Carbamoyl Fluoride-Enabled Enantioselective Ni-Catalyzed Carbocarbamoylation of Unactivated Alkenes

Article abstract of DOI:10.1021/jacs.0c09949

A carbamoyl fluoride-enabled enantioselective Ni-catalyzed carbocarbamoylation of unactivated alkenes was developed, providing a broad range of chiral γ-lactams bearing an all-carbon quaternary center in 45-96% yield and 38-97% ee.

Full text of DOI:10.1021/jacs.0c09949

pubs.acs.org/JACS
Communication
Carbamoyl Fluoride-Enabled Enantioselective Ni-Catalyzed
Carbocarbamoylation of Unactivated Alkenes
Yue Li, Feng-Ping Zhang, Rong-Hua Wang, Shao-Long Qi, Yu-Xin Luan,* and Mengchun Ye*
Cite This: https://dx.doi.org/10.1021/jacs.0c09949
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: A carbamoyl fluoride-enabled enantioselective Ni-catalyzed carbocarbamoylation of unactivated alkenes was
developed, providing a broad range of chiral γ-lactams bearing an all-carbon quaternary center in 45−96% yield and 38−97% ee.
Scheme 1. Enantioselective Dicarbofunctionalization of
Unactivated Alkenes
he transition metal-catalyzed asymmetric dicarbofunc-
tionalization of alkenes has received considerable interest
T
during the past decade, because it provides an easy and rapid
route to a diverse range of chiral compounds.1 Compared with
widely explored activated alkenes,2−5 unactivated alkenes,
despite more readily available chemical sources, have been
rarely applied in these reaction owing to low reactivity and
difficult stereoselective control. Until recent years, the use of
tethered-alkene strategies successfully allowed unactivated
alkenes to undergo highly enantioselective reactions. Most of
such tethered strategies proceeded via arylmetal intermediates,
in which an aryl ring was incorporated into substrates as a
critical structural motif to enhance both the reactivity and the
selectivity (Scheme 1a). With this strategy, a series of
enantioselective dicarbofunctionalizations have been devel-
oped for various aryl substrates such as arylborons,6
arylhalides,7 aryldiazoniums,8 arylketones,9 and arylnitriles.10
To break through the restriction of aromatic rings to achieve
more diverse product structures, a distinctive tethered-alkene
strategy proceeding via an acylmetal intermediate has also been
devised (Scheme 1b). The strategy used carbamoyls or
analogues as carbonyl sources,11 not only rendering the
preparation of substrates easier but also allowing a more
convenient product elaboration. However, major advances of
the strategy have been limited to activated alkenes (typical
analogues, Scheme 1b),12,13 and enantioselective carbocarba-
moylation of unactivated alkenes has been a formidable
challenge.14 In 2010, Takemoto and co-workers reported a
seminal investigation, in which a stable carbamoylnitrile was
used to facilitate an enantioselective dicarbofunctionalization
of unactivated alkenes, obtaining 15% yield and 27% ee for the
sole example.15 In 2017, Douglas and co-workers hoped to
introduce a chiral auxiliary to enhance the stereoselective
control but achieved only a limited success.16 To address the
challenge, most recently, Chen and co-workers used a radical
pathway to achieve a highly enantioselective reductive
carbocarbamoylation of unactivated alkenes with carbamoyl
chlorides and alkyl iodides.17 Herein, we reported a distinctive
solution in which carbamoyl fluoride was used as a stable
carbamoyl source instead of chloride analogues, achieving a
highly enantioselective dicarbofunctionalization of unactivated
alkenes. The reaction used nickel as a catalyst and readily
Received: September 17, 2020
https://dx.doi.org/10.1021/jacs.0c09949
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
© XXXX American Chemical Society
A

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
available organoboronic acid as a reaction partner to provide a
series of γ-lactams bearing an all-carbon quaternary center in
45−96% yield and with 38−97% ee (Scheme 1c).18
substituted ligands in general worked well, providing good ees
varying from 55% to 88% (entries 6−8). The removal of Ni
metal completely shut down the reaction (entry 9), but the use
of NiBr2 (10 mol) with Zn (50 mol %) instead of Ni(cod)2 still
gave a comparable ee, albeit with a little lower yield (entry 10).
Base acted as another critical role in the reaction. Only cesium
salts such as Cs2CO3 and CsF were effective (entries 11 and
12), whereas other potassium and sodium salts did not
promote the reaction at all. The reduction of the loadings of
either Ni metal or the ligand resulted in lower yields (entries
13 and 14).
