Nickel-Catalyzed Benzylic Substitution of Benzyl Esters with Malonates as a Soft Carbon Nucleophile

Article abstract of DOI:10.1021/acs.orglett.9b03475

The nickel-catalyzed benzylic substitution of benzyl alcohol derivatives with a soft carbon nucleophile is extremely rare compared to that with a hard carbon nucleophile. We have achieved the nickel-catalyzed benzylic substitution of benzyl esters with malonates as a soft carbon nucleophile. Primary and secondary benzyl 2,3,4,5,6-pentafluorobenzoates as well as a wide variety of malonate derivatives were well tolerated in the nickel-catalyzed reaction, providing the corresponding alkylation products in 46-86% yields (34 examples). Additionally, we propose a possible reaction mechanism that would undergo via the ??¹- A nd ??³-benzylnickel intermediates.

Full text of DOI:10.1021/acs.orglett.9b03475

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Nickel-Catalyzed Benzylic Substitution of Benzyl Esters with
Malonates as a Soft Carbon Nucleophile
Hiroaki Tsuji,* Keisuke Hashimoto, and Motoi Kawatsura*
Department of Chemistry, College of Humanities & Sciences, Nihon University, Sakurajosui, Setagaya-ku, Tokyo 156-8550, Japan
S
* Supporting Information
ABSTRACT: The nickel-catalyzed benzylic substitution of
benzyl alcohol derivatives with a soft carbon nucleophile is
extremely rare compared to that with a hard carbon
nucleophile. We have achieved the nickel-catalyzed benzylic
substitution of benzyl esters with malonates as a soft carbon
nucleophile. Primary and secondary benzyl 2,3,4,5,6-penta-
fluorobenzoates as well as a wide variety of malonate derivatives were well tolerated in the nickel-catalyzed reaction, providing
the corresponding alkylation products in 46−86% yields (34 examples). Additionally, we propose a possible reaction
mechanism that would undergo via the η1- and η3-benzylnickel intermediates.
he transition-metal-catalyzed benzylic substitution of
benzyl alcohol derivatives with carbon nucleophiles offers
that are one of the important synthetic precursor in organic
synthesis.13 In addition, developing the reaction using a soft
carbon nucleophile is considered to be highly desirable in
terms of the functional group compatibility. In this context, we
report the nickel-catalyzed benzylic substitution of benzyl
esters with malonates as a soft carbon nucleophile (Scheme
1b).
T
a useful tool for the formation of carbon−carbon bonds in
organic synthesis.1 The palladium-catalyzed benzylic substitu-
tion of benzyl esters with carbon nucleophiles has been
thoroughly studied2 and enabled a number of carbon−carbon
bond-forming reactions3 including their asymmetric variants.4
As an alternative approach, the nickel-catalyzed benzylic
substitution of benzyl ethers and benzyl esters with carbon
nucleophiles has been explored in the past decade, and the
nickel catalysis provides an efficient method that realizes the
benzylic carbon−carbon bond formation.5 Although various
organometallic reagents such as Grignard,6 organozinc,7
organoboron reagents,8 and others9 have been employed in
the reaction systems as a hard carbon nucleophile, the use of a
soft carbon nucleophile remains underdeveloped.10 Chen, Han,
and co-workers reported the nickel-catalyzed benzylic
alkylation of benzyl esters with arylacetonitriles, providing
the corresponding α-alkylated arylacetonitriles in 44−95%
yields (Scheme 1a).11,12 To the best of our knowledge, there is
no example for the nickel-catalyzed benzylic substitution of
benzyl esters with malonates, even though the reaction would
provide an efficient method for the manipulation of malonates
We began our investigation with the optimization of the
reaction conditions (Table 1). Based on the seminal report by
Kuwano and co-workers about the palladium-catalyzed
benzylic substitution of benzyl esters with malonates, we
initially chose DPPF and bis(trimethylsilyl)acetamide (BSA)
as the ligand and the base, respectively.3c The reaction of
benzyl methyl carbonate (1) with diethyl methylmalonate (7a)
was performed in the presence of Ni(cod)2 (10 mol %), DPPF
(10 mol %), and BSA (1.1 equiv) in toluene at 80 °C for 18 h
to give the desired alkylation product 8a in 39% yield (Table 1,
entry 1). Based on this initial result, we next tested the other
bidentate phosphine ligands (entries 2−8). While the Ni-
(cod)2/DPPB or BINAP system exhibited the catalytic activity
in the transformation, the reaction with DPPM, DPPE, DPPP,
DPPPent, and Xantphos failed to give the desired product. In
addition, alkylation product 8a was not formed using PPh3 as
the ligand (entry 9). These results indicated that DPPF (10
mol %) is the most suitable ligand of choice for the nickel
catalyst system. To improve the yield of 8a, we next evaluated
the effect of leaving groups of the substrate (entries 10−14).
