Reductive coupling of benzyl oxalates with highly functionalized alkyl bromides by nickel catalysis

Article abstract of DOI:10.1039/c8sc00609a

Coupling reactions involving non-sulfonated C-O electrophiles provide a promising method for forming C-C bonds, but the incorporation of functionalized or secondary alkyl groups remains a challenge due to the requirement for well-defined alkylmetal specie

Full text of DOI:10.1039/c8sc00609a

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Reductive Coupling of Benzyl Oxalates with Highly Functionalized
Alkyl Bromides by Nickel Catalysis
Received 00th January 20xx,
Accepted 00th January 20xx
Xiao-Biao Yan, Chun-Ling Li, Wen-Jie Jin, Peng Guo, Xing-Zhong Shu*
Coupling reactions involving non-sulfonated C–O electrophiles provide a promising method for forming C–C bonds, but the
incorporation of functionalized or secondary alkyl groups remains a challenge due to the requirement for well-defined
alkylmetal species. In this study, we report a reductive nickel-catalyzed cross-coupling of benzyl oxalates with alkyl
bromides, using oxalate as a new leaving group. A broad range of highly functionalized alkyl units (such as functional
groups: alkyl chloride, alcohol, aldehyde, amine, amide, boronate ester, ether, ester, heterocycle, phosphonate, strained
ring) were efficiently incorporated at the benzylic position. The utility of this synthetic method was further demonstrated
by late-stage modification of complex bioactive compounds. Preliminary mechanistic experiments revealed that a radical
process might be involved in the reaction.
DOI: 10.1039/x0xx00000x
www.rsc.org/
unreactive C–O electrophiles.
The incorporation of
Introduction
functionalized or secondary alkyl groups remains a particular
challenge,6 which can partially be ascribed to the low
availability and high reactivity profiles of alkylmetal reagents.
The development of protocols using electrophiles instead of
organometallic reagents to couple with C–O electrophiles may
provide a solution to these problems, offering a unique
opportunity to discover new reactivities within this field
(Scheme 1, path b).7
Transition metal-catalyzed cross-coupling reactions have
become one of the most important tools in organic synthesis.1
Recent efforts have been focused on the use of non-sulfonated
C–O electrophiles (e.g., carboxylates, ethers) as coupling
partners versus organic halides.2 Their advantages involve low
toxicity, low cost and ready availability, and abundant C–O
bonds in a wide range of natural and artificial compounds. The
high activation barrier for C–O cleavage and selectivity
challenge in the presence of multiple C–O bonds3 mean that
their coupling reactions have been realized only recently by
using organometallic species (e.g., Grignards, organozincs, and
boronic acids) as coupling partners (Scheme 1, path a).2 In
contrast to the major advances achieved in the field of
arylation reactions,4 the development of alkylation reactions
has proved more difficult.5 To date, only a few elegant studies
have demonstrated the Csp3–Csp3 coupling of relatively
The reductive cross-coupling of two electrophiles has
emerged as an increasingly popular approach for constructing
the C–C bond.8 One of the major challenges in this field is to
expand the scope of electrophiles. Encouraged by the pioneer
work of Weix,8e the groups of Martin, Jarvo, Shi, Molander,
and Shu have launched a program to disclose the potential of
nickel-catalyzed reductive cross-coupling of relatively
unreactive C–O electrophiles.7d-l Notably Jarvo’s group has
disclosed intramolecular Csp3–Csp3 coupling of benzyl ethers
with alkyl halides (Scheme 2a).7k However, intermolecular
Csp3–Csp3 coupling is still unresolved because of difficulty and
δ−
δ+
δ+
C O
C
M
C
X
a) Intramolecular cross-coupling reaction (
Jarvo
)
C
C
C
C
cat.
cat., reductant
path b (underdeveloped)
OH
Ni (
cat.
)
O
path a (well known)
Ar
MeMgI (2 equiv.)
Ar
Cl
M: MgX, ZnX, Li, B(OR)2 etc. X: Cl, Br etc. cheap/mild reagents
well-defined R M abundant, stable, and easy to handle
−
b) Intermolecular cross-coupling reaction (
)
this work
Scheme 1 Catalytic cross-coupling reactions via C–O bond cleavage.
