Nickel-Catalyzed 1,2-Diarylation of Alkenyl Carboxylates: A Gateway to 1,2,3-Trifunctionalized Building Blocks

Article abstract of DOI:10.1002/anie.201913062

A nickel-catalyzed conjunctive cross-coupling of alkenyl carboxylic acids, aryl iodides, and aryl/alkenyl boronic esters is reported. The reaction delivers the desired 1,2-diarylated and 1,2-arylalkenylated products with excellent regiocontrol. To demonstrate the synthetic utility of the method, a representative product is prepared on gram scale and then diversified to eight 1,2,3-trifunctionalized building blocks using two-electron and one-electron logic. Using this method, three routes toward bioactive molecules are improved in terms of yield and/or step count. This method represents the first example of catalytic 1,2-diarylation of an alkene directed by a native carboxylate group.

Full text of DOI:10.1002/anie.201913062

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
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Accepted Article
Title: Nickel-Catalyzed 1,2-Diarylation of Alkenyl Carboxylates: A
Gateway to 1,2,3-Trifunctionalized Building Blocks
Authors: Joseph Derosa, Taeho Kang, Van T. Tran, Steven
Wisniewski, Malkanthi K. Karunananda, Tanner C. Jankins,
Kane L. Xu, and Keary Mark Engle
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201913062
Angew. Chem. 10.1002/ange.201913062
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10.1002/anie.201913062
Angewandte Chemie International Edition
COMMUNICATION
Nickel-Catalyzed 1,2-Diarylation of Alkenyl Carboxylates: A
Gateway to 1,2,3-Trifunctionalized Building Blocks
Joseph Derosa†[a], Taeho Kang†[a], Van T. Tran[a], Steven R. Wisniewski[b], Malkanthi K. Karunananda[a],
Tanner C. Jankins[a], Kane L. Xu[a], and Keary M. Engle[a]*
of carboxylic acids as diversifiable starting materials and their
abundance as chemical feedstocks,[9,10] we envisioned that the
development of
alkenes would be synthetically enabling. Hence, the goal of the
present study was to demonstrate the feasibility of using free
alkenyl carboxylic acid starting materials in nickel-catalyzed
conjunctive cross-coupling (Scheme 1C).
Abstract: A nickel-catalyzed conjunctive cross-coupling of alkenyl
carboxylic acids, aryl iodides, and aryl/alkenyl boronic esters is
reported. The reaction delivers the desired 1,2-diarylated and 1,2-
arylalkenylated products with excellent regiocontrol. To demonstrate
the synthetic utility of the method, a representative product is
prepared on gram scale and then diversified to eight 1,2,3-
trifunctionalized building blocks using two-electron and one-electron
logic. Using this method, three routes toward bioactive molecules
are improved in terms of yield and/or step count. This method
represents the first example of catalytic 1,2-diarylation of an alkene
directed by a native carboxylate group.
a
carboxylate-directed[11] 1,2-diarylation of
Scheme 1. Background and Synopsis of Current Work
A. Comparison of different approaches to directed alkene difunctionalization
auxiliary approach (3 steps)
amide
coupling
NH2
hydrolysis
NH2
O
N
N
Alkene starting materials serve as ubiquitous chemical
feedstocks that can be readily transformed in a variety of ways
to build complex molecules.[1] Transition-metal-catalyzed
conjunctive cross-coupling has garnered widespread interest in
recent years as a powerful tool for installing two different groups
across a C–C π-bond.[2] Traditionally, 1,2-diarylation methods
have been largely limited to conjugated alkene substrates; in this
case, after the key 1,2-migratory insertion event, the an
electronically stabilized allyl or benzyl metal species is formed,
from which β-H elimination is sluggish.[3] In an effort to expand
this mode of reactivity to unactivated, nonconjugated alkenes,
our lab and other groups have employed an auxiliary-based
chelation control strategy to stabilize the analogous alkyl metal
intermediate as a metalacycle.[4] Specifically, our laboratory has
developed a suite of modular nickel-catalyzed alkene 1,2-
difunctionalization reactions, in which reactivity and selectivity
are facilitated by an 8-aminoquinoline (AQ) amide-based
bidentate auxiliary[5] through the presumed intermediacy of 5-
and 6-membered nickelacycles.[4a,6] Practically speaking, the
necessity for installation and removal of the AQ-directing group
greatly diminishes the synthetic utility of such methods, requiring
at least two concession steps (Scheme 1A).
