Enantioselective Intermolecular Heck and Reductive Heck Reactions of Aryl Triflates, Mesylates, and Tosylates Catalyzed by Nickel

Article abstract of DOI:10.1002/anie.202011036

Nickel-catalyzed intermolecular Heck reaction of cycloalkenes proceeds well with aryl triflates, mesylates and tosylates in excellent enantiomeric ratios. The asymmetric reductive Heck reaction also works with a 2-cyclopentenone ketal, which is equivalent to conjugate arylation of the enone itself.

Full text of DOI:10.1002/anie.202011036

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Enantioselective Intermolecular Heck Reaction of Aryl Triflates,
Mesylates and Tosylates Catalyzed by Nickel
Authors: Xiaolei Huang, Shenghan Teng, Yonggui Robin Chi,
Wenqiang Xu, Maoping Pu, Yun-Dong Wu, and Jianrong
Steve Zhou
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202011036
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10.1002/anie.202011036
Angewandte Chemie International Edition
COMMUNICATION
Enantioselective Intermolecular Heck and Reductive Heck
Reactions of Aryl Triflates, Mesylates and Tosylates Catalyzed by
Nickel
Xiaolei Huang, Shenghan Teng,# Yonggui Robin Chi, Wenqiang Xu, Maoping Pu,# Yun-Dong Wu and
Jianrong Steve Zhou*
Abstract: Nickel-catalyzed intermolecular Heck reaction of
cycloalkenes proceeds well with aryl triflates, mesylates and tosylates
in excellent enantiomeric ratios. The asymmetric reductive Heck
reaction also works with a 2-cyclopentenone ketal, which is equivalent
to conjugate arylation of the enone itself.
cyclization of aryl halides to form oxindoles with quaternary
stereocenters (Scheme 1a),[5] but only a few examples with over
90% ee was reported. Lately, our group disclosed
nickel/semicorrin catalysts for asymmetric reductive Heck
cyclization of aryl halides, which afforded substituted indolines
(see Scheme 1b) and indanones.[6] More recently, Wang et al.
applied nickel/PyrOx catalysts to enantioselective reductive
cyclization of unactivated alkenes.[7] Notably, recent years also
Asymmetric Heck reaction[1] and reductive Heck reaction[2]
allow arylation of alkenes using readily available aryl halides and
sulfonates (see examples in Scheme 1). To this end, many
palladium-catalyzed methods have been developed and some
have been successfully utilized in stereoselective synthesis of
bioactive complex compounds. Unlike palladium, which is an
expensive, rare noble metal, nickel is an earth-abundant,
extremely cheap 3d metal. The latter is being produced over two
million tons a year. Nickel is more electropositive than palladium,
so oxidative addition of Ni(0) to aryl C-O bonds of mesylates,
tosylates and pivalates is exergonic and has lower barriers of
oxidative addition than that of Pd(0). In Heck reaction, b-insertion
of aryl nickel(II) species to alkenes has low barriers than Pd(II),
but b-hydride elimination from alkyl nickel(II) species is more
difficult than palladium(II).[3] To date, the mesylates and tosylates
in palladium-catalyzed Heck reaction have been limited to alkenyl
and electron-deficient heteroaryl ones. In contrast, nickel-
catalyzed Heck reaction occurred smoothly with mesylates,
tosylates and pivalates.[4] Until now, asymmetric variants of
nickel-catalyzed Heck and reductive Heck reactions still remain
under-developed and are limited to intramolecular cyclization. For
instance, in 2017, Desrosiers and Kozlowski et al. reported a
nickel chloride complex of QuinoxP* for enantioselective Heck
witnessed
a surge of interest in Ni-catalyzed asymmetric
bifunctionalization of alkenes.[8]
Herein, we disclose our finding on first examples of
asymmetric intermolecular Heck reaction using nickel catalysts.
