Synthesis of an enantiomerically pure 1,3-thiazole-5(4H)-thione and its stereoselective 1,3-dipolar cycloaddition with an azomethine ylide

Article abstract of DOI:10.1002/1522-2675(200207)85:7<2073::AID-HLCA2073>3.0.CO;2-1

Starting from the enantiomerically pure 2H-azirin-3-amines (R,S)-4 and (S,S)-4, the enantiomeric, optically active 4-benzyl-4-methyl-2-phenyl-1,3-thiazole-5(4H)-thiones (R)-1 and (S)-1, respectively, have been prepared (Schemes 2 and 3). In each case, the

Full text of DOI:10.1002/1522-2675(200207)85:7<2073::AID-HLCA2073>3.0.CO;2-1

Helvetica Chimica Acta Vol. 85 (2002)
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Synthesis of an Enantiomerically Pure 1,3-Thiazole-5(4H)-thione and Its
Stereoselective 1,3-Dipolar Cycloaddition with an Azomethine Ylide
by Andreas Gebert1) and Heinz Heimgartner*
Organisch-chemisches Institut der Universit‰t Z¸rich, Winterthurerstrasse 190, CH-8057 Z¸rich
Starting from the enantiomerically pure 2H-azirin-3-amines (R,S)-4 and (S,S)-4, the enantiomeric,
optically active 4-benzyl-4-methyl-2-phenyl-1,3-thiazole-5(4H)-thiones (R)-1 and (S)-1, respectively, have been
prepared (Schemes 2 and 3). In each case, the reaction of 1 with N-(benzylidene)[(trimethylsilyl)methyl]amine
(2) in HMPA in the presence of CsF and trimethylsilyl triflate gave a mixture of four optically active spirocyclic
cycloadducts (Scheme 4). Separation by preparative HPLC yielded two pure diastereoisomers, e.g., (4R,5R,9S)-
10 and (4R,5R,9R)-10. The regioisomeric compounds 11 were obtained as a mixture of diastereoisomers. The
products were formed by a 1,3-dipolar cycloaddition of 1 with in situ generated azomethine ylide 3, which
attacks 1 stereoselectively from the sterically less-hindered side, i.e., with (R)-1 the attack occurs from the re-
side and in the case of (S)-1 from the si-side.
1. Introduction. Since the first [2 ‡ 3] cycloadditions, described by Huisgen and co-
workers [1 5], azomethine ylides became a well-known class of 1,3-dipoles, and they
found many applications in the synthesis of five-membered heterocycles [6 17]. The
1,3-cycloaddition with olefins and acetylenes has frequently been used for the
preparation of pyrrolidines and pyrroles with a large range of substitution
[3][7][18 24], and DeShong et al. described an intramolecular variation for the
synthesis of bicyclic pyrrolidines and pyrroles [25]. Azomethine ylides were also used in
the synthesis of indolizines [26] and other natural products [12][27 29], recent
examples being those of epibatidine and epiboxidine, which were found to have
potential analgesic activity [30][31]. On the other hand, analogous reactions with
thiocarbonyl compounds leading to 1,3-thiazolidines are rarely described [32 37], but
recently, Gallagher and co-workers published an elegant synthesis of penam and penem
skeletons by 1,3-dipolar cycloadditions of azomethine ylides with thioketones [38].
Convenient methods to generate nonstabilized azomethine ylides are the desily-
lation of a-silyliminium salts [11][12][39][40] and a-cyano-a'-silylamines, [32] or the
treatment of a-silylated imines with trimethylsilyl triflate [41] (for other methods see
[42 50]).
For many years, our research interest has been focused on the reactivity of the
thiocarbonyl group in 1,3-dipolar cycloaddition reactions [51 56]. In the last few years,
we reported on the cycloadditions of azomethine ylides with aromatic thioketones
[57][58] and 1,3-thiazole-5(4H)-thiones [59][60]. Recently, we reported on a stereo-
selective cycloaddition of an azomethine ylide, generated via thermal ring opening of
cis-1-methyl-2,3-diphenylaziridine, with a chiral 1,3-thiazole-5(4H)-thione [61].
1
)
Part of the Ph.D. thesis of A.G., Universit‰t Z¸rich, 2001; present address: F. Hoffmann-La Roche AG,
Basel.

2074
Helvetica Chimica Acta Vol. 85 (2002)
Scheme 1
Me3Si
N
Ph
2
Ph
HMPA, CsF
Me3Si-triflate
N
N
S
Ph
Ph
N
Ph
Ph
N
N
S
H
Ph
N
+
+
SiMe3
Ph
Ph
S
S
Ph
S
(RS)-1
3
S
H
In the present paper, we present our results on the stereoselectivity of the
cycloaddition of azomethine ylide 3, generated via a-desilylation of N-(benzyli-
dene)[(trimethylsilyl)methyl]amine (2) with CsF as desilylation reagent in the
presence of trimethylsilyl triflate [41][43], with enantiomerically pure 4-benzyl-4-
methyl-2-phenyl-1,3-thiazole-5(4H)-thiones 1 (Scheme 1).