O
[A]
R
R
1,2-difunctionalization
HO
HO
n
n
[B]
n = 1, 2
native directing group approach (1 step)
B. Previous work: nickel-catalyzed 1,2-diarylation of simple alkenyl amides
amide
coupling
cat. Ni
cat. DMFu
O
O
O
Ar2
Ar1
R
R
HO
N
R
Ar1–I
Ar2–B(nep)2
N
R
n
n
[R2NH]
n
n = 1, 2
(diverse amines)
C. This work: nickel-catalyzed 1,2-dicarbofunctionalization of alkenyl carboxylic acids
Ar2
O
Ar2
O
cat. Ni
[X]
Ar1
[X]
Ar1
Ar1–I
Ar2–B(nep)
HO
HO
diversification
(1e– or 2e– logic)
To initiate our investigation, we elected to use 3-butenoic acid
1a as our standard substrate, with 4-iodotoluene and
phenylboronic acid neopentyl glycol ester (PhB(nep)) as
coupling partners, and Ni(cod)2 as the precatalyst (Table 1).
After extensive optimization, we were able to identify “ligand-
free” conditions that delivered the desired product in 77%
isolated yield (entry 1). Key findings were that sterically bulky
secondary and tertiary alcohol solvents were beneficial, metal
hydroxide bases (particularly with sodium as the countercation)
led to enhanced reactivity, and neopentyl glycol boronic esters
outperformed other organoboron nucleophiles. Under our
previously published reaction conditions for simple alkenyl
amide substrates, the desired product could be detected in only
15% yield with ~20% Mizoroki–Heck product and ~10%
hydroarylation product (entry 2). Interestingly, the use of
commonly employed ancillary ligands such as bipyridine and
triphenylphosphine resulted in only Mizoroki–Heck byproducts
and Suzuki–Miyaura biaryl formation with trace amount of
desired product (entries 3 and 4). Aryl bromides were found to
be incompetent coupling partners (entry 5). The corresponding
free boronic acid gave the product in low yield, while the pinacol
boronic ester reacted in moderate yield (entries 6 and 7).[16]
Various Ni(II) precatalysts were ineffective (entry 10).
Recently, we developed
a nickel-catalyzed 1,2-diarylation
reaction with a diverse array of simple alkenyl amides using
dimethyl fumarate (DMFu) as ligand, which obviates the need for
strong directing group and enables native amide groups to serve
as efficient directors in conjunctive cross-coupling (Scheme
1B).[7] We reasoned that the utility of this chemistry could be
enhanced if other functional groups commonly encountered in
synthesis could serve as directing groups.[8] Given the versatility
[a]
[b]
J. Derosa, T. Kang, V. T. Tran, Dr. M. K. Karunananda, T. C.
Jankins, K. L. Xu, Dr. K. M. Engle
Department of Chemistry, The Scripps Research Institute, 10550
North Torrey Pines Road, La Jolla, California 92037, United States
E-mail: keary@scripps.edu
Dr. S. R. Wisniewski
Chemical & Synthetic Development, Bristol-Myers Squibb, 1 Squibb
Drive, New Brunswick, New Jersey 08903, United States
Supporting information for this article is given via a link at the end of
the document.
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COMMUNICATION
Table 1. Optimization of Reaction[a]
Me
Me
O
B
15 mol% Ni(cod)2
2 equiv NaOH
Me
O
I
O
+
+
O
HO
HO
Me
(2 equiv)
[B(nep)]
s-BuOH, 50 ºC, 12 h
2a
% Yield 2ab
1a
(2 equiv)
Entry
variation from standard conditions
none
1
2
3
4
5
81 (77)c
15
conditions for diarylation of alkenyl amides (Ref. 6)d
with 15 mol% bipyridine
n.d.
with 30 mol% PPh3
< 5%
n.d.
bromobenzene instead of iodobenzene
6
7
PhB(OH)2 instead of PhB(nep)
PhBpin instead of PhB(nep)
16
51
8
dioxane instead of s-BuOH
30
9
KOH instead of NaOH
38
NiCl2, NiBr2, Ni(acac)2, or NiI2 instead of Ni(cod)2
r.t. instead of 50 °C
10
11
n.d.
29
[a] Reaction conditions: 1a (0.1 mmol), 0.1 M s-BuOH. bPercentages represent 1H NMR yields using CH2Br2 as internal standard; n.d. = not detected.
d
cValues in parentheses are isolated yields. Reaction conditions: 15 mol% Ni(cod)2, 15 mol% dimethylfumarate, 1.5 equiv ArI, 1.5 equiv ArB(nep), 2 equiv
NaOH, 0.1 M i-BuOH at r.t.
