Base-promoted aminoethylation of thiols with 2-oxazolidinones: A simple synthesis of 2-aminoethyl sulfides

Article abstract of DOI:10.1016/S0040-4020(01)00061-8

A simple synthesis of 2-aminoethyl sulfides using a base-promoted reaction of 2-oxazolidinones with thiols is described. An application of this method to the synthesis of chiral 2-aminoethyl sulfides and sulfur-containing heterocyclic compounds is also presented.

Full text of DOI:10.1016/S0040-4020(01)00061-8

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 2115±2120
Base-promoted aminoethylation of thiols with 2-oxazolidinones:
a simple synthesis of 2-aminoethyl sul®des
Hiroyuki Ishibashi,p Masayuki Uegaki, Manami Sakai and Yoshifumi Takeda
Faculty of Pharmaceutical Sciences, Kanazawa University, Takara-machi, Kanazawa 920-0934, Japan
Received 4 December 2000; accepted 10 January 2001
AbstractÐA simple synthesis of 2-aminoethyl sul®des using a base-promoted reaction of 2-oxazolidinones with thiols is described. An
application of this method to the synthesis of chiral 2-aminoethyl sul®des and sulfur-containing heterocyclic compounds is also presented.
q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
be obtained in high yield simply by heating a mixture of
2-oxazolidinone (1) and benzenethiol in the presence of
alkoxides.6 This method could also be extended to the
reaction with alkanethiols to give the corresponding
2-aminoethyl sul®des. The present paper describes a full
account of the work in this area, including an application
of the method to the synthesis of chiral 2-aminoethyl
sul®des and sulfur-containing heterocyclic compounds.
2-Aminoethyl sul®des are versatile intermediates in organic
synthesis.1 Some of them have been employed as key struc-
tural elements of biologically active compounds.2 Of the
several methods available for the synthesis of 2-aminoethyl
sul®des,1±3 probably the simplest one is the reaction of
thiols with aziridines.2c,3a,d,h However, aziridine and its
derivatives are not commercially available at the present
time due to their toxic and carcinogenic properties.4 There-
fore, 2-aminoethyl sul®des have commonly been prepared
from the corresponding 2-aminoethyl alcohols via several
steps.1c±e,i,2b,3e,g On the other hand, Poindexter and his
coworkers reported that heating a mixture of 2-oxazoli-
dinone (1) and benzenethiol (2a) at 1508C without a solvent
provided 2-(phenylthio)ethylamine (3a) in 60% yield
(Scheme 1).5 Formation of 3a from 1 and 2a has been
suggested to proceed via protonation at the carbonyl oxygen
atom of 1 with acidic benzenethiol followed by an attack of
the resulting thiolate anion on the 5-position of the proto-
nated 1 (Scheme 1). The method, therefore, was applicable
for acidic aromatic thiols but not for non-acidic aliphatic
thiols such as octanethiol.
2. Results and discussion
A mixture of 1 and a stoichiometric amount of sodium
benzenethiolate (prepared from benzenethiol (2a) and
sodium ethoxide) was heated in boiling EtOH for 24 h to
give 3a in 60% yield, along with N-ethoxycarbonyl-2-
²
aminoethanol (4: RˆEt) (24% yield) and a small quantity
of the starting material 1 (Scheme 2).
Formation of 3a from 1 can be best explained in terms of a
nucleophilic attack of benzenethiolate anion on the 5-posi-
tion of 17 followed by an elimination of carbon dioxide. A
partial anion exchange between sodium benzenethiolate and
EtOH used as a solvent might occur under the reaction
conditions, and hence the resulting ethoxide anion would
We have recently found that 2-aminoethyl sul®de (3a) could
Scheme 1.
²
1
An oil; IR (CHCl3) n 3300, 1700 cm21; H NMR (CDCl3, 500 MHz) d
Keywords: oxazolidines/oxazolidinones; sul®des; thiazines; thiols.
