Nickel-Catalyzed trans-Carboamination across Internal Alkynes to Access Multifunctionalized Indoles

Article abstract of DOI:10.1021/acs.orglett.0c03148

A Ni-catalyzed reaction was developed for the synthesis of multifunctionalized indoles. The reaction proceeded through oxidative cyclization of the Ni(0)/P^N complex with an enyne system, 2-alkynyl anilinoacrylate, to provide a nickelacycle intermediate. The trans-carboamination around the internal alkyne was achieved by syn/anti-rotation of the Ni-carbenoid intermediate formed by C-N bond cleavage of the nickelacycle, and 3-alkenylated indoles were formed by C-N bond-forming reductive elimination. Notably, the synthesized indoles could be successfully transformed to functionalized carbazoles.

Full text of DOI:10.1021/acs.orglett.0c03148

pubs.acs.org/OrgLett
Letter
Nickel-Catalyzed trans-Carboamination across Internal Alkynes to
Access Multifunctionalized Indoles
Shrikant D. Tambe, Naeem Iqbal, and Eun Jin Cho*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c03148
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: A Ni-catalyzed reaction was developed for the synthesis of
multifunctionalized indoles. The reaction proceeded through oxidative cyclization
of the Ni(0)/P^N complex with an enyne system, 2-alkynyl anilinoacrylate, to
provide a nickelacycle intermediate. The trans-carboamination around the internal
alkyne was achieved by syn/anti-rotation of the Ni-carbenoid intermediate formed
by C−N bond cleavage of the nickelacycle, and 3-alkenylated indoles were formed
by C−N bond-forming reductive elimination. Notably, the synthesized indoles
could be successfully transformed to functionalized carbazoles.
ndoles are considered one of the most privileged structural
motifs in drug development, particularly because of their
Scheme 1. Metal-Catalyzed Cycloisomerization for Indole
Synthesis
I
compatibility with the human body. The compatibility stems
from the fact that the indole moiety is present in an essential
amino acid, tryptophan, and is also an important skeletal
backbone of naturally occurring alkaloids and biologically active
molecules.1 Various electronic materials also contain the indole
moiety.2 Due to their physiological relevance and their scope in
practical applications, various synthetic methodologies have
been developed over the years to construct indole systems.3
Transition-metal-catalyzed annulation of 2-alkynyl aniline
derivatives has gained significant attention due to the ease of
substrate synthesis and high atom economy of the process.3−5
The transformations involve the formation of alkenyl−metal
(Pd, Pt, Rh, Ir, Au, Cu, Co, In) complex intermediates that
undergo either electrophilic trapping or 1,3-migration of a broad
range of functional groups including methyl, allyl, benzyl,
propargyl, α-alkoxyalkyl, acyl, silyl, sulfonyl, and B(OR)2 groups
to afford diverse indole structures (Scheme 1a). Despite the
efficiency and broad applications of this reaction, it has certain
drawbacks. This includes a limited substrate scope, wherein no
alkenyl group migration occurs, and the requirement of a high
temperature.6
To overcome these limitations, we envisioned an alternative
Ni-catalyzed trans-carboamination approach. A suitable ligand
for driving the alkenyl group migration was chosen to afford 3-
alkenyl indoles at ambient temperature. We hypothesized that
alkenyl group migration can be achieved by nickelacycle
formation7 with an enyne system, 2-alkynyl anilinoacrylate,
followed by the C−N bond cleavage to give a Ni-carbenoid
intermediate. Then, the key process, trans-carboamination
around the alkyne, could be achieved by the syn/anti-rotation
of the Ni-carbenoid intermediate,8 followed by a new C−N
bond-forming reductive elimination (Scheme 1b). This trans-
formation would allow rapid access to multisubstituted indoles
Received: September 18, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03148
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
in an atom-economical manner at ambient temperature.
Additionally, the substituent at the 2-position of the indoles
could be easily varied by modifying the alkyne moiety in the
substrate, allowing the rapid buildup of diversity.