Having identified optimized reaction conditions, we next
explored the scope and limitations of this methodology by
testing other representative alkenyl carboxylates (Scheme
2). Given that previous methods in the literature employing
monodentate N(sp2)- or O(sp2)-based directing groups are
incompatible with internal alkenes, we were delighted to
find that the present 1,2-diarylation reaction took place with
both E- and Z-configured alkenes, giving the final products
3a and 3b as single regio- and diastereoisomers, albeit in
low yields. The reaction is highly sensitive to the alkene
substitution pattern and the distance between the
carboxylate and the alkene, as 1,1-disubstituted, α-
substituted, and γ,δ- or δ,ε-unsaturated alkenes did not
react well.[17]
hindered aryl iodides, alkenyl iodide, and alkynyl iodide
coupling partners were incompatible under the optimized
reaction conditions.
Next, we investigated the nucleophile scope of the
reaction using 1-iodo-3,5-dimethoxybenzene as the
electrophilic component. In general, a wide range of
electron-rich and electron-poor ArB(nep) coupling partners
performed well under optimized conditions, giving the
desired products in good to excellent yield (2m–2v).
Tethered alcohols and ketones could be tolerated in
excellent yields (2p and 2v). In order to expand the utility of
this reaction platform, we wondered whether alkenyl B(nep)
nucleophiles
would
be
compatible
toward
1,2-
alkenylarylation. Gratifyingly, several alkenyl coupling
partners were competent, delivering the corresponding 1,2-
difunctionalized products in good to excellent yields (2w–
2z). Notably, this reactivity allowed for the installation of
styrenyl fragments that could be diversified downstream
(2x), along with a vinyl cyclopropane motif (2z). Similar to
the trend observed with aryl iodide coupling partners,
heterocycle-containing B(nep) coupling partners were found
to be incompatible at this stage of development.
Scheme 2. Preliminary Alkene Scope[a]
O
Ph
O
Ph
Et
p-Tol
HO
HO
p-Tol
Me
(±)-3a, 26%
(>20:1 d.r.)
(from E)
(±)-3b, 28%
(>20:1 d.r.)
(from Z)
[X-ray]
In an effort to showcase the synthetic versatility of
carboxylic acid directing group, we conducted a series of
diversifications on standard product 2a (Scheme 3), which
could be readily prepared on gram scale. Using the
classical two-electron reactivity associated with carboxylic
acid starting materials, we converted the difunctionalized
products into the corresponding ester, amide, alcohol, and
amine (4a–4d), enabling access to valuable bioactive
substructures (vide infra). Additionally, viewing the
carboxylic acid through the lens of one-electron synthetic
logic,[9,10] we examined several decarboxylative cross-
coupling methods through the intermediacy of a redox-
active ester. Indeed, decarboxylative arylation provided
modular entry into 1,2,3-triarylpropane motifs (4e).
Moreover, decarboxylative vinylation and borylation gave
the corresponding products in moderate yield, effectively
introducing functional handles for further modification (4f
and 4g). Finally, decarboxylative Giese addition provided
δ,ε-diarylated compound 4h, the product of a formal double
homologation.
limitations
(<10% yield)
O
O
HO
O
Me
n
HO
γ,δ-unsaturated
alkene (n = 1)
or
δ,ε-unsaturated
alkene (n = 2)
HO
Me
1,1-disubstituted
α-substituted
alkene
alkene
[a] Reactions performed on 0.1 mmol scale. Percentages represent
isolated yields.