Corresponding author. Tel.: 181-76-234-4474; fax: 181-76-234-4476;
e-mail: isibasi@dbs.p.kanazawa-u.ac.jp
1.25 (t, Jˆ7.3 Hz, 3H, CH3), 2.48 (br s, 1H, OH), 3.34 (dt, Jˆ5.4, 4.9 Hz,
2H, NCH2), 3.71 (t, Jˆ4.9 Hz, 2H, CH2OH), 4.12 (q, Jˆ7.3 Hz, 2H,
CH2CH3), 5.13 (br s, 1H, NH).
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00061-8

2116
H. Ishibashi et al. / Tetrahedron 57 (2001) 2115±2120
Scheme 2.
Table 1. Reaction of 1 and benzenethiol (2a)
(978C) is higher than that (788C) of EtOH, not only was the
reaction time signi®cantly reduced (6 h) but the yield of 3a
was also improved to 98% (entry 6). Another good result
was obtained by heating a 1:2:1 mixture of 1, 2a and tert-
BuOK in boiling tert-BuOH (bp 838C) for 6 h; these con-
ditions gave 3a in 90% yield (entry 7). This aminoethylation
reaction could also be performed in an aprotic solvent such
as tetrahydrofuran (THF) by using sodium hydride or 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) as a base, but the
yields of 3a were relatively lower (56±79%) (entries
8±11) than those obtained using alcohol as a solvent.
Entry Solvent
Base
1:2a:Base Time (h) Products, % Yielda
3a
4
1
2
3
4
5
6
EtOH
EtOH
EtOH
PrOH
PrOH
PrOH
EtONa 1:1:1
EtONa 1:2:1
EtONa 1:3:2
PrONa 1:1:1
PrONa 1:2:1
PrONa 1:3:2
24
24
24
24
12
6
60b
24 (RˆEt)
73b
81b
74b
88
trace (RˆEt)
trace (RˆEt)
7 (RˆPr)
0
0
0
±
±
±
±
98
7
t-BuOH t-BuOK 1:2:1
6
90
8
9
10
11
THF
THF
THF
THF
NaH
NaH
NaH
DBU
1:1:1
1:2:1
1:3:2
1:3:2
24
15
8
56b
74
79
63b
Unless otherwise stated, the following experiments were
carried out by heating a 1:3:2 mixture of 2-oxazolidinones,
thiols and PrONa in boiling PrOH as described above for
entry 6 in Table 1.
24
a
Yields are based on 1.
A small quantity of 1 was detected in the crude reaction mixture but not
isolated.
b
The reaction of p-toluenethiol (2b) with 1 gave 3b in 93%
yield (Scheme 2). However, the reaction of p-nitro-
benzenethiol (2c) with 1 was very sluggish, giving a
complex mixture of products after prolonged heating. This
is probably because the thiolate anion formed from 2c is
highly stabilized by the p-nitro group, thereby reducing
the nucleophilicity of the anion. The aliphatic thiols such
Scheme 3.
Scheme 4.
³
attack the carbonyl carbon atom of 1 to give 4 (RˆEt). We
therefore next examined a similar reaction with 2 equiv. of
benzenethiol, whereupon the formation of 4 (RˆEt) was
greatly diminished and compound 3a was obtained in 73%
yield (based on 1).
as octanethiol (2d) and cyclohexanethiol (2e) reacted
smoothly with 1 to give the corresponding 2-aminoethyl
sul®des 3d and 3e in 81 and 74% yields, respectively.
N-Methyl-2-oxazolidinone (5) reacted with benzenethiol
much faster than did 2-oxazolidinone (1). The reaction
was completed within 30 min (compare with that for entry
6 in Table 1) to give N-methyl-2-(phenylthio)ethylamine (6)
in 84% yield (Scheme 3). It is assumed that in the case of
2-oxazolidinone (1), the NH proton is partially removed
under basic conditions, thereby causing the electrophilicity
to descend towards the benzenethiolate anion.
A more detailed study of the reaction of 1 with benzenethiol
(2a) was carried out. The results are summarized in Table 1.
