Cycloaddition reactions of thiazolium azomethine ylides: Application to pyrrolo[2,1-b]thiazoles

Article abstract of DOI:10.1021/ol071229n

Thiazolium azomethine ylides, equipped with a C-2 methanethiol group, participate in an efficient [3 + 2] cycloaddition reaction with acetylene derivatives to yield unique pyrrolo[2,1-b]thiazoles. The elimination of the methanethiol leaving group from the cycloadduct has replaced the need for a separate oxidation step and suppresses ring-opening side reactions. Products were obtained in short synthetic sequences to demonstrate their use as a scaffold for compound libraries.

Full text of DOI:10.1021/ol071229n

ORGANIC
LETTERS
2007
Vol. 9, No. 21
4099-4102
Cycloaddition Reactions of Thiazolium
Azomethine Ylides: Application to
Pyrrolo[2,1-b]thiazoles
Craig R. Berry, Craig A. Zificsak, Alan C. Gibbs, and Dennis J. Hlasta*
Johnson & Johnson Pharmaceutical Research & DeVelopment, L.L.C., 8 Clarke DriVe,
Cranbury, New Jersey 08512
dhlasta@prdus.jnj.com
Received May 24, 2007
ABSTRACT
Thiazolium azomethine ylides, equipped with a C-2 methanethiol group, participate in an efficient [3
+
2] cycloaddition reaction with acetylene
derivatives to yield unique pyrrolo[2,1-b]thiazoles. The elimination of the methanethiol leaving group from the cycloadduct has replaced the
need for a separate oxidation step and suppresses ring-opening side reactions. Products were obtained in short synthetic sequences to
demonstrate their use as a scaffold for compound libraries.
1,3-Dipolar cycloadditions of azomethine ylides are one of
the most powerful methods for the construction of five-
membered nitrogen heteroaromatic ring systems, both inter-
and intramolecularly.1 Huisgen was first to show that pairing
acrylate- or propiolate-derived dipolarophiles with appro-
priately stabilized azomethine ylides was an effective strategy
for the synthesis of pyrroles, pyrrolines, or pyrrolizidines.2
Vedejs, through a fluoride-induced desilylation of (trimeth-
ylsilyl)methylammonium salts, showed that nonstabilized
acyclic azomethine ylides could be used to generate pyrroline
derivatives.3
We envisioned that cyclic azomethine ylides could form
a fused 5-5 heteroaromatic system that would comprise the
core structural motif for the generation of a diverse library
of compounds not previously reported in the literature (Figure
1). Although the pyrrolo[2,1-b]thiazole system (Figure 1, Z
) S) is not new, and has been prepared by a variety of
methods,4 few patents have been filed with this core scaffold,
thereby providing chemical space that is relatively unen-
cumbranced by intellectual property issues. Drug target
screening hits from chemical libraries prepared through our
novel reaction would not be bound by existing patents.
Early research by Boekelheide with imidazolium azo-
methine ylides gave initial cycloadducts in which on oxida-
tion (presumably by air) formed the fully aromatic 5-5
(1) For some excellent reviews on azomethine chemistry, see: Najera,
C.; Sansano, J. M. Curr. Org. Chem. 2003, 7, 1105-1150. Tsuge, O.;
Kanemasa, S. AdV. Heterocycl. Chem. 1989, 45, 231-239. Vedejs, E. AdV.
Cycloaddit. 1988, 1, 33-51. Vedejs, E.; West, F. G. Chem. ReV. 1986, 86,
941-955. Padwa, A. 1,3-Dipolar Cycloaddition Chemistry; Wiley-Inter-
science: New York, 1984; Vol. 2, p 277.
(2) Huisgen, R. J. Org. Chem. 1976, 41, 403-419. Hermann, H.;
Huisgen, R.; Mader, H. J. Am. Chem. Soc. 1971, 93, 1779-1780 and
references therein.
(4) The syntheses of substituted pyrrolo[2,1-b]thiazoles is described in
the following leading references: Seregin, I. V.; Gevorgyan, V. J. Am.
Chem. Soc. 2006, 128, 12050-12051. Tverdokhlebov, A. V.; Andrushko,
A. P.; Tolmachev, A. A. Synthesis 2006, 1433-1436. Landreau, C.; Janvier,
P.; Julienne, K.; Meslin, J. C.; Deniaud, D. Tetrahedron 2006, 62, 9226-
9231. Bedjeguelal, K.; Bienayme, H.; Poigny, S.; Schmitt, Ph.; Tam, E.
QSAR & Comb. Sci. 2006, 25, 504-508. Kel’in, A. V.; Sromek, A. W.;
Gevorgyan, V. J. Am. Chem. Soc. 2001, 123, 2074-2075.