The use of the analogous tert-butyl carbonate group (2) led to
diminished yield (entry 10). The substrates bearing pivalate
(3) and benzoate (4) groups were ineffective for this
transformation (entries 11 and 12). We confirmed that benzyl
phosphonate 5 displayed similar reactivity to benzyl methyl
carbonate (1), giving the desired product 8a in 42% yield
Scheme 1. Nickel-Catalyzed Benzylic Substitution of Benzyl
Esters with a Soft Carbon Nucleophile
Received: October 1, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03475
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Optimization of Reaction Conditions
Scheme 2. Scope of Benzyl 2,3,4,5,6-Perfluorobenzoates
b
entry
X
L
yield (%)
1
2
3
4
5
6
7
8
CO2Me (1)
CO2Me (1)
CO2Me (1)
CO2Me (1)
CO2Me (1)
CO2Me (1)
CO2Me (1)
CO2Me (1)
CO2Me (1)
Boc (2)
Piv (3)
Bz (4)
P(O)(OEt)2 (5)
C(O)C6F5 (6a)
C(O)C6F5 (6a)
DPPF
DPPM
DPPE
DPPP
DPPB
DPPPent
BINAP
Xantphos
PPh3
DPPF
DPPF
DPPF
DPPF
DPPF
DPPF
39
<1
<1
<1
28
<1
30
<1
<1
25
6
c
9
10
11
12
13
14
22
42
72
d
e
15
87 (79)
a
Reaction conditions: 1−6a (0.30 mmol), 7a (0.33 mmol), Ni(cod)2
(0.03 mmol), L (0.03 mmol), BSA (0.33 mmol) in toluene (1.2 mL,
b
1
0.25 M) at 80 °C for 18 h. The yield was determined by H NMR
analysis of the crude mixture using phenanthrene as an internal
standard. 20 mol % of PPh3 was used. The reaction was performed
in 0.3 mL of toluene (1 M). Isolated yield.
c
d
e
a
Reaction conditions: 6 (0.30 mmol), 7a or 7b (0.33 mmol),
Ni(cod)2 (0.03 mmol), DPPF (0.03 mmol), BSA (0.33 mmol) in
(entry 13). To our delight, the use of the 2,3,4,5,6-
pentafluorobenzoate group was found to be effective as a
leaving group, giving the desired alkylation product 8a in 72%
yield (entry 14). Changing the reaction concentration of the
reaction from 0.25 to 1 M increased the yield of the desired
product 8a to 87% (79% isolated yield) from 72%.
