Reaction of α-halo ketone with 2-aminothiol: a new synthesis of thiazolidines with the oxo group migrated to the original position occupied by halogen atom

Article abstract of DOI:10.1016/j.tet.2007.06.041

The reaction of 2-bromo-3-oxo steroids with 2-aminoethanethiol led to the stereoselective formation of spiro[steroid-3,2′-thiazolidin]-2-ones as the major product. With both cyclic and acyclic α-halo alkanones, the reaction gave the thiazolidines with the oxo group migrated to the original position occupied by the halogen atom. In addition, it was found that the use of microwaves affords improvement of?yields and shortening the reaction time in comparison with usual conditions.

Full text of DOI:10.1016/j.tet.2007.06.041

Tetrahedron 63 (2007) 8932–8938
Reaction of a-halo ketone with 2-aminothiol: a new synthesis
of thiazolidines with the oxo group migrated to the original
position occupied by halogen atom
a
Masatoshi Matsushita,a T. Tomoyoshi Takahashi,b, Takamitsu Utsukihara,
*
Yohei Shimizu,a Rob J. Jansenc and C. Akira Horiuchia,
*
aDepartment of Chemistry, Faculty of Science, Rikkyo (St. Paul’s) University, Nishi-Ikebukuro, Toshima-ku, Tokyo 171-8501, Japan
bDepartment of Chemistry, The Jikei University School of Medicine, Kokuryo-cho, Chofu-shi, Tokyo 182-8570, Japan
cDepartment of Organic Chemistry, University of Nijmegen, Fleminghstraat 756532 XE, Nijmegen, The Netherlands
Received 24 April 2007; revised 4 June 2007; accepted 5 June 2007
Available online 20 June 2007
Abstract—The reaction of 2-bromo-3-oxo steroids with 2-aminoethanethiol led to the stereoselective formation of spiro[steroid-3,20-thi-
azolidin]-2-ones as the major product. With both cyclic and acyclic a-halo alkanones, the reaction gave the thiazolidines with the oxo group
migrated to the original position occupied by the halogen atom. In addition, it was found that the use of microwaves affords improvement
of yields and shortening the reaction time in comparison with usual conditions.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
The chemistry1–6 and pharmacology7–9 of thiazolidines have
been widely investigated. Some thiazolidines possess radio-
protective7 and antihypertensive effects.8 Our interests in
new synthetic approaches to biologically active steroids
possessing functional nitrogen and sulfur groups led us to
investigate spiro[steroid-3,20-thiazolidine]s. Recently con-
siderable attention has been focused on the reactions of
carbonyl compounds with 2-aminoethanethiols to form
thiazolidines.10,11
The condensation of 2-bromo-3-oxo steroids 1, 2, 4 with 2-
amino thiols led to the stereoselective formation of spiro-
[steroid-3,20-thiazolidin]-2-ones 1a, 2a, 4a (Table 1). As
can be seen from Table 1, it was found that the reaction gives
preferentially the corresponding spiro[steroid-3,20-thiazol-
idin]-2-ones as the major product. Thus in order to discuss
the reactivity for low solubility of a-bromo steroidal ketone,
it was compared with that of benzene (entry 2). The use of
benzene as the reaction solvent was found to improve the
reaction yield significantly. So, we employed benzene as
the reaction solvent for the reaction of a-halo cycloalkanone
and a-halo acyclic ketone. Reaction of 1 for 1.5 h gave the
intermediate 1b (entry 3). Compound 1b is converted into
the spiro[steroid-3,20-thiazolidin]-2-one 1a under the same
conditions (entry 5). In the case of 4b-bromo 3-oxo 5b-steroid
3, spiro[steroid-3,20-thiazolidin]-4-one 3a and spiro[5b-cho-
lestan-3,20-thiazolidine] (3d) were obtained (entry 7). From
these results, it is considered that in the case of 4b-bromo de-
rivative 3, the unstable properties are based on 1:3-interac-
tion between the C-6,7 bond and C-4a bond.
In the previous paper,12 we reported that condensation of
2a-bromo-3-oxo steroids with 2-amino thiols (2-aminoeth-
anethiol or 2-aminobenzenethiol) gives spiro[steroid-3,20-
thiazolidin]-2-ones. In the resulting product, the oxo group
migrated to the original position occupied by the bromine
atom. Moreover, in order to clarify the generality of migra-
tion for oxo group, the reaction of cyclic and acyclic a-halo
alkanones with aminothiol gave the corresponding thiazol-
idine derivatives. Herein, we report the details concerning
these reactions.
If the condensation did not proceed stereospecifically, the
13C NMR spectrum would show two absorptions for the spiro
carbon.13 The 13C NMR spectral data supported the con-
sideration that only one of two possible C-3 isomers was ob-
tained during thiazolidine formation under these conditions.
Therefore, it is considered that in this condensation, the ring
Keywords: a-Bromo ketone; 2-Aminoethanethiol; Spiro[steroid-3,20-thi-
azolidine]s; Condensation; 1-Thia-4-azaspiro[4.5]decan-6-one; Microwave.