Heating a mixture of 1, 2a and NaOEt in a ratio of 1:3:2
gave much higher yield (81% based on 1) of 3a as compared
to entry 2 after 24 h of heating (entry 3). When a similar
reaction was carried out in PrOH, the boiling point of which
Chiral 2-aminoethyl sul®des and the corresponding thiols
have frequently been used as catalysts for the enantio-
selective addition of organometallic reagents to carbonyl
³
Compound 4 (RˆEt) seems to be in equilibrium with 1 under the reaction
conditions. Indeed, treatment of 4 (RˆEt) with EtONa (2 equiv.) in
re¯uxing EtOH for 30 min gave a 1.3:1 mixture of 4 (RˆEt) and 1.

H. Ishibashi et al. / Tetrahedron 57 (2001) 2115±2120
2117
Encouraged by the success of the aminoethylation of ali-
phatic thiols such as 2d,e, ethyl thioglycolate was treated
with 1 to give 3-thiomorpholinone (12) in 77% yield
(Scheme 6). When a similar reaction was carried out with
tert-BuOK in boiling tert-BuOH, only an 18% yield of 12
was obtained. These results may be explained by assuming
that the thiolate anion derived from ethyl thiogylcolate is
Scheme 5.
Scheme 6.
compounds.1a±c,f,g The reactions of (4S)-substituted
2-oxazolidinones (S)-7a±e with benzenethiol gave the
corresponding chiral (1S)-substituted 2-(phenylthio)ethyl-
amines 8a±e in 78±90% yields, respectively (Scheme 4).
The 4,5-disubstituted 2-oxazolidinone 9, however,
provided no desired 2-aminoethyl sul®de. This is probably
because an SN2 attack of the thiolate anion on the 5-position
of 9 is prevented by the sterically more-demanding phenyl
group.
relatively stable due to the presence of an electron-attracting
ethoxycarbonyl group, and hence the reaction with oxazo-
lidinone (1) requires a much higher reaction temperature.
The N-methyl congener 5 also provided N-methylthio-
morpholinone (13) in 94% yield. (S)-4-Benzyl-2-oxazolidi-
none ((S)-7d) and its antipode (R)-7d afforded the optically
active thiomorpholinone (S)-14d and (R)-14d in 72 and 71%
yields, respectively. Similarly, (S)-4-phenyl-2-oxazoilidi-
none ((S)-7e) and (R)-7e afforded (S)-14e and (R)-14e,
respectively, though their yields were relatively low (47
and 45% yields, respectively). On the other hand, the reac-
tion of 10 with ethyl thioglycolate gave the chiral bicyclic
compound 15 in 93% yield (Scheme 7).
The chiral bicyclic 2-oxazolidinone 10, prepared from
l-prolinol in one step,8 was treated with benzenethiol in
the presence of tert-BuOK in boiling tert-BuOH to give
the expected chiral 2-aminoethyl sul®de 11 in 83% yield
(Scheme 5).
The reaction of 2-oxazolidinone (1) with methyl thiosalicyl-
ate gave benzo-1,4-thiazepin-5(2H)-one (16) in 45% yield.
Similarly, compound 10 reacted with methyl thiosalicylate
to give chiral tricyclic compound 17 in 29% yield, along
with several by-products (Scheme 8).
In summary, we have shown that 2-oxazolidinones work as
latent aziridine equivalents in the reaction of thiolates to
give 2-aminoethyl sul®des including chiral derivatives and
sulfur-containing heterocyclic compounds. Clearly, the
Scheme 7.
Scheme 8.

2118
H. Ishibashi et al. / Tetrahedron 57 (2001) 2115±2120
present method is far superior in simplicity and yield to any
thus far reported for the syntheis of 2-aminoethyl sul®des
such as 3, 6, 8 and 11.
3.1.4. 2-(Cyclohexylthio)ethylamine (3e).2d Yield 74%; an
oil; IR (CHCl3) n 3380 cm21; 1H NMR (500 MHz) d 1.20±
1.37 (m, 5H), 1.59±1.63 (m, 1H), 1.75±1.78 (m, 2H), 1.80±
1.99 (m, 2H), 2.45 (brs, 2H), 2.61±2.68 (m, 1H), 2.67 (t,
Jˆ6.4 Hz, 2H), 2.90 (t, Jˆ6.4 Hz, 2H).
