Chromium-Catalyzed Regioselective Hydropyridination of Styrenes

Article abstract of DOI:10.1021/acs.organomet.5b01021

The first chromium-catalyzed regioselective addition of para-C-H bonds of pyridines across styrenes is disclosed. The hydrofunctionalization reaction was promoted by a low-cost chromium(III) chloride combining with a cyclohexyl Grignard reagent and 2,2′-bipyridine, which allows for the highly selective formation of branched products via the cleavage of inert C-H bonds of pyridines.

Full text of DOI:10.1021/acs.organomet.5b01021

Article
pubs.acs.org/Organometallics
Chromium-Catalyzed Regioselective Hydropyridination of Styrenes
Yuexuan Li, Gongda Deng, and Xiaoming Zeng*
Center for Organic Chemistry, Frontier Institute of Science and Technology, Xi’an Jiaotong University, Xi’an, Shaanxi, 710054, P. R.
China
S
* Supporting Information
ABSTRACT: The first chromium-catalyzed regioselective
addition of para-C−H bonds of pyridines across styrenes is
disclosed. The hydrofunctionalization reaction was promoted
by a low-cost chromium(III) chloride combining with a
cyclohexyl Grignard reagent and 2,2′-bipyridine, which allows
for the highly selective formation of branched products via the
cleavage of inert C−H bonds of pyridines.
yridines are important structural motifs that exist in a
diverse range of pharmaceuticals, natural products, ligands,
triethylborane as a crucial additive for achieving high
regioselectivity.11,12
P
and materials.1 Thus, the development of straightforward, step-
economical strategies to achieve pyridine functionalization
gained broad interests of chemists.2,3 Among the various
methods for the modification of pyridines, the direct addition of
C−H bonds across unsaturated C−C bonds provides a
practical route to introduce a functional alkyl or alkenyl
substituent with 100% atom efficiency but remains a great
challenge because of the low reactivity of pyridine and the site-
selectivity issue.4 Compared to the remarkable achievements in
the transformation of ortho-C−H bonds of pyridines with Rh,5
Ru,6 Ni,7 Zr,8 and Ln catalysts,9 examples of hydropyridination
reaction by the direct addition of para-C−H bonds are still rare
(Scheme 1a). Nakao, Hiyama, and Ong’s pioneering work
disclosed the selective modification of pyridines via the
activation of para-C−H bonds with a nickel/Lewis acid
catalytic system.10 Cobalt-promoted alkylation of pyridines
was recently described by Matsunaga and Kanai by use of
In the past years, the employment of earth-abundant first-
row transition metals as alternatives to expensive late transition-
metal catalysts attracted immense attention for developing cost-
effective synthetic protocols.13,14 As one of the earth-abundant
sources,15 chromium salts have been widely used in the
promotion of ethylene oligomerization16 and classic Nozaki−
Hiyama−Kishi reactions,17 but their catalytic ability in the
cleavage of inert chemical bonds has rarely been inves-
tigated.18−21 Herein, we report a chromium-catalyzed selective
addition of pyridines across styrenes via the cleavage of para-
C−H bonds (Scheme 1b). This hydrofunctionalization reaction
was enabled by a simple, inexpensive chromium(III) chloride
combining with a Grignard reagent as reductant, leading to
branch-selective pyridine derivatives under mild conditions.
At the beginning, the effect of Grignard reagents on the
selective addition of pyridine into styrene was studied. Using a
mixture of CrCl2, 2,2′-bipyridine, and methyl Grignard reagent,
we were pleased to find that the branch-selective adduct 3a was
produced via the activation of the para-C−H bond of pyridine
(Table 1, entry 2). Replacement with an alternative cyclohexyl
Grignard resulted in an increased conversion (entry 3).
Interestingly, the employment of chromium(III) chloride
slightly improved the reaction, leading to 3a in 40% yield and
high branch selectivity (entry 4). Other ligands, including 4,4′-
di-tert-butyl bipyridine (dtbpy), 1,10-phenanthroline, 1,3-
dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU),
phosphines (S-Phos and Dppe), and N-heterocyclic carbene
(IPr), cannot improve the transformation (entries 5−10).
