Highly stereoselective C-allylation of an enantiopure α-sulfinyl thioacetamide

Article abstract of DOI:10.1021/jo0258610

The alkylation of the lithium enolate of enantiopure α-cyclohexylsulfinyl thioacetamide 1 with allyl bromides 5 possessing an electron-withdrawing group at the vinylic position does not occur at the sulfur center - as expected in the sulfur series - but a

Full text of DOI:10.1021/jo0258610

High ly Ster eoselective C-Allyla tion of a n
En a n tiop u r e r-Su lfin yl Th ioa ceta m id e
SCHEME 1
†
,†
St e´ phanie Nowaczyk, Carole Alayrac,*
Patrick Metzner,*,† and
Marie-Th e´ r e` se Averbuch-Pouchot‡
Laboratoire de Chimie Mol e´ culaire et Thio-organique
UMR CNRS 6507), ISMRA-Universit e´ de Caen, 6
(
Boulevard du Mar e´ chal J uin, F-14050 Caen, France, and
LEDSS (UMR CNRS 5616), Universit e´ J oseph Fourier,
BP 53, F-38041 Grenoble, France
patrick.metzner@ismra.fr
Received April 25, 2002
Abstr a ct: The alkylation of the lithium enolate of enan-
tiopure R-cyclohexylsulfinyl thioacetamide 1 with allyl bro-
mides 5 possessing an electron-withdrawing group at the
vinylic position does not occur at the sulfur center - as
expected in the sulfur series - but at the carbon center
through conjugate addition followed by bromide elimination.
The modest to excellent 1,2-asymmetric induction achieved
by the alkylsulfinyl group (dr up to 100:0) is explained by
an electronic model.
a modest to excellent 1,2-asymmetric induction of the
sulfinyl group.
The Claisen rearrangement is an invaluable method
for the stereoselective formation of the C-C bond,
7
especially in acyclic series. We have recently reported
the first examples of asymmetric [3.3] sigmatropic rear-
8
rangements mediated by racemic alkylsulfinyl groups.
The methodology was then successfully extended to the
5
enantiopure series. Indeed, ketene aminothioacetals 2
bearing an enantiopure vinylic alkylsulfinyl substituent
were readily prepared from (R)-2-cyclohexylsulfinyl-N,N-
dimethylethanethioamide (1) with full control of the
geometry of their double bonds. Compounds 2 underwent
a diastereoselective Claisen rearrangement (100% de)
upon heating at THF reflux and the resulting R-sulfinyl
γ-unsaturated thioamides were readily converted into the
parent amides 3 by oxidation with dimethyldioxirane.
As the introduction of electron-withdrawing substitu-
ents on the allylic moiety of ketene acetals is known to
The direct allylation of R-sulfinyl carbonyl compounds
is usually poorly stereoselective as exemplified by the
reaction of anions of R-sulfinyl esters or ketones with allyl
1
halides. The only case leading to good diastereoisomeric
excess was described by Fujita and involved the alkyla-
2
tion of R-sulfinyl R-alkylated ketones. Two other par-
ticular examples can be noted: the allylation of R-sulfinyl
3
R-alkylated radicals and the allylation of a cyclic R-sulfin-
4
yl ketone under phase-transfer catalysis.