3. Experimental
3.1.5. N-Methyl-2-(phenylthio)ethylamine (6).3b Yield
1
84%; an oil; H NMR (270 MHz) d 2.39 (br s, 3H), 2.75±
Melting points are uncorrected. IR spectra were recorded
with a Shimadzu FTIR-8100 spectrophotometer. H NMR
1
2.88 (m, 2H), 3.01±3.14 (m, 2H), 3.30 (s, 1H), 7.12±7.55
(m, 5H).
spectra were measured on a JEOL JNM-EX-270 or a JEOL
JNM-GSX 500 spectrometer for solutions in CDCl3. d
values quoted are relative to tetramethylsilane. Optical
rotations were measured with a Horiba SEPA-300 polari-
meter. High-resolution mass spectra (HRMS) were obtained
with a JEOL JMS-SX 102A instrument. Column chroma-
tography was performed on silica gel 60 PF254 (Nacalai
Tesque) under pressure.
3.1.6. (S)-1-Methyl-2-(phenylthio)ethylamine (8a).1m
1
Yield 89%; an oil; IR (CHCl3) n 3370 cm21; H NMR
(270 MHz) d 1.17 (d, Jˆ6.3 Hz, 3H), 1.79 (brs, 2H),
2.70±2.81 (m, 1H), 3.00±3.14 (m, 2H), 7.15±7.39 (m,
5H); [a]24 ˆ152.6 (c 2.0, CHCl3) [lit.1m [a]26 ˆ142.7
D
D
(c 1.01, CHCl3)]; HRMS Calcd for C9H13NS: 167.0769.
Found: 167.0770.
3.1. Materials
3.1.7. (S)-1-(Phenylthiomethyl)propylamine (8b). Yield
1
80%; colorless oil; IR (CHCl3) n 3370 cm21; H NMR
2-Oxazolidinone (1), N-methyl-2-oxazolidinone (5), (S)-4-
benzyl-2-oxazolidinone ((S)-7d), (R)-4-benzyl-2-oxazolidi-
none ((R)-7d), (S)-4-phenyl-2-oxazolidinone ((S)-7e), and
(R)-4-phenyl-2-oxazolidinone ((R)-7e) were commercially
available. (S)-4-methyl-2-oxazolidinone ((S)-7a),9 (S)-4-
ethyl-2-oxazolidinone ((S)-7b),9 and (S)-4-isopropyl-2-
oxazolidinone ((S)-7c)9,10 were prepared according to
the reported procedure. (7aS)-Perhydro-7H-pyrrolo[1,2-c]-
(270 MHz) d 0.95 (t, Jˆ7.3 Hz, 3H), 1.36±1.56 (m, 2H),
1.80 (brs, 2H), 2.74 (dd, Jˆ12.5 and 8.6 Hz, 1H), 2.78±2.89
(m 1H), 3.13 (dd, Jˆ12.5 and 3.3 Hz, 1H), 7.15±7.38 (m,
5H); [a]24 ˆ161.8 (c 1.7, CHCl3); HRMS Calcd for
D
C10H15NS: 181.0925. Found: 181.0930.
3.1.8. (S)-2-Methyl-1-(phenylthiomethyl)propylamine
1
(8c). Yield 78%; an oil; IR (CHCl3) n 3465 cm21; H
oxazol-3-one (10) ([a]23 ˆ231.6 (c 1.5, CHCl3), lit.11
D
[a]20 ˆ235.1 (c 0.702, CHCl3)) was prepared according
NMR (270 MHz) d 0.92 (d, Jˆ6.6 Hz, 3H), 0.94 (d, Jˆ
6.6 Hz, 3H), 1.61±1.70 (m, 1H), 1.65 (brs, 2H), 2.66±2.77
(m, 2H), 3.12±3.23 (m 1H), 7.19±7.37 (m, 5H);
D
to the procedure described for the preparation of the corre-
sponding (7aR)-isomer.8
[a]27 ˆ193.6 (c 0.4, CHCl3); Anal. Calcd for C11H17NS:
D
C, 67.63; H, 8.77; N, 7.17. Found: C, 67.34; H, 8.84; N,
6.87.