2. Results and Discussion. A few years ago, Bucher et al. developed a synthesis and
a preparative method for the chromatographic separation of the diastereoisomeric 2-
benzyl-2-methyl-3-amino-2H-azirines (R,S)-4 and (S,S)-4 [62]. We synthesized the
chiral amine 5 (Scheme 2) from (S)-proline in four steps according to the procedure of
Bucher et al. While in [62] a malonic ester synthesis according to Wipf [63] was applied
to prepare 2-methyl-3-phenylpropanoyl chloride, which was reacted with amine 5 to
yield the amide 6, we followed the procedure depicted in Scheme 2. Reaction of 5 with
propanoyl chloride yielded amide 7 in accordance with the procedure described by
Brun et al. [64]. Deprotonation with LDA followed by benzylation gave 6 in good yield
as a mixture of two diastereoisomers (ratio ca. 0.6 :1 (NMR)). Thionation with
Lawesson reagent provided the thioamide 8 in 94% yield, which was converted to the 2-
benzyl-2-methyl-2H-azirin-3-amine 4 as a mixture of two diastereoisomers2).
The diastereoisomers (R,S)-4 and (S,S)-4 were separated chromatographically
according to [62], and the reaction with PhCOSH led to the monothioamides (R,S)-9
and (S,S)-9, respectively (Scheme 3). The enantiomerically pure 4-benzyl-4-methyl-2-
phenyl-1,3-thiazole-5(4H)-thiones (R)-1 and (S)-1 were obtained in 69 and 65% yield,
respectively, via thionation and cyclization of (R,S)-9 and (S,S)-9 with Lawesson
reagent in toluene at 80 9083). In both cases, the IR, NMR, and MS data were
identical with those of rac-1 [65]. The optical rotation in CHCl3 was [a]2D2 ˆ ‡106.4 for
(R)-1 and À120.6 for the (S)-1 isomer.
2
)
The detour via 8 gave a better yield (57%) of the azirine 4 compared with the direct treatment of 6 with
COCl2. One reason is that the reaction via thioamide 8 is much faster, thereby suppressing the formation of
side products. Another advantage is that one can use commercially available 2m COCl2 solution in toluene
instead of condensing COCl2 into the reaction vessel.
3
)
Only the reaction sequence leading to (R)-1 is shown.

Helvetica Chimica Acta Vol. 85 (2002)
2075
Scheme 2
O
O
LDA, –78°,
LiClO4,
O
HN
Et3N, AcOEt
N
Ph
N
+
Cl
PhCH2Br
OMe
OMe
OMe
5
7
6
L. R.,
toluene
S
1. COCl2, CH2Cl2
2. DABCO, THF
Ph
N
Ph
N
N
3. NaN3, THF
OMe
OMe
(R,S)-4
(S,S)-4
8
Scheme 3
Ph
Ph
S
L. R.,
O
O
Et2O
toluene,
N
Ph
+ (R,S)-4
N
Ph
N
H
S
0°, 5h
80–90°
SH
Ph
S
OMe
(R)-1
(R,S)-9
A solution of equimolar amounts (0.8mmol) of ( R)-1 and (S)-1, respectively, and
imine 2 in HMPA was slowly dropped into a solution of 0.2 mmol trimethylsilyl triflate
and 0.2 mmol of CsF in HMPA. The mixture was stirred at room temperature for 3 d.
After that time, 1 was completely consumed, and after the usual workup, the mixture of
four isomers was separated by preparative HPLC (SiO2). The first separation with
hexane/AcOEt 4 :1 gave two fractions with 10 and 11, respectively, both as mixtures of
diastereoisomers (Scheme 4). The more-polar fraction was separated in a second run
with hexane/AcOEt 9 :1 to yield pure diastereoisomers of 10. The diastereoisomers of
11 (less-polar fraction) could not be separated by preparative HPLC.
For example, from the reaction of (R)-1 with 2 (Scheme 4), a mixture of products
was isolated in 59% yield. After HPLC, the regioisomer 11 was obtained as a ca. 1 :1
mixture of diastereoisomers ((4R,5R,7RS)-11) in 23% yield, whereas (4R,5R,9S)-10
(19%) and (4R,5R,9R)-10 (17%) were obtained as pure diastereoisomers. The ratio of
the isolated regioisomers 10 and 11 was, therefore, 1.6 :1.