We commenced our investigation with tosylated methyl 2-
propynyl anilinoacrylate 1a as the model substrate, using
Ni(COD)2 as the catalyst. The reaction was conducted at
ambient temperature in CH3CN (Table 1). The desired indole
other solvents employed could produce 2a in significant yields
(Table 1, entries 12−18). The presence of molecular oxygen
lowered the reaction efficacy (Table 1, entry 19), whereas
controlled experiments revealed that Ni and the ligand were
essential for the reaction to proceed (Table 1, entries 20 and 21).
The selective alkenyl group migration over the tosyl group
migration is noteworthy.4a
With the optimized conditions in hand, various indole
derivatives were synthesized to confirm the generality of this
transformation. First, the substituent in the alkynyl moiety (R)
was varied to obtain different substitution patterns at the 2-
position (Scheme 2). Substrates with both aliphatic (2a−2f)
a
Table 1. Optimization of Reaction Conditions
Scheme 2. Substrate Scope with Variations on Alkyne
a bc
, ,
Moiety
b
entry
ligand
DPPF
DPPP
solvent
yield (%)
1
2
3
4
5
6
7
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DCM
THF
dioxane
DMF
toluene
TFE
CH3OH
CH3CN
CH3CN
32
0
11
11
0
DPEPhos
BINAP
(S)-SEGPhos
bpy
10
3
tBubpy
8
9
TerPy
PCy3
0
95 (E/Z = 2.5/1)
85 (E/Z = 1.2/1)
10
11
12
13
14
15
16
17
18
(p-tolyl)3P
PyPhos
PyPhos
PyPhos
PyPhos
PyPhos
PyPhos
PyPhos
PyPhos
PyPhos
PyPhos
98
13
19
11
30
0
0
trace
29
0
c
19
20
d
21
CH3CN
0
a
b
Reaction conditions: 1a (0.1 mmol). Yields were determined by 1H
NMR using 1,3,5-trimethoxybenzene as an internal standard.
c
d
Reaction under air. Reaction without Ni(COD)2. DPPF {1,1′-
a
ferrocenediyl-bis(diphenylphosphine)}, DPPP {1,3-bis-
( d i p h e n y lp h o s p h i n o ) p ro p an e } , D P EP h o s { bi s [ ( 2 -
diphenylphosphino)phenyl]ether}, BINAP {(2,2′-bis-
(diphenylphosphino)-1,1′-binaphthyl)}, (S)-SEGPhos {(S)-(−)-5,5′-
bis(diphenylphosphino)-4,4′-bi-1,3-benzodioxole}, bpy {2,2′-bipyri-
Reaction conditions: 1 (0.3 mmol), under inert atmosphere.
Isolated yields are reported. In some reactions, E/Z isomerization
b
c
was observed during the reaction course, and the E/Z ratio is based
on an average of at least two runs. 3 mmol scale. The reaction was
conducted at 80 °C.
d
e
t
dine}, Bubpy {4,4′-di-tert-butyl-2,2′-dipyridyl}, PCy3 {tricyclohex-
ylphosphine}, TerPy {2,2′:6′,2″-terpyridine}, (p-tolyl)3P {tri(p-tolyl)
phosphine}, PyPhos {2-[2-(diphenylphosphanyl)ethyl]pyridine}
and (hetero)aromatic (2g−2o) substituents at this position
underwent trans-carboamination to provide the corresponding
indole derivatives, demonstrating the generality of this reaction.
Substrates with aromatic R substituents containing an electron-
withdrawing group required a longer reaction time (2h−2k vs
2l, 2m). Functional groups such as benzylic C−H (2h) and aryl
halides (2l, 2m) remained intact during this transformation,
suggesting that the reaction proceeded under mild conditions. It
is noteworthy that heteroaryl moieties such as pyridine (2n) and
thiophene (2o) can be easily substituted at the 2-position of the
indoles. Such compounds are not only potential bidentate
ligands but also important from a medicinal point of view. The
silyl variant (2p) did not work for the transformation.6b The
scale-up of 2a from 1a at the 3 mmol scale was straightforward
despite the slower conversion.