5
Recently we described an original access to optically
9
accelerate their sigmatropic transposition, we wished to
pure R-allyl R-sulfinyl acetamides 3 (Scheme 1) via
chemoselective oxidation of the analogous thioacetamides
resulting from the asymmetric thio-Claisen rearrange-
ment of (ZZ)-ketene aminothioacetals 2, prepared by
examine the Claisen rearrangement of substrates 4a -d
5
(
Scheme 2). According to our previous studies, substrates
4
a -d should be readily accessible from the reaction of
the lithium enolate of thioamide 1 at -40 °C respectively
with 2-(bromomethyl)acrylic acid 5a (R ) CO H) and allyl
Me, CN, SO t-Bu), which prepa-
6
S-allylation of the enolate of thioacetamide 1 with allyl
2
bromides. In this Note, we report that with allyl reagents
possessing electron-withdrawing substituents, the eneth-
iolate of 1 does not undergo the generally observed
S-allylation but an unexpected direct C-allylation with
halides 5b-d (R ) CO
2
2
10
ration is described in the literature. However, to our
surprise, the S-allylation products 4a -d could not be
1
detected by either TLC or H NMR and the only isolated
products were thioamides 6a -d sthe expected Claisen
rearrangement products of 4a -d (Scheme 2). Moreover,
*
Author to whom correspondence should be addressed. Fax: +33
2
31 452 877.
†
ISMRA-Universit e´ de Caen.
Universit e´ J oseph Fourier, Grenoble.
‡
(7) For reviews about asymmetric Claisen rearrangement, see: (a)
Enders, D.; Knopp, M.; Schiffers, R. Tetrahedron: Asymmetry 1996,
7, 1847-1882. (b) Ito, H.; Taguchi, T. Chem. Soc. Rev. 1999, 28, 43-
50. (c) Chai, Y.; Hong, S.-p.; Lindsay, H. A.; McFarland, C.; McIntosh,
M. C. Tetrahedron 2002, 58, 2905-2928. For recent examples of
asymmetric thio-Claisen rearrangement see: (d) Devine, P. N.; Meyers,
A. I. J . Am. Chem. Soc. 1994, 116, 2633-2634. (e) Lemieux, R. M.;
Meyers, A. I. J . Am. Chem. Soc. 1998, 120, 5453-5457. (f) Lemieux,
R. M.; Devine, P. N.; Mechelke, M. F.; Meyers, A. I. J . Org. Chem.
1999, 64, 3585-3591. (g) He, S.; Kozmin, S. A.; Rawal, V. H. J . Am.
Chem. Soc. 2000, 122, 190-191.
(8) Alayrac, C.; Fromont, C.; Metzner, P.; Anh, N. T. Angew. Chem.,
Int. Ed. 1997, 36, 371-374.
(9) Khan, S. D.; Hehre, W. J . J . Org. Chem. 1988, 53, 301-305.
(10) Csuk, R.; H o¨ ring, U.; Schaade, M. Tetrahedron 1996, 52, 9759-
9776. Knochel, P.; Normant, J . F. Tetrahedron Lett. 1985, 26, 425-
428.
(1) Solladi e´ , G.; Matloubi-Moghadam, F.; Luttmann, C.; Mioskowski,
C. Helv. Chim. Acta 1982, 65, 1602-1606. Snider, B. B.; Wan, B. Y.-
F.; Buckman, B. O.; Foxman, B. M. J . Org. Chem. 1991, 56, 328-334.
Barros, D.; Carreno, C.; Garcia Ruano, J . L.; Maestro M. C. Tetrahe-
dron Lett. 1992, 33, 2733-2736.
(
2) Fujita, M.; Ishida, M.; Manako, K.; Sato, K.; Ogura, K. Tetra-
hedron Lett. 1993, 34, 645-648.
3) Beckwith, A. L. J .; Hersperger, R.; White, J . M. J . Chem. Soc.,
(
Chem. Commun. 1991, 1151-1152. De Mesmaeker, A.; Waldner, A.;
Hoffmann, P.; Mindt, T. Synlett 1993, 871-874.
(4) Garcia Ruano, J . L.; Rumbero, A. Tetrahedron: Asymmetry 1999,
1
0, 4427-4436.
5) Nowaczyk, S.; Alayrac, C.; Reboul, V.; Metzner, P.; Averbuch,
M. T. J . Org. Chem. 2001, 66, 7841-7848.
6) Alayrac, C.; Nowaczyk, S.; Lemari e´ , M.; Metzner, P. Synthesis
999, 669-675.