Considering that commonly used carbamoyl chlorides were
unstable and prone to undergo decarbonylation in the
reactions,19 we envisioned that more stable carbamoyl
fluoride20 may provide a good opportunity for developing
enantioselective carbocarbamoylation of unactivated alkenes,
albeit with some new potential challenges, such as low
reactivity and difficult transmetalation of fluoride. We selected
carbamoyl fluoride 1a bearing a bulky N protecting group
(2,4,6-trimethylbenzyl, TMBn) as the model substrate, hoping
that the increased steric hindrance could make the acylmetal
intermediate approach the alkene more closely, thus favoring
the subsequent cyclization (Scheme 2). The carbamoyl
With the optimized conditions in hand, the influence of the
N-protecting groups and alkene substituents was investigated
first (Scheme 3). Except for aryl and acyl protecting groups
a
Scheme 3. Scope of Alkenes
a
Scheme 2. Reaction Optimization
a
Reaction conditions: 1a (0.2 mmol), PhB(OH)2 (0.4 mmol), and
toluene (1.0 mL) at 100 °C under N2 for 12 h; yield was determined
by 1H NMR with CH2Br2 as the internal standard; ee was determined
b
by chiral HPLC. NiBr2·DME (10 mol %), Zn (50 mol %).
a
fluoride 1a, easily accessed from the corresponding chloride
with cesium fluoride, proved to be a bench-stable reagent, and
it can be kept in a regular refrigerator under an air atmosphere
for more than half a year without significant decomposition.
Through systematic examination of the metal catalyst, ligand,
base, and other reaction parameters such as temperature,
solvent, and time, the optimal conditions were finally obtained,
providing the desired γ-lactam 2a in 82% yield and 96% ee
(entry 1). Control experiments showed that the ligand played
an important role in the reaction. Most alkyl-substituted
phosphines (entries 2−4) and monophosphines (entry 5) were
ineffective, leading to either low yields or low ee, while triaryl-
Reaction conditions: 1 (0.2 mmol), PhB(OH)2 (0.4 mmol), Cs2CO3
(0.4 mmol), and toluene (1.0 mL) at 100 °C under N2 for 12 h; yield
of isolated products; ee was determined by chiral HPLC; Ar = 4-
methoxyphenyl.
that were ineffective, various removable benzyl-type protecting
groups such as benzyl (2b), methylbenzyl (2c, 2d, and 2e),
methoxybenzyl (2f), fluorobenzyl (2g), and phenylbenzyl (2h)
were all compatible with the reaction, providing the
corresponding products in 57−92% yield and 90−95% ee.
Other alkyl protecting groups such as linear alkyls (2i and 2j)
and cyclic alkyls (2k, 2l, and 2m) also proved to be suitable
B
https://dx.doi.org/10.1021/jacs.0c09949
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
groups, affording 56−82% yield and 84−93% ee. The
examination of alkene substituents also disclosed a wide
compatibility, for example, alkenes bearing simple alkyl (2n),
functionalized alkyl (2o), benzyl (2p), bulky cyclohexyl (2q),
and aryl (2r) all proceeded well in the reactions, providing the
corresponding products in 56−78% yield and 93−97% ee. The
only exception was the aryl group that required the use of less
hindered methoxybenzyl as the protecting group for good yield
and high ee (2r). However, 1,1-disubstituted alkenes were in
general required for this reaction; otherwise, either significant
β-H-elimination occurs for monosubstituted alkenes (2s) or no
reactivity was observed for internal alkenes. In addition, the
investigation on the length and rigidity of the linker showed
that the longer linker inhibited the reaction (2t), but the rigid
one still delivered the desired product (2u).
and 3k) was slightly lower, which was ascribed to a difficult
transmetalation. We also checked other type of boronic acids
and found that, except the alkyl boronic acids (3r), various
heteroaryl (3n, 3o, and 3p) and alkenyl (3q) boronic acids
underwent the reaction smoothly, providing 45−86% yield and
90−95% ee.
A gram-scale reaction of 1b was conducted, and no
significant loss of yield and ee was observed (Scheme 5a). In
Scheme 5. Reaction Utility
Next, various organoboronic acids were systematically
surveyed (Scheme 4). The type of boron agents proved to
a
Scheme 4. Scope of Arylboronic Acids
addition, the bulky protecting group, TMBn, can be easily
removed under the acidic conditions, and the followed ring-
opening process delivered a synthetically useful β-amino acid
bearing an all-carbon quaternary center (Scheme 5b). As a
comparison, carbamoyl chloride was subjected to the standard
conditions (Scheme 5c), achieving 40% yield and 54% ee,
which suggested that the presence of F enhanced both the
reactivity and the enantioselectivity.
To gain more insights into the mechanism, relevant
mechanistic experiments were conducted. Considering that it
was difficult to get clear Ni−F signals when using BINAP as
the ligand, we replaced BINAP with PCy3 for the mechanistic
experiments. Under similar conditions, substrate 1a smoothly
underwent the cyclization to give product 2a in 84% yield,
whereas substrate 1a′ bearing a saturated alkyl chain produced
only a trace amount of direct coupling product 2a′, suggesting
that the direct coupling of carbamoyl fluoride with PhB(OH)2
was a quite slow process (Scheme 6a). With stoichiometric
amounts of Ni(cod)2 (1 equiv) and PCy3 (2 equiv) at 50 °C, a
stable nickel intermediate was obtained. Despite not acquiring
its single crystal, relevant characterizations such as 19F NMR,
1H NMR, 31P NMR, and HRMS suggested that it should be a
cyclized Ni−F species (Scheme 6b). When subjected to
PhB(OH)2 or AlMe3, the species can provide the correspond-
ing coupling product rac-2a and 6, respectively. On the basis of
these data, a plausible mechanism was then proposed in
Scheme 6c: the rotamer (top one) of carbamoyl fluoride with
the C−F bond and the alkene motif at the same side would act
as the favored isomer to participate in an initial oxidative
addition with the Ni, generating an intermediate A, which then
quickly cyclized to form an intermediate B. Subsequent
transmetalation with phenylboronic acid, followed by reductive
elimination, resulted in the desired product. However, an
alternative pathway via first transmetalation of species A with
a
Reaction conditions: 1a (0.2 mmol), ArB(OH)2 (0.4 mmol),
Cs2CO3 (0.4 mmol), and toluene (1.0 mL) at 100 °C under N2 for
12 h; yield of isolated products; ee was determined by chiral HPLC;
PMB = p-methoxybenzyl.
