Direct benzylic functionalization of pyridines: Palladium-catalyzed mono-α-arylation of α-(2-pyridinyl)acetates with heteroaryl halides

Article abstract of DOI:10.1016/j.cclet.2019.06.028

Herein, we report a Pd-catalyzed mono-α-arylation reaction for pyridine benzylic functionalization. This approach serves as an efficient alternative to synthesize di-heteroaryl acetates in good yields and selectivities. Moreover, the method is applicable to heteroaryl substrate combinations, and exhibits great functional group tolerance. A streamlined protocol also enables the rapid synthesis of diheteroaryl ketones. The synthetic value was also demonstrated by scale-up experiments

Full text of DOI:10.1016/j.cclet.2019.06.028

Accepted Manuscript
Title: Direct benzylic functionalization of pyridines:
Palladium-catalyzed mono-α-arylation of
α-(2-pyridinyl)acetates with heteroaryl halides
Authors: Chaochao Jin, Kun Xu, Xiao Fan, Changyao Liu,
Jiajing Tan
PII:
DOI:
Reference:
S1001-8417(19)30357-2
https://doi.org/10.1016/j.cclet.2019.06.028
CCLET 5059
To appear in:
Chinese Chemical Letters
Received date:
Revised date:
Accepted date:
9 April 2019
10 June 2019
14 June 2019
Please cite this article as: Jin C, Xu K, Fan X, Liu C, Tan J, Direct
benzylic functionalization of pyridines: Palladium-catalyzed mono-α-arylation of
α-(2-pyridinyl)acetates with heteroaryl halides, Chinese Chemical Letters (2019),
https://doi.org/10.1016/j.cclet.2019.06.028
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Communication
Direct benzylic functionalization of pyridines: Palladium-catalyzed mono-α-arylation
of α-(2-pyridinyl)acetates with heteroaryl halides
Chaochao Jina, Kun Xub, Xiao Fana, Changyao Liuc, Jiajing Tana, tanjj@mail.buct.edu.cn
aDepartment of Organic Chemistry, College of Chemsitry, Beijing Advanced Innovation Center for Soft Matter Science and Engineering, Beijing University of
Chemical Technology, Beijing 100029, China
bCollege of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang 473061, China
cSchool of Food and Chemical Engineering, Beijing Technology and Business University, Beijing 100048, China
Corresponding author.
Graphical Abstract
Herein, we report a Pd-catalyzed mono-α-arylation reaction to synthesize di-heteroaryl acetates in good yields and selectivities.
The method is applicable to challenging heteroaryl substrate combinations, and exhibits great functional group tolerance.
ARTICLE INFO
Article history:
Received 9 April 2019
Received in revised form 10 June 2019
Accepted 11 June 2019
Available online
ABSTRACT
Herein, we report a Pd-catalyzed mono-α-arylation reaction for pyridine benzylic functionalization. This approach serves as an efficient alternative to synthesize
di-heteroaryl acetates in good yields and selectivities. Moreover, the method is applicable to heteroaryl substrate combinations, and exhibits great functional
group tolerance. A streamlined protocol also enables the rapid synthesis of diheteroaryl ketones. The synthetic value was also demonstrated by scale-up
experiments
Keywords:
α-Arylation
Palladium
Heterocycles
———

