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SYNLETT0936-52141437-2096 © Georg Thieme Verlag Stuttgart · New York 2015, 26, 1391–1394 letter

Syn lett

1391

Letter

M. Salman et al.

Highly Chemoselective and Regioselective Dehydrogenative Cross-Coupling Reaction between Pyridines and Ethers Muhammad Salmana R

R H

Zhi-Zhen Huang*a,b

H

b

Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071, P. R. of China a Department of Chemistry, Zhejiang University, Xixi Campus, Hangzhou 310028, P. R. of China [email protected]

N

+

Sc(OTf)3 (10 mol%) O

DTBP (2 equiv) 140 °C, 8 h

R = H, Me or Ph DTBP = di-tert-butyl peroxide

Received: 25.02.2015 Accepted after revision: 06.04.2015 Published online: 08.05.2015 DOI: 10.1055/s-0034-1380694; Art ID: st-2015-w0133-l

Abstract A highly chemoselective and regioselective dehydrogenative cross-coupling (DCC) reaction of unactivated pyridines with cyclic or acyclic ethers has been developed to give the corresponding 2- or 4coupled pyridines in satisfactory yields. The DCC reaction affords an efficient and greener synthesis for a range of new pyridines. A possible mechanism involving radical substitution is also proposed.

Key words dehydrogenative, cross-coupling, pyridine, ether, synthesis

A lot of pyridine derivatives have important biological activities and have been widely applied in drug discovery, natural product synthesis, and heterocyclic chemistry.1 Owing to their importance, many methods have been developed for the synthesis of them.2 As dehydrogenative cross-coupling (DCC) reactions avoid prefunctionalization of substrates, they are more atom economic and environmentally friendly than other cross-coupling reactions.3 In this century, DCC reactions has become a potent strategy for C–C bond formation. However, the synthesis of pyridine derivatives through DCC reaction between a sp2 C–H bond of pyridine and a C–H bond of another substrate is still a challenging subject. In 1980, Gilbert et al. reported a DCC reaction between a sp2 C–H bond of pyridine and an α-C–H bond of diethylamine or triethylamine to give the corresponding both 2- and 4-substituted pyridines under illumination.4 In 2009, Li and co-workers developed a DCC reaction of pyridines with cyclooctane using Sc(OTf)3 as a Lewis acid catalyst and t-BuOOt-Bu (DTBP) as an oxidant.5a Although cyclooctanyl-coupled pyridine derivatives were obtained in moderate yields, most of unactivated pyridines as substrates led to almost equal amounts of 2-cyclooctanyl and 2,6-dicyclooctanyl pyridines. Furthermore, Tiecco et al.

N

O

18 examples 50–81% yield

disclosed a DCC reaction of activated pyridines, which connected with electron-withdrawing groups, with dioxane to give dioxanyl pyridine derivatives in relatively lower yields in the early stage of 1980s.6a,b In 2013, Shi et al. reported that 4-cyanopyridine as an activated pyridine underwent a DCC reaction with tetrahydrofuran or 1,2-dimethoxyethane to give the corresponding 2-coupled pyridine derivatives.6c When nonsubstituted pyridine was employed to perform the DCC reaction with dioxane, 2,4,6-tridioxanyl pyridine was obtained. In the aforementioned paper, Gilbert et al. reported one example of a DCC reaction between pyridine and diethyl ether to give both 2- and 4-(1-ethoxyethyl)pyridine in low regioselectivity (1:2).4 To the best of our knowledge, a highly chemoselective and regioselective DCC reaction of nonsubstituted or other unactivated simple pyridines with ethers for the synthesis of a series of monocoupled pyridines still remains unknown. Herein we wish to present our recent work on the DCC reaction of nonsubstituted or other unactivated pyridines with cyclic or acyclic ethers for highly chemoselective and regioselective synthesis of monocoupled pyridines under Lewis acid catalysis. Initially, we employed pyridine (1a) and ether 2a as model substrates to explore and optimize their DCC reaction. When 10 mol% Cu(OTf)2 and DTBP was employed as a Lewis acid catalyst and an oxidant, respectively, we were pleased to find that the desired monocoupled product 2(tetrahydrofuranyl)pyridine 3aa was obtained, albeit in a low yield (Table 1, entry 1). Then, other transition-metal catalysts were examined as Lewis acids in the reaction. The experiment results indicated that among these transitionmetal catalysts Sc(OTf)3 exhibited best catalytic activity to give the desired 2-coupled pyridine 3aa in 61% yield (Table 1, compare entry 4 with entries 1–3; also see SI). It should be noted that in the absence of Sc(OTf)3, only a trace amount of 3aa was observed (Table 1, entry 5). When other

© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1391–1394

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1392

Letter

M. Salman et al.

oxidants rather than DTBP were employed, lower or no yields of 3aa were obtained (Table 1, compare entry 4 with entries 6–9; also see SI). Raising the temperature from 120 °C to 140 °C led to a significant increase in the yield of 3aa (Table 1, entry 10). Further raising the temperature to 160 °C was not beneficial to the reaction (Table 1, compare entry 11 with entry 10; also see SI).

H Alk

+ H

N 1a–d

Table 1 Optimization of DCC Reaction between Pyridine (1a) and Tet-

Sc(OTf)3 (10 mol%) Alk O 2a–g

O

N

N

DTBP (2 equiv) 140 °C, 8 h

O 3aa–ag,ba–da,cb,dd

O

N

rahydrofuran (2a)

O

[M]

+ oxidant

N 1a Entry

2a M (mol%)

3ac 65%

O N

Oxidant (equiv)

O

N

3aa Yield (%)b

1

Cu(OTf)2 (10)

DTBP (2)

22

2

Co(acac)3 (10)

DTBP (2)

31

3

Fe(acac)3 (10)

DTBP (2)

35

4

Sc(OTf)3 (10)

DTBP (2)

61

5



DTBP (2)