Direct C-2 arylation of alkyl 4-thiazolecarboxylates: New insights in synthesis of heterocyclic core of thiopeptide antibiotics

Article abstract of DOI:10.1021/ol801035c

(Chemical Equation Presented) The Pd(0)-catalyzed regioselective C-2 (hetero)arylation of tert-butyl 4-thiazolecarboxylate with a broad (hetero)aryl halide is reported, including the direct coupling of pyridinyl halides. The process has allowed the preparation of valuable 2-pyridynyl-4- thiazolecarboxylates which are components of the complex heterocyclic core of thiopeptides antibiotics. As a first application, a synthesis of a tert-butyl sulfomycinamate thio-analogue from tert-butyl 4-thiazolecarboxylate is here described through a three-step direct pyridinylation, halogenation, and Stille cross-coupling sequence.

Full text of DOI:10.1021/ol801035c

ORGANIC
LETTERS
2008
Vol. 10, No. 13
2909-2912
Direct C-2 Arylation of Alkyl
4-Thiazolecarboxylates: New Insights in
Synthesis of Heterocyclic Core of
Thiopeptide Antibiotics
Thibaut Martin, Ce´cile Verrier, Christophe Hoarau,* and Francis Marsais
Institut de Chimie Organique Fine (IRCOF) associe´ au CNRS (UMR 6014),
INSA et UniVersite´ de Rouen, BP08 76131 Mont Saint Aignan, France
christophe.hoarau@insa-rouen.fr
Received May 5, 2008
ABSTRACT
The Pd(0)-catalyzed regioselective C-2 (hetero)arylation of tert-butyl 4-thiazolecarboxylate with a broad (hetero)aryl halide is reported, including
the direct coupling of pyridinyl halides. The process has allowed the preparation of valuable 2-pyridynyl-4-thiazolecarboxylates which are
components of the complex heterocyclic core of thiopeptides antibiotics. As a first application, a synthesis of a tert-butyl sulfomycinamate
thio-analogue from tert-butyl 4-thiazolecarboxylate is here described through a three-step direct pyridinylation, halogenation, and Stille cross-
coupling sequence.
Aryl-substituted thiazoles are common features of a wide
range of biologically active natural products exemplified by
the thiopeptide antibiotics family.1 They are also of consider-
able interest in medicinal chemistry and as organic materials
such as liquid crystal and cosmetic sunscreens.2 Current
arylating methods employed to build up diaromatic systems
are based upon a preliminary halogenation or metalation
reaction followed by transition-metal-catalyzed cross-
coupling reactions with arylmetals or aryl halides. In recent
years, direct C-H arylation has emerged as an attractive
alternative to the commonly employed cross-coupling reac-
tions since it does not require the rather tricky preliminary
preparation of the requisite organometallic or halogenated
arenes. Several reviews highlight the broad scope, the high
functional group tolerance, the atom economy, and the mild
reaction conditions of this strategy.3 The palladium-catalyzed
direct C-H arylation of thiazole is well precedented.2b,4 In
(1) Reviews: (a) Hughes, R. A.; Moody, C. Angew. Chem., Int. Ed. 2007,
46, 2–27. (b) Bagley, M. C.; Dale, J. W.; Meritt, E. A. E.; Xiong, X. Chem.
ReV. 2005, 105, 685–714. (c) Roy, R. S.; Gehring, A. M.; Milne, J. C.;
Belshaw, P. J.; Walsh, C. T. Nat. Prod. Rep. 1999, 16, 249–263. (d) Li,
Y.-M.; Milne, J. C.; Madison, L. L.; Kolter, R.; Walsh, C. T. Science 1996,
274, 1188–1193.
