Arylation of 2-substituted pyridines via Pd-catalyzed decarboxylative cross-coupling reactions of 2-picolinic acid

Article abstract of DOI:10.1039/c2cc36720c

The novel palladium-catalyzed decarboxylative cross-coupling reactions of 2-picolinic acid with aryl and heteroaryl bromides including benzenes, naphthalenes, pyridines and quinolines for C-C bond formation have been successfully achieved. This journal is

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Arylation of 2- Substituted pyridines via Pd-Catalyzed Decarboxylative
Cross-Coupling Reactions of 2-Picolinic acid
Xinjian lia,b, Dapeng Zoua,b, Faqiang Lenga,b, Chunxia Suna,b, Jingya Lib, Yangjie Wua,*, Yusheng Wub, c*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
50 blocks, picolinic acids represent a kind of cheap, stable and
readily available structures. However, examples of the crossꢀ
coupling of 2ꢀpicolinic acid with aryl halides have not been
reported.
The novel palladium-catalyzed decarboxylative cross-
coupling reactions of 2-picolinic acid with aryl and heteroaryl
bromides including benzenes, naphthalenes, pyridines and
quinolines for C-C bond formation has been successfully
The decarboxylative crossꢀcoupling reaction of 2ꢀpicolinic
55 acids was considered not favored comparing to the
decarboxylative crossꢀcoupling of similar benzene acids based on
the literature presence.13ꢀ15 However, the occurrence possibility of
this reaction is exist and it was worth to be investigated. Salvador
Conejero and coꢀworkers reported a simple, general route to a 2ꢀ
60 pyridylidene transition metal complexes.16 This result encouraged
us to study the decarboxylative crossꢀcoupling reaction of 2ꢀ
picolinic acid with arylꢀ and heteroarylꢀbromides.
Firstly, the decarboxylative crossꢀcoupling reaction of 2ꢀ
picolinic acid (1a) and 4ꢀbromobenzonitrile (2a) was investigated
65 as the model reaction as shown in Table 1. We investigated
various Pd source (5 mol% loading) and ligands initially (Table 1,
entries 1ꢀ14). When BINAP was used as the ligand, 75% yield of
the desired decarboxylative crossꢀcoupling product was obtained
(Table 1, entry 10). Obviously, the BINAP was more effective
70 than the other ligands in this reaction (Table 1, entries 1ꢀ9). We
speculated the bidentate ligand with a rigid angle like BINAP
must be fitting for the crossꢀcoupling and reducing the Ullmannꢀ
type products due to steric hindrance around the metal.17
Moreover, BINAP is the ligand of copper (І)18 stabilizing 2ꢀ
75 pyridyl metal compounds.8
Secondly, the additives were investigated. Copper (І) as an
additive shows an excellent result in this reaction (Table 1,
entries 10, 15ꢀ17). Owing to the facile protonation of pyridine αꢀ
position and the speed of oxidative addition of aryl halides to
80 palladium, the Ullmann reaction19 and decarboxy coupling
reaction are the competing reactions. Cu2O was then selected and
found to be the optimal additive for the current reaction (Table 1,
entry 10). Other copper salts were also investigated with no better
than Cu2O (Table 1, entries 16ꢀ20). Su and coꢀworkers reported
85 the Agꢀpromoted decarboxylation.12 So we tried the reaction with
Ag2CO3, but it resulted in much worse than Cu2O (Table 1, entry
21). The main reason is due to the fast decarboxylation which
leads to the protonation of pyridine αꢀposition other than the
crossꢀcoupling reaction. To investigate our hypothesis, 5ꢀ
90 phenylpicolinic acid was selected as the decarboxylative crossꢀ
coupling reaction substrate. The reaction was monitored by GCꢀ
MS. When we replaced copper (І) with Ag2CO3, the
decarboxylationꢀprotonation product, 3ꢀphenylpyridine, was
10 achieved.