be critical: only simple organoboronic acids worked well in the
reaction, whereas various borate esters, especially common
pinacolborates, were ineffective. A broad range of arylboronic
acids bearing either electron-rich or electron-deficient
substituents at different positions on the aryl ring were well
compatible with the reaction, providing 91−97% ee (3a to
3m). However, the yield for ortho-methyl (3a and 3m) and
electron-deficient substituents on the arylboronic acids (3i, 3j,
C
https://dx.doi.org/10.1021/jacs.0c09949
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
University, Tianjin 300071, China; orcid.org/0000-
0001-5364-4895; Email: yxluan@nankai.edu.cn
Scheme 6. Mechanistic Experiments and Proposed
Mechansim
Mengchun Ye − State Key Laboratory and Institute of
Elemento-Organic Chemistry, College of Chemistry, Nankai
University, Tianjin 300071, China; orcid.org/0000-
0002-2019-5365; Email: mcye@nankai.edu.cn
Authors
Yue Li − State Key Laboratory and Institute of Elemento-
Organic Chemistry, College of Chemistry, Nankai University,
Tianjin 300071, China
Feng-Ping Zhang − State Key Laboratory and Institute of
Elemento-Organic Chemistry, College of Chemistry, Nankai
University, Tianjin 300071, China
Rong-Hua Wang − State Key Laboratory and Institute of
Elemento-Organic Chemistry, College of Chemistry, Nankai
University, Tianjin 300071, China
Shao-Long Qi − State Key Laboratory and Institute of
Elemento-Organic Chemistry, College of Chemistry, Nankai
University, Tianjin 300071, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c09949
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(91856104, 21871145, and 21672107), China Postdoctoral
Science Foundation (2018M641625), Tianjin Applied Basic
Research Project and Cutting-Edge Technology Research Plan
(19JCZDJC37900), and “the Fundamental Research Funds for
the Central Universities”, Nankai University (63191601) for
financial support.
REFERENCES
■
(1) For selected reviews on dicarbofunctionalizations, see: (a) Giri,
R.; Kc, S. Strategies toward Dicarbofunctionalization of Unactivated
Olefins by Combined Heck Carbometalation and Cross-Coupling. J.
Org. Chem. 2018, 83, 3013−3022. (b) Dhungana, R. K.; Kc, S.;
Basnet, P.; Giri, R. Transition Metal-Catalyzed Dicarbofunctionaliza-
tion of Unactivated Olefins. Chem. Rec. 2018, 18, 1314−1340.
(c) Ping, Y.; Li, Y.; Zhu, J.; Kong, W. Construction of Quaternary
Stereocenters by Palladium-Catalyzed Carbopalladation-Initiated
Cascade Reactions. Angew. Chem., Int. Ed. 2019, 58, 1562−1573.
(d) Li, Y.; Wu, D.; Cheng, H.-G.; Yin, G. Difunctionalization of
Alkenes Involving Metal Migration. Angew. Chem., Int. Ed. 2020, 59,
7990−8003. (e) Poremba, K. E.; Dibrell, S. E.; Reisman, S. E. Nickel-
Catalyzed Enantioselective Reductive Cross-Coupling Reactions. ACS
Catal. 2020, 10, 8237−8246. (f) Qi, X.; Diao, T. Nickel-Catalyzed
Dicarbofunctionalization of Alkenes. ACS Catal. 2020, 10, 8542−
8556.
(2) For enantioselective dicarbofunctionalizations of dienes, see:
(a) Stokes, B. J.; Liao, L.; de Andrade, A. M.; Wang, Q.; Sigman, M. S.
A Palladium-Catalyzed Three-Component-Coupling Strategy for the
Differential Vicinal Diarylation of Terminal 1,3-Dienes. Org. Lett.
2014, 16, 4666−4669. (b) You, W.; Brown, M. K. Catalytic
Enantioselective Diarylation of Alkenes. J. Am. Chem. Soc. 2015,
137, 14578−14581. (c) Wu, X.; Lin, H.-C.; Li, M.-L.; Li, L.-L.; Han,
Z.-Y.; Gong, L.-Z. Enantioselective 1,2-Difunctionalization of Dienes
Enabled by Chiral Palladium Complex-Catalyzed Cascade Arylation/
Allylic Alkylation Reaction. J. Am. Chem. Soc. 2015, 137, 13476−
13479. (d) Xiong, Y.; Zhang, G. Enantioselective 1,2-Difunctionaliza-
tion of 1,3-Butadiene by Sequential Alkylation and Carbonyl
Allylation. J. Am. Chem. Soc. 2018, 140, 2735−2738. (e) Ohshima,
phenylboronic acid and a followed alkene insertion can still not
be excluded.