O
R
FG
OMe
O
Ni (cat.)
n
Ar
Br
Ar
FG
n
Mn
R
O
1o and 2o alkyl bromides
New leaving group
Broad substrate scope
Highly functionalized alkyl groups (-Bpin, -CO2R, -CHO, -NHBoc, -OH etc.)
Scheme 2 Reductive Csp3–Csp3 cross-coupling reactions via benzylic C–O bond cleavage.
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complexity with controlling selectivity for the cross-product.9 inhibited formation of the ArCH2–OH side product (entries 9–
Herein, we demonstrate the use of oxalate10 as a leaving group 13). No reaction was observed in the absence of the Ni catalyst
to allow an intermolecular Csp3–Csp3 coupling between benzyl or Mn reductant (entries 14–15). Due to the solubility problem,
carboxylates and alkyl bromides (Scheme 2b). This method reactions using non-polar alkyl bromides for the preparation of
accomplishes the incorporation of a wide range of highly 3b-3e and 3y-3aa were sluggish in DMSO. Thus, the conditions
functionalized alkyl groups at the benzylic position and of entry 13 using DMSO/DMF (1:1) were used as standard
tolerates both primary and secondary alkyl bromides. Our conditions under which the gram-scale reaction of 1a gave 3a
study demonstrates this method is an attractive alternative for with 82% yield.
the alkylation of benzylic derivatives using alkyl
nucleophiles.6,11
The effects of various leaving groups were then studied
(Table 2). Simple benzyl ether ( ) was unreactive. While
4
carboxylates were more reactive than methyl ether, reactions
of commonly used carboxylates gave no or very low yields of
Results and discussion
the desired product (
materials of remained unchanged. By increasing the
leaving ability of carboxylate,12
full conversion of
5–9). In these cases, most starting
4–9
We started our investigations by exploring the reaction of
oxalate 1a with alkyl bromide 2a (Table 1, see Table S1-S2 for
more details). Initial experiments revealed that reactions
under the conditions of NiBr2 (10 mol%), Mn (4.0 equiv.) in
DMF using nitrogen ligands gave no or low yields of the
desired product 3a (entries 1–4), along with large amounts of
a
trifluoroacetate 10 was observed, affording 3a with 19% yield
along with large amounts of ArCH2–CH2Ar (30%), ArCH2–OH
(15%), and ArCH3 (11%) side products. While 3-pyridyl ester 11
was totally unreactive under standard conditions, the reaction
of 2-pyridyl ester 12 gave 3a with 22% yield. This result
indicated that use of the bidentate leaving group was
beneficial to this reaction,13 prompting us to examine the
effects of several others. Ether 13 and acetate 14 were found
to be unreactive, even though they were active leaving groups
for the benzylic C–O cleavage.7e,13 The use of a stronger
coordinating group, 2-(methylthio)acetate (15), led to trace
amounts of 3a. The reaction of ethyl oxalate 16 gave a
comparable result to that of methyl oxalate 1a, affording 3a
with 72% NMR yield.14
ArCH3
(2-methylnaphthalene)
and
ArCH2–OH
(2-
naphthalenemethanol) side products.
A
review of the
literature revealed that phosphine ligands were mostly
ineffective for reductive cross-coupling reactions.8 However,
the use of PPh3 gave 3a with an unexpected 34% yield (entry 5),
encouraging us to study the electronic and steric effects of the
ligands. We found that P(4-CF3Ph)3 was the most effective
(entries 6–9). Screening of solvents revealed that DMSO was
crucial to increasing reaction efficiency, as it significantly
Table 1 Nickel-catalyzed reductive coupling of 1a with 2a.a
We subsequently focused on examining the generality of
this protocol. The incorporation of functionalized alkyl units is
important in the synthesis of complex molecules. The use of
functionalized alkylmetal reagents is severely restricted
because of limited availability and high reactivity profiles of
the reagent itself.5b The use of alkyl halides would circumvent
these problems. In this work, both simple long-chain alkyl
entry
1
ligand
L1
solvent
DMF
yield (%)
20
substrates (3b–3d) and a wide range of functionalized alkyl
2
L2
DMF
18
3
L3
DMF
32
Table 2. Evaluation of leaving groups.a
4
L4
DMF
0
5
PPh3
DMF
34
2a (2.0 equiv.), 10 mol% NiBr2
30 mol% P(4-CF Ph) , Mn (4.0
CO2Et
OR
)
equiv.