* Corresponding authors. Tel./fax: +81 3 3985 4766 (C.A.H.); tel.: +81 3
3480 1151; fax: +81 3 3480 4591 (T.T.T.); e-mail addresses: tom.
takahashi@jikei.ac.jp; cahoriuchi@nifty.com; horiuchi@rikkyo.ac.jp
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.06.041

M. Matsushita et al. / Tetrahedron 63 (2007) 8932–8938
8933
Table 1. Reaction of a-halo steroidal ketone with 2-aminoethanethiol or 2-aminobenzenethiol at room temperature
Entry
Substrate
Time (h)
Solvent
Product
Yieldc (%)
C8H17
C8H17
O
Br
1a
a
1
120
Pyridine
43
1
HN
O
H
S
H
2
3
1a
168
Benzene
Pyridine
1a
66
22
C8H17
Br
1a
1.5
1b
HN
S
H
C8H17
O
4
1b
100
Pyridine
61
HN
1c
S
H
5
6
1b
100
120
Pyridine
Pyridine
1a
48
49
C8H17
C8H17
O
Br
a
2
2a
S
S
O
NH
H
H
C8H17
C8H17
a
3
7
120
Pyridine
8
3a
O
H
NH
NH
H
H
O
Br
C8H17
11
S
3d
C8H17
C8H17
O
S
Br
O
8
a
120
Pyridine
64
H
N
4
4a
H
H
a
Reaction condition: substrate (10 mmol), 2-aminoethanethiol (60 mmol), and solvent (50 ml) were employed.
Reaction condition: substrate (1 mmol), 2-aminobenzenethiol (6 mmol), and solvent (10 ml) were employed.
Isolated yield.
b
c

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M. Matsushita et al. / Tetrahedron 63 (2007) 8932–8938
opening–ring closing equilibrium between the two isomers
did not occur. It was found that the thiazolidines 1a–4a ex-
isted in the reaction mixtures as single isomers from the
NMR spectrum. In this condensation, the carbonyl group ap-
parently rearranged to the carbon atom possessing bromine
atom in the starting bromo ketones 1–4. This condensation
led to the first isolation of pure spiro[steroid-3,20-thiazol-
idine]s by a simple procedure.
derivatives were obtained. In the cases of 2-bromo-4-tert-
butylcyclohexanone (9), 2-bromo-4-methylcyclohexanone
(10), or 2-bromo-1-tetralone (15), the product of migration
of the oxo group, 1-thia-4-aza-8-tert-butylspiro[4.5]decan-
6-one (9a), 1-thia-4-aza-8-methylspiro[4.5]decan-6-one
(10a) or spiro[naphthalene-1(2H),20-[1,3]thiazolidine]-30,40-
dihydro-20-one (15a) was obtained. Also, it was found that
in the case of a-halo acyclic ketones 16–21, the oxo group
migrated to the position occupied by the halogen atom
(Table 3).
The probable mechanism for the condensation is shown in
Scheme 1. The conversion of a-bromo ketone 1 into spiro-
[steroid-3,20-thiazolidin]-2-one 1a presumably involves the
autoxidation of 1,4-thiazine intermediate B. 13C NMR
measurement was applied to the 2a-bromo-3-oxo steroid
1–2-aminoethanethiol system in order to clarify the spectro-
scopic evidence for dihydro-1,4-thiazine intermediate B.
The bromo ketone 1 was allowed to react with 2-aminoeth-
anethiol under an argon atmosphere in the NMR tube. If the
intermediate B is present at high concentrations, the two
sp2 carbon atoms’ (–S–C]C–NH–) resonance should be
identified easily. The initial NMR spectrum (2 h, 25 ꢀC)
showed two sp2 carbon absorptions at 93.81 ppm and
129.28 ppm due to the dihydro-1,4-thiazine intermediate
B. However, the reactions under argon atmosphere did not
proceed.
However, for the synthesis of simple thiazolidine, the
method mentioned above requires long reaction times. It is
known that the microwave irradiation method has become
a powerful tool for preparation of various organic com-
pounds. So we conducted the present reactions under micro-
wave conditions in water from the viewpoint of green
chemistry. The reaction of 2-bromocyclohexanone (7) with
2-aminoethanethiol in water under microwave irradiation
gave the corresponding 1-thia-4-azaspiro[4.5]decan-6-one
(6a) within 10 min at 40 ꢀC. The reaction under heating con-
ditions in water with no microwave irradiation proceeded
gradually in low yield (<5%). Several examples are shown
in Table 4. From these results, it was found that the micro-
wave irradiation has the power to shorten the reaction time
of the key step reactions using water in comparison with
heating conditions.
After the NMR spin tube reaction for 2 h, dry oxygen was
bubbled into the reaction mixtures for 1 h. The 13C NMR
spectrum showed the peak at 205.37 ppm, due to the carbonyl
group. The final 13C NMR spectrum (24 h, 25 ꢀC) showed the
signals for compound 1a at 205.37 ppm for the C-2 carbonyl
carbon and at 82.92 ppm for the C-3 spiro carbon. The ab-
sorptions of –S–C]C–NH– due to the intermediate B dis-
appeared almost completely after 24 h. In general, it is
known that the alkyl-substituted dihydro-1,4-thiazines are
readily converted into the corresponding S-monoxides.14 Di-
hydro-1,4-thiazine B converts into the S-monoxide D or the
hydroperoxide intermediate C by oxygen.5 And then the
spiro compound 1a was probably generated by the ring con-
traction of C or D. Attempts to secure the desired intermedi-
ate C or D were unsuccessful. However, the intermediate 1b
could be isolated from the reaction mixtures. The compound
1b is converted into the spiro[steroid-3,20-thiazolidin]-2-one
1a under the same conditions.
The mass spectra of thiazolidines 1a and 2a had characteris-
tic fragment ions at m/z 140 (1a, 33%; 2a, 35%) (Scheme 2).