b
c
toluene (0.3 mL) at 80 °C for 18 h. 3 mmol (1.08 g) scale. 20 mol
d
% of Ni(cod)2 and DPPF were used. 2-Vinylnaphthalene was formed
e
f
in 50% NMR yield. The reaction was performed at 40 °C. 2-
g
Vinylnaphthalene was formed in 14% NMR yield. 6-Methoxy-2-
vinylnaphthalene was detected by GC−MS analyses of the reaction
h
mixture. Styrene was detected by GC−MS analyses of the reaction
With the optimized reaction conditions in hand, we
investigated the scope of the benzyl 2,3,4,5,6-pentafluoroben-
zoates 6 using diethyl methylmalonate (7a) as a soft carbon
nucleophile (Scheme 2). The reactions of 6b and 6c having
trifluoromethyl and methyl ester groups at the para position on
their phenyl rings proceeded smoothly to give the desired
alkylation products 8b and 8c in 74% and 81% yield,
respectively. It should be noted that the reaction on a 3
mmol (1.08 g) scale proceeded to afford 8c in 87% yield. On
the other hand, the reactivity of 6d and 6e bearing methyl and
methoxy groups was lower than that of 6b and 6c, resulting in
the moderate yields of 8d and 8e. The yield of the electron-
rich substrate could be improved by increasing the loading
amount of the catalyst. For example, the reaction of 6d in the
presence of 20 mol % of Ni(cod)2 and DPPF provided 8d in
70% yield. Benzyl 2,3,4,5,6-pentafluorobenzoates 6f and 6g
bearing a fluoro atom and a phenyl group on their aromatic
rings underwent the reaction to give the desired alkylation
products 8f and 8g in 70% and 83% yield, respectively. Both
electron-donating (6h, 6i) and -withdrawing (6j) substituents
at the meta position on the phenyl rings were well tolerated to
give the corresponding alkylation products 8h−j in 72−82%
yields. The use of 6k and 6l bearing o-methylphenyl and o-
methoxyphenyl groups led to diminished yield probably due to
the electronic and steric effects of the substituents. When 6l
mixture.
was subjected to the reaction in the presence of 20 mol % of
Ni(cod)2 and DPPF, the desired product 8l was obtained in
62% yield. Substrates 6m−p having piperonyl and naphtha-
lenyl rings participated in the reaction, furnishing the desired
products 8m−p in good yields. Heterocycles such as furan
(6q), benzofuran (6r), and thiophene (6s) were compatible
with the reaction system, thus providing the corresponding
alkylation products 8q−s in 65−86% yields. We next carried
out the reaction of secondary benzyl 2,3,4,5,6-pentafluor-
obenzoates.
The reaction of 6t with diethyl methylmalonate (7a) under
the optimized reaction conditions afforded the desired product
8t in 27% yield along with the formation of 2-vinylnaphthalene
(50% NMR yield). Fortunately, when diethyl malonate (7b)
was used as the nucleophile at 40 °C, the formation of 2-
vinylnaphthalene could be suppressed, giving the desired
alkylation product 8t′ in 74% yield. Secondary benzyl 2,3,4,5,6-
pentafluorobenzoate 6u bearing a methoxy group at the 6
position on the naphthalene ring also underwent the reaction
to give 8u in 47% yield. Unfortunately, the catalyst system did
not work well in the reaction of 6v and 6w bearing a nonfused
aromatic ring with 7b. We also examined the reaction of benzyl
B
DOI: 10.1021/acs.orglett.9b03475
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
2,3,4,5,6-pentafluorobenzoates bearing a nitro group and a
chloro atom at the para position on the phenyl rings. In
addition, 3-pyridyl 2,3,4,5,6-pentafluorobenzoate was also
subjected to the reaction conditions. However, we could not
obtain desired alkylation products.
