Decarboxylative C-H cross-coupling of azoles

Article abstract of DOI:10.1002/anie.200906921

(Figure Presented) Cote d'Azole: The title reaction demon-strates the use of diverse oxazoles 2 as suitable substrates in cross-coupling reactions with azole-5-carboxylic acids 1 under palladium catalysis in the presence of copper carbonate. The reaction

Full text of DOI:10.1002/anie.200906921

Communications
DOI: 10.1002/anie.200906921
À
Decarboxylative C H Activation
À
Decarboxylative C H Cross-Coupling of Azoles**
Fengzhi Zhang and Michael F. Greaney*
The use of carboxylic acids as functional handles for transition
metal catalyzed cross-coupling reactions is a fast growing area
of research.[1] Pioneering work has established that metal-
mediated decarboxylation affords organometallic intermedi-
À
ates that can participate in palladium-catalyzed C C bond-
forming processes such as the Heck reaction[2] and cross-
coupling reactions with aryl halides (Steglich,[3] Miura,[4]
Goossen,[5] and Forgione[6]).[7] The concept has recently
À
been extended to the C H activation field. Glorius and co-
workers have demonstrated the intramolecular decarboxyla-
À
tive C H activation of ortho-phenoxy benzoic acids for the
synthesis of dibenzofurans,[8] whereas Crabtree and co-work-
ers and Larrosa and co-workers have described the intermo-
lecular cross-coupling of ortho-substituted benzoic acids with
anisole and indoles, respectively.[9,10] The union of two
À
emerging areas of catalytic C C bond-forming chemistry,
both of which eschew preformed organometallic substrates,
Scheme 1. Representative azole structures.
holds great potential for new bond-forming strategies in
synthesis. The reaction would be particularly powerful for the
synthesis of polyheteroaromatic compounds. The regiocon-
trolled union of heteroaromatics, requiring no significant
prefunctionalization and proceeding under catalytic condi-
tions, could lead to dramatically streamlined syntheses of this
fundamental compound class. To investigate this possibility,
À
The development of such a decarboxylative C H arylation
reaction would constitute a novel and convenient entry point
into biologically active polyheteroaromatic structures.
We first established reaction conditions for the decarbox-
À
ylative C H coupling of thiazole 1a with oxazole 2a. We were
À
we have developed an intermolecular decarboxylative C H
pleased to discover that the reaction was viable using
Pd(OAc)2 in dioxane/DMSO in the presence of stoichiomet-
ric amounts of silver or copper salts and a ligand (Table 1).
The 2,5-linked bis(azole) 3a was formed along with two
side products, the homocoupled oxazole 4 and the decar-
boxylated starting thiazole. Small amounts of the decarbox-
ylation product were always observed, as the thiazole was
used in excess during the optimization process. The principal
challenge in optimization centered upon increasing the yields
of 3a at the expense of the undesired homocoupling product
4.
The screening of ligands established that various sterically
hindered monodentate phosphines (Table 1, entries 1–2) and
dipyridyl ligands (entry 3) together with silver carbonate led
to the production of 3a in modest yield and selectivity. Ethyl
nicotinate was more effective (entry 4), and sterically hin-
dered bidentate bis(dicyclohexylphosphino)ethane (entry 5)
provided the best selectivity with a 22:1 ratio in favor of 3a,
and the product was isolated in 51% yield. A combination of
the cheaper copper carbonate and the dcpe ligand proved
best, providing similar yields of 3a, although the overall
selectivity was lower than that for silver carbonate (entry 9).
Other copper and silver salts showed no improvement over
their respective carbonate salts (entries 6–8). Fine tuning of
the ligand to palladium ratio provided optimized product
yields of 64% (entry 11) and 77% (entry 12). Control experi-
ments run in the absence of palladium, copper or silver
carbonate, and the ligand were all negative.[14]
cross-coupling between oxazoles and thiazoles with the rapid
synthesis of functionalized polyazoles.
In recent years, azole heterocycles have proven to be
useful substrates for the development of synthetic and
[11]
À
mechanistic C H arylation chemistry. Oxazoles, thiazoles,
and imidazoles are important heterocyclic components of
bioactive natural products, pharmaceuticals, and functional
materials, making their efficient synthesis of great interest
(Scheme 1).[12] The development of new C H arylation
À
methods is particularly apposite for this class of heterocycle,
as the stoichiometric amounts of organometallic reagents
required in classic cross-coupling reactions are difficult to
prepare at certain positions on the azole ring.[13] In contrast,
carboxylate groups are commonly found in both synthetic and
naturally occurring azole structures, and represent versatile
synthetic handles for regioselective cross-coupling reactions.
