Nickel-catalyzed Heck reaction of cycloalkenes using aryl sulfonates and pivalates

Article abstract of DOI:10.1039/d1cc00634g

Nickel-catalyzed Heck reaction of cycloalkenes delivers unusual conjugated arylated isomers. Nickel(0) catalysts ligated by chelating dialkylphosphines effectively activate not only aryl triflates as electrophiles, but also less reactive aryl mesylates, t

Full text of DOI:10.1039/d1cc00634g

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Nickel-catalyzed Heck reaction of cycloalkenes
using aryl sulfonates and pivalates†
Cite this: Chem. Commun., 2021,
57, 3933
b
Jianrong Steve Zhou, *a Xiaolei Huang,
Shenghan Teng ‡b and
b
Received 3rd February 2021,
Accepted 12th March 2021
Yonggui Robin Chi
DOI: 10.1039/d1cc00634g
rsc.li/chemcomm
Nickel-catalyzed Heck reaction of cycloalkenes delivers unusual 2,3-dihydrofuran and N-Boc-dihydropyrrole derivatives, which
conjugated arylated isomers. Nickel(0) catalysts ligated by chelating involved fast isomerization of the initial Heck isomers as com-
dialkylphosphines effectively activate not only aryl triflates as pared to more stable ones.4e Nickel(0) catalysts can effectively
electrophiles, but also less reactive aryl mesylates, tosylates and activate strong C–O bonds in aryl pivalates, mesylates and
pivalates. The omission of bases allows nickel hydride species to tosylates.6 The oxidative addition of nickel(0) complexes to
exist long enough to perform in situ olefin isomerization of initial organic electrophiles is exogonic and has a lower barrier than
Heck adducts.
analogous palladium complexes. Additionally, arylnickel(II)
species can have a faster insertion of alkenes than palladium
Palladium catalysts have been working horses of Heck reaction, analogues, although the subsequent b-hydrogen elimination
which routinely arylates alkenes and provides aryl olefins after from alkylnickel(II) species may be slower.7
syn b-hydrogen elimination.1 One limitation, however, is the
In typical Heck reactions of cyclic alkenes, non-conjugated
slow oxidative addition of common palladium(0) complexes isomers are usually formed as major isomers, owing to syn
towards unactivated aryl electrophiles such as mesylates, tosylates requirement of b-hydrogen elimination,8 which formed the
and pivalates. For example, Pd-catalyzed intermolecular Heck basis of asymmetric Heck reaction of cycloalkenes.9 Our group
reaction of tosylates is limited to alkenyl and activated heteroaryl previously reported palladium-catalyzed Heck reactions that
ones.2
afforded conjugated arylcycloalkenes using aryl triflates and
The application of cheap, easily available nickel complexes bromides.10 Mechanistically, palladium hydride species, under
in Heck-type reactions dates back to the late 1980s, which has optimal conditions, promoted extensive alkene migration of
enabled Heck-type reactions of various types of alkenes of the initially Heck isomers into conjugation with the added
different electronic properties.3 For example, nickel/dppf aryl rings.
enabled Heck reaction of styrenes with aryl pivalates and
Aryl electrophiles herein are expanded beyond reactive tri-
tosylates leading to (E)-stilbenes.3f In another case, nickel/1, flates, including more challenging aryl mesylates, tosylates and
4-bis(dicyclopentylphosphino)butane promoted branched-selective pivalates. Usually, during the synthesis of conjugated arylalkenes,
arylation of a-olefins using aryl triflates, mesylates, tosylates and cross-coupling reactions using alkenyl electrophiles or alkenyl
carbamates.3i Recently, there has been a surge of interest in metal reagents are required otherwise.11 These arylated cycloalkenes
applying nickel catalysts to achieve asymmetric Heck-type reac- are often used in the stereoselective synthesis of natural products12
tions4 and domino bifunctionalization of alkenes.5 For example, and medicines.13 Importantly, there is increasing recognition in
our group disclosed nickel-catalyzed asymmetric Heck reaction of medicinal research that incorporation of saturated carbocycles with
distinct 3D shapes, in place of flat (hetero)aryl rings, can help to
develop high-affinity binders and/or prevent promiscuous binding.14
a State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical
Herein, we disclose the nickel-catalyzed Heck process of
Genomics, School of Chemical Biology and Biotechnology,
cycloalkenes, which affords conjugated isomers of arylalkenes.
