
-mediated condensations do not proceed
4
butanesulfinyl ketimines. This is the first general syn-
thesis of sulfinyl ketimines, including the previously
inaccessible aliphatic derivatives. The straightforward
and high-yielding one-step procedures developed for the
preparation of tert-butanesulfinyl imines should signifi-
cantly enhance the utility of these important chiral
intermediates for the asymmetric synthesis of chiral
amines, which are key components of many natural
products, synthetic pharmaceuticals, materials, and asym-
metric catalysts.
Exp er im en ta l Section
(35-40 °C) under reduced pressure. The relative stabili-
Gen er a l. All aldehydes and ketones were obtained from
commercial suppliers and were distilled before use. Lewis acids
ties of the tert-butanesulfinyl imines to silica chroma-
tography correspond to the rates of hydrolysis in air.
Except for 2l, all of the sulfinyl imines prepared in this
study could be quickly chromatographed with hexanes/
were also obtained from commercial suppliers, and Ti(OEt)
and Ti(O-i-Pr) were used without purification from fresh
4
4
bottles or were distilled under reduced pressure. Tetrahydro-
furan (THF) was distilled from Na/benzophenone ketyl, and
toluene was distilled from Na. All reactions were carried out
2
Et O as eluent, allowing for the isolation of higher molec-
ular weight sulfinyl imines in analytically pure form.
Su lfin im in e Geom et r y. tert-Butanesulfinyl aldi-
2
in flame- or oven-dried glassware under an inert N atmo-
mines, like arenesulfinyl aldimines,7b are observed ex-
sphere. Chromatography was carried out using Merck 60 230-
400 mesh silica gel. IR spectra of liquids were recorded as thin
films on NaCl plates, and IR spectra of solids were recorded
as KBr pellets. Chemical shifts in NMR spectra are expressed
clusively as the E-imine isomers (Table 4).19 Steric effects
also control the E/ Z isomer ratios observed for tert-
butanesulfinyl ketimines. Only the E isomer is observed
3
in ppm. All NMR spectra were obtained in CDCl with TMS
1
13
3
by 400 MHz H and 101 MHz C NMR in CDCl for
as an internal standard at room temperature. Sulfinamide 1
sulfinyl ketimines derived from aryl n-alkyl ketones and
isopropyl n-alkyl ketones (2k , 2m -p , and 2s). The 5:1
mixture of E and Z isomers observed for the tert-
butanesulfinyl ketimine derived from 2-hexanone (2r ; see
Table 4) is impressive considering the small difference
in steric demand about the imine. Although two isomers
of 2q and 2r are detectable by NMR, in each case, only
one compound is seen by chromatography (TLC and
HPLC). The rapid rate of E/ Z interconversion precludes
isolation of the E isomer20 but makes possible diastere-
omeric ratios of addition products that exceed the initial
E/ Z ratios of the corresponding tert-butanesulfinyl
ketimine precursors. This has already been observed for
was prepared as previously described.2e,9
Gen er a l P r oced u r e for th e Syn th esis of ter t-Bu ta n e-
su lfin yl Ald im in es 2 fr om MgSO
To a 0.5 M solution of (R)-1 (1 equiv) in CH
.05 equiv of PPTS and 5 equiv of anhydrous MgSO
4
a n d P P TS (Meth od A).
Cl were added
followed
2
2
0
4
by the aldehyde. The mixture was stirred at room temperature
for 24 h. Upon completion, the reaction mixture was filtered
through a pad of Celite and the filter cake was washed well
with CH Cl . The residue obtained after filtration was purified
2 2
by chromatography.
Gen er a l P r oced u r e for th e Syn th esis of ter t-Bu ta n e-
su lfin yl Ald im in es 2 fr om Cu SO
solution of (R)-1 (1 equiv) in CH Cl
anhydrous CuSO followed by the aldehyde (1.1 equiv). The
4
(Meth od B). To a 0.5 M
2
2
was added 2.2 equiv of
4
mixture was stirred at room temperature for 12-24 h. The
reaction mixture was filtered through a pad of Celite, and the
filter cake was washed well with CH Cl . The residue obtained
2 2
3
the Me Al-mediated 1,2-addition of organolithiums to 2r
3
to afford sulfinamides with a 9:1 diastereomeric ratio.
after filtration was purified by chromatography.
