Nickel-catalyzed sp2 C-H bonds arylation of N-aromatic heterocycles with Grignard reagents at room temperature

Article abstract of DOI:10.1039/c1cc14558d

A novel protocol for nickel-catalyzed direct sp² C-H bond arylation of purines has been developed. This new reaction proceeded efficiently at room temperature using Grignard reagent as the coupling partner within 5 hours in good to high yields.

Full text of DOI:10.1039/c1cc14558d

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COMMUNICATION
Nickel-catalyzed sp2 C–H bonds arylation of N-aromatic heterocycles
with Grignard reagents at room temperaturew
Gui-Rong Qu,*a Peng-Yang Xin,a Hong-Ying Niu,b Dong-Chao Wang,a Rui-Fang Dinga and
Hai-Ming Guo*a
Received 26th July 2011, Accepted 26th August 2011
DOI: 10.1039/c1cc14558d
A novel protocol for nickel-catalyzed direct sp2 C–H bond aryla-
tion of purines has been developed. This new reaction proceeded
efficiently at room temperature using Grignard reagent as the
coupling partner within 5 hours in good to high yields. This
approach provides a new access to a variety of C8-arylpurines
which are potentially of great importance in medicinal chemistry.
The bis(hetero)aryl moiety is a key structure motif in many
Scheme 1 Synthesis of bis(hetero)aryls via C–H activation.
advanced materials, natural products and other biologically
active compounds.1 Over the past few decades, transition
(such as arylzinc reagents,6 arylboron reagents7) as another
metal-catalyzed cross-coupling reactions that rely on the use
kind of coupling partners have received considerable attention
(Scheme 1, route c). Among them, Nakamura’s group6a,b and
Chatani’s group6c reported the direct arylation of heteroaromatic
compounds with arylzinc reagents as the coupling partners,
respectively. It is well known that either arylboron reagents or
arylzinc reagents are often prepared from the corresponding
magnesium or lithium species. Based on the review of the
related literatures, we found that there are only two reports on
the use of the arlymagnesium reagent as the coupling partner
to perform direct arylation of the sp2 C–H bond via C–H bond
activation. Professor Shi and co-workers8 reported a cobalt-
catalyzed direct cross-coupling reaction of Grignard reagent
with a nitrogen-containing arene possessing a directing group
through C–H transformation. In addition, Professor Nakamura9
reported an iron-catalyzed reaction of aryl Grignard reagent
with an olefin possessing a directing group via olefinic C–H
bond activation. So there remains much room to improve the
direct C–H arylation though a significant progress has been
made in recent years. For example, finding a new and broad
adaptable coupling partner without a directing group is still a
major challenge and will dramatically expand the scope of the
direct C–H arylation process. According to our study on
synthesis of purine analogues,10 herein, we report our investi-
gations aiming at the establishment of an alternative strategy
based on the use of aryl Grignard reagent as a new and
efficient coupling partner for nickel-catalyzed purine arylation
at room temperature.
of (hetero)aryl halides and organometallic reagents as pre-
activated substrates have become the standard method for the
synthesis of this kind of compounds (i.e., Suzuki–Miyaura,
Stille, Hiyama, Kumada, and Negishi reactions).2 This protocol
can afford various bis(hetero)aryl products, but the preparation
of preactivated substrates will add one or more additional
steps to the synthetic sequence and cause the formation of
byproducts. Therefore, transition-metal-catalyzed C–H bond
activation as a potentially green and efficient process has
received great attention over the past few years.3 Generally,
the direct C–H arylation of (hetero)arene is performed by a
coupling reaction of an unactivated (hetero)arene with a
coupling partner. As we know, (hetero)aryl halides as coupling
partners are widely used in the direct C–H arylation of
(hetero)arene (Scheme 1, route a).4 While these transformations
have been well developed, they suffer from strict reaction
conditions (such as long reaction time and high temperature)
and poor selectivities. (Hetero)arylation can also be performed by
coupling
two
unactivated
(hetero)arenes,
affording
bis(hetero)aryl products with high efficiency (Scheme 1, route b),5
but the reported methods are still restricted to a narrow
substrate scope and it is difficult to prevent the undesired
homodimer formations. In addition, organometallic reagents
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: guohm518@hotmail.com, quguir@sina.com;
Initially, we tried to optimize the catalytic system and reaction
conditions on the model reaction of 9-benzyl-6-methoxy-
9H-purine with phenylmagnesium bromide. Several classic catalysts
for transition-metal-catalyzed C–H functionalization reactions
were used in this experiment. As shown in Table 1, the reaction
Fax: +86 373 3329276; Tel: +86 373 3329255
b School of Chemistry and Chemical Engineering, Henan Institute of
Science and Technology, Xinxiang 453003, China
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/c1cc14558d
c
11140 Chem. Commun., 2011, 47, 11140–11142