(
(
1
1
0.1021/jo0258610 CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/29/2002
6
852
J . Org. Chem. 2002, 67, 6852-6855

SCHEME 2
determined by HPLC analysis (Daicel AD column) as
identical with that of the precursor (R)-1 (98% ee),
demonstrating that the stereopurity of the initial sulfox-
ide was preserved.
S
The (2S,S ) configuration of the major isomer of 6c was
deduced from the X-ray crystallographic analysis of a
single crystal of its minor isomer. The same configuration
was assigned to 6a and to the major isomer of 6b,d
according to similar trends observed in the proton NMR
spectra.
The (2S,S
Claisen rearrangement products obtained from thioamide
. However, the fact that the formation of 6b,c was quasi
S
) configuration was common to all thio-
1
instantaneous at very low temperature made us question
whether the mechanism was really an S-allylation reac-
tion of the enethiolate of 1 and subsequent Claisen
rearrangement.
Enethiolates11,12 are soft, ambident nucleophiles which
may react through the carbon atom (with ketones and
aldehydes) or through the sulfur atom (with alkyl halides)
TABLE 1. C-Allyla tion of Su lfin yl Th ioa m id e 1
temp
(°C)
time
(min) product
yield
(%)
entry
R
dr
1
2
3
4
5
6
7
8
9
0
1
2
3
4
CO2H
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CN
-40 to rt
-90
-70
-40
0
20
45
60
90
10
5
6a
6b
6b
6b
6b
6b
6b
6b
6c
6c
6c
6d
6d
6d
100:0
78:22 100
78:22
85:15
92:8
97:3
96:4
90:10
88:12
91:9
42
a
a
depending on the electrophile. In particular, with Michael
90
82
55
57
45
46
80
87
76
73
70
70
acceptors,1
2,13
dithioester enolates undergo C-alkylation
5
10
10
10
5
10
10
and the reaction is known to be very fast even at low
temperatures. Now, allyl halides 5a -d can be viewed as
Michael acceptors. Then the reaction between the lithium
enolate of thioamide 1 with 5a -d probably proceeds via
a conjugate addition at the carbon center, followed by
elimination of the bromide anion. Such a mechanism
would explain why the S-allylation products 4a -d were
not detected. Moreover, the fact that the reaction was
slower in the case of 6a may be related to the less strong
electron-withdrawing character of the carboxylate group
as compared to that of the ester or cyano functions.
We observed that the selectivity of the formation of the
thioamides 6b,c was higher when the temperature of
allylation increased (entries 2 to 6 and 9 to 11). We
checked that no isomerization was occurring at room
temperature or by heating. These results may be ex-
plained by the isoinversion principle developed by
Scharf.14 As most encountered reactions are enthalpy
dominated, the general opinion presumes that the lower
the temperature is, the higher the stereoselectivity will
be. However the opposite relation may also be true if the
reaction is entropy dominated. This phenomenon is
related to the reaction intermediates which may adopt
different conformations, determined by enthalpy and
entropy factors, leading to diastereomeric products. In
our case, chelated or nonchelated species might be
involved according to the temperature. Scharf has intro-
duced the notion of isoinversion temperature as a frontier
between the two regions. At the isoinversion tempera-
ture, the diasteroselectivity is the highest. Below this
temperature, the diastereoselectivity increases with the
temperature while the reverse relation is observed at
temperatures higher than the isoinversion temperature.
According to Table 1, the isoinversion temperature of the
-70
-40
0
1
1
1
1
1
CN
CN
10
95:5
SO2t-Bu -30
SO2t-Bu -70
SO2t-Bu -90
10
35
50
58:42
65:35
66:34
a
Crude yield.
in the case of 6b,c, the reaction was complete after only
to 10 min at -40 °C. This result was quite unforeseen
in view of the sigmatropic transposition of substrates 2
Scheme 1), which proceeded in a few hours at THF
5
(
5
reflux. 6a was obtained as a single isomer (100% de).