Derivatives of 2ꢀarylpyridine are among the most important
heterocyclic structural motifs and are found in a large number of
natural products, pharmaceuticals, materials and ligands.1 Some
crossꢀcoupling reactions have been applied for the synthesize of
15 2ꢀarylpyridines with
a wide range of aryl halides and
organometallics. But due to the instability and the synthetic
difficulty of 2ꢀpyridyl organometallics, their application is
severely limited. For example, the SuzukiꢀMiyaura coupling of 2ꢀ
pyridyl boron derivatives is probably the most widely used.2
20 However, the inherent instability of 2ꢀpyridyl boronic acid makes
very few examples of 2ꢀpyridyl boronates serving as the
nucleophile source included in crossꢀcoupling reactions.3ꢀ5 Until
recently, Burke’s group firstly reported the identified 2ꢀpyridyl
Nꢀmethyliminodiacetic acid (MIDA) boronate which is both air
25 stable and can be isolated in a chemically pure form.5e,5f
Since Nilsson first reported the transitionꢀmetal mediated
decarboxylative biaryl coupling,6 the exciting breakthroughs have
been achieved by Myers,7 Goossen,8 and others9 as an attractive
alternative to typical crossꢀcoupling reactions. Liu et al.
30 developed the excellent procedures for the copperꢀcatalyzed
decarboxylative coupling of polyfluorobenzoic acids.10
Meanwhile some sliverꢀcatalyzed aryl acid decarboxylation was
described by Su et al. and others.11, 12 Although decarboxylative
coupling has been utilized in organic synthesis, only a few reports
35 of heteroarylcarboxylic acids including oxazole, thiophene and
furan carboxylic acid is available.9d,9g As the substrate of a
powerful alternative to the conventional organometallic building
a The College of Chemistry and Molecular Engineering, Zhengzhou
40 University, Zhengzhou, PR China.
b Tetranov Biopharm, LLC,75 Daxue Road, Zhengzhou, PR China
c Tetranov International, Inc. 100 Jersey Avenue, Suite A340, New
Brunswick, NJ 08901, USA.
*Corresponding Authors: Yusheng Wu; Email:
45 yusheng.wu@tetranovglobal.com, Tel. 001 732 253 7326, Fax 001 732
253 7327; Yangjie Wu, Email: wyj@zzu.edu.cn, Tel. 86 371 6776 7993.
† Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
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30 Table 2 Screen of the Base and Solvents for the Crossꢀcoupling of 2ꢀ
Picolinic Acid with 4ꢀBromobenzonitrilea
Table 1 Screen of Catalysts, Ligands and Additive for the Crossꢀcoupling
of 2ꢀPicolinic acid with 4ꢀBromobenzonitrilea
Yieldb
[%]
20
52
40
46
48
57
38
64
31
75
74
40
trace
trace
43
Entry
base
solvent
Yieldb [%]
Tem.[℃]
Entry
Pd Source
Ligand
Additive
1
2
3
4
5
6
7
8
9
K2CO3
Cs2CO3
K3PO4
Na2CO3
tꢀBuOK
NEt3
KOAc
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMA
DMA
DMA
DMA
DMA
DMA
DMA
NMP
DMF
150
150
150
150
150
150
150
150
150
150
150
120
75
trace
74
39
no
no
66
20
35
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdBr2
Pd2(dba)3
Pd(acac)2
Pd(AcO)2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
P(Cy)3
Ph3P
CyJohnPhos
DavePhos
SPhos
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
CuI
CuBr
CuCl
XPhos
RuPhos
Xantphos
DPPF
10
11
12
DMAB
DMA:DMSO(40:1)
DMA
43
33
56
BINAP
BINAP
BINAP
BINAP
BINAP
BINAP
BINAP
BINAP
BINAP
BINAP
BINAP
BINAP
a Reaction conditions: 0.6 mmol 1a, 0.9 mmol 2a, 5 mol% PdCl2, 6 mol%
BINAP, 1.8 mmol base, 3.5 mL Solvent, 0.3 mmol Cu2O, 24 h, argon
atmosphere, 200 mg 3Ǻ MS.
28
35 b Isolated yields based on 1a.
trace
trace
trace
trace
trace
CuBr2
CuCO3
Cu(CH3COO)2
Ag2CO3
to good yields. As shown in Table 3, the reaction condition could
be compatible to a wide range of functional groups such as ethers,
ketones, esters, nitriles, trifluoromethyl, alkyls and nitro groups.
