Synthesis of 2-amino-5-arylthiazoles by palladium-catalyzed arylation at the C5 position with aryl iodides

Article abstract of DOI:10.1055/s-2007-992368

A new synthetic route to afford 2-amino-5-aryl thiazoles has been developed. The starting aminothiazole derivative can be arylated at position 5 with aryl iodides under palladium-catalyzed conditions. Mechanistic studies suggest a proton-abstraction pathw

Full text of DOI:10.1055/s-2007-992368

LETTER
2957
Synthesis of 2-Amino-5-arylthiazoles by Palladium-Catalyzed Arylation at the
C5 Position with Aryl Iodides
Synthesis
uof 2-Amino-
l
5-arylth
i
iazolesán Priego,* Sonia Gutiérrez, Rafael Ferritto, Howard B. Broughton
Centro de Investigación, Lilly, S.A., Avenida de la Industria 30, 28108 Alcobendas, Madrid, Spain
Fax +34(91)6233591; E-mail: julian_priego@lilly.com
Received 21 May 2007
Herein, we describe a novel strategy for the synthesis of 4
Abstract: A new synthetic route to afford 2-amino-5-aryl thiazoles
has been developed. The starting aminothiazole derivative can be
arylated at position 5 with aryl iodides under palladium-catalyzed
conditions. Mechanistic studies suggest a proton-abstraction path-
way for this transformation.
based on Pd-catalyzed arylation at the C5 position of com-
pound 2 (Scheme 2). The direct arylation of 2-aminothi-
azoles has not been reported to date.7 Nonetheless, related
studies in other heterocyclic systems, such as thiophenes,
imidazopyrimidines, indolizines, furans and indoles are
described in the literature.8
Key words: palladium, catalysis, cross-coupling, heterocycles,
Heck reaction
Table 1 Pd-Catalyzed Reaction of Thiazole 2 with Iodobenzenea
Pd(OAc)2
ligand
base, solvent
120 °C
1.
Aryl-substituted thiazoles have not only shown pharma-
cological activities,1 but are also important as organic ma-
terials such as fluorescent dyes2 and liquid crystals.3
Usually, catalytic methods to prepare aryl heterocycles in-
volve transition-metal-catalyzed coupling between an or-
ganometallic element and an aryl halide.4
EtO2C
EtO2C
Ph
N
N
+
PhI
NHBoc
NH2
S
S
2. TFA, CH2Cl2
2
3a
4a
Entry
1
Ligand Base
Solvent
Yield (%)b
More recently, as a major challenge in organic synthesis,
significant attention has been given to the direct arylation
of heteroarenes (without prior functionalization via meta-
lation), achieved via cross-coupling of heteroaromatic sp2
C–H bonds and aryl halides.5
PPh3
Cs2CO3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
THF
11c
68
72
80
–
2
5
6
7
7
7
7
7
7
7
7
7
Cs2CO3
Cs2CO3
Cs2CO3
K3PO4
3
4
S
EtO2C
Ar
X
N
H2N
NH2
5
CO2Et
NH2
O
Ar
MeOH
S
6
K2CO3
Na2CO3
KOAc
10c
–
∆
4
1
7
X = Cl or CN
8
–
Scheme 1
9
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
33c
23c
–
To the best of our knowledge, the only method described
in the literature to obtain 2-aminothiazoles 4 consists of
the reaction between the corresponding chloro/cyanogly-
cidate ester 1 and thiourea6 (Scheme 1). The glycidate es-
ter 1, commonly prepared in two steps from the
corresponding aryl aldehyde, is not very reactive and the
final yields of these reactions are only moderate.
10
11
12
MeCN
toluene
dioxane
31c
a Reaction conditions: (1) Pd(OAc)2 (5 mol%), ligand (10 mol%),
base (2 equiv), iodobenzene (1.5 equiv) in the corresponding solvent
at 120 °C, 24 h; (2) TFA, CH2Cl2.
b Isolated yields.
EtO2C
EtO2C
c LC-MS yield.