The existence of the spiro-thiazolidine ring at C-3 was indi-
cated by these fragment ions (i). Similarly, the presence of
the benzothiazoline ring at C-3 for 1c was also indicated
by the fragment ion (iii). Djerassi et al. mentioned that the
mass spectrum of 5a-androstan-3-one ethylene thioketals
had characteristic peaks at m/z 157 (iv, fission at the C-2,3,
C-5,10, C-7,8) and m/z 131 (vi, X¼S, fission at the C-3,4,
C-1,10).15 The fragment ions (i) of the thiazolidine deriva-
tives are analogous to those of the corresponding ethylene
thioketals. The existence of the carbonyl group at C-2 was
indicated indirectly by lack of the fragment ion (v)
(X¼NH) that corresponds to the fragment ion (vi) (X¼S)
in the case of ethylene thioketals. In the case of 4-oxo deriv-
ative 3a, the mass spectrum showed a peak at m/z 114 (23%)
due to the fragment (v) (X¼NH) arising from fission of the
C-1,10 and C-3,4 bonds. The presence of the thiazolidine
ring at C-3 and the carbonyl group at C-4 was indicated by
Moreover, in order to clarify the generality of migration of
the oxo group (Table 2, entries 6–8, 14), the reactions of
a-halo cycloalkanones with 2-aminoethanethiol were con-
ducted and in all cases the corresponding thiazolidine
1
the fragment. The H NMR spectrum showed a singlet at
d 1.109 which was assigned to the C-19 methyl group and
S
Br
Br
S
+
S
O
N
H
H
H
H
H
NH
NH
(A)
(B)
1b
1
O
S
OOH
O
H
N
S
N
or
H
N
S
H
(C)
H
(D)
1a
Scheme 1. The mechanism for the condensation reaction of 2a-bromo steroidal 3-ones.

M. Matsushita et al. / Tetrahedron 63 (2007) 8932–8938
8935
Table 2. Reaction of a-halo cycloalkanone with 2-aminoethanethiol at room
temperature
Table 3. Reaction of a-halo acyclic ketone with 2-aminoethanethiola
O
N
R1
S
NH2
Substratea
Time Solvent
(h)
Product
Yieldb
(%)
R2
R2
Entry
HS
R1
R.T.
O
16a-21a
X
16-21
O
O
S
Cl
1
2
1
1
Benzene
MeOH
88
83
5a
Entry Compound R1
R2
X
Solvent Time Productb
N
H
5
(h)
(%)
5
5a
1
2
3
4
5
6
7
8
16
17
18
19
20
21
CH3
CH3 Cl Benzene
MeOH
1
1
16a (71)
16a (60)
17a (94)
17a (86)
18a (94)
18a (86)
19a (100)
19a (96)
20a (100)
20a (95)
21a (98)
21a (97)
O
O
O
O
S
Cl
Br
I
C3H7 C2H5 Br Benzene 82
MeOH
C4H9 C3H7 Br Benzene 82
MeOH
C5H11 C4H9 Br Benzene 55
MeOH
CH3 Br Benzene 24
3
4
5
6
Benzene
100
98
6a
7
6
7
8
N
H
5
3.5 Benzene
6a
4
9
Ph
Ph
O
10
11
12
MeOH
C3H7 Br Benzene
MeOH
1
2
1
6
10
6
Benzene
Benzene
Benzene
Benzene
93
6d
a
O
O
O
Reaction condition: substrate (1 mmol), 2-aminoethanethiol (6 mmol),
and solvent (10 ml) were employed.
Isolated yield.
Br
S
b
6
7
8
100
94
O
9a
N
H
9
Br
dispersion measurement has indicated the presence of 99%
5a-isomer at equilibrium.16 In our case, the corresponding
5a-derivative was not detected. The 13C NMR spectrum
indicated that the thiazolidine derivative 3a existed as very
stable isomer in solution. Because of the high stability of
a-keto spiro-thiazolidine systems, equilibrium did not occur.
S
O
10a
11a
12a
N
H
10
11
Br
S
6
65
O
N
H
O
The mass spectrum of 4a showed peaks at m/z 499 (M+) and
456 (M+ꢁCH2]C]O+H, fission at the C-1,10, C-2,3). The
1H NMR spectrum showed two doublets for H2-1 at d 2.480
(J¼12.91 Hz, H-1a) and 3.041 (J¼12.91 Hz, H-1b). These
spectral data clearly supported the presence of the carbonyl
group at C-2 and spiro-thiazolidine moiety at C-3. In the case
of the substrate having 4,4-dimethyl group, it was found that
the condensation also occurs.
O
Cl
S
9
46
Benzene
83
12
N
H
O
Br
10
11
24
4
Benzene
MeOH
12a
12a
93
96
13
13
O
O
S
Br
In conclusion, it was found that the reaction of 2a-bromo-
3-oxo steroids, 2-bromo-4-tert-butylcyclohexanone, or 2-
bromo-4-methylcyclohexanone, with 2-aminothiol gave
diastereomerically pure spiro[steroid-3,20-thiazolidin]-2-ones,
12
13
62
4
Benzene
MeOH
80
14
86
14
N
H
14a
14
14a
O
Table 4. Reaction of a-bromo ketone with 2-aminoethanethiol using micro-
wave or heat at 40 ꢀC
14d
Entry Substrate Reaction Time
type
Solvent
Product Yieldb
(%)
O
Br
15
HN
S
7a
MW
Heat
MW
Heat
MW
Heat
MW
Heat
MW
Heat
MW
Heat
10 min Water
3 h Benzene 6a
10 min Water 9a
9 h Benzene 9a
10 min Water 10a
5 h Benzene 10a
10 min Water 11a
5 h Benzene 11a
10 min Water 12a
14 h Benzene 12a
10 min Water 14a
62 h Benzene 14a
6a
74
91
63
100
71
94
68
65
71
82
68
80
O
15a
1
2
3
4
5
6
7
8
14
1
Benzene
100
7
9a
a
9
Reaction condition: substrate (1 mmol), 2-aminoethanethiol (6 mmol),
and solvent were employed.