Pyridines
Cross-coupling
Heterocycles are of great significance to the pharmaceutical industry due to their ability to interact with biological systems through
polar interactions [1]. In particular, the unique electronic and conformational properties of pyridine rings renders them one simple yet
privileged class of structure motifs in medicinal chemistry (Fig. 1) [2]. The incorporation of pyridine rings often had profound impacts
on the biological properties of natural products. For instance, azatyrosine, with replacement of phenyl ring with pyridine, displays potent
antibiotic and antitumor properties, when compared to corrsponding tyrosine [3].
The major progress of synthetic approaches to pyridine-containing molecules relied on the manipulation of pre-functionalized
structural motifs [4]. Among those progress, the benzylic functionalization of pyridines is of great importance, as it provides access to
useful building blocks such as α-pyridyl carbonyl, germinal dipyridyl moiety [5]. A common procedure for the benzylic functionalization
of pyridines involved the deprotonation of picoline precursors with organometallic reagents, followed by the treatment with electrophiles
(Scheme 1) [6]. Recently, alternative approaches have also been reported. For instance, Londregan and co-workers reported the PyBroP-
mediated the addition of silyl ketene acetals to azine-N-oxides [7]. Nevertheless, these protocols showed broad synthetic appeal and were
useful in certain contexts, but the reaction reagent nature still limited their utilities to a certain degree [6,8].
Fig. 1. Pyridine motifs in medicinal chemistry.
Scheme 1. Pyridine benzylic functionalization.
Given our group’s continuous efforts in heterocyclic chemistry and transition metal catalysis [9], our attention was therefore drawn
to employ the Pd-catalyzed α-arylation reaction to achieve the pyridyl-benzylic functionalization. Since the seminal work from Buchwald,
Hartwig and Miura groups, the Pd-catalyzed α-arylation of carbonyl moiety has emerged as an effective Csp2-Csp3 bond formation
strategy [10]. A wide array of protocols has been found to be effective to connect highly functionalized substrates. Moreover, these
progresses have transformed the way in which synthetic chemists designed and implemented synthesis on both bench-top and industrial
scales [11]. Notwithstanding such progress, the substrate scope of both coupling partners remains challenging with respect to the pyridine
functionality. In principle, any Pd-catalyzed α-arylation reactions that is tolerable to both the Lewis basic functionality as well as the
inherent electronic deficient property of pyridine rings, would be highly appreciated, and offer alternative efficient solution to pyridine
benzylic functionalization [9a,12]. Another critical task is to identify the suitable reaction conditions to avoid the inhibition caused by
the enolization of 2-(pyridin-2-yl)acetate and resulting coordination with palladium center as the ligand. Despite these challenges, we
would like to report a highly efficient pyridyl-benzylic functionalization protocol via the palladium-catalyzed mono-α-arylation reaction
of α-(2-azaheteroaryl) acetates with heteroaryl halides. Due to the immense usefulness of pyridine motifs, this protocol in principle
should be of great interests to the community.
Table 1

Optimization of the reaction conditions.a
Entry
1
2
3
4
5
6
7
8
Pd catalyst
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3
[PdCl(allyl)]2
PdCl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Ligand
L1
L2
L3
L4
L5
L6
L6
L6
L6
L6
L6
L6
L6
L6
Solvent
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Glyme
Yield (%)b
23
29
20
85
69
96
94
91
90
13
67
79
50
82
9
10
11
12
13c
14d
DCE
Toluene
Dioxane
Dioxane
a 1a (0.3 mmol), 2a (0.4 mmol), Pd catalyst (0.015 mmol), ligand (0.015 mmol), and Cs2CO3 (0.9 mmol) in dioxane (1 mL), 100 oC, N2, 10 h.
b Isolated yields.
c Na2CO3 used instead.
d K3PO4 used instead.
We initiated the optimization study with commercially available ethyl 2-(pyridin-2-yl)acetate (1a) and 6-bromoquinoline (2a) (Table
1). Among the phosphine ligands examined, the highest yield of ethyl 2-(pyridin-2-yl)-2-(quinolin-6-yl)acetate (3aa) was obtained in the
presence of X-Phos (L6) (Fig. 2) [13]. Next, a series of palladium sources were examined, all of which led to slightly lower yields, when
compared to palladium acetate. Attention was then switched to determine the optimal solvent for the reaction. The control experiments
revealed that dioxane was the ideal choice (entries 8-12). Keeping all other variables constant, the coupling reactions with either Na2CO3
or K3PO4 were then performed, and both failed to offer better results (entry 6 vs. entry 13-14).
Fig. 2. Structures of ligands (L1-L6).