(3) (a) Alberico, D.; Scott, M. E.; Lautens, M. Chem. ReV. 2007, 107,
174–238. (b) Campeau, L.-C.; Stuart, D. R.; Fagnou, K. Aldrichim. Acta
2007, 40, 35–41. (c) Stuart, D. R.; Fagnou, K. Science 2007, 316, 1131–
1132. (d) Kakiuchi, F.; Chatani, N. AdV. Synth. Catal. 2003, 354, 1077–
1101. (e) Lablinger, J. A.; Bercaw, J. E. Nature 2002, 417, 507–514. (f)
Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. ReV. 2002, 102, 1731. (g) Miura,
M.; Nomura, M. Top. Curr. Chem. 2002, 219, 211–241. (h) Fujiwara, Y.;
Chengguo, J. Pure Appl. Chem. 2001, 73, 319–324. (i) Dyker, G. Angew.
Chem., Int. Ed. 1999, 38, 1698–1712. (j) Shilov, A.; Shul’pin, G. Chem.
ReV. 1997, 97, 2879–2932.
(2) (a) Vin´ıcius, M.; De Souza, N. J. Sulfur Chem. 2005, 26, 429–449.
(b) Mori, A.; Sekigushi, A.; Masui, K.; Shimada, T.; Horie, M.; Osakada,
K.; Kawamoto, M.; Ikeda, T. J. Am. Chem. Soc. 2003, 125, 1700–1701.
(c) Kiryanov, A. A.; Sampson, P.; Seed, A. J. J. Org. Chem. 2001, 66,
7925–7929. (d) Bach, T.; Heuser, S. Tetrahedron Lett. 2000, 41, 1707–
1710.
10.1021/ol801035c CCC: $40.75
Published on Web 06/10/2008
2008 American Chemical Society

this paper, we report the first developments on direct arylation
of 4-thiazolecarboxylic esters scaffolds 1 and 2 which are
common features of the heterocyclic core in the important d
series of thiopeptide antibiotics exemplified by the sulfo-
mycinamate and micrococcinate esters 3-5 (Figure 1).
zolecarboxylate.6 Accordingly, as a first set of arylation
experiments, the methyl 4-thiazolecarboxylate 1 was reacted
with 1 equiv of phenyl iodide, 5 mol % of Pd(OAc)2, and 2
equiv of Cs2CO3 at 110 °C in a sealed tube, and the two
parameters, ligand and solvent, were screened. It was
immediately clear that the polarity of the solvent was the
most significant factor for controlling the regioselectivity of
the direct arylation. This trend is summarized graphically in
Scheme 1. The apolar toluene solvent delivered a mixture
Scheme 1. Study of Direct Phenylation of 1
Figure 1. 4-Thiazolylcarboxylic esters are units of the heterocyclic
core in the d series of thiopeptide antibiotics exemplified by
sulfomycinamte and micrococcinate.
Current synthetic strategies for the connection at an early
stage of the 4-thiazole carboxylate motif to the central
pyridine molecule employ mainly the Negishi cross-coupling
process.1a,5 We reasoned that with direct arylation coupling
of 4-thiazole carboxylate at 2-position methodology, the
current synthesis of the pyridine central core of trisubstituted
pyridine thiopeptide antibiotics (series d) could be simplified
avoiding the preparation of thiazolyl or pyridinyl metals by
designing novel synthetic routes. Herein we developed a
highly effective protocol for palladium-catalyzed C-2 aryl-
ation of tert-butyl 4-thiazole carboxylate 2 with a wide range
of iodo-, bromo-, and chloroaromatics including halogeno-
pyridines. In the first application, we developed a first route
toward the tert-butyl sulfomycinamate thio-analogue 4 from
2 through a three-step direct pyridinylation, halogenation,
and Stille cross-coupling sequence.
a
1H NMR yield based on the amount of 1 used. bJP ) Buchwald’s
c
JohnPhos ligand. NL ) no ligand.
of mono- and diphenylated products in which the 5-phen-
ylated compound was slightly predominant. Therefore, the
highly polar DMF was tried; it favored the C-2 phenylation
of 1. Moreover it appeared that the nature of the ligand
slightly influenced the regiochemical outcome of the phen-
ylation of 1 since reactions with or without phosphine ligand
provided the 2-phenylated compound in rather uniform albeit
moderate yields (27-58%). It should be noted interestingly
that only a trace amount of biphenyl arising from Pd(0)-
catalyzed homocoupling side reaction was detected.
