Expanded scope of heterocyclic biaryl synthesis via a palladium-catalysed thermal decarboxylative cross-coupling reaction

Article abstract of DOI:10.1016/j.tetlet.2011.11.051

The palladium-catalysed decarboxylative cross-coupling of heterocyclic aromatic carboxylates and aryl halides is described. The cross-coupling proceeds under relatively mild conditions using catalytic Pd(0) and tetrabutylammonium bromide (TBAB). Utilizing

Full text of DOI:10.1016/j.tetlet.2011.11.051

Tetrahedron Letters 53 (2012) 403–405
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Tetrahedron Letters
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Expanded scope of heterocyclic biaryl synthesis via a palladium-catalysed
thermal decarboxylative cross-coupling reaction
Marie Kissane a, Orla A. McNamara a, David Mitchell b, David M. Coppert b, Humphrey A. Moynihan c,
Kurt T. Lorenz c, Anita R. Maguire a,
⇑
a Department of Chemistry and School of Pharmacy, Analytical and Biological Chemistry Research Facility, University College Cork, Cork, Ireland
b Chemical Product R & D, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
c Manufacturing Science and Technology Business, Eli Lilly SA, Dunderrow, Kinsale, Co Cork, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 June 2011
Revised 28 October 2011
Accepted 11 November 2011
Available online 22 November 2011
The palladium-catalysed decarboxylative cross-coupling of heterocyclic aromatic carboxylates and aryl
halides is described. The cross-coupling proceeds under relatively mild conditions using catalytic
Pd(0) and tetrabutylammonium bromide (TBAB). Utilizing
a mixed solvent system consisting of
N,N-dimethylformamide (DMF) and N-methyl-2-pyrrolidone (NMP), the cross-coupling system operated
at temperatures ranging from 80 to 140 °C.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Cross-coupling
Palladium
Heterocycles
Biaryls
Aryl halides
The metal-catalysed decarboxylative cross-coupling of aryl
halides and triflates with arene carboxylic acids has received
considerable attention recently as an attractive tool for biaryl
formation.1–15 In contrast to traditional coupling methods, the
decarboxylative coupling process eliminates the need to prepare
organometallic reagents, which require the use of a stoichiometric
amount of expensive organometallic compounds. In addition, the
carboxylic acid coupling partners are more readily available when
compared to their organometallic counterparts. Current reported
applications of the palladium-catalysed decarboxylative coupling
reaction often involve copper as a co-catalyst or require microwave
technology, and generally temperatures of 130ꢀ170 °C are neces-
sary to promote the reaction.
We previously described the synthesis of multigram quantities
of 3-amino-2-(4-chlorophenyl)-thiophene via a decarboxylative
cross-coupling using potassium 3-aminothiophene-2-carboxylate
(1a) and 4-bromochlorobenzene (2a) as the coupling partners.16
Optimisation of the reaction led to a robust decarboxylative
cross-coupling at 80 °C with catalytic (5 mol %) palladium(0) and
catalytic TBAB (15 mol %) in a 9:1 DMF/NMP solvent mixture,
affording 3a in 77% yield on a 0.5 mol scale (Scheme 1).16
Having established the optimum conditions for the decarboxy-
lative cross-coupling of 1a and 2a, we investigated the scope and
generality of the reaction. Herein is described the palladium-
catalysed decarboxylative cross-coupling of a range of heterocyclic
aromatic carboxylates and aryl halides.
The effect of varying the aryl halide coupling partner was
examined first, by reacting 1.05 equiv of potassium 3-amino-2-thi-
ophene carboxylate (1a) with 1 equiv of a range of aryl halides,
5 mol % PdCl2, 6 mol % dppf and 15 mol % TBAB in a 9:1 DMF–NMP
mixture. The biaryl products 3b–3f were isolated as the hydrochlo-
ride salts in yields ranging from 57–82%, or as the free amines in
yields of 31–62% following chromatographic purification. Table 1
summarises the results of these experiments.17
Replacing the electron-withdrawing chlorine in 4-bromochloro-
benzene with the electron-donating methoxy group in 4-bromoani-
sole led to a reduction in the reactivity in the cross-coupling reaction
with 1a (Table 1, entry 1). The introduction of the inductively elec-
tron-donating methyl group at the para position also led to a de-
crease in the reactivity compared to 4-bromochlorobenzene (Table
Cl
NH2
OK
5 mol% Pd(0), 6 mol% dppf
15 mol% TBAB
NH2
+
S
S
DMF/NMP (9:1), 80 °C
O
Br
Cl
1a
2a
3a
⇑
Corresponding author. Fax: +353 214901770.