Con clu sion
Gen er a l P r oced u r e for th e Syn th esis of ter t-Bu ta n e-
su lfin yl Im in es 2 fr om Ti(OEt)
solution of Ti(OEt)
(technical grade, ∼20% Ti; ∼2 equiv) and
aldehyde or ketone (1-1.1 equiv) in THF was prepared under
a N atmosphere. Then, (R)-1 (1-1.1 equiv) was added and
4
(Meth od C). A 0.5 M
Sulfinyl imines are versatile intermediates for the
asymmetric synthesis of amines bearing an R-stereogenic
center (Figure 1). Therefore, the synthesis of tert-butane-
sulfinyl aldimines and ketimines from the corresponding
aldehydes and ketones and the inexpensive chiral am-
monia synthon, tert-butanesulfinamide 1, provides prac-
4
2
the flask was heated. Conversion was followed by TLC, and
the mixture cooled immediately upon completion. Once at room
temperature, the mixture was poured into an equal volume of
brine while rapidly stirring. The resulting suspension was
filtered through a plug of Celite, and the filter cake was
washed with EtOAc. The filtrate was transferred to a sepa-
ratory funnel where the organic layer was washed with brine.
The brine layer was extracted once with a small volume of
(
18) Davis, F. A.; Friedman, A. J .; Nadir, U. K. J . Am. Chem. Soc.
978, 100, 2844-2852.
19) The E assignment is made by analogy to p-toluenesulfinyl
1
(
imines, whose conformations were determined from X-ray crystal
structures: Robinson, P. D.; Hua, D. H.; Shan, J . S.; Saha, S. Acta
Crystallogr. 1991, C47, 594-596, and ref 7b.
EtOAc, and the combined organic portions were dried (Na
SO ), filtered, and concentrated. The sulfinyl imines, 2, were
purified either by distillation or silica gel chromatography.
2
-
4
(
20) Davis and Hua have investigated the barrier of rotation of
arenesulfinyl ketimines and found it to be between 13.1 and 17 kcal/
mol: (a) Davis, F. A.; Friedman, A. J .; Kluger, E. W. J . Am. Chem.
Soc. 1974, 96, 5000-5001. (b) Davis, F. A.; Kluger, E. W. J . Am. Chem.
Soc. 1976, 98, 302-303
(
R)-(-)-N-(2-Meth ylp r op ylid en e)-2-m eth ylp r op a n esu l-
fin a m id e (2a ). Meth od A. The general procedure was fol-
lowed with 500 mg (4.13 mmol) of (R)-1, 52 mg (0.20 mmol) of

Enantiomerically Pure N-tert-Butanesulfinyl Imines
J . Org. Chem., Vol. 64, No. 4, 1999 1283
PPTS, and 595 mg (8.26 mmol) of isobutyraldehyde. Chroma-
Chromatography (4:1 hexanes/EtOAc) delivered 2.50 g (65%)
2
3
tography (95:5 CH
2
Cl
2
/hexanes) delivered 650 mg (91%) of 2a .
of 2f as a colorless oil: [R]
D
3
-305° (c 1.0, CHCl ); IR 1752,
-
1
1
Meth od B. The general procedure was followed with 500
mg (4.13 mmol) of (R)-1, 328 mg (4.54 mmol) of isobutyralde-
1736, 1096 cm ; H NMR (300 MHz) δ 1.28 (s, 9H), 3.93 (s,
3H), 8.01 (s, 1H); 13C NMR (101 MHz) δ 23.0, 53.4, 59.2, 155.4,
161.8. Anal. Calcd for C H13NO S: C, 43.96, H, 6.85, N, 7.32.
7 3
hyde, and 1.45 g (9.08 mmol) of CuSO
Cl ) delivered 585 mg (81%) of 2a : [R]
CHCl
4
. Chromatography (CH
2
-
2
3
-259.4° (c 1.0,
Found: C, 43.82, H, 6.73, N, 7.44.