Common chromium salts such as Cr(acac)3 and Cr(CO)6 led
to a low conversion, implying an important anion effect in the
catalysis (entries 11 and 12). Further screening revealed that
the use of organic base as additive could dramatically increase
the reaction rate. A good result was obtained when using 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) (1.5 equiv) (entry
Scheme 1. Transition-Metal-Catalyzed Hydropyridination
Received: December 22, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.organomet.5b01021
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
a b
,
Table 1. Optimizing Reaction Conditions
c
entry
metal salt
ligand
R
additive
3a (%)
3a/4a
1
none
2,2′-bpy
2,2′-bpy
2,2′-bpy
2,2′-bpy
dtbpy
Me
Me
Cy
Cy
Cy
Cy
Cy
Cy
Cy
Cy
Cy
Cy
Cy
Cy
Cy
Cy
Cy
Cy
nd
9
2
CrCl2
CrCl2
CrCl3
CrCl3
CrCl3
CrCl3
CrCl3
CrCl3
CrCl3
Cr(acac)3
Cr(CO)6
CrCl3
CrCl3
CrCl3
CrCl3
CrCl3
CrCl3
CrCl3
CrCl3
CrCl3
Ni(cod)2
FeCl3
CoCl2
3
36
40
32
36
33
30
20
22
15
<2
48
43
50
63
76
54
nd
nd
nd
23
<5
20
4
>30:1
>50:1
>50:1
>30:1
>99:1
>50:1
>50:1
5
6
1,10-phen
DMPU
S-Phos
7
8
9
Dppe
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
IPr·HCl
IPr·HCl
IPr·HCl
2,2′-bpy
2,2′-bpy
2,2′-bpy
2,2′-bpy
2,2′-bpy
2,2′-bpy
2,2′-bpy
2,2′-bpy
2,2′-bpy
2,2′-bpy
2,2′-bpy
2,2′-bpy
d
d
d
>50:1
>50:1
>30:1
>30:1
>30:1
>30:1
Et3N (1.0)
DBU (1.0)
DBU (1.0)
DBU (1.5)
de
,
def
, ,
def
, ,
deg
, ,
nBuLi
DBU (1.5)
DBU (1.5)
DBU (1.5)
DBU (1.5)
DBU (1.5)
DBU (1.5)
deh
, ,
Zn
deg
, ,
DIBA-H
Cy
de
,
de
,
Cy
de
,
Cy
a
Conditions: 1a (0.5 mmol), 2a (0.65 mmol), Cr salt (0.05 mmol), RMgBr (0.5 mmol, 1.0 M in THF), ligand (0.05 mmol), additive (X equiv), 60
b
c
°C, 20 h. 1H NMR yield using dibromomethane as internal standard. The regioisomeric ratio was estimated by H NMR analysis of crude
1
d
e
f
g
h
products. 2,2′-Bipyridine (0.1 mmol) was employed. 80 °C. 48 h, isolated yield nBuLi or DIBA-H (0.25 mmol) was employed. Zn (1 mmol)
was employed.
17).22 It was worth mentioning that the hydrofunctionalization
was carried out with high site selectivity, typically producing
para- and branch-selective alkylated compounds. Notably,
forming a small amount of bicyclohexane as byproduct was
observed in these cases. The corresponding ortho- and meta-
alkylated products of pyridine, as well as the alkylation product
of 2,2′-bipyridine, were not detected. On the other hand, the
addition of pyridine to styrene did not take place by use of
nBuLi, zinc powder, or DIBA-H as reductive reagent (entries
19−21). Other first-row transition-metal salts including Ni-
(cod)2, FeCl3, and CoCl2 cannot improve the conversion under
the present conditions (entries 22−24).
Inspired by the results, the substrate scope was next
examined. As shown in Table 2, with a mixed CrCl3, 2,2′-
bipyridine, cyclohexylmagnesium bromide, and DBU, the
hydropyridination reaction using 4-methyl and tert-butyl-
substituted styrenes occurred effectively, leading to branched
compounds 3b and 3c in good yields (entries 2 and 3). The
incorporation of substituents of methyl and ethyl into the ortho-
position of pyridine has no obvious influence on the
transformation (entries 4−9). Strikingly, the hydrofunctional-
ization reaction with 3-methylpyridine took place smoothly,
suggesting that the steric hindrance around the para-C−H
bond does not hamper the efficiency of the conversion (entries
10−12). Similarly, introducing the electron-donating methoxy
group into the meta-position of pyridine allowed for forming
the branched adducts 3m−3p in moderate to good yields
(entries 13−16). Note that 2-phenylpyridine is suitable for the
hydrofunctionalization reaction with absolute cleavage of the
para-C−H bond of pyridine (entry 17). Moreover, the
reactions of 5,6,7,8-tetrahydroquinoline and 2,3-cyclopenteno-
pyridine with styrene provide easy access to the branched
products 3r and 3s (entries 18 and 19). However, the addition
of other N-heterocycles such as quinoline, pyrazine, and
pyrimidine across styrene does not take place in our case.