The methyl 4-thiazolecarboxylate 1 was obtained in high
yield in multigram quantities by treatment of commercially
available 4-thiazolecarboxylic acid with thionyl chloride in
methanol. We previously reported that the combination of
palladium diacetate and cesium carbonate is effective for
phenylation of the structurally related model ethyl 4-oxa-
(4) For examples of direct arylation of thiazole, see: (a) Campeau, L. C.;
Bertrand-Laperle, M.; Leclerc, S. P.; Villemure, E.; Gorelsky, S.; Fagnou,
K. J. Am. Chem. Soc. 2008, 130, 3276–3277. (b) Nandurkar, N. S.;
Bhanushali, M. Y.; Bhor, M. D.; Bhanage, B. M. Tetrahedron Lett. 2008,
49, 1045–1048. (c) Turner, G. L.; Morris, J. A.; Greaney, M. F. Angew.
Chem., Int. Ed. 2007, 46, 1–6. (d) Do, H.-Q.; Daugulis, O. J. Am. Chem.
Soc. 2007, 129, 12404–12405. (e) Bellina, F.; Calandri, C.; Cauteruccio,
S.; Rossi, R. Tetrahedron 2007, 63, 1970–1980. (f) Bellina, F.; Cauteruccio,
S.; Rossi, R. Eur. J. Org. Chem. 2006, 71, 1379–1382. (g) Parisien, M.;
Valette, D.; Fagnou, K. J. Org. Chem. 2005, 70, 7578–7584. (h) Masui,
K.; Mori, A.; Okano, K.; Takamura, K.; Kinoshita, M.; Ikeda, T. Org. Lett.
2004, 6, 2011–2014. (i) Yokooji, A.; Okazawa, T.; Satoh, T.; Miura, M.;
Nomura, M. Tetrahedron 2003, 59, 5685–5689. (j) Kondo, Y.; Komine,
T.; Sakamoto, T. Org. Lett. 2000, 2, 3111–3113. (k) Pivsa-Art, S.; Satoh,
T.; Kawamura, Y.; Nomura, M. Bull. Chem. Soc. Jpn. 1998, 71, 467–473.
(l) Aoyagi, Y.; Inoue, A.; Koizumi, I.; Hashimoto, R.; Tokunaga, K.; Gohma,
K.; Komatsu, J.; Sekine, K.; Miyafuji, A.; Kunoh, J.; Honma, R.; Akita,
Y.; Ohta, A. Heterocycles 1992, 33, 257–272.
DMF was then chosen to secure the regioselective C-2
phenylation of 1, and we further directed our efforts to reduce
the contamination with the diphenylated compound formed
in 5-20% yield. To this end, we reasoned that the addition
of internal steric effects (bulky ester) might reduce the
undesired subsequent C-5 phenylating process. Thus, the tert-
butyl 4-thiazole carboxylate 2 was prepared by treatment of
4-carboxythiazole with tert-butyl alcohol under CDI activa-
tion. Direct phenylation of 2 with phenyl iodide was achieved
following a thorough screening of ligands that included bulky
P(o-tol)3, P(biphenyl-2-yl)Cy2 (Buchwald’s JohnPhos ligand),
P(tBu)3, and 1,3-bis-(mesitylimidazolyl)carbene (IMes) ligands
(Table 1). Gratifyingly, the P(o-tol)3 and P(biphenyl-2-yl)Cy2
(5) Heckmann and Bach reported a first synthesis of an heterocyclic
core of a thiopeptide antibiotic (GE2270A) in a complete cross-coupling
approach: Heckmann, G.; Bach, T. Angew. Chem., Int. Ed. 2005, 44, 1199–
(6) Hoarau, C.; Du Fou de Kerdaniel, A.; Bracq, N.; Grandclaudon, P.;
Couture, A.; Marsais, F. Tetrahedron Lett. 2005, 46, 8573–8577.
