Nickel-catalyzed reductive alkylation of halogenated pyridines with secondary alkyl bromides

Article abstract of DOI:10.1080/00397911.2014.924141

This article highlights Ni-catalyzed cross-electrophile coupling of halogenated pyridines with secondary alkyl bromides using zinc as the terminal reductant. With this protocol, we have successfully achieved different alkyl-substituted pyridines in modera

Full text of DOI:10.1080/00397911.2014.924141

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Nickel-Catalyzed Reductive Alkylation of
Halogenated Pyridines with Secondary
Alkyl Bromides
Huiyan Liu a , Zhuye Liang b , Qun Qian a & Kunhua Lin a
a Department of Chemistry , Shanghai University , Shanghai , China
b College of Chemistry and Molecular Engineering , Zhengzhou
University , Zhengzhou , China
Accepted author version posted online: 11 Jun 2014.Published
online: 08 Aug 2014.
To cite this article: Huiyan Liu , Zhuye Liang , Qun Qian & Kunhua Lin (2014) Nickel-Catalyzed
Reductive Alkylation of Halogenated Pyridines with Secondary Alkyl Bromides, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
44:20, 2999-3007, DOI: 10.1080/00397911.2014.924141
To link to this article: http://dx.doi.org/10.1080/00397911.2014.924141
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Synthetic Communications1, 44: 2999–3007, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2014.924141
NICKEL-CATALYZED REDUCTIVE ALKYLATION
OF HALOGENATED PYRIDINES WITH SECONDARY
ALKYL BROMIDES
Huiyan Liu,1 Zhuye Liang,2 Qun Qian,1 and Kunhua Lin1
1Department of Chemistry, Shanghai University, Shanghai, China
2College of Chemistry and Molecular Engineering, Zhengzhou University,
Zhengzhou, China
GRAPHICAL ABSTRACT
Abstract This article highlights Ni-catalyzed cross-electrophile coupling of halogenated
pyridines with secondary alkyl bromides using zinc as the terminal reductant. With this
protocol, we have successfully achieved different alkyl-substituted pyridines in moderate
to excellent yields.
Keywords Alkylation; cross-coupling; Ni-catalyzed; pyridines; zinc
INTRODUCTION
Many pyridine derivatives are known as bioactive and medicinally important
compounds and have been widely used as the agricultural products.[1] The pyridines
are also recognized as important ligands in organometallic processes. As a result,
numerous methods have been developed for the functionalization of pyridine
rings. In particular, decoration of pyridine rings with alkyl moieties has attracted
increasing attention. Conventionally, alkylated pyridines can be synthetized via
transition-metal-catalyzed cross-coupling reactions of alkyl-metallic reagents with
pyridyl electrophiles and pyridyl-metallic reagents with alkyl electrophiles.[2,3] How-
ever, both these approaches require the synthesis of functionalized organometallic
reagents, which not only need additional steps but also constrain functional-group
Received March 31, 2014.
Authors Huiyan Liu and Zhuye Liang contributed equally to this work.
Address correspondence to Huiyan Liu or Qun Qian, Department of Chemistry, Shanghai
University, 99 Shang-Da Road, Shanghai 200444, China. E-mail: khlin@shu.edu.com; qianqun@shu.
edu.cn
Color versions of one or more of the figures in the article can be found online at www.tandfonline.
com/lsyc.
2999

