Remarkable synthesis of 2-(Z)-6-(E)-4H- [1,4]-thiazepin-5-ones by zwitterionic rhodium-catalyzed chemo- and regioselective cyclohydrocarbonylative ring expansion of acetylenic thiazoles

Article abstract of DOI:10.1021/ja003085c

Cyclohydrocarbonylative ring expansion of acetylenic thiazoles in the presence of CO, H₂, and catalytic quantities of the zwitterionic rhodium complex η⁶-C₆H₅BPh₃) ^-Rh⁺(1,5-COD) and triphenyl phosphite affords thiazepinones in 61 to 90% yields. This novel transformation of a 5- to a 7-membered heterocycle is readily applied to acetylenic thiazoles containing hydro, alkyl, alkyl halide, vinyl, and benzo substitutents in positions 4 and 5 of the thiazole ring in addition to alkyl-, ether-, ester-, vinyl-, and aryl-substituted alkynes at position 2.

Full text of DOI:10.1021/ja003085c

VOLUME 123, NUMBER 6
FEBRUARY 14, 2001
© Copyright 2001 by the
American Chemical Society
Remarkable Synthesis of 2-(Z)-6-(E)-4H-[1,4]-Thiazepin-5-ones by
Zwitterionic Rhodium-Catalyzed Chemo- and Regioselective
Cyclohydrocarbonylative Ring Expansion of Acetylenic Thiazoles
Bernard G. Van den Hoven and Howard Alper*
Contribution from the Centre for Catalysis Research and InnoVation, Department of Chemistry,
UniVersity of Ottawa, 10 Marie Curie St., Ottawa, Ontario, Canada K1N 6N5
ReceiVed August 18, 2000
Abstract: Cyclohydrocarbonylative ring expansion of acetylenic thiazoles in the presence of CO, H2, and
catalytic quantities of the zwitterionic rhodium complex (η6-C6H5BPh3)-Rh+(1,5-COD) and triphenyl phosphite
affords thiazepinones in 61 to 90% yields. This novel transformation of a 5- to a 7-membered heterocycle is
readily applied to acetylenic thiazoles containing hydro, alkyl, alkyl halide, vinyl, and benzo substitutents in
positions 4 and 5 of the thiazole ring in addition to alkyl-, ether-, ester-, vinyl-, and aryl-substituted alkynes
at position 2.
Introduction
in multistep syntheses. In these examples, chirality is introduced
prior to or during these transformations. The preparation of a
completely unsaturated thiazepinone ring has not been described
in the literature. This material would have the potential to be
modified and chirality introduced by asymmetric hydrogenation,
dihydroxylation,9 aminohydroxylation,10 and selenomethoxyla-
tion11 of one of its double bonds.
Transition metal complexes have been advantageously used
as catalysts for ring-expansion reactions,12 and a number of
synthetic applications have been simplified due to the availability
of these materials. Rhodium complexes have been used for the
Thiazepinones are pharmacologically important compounds
for the treatment of cancer, heart, and inflammatory diseases.
These heterocycles aid in treating disease by acting as inhibitors
to angitensin converting enzyme (ACE), neutral endopeptidase
(NEP),1 leukocyte adherence,2 and the inhibition of calcium
release in heart mitochondria.3 These seven-membered hetero-
cycles have been prepared by incorporating addition,4 condensa-
tion,5 coupling,6 rearrangement,7 and thermolysis8 methodologies
(1) (a) Amblard, M.; Daffix, I.; Bedos, P.; Berge´, G.; Pruneau, D.; Paquet,
J.-L.; Luccarini, J.-M.; Be´lichard, P.; Dodey, P.; Martinez, J. J. Med. Chem.
1999, 42, 4185. (b) Amblard, M.; Daffix, I.; Berge´, G.; Calme`s, M.; Dodey,
P.; Pruneau, D.; Paquet, J.-L.; Luccarini, J.-M.; Be´lichard, P.; Martinez, J.
J. Med. Chem. 1999, 42, 4193. (c) Robl, J. A.; Sun, C.-Q.; Stevenson, J.;
Ryono, D. E.; Simpkins, L. M.; Cimarusti, M. P.; Dejneka, T.; Slusarchyk,
W. A.; Chao, S.; Stratton, L.; Misra, R. N.; Bednarz, M. S.; Asaad, M. M.;
Cheung, H. S.; Abboa-Offei, B. E.; Smith, P. L.; Mathers, P. D.; Fox, M.;
Schaeffer, T. R.; Seymour, A. A.; Trippodo, N. C. J. Med. Chem. 1997,
40, 1570.
(4) (a) Crescenza, A.; Botta, M.; Corelli, F.; Santini, A.; Tafi, A. J. Org.
Chem. 1999, 64, 3019. (b) Bohrisch, J.; Faltz, H.; Pa¨tzel, M.; Liebscher, J.
Tetrahedron 1994, 50, 10701.