1201
.
2910
Org. Lett., Vol. 10, No. 13, 2008

Table 1. Study of the Direct Phenylation of 2
Table 2. Direct regioselective C-2 arylation of 2
entry
ligand
none
9a (%)
10a (%)
11a (%)
1
2
3
4
5
6
a
0
8
0
5
23
10
PPh3
47
2
0
2
6
5
P(o-tol)3
JohnPhosb
PtBu3
82 (81)d
68 (65)d
38
IMesc
50
1H NMR yield based on the amount of 2 used. b Buchwald’s JohnPhos
ligand:2-(dicyclohexylphosphino)-biphenyl.c IMes:1,3-bis-(mesitylimidazolyl)-
carbene. d Isolated yield.
ligands proved highly effective in selective direct C-2
phenylation of 2, providing the 2-phenylated thiazolecar-
boxylate 9 in 82% and 68% yields respectively (entries 3,4).
Remarkably, the reaction became fully regioselective using
P(o-tol)3 as ligand.
With an optimized palladium-catalyzed C-2 phenylating
process of 2 in place using P(o-tol)3 and P(biphenyl-2-yl)Cy2,
we first examined the C-2 arylation of 2 with a wide range
of iodoaromatics. All aryl iodides bearing either electron-
withdrawing or electron-donating groups underwent C-2
arylation with 2 using P(o-tol)3 as ligand affording the
2-arylated thiazoles 12-15 in fair 65-71% yields (Table 2,
entries 1-4). Thus, the previous conditions were verified
for the C-2 heteroarylation of 2 with various commercially
available iodo-, bromo-, and chloroheteroaromatics, espe-
cially pyridine substrates. Initial screens were executed with
three 2-halogenopyridine models. Surprisingly, although P(o-
tol)3 proved effective for the direct coupling of 2 with
2-iodopyridine, leading to the corresponding 2-pyridin-2-
ylthiazolecarboxylate 16 in 73% yield (Table 2, entry 5),
the direct coupling of 2 proceeded smoothly with 2-bromo-
pyridine (42%) and failed with 2-chloropyridine using the
same ligand. Buchwald’s JohnPhos ligand proved to be more
appropriate than P(o-tol)3 for the direct coupling of 2 with
bromo- and chloroheteroaromatics. Indeed, the first set of
direct couplings of 2 with 2-bromo- and 2-chloropyridines
using P(biphenyl-2-yl)Cy2 provided the expected 2-pyridin-
2-ylthiazolecarboxylate 16 in a fair (65%) and excellent
(95%) yield (Table 2, entries 6 and 7) and notably without
side formation of any other coupling product.
a Isolated yield. b Halogenoaromatic (2 equiv). c Halogenoaromatic (3
equiv). d Halogenoaromatic (3 equiv), Pd(OAc)2/L (10:20 mol %). e The
2,5-pyridiny-3-yl thiazolecarboxylate was isolated in 15% yield. f The 2,5-
pyridin-3-yl thiazolecarboxylate was isolated in 45% yield.
Further direct C-2 heteroarylations of 2 including numbers
of pyridine halides were then investigated using P(biphenyl-
2-yl)Cy2 (Table 2, entries 8-18). Two major classes of
heteroaryl halides have to be distinguished. Several bromo-
and chloroheteroaromatics such as 2-bromo-6-methoxy-
pyridine, 3-bromoquinoline, 2-chloropyrazine, and 2-iodo-
thiophene underwent direct arylation with 2 providing the
expected 2-heteroaryl thiazolecarboxylates in good yields
(71-84%) (entries 12, 14, 17, and 18). With other heteroaro-
matics, direct coupling with 2 proceeded smoothly due to
the formation of the biheteroarene arising from the competi-
tive homocoupling reaction of the heteroaryl halide. Nev-
Org. Lett., Vol. 10, No. 13, 2008
2911

ertheless, except for 3-bromopyridine (entry 9), only traces
of 5-heteroarylated and 2,5-diheteroarylated compounds were
detected, indicating that the second C-5 arylation was slower
than the first C-2 arylation under these conditions. Thus, as
expected, complete conversion of 2 and a significant yield
increase of 2-heteroaryl thiazolecarboxylates 17, 18, 20, 22,
and 23 could thereby be obtained by using an excess of
heteroaryl halides (2- or 3-fold excess) while adjusting
amounts of catalyst and ligand (entries 8, 10, 11, 13, 15,
and 16).