2
D
-
1 1
); IR 1085, 1622 cm ; H NMR (300 MHz) δ 1.10-1.23
(R)-(-)-N-(2-P yr id in em eth ylid en e)-2-m eth ylp r op a n e-
su lfin a m id e (2g). Meth od B. The general procedure was
followed with 121 mg (1.00 mmol) of (R)-1, 107 mg (1.00 mmol)
of 2-pyridinecarboxaldehyde, and 320 mg (2.00 mmol) of
3
1
3
(m, 15H), 2.66-2.77 (m, 1H), 7.98 (d, J ) 4.4 Hz, 1H); C NMR
(101 MHz) δ 18.7, 22.1, 34.7, 56.4, 173.4. Anal. Calcd for C H -
8
17
NOS: C, 54.82; H, 9.78; N, 7.99. Found: C, 54.68; H, 9.51; N,
.17.
R)-(-)-N -(P r op ylid en e)-2-m et h ylp r op a n esu lfin a m -
id e (2b). Meth od A. The general procedure was followed with
.00 g (8.26 mmol) of (R)-1, 103 mg (0.413 mmol) of PPTS,
and 957 mg (16.5 mmol) of propionaldehyde. Chromatography
CH Cl ) delivered 1.28 g (96%) of 2b.
Meth od B. The general procedure was followed with 1.00
g (8.26 mmol) of (R)-1, 527 mg (9.08 mmol) of propionaldehyde,
and 2.90 g (18.2 mmol) of CuSO . Chromatography (CH Cl
); IR
082, 1627 cm ; H NMR (300 MHz) δ 1.15-1.31 (m, 12H),
8
CuSO
4
. Chromatography (3:1 hexanes/EtOAc) delivered 203
2
3
mg (95%) of 2g as a colorless oil: [R]
IR 1607, 1088 cm ; H NMR (300 MHz) δ 1.29 (s, 9H), 7.42
D
-172° (c 1.0, CHCl
3
);
(
-
1
1
(
8
1
m, 1H), 7.82 (m, 1H), 8.01 (d, J ) 7.8 Hz, 1H), 8.71 (s, 1H),
1
.75 (d, J ) 5.0 Hz, 1H); 13C NMR (101 MHz) δ 22.9, 58.3,
23.3, 126.2, 137.1, 150.4, 152.7, 164.0. Anal. Calcd for
(
2
2
C
10
H
14
N
2
OS: C, 57.12; H, 6.71; N, 13.32. Found: C, 56.96; H,
.65; N, 13.30.
R)-(-)-N-(3-P yr id in em eth ylid en e)-2-m eth ylp r op a n e-
su lfin a m id e (2h ). Meth od C. A mixture of 0.86 mL (0.91
mmol) of 3-pyridinecarboxaldehyde, 0.86 g of Ti(OEt)
6
(
4
2
2
)
2
3
delivered 1.25 g (94%) of 2b: [R]
D
-328.5° (c 1.0, CHCl
3
-
1
1
4
(∼1.7
1
2
1
3
mmol), and 0.10 g of (R)-1 (0.86 mmol) in 1.6 mL of THF was
stirred at room temperature for 2 h. Chromatography (3:1
hexanes/EtOAc) delivered 180 mg (quantitative yield) of 2h :
.50-2.58 (m, 2H), 8.10 (t, J ) 4.2 Hz, 1H); C NMR (101
MHz) δ 9.40, 22.1, 29.30, 56.3, 170.0. Anal. Calcd for C
NOS: C, 52.14; H, 9.38; N, 8.69. Found: C, 51.96; H, 9.44; N,
.88.
7 15
H -
2
3
-1
[
R]
D
-136° (c 1.0, CHCl
H NMR (500 MHz) δ 1.24 (s, 9H), 7.40 (m, 1H), 8.13 (m, 1H),
.61 (s, 1H), 8.70 (m, 1H), 9.00 (m, 1H); 13C NMR (121 MHz)
δ 22.5, 58.0, 123.9, 129.6, 135.6, 151.0, 152.9, 160.4. Anal.
