DOI: 10.1002/chem.

201500639

Communication

& Synthetic Methods

Carboxylate Assisted Ni-Catalyzed CH Bond Allylation of

Benzamides
Nagaraju Barsu, Deepti Kalsi, and Basker Sundararaju*[a]
Abstract: A one-step synthetic method was developed for
allylation of benzamides using Ni(COD)2/RCO2H and [Ni(mH2O)(OOCCMe3)2(HOOCCMe3)2]2 (A) catalytic system. Efficient, well-defined, air and moisture-stable Nipivalate
complex was isolated and employed in catalytic allylation.
The influence of solvent on product selectivity was also investigated.

Functionalization of CH bonds is an active area of research

which became more intense after the discovery of catalytic C
H bond functionalization using precious metal catalyst[1, 2] developed by Murai et al. However, the recent focus on developing synthetic methodology for various functionalizations using
inexpensive and more abundant metal catalysts is a challenging
task.[3] In particular nickel catalysts attract interest as Ni0 species offer facile oxidative addition and nickel complexes provide accessible variable oxidation states which are key requirements for effective catalysts, successfully employed in numerous novel transformations.[4] Importance of bidentate chelate
assisted activation/functionalization of CH bond was introduced by Daugulis and co-worker.[5] Contributions for further
development of this approach using nickel catalyst by Chatani
et al. and others appear very promising.[6, 7] Although emerging
results with these catalysts are encouraging, the use of nickel
catalysts for chemical transformation is quite rare, likely due to
the lack of understanding of the mechanism and reaction
pathway as compared to precious metal catalysts. Owing to
the advantage of the allyl group for various useful synthetic
modifications in functionalization of the C=C bond and alkene
metathesis, assessment of an efficient approach to introduce
an allyl moiety without isomerization has attracted much attention for numerous regio- and stereoselective transformations.[8] In addition, allyl arenes are found to be in various natural products and biologically active compounds.[9] The existing
methodology available for allylation of arene requires reactive
organometallic reagent for cross coupling, which suffers from
functional group tolerance. Chelate-assisted CH bond allylation is known with Rh and Fe metal complexes, however reports based on nickel catalysts are rare in the literature.[10] Cha[a] N. Barsu, D. Kalsi, Prof. B. Sundararaju
Department of Chemistry
Indian Institute of Technology Kanpur, Kanpur (India)
E-mail: basker@iitk.ac.in
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201500639.
Chem. Eur. J. 2015, 21, 9364 9368

tani et al. showed in the course of alkylation of arene with NiII/

PPh3 catalysts, only one example of allylation with allyl bromide.[7a] In this line, we report now a novel synthetic method for
allylation of arenes using nickel-carboxylate[11] catalyst without
significant isomerization. Allylation of benzamides with 8-aminoquinoline (NHQ) as a bidentate auxiliary directing group in
the presence of Ni(COD)2 as a catalyst precursor along with
carboxylic acid, progress remarkably.
To find out functional group tolerances and their regioselectivity using nickel as a catalyst various nickel precursors were
screened (Table 1). Among all Ni(COD)2 (10 mol %) in combination with m-toluic acid as a co-catalyst (20 mol %) with amide
1 a (0.1 mmol), allyl bromide 2 (0.3 mmol) and Na2CO3 in DMF
at 140 8C (oil-bath temperature) for 18 h gave complete conversion with 89 % isolated yield of o-allylated amide 3 a along
with isomerized product 4 a in 11:1 ratio (Table 1, entry 6).[12]
Further screening of the solvent revealed that complete conversion was achieved with DMA and o-xylene (Table 1, entry 9
and 10), whereas toluene gave only 15 % conversion (entry 1,
Table S2 in the Supporting Information). Replacement of mtoluic acid by a sterically hindered acid such as pivalic acid,
1,3,5-trimethylbenzoic acid and adamantyl carboxylic acid gave
complete conversion with a similar 3 a/4 a ratio. The allylation
reaction was unsuccessful upon changing the allylic substrate
from bromide to chloride or carbonate or alcohol. Switching
the base from Na2CO3 to KHCO3 did not alter the outcome of
the allylation reaction and complete conversion was also observed. Further optimization revealed that the reaction goes
for completion in 6 h (entry 11, Table 1). While our studies were
ongoing, allylation reaction of functional arene using allyl
phosphate as a coupling partner with Ni(COD)2/PCy3 catalytic
system was reported.[7g] The reaction performed under our reaction condition using allyl phosphate did not give us the expected product 3 a. This clearly emphasizes that the synthetic
method (or the catalyst) developed by us is distinctly different
from the recent report with better yield and product selectivity.[7g]
In order to enlarge the scope of the developed synthetic
method, various substituted arenes were investigated in detail
(Table 2). Good yields were obtained while employing electrondonating substituent on the arene ring 3 bc (7487 %) compared with electron-withdrawing substituent 3 dg (3653 %).
Further, we noticed that allylation occurs on a less hindered
site of arene when meta-substituted benzamides were employed which is likely due to steric influence of 3 bc, 3 f. Allylation reaction works remarkably with heteroaromatic amide in
moderate yield of 3 h (46 %).