2a with alkenyl substitution at the 3-position could be obtained
with several types of ligands. The P^P-, N^N-, and N^N^N-type
ligands were found to be less effective for the transformation
(Table 1, entries 1−8).9 A dramatic increase in reactivity was
observed when monodentate phosphorus ligands were
employed, although E/Z mixtures were obtained (Table 1,
entries 9 and 10). Notably, the use of a P^N-type bidentate
ligand, PyPhos,10 which has not been explored much with Ni(0)
complexes,11 showed excellent reactivity, affording 2a in 98%
yield as only the E-isomer. This suggested that the reactivity
could be tuned by carefully selecting the ligand (Table 1, entry
11). The choice of solvent was also critical for this reaction, as no
Next, the substituent on the aniline moiety was varied
(Scheme 3). Regardless of the electron density of the
B
https://dx.doi.org/10.1021/acs.orglett.0c03148
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
a b
,
reaction conditions (Scheme 4b). E/Z isomerization might
occur under the Ni-catalyzed conditions through coordination
with the acrylate system.8,12,13 The change of the E/Z ratio
during the reaction course was also observed in the reaction of
1d, where unpredictably the E-isomer was changed to Z,
resulting in the formation of (Z)-2d as the major product
(Scheme S1). It is likely that the steric hindrance of the isopropyl
substituent affected the Z-selectivity. In the same context, only
Z-isomers of 3b and 3f having substitution at the 3- or 6-position
reacted to yield (Z)-4b and (Z)-4f, respectively (Scheme 3).
Further, a cross-over experiment of 3g and 3j did not show
crossing-over phenomena, supporting the efficient intramolec-
ular process (Scheme S2).
Scheme 3. Substrate Scope
Based on the above observations, a plausible mechanism for
the reaction of 1a is proposed (Scheme 5). The Ni(0) complex
Scheme 5. Proposed Mechanism
a
Reaction conditions: 1 (0.3 mmol), under inert atmosphere.
b
c
Isolated yields are reported. Only Z-isomer of the starting material
d
reacted to give Z-isomer of the product. The reaction was conducted
at 80 °C.
substituents, reactions proceeded efficiently to give the
corresponding indole derivatives in good to excellent yields
(4a−4i). Interestingly, in the case of 3- or 6-substituted aniline
substrates, only Z-isomers reacted to give the corresponding
indoles with Z-selectivity (4b, 4f). The modification of the
methylester moiety to ethylester (4j) and ketone (4k) analogues
was not problematic to give the corresponding products,
whereas the terminal enamine (4l) was not a suitable substrate.
N-Substitution with benzoyl instead of the tosyl group also led
to product formation (4n) despite longer reaction time and
higher temperature. However, the N-Me derivative (4m) did not
work for the transformation well.
Some reactions provided E/Z mixtures of the product
dependent on the substituent pattern. The control experiments
showed that E/Z isomerization occurred over time during the
reaction course (Scheme 4). The reaction with E/Z mixtures of
substrate 1n produced only the corresponding E product under
standard conditions (Scheme 4a). The E/Z ratio was changed
when isolated E/Z mixtures of 2b was resubjected to the
A formed by the chelation between Ni(0) and PyPhos
undergoes an oxidative cyclization with the alkyne and alkene
moiety of 2-propynyl anilinoacrylate 1a to give nickelacycle
intermediate B. Then B undergoes C−N bond cleavage to
generate Ni-carbenoid intermediate C. The syn/anti rotation of
C to give a zwitterionic Ni intermediate C′,8 followed by N−Ni
coordination, generates six-membered intermediate D. Finally,
D undergoes reductive elimination to give the corresponding
indole 2a with 3-alkenyl substitution.
The developed method could be extended to the benzofuran
synthesis, showing the generality of the process (Scheme 6). An
O analogue 5 was converted to the corresponding benzofuran 6
in 98% yield.14
Scheme 6. Benzofuran Synthesis
Scheme 4. Control Experiment to Investigate E/Z Selectivity
Next, the synthetic utility of this reaction was successfully
verified by its application for the synthesis of functionalized
carbazole (Scheme 7). Carbazole is also considered to be a
highly important N-heterocycle because of the ubiquity of its
structural motif in numerous bioactive natural products,
pharmaceutical agents, and diverse novel functional materials.15
Indole products obtained via the present reaction pathway could
C
https://dx.doi.org/10.1021/acs.orglett.0c03148
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Notes
Scheme 7. Application of the Product for Carbazole Synthesis
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the support from the National
Research Foundation of Korea (NRF-2012M3A7B4049657,
NRF-2014011165, and NRF-2015M3D1A1070639).