3.1.1. 2-(Phenylthio)ethylamine (3a). General procedure.
After sodium (97 mg, 4.22 mmol) had been dissolved in
PrOH (20 ml), benzenethiol (655 mg, 6.04 mmol) was
added and the mixture was stirred at room temperature for
30 min. To this was added 2-oxazolidinone (1) (181 mg,
2.08 mmol) and the mixture was heated under re¯ux for
6 h. The solvent was evaporated off, water was added to
the residue, and the whole mixture was extracted with
Et2O. The extract was dried (MgSO4) and concentrated,
and the residue was chromatographed on silica gel
(CHCl3±MeOH (10:1)) to give 3a3b (312 mg, 98%) as an
oil: IR (CHCl3) n 3360, 3290 cm21; 1H NMR (270 MHz) d
2.50 (brs, 2H), 2.93 (t, Jˆ5.6 Hz, 2H), 3.04 (t, Jˆ5.6 Hz,
2H), 7.15±7.40 (m, 5H). Using a procedure similar to that
described for the preparation of 3a, the following
compounds were obtained.
3.1.9. (S)-2-Phenyl-1-(phenylthiomethyl)ethylamine (8d).3d
1
Yield 90%; an oil; IR (CHCl3) n 3360 cm21; H NMR
(270 MHz) d 1.52 (brs, 2H), 2.66 (dd, Jˆ13.2 and 7.9 Hz,
1H), 2.80 (dd, Jˆ13.2 and 7.5 Hz, 1H), 2.88 (dd, Jˆ16.5
and 4.4 Hz, 1H), 3.09±3.24 (m 2H), 7.15±7.33 (m, 10H);
[a]24 ˆ143.7 (c 1.00, CHCl3); HRMS Calcd for
D
C15H17NS: 243.1081. Found: 243.1080.
3.1.10. (S)-1-Phenyl-2-(phenylthio)ethylamine (8e). Yield
89%; colorless crystals; mp: 69±708C; IR (CHCl3) n
1
3370 cm21; H NMR (270 MHz) d 1.76 (brs, 2H), 3.02
(dd, Jˆ13.9 and 9.6 Hz, 1H), 3.30 (dd, Jˆ13.9 and
4.0 Hz, 1H), 4.10 (dd, Jˆ9.5 and 4.0 Hz, 1H), 7.18±7.41
(m, 10H); [a]24 ˆ224.2 (c 1.00, CHCl3); HRMS Calcd for
D
C14H15NS: 229.0925. Found: 229.0924.
3.1.2. 2-(4-Methylphenylthio)ethylamine (3b). Yield
93%; an oil; IR (CHCl3) n 3380 cm21; H NMR (500
1
3.1.11. (S)-(1)-2-[(Phenylthio)methyl]pyrrolidine (11).1c,3c
MHz) d 1.45 (s, 2H), 2.32 (s, 3H), 2.85±2.88 (m, 2H),
2.94±2.98 (m, 2H), 7.09 (d, Jˆ7.8 Hz, 2H), 7.27±7.29
(m, 2H). HRMS Calcd for C9H13NS: 167.0769. Found:
167.0771.
1
Yield 83%; an oil; IR (CHCl3) n 3345 cm21; H NMR
(270 MHz) d 1.42±2.02 (m, 4H), 2.84±3.09 (m, 4H), 3.03
(s, 1H), 3.25±3.35 (m, 1H), 7.11±7.39 (m, 5H); [a]26
ˆ
D
116.8 (c 1.12, CHCl3) (lit.1c [a]20 ˆ116.8 (c 0.56,
D
CHCl3), lit.3e [a]20 ˆ120 (c 0.56, CHCl3)).