(5) Mohacsi, E.; O’Brien, J. P. J. Heterocycl. Chem. 1991, 28, 2051.
(6) (a) Karikomi, M.; Yamazaki, T.; Abematsu, Y.; Masuzawa, K.; Toda,
T. Heterocycles 1998, 48, 1523. (b) Mohsine, A.; Christiaens, L. Hetero-
cycles 1996, 43, 2567. (c) Mohacsi, E.; O’Brien, J. P.; Todara, L. J. J.
Heterocycl. Chem. 1992, 29, 193.
(2) Boschelli, D. H.; Connor, D. T.; Kramer, J. B.; Unangst, P. C. U.S.
Patent 5,489,586, 1996.
(3) (a) Medh, J. D.; Rex, K. A.; Benedict, C. R.; Sordahl, L. A. J.
CardioVasc. Pharmacol. 1991, 18, 473. (b) Kawai, A.; Inoue, H.; Narita,
H.; Nagao, T. European Patent 416,479, 1991.
(7) Crescenza, A.; Botta, M.; Corelli, F.; Tafi, A. Heterocycles 1999,
51, 1639.
(8) Jourdain, F.; Pommelet, J. C. Synth. Commun. 1997, 27, 483.
(9) Ojima, I. In Catalytic Asymmetric Synthesis; VCH Publishers: New
York, 1993; pp 6-19 and 245-260.
10.1021/ja003085c CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/17/2001

1018 J. Am. Chem. Soc., Vol. 123, No. 6, 2001
Van den HoVen and Alper
catalytic synthesis of dithionanenones,13 dioxacycloalkenones,14
thiazolidines,15 and diazepinediones.16 Palladium reagents have
provided the means to build isoquinolones,17 tricyclic com-
pounds,18 pentadieneamides,19 thiazenimines,20 and imino-
cyclobutanes21 by catalyzed reactions from appropriate reactants.
Piperidinones,22 mono-cyclic-â-lactams and trans bicyclic-â-
lactams,23 and isoquinoline24 were obtained by cobalt complexes.
Metathesis catalysts were incorporated in the synthesis of
bicyclic-â-lactams25 as well as oxocene derivatives.26
2-(Z)-6-(E)-4H-[1,4]-thiazepin-5-ones in 61 to 90% yields, and
in good to excellent chemo- and regioselectivities.
Results and Discussion
The requisite acetylenic thiazoles (eq 1) are readily obtained
in 56 to 95% yields by the cross-coupling reaction of com-
mercial 2-bromothiazole or presynthesized 2-iodothiazoles with
terminal alkynes using catalytic quantities of Pd(PPh3)2Cl2 and
CuI under basic conditions (Table S1).30 2-Iodothiazoles were
prepared by subsequent lithiation and iodination of both 4- and
4,5-substituted thiazoles (eq 2) (Table S2).31 In this manner,
2-acetylenic thiazoles were prepared which contained alkyl-,
vinyl-, aryl-, ether-, chloroalkyl-, and ester-substituted groups
attached to the heterocyclic ring or the acetylenic unit.
Recently, we reported that the zwitterionic rhodium complex,
(η6-C6H5BPh3)-Rh+(1,5-COD) (1), with added triphenyl phos-
phite is an excellent catalytic system for some interesting
hydroformylation reactions of R-functionalized alkynes. Treat-
ment of conjugated enynes with CO/H2 and (PhO)3P afforded
branched formyl dienes,27 while acetylenic thiophenes prefer-
entially formed unsaturated aldehydes branched to the thiophene
ring.28 Furanones were the dominant products from the cyclo-
hydrocarbonylation of R-ketoalkynes.29 The functional group
adjacent to the triple bond controls the overall chemo- and
regioselectivities for these reactions. We reasoned that utilizing
the noted catalytic system on conjugated thiazolynes would
result in a combination of the chemistry just described.
Acetylenic thiazoles incorporate the aromatic sulfur component
of a thiophene ring, as well as an imine-like fragment that would
compare to a conjugated alkynone. Consequently, it was
anticipated that the resulting product would embody an unsatur-
ated thiolactam. We now describe the novel zwitterionic
rhodium-catalyzed reaction of simple and functionalized acety-
lenic thiazoles with carbon monoxide and hydrogen to form
Reaction of an acetylenic thiazole 4 (1.5-3.0 mmol) with
carbon monoxide (10.5-17.5 atm) and hydrogen (3.5-10.5
atm), in the presence of the zwitterionic rhodium complex 1 (2
mol %) and triphenyl phosphite (8 mol %), at 70-110 °C for
18 to 36 h, afforded the unexpected 2-(Z)-6-(E)-4H-[1,4]-
thiazepin-5-ones as the major product with the anticipated
unsaturated aldehyde (6) and the saturated aldehyde analogue
(7) as byproducts.
(10) (a) Li, G.; Chang, H.-T.; Sharpless, K. B. Angew. Chem., Int. Ed.
Engl. 1996, 35, 451. (b) Bruncko, M.; Schlingloff, G.; Sharpless, K. B.
