Highly regioselective synthesis of tetrahydro-2H-1,3-thiazin-2-ones via rhodium-catalyzed carbonylation of N-alkylisothiazolidines

Article abstract of DOI:10.1021/ol048706b

(Chemical Equation Presented) The [Rh(COD)Cl]₂- and Kl-catalyzed carbonylation of functionalized N-alkylisothiazolidines in toluene gives the corresponding tetrahydro-2H-1,3-thiazin-2-ones in good yield. The carbonylation reaction occurred site

Full text of DOI:10.1021/ol048706b

ORGANIC
LETTERS
2004
Vol. 6, No. 20
3489-3492
Highly Regioselective Synthesis of
Tetrahydro-2H-1,3-thiazin-2-ones via
Rhodium-Catalyzed Carbonylation of
N-Alkylisothiazolidines
Chune Dong and Howard Alper*
Centre for Catalysis Research and InnoVation, Department of Chemistry,
UniVersity of Ottawa, 10 Marie Curie, Ottawa, Ontario, Canada K1N 6N5
halper@science.uottawa.ca
Received July 7, 2004
ABSTRACT
The [Rh(COD)Cl]2- and KI-catalyzed carbonylation of functionalized N-alkylisothiazolidines in toluene gives the corresponding tetrahydro-2H-
1,3-thiazin-2-ones in good yield. The carbonylation reaction occurred site-selectively at the S N bond of the isothiazolidine ring. The reaction
−
is believed to proceed via oxidative addition, followed by CO insertion and reductive elimination to form the tetrahydro-2H-1,3-thiazin-2-one
derivatives.
The transition-metal-catalyzed carbonylation of heterocycles
is an attractive method in organic synthesis. In most cases,
the carbonylation reaction provides a very convenient and
effective one-step procedure for ring homologation and gives
rise to heterocyclic derivatives that are not readily accessible
or are unavailable through conventional methods. A number
of valuable carbonyl-containing compounds can be prepared
in this way from the corresponding simple heterocyclic
substrates.1 Most examples of this type of reaction have
involved the ring-expanding or ring-opening carbonylation
of substrates with considerable ring strain.2-9 Although the
carbonylation of heterocycles containing one heteroatom has
been investigated in considerable detail, few examples have
been reported so far using heterocycles with two or more
heteroatoms. During the course of our studies of the