Calcd for C10 OS: C, 57.11; H, 6.71; N, 13.32. Found: C,
6.93, H, 6.56, N, 13.39.
3
); IR 1087, 1588, 1586, 1610 cm ;
8
1
(
R)-(-)-N-(2-P h en yleth yliden e)su lfin am ide (2c). Meth od
8
A. The general procedure was followed with 1.70 g (14.0 mmol)
of (R)-1, 180 mg (0.700 mmol) of PPTS, and 2.53 g (21.0 mmol)
14 2
H N
of phenylacetaldehyde. Chromatography (CH
.61 g (84%) of 2c as a pale yellow oil.
Meth od B. The general procedure was followed with 1.00
g (8.26 mmol) of (R)-1, 1.09 g (9.08 mmol) of phenylacetalde-
2 2
Cl ) delivered
5
2
(
R)-(-)-N-(2-F u r ylm eth ylen e)-2-m eth ylp r op a n esu lfin -
a m id e (2i). Meth od B. The general procedure was followed
with 242 mg (2.00 mmol) of (R)-1, 192 mg (2.00 mmol) of
hyde, and 2.90 g (18.2 mmol) of CuSO
Cl
618 cm ; [R]
4
2
. Chromatography (CH -
furfural, and 640 mg (4.00 mmol) of CuSO
(Et O) delivered 159 mg (40%) of 2i as a colorless oil.
Meth od C. A mixture of 192 mg (2.00 mmol) of furfural,
1.14 g of Ti(OEt)
4
. Chromatography
2
) delivered 1.46 g (79%) of 2c as a pale yellow oil: IR 1076,
-230.0° (c 1.0, CHCl ); H (300 MHz) δ 1.18
s, 9H), 3.81-3.84 (m, 2H), 7.21-7.36 (m, 5H), 8.13 (t, J ) 5.3
-
1
23
1
2
1
(
D
3
13
4
(∼4.0 mmol), and 242 mg of (R)-1 (1.00
Hz, 1H); C (125 MHz) δ 22.4, 42.6, 56.9, 127.1, 128.8, 129.2,
34.8, 167.4. Anal. Calcd for C12 17NOS: C, 64.54; H, 7.67;
N, 6.27. Found: C, 64.60; H, 7.54; N, 6.07.
R)-(-)-N -(Ben zylid en e)-2-m et h ylp r op a n esu lfin a m -
id e (2d ). Meth od A. The general procedure was followed with
.00 g (8.26 mmol) of (R)-1, 103 mg (0.413 mmol) of PPTS,
and 2.63 g (24.8 mmol) of benzaldehyde. Chromatography
CH Cl ) delivered 1.56 g (90%) of 2d .
Meth od B. The general procedure was followed with 0.300
g (2.48 mmol) of (R)-1, 0.289 g (2.73 mmol) of benzaldehyde,
and 0.592 g (3.72 mmol) CuSO . Chromatography (CH Cl
mmol) in 4 mL of THF was stirred at room temperature for 4
1
H
h. Pure 2i was obtained (326 mg, 82%) as a clear oil from
chromatography (Et
2
O): [R]23
D
3
-168° (c 1.0, CHCl ); IR 1081,
(
-
1
1
1
3
8
1
6
613 cm ; H NMR (300 MHz) δ 1.26 (s, 9H), 6.57 (dd, J )
.5, 1.8 Hz, 1H), 7.01 (dd, J ) 0.7, 3.5 Hz, 1H), 7.65 (m, 1H),
,40 (s, 1H); 13C NMR (75 MHz) δ 22.8, 58.1, 112.8, 119.0,
47.1, 150.1, 151.1. Anal. Calcd for C
.57; N, 7.03. Found: C, 54.49; H, 6.30; N, 6.82.