Determined by GLC analysis using n-dodecane as internal hydrocarbon
standard.
10a
10
11a
11
13a
13
14a
14a
b
9
10
11
12
a one proton double doublet at d 2.602 (J¼1.91 and 4.55 Hz)
due to 5b-H that agrees with the 5b-structure of compound
3a. The inversion of the stereochemistry at C-5, from the
less common 4-oxo 5b-steroids to more frequently encoun-
tered 4-oxo 5a-steroids, occurred readily in the course of the
reaction. For the 4-oxocholestane system, optical rotatory
a
Reaction condition: substrate (0.1 mmol), 2-aminoethanethiol
(0.2 mmol), and water (5 ml) were irradiated at 40 ꢀC for 10 min.
Determined by GLC analysis using n-dodecane as internal hydrocarbon
standard.
b

8936
M. Matsushita et al. / Tetrahedron 63 (2007) 8932–8938
was stirred at room temperature for 1 h, the solvent was re-
O
O
O
R
N
R
N
R
N
moved under reduced pressure. Water was added to the resi-
due, which was extracted with diethylether (2ꢂ25 ml). The
ethereal solution was washed successively with saturated
aq NaCl (10 ml), aq sodium hydrogencarbonate solution
(10 ml), and water (10 ml), dried over Na2SO4, and concen-
trated under vacuum. The resulting oil was chromatographed
on silica gel. Elution with hexane–ether (2:1) gave 1-thia-4-
azaspiro[4.5]decan-6-one (6a) as needles (0.0879 g, 56%).
H
H
H
+
+
S
H
S
H
H
S
S
+
H
H
O
+
O
+
R
N
R
N
R
N
H
H
+
S
S
(i) R=H (m/z 140)
(ii) R=COCH3 (m/z 182)
H
3.1.3. General procedure for preparation of 1-thia-4-aza-
8-methylspiro[4.5]decan-6-one (10a) in water using
microwave method. A mixture of 2-bromo-4-methylcyclo-
hexanone (10) (0.1 mmol), 2-aminoethanethiol (0.2 mmol),
and water (5 ml) was irradiated using a microwave generat-
ing equipment Model (DISCOVERÒLabMate, CEM Corpo-
ration) for 10 min at 40 ꢀC. The progress of the reaction was
monitored by GLC; after the irradiation was completed, the
reaction mixture was extracted with diethylether and washed
with saturated NaCl solution. The ethereal solution was
dried over Na2SO4 and concentrated in vacuum. The result-
ing oil was chromatographed on silica gel. Elution with
hexane–diethylether (5:1) gave 1-thia-4-aza-7-methyl-
spiro[4.5]decan-6-one (10a) as a pale yellow oil (0.0156 g,
87%).
X
S
N
+
+
S
S
S
(iii) m/z 188
(iv) m/z 157
(v) X=NH (m/z 114)
(vi) X=S (m/z 131)
Scheme 2. Mass spectra of 2-oxo 3-spiro-thiazolidine derivatives.
1-thia-4-aza-8-tert-butylspiro[4.5]-decan-6-one (9a) or 1-
thia-4-aza-8-methylspiro[4.5]decan-6-one (10a). From these
results it is evident that the oxo group migrates to the position
originally occupied by the bromine atom. Also, this reaction
is applicable to acyclic a-halo alkanone. Moreover, it was
found that microwave irradiation can shorten significantly
the reaction time of the key step using water.
3.1.3.1.
2a-Bromospiro[5a-cholestane-3,20-thiazol-
idine] (1b). Needles (from acetone); mp 200–205 ꢀC; IR
3. Experimental
3.1. General
(KBr)¼3300 and 823 cmꢁ1
;
1H NMR (CDCl3) d: 4.72
(q, 1H, J¼4.0, 13.0 Hz, 2b-H), 3.65 (m, 1H, –CH–NH–),
3.17 (m, 1H, –CH–N–), 2.97 (m, 1H, –CH–S–), 2.80 (m,
1H, –CH–S–), 2.35 (dd, 1H, J¼4.0, 13.0 Hz, 1b-H), 0.82
(s, 3H, C19), and 0.65 (s, 3H, C18); HRMS m/z 523.2847
(M+); calcd for C29H50BrNS: M, 523.2849.
Melting points were determined with a Yanagimoto appara-
tus, and are uncorrected. IR spectra were recorded in KBr
on a Hitachi Model 270-30 grating infrared spectrometer.
Mass spectra were measured with a JEOL JMS-SX102A
spectrometer. The NMR spectral data were measured on
a JOEL GSX 400 spectrometer in deuteriochloroform with
TMS as the internal standard. Thin-layer chromatography
(TLC) was performed on silica gel 60 F254 (Merck).
Column chromatography was performed with silica gel
(230–400 mesh).
3.1.3.2. Spiro[5a-cholestane-3,20-thiazolidin]-2-one
(1a). Needles (from acetone); mp 125–127 ꢀC; IR (KBr)¼
1
3300, 1700, and 792 cmꢁ1; H NMR (CDCl3) d: 3.61 (m,
1H, –CH–N–), 3.17 (m, 1H, –CH–N–), 2.99 (m, 1H, –CH–
S–), 2.78 (m, 1H, –CH–S–), 2.53 (d, 1H, J¼13.89 Hz, 1b-
H), 2.41 (d, 1H, J¼13.89 Hz, 1a-H), 2.00 (t, 1H,
J¼12.82 Hz, 4b-H), 0.77 (s, 3H, C19), and 0.64 (s, 3H,
C18); 13C NMR (CDCl3) d: 205.37 (C2), 82.92 (C3),
12.49 (C18), and 11.99 (C19). Anal. Found: C, 75.80%; H,
10.85%. Calcd for C29H49NOS: C, 75.76%; H, 10.74%.