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Helvetica Chimica Acta Vol. 85 (2002)
Scheme 4
1. HMPA, CsF,
Ph
S
Ph
S
Ph
Me3Si-triflate
H2O, Et2O
2.
3.
Ph
H
N
N
7
+
+ 2
N
4
4
HPLC hexane/AcOEt 4:1
Ph
N
Ph
N
5
5
S
S
S
9
Nucleosil 100-7
Ph
S
H
Ph
(4R,5R,9RS)-10
(4R,5R,7RS)-11
(R)-1
HPLC hexane/AcOEt 9:1
Nucleosil 100-7
1.70 ppm
+
N
1.09 ppm
Ph
S
Ph
S
N
Ph
N
Ph
S
Ph
N
H
S
H
Ph
(4R,5R,9S)-10
(4R,5R,9R)-10
The two stereoisomers of type 10 differ in the orientation of the Ph group at C(9).
In the case of (4R,5R,9S)-10, the Ph group is cis-oriented to the Me group located at
C(4), whereas the relation is trans in (4R,5R,9R)-10. Therefore, the Me signal in the
1H-NMR spectrum is shifted to higher field (1.09 ppm) in the case of (4R,5R,9S)-10 as a
consequence of the anisotropic effect of Ph, while it appears in the expected range at
1.70 ppm in (4R,5R,9R)-10.
Analogous reactions were carried out with the enantiomeric 1,3-thiazole-5(4H)-
thione (S)-1. The cycloadducts were isolated in a total yield of 48% after workup and
preparative HPLC. Under the same HPLC conditions as in the case of (R)-1, the
diastereoisomers (4S,5S,9R)-10 and (4S,5S,9S)-10 were obtained in 11 and 15% yield,
respectively. The second regioisomer 11 was obtained in 22% yield as a mixture of the
diastereoisomers (4S,5S,7RS)-11. The regioisomers 10 and 11 were isolated in a ratio of
1.2 : 1.
The IR, NMR and MS data of compound (4R,5R,9S)-10 were identical to those of
(4S,5S,9R)-10, as well as the data for (4R,5R,9R)-10 and (4S,5S,9S)-10, and for the two
mixtures of diastereoisomers (4R,5R,7RS)-11 and (4S,5S,9RS)-11, indicating enantio-
meric structures in each case. On the other hand, [a]D values were opposite, e.g., ‡ 52.3
(CHCl3) in the case of (4R,5R,9R)-10 and À52.0 (CHCl3) for (4S,5S,9S)-10. The
presence of enantiomers is also shown by the CD spectra of (4R,5R,9S)-10 and
(4S,5S,9R)-10, measured in EtOH between 210 and 400 nm (Fig.).
The stereoselective formation of the [2 ‡ 3] cycloadducts is the result of an addition
of the azomethine ylide 3 from the sterically less-hindered side of the 1,3-thiazole-
5(4H)-thione 1, i.e., anti to the PhCH2 group at C(4). In the case of (R)-1, the attack
occurs from the Re side, and from the Si side in (S)-1. Furthermore, for the formation of
(4R,5R,9S)-10 and its enantiomer, the Ph group in the azomethine ylide 3 has to be cis

Helvetica Chimica Acta Vol. 85 (2002)
2077
Figure. CD Spectra ofthe enantiomers (4 R,5R,9S)-10 and (4S,5S,9R)-10
in relation, whereas the reaction with the trans-configured azomethine ylide leads to
(4R,5R,9R)-10 and (4S,5S,9S)-10 (Scheme 5)4).
The formation of the 7-Ph derivatives occurs also stereoselectively by addition of
cis- and trans-azomethine ylide from the less-hindered side of 1, but with the other
regioselectivity.
3. Conclusions.
In conclusion, we have shown that the in situ generated
azomethine ylide 3 can be trapped by the unsymmetrically substituted 1,3-thiazole-
5(4H)-thione 1 in a stereoselective [2 ‡ 3] cycloaddition reaction. The attack of the
ylide occurs stereoselectively from the Re side with (R)-1 and from the Si side with (S)-
1. The regioselectivity of the reaction is low.
We thank the analytical units of our institute for spectra and analyses, and the Swiss National Science
Foundation and F. Hoffmann-La Roche AG, Basel, for financial support.
Experimental Part
1. General. See [64]. N-(Benzylidene)[(trimethylsilyl)methyl]amine (2) was prepared according to [66].
THF and toluene were dried over Na before distillation. TLC: Merck 60 F254 SiO2-coated glass plates, 0.25 mm;
detection of the substances on the TLC plates (Merck) under UV light of 254nm wavelength. Column
4
)
A nonstereospecific two-step mechanism for the cycloaddition of 3 is another conceivable explanation.