R)-(-)-N-(2,2-Dim eth ylpr opyliden e)-2-m eth ylpr opan e-
su lfin a m id e (2j). Meth od C. A mixture of 103 mg (1.20
mmol) of 2,2-dimethylpropionaldehyde, 690 mg of Ti(OEt)
∼3.0 mmol), and 121 mg of (R)-1 (1.00 mmol) in 3 mL of THF
was stirred at room temperature for 5 h. Pure 2j was obtained
1
9 2
H13NO S: C, 54.24; H,
(
2
2
(
4
2
2
)
4
delivered 0.470 g (91%) of 2d . No racemization was observed
by HPLC analysis (Diacel Chiralpak OD column, 90:10 hex-
(
anes/IPA; 1.0 mL/min; 254 nm; (S)-2d t
R
) 4.8 min, (R)-2d t
R
(
155 mg, 82%) as a clear oil from chromatography (4:1 hexanes/
2
3
)
5.9 min). 2d : [R]
D
-122.0° (c 1.0, CHCl ); IR 1084, 1643
3
23
-1
1
EtOAc): [R]
D
3
-285° (c 1.0, CHCl ); IR 1620, 1089 cm ; H
-
1
1
cm ; H NMR (300 MHz) δ 1.30 (s, 9H), 7.44-7.55 (m, 3H),
13
NMR (300 MHz) δ 1.16 (s, 9H), 1.18 (s, 9H), 7.92 (s, 1H);
C
7
5
.84-7.87 (m, 2H), 8.59 (s, 1H); 13C NMR (101 MHz) δ 22.5,
15
7.6, 128.8, 129.2, 132.3, 134.0, 162.6. Anal. Calcd for C11H -
(
101 MHz) δ 22.3, 26.7, 37.9, 56.45, 175.6. Anal. Calcd for
19NOS: C, 57.10; H, 10.12; N, 7.40. Found: C, 57.20, H,
0.31, N, 7.53.
R)-(-)-N-(1-P h en ylet h ylid en e)-2-m et h ylp r op a n esu l-
fin a m id e (2k ). Meth od C. A mixture of 2.11 mL of acetophe-
none (18.2 mmol), 8.7 g of Ti(OEt)
(∼36.4 mmol), and 2.00 g
of (R)-1 (16.5 mmol) in 36 mL of THF was heated to reflux for
5h. Pure 2k was obtained (3.22 g, 88%) as a yellow crystalline
9
C H
1
NOS: C, 63.13; H, 7.22; N, 6.69. Found: C, 62.94; H, 6.94; N,
.47.
6
(
(
R)-(-)-N-(4-Met h oxyb en zylid en e)-2-m et h ylp r op a n e-
su lfin a m id e (2e). Meth od B. The general procedure was
followed with 1.00 g (8.26 mmol) of (R)-1, 1.23 g (9.08 mmol)
4
of p-anisaldehyde, and 2.90 g (18.2 mmol) of CuSO
tography (CH Cl ) delivered 1.59 g (81%) of 2e as a white
3
solid: mp 91-93 °C; [R] ); IR 1080, 1592
4
. Chroma-
1
2
2
solid from silica chromatography (85:15 hexanes/EtOAc). No
racemization was observed by chiral HPLC analysis (Diacel
2
3
D
-70.2° (c 1.0, CHCl
cm ; H NMR (500 MHz) δ 1.25 (s, 9H), 3.87 (s, 3H), 6.96 (d,
J ) 8.5 Hz, 2H), 7.79 (d, J ) 8.5 Hz, 2H), 8.51 (s, 1H). 13
NMR (125 MHz) δ 59.4, 70.0, 70.7, 89.1, 93.3, 94.6, 104.4,
04.9. Anal. Calcd for C12 S: C, 60.22; H, 7.16; N, 5.85.
Found: C, 60.32; H, 6.89; N, 5.91.
-
1 1
Chiralpak OD column, 90:10 hexanes/IPA; 1.0 mL/min; 250
C
23
nm; (R)-2k t
.0, CHCl
MHz) δ 1.32 (s, 9H), 2.77 (s, 3H), 7.26-7.89 (m, 5H); C NMR
125 MHz) δ 22.5, 24.2, 57.4, 127.2, 128.4, 131.6, 138.7, 176.4.
Anal. Calcd for C12 17NOS: C, 64.54; H, 7.67; N, 6.27.
Found: C, 64.66; H, 7.47; N, 6.32.