REFERENCES
■
(1) (a) Sharma, V.; Kumar, P.; Pathak, D. Biological importance of the
indole nucleus in recent years: A comprehensive review. J. Heterocycl.
Chem. 2010, 47, 491−502. (b) Kaushik, N. K.; Kaushik, N.; Attri, P.;
Kumar, N.; Kim, C. H.; Verma, A. K.; Choi, E. H. Biomedical
Importance of Indoles. Molecules 2013, 18, 6620−6662. (c) Zhang, M.-
Z.; Chen, Q.; Yang, G.-F. A review on recent developments of indole-
containing antiviral agents. Eur. J. Med. Chem. 2015, 89, 421−441.
(d) Singh, T. P.; Singh, O. M. Recent Progress in Biological Activities of
Indole and Indole Alkaloids. Mini-Rev. Med. Chem. 2018, 18, 9−25.
(2) For a recent review, see: Urieta-Mora, J.; García-Benito, I.; Molina-
Ontoria, A.; Martín, N. Hole transporting materials for perovskite solar
cells: a chemical approach. Chem. Soc. Rev. 2018, 47, 8541−8571.
(3) Some reviews on indole synthetic methods: (a) Humphrey, G. R.;
Kuethe, J. T. Practical Methodologies for the Synthesis of Indoles.
Chem. Rev. 2006, 106, 2875−2911. (b) Cacchi, S.; Fabrizi, G. Update 1
of: Synthesis and Functionalization of Indoles Through Palladium-
Catalyzed Reactions. Chem. Rev. 2011, 111, PR215−PR283. (c) Bartoli,
G.; Dalpozzo, R.; Nardi, M. Applications of Bartoli indole synthesis.
Chem. Soc. Rev. 2014, 43, 4728−4750. (d) Youn, S. W.; Ko, T. Y. Metal-
Catalyzed Synthesis of Substituted Indoles. Asian J. Org. Chem. 2018, 7,
1467−1487.
(4) Some examples on indole synthesis by annulation of 2-
alkynylanilines: (a) Nakamura, I.; Yamagishi, U.; Song, D.; Konta, S.;
Yamamoto, Y. Gold- and Indium-Catalyzed Synthesis of 3- and 6-
Sulfonylindoles from ortho-Alkynyl-N-sulfonylanilines. Angew. Chem.,
Int. Ed. 2007, 46, 2284−2287. (b) Nakamura, I.; Sato, Y.; Konta, S.;
Terada, M. Platinum-catalyzed consecutive C−N bond formation-[1,3]
shift of carbamoyl and ester groups. Tetrahedron Lett. 2009, 50, 2075−
2077. (c) Oh, C. H.; Karmakar, S.; Park, H.; Ahn, Y.; Kim, J. W.
Domino Process in Silver-Catalyzed Reactions of N-Arylformimidates
and Active Methylene Compounds Involving Cycloisomerization and
1,3-Alkenyl Shift. J. Am. Chem. Soc. 2010, 132, 1792−1793. (d) Lu, B.;
Luo, Y.; Liu, L.; Ye, L.; Wang, Y.; Zhang, L. Umpolung Reactivity of
Indole through Gold Catalysis. Angew. Chem., Int. Ed. 2011, 50, 8358−
8362. (e) Yao, B.; Wang, Q.; Zhu, J. Palladium-Catalyzed Coupling of
ortho-Alkynylanilines with Terminal Alkynes Under Aerobic Con-
ditions: Efficient Synthesis of 2,3-Disubstituted 3-Alkynylindoles.
Angew. Chem., Int. Ed. 2012, 51, 12311−12315. (f) Wu, C.-Y.; Hu,
M.; Liu, Y.; Song, R.-J.; Lei, Y.; Tang, B.-X.; Li, R.-J.; Li, J.-H.
Ruthenium-catalyzed annulation of alkynes with amidesviaformyl
translocation. Chem. Commun. 2012, 48, 3197−3199. (g) Zhao, F.;
Zhang, D.; Nian, Y.; Zhang, L.; Yang, W.; Liu, H. Palladium-Catalyzed
Difunctionalization of Alkynes via C−N and S−N Cleavages: A
Versatile Approach to Highly Functional Indoles. Org. Lett. 2014, 16,
5124−5127. (h) Kumaran, E.; Fan, W. Y.; Leong, W. K. [Cp*IrCl2]2
Catalyzed Formation of 2,2′-Biindoles from 2-Ethynylanilines. Org.
