Nickel catalyzed alkylation of N-aromatic heterocycles with Grignard reagents through direct C-H bond functionalization

Article abstract of DOI:10.1039/c2cc32396f

A novel protocol for nickel-catalyzed direct sp² C-H bond alkylation of N-aromatic heterocycles has been developed. This new reaction proceeded efficiently at room temperature using a Grignard reagent as the coupling partner. This approach prov

Full text of DOI:10.1039/c2cc32396f

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Nickel catalyzed alkylation of N-aromatic heterocycles with Grignard
reagents through direct C–H bond functionalizationw
Peng-Yang Xin,a Hong-Ying Niu,b Gui-Rong Qu,*a Rui-Fang Dinga and Hai-Ming Guo*a
Received 3rd April 2012, Accepted 8th May 2012
DOI: 10.1039/c2cc32396f
A novel protocol for nickel-catalyzed direct sp2 C–H bond
alkylation of N-aromatic heterocycles has been developed. This
new reaction proceeded efficiently at room temperature using a
Grignard reagent as the coupling partner. This approach provides
new access to a variety of alkylated N-aromatic heterocycles which
are potentially of great importance in medicinal chemistry.
despite a few reports12 which are usually restricted to the
undesired isomerization products and poor yields.
Recently, as inexpensive and readily available catalysts, the
first-row transition metals have shown a strong competitiveness
in C–H bond functionalization chemistry.3c,8c,e,f Herein we report
our investigations aiming at the establishment of an alternative
strategy based on the use of an alkyl Grignard reagent as a new
and efficient coupling partner for directing group free N-aromatic
heterocycles alkylation with a nickel catalyst.
The (hetero)aryl moieties are important components in many
advanced materials, natural products and pharmaceutical drugs.1
Consequently, development of an efficient method for the synthesis
of diversely substituted (hetero)arenes has become a hot topic in
synthetic chemistry.2 To date, direct C–H bond functionalization
has been one of the most important strategies for the synthesis of
this kind of compounds. Transition metal-catalyzed direct C–H
bond arylation of (hetero)arenes has been used extensively in
organic synthesis over the past few years.3 And the direct C–H
bond alkenylation of (hetero)arenes also made significant progress
in recent years.4 But due to the easy b-H elimination of alkyl
species, the direct C–H alkylation of (hetero)arenes is still in its
incipient stage.5 Based on the review of related literature reports, we
found that most of the successful direct C–H alkylation examples
rely on the use of directing groups containing heteroatoms and give
ortho-alkylated products from alkyl halides,6 olefins7 or organo-
metallic reagents8 under transition metal catalysis. Generally, the
second-row transition metal catalysts are particularly needed for
these reactions, which participate in cyclometalation with various
directing groups to complete the anchoring process.9 While
these protocols can afford various ortho-alkylated products, these
directing groups are not easily removed from the desired products,
thus limiting the generality of the reaction. So development of a
directing group free procedure for the alkylation of an aromatic
C–H bond is of great significance. Recently, Yu et al.10 and others11
have successfully developed nondirected C–H bond arylation and
alkenylation procedures. However, the direct C–H bond alkylation
of (hetero)arenes without a directing group is still a challenge
We started our studies with the optimization of the catalytic
system and reaction conditions for the model reaction of 9-benzyl-
6-methoxy-9H-purine with cyclopentylmagnesium bromide. Several
classic catalysts for transition-metal-catalyzed C–H functionaliza-
tion reaction were tested in this experiment. As shown in Table 1,
the reaction did not work with Pd(OAc)2 and Fe(acac)3 (entries 1
and 2). When Ni(dppp)Cl2 was used as the catalyst, acceptable
conversion of 1a was obtained (entry 3). Therefore, other nickel
catalysts were tested, and none showed better activities than
Ni(dppp)Cl2 (entries 4 and 5), so Ni(dppp)Cl2 was the suitable
catalyst for this reaction. Then, the effect of the catalyst amount
was examined, and the results showed that reduction of the
amount of the catalyst led to lower conversion of 1a (entries 6
and 7). When we used 20% mol Ni(dppp)Cl2 and 8 equiv. of
cyclopentylmagnesium bromide, a full conversion was obtained
and the isolated yield of 3a reached 81% (entry 8). Disappointedly,
Table 1 Optimization of reaction conditionsa
Entry
Catalyst (mol%)
Conv. (%)b
1
2
3
4
5
6
Pd(OAc)2 (30)
Fe(acac)3 (30)
Ni(dppp)Cl2 (30)
NiCl2 (30)
Ni(acac)2 (30)
Ni(dppp)Cl2 (10)
Ni(dppp)Cl2 (20)
Ni(dppp)Cl2 (20)
Ni(dppp)Cl2 (10)
Trace
Trace
91 (74)
83 (58)
79 (51)
43
65
100 (81)
86 (67)
a College of Chemistry and Environmental Science, Key Laboratory of
Green Chemical Media and Reactions of Ministry of Education,
Henan Normal University, Xinxiang 453007, Henan, China.
E-mail: quguir@sina.com, guohm518@hotmail.com;
7
8c
9c
Fax: +86 373 3329276; Tel: +86 373 3329255
a
b School of Chemistry and Chemical Engineering, Henan Institute of
Science and Technology, Xinxiang 453003, China
Reaction conditions: 1a (0.125 mmol), 2a (0.625 mmol), DCE
(3 equiv.), THF (1 mL), at room temperature, under a N2 atmosphere,
b
24 h. Determined by HPLC, and the yields in parentheses are
c
isolated yields. 8 equiv. of 2a was used.
w Electronic supplementary information (ESI) available: Experimental
procedures, compound characterizations, and the copies of H NMR
1
and 13C NMR spectra. See DOI: 10.1039/c2cc32396f
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 6717–6719 6717