2078
Helvetica Chimica Acta Vol. 85 (2002)
Scheme 5
Ph
Ph
N
N
(R)-1
(S)-1
S
S
Ph
Ph
S
S
attack from Re side
attack from Si side
Ph
Ph
Ph
S
Ph
S
N
Ph
S
Ph
N
Ph
N
S
N
H
Ph
N
S
Ph
N
N
Ph
Ph
S
S
Ph
S
SiMe3
H
N
SiMe3
(4R,5R,9S)-10
(4S,5S,9R)-10
Ph
Ph
Ph
Ph
N
N
H
N
S
N
Ph
S
S
Ph
N
N
Ph
N
S
Ph
S
Ph
S
S
S
H
SiMe3
H
N
Ph
Ph
Ph
SiMe3
(4S,5S,9S)-10
(4R,5R,9R)-10
Ph
Ph
Ph
Ph
N
N
Ph
H
H
N
S
N
Ph
S
S
N
S
Ph
Ph
Ph
N
N
S
Ph
S
S
S
Ph
N
Ph
SiMe3
SiMe3
(4R,5R,7RS)-11
(4S,5S,7RS)-11
chromatography (CC): Merck 60 230 400 mesh SiO2. Prep. HPLC: Jasco PU-987; UV detection (254 nm). [a]D
Values on a Zeiss LEP-A2 instrument at 20 238, in CDCl3. CD Spectra in CHCl3 on a Jasco Spectropolarimeter
J-715 with Jasco Spectra-Manager. If not otherwise stated, IR spectra in KBr, NMR spectra in CDCl3 at 300 (1H)
and 50.4 (13C) MHz, and CI-MS with NH3.
2. Synthesis ofChiral 1,3-Thiazole-5(4 H)-thiones 1. (S)-1-[2-(1-Methoxy-1-methylethyl)pyrrolidin-1-
yl]propan-1-one (7). A soln. of 2-(1-methoxy-1-methylethyl)pyrrolidine (5; 16.67 g, 116 mmol) in AcOEt
(800 ml) was cooled to À108 (acetone/ice), and Et3N (16.2 ml, 11.74 g, 116 mmol) was added. Then, propanoyl
chloride (10.14 ml, 10.73 g, 116 mmol) was slowly dropped into the cooled soln., keeping the temp. below ‡ 58.
After further stirring for 30 min and precipitation of Et3N ¥ HCl, the mixture was washed with 2m HCl and sat.
aq. NaCl soln. (400 ml each), dried (MgSO4), and evaporated: 21.25 g (92%) of crude 7, which was used directly
for the next reaction. 1H-NMR: 4.35 (d, J ˆ 8.1, 1 H); 3.53 3.45 (m, 1 H); 3.43 3.40 (m, 1 H); 3.17 (s, MeO);
2.33 (q, J ˆ 7.4, MeCH2); 2.07 2.03, 1.81 1.73 (2m, 4 H); 1.14 (t, J ˆ 7.45, Me); 1.13 (s, 2 Me). 13C-NMR: 173.5
(s, CO); 78.3 (s, Me2C); 62.9 (d, CHN); 49.1 (q, MeO); 47.5, 28.2, 25.1, 24.6 (4t, 4 CH2); 22.7, 22.0 (2q, Me2C);
‡
9.25 (q, MeCH2). CI-MS: 201 (23), 200 (100, [M ‡ 1] ).
(R,S)- and (S,S)-1-[2-(1-Methoxy-1-methylethyl)pyrrolidin-1-yl]-2-methyl-3-phenylpropan-1-one (6). To a
soln. of 7 (19.2 g, 96.5 mmol) in abs. THF (250 ml), LiClO4 (10.2 g, 96.5 mmol) was added, the mixture was

Helvetica Chimica Acta Vol. 85 (2002)
2079
cooled to À788 (acetone/dry ice), and LDA (58ml, 116 mmol) was added. After stirring for 45 min, PhCH 2Br
(14 ml, 116 mmol) was added dropwise, and the mixture was stirred at r.t. overnight. Then, it was poured into
200 ml of ice/H2O, acidified to pH 6 with 100 ml of 1n HCl, and extracted with EtO2 (300 ml). The org. layer was
washed with sat. aq. NaCl soln., dried (MgSO4), and the solvent was evaporated. The crude 6 was purified by
distillation (1508/0.004 mbar) to yield 20.81 g (75%) 6 as a mixture of diastereoisomers (ca. 0.6 :1). Colorless oil.