E-mail address: a.maguire@ucc.ie (A.R. Maguire).
Scheme 1. Optimised conditions for cross-coupling of 1a and 2a.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.051

404
M. Kissane et al. / Tetrahedron Letters 53 (2012) 403–405
Table 1
Variation of the aryl halide
X
S
Y
5 mol% PdCl2, 6 mol% dppf
1a
+
15 mol% TBAB, 9:1 DMF:NMP
NH2
3
Y
2
Entry
Aryl halide
T (°C)
Product
% Yield (free base)a
% Yield (HCl salt)
1
2
3
4
5
6
7
4-bromoanisole (2b)
4-bromotoluene (2c)
4-iodotoluene (2d)
bromobenzene (2e)
3-nitrobromo benzene (2f)
1-chloro-4-iodobenzene (2g)
3-bromoanisole (2h)
120
120
100
90
80
100
120
3b
3c
3d
3e
3f
40
62
36
46
—
64b
76b
57b
76b
59c
48b
82b
3g
3h
47
31
a
b
c
Yield following chromatographic purification.
Crude yield.
Yield following isolation of the hydrochloride salt and subsequent purification by slurrying the product in acetone.
1, entry 2). 4-Iodotoluene was found to be more reactive than 4-bro-
motoluene (entry 3, Table 1), while the cross-coupling of 1a with
bromobenzene proceeded to completion at 90 °C (Table 1, entry
4). 3-Nitrobromobenzene was found to have similar reactivity to
4-bromochlorobenzene, with complete consumption of the halide
at 80 °C (Table 1, entry 5). The use of 1-chloro-4-iodobenzene led
to a slight reduction in the rate of the cross-coupling reaction com-
pared to 4-bromochlorobenzene (Table 1, entry 6). Finally the effect
of varying the position of the substituent on the aryl halide was
investigated; 3-bromoanisole was selected for this study as 4-
bromoanisole had proved to be much less reactive than 4-bromo-
chlorobenzene and we were interested in determining if changing
the position of the electron-donating methoxy group would increase
the reactivity. 3-Bromoanisole was found to be similar in reactivity
to 4-bromoanisole (Table 1, entry 7).
products were complex mixtures, and attainment of analytically
pure samples of the cross-coupled products was difficult. In some
instances, incomplete consumption of 4-bromochlorobenzene
was observed (Table 2, entries 2 and 3), however when the temper-
ature was increased to 140 °C additional side-product formation
was detected.
The mechanism of this decarboxylative cross coupling is be-
lieved to involve oxidative addition of aryl halides to the Pd(0) spe-
cies (prepared in situ from PdCl2dppf), followed by anion
metathesis to the resulting Pd(II) species with the elimination of
KBr. Decarboxylation followed by reductive elimination gives the
desired biaryl product (see Fig. 1). Concomitant decarboxylation
and product formation supports the proposed pathway.16 In con-
trast to other proposed mechanisms,14 our system produces stoi-
chiometric CO2 only when both coupling partners are present.
Our observations are consistent with the mechanism proposed
by Forgione.15
The effect of varying the carboxylate salt was also investigated.
Table 2 summarises the results of these studies.