3.1.3. 2-(Octylthio)ethylamine (3d).2f Yield 81%; an oil;
D
IR (CHCl3) n 3400 cm21; H NMR (500 MHz) d 0.88 (t,
1
3.1.12. 3-Thiomorpholinone (12).3a Yield 77%; mp: 90±
Jˆ6.8 Hz, 3H), 1.27±1.33 (m, 8H), 1.37 (qn, Jˆ6.8 Hz,
2H), 1.58 (qn, Jˆ7.3 Hz, 2H), 2.51 (t, Jˆ7.3 Hz, 2H),
2.65 (t, Jˆ6.4 Hz, 2H), 2.71 (br s, 2H), 2.92 (t, Jˆ6.4 Hz,
2H).
918C (lit.3a mp 90±918C); IR (CHCl3) n 3405, 1665 cm21
;
1H NMR (500 MHz) d 2.80±2.84 (m, 2H), 3.31 (s, 2H),
3.61±3.65 (m, 2H), 6.59 (brs, 1H).

H. Ishibashi et al. / Tetrahedron 57 (2001) 2115±2120
2119
3.1.13. 4-Methyl-3-thiomorpholinone (13).3a Yield 94%;
References
1
an oil; IR (CHCl3) n 1650 cm21; H NMR (500 MHz) d
2.85±2.88 (m, 2H), 3.01 (s, 3H), 3.32 (s, 2H), 3.60±3.63
(m, 2H).
1. (a) Leyendecker, F.; Laucher, D. Tetrahedron Lett. 1983, 24,
3517. (b) Leyendecker, F.; Laucher, D. Nouv. J. Chim. 1985,
9, 13. (c) Dieter, R. K.; Tokles, M. J. Am. Chem. Soc. 1987,
109, 2040. (d) Davies, I. W.; Gallagher, T.; Lamont, R. B.;
Scopes, D. I. C. J. Chem. Soc. Chem. Commun. 1992 (1987),
335. (e) Takano, S.; Iida, H.; Inomata, K.; Ogasawara, K.
Heterocycles 1993, 35, 47. (f) Hof, R. P.; Poelert, M. A.;
Peter, N. C. M. W.; Kellog, R. M. Tetrahedron: Asymmetry
1994, 5, 31. (g) Kang, J.; Kim, D. S.; Kim, J. I. Synlett 1994,
842. (h) Matsuo, K.; Arase, T. Chem. Pharm. Bull. 1995, 43,
2091. (i) Donner, B. G. Tetrahedron Lett. 1995, 36, 1223.
(j) Gibson, C. L. Tetrahedron: Asymmetry 1996, 7, 3357.
(k) Shinohara, T.; Toda, J.; Sano, T. Chem. Pharm. Bull.
1997, 45, 813. (l) Shinohara, T.; Takeda, A.; Toda, J.;
Terasawa, N.; Sano, T. Heterocycles 1997, 46, 555.
(m) Toda, J.; Matsumoto, S.; Saito, T.; Sano, T. Chem.
Pharm. Bull. 2000, 48, 91. (n) Ishibashi, H.; Ohata, K.;
Niihara, M.; Sato, T.; Ikeda, M. J. Chem. Soc., Perkin
Trans. 1 2000, 547.
3.1.14. (5S)-5-Benzyl-3-thiomorpholinone [(S)-14d].
Yield 72%; mp: 126±127.58C; IR (CHCl3) n 3400,
1
1655 cm21; H NMR (270 MHz) d 2.61 (dd, Jˆ13.5 and
8.3 Hz, 1H), 2.73±2.88 (m, 2H), 2.96 (dd, Jˆ13.5 and
5.9 Hz, 1H), 3.25 (dd, Jˆ16.8 and 1.3 Hz, 1H), 3.35 (d,
Jˆ17.2 Hz, 1H), 3.91 (dddd, Jˆ8.3, 5.9, 3.1 and 1.3 Hz,
1H), 5.94 (brs, 1H), 7.15±7.40 (m, 5H); [a]22 ˆ243.1 (c
D
0.5, CHCl3); Anal. Calcd for C11H13NOS: C, 63.73; H, 6.32;
N, 6.76. Found: C, 63.79; H, 6.31; N, 6.73.