IR (Film): 3055w, 3020w, 2970s, 2925s, 2820m, 1635s, 1450m, 1425s, 1380m, 1360m, 1320w, 1270w, 1175m, 1145m,
1
1085s, 1060m, 915w, 755m, 740m, 700s. H-NMR: 7.25 7.12 (m, 5 arom. H); 4.32 (d, J ˆ 6.7, 0.6 H); 3.81 3.74
(m,0.4 H); 3.72 3.52 (m, 0.6 H); 3.36 3.25 (m, 1.4 H); 3.08, 3.04 (2s, MeO); 3.15 2.92 (m, 1.6 H); 2.90 2.75
(m, 0.4 H); 2.68 2.58( m, 1 H); 2.02 1.91 (m,1.4 H); 1.78 1.57 ( m, 1.6 H); 1.50 1.26 (m, 1 H); 1.23, 1.10 (2d,
1.1 :1.9, MeÀC(2)); 1.04, 0.98, 0.93, 0.86 (4s, Me2C). 13C-NMR: 176.2, 175.1 (2s, CO); 140.1, 139.9 (2s,
1 arom. C); 128.9, 128.7, 128.0, 125.9 (4d, 5 arom. CH); 78.3, 78.0 (2s, Me2C); 64.9, 62.6 (2d, CHN); 49.0, 48.8
(2q, MeO); 47.5, 45.8(2 t, PhCH2); 42.1, 40.6 (2t, 1 CH2); 40.0, 39.7 (2d, C(2)); 26.2, 24.9, 24.5, 22.2 (4t, 2 CH2);
‡
23.0, 21.7, 21.4, 19.1, 18.1, 16.8 (6q, MeÀC(2), Me2C). CI-MS: 291 (17), 290 (100, [M ‡ 1] ), 200 (12).
(R,S)- and (S,S)-1-[2-(1-Methoxy-1-methylethyl)pyrrolidin-1-yl]-2-methyl-3-phenylpropan-1-thione (8). A
mixture of 6 (20.3 g, 70.24 mmol) and Lawesson reagent (17 g, 46.83 mmol) in abs. toluene (150 ml) was
refluxed overnight. Then, the solvent was evaporated, and the crude product was purified by chromatography to
yield 20.06 g (94%) of 8 as a mixture of diastereoisomers. Pale yellow solid. M.p. 91.5 92.38. IR (Film): 2977m,
2828w, 1444s, 1381m, 1364m, 1224m, 1178m, 1086m, 1055s. 1H-NMR: 7.26 7.13 (m, 5 arom. H); 4.26 4.15
(m, 1 H); 3.78( d, J ˆ 8.4, 0.8 H); 3.79 3.47 (m, 2.2 H); 3.20 2.73 (m, 2 H); 3.10, 3.02 (2s, MeO); 1.82 0.85
(m, 3.3 H); 1.41, 1.24 (2d, MeÀC(2)); 1.10, 1.03, 0.97, 0.89 (4s, MeÀC(2), Me2C). 13C-NMR: 208.6 (s, CˆS);
139.9 (s, 1 arom. C); 129.3, 128.7, 128.1, 126.1 (4d, 5 arom. CH); 77.9, 77.3, 76.9, 76.5 (4s, Me2C); 68.6, 68.3 (2d,
CHN); 54.2, 50.8(2 t, PhCH2); 48.9, 48.7, 46.7, 46.4 (4q, MeO); 45.2, 44.4 (2t, 1 CH2); 45.2 (1d, C(2)); 26.0, 24.1,
‡
21.4 (3t, 2 CH2); 22.7, 22.5, 21.9, 19.9 (4q, MeÀC(2), Me2C). CI-MS: 308(5), 307 (19), 306 (100, [ M ‡ 1] ), 217
(4), 216 (42).
(R,S)- and (S,S)-1-[2-Benzyl-2-methyl-2H-azirin-3-yl]-2-(1-methoxy-1-methylethyl)pyrrolidine ((R,S)-4
and (S,S)-4). To a soln. of 8 (2.834 g, 9.29 mmol) and 3 drops of abs. DMF in abs. CH2Cl2 (9 ml) at 08, a 2n
COCl2 soln. in toluene (6.5 ml, 9.29 mmol, 1.4 equiv.) was added, the mixture was stirred for 60 min at 08, and
then the solvent was evaporated. The pale yellow residue was dissolved in abs. THF (10 ml), 1,4-
diazabicyclo[2.2.2]octane (DABCO; 1.04 g, 9.29 mmol, 1 equiv.) was added, and the mixture was stirred for
another 20 min at 08. After filtration, NaN3 (1.208g, 18.58mmol, 2 equiv.) was added, the mixture was stirred at
r.t. overnight, filtered over Celite, and the filtrate was evaporated. The residue was dissolved in CH2Cl2, washed
with sat. aq. NaHCO3 soln. (2Â), dried (MgSO4), and evaporated. CC (SiO2) yielded 530 mg (20%) of (R,S)-4,
611 mg of a mixture of diastereoisomers and 354 mg (13%) of (S,S)-4 (total yield: 1.5 g (56%)). The mixture of
diastereoisomers was separated by MPLC (hexane/AcOEt 1 :1, flow: 46 47 ml/min, detect.: l ˆ 254 nm). TLC
(hexane/AcOEt 1:1): R1f 0.53; Rf2 0.43 (cf. [62]).