HRMS m/z 459.3536 (M+). Calcd for C29H49NOS: M,
459.3537.
3.1.1. General procedure for preparation of spiro[ste-
roid-3,20-thiazolidin]-2-ones. A mixture of 2a-bromo-
5a-cholestan-3-one (1) (10 mmol), 2-aminoethanethiol
(60 mmol), and pyridine (50 ml) was stirred at room temper-
ature. After the appropriate reaction time (best determined
by TLC monitoring for unreacted a-bromo ketone), the
mixture was diluted with ether and washed successively
with 100 ml portions of water. After being dried over
Na2SO4 and then concentrated, the residue was purified by
silica-gel column chromatography. Elution with benzene
gave 5a-cholestan-3-one (0.425 g, 11%). Further elution
with benzene–ethyl acetate (19:1) gave thiazolidine deriva-
tive 1a, which crystallized from acetone as needles
(1.98 g, 43%).
3.1.3.3. From 2a-bromospiro[5a-cholestan-3,20-thi-
azolidine] (1b). A mixture of 1b (0.200 g, 0.381 mmol), 2-
aminoethanethiol (0.176 g, 2.286 mmol), and pyridine
(3 ml) was stirred at room temperature. After the appropriate
reaction time (best determined by TLC monitoring for start-
ing material), the mixture was diluted with ether and washed
successively with 30 ml portions of water. After drying
(anhydrous Na2SO4) and concentration, the residue was
purified by silica-gel column chromatography. Elution with
benzene–ethyl acetate (19:1) gave thiazolidine derivative
1a, which crystallized from acetone (0.085 g, 48%).
3.1.2. General procedure for prepararion of 1-thia-4-
azaspiro[4.5]decan-6-one (6a) using 2-chlorocyclohex-
anone (6) with 2-aminoethanethiol in benzene. After a mix-
ture of 2-chlorocyclohexanone (6) (0.1326 g, 1 mmol) and
2-aminoethanethiol (0.4629 g, 6 mmol) in benzene (10 ml)
3.1.3.4. Spiro[benzothiazole-2(3H),30-(5a-cholestan)]-
20-one (1c). Needles (from ethanol–ether); mp 194–
1
196 ꢀC; IR (KBr)¼3290, 1708, 1582, and 735 cmꢁ1; H

M. Matsushita et al. / Tetrahedron 63 (2007) 8932–8938
8937
NMR (CDCl3) d: 6.76–7.00 (m, 4H, aromatic protons), 2.54
(d, 1H, J¼13.18 Hz, 1b-H), 2.45 (d, 1H, J¼13.18 Hz, 1a-
H), 2.35 (dd, 1H, J¼3.02, 14.01 Hz, 4a-H), 1.95 (t, 1H,
J¼13.46 Hz, 4b-H), 0.76 (s, 3H, C19), and 0.65 (s, 3H,
C18); 13C NMR (CDCl3) d: 205.82 (C2) and 81.03 (C3).
Anal. Found: C, 78.10%; H, 9.79%. Calcd for
C33H49ONS: C, 78.05%; H, 9.73%. HRMS m/z 507.3549
(M+). Calcd for C33H49ONS: M, 507.3565.
3.1.3.10. 1-Thia-4-azaspiro[4.5]decan-6-one (6a). Nee-
dles (from hexane–acetone¼10:1); mp 80.2–81.2 ꢀC; IR
1
(KBr)¼3291 and 1709 cmꢁ1; H NMR (CDCl3) d: 3.63
(m, 1H), 3.13 (m, 1H), 2.99 (m, 1H), 2.93 (br s, 1H), 2.75
(m, 2H), 2.53 (m, 1H), 2.28 (m, 1H), 2.01 (m, 2H), 1.90
(m, 1H), 1.75 (m, 1H), and 1.63 (m, 1H); 13C NMR
(CDCl3) d: 205.54, 83.23, 52.25, 41.57, 36.23, 36.91,
25.88, and 22.21. Anal. Found: C, 56.18%; H, 7.59%. Calcd
for C8H13ONS: C, 56.10%; H, 7.65%. HRMS m/z 171.0761
(M+). Calcd for C8H13ONS: M, 171.0719.
3.1.3.5.
Spiro[5b-cholestan-3,20-thiazolidin]-2-one
(2a). Needles (from acetone); mp 108–111 ꢀC; IR (KBr)¼
3300, 1716, and 788 cmꢁ1; H NMR (CDCl3) d: 3.58 (m,
3.1.3.11. 1-Thia-4-aza-8-tert-butylspiro[4.5]decan-6-
one (9a). Needles (from hexane–acetone¼10:1); mp 101.0–
1
1H, –CH–N–), 3.20 (m, 1H, –CH–N–), 2.99 (m, 1H, –CH–
S–), 2.82 (m, 1H, –CH–S–), 2.63 (t, 1H, J¼14.35 Hz, 4a-
H), 2.60 (d, 1H, J¼14.35 Hz, 1a-H), 2.50 (d, 1H,
J¼14.35 Hz, 1b-H), 1.07 (s, 3H, C19), and 0.63 (s, 3H,
C18); 13C NMR (CDCl3) d: 205.64 (C2), 82.79 (C3),
22.78 (C19), and 12.09 (18C). Anal. Found: C, 75.82%; H,
10.80%. Calcd for C29H49ONS: C, 75.76%; H, 10.74%.