The diastereomeric ratio of 6b-d was measured by
1
integration of the H NMR signal of the diastereomeric
proton and ranged from 58:42 to 91:9 (Table 1, entries 4,
1
1
0, and 12). In all cases, the H NMR signals of the proton
linked to the stereogenic carbon center of the major
isomer were shifted toward lower δ values.
Thorough examination of the influence of the temper-
ature of alkylation on the diastereopurity of 6b (R ) CO -
2
Me) led to another unanticipated result: the diastereo-
meric ratio decreased at lower temperature than -40 °C
(entries 2-3) but increased at higher temperature to
reach a maximum of 97:3 at 20 °C (entry 6). A further
increase of the temperature of allylation led to a lower
diastereomeric ratio (entry 8). A similar trend was
observed in the case of 6c (entries 9-11) and the best
diastereoselectivity (95:5 dr) was obtained at 0 °C (entry
1
1). By contrast, the diastereomeric ratio of 6d was
improved at lower temperature but still remained modest
(
66:34 at -90 °C). While the formation of 6b,c was
(
11) Metzner, P. In Topics in current ChemistrysOrganosulfur
extremely fast, being complete after less than 10 min
even at -70 °C, that of 6a ,d was slower (entries 1 and
1
separated either by flash chromatography on silica gel
or by crystallization. The enantiomeric excess of the
major isomer of 6b,c (respectively 96% and 98%) was
Chemistry I; Springer: Berlin, Germany, 1999; Vol. 204, pp 127-184.
(
12) Metzner, P. Synthesis 1992, 1185-1199.
3). Both diastereomers of thioamides 6b-d could be
(13) Metzner, P. J . Chem. Soc., Chem. Commun. 1982, 335-336.
Berrada, S.; Metzner, P.; Rakotonirina, R. Bull. Soc. Chim. Fr. 1985,
8
81-890.
14) Buschmann, H.; Scharf, H.-D.; Hoffmann, N.; Esser, P. Angew.
Chem., Int. Ed. Engl. 1991, 30, 477-515.
(
J . Org. Chem, Vol. 67, No. 19, 2002 6853

SCHEME 3
R-sulfinyl γ-unsaturated thioamides 6. Compounds 6 are
highly functionalized molecules and versatile synthons
as the thiocarbonyl moiety may be converted into various
sulfur-free functional groups such as carbonyl or alkoxy-
carbonyl groups.5
,12,15
Work is underway to use the
stereogenic sulfinyl group once more to create a C-C
bond, and to eliminate the chiral auxiliary as late as
possible.
Exp er im en ta l Section
Gen er a l In for m a tion . Solvents were dried immediately
prior use. Dry THF was distilled from sodium/benzophenone
under N . Commercial reagents were used directly as received.
2
All reactions were monitored by TLC carried out on analytical
silica gel TLC plates purchased from Merck silica gel and
visualized with UV light and iodine. Preparative flash liquid
chromatography was performed with Merck 60 silica gel (63-
1
2
00 µm) in the eluting solvents indicated below. H NMR spectra
1
3
were recorded on a 250-MHz spectrometer. C NMR spectra
were determined with the same spectrometer operating with
broad-band H decoupling. Elemental analyses were performed
1
SCHEME 4
by the Service central d’Analyse of CNRS at Vernaison or by
the “Service d’Analyse de l’ICSN-CNRS” at Gif sur Yvette for
C, H, N, and O or by LCMT for C, H, S, N, and O. Melting points
are uncorrected.
Th ioa m id es 6a -d . Only the signals of the minor isomer
which were clearly identified are given. The (2S,S ) configuration
S
of 6a and that of the major isomer of 6b-d was deduced from
that of the minor isomer of 6c.