In summary, we have developed an enantioselective Ni-
catalyzed carbocarbamoylation of unactivated alkenes with
organoboronic acids, providing a series of synthetically useful
γ-lactams bearing an all-carbon quaternary center in 45−96%
yield and with 38−97% ee. Stable carbamoyl fluoride was used
in this type of reaction for the first time, effectively enhancing
both the reactivity and the stereoselectivity. This discovery will
benefit the future development of other types of asymmetric
carbonylation reactions.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c09949.
■
sı
Experimental procedures, characterization data, and
spectra of new compounds (PDF)
X-ray structural information of 3g (CCDC-2018615)
(CIF)
AUTHOR INFORMATION
Corresponding Authors
Yu-Xin Luan − State Key Laboratory and Institute of
Elemento-Organic Chemistry, College of Chemistry, Nankai
■
D
https://dx.doi.org/10.1021/jacs.0c09949
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
T.; Kagechika, K.; Adachi, M.; Sodeoka, M.; Shibasaki, M.
Asymmetric Heck Reaction-Carbanion Capture Process: Catalytic
Asymmetric Total Synthesis of (−)-m9(12)-Capnellene. J. Am. Chem.
Soc. 1996, 118, 7108−7116.
activated Olefins through Nickel-Catalyzed Cross-Electrophile Cou-
pling. J. Am. Chem. Soc. 2020, 142, 9604−9611.
(6) For examples on arylborons, see: (a) Cong, H.; Fu, G. C.
Catalytic Enantioselective Cyclization/Cross-Coupling with Alkyl
Electrophiles. J. Am. Chem. Soc. 2014, 136, 3788−3791. (b) You,
W.; Brown, M. K. Catalytic Enantioselective Diarylation of Alkenes. J.
Am. Chem. Soc. 2015, 137, 14578−14581.
(3) For enantioselective dicarbofunctionalizations of activated
alkenes with unique electronic properties, see: (a) Pinto, A.; Jia, Y.;
Neuville, L.; Zhu, J. Palladium-Catalyzed Enantioselective Domino
Heck-Cyanation Sequence: Development and Application to the
Total Synthesis of Esermethole and Physostigmine. Chem. - Eur. J.
2007, 13, 961−967. (b) Kong, W.; Wang, Q.; Zhu, J. Palladium-
Catalyzed Enantioselective Domino Heck/Intermolecular C-H Bond
Functionalization: Development and Application to the Synthesis of
(+)-Esermethole. J. Am. Chem. Soc. 2015, 137, 16028−16031.
(c) Kong, W.; Wang, Q.; Zhu, J. Synthesis of Diversely Functionalized
Oxindoles Enabled by Migratory Insertion of Isocyanide to a
Transient s-Alkylpalladium(II) Complex. Angew. Chem., Int. Ed.
2016, 55, 9714−9718. (d) Tong, S.; Limouni, A.; Wang, Q.; Wang,
M.-X.; Zhu, J. Catalytic Enantioselective Double Carbopalladation/C-
H Functionalization with Statistical Amplification of Product
Enantiopurity: A Convertible Linker Approach. Angew. Chem., Int.
Ed. 2017, 56, 14192−14196. (e) Orlandi, M.; Hilton, M. J.;
Yamamoto, E.; Toste, F. D.; Sigman, M. S. Mechanistic Investigations
of the Pd(0)-Catalyzed Enantioselective 1,1-Diarylation of Benzyl
Acrylates. J. Am. Chem. Soc. 2017, 139, 12688−12695. (f) Wang, K.;
Ding, Z.; Zhou, Z.; Kong, W. Ni-Catalyzed Enantioselective
Reductive Diarylation of Activated Alkenes by Domino Cyclization/
Cross-Coupling. J. Am. Chem. Soc. 2018, 140, 12364−12368. (g) Hu,
H.; Teng, F.; Liu, J.; Hu, W.; Luo, S.; Zhu, Q. Enantioselective
Synthesis of 2-Oxindole Spirofused Lactones and Lactams by Heck/
Carbonylative Cylization Sequences: Method Development and
Applications. Angew. Chem., Int. Ed. 2019, 58, 9225−9229. (h) Li,
Y.; Ding, Z.; Lei, A.; Kong, W. Ni-Catalyzed enantioselective
reductive aryl-alkenylation of alkenes: application to the synthesis of
(+)-physovenine and (+)-physostigmine. Org. Chem. Front. 2019, 6,
3305−3309. (i) Chierchia, M.; Xu, P.; Lovinger, G. J.; Morken, J. P.
Enantioselective Radical Addition/Cross-Coupling of Organozinc
Reagents, Alkyl Iodides, and Alkenyl Boron Reagents. Angew. Chem.,
Int. Ed. 2019, 58, 14245−14249. (j) Wei, X.; Shu, W.; García-
Domínguez, A.; Merino, E.; Nevado, C. Asymmetric Ni-Catalyzed
Radical Relayed Reductive Coupling. J. Am. Chem. Soc. 2020, 142,
13515−13522.