Initially, we used a model reaction of 4-methoxyphenyl triflate
and cyclopentene and aimed to optimize nickel catalysts
(Fig. 1). In the screening of common diphosphines, we found
that 1,2-bis(dicyclohexylphosphino)ethane (dcype) afforded an
83% yield of 1-arylcyclopenteene 2a as the sole isomer detected
in the mixture. No allylic Heck isomers were detected in the
Peking University Shenzhen Graduate School, Room F312, 2199 Lishui Road,
Nanshan, Shenzhen 518055, China. E-mail: jrzhou@pku.edu.cn
b Division of Chemistry and Biological Chemistry, School of Physical and
Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link,
637371, Singapore
† Electronic supplementary information (ESI) available: Experimental procedures
and characterization of isolated products. See DOI: 10.1039/d1cc00634g
‡ Shenghan Teng is co-first author of this work.
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Fig. 1 Optimizations of diphosphines for the nickel-catalyzed model
reaction.
early hours of the reaction (by GC and GCMS). Dippe led to a
76% yield. At 1 mmol scale, 83% conversion and 72% yield of
2a were detected after 72 hours, along with some anisole as a
side product. Dcypp and dcypb on propylene and butylene
backbones, however, afforded o20% yield of 2a, along with
reduction to arene as the main side reaction. Nickel complexes
of chelating diphenylphosphines such as dppe, dppp and dppb
had very low reactivity toward aryl triflate and no olefin inser-
tion occurred. In the presence of nickel complexes of dppf,
Xantphos and DPEphos, however, high conversion of aryl
triflate was detected, but the reduction to anisole became the
main process. Moreover, a diphospholane Ph-BPE formed a
very active nickel catalyst, which delivered 2a in 99% yield.
Nickel salts of chloride, bromide, iodide, acetate and acetoace-
tate can form active nickel(0) catalysts of dcype in situ.
Scheme 1 Heck reaction of (hetero)aryl triflates with cycloalkenes, styr-
enes and aliphatic olefins.
procedure also produced arylcycloalkenes in good yields from
DMA was the optimal solvent for this process, while in other cyclohexene, cycloheptene and cyclooctene (2x–z), but a low yield
polar solvents such as DMF, NMP and DMSO, the model Heck from cyclononene. 3-Phenylcyclohexene was also tested, but it
reaction also proceeded well. Zinc dust from Aldrich with had lower reactivity.
particle size o10 mm was chosen to reduce (dcype)NiCl2 to
In anisylation of 1-octene, nickel/dcype afforded full con-
the active nickel(0) species. No external bases were added, and version and 33% yield of three Heck isomers (branched/linear
thus zinc dust also helped to reduce nickel hydride species to 4.4 : 1). The main isomer 3a was derived from fast olefin
nickel(0). Moreover, activated molecular sieves were added to isomerization of the initial Heck adduct. Nickel/Ph-BPE
prevent unwanted hydrolysis of aryl triflates at high tempera- improved branched selectivity to 14 : 1, although the yield
tures caused by trace amounts of water in DMA.
(35%) was not better and the reduction still remained
Next, we used the Ni(OAc)2/dcype catalyst in Heck reactions significant. In the reaction of cyclohexylethene, internal aryla-
of cyclopentene as a model cycloalkene with a wide range of aryl tion was the dominant process to yield adduct 3b as the
triflates (Scheme 1). Many aryl triflates reacted efficiently, sole isomer. The internal regioselectivity observed herein is
including those with electron-donating and withdrawing opposite to terminal arylation of allylbenzene as reported by
groups (2j–p), as well as those with ortho-substituents on the Watson et al.3f
aryl rings (2l, 2r). Polar groups, esters and nitriles were compa-
The procedure was also applied to anisylation with styrene
tible (2q–s), but ketones and aldehydes underwent side reactions and trans-phenyl-1-propene, affording (E)-stilbene derivatives3f
including aldol condensation. Triflates of nitrogen-containing 3c and 3d selectively. In the reaction of styrene, nickel/dcype
heterocycles, quinoline and benzothiazole gave the desired furnished only 30% conversion and 30% of 3c, which was
adducts in good yields (2v–w), but not pyridyl ones. The optimal improved to full conversion and 85% yield by nickel/dppp.