HRMS m/z 459.3544 (M+). Calcd for C29H49ONS: M,
459.3537.
102.6 ꢀC; IR (KBr)¼3222 and 1705 cmꢁ1
;
1H NMR
(CDCl3) d: 3.63 (m, 1H), 3.14 (m, 1H), 2.98 (m, 1H), 2.95
(br s, 1H), 2.77 (m, 1H), 2.53 (m, 2H), 2.29 (m, 1H), 1.94 (m,
2H), 1.49 (m, 2H), and 0.90 (s, 9H); 13C NMR (CDCl3) d:
206.31, 82.70, 52.30, 48.32, 40.92, 40.51, 36.92, 32.65,
27.16, and 24.34; HRMS m/z 227.1361 (M+). Calcd for
C12H21ONS: M, 227.13453.
3.1.3.12. 1-Thia-4-aza-8-methylspiro[4.5]decan-6-one
(10a). Needles (from hexane–acetone¼10ꢁ:11); mp 53.2–
3.1.3.6.
Spiro[5b-cholestan-3,20-thiazolidin]-4-one
(3a). Plates (from acetone); mp 124–127 ꢀC; IR (KBr)¼
53.8 ꢀC; IR (KBr)¼3294 and 1709 cm
;
1H NMR
3300, 1704, 844, 774, and 724 cmꢁ1; H NMR (CDCl3)
(CDCl3) d: 3.63 (m, 1H), 3.13 (m, 1H), 2.99 (br s, 1H),
2.75 (m, 2H), 2.52 (m, 1H), 2.43 (m, 1H), 2.01 (m, 2H),
1.86 (m, 1H), and 1.03 (d, 3H); 13C NMR (CDCl3) d:
204.92, 82.45, 52.28, 47.28, 40.46, 36.93, 33.50, 31.62,
and 22.11; HRMS m/z 185.0833 (M+). Calcd for
C9H15ONS: M, 185.0876.
1
d: 3.68 (m, 1H, –CH–N–), 3.12 (m, 1H, –CH–N–), 2.93
(m, 1H, –CH–S–), 2.75 (m, 1H, –CH–S–), 2.60 (dd,
1H, J¼1.91, 4.55 Hz, 5b-H), 2.11 (m, 2H, C2), 1.11 (s,
3H, C19), and 0.63 (s, 3H, C18); 13C NMR (CDCl3) d:
206.71 (C4), 82.56 (C3), 22.59 (C19), and 11.94 (C18);
HRMS m/z 459.3543 (M+). Calcd for C29H49ONS: M,
459.3537.
3.1.3.13. 1-Thia-4-aza-7,9-dimethylspiro[4.5]decan-6-
one (11a). Pale yellow oil; IR (NaCl)¼3293 and 1708 cmꢁ1
;
3.1.3.7. Spiro[5b-cholestan-3,20-thiazolidine] (3d).
Needles (from acetone); mp 82–84 ꢀC; IR (KBr)¼3420,
1H NMR (CDCl3) d: 3.63 (m, 1H), 3.10 (m, 1H), 2.99 (m,
1H), 2.88 (m, 1H), 2.75 (m, 1H), 2.06 (m, 1H), 1.96 (m,
1H), 1.74 (m, 1H), 1.09 (d, 3H), and 1.00 (d, 3H); 13C
NMR (CDCl3) d: 207.44, 82.16, 52.04, 50.20, 42.94, 41.72,
37.07, 29.29, 21.05, and 14.60; HRMS m/z 199.1063 (M+).
Calcd for C10H17ONS: M, 199.1032.
3250, 805, and 785 cmꢁ1; H NMR (CDCl3) d: 0.973 (s,
1
3H, C19, C–Nequatorial), 0.936 (s, 3H, C19, C–Naxial),
and 0.640 (s, 3H, C18); 13C NMR (CDCl3) d: 83.87 and
81.24 (C3). Anal. Found: C, 78.20%; H, 11.61%. Calcd
for C29H51NS: C, 78.13%; H, 11.53%. HRMS m/z
446.3834 (MH+). Calcd for C29H52NS: MH, 446.3823.
3.1.3.14. 1-Thia-4-azaspiro[4.5]undecan-6-one (12a).
Needles (from hexane–acetone¼10:1); mp 55.5–56.7 ꢀC;
1
3.1.3.8. Spiro[5a-lanost-8-en-3,20-thiazolidin]-2-one
(4a). Needles (from acetone); mp 138–139 ꢀC; IR
IR (KBr) 3290 and 1709 cmꢁ1; H NMR (CDCl3) d: 3.71
(m, 1H), 3.28 (br d, 1H), 3.06 (m, 1H), 3.00 (m, 1H), 2.76
(m, 1H), 2.62 (m, 2H), 2.24 (m, 1H), 1.83 (m, 3H), 1.46
(m, 2H), and 1.27 (m, 2H); 13C NMR (CDCl3) d: 207.40,
83.91, 52.97, 40.44, 40.30, 37.66, 30.21, 27.04, and 26.21;
HRMS m/z 185.0856 (M+). Calcd for C9H15ONS: M,
185.0876.
(KBr)¼3304, 1706, and 748 cmꢁ1; H NMR (CDCl3) d:
1
3.312 (m, 2H, –CH2–N–), 2.786 (m, 2H, –CH2–S–), 3.041
(d, 1H, J¼12.91 Hz, 1b-H), 2.786 (t, 2H, J¼5.50 Hz,
–CH2–S–), 2.480 (d, 1H, J¼12.91 Hz, 1a-H), 1.132 (s,
3H, CH3), 0.981 (s, 3H, CH3), 0.925 (s, 6H, 2ꢂCH3), and
0.672 (s, 3H, C18); 13C NMR (CDCl3) d: 207.39 (C2),
135.43 (C8 or C9), 132.91 (C8 or C9), and 90.70 (C3);
HRMS m/z 499.3395 (M+). Calcd for C32H53ONS: M,
499.3848.