[*] Dr. F. Zhang, Dr. M. F. Greaney
School of Chemistry, University of Edinburgh
King’s Buildings, West Mains Rd., Edinburgh, EH9 3JJ (UK)
Fax: (+44)131-650-4743
E-mail: michael.greaney@ed.ac.uk
[**] We thank the EPSRC for funding (Leadership Fellowship to MFG)
and the EPSRC mass spectrometry service at the University of
Swansea.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200906921.
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Chemie
Table 1: Decarboxylative coupling: Reaction optimization.
reaction using a variety of oxazoles
(Scheme 2). The 4-substituted ester
and sulfone derivatives proved to
be good substrates — they could be
prepared by simple literature meth-
ods,
the
electron-withdrawing
group promoted the reaction, and
it was also present as a functional
handle in the coupled product 3 for
additional elaboration (see below).
Yields for these bis(azole)s ranged
from moderate to very good (45%–
82%), and featured both alkyl
(Scheme 2; 3b, 3c, 3d, and 3 f),
and aryl (Scheme 2; 3e and 3g)
substituents at the 5-position. Esters
(Scheme 2; 3b–3e and 3h), sulfones
(Scheme 2; 3 f and 3g), nitro
(Scheme 2; 3e), and chloro
(Scheme 2, 3j) groups were toler-
ated in the reaction, therefore pro-
viding sites for additional elabora-
tion of the heteroaromatic products.
Regiocontrol for oxazoles con-
Entry[a]
Pd(OAc)2
[mol%]
Ligand (mol %)
Base
3a/4[b]
Yield of 3a [%][b]
1[c]
2[c]
3[c]
4[c]
5[c]
6
7
8
9
10
10
10
10
10
10
10
10
10
10
10
20
SPhos (10)
tBuXPhos (10)
2,2’-dipyridyl (10)
ethyl nicotinate (10)
dcpe (10)
dcpe (10)
dcpe (10)
dcpe (10)
dcpe (10)
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
AgNO3
Cu2O
AgOAc
CuCO3
CuCO3
CuCO3
CuCO3
2:1
3:1
4:1
8:1
22:1
–
34
31
33
57
68 (51)[d]
0
0
34
–
3:1
8:1
8:1
5:1
10:1
64
10
11
12
dcpe (20)
dcpe (5)
dcpe (10)
51[d]
75 (64)[d]
82 (77)[d]
[a] Reaction conditions: Thiazole 1 (1.5 equiv), oxazole 2 (1 equiv), catalytic Pd(OAc)2, base (3 equiv),
and 4 ꢀ molecular sieves (100 mg) in dioxane/DMSO (9:1, 1.5 mL, 0.2m). Reactions were carried out on
a 0.1 mmol scale and heated to 1408C for 16 hours in a sealed tube. [b] Ratio and yield determined by
NMR spectroscopy of the crude raection mixture by using an internal standard. [c] Performed in DMSO.
[d] Yield of isolated product. dcpe=bis(dicyclohexylphosphino)ethane, DMSO=dimethyl sulfoxide,
SPhos=2-dicyclohexylphosphino-2’,6’-dimethoxybiphenyl, tBuXPhos=2-di-tert-butylphosphino-2’,4’,6’-
triisopropylbiphenyl.
À
taining two C H bonds proved
difficult as mixtures of products
were obtained because of the diffi-
culty in discriminating between the
2- and 5-positions. The facility of
With an optimized process for the coupling of thiazole 1a
with oxazole 2a, we next examined the scope of the reaction
for bis(azole) synthesis. Using copper carbonate as the base,
the electron-rich azole 5-position to undergo palladation is
well-known, as exemplified in a number of direct arylation
systems.[11] Oxazoles containing C H bonds at C2 and C4,
À
À
we first varied the C H component in the cross-coupling
however, proved to be viable substrates. The C4 position is
À
known to be quite unreactive towards C H
activation, as it is lacking in both nucleophilicity
and acidity.[15] We could employ monosubstituted
oxazoles, having either ester or aryl groups at the
5-position, in the decarboxylative cross-coupling
reactions to afford bis(azole)s 3h, 3i, and 3j in
45%, 62%, and 48% yields, respectively.