Lett. 2014, 16, 1342−1345. (i) Chong, E.; Blum, S. A. Aminoboration:
Addition of B−N σ Bonds across C−C π Bonds. J. Am. Chem. Soc. 2015,
137, 10144−10147. (j) Hu, Z.; Tong, X.; Liu, G. Rhodium(III)-
Catalyzed Cascade Cyclization/Electrophilic Amidation for the
Synthesis of 3-Amidoindoles and 3-Amidofurans. Org. Lett. 2016, 18,
2058−2061. (k) Wu, C.; Zhao, F.; Du, Y.; Zhao, L.; Chen, L.; Wang, J.;
Liu, H. Highly selective intramolecular addition of C−N and S−N
bonds to alkynes catalyzed by palladium: a practical access to two
distinct functional indoles. RSC Adv. 2016, 6, 70682−70690. (l) Yuan,
K.; Wang, S. trans-Aminoboration across Internal Alkynes Catalyzed by
B(C6F5)3 for the Synthesis of Borylated Indoles. Org. Lett. 2017, 19,
1462−1465. (m) Ii, Y.; Hirabayashi, S.; Yoshioka, S.; Aoyama, H.;
Murai, K.; Fujioka, H.; Arisawa, M. Pd-Catalyzed Migratory Cyclo-
a
Reaction conditions: 2a/4c/4d (0.2 mmol), N,N-dimethylforma-
mide dimethyl acetal 7 (0.4 mmol), pyrrolidine (0.08 mL) under inert
atmosphere. Isolated yields, containing small amounts of N-methyl
substituent of 8, are reported.
b
be easily transformed to the corresponding functionalized
carbazoles by a simple method.16 Methyl 3-(2-methyl-1H-indol-
3-yl)acrylates (2a, 4c, and 4d) with N,N-dimethylformamide
dimethyl acetal (7) in pyrrolidine/DMF solution sequentially
underwent cyclization to carbazole and detosylation, producing
the corresponding functionalized N−H carbazoles. Both
electron-donating −OMe (8b) and electron-withdrawing −F
(8c) substituents were suitable for the transformation. Notably,
carbazoles 8a and 8b are naturally occurring alkaloids.17
In conclusion, a synthetic route for accessing multifunction-
alized indoles was developed through Ni-catalyzed trans-
carboamination using 2-alkynylanilinoacrylate. C−N bond
cleavage of a nickelacycle intermediate and syn/anti-rotation
of the alkenyl-Ni intermediate are the key steps of this trans-
carboamination. This approach allows the synthesis of 3-alkenyl
indoles, which is otherwise challenging through the previous
method that uses 2-alkynyl aniline derivatives. Notably, these
functionalized indoles could undergo one-step conversion to the
relevant carbazoles, another highly important N-heterocyclic
compound, thus indicating the high utility of the product.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03148.
Experimental details, analytical data of the synthesized
compounds, and NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
Eun Jin Cho − Department of Chemistry, Chung-Ang University,
Seoul 06974, Republic of Korea; orcid.org/0000-0002-
6607-1851; Email: ejcho@cau.ac.kr
Authors
Shrikant D. Tambe − Department of Chemistry, Chung-Ang
University, Seoul 06974, Republic of Korea
Naeem Iqbal − Department of Chemistry, Chung-Ang University,
Seoul 06974, Republic of Korea
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03148
D
https://dx.doi.org/10.1021/acs.orglett.0c03148
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
isomerization of N-Allyl-o-allenylaniline Derivatives. Org. Lett. 2019,
21, 3501−3504.
Org. Chem. 2019, 84, 11612−11622. (b) Ho, G.-M.; Sommer, H.;
Marek, I. Highly E-Selective, Stereoconvergent Nickel-Catalyzed
Suzuki−Miyaura Cross-Coupling of Alkenyl Ethers. Org. Lett. 2019,
21, 2913−2917. (c) Murugesan, K.; Bheeter, C. B.; Linnebank, P. R.;
Spannenberg, A.; Reek, J. N. H.; Jagadeesh, R. V.; Beller, M. Nickel-
Catalyzed Stereodivergent Synthesis of E- and Z-Alkenes by Hydro-
genation of Alkynes. ChemSusChem 2019, 12, 3363−3369.