3.1.3.15. 1-Thia-4-azaspiro[4.5]dodecan-6-one (14a).
;
1H NMR
Yellow oil; IR (NaCl)¼3291 and 1697 cmꢁ1
(CDCl3) d: 3.71 (m, 1H), 3.13 (m, 1H), 3.03 (m, 1H), 2.95
(br s, 1H), 2.79 (m, 1H), 2.65 (m, 1H), 2.51 (m, 2H), 2.16
(m, 1H), 1.93 (m, 1H), 1.78 (m, 3H), 1.67 (m, 1H), 1.36
(m, 2H), and 0.98 (m, 1H); 13C NMR (CDCl3) d: 209.33,
85.24, 53.64, 37.96, 36.96, 36.08, 30.31, 25.78, 25.52, and
24.06. HRMS m/z199.1072 (M+). Calcd for C10H17ONS:
M, 199.1032.
3.1.3.9. 1-Thia-4-azaspiro[4.5]nonan-6-one (5a). Nee-
dles (from hexane–acetone¼10:1); mp 55.2–56.2 ꢀC; IR
(KBr)¼3275 and 1744 cmꢁ1; H NMR (CDCl3) d: 3.73
1
(m, 1H), 3.14 (m, 1H), 2.90 (m, 1H), 2.54 (m, 1H), 2.49
(br s, 1H), 2.33 (m, 1H), 2.15 (m, 2H), 1.85 (m, 1H); 13C
NMR (CDCl3) d: 212.82, 83.76, 53.44, 38.55, 36.94,
34.05, and18.18. Anal. Found: C, 53.55%; H, 7.01%. Calcd
for C7H11ONS: C, 53.47%; H, 7.05%. HRMS m/z 157.0587
(M+). Calcd for C7H11ONS: M, 157.0562.
3.1.3.16.
Spiro[naphthalene-1(2H),20-[1,3]thiazol-
idine]-30,40-dihydro-20-one (15a). Needles (from hexane–
acetone¼10:1); mp 86.2–87.1 ꢀC; IR (KBr)¼3294, 3066,

8938
M. Matsushita et al. / Tetrahedron 63 (2007) 8932–8938
1
1
3029, and 1711 cmꢁ1; H NMR (CDCl3) d: 7.535 (d, 1H),
7.22 (m, 3H), 3.95 (m, 1H), 3.47 (br s, 1H), 3.32 (m, 2H),
3.165 (m, 1H), 3.05 (m, 1H), 2.95 (m, 1H), 2.75 (m, 1H),
and 2.28 (m, 1H); 13C NMR (CDCl3) d: 204.16, 139.48,
136.06, 127.94, 127.66, 127.41, 124.24, 80.30, 55.43,
37.96, 34.14, and 27.31; HRMS m/z 219.0747 (M+). Calcd
for C12H13ONS: M, 219.0719.
1709 cmꢁ1; H NMR (CDCl3) d: 7.28–7.72 (m, 5H), 3.57
(m, 1H), 3.30 (br s, 1H), 3.06 (m, 1H), 2.87 (m, 2H), 2.42
(m, 1H), 2.02 (m, 1H), 1.49 (m, 2H), and 0.76 (s, 3H); 13C
NMR (CDCl3) d: 203.29, 140.31, 128.48, 128.32, 128.25,
89.94, 52.19, 40.29, 37.58, 17.81, and 13.48; HRMS m/z
235.1011 (M+). Calcd for C13H17ONS: M, 235.1031.
3.1.4. Spectroscopic (13C NMR) evidence for dihydro-1,4-
thiazine intermediate (B). 2a-Bromo-5a-cholestan-3-one
(1) (50 mg) and 2-aminoethanethiol (50 mg) were added in
NMR tube (0.5 ml CDCl3). The 13C NMR spectrum was
recorded at 25 ꢀC probe temperature.
3.1.3.17. Butan-2-oxo-spiro-3-(10,30-thiazolidine) (16a).
Pale yellow oil; IR (NaCl)¼3295 and 1705 cmꢁ1; 1H NMR
(CDCl3) d: 4.70 (br s, 1H), 3.57 (m, 1H), 3.21 (m, 1H), 3.07
(m, 1H), 2.76 (m, 1H), 2.34 (s, 3H), and 1.73 (s, 3H); 13C
NMR (CDCl3) d: 203.89, 81.47, 52.93, 37.79, 26.97, and
25.30; HRMS m/z 145.0567 (M+). Calcd for C6H11ONS:
M, 145.0561.
Acknowledgements
3.1.3.18.
Heptan-3-oxo-spiro-4-(10,30-thiazolidine)
The authors are grateful to Prof. Yoshiaki Kamano, Kana-
gawa University, for valuable suggestions. This work was
partially supported by Frontier Project ‘Adaptation and
Evolution of Extremophile’ and a Grant-in-Aid for Science
Research (no. 18550142).
(17a). Pale yellow oil; IR (NaCl)¼3302 and 1707 cmꢁ1
;
1H NMR (CDCl3) d: 3.55 (m, 1H), 3.14 (m, 1H), 2.98 (m,
1H), 2.85 (br s, 1H), 2.79 (m, 1H), 2.67 (m, 1H), 2.46 (m,
1H), 1.97 (m, 2H), 1.55 (m, 1H), 1.15 (t, J¼7.27 Hz, 3H),
1.09 (m, 1H), and 0.92 (t, J¼7.27 Hz, 3H); 13C NMR
(CDCl3) d: 206.91, 85.61, 53.02, 42.46, 36.82, 30.92,
19.47, 14.25, and 8.49; HRMS m/z 187.1060 (M+). Calcd
for C9H17ONS: M, 187.1031.