We prepared a selection of 2- and 4-substituted
oxazoles, and thiazole-5-carboxylic acids to inves-
tigate the substrate scope for the acid component
(Scheme 3). We placed a small group at C4 (Me or
H), to avoid undue steric hindrance during the
decarboxylation event. A variety of alkyl and aryl
substituents were tolerated at C2 for both the
oxazole and thiazole components, affording a
range of bis(azole)s (3k–q) in 52%–79% yield.
The C4 position on the acid component could be
unsubstituted, with bis(oxazole) 3k being formed
in 61% yield. The isomeric C4-carboxylic acids
with no substitution at C5 again proved to be
problematic in terms of multiple arylations. As an
example, we could isolate the novel trisoxazole 5
in 35% yield by treating 2a with 2-methyloxazole-
4-carboxylic acid. A decarboxylative coupling
with 2a at the 4-position is accompanied by a
À
Scheme 2. Substrate scope: C H component.
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Scheme 4. Tris- and tetrakisazole synthesis.
À
copper-catalyzed decarboxylation cycle and a C H arylation
cycle (Scheme 5). Decarboxylation using metal carbonates is
well-established in the literature, with a number of recent
advancements taking place as part of decarboxylative cross-
coupling investigations.[10,17] We confirmed that thiazole acid
1a underwent smooth decarboxylation when treated with
stoichiometric amounts of copper carbonate, in the absence of
palladium, under the optimized reaction conditions, produc-
ing 2-phenyl-4-methylthiazole in 87% yield. The thiazoyl
cuprate 11 must intercept the C2-palladated intermediate 13
in the arylation cycle for successful coupling. Palladation at
the azole 2-position with PdII salts has been rigorously
demonstrated in the benzoxazole series by Sꢀnchez and
Scheme 3. Substrate scope: CO2H component.
À
À
second oxidative C H/C H coupling with 2a at
the 5-position.
The carboxylic ester group in many of the
bis(azole) products presents a useful handle to
repeat the decarboxylative cross-coupling in a
À
second C C bond-forming reaction. Prelimi-
nary efforts for this coupling are shown in
Scheme 4. Ester 3d could be hydrolyzed into
the carboxylic acid 6 without any problem, and
then used in a coupling reaction with oxazole
2b to afford trisazole 7 in 36% yield. Subse-
quently, a coupling with bis(oxazole) 8[16] pro-
duced the tetrazole 9 in 30% yield. Although
the yields are modest, the synthesis of such 2,5-
linked tris- and tetrakisazole structures have
not been reported in the literature to date.
Literature syntheses of analogous 2,4-linked
polyoxazoles have involved multistep (> 12
steps), linear routes frequently using peptide
chemistry.[12] Our current approach is extremely
quick, modular, and convergent, and has scope
for optimization.
Mechanistically, the decarboxylative cou-
pling may be considered in terms of a silver- or
Scheme 5. Possible mechanism for the decarboxylative cross-coupling reaction.
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Chemie
Zhuravlev,[18] as well as being implicit in a range of oxazole
C2-directed arylation systems with aryl halides.[11]
10022 – 10025; b) L. J. Goossen, N. Rodriguez, K. Goossen,
Angew. Chem. 2008, 120, 10172 – 10175; Angew. Chem. Int. Ed.
2008, 47, 3100 – 3120; c) O. Baudoin, Angew. Chem. 2007, 119,
1395 – 1397; Angew. Chem. Int. Ed. 2007, 46, 1373 – 1375.
[2] A. G. Myers, D. Tanaka, M. R. Mannion, J. Am. Chem. Soc.
2002, 124, 11250 – 11251.
[3] C. Peschko, C. Winklhofer, W. Steglich, Chem. Eur. J. 2000, 6,
1147 – 1152.
[4] T. Okazawa, T. Satoh, M. Miura, M. Nomura, J. Am. Chem. Soc.
2002, 124, 5286 – 5287.