Scheme 2
.
Synthesis of tert-Butyl Sulfomycinamate
Thio-Analogue 4
As an application of the previous methodology in the
course of a research program to design neat synthetic routes
toward heterocyclic core of thiopeptide antibiotics, the tert-
butyl sulfomycinamate thio-analogue 47 was synthesized
from 2 in five synthetic steps and 45% overall yield. The
synthesis is depicted in Scheme 2. Direct C-H coupling of
2 with tert-butyl 5-bromopicolinate 26 at its 2-position led
to the pyridinylthiazolecarboxylate 27 in good 70% yield.
The regiocontrolled chlorination of 27 was then accomplished
through a selective N-pyridine oxidation with UHP8 followed
by treatment of the N-oxide intermediate with POCl3 under
Fagnou’s conditions9 providing 28 in excellent 78% yield.
Stille cross-coupling between chloropyridinylthiazolecar-
boxylate 28 and the 4-thiazolylstannane 2910 afforded the
tert-butyl sulfomycinamate thio-analogue 4 in 82% yield after
Pd(II)-catalyzed acetal deprotection.11
iodo-, bromo-, and chloro(hetero)arenes including halo-
genopyridines, providing rapid access to valuable 2-pyr-
idynyl-4-thiazolylcarboxylates, which are unit of the complex
heterocyclic thiopeptides antibiotics. Thanks to this route,
the tert-butyl sulfomycinamate thio-analogue 4 could be
prepared from 2 in three-step via direct C-2 pyridinylation,
C-2 chlorination of the pyridine, and Stille cross-coupling
in 45% overall yield.
In summary, our study of the regioselective direct phenyl-
ation of 4-thiazolecarboxylate esters 1 and 2 has demon-
strated that the process is viable. Our methodology provides
efficient conditions for highly selective direct C-2 arylation
of tert-butyl-4-thiazolecarboxylate 2 with a wide range of
Acknowledgment. This work has been supported by the
CNRS, the interregional CRUNCH network, INSA, and the
University of Rouen (I.U.T.).
(7) For previous reports on syntheses of dimethyl sulfomycinamate, see:
(a) Bagley, M. C.; Chapaneri, K.; Dale, J. W.; Xiong, X.; Bower, J. J. Org.
Chem. 2005, 70, 1389–1399. (b) Xiong, X.; Bagley, M. C.; Chapaneri, K.
Tetrahedron Lett. 2004, 45, 6121–6124. (c) Bagley, M. C.; Dale, J. W.;
Xiong, X.; Bower, J. Org. Lett. 2003, 5, 4421–4424. (d) Kelly, T. R.; Lang,
F. J. Org. Chem. 1996, 61, 4623–4633.
(8) Caron, S.; Do, N. M.; Sieser, J. Tetrahedron Lett. 2000, 41, 2299–
2302.
Supporting Information Available: Experimental pro-
cedures and spectroscopic characterization (IR, analytical
analysis, 1H, 13C data) of all new (het)arylated thiazoles. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(9) Leclerc, J.-P.; Fagnou, K. Angew. Chem., Int. Ed. 2006, 45, 7781–
7786.
(10) Compound 28 was prepared through a three-step C-2 acylation,
acetal protection, and C-4 stanylation sequence from commercially available
2,4-dibromothiazole (see the Supporting Information).
(11) Ung, A.; Pyne, S. G.; Skelton, B. W.; White, A. H. Tetrahedron
1996, 52, 14069–14078.
OL801035C
2912
Org. Lett., Vol. 10, No. 13, 2008