3000
H. LIU ET AL.
compatibility. Furthermore, the cross coupling of an alkyl halide with a pyridyl
organometallic reagent is often problematic.[3b] Recently, the alkylation of pyridyl
C-H bonds has also received pronounced attention, which provides ortho-substituted
alkyl pyridine effectively.[4] However, although this strategy is ideal in term of atom
economy, it generally requires Pd and is limited to ortho C-H bonds. In addition,
alkylated pyridines can be made through decarboxylative coupling reactions or using
an alkylation=double decarboxylation strategy.[5]
On the other hand, we and others have disclosed the transition-metal-catalyzed
reductive coupling reactions of two electrophiles, which afford an alternative choice
by facile carbon–carbon bond formation without prepreparation of organometallic
nucleophiles.[6,7] The pre-installation of halides on to the specific pyridyl carbon pos-
ition allows easy access to differently substituted pyridines.[7h,8] In 2012, our group
reported an efficient Ni-catalyzed method for the reductive coupling of aryl halides
with secondary alkyl bromides, in which 2-bromopyridine, as an example of hetero-
aromatic compound, provided a yield of 38% of the desired product.[8] Following
this work, Weix and coworkers revealed a similar Ni-catalyzed cross-electrophile
coupling of halogenated pyridines with alkylated halides.[9] However, Weix’s work
is mainly limited to primary bromides; there is only one example of secondary alkyl
bromide, namely, cyclohexyl bromide, which was disclosed for the coupling with
2-bromopyridine. With 2 equiv of cylcohexyl bromide, 2-cyclohexylpyridine was
obtained in 48% yield. This is not surprising, as secondary alkyl halides are generally
more difficult in the transition-metal-catalyzed reactions due partially to sterically
more hindrance. In addition, the use of bromopyridines in that work appears
to be less effective; only 26% yield for the coupling of 2-bromopyridine with
1-bromooctane was obtained.[7h]
Considering the potential value of application of alkylated pyridines, further
studies of the alkylation of halogenated pyridines with emphasis on more sterically
hindered secondary alkyl halides are nontrivial. In this article, we present our con-
tinuing efforts to the studies of Ni-catalyzed reductive coupling of secondary alkyl
bromides with a variety of bromo-substituted pyridine derivatives. Our results are
complementary to the concurrent reductive alkylation of halo-pyridines with alkyl
halides.
RESULTS AND DISCUSSION
To begin with, the coupling of 2-bromopyridine (1a) with 4-bromo-1-tosylpi-
peridine (2a) was chosen as the model reaction. After considerable efforts, we
eventually determined the optimal conditions, namely, 1 equiv of 1a and 2 equiv
of 2a in the presence of NiBr2 (10 mol%), 4,40-di-tert-butyl-2,20-bipyridine 4a
(10 mol%), and additives MgCl2 (100 mol%)=pyridine (1:1) and Bu4NBr (50 mol%)
in dimethylacetamide (DMA) at 30 ꢀC. These conditions provided the coupling
product (3a) in a 70% yield (shown in Table 1, entry 1). With 1.0 equiv. of Bu4NBr,
other ligands such as 4b–9 (shown in Fig. 1) were less effective than 4a, which was
able to generate the desired product in 58% yield (entries 2–13). When the ligand
loading was reduced to half (from 20% to 10%), the yield only showed a little
decrease (from 58% to 55%, entries 13 and 14). Therefore, 10 mol% of ligand loading
was chosen, due to lower cost. Other nickel sources such as Ni(COD)2 were not

Ni-CATALYZED REDUCTIVE CROSS COUPLING
3001
Table 1. Screening of conditionsa
Entry
Variation from the ‘‘standard’’ conditions
Yield of 3a (%)b
1
2c
None
70
51
51
50
56
49
41
36
52
46
55
20
58
55
46
45
Trace
40
46
50
59
12
43
1 equiv. of Bu4NBr; 4b instead of 4a
1 equiv. of Bu4NBr; 4c instead of 4a
1 equiv. of Bu4NBr; 4d instead of 4a
1 equiv. of Bu4NBr; 5a instead of 4a
1 equiv. of Bu4NBr; 5b instead of 4a
1 equiv. of Bu4NBr; 5c instead of 4a
1 equiv. of Bu4NBr; 6 instead of 4a
1 equiv. of Bu4NBr; 7a instead of 4a
1 equiv. of Bu4NBr; 7b instead of 4a
1 equiv. of Bu4NBr; 8 instead of 4a
1 equiv. of Bu4NBr; 9 instead of 4a
1 equiv. of Bu4NBr
3c
4c
5c
6c
7c
8c
9c
10c
11c
12c
13c
14
15
16
17
18
19
20
21
22
23
1 equiv. of Bu4NBr
1 equiv. of Bu4NBr; Ni(COD)2 instead of NiBr2
1 equiv. of Bu4NBr; DMF instead of DMA
1 equiv. of Bu4NBr; THF instead of DMA
Reaction run at 0 ꢀC
Reaction run at 50 ꢀC
0.5 equiv. of pyridine
1.5 equiv. of pyridine
No MgCl2
0.1 equiv. of Bu4NBr
aReaction conditions: 1a (0.15 mmol, 100 mol%), 2a (0.30 mmol, 200 mol%), NiBr2 (10 mol%), ligand
(10 mol%), Zn (300 mol%), Bu4NBr (50 mol%), MgCl2 (0.15 mmol)–pyridine (1:1), and DMA (1 mL).
bIsolated yield.
c20% ligand was used.
Figure 1. Structures of the ligands.