3
3
6
P(4-MePh)3
P(2-MePh)3
P(4-FPh)3
P(4-CF3Ph)3
P(4-CF3Ph)3
P(4-CF3Ph)3
P(4-CF3Ph)3
P(4-CF3Ph)3
P(4-CF3Ph)3
P(4-CF3Ph)3
DMF
16
DMSO/DMF (1:1, 0.4 M), 30 o
C
7
DMF
0
3a
4-16
8
DMF
50
9
DMF
58
O
O
O
10
11
12
13
14d
15e
DMA
52
73 (79)b
68 (73)b
70 (75)b (82)c
0
O
OMe
tBu
, 0%
DMSO
O
Me
O
OtBu
O
O
NMe2
DMSO/DMA 1:1
DMSO/DMF 1:1
DMSO/DMF 1:1
DMSO/DMF 1:1
, 0%
, 0%
, 0%
4
5
6
7
8
, 0%
O
O
O
O
N
O
N
O
O
OMe
9, 7%
O
CF3
0
11, 0%
12, 22%
10, 19%
O
O
O
O
OMe
SMe
O
O
OMe
O
O
Jarvo, 201213
Jarvo, 20136c
Martin, 20147e
OEt
a Substrates 1a (0.2 mmol), monodentate ligand (30 mol%), or bidentate ligand
(15 mol%) were used and reacted for 24 h; Yields were determined by 1H NMR
using anisole as an internal standard. b Yields are isolated yields. c 1a (4 mmol,
0.976 g) was used; isolated yield. d No Ni catalyst. e No Mn.
13, 0%
14, 0%
, 3%
15
16, 72%
a
Substrates 4-16 (0.2 mmol) were used and reacted for 24 h; Yields were
determined by 1H NMR using anisole as an internal standard.
2 | J. Name., 2012, 00, 1-3
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Table 3 Scope of alkyl bromides.a
A wide range of benzyl oxalates coupled with functionalized
alkyl bromide 2n efficiently under standard conditions (Table
4). The reaction was highly chemoselective for alkylation of
benzyl esters, leaving a number of aryl esters intact (3ab–
3af).2
Functional units such as strained rings, amino acid and α-oxy
acid derivatives, as well as acidic carbamates were tolerated
under reductive conditions
(3ac–3ag). No erosion in
enantioselectivity was found en route to either 3ae or 3af. The
reaction of 1-naphthyl oxalate (3ai) gave a comparable result
to that for 3ah. Nitrogen and sulfur heterocycles are prevalent
in pharmaceuticals but always represent a challenge for metal
catalysis. The expected products 3aj–3an were formed with
moderate yields under standard conditions. Unfortunately, our
method did not allow the coupling reaction of secondary
benzyl electrophiles (3ap).
To date, most Ni-catalyzed cross-coupling reactions via inert
C–O bond cleavage are limited to substrates with π-extended
systems like naphthalene.2 One possible explanation is that,
unlike
a regular arene, the π-extended system can be
coordinated to Ni(0) efficiently,15 because the binding complex
might retain a certain aromaticity and might still be partially
stable.7e Indeed, under standard conditions the reaction of a
regular benzyl oxalate only gave trace amounts of product
3ao. The vast majority of substrate was converted to benzyl
alcohol. This prompted us to study the reaction conditions
again. Finally, we found that by changing the ligand to dppb
and using MgBr2 (1.5 equiv.) and 3-CF3-Py (5 mol%) as
additives, the reaction afforded a useful 63% yield of 3ao
.
Although the role of additives is unclear, the use of MgBr2
significantly
Table 4 Scope of benzyl oxalates.a
a
b
O
Reactions for 24 h, isolated yields, average of two experiments. Solvent:
DMSO. c Catalyst: 20 mol% NiBr2.
CO2Me
see Table 2
OMe
O
Ar
Ar
Br
CO2Me
O
3ab-3ap
1b-1p
2n (2.0 equiv.)
bromides coupled with 1a efficiently under standard
conditions (Table 3). The incorporation of β-substituted alkyl
unit represents a challenge due to the fast β–H elimination of
alkylmetal intermediates.6e Product 3e was formed in a
moderate yield under our conditions. The reaction was highly
chemoselective for functionalization of the C–Br bond over C–
Functional group tolerance
O
O
O
tBu
O
O
O
3ab, 79%
3ac, 82%
3ad, 84%
F
(
3f
functionalities such as methyl and silyl ethers (3h
esters (3i 3j 3n), heterocycle (3j), tertiary amides (3k
)
and C–Cl
(
3g
)
bonds. Moreover,
a
gamut of
3s, 3t),
3o 3p),
O
O
O
,
iPr
Ph
O
tBuO
N
H
O
,
,
,
,
NHBoc
OTBS
3ae, 90%, 99.9% ee
3af, 88%, 99.2% ee
3ag, 70%
amine (3l), phosphonate (3m), acidic amide (3q), alcohol (3r),
aldehyde (3v), and boronate ester (3w) were accommodated.
