Nickel-Catalyzed Desymmetrizing Cross-Electrophile Coupling of Cyclic Meso-Anhydrides

Article abstract of DOI:10.1021/acs.orglett.8b00114

A Ni-catalyzed desymmetrizing cross-electrophile coupling of cyclic meso-anhydrides with aryl triflates has been successfully demonstrated. This is the only example using cyclic meso-anhydrides in cross-electrophile coupling reactions. A diverse array of valuable γ-keto acid building blocks can be generated under these conditions with excellent functional group tolerance and stereochemical fidelity.

Full text of DOI:10.1021/acs.orglett.8b00114

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Nickel-Catalyzed Desymmetrizing Cross-Electrophile Coupling of
Cyclic Meso-Anhydrides
Tingzhi Lin,† Jianjun Mi,†,∥ Lichao Song,†,∥ Jiamin Gan,† Pan Luo,† Jianyou Mao,*,†
and Patrick J. Walsh*,†,‡
†Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering, Jiangsu National Synergetic Innovation Center for
Advanced Materials, Nanjing Tech University, 30 South Puzhu Road, Nanjing 211800, P. R. China
‡Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia,
Pennsylvania 19104-6323, United States
S
* Supporting Information
ABSTRACT: A Ni-catalyzed desymmetrizing cross-electrophile cou-
pling of cyclic meso-anhydrides with aryl triflates has been successfully
demonstrated. This is the only example using cyclic meso-anhydrides in
cross-electrophile coupling reactions. A diverse array of valuable γ-keto
acid building blocks can be generated under these conditions with
excellent functional group tolerance and stereochemical fidelity.
ransition-metal catalyzed cross-coupling reactions be-
Ttween electrophiles and preformed nucleophiles, such as
organomagnesium (Kumada coupling), boron (Suzuki−
Miyaura coupling), and zinc (Negishi coupling) reagents,
have emerged as powerful tools to build C−C bonds.1 Driven
by the desire to simplify these reactions by avoiding the use of
moisture- and air-sensitive organometallic reagents, transition-
metal-catalyzed cross-coupling of two different electrophiles,
cross-electrophile coupling, has recently attracted great interest
as a synthetic strategy.2
A major challenge of cross-electrophile coupling reactions is
suppressing homocoupling (dimerization) byproducts so that
cross-coupled products can be obtained with synthetically
useful levels of selectivity.3 This challenge has been recently
solved by employing first-row transition metals, such as cobalt,
nickel, and copper, as catalysts with one electrophile in
significant excess.2a,f Recent examples in cross-electrophile
coupling fall mainly into three categories (Scheme 1): (1)
cobalt- or nickel-catalyzed asymmetric biaryl formations using
two different aryl electrophiles,4 (2) cobalt- or nickel-catalyzed
reductive arylation of alkyl halides and pseudohalides,5 and (3)
copper- or nickel-catalyzed cross-coupling of two different alkyl
electrophiles.6 As a valuable complement, Weix and co-workers
reported dual nickel- and palladium-catalyzed cross-coupling of
aryl bromides with equimolar aryl triflates (Scheme 1, eq 4).7
In the past decades, cross-electrophile coupling has been
demonstrated with generality and excellent functional group
compatibility compared with conventional coupling counter-
parts.2a In addition to the traditional electrophiles mentioned
above, some challenging electrophiles, such as vinyl bromides,
bromoalkynes, carbon dioxide, and allylic alcohols, also have
been explored recently by Gong,8 Weix,9 Martin,10 and Shu,11
respectively. Despite these successes, the need still exists to
broaden the classes of electrophiles that can undergo this very
synthetically useful cross-electrophile coupling transformation.
Furthermore, cyclic meso-electrophiles, such as cyclic anhy-
drides, have not been explored in this transformation.12 The
desymmetrization of anhydrides with more general electro-
philes could afford valuable γ-keto acid building blocks (Figure
1).13
Scheme 1. Transition-Metal-Catalyzed Cross-Electrophile
Coupling Reactions
Figure 1. Selected bioactive compounds bearing the γ-keto acid motif.