We moved on to examine the electrophile scope of the
reaction using PhB(nep) as the nucleophilic coupling
partner (Table 2). Aryl iodides bearing electron-donating
substituents in the para- and meta-positions reacted in
good to excellent yields to deliver the desired products (2a–
2j). Notably, aryl iodides containing –Cl and –NHAc groups
were compatible in this reaction, allowing for potential
downstream modification (2d and 2f). Electron-withdrawing
substituents resulted in diminished reactivity, but still
delivered the desired products in moderate yields (2k and
2l). In general, heterocycle-containing and sterically
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Table 2. Electrophile and Nucleophile Scope[a]
O
R/Ar2
O
15 mol% Ni(cod)2
2 equiv NaOH
I
O
O
B(nep)
+
+
Ar1
R
R
HO
HO
s-BuOH, 50 ºC, 12 h
1a
2a–2z
electrophile scope
Ph
i-Pr
Me
NHAc
Ph
O
Ph
O
Ph
O
Ph
HO
HO
HO
HO
2a, 75%
[X-ray]
2b, 71%
2c, 84%
2d, 66%
OMe
Me
Cl
OMe
O
Ph
O
Ph
Ph
O
Ph
HO
OMe
HO
Me
HO
HO
2e, 70%
2f, 65%
Ph
2g, 80%
2h, 74%
OH
O
Ph
O
Ph
O
Ph
O
Me
HO
HO
F
HO
OMe
HO
O
2i, 72%
2j, 81%
2k, 32%
2l, 26%
aryl nucleophile scope
OH
R
F
OMe
OMe
OMe
R = Me (2m), 81%
R = OMe (2n), 59%
R = t-Bu (2o), 76%
R =CF3 (2p), 76%
O
O
O
HO
OMe
HO
OMe
HO
OMe
2r, 58%
2q, 81%
F3C
O
CF3
OMe
COMe
OMe
Me
OMe
OMe
O
O
O
HO
OMe
HO
OMe
HO
OMe
HO
OMe
2s, 78%
2u, 80%
2v, 80%
2t, 77%
alkenyl nucleophile scope
Bn OMe
Ph
OMe
t-Bu OMe
OMe
O
O
O
O
HO
OMe
HO
OMe
HO
OMe
HO
OMe
2w, 83%
2x, 86%
2y, 48%
2z, 52%
limitations (<10% yield)
Me
B(nep)
BPin
F3C
I
Ph
I
I
I
OHC
I
B(nep)
BocHN
B(nep)
TIPS
Ph
N
BocN
BocN
Me
[a] Reactions performed on 0.1 mmol scale. Percentages represent isolated yields.
Scheme 3. Product Diversification
Ph
O
Ph
a
e
f
Ph
p-Tol
p-Tol
MeO
4e, 56%
4a, 93%
Ph
O
Ph
b
c
p-Tol
p-Tol
p-Tol
N
O
Ph
2e– logic
1e– logic
O
4b, 66%
p-Tol
4f, 32%
HO
Ph
2a, 80% (1.02 g)
[5 mmol scale]
Ph
g
p-Tol
p-Tol
pinB
O
HO
[in situ]
4c, 95%
4g, 50%
O
Ph
Ph
d
h
p-Tol
H2N
HO
MeO
($2.92/g)
[in situ]
4d, 64%
4h, 41%
[a] 12M HCl (aq.), MeOH, reflux. [b] Morpholine, HATU, pyridine, DCM, 25 ºC. [c] LiAlH4, anhydrous THF, 0 ºC to 25 ºC. [d] (i) DPPA, Et3N, t-BuOH, 100 ºC;
(ii) 6 M HCl. [e] (i) TCNHPI, DIC, 10 mol% DMAP, 1,4-dioxane, 75 ºC; (ii) 20 mol% NiCl2•6H2O, 20 mol% bathophen, PhB(OH)2, Et3N, 1,4-dioxane/DMF, 75
º
º
ºC. [f] (i) TCNHPI, DIC, 10 mol% DMAP, DCM, 25 C; (ii) 10 mol% Ni(acac)2•xH2O, 10 mol% bipy, alkenyl zinc reagent, DMF, 25 C. [g] (i) NHPI, DIC, 10
mol% DMAP, DCM, 25 ºC; (ii) 30 mol% Cu(acac)2, B2Pin2, LiOH•H2O, MgCl2, 1,4-dioxane/DMF, 25 ºC. [h] (i) NHPI, DIC, 10 mol% DMAP, DCM, 25 ºC; (ii) 20
mol% Ni(ClO4)2 •6H2O, Zn, LiCl, methyl acrylate, MeCN, 25 ºC.