N
N
[Pd]
ArI
+
NHBoc
NH2
Ar
S
S
Initial attempts to perform the metal-catalyzed cross-cou-
pling reaction between iodobenzene and protected 2-ami-
nothiazole 29 were carried out under the standard
conditions employed by Miura et al.,7b and only 11% yield
of 4a was achieved (entry 1, Table 1). After this promis-
ing result, optimization was carried out to find favorable
conditions for the Pd cross-coupling reaction with aryl io-
3
2
4
Scheme 2
SYNLETT 2007, No. 19, pp 2957–2960
Advanced online publication: 08.11.2007
DOI: 10.1055/s-2007-992368; Art ID: D15507ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
0
7

2958
J. Priego et al.
LETTER
Table 2 Pd-Catalyzed Arylation of Thiazole 2a
dides. The study was executed taking iodobenzene as the
standard aryl iodide to react with thiazole derivative 2.
The influence of the ligand, base and solvent was investi-
gated (Table 1), and in addition to optimizing the reaction
yield, provided valuable information about the likely
mechanism.
Pd(OAc)2
1.
ligand 7
Cs2CO3, DMF
EtO2C
Ar
EtO2C
N
N
ArI
+
120 °C
NH2
S
NHBoc
S
2
2. TFA, CH2Cl2
3
4
The biphenyl phosphine ligands, such as 5, 6, or 7
(Figure 1), were the most appropriate ligands to carry out
the Pd coupling reaction, affording the desired product 4a
in good yields10 (entries 2–4, Table 1). The choice of the
base was very important for this reaction, and only
Cs2CO3 gave the coupling product with acceptable yield11
(entries 4–8, Table 1). The solvent also plays a crucial
role, DMF being the best for good conversions (entries 4,
9–12, Table 1), while nonpolar solvents are not suitable.
Entry
1
ArI
Yield (%)b
4a (80)
I
I
2
3
4b (76)
4c (90)
I
I
P(C6H11 2
)
4
4d (87)
P(C6H11 2
)
P(t-Bu)2
i-Pr
i-Pr
NMe2
5
6
4e (40)
4f (48)
N
I
i-Pr
5
6
7
O2N
I
Figure 1 Biphenyl phosphino ligands
I
Once the optimal conditions for the coupling reaction be-
tween iodobenzene and thiazole derivative 2 had been
found (entry 4, Table 1), the scope of this reaction was ex-
plored with a set of electronically and structurally diverse
aryl iodides.12
7
4g (45)
O2N
I
8
9
4h (79)
4i (85)
4j (75)
Cl
Cl
As can be seen in Table 2, thiazole 2 can be effectively
arylated with different aryl iodides in moderate to good
yields. As shown, a variety of substituents are tolerated in
meta and para positions; substituents in ortho positions
are also tolerated, however, these results are not shown
here for reasons of compound legal protection. Substrates
with electron-donating and some substrates with electron-
withdrawing substituents show similar behaviors, leading
to good yields of products (entries 2, 3 and 8–10, respec-
tively). On the other hand, other electron-poor aryl iodides
provide more moderate yields (entries 5–7).
I
I
Cl
10
Cl
a Reactions conditions: (1) Pd(OAc)2 (5 mol%), ligand 7 (10 mol%),
base (2 equiv), iodobenzene (1.5 equiv) in DMF at 120 °C, 24 h; (2)
TFA, CH2Cl2.
b Isolated yields.
The mechanism of this reaction could be explained in
terms of three alternative routes, involving the structures
shown in Figure 2. While none of these mechanistic pos-
sibilities can be definitively ruled out, we sought to deter-
mine which might be the most probable of the three. One
possibility would be a Heck-like pathway,13 where an in-
sertion into the heterocycle would give an intermediate 8
and the corresponding arylated product 4 would then be
obtained after a trans-b-hydrogen elimination. We be-
lieve that on balance this mechanism is less probable than
the other two.