We confirmed that oxazole 2a undergoes deprotonation
with copper carbonate in DMSO at 1408C with a deuterium
exchange reaction. Interestingly, the well-known ability of 2-
oxazole anions to undergo ring-opening possibly allows the
isonitrile isomer 13b to act as a palladated intermediate.
Transmetallation with cuprate 11 would then afford the
palladium intermediate 14 which can reductively eliminate
Pd0 to produce the coupled product 3. Oxidation of Pd0 with
excess CuII then restarts the catalytic cycle. The replacement
of excess copper salts with cheaper and more environmentally
friendly oxidizing agents is conceivable for this step, and will
form part of our future work in the area.
[5] L. J. Goossen, G. Deng, L. M. Levy, Science 2006, 313, 662 – 664.
[6] P. Forgione, M. C. Brochu, M. St Onge, K. H. Thesen, M. D.
Bailey, F. Bilodeau, J. Am. Chem. Soc. 2006, 128, 11350 – 11351.
[7] For recent applications, see: a) M. Miyasaka, K. Hirano, T.
Satoh, M. Miura, Adv. Synth. Catal. 2009, 351, 2683 – 2688;
b) L. J. Goossen, B. Zimmermann, C. Linder, N. Rodriguez, P. P.
Lange, J. Hartung, Adv. Synth. Catal. 2009, 351, 2667 – 2674;
c) L. J. Goossen, C. Linder, N. Rodriguez, P. P. Lange, Chem.
Eur. J. 2009, 15, 9336 – 9349; d) M. Miyasaka, A. Fukushima, T.
Satoh, K. Hirano, M. Miura, Chem. Eur. J. 2009, 15, 3674 – 3677;
e) H. P. Bi, L. Zhao, Y. M. Liang, C. J. Li, Angew. Chem. 2009,
121, 806 – 809; Angew. Chem. Int. Ed. 2009, 48, 792 – 795; f) L. J.
Goossen, B. Zimmermann, T. Knauber, Angew. Chem. 2008, 120,
7211 – 7214; Angew. Chem. Int. Ed. 2008, 47, 7103 – 7106; g) L. J.
Goossen, N. Rodriguez, C. Linder, J. Am. Chem. Soc. 2008, 130,
15248 – 15249; h) J. M. Becht, C. Le Drian, Org. Lett. 2008, 10,
3161 – 3164; i) M. Nakano, H. Tsurugi, T. Satoh, M. Miura, Org.
Lett. 2008, 10, 1851 – 1854; j) A. Maehara, H. Tsurugi, T. Satoh,
M. Miura, Org. Lett. 2008, 10, 1159 – 1162; k) J. M. Becht, C.
Catala, C. Le Drian, A. Wagner, Org. Lett. 2007, 9, 1781 – 1783;
l) L. J. Goossen, N. Rodriguez, B. Melzer, C. Linder, G. Deng,
L. M. Levy, J. Am. Chem. Soc. 2007, 129, 4824 – 4833; m) D.
Tanaka, A. S. P. Romeril, A. G. Myers, J. Am. Chem. Soc. 2005,
127, 10323 – 10333; n) D. Tanaka, A. G. Myers, Org. Lett. 2004, 6,
433 – 436.
[8] C. Wang, I. Piel, F. Glorius, J. Am. Chem. Soc. 2009, 131, 4194 –
4195.
[9] A. Voutchkova, A. Coplin, N. E. Leadbeater, R. H. Crabtree,
Chem. Commun. 2008, 6312 – 6314.
[10] J. Cornella, P. Lu, I. Larrosa, Org. Lett. 2009, 11, 5506 – 5509.
[11] For a recent review, see: L. Ackermann, R. Vicente, A. R.
Kapdi, Angew. Chem. 2009, 121, 9976 – 10011; Angew. Chem.
Int. Ed. 2009, 48, 9792 – 9826.
[12] E. Riego, D. Hernꢀndez, F. Albericio, M. ꢃlvarez, Synthesis
2005, 1907 – 1922.
[13] M. Schnꢄrch, R. Flasik, A. Farooq Khan, M. Spina, M. D.
Mihovilovic, P. Stanetty, Eur. J. Org. Chem. 2006, 3283 – 3307.
[14] See the Supporting Information.
[15] B. Liꢅgault, D. Lapointe, L. Caron, A. Vlassova, K. Fagnou, J.
Org. Chem. 2009, 74, 1826 – 1834.