Received: January 10, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00114
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Since 2002, Rovis and co-workers have reported excellent
methods for ring opening of cyclic meso-anhydrides with
organozinc compounds based on a transition-metal-catalyzed
cross-coupling strategy; however, the process required highly
water sensitive organozinc reagents (diaryl zinc or dialkyl zinc)
to render acceptable yields (Scheme 2, eq 1).14 More recently,
Table 1. Optimization of the Reaction Conditions
a
Scheme 2. Nickel-Catalyzed Desymmetrization of Cyclic
yield (%)
Meso-Anhydride
entry
X
solvent
1a/2
3aa
4aa
5aa
1
2
3
4
5
6
7
8
9
Br
DMA
DMF
DMPU
DMSO
DMA
DMA
DMA
DMA
DMA
DMA
DMA
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1
18
13
0
17
24
3
18
12
0
Br
Br
Br
0
0
0
I
18
39
0
23
8
7
OTf
Cl
6
0
0
OTs
OTf
OTf
OTf
0
0
0
43
67
86
3
7
b
10
1:1
0
2
Doyle and Rovis reported enantioselective desymmetrization of
cyclic meso-anhydrides via a dual nickel- and photoredox-
catalyzed single electron transmetalation process.15 In this
advance, bench stable benzyltrifluoroborates were employed
instead of organozinc reagents (Scheme 2, eq 2).
c
11
1:1
0
4
a
b
Yields determined by HPLC analysis. ZnI2 additive. For details on
c
additive screening, see the Supporting Information. 20 mol %
Ni(COD)2.
Herein, we introduce a method to generate a diverse array of
γ-keto acids via a nickel-catalyzed desymmetrizing cross-
electrophile coupling (DCEC) process. This strategy does
not require preformed nucleophiles and features excellent
functional group tolerance and stereochemical fidelity (Scheme
3).
byproducts could be successfully inhibited using phenyl triflate
with a higher yield of 3aa (39%) (Table 1, entry 6); however,
phenyl chloride and tosylate did not participate in the
transformation at all (Table 1, entries 7 and 8). Decreasing
the amount of phenyl triflate 2a to 1 equiv from 1.5 equiv
improved the yield of 3aa (43%) (Table 1, entry 9) and did not
lead to an increase in byproduct formation.
Scheme 3. Desymmetrization of Cyclic Meso-Anhydride via
DCEC
We next examined 14 diverse bipyridine derivatives and
found that simple bipy outperformed other ligands (see the
Supporting Information for full ligand structures and results).
We also determined that adding ZnI2 led to an improvement in
the yield of 3aa to 67% (Table 1, entry 10) (see the Supporting
Information for details about other additives examined).
Finally, increasing the nickel loading from 10 to 20 mol %
increased the product yield to 86% (Table 1, entry 11).
With the optimized conditions in hand, we next explored the
scope of aryl triflates that could be employed successfully in the
reaction with cis-1,2-cyclohexanedicarboxylic anhydride 1a
(Scheme 4). It was found that the reaction tolerated a wide
range of functional groups and substitution patterns on this
coupling partner. The parent phenyl triflate 2a reacted to give
the desired product 3aa in 78% isolated yield. Aryl triflates
containing electron-neutral and electron-donating groups, such
as 4-phenyl, 4-methyl, 4-tert-butyl, and 4-methoxy, consistently
exhibited very good reactivity, affording 3ab−ae in 78−86%
yields. Aryl triflates bearing electron-withdrawing groups, such
as 4-fluorophenyl triflate 2f and 4-chlorophenyl triflate 2g,
produced the corresponding products in 75 and 94% yield,
respectively. Sterically hindered aryl triflates, such as 2-tolyl
triflate 2h and 1-naphthyl triflate 2i, coupled with 1a to provide
the products in 82 and 73% yield, respectively. Meta-substituted
3,5-dimethylphenyl triflate 2j gave the desired product in 83%
isolated yield, and trimethoxy phenyl triflate 2k afforded 3ak in
84% yield. Lastly, it is noteworthy that functionalized aryl
triflates bearing ester, cyano, acetal, and even boronic acid ester
functional groups also coupled smoothly with 1a to give the
corresponding products 3al−ap with 74−87% isolated yield.
