Organoselenium-induced cyclization of 2-alkenylthiazolines to functionalized γ-lactams

Article abstract of DOI:10.1055/s-1999-2728

The reaction of alkenylthiazolines with benzeneselenenyl bromide in a mixed solvent of acetonitrile and water saturated with sodium bicarbonate gives lactams bearing both mercaptoethyl and phenylselenenyl groups in moderated to good yields. Intramolecular amidoselenation and subsequent hydrolysis will be involved.

Full text of DOI:10.1055/s-1999-2728

LETTER
733
Organoselenium-Induced Cyclization of 2-Alkenylthiazolines to
Functionalized g-Lactams
Keiji Terao,*a Munetaka Kunishima,*b Shohei Tanib
aWacker Chemicals East Asia Ltd., 2-14-1 Nishi-Waseda, Shinjuku-ku, Tokyo 169-0051, Japan
E-mail: kei.terao@wacker.de
bFaculty of Pharmaceutical Sciences, Kobe Gakuin University, Nishi-ku, Kobe 651-2180, Japan
E-mail: kunisima@pharm.kobegakuin.ac.jp
Received 16 March 1999
Table 1 Formation of γ-lactams (2) via amidoselenation.
Abstract: The reaction of alkenylthiazolines with benzeneselen-
Run Substrate
Solvent
Conditions Yield 2 (%)a
enyl bromide in a mixed solvent of acetonitrile and water saturated
with sodium bicarbonate gives lactams bearing both mercaptoethyl
and phenylselenenyl groups in moderated to good yields. Intramo-
lecular amidoselenation and subsequent hydrolysis will be in-
volved.
1
2
1a
1a
1a
1a
1a
1a
1a
1b
1b
1c
1c
MeCN
rt, 24hr
rt, 24hr
rt, 24hr
rt, 24hr
rt, 24hr
rt, 24hr
rt, 24hr
rt, 24hr
0
21
66
56
35
54
46
92
15
90
57
MeCN–H2O (10 : 1)
3
MeCN–sat.NaHCO3 (10 : 1)
MeCN–sat.Na2CO3 (10 : 1)
CHCl3–sat.NaHCO3 (10 : 1)
THF–sat.NaHCO3 (10 : 1)
Et2O–sat.NaHCO3 (10 : 1)
MeCN–sat.NaHCO3 (10 : 1)
4
5
Key words: amidoselenation, thiazolines, g-lactams, selenides, thi-
ols
6
7
8
9
MeCN–sat.NaHCO3 (10 : 1) reflux, 5hr
An enormous number of mono- and bicyclic lactam ring
systems are well adapted as biologically active com-
pounds so that findings of new synthetic ways of versatile
functionalized lactams are of great interest.1 In this con-
nection much attention has been paid to the methodology
for the lactam ring formation by selenium-induced or io-
donium-induced cyclization of alkenyl imidates,2 alkenyl
cyclic imidates,3 alkenyl bis(trimethylsilyl) amides,4 alk-
enylurethanes,5 alkenyl imines,6 and alkenyl thioimi-
dates.7 Among them, in particular, the reaction of
alkenyloxazolines with benzeneselenenyl halides is high-
ly useful because two functional groups, halogeno and
phenylselenenyl groups, of resulting lactams allow further
transformation of them into various bicyclic lactams pos-
sessing nitrogen atom at a bridgehead.3 Herein, we report
our preliminary studies on a new direct approach to g-lac-
tams bearing both mercaptoethyl and (phenylselene-
nyl)methyl substituents by use of alkenylthiazolines.
10
11b
MeCN–sat.NaHCO3 (1 : 1)
MeCN–sat.NaHCO3 (1 : 1)
rt, 24hr
rt, 4days
a Isolated yield. b Performed in a large scale (0.1 mol).
of 2a was improved to 66% by replacement of water with
a saturated sodium bicarbonate solution.9 The use of an-
other solvent system (chloroform, THF, and diethyl ether)
under similar conditions resulted in somewhat low yields.
The immiscible property of chloroform or ether with wa-
ter might be responsible for a low yield observed in those
solvents. The reaction with thiazolines, having an alkyl
group like benzyl 1b or methyl group 1c at the 1-position
of 3-butenyl group, were found to proceed in a good yield
to afford 2b (7:3 mixture of diastereoisomers) and 2c
(57:43), respectively (Runs 8 and 10).9-12 The observed
substituent effect on the yield of amidoselenation is in
agreement with the result reported by Toshimitsu et al.3
R
R
PhSeBr
The functionalized g-lactams are most likely formed by a
mechanism illustrated in the Scheme. Intramolecular ami-
doselenation of 1 generates a bicyclic iminium salt 3,
which undergoes attack by a hydroxyl anion (or a water
molecule) at the iminium carbon to give 4. Ring opening
of the thiazoline with carbonyl formation gives the lactam
2. Since no cyclization occurs in the absence of hydroxyl
anion, the first amidoselenation step can be reversible. In
contrast to the result observed in a similar reaction of alk-
enyloxazoline,3 where N-(2-bromoethyl) lactams are
formed, no corresponding bromide 5 was observed.
O
S
N
N
PhSe
SH
1
2
a: R = H
b: R = Bn
c: R = Me
Results are summarized in Table 1. Our first attempt to
obtain a g-lactam by the reaction of 2-(3-butenyl)-1,3-thi-
azoline 1a8 with benzeneselenenyl bromide in acetonitrile
was unsuccessful giving various non-cyclic materials that
could not be identified (Run 1). Desired selenium-induced
cyclization took place by addition of 10% water, and N-
mercaptoethyl 5-[(phenylselenenyl)methyl] g-lactam 2a
was obtained albeit in low yield (21%, Run 2). The yield
It would be desirable to introduce sulfur functionalities
into lactam systems from the viewpoint of biological ac-
tivity. Introduction of such functional groups by known
methods, using a reagent like hydrogen sulfides or carbon
Synlett 1999, No. 6, 733–734 ISSN 0936-5214 © Thieme Stuttgart · New York