It was conjectured that the lower yield of 2ꢀ(acetylꢀphenyl)
40 pyridine is due to the carbonyl oxygen coordination role with
copper (І). Furthermore, the functional groups of aryl bromides
positions were not more of an impact (Table 3: 3a, 3m; 3b, 3l; 3d,
3n; 3i, 3j.), but steric hindrance of aryl bromides had a great
effect on products yields (Table 3, 3k). For bromoꢀnaphthalene,
PdCl2
PdCl2
a Reaction conditions: 0.6 mmol 1a, 0.9 mmol 2a, 5 mol% catalyst, 6
mol% ligand, 1.8 mmol K2CO3, 3.5 mL DMA, 0.3 mmol addition, 150 ℃
, 24 h, argon atmosphere, 200mg 3Ǻ MS.
5
b Isolated yields based on 1a.
found as a major product with no desired decarboxylationꢀcrossꢀ
coupling product detected (Scheme 1).
45 Table 3 The Palladiumꢀcatalyzed Decarboxylative Crossꢀcoupling
Reactions of 2ꢀPicolinic Acid with Aryl bromidesa
10 Scheme 1 Decarboxylative Coupling Reaction of 5ꢀPhenylpicolinic Acid
with 4ꢀBromobenzonitrile
Thirdly, the influence of various bases for this transformation was
studied in the presence of Cu2O. K2CO3 and K3PO4 were found to
give good yield of the desired decaboxylationꢀcrossꢀcoupling
15 product (Table 2, entries 1ꢀ7). KOAc was known as an inhibitor
in the Ullmannꢀtype coupling of aryl halides.20 But KOAc did not
result in better result in this reaction. It was also important to
point out that the solvent played a critical role for this reaction
(Table 2, entry 1, 8ꢀ11). The desired product was obtained in 75%
20 yield when DMA was used as solvent (Table 2, entry 1). When
the reaction temperature was reduced to 120℃, the isolated yields
were also reduced. The conclusion for this study is that the
combination of 5 mol% PdCl2, 6 mol % BINAP in DMA in the
presence of K2CO3 or K3PO4 and Cu2O at 150 ℃ is the optimum
25 condition.
a Reaction conditions: 0.6 mmol 1a, 0.9 mmol 2, 5 mol% PdCl2, 6 mol%
BINAP, 1.8 mmol K2CO3, 3.5 mL DMA, 0.3 mmol Cu2O, 150 ℃, 24 h,
argon atmosphere, 200 mg 3Ǻ MS.
Under the optimized reaction conditions, a wide range of aryl
bromides were investigated for this reaction. It was found that
both electronꢀrich and electronꢀpoor aryl bromides could be
successfully converted to the corresponding products in moderate
50 b Isolated yields based on 1a.
2
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both αꢀbromonaphthalene and βꢀbromonaphthalene gave the
Notes and references
desired products in good yields (Table 3, 3p, 3q). The reaction of
2ꢀpicolinic acid with iodobenzene and chlorobenzene were
investigated. In case of iodobenzene, only 28% yield was
obtained due to the homoꢀcoupling of iodobenzene.
Chlorobenzene was so inactive that only trace product was
monitored by GCꢀMS in the reaction.
1
a) G. D. Henry, Tetrahedron 2004, 60, 6043; b) J. P. Michael, Nat.
Prod. Rep. 2005, 22, 627; c) M. Schlosser, F. Mongin, Chem. Soc.
Rev. 2007, 36, 1161; d) C. G. Arena, G. Arico, Curr. Org. Chem.
2010, 14, 546.
50
55
60
65
70
75
80
85
90
95
100
5
2
3
A. Maureen Rouhi, Chem. Eng. News 2004, 82, 49.
a) N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457; b) A. Suzuki,
J. Organomet. Chem. 1999, 576, 147; c) L. C. Campeau, K. Fagnou,
Chem. Soc. Rev 2007, 36, 1058; d) Y. Yamamoto, M. Takizawa, X.
Q. Yu, N. Miuaura, Angew. Chem. Int. Ed. 2008, 47, 928ꢀ931; e) G.
A. Molander, B. Biolatto, J. Org. Chem. 2003, 68, 4302.
a) L. Ackermann, H. K. Potukuchi, Synlett 2009, 2852ꢀ2856; b) K. L.