In conclusion, we have developed a novel decarboxylative
À
C H arylation reaction that features the intermolecular union
of two azole heteroarenes. The prevalence of carboxylate
groups in simple azole building blocks enables the rapid
synthesis of functionalized bis(azole)s and their higher
congeners, without any prefunctionalization chemistry being
necessary.
Experimental Section
Typical procedure for the synthesis of 2-(4-Methyl-2-phenyl-thiazol-
5-yl)-5-phenyl-oxazole-4-carboxylic acid ethyl ester, (3a):
An oven-dried microwave tube was charged with thiazole 1a
(99 mg, 0.45 mmol, 1.5 equiv), copper carbonate (199 mg, 0.90 mmol,
3 equiv), palladium acetate (13.4 mg, 0.06 mmol 20 mol%), dcpe
(12.7 mg, 0.03 mmol, 10 mol%), and 4 ꢁ molecular sieves (100 mg).
The reaction vessel was then flushed with nitrogen three times. A
solution of oxazole 2a (65 mg, 0.30 mmol, 1 equiv) in dioxane/DMSO
(1.5 mL, 9:1, 0.2m) was then added to the above mixture. The
resulting mixture was stirred in a preheated oil bath at 1408C for
16 hours before being cooled to room temperature, filtered and
washed with EtOAc (50 mL). The resulting organic solution was
washed with water (10 mL) and brine (10 mL), dried over anhydrous
MgSO4, filtered, and then the solvent was removed in vacuo. The
residue was purified by column chromatography on silica gel (eluent:
n-hexane/EtOAc from 10:1 to 4:1) to give the coupled product 3a as a
pale yellow solid (96 mg, 77% yield); M.p. 154–1568C; 1H NMR
(360 MHz, CDCl3): d = 8.07–8.11 (m, 2H), 7.96–7.99 (m, 2H), 7.45–
7.51 (m, 6H), 4.45 (q, 2H, J = 7.1 Hz), 1.43 (s, 3H), 1.42 ppm (t, 3H
J = 7.1 Hz); 13C NMR (90 MHz, CDCl3): d = 168.2 (C), 162.0 (C),
155.8 (C), 154.9 (C), 154.6 (C), 132.9 (C), 130.8 (CH), 130.4 (CH),
129.1 (2 ꢂ CH), 128.5 (2 ꢂ CH), 128.4 (2 ꢂ CH), 128.2 (C), 126.8 (C),
126.7 (2 ꢂ CH), 117.9 (C), 61.5 (CH2), 17.5 (CH3), 14.2 ppm (CH3); IR
[16] E. Ferrer Flegeau, M. E. Popkin, M. F. Greaney, J. Org. Chem.
2008, 73, 3303 – 3306.
À1
~
(film): n = 2972, 1718, 1560, 1492, 1215, 1090, 770, 712, 689 cm
;
HRMS (ESI) m/z: calc for C22H19N2O3S: 391.1111 [M+H]+; found:
[17] a) P. Lu, C. Sanchez, J. Cornella, I. Larossa, Org. Lett. 2009, 11,
5710 – 5713; b) J. Cornella, C. Sanchez, D. Banawa, I. Larrosa,
Chem. Commun. 2009, 7176 – 7178; c) L. J. Goossen, C. Linder,
N. Rodriguez, P. P. Lange, A. Fromm, Chem. Commun. 2009,
7173 – 7175; d) L. J. Goossen, F. Manjolinho, B. A. Khan, N.
Rodriguez, J. Org. Chem. 2009, 74, 2620 – 2623; e) L. J. Goossen,
W. R. Thiel, N. Rodriguez, C. Linder, B. Melzer, Adv. Synth.
Catal. 2007, 349, 2241 – 2246.
391.1117.
Received: December 8, 2009
Published online: March 16, 2010
À
Keywords: catalysis · cross-coupling · C H activation ·
heterocycles · palladium
.
[18] R. S. Sꢀnchez, F. A. Zhuravlev, J. Am. Chem. Soc. 2007, 129,
5824 – 5825.
[1] For reviews, see: a) S. M. Bonesi, M. Fagnoni, A. Albini, Angew.
Chem. 2008, 120, 10172 – 10175; Angew. Chem. Int. Ed. 2008, 47,
Angew. Chem. Int. Ed. 2010, 49, 2768 –2771
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