Cheap aryl mesylates and tosylates, which are readily prepared
from phenols, coupled efficiently, as well as more reactive aryl
triflates. The nickel catalysts were also successfully applied to
asymmetric intermolecular reductive Heck reaction of a ketal
made from 2-cyclopentenone (Scheme 1c).
a) Asymmetric intramolecular Heck cyclization of aryl bromides
Br
Me
O
NiCl2(R,R)-QuinoxP*
Me
O
N
Me
Mn, LiI, Na2CO3, DMF
N
Me
Me
(Desrosiers et al. 2017)
5 examples with >90% ee
b) Asymmetric intramolecular reductive Heck cyclization of aryl chlorides
CN
R
R
Cl
O
O
Ni(OAc)2, semicorrin
N
O
N
O
N
HN
Mn, NaOAc, H2O, DMF
Ph
Ph
(Zhou et al. 2017)
most >90% ee
semicorrin
c) Asymmetric Intermolecular (reductive) Heck reaction of aryl sulfonates (this work)
t-Bu
[*†]
Prof. Dr. J. S. Zhou
Me
N
N
P
nickel catalyst
Y
State Key Laboratory of Chemical Oncogenomics, Key Laboratory
of Chemical Genomics, School of Chemical Biology and
Biotechnology, Peking University Shenzhen Graduate School,
2199 Lishui Road, Room F312, Nanshan District, Shenzhen
518055 (China)
Ar
(R,R)-QuinoxP*
Y
Ar-X
P
Zn, DMSO
Me
Y=O, NCbz
X = OTf
OMs
OTs
t-Bu
(R,R)-QuinoxP*
45 examples
most >90% ee
E-mail: jrzhou@pku.edu.cn
Mr. W. Xu, Prof. Dr. Y.-D. Wu
nickel catalyst
(R)-DuanPhos
H
O
O
O
O
Ar-OTf
Lab of Computational Chemistry and Drug Design, State Key
Laboratory of Chemical Oncogenomics, Peking University
Shenzhen Graduate School, Shenzhen (China)
Dr. M. Pu[#]
Shenzhen Bay Laboratory, Shenzhen 518055 (China)
Dr. X. Huang, Dr. Shenghan Teng,[#] Prof. Dr. Y. R. Chi
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University, 21 Nanyang Link, 637371
Singapore (Singapore)
P
P
Ar
H
Zn, water, DMSO
t-Bu
(R)-DuanPhos
7 examples
82-94% ee
t-Bu
Scheme 1. Nickel-catalyzed asymmetric Heck and reductive Heck
reactions (OTf = trifluoromethanesulfonyl, Ts = p-toluenesulfonyl, OMs =
methanesulfonyl, Cbz = benzyloxycarbamate)
For a model asymmetric Heck reaction, we initially chose 4-t-
butylphenyl mesylate 1a and 2,3-dihydrofuran 3a (Fig 1). After
extensive screening of nickel catalysts, we were gratified to find
that a complex of NiCl2[(R,R)-QuinoxP*] efficiently catalyzed the
model reaction to give desired product 4a in 85% yield and 99%
[#]
Co-first authors
Supporting information for this article is given via a link at the end
of the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.202011036
Angewandte Chemie International Edition
COMMUNICATION
ee in DMSO at 100 °C. The ratio of three isomers of Heck
products was 95/3/2 by GC and GCMS. The dominant isomer 4a
was formed via extensive double bond migration of initial Heck
adduct 4a' in situ. Aryl triflate and aryl tosylate also coupled as
well to give 4a in good yield and excellent ee values, although
about 10% of isomer 4a'' was produced. However, when p-tolyl
halides (Cl, Br, and I) were tested under the same conditions, the
desired isomer 4a decreased to about 70% among three isomers,
unfortunately (Fig 1). A stoichiometric amount of zinc dust
(particle size <10 µm; purchased from Aldrich) was also needed
to generate the active Ni(0) catalyst and to reduce nickel hydride
species back to nickel(0) at the end of each catalytic cycle, with
co-production of hydrogen gas.[4f] Without zinc dust, no desired
Heck adduct was detected. Notably, replacement by zinc powder,
manganese powder or indium powder significantly reduced the
yield of 4a. Moreover, addition of inorganic bases or alkylamines
did not improve the process. We noticed that no Heck adduct was
produced from the aryl mesylate in solvents other than DMSO
(see Table 1). In the reaction of the aryl triflate, Heck adduct 4a
was also formed in good yield in DMSO, but less than 10% in DMF
or DMA.