N-((R)-1-Benzyl-1-methyl-2-{2-[(S)-1-methoxy-1-methylethyl]pyrrolidin-1-yl}-2-thioxoethyl)benzamide
((R,S)-9). A soln. of (R,S)-4 (2.18g, 7.64 mmol) in dry Et 2O (40 ml) was cooled to 08, and PhCOSH (1.05 g,
7.64 mmol) was slowly added. The mixture was stirred for 5 h, and the solvent was evaporated. CC (hexane/
AcOEt 4 :1) yielded 2.99 g (92%) of (R,S)-9 as a white foam. IR: 3200m (br.), 2980s, 1670s, 1650m, 1580w,
1510s, 1485s, 1455s, 1430s, 1380m, 1140w, 1080s, 700m. 1H-NMR: 8.30 (br. s, NH); 7.75 7.02 (4m, 10 arom. H);
5.74 (d, J ˆ 6.6, CHN); 4.35 4.30 (m, 1 H); 4.12, 3.57 (AB, J ˆ 14.3, PhCH2); 3.65 3.60 (m, 1 H); 3.15
(s, MeO); 2.15 2.00 (m, 2 H); 2.03 (s, Me); 2.02 1.85 (m, 2 H); 1.33, 1.22 (2s, Me2C). 13C-NMR: 204.5
(s, CˆS); 165.1 (s, CˆO); 136.9, 135.4 (2s, 2 arom. C); 131.1, 130.5, 128.4, 127.8, 126.8, 126.6 (6d, 10 arom. CH);
79.3 (s, Me2C); 72.5 (d, CHN); 64.9 (s, MeOC); 52.7, 42.7 (2t, 2 CH2); 48.7 (q, MeO); 24.6 (t, CH2); 24.2, 22.5,
‡
21.5 (3q, 3 Me); 22.4 (t, CH2). CI-MS: 425 (100, [M ‡ 1] ).
N-((S)-1-Benzyl-1-methyl-2-{2-[(S)-1-methoxy-1-methylethyl]pyrrolidin-1-yl}-2-thioxoethyl)benzamide
((S,S)-9). The analogous reaction of (S,S)-4 (1.9 g, 6.6 mmol) with PhCOSH yielded, after CC (hexane/AcOEt
4 :1), 2.5 g (90%) of (S,S)-9 as a white foam. 1H-NMR: 8.62 (br. s, NH); 7.82 7.23 (4m, 10 arom. H); 5.66
(d, J ˆ 8.5, CHN); 4.10 4.05 (m, 1 H); 4.05, 3.43 (AB, J ˆ 14.4, PhCH2); 3.62 3.55 (m, 1 H); 3.11 (s, MeO);
2.15 1.65 (m, 4 H); 2.04 (s, Me); 1.16, 1.02 (2s, Me2C). 13C-NMR: 204.6 (s, CˆS); 164.6 (s, CˆO); 136.5, 135.4
(2s, 2 arom. C); 131.2, 129.8, 128.5, 128.4, 127.0, 126.8 (6d, 10 arom. CH); 79.5 (s, Me2C); 72.6 (d, CHN); 65.3
(s, MeOC); 52.9, 43.1 (2t, 2 CH2); 48.6 (q, MeO); 27.5 (q, Me); 24.5, 22.6 (2t, 2 CH2); 22.5, 21.9 (2q, 2 Me). CI-
‡
MS: 425 (100, [M ‡ 1] ).