References and notes
1. Crossley, N. S.; Djerassi, C.; Kielczewski, M. A. J. Chem. Soc.
1965, 6253.
2. Paryzek, Z.; Kielczewski, M. Bull. Acad. Polon. Sci. Ser. Sci.
Chim. 1975, 23, 191.
3. Paryzek, Z.; Kielczewski, M. Bull. Acad. Polon. Sci. Ser. Sci.
Chim. 1975, 23, 9.
4. Paryzek, Z.; Kielczewski, M. Bull. Acad. Polon. Sci. Ser. Sci.
Chim. 1975, 23, 91.
5. Altenbach, H.-J. P.; Roth, R.; Braner, D. J. Liebigs Ann. Chem.
1995, 1427.
6. Ando, W.; Takada, T.; Huang, L.; Tamura, Y. Tetrahedron Lett.
1985, 26, 869.
7. Robbe, Y.; Fernandez, J. P.; Dubieff, R.; Chapat, J. P.;
Sentanac-Roumanou, H.; Fatome, M.; Laval, J. D. Eur. J.
Med. Chem. 1982, 17, 235.
8. Oya, M.; Kato, E.; Iwao, J.; Yasuoka, N. Chem. Pharm. Bull.
1982, 30, 484.
3.1.3.19.
Nonan-4-oxo-spiro-5-(10,30-thiazolidine)
(18a). Pale yellow oil; IR (NaCl)¼3302 and 1706 cmꢁ1
;
1H NMR (CDCl3) d: 3.55 (m, 1H), 3.14 (m, 1H), 2.98 (m,
1H), 2.85 (br s, 1H), 2.79 (m, 1H), 2.71 (m, 2H), 2.42
(m, 1H), 1.99 (m, 2H), 1.70 (m, 2H), 1.52 (m, 1H), 1.33
(m, 2H), 1.05 (m, 1H), 0.96 (t, J¼7.38 Hz, 3H), and 0.88
(t, J¼7.38 Hz, 3H); 13C NMR (CDCl3) d: 206.04, 85.69,
52.98, 39.92, 39.59, 36.78, 28.23, 22.91, 17.59, 13.88, and
13.75; HRMS m/z 215.1346 (M+). Calcd for C11H21ONS:
M, 215.1344.
3.1.3.20. Undecan-5-oxo-spiro-6-(10,30-thiazolidine)
(19a). Pale yellow oil; IR (NaCl)¼3302 and 1705 cmꢁ1
;
1H NMR (CDCl3) d: 3.55 (m, 1H), 3.14 (m, 1H), 2.98 (m,
1H), 2.85 (br s, 1H), 2.72 (m, 2H), 2.41 (m, 1H), 1.98
(m, 2H), 1.66 (m, 2H), 1.55 (m, 1H), 1.32 (m, 6H), 1.06
(m, 1H), 0.94 (t, J¼7.38 Hz, 3H), and 0.88 (t, J¼7.38 Hz,
3H); 13C NMR (CDCl3) d: 206.24, 85.77, 52.97, 40.19,
37.39, 36.78, 31.97, 26.31, 25.80, 22.45, 22.32, 13.97, and
13.91; HRMS m/z 243.1636 (M+). Calcd for C13H25ONS:
M, 243.1657.
9. Bodor, N.; Sloan, K. B. J. Pharm. Sci. 1982, 71, 514.
10. Schmidt, K.; O’Neal, S.; Chan, T. C.; Alexis, C. P.; Uribe, J. M.;
Lossener, K.; Gutierrez, C. G. Tetrahedron Lett. 1989, 30,
7301.
11. Alvernhe, G.; Langlois, B.; Laurent, A.; Le Drean, I.; Selmi, A.
Tetrahedron Lett. 1991, 32, 643.
3.1.3.21. 1-Phenyl-spiro-1-(10,30-thiazolidine)propan-
12. Takahashi, T.; Takahashi, M.; Hashimoto, A.; Satoh, Y. Chem.
Lett. 1990, 1963.
2-one (20a). Pale yellow oil; IR (NaCl)¼3299 and
1710 cmꢁ1; H NMR (CDCl3) d: 7.29–7.71 (m, 5H), 3.53
13. Szilagyi, L.; Gyorgydeak, Z. J. Am. Chem. Soc. 1979, 101, 427.
14. Katritzky, A. R.; Rees, C. W. Comprehensive Heterocyclic
Chemistry; Pergamon: Oxford, 1984; Vol. 3.
15. Budzikiewicz, H.; Djerassi, C.; Williams, D. H. Interpretation
of Mass Spectra of Organic Compounds; Holden-Day: San
Francisco, CA, 1964.
1
(m, 1H), 3.06 (m, 1H), 3.07 (br s, 1H), 2.91 (m, 2H), and
2.02 (s, 3H); 13C NMR (CDCl3) d: 201.13, 140.05, 128.51,
128.37, 128.28, 90.06, 52.31, 37.58, and 25.97; HRMS m/z
207.0693 (M+). Calcd for C11H13ONS: M, 207.0718.
3.1.3.22. 1-Phenyl-spiro-1-(10,30-thiazolidine)pentan-
2-one (21a). Pale yellow oil; IR (NaCl)¼3300 and
16. Allinger, N. L.; Darooge, M. A.; Hermann, R. B. J. Org. Chem.
1961, 26, 3626.