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when we reduced the amount of the catalyst to 10% mol, the lower
conversion of 1a was obtained even when increasing the amount of
cyclopentylmagnesium bromide to 8 equiv. (entries 9). Further
screening of reaction time showed that 24 h was the best choice.
Therefore, optimal reaction conditions involved Ni(dppp)Cl2
(20% mol) as the catalyst, 1,2-dichloroethane (3 equiv.) as the
oxidant and 8 equiv. of cyclopentylmagnesium bromide as the
coupling partner at room temperature for 24 h under a N2
atmosphere.
Table 3 Direct C–H alkylation of various benzimidazoles with
Grignard reagentsa
Entry
R
Alk-MgBr
Product
Yield/%b
1
2
3
Bn
5a
5b
5c
79
71
82
Phenethyl
Me
To evaluate the generality of the reaction, this new direct C–H
alkylation protocol was extended to a scope of purine derivatives,
and the results are shown in Table 2. Firstly, a series of purine
derivatives were subjected to the optimized reaction conditions and
the corresponding products were obtained in good to high yields
(entries 1–6, 75–91%). As expected, different types of substituents
at C-6 and N-9 had little impact on the yields of the products.
When 6-chloro-9-cyclopentyl-9H-purine was used as a substrate,
the traditional Kumada cross-coupling reaction and direct C–H
alkylation reaction occurred simultaneously to give the multi-
cyclopentyl product in good yield (entry 5, 77%). And then, a
series of alkyl Grignard reagents were chosen as coupling partners
to probe whether the direct sp2 C–H bond alkylation of purines
could be easily accessed. To our delight, the reaction with different
primary and secondary alkyl magnesium bromides proceeded
efficiently (entries 7–10, 53–94%).
4
5
6
n-Pentyl
Bn
5d
5e
5f
68
57
86
Bn
7
8
Bn
Bn
5g
5h
61
47
a
Reaction conditions: 0.125 mmol of 4, 8 equiv. of 2, 20 mol% of
Ni(dppp)Cl2, 3 equiv. of 1,2-dichloroethane, and 1 mL of THF in a
b
Schlenk tube at rt for 24 h under a N2 atmosphere. Isolated yields.
When we used i-PrMgBr as a coupling partner to perform this
reaction, a mixture of 1-benzyl-2-isopropyl-1H-benzoimidazole
(5i, 29% yield) and 1-benzyl-2-propyl-1H-benzoimidazole
(5j, 36% yield) was obtained (Scheme 1), which might be
due to the b-hydride elimination of i-PrMgBr.
Other N-aromatic heterocycles such as benzothiazole were
also tolerated by this novel coupling reaction and afforded the
target product 7 (21%, Scheme 2).
Intrigued by the results described above, various benzimidazole
derivatives were chosen as substrates to probe the generality of this
direct sp2 C–H bond alkylation reaction. The results are shown in
Table 3. Fortunately, various N-1 substituted benzimidazoles
could be cyclopentylated in good to high yields (entries 1–4,
68–82%). And the reactions between 1-benzyl-1H-benzoimidazole
and various alkyl Grignard reagents also smoothly gave satisfactory
yields (entries 5–8, 47–86%).
Interestingly, we got a minimal amount of product 5k (o5%)
as well as the desired product 5 when we used benzimidazole
derivatives as substrates to evaluate the generality of the reaction.
In accord with the established precedent mechanisms in previous
studies,13 a possible mechanism that accounts for C–H bonds
alkylation of N-aromatic heterocycles with Grignard reagents
is presented in Scheme 3. A combination of 4 and Ni(dppp)Cl2
provides the metalated intermediate B. Subsequently, an
(alkyl)-nickel(II) intermediate C is generated by transmetalation
between alkyl Grignard reagents and the metalated intermediate
B. Followed by reductive elimination to produce the desired
product 5, the Ni(0) species D is generated. We speculate
that most of Ni(0) species D is reoxidized to Ni(II) species by
DCE, but a minimal amount of Ni(0) species D conducts oxidative
Table 2 Direct C–H alkylation of various purines with Grignard reagentsa
Entry R1
R2
Alk-MgBr Product Yield/%b
1
2
3
4
5
6
OMe
Bn
3a
3b
3c
3d
3e
3f
81
87
91
75
77
89
OMe
OMe
OMe
Cl
Me
Et
Cyclo-pentyl
Cyclo-pentyl
4-Ethyl-phenyl Bn
7
8
OMe
OMe
Bn
Bn
3g
3h
76
72
Scheme 1 Direct C–H alkylation of 1-benzyl-1H-benzoimidazole
with i-PrMgBr.
OMe
Bn
3i
3j
94
53
9
10
4-Ethyl-phenyl Bn
a
Reaction conditions: 0.125 mmol of 1, 8 equiv. of 2, 20 mol% of
Ni(dppp)Cl2, 3 equiv. of 1,2-dichloroethane, and 1 mL of THF in a
b
Schlenk tube at rt for 24 h under a N2 atmosphere. Isolated yields.
Scheme 2 Direct C–H alkylation of benzothiazole with cyclopentyl-
magnesium bromide.
c
6718 Chem. Commun., 2012, 48, 6717–6719
This journal is The Royal Society of Chemistry 2012