Scheme 4. Proposed Reaction Mechanism
We next examined the reaction of benzyl 2,3,4,5,6-
pentafluorobenzoate 6a with a wide variety of the malonate
derivatives 7 under the optimized reaction conditions (Scheme
3). The reaction of 6a with diethyl ethylmalonate (7c) and
a
Scheme 3. Scope of Malonate Derivatives
of the η1-benzylnickel intermediate I would be supported by
the experimental results as follows: the β-hydrogen elimination
products were formed during the reaction of secondary benzyl
2,3,4,5,6-pentafluorobenzoates 6t, 6u, and 6v as shown in
Scheme 2. The intermediate I would isomerize into the η3-
benzylnickel intermediate II, and the intermediates I and II
might be in equilibrium.14,15 Finally, the reaction of the
cationic η3-benzylnickel intermediate II with a malonate anion
seems to take place to produce the desired alkylation product 8
or 9. Although the reactivity difference between the
benzylnickel species I and II with a malonate anion is unclear
at this stage, we believe that the malonate anion would attack
the cationic η3-benzylnickel II based on the detailed
mechanistic study of the palladium-catalyzed benzylic
alkylation reaction recently reported by Kuwano and co-
workers.16
a
Reaction conditions: 6a (0.30 mmol), 7 (0.33 mmol), Ni(cod)2
(0.03 mmol), DPPF (0.03 mmol), BSA (0.33 mmol) in toluene (0.3
mL) at 80 °C for 18 h. 20 mol % of Ni(cod)2 and DPPF were used.
b
In conclusion, we have developed the nickel-catalyzed
benzylic substitution of benzyl esters bearing 2,3,4,5,6-
pentafluorobenzoate as the leaving group with malonates as
the soft carbon nucleophile that is still a rare class of carbon
nucleophiles in the nickel catalyst system. The Ni(cod)2/
DPPF catalyst system enabled the benzylic substitution of
functionalized benzyl 2,3,4,5,6-pentafluorobenzoates with a
series of malonate derivatives to provide the corresponding
alkylation products in good yields. Although the detailed
reaction mechanism is still unclear, we proposed the possible
catalytic cycle for the nickel catalysis that would be involved in
the η1- and η3-benzylnickel intermediates. The nickel-catalyzed
benzylic substitution of the promising benzyl esters with the
other soft carbon and heteroatom-centered nucleophiles and
the detailed mechanistic study are currently underway in our
laboratory.
diethyl butylmalonate (7d) afforded the desired alkylation
products 9c and 9d in 68% and 61% yield, respectively. The
reactivity of malonates 7e−g bearing functionalized linear alkyl
chains such as the phenethyl, cyanoethyl, and chloropropyl
groups was inferior to that of the other malonates. Therefore,
the reaction with these malonates was performed in the
presence of 20 mol % of Ni(cod)2 and DPPF to afford the
alkylation products 9e−g in 46−59% yields. Diethyl 2-(3-
oxobutyl)malonate (7h) reacted with 6a under the reaction
conditions to give the desired product 9h in 60% yield.
Sterically congested malonates such as 7i and 7j also
participated in the reaction, providing the alkylation products
9i and 9j in 67% and 63% yield, respectively. The presence of a
fluoro substituent on the active methylene carbon did not
affect the alkylation reaction, furnishing the desired product 9k
in 70% yield. Replacement of the ethyl ester groups of the
malonate to methyl esters (7l), benzyl esters (7m), and
isopropyl esters (7n) did not show any significant influence for
the transformation, thus providing the corresponding alkyla-
tion products 9l−n in 70−74% yields. Unfortunately, the other
active methylene compounds such as ethyl 2-methylacetoace-
tate, ethyl benzoylacetate, ethyl 2-cyanopropionate, and ethyl
cyanoacetate could not be applicable to the reaction, and the
desired alkylation products were not formed.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03475.
Experimental procedures; NMR spectra (PDF)
We propose the possible reaction mechanism for the nickel-
catalyzed benzylic substitution of benzyl 2,3,4,5,6-pentafluor-
obenzoates with malonates as shown in Scheme 4. Initially,
benzyl ester 6 would oxidatively add to the nickel (0) species
to generate the η1-benzylnickel intermediate I. The formation
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: tsuji@chs.nihon-u.ac.jp.
*E-mail: kawatsur@chs.nihon-u.ac.jp.
C
DOI: 10.1021/acs.orglett.9b03475
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
ORCID
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Hiroaki Tsuji: 0000-0002-8899-3435
Motoi Kawatsura: 0000-0002-8341-6866
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by a Research Grant of Institute of
Natural Sciences at Nihon University for 2019 and a Grant-in
Aid for Scientific Research (C) from the Japan Society for the
Promotion of Science (17K05794). We thank Mr. Koki Suzuki
(Nihon University) for his experimental support.