Typ ica l P r oced u r e. (R)-2-Cyclohexylsulfinyl-N,N-dimeth-
ylethanethioamide (1, 1 equiv) was diluted in freshly distilled
THF (2 mL) and a 1.5 M solution of t-BuLi in pentane (1.05
equiv, except for carboxylic acid 6a for which 2.1 equiv were
used) was slowly added at -40 °C under nitrogen. After 1 h of
stirring at -40 °C, the reaction mixture was allowed to warm
to 0 °C then it was brought to a specific temperature and a
solution of allyl halides 5a -d (1.1 equiv) in THF (1 mL) was
added. The reaction was monitored by TLC. After completion,
the reaction mixture was hydrolyzed at 0 °C (5 mL) except for
formation of 6b would lie between 20 and 60 °C and that
of the formation of 6c would be higher than 0 °C.
As indicated above, the configuration of 6a and of the
S
major isomer of 6b-d was assigned as (2S,S ). The
stereochemical outcome of the reaction can be explained
by an electronic control that prevails over steric control
by analogy with the model that we proposed for the
Claisen rearrangement5 and in agreement with the
π-facial stereoselection demonstrated by Fujita for the
electrophilic addition reactions to vinylic sulfoxides
6
d . The aqueous phase was acidified with diluted sulfuric acid
,8
and extracted with CH Cl
layers were washed with water (5 mL), dried over MgSO , then
2
2
(3 × 5 mL). The combined organic
4
concentrated to dryness for analysis.
(
Scheme 3).2
(2S,S
ba m oyl)eth yl}p r op -2-en oic Acid (6a ). 6a was prepared from
R)-1 (230 mg, 1 mmol) and 2-(bromomethyl)acrylic acid (5a , 182
S
)-2-{[2-Cycloh exylsu lfin yl]-2-(N,N-d im et h ylca r -
The best donor substituent, that is the lone pair of the
(
sulfinyl moiety, is oriented anti to maximize σ-π overlap
that increases the energy level of the alkene HOMO. The
most electron-withdrawing group, that is the oxygen
atom, is placed at the inside allylic position to minimize
the σ*-π overlap that decreases the HOMO energy level.
To optimize the electronic transfer, the electrophile
approach is antiperiplanar to the lone pair leading
mg, 1.1 mmol). 5a was added at -40 °C then the temperature
was increased to room temperature within 90 min. Flash
chromatography on silica gel (ethyl acetate) afforded 132 mg
2
1
(42% yield, dr 100:0) of 6a as a yellow solid. Mp 124 °C; [R]
D
1
-
318 (c 1, CHCl
0H; 5 CH ), 3.05-3.20 (m, 2H; CH
m, 1H; CH ), 3.40 (s, 3H; NCH ), 3.45 (s, 3H; NCH
.02 (m, 1H; SOCH), 5.81 (s, 1H; CH d), 6.27 (s, 1H; CH
) δ 23.1, 25.2, 25.5, 25.9, 28.4 (5 CH
2
3
); H NMR (250 MHz, CDCl
and CH of Cy), 3.35-3.50
), 4.95-
d);
),
3
) δ 1.15-2.05 (m,
1
2
2
(
2
3
3
5
2
2
preferentially to the (2S,S
amides 6a -d .
S
) diastereomer of the thio-
13
C NMR (62.9 MHz, CDCl
3
36.5 (CH ), 42.0, 43.8 (N(CH ) ), 55.2 (CH of Cy), 66.1 (SOCH),
2
3
2
1
2
29.8 (CH d), 135.7 (Cd), 169.1 (CdO), 196.3 (CdS); IR (KBr)
Interestingly, the allylation of R-cyclohexylsulfinyl
acetamide 7 (Scheme 4) proceeded with a lower selectivity
-
1
ν 2930, 2854, 1690, 1524, 1002, 982 cm ; MS (70 eV, EI) m/z
+
(%) 318 (MH , 71), 247 (27), 188 (100), 133 (44), 83 (9); HRMS
S
(36% de) and, to our surprise, in favor of the (2R,S )
+
found 317.1201, C14
Calcd for C14
20.16. Found: C, 52.83; H, 7.37; N, 4.37; O, 14.93; S, 19.99.
(2S,S )-Meth yl 2-{[2-Cycloh exylsu lfin yl]-2-(N,N-d im eth -
H
23NO
3
S
2
(M ) requires 317.1119. Anal.
diastereomer of amide 8, suggesting that the steric
control is more significant in the oxygen series.