50% yield in DMSO, which was increased to 67% in DMF. 1-
Naphthyl triflate also delivered products 4s in a reasonable yield
(Scheme 2b). Moreover, several quinolyl triflates also became
suitable substrates (4t-v), but pyridyl triflates did not. To our
delight, the modified procedure was also applicable to alkenyl
triflates (4w-z), which were readily prepared from cyclic ketones.
NiCl2[(R,R)-QuinoxP*]
t-Bu
O
(a)
5 mol%
O
t-Bu
X
Zn 1.2 equiv, DMSO
100 oC, 48 h
4a
X = OTf 2a
X = OMs 1a
3a
OTf: 73% yield, 99% ee
OMs: 80% yield, 99% ee
Other examples
Me
Me
Me
Me
Me
4c
4b
4d
4e
OTf : 65% yield, 90% ee
OMs: 71% yield, 90% ee
62% yield, 90% ee
71% yield, 90% ee
66% yield, 91% ee
78% yield, 91% ee
48% yield, 97% ee
75% yield, 97% ee
Et
MeO
t-Bu
MeO
4g
4h
4f
4i
71% yield, 92% ee
72% yield, 92% ee
69% yield, 91% ee
62% yield, 91% ee
69% yield, 90% ee
68% yield, 90% ee
68% yield, 93% ee
79% yield, 93% ee
F
MeO
NiCl2[(R,R)-QuinoxP*]
PhO
F
MeO
4j
4l
O
4m
O
4k
O
5 mol%
O
Ar
Ar
Ar
ArX
61% yield, 93% ee
58% yield, 93% ee
62% yield, 92% ee
64 yield, 92% ee
68% yield, 94% ee
73% yield, 94% ee
64% yield, 92% ee
74 yield, 92% ee
Zn 1.2 equiv, DMSO
100 oC, 48 h
3a
4a
4a'
4a''
Me
Me
EtO2C
NC
O
Yield of 4a (%)
Ee of 4a (%) Ratio (4a/4a'/4a'')
ArX
F3C
4p
4n
4o
4q
52% yield, 87% ee
50% yield, 87% ee
64% yield, 94% ee
72% yield, 94% ee
p-t-BuC6H4OMs
p-t-BuC6H4OTf
p-t-BuC6H4OTs
p-MeC6H4Cl
OTf:
95/3/2
86/1/13
86/2/12
70/14/16
78/3/19
66/10/24
99
99
99
92
90
91
85
77
70
34
40
26
OMs:
48% yield, 96% ee
60% yield, 95% ee
Ni(cod)2 5 mol%
(R,R)-QuinoxP* 6 mol%
O
OTf
O
(b)
p-MeC6H4Br
p-MeC6H4I
i-Pr2NEt, DMF
100 oC, 48 h
4r
67% yield, 93% ee
2q
3a
other examples
Figure 1. Effect of aryl electrophiles on nickel-catalyzed Heck reaction
with 2,3-dihydrofuran. 2.5 and 10 mol% nickel used for ArOTf and
ArOTs.
N
N
N
4v
4s
4t
4u
72% yield, 98% ee
65% yield, 95% ee
74% yield, 94% ee
65% yield, 97% ee
With the optimal protocol in hand, we examined the scope of
aryl triflates and mesylates with 2,3-dihydrofuran 3a. As
summarized in Scheme 2a, various aryl triflates and mesylates
with alkyl groups on aryl rings smoothly reacted to afford the Heck
products in good yield with excellent ee values (4a-4g). The
configuration of the major Heck adducts was determined to be (R),
by comparison with optical rotation data of known compounds.[9]
The methoxy ethers (4h, 4i and 4k), diaryl ether (4j), aryl fluoride
(4l -m), benzotrifluoride (4n) and ester (4o) were all well tolerated.