development of transition-metal-catalyzed carbonylation
methods,9-12 we recently reported that the carbonylation of
isoxazolidines proceeded with insertion of CO into the N-O
(5) (a) Boeckman, R. K.; Reed, J. E.; Ge, P. Org. Lett. 2001, 3, 3651.
(b) Yoneda, E.; Kaneko, T.; Zhang, S. W.; Onitsuka, K.; Takahashi, S.
Org. Lett. 2000, 2, 441.
(6) (a) Allmendinger, M.; Eberhardt, R.; Luinstra, G.; Rieger, B. J. Am.
Chem. Soc. 2002, 124, 5646. (b) Jia, L.; Ding, E.; Anderson, W. R. Chem.
Commun. 2001, 1436.
(7) (a) Dhawan, R.; Dghaym, R. D.; Arndtsen, B. A. J. Am. Chem. Soc.
2003, 125, 1474. (b) Dghaym, R. D.; Dhawan, R.; Arndtsen, B. A. Angew.
Chem., Int. Ed. 2001, 40, 3228.
(8) (a) Lafrance, D.; Davis, J. L.; Dhawan, R.; Arndtsen, B. A.
Organometallics 2001, 20, 1128. (b) Davis, J. L.; Arndtsen, B. A.
Organometallics 2000, 19, 4657.
(1) (a) Ryu, I.; Sonoda, N.; Curran, D. P. Chem. ReV. 1996, 96, 177. (b)
Chatgilialoglu, C.; Crich, D.; Komatsu, M.; Ryu, I. Chem. ReV. 1999, 99,
1991. (c) Colquhoun, H. M.; Thompson, D. G.; Twigg, M. V. Carbony-
lation; Plenum Press: New York, 1991; pp 191-203.
(2) Khumtaveeporn, K.; Alper, H. Acc. Chem. Res. 1995, 28, 414.
(3) (a) Molnar, F.; Luinstra, G.; Allmendinger, M.; Rieger, B. Chem.
Eur. J. 2003, 9, 1273. (b) Mahadevan, V.; Getzler, Y. D. Y. L.; Coates, G.
W. Angew. Chem., Int. Ed. 2002, 41, 2781. (c) Gethzler, Y. D. Y. L.;
Mahadevan, V.; Lobkovsky, E. B.; Coates, G. W. J. Am. Chem. Soc. 2002,
124, 1174.
(9) (a) Lee, T. L.; Thomas, P. J.; Alper, H. J. Org. Chem. 2001, 166,
5424. (b) Alper, H.; Wang, M. D. J. Am. Chem. Soc. 1992, 114, 7018. (c)
Van den Hoven, B. G.; Alper, H. J. Am. Chem. Soc. 2001, 123, 1017. (d)
Van den Hoven, B. G.; Alper, H. J. Am. Chem. Soc. 2001, 123, 10214.
(10) Van den Hoven, B. G.; Alper, H. J. Org. Chem. 2000, 65, 4131.
(11) Larksarp, C.; Alper, H. Org. Lett. 1999, 1, 1619.
(4) Davoli, P.; Forni, A.; Moretti, I.; Prati, F.; Torre, G. Tetrahedron
2001, 57, 1801.
(12) (a) Larksarp, C.; Alper, J. Org. Chem. 2000, 65, 2773. (b) Davoli,
P.; Moretti, I.; Prati, F.; Alper, H. J. Org. Chem. 1999, 64, 518.
10.1021/ol048706b CCC: $27.50
© 2004 American Chemical Society
Published on Web 09/10/2004