734
K. Terao et al.
LETTER
(7) Takahata, H.; Wang, E. C.; Ikuro, K.; Yamazaki, T.; Momose,
T. Heterocycles 1992, 34, 435.
(8) Starting 1a was synthesized from 1-methyl-1,3-thiazoline by
allylation with nBuLi/allyl bromide. Similarly, 1b and 1c
were prepared from 1a (n-BuLi/benzyl bromide or n-BuLi/
iodomethane).
sulfide, often suffers the disadvantage caused by toxicity
and unpleasant smell of the reagent used. Thus, present re-
action appears to be very useful because g-lactams having
a mercapto group can be formed directly in only one step
reaction. Further experimental studies for the derivation
of g-lactams are in progress.
(9) The structures of 2 were confirmed on the bases of
spectroscopic data (1H NMR, IR, and MS).
(10) The stereochemistries were not determined.
R
R
R
HO–
(11) In order to comfirm of the existence of mercapto group (not
hydroxy group), further transformation of 2b was attempted
by use of methyl iodide/sodium borohydride in EtOH. The
chemical shift at 2.07 or 2.08 ppm observed by 1H NMR
analysis of the resulting diastereoisomeric products indicates
the formation of methylmercapto group.
PhSeBr
OH
S
PhSe
PhSe
S
S
N
N
N
Br–
4
1
3
a: R = H
b: R = Bn
c: R = Me
R
R
(12) For a typical procedure: To a stirred solution of 1c (155 mg,
1.0 mmol) in 5 mL CH3CN was added benzeneselenenyl
bromide (260 mg, 1.1 mmol) at rt. After 30 min of stirring at
rt, the mixture was cooled to 0 °C, and 5mL of a saturated
NaHCO3 was added dropwise over a period of 30 min at 0 °C.
The mixture was allowed to warm to rt and stirred for 24 h.
The reaction mixture was diluted with water, and extracted
with AcOEt. The resulting residue was purified by silica gel
column chromatography (AcOEt) to give 2c (295 mg, 90%, a
mixture of diastereoisomers): pale yellow oil, IR (neat) 3056,
2973, 1683 cm-1; 1H NMR (400 MHz CDCl3) for the major
isomer: d 1.22 (d, J = 6.9, 3H), 1.36-1.45 (m, 1H), 2.38-2.54
(m, 2H), 2.64-2.84 (m, 2H), 2.87-2.94 (m, 1H), 3.06-3.28 (m,
2H), 3.64-3.85 (m, 2H), 7.26-7.30 (m, 3H), 7.50-7.55 (m, 2H);
for the minor isomer: d 1.17 (d, J = 7.2, 3H), 1.78-1.87 (m,
1H), 2.13-2.21 (m, 1H), 2.57-2.84 (m, 3H), 2.87-2.94 (m, 1H),
3.06-3.28 (m, 2H), 3.64-3.85 (m, 2H), 7.26-7.30 (m, 3H),
7.50-7.55 (m, 2H). HRMS m/z Calcd for C14H19NOSSe:
329.0352. Found:329.0336.
O
S
PhSe
N
PhSe
N
SH
Br
2
5
Scheme
References and Notes
(1) For example: Dowle, M. D.; Davis, D. J. Chem. Soc. Rev.
1979, 171.
(2) Terao, K.; Toshimitsu, A.; Uemura, S. J. Chem. Soc., Perkin
Trans. 1 1986, 1837.
(3) Toshimitsu, A.; Terao, K.; Uemura, S. J. Org. Chem. 1987,
52, 2018.
(4) Knapp, S.; Levorse, A. T.; J. Org. Chem. 1988, 53, 4006.
(5) Webb II, R. R.; Danishefsky, S. Tetrahedron Lett. 1983, 24,
1357.
(6) Kimpe, N. D.; Boelens, M. J. Chem. Soc., Chem. Commun.
1993, 916.
Article Identifier:
1437-2096,E;1999,0,06,0733,0734,ftx,en;Y01699ST.pdf
Synlett 1999, No. 6, 733–734 ISSN 0936-5214 © Thieme Stuttgart · New York