Angew. Chem., Int. Ed. Engl. 1997, 36, 1483. (c) Goossen, L. J.; Liu, H.;
Dress, K. R.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1999, 38, 1080.
(11) (a) De´ziel, R.; Goulet, S.; Grenier, L.; Bordeleau, J.; Bernier, J. J.
Org. Chem. 1993, 58, 3619. (b) De´ziel, R.; Malenfant, E.; Thibault, C.;
Fre´chette, S.; Gravel, M. Tetrahedron Lett. 1997, 38, 4753. (c) Back, T.
G.; Nan, S. J. Chem. Soc., Perkin Trans. 1 1998, 3123.
(12) Khumtaveeporn, K.; Alper, H. Acc. Chem. Res. 1995, 28, 414.
(13) Mori, T.; Sawada, Y.; Oku, A. J. Org. Chem. 2000, 65, 3620.
(14) (a) Mori, T.; Oku, A. Chem. Commun. 1999, 1339. (b) Oku, A.;
Murai, N.; Baird, J. J. Org. Chem. 1997, 62, 2123.
(15) Khumtaveeporn, K.; Alper, H. J. Am. Chem. Soc. 1994, 116, 5662.
(16) Ohno, M.; Noda, M.; Yamamoto, Y.; Eguchi, S. J. Org. Chem. 1999,
64, 707.
(17) Jeong, I.-Y.; Nagao, Y. Tetrahedron Lett. 1998, 39, 8677.
(18) (a) Holzapfel, C. W.; Marais, L. Tetrahedro Lett. 1997, 38, 8585.
(b) Umehara, M.; Honnami, H.; Hishida, S.; Kawata, T.; Ohba, S.; Zen, S.
Bull. Chem. Soc. Jpn. 1993, 66, 562.
(19) Satake, A.; Ishii, H.; Shimizu, I.; Inoue, Y.; Hasegawa, H.;
Yamamoto, A. Tetrahedron 1995, 51, 5331.
(20) Baeg, J.-O.; Alper, H. J. Org. Chem. 1995, 60, 3092.
(21) Nguyen, P. T.; Palmer, W. S.; Woerpel, K. A. J. Org. Chem. 1999,
64, 1843.
(22) Wang, M. D.; Alper, H. J. Am. Chem. Soc. 1992, 114, 7018.
(23) (a) Davoli, P.; Moretti, I.; Prati, F.; Alper, H. J. Org. Chem. 1999,
64, 518. (b) Piotti, M. E.; Alper, H. J. Am. Chem. Soc. 1996, 118, 111.
(24) Grotjahn, D. B.; Vollhardt, K. P. C. Synthesis 1993, 579.
(25) Barrett, A. G. M.; Ahmed, M.; Baker, S. P.; Baugh, S. P. D.;
Braddock, D. C.; Procopiou, P. A.; White, A. J. P.; Williams, D. J. J. Org.
Chem. 2000, 65, 3716.
Given the novel results, the cyclohydrocarbonylation and ring
expansion of 2-acetylenic thiazoles was optimized by using
2-hex-1-ynylthiazole (4a) as a model substrate. Treating 1.5
mmol of 4a with 2 mol % 1, 8 mol % (PhO)3P, 10 mL of CH2-
Cl2, 14 atm of CO, 7 atm of H2 in a 45 mL autoclave from 70
to 110 °C resulted in a preference for 5a ranging from 50 to
85% after 20 h and the remainder consisting of a mixture of 6a
and 7a (Table 1; entries 1, 2, 4, and 6). Changing the pressure
to 17.5 atm of CO and 3.5 atm of H2 from 90 to 110 °C afforded
a mixture of 5a and 6a in which the selectivity of 5a was 77 to
(26) Crimmins, M. T.; Tabet, E. A. J. Am. Chem. Soc. 2000, 122, 5473.
(27) Van den Hoven, B. G.; Alper, H. J. Org. Chem. 1999, 64, 3964.
(28) Van den Hoven, B. G.; Alper, H. J. Org. Chem. 1999, 64, 9640.
(29) Van den Hoven, B. G.; El Ali, B.; Alper, H. J. Org. Chem. 2000,
65, 4131.
(30) Diederich, F.; Stang, P. J. In Metal-catalyzed Cross-coupling
Reactions; Wiley-VCH: Weinheim, 1998; pp 203-229.
(31) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici, A.; Pedrini, P. J.
Org. Chem. 1988, 53, 1748.

Synthesis of 2-(Z)-6-(E)-4H-[1,4]-Thiazepin-5-ones
J. Am. Chem. Soc., Vol. 123, No. 6, 2001 1019
Table 1. Reaction Optimization Using 4aa
Table 2. Cyclohydrocarbonylation of Acetylenic Thiazoles with
Different Substituents in the Acetylenic Unita
4a
pressure
(atm)
T
convb
(%)
% of
entry (mmol)
CO:H2 (°C)
5:6:7c
5ad
1
2
3
4
5
6
7
8
9
1.5
21
21
21
21
21
21
21
21
14
21
21
2:1
2:1
5:1
2:1
5:1
2:1
5:1
1:1
1:1
2:1
1:1
70
90
90
90
100
95
100
95
100
100
100
100
90
1:1:t
3:1:t
50
75
77
77
79
85
87
90
89
83
88
3.3:1:t
3.3:1:t
3.8:1:t
11:1:1
6.8:1:t
9.1:t:1
16:1:1
4.9:1:t
15:1:1
100
100
110
110
110
110
110
110
10
11
3.0
95
a Reaction conditions: 4a, 1.5-3.0 mmol; 1, 0.03 mmol (entries
1-9) or 0.06 mmol (entries 10,11) (2 mol %); (PhO)3P, 0.12 mmol
(entries 1-9) or 0.24 mmol (entries 10,11) (8 mol %); CH2Cl2, 10 mL
(entries 1-9) or 20 mL (entries 10,11); 70-110 °C, 20 h. b The percent
conversion was determined by 1H NMR. c The ratio of 5:6:7 was
determined by 1H NMR. d The percentage of 5a is based on the ratios
of 5:6:7.
87% (Table 1; entries 3, 5, and 7). Applying a temperature of
110 °C and a 1:1 ratio of CO/H2 at a total pressure of 14 and
21 atm resulted in a selectivity for 5a of 89 and 90%,
respectively (Table 1, entries 8 and 9). Increasing the substrate
(4) from 1.5 to 3.0 mmol and the total volume from 10 to 20
mL of CH2Cl2 at 110 °C affords 5a in 83% selectivity using 21
atm of CO/H2 in a 2:1 ratio (Table 1, entry 10) and 5a in 88%
selectivity (86% isolated yield) with use of a 1:1 ratio of CO/
H2 (Table 1, entry 11). The latter entry demonstrates thiazepi-
none production is readily achieved in a reasonable time frame
using moderate temperatures and mild CO/H2 pressures.
Additional ligands and rhodium complexes were examined
to determine the uniqueness of the present catalytic system
incorporating the conditons of Table 1, entry 8. No reaction
takes place with the zwitterionic rhodium complex 1 in the
absence of an added ligand. Changing the ligand from (PhO)3P
to (iPrO)3P, Ph3P, and dppb gives 5a in low selectivity and
conversion with the addition of the hydrogenated thiazolyne 8a.
The rhodium complexes Rh(CO)2acac, [Cl(C2H4)2Rh]2, and [Cl-
(CO)2Rh]2 favor 5a in lower selectivity along with a mixture
of the hydroformylated products 6a and 7a. No reaction occurred
using catalytic quantities of RhCl3 and (PhO)3P. The catalytic
system comprised of the zwitterionic rhodium complex (1) and
triphenyl phosphite is preferred for obtaining thiazepin-5(4H)-
one in excellent chemo- and regioselectivity, compared with
other rhodium complexes and phosphorus ligands.
a Reaction conditions: 4, 3.0 mmol; 1, 0.06 mmol (2 mol %);
(PhO)3P, 0.24 mmol (8 mol %); CH2Cl2, 20 mL; CO, 10.5 atm; H2,
10.5 atm; 110 °C. b The reactions proceeded to full conversion (obtained
by NMR), and products were isolated by silica gel chromatography
with 0:100 to 5:95 MeOH:CH2Cl2. c 70 °C.
an alkyl ether, alkyl ester, or vinyl substituent (Table 2, entries
5 to 7). Note that 2-(3-methylbut-3-en-1-ynyl)thiazole (4e)
afforded only one thiazepinone in 72% yield (Table 2. entry
5). Effecting reactions of 4e-f at 110 °C instead of 70 °C
reduced the yields of 5e-g and substantially increased the
proportions of 6 and 7. Therefore, these substrates react in a
significantly temperature-dependent fashion. The occurrence of
more 6 and 7 using 4e-g may be explained by the ability of
the rhodium catalyst to coordinate with ether, ester, and vinyl
functionalities prior to the intramolecular insertion of the catalyst
to the triple bond of the thiazolyne. Prior coordination stimulates
rhodium insertion to occur on either side of the triple bond near
a functionality, as observed in previous studies.27-29 At lower
temperature coordination of the metal to the thiazole ring is
preferred to coordination of the metal to the competing
functionality.
The scope of the acetylenic thiazole/thiazepin-5-one reaction
was investigated using thiazolynes with modified alkyne
components (Table 2) and altered thiazole rings (Table 3), and
imploying the reaction conditions described in Table 1, entry
11 (eq 4). Thiazolynes 4, unsubstituted at the 4- and 5-positions
The conversion of acetylenic thiazoles to 2-(Z)-6-(E)-4H-
[1,4]-thiazepin-5-ones also proceeds nicely using substrates
substituted at the 4- or 4,5-positions of the reactant. The
thiazepin-5-one, 5h, was isolated in 83% yield using 4h (R1 )
H, R2 ) Me, and R3 ) n-Bu; Table 3, entry 1). Changing R1
from H to methyl, chloroethyl, or vinyl afforded the thiazepin-
5-ones in 78-81% yields (Table 3, entries 2-4). While the
chloroethyl substituent is completely inert under the reaction
conditions, the vinyl group reacts in a completely regioselective
manner to form the branched chain aldehydic thiazepin-5-one.
Finally, the cyclohydrocarbonylation/ring expansion process is
applicable to a benzothiazole, i.e., 4l gave the benzothiazepin-
4(5H)-one (5l) in 76% isolated yield (Table 3, entry 5). This is
a particularly impressive result for the cyclohydrocarbonylative
of the heterocycle (i.e. R1 ) R2 ) H), and where the acetylenic
unit contains an alkyl or aryl substituent (i.e. R3), react under
the noted conditions affording 5a-d in 86 to 90% isolated yields
of pure thiazepin-5-ones (Table 2, entries 1 to 4). The 2-(Z)-
6-(E)-4H-[1,4]-thiazepin-5-ones, 5e-g, were obtained in 61 to
74% isolated yields when the R3 group of the alkyne unit was

1020 J. Am. Chem. Soc., Vol. 123, No. 6, 2001
Van den HoVen and Alper
Table 3. Cyclohydrocarbonylation of Acetylenic Thiazoles
Containing Substituents at the 4- and 4,5-Positionsa
a Reaction conditions: 4, 3.0 mmol; 1, 0.06 mmol (2 mol %);
(PhO)3P, 0.24 mmol (8 mol %); CH2Cl2, 20 mL; CO, 10.5 atm; H2,
10.5 atm; 110 °C. b The reactions proceeded to full conversion (obtained
by NMR), and products were isolated by silica gel chromatography
with 0:100 to 5:95 MeOH:CH2Cl2.
Experimental Section
Materials. 2-Bromothiazole, all thiazoles, and terminal alkynes were
purchased from commercial sources. The rhodium complexes chlorobis-
(ethylene)rhodium(I) dimer, chlorodicarbonylrhodium(I) dimer, dicar-
bonylrhodium(I) acetoacetonate, and rhodium(III) chloride were pur-
chased from Strem. The zwitterionic rhodium complex (η6-C6H5B-
Ph3)-Rh+(1,5-COD) (1) was prepared according to the procedure of
Schrock and Osborn.32 All solvents were dried and distilled under N2
prior to use.
ring expansion reaction, as benzothiazepinones are excellent
candidates for evaluation as pharmacologically active com-
pounds.
A possible mechanism for the conversion of acetylenic
thiazoles to the thiazepin-5-ones is outlined in Scheme 1. The
active rhodium complex (9), formed from complex 1, binds to
the thiazolyne via the triple bond and a heteroatom (10) or
possibly by H-bonding to the thiazole ring (11). Depending on
the equilibrium between 10 and 11 two products will result. If
11 is favored, subsequent intramolecular insertion of the H-Rh
bond to the alkyne would generate 12. Carbonylation (13) of
the latter and subsequent addition of hydrogen would give the
hydroformylation product 6. However, if 10 is favored, the
intramolecular hydrorhodation would proceed in the opposite
manner to form 14, carbonylation of which would give 15,
coordination with the heterocyclic nitrogen could then afford
16. Intermediate 16 can undergo intramolecular cyclization
resulting in the formation of a â-lactam with allyl-type bonding
to Rh (17). Hydrogen addition to 17 may afford a strained
azetinone-Rh hydride (18). Hydrogen transfer with ring opening
would form 19 as the E-isomer with nitrogen coordinated to
the rhodium. Addition of hydrogen completes the thiazepinone
ring (5) and regenerates the rhodium complex 9.
General Procedure for the Pd/CuI Coupling of 2-Halothiazoles
to Terminal Alkynes. To a 100-mL round-bottom flask purged with
N2 was added triethylamine (20 mL), the terminal alkyne (3) (25-30
mmol), CH2Cl2 (40 mL), the 2-halothiazole (2) (20 mmol), Pd(PPh3)2-
Cl2 (0.2 mmol), and CuI (0.2 mmol), and the mixture was heated to
reflux (65 °C) for 6-18 h. Ether (50 mL) was added to the reaction
mixture leading to the precipitation of Et3NH+X-. The resulting mixture
was filtered, evaporated, isolated by silica gel chromatography using a
MeOH:CH2Cl2 gradient ranging from 0:100 to 5:95, and further purified
if necessary by Kugelrohr distillation to give 4 (Table S1).33
General Procedure for the Preparation of Substituted 2-Iodo-
thiazoles. To a 250-mL round-bottom flask purged with N2 was added
ether (100 mL) and the thiazole (50 mmol), and the mixture was cooled
in a dry ice/MeOH bath. An excess amount of 1.4 M MeLi (40 mL)
was added over a 15 min time period followed by I2 (60 mmol), and
the reaction mixture was allowed to warm to room temperatue. The
reaction mixture was transferred to a separatory funnel, ether (300 mL)
was added, and then the organic layer was washed with water (100
mL) and brine (50 mL), dried over anhydrous MgSO4, and evaporated.
The product (2) was isolated by silica gel chromatography with CH2-
Cl2 as eluant, and further purified by sublimation (Table S2).33
General Procedure for the Cyclohydrocarbonylative Ring Ex-
pansion of Conjugated Thiazolynes. To a 45-mL autoclave containing
a glass liner and stirring bar was placed the zwitterionic rhodium
complex 1 (0.06 mmol), triphenyl phosphite (0.24 mmol), acetylenic
thiazole 4 (3 mmol), and CH2Cl2 (20 mL). The autoclave was flushed
three times with carbon monoxide and pressurized to 10.5 atm followed
by the introduction of hydrogen to a total pressure of 21 atm. The
autoclave was placed in an oil bath at 110 °C for 18 to 36 h, and then
In conclusion, a remarkable synthesis of 2-(Z)-6-(E)-[1,4]-
thiazepin-5-ones was discovered by the reaction of acetylenic
thiazoles with CO/H2 in the presence of catalytic amounts of 1
and triphenyl phosphite. The process is general, and tolerates
the presence of functional groups including ether, ester, and
chloro. The reactions are simple in execution and workup, and
while the thiazepin-5(4H)-ones are of significant intrinsic
interest, modification of the heterocycles may lead to valuable
pharmaceuticals such as diltiazem, BMS-186716, and their
analogues.
(32) Schrock, P. R.; Osborn, J. A. Inorg. Chem. 1970, 9, 2339.
(33) Please see the Supporting Information for additional information
on the preparation of acetylenic thiazoles (4) and iodothiazoles (2).

Synthesis of 2-(Z)-6-(E)-4H-[1,4]-Thiazepin-5-ones
J. Am. Chem. Soc., Vol. 123, No. 6, 2001 1021
Scheme 1. Proposed Mechanism
allowed to cool to room temperature. The autoclave was depressurized,
the reaction mixture was filtered through Celite, and the solvent was
removed by rotary evaporation. The resulting residue was purified by
silica gel chromatography with use of a MeOH:CH2Cl2 gradient ranging
from 0:100 to 5:95 as the eluant to afford product 5 (Tables 2 and 3).
2-(Z)-6-(E)-6-Pentyl-4H-[1,4]-thiazepin-5-one (5a): colorless liq-
1H, J ) 3.2 Hz), 7.55 (d, 1H, J ) 3.2 Hz), 7.39 (s, 1H), 2.72 (t, 2H,
J ) 7.4 Hz), 1.36-1.45 (m, 4H), 0.89 (t, 3H, J ) 7.2 Hz); 13C NMR
(200 MHz, CDCl3) δ 194.5, 162.0, 145.1, 144.6, 139.5, 122.6, 29.7,
25.2, 23.0, 13.8; EI MS (m/z) 195 [M+]; HRMS calculated for C10H13-
NOS [M+] 195.07178, found 195.07199.
2-(Z)-6-(E)-6-(2,2-Dimethylpropyl)-4H-[1,4]-thiazepin-5-one (5b):
colorless liquid; IR ν(CdO) 1619 cm-1; 1H NMR (200 MHz, CDCl3)
δ 13.01 (br, 1H), 7.61 (d, 1H, J ) 3.2 Hz), 7.03 (d, 1H, J ) 3.2 Hz),
6.89 (s, 1H), 2.20 (s, 2H), 0.90 (s, 9H); 13C NMR (200 MHz, CDCl3)
δ 172.4, 152.9, 139.8, 113.9, 104.3, 44.2, 32.4, 29.6; EI MS (m/z) 197
[M+]; HRMS calculated for C10H15NOS [M+] 197.08743, found
197.08783.
1
uid; IR ν(CdO) 1626 cm-1; H NMR (200 MHz, CDCl3) δ 12.61 (s,
1H), 7.66 (d, 1H, J ) 3.4 Hz), 7.03 (d, 1H, J ) 3.6 Hz), 6.87 (s, 1H),
2.27 (t, 2H, J ) 6.8 Hz), 1.47-1.60 (m, 2H), 1.26-1.36 (m, 4H), 0.87
(t, 3H, J ) 7.0 Hz); 13C NMR (200 MHz, CDCl3) δ 170.8, 149.9,
144.4, 114.4, 107.1, 31.5, 30.5, 28.7, 28.7, 22.4, 14.0; EI MS (m/z)
197 [M+]; HRMS calculated for C10H15NOS [M+] 197.08743, found
197.08876.
2-(Z)-6-(E)-6-Benzyl-4H-[1,4]-thiazepin-5-one (5c): yellow liquid;
IR ν(CdO) 1627 cm-1; 1H NMR (200 MHz, CDCl3) δ 12.91 (br, 1H),
7.72 (d, 1H, J ) 3.4 Hz), 7.30-7.37 (m, 5H), 7.08 (d, 1H, J ) 3.6
(E)-2-Butyl-3-thiazol-2-ylpropenal (6a): colorless liquid; IR ν(Cd
1
O) 1685 cm-1; H NMR (200 MHz, CDCl3) δ 9.55 (s, 1H), 7.99 (d,

1022 J. Am. Chem. Soc., Vol. 123, No. 6, 2001
Van den HoVen and Alper
Hz), 7.07 (s, 1H), 3.71 (s, 2H); 13C NMR (200 MHz, CDCl3) δ 170.6,
151.6, 140.0, 138.7, 128.5, 128.3, 126.5, 114.9, 106.2, 36.4; EI MS
(m/z) 217 [M+]; HRMS calculated for C12H11NOS [M+] 217.05613,
found 217.05522.
δ 12.78 (br, 1H), 6.90 (s, 1H), 2.36 (s, 3H), 2.31 (s, 3H), 2.23 (t, 2H,
J ) 7.0 Hz), 1.59-1.63 (m, 2H), 1.32-1.39 (m, 4H), 0.95 (t, 3H, J )
6.6 Hz); 13C NMR (200 MHz, CDCl3) δ 166.0, 149.5, 145.3, 121.5,
106.6, 31.3, 30.1, 28.8, 22.3, 14.1, 13.9, 10.9; EI MS (m/z) 225 [M+];
HRMS calculated for C12H19NOS [M+] 225.11873, found 225.12050.
2-(Z)-6-(E)-6-(4-Methylbenzyl)-4H-[1,4]-thiazepin-5-one (5d): yel-
1
low liquid; IR ν(CdO) 1627 cm-1; H NMR (200 MHz, CDCl3) δ
2-(Z)-6-(E)-(2-Chloroethyl)-3-methyl-6-pentyl-4H-[1,4]-thiazepin-
12.80 (br, 1H), 7.72 (d, 1H, J ) 3.4 Hz), 7.28 (d, 2H, J ) 8.0 Hz),
7.18 (d, 2H, J ) 8.2 Hz), 7.09 (s, 1H), 7.08 (d, 1H, J ) 3.6 Hz), 3.68
(s, 2H), 2.40 (s, 3H); 13C NMR (200 MHz, CDCl3) δ 170.0, 151.4,
139.9, 136.0, 135.6, 129.0, 128.4, 114.8, 106.3, 35.9, 20.9; EI MS (m/
z) 231 [M+]; HRMS calculated for C13H13NOS [M+] 231.07178, found
231.07116.
2-(Z)-6-(E)-6-(2-Methylpropenyl)-4H-[1,4]-thiazepin-5-one (5e):
yellow liquid; IR ν(CdO) 1614 cm-1; 1H NMR (200 MHz, CDCl3) δ
12.43 (br, 1H), 7.64 (d, 1H, J ) 3.4 Hz), 7.03 (d, 1H, J ) 3.4 Hz),
6.89 (s, 1H), 5.74 (s, 1H), 1.82 (s, 3H), 1.72 (s, 3H); 13C NMR (200
MHz, CDCl3) δ 170.9, 152.1, 140.2, 138.6, 117.9, 114.8, 106.1, 25.6,
19.4; EI MS (m/z) 181 [M+]; HRMS calculated for C9H11NOS [M+]
181.05613, found 181.05572.
1
5-one (5j): yellow oil; IR ν(CdO) 1626 cm-1; H NMR (200 MHz,
CDCl3) δ 12.60 (br, 1H), 6.85 (s, 1H), 3.64 (t, 2H, J ) 7.4 Hz), 3.15
(t, 2H, J ) 7.2 Hz), 2.30 (s, 3H), 2.20 (t, 2H, J ) 7.2 Hz), 1.49-1.60
(m, 2H), 1.25-1.32 (m, 4H), 0.87 (t, 3H, J ) 6.8 Hz); 13C NMR (200
MHz, CDCl3) δ 167.6, 150.1, 147.0, 122.7, 106.8, 44.3, 31.4, 30.2,
29.6, 28.8, 22.4, 14.6, 14.0; EI MS (m/z) 273 [M+]; HRMS calculated
for C13H20NOClS [M+] 273.09541, found 273.09470.
2-(2-(Z)-6-(E)-3-Methyl-5-oxo-6-pentyl-4,5-dihydro-[1,4]-thiazepin-
2-yl)propanal (5k): yellow oil; IR ν1(CdO) 1731 cm-1, ν2(CdO) 1625
cm-1; 1H NMR (200 MHz, CDCl3) δ 12.58 (br, 1H), 9.62 (d, 1H, J )
1.4 Hz), 6.90 (s, 1H), 3.93 (qd, 1H, J ) 7.2, 1.6 Hz), 2.38 (s, 3H),
2.26 (t, 2H, J ) 7.0 Hz), 1.48-1.61 (m, 2H), 1.50 (d, 3H, J ) 7.0
Hz), 1.30-1.39 (m, 4H), 0.92 (t, 3H, J ) 6.8 Hz); 13C NMR (200
MHz, CDCl3) δ 198.8, 169.2, 150.6, 148.0, 123.9, 107.5, 45.7, 32.0,
30.9, 29.4, 23.0, 16.3, 15.5, 14.6; EI MS (m/z) 267 [M+]; HRMS
calculated for C14H21NO2S [M+] 267.12930, found 267.13017.
2-(Z)-6-(E)-6-(2-Methoxyethyl)-4H-[1,4]-thiazepin-5-one (5f): col-
1
orless liquid; IR ν(CdO) 1626 cm-1; H NMR (200 MHz, CDCl3) δ
12.75 (br, 1H), 7.67 (d, 1H, J ) 3.4 Hz), 7.10 (d, 1H, J ) 3.6 Hz),
6.95 (s, 1H), 3.63 (t, 2H, J ) 7.2 Hz), 3.33 (s, 3H), 2.56 (t, 2H, J )
7.0 Hz); 13C NMR (200 MHz, CDCl3) δ 170.5, 151.6, 140.4, 114.4,
103.8, 71.7, 58.6, 30.9; EI MS (m/z) 185 [M+]; HRMS calculated for
C8H11NO2S [M+] 185.05105, found 185.05066.
2-(Z)-6-(E)-6-(2-Acetylethoxy)-4H-[1,4]-thiazepin-5-one (5f): col-
orless liquid; IR ν1(CdO) 1739 cm-1, ν2(CdO) 1627 cm-1; 1H NMR
(200 MHz, CDCl3) δ 12.82 (br, 1H), 7.70 (d, 1H, J ) 3.6 Hz), 7.14
(d, 1H, J ) 3.4 Hz), 6.99 (s, 1H), 4.23 (f, 2H, J ) 6.8 Hz), 2.64 (t,
2H, J ) 7.0 Hz), 2.05 (s, 3H); 13C NMR (200 MHz, CDCl3) δ 170.9,
169.9, 152.0, 143.8, 140.4, 114.5, 102.9, 63.0, 29.9, 20.9; EI MS (m/z)
213 [M+]; HRMS calculated for C9H11NO3S [M+] 213.04596, found
213.04697.
2-(E)-3-Pentyl-5H-[1,4]-benzothiazepin-4-one (5l): yellow oil; IR
1
ν(CdO) 1621 cm-1; H NMR (200 MHz, CDCl3) δ 13.25 (s, 1H),
7.74 (d, 2H, J ) 8.2 Hz), 7.43-7.51 (m, 1H), 7.27-7.34 (m, 1H),
7.23 (s, 1H), 2.37 (t, 2H, J ) 7.6 Hz), 1.62-1.73 (m, 2H), 1.36-1.45
(m, 4H), 0.97 (t, 3H, J ) 6.6 Hz); 13C NMR (200 MHz, CDCl3) δ
171.0, 155.6, 151.4, 131.8, 127.0, 124.7, 122.0, 120.9, 107.6, 32.0,
30.9, 29.8, 23.1, 14.7; EI MS (m/z) 247 [M+]; HRMS calculated for
C14H17NOS [M+] 247.10308, found 247.10076. Anal. Calcd for C14H17-
NOS: C, 67.98; H, 6.93; N, 5.66. Found: C, 68.25; H, 6.95; N, 5.84.
Acknowledgment. We are grateful to the Natural Sciences
and Engineering Research Council of Canada for support of
this research.
2-(Z)-6-(E)-3-Methyl-6-pentyl-4H-[1,4]-thiazepin-5-one (5h): col-
1
orless liquid; IR ν(CdO) 1627 cm-1; H NMR (200 MHz, CDCl3) δ
12.78 (br, 1H), 6.88 (s, 1H), 6.63 (s, 1H), 2.39 (s, 3H), 2.24 (t, 2H,
J ) 7.4 Hz), 1.51-1.58 (m, 2H), 1.27-1.34 (m, 4H), 0.88 (t, 3H, J )
6.8 Hz); 13C NMR (200 MHz, CDCl3) δ 170.0, 150.5, 150.0, 108.9,
107.0, 31.4, 30.2, 28.8, 22.4, 16.7, 14.0; EI MS (m/z) 211 [M+]; HRMS
calculated for C11H17NOS [M+] 211.10308, found 211.10110.
2-(Z)-6-(E)-2,3-Dimethyl-6-pentyl-4H-[1,4]-thiazepin-5-one (5i):
colorless liquid; IR ν(CdO) 1628 cm-1; 1H NMR (200 MHz, CDCl3)
Supporting Information Available: 1H and 13C NMR
spectra for 2b-2f, 4a-4l, 5a-5l, and 6a (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
JA003085C