Each of the carboxylate salts examined proved to be much less
reactive than potassium 3-aminothiophene-2-carboxylate (1a) in
decarboxylative cross-coupling reactions with 4-bromochloroben-
zene at temperatures of 100–150 °C (cf. 80 °C in the analogous cou-
pling with 1a). In all cases, the 1H NMR spectra of the crude
Interestingly, while cross-coupling has been effected across a
range of different substituents in modest yields, in all instances ex-
cept 3f the reaction temperatures required were higher than that
described for the optimised procedure for the synthesis of 3a de-
scribed in our earlier report.16 However, the reaction temperatures
Table 2
Variation of the carboxylate salt
5 mol% PdCl2, 6mol% dppf
+
2a
1
R
Cl
15 mol% TBAB, 9:1 DMF:NMP
3
Entry
1
RCO2K
T (°C)
Product
Outcomea
Yieldb (%)
25
CO2K
N
100
120
3i
Complete reaction
1b
CO2K
CO2K
N
2
3
4
3j
Incomplete reaction, 2a remaining
17
31
11
1c
O
120
140
3k
3l
Incomplete reaction, 30% 2a remaining
1d
N
CO2K
Complete reaction
S
1e
a
By 1H NMR spectroscopy.
Yield following purification by chromatography on silica gel.
b

M. Kissane et al. / Tetrahedron Letters 53 (2012) 403–405
8. Becht, J. M.; Le Drian, C. Org. Lett. 2008, 10, 3161–3164.
405
NH2
Ar
9. Goossen, L. J.; Rodriguez, N.; Linder, C. J. Am. Chem. Soc. 2008, 130, 15248–
15249.
10. Baudoin, O. Angew. Chem., Int. Ed. 2007, 46, 1373–1375.
11. Goossen, L. J.; Rodriguez, N.; Melzer, B.; Linder, C.; Deng, G.; Levy, L. M. J. Am.
Chem. Soc. 2007, 129, 4824–4833.
Br-Ar
S
Pd(0)
12. Becht, J. M.; Catala, C.; Le Drian, C.; Wagner, A. Org. Lett. 2007, 9, 1781–1783.
13. Dickstein, J. S.; Mulrooney, C. A.; O’Brien, E. M.; Morgan, B. J.; Kozlowski, M. C.
Org. Lett. 2007, 9, 2441–2444.
14. Myers, A. G.; Tanaka, D.; Mannion, M. R. J. Am. Chem. Soc. 2002, 124, 11250–
11251.
Br
Pd Ar
NH2
L
Ar
Pd
L
S
NH2
15. Bilodeau, F.; Brochu, M.; Guimond, N.; Thesen, K. H.; Forgione, P. J. Org. Chem.
2010, 75, 1550–1560.
CO2K
S
16. Mitchell, D.; Coppert, D. M. C.; Moynihan, H.; Kissane, M.; McNamara, O.;
Maguire, A. R. Org. Proc. Res. Dev. 2011, 15, 981–985.
CO2
NH2
KBr
17. Representative
Experimental
Procedure:
Preparation
of
2-(4-
O
Ar
Methoxyphenyl)thiophenyl-3-amine (3b) Method A. Potassium 3-
aminothiophene-2-carboxylate (1a) (0.95 g, 5.25 mmol), 4-bromoanisole
(0.63 mL, 5.00 mmol), TBAB (0.25 g, 0.75 mmol), 1,10-bis(diphenylphosphino)-
ferrocene (0.16 g, 0.3 mmol) and PdCl2 (44.78 mg, 0.25 mmol) were mixed under
a flow of N2. The vessel was evacuated and back-filled three times. DMF (18 mL)
and NMP (2 mL) were added and the system was again evacuated and back-filled
with N2 three times. The resulting mixture was heated at 120 °C for 16 h. The
mixture was allowed to cool to room temperature. Celite (ꢁ1 g) and H2O (50 mL)
were added and following stirring for 10 min, the mixture was filtered through a
bed of Celite. The Celite cake was washed with EtOAc (50 mL). The filtrate was
transferred to a separating funnel, and the layers separated. The aqueous layer
was extracted with EtOAc (50 mL). The EtOAc layers were combined and washed
with H2O (4 ꢂ 50 mL) and brine (2 ꢂ 50 mL), dried, filtered and concentrated at
reduced pressure. Following purification by column chromatography on silica
gel using hexane–EtOAc (gradient elution 0–20% EtOAc), 3b was isolated as a
S
Pd
L
O
Figure 1. Proposed mechanistic pathway for decarboxylative cross-coupling.