H
23NO S : C, 52.98; H, 7.31; N, 4.42; O, 15.13; S,
3 2
In summary, efficient 1,2-asymmetric induction by a
cyclohexylsulfinyl group was achieved through the ally-
lation of a thioacetamide enolate with allyl halides
possessing an electron-withdrawing group at the vinylic
position. The reaction was fast at low temperature, and
isoinversion was observed. We propose that a direct
C-allylation has taken place, but an S-allylation followed
by Claisen rearrangement cannot be ruled out. It led to
S
ylca r ba m oyl)eth yl}p r op -2-en oa te (6b). 6a was prepared
from (R)-1 (99 mg, 0.43 mmol) and methyl 2-(bromomethyl)-
propenoate (5b, 85 mg, 0.47 mmol). 5b was added at 20 °C and
the reaction mixture was stirred for 10 min at room temperature.
(
15) Schuijl, P. J . W.; Brandsma, L. Recl. Trav. Chim. Pays-Bas
968, 87, 929-939. Takahashi, H.; Oshima, K.; Yamamoto, H.; Nozaki,
H. J . Am. Chem. Soc. 1973, 95, 5803-5804.
1
6
854 J . Org. Chem., Vol. 67, No. 19, 2002

Flash chromatography on silica gel (ethyl acetate) afforded 81
mg (57% yield, dr 97:3) of 6b as a yellow oil. (2S,S )-6b (96%
de) was obtained after flash chromatography on silica gel (ethyl
acetate). Its enantiopurity (96% ee) was measured by HPLC on
a Chiralpack AD Daicel column (n-hexane/i-PrOH 85:15, λ )
(s, 2H; CH
CDCl ) δ 21.7, 24.3, 24.4, 25.4, 27.6 (5 CH
44.8 (N(CH ), 54.5 (CH of Cy), 61.3 (SOCH), 116.8 (CN or
Cd), 117.1 (CN or Cd), 133.9 (CH d), 192.9 (CdS).
2S,S )-2-Cycloh exylsu lfin yl-4-(ter t-bu tylsu lfon yl)-N,N-
d im eth ylp en t-4-en eth ioa m id e (6d ). 6d was prepared from
R)-1 (101 mg, 0.43 mmol) and 3-bromo-2-(tert-butylsulfonyl)-
2
d); 13C NMR of the (2R,S
S
) minor isomer (62.9 MHz,
S
3
2
), 33.6 (CH ), 41.6,
2
3 2
)
2
(
S
2
1
1
2
82.1 nm). [R]
D
-230 (c 0.5, CHCl
), 2.79-2.97 (m, 1H; CH of Cy), 3.10-
), 3.35-3.54 (m, 1H; CH ), 3.33 (s, 3H; NCH ),
), 4.46 (dd, J ) 5.0 Hz,
d), 6.24 (s, 1H; CH d);
),
), 55.3 (CH of Cy),
d), 135.3 (Cd), 167.4 (CdO), 196.4 (Cd
3 3
); H NMR (250 MHz, CDCl )
δ 1.10-2.05 (m, 10H; 5 CH
.24 (m, 1H; CH
.43 (s, 3H; NCH
2
(
3
3
2
2
3
propene (5d , 120 mg, 0.49 mmol). 5d was added at -70 °C and
the reaction mixture was stirred for 35 min then quenched at
this temperature with a mixture of THF/water 1:1 (5 mL). Flash
chromatography on silica gel (ethyl acetate/petroleum ether 1:1)
afforded 117 mg of 6d as a yellow solid (70% yield, dr 65:35).