R)-(-)-N-Cycloh exylid en e-2-m eth ylp r op a n esu lfin a m -
id e (2l). Meth od C. A mixture of 518 µL of cyclohexanone
5.00 mmol), 2.0 g of technical grade Ti(OEt)
R
) 6.1 min, (S)-2k t
R
) 7.6 min): [R]
D
-2.1° (c
-1
1
1
3
); IR 1067, 1572, 1593, 1605 cm ; H NMR (500
1
H
17NO
2
13
(
(
R)-(-)-N-(2-Met h oxyca r b on ylet h ylid en e)-2-m et h yl-
H
p r op a n esu lfin a m id e (2f). Meth od B. The general procedure
was followed with 2.41 g (20.0 mmol) of (R)-1, 2.13 g (24.0
mmol) of methyl glyoxalate, and 6.36 g (40.0 mmol) of CuSO .
4
(
2
1
(
4
(∼8.5 mmol),
(
21) Kelly, T. R.; Schmidt, T. E.; Haggerty, J . G. Synthesis 1972,
and 666 mg of (R)-1 (5.50 mmol) in 9 mL of THF was warmed
to 60 °C for 4 h. Pure 2l was obtained (918 mg, 91%) as a clear
5
44.

1
284 J . Org. Chem., Vol. 64, No. 4, 1999
Liu et al.
and colorless oil from Kugelrohr distillation (40 °C at 5
7.92 (d, J ) 7.5 Hz, 1H), 8.07 (d, J ) 7.5 Hz, 1H), 8.30 (s, 1H);
2
3
1
13
µTorr): [R]
D
-184.0° (c 1.0, CHCl
3
); H NMR (400 MHz) δ
C NMR (101 MHz) δ 19.72, 22.53, 57.49, 123.79, 126.61,
1
2
3
5
.21 (s, 9H), 1.62-1.86 (m, 6H), 2.41 (m, 2H), 2.70 (m, 1H),
127.62, 127.85, 128.11, 129.16, 132.61, 134.82, 136.04, 176.08.
Anal. Calcd for C16H19NOS: C, 70.29; H, 7.00; N, 5.12.
Found: C, 70.15; H, 6.81; 5.07.
(R)-(-)-N-(4-Meth yl-2-p en tylid en e)-2-m eth ylp r op a n e-
su lfin a m id e (2q). Meth od C. A mixture of 1.87 mL of
1
3
.87 (m, 1H); C NMR (100 MHz) δ 22.03, 25.26, 27.32, 27.83,
4.34, 40.60, 55.88, 188.59. Anal. Calcd for C10 19NOS: C,
9.66; H, 9.51; N, 6.96. Found: C, 59.34; H, 9.49; N, 7.27.
R)--(-)-N-(3-Meth yl-2-bu tylid en e)-2-m eth ylp r op a n e-
su lfin a m id e (2m ). Meth od C. A mixture of 534 µL of
-methyl-2-butanone (5.00 mmol), 2.0 g of Ti(OEt)
H
(
4-methyl-2-pentanone (15.0 mmol), 4.0 g of Ti(OEt)
4
(∼30
3
4
(∼ 8.5
mmol), and 1.00 g of (R)-1 (16.5 mmol) in 30 mL of THF was
warmed to 70 °C for 10 h. Pure 2q was obtained (2.67 g, 88%)
as a clear and colorless oil from Kugelrohr distillation (36 °C
mmol), and 605 mg of (R)-1 (8.5 mmol) in 9 mL of THF was
warmed to 60 °C for 7 h. Pure 2m was obtained (874 mg, 84%)