Scheme 2. Substrate scope. Reaction conditions: 1a (0.3 mmol), 2 (0.4 mmol), Pd(OAc)2 (0.015 mmol), X-Phos (0.015 mmol) and Cs2CO3 (0.9
mmol) in dioxane (1 mL), 100 oC, N2, 10 h. Isolated yields.
With the optimal conditions in hands, the transformation was demonstrated on a range of heteroaryl halides. As shown in Scheme 2,
investigations of the heteroaryl bromide scope showed that quinoline-based heteroaryl bromides were viable substrates to give desired
products in excellent yields (3aa-3ae, 75%-96% yields). Moreover, pyridine-containing substrates proved to be well-tolerant to give the
desired adducts 3af-3am in 83%-97% yields. It is worth mentioning that these substrate classes are discovered to be non-sensitive to the
electronic effect of substitution groups on the pyridine rings. Besides, thiophene derived substrates, which are also widely present in
medicinally relevant compounds, underwent the reaction smoothly to deliver coupling products (3an, 3bd, 3be, 63%-83% yields). As
expected, when simple bromobenzene was employed, the desired arylation product 3ao was obtained in 95% yield.
Next, we examined the generality of our coupling protocol with respect to the heteroaryl substituted acetates (Scheme 3). The methyl
and t-Bu 2-(pyridin-2-yl)acetate are viable substrates, providing quick access to desired products (3ba-3cg) in good yields (63%-97%
yields). We were also glad to discovery that the protocol can be extended to quinolidyl acetates, which performed well under the standard
conditions to give 3dh in 88% yield. More importantly, the mono-arylation product could be utilized to further react with
bromocyclopropane to construct the all carbon quaternary center on 5, which is presumably involve β-elimination before coupling [14,15].
Unfortunately, when we employed 1e, the palladium complex 6 was obtained instead of the corresponding coupling products (Scheme
4). Single crystals suitable for X-ray diffraction analysis were grown from a mixture of dichloromethane and petroleum ether. The central
palladium atom displayed a square-planar arrangement with the nitrogen atoms of the pyridine ring and oxygen of the enol moiety
situated mutually in the trans position.
Scheme 3. Substrate scope. Reaction conditions: 1 (0.3 mmol), 2 (0.4 mmol), Pd(OAc)2 (0.015 mmol), X-Phos (0.015 mmol) and Cs2CO3 (0.9
mmol) in dioxane (1 mL), 100 oC, N2, 10 h. Isolated yields.

Scheme 4. Ketone substrate and resulting palladium complex. Crystal data: C26H20N2O2Pd, M = 498.84, triclinic, P1,̅ a = 9.8373(3), b =
12.0510(4), c = 17.9512(6) Å, α = 105.345(3), β = 95.871(3), γ = 93.103(3), V = 2034.16(11) Å3, Z = 4, Mo Kα radiation (λ = 0.71073). For
details, see Supporting information.
Alteration of the halide fragments was evaluated next, using heteroaryl chlorides, triflates and tosylates as the coupling partners. Under
optimized conditions, the arylated products 3aa were still obtained in good chemical yields, respectively. Additionally, our protocol was
effective to incorporate benzothiazole units into arylation products using 5-chloro-2-methylbenzothiazole (Scheme 5). Noteworthy, all
the above-mentioned reactions showed no evidence of over-arylation by-products, which is a major side pathway for the arylation
reactions of α-carbonyl compounds [16].
Scheme 5. Substrate scope.
This arylation protocol is amenable to gram-scale preparation of 3aa. We reacted 6 mmol of 1a with a slight excess amount (1.3
equiv., 7.8 mmol) of 2a. Under the same reaction conditions, 3aa was produced in 91% yield (Scheme 6). Next, the hydrolysis and
subsequent decarboxylation went without issue to provide the diheteroaryl ketone product 10 in good efficiency. This one-pot, two-step
protocol was further demonstrated by the quick synthesis of 11 and 12, which often displayed photochemical reactivities [17].
Scheme 6. Synthetic applications.
In conclusion, we have developed an efficient Pd-catalyzed mono-α-arylation reaction of α-(2-azaheteroaryl) ester with heteroaryl
halides. The broad heterocyclic substrate scope enabled the rapid synthesis of a wide array of functionalized α,α'-di-heteroaryl acetate
products with consistently good yields. Remarkably, our protocol proved to be not only efficient in scale-up reactions, but further