As a starting point for the DCEC with cis-1,2-cyclo-
hexanedicarboxylic anhydride 1a and bromobenzene, we
chose Ni(COD)2/bipy as the catalyst, zinc powder as the
reductant, TMSCl as the additive, and dimethylacetamide
(DMA) as the solvent. The desired product 3aa was obtained
in 18% yield after 12 h at 80 °C, along with the byproducts
biphenyl 4aa (17%) and benzophenone 5aa (18%) (Table 1,
entry 1). The high degree of dimerization and decarbonylation
that was observed in this reaction demonstrates the central
challenge for successful application of this type of trans-
formation. In order to address this challenge, we began by
screening three solvents (DMF, DMPU, and DMSO) to
observe the effects on yield of the desired cross-coupling
product and the byproducts. Unfortunately, these solvents
either did not promote the transformation (DMPU and
DMSO) (Table 1, entries 2 and 3) or gave a low yield of
3aa (DMF) (Table 1, entry 4). Based on these results, DMA
was identified as the best solvent choice and was used in all
subsequent reactions. When we probed the impact of different
aryl halides or pseudohalides on the reaction yields, it was
found that phenyl iodide gave the same yield of 3aa compared
to phenyl bromide, but biphenyl 4aa formation increased
(23%) (Table 1, entry 5). The biphenyl and benzophenone
B
DOI: 10.1021/acs.orglett.8b00114
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Scheme 4. Substrate Scope of Aryl Triflates
Scheme 5. Substrate Scope of Anhydrides
a
Reactions performed on a 0.1 mmol scale.
Scheme 6. Scale-up the Transformation on 1 mmol Scale
a
b
Reactions performed on a 0.1 mmol scale. 2 equiv of aryl triflate
c
used. 1.5 equiv of aryl triflate employed.
We next turned our attention to the cyclic anhydride scope
(Scheme 5). Compared with cis anhydride 1a, the diastereo-
meric trans anhydride 1b exhibited increased reactivity,
affording 3bj and 3bm in 91 and 94% yield, respectively,
with no loss of stereochemical fidelity. Unsaturated anhydrides,
such as cis-cyclohexenedicarboxylic anhydride 1c and its
dimethyl-substituted analogue 1d, were successful coupling
partners under our reaction conditions (73−92% yield), as was
cis-cyclopentyl succinic anhydride 1e (71−82% yield). Notably,
we also were able to generate acyclic products 3fe, 3fd, 3gd, and
3gj in 72−87% yield by using monocyclic succinic anhydrides
1f and 1g. In the case of 1g, the stereochemical information was
retained in the products.
example using cyclic anhydrides in a cross-electrophile coupling
reaction. A broad array of valuable γ-keto acid building blocks
can be generated with good functional group tolerance and
excellent stereochemical fidelity.
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.8b00114.
To test the scalability, 1 mmol of cis anhydride 1a was
coupled with phenyl triflate 2a. An 90% yield of 3aa was
obtained with 20 mol % nickel loading. The yield of 3aa
dropped to 65% when the catalyst loading was decreased to 10
mol % (Scheme 6).
In summary, we have successfully developed a Ni-catalyzed
desymmetrizing cross-electrophile coupling of cyclic meso-
anhydrides with aryl triflates. To our knowledge, this is the first
Experimental procedures, characterization data, and
NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: pwalsh@sas.upenn.edu.
*E-mail: ias_jymao@njtech.edu.cn.
C
DOI: 10.1021/acs.orglett.8b00114
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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Jianyou Mao: 0000-0003-0581-3978
Patrick J. Walsh: 0000-0001-8392-4150
Author Contributions
∥J.M. and L.S. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors acknowledge the Nanjing Tech University and
Natural Science Foundation of Jiangsu Province, China
(BK20170965) for financial support. P.J.W. thanks the US
National Science Foundation (CHE-1464744). We are grateful
for financial support by the SICAM Fellowship by Jiangsu
National Synergetic Innovation Center for Advanced Materials.
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