Indeed, in the case of the IPR series of anti-tumor agents in
breast cancer treatments, we could access the desired
To illustrate the utility of this carboxylate-directed alkene
1,2-diarylation in synthesis, we tested the method in several
real-world scenarios involving biologically active target
compounds containing a 1,2-diaryl motif (Scheme 4).
carboxylic acid intermediate 2aa in a single step in 71%
yield compared to four steps in 33% yield.[12] Similarly,
carboxylic acid intermediate 2ab relevant to a family of
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10.1002/anie.201913062
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COMMUNICATION
fungicides was acquired in 70% in a single step.[13] A third
target, TRPV1 antagonist 2ad was synthesized in a 2-step
sequence involving our developed reaction and an
interrupted Curtius rearrangement.[14] In addition to
reducing the step count, our method offers a new divergent
platform for probing structure–activity relationships in future
industrial campaigns.
either an L-type[11a,e,f] or X-type fashion[11b,c,d,g], and the
coordination mode could be dynamic throughout the
catalytic cycle. For simplicity the L-type binding mode is
shown in Scheme 5 in analogy to our earlier amide-directed
system.[7a] First, nickel(0) oxidatively adds to the aryl iodide,
and coordinates the alkene substrate. Next, 1,2-migratory
insertion takes place to give carboxlate-bound alkyl-
nickelacycle. The involvement of closed-shell intermediates
is supported by the observation of a single diastereomer in
the case of syn-1,2-diarylated product with an internal
alkene starting material. Subsequent transmetalation
followed by reductive elimination yields the desired product.
The competitive formation of γ-arylated Heck-type
byproducts in our early optimization efforts is consistent
with the intermediacy of the proposed alkyl-nickelacycle.
Scheme 4. Applications of 1,2-Diarylation Reaction[a]
O
O
O
O
Ref. 11
O
R
(4 steps)
N
HO
H
2aa, 71%
[current] 1 step
[previous] 4 steps
IPR series
anti-tumor agents
Scheme 5. Proposed Catalytic Cycle
O
O
Ar2
OPh
OPh
Ar1
+
Ar1
I
NaO
LnNi0
NaO
O
Ref. 12
O
O
reductive
elimination
oxidative addition/
substrate coordination
HO
R
(2 steps)
N
2a
HO
H
Ar2–B(nep)
Ar1–I
2ab, 70%
ONa
fungicides
ONa
[current] 1 step
[previous] 4 steps
O
OMe
O
NiII
standard
conditions
I
NiII
Ar1
L
Ar1
OMe
Ar2
N
H
H
1. DPPA
2. ArNH2
N
N
O
NaOR
O
ONa
HO
RO Bnep
2ad
TRPV1 antagonist
2ac, 61%
O
NiII
migratory insertion/
ligand exchange
transmetalation
Ar2
L
Bnep
NaI
Ar1
[current] 2 steps (24%)
[previous] 5 steps (19–25%)
OR
[a] Reactions performed on 0.1 mmol scale. Percentages represent
isolated yields.
In conclusion, we have demonstrated that a simple
carboxylate group can be used to direct nickel-catalyzed
1,2-diarylation of nonconjugated alkenes using aryl iodides
and aryl boronates in the absence of an ancillary ligand.
These products can be further manipulated to yield a wide
range of valuable building blocks that would be difficult to
synthesize using existing methods.
To gain insight into the reaction mechanism, we carried
out a series of preliminary kinetic experiments. First, we
compared the initial reaction rates of
a series of
arylboronates and aryl iodides with systematically varied
electronic characteristics. In our earlier work with
monodentate amide directing groups,[7] we found that
electron-rich aryl iodides led to faster reaction rates and
there was no influence of aryl boronate electronic
properties on rate. In contrast, in the present system we
observed no clear initial rate trends across either the aryl
boronate or aryl iodide series (Figure 1).[15]
Experimental Section
General Procedure: To an oven-dried 8-mL scintillation
vial equipped with a Teflon-coated magnetic stir bar were
added the alkene substrate (0.1 mmol), the appropriate aryl
iodide electrophile (0.2 mmol), and the appropriate aryl
boronic acid neopentylglycol ester (0.2 mmol). The vial was
then equipped with a septum cap, which was pierced by a
20-gauge needle and introduced into an argon-filled
glovebox antechamber. Once transferred inside the
glovebox, Ni(cod)2 (15 mol%), anhydrous NaOH (0.2 mmol),
and anhydrous sec-butanol (1 mL) were added. The vial
was sealed with a screw-top septum cap, removed from the
glovebox, and left to stir at 50 ºC for 12 h. After this time,
the reaction mixture was diluted with 1M HCl (15 mL) and
extracted with EtOAc (5 × 10 mL). The organic layers were
combined, and the solvent was removed in vacuo to leave
a yellow residue, which afforded pure product after silica
gel column chromatography or preparative thin-layer
chromatography (PTLC).