3002
H. LIU ET AL.
Table 2. Scope of the cross coupling of halogenated pyridines with secondary alkyl bromidesa
Entry
Reactant
Halopyridine
Product
Yield (%)b
=
=
1
2
X
Br 70
X
Cl 42
3
4
45
41
=
5
6
X
X
Br 68
Cl 38
=
7
8
61
60
9
50
10
11
64
55
12
27
(Continued )

Ni-CATALYZED REDUCTIVE CROSS COUPLING
3003
Table 2. Continued
Entry
13
Reactant
Halopyridine
Product
Yield (%)b
21
18
(dr > 20:1)
14
15
16
27
31
17
18
<10
<10
19
20
Trace
Trace
aReaction conditions: alkyl bromide (0.15 mmol), halogenated pyridine (0.30 mmol, 200 mol%), NiBr2
(10 mol%), ligand (10 mol%), Zn (300 mol%), Bu4NBr (50 mol%), MgCl2 (0.15 mmol)–pyridine (1:1),
DMA (1 mL).
bIsolated yield.
satisfactory (entry 15). The use of solvents other than DMA gave the product in poor
yields or with trace amount (entries 16 and 17). Varying the reaction temperature
was not successful (entries 18 and 19). Use of 1.5 equiv pyridine gave the product
3a in 59% yield, which was greater than that with 0.5 equiv of pyridine (entries 20
and 21). We reasoned that pyridine here also serves to promote the reactivity
through the combination with a bidentate ligand.[8] Without MgCl2, a significant
decrease of the yield was observed (entry 22). Finally, variation of the loading of

3004
H. LIU ET AL.
Bu4NBr with 0.1 equiv and 0.5 equiv disclosed that the latter resulted in a dramatic
increase of the yield to 70% (entries 1 and 23). We speculated that the role of MgCl2
and Bu4NBr is possibly to activate zinc powder by removal salts on its surface. How-
ever, it is also possible that MgCl2 can affect the dielectric nature of the solvent, and
possibly coordinates with the Ni intermediates.[10]
With the optimized conditions in hand, the limitation and scope of the haloge-
nated pyridines were examined, as shown in Table 2. In general, chloropyridines
were less effective (entries 2 and 6). The coupling of 1a with 2-bromo-3- and
2-bromo-4-mehtyl pyridines gave moderate yields (entries 3 and 4). When
2-bromo-2,3-dihydro-1H-indene was exposed to 2-bromopyridine, the yields had
an increase about 10% (entries 7 and 10). For the cross coupling of 2-bromo-2,3-
dihydro-1H-indene with 2-bromopyridine, the yield was comparable to that
obtained from 1a (entry 5). For 3-bromopyridine and 2-methyl-4-bromopryidine,
68% and 61% of the coupling products were obtained (entries 7 and 8). With
2-bromopyridines bearing 4-methyl, 5-methyl, and 5-methoxy substituents, good
results were generated (entries 9–11). However, 6-methyl-2-bromopyridines only
gave rise to a very poor yield, probably due to the sterical hindrance (entry 12). In
contrast, when electron-withdrawing groups such as CF3 were introduced, the coup-
ling yield was reduced significantly; the product was obtained in only 21% yield
(entry 13). The sterically more hindered trans-2-bromocyclopentyloxy (tert-butyl)
dimethylsilane only yielded the desired product in 18% yield (entry 14). The
open-chain secondary bromide seemed to be less efficient (entries 15 and 16). Next,
we also compared the coupling efficiency for the coupling of bromocyclohexane with
2-bromopyridine using our conditions with Weix’s result. Unfortunately, a very poor
Scheme 1. Proposed reaction mechanism for Py-Ralkyl formation.