In the case of p-cyanophenyl triflate (4p), the formation of
benzonitrile and biaryl accounted for the moderate yield of product
4z
4x
4y
MeO
4w
F
63% yield, 96% ee
72% yield, 95% ee
61% yield, 90% ee
70% yield, 97% ee
Scheme 2. (a) Intermolecular Heck reaction of 2,3-dihydrofuran of
(hetero)aryl triflates and mesylates; (b) Intermolecular Heck reaction
of (hetero)aryl and alkenyl triflates with extended p systems (cod =
1,5-cyclooctadiene. DIPEA = N,N,N-di-isopropylethylamine)
Aryl tosylates are more stable towards bases than triflates
during reactions and storage. The former are also much cheaper
to prepare, but they need palladium catalysts ligated by strongly
donating phosphines or N-heterocyclic carbenes for oxidative
addition. We found that the nickel catalyst of QuinoxP* allowed
aryl tosylates to react efficiently (Scheme 3). The aryl rings of
tosylates can carry electron-withdrawing esters (4e, 6k), electron-
donating groups of methoxy (4d) and dimethylamino (6l). In
particular, ortho substituents can be present on aryl rings (6g-j).
In those reactions, reduction to arenes were the main side
reactions, which accounted for most of the rest material.
4p. Additionally,
a hindered dihydrobenzofur-7-yl mesylate
provided adduct 4q in 60% yield.
In the investigation of 2-naphthyl sulfonates and other aryl
sulfonates carrying extended p rings under "standard" conditions
described in Scheme 2a, 2-naphthyl triflate unfortunately afforded
<30% yield of product 4r, while 2-naphthyl mesylate and tosylate
led to little products. The main side reaction was reduction to
arenes. Later, we switched the pre-catalyst to a mixture of
Ni(cod)2 and (R,R)-Quinoxp*, and added diisopropylethylamine to
convert nickel hydride species back to nickel(0) in the catalytic
cycle. The reaction of 2-naphthyl triflate delivered products 4r in
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10.1002/anie.202011036
Angewandte Chemie International Edition
COMMUNICATION
NiCl2[(R,R)-QuinoxP*]
the reaction is equivalent to asymmetric conjugate arylation of
cyclic enones using aryl electrophiles, which still remains an
elusive process at present. We found that a nickel chloride
complex of (R)-DuanPhos provided better yields and ee values of
the products than that of (R,R)-QuinoxP*. Electron-rich aryl
triflates reacted well (8a-d), as well as naphthyl and biphenyl
derivatives (8e-f). Unfortunately, electron-deficient aryl triflates
carrying trifluoromethyl and ester groups only afforded a trace
amount of products. Cyclohexenone ketals did not react, either.
We hypothesized that after aryl insertion, the nickel-carbon bond
in the key intermediate was protonated by water to release the
final products. When 2 equiv of D2O was added to a catalytic
reaction of 4-biphenyl triflate and 3c in DMSO, the b-hydrogen
syn to the aryl ring in isolated product 8d contained 32%
deuterium (33% deuterium before purification as estimated by
GCMS). The low extent of deuteration is attributed to trace
amounts of water in DMSO solvent. Consistent with this, no trace
amount of deuterium was incorporated to the product from
DMSO-d6.
O
10 mol%
O
ArOTs
Ar
Zn 1.2 equiv, DMSO
100 oC, 48 h
5
3a
Other examples
Me
Ph
MeO
Me
Me
6c
6b
4d
6a
64% yield, 93% ee
74% yield, 93% ee
71% yield, 94% ee
71% yield, 95% ee
Me
OEt
F3C
EtO2C
6f
4e
6g
6h
50% yield, 87% ee
70% yield, 94% ee
67% yield, 99% ee
60% yield, 96% ee
F
CF3
MeO2C
Me2N
6i
6l
6j
6k
58% yield, 98% ee
65% yield, 95% ee
66% yield, 98% ee
63% yield, 92% ee
Scheme 3. Examples of intermolecular Heck reaction of aryl tosylates
and of 2,3-dihydrofuran.