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addition by an sp2 C–H bond to give nickel hydride F through
Z2-arenenickel E. A combination of ethylene and nickel hydride F
gives vinylarenes G. Then, hydronickelation of vinylarenes G
provides metalated intermediate H, which then produces the
product 5k by reductive elimination.
In conclusion, a novel protocol for the nickel-catalyzed sp2
C–H bond alkylation of N-aromatic heterocycles with Grignard
reagents has been developed. Different types of heterocycles are
compatible under these mild reaction conditions. To the best of
our knowledge, this reaction is the first example that uses
Grignard reagents as coupling partners to perform direct sp2
C–H bond alkylation of N-aromatic heterocycles without a
directing group. And this protocol will dramatically expand the
scope of a direct C–H alkylation process. Further investigation of
the detailed mechanism and expansion of this novel method to a
broad spectrum of substrates are underway in our laboratory.
We are grateful for financial support from the National
Nature Science Foundation of China (Grant No. 21072047,
and 21172059), the Program for New Century Excellent Talents
in University of Ministry of Education (No. NCET-09-0122),
Excellent Youth Foundation of Henan Scientific Committee
(No. 114100510012), the Program for Innovative Research
Team in University of Henan Province (2012IRTSTHN006),
the Program for Changjiang Scholars and Innovative Research
Team in University (IRT1061), and Foundation for University
Key Teacher by Henan Province (No. 2011GGJS-132).
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c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 6717–6719 6719