Billingsley, S. L. Buchwald, Angew. Chem. Int. Ed. 2008, 47, 4695;
c) K. L. Billingsley, S. L. Buchwald, J. Am. Chem. Soc. 2007, 129,
3358.
a) J. Z. Deng, D. V. Paone, A. T. Ginnetti, H. Kurihara, S. D. Dreher,
S. A. Weissman, S. R. Stauffer, C. S. Burgey, Org. Lett. 2009, 11,
345; b) D. M. Knapp, E. P. Gillis, M. D. Burke, J. Am. Chem. Soc.
2009, 131, 6961; c) P. B. Hodgson, F. H. Salingue, Tetrahedron Lett.
2004, 45, 685; d) A. Bouillon, J. C. Lancelot, J. Sopkova de Oliveira
Santos, V. Collot, P. R. Bovy, S. Rault, Tetrahedron 2003, 59,
10043; e) G. R. Dick, D. M. Knapp, E. P. Gillis, M. D. Burke, Org.
Lett. 2010, 12, 2314; f) G. R. Dick, E. M. Woerly, M. D. Burke,
Angew. Chem. Int. Ed. 2012, 51, 2667.
To extend the reaction scope, we proceeded to study the crossꢀ
coupling reactions of picolinic acid with heteroaryl bromides
10 under the optimized reaction conditions. The results are
summarized in Table 4. At first, a variety of bromoꢀpyridines as
crossꢀcoupling partners were examined. 2ꢀbromopyridine, 3ꢀ
bromopyridine and 4ꢀbromopyridine afforded the corresponding
dipyridine in 46%, 35% and 45% yields respectively. Both 2ꢀ
15 bromoquinoline and 3ꢀbromoquinoline were all the selectable
substrate, and affording the corresponding product 3u and 3v
separately in 46% and 59% yields.
4
5
Table 4 The palladiumꢀcatalyzed decarboxylative crossꢀcoupling
reactions of 2ꢀpicolinic acid with heteroaryl bromidesa.
6
7
M. Nilsson, Acta Chem. Scand. 1966, 20, 423.
a) A. G. Myers, D. Tanaka, M. R. Mannion, J. Am. Chem. Soc. 2002,
124, 11250; b) D. Tanaka, A. G. Myers, Org. Lett. 2004, 6, 433; c)
D. Tanaka, S. P. Romeril, A. G. Myers, J. Am. Chem. Soc. 2005,
127, 10323.
a) L. J. Goossen, G. Deng, L. M. Levy, Science 2006, 313, 662; b) L.
J. Goossen, N. Rodriguez, B. Melzer, C. Linder, G. Deng, L. M.
Levy, J. Am. Chem. Soc. 2007, 129, 4824; c) L. J. Goossen, B.
Melzer, J. Org. Chem. 2007, 72, 7473; d) L. J. Goossen, F.
Rudolphi, C. Oppel, N. Rodriguez, Angew. Chem. Int. Ed. 2008, 47,
3043; e) L. J. Goossen, N. Rodriguez, K. Goossen, Angew. Chem.
Int. Ed. 2008, 47, 3100; f) L. J. Goossen, B. Zimmermann , Adv.
Synth. Catal. 2009, 351, 2667; g) L. J. Goossen, N. Rodriguez, C.
Linder, J. Am. Chem. Soc. 2008, 130,15248.
a) G. Lalic, A. D. Aloise, M. D. Shair, J. Am. Chem. Soc. 2003, 125,
2852; b) S. Lou, J. A. Westbrook, S. E. Schaus, J. Am. Chem. Soc.
2004, 126, 11440; c) D. K. Rayabarapu, J. A. Tunge, J. Am. Chem.
Soc. 2005, 127, 13510; d) P. Forgione, M. C. Brochu, M. StꢀOnge,
K. H. Thesen, M. D. Bailey, F. Bilodeau, J. Am. Chem. Soc. 2006,
128, 11350; e) J.ꢀM. Becht, C. Catala, C. Le Drian, A. Wagner, Org.