3.1.15. (5R)-Benzyl-3-thiomorpholinone [(R)-14d]. Yield
71%; mp: 126±1288C; [a]21 ˆ144.6 (c 0.5, CHCl3); Anal.
D
Calcd for C11H13NOS: C, 63.73; H, 6.32; N, 6.76. Found: C,
63.56; H, 6.24; N, 6.60.
3.1.16. (5S)-Phenyl-3-thiomorpholinone [(S)-14e]. Yield
1
47%; mp: 137±1388C; IR (CHCl3) n 3385, 1655 cm21; H
2. (a) Tank, L. I. Med. Radiol. 1961, 6, 76, Chem. Abstr. 1962,
56, 7664f. (b) Commercial Solvents Corp. Neth. Patent
6404644, 1964, Chem. Abstr., 1965, 62, 16131c. (c) Krongerg,
G. H.; Leard, R. S.; Takman, B. H. J. Med. Chem. 1973, 16,
739. (d) Tucker, H.; Coope, J. F. J. Med. Chem. 1978, 21, 769.
(e) Herman, H. H.; Husain, P. A.; Colbert, J. E.; Schweri,
M. M.; Pollock, S. H.; Fowler, L. C.; May, S. W. J. Med.
Chem. 1991, 34, 1082. (f) Relenyi, A. G.; Walter, R. W.;
Gartner, C. D. US Patent 5118534, 1992; Chem. Abstr.,
1992, 117, 89850g. (g) Tomkins, J. M.; Barnes, K. J.; Blacker,
A. J.; Watkins, W. J.; Abell, C. Tetrahedron Lett. 1997, 38,
691.
NMR (270 MHz) d 2.81 (dd, Jˆ13.7 and 9.8 Hz, 1H), 2.92
(ddq, Jˆ13.7, 3.9 and 1.0 Hz, 1H), 3.33 (dd, Jˆ17.1 and
1.5 Hz, 1H), 3.49 (d, Jˆ17.1 Hz, 1H), 4.84 (ddd, Jˆ9.0, 3.2,
and 1.5 Hz, 1H), 6.02 (brs, 1H), 7.30±7.40 (m, 5H);
[a]23 ˆ1168.5 (c 0.5, CHCl3); Anal. Calcd for
D
C10H11NOS: C, 62.15; H, 5.74; N, 7.25. Found: C, 62.15;
H, 5.67; N, 7.19.
3.1.17. (5R)-5-Phenyl-3-thiomorpholinone [(R)-14e].
Yield 45%; mp: 136.5±1378C; [a]23 ˆ2176.5 (c 0.5,
D
CHCl3); Anal. Calcd for C10H11NOS: C, 62.15; H, 5.74;
N, 7.25. Found: C, 62.22; H, 5.69; N, 7.14.
3. (a) Lehr, H.; Karlan, S.; Goldberg, M. W. J. Med. Chem. 1963,
6, 136. (b) Wehrmeister, H. L. J. Org. Chem. 1963, 28, 2589.
(c) Bewick, A.; Mellor, J. M.; Owton, W. M. J. Chem. Soc.,
Perkin Trans. 1 1985, 1039. (d) Osborn, H. M. I.; Sweeney,
J. B. Synlett 1994, 145. (e) Cran, G. A.; Gibson, C. L.; Handa,
S. Tetrahedron: Asymmetry 1995, 6, 1553. (f) Orlek, B. S.
Synlett 1996, 477. (g) Siedlecka, R.; Skarzewski, J. Synlett
1996, 757. (h) Hayashi, M.; Ono, K.; Hoshimi, H.; Oguni,
N. Tetrahedron 1996, 52, 7817.
3.1.18. (6S)-1-Aza-4-thiabicyclo[4.3.0]nonan-2-one (15).