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Table 1 Optimization of reaction conditionsa
Table 2 Direct C–H arylation of various purines with PhMgBra
Entry
R1
R2
R3
Product
Yieldb/%
Entry
Catalyst (mol %)
Oxidant (equiv.)
Conv.b (%)
1
2
3
4
5
6
7
8
OMe
OMe
OMe
OMe
OMe
OMe
OMe
Ph
Cl
Cl
Bn
Bn
H
H
Cl
H
H
H
H
H
H
Cl
H
H
H
Bn
3a
3b
3c
3d
3e
3f
3g
3h
3i
87
82
78
86
81
82
76
89
91
83
84
87
88
1c
2c
3c
4c
5c
6c
7
Pd(OAc)2 (30)
Pd(dppf)Cl2 (30)
Fe(acac)3 (30)
Ni(dppp)Cl2 (30)
NiCl2 (30)
Ni(acac)2 (30)
Ni(dppp)Cl2 (30)
Ni(dppp)Cl2 (30)
Ni(dppp)Cl2 (30)
Ni(dppp)Cl2 (30)
Ni(dppp)Cl2 (10)
Ni(dppp)Cl2 (20)
Ni(dppp)Cl2 (20)
Ni(dppp)Cl2 (30)
O2
O2
O2
O2
O2
O2
Trace
Trace
15
88(67)
21
38
58
52
46
100(89)
63(43)
81(61)
86(66)
100(87)
Phenethyl
Bn
Me
Et
n-Pr
Cyclopentyl
Me
Bn
Bn
Bn
n-Bu
Me
Oxone (3)
K2S2O8 (3)
K2Cr2O7 (3)
DCE (3)
DCE (3)
DCE (3)
DCE (5)
DCE (3)
8
9
9c
10d
11
12
13c
3j
3k
3l
10
11
12
13
14d
Benzylthio
3h
a
Reaction conditions: 0.125 mmol of 1, 5 equiv. of 2a, 30 mol% of
Ni(dppp)Cl2, 3 equiv. of 1,2-dichloroethane, and 1 mL of THF in a
a
Reaction conditions: 1a (0.125 mmol), 2a (0.625 mmol), THF
b
(1 mL), at room temperature, under a N2 atmosphere, 24 h. Deter-
b
Schlenk tube at rt for 5 h under a N2 atmosphere. Isolated yields.
c
d
6 equiv. of 2a was used. 8 equiv. of 2a was used.
mined by HPLC, and the yields in parentheses are isolated yields.
c
d
Under a O2 atmosphere. For 5 h.
arylation reaction occurred. This might be a good protocol to
provide multi-arylation products. Disappointedly, these reactions
with other N-aromatic heterocycles (such as benzimidazoles,
oxazoles, indoles, benzothiazoles etc.) did not work under present
optimal reaction conditions.
did not work with Pd(OAc)2 and Pd(dppf)Cl2 (entries 1–2).
When Fe(acac)3 was used as the catalyst, a minimal conversion
of 1a was observed (entry 3). The reaction gave a moderate
conversion of 1a in the presence of Ni(dppp)Cl2 (entry 4).
Therefore, we considered that nickel catalysts might be an
appropriate choice for this reaction. Then, other nickel catalysts
were tested, and none showed better activities than
Ni(dppp)Cl2 (entries 5–6), so we chose Ni(dppp)Cl2 as the
suitable catalyst. Next, we investigated the effect of oxidants.
Disappointedly, oxone, K2S2O8 and K2Cr2O7 did not give
acceptable conversions of 1a (entries 7–9). When we used
1,2-dichloroethane (DCE) as the oxidant, a full conversion was
obtained and the isolated yield of 3a reached 89% (entry 10).
Reducing the amount of the catalyst led to lower conversion of
1a even increasing the amount of the oxidant (entries 11–13).
Further screening of reaction time showed that 5 h was the
best choice (entry 14). Therefore, the optimal reaction conditions
involve in Ni(dppp)Cl2 as the catalyst, 1,2-dichloroethane as
the oxidant at room temperature for 5 h under a N2
atmosphere.
Intrigued by the results described above, a series of aryl
Grignard reagents were chosen as aryl agents to probe whether
the direct sp2 C–H bond arylation of purines could be easily
accessed. The results are shown in Table 3. As expected, the
reaction with various electron-donating substituted Grignard
reagents (i.e., p-Me, m-Me, p-Et, p-MeO and 3,5-dimethyl)
proceeded efficiently (entries 1–5, 74–89%) except that the yield
of the desired product 3r was somewhat low (entry 6, 42%),
which might be due to the steric hindrance of o-Me. The electron-
withdrawing substituted Grignard reagent (i.e., p-Ph) was also
tolerated under this novel coupling reaction and afforded the
targeted products in moderate yield (entry 7, 61%).
Interestingly, when (4-fluorophenyl)-magnesium bromide
was used as a coupling partner, the reaction proceeded to give
Table 3 Direct C–H arylation of 9-benzyl-6-methoxy-9H-purine with
various aryl Grignard reagentsa
To evaluate the generality of the reaction, this new direct C–H
arylation protocol was extended to a scope of purines, and the
results are shown in Table 2. A series of 6-methoxy-9-substituted
purines were subjected to the optimized reaction conditions and
the corresponding products were obtained in high yields (entries
1–7, 76–87%). And then, we investigated whether different types
of substituents at C-6 have impact on the yields. The results
demonstrated that different substituents at C-6, including chloro,
benzyl, benzylthio and phenyl, had little impact on the yields of
the products (entries 8–13, 83–91%). Interestingly, when
9-benzyl-6-chloro-9H-purine, 9-benzyl-2,6-dichloro-9H-purine
and 6-(benzylthio)-9-methyl-9H-purine were used as substrates,
the reactions proceeded to give the multi-arylation products in
good to high yields (entries 9–10, 13). In these reactions, both the
traditional Kumada cross-coupling reaction and the direct C–H
Entry
Ar
Product
Yieldb/%
1
2
3
4
5
6
7
4-Me-Ph
3-Me-Ph
4-Et-Ph
4-OMe-Ph
3,5-diMe-Ph
2-Me-Ph
4-Ph-Ph
3m
3n
3o
3p
3q
3r
85
82
89
74
87
42
61
3s
a
Reaction conditions: 0.125 mmol of 1a, 5 equiv. of 2, 30 mol% of
Ni(dppp)Cl2, 3 equiv. of 1,2-dichloroethane, and 1 mL of THF in a
b
Schlenk tube at rt for 5 h under a N2 atmosphere. Isolated yields.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 11140–11142 11141