Although the direct coupling of aldehyde substrate (3v) was
less effective, the use of alkyl bromides bearing protected
aldehyde function gave a good yield of product 3u. The
reaction was selective for functionalization of the C–Br bond,
leaving the nucleophilic C–B bond for additional
transformation (3w). Furthermore, the scope of this alkylation
protocol could be extended to secondary alkyl bromides to
Arenes and heteroarenes
N
MeO
N
3ah, 66%
3ai, 64%
3aj, 64%
3ak, 76%
Me
N
N
Ts
3al, 64%
S
MeO
Ts
3an, 64%b
3ao, 63%c
3am, 45%
3ap, trace
give cyclic (3x, 3y) and acyclic (3z, 3aa) products. The reaction
could be scaled up to gram-scale and produced 3h with 73%
a Reactions for 24 h, isolated yields, average of two experiments. b Reaction at 45
oC. c Conditions: 10 mol% NiBr2(diglyme), 20 mol% dppb, 5 mol% 3-CF3-Py, MgBr2
(1.5 equiv.), Mn (4.0 equiv.), DMSO/CH3CN (4:1, 0.4 M), 45 oC, 36 h.
yield.
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with 54% yield. The presence of highly coordinative thioether
and amide groups makes functionalization of D-Biotin a
challenge for metal catalysis. The expected product 20 was
formed with 63% yield under standard conditions. Lithocholic
acid derivate 21 selectively coupled with oxalate 1a, leaving a
free alcohol group intact. In addition, this approach allows for
incorporation of a naphthyl group at the secondary alkyl
carbon, affording 24 with moderate yield.
Use of the optically pure alkyl bromide 23 gave 24 with a dr
of 6.7:1, indicating a potential radical mechanism (Scheme 3d).
The reaction of 1a and 2a was significantly inhibited in the
presence of a radical scavenger such as TEMPO and 1,1-
diphenylethylene (Scheme 4a). The radical trapping product 25
was obtained with 50% NMR yield. Further, radical clock
experiments revealed that the reaction of cyclopropylmethyl
bromide 26 only produced the ring opening product 28
(Scheme 4b), which is consistent with the process of
rearrangement of the cyclopropylmethyl radical to the
homoallyl radical.16 These results suggest the presence of a C-
centered radical in the reaction pathway.
Me
Me
O
O
Me
Br
see Table 2a
Me
O
O
O
(a)
O
1a, 24 h
O
O
O
O
Me
Me
18, 54% yield
Me
Me
17 (from -D-(+)-Glucose)
H
N
H
N
Br
see Table 2b
O
O
(b)
NH
NH
1a, 24 h
S
S
, 63% yield
19 (from D-Biotin)
20
Br
H
H
Me
Me
Me
Me
Me
Me
see Table 2c
(c)
1a, 24 h
HO
HO
21 (from Lithocholic Acid)
, 57% yield
Me
22
Me
Me
Me
see Table 2
(d)
O
23 (from epiandrosterone)
1a
, 24 h
O
Br
24, 58
% yield
, d.r. =
6.7:1
To verify a potential radical chain mechanism, the effect of
catalyst concentrations on products of reaction 1a with 6-
bromo-1-hexene 29 was then studied (Scheme 4c).17 Under
higher catalyst concentrations, the C-centered radical was
more easily trapped by catalysts before cyclization.17 We
expected that if a radical chain mechanism was to apply, the
a
Scheme 3 Late-stage modification of biologically active molecules. Oxalate 1a (2.0
equiv.), 20 mol% NiBr2, 45 oC. b 20 mol% NiBr2, 45 oC. c 20 mol% NiBr2.
improved selectivity for 3ao over benzyl alcohol, and the
addition of 3-CF3-Py inhibited the formation of benzyl dimer.