(7) For examples on arylhalides, see: (a) Hu, J.; Hirao, H.; Li, Y.;
Zhou, J. Palladium-Catalyzed Asymmetric Intermolecular Cyclization.
Angew. Chem., Int. Ed. 2013, 52, 8676−8680. (b) Yoon, H.; Petrone,
D. A.; Lautens, M. Diastereoselective Palladium-Catalyzed Arylcya-
nation/ Heteroarylcyanation of Enantioenriched N-Allylcarboxa-
mides. Org. Lett. 2014, 16, 6420−6423. (c) Zhang, Z.-M.; Xu, B.;
Wu, L.; Wu, Y.; Qian, Y.; Zhou, L.; Liu, Y.; Zhang, J. Enantioselective
Dicarbofunctionalization of Unactivated Alkenes by Palladium-
Catalyzed Tandem Heck/Suzuki Coupling Reaction. Angew. Chem.,
Int. Ed. 2019, 58, 14653−14659. (d) Jin, Y.; Wang, C. Nickel-
Catalyzed Asymmetric Reductive Arylalkylation of Unactivated
Alkenes. Angew. Chem., Int. Ed. 2019, 58, 6722−6726. (e) Tian, Z.-
X.; Qiao, J.-B.; Xu, G.-L.; Pang, X.; Qi, L.; Ma, W.-Y.; Zhao, Z.-Z.;
Duan, J.; Du, Y.-F.; Su, P.; Liu, X.-Y.; Shu, X.-Z. Highly
Enantioselective Cross-Electrophile Aryl-Alkenylation of Unactivated
Alkenes. J. Am. Chem. Soc. 2019, 141, 7637−7643. (f) Cheng, C.;
Wan, B.; Zhou, B.; Gu, Y.; Zhang, Y. Enantioselective synthesis of
quaternary 3,4-dihydroisoquinolinones via Heck carbonylation
reactions: development and application to the synthesis of Minalrestat
analogues. Chem. Sci. 2019, 10, 9853−9858. (g) Jin, Y.; Wang, C. Ni-
catalysed reductive arylalkylation of unactivated alkenes. Chem. Sci.
2019, 10, 1780−1785. (h) Yang, F.; Jin, Y.; Wang, C. Nickel-
Catalyzed Asymmetric Intramolecular Reductive Heck Reaction of
Unactivated Alkenes. Org. Lett. 2019, 21, 6989−6994. (i) Jin, Y.;
Yang, H.; Wang, C. Nickel-Catalyzed Asymmetric Reductive
Arylbenzylation of Unactivated Alkenes. Org. Lett. 2020, 22, 2724−
2729. (j) Zhou, L.; Li, S.; Xu, B.; Ji, D.; Wu, L.; Liu, Y.; Zhang, Z.-M.;
Zhang, J. Enantioselective Difunctionalization of Alkenes by a
Palladium-Catalyzed Heck/Sonogashira Sequence. Angew. Chem.,
Int. Ed. 2020, 59, 2769−2775.
(8) For examples on aryldiazoniums, see: Carmona, R. C.; Koster, O.
D.; Correia, C. R. D. Chiral N,N Ligands Enabling Palladium-
Catalyzed Enantioselective Intramolecular Heck-Matsuda Carbon-
ylation Reactions by Sequential Migratory and CO Insertions. Angew.
Chem., Int. Ed. 2018, 57, 12067−12070.
(4) For enantioselective dicarbofunctionalizations of styrene and
derivatives, see: (a) Wu, H.; Wang, Q.; Zhu, J. Copper-Catalyzed
Enantioselective Domino Arylation/Semipinacol Rearrangement of
Allylic Alcohols with Diaryliodonium Salts. Chem. - Eur. J. 2017, 23,
13037−13041. (b) Liu, R.-R.; Wang, Y.-G.; Li, Y.-L.; Huan, B.-B.;
Liang, R.-X.; Jia, Y.-X. Enantioselective Dearomative Difunctionaliza-
tion of Indoles by Palladium-Catalyzed Heck/Sonogashira Sequence.
Angew. Chem., Int. Ed. 2017, 56, 7475−7478. (c) Wu, L.; Wang, F.;
Wan, X.; Wang, D.; Chen, P.; Liu, G. Asymmetric Cu-Catalyzed
Intermolecular Trifluoromethylarylation of Styrenes: Enantioselective
Arylation of Benzylic Radicals. J. Am. Chem. Soc. 2017, 139, 2904−
2907. (d) Gao, P.; Chen, L.-A.; Brown, M. K. Nickel-Catalyzed
Stereoselective Diarylation of Alkenylarenes. J. Am. Chem. Soc. 2018,
140, 10653−10657. (e) Anthony, D.; Lin, Q.; Baudet, J.; Diao, T.
Nickel-Catalyzed Asymmetric Reductive Diarylation of Vinylarenes.
Angew. Chem., Int. Ed. 2019, 58, 3198−3202. (f) Fu, L.; Zhou, S.;
Wan, X.; Chen, P.; Liu, G. Enantioselective Trifluoromethylalkyny-
lation of Alkenes via Copper-Catalyzed Radical Relay. J. Am. Chem.