of 80–150 °C are notably lower than most reports in the literature
for cross-couplings of this nature. Thus, a decarboxylative cross-
coupling has been demonstrated on a variety of heterocyclic car-
boxylic acids and aryl halides, using catalytic amounts of Pd(0)
and TBAB at relatively low temperatures of 80–140 °C, and avoid-
ing the use of a metal co-catalyst or microwave irradiation.
yellow oil (0.41 g, 40%); m
max/cmꢀ1 3346, 1608, 1561, 1510; dH (300 MHz, CDCl3)
3.71 (2H, br s, NH2), 3.84 (3H, s, OCH3), 6.65 (1H, d, J 5.4, ArH), 6.95 (2H, d, J 9.0,
ArH), 7.08 (1H, d, J 5.4, ArH), 7.44 (2H, d, J 9.0, ArH); dC (75.5 MHz, CDCl3) 55.4
(CH3, OCH3), 114.5 (CH, ArCH), 116.7 (C, ArC), 122.0, 122.8 (2ꢂCH, ArCH), 126.7
(C, ArC), 129.1 (CH, ArCH), 139.9 (C, ArC), 158.3 (C, ArC); HRMS (ES+): Exact mass
calculated for C11H12NOS [(M+H)+], 206.0640. Found 206.0631; m/z (ES+) 206.0
{[(M+H)+], 52%}.
Acknowledgment
Enterprise Ireland is acknowledged for financial support for
M.K. and O.A.McN.
Method B. Compound 3b was also isolated as the hydrochloride salt, using the
same procedure outlined above. After drying, the organic layer was concentrated
to approximately 10 mL. An HCl solution (6 mL of a 1.75 M HCl solution in EtOAc)
was added dropwise at 0 °C. A brown solid precipitated from the solution almost
immediately. The mixture was stirred at 0 °C for 30 min. The brown solid was
filtered to give the hydrochloride salt of 3b (0.77 g, 64%). An analytically pure
sample was obtained by slurrying the crude product in acetone (5 mL) at room
temperature for 10 min, to give the hydrochloride salt of 3b as an off-white solid
References and notes
1. Goossen, L. J.; Zimmermann, B.; Linder, C.; Rodriguez, N.; Lange, P. P.; Hartung,
J. Adv. Synth. Catal. 2009, 351, 2667–2674.
2. Wang, Z.; Ding, Q.; He, X.; Wu, J. Tetrahedron 2009, 65, 4635–4638.
3. Goossen, L. J.; Deng, G.; Levy, L. M. Science 2006, 313, 662–664.
4. Forgione, P.; Brochu, M. C.; St Onge, M.; Thesen, K. H.; Bailey, M. D.; Bilodeau, F.
J. Am. Chem. Soc. 2006, 128, 11350–11351.
(0.35 g, 29%); m
max/cmꢀ1 2806, 1610, 1578, 1511; dH (300 MHz, DMSO-d6) 3.83
5. Zhang, F.; Greaney, M. F. Org. Lett. 2010, 12, 4745–4747.
6. Goossen, L. J.; Lange, P. P.; Rodriguez, N.; Linder, C. Chem. Eur. J. 2010, 16, 3906–
3909.
7. Goossen, L. J.; Linder, C.; Rodriguez, N.; Lange, P. P. Chem. Eur. J. 2009, 15, 9336–
9349.
(3H, s, OCH3), 7.09 (2H, d, J 8.7, ArH), 7.24 (1H, d, J 5.7, ArH), 7.62 (2H, d, J 8.7, ArH),
7.66 (1H, d, J 5.7, ArH); dC (75.5 MHz, DMSO-d6) 55.3 (CH3, OCH3), 114.6 (CH,
ArCH), 123.2, 123.5 (2ꢂC, ArC), 125.0, 125.2, 129.9 (3ꢂCH, ArCH), 134.8, 159.6
(2ꢂC, ArC); HRMS (ES+): Exact mass calculated for C11H12NOS [(M+H)+-HCl],
206.0640. Found 206.0632; m/z (ES+) 206.0 {[(M+H)+-HCl], 42%}.