The late-stage modification of complex molecules provides a
promising approach to altering the pharmacological profiles of
natural products. To further demonstrate the synthetic utility
of our method, we studied the alkylation reactions of several
complex bioactive compounds (Scheme 3). The reaction of α-
D-(+)-Glucose derivate 17 with oxalate 1a gave product 18
ratio of un-rearranged to rearranged products (30
increase with increasing catalyst concentration. However, our
result in Scheme 4c shows that 30 31 was not dependent upon
/31) would
/
catalyst concentrations. This result indicates that the oxidative
addition of the alkyl halide appears to occur via a non-chain
process. 18
a) Radical inhibition experiments
CO2Et
TEMPO (1.5 equiv.)
X
Br
Conclusions
3a, 0%
1a
see Table 2
CO2Et
24 h
In summary, we have demonstrated a nickel-catalyzed
cross-coupling of benzyl carboxylate with alkyl bromide by
using oxalate as a leaving group. This study suggests that the
reductive cross-coupling of electrophiles might be the
foundation for new discoveries in the field of metal-catalyzed
cleavages of the C–O bond. This method’s excellent functional
group compatibility suggests that it can be a powerful
alternative to established protocols using alkyl nucleophiles for
the alkylation of benzylic derivatives. Further mechanistic
investigation and extension to other electrophiles are ongoing
in our laboratory.
Ph
Ph
CO2Et
2a
3a, 20%
+
1,1-diphenylethylene
25, 50%
(1.5 equiv.)
b) Radical clock experiments
Br
see Table 2
1a, 24 h
26
27, 0%
28, 50%
c) The effect of catalyst concentration on 30/31
1a, NiBr2 (30-100 mM)
Br
P(4-CF3Ph)3 ( 90-300 mM)
DMSO/DMF (1:1, 0.5 mL)
Mn (4.0 equiv.), 30 oC, 24 h
30
29 (2.0 equiv.)
Conflicts of interest
There are no conflicts to declare.
31
30
Acknowledgements
NiBr2
31
10 mol%
(40 mM)
61%
13%
We thank the financial support from NSFC (21502078,
21772072), FRFCU (lzujbky-2016-ct09), and 1000 Talents Plan
Program.
Scheme 4 Mechanistic studies.
4 | J. Name., 2012, 00, 1-3
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100, 3187.; (b) D. A. Everson, D. J. Weix, J. Org. Chem.
2014, 79, 4793.
10 Oxalate substrates are readily available from Methyl
chlorooxoacetate (0.56$/g, HEOWNS). For elegant
works using oxalate acids as radical precursors to
couple with aryl halides and activated alkenes by
metallophotoredox catalysis, see: (a) C. C. Nawrat, C. R.
Jamison, Y. Slutskyy, D. W. C. MacMillan, L. E.
Overman, J. Am. Chem. Soc. 2015, 137, 11270; (b) X.
5
Selected reviews on catalytic alkylation reactions with
alkylmetal reagents: (a) J Choi, G. C. Fu, Science 2017,
356, 152; (b) R. Jana, T. P. Pathak, M. S. Sigman, Chem.
Rev. 2011, 111, 1417. Recent elegant works on the
alkylation of unreactive C-O electrophiles: (c) M.
Leiendecker, C.-C. Hsiao, L. Guo, N. Alandini, M.
Rueping, Angew. Chem. Int. Ed. 2014, 53, 12912; (d) D.
Gärtner, A. L. Stein, S. Grupe, J. Arp, A. Jacobi von
Wangelin, Angew. Chem. Int. Ed. 2015, 54, 10545; (e)
M. Tobisu, T. Takahira, T. Morioka, N. Chatani, J. Am.
Chem. Soc. 2016, 138, 6711.
Zhang, D. W. C. MacMillan, J. Am. Chem. Soc. 2016
,
138, 13862.
11 Selected reviews: (a) B. Liégault, J.-L. Renaud, C.
Bruneau, Chem. Soc. Rev. 2008, 37, 290; (b) J. L. Bras, J.
Muzart, Eur. J. Org. Chem. 2016, 2565. Selected
6
Selected elegant works: (a) B.-T. Guan, S.-K. Xiang, B.-
Q. Wang, Z.-P. Sun, Y. Wang, K.-Q. Zhao, Z.-J. Shi, J. Am.
Chem. Soc. 2008, 130, 3268; (b) B. L. H. Taylor, E. C.
examples: (a) R. Kuwano, Y. Kondo, Y. Matsuyama, J.