OEt
XPd
EtO2C
H
O
X
EtO2C
Ar
N
N
N
Ar
+
Pd
NHR
NHR
NHR
S
S
S
H
H
ArPd
O
O
O
8
9
10
Figure 2 Possible intermediates for Pd-catalyzed arylation of thia-
zole
procedure used by Gevorgyan et al.15 to support this pro-
posed mechanism, we carried out a density functional the-
ory (DFT)16 geometry optimization calculation
(B3LYP17/6-31G**) on the thiazole core of 2. Although
An electrophilic aromatic substitution pathway (interme-
diate 10) has often been considered as the most probable
mechanism for arylation of heterocycles.14 Following the
Synlett 2007, No. 19, 2957–2960 © Thieme Stuttgart · New York

LETTER
Synthesis of 2-Amino-5-arylthiazoles
2959
this heterocycle has a HOMO (EHOMO = –6.87 eV) that The computed structures for reactant, transition state
could participate in an electrophilic aromatic substitution (only one negative frequency, corresponding to the de-
reaction, it is not an electron-rich ring. The HOMO of this sired proton transfer, is observed, at –915.22 cm–1), and
thiazole is 1.91 eV lower in energy than the HOMO of the product are shown in Figure 3. The energy barrier is as
reference indolizine described in the literature.15 Partial low as 6.11 kcal/mol, a readily acceptable value for a re-
charges derived from the same calculation were also nota- action carried out at 120 °C and indeed one which would
bly more negative for the indolizine (–0.43) than for the strongly suggest that this would not be the rate-determin-
thiazole (–0.28) at the reacting center. These observations ing step for the overall process. This value may be com-
disfavor but do not eliminate the possible involvement of pared with 23.5 kcal/mol reported for the Pd-catalyzed
this pathway.
intramolecular arylation described by Echavarren, Maser-
as et al.18
The last of the proposed pathways is a mechanism in
which Pd-catalyzed arylation involving a proton abstrac-
tion by a carbonate or related ligand could give a C3-ary-
lated transition state 9; this mechanism (which is also
consistent with our observations in Table 1) is similar to
that recently proposed by Echavarren, Maseras et al.18 for
a related intramolecular direct arylation reaction.19 If a
proton-abstraction pathway involved proton transfer as
the rate-determining step, a kinetic isotope effect (KIE)
should be seen and a study was performed in the arylation
of thiazole 2-d with iodobenzene (Scheme 3).
Figure 3 Reactant, transition state and product (left to right)
No KIE (KH/D = 1) was detected in a competition experi-
ment when a mixture of 2 and 2-d was subjected to stan-
dard arylation conditions and stopped at 50% conversion.
This result does not exclude this mechanism; lack of a
KIE could be due to turnover-limiting oxidative addition,
which occurs before the proton-abstraction step.20
We therefore conducted a further experiment demonstrat-
ing significant rate enhancement in the presence of CuI
(20 mol%), which has been suggested by Gevorgyan et
al.15 to strongly support the proton-abstraction mecha-
nism.
In summary, direct Pd-catalyzed arylation at the C5 posi-
tion of 2-aminothiazole 2 with different aryl iodides has
been studied. This new methodology can be used to pre-
pare 2-amino-5-aryl-substituted thiazoles in one step in
moderate to good yields. While we cannot exclude any of
the three mechanisms, our experimental and theoretical
results suggest that the reaction probably goes through a
proton-abstraction mechanism, in which the proton trans-
fer itself is not the rate-determining step.
1.
PhI
Pd(OAc)2
ligand 7
EtO2C
(D)H
EtO2C
Ph
Cs2CO3, DMF
N
N
120 °C, 5 h
NHBoc
NH2
2. TFA, CH2Cl2
KH/D = 1
S
S
2-d
4a
Scheme 3 Isotope-effect study
We therefore undertook another DFT study, to see wheth-
er the calculated transition-state energy would be consis-
tent with the idea that this Pd-catalyzed arylation
reaction21 could go via proton abstraction by carbonate in-
stead of electrophilic aromatic substitution.22 The DFT
calculations employed the B3LYP functional on a model
system where the phosphine ligand was modeled by PH3,
and the ester was replaced by a carboxylic acid on the thi-
azole ring to reduce computational cost. Initial coordi-
nates were based on the transition state reported for a
related system by Echavarren, Maseras et al.18 The stan-
dard 6-31G** basis set was used for all atoms, except for
palladium, which was described by the LACVP valence
basis set. Geometries were fully optimized, without sym-
metry constraints, in the gas phase. A transition state was
located from a linear transit scan in which the C–H bond
length of the migrating hydrogen was kept fixed at various
distances, while all other degrees of freedom were opti-
mized. The transition state was then optimized using DFT
quadratic synchronous transit.