(R)-4-Benzyl-4-methyl-2-phenyl-1,3-thiazole-5(4H)-thione ((R)-1). A suspension of (R,S)-9 (2.99 g,
7.05 mmol) and Lawesson reagent (3.4 g, 8.4 mmol) in toluene (80 ml) was heated to reflux for 14 h. The
solvent was evaporated, Et2O was added, the mixture was filtered through a short SiO2 column, and washed with

2080
Helvetica Chimica Acta Vol. 85 (2002)
Et2O. Evaporation and CC (hexane/AcOEt 25 :1) yielded 1.43 g (69%) of (R)-1. Orange oil. [a]D ˆ ‡106.4 (c ˆ
0.73, CHCl3). IR: 3203w, 3084m, 3062m, 3030s, 2977m, 2926m, 2860w, 1608s, 1581s, 1493s, 1447s, 1364m, 1330w,
1313m, 1297m, 1258s, 1153s, 1096s, 1070m, 1029m, 1001m, 957s, 913s, 8 8 8s, 8 48s, 8 07w, 765s, 752s, 733s, 68 8s, 674s,
653s, 644m, 616m, 607m. 1H-NMR: 7.70 7.66 (m, 2 arom. H); 7.46 7.35 (m, 3 arom. H); 7.15 7.06 (m, 5 ar-
om. H); 3.44, 3.22 (AB, J ˆ 13.0, PhCH2); 1.68( s, Me). 13C-NMR: 248.8 (s, CˆS); 162.8( s, CˆN); 135.5, 131.8
(2s, 2 arom. C); 131.9, 130.5, 128.9, 128.1, 127.7, 126.8 (6d, 10 arom. CH); 100.3 (s, C(4)); 49.3 (t, PhCH2); 28.6
‡
(q, Me). CI-MS: 300 (10), 299 (20), 298(100, [ M ‡ 1] ), 208(9).
(S)-4-Benzyl-4-methyl-2-phenyl-1,3-thiazole-5(4H)-thione ((S)-1). The analogous reaction of (S,S)-9
(2.5 g, 5.89 mmol) with Lawesson reagent (2.8g, 7.07 mmol) gave 1.13 g (65%) of ( S)-1. Orange oil. [a]D
À120.6 (c ˆ 0.49, CHCl3).
ˆ
3. Cycloaddition of 1 with 2. General Procedure. A soln. of 1 (238mg, 0.8mmol) and 2 (153 mg, 0.8mmol)
in HMPA (5 ml) was added dropwise to a soln. of trimethylsilyl triflate (TMS-triflate; 45 mg, 0.04 ml) and CsF
(30 mg, 0.2 mmol) in HMPA (5 ml). The mixture was stirred for 3 d at r.t., poured into 150 200 ml of ice/H2O
and extracted with Et2O (3Â). The combined org. layers were dried (MgSO4), the solvent was partially
evaporated, and the crude products were filtered over a short SiO2 column (hexane/AcOEt 5 :1). Then, the
mixture of products was separated by prep. HPLC (SiO2, Nucleosil 100-7). First run (hexane/AcOEt 4 :1)
yielded two fractions, each as a mixture of diastereoisomers. The more-polar fraction was separated in a second
run with hexane/AcOEt 9 :1 yielding pure isomers.
(4R,5R,9S)-4-Benzyl-4-methyl-2,9-diphenyl-1,6-dithia-3,8-diazaspiro[4.4]non-2-ene ((4R,5R,9S)-10). Less-
polar fraction of second HPLC separation: 63 mg (19%). White foam. [a]D ˆ À196.3 (c ˆ 1.25, CHCl3). IR
(KBr): 3322m, 3059m, 3025m, 2924m, 1594s, 1574s, 1492s, 1447s, 1366m, 1312m, 1255s, 1174m, 1098m, 1076m,
1029m, 960s, 8 42m, 763s, 740m, 702s, 690s. 1H-NMR: 7.78 7.74 ( m, 2 arom. H); 7.61 7.58( m, 2 arom. H); 7.47
7.35 (m, 3 arom. H); 7.30 7.25 (m, 3 arom. H); 7.32 7.01 (m, 3 arom. H); 6.99 6.97 (m, 2 arom. H); 4.84
(s, HÀC(9)); 4.61, 4.53 (AB, J ˆ 9.3, CH2(7)); 3.41, 2.64 (AB, J ˆ 13.1, PhCH2); 2.45 (br. s, NH); 1.09 (s, Me).
13C-NMR: 162.8( s, CˆN); 138.5, 138.1, 133.6 (3s, 3 arom. C); 131.1, 129.1, 128.4, 128.3, 128.1, 128.0, 127.4, 126.0
(8d, 15 arom. CH); 95.5, 80.7 (2s, C(4), C(5)); 76.6 (d, C(9)); 52.8( t, C(7)); 44.5 (t, PhCH2); 17.6 (q, Me). ESI-
‡
‡
MS: 439 (12, [M ‡ Na] ), 417 (100, [M ‡ 1] ), 388(20), 298(40), 280 (39).
(4R,5R,9R)-4-Benzyl-4-methyl-2,9-diphenyl-1,6-dithia-3,8-diazaspiro[4.4]non-2-ene ((4R,5R,9R)-10).