as a clear and colorless oil from Kugelrohr distillation (32 °C
at 5 µTorr). No racemization was observed by chiral HPLC
analysis (Diacel Chiralpak OD column, 95:5 hexanes/IPA; 0.9
1
at 5 µTorr) as a mixture of E/Z isomers (6:1 by H NMR in
-1
1
CDCl
3
): [R]23
D
3
-185.0° (c 1.0, CHCl ); IR 1076, 1621 cm ; H
NMR (400 MHz) E isomer δ 0.93-0.97 (m, 6H), 1.24 (s, 9H),
2.04-2.22 (m, 1H), 2.23-2.34 (m, 2H), 2.37 (s, 3H), Z isomer
δ 0.93-0.97 (m, 6H), 1.24 (s, 9H), 2.04-2.22 (m, 1H), 2.16 (s,
3H), 2.53-2.57 (m, 1H), 2.69-2.76 (m, 1H); 13C NMR (101
MHz) E isomer δ 22.10, 22.45, 22.48, 22.13, 25.57, 52.45, 56.10,
185.11. Anal. Calcd for C10H21NOS: C, 59.07; H, 10.41; N, 6.89.
Found: C, 58.90; H, 10.30; N, 7.03.
(R)-(-)-N-(2-H exylid en e)-2-m et h ylp r op a n esu lfin a m -
id e (2r ). Meth od C. A mixture of 1.12 mL of 2-hexanone (9.09
mL/min; 244 nm; (R)-2m t
R
) 5.7 min, (S)-2m t ) 6.7 min):
R
-1
2
3
1
[
(
1
(
R]
D
3
-185.7° (c 1.0, CHCl ); IR 1074, 1624 cm ; H NMR
400 MHz) δ 1.09 (d, J ) 6.8 Hz, 3H), 1.10 (d, J ) 6.8 Hz, 3H),
.20 (s, 9H), 2.28 (s, 3H), 2.53 (septet, J ) 6.8, 1H); 13C NMR
101 MHz) δ 19.48, 19.72, 20.99, 22.10, 41.24, 56.35, 189.10.
Anal. Calcd for C 19NOS: C, 57.10; H, 10.12; N, 7.40.
Found: C, 57.13; H, 10.32; N, 7.58.
R)-(-)-N-(2-Meth yl-3-h ep tylid en e)-2-m eth ylp r op a n e-
su lfin a m id e (2n ). Meth od C. A mixture of 571 mL of
-methyl-3-heptanone (3.64 mmol), 1.6 g of Ti(OEt)
9
H
(
mmol), 4.0 g of Ti(OEt)
mmol) in 18 mL of THF was warmed to 70 °C for 10 h. Pure
4
(∼17 mmol), and 1.00 g of (R)-1 (8.26
2
4
(∼ 6.62
mmol), and 400 mg of (R)-1 (3.31 mmol) in 6.6 mL of THF
was warmed to 75 °C for 24 h. Pure 2n was obtained (591 mg,
2r was obtained (1.29 g, 77%) as a clear and colorless oil from
chromatography (5:1 hexanes/Et
isomers (5:1 by 1H NMR in CDCl
-164.4° (c 1.0, CHCl ); IR 1076, 1625 cm ; H NMR (400 MHz)
2
O) as a mixture of E/Z
23
7
7%) as a clear and colorless oil from chromaotography (5:1
3
and toluene-d
8
): [R]
D
2
3
-1 1
hexanes/Et
2
O): [R]
D
-181.2° (c 1.0, CHCl
3
); IR 1076, 1623
3
-
1
1
cm ; H NMR (400 MHz) δ 0.92 (t, J ) 7.3, 3H), 1.10-1.17
E isomer δ 0.85 (m, 3H), 1.5 (s, 9H), 1.20-1.31 (m, 2H), 1.46-
1.54 (m, 2H), 2.23 (s, 3H), 2.26-2.39 (m, 2H), Z isomer δ 0.85
(m, 3H), 1.5 (s, 9H), 1.20-1.31 (m, 2H), 1.46-1.54 (m, 2H),
2,08 (s, 3H), 2.60-2.64 (br m, 2H); 13C NMR (101 MHz) E
isomer δ 13.77, 22.05, 22.13, 22.84, 27.58, 43.07, 56.11, 185.51,
Z isomer δ 15.05, 22.05, 22.73, 27.96, 29.26, 36.86, 55.82,
186.32. Anal. Calcd for C10H21NOS: C, 59.07; H, 10.41; N, 6.89.
Found: C, 59.17; H, 10.56; N, 7.04.