Lett. 2007, 9, 1781. f) S. R. Waetzig, J. A. Tunge, J. Am. Chem. Soc.
2007, 129, 148601; g) F. Zhang, M. F. Greaney, Org. Lett. 2010,
12, 4745; h) M. Nilssen, C. Ullenius, Acta. Chem. Scand. 1968, 22,
1998.
8
20 a Reaction conditions: 0.6 mmol 1a, 0.9mmol 2, 5 mol% PdCl2, 6 mol%
BINAP, 1.8 mmol K2CO3, 3.5 mL DMA, 0.3 mmol Cu2O, 150 ℃, 24 h,
argon atmosphere, 200 mg 3Ǻ MS.
b Isolated yields based on 1a.
9
In order to further conjecture the probable reason of the low
25 chemical yields, the reaction of 2ꢀpicolinic acid (1a) and 1ꢀ
bromoꢀ4ꢀmethoxybenzene (2b) was detected by GCꢀMS and
HPLC，HPLC showed that the 2ꢀpicolinic acid was consumed
totally and pyridine(38%) was detected. Meanwhile, 1ꢀbromoꢀ4ꢀ
methoxybenzene (2b) was not exist, except the expected product,
30 4,4'ꢀdimethoxybiphenyl was found as mainly byꢀproduct. So the
protonation of 1a and the Ullmannꢀtype reaction of 2b produced
the low chemical yields.
In conclusion, a novel synthetic route to 2ꢀarylꢀ and heteroarylꢀ
pyridines was discovered and developed via the palladiumꢀ
35 catalyzed decarboxylative crossꢀcoupling reactions of 2ꢀpicolinic
acid with arylꢀ and heteroarylꢀbromides. In this reaction, an
efficient new catalytic system has been developed. Both the
catalyst and ligand are commercially available. In addition, cheap
and stable 2ꢀpicolinic acid has been used. We believe that the
40 process combined with the condition would be attractive and
beneficial for its further development. Further exploration of this
reaction is currently under investigation in our lab.
10 R. Shang, Y. Fu, Y. Wang, Q. Xu, H. Z. Yu, L. Liu, Angew. Chem.,
Int. Ed. 2009, 48, 9350.
11 a) L. J. Goossen, C. Linder, N. Rodriguez, P. P. Lange, A. Fromm,
Chem. Commun. 2009, 7173; b) J. Cornella, C. Sanchez, D. Banawa,
I. Larrosa, Chem. Commun. 2009, 7176; c) P. F. Lu, C. Sanchez, J.
Cornella, I. Larrosa, Org. Lett., 2009, 11, 5710.
12 a) P. Hu, M. Zhang, X. M. Jie, W. P. Su, Angew. Chem. Int. Ed. 2012,
51, 227; b) P. Hu, Y. Shang, W. P. Su, Angew. Chem. Int. Ed. 2012,
51, 5945.
105 13 L. C. Campeau, S. Rousseaux, K. Fagnou, J. Am. Chem. Soc. 2005,
127, 18020.
14 R. J. Moser, E. V. Brown , J. Org. Chem. 1972, 37, 3938.
15 a) H. Quast, E. Schmitt, Liebigs Justus Ann. Chem. 1970, 732, 43; b)
A. R. Katritzky , H. M. Faid ꢀ Allah, Synthesis, 1983, 149.
110 16 M. RosellóꢀMerino, J. Díezb, S. Conejero, Chem. Commun. 2010, 46,
9247.
Acknowledgement
17 A. Jutand, A. Mosleh, J. Org. Chem. 1997, 62, 261.
18 E. D. Blue, A. Davis, D. Conner, T. B. Gunnoe, P. D. Boyle, P. S.
White, J. Am. Chem. Soc. 2003, 125, 9435.
We are grateful to the Natural Science Foundation of China
45 (20772114, 21172200), the Research Program of Fundamental
and Advanced Technology of Henan Province (122300413203)
for financial support.
115 19 F. Ullmann, J. Bielecki, Chem. Ber. 1901, 34, 2174.
20 T. Ishiyama, M. Murata, N. Miyaura. J. Org. Chem. 1995, 60, 7508.
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