Scheme 1
Table 1. Carbonylation of N-Benzylisothiazolidine to
2H-1,3-Thiazin-2-one, Tetrahydro-3-(phenyl methyl)a
CO
temp yield
entry
catalyst (%)
solvent
(psi)
(°C)
(%)b
1
2
3
4
5
6
7
8
[RhCODCl]2 (5)
Co2(CO)8 (5)
benzene 1000
benzene 1000
benzene 1000
benzene 1000
130
130
130
130
130
100
130
130
130
130
130
130
120
70c
30
58
45c
66c
[RhCODCl]2 (5)
[RhCODCl]2 (2.5)
[RhCODCl]2 (5)
[RhCODCl]2 (5)
[RhCODCl]2 (5)
[RhCODCl]2 (5)
[RhCODCl]2 (5)
Pd(OAc)2 (5)
benzene
benzene
toluene
toluene
CH2Cl2
800
600
600
1000
1000
65c
75c
35
9
10
11
12
13
benzene 1000
benzene 1000
10
RuCl2(PPh3)2 (5)
Pd(OAc)2 (5) PPh3 (20) benzene 1000
Pd2(dba)3 (5) benzene 1000
a Reaction conditions: N-benzylisothiazolidine (0.5 mmol), catalyst, CO
for 24 h. b Isolated yield. c 5 mol % KI was added.
conditions (Table 1). When N-benzylisothiazolidine was
reacted with 5 mol % (1,5-cyclooctadiene)rhodium(I) dimer
as the catalyst in benzene, at 130 °C and 1000 psi of carbon
monoxide for 24 h, the corresponding 2H-1,3-thiazin-2-one,
tetrahydro-3-(phenylmethyl) was obtained in 58% yield
(entry 3, Table 1). In the presence of 5 mol % of potassium
iodide, carbonylation proceeded very well, forming the
thiazin-2-one as the major product in 70% yield under the
same reaction conditions (entry 1, Table 1). In all reactions
investigated, the carbonylation reaction occurred selectively
at the N-S bond of the isothiazolidine. No product of
insertion into the C-N or C-S bond was detected. In the
1H NMR spectra of the product, the signals for the proton
attached to the carbon next to the N atom are shifted
downfield by approximately 1 ppm on introduction of a CO
unit. The 13C NMR spectra display the carbonyl signal in
the expected chemical shift region of 165 ppm.
bond, affording tetrahydro-1,3-oxazin-2-ones in 20-82%
yield with [Rh(COD)Cl]2 as the catalyst.13 Also, an unusual
regiospecific insertion of carbon monoxide and ketene
elimination were observed for the rhodium-catalyzed car-
bonylation of thiazolidines, with thiazolidinones formed in
good yield (eq 1).14 However, quite drastic reaction condi-
tions (e.g., high temperature) are required for these trans-
formations, presumably because the five-membered ring
compounds lack strain energy and are quite stable.
In contrast, to our knowledge there is no report on the
effective carbonylation of isothiazolidines. It was anticipated
that should such a reaction take place, it would lead to the
formation of tetrahydro-2H-1,3-thiazin-2-ones, which are
important building blocks for the synthesis of some natural
and biologically active compounds.15 In particular, the
regioselectivity of the ring-expansion reaction of N-S
containing five-membered ring heterocycles is a matter of
considerable interest. Herein, we describe the first rhodium-
catalyzed site-selective carbonylation reaction of N-alkyl-
isothiazolidines for the synthesis of tetrahydro-2H-1,3-
thiazin-2-ones in good yield under relatively mild reaction
conditions.
Other catalysts were employed for the carbonylation
reaction of 1a. Whereas cobalt carbonyl gave 2a in 30% yield
(entry 2, Table 1), no carbonylation occurred when Pd(OAc)2,
RuCl2(PPh3)2, Pd2(dba)3, or Pd(OAc)2/PPh3 were used as
catalysts (entries 10-13). The solvent was next examined.
When toluene was used for the reaction of 1a, 2a was formed
in 75% yield (entry 8, Table 1), whereas the yield was 35%
using CH2Cl2 (entry 9, Table 1). When the reaction of 1a
was conducted using 600 psi of carbon monoxide (i.e., at
lower CO pressure) and 5 mol % [Rh(COD)Cl]2 at 100 °C,
N-benzylisothiazolidine was recovered unchanged (entry 6,
Table 1).
On the basis of these results, we concluded that the
catalytic system consisting of 5 mol % [Rh(COD)Cl]2 and
KI under 1000 psi CO in toluene is the best for this
carbonylation reaction. The scope of the reaction was
investigated with a variety of isothiazolidines (Scheme 1),
and the results are summarized in Table 2. The reactant
isothiazolidines (1a-i) were prepared according to the
literature by [2,3]-sigmatropic rearrangement of allyl-3-
alkylaminopropyl sulfoxide to the sulfenates, followed by
The reaction of N-benzylisothiazolidine (1a) with carbon
monoxide was first investigated under different reaction
(13) Khumtaveeporn, K.; Alper, H. J. Org. Chem. 1995, 60, 8142.
(14) Khumtaveeporn, K.; Alper, H. J. Am. Chem. Soc. 1994, 116, 5662.
(15) (a) Gaudilliere, B.; Jacobelli, H. Preparation of Thiazine and Oxazine
Derivatives as MMP-13 Inhibitors for Treating Arthritis. PCT Int. Appl.
2003, 46. (b) Bukowski, L. Pharmazie 2001, 1, 23. (c) Walsmann, P.;
Markwardt, F.; Stuerzebecher, J.; Wagner, G.; Wunderlich, I. Pharmazie
1979, 3, 34. (d) Hanefeld, W. Arch. Pharm. 1976, 309, 161.
3490
Org. Lett., Vol. 6, No. 20, 2004