1
Yield 93%; an oil; IR (CHCl3) n 1620 cm21; H NMR
(270 MHz) d 1.54±2.27 (m, 4H), 2.57 (dd, Jˆ12.5 and
11.5 Hz, 1H), 2.89 (dd, Jˆ12.5 and 3.0 Hz, 1H), 3.28 (d,
Jˆ16.1 Hz, 1H), 3.38 (d, Jˆ16.5 Hz, 1H), 3.52±3.58 (m,
2H), 3.75±3.85 (m, 1H); [a]23 ˆ138.7 (c 1.25, CHCl3);
D
HRMS Calcd for C7H11NOS: 157.0561. Found: 157.0564.
3.1.19. 1,4-Benzothiazepin-5(2H)-one (16).12 Yield 45%;
mp: 194±1958C (lit.12 mp 191±191.58C); IR (CHCl3) n
4. Hata, Y.; Watanabe, M.; Shiratori, O.; Takase, S. Biochem.
Biophys. Res. Commun. 1978, 80, 911. Fishbein, L. J. Toxicol.
Environ. Health (USA) 1980, 6, 1133.
1
3420, 1655 cm21; H NMR (270 MHz) d 3.14±3.20 (m,
2H), 3.33±3.44 (m, 2H), 7.27 (brs, 1H), 7.35±7.75 (m, 4H).
5. Poindexter, G. S.; Owens, D. A.; Dolan, P. L.; Woo, E. J. Org.
Chem. 1992, 57, 6257.
6. Ishibashi, H.; Uegaki, M.; Sakai, M. Synlett. 1997, 915.
7. Several examples of cleavage of the C±O bond of the
alkoxy group with thiolate anions have been reported.
For esters, see: Bartlett, P. A.; Johnson, W. S. Tetrahedron
Lett. 1970, 4459. For lactones, see: Plieninger, H. Chem.
Ber. 1950, 83, 265. For ethylene carbonates, see:
Tamura, Y.; Saito, T.; Ishibashi, H.; Ikeda, M. Synthesis
1975, 641.
3.1.20. (11aS)-2,3,11,11a-Tetrahydro-5-oxo-1H,5H-pyrrolo-
[2,1-c][1,4]benzothiazepine (17).13 Yield 29%; an oil; IR
1
(CHCl3) n 1630 cm21; H NMR (270 MHz) d 1.80±2.16
(m, 4H), 2.88 (t, Jˆ11.9 Hz, 1H), 3.31 (dd, Jˆ11.9 and
4.6 Hz, 1H), 3.59±3.76 (m, 2H), 3.81±3.90 (m, 1H),
7.21±7.73 (m, 4H); [a]24 ˆ1508.8 (c 1.0, CHCl3) (lit.13
D
[a]23 ˆ1502 (c 1.0, CHCl3)).
D
8. Aoyagi, Y.; Manabe, T.; Ohta, A.; Kurihara, T.; Pang, G. L.;
Yuhara, T. Tetrahedron 1996, 52, 869.
9. Rein, K.; Goicoechea-Pappas, M.; Anklekar, T. V.; Hart,
G. C.; Smith, G. A.; Gawley, R. E. J. Am. Chem. Soc. 1989,
111, 2211.
Acknowledgements
This work was supported by a Grant-in-Aid for Scienti®c
Research from the Ministry of Education, Science, Sports
and Culture of Japan (YT).
10. Evans, D. A.; Mathre, D. J.; Scott, W. L. J. Org. Chem. 1985,
50, 1830.

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H. Ishibashi et al. / Tetrahedron 57 (2001) 2115±2120
11. Wiegrebe, W.; Herrmann, E. G.; Schlunegger, U. P.;
Budzikiewicz, H. Helv. Chim. Acta 1974, 57, 301.
12. WuÈnsch, K. H.; Ehlers, A.; Beyer, H. Chem. Ber. 1969, 102,
1618.
13. Nacci, V.; Garofalo, A.; Anzini, M.; Campiani, G.
J. Heterocycl. Chem. 1988, 25, 1007.