Soc. 2018, 140, 10965−10969. (g) Lin, J.-S.; Li, T.-T.; Liu, J.-R.; Jiao,
G.-Y.; Gu, Q.-S.; Cheng, J.-T.; Guo, Y.-L.; Hong, X.; Liu, X.-Y. Cu/
Chiral Phosphoric Acid-Catalyzed Asymmetric Three-Component
Radical-Initiated 1,2-Dicarbofunctionalization of Alkenes. J. Am.
Chem. Soc. 2019, 141, 1074−1083.
(9) For examples on arylketones, see: (a) Xu, T.; Ko, H. M.; Savage,
N. A.; Dong, G. Highly Enantioselective Rh-Catalyzed Carboacylation
of Olefins: Efficient Syntheses of Chiral Poly-Fused Rings. J. Am.
Chem. Soc. 2012, 134, 20005−20008. (b) Deng, L.; Chen, M.; Dong,
G. Concise Synthesis of (−)-Cycloclavine and (−)-5-epi-Cycloclavine
via Asymmetric C-C Activation. J. Am. Chem. Soc. 2018, 140, 9652−
9658.
(10) For examples on arylnitriles, see: (a) Nakao, Y.; Ebata, S.; Yada,
A.; Hiyama, T.; Ikawa, M.; Ogoshi, S. Intramolecular Arylcyanation of
Alkenes Catalyzed by Nickel/AlMe2Cl. J. Am. Chem. Soc. 2008, 130,
12874−12875. (b) Watson, M. P.; Jacobsen, E. N. Asymmetric
Intramolecular Arylcyanation of Unactivated Olefins via C-CN Bond
Activation. J. Am. Chem. Soc. 2008, 130, 12594−12595. (c) Hsieh, J.-
C.; Ebata, S.; Nakao, Y.; Hiyama, T. Asymmetric Synthesis of
Indolines Bearing a Benzylic Quaternary Stereocenter through
Intramolecular Arylcyanation of Alkenes. Synlett 2010, 2010, 1709−
1711.
(11) For selected racemic dicarbofunctionalization of alkenes with
carbamoyls, see: (a) Fielding, M. R.; Grigg, R.; Urch, C. J. Novel
synthesis of oxindoles from carbamoyl chlorides via palladium
catalyzed cyclisation-anion capture. Chem. Commun. 2000, 2239−
2240. (b) Anwar, U.; Fielding, M. R.; Grigg, R.; Sridharan, V.; Urch,
C. J. Palladium catalysed tandem cyclisation-anion capture processes.
Part 8 [1]: In situ and preformed organostannanes. Carbamoyl
chlorides and other starter species. J. Organomet. Chem. 2006, 691,
1476−1487. (c) Kobayashi, Y.; Kamisaki, H.; Yanada, R.; Takemoto,
Y. Palladium-Catalyzed Intramolecular Cyanoamidation of Alkynyl
(5) For an enantioselective dicarbofunctionalization of unactivated
alkenes from allylic alcohols bearing a chelating group, see: Tu, H.-Y.;
Wang, F.; Huo, L.; Li, Y.; Zhu, S.; Zhao, X.; Li, H.; Qing, F.-L.; Chu,
L. Enantioselective Three-Component Fluoroalkylarylation of Un-
E
https://dx.doi.org/10.1021/jacs.0c09949
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
and Alkenyl Cyanoformamides. Org. Lett. 2006, 8, 2711−2713.
(d) Kobayashi, Y.; Kamisaki, H.; Takeda, H.; Yasui, Y.; Yanadab, R.;
Takemoto, Y. Intramolecular cyanoamidation of unsaturated
cyanoformamides catalyzed by palladium: an efficient synthesis of
multi-functionalized lactams. Tetrahedron 2007, 63, 2978−2989.
(e) Kamisaki, H.; Yasui, Y.; Takemoto, Y. Pd-catalyzed intramolecular
amidation of 2-(buta-1,3-dienyl) phenylcarbamoyl chloride: a concise
synthesis of spiro[indoline-3,30- pyrrolidine]. Tetrahedron Lett. 2009,
50, 2589−2592. (f) Hande, S. M.; Nakajima, M.; Kamisaki, H.;
Tsukano, C.; Takemoto, Y. Flexible Strategy for Syntheses of
Spirooxindoles using Palladium-Catalyzed Carbosilylation and Sakur-
ai-Type Cyclization. Org. Lett. 2011, 13, 1828−1831. (g) Eastwood,
M. S.; Douglas, C. J. Synthesis of the Madangamine Alkaloid Core by
a C-C Bond Activation Cascade. Org. Lett. 2019, 21, 6149−6154.
(h) Wu, X.; Tang, Z.; Zhang, C.; Wang, C.; Wu, L.; Qu, J.; Chen, Y.
Pd-Catalyzed Regiodivergent Synthesis of Diverse Oxindoles Enabled
by the Versatile Heck Reaction of Carbamoyl Chlorides. Org. Lett.
2020, 22, 3915−3921.