Acknowledgment
We thank Prof. Antonio M. Echavarren (ICIQ, Tarragona) for help-
ful comments, exchange of information and advice on the prepara-
tion of this manuscript; Prof. Erick M. Carreira (ETH, Zurich) for
helpful suggestions and Cristina Anta (Analytical Technologies, Li-
lly, S. A.) for purification support.
References and Notes
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Tetrahedron Lett. 2000, 41, 425.
(2) (a) Schwander, H. In Ullman’s Encyclopedia of Industrial
Chemistry, Vol. A11; VCH: Weinheim, 1988, 279.
(b) Mori, A.; Sekiguchi, A.; Masui, K.; Shimada, T.; Horie,
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Soc. 2003, 125, 1700.
(3) (a) Dölling, K.; Zaschke, H.; Schubert, H. J. Prakt. Chem.
1979, 321, 643. (b) See also ref. 2b.
Synlett 2007, No. 19, 2957–2960 © Thieme Stuttgart · New York

2960
J. Priego et al.
LETTER
(4) (a) Hassan, J.; Sévignon, M.; Gozzi, C.; Schulz, E.; Lemaire,
M. Chem. Rev. 2002, 102, 1359. (b) Anastasia, L.; Negishi,
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Bittner, S.; Majcen Le Marechal, A. ARKIVOC 2003, (xiv),
49.
2-Amino-5-phenylthiazole-4-carboxylic acid ethyl ester
(4a): white solid (73 mg, 80%). 1H NMR (300 MHz,
CDCl3): d = 7.47–7.38 (m, 5 H), 5.48–5.39 (m, 2 H), 4.23 (q,
J = 7.1 Hz, 2 H), 1.19 (t, J = 7.1 Hz, 3 H). 13C NMR (75
MHz, CDCl3): d = 163.91, 160.92, 135.83, 134.10, 129.81,
129.02, 127.62, 126.99, 59.99, 13.02.
(13) (a) Grigg, R.; Sridharan, V.; Stevenson, P.; Sukirthalingam,
S.; Worakum, T. Tetrahedron 1990, 46, 4003. (b) Hughes,
C. C.; Trauner, D. Angew. Chem. Int. Ed. 2002, 41, 1569.
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(d) Glover, B.; Harvey, K. A.; Liu, B.; Sharp, M. J.;
Tymoschenko, M. Org. Lett. 2003, 5, 301.
(7) For Pd-catalyzed direct arylation of thiazoles, see:
(a) Pivsa-Art, S.; Satoh, T.; Awamura, Y.; Miura, M.;
Nomura, M. Bull. Chem. Soc. Jpn. 1998, 71, 467.
(b) Yokooji, A.; Okazawa, T.; Satoh, T.; Miura, M.;
Nomura, M. Tetrahedron 2003, 59, 5685. (c) Masui, K.;
Mori, A.; Okano, K.; Takamura, K.; Kinoshita, M.; Ikeda, T.
Org. Lett. 2004, 6, 2011. (d) Parisien, M.; Valette, D.;
Fagnou, K. J. Org. Chem. 2005, 70, 7578. (e) Bellina, F.;
Cauteruccio, S.; Rossi, R. Eur. J. Org. Chem. 2006, 1379.
(f) See also ref. 2b.
(14) (a) Catellani, M.; Chiusoli, G. P. J. Organomet. Chem. 1992,
425, 151. (b) Martín-Matute, B.; Mateo, C.; Cárdenas, D. J.;
Echavarren, A. M. Chem. Eur. J. 2001, 7, 2341. (c) Lane,
B. S.; Sames, D. Org. Lett. 2004, 6, 2897. (d) Lane, B. S.;
Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2005, 127,
8050.
(15) Park, C.-H.; Ryabova, V.; Seregin, I. V.; Sromek, A. W.;
Gevorgyan, V. Org. Lett. 2004, 6, 1159.
(16) Calculations were done using Maestro Version 7.5.112 and
Jaguar Version 6.5, Schrödinger, LLC., Portland, Oregon:
Vacek, G.; Perry, J. K.; Langlois, J.-M. Chem. Phys. Lett.
1999, 310, 189.