(3) Vedejs, E.; Larsen, S.; West, F. G. J. Org. Chem. 1985, 50, 2170-
2174. Vedejs, E.; Martinez, G. R. J. Am. Chem. Soc. 1979, 101, 6452-
6454.
10.1021/ol071229n CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/14/2007

Table 1. 1,3-Dipolar Cycloaddition of Thiazolium Azomethine
Ylides with Acetylene Dicarboxylates
yieldb
R3 ) prdt (%)
entrya
R1 )
R2 )
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
benzo
H
H
H
Ph
Me
Et
t-Bu
Me
2
3
4
5
6
7
8
9
66
58
72
37
35
10
0
34
30
10
0
3,5-dimethylphenyl Me
2-methoxyphenyl
Br
Figure 1. Reaction pathway to the key structural motif.
Me
Me
t-Bu
Me
t-Bu 11
Me 12
system, however in low yields (Figure 1, Z ) NR2, X )
H).5 Wang published similar work with benzimidazoles
where the addition of CrO3 as an oxidant afforded the desired
compound with modest to good success.6 In our hands,
multiple reaction conditions with imidazole derivatives did
not provide the desired system or gave very low yields
(Figure 1, Z ) NR2, X ) H).7
2-methoxybenzo
Ph
t-Bu
10
10
11
H
H
a Inverse addition used with 1.4 equiv of CsF, 4.0 equiv of dimethyl-
acetylene dicarboxylate in CH3CN at ambient temperature for 2 h. For exact
conditions, see the Supporting Information. b Isolated yields.
A potential pitfall in this chemistry was the oxidation of
the cycloadduct intermediate to the aromatic final product
(Figure 1, X ) H). Slow aromatization appears to compete
with ring-opening reactions due to the ring strain of the fused
5-5 system.8 An elimination reaction rather than a formal
oxidation would be a better alternative to achieve this final
transformation. The addition of a leaving group at C-2 would
replace the need for an oxidation step as elimination to a
fully aromatic ring system would be thermodynamically
favored. This strategy was employed by Vedejs and Padwa
in alicyclic and acyclic azomethine ylide examples.9
Clean quaternization of 2-methylthio-1,3-thiazole (1) oc-
curred with TMSCH2OTf as monitored by 1H NMR experi-
ments, and after optimization of reaction conditions10 the
cycloadduct 2 was obtained in 66% yield (entry 1, Table 1).
The methylmercaptan eliminated from the initial cycloadduct
was trapped by excess DMAD present in the reaction mixture
to give dimethyl 2-methylthiomaleate, which was isolated.
Our attempts to apply these reaction conditions to 1-benzyl-
2-methylthioimidazole (Figure 1, Z ) NCH2Ph, X ) SCH3)
to form the analogous pyrrolo[1,2-a]imidazole were unsuc-
cessful. The reaction of 1-benzyl-2-methylthioimidazole with
TMSCH2OTf in CD3CN was monitored by NMR, and in
1-2 h at room temperature the quaternary species was
cleanly formed. However, the reaction of the imidazolium
ylide with dimethyl acetylenedicarboxylate gave a dark
reaction mixture that contained multiple spots by TLC.
Applying our inverse addition conditions10 to substituted
thiazoles provided pyrrolothiazoles 3-11. Substitution at C-5
(entries 4-7) provided lower yields of the cycloadduct as
compared with the unsubstituted thiazoles. Substituents that
reduced the thiazole nitrogen electron density (cf. entries
7-9) or that increased steric hindrance at the thiazole
nitrogen (cf. entries 8-11) all gave low yields (10-34%)
or none of the desired product.
When ethyl propiolate was used as the dipolarophile in
this cycloaddition reaction (Table 2), CsF was added to the
preformed azolium species and then alkyne added in one
portion, only a 32% isolated yield of 13 was obtained (entry
1). The other regioisomer was observed as a ∼5% unsepa-
rable impurity in the reaction mixture for all examples.
However, when the azolium species and alkyne were added
dropwise via an additional funnel to a stirred solution of CsF,
the yield was increased to 53% (entry 2). Using this “inverse
addition” method, modification of the ethyl propiolate
stoichiometry (1-10 equiv), the reaction concentration
(0.05-1 M), the temperature (rt to -5 °C), or the addition
of CuI, all had no effect on the isolated yield. Substituting
tetramethylammonium fluoride (TMAF) for CsF (entry 3)
or varying the equivalents of TMSCH2OTf (entry 4) reduced
the yield. TBAF gave even poorer results, presumably due
to traces of water present. The best yield was obtained when
the preformed thiazolium salt, combined with 1.5 equiv of
ethyl propiolate in acetonitrile, was added at room temper-
ature over 1 h to a stirred solution of CsF and 1.5 equiv of
ethyl propiolate in acetonitrile (entry 6). After workup and
purification, a 69% isolated yield of the pyrrolo[2,1-b]-
thiazole 13 was obtained on a 15 mmol reaction scale.10,11
(5) Boekelheide, V.; Fedoruk, J. J. Am. Chem. Soc. 1968, 90, 3830-
3834.