(12) For enantioselective dicarbofunctionalization of activated
alkenes with carbamoyls and analogues, see: (a) Yasui, Y.;
Kamisaki, H.; Takemoto, Y. Enantioselective Synthesis of 3,3-
Disubstituted Oxindoles through Pd-Catalyzed Cyanoamidation.
Org. Lett. 2008, 10, 3303−3306. (b) Fan, P.; Lan, Y.; Zhang, C.;
Wang, C. Nickel/Photo-Cocatalyzed Asymmetric Acyl-Carbamoyla-
tion of Alkenes. J. Am. Chem. Soc. 2020, 142, 2180−2186. (c) Lan, Y.;
Wang, C. Nickel-catalyzed enantioselective reductivecarbo-acylation
of alkenes. Commun. Chem. 2020, 3, 45−53. (d) Liu, L.; Ishida, N.;
Murakami, M. Atom- and Step-Economical Pathway to Chiral
Benzobicyclo-[2.2.2]octenones through Carbon-Carbon Bond Cleav-
age. Angew. Chem., Int. Ed. 2012, 51, 2485−2488. (e) Souillart, L.;
Parker, E.; Cramer, N. Highly Enantioselective Rhodium(I)-Catalyzed
Activation of Enantiotopic Cyclobutanone C-C Bonds. Angew. Chem.,
Int. Ed. 2014, 53, 3001−3005. (f) Parker, E.; Cramer, N. Asymmetric
Rhodium(I)-Catalyzed C-C Activations with Zwitterionic Bis-
phospholane Ligands. Organometallics 2014, 33, 780−787.
(g) Zhou, X.; Dong, G. (4 + 1) vs (4 + 2): Catalytic Intramolecular
Coupling between Cyclobutanones and Trisubstituted Allenes via C-
C Activation. J. Am. Chem. Soc. 2015, 137, 13715−13721.
(13) For enantioselective carbofunctionalizations of activated
alkenes with carbamoyls, see: (a) Whyte, A.; Burton, K. I.; Zhang,
J.; Lautens, M. Enantioselective Intramolecular Copper-Catalyzed
Borylacylation. Angew. Chem., Int. Ed. 2018, 57, 13927−13930.
(b) Marchese, A. D.; Wollenburg, M.; Mirabi, B.; Abel-Snape, X.;
Whyte, A.; Glorius, F.; Lautens, M. Nickel-Catalyzed Enantioselective
Carbamoyl Iodination: A Surrogate for Carbamoyl Iodides. ACS
Catal. 2020, 10, 4780−4785.
(14) For recent examples on racemic carbocarbonylations of
unactivated alkenes with stable carboxylates, see: (a) Walker, J. A.,
Jr; Vickerman, K. L.; Humke, J. N.; Stanley, L. M. Ni-Catalyzed
Alkene Carboacylation via Amide C-N Bond Activation. J. Am. Chem.
Soc. 2017, 139, 10228−10231. (b) Zheng, Y.-L.; Newman, S. G.
Nickel-Catalyzed Domino Heck-Type Reactions Using Methyl Esters
as Cross-Coupling Electrophiles. Angew. Chem., Int. Ed. 2019, 58,
18159−18164. (c) Weires, N. A.; Slutskyy, Y.; Overman, L. E. Facile
Preparation of Spirolactones by an Alkoxycarbonyl Radical Cycliza-
tion-Cross-Coupling Cascade. Angew. Chem., Int. Ed. 2019, 58, 8561−
8565.
(18) For selected reviews on quaternary centers, see: (a) Christoffers,
J.; Baro, A. Stereoselective Construction of Quaternary Stereocenters.
Adv. Synth. Catal. 2005, 347, 1473−1482. (b) Trost, B. M.; Jiang, C.
Catalytic enantioselective construction of all-carbon quaternary
stereocenters. Synthesis 2006, 369−396. (c) Cozzi, P. G.; Hilgraf,
R.; Zimmermann, N. Enantioselective Catalytic Formation of
Quaternary Stereogenic Centers. Eur. J. Org. Chem. 2007, 2007,
5969−5994. (d) Quasdorf, K. W.; Overman, L. E. Catalytic
enantioselective synthesis of quaternary carbon stereocentres. Nature
2014, 516, 181−191. (e) Marek, I.; Minko, Y.; Pasco, M.; Mejuch, T.;
Gilboa, N.; Chechik, H.; Das, J. P. All-Carbon Quaternary Stereogenic
Centers in Acyclic Systems through the Creation of Several C-C
Bonds per Chemical Step. J. Am. Chem. Soc. 2014, 136, 2682−2694.
(f) Zeng, X.; Cao, Z.; Wang, Y.; Zhou, Y.; Zhou, J. Catalytic
Enantioselective Desymmetrization Reactions to All-Carbon Quater-
nary Stereocenters. Chem. Rev. 2016, 116, 7330−7396.
(19) For examples on carbamoyl chloride in C−H activation with
partial decomposition, see: (a) Kochi, T.; Urano, S.; Seki, H.;
Mizushima, E.; Sato, M.; Kakiuchi, F. Ruthenium-Catalyzed Amino-
and Alkoxycarbonylations with Carbamoyl Chlorides and Alkyl
Chloroformates via Aromatic C-H Bond Cleavage. J. Am. Chem.