(8) For a recent review, see: Alberico, D.; Scott, M. E.; Lautens,
M. Chem. Rev. 2007, 107, 174.
(9) The Pd-coupling reaction with free 2-aminothiazole
(17) (a) Lee, C.; Parr, R. G.; Yang, W. Phys. Rev. 1988, 37,
B785. (b) Becke, A. D. J. Phys. Chem. 1993, 98, 5648.
(c) Stephens, P. J.; Devlin, F. J.; Chabalowski, C. F.; Frisch,
M. J. J. Phys. Chem. 1994, 98, 11623.
(18) García-Cuadrado, D.; Braga, A. A.; Maseras, F.;
Echavarren, A. M. J. Am. Chem. Soc. 2006, 128, 1066.
(19) A similar mechanism has also been recently proposed by
Fagnou et al.: (a) Lafrance, M.; Rowley, C. N.; Woo, T. K.;
Fagnou, K. J. Am. Chem. Soc. 2006, 128, 8754. See also
other recent examples: (b) Campeau, L.-C.; Parisien, M.;
Leblanc, M.; Fagnou, K. J. Am. Chem. Soc. 2004, 126,
9186. (c) Parisien, M.; Valette, D.; Fagnou, K. J. Org. Chem.
2005, 70, 7578. (d) Campeau, L.-C.; Parisien, M.; Jean, A.;
Fagnou, K. J. Am. Chem. Soc. 2006, 128, 581.
(20) See kinetic isotope effects of C–H functionalization in:
Hennessy, E. J.; Buchwald, S. L. J. Am. Chem. Soc. 2003,
125, 12084.
(21) Recent DFT calculations in cross-coupling reactions:
(a) Goossen, L. J.; Koley, D.; Hermann, H. L.; Thiel, W.
J. Am. Chem. Soc. 2005, 127, 11102. (b) Braga, A. A. C.;
Morgon, N. H.; Ujaque, G.; Maseras, F. J. Am. Chem. Soc.
2005, 127, 9298. (c) Mota, A. J.; Dedieu, A.; Bour, C.;
Suffert, J. J. Am. Chem. Soc. 2005, 127, 7171.
provided the corresponding amination product.
(10) Lower yields were obtained with bidentate phosphine
ligands, such as XantPhos (4,5-bis-diphenylphosphanyl-9,9-
dimethyl-9H-xanthene, 64%), BINAP (60%) or DPPF [1,1¢-
bis(diphenylphosphino)ferrocene, 58%].
(11) A similar effect was observed by Li et al.: Li, W.; Nelson, D.
P.; Jensen, M. S.; Hoerrner, R. S.; Javadi, G. J.; Cai, D.;
Larsen, R. D. Org. Lett. 2003, 5, 4835.
(12) Typical Experimental Procedure
A 16 × 100 tube was charged with thiazole 2 (0.37 mmol),
aryl iodide (0.55 mmol), Cs2CO3 (0.239 g, 0.73 mmol),
Pd(OAc)2 (0.004 g, 5 mol%, 0.02 mmol), ligand 7 (0.014 g,
10 mol%, 0.04 mmol) and DMF (2 mL, 0.2 M). The
resulting mixture was stirred at 120 °C for 24 h under a
nitrogen atmosphere. The mixture was then filtered through
Celite and concentrated to dryness. The residue was purified
first on silica gel (4:1 hexane–EtOAc) and then with an HLB
cartridge [using NH4HCO3 (pH 10) and MeCN as eluents].
Next, the compound was dissolved in CH2CH2 (1 mL) and
TFA in CH2CH2 (25%, 1 mL) was added. The corresponding
solution was shaken on an arm shaker overnight. After that,
the mixture was concentrated to dryness, dissolved in
MeOH, passed through an SCX-2 cartridge; two volumes of
MeOH and two volumes of NH3–MeOH (2 N) were eluted.
The NH3–MeOH washings were concentrated to dryness to
afford the desired compound.
(22) Recent examples: (a) Pivsa-Art, S.; Satoh, T.; Awamura, Y.;
Miura, M.; Nomura, M. Bull. Chem. Soc. Jpn. 1998, 71,
467. (b) See also ref. 14c,d, 15.
Synlett 2007, No. 19, 2957–2960 © Thieme Stuttgart · New York