More-polar fraction of the second HPLC separation: 57 mg (17%). White foam. [a]D ˆ ‡52.3 (CHCl3). IR
(KBr): 3299m, 3060m, 3026m, 2977m, 2931m, 1592s, 1574s, 1492s, 1446s, 1364m, 1312m, 1258s, 1234s, 1174m,
1156m, 1084m, 1029m, 1001w, 953s, 908m, 8 70w, 8 14m, 763s, 690s, 657s. 1H-NMR: 7.37 7.23 (m, 5 arom. H);
7.21 7.03 (m, 7 arom. H); 6.98 6.85 ( m, 3 arom. H); 4.41 (s, HÀC(9)); 4.32, 4.19 (AB, J ˆ 9.3, CH2(7)); 3.80,
2.84 (AB, J ˆ 12.7, PhCH2); 1.70 (s, Me). 13C-NMR: 166.2 (s, CˆN); 137.3, 135.7, 132.6 (3s, 3 arom. C); 131.3,
130.9, 128.8, 128.0, 127.8, 127.6, 127.5, 127.2, 126.2 (9d, 15 arom. CH); 93.4, 81.5 (2s, C(4), C(5)); 76.5 (d, C(9));
‡
52.0 (t, C(7)); 46.0 (t, PhCH2); 17.9 (q, Me). ESI-MS: 417 (100, [M ‡ 1] ), 298(61), 266 (17).
(4R,5R,7R)- and (4R,5R,7S)-4-Benzyl-4-methyl-2,7-diphenyl-1,6-dithia-3,8-diazaspiro[4.4]non-2-ene
((4R,5R,7RS)-11). Less-polar fraction of the first HPLC separation. Mixture of diastereoisomers (ca. 1 :1):
76 mg (23%). White foam. IR (KBr): 3299w, 3059m, 3026m, 2978m, 2931m, 1592s, 1574s, 1492s, 1446s, 1365m,
1312m, 1258s, 1234s, 1175m, 1157m, 1084m, 1029m, 1001w, 953s, 908m, 8 70w, 8 14m, 763s, 740m, 690s, 657w.
1H-NMR (2 diastereoisomers): 7.74 6.83 (m, 15 arom. H); 4.88, 4.49 (2s, HÀC(7)); 4.54, 4.47, and 4.31, 4.21
(2 AB, J ˆ 9.3, CH2(9)); 3.69, 3.44, and 3.05, 2.51 (2 AB, J ˆ 12.7, PhCH2); 1.29, 1.23 (2s, Me). 13C-NMR (2
diastereoisomers): 165.3, 165.1 (2s, CˆN); 138.8, 138.5, 138.2, 137.2, 136.1, 133.2 (6s, 3 arom. C); 131.5, 131.3,
131.1, 131.0, 130.7, 129.1, 128.9, 128.8, 128.6, 128.4, 128.2, 127.9, 127.8, 127.6, 127.4, 126.8, 126.3, 126.1 (18d,
15 arom. CH); 94.1, 93.3, 81.4, 81.1 (4s, C(4), C(5)); 75.0, 71.8(2 d, C(7)); 64.4, 63.2 (2t, C(9)); 52.5, 51.8(2 t,
‡
PhCH2); 18.6, 17.9 (2q, Me). ESI-MS: 417 (95, [M ‡ 1] ), 388 (16), 298 (100), 280 (89), 266 (40).
(4S,5S,9R)-4-Benzyl-4-methyl-2,9-diphenyl-1,6-dithia-3,8-diazaspiro[4.4]non-2-ene ((4S,5S,9R)-10). Ac-
cording to the General Procedure, (S)-1 (227 mg, 0.77 mmol) was reacted with 2 (147 mg, 0.77 mmol). The
second HPLC separation yielded 35 mg (11%) of (4S,5S,9R)-10 as the less-polar fraction. White foam. The IR,
NMR, and MS data are identical with those of (4R,5R,9S)-10. [a]D ˆ ‡184.1 (CHCl3).
(4S,5S,9S)-4-Benzyl-4-methyl-2,9-diphenyl-1,6-dithia-3,8-diazaspiro[4.4]non-2-ene ((4S,5S,9S)-10). More-
polar fraction of the second HPLC separation: 48mg (15%). White foam. The IR, NMR, and MS data are
identical to those of (4R,5R,9R)-10. [a]D ˆ À52.0 (CHCl3).
(4S,5S,7R)- and (4S,5S,7S)-4-Benzyl-4-methyl-2,7-diphenyl-1,6-dithia-3,8-diazaspiro[4.4]non-2-ene
((4S,5S,7RS)-11). Less-polar fraction of the first HPLC separation. Mixture of diastereoisomers (ca. 1 :1):
70 mg (22%). White foam. The IR, NMR, and MS data are identical to those of (4R,5R,7RS)-11.

Helvetica Chimica Acta Vol. 85 (2002)
2081
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Received May 2, 2002