(6) Wang, B.; Hu, J.; Zhang, X.; Hu, Y.; Hu, H. J. Heterocycl. Chem.
2000, 37, 1533-1537.
(7) Extensive experimentation with imidazole derivatives under a variety
of conditions (solvent, time, temperature, different substrates such as
1-benzylimidazole, 1-methylimidazole, acetylene derivatives, and oxidants)
led to little or no desired products being isolated.
(8) Padwa, A.; Chiacchio, U.; Venkatramanan, M. K. Chem. Commun.
1985, 1108.
(9) Vedejs, E.; West, F. G. J. Org. Chem. 1983, 48, 4773-4774. Padwa,
A.; Haffmanns, G.; Tomas, M. J. Org. Chem. 1984, 49, 3314-3322.
(10) For details of the optimized protocol, see the Supporting Information.
4100
Org. Lett., Vol. 9, No. 21, 2007

In fact, the imidazolium reaction is slightly more favored
than the thiazolium case. These results imply that the low
yields with the imidazolium ylide result from an adduct ring-
opening reaction to byproducts. Since C-N bonds are shorter
than the C-S bonds, the imidazolium ylide cycloadduct (II,
Z ) NMe) would have more ring strain than the thiazolium
ylide cycloadduct (II, Z ) S), thereby favoring ring opening
of II (Z ) NMe) instead of MeSH elimination to aromatize
to form the fused 5-5 system. The molecular orbital
coefficients and atomic charges of the methyl propiolate
LUMO and the thiazolium ylide HOMO predict the observed
regioselectivity in the formation of the cycloaddition product
13.15
Table 2. Optimization of Reaction Conditions with Ethyl
Propiolate
entrya
A (equiv)
B (equiv)
C (equiv)
yieldb (%)
1c
2
1.05
1.05
1.05
2.0
1.05
1.05
4.0
4.0
4.0
4.0
4.0
3.0
1.4
1.4
1.4
2.0
1.4
1.4
32
53
19
32
48
69
3d
4
5e
6f
Manipulation of these cycloadducts 4 and 13 was then
undertaken to enable the preparation of diverse compound
libraries (Scheme 1). Cycloadduct 4 was treated with
a Reactions were run with inverse addition over 2 h at 0.1 M in
acetonitrile at rt. b Isolated yields. All crude products contained ∼5% of
the other regioisomer. c No inverse addition. d TMAF was used in place of
CsF. e Azolium plus alkyne added to CsF. f Half alkyne with azolium and
half alkyne with CsF.
Scheme 1. Manipulation of the Pyrrolo[2,1-b]thiazole Core
Under these inverse addition conditions, we postulate that
as the thiazolium species is added to the CsF/ethyl propiolate
solution, the ylide I is rapidly formed under dilute reaction
conditions, but in the presense of higher concentrations of
ethyl propiolate which facilitates the formation of the initial
cycloadduct II (Z ) S, R ) H, X ) SCH3). These inverse
addition conditions would serve to minimize the dimerization
of the ylide I or the condensation of the ylide I to the
thiazolium precursor; side reactions that are well-known for
reactive dipoles.12
The use of other unsymmetrical acetylenes with this
cycloaddition was investigated. 3-Butyne-2-one, ethynyl
p-tolyl sulfone, and N-phenyl-2-propynamide13 gave low-
yielding, complex mixtures that were difficult to purify.
Phenylacetylene and N-phenylmaleimide provided total
decomposition of the reaction mixture.
In an ab initio study, full optimizations of the reactants,
which included the ylides I (Z ) NMe and S, R ) H, X )
SMe), dimethyl acetylene dicarboxylate, and methyl pro-
piolate, was carried out using the density functional B3LYP,
at the 6-31++g(2d,p) level of theory. The results indicate
that the cycloaddition reaction is charge or orbital controlled.
This confirms that the reaction is a Sustmann Type 1 1,3-
dipolar cycloaddition reaction, where the dominant frontier
molecular orbital interaction is between the dipole HOMO
and the dipolarophile LUMO.14 The similar HOMO-LUMO
gap energies as well as similar orbital coefficients predict
that the cycloaddition reactions of both the imidazolium ylide
(I, Z ) NMe) and thiazolium ylide (I, Z ) S) should occur.
trifluoroacetic acid, concentrated, and without purification
was placed into a microwave reactor (150 °C) for 10 min in
DMF to provide the 6-substituted monoacid 14 in very high
yields. Ester formation with EtI and K2CO3 provided the
6-ethyl ester 15. Alternatively, the monoacid 14 could be
coupled with amines to provide amides 16a and 16b in good
yield.