O
NiCl2[(R)-DuanPhos] 5 mol%
O
ArOTf
O
Ar
Zn 1 equiv, H2O 1 equiv
DMSO, 100 oC, 48 h
O
The nickel chloride complex of QuinoxP* also catalyzed the
arylation of N-Cbz-2,3-dihydropyrrole 3b as well; in comparison,
the more congested N-Boc derivative reacted very sluggishly. As
shown in Scheme 4, aryl triflates bearing alkyl groups smoothly
coupled to generate Heck products (7a-c) in reasonably good
yields and excellent enantioselectivities. 2-Naphthyl triflate
successfully coupled to afford 7d in 67% yields and 91% ee. While
electron-rich aryl triflates reacted efficiently, most electron-poor
aryl electrophiles gave poor yields with an exception of 4-
fluorophenyl triflate (7e-g). In cases that gave moderate yields,
significant reduction to arenes was observed. Reactions with
cyclopentene and cyclohexene, however, led to the formation of
conjugated Heck isomers as major products, however. Both aryl
mesylates and tosylates were also tested, but only low conversion
was detected.
8
3c
examples
t-Bu
Ar =
t-Bu
Et
Ph
8c
8b
8d
8a
82% yield, 90% ee
89% yield, 88% ee
84% yield, 92% ee
62% yield, 82% ee
PhO
MeO
8f
8g
8e
72% yield, 87% ee
88% yield, 90% ee
64% yield, 94% ee
Scheme 5. Asymmetric reductive Heck reaction of aryl triflates and a
2-cyclopentenone ketal.
In our preliminary mechanistic studies, we found that
[NiCl2(QuinoxP*)] was quickly reduced by zinc dust at RT in
DMSO to give a dark blue solution of [NiCl(QuinoxP*)]2 (31P
singlet at 23.3 ppm). It didn't react with 4-methoxyphenyl mesylate
at RT, while it reacted with the aryl triflate gave a complex,
unidentifiable mixture unfortunately. Treatment of the above
mixtures of aryl mesylate or triflate with 5 equiv dihydrofuran didn't
Cbz
Cbz
N
NiCl2[(R,R)-QuinoxP*] 5 mol%
N
Ar
ArOTf
Zn 1.2 equiv
DMSO, 100 oC, 48 h
7
3b
examples
Et
Me
t-Bu
o
afford any Heck adduct at RT. After heating at 100 C for 10 h,
Me
7b
Heck isomer 4a was detected by GC in 30-60% yields and 93%
ee. Additionally, [Ni(cod)(QuinoxP*)] (31P singlet at 34.0 ppm) was
prepared from Ni(cod)2 and QuinoxP*, but it didn't react with aryl
mesylate or triflate at RT.
7c
7d
7a
74% yield, 92% ee
72% yield, 92% ee
67% yield, 91% ee
62% yield, 92% ee
F
MeO
MeO
MeO
Next, we resorted to DFT calculations to examine insertion of
7g
7e
of 2,3-dihydrofuran, in order to differentiate if
a cationic
7f
64% yield, 90% ee
phenylnickel(II) complex[10] or
a
neutral phenylnikcel(I)
58% yield, 90% ee
68% yield, 92% ee
complex[4s,11] is the actual species for olefin insertion, at
M06L/Def2TZVP, SMD(DMSO)//M06L/6-31g*,SDD(Ni) level.
Some conclusions are drawn as follows. (a) Both Ni(II) and Ni(I)
complexes leads to the (R)-isomer 4b as the major (90% ee
observed at 100 oC), with insertion barriers of 10.2 and 9.2
kcalmol-1, respectively. (b) On the Ni(II) and Ni(I) pathways, the
energy gap between diastereomeric transition states of insertion
is 1.6 and 2.3 kcalmol-1, respectively. (c) Both favored transition
Scheme 4. Examples of intermolecular Heck of aryl triflates with N-
Cbz-2,3-dihydropyrrole.