Am. Chem. Soc. 2003, 125, 12104; (b) B. M. Trost, L. C.
Czabaniuk, J. Am. Chem. Soc. 2012, 134, 5778.
Swift, J. D. Waetzig, E. R. Jarvo, J. Am. Chem. Soc. 2011
,
12 E. V. Anslyn, D. A. Dougherty, Modern Physical Organic
Chemistry, University Science Books, Sausalito, CA
133, 389; (c) H. M. Wisniewska, E. C. Swift, E. R. Jarvo,
J. Am. Chem. Soc. 2013, 135, 9083; (d) E. J. Tollefson, D.
D. Dawson, C. A. Osborne, E. R. Jarvo, J. Am. Chem. Soc.
2014, 136, 14951; (e) I. M. Yonova, A. G. Johnson, C. A.
Osborne, C. E. Moore, N. S. Morrissette, E. R. Jarvo,
Angew. Chem. Int. Ed. 2014, 53, 2422.
Selected elegant works on the coupling of activated
allylic carboxylates with alkyl electrophiles, see: (a) X.
Qian, A. Auffrant, A. Felouat, C. Gosmini, Angew. Chem.
Int. Ed. 2011, 50, 10402; (b) L. L. Anka-Lufford, M. R.
Prinsell, D. J. Weix, J. Org. Chem. 2012, 77, 9989; (c) H.
Chen, X. Jia, Y. Yu, Q. Qian, H. Gong, Angew. Chem. Int.
Ed. 2017, 56, 13103. Limited reports on reductive
coupling of unreactive C–O electrophiles, see: Homo-
(USA), 2006
.
13 The chelation of in situ formed Mn2+ to bidentate
leaving groups might weaken the C–O bond, thus
accelerating the rate of oxidative addition. For related
references, see: B. L. Taylor, M. R. Harris, E. R. Jarvo,
Angew. Chem. Int. Ed. 2012, 51, 7790. Also see: ref. 6c
and ref. 7e. We also observed that the use of extra
Lewis acid significantly accelerated the conversion of
oxalate (see Figure S1 and S2). Unfortunately, those
reactions using Lewis acids did not improve the yields
of the desired product.
7
14 At present, the reasons for the success of the oxalate is
still not clear. We tentatively suggested that both the
high leaving ability (pKa: oxalic acid 1.27, CF3CO2H 0.52,
CH3CO2H 4.76) and bidentate nature of oxalate might
be important for the reaction.
15 D. J. Brauer, C. Krueger, Inorg. Chem. 1977, 16, 884.
16 J. P. Stevenson, W. F. Jackson, J. M. Tanko, J. Am. Chem.
Soc. 2002, 124, 4271.
coupling: (d) Z.-C. Cao, Z.-J. Shi, J. Am. Chem. Soc. 2017
,
139, 6546. With π-electrophiles: (e) A. Correa, T. León,
R. Martin, J. Am. Chem. Soc. 2014, 136, 1062; (f) A.
Correa, R. Martin, J. Am. Chem. Soc. 2014, 136, 7253.
With aryl electrophiles: (g) M. O. Konev, L. E. Hanna, E.
R. Jarvo, Angew. Chem. Int. Ed. 2016, 55, 6730; (h) Z.-C.
Cao, Q.-Y. Luo, Z.-J. Shi, Org. Lett. 2016, 18, 5978; (i) B.
A. Vara, N. R. Patel, G. A. Molander, ACS Catal. 2017, 7,
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ARTICLE
17 (a) S. Biswas, D. J. Weix, J. Am. Chem. Soc. 2013, 135,
Journal Name
16192; (b) J. Breitenfeld, J. Ruiz, M. D. Wodrich, X. Hu,
J. Am. Chem. Soc. 2013, 135, 12004.
18 (a) G. D. Jones, J. L. Martin, C. McFarland, O. R. Allen, R.
E. Hall, A. D. Haley, R. J. Brandon, T. Konovalova, P. J.
Desrochers, P. Pulay, D. A. Vicic, J. Am. Chem.
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DOI: 10.1039/C8SC00609A
A nickel-catalyzed reductive Csp3-Csp3 coupling of benzyl oxalates with highly functionalized alkyl
bromides was disclosed.