functionalization was also readily possible, setting the base for rapidly accessing diheteroaryl ketone derivatives. In comparison to
classical approaches for pyridine benzylic functionalization, we anticipate that our catalytic protocol will provide an efficient alternative
for divergent parallel synthesis efforts.
Acknowledgments
Tan is grateful to the support by the National Natural Science Foundation of China (No. 21702013), Beijing Natural Science
Foundation (No. 2184115) and the Fundamental Research Funds from the Central Universities (No. XK1802-6, buctrc201721) in Beijing
University of Chemical Technology.
References
[1] (a) R.E. Dolle, B.L. Bourdonnec, K. Worm, et al., Comb. Chem. 12 (2010) 765-806;
(b) A. Facchetti, Chem. Mater. 23 (2011) 733-758;
(c) L.M. Blair, J. Sperry, J. Nat. Prod. 76 (2013) 794-812;
(d) E. Vitaku, D.T. Smith, J.T. Njardarson, J. Med. Chem. 57 (2014) 10257-10274;
(e) U.H.F. Bunz, Acc. Chem. Res. 48 (2015) 1676-1686;
(f) R.K. Alan, A.R. Christopher, F.V.S. Eric, et al., Comprehensive Heterocyclic Chemistry III, Elsevier, Oxford, 2008;
(g) K.C. Majumdar, S.K. Chattopadhyay, Heterocycles in Natural Product Synthesis, Wiley-VCH, Weinheim, 2011.
[2] (a) J. Alvarez-Builla, J.J. Vaquero, J. Barluenga, Modern Heterocyclic Chemistry, Wiley-VCH, Weinheim, 2011;
(b) M. Baumann, I.R. Baxendale, Beilstein, J. Org. Chem. (9) 2013 2265-2319;
(c) M.D. Hill, Chem. -Eur. J. 16 (2010) 12052-12062;
(d) J.S. Carey, D. Laffan, C. Thomson, et al., Org. Biomol. Chem. 4 (2006) 2337-2347;
(e) M. Schlosser, F. Mongin, Chem. Soc. Rev. 36 (2007) 1161-1172;
(f) L. Ackermann, H.K. Potukuchi, A.R. Kapdi, et al., Chem. -Eur. J. 16 (2010) 3300-3303;
(g) Y. S. Kumar, F. -R. N. Khan, Chin. Chem. Lett. 28 (2017) 1607-1612;
(h) A. P. Krinochkin, D. S. Kopchuk, N. V. Chepchugov, et al., Chin. Chem. Lett. 28 (2017) 1099-1103.
[3] R.A. Aycock, D.B. Vogt, N. T. Jui, Chem. Sci. 8 (2017) 7998-8003.
[4] (a) A. Kotschy, G. Timári, Heterocycles from Transition Metal Catalysis, Springer, Dordrecht, 2005;
(b) S. Schrꢀter, C. Stock, T. Bach, Tetrahedron, 61 (2005) 2245-2267;
(c) M. Beller, C. Bolm, Transition Metals for Organic Synthesis: Building Blocks and Fine Chemicals, 2nd ed. Wiley-VCH, Weinheim, 2004.
[5] (a) H.-Y. Lin, B. B. Snider, J. Org. Chem. 77 (2012) 4832-4836;
(b) J.A. Lowe, D.L. Hageman, S.E. Drozda, et al., J. Med. Chem. 37 (1994) 3789-3811;
(c) J.J. Mousseau, A. Larivée, A.B. Charette, Org. Lett. 10 (2008) 1641-1643;
(d) S. Duez, A.K. Steib, S.M. Manolikakes, et al., Angew. Chem. Int. Ed. 50 (2011) 7686-7690;
(e) K.P. Bogeso, A.V. Christensen, J. Hyttel, et al., J. Med. Chem. 28 (1985) 1817-1828;
[6] (a) R.B. Woodward, E.C. Kornfeld, Org. Synth. 29 (1949) 44-44;
(b) W.G. Kofron L.M. Baclawski, Org. Synth. 52 (1972) 75-75.
(c) R. Zhu, G. Cheng, C. Jia, et al., J. Org. Chem. 81 (2016) 7539-7544.
[7] (a) A.T. Londregan, S. Jennings, L. Wei, Org. Lett. 12 (2010) 5254-5257;
(b) A.T. Londregan, S. Jennings, L. Wei, Org. Lett. 13 (2011) 1840-1843.
[8] (a) P.S. Fier, J. Am. Chem. Soc. 139 (2017) 9499-9502;
(b) D.D. Zhai, X.Y. Zhang, Y.F. Liu, et al., Angew. Chem. Int. Ed. 57 (2018) 1650-1653. and references therein.
[9] (a) J.J. Tan, Y. Chen, H. Li, et al., J. Org. Chem. 79 (2014) 8871-8876;
(b) H.Q. Wang, W.T. Xu, Z.Q. Wang, et al., J. Org. Chem. 80 (2015) 2431-2435;
(c) L. Liu, C. Tan, R. Fan, et al., Org. Biomol. Chem. 17 (2019) 252-256.
[10] (a) S. Lee, N.A. Beare, J.F. Hartwig, J. Am. Chem. Soc. 123 (2001) 8410-8411;
(b) M. Jorgensen, S. Lee, X. Liu, et al., J. Am. Chem. Soc. 124 (2002) 12557-12565;
(c) T. Hama, X. Liu, D.A. Culkin, et al., J. Am. Chem. Soc. 125 (2003) 11176-11177;
(d) X. Liu, J.F. Hartwig, J. Am. Chem. Soc. 126 (2004) 5182-5191;
(e) T. Hama, J.F. Hartwig, Org. Lett. 10 (2008) 1545-1548;
(f) M.R. Biscoe, S.L. Buchwald, Org. Lett. 11 (2009) 1773-1775;
(g) T. Hama, D.A. Culkin, J.F. Hartwig, J. Am. Chem. Soc. 128 (2006) 4976-4985;
(h) B. Zheng, T. Jia, P.J. Walsh, Org. Lett. 15 (2013) 4190-4193;
(i) R. Martin, S.L. Buchwald, Angew. Chem. Int. Ed. 46 (2007) 7236-7239;
(j) G.D. Vo, J.F. Hartwig, Angew. Chem. Int. Ed. 47 (2008) 2127-2130;
(k) R. Martin, S.L. Buchwald, Org. Lett. 10 (2008) 4561-4564;
(l) D.A. Culkin, J.F. Hartwig, Acc. Chem. Res. 36 (2003) 234-245;
(m) F. Bellina, R. Rossi, Chem. Rev. 110 (2010) 3850-3850;
(n) C.C.C. Johansson, T.J. Colacot, Angew. Chem. Int. Ed. 49 (2010) 676-707;
(o) Z. Liu, M. Li, B. Wang, et al., Org. Chem. Front. 5 (2018) 1870-1876;
(p) G. Gao, Y. Fu, M. Li, et al., Adv. Synth. Catal. 359 (2017) 2890-2894;
(q) K. Ablajan, G.B Panetti, X. Yang, et al., Adv. Synth. Catal. 359 (2017) 1927-1932;
(r) G. Saini, P. Kumar, G.S. Kumar, et al., Org. Lett. 20 (2018) 441-444;
(s) I. Astarloa, R. SanMartin, M.T. Herrero, et al., Adv. Synth. Catal. 360 (2018) 1711-1718;
(t) D.J. Leonard, J.W. Ward, J. Clayden, Nature 562 (2018) 105-109.
[11] (a) Á. Molnár, Palladium-Catalyzed Coupling Reactions - Practical Aspects and Future Developments, Wiley-WCH, Weinheim, 2013;
(b) M.L. Crawley, B.M. Trost, Applications of Transition Metal Catalysis in Drug Discovery and Development, Wiley, New York, 2012;
(c) C. Torborg, M. Beller, Adv. Synth. Catal. 351 (2009) 3027-3043.
[12] (a) M.A. Oberli, S.L. Buchwald, Org. Lett. 14 (2012) 4606-4609;
(b) P.E. Maligres, J. Li, S.W. Krska, et al., Angew. Chem. Int. Ed. 51 (2012) 9071-9074;
(c) J.C. Tellis, D.N. Primer, G.A. Molander, Science 345 (2014) 433-436.