Figure 1. Hammett analysis of coupling partners in 1,2-Diarylation
Reaction
p-OMe p-Me
p-H
p-Cl
p-CF3
σ value
–0.27 –0.17
0.00
0.23
0.54
1.3
2.4
1.3
0.5
1.0
1.0
0.8
1.5
1.9
1.1
Ar B(nep) (krel
)
Ar
I
(krel
)
The lack of clear electronic influence of both coupling
partners eliminates many possibilities regarding the identity
of the turnover-limiting step. One possibility is that the
turnover-limiting step changes as a function of the aryl
group electronics. Alternatively, a step not involving either
of the two aryl groups could be turnover-limiting, such as
substrate binding or product dissociation. Additional details
on this and other aspects of the reaction mechanism are
currently under investigation in our lab.
A plausible catalytic cycle[18] for this nickel-catalyzed 1,2-
diarylation of alkenyl carboxylates is shown in Scheme 5.[7a]
Under the basic conditions, the substrate is expected to
exist primarily as the corresponding sodium carboxylate salt,
which could potentially coordinate to the nickel catalyst in
Acknowledgements
.
This work was financially supported by Bristol-Myers
Squibb (Unrestricted Grant), the National Science
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COMMUNICATION
[9]
J. M. Smith, S. J. Harwood, P. S. Baran, Acc. Chem. Res. 2018,
51, 1807–1817.
Foundation (CHE-1800280), the Alfred P. Sloan Fellowship
Program, and the Camille Dreyfus Teacher-Scholar
Program. We further acknowledge the NSF for a Graduate
Research Fellowship (DGE-1346837, J.D.), the Kwanjeong
Educational Foundation for a Graduate Fellowship (T.K.),
and Dr. Art Olson and Shirley King for funding a high school
internship (K.L.X.). We thank Professor Phil S. Baran for
helpful discussions. We further thank Prof. Arnold L.
Rheingold and Dr. Milan Gembicky (UCSD) for X-ray
crystallographic analysis.
[10] For examples of decarboxylative cross-coupling using redox-
active esters, see: a) J. Cornella, J. T. Edwards, T. Qin, S.
Kawamura, J. Wang, C.-M. Pan, R. Gianatassio, M. A. Schmidt,
M. D. Eastgate, P. S. Baran, J. Am. Chem. Soc. 2016, 138,
2174–2177; b) C. Li, J. Wang, L. M. Barton, S. Yu, M. Tian, D. S.
Peters, M. Kumar, A. W. Yu, K. A. Johnson, A. K. Chatterjee, M.
Yan, P. S. Baran, Science 2017, 356, eeam7355; c) J. T.
Edwards, R. R. Merchant, K. S. McClymont, K. W. Knouse, T.
Qin, L. R. Malins, B. Vokits, S. A. Shaw, D.-H. Bao, F.-L. Wei, T.
Zhou, M. D. Eastgate, P. S. Baran, Nature 2017, 545, 213–218.
For examples of carboxylate/carboxamide-directed C(sp3)–H
activation followed by decarboxylative coupling, see: d) J. C.
Beck, C. R. Lacker, L. M. Chapman, S. E. Reisman, Chem. Sci.
2019, 10, 2315–2319; e) M. Shang, K. S. Feu, J. C. Vantourout,
L. M. Barton, H. L. Osswald, N. Kato, K. Gagaring, C. W.
McNamara, G. Chen, L. Hu, S. Ni, P. Fernández-Canelas, M.
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Keywords: nickel • diarylation • carboxylic acid •
trifunctionalization
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This article is protected by copyright. All rights reserved.

10.1002/anie.201913062
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
J. Derosa†, T. Kang†, V. T. Tran, S. R.
Wisniewski, M. K. Karunananda, T. C.
Jankins, K. L. Xu, K. M. Engle*
Ar2
O
Ar2
O
cat. Ni
[X]
Ar1
[X]
Ar1
Ar1–I
Ar2–B(nep)
HO
HO
diversification
(1e– or 2e– logic)
Page No. – Page No.
Nickel-Catalyzed 1,2-Diarylation of
Alkenyl Carboxylates: A Gateway to
1,2,3-Trifunctionalized Building
Blocks
Easy as 1, 2, 3: Under nickel catalysis, alkenyl carboxylic acids undergo selective
1,2-diarylation. The resulting products can then be readily converted into diverse
1,2,3-trifunctionalized motifs via classical carboxylic acid interconversions and
modern decarboxylative cross-couplings.
This article is protected by copyright. All rights reserved.