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occurred as a second step.
A possible mechanism that accounts for C–H bonds arylation
of purine with Grignard reagents is presented in Scheme 3.
Combination of 1 and Ni(dppp)Cl2 provides the metalated
intermediate B. Subsequently, an (aryl)-nickel(II) intermediate
C is generated by transmetalation between aryl Grignard
reagent and the metalated intermediate B. Followed by
reductive elimination to produce the desired product 3, the
Ni(0) species D is generated, which is reoxidized to Ni(II)
species by DCE to complete the catalytic cycle.
In conclusion, a novel protocol for the nickel-catalyzed sp2
C–H bond arylation of purines with Grignard reagents has
been developed. To the best of our knowledge, this reaction is
the first example that uses Grignard reagent as the coupling
partner to perform direct sp2 C–H bond arylation of
N-aromatic heterocycles without a directing group. Further
investigation on the detailed mechanism and expanding this
novel method to broad spectrum substrates are underway in
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We are grateful for financial support from the National
Nature Science Foundation of China (Grant No. 20802016,
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
Changjiang Scholars and Innovative Research Team in University
(IRT1061), and the Excellent Youth Program of Henan
Normal University.
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11142 Chem. Commun., 2011, 47, 11140–11142
This journal is The Royal Society of Chemistry 2011