We now had in place efficient synthetic schemes to prepare
both ethyl ester regiosiomers (13 and 15) for further
experimentation. We found that NBS bromination of 13 gave
the best yield and isolated purity of the 6-bromo-pyrrolo-
[2,1-b]thiazole. This bromide could be isolated by column
chromatography, however in lower yield, and on standing
at room temperature the compound decomposed overnight.
Bromination of the ethyl ester 15 provided a complex mixture
of regioisomers and purification proved extremely difficult.
Other halogenation protocols resulted in little to no desired
products being detected.16
The crude product from the NBS bromination of 13
following aqueous workup and concentration was im-
mediately reacted with arylboronic acids in the Suzuki
1
(11) The H NMR coupling of the aromatic signals of the pyrrolo[2,1-
b]thiazole 13 support the structural assignment. For details of the coupling
constant assignments for 13 and 1H-NMR spectra, see the Supporting
Information.
(12) Padwa, A. 1,3-Dipolar Cycloaddition Chemistry; Wiley-Inter-
science: New York, 1984; Vols. 1 and 2.
(15) See the Supporting Information for details on the ab initio
calculations, the FMO correlation diagrams, and the HOMO-LUMO orbital
coefficient diagrams.
(16) Other iodination conditions (I2 and AgO2CCF3, NIS, for example)
and bromination conditions (Br2, Br2 and acetic acid, for example) provided
little to no desired compound.
(13) For synthesis, see: Coppola, G. M.; Damon, R. E. Synth. Commun.
1993, 23, 2003-2010.
(14) Sustmann, R. Tetrahedron Lett. 1971, 2717-2720. Sustmann, R.
Pure Appl. Chem. 1974, 40, 569-593. Gothelf, K. V.; Jorgensen, K. A.
Chem. ReV. 1998, 98, 863-909.
Org. Lett., Vol. 9, No. 21, 2007
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reaction to provide the 6-aryl pyrrolo[2,1-b]thiazoles 17a-e
in good overall yields for two steps (Table 3). Both electron-
oxalyl chloride and 2,4-dichlorobenzylamine in the presence
of catalytic DMF, provided the expected amide 18 in very
good overall yields for two steps (Scheme 2).17
Table 3. Bromination/Suzuki Coupling of Cycloadduct 13
Scheme 2. Preparation of
Pyrrolo[2,1-b]thiazole-7-carboxamide
entrya
R )
phenyl
product
yieldb (%)
1
2
3
4
5
17a
17b
17c
17d
17e
69
72
58
62
53
4-Cl-phenyl
In conclusion, we have shown that thiazolium azomethine
ylides equipped with a C-2 methanethiol leaving group
readily participate in 1,3-dipolar cycloadditions when paired
with appropriate dipolarophiles. It was also shown that
elimination of methanethiol was indeed a suitable replace-
ment for the known oxidation of the initial cycloadduct to
form the fully aromatic pyrrolo[2,1-b]thiazole and in gram
quantities. There are very limited examples of the pyrrolo-
[2,1-b]thiazole scaffold in the literature.4 Our successful
synthesis of this aromatic 5-5 system and the subsequent
substitution chemistry has given us a scaffold from which
novel, diverse, and druglike compound libraries can be
prepared.
4-OMe-phenyl
4-SO2Me-phenyl
3-pyridinyl
a For reaction conditions, see the Supporting Information. b Isolated yields
over two steps.
rich (17c) and electron-poor (17b and 17d) boronic acids
gave similar results in the Suzuki coupling with the bromi-
nated pyrrolo[2,1-b]thiazole 13. In addition, 3-pyridinyl-
boronic acid underwent successful coupling to give com-
pound 17e. These products were stable and could be stored
with ease. Other electrophilic aromatic substitution reactions
such as Friedel-Crafts acylation of 13 or 15 led to significant
decomposition or products that were obtained in very low
yield.
Acknowledgment. We thank William Jones (J&JPRD)
for assistance with HRMS data acquistion and George Elgar
1
(J&JPRD) for H NMR assistance.
Finally, the arylated cycloadduct 17a was saponified to
provide the crystalline free acid, which upon treatment with
Supporting Information Available: Experimental details
and characterization data for new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(17) Procedure from: Doherty, E. M.; Fotsch, C.; Bo, Y.; Chakrabarti,
P. P.; Chen, N.; Gavva, N.; Han, N.; Kelly, M. G.; Kincaid, J.; Klionsky,
L.; Liu, Q.; Ognyanov, V. I.; Tamir, R.; Wang, X.; Zhu, J.; Norman, M.
H.; Treanor, J. J. S. J. Med. Chem. 2005, 48, 71-90.
OL071229N
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Org. Lett., Vol. 9, No. 21, 2007