Crystallization (ethyl acetate/pentane) gave isomerically pure
3
), 3.76 (s, 3H; CO
2
CH
3
2
J ) 8.8 Hz, 1H; SOCH), 5.85 (s, 1H; CH
2
1
3
C NMR (62.9 MHz, CDCl
4.6 (CH ), 41.9, 44.0 (N(CH
6.4 (SOCH), 129.9 (CH
3
) δ 22.9, 24.4, 25.4, 26.0, 28.4 (5 CH
2
3
6
2
3
)
2
), 52.2 (OCH
3
2
S); IR (NaCl) ν 2932, 2856, 1716, 1518, 1444, 1394, 1296, 1272,
19
1
6
(
(
d (100% de). Mp 110 °C, [R]
250 MHz, CDCl ) δ 1.15-2.10 (m, 10H; 5 CH
CH ), 2.68 (tt, J ) 3.8 Hz, J ) 11.9 Hz, 1H; CH of Cy), 3.32-
.57 (m, 2H; CH ), 3.43 (s, 3H; NCH ), 3.45 (s, 3H; NCH ), 4.81
D
-152 (c 1.16, CHCl
3
); H NMR
-
1
+
1
2
(
198, 1142, 1040 cm ; MS (70 eV, EI) m/z (%) 332 (MH , 1),
3
2
), 1.40 (s, 9H;
84 (1), 272 (3), 248 (19), 200 (76), 168 (21), 140 (73), 88 (30), 83
3 3
)
1
100), 55 (100), 44 (30). H NMR signals of the (2R,S
S
) minor
), 3.51 (s, 3H;
), 5.01 (dd, J ) 3.4 Hz, J ) 10.7 Hz,
H; SOCH), 5.86 (s, 1H; CH d), 6.21 (s, 1 H; CH d).
2S,S )-4-Cya n o-2-cycloh exylsu lfin yl-N,N-d im eth ylp en t-
-en eth ioa m id e (6c). 6c was prepared from (R)-1 (93 mg, 0.4
3
2
3
3
isomer (250 MHz, CDCl
3
) δ 3.33 (s, 3H; NCH
3
(
dd, J ) 4.1 Hz, J ) 10.6 Hz, 1H; SOCH), 6.15 (s, 1H; CHd),
NCH
1
3
), 3.78 (s, 3H; CO
2
CH
3
13
6
2
5
1
1
.22 (s, 1H; CHd); C NMR (62.9 MHz, CDCl
2.4, 25.4, 25.9, 28.2 (5 CH ), 36.1 (CH ), 42.7, 44.4 (N(CH
6.1 (CH of Cy), 61.0 (C(CH ), 66.3 (SOCH), 134.2 (CH
42.5 (Cd), 195.8 (CdS); IR (KBr) ν 3424, 2934, 2856, 1520,
3
) δ 23.2 ((CH
3
)
3
),
2
2
)
2
),
2
2
3
(
S
3
)
3
2
d),
4
mmol) and 2-(bromomethyl)acrylonitrile (5c, 73 mg, 0.5 mmol).