Soc. 2009, 131, 2792−2793. (b) Iwai, T.; Fujihara, T.; Terao, J.; Tsuji,
Y. Iridium-Catalyzed Annulation of N-Arylcarbamoyl Chlorides with
Internal Alkynes. J. Am. Chem. Soc. 2010, 132, 9602−9603.
(c) Tsukano, C.; Okuno, M.; Takemoto, Y. Palladium-Catalyzed
Amidation by Chemoselective C(sp3))H Activation: Concise Route
to Oxindoles Using a Carbamoyl Chloride Precursor. Angew. Chem.,
Int. Ed. 2012, 51, 2763−2766. (d) Tsukano, C.; Okuno, M.;
Takemoto, Y. Synthesis of Spirooxindoles from Carbamoyl Chlorides
via Cyclopropyl Methine C(sp3)-H Activation Using Palladium
Catalyst. Chem. Lett. 2013, 42, 753−755. (e) Dailler, D.; Rocaboy,
R.; Baudoin, O. Synthesis of S-Lactams by Palladium(0)-Catalyzed
C(sp3)-H Carbamoylation. Angew. Chem., Int. Ed. 2017, 56, 7218−
7222.
(20) For selected examples on acyl fluoride-involved C−C
couplings, see: (a) Zhang, Y.; Rovis, T. A Unique Catalyst Effects
the Rapid Room-Temperature Cross-Coupling of Organozinc
Reagents with Carboxylic Acid Fluorides, Chlorides, Anhydrides,
and Thioesters. J. Am. Chem. Soc. 2004, 126, 15964−15965.
(b) Ogiwara, Y.; Sakino, D.; Sakurai, Y.; Sakai, N. Acid Fluorides as
Acyl Electrophiles in Suzuki-Miyaura Coupling. Eur. J. Org. Chem.
2017, 2017, 4324−4327. (c) Boreux, A.; Indukuri, K.; Gagosz, F.;
Riant, O. Acyl Fluorides as Efficient Electrophiles for the Copper-
Catalyzed Boroacylation of Allenes. ACS Catal. 2017, 7, 8200−8204.
(d) Malapit, C. A.; Bour, J. R.; Brigham, C. E.; Sanford, M. S. Base-
free nickel-catalysed decarbonylative Suzuki-Miyaura coupling of acid
fluorides. Nature 2018, 563, 100−104. (e) Keaveney, S. T.;
Schoenebeck, F. Palladium-Catalyzed Decarbonylative Trifluorome-
thylation of Acid Fluorides. Angew. Chem., Int. Ed. 2018, 57, 4073−
4077. (f) Okuda, Y.; Xu, J.; Ishida, T.; Wang, C.; Nishihara, Y. Nickel-
Catalyzed Decarbonylative Alkylation of Aroyl Fluorides Assisted by
Lewis-Acidic Organoboranes. ACS Omega 2018, 3, 13129−13140.
(g) Pan, F.-F.; Guo, P.; Li, C.-L.; Su, P.; Shu, X.-Z. Enones from Acid
Fluorides and Vinyl Triflates by Reductive Nickel Catalysis. Org. Lett.
2019, 21, 3701−3705. (h) Ogiwara, Y.; Iino, Y.; Sakai, N. Catalytic C-
H/C-F Coupling of Azoles and Acyl Fluorides. Chem. - Eur. J. 2019,
25, 6513−6516. (i) Ueda, Y.; Iwai, T.; Sawamura, M. Nickel-Copper-
Catalyzed Hydroacylation of Vinylarenes with Acyl Fluorides and
Hydrosilanes. Chem. - Eur. J. 2019, 25, 9410−9414. For relevant
reviews, see: (j) Prabhu, G.; Narendra, N.; Basavaprabhu Panduranga,
V.; Sureshbabu, V. V. Amino acid fluorides: viable tools for synthesis
of peptides, peptidomimetics and enantiopure heterocycles. RSC Adv.
2015, 5, 48331−48362. (k) Blanchard, N.; Bizet, V. Acid Fluorides in
Transition-Metal Catalysis: A Good Balance between Stability and
Reactivity. Angew. Chem., Int. Ed. 2019, 58, 6814−6817.
(15) Yasui, Y.; Kamisaki, H.; Ishida, T.; Takemoto, Y. Synthesis of
3,3-disubstituted oxindoles through Pd-catalyzed intramolecular
cyanoamidation. Tetrahedron 2010, 66, 1980−1989.
(16) Dreis, A. M.; Otte, S. C.; Eastwood, M. S.; Alonzi, E. R.;
Brethorst, J. T.; Douglas, C. J. Diastereoselective Intramolecular
Cyanoamidation with Alkenes. Eur. J. Org. Chem. 2017, 2017, 45−48.
(17) During our submission, an enantioselective example using
carbamoyl chloride as the substrate via the Ni-catalyzed radical
pathway was reported, see: Wu, X.; Qu, J.; Chen, Y. Quinim: A New
Ligand Scaffold Enables Nickel-Catalyzed Enantioselective Synthesis
of α-Alkylated γ-Lactam. J. Am. Chem. Soc. 2020, 142, 15654−15660.
F
https://dx.doi.org/10.1021/jacs.0c09949
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX