Palladium-catalyzed domino ring-opening/carboxamidation reactions of N -tosyl aziridines and 2-iodothiophenols: A facile and efficient approach to 1,4-benzothiazepin-5-ones

Article abstract of DOI:10.1021/ol102394h

A novel and efficient domino procedure has been developed for the synthesis of 1,4-benzothiazepin-5-ones from simple and readily accessible N-tosyl aziridines and o-iodothiophenols. This process involves aziridines ring-opening with o-iodothiophenols, followed by palladium-catalyzed intramolecular carboxamidation. The scope and limitation of this transformation have been investigated in detail by using various aziridines and o-iodothiophenols.

Full text of DOI:10.1021/ol102394h

ORGANIC
LETTERS
2010
Vol. 12, No. 23
5567-5569
Palladium-Catalyzed Domino
Ring-Opening/Carboxamidation
Reactions of N-Tosyl Aziridines and
2-Iodothiophenols: A Facile and Efficient
Approach to 1,4-Benzothiazepin-5-ones
Fanlong Zeng and Howard Alper*
Centre for Catalysis Research and InnoVation, Department of Chemistry, UniVersity of
Ottawa, 10 Marie Curie, Ottawa, Ontario, Canada, K1N 6N5
howard.alper@uottawa.ca
Received October 4, 2010
ABSTRACT
A novel and efficient domino procedure has been developed for the synthesis of 1,4-benzothiazepin-5-ones from simple and readily accessible
N-tosyl aziridines and o-iodothiophenols. This process involves aziridines ring-opening with o-iodothiophenols, followed by palladium-catalyzed
intramolecular carboxamidation. The scope and limitation of this transformation have been investigated in detail by using various aziridines
and o-iodothiophenols.
1,4-Thiazepinone moieties represent an important class of
heterocyclic compounds with diverse potential biological and
pharmacological activities. For example, they can be used
as calcium channel blockers,1 bradykinin agonists,2 HIV-1
integrase and reverse transcriptase inhibitors,3 and antitumor,4
antiplatelet,5 and antidepressant agents.6 The traditional
methods for the synthesis of 1,4-thiazepinone scaffolds
include metal-free reactions, which often afford disulfides
as accompanying products, harsh reaction conditions, low
regioselectivity, multistep reactions, and low yields.7 Transi-
tion metal-catalyzed synthesis of sulfur-containing com-
pounds has attracted considerable attention in the past
decade.8 Several complexes of transition metals such as
palladium,9 nickel,10 copper,11 cobalt,12 indium,13 zirco-
nium,14 rhodium,15 and iron16 have been used for this
purpose. Nevertheless, these transformations can also result
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10.1021/ol102394h  2010 American Chemical Society
Published on Web 11/04/2010

in the deactivation of catalysts by sulfur-containing com-
pounds owing to their strong coordination and absorption
properties with transition metals. Hence, exploring new
strategies to circumvent these drawbacks is still a highly
desirable goal.
synthesize 1,4-benzothiazepin-5-ones from readily accessible
N-tosyl aziridines and o-iodothiophenols.
Initially, the reaction of 2-iodothiophenol (1a) with the
N-tosyl aziridine of cyclohexene (2a) was selected as the model
reaction to investigate the feasibility and efficiency of the new
domino protocol (Table 1). Under 500 psi of CO in the presence
Domino reactions are emerging as one of most efficient
and powerful tools in generating complex molecular archi-
tectures from readily available intermediates.17 This strategy
is characterized by the concomitant formation of multiple
new bonds in a single operation, which can minimize the
amount of requisite regents, separation processes, chemical
waste, energy, time, and cost. Our research focuses on the
pursuit of highly efficient and environmentally benign
protocols for the synthesis of carbonyl-containing compounds
via carbonylation reactions. Recently, we described new
domino approaches for the synthesis of quinazolino[3,2-a]-
quinazolinones,18 quinazolin-4(3H)-ones,19 isoquinolin-
ones,20 1,4-benzo- or pyrido-oxazepinones,21 2-acetyl-3,4-
dihydronaphthalenones,22 and 2-carboxyindoles.23 Herein, we
report a highly novel and efficient domino strategy to
Table 1. Optimization of the Reaction Conditions Using
2-Iodothiophenol with 7-Tosyl-7-azabicyclo[4.1.0]heptanea
entry ligand (L/[Pd]) solvent
base
3a (%)b 3a′ (%)b
1
2
3
4
5
6
7
8
dppf (1.0)
THF
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
trace
41
n.d.
36
41
83
67
93
80
80
67
n.d.
69
xantphos (1.0) THF
xantphos (2.0) THF
xantphos (1.0) THF
(()-binap (1.0) THF
tracec
n.d.
n.d.
18
dppb (1.0)
THF
Johnphos (2.0) THF
Johnphos (1.0) THF
Johnphos (1.0) THF
Johnphos (1.0) THF
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n.d.
traced
16e
n.d.
n.d.
trace
n.d.
n.d.
9
10
11
12
13
14
15
Johnphos (1.0) CH3CN Et3N
85
88
20
89
Johnphos (1.0) PhMe
Johnphos (1.0) THF
Johnphos (1.0) THF
Et3N
Cs2CO3
K2CO3
Johnphos (1.0) dioxane K2CO3
93
a All reactions were carried out with 0.5 mmol of 1a, 0.55 mmol of 2a,
0.02 mmol of Pd(OAc)2, 3.0 equiv of base, 6 mL of solvent, 500 psi of
CO, 100 °C, 17 h. b Isolated yield based on 2-iodothiophenol. c [Pd] )
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d
Pd2(dba)3·CHCl3. PCO ) 300 psi. e [Pd] ) 0.01 mmol of Pd(OAc)2.
of 3.0 equiv of Et3N, 4 mol % of Pd(OAc)2, and dppf, at 100
°C for 17 h, the reaction gave only trace amounts of the desired
product 3a, forming the ring-opening product 3a′ in 67%
isolated yield (Table 1, entry 1). When xantphos, (()-binap,
and dppb were employed as ligands instead of dppf, the desired
1,4-thiazepinone 3a was isolated in 41%, 41%, and 83% yield,
respectively (Table 1, entries 2, 5, and 6). We were pleased to
observe that performing the same reaction but using (2-
biphenyl)di-tert-butylphosphine (Johnphos) as the ligand in-
creased the yield of 3a to 93% (Table 1, entry 8). It is
noteworthy that using 2.0 equiv of phosphine ligands, i.e.,
xantphos, afforded the intermediate 3a′ as the main product,
which reveals that the ligand/catalyst ratios play a key role in
this process (Table 1, entry 3). Running the reaction at lower
loading of palladium precursors or at lower pressure of carbon
monoxide hampered the reaction efficiency (Table 1, entries 9
and 10). Surprisingly, the inorganic base, Cs2CO3, is inferior
to other bases, such as K2CO3 and Et3N (Table 1, entry 13).
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Org. Lett., Vol. 12, No. 23, 2010

The trans stereochemistry of the product 3a was deter-
mined by measuring the coupling constant of the methine
proton Ha (ddd, J ) 11.6, 11.6, and 3.4 Hz) at 3.80 ppm
Table 2. Domino Ring-Opening/Carboxamidation Reactions of
2-Halothiophenols 1a-d with N-Tosyl Aziridinesa
1
(-CH-N-) in H NMR spectrum, and further confirmed
by NOESY spectra as no NOE effects were detected between
Ha and Hb (see the Supporting Information).
Under the optimized reaction conditions, the scope and
generality of the present cascade strategy were explored by
reacting o-halothiophenols (1a-d) with various N-tosyl
aziridines, and the results are summarized in Table 2.
The reaction of the N-tosyl aziridine of cyclohexene with
2-iodothiophenol, 4-methyl-2-iodothiophenol, and 4-chloro-2-
iodothiophenol furnished the corresponding 1,4-thiazepinone
moieties 3a-c in 93%, 95%, and 94% yield, respectively,
demonstrating that this transformation tolerates both electron-
donating (p-Me) and electron-withdrawing (p-Cl) groups on the
phenyl group of the thiophenol (Table 2, entries 1-3). With
the five- and seven-membered ring-fused aziridines instead of
2a, the yields of the desired products 3e-h decreased slightly
(64%-79%, entries 5-8). However, when the eight-membered
ring-fused aziridine 2d was employed, the desired product was
not formed, only giving the intermediate 3i′ in 25% yield (Table
2, entry 9). Treatment of 2-bromothiophenol with 2a afforded
the intermediate 3d′ in an 84% yield. The difference in behavior,
compared to that of o-iodothiophenol (1a), may be due to the
lower rate of oxidative addition of the Ar-Br moiety to the in
situ formed palladium(0) species. The same transformations of
2-iodothiophenol with unsaturated ring-fused aziridines and
acyclic aziridine work efficiently, leading to the corresponding
1,4-thiazepinone moieties 3j-l in good isolated yields (Table
2, entries 10-12). The stereochemistry of the products 3k and
3l was confirmed by the HSQC and DEPT-135 NMR spec-
troscopic analysis.
In conclusion, a highly novel and efficient protocol for
the synthesis of 1,4-benzothiazepin-5-one moieties has been
developed based on the one-pot palladium-catalyzed tandem
ring-opening/carboxamidation reactions. A range of 1,4-
benzothiazepin-5-one scaffolds were obtained in good to
excellent yields. This methodology provides a versatile,
practical, and straightforward access to these potentially
useful sulfur-containing compounds.
Acknowledgment. We are grateful to the Natural Sciences
and Engineering Research Council of Canada (NSERC) for
support of this research.
a All reactions were carried out with 0.50 mmol of 1, 0.55 mmol of 2,
Pd(OAc)2/Johnphos/1 ) 4:4:100, 3.0 equiv of Et3N, 6 mL of THF, 500 psi
of CO, 100 °C, 17 h. b Isolated yield based on 2-halothiophenol. c All
reactions were carried out with 0.50 mmol of 1, 0.55 mmol of 2, Pd(OAc)2/
Johnphos/1 ) 4:4:100, 3.0 equiv of K2CO3, 6 mL of dioxane, 500 psi of
CO, 100 °C, 17 h.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL102394H
Org. Lett., Vol. 12, No. 23, 2010
5569