Further study shows that the hydrofunctionalization of
unactivated aliphatic alkene cannot form the desired adduct.
To gain insight into the mechanism, the deuterium
experiment was carried out by the treatment of 1a-d5 (>99%
D) with styrene (Scheme 2a). It was found that almost no
deuterium was lost at the electrophilic ortho-position of
pyridine. It may imply that a nucleophilic addition/rear-
omatization process can be excluded.11 Similar to the result of
Nakao/Hiyama’s reaction, only a trace amount of hydrogen was
detected at the meta-position of pyridine.10a We then
performed the intermolecular kinetic isotope effect (KIE)
experiment (Scheme 2b). A slightly lower value of 1.2 was
obtained, suggesting that the cleavage of the C−H bond of
pyridine may not be the turnover-limiting step. In the absence
of pyridine, forming ethylbenzene in 20% yield was observed
B
DOI: 10.1021/acs.organomet.5b01021
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
a b
,
Table 2. Cr-Catalyzed Hydropyridination of Styrenes
Scheme 2. H/D Scrambling Experiments
In summary, we have disclosed a new chromium-catalyzed
regioselective hydropyridination of styrenes by the cleavage of
para-C−H bonds of pyridines. It is the first time to
demonstrate that chromium possesses practical ability in the
activation of inert C−H bonds by dispensing with a Grignard
partner. This reaction provides a cost-effective strategy for the
direct functionalization of synthetically appealing pyridines.
Further mechanistic studies on the synthesis and character-
ization of active intermediates and exploring a plausible
reaction pathway are ongoing.
a
Conditions: 1 (0.5 mmol), 2 (0.65 mmol), CrCl3 (0.05 mmol), 2,2′-
bpy (0.1 mmol), CyMgBr (0.5 mmol, 1.0 M in THF), DBU (0.75
mmol), 80 °C, 48 h. Isolated yield. IPr·HCl (0.1 mmol) was
employed without DBU.
b
c
EXPERIMENTAL SECTION
■
General Procedure for Chromium-Catalyzed Hydropyridi-
nation of Styrenes. In a dried Schlenk flask were placed CrCl3 (8
mg, 0.05 mmol), 2,2′-bipyridine (16 mg, 0.1 mmol), pyridine (40 μL,
0.5 mmol), and DBU (112 μL, 0.75 mmol). Then, a solution of
cyclohexylmagnesium bromide in THF (0.5 mmol, 0.5 mL) was added
dropwise at 0 °C. After stirring for 30 min, styrene (75 μL, 0.65 mmol)
was added, and the reaction mixture was stirred at 80 °C for 48 h.
Subsequently, the mixture was cooled to room temperature and
quenched with a solution of NH4Cl. The crude product was extracted
with ethyl acetate and dried with anhydrous Na2SO4. After removing
the volatiles under vacuum, the residue was purified by flash silica gel
column chromatography (eluent: petroleum/EtOAc/Et3N = 25/5/1)
to give the adduct compound.
(eq 1). Notably, by treating pyridine with a benzyl Grignard
reagent under the standard conditions, only a trace amount of
the related coupling product 6 was obtained (eq 2). These
indicate that a pathway by forming a Grignard reagent with
styrene, followed by coupling with pyridine, may not be
involved in the transformation.12
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.5b01021.
■
S
C
DOI: 10.1021/acs.organomet.5b01021
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Detailed optimization data, experimental procedures, and
Article
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characterization data of all compounds (PDF)
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: zengxiaoming@mail.xjtu.edu.cn.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
Support for this work by the National Natural Science
Foundation of China [Nos. 21202128, 21572175] and XJTU
is gratefully acknowledged.
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DOI: 10.1021/acs.organomet.5b01021
Organometallics XXXX, XXX, XXX−XXX