(R)-(-)-N-(3,3-Dim eth yl-2-bu tyliden e)-2-m eth ylpr opan e-
su lfin a m id e (2s). Meth od C. A mixture of 361 mg of
(m, 6H), 1.23 (s, 9H), 1.32-1.41 (m, 2H), 1.53-1.59 (m, 2H),
2
1
1
.61-2.80 (m, 2H), 2.73-2.80 (m, 1H); 13C NMR (101 MHz) δ
3.72, 20.14, 20.37, 22.25, 23.02, 29.53, 34.85, 39.00, 56.38,
92.48. Anal. Calcd for C12H25NOS: C, 62.29; H, 10.89; N, 6.05.
Found: C, 62.15; H, 10.69; N, 6.21.
R)-(-)-N-(1-P h en ylp en tylid en e)-2-m eth ylp r op a n esu l-
fin a m id e (2o). Meth od C. A mixture of 1.47 g of 1-phenyl-
pentanone (9.09 mmol), 3.4 g of Ti(OEt)
(
4
(∼14 mmol), and 1.00
g of (R)-1 (8.26 mmol) in 18 mL of THF was heated to reflux
for 5h. Pure 2o was obtained (1.68 g, 77%) as a yellow viscous
pinacolone (3.64 mmol), 1.6 g of Ti(OEt)
4
(∼6.6 mmol), and
2
3
oil from silica chromatography (80:20 hexanes/EtOAc): [R]
D
400 mg of (R)-1 (3.31 mmol) in 6 mL of THF was warmed to
70 °C for 24 h. Pure 2s was obtained (553 mg, 82%) as a clear
and colorless oil from Kugelrohr distillation (37 °C, 5 µTorr):
-1 1
-
30.3° (c 1.0, CHCl
400 MHz) δ 0.95 (t, J ) 7.3, 3H), 1.33 (s, 9H), 1.38-1.49 (m,
H), 1.60-1.70 (m, 2H), 3.18 (m, 1H), 3.28 (m, 1H), 7.41-7.49
3
); IR 1073, 1570, 1591, 1603 cm ; H NMR
(
[R]23
-1
1
2
(
2
1
D
3
-189.0° (c 1.0, CHCl ); IR 1076, 1615 cm ; H NMR
1
3
13
m, 3H), 7.85-7.87 (m, 2H); C NMR (101 MHz) δ 13.73, 22.58,
(400 MHz) δ 1.14 (s, 9H), 1.22 (s, 9H), 2.29 (s, 3H); C NMR
(101 MHz) δ 18.2, 22.2, 27.5, 42.9, 56.5, 190.8. Anal. Calcd for
2.95, 30.67, 32.32, 57.30, 127.43, 128.49, 131.41, 137.90,
80.31. Anal. Calcd for C15 23NOS: C, 67.88; H, 8.73; N, 5.28.
H
10
C H21NOS: C, 59.07; H, 10.41; N, 6.89. Found: C, 58.90; H,
Found: C, 67.94; H, 8.55; N, 5.21.
R)-(+)-N-(1-(2′-Na p h t h yl)et h ylid en e)-ter t-bu t a n esu l-
fin a m id e (2p ). Meth od C. A mixture of 1.55 g of 2′-aceto-
naphthone (9.10 mmol), 3.4 g of Ti(OEt)
10.65; N, 7.04.
(
Ack n ow led gm en t. The support of the NSF, Abbott
Laboratories, and Berlex Biosciences is gratefully ac-
knowledged. D.A.C. thanks Pharmacia & Upjohn for a
graduate fellowship.
4
(∼14 mmol), and 1.00
g of (R)-1 (8.26 mmol) in 18 mL of THF was heated to reflux
for 15h. Pure 2p was obtained (1.81 g, 86%) as a yellow powder
from silica chromatography (85:15 hexanes/EtOAc): [R]23
D
-1 1
+
11.7° (c 1.0, CHCl
3
); IR 1078, 1572, 1589 cm ; H NMR (400
MHz) δ 1.36 (s, 9H), 1.60 (s, 3H), 7.56 (m, 2H), 7.86 (m, 2H),
J O982059I