-1
454, 1394, 1286, 1100, 1042 cm ; MS (70 eV, EI) m/z (%) 394
5
c was added at 0 °C and the reaction mixture was stirred for
+
(
MH , 4), 264 (18), 247 (18), 189 (29), 147 (22), 133 (100), 83
7). Anal. Calcd for C17 : C, 51.89; H, 7.95; N, 3.56; S,
4.40. Found: C, 51.82; H, 7.88; N, 3.65; S, 24.07. H NMR
signals of the (2R,S ) minor isomer (250 MHz, CDCl ) δ 1.15-
.10 (m, 10H; 5 CH ), 1.39 (s, 9H; (CH ), 2.78 (tt, J ) 3.5 Hz,
J ) 11.8 Hz, 1H; CH of Cy), 3.32-3.57 (m, 2H; CH ), 3.45 (s,
H; NCH ), 3.54 (s, 3H; NCH ), 5.20 (dd, J ) 2.8 Hz, J ) 10.9
Hz, 1H; SOCH), 6.15 (s, 1H; CH
signals of the (2R,S ) minor isomer (62.9 MHz, CDCl
5.5, 26.2, 28.4 (4 CH ), 33.9 (CH ), 42.7, 45.7 (N(CH
), 63.5 (SOCH), 134.0 (CH d), 141.8
1
0 min. Flash chromatography on silica gel (ethyl acetate)
(
2
H
3 3
31NO S
afforded 90 mg of 6c as a yellow solid (76% yield, dr 95:5). Both
isomers were separated by flash chromatography on silica gel
1
S
3
(
ethyl acetate). The (2R,S
was assigned by X-ray crystallographic analysis. The enantio-
purity (98% ee) of the (2S,S ) major isomer (100% de) was
measured by HPLC on a Chiralpack AD Daicel column (n-
S
) configuration of the minor isomer
2
2
3 3
)
2
S
3
3
3
13
2
d), 6.26 (s, 1H; CH
2
d); C NMR
) δ 21.1,
), 55.7
2
1
hexane/i-PrOH 90:10, λ ) 284.0 nm). Mp 79 °C; [R]
D
-299 (c
) δ 1.10-2.10 (m, 10H;
), 2.65-2.75 (m, 1H; CH of Cy), 3.26-3.45 (m, 2H; CH ),
.47 (s, 3H; NCH ), 3.48 (s, 3H; NCH ), 4.39 (dd, J ) 4.2 Hz, J
10.5 Hz, 1H; SOCH), 5.96 (s, 1H; CH d), 5.97 (s, 1H; CH d);
) δ 23.1, 25.3, 25.4, 26.0, 28.6 (5 CH ),
), 42.4, 44.4 (N(CH ), 55.4 (CH of Cy), 65.9 (SOCH),
18.1 (CN or Cd), 118.2 (CN or Cd), 135.2 (CH d), 194.6
S
3
1
1
5
3
.25, CHCl
CH
3 3
); H NMR (250 MHz, CDCl
2
2
2
3 2
)
2
2
(
(
CH of Cy), 60.4 (C(CH
Cd), 195.2 (CdS).
)
3
3
2
3
3
)
2
2
1
3
C NMR (62.9 MHz, CDCl
7.5 (CH
3
2
Ack n ow led gm en t. We gratefully acknowledge the
CNRS and the R e´ gion Basse-Normandie for financial
support to St e´ phanie Nowaczyk.
3
1
2
3 2
)
2
(
CdS); IR (KBr) ν 3418, 2932, 2854, 2222, 1518, 1448, 1394, 1038
-
1
+
cm ; MS (70 eV, EI) m/z (%) 298 (M , 1), 247 (2), 167 (58), 83
100), 69 (20), 55 (98), 44 (96). Anal. Calcd for C14 OS : C,
6.35; H, 7.44; N, 9.39; S, 21.45. Found: C, 56.72; H, 7.42; N,
(
H
22
N
2
2
Su p p or tin g In for m a tion Ava ila ble: X-ray crystallo-
graphic data of (2R,S )-6c and HPLC chromatograms of 6b,c.
S
This material is available free of charge via the Internet at
http://pubs.acs.org.
5
9
1
.50; S, 21.32. H NMR signals of the (2R,S
) δ 1.10-2.10 (m, 10H; 5 CH ), 2.70-2.87 (m, 1H;
CH of Cy), 3.26-3.45 (m, 2H; CH ), 3.44 (s, 3H; NCH ), 3.48 (s,
H; NCH ), 4.76 (dd, J ) 3.1 Hz, J ) 11.0 Hz, 1H; SOCH), 5.88
S
) minor isomer (250
MHz, CDCl
3
2
2
3
3
3
J O0258610
J . Org. Chem, Vol. 67, No. 19, 2002 6855