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Scheme 2 Heck reaction of a model aryl mesylate and tosylate.
The nickel/diphosphine catalysts can effectively activate aryl
mesylates and tosylates. In a model study of 2-naphthyl mesylate,
for example, nickel/dcype furnished 40% of product 2t along with
50% yield of naphthalene. After fine-tuning of the catalysts,
nickel/dppp helped to minimize the reduction and produced
adduct 2t in 83% yield in 1,4-dioxane (see Scheme 2a). Nickel/
dppp also afforded a 60% yield of 2t from 2-naphthyl tosylate,
along with some naphthalene. The yield of 2t was improved to
85% yield, on using strongly donating Ph-BPE as ancillary ligands
in DMF (Scheme 2b).
Nickel/Ph-BPE also efficiently promoted the Heck reaction of
aryl pivalates with cyclopentene. Aryl pivalates with both
electron-rich and electron-deficient groups on phenyl rings
(2j, 2n, 2p) reacted with cyclopentene in moderate yields,
while reduction accounted for most of the material balance
(Scheme 3a). Notably, the nickel(0) catalysis was not impeded
by extended p rings such as phenanthrene and quinoline (4l–o).
The reactions of cyclohexene and cycloheptene also gave excel-
lent yields (4p–q). But coupling with 1-octene failed to occur
with less than 10% conversion of the 2-naphthyl pivalate and
reduction detected. Another catalyst nickel/dippe promoted
similar Heck reactions and provided conjugated isomers in
50–70% yields in most cases (Scheme 3b). At 1 mmol scale, 76%
conversion and 67% yield of 2t were received after 72 h, in the
presence of nickel/(R,R)-Ph-BPE; with the dippe ligand, 100%
conversion and 71% yield of 2t along with some naphthalene.
Notably, in the model reaction of 2-naphthyl pivalate with
cyclopentene under Watson’s conditions, Ni(cod)2/dppf
afforded 81% conversion and the allylic isomer in 60% yield
(allylic vs. conjugated isomers 14 : 1). Details: 10% Ni(cod)2,
12% dppf and K3PO4 in toluene; heating at 125 1C for 36 h.3f
Obviously, isomerization of the initial Heck products was
absent due to fast removal of nickel hydride species by K3PO4
at high temperature. Under another Watson’s conditions (10%
NiCl2DME, 12% dppf and zinc dust), only 20% conversion and
reduction were detected without any Heck isomer formed. For
example, on reacting with 1-octene, Ni(cod)2/dppf provided
83% conversion and Heck isomers with 47% yield (branched/
linear ratio 1 : 4.7). Thus, its terminal selectivity with a-olefins
was opposite to our internal selectivity (see 3a in Scheme 1).
In summary, nickel complexes ligated through strongly donating
diphosphines, for example, dcype and Ph-BPE, catalyzed selective
Heck reaction of cycloalkenes to produce conjugated arylalkenes
exclusively. In contrast, non-conjugated isomers were produced
under other Ni-catalyzed Heck procedures.3f,3m As a key feature,
external bases were intentionally omitted so that nickel hydride
Scheme 3 Heck reaction of aryl pivalates and cycloalkenes.
species can live long enough to allow extensive olefin isomerization
of the initial Heck isomers.
We acknowledge financial support from Peking University
Shenzhen Graduate School and Shenzhen Bay Laboratory Institute
of Chemical Biology for JSZ, Nanyang Technological University,
GlaxoSmithKline and the Singapore Economic Development Board
Trust Fund (2017 GSK-EDB Green & Sustainable Manufacturing
Award) and A*STAR Science & Engineering Research Council (AME
IRG A1783c0010) for YRC.
Conflicts of interest
There are no conflicts to declare.
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