Ni-CATALYZED REDUCTIVE CROSS COUPLING
3005
Scheme 2. Reductive coupling of bromomethylcyclopropane with 1-bromopyridine.
yield was observed (entries 17), suggesting that this reductive coupling conditions
were substrate sensitive, with those alkyl halides bearing electronegative functional-
ities being more effective. Indeed the coupling of 2-bromopropane revealed similar
result as that from bromocyclohexane (entry 18). Finally, we also tested the compati-
bility of other heteroaryl halides such as 2-bromoquinoline and 2-bromothiophene,
and only trace amounts of the desired products were detected (entries 19 and 20).
Overall, it appears that the coupling conditions are sensitive to the both alkyl halides
and pyridyl bromides with different substitution patterns and electronic properties.
Given the difficulties of preparation of alkylated pyridines, this work may still find
interesting applications for compounds of interest.
According to the recent mechanistic studies from Weix’s Ni-catalyzed reductive
coupling of aryl and alkyl halides, it appears that oxidative addition of pyridyl bro-
mide to Ni(0) forming Py-Ni(II)-Br proceeds faster than that of alkyl bromide to
Ni(0).[11] Initiation of the reaction was achieved when the Py-Ni(II)-Br intermediate
abstracts bromine from alkyl bromide to generate Py-Ni(III)-(Br)2, and the alkyl
radical then adds to Py-Ni(II)-Br, giving Py-Ni(III)-(alkyl)-Br, which undergoes
reductive elimination to give the Py-alkyl product and Ni(I). Halide abstraction of
alkyl bromide by the Ni(I) produces Ni(II)-Br2 and alkyl radical. While the alkyl
radical undergoes radial addition to Py-Ni(II)-Br, the Ni(II)-Br2 is reduced by Zn
to regenerate Ni(0), which undergoes oxidative addition by Py-Br (Scheme 1). Indeed
the radical property of this coupling event was evidenced in the coupling of bromo-
methylcyclopropane with 1-bromopyridine where only a ring opening product was
observed, albeit with a poor yield (Scheme 2).
CONCLUSIONS
In conclusion, we have disclosed a method for the cross coupling of differently
substituted pyridines with secondary alkyl bromides, which provides a complemen-
tary solution to the unreported examples in the previous studies on alkylation of
halo-pyridines. Although the alkyl substrate scope has limited to those bearing
electronegative functional groups, the current conditions are still convenient for
relevant pyridine ring alkylation.
EXPERIMENTAL
All reactions were carried out under an atmosphere of nitrogen. All NMR
spectra were recorded on Bruker Avance 500-MHz spectrometer at STP unless
otherwise indicated. High-resolution mass spectra (HRMS) were obtained using
an Agilent 7890-5975. Melting points were recorded on a micro-melting-point

3006
H. LIU ET AL.
apparatus (X-4, Yuhua Co., Ltd, Gongyi, China). Column chromatography was
performed using silica gel, 300–400 mesh (purchased from Qingdao-Haiyang Co.
China) as the solid support. Unless otherwise noted, all other reagents and starting
materials were purchased from commercial sources and used without further
purification. 4-Bromo-1-tosylpiperidine and 2-bromo-2,3-dihydro-1H-indene were
synthesized according to the literature procedures.
A flame-dried Schlenk tube equipped with a magnetic stir bar was loaded with
alkyl bromide (0.15 mmol, 100 mol%, solid), halogenated pyridine (0.30 mmol,
300 mol%, solid), ligand (0.015 mmol, 10 mol%), and zinc powder (0.45 mmol,
300 mol%). The tube was capped with a rubber septum and moved to a dry glove
box, to which NiBr2 (0.015 mmol, 10 mol%), MgCl2 (0.15 mmol, 100 mol%), and
Bu4NBr (0.075 mmol, 50 mol%) were added. Then the tube was moved out of the
glove box. Alkyl bromide (0.15 mmol, 100 mol%, liquid), halogenated pyridine
(0.30 mmol, 300 mol%, liquid), pyridine (0.15 mmol, 100 mol%), and DMA
(1.0 mL) were added via syringe. After the reaction mixture was allowed to stir over-
night under N2 atmosphere at 30 ꢀC, it was directly loaded onto a silica column with-
out workup. The residue in the reaction vessel was rinsed with small amount of
DCM or eluent. Flash column chromatography provided the product as solid or oil.
ACKNOWLEDGMENTS
Hongmei Deng (Shanghai University) is thanked for use of the NMR facility.
FUNDING
Financial support was provided by the Chinese NSF (Nos. 2097209 and
21172140), the Program for Professor of Special Appointment (Eastern Scholar)
at Shanghai Institutions of Higher Learning, Shanghai Education Committee (No.
10YZ04), and Shanghai Leading Academic Discipline Project (No. S30107).
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
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