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Intramolecular Heck Reactions of Secondary Benzylic Ethers. J. Am.
Chem. Soc. 2014, 136, 7825−7828. (b) Xiao, J.; Chen, T.; Han, L.-B.
Nickel-Catalyzed Direct C−H/C−O Cross Couplings Generating
Fluorobenzenes and Heteroarenes. Org. Lett. 2015, 17, 812−815.
(11) Xiao, J.; Yang, J.; Chen, T.; Han, L.-B. Nickel-Catalyzed α-
Benzylation of Arylacetonitriles via C-O Activation. Adv. Synth. Catal.
2016, 358, 816−819.
(12) For the classification of the soft and hard nucleophiles, see:
(a) Trost, B. M.; Thaisrivongs, D. A. Strategy for Employing
Unstabilized Nucleophiles in Palladium-Catalyzed Asymmetric Allylic
Alkylations. J. Am. Chem. Soc. 2008, 130, 14092−14093. (b) Sha, S.-
C.; Zhang, J.; Carroll, P. J.; Walsh, P. J. Raising the pKa Limit of
“Soft” Nucleophiles in Palladium-Catalyzed Allylic Substitutions:
Application of Diarylmethane Pronucleophiles. J. Am. Chem. Soc.
2013, 135, 17602−17609.
́
(13) For examples, see: Kurti, L.; Czako, B. Strategic Applications of
̈
Named Reactions in Organic Synthesis; Elsevier, 2005; pp 2−3, 242−
243, 272−273, 286−287, 458−459, and references cited therein.
(14) Examples of the isolation and characterization of benzylnickel
species: (a) Carmona, E.; Marín, J. M.; Paneque, M.; Poveda, M. L.
New Nickel o-Methylbenzyl Complexes. Crystal and Molecular
Structures of Ni(η3-CH2C6H4-o-Me)Cl(PMe3) and Ni3(η1-
CH2C6H4-o-Me)4(PMe3)2(μ3-OH)2. Organometallics 1987, 6, 1757−
1765. (b) Carmona, E.; Paneque, M.; Poveda, M. L. Synthesis and
Characterization of Some New Organometallic Complexes of
Nickel(II) Containing Trimethylphosphine. Polyhedron 1989, 8,
285−291. (c) Ascenso, J. R.; Carrondo, M. A. A. F. de C. T.; Dias,
A. R.; Gomes, P. T.; Piedade, M. F. M.; Romao, C. C.; Revillon, A.;
̃
Tkatchenko, I. Cationic Benzyl Nickel Complexes as Homogeneous
Catalysts for Styrene Oligomerization. X-ray Crystal Structure of
[Ni(η3-CH2C6H5)(PPh3)2]PF6 ·CH2Cl2. Polyhedron 1989, 8, 2449−
́
́
2457. (d) Albers, I.; Alvarez, E.; Campora, J.; Maya, C. M.; Palma, P.;
́
3
Sanchez, L. J.; Passaglia, E. Cationic η -Benzyl Nickel Compounds
with Diphosphine Ligands as Catalyst Precursors for Ethylene
Oligomerization/Polymerization: Influence of the Diphosphine Bite
Angle. J. Organomet. Chem. 2004, 689, 833−839.
(15) The involvement of benzylnickel intermediates was suggested
in the nickel-catalyzed benzylic alkylation and arylation; see refs 6f
and 8e.
(16) Kuwano, R.; Yokogi, M.; Sakai, K.; Masaoka, S.; Miura, T.;
Won, S. Room-Temperature Benzylic Alkylation of Benzylic
Carbonates: Improvement of Palladium Catalyst and Mechanistic
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E
DOI: 10.1021/acs.orglett.9b03475
Org. Lett. XXXX, XXX, XXX−XXX