We also successfully applied nickel chloride complex of (R)-
DuanPhos to asymmetric reductive Heck reaction of 2-
cyclopentenone ketal 3c in dry DMSO. 1 equiv water was added
to provide the proton to the final product, which improved
reproducibility of the results (Scheme 5a). After ketal hydrolysis,
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10.1002/anie.202011036
Angewandte Chemie International Edition
COMMUNICATION
states of Ni(II) and Ni(I) leading to the (R)-isomer share very
similar square planar geometry with some distortion (Figure 2).
The bound alkene is accommodated in the quadrant defined by a
P-methyl group of DuPhos, while the Ni-phenyl group is tilted
towards the diagonal quadrant of the other P-methyl group. (d)
The barrier of subsequent hydrogen elimination is larger on the
Ni(II) pathway than Ni(I), in 11.2 and 4.1 kcalmol-1, respectively.
Thus, olefin isomerization along the nickel(I) pathway should be
much more facile than that of nickel(II). (e) Experimentally, alkene
insertion of 4-t-butylphenyl sulfonates gave adduct 4a in 99% ee
(see Scheme 2). In calculations, energy gap between
diastereomeric TSs for insertion of 4-t-butylphenyl nickel(II) and
nickel(I) also increases to 2.3 and 2.7 kcalmol-1, respectively. In
disfavored transition states of insertion of both pathways, a large
P-t-butyl group pushes 2,3-dihydrofuran away from itself so that
the alkene fragment is positioned well above the coordination
plane; the other P-t-butyl group forces the Ni-aryl group to tilt in
the quadrant of P-methyl group. No close contact between
quinoxP* and the distal t-butyl group on the inserting aryl ring is
identified, so we conclude excellent stereoselectivity of 4a is
electronic in origin.
Keywords: nickel catalysis • Heck reaction • reductive Heck
reaction • aryl sulfonates • aryl halides
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Overall, both nickel(I) and nickel(II) pathways seem to be
plausible based on the calculations. Experimentally, Ni(cod)2 and
QuninoxP* cleanly formed a precatalyst [Ni(cod)(QuinoxP*)],
o
which promoted Heck insertion of some aryl triflates at 100 C,
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23, 2114; b) V. H. Menezes da Silva, A. A. C. Braga, T. R. Cundari,
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F. Schoenebeck, Chem. Sci. 2016, 7, 1076; d) S. Bajo, G. Laidlaw, A. R.
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Figure 2. Insertion transition states of a cationic phenylnickel(II)
complex of (R)-DuPhos (right) and a neutral phenylnickel(I) complex
(left), both leading to the major (R)-enantiomer.
In conclusion, we identified that nickel complexes ligated by
strongly donating diphosphines were effective for intermolecular
asymmetric Heck reaction of aryl triflates, mesylates and
tosylates. The nickel complexes also promoted asymmetric
reductive Heck arylation of a ketal of 2-cyclopentenone.
Acknowledgements
We acknowledge financial supports from Peking University
Shenzhen Graduate School, Shenzhen Bay Laboratory Institute
of Chemical Biology, Nanyang Technological University, GSK-
EDB Trust Fund (2017 GSK-EDB Green and Sustainable
Manufacturing Award) and A*STAR Science and Engineering
Research Council (A1783c0010).
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COMMUNICATION
Xiaolei Huang, Shenghan Teng, Yonggui
Robin Chi, Wenqiang Xu, Maoping Pu,
Yun-Dong Wu and Jianrong Steve Zhou*
nickel catalyst
ligand: (R,R)-QuinoxP*
Y
Ar
Y
Ar-X
Zn, DMSO
Y=O, NCbz
X = OTf
OMs
OTs
most >90% ee
45 examples
nickel catalyst
ligand: (R)-DuanPhos
Page No. – Page No.
O
O
O
Ar-OTf
O
Ar
Zn, water, DMSO
Enantioselective Intermolecular Heck
and Reductive Heck Reactions of Aryl
Triflates, Mesylates and Tosylates
Catalyzed by Nickel
82-94% ee
7 examples
Nickel catalysts efficiently promote enantioselective Heck reaction of aryl triflates,
mesylates and tosylates in excellent ee values. Asymmetric reductive Heck reaction
with a ketal of 2-cyclopentenone also proceeds well.
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