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Communication
Table 1. Optimization of allylation of benzamide with allyl bromide.[a]

Entry[a]

[Ni]

R-CO2H

T [8C]

1
2
3
4
5
6
7
8
9
10
11
12
13

Ni(acac)2
Ni(OAc)2
NiCl26 H2O
Ni(OTf)2
Ni(OH)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(OTf)2

m-toluic acid
m-toluic acid
m-toluic acid
m-toluic acid
m-toluic acid
m-toluic acid
Mes-CO2H
pivalic acid
m-toluic acid
m-toluic acid
m-toluic acid
PCy3
PPh3

140
140
140
140
140
140
140
140
140
140
140
140
140

3 a/4 a[b]

1.3:1
1.1:1
3:1
10:1
11:1
11:1
10:1
6:1
2:1
11:1
13:1
12:1

Table 3. [Ni]-catalysed bis allylation of benzamide.

Yield [%][c]
n.r.[d]
53
66
68
85
89
> 99[e]
> 99[e]
> 99[e, f]
> 99[e, g]
> 99[h]
89[e]
72[e]

[a] All reactions were carried out in nitrogen atmosphere using 1 a/2/[Ni]/
acid/base in 0.2/0.6/0.02/0.04/0.4 mmol in 1 mL DMF at 140 8C (oil-bath
temperature) for 18 h. [b] Ratio was determined by 1H NMR spectroscopy
from crude mixture. [c] Isolated yield of amide 3 a. [d] No reaction.
[e] Conversion instead of yield, calculated using gas chromatogram in the
presence of dodecane as an internal standard. [f] Dimethyl acetamide
used as a solvent. [g] o-Xylene used as a solvent. [h] Reaction was carried
out in 6 h.

[a] All reactions were carried out in nitrogen atmosphere using 1 a/2/
Ni(COD)2/3-methylbenzoicacid/base in 0.2/1.0/0.02/0.04/0.4 mmol in 1 mL
solvent at 140 8C (oil-bath temperature) for 22 h; [b] 20 mol % of 2,4,6-trimethyl benzoic acid used.

Next we further extended the reaction scope with other allylic substrates. Undeniably the reaction worked well when
other allylic substrates were employed, in moderate
to good yield. All reactions were regioselective and
Table 2. Optimization of allylation of benzamide with allyl bromide.
linear isomers were obtained in a mixture of stereoisomers 3 il. Addition of CH2 group in 1 i between
benzene and carbonyl group of amide did not give
any conversion reflecting the necessity of the alphasubstituent next to the carbonyl group. Homocoupling reaction is preferred over the desired allylation
when the reaction is performed with cinnamyl bromide and 1 a under the optimized reaction conditions. Changing the reaction parameters such as temperature, time or solvent did not give us the desired
results with our catalytic system.
Selective bis-allylation of CH bonds of benzamide
is difficult to perform under normal circumstances, as
it often tends to give a mixture of mono- and bis-allylated amide. Selective bis-allylated amide is of interest for acyclic diene metathesis (ADMET) polymerization. Our investigation revealed that bis-allylation
could be possible by switching solvent from DMF to
NMP (N-methylpyrrolidine) with various benzamide
and allyl bromides at 140 8C for 18 h. Bis-allylated
electron-rich aromatic amides were obtained as
major compounds in good yield (6190 %; Table 3).
Electron-poor aromatics gave complete conversion
but resulted in a mixture of mono- and bis-allylated
product.
The developed synthetic methodology for mono[a] All reactions were carried out in Nitrogen atmosphere using 1 a/2/[Ni]/3-methylbenzoic acid/base in 0.2/0.6/0.02/0.04/0.4 mmol in 1 mL solvent at 140 8C (oil-bath
allylation was tested for bulk-scale production and it
temperature) for 18 h; [b] 20 mol % of 2,4,6-trimethyl benzoic acid used. [c] In parenworked excellently with an expected allylated prodthesis ratio of 3:4.
uct in 70 % yield (Scheme 1). Several control experi-