Scheme 2. Proposed Mechanism for Rhodium-Catalyzed Carbonylation of N-Alkylisothiazolidines
intramolecular thiophilic substitution of N-alkylamino moi-
result of the steric hindrance of the methoxy functionality.
Carbonylation of N-[(1-naphthalenyl)methyl)isothiazolidine
(1g) afforded 2H-1,3-thiazin-2-one, tetrahydro-3-[(1-naph-
thalenyl) methyl] (2g) in 65% yield (entry 7, Table 2). The
structure of 2c was unambiguously confirmed by X-ray
crystallographic analyses as shown in Figure 1. We also
eties.16 The carbonylation reactions of N-alkylisothiazolidines
1a-i were efficient, and the products were formed in
reasonable yields. Furthermore, this reaction tolerates various
substituents such as methyl (1b), methoxy (1c, 1d, 1e, and
1g), and ethoxy (1f), affording the corresponding 2H-1,3-
thiazin-2-ones in 35-85% yield. In the case of N-(4-
methylbenzyl) isothiazolidine (1b), 2H-1,3-thiazin-2-one,
tetrahydro-3-[(4-methylphenyl) methyl] (2b) was obtained
in 80% yield (entry 2, Table 2). Moreover, in the reaction
Table 2. Rhodium-Catalyzed Carbonylation of
Isothiazolidinesa
entry
reactants
products
yield (%)b
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
2a
2b
2c
2d
2e
2f
2g
2h
2i
75
80
72
50
35
48
65
85
80
Figure 1. ORTEP view of compound 2c.
considered the isothiazolidines which contain one more CH2
unit between the N atom and the phenyl ring. For example,
the reaction of N-(2-phenylethyl) isothiazolidine 1h provided
2h in 85% yield (entry 7, Table 2). The methoxyl substituent
isothiazolidine 1i gave 2H-1,3-thiazin-2-one, tetrahydro-3-
[2-(4-methoxyphenyl)ethyl] (2i) in 80% yield (entry 8, Table
2).
a Reaction conditions: (1.0 mmol) of N-alkylisothiazolidine, (0.05 mmol)
of [Rh(COD)Cl]2, (0.05 mmol) of KI, 6 mL of toluene, CO 1000 psi, 24 h.
b Yield of purified product.
A proposed mechanism for the carbonylation reaction of
N-alkylisothiazolidines is outlined in Scheme 2. First, oxida-
tive addition of the rhodium(I) complex to the S-N bond
of substrate 1 gives intermediate 3. Subsequent insertion of
carbon monoxide into the S-Rh bond or N-Rh bond of 3
would generate 4. Finally, reductive elimination affords the
tetrahydro-2H-1,3-thiazin-2-ones and regenerates the catalyst.
of 1c, 1d, and 1e, the position of the methoxyl substituent
on the phenyl ring has an obvious effect on the product. The
reaction of N-(4-methoxylbenzyl) isothiazolidine (1c) gave
2c as major product in 72% yield, and 1d gave the product
in 50% yield, whereas in the case of 1e, 2H-1,3-thiazin-2-
one, tetrahydro-3-[(2-methoxyphenyl) methyl] was formed
in a low yield of 35% (entries 3-5, Table 2), perhaps as a
In conclusion, we have demonstrated for the first time that
tetrahydro-2H-1,3-thiazin-2-one derivatives can be easily
synthesized in good yield by reaction of N-alkylisothiazo-
(16) Matsuyama, H.; Izuoka, A.; Kobayashi, M. Heterocycles 1985, 23,
1897.
Org. Lett., Vol. 6, No. 20, 2004
3491

lidines with carbon monoxide in the presence of a rhodium
catalyst and potassium iodide. The present method provides
a novel approach for the synthesis of tetrahydro-2H-1,3-
thiazin-2-one derivatives in one step.
Supporting Information Available: General experimen-
tal procedures for the carbonylation of isothiazolidines,
1
spectral data of compound 2a-i, H and 13C NMR spectra
of compounds 2b and 2c, and X-ray crystallographic data
for 2c in CIF format. This material is available free of charge
via the Internet at http://pubs.acs.org.
Acknowledgment. We are grateful to the Natural Sci-
ences and Engineering Research Council of Canada for
support of this research.
OL048706B
3492
Org. Lett., Vol. 6, No. 20, 2004