[13] (a) X. Huang, K.W. Anderson, D. Zim, J. Am. Chem. Soc. 125 (2003) 6653-6655;
(b) N.C. Bruno, M.T. Tudge, S.L. Buchwald, Chem. Sci. 4 (2013) 916-920;
(c) P. Novak, R. Martin, Curr. Org. Chem. 15 (2011) 3233-3262.
[14] (a) C.J. Douglas, L.E. Overman, Proc. Natl. Acad. Sci. U. S. A. 101 (2004) 5363-5367;
(b) J. Christoffers, A. Baro, Adv. Synth. Catal. 347 (2005) 1473-1482;
(c) K.W. Quasdorf, L.E. Overman, Nature 516 (2014) 181-191.
[15] (a) J. Gu, X. Wang, W. Xue, Org. Chem. Front. 2 (2015) 1411-1421;
(b) X. Wang, S.Z. Stankovich, R.A. Widenhoefer, Organometallics 21 (2002) 901-905.
[16] (a) W.A. Moradi, S.L. Buchwald, J. Am. Chem. Soc. 123 (2001) 7996-8002;
(b) T. Hama, J.F. Hartwig, Org. Lett. 10 (2008) 1549-1552;
(c) F. Churruca, R. SanMartin, R. Tellitu, Tetrahedron Lett. 44 (2003) 5925-5929;
(d) K.B. Urkalan, M.S. Sigman, Angew. Chem. Int. Ed. 48 (2009) 3146-3149;
(e) F. Churruca, R. SanMartin, M. Carril, Tetrahedron 60 (2004) 2393-2408.
[17] G. Favaro, F. Ortica, A. Romani, J. Photochem. Photobiol. C 16 (2013) 22-45.