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2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication

Scheme 1. Gram-scale synthesis of CH allylated benzamide.

ments were conducted to understand the reaction pathways

and mechanism.
Competitive experiments performed with electron-rich and
electron-poor amide using allyl bromide under our reaction
conditions show that allylation is favoured with electron-rich
substrates (Scheme 2 a). The reaction performed in the presence of excess 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO;
3 equiv) did not affect the product formation, which may possibly explain the non-radical reaction pathway involved in the
catalytic cycle (Scheme 2 b).
We next, turned our attention to the isolation of the in situ
Scheme 2. Control experiments.
formed nickel-carboxylate complex either from nickel(0) or
nickel(II) precursors. Numerous attempts made to isolate the in
situ formed nickel-carboxylate complex from Ni(COD)2 were
with RCO2H of NiN bond to give 3 with the regeneration of
not successful. The reaction conditions utilized in optimization
catalyst.
enforced us to try nickel(II) precursor. Nickel hydroxide with
In summary, we have reported a novel carboxylate-assisted
pivalic acid (excess) in toluene at reflux conditions in 3 h
allylation of various benzamides using nickel(II) catalyst, easily
guided us to stabilize the air and moisture-stable [Ni(mmade on addition of RCO2H to Ni(COD)2 and a preformed
[Ni(m-H2O)(OOCCMe3)2(HOOCCMe3)2]2 (A) catalyst. The develH2O)(OOCCMe3)2(HOOCCMe3)2]2 dimer complex A, which is in
accord with the reported literature.[13] The isolated complex
oped phosphine-free synthetic methodology is much more
convenient than the existing synthetic methods.[7a, g] Moreover,
was further tested for catalytic allylation of 1 a with allyl bromide and gave the expected product in 74 % yield without any
the reported reaction conditions are suitable for various substiisomerization in 5 h as compared with the reported Ni(OTf)2/
tuted arenes. Air and moisture-stable nickelpivalate complex
was isolated and the activity was examined in allylation reacPPh3[7a, h] or Ni(COD)2/PCy3[7g] catalytic systems requiring 24
tions. Also, we have shown the influence of solvent on achiev30 h, respectively (Scheme 3). The isolated nickel pivalate cataing bis-allylated product, which is extremely rare in the literalyst A was efficient when we employed with other substrate
ture. To fine-tune the catalytic activity and understand the role
with shorter reaction time compared with the in situ nickel catalyst. Final conclusions cannot be drawn at this stage
regarding whether the in situ formed complex is
monomeric or dimeric in nature. Further stoichiometric reactions are currently underway to find the active
species.
Based on the above observation, a proposed
mechanism for the CH allylation of amide is given
in Scheme 4. This was based on the high catalytic activity observed both with Ni0 and NiII precatalysts
during our screening (Table 1). The formation of the
active catalytic species Ni(OCOR)2 (A) was proposed
to form either from Ni0 (Path I)[13b] or NiII species
(Path II).
Amide 1 a is expected to coordinate with complex
A through N,N coordination to generate B, which
upon base-assisted deprotonation of CH bond provides reversible cyclometallated complex C. High
valent cationic p-allyl nickel(IV) complex D is expected to be formed from intermediate C with allyl bromide through oxidative addition.[7a, h] Complex D undergoes subsequent reductive elimination leading to
intermediate E or E which then undergo protonation Scheme 3. CH allylation of amide with isolated Nipivalate complex A.
Chem. Eur. J. 2015, 21, 9364 9368

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2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication

Scheme 4. Proposed mechanism.

of solvent in promoting bis-allylation and its detailed reaction

mechanism further studies are required which are currently in
progress.

[6]

Acknowledgements
[7]

B.S. wishes to thank the Indian Institute of Technology Kanpur

for financial support (IITK/CHM/20130187). D.K. and N.B. acknowledge IITK and CSIR for their fellowships, respectively. We
thank Johnson Matthey for their generous support of metal
precursors. We wish to thank Prof. V. Chandrashekar for allowing us to use his lab facilities.
Keywords: allylation catalysts CH bond activation nickel
synthetic methods

[8]
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Received: February 14, 2015

Published online on May 26, 2015

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