(13) The reaction of 2b in the absence of Ni(COD)2 did not make any
changes in the E/Z ratio, indicating that Ni involves in the E/Z
isomerization.
(14) Previously, it was generated with TerPy ligand at 120 °C in 73%
yield; see ref 6b.
(15) Some reviews on carbazoles: (a) Li, J.; Grimsdale, A. C.
Carbazole-based polymers for organic photovoltaic devices. Chem. Soc.
(5) Some examples by metal-catalyzed 1,3-migration: (a) Nakamura,
I.; Mizushima, Y.; Yamamoto, Y. Synthesis of 2,3-Disubstituted
Benzofurans by Platinum−Olefin-Catalyzed Carboalkoxylation of o-
Alkynylphenyl Acetals. J. Am. Chem. Soc. 2005, 127, 15022−15023.
(b) Furstner, A.; Davies, P. W. Heterocycles by PtCl2-Catalyzed
̈
Intramolecular Carboalkoxylation or Carboamination of Alkynes. J.
Am. Chem. Soc. 2005, 127, 15024−15025. (c) Zeng, X.; Kinjo, R.;
Donnadieu, B.; Bertrand, G. Serendipitous Discovery of the Catalytic
Hydroammoniumation and Methylamination of Alkynes. Angew.
Chem., Int. Ed. 2010, 49, 942−945. (d) Hirner, J. J.; Faizi, D. J.;
Blum, S. A. Alkoxyboration: Ring-Closing Addition of B−O σ Bonds
across Alkynes. J. Am. Chem. Soc. 2014, 136, 4740−4745. (e) Rong, M.-
G.; Qin, T.-Z.; Zi, W. Rhenium-Catalyzed Intramolecular Carboalkox-
ylation and Carboamination of Alkynes for the Synthesis of C3-
Substituted Benzofurans and Indoles. Org. Lett. 2019, 21, 5421−5425.
(6) Examples on benzofuran synthesis by alkenyl migration:
(a) Sakiyama, N.; Noguchi, K.; Tanaka, K. Rhodium-Catalyzed
Intramolecular Cyclization of Naphthol- or Phenol-Linked 1,6-Enynes
Through the Cleavage and Formation of sp2 C-O Bonds. Angew. Chem.,
Int. Ed. 2012, 51, 5976−5980. (b) Ohno, S.; Qiu, J.; Miyazaki, R.;
Aoyama, H.; Murai, K.; Hasegawa, J.-y.; Arisawa, M. Ni-Catalyzed
Cycloisomerization between 3-Phenoxy Acrylic Acid Derivatives and
Alkynes via Intramolecular Cleavage and Formation of the C−O Bond
To Give 2,3-Disubstituted Benzofurans. Org. Lett. 2019, 21, 8400−
8403.
̈
Rev. 2010, 39, 2399−2410. (b) Schmidt, A. W.; Reddy, K. R.; Knolker,
H.-J. Occurrence, Biogenesis, and Synthesis of Biologically Active
Carbazole Alkaloids. Chem. Rev. 2012, 112, 3193−3328. (c) Janosik, T.;
̈
̈
Rannug, A.; Rannug, U.; Wahlstrom, N.; Slatt, J.; Bergman, J. Chemistry
and Properties of Indolocarbazoles. Chem. Rev. 2018, 118, 9058−9128.
(16) Sureshbabu, R.; Mohanakrishnan, A. K. An Improved Synthesis
of Carbazoles via Domino Reaction of N-Protected-2-methylindoles
with DMF-DMA/DMA-DMA. J. Heterocycl. Chem. 2012, 49, 913−918.
(17) Rasheed, S.; Rao, D. N.; Reddy, K. R.; Aravinda, S.; Vishwakarma,
R. A.; Das, P. C−N bond formation via Cu-catalyzed cross-coupling
with boronic acids leading to methyl carbazole-3-carboxylate: synthesis
of carbazole alkaloids. RSC Adv. 2014, 4, 4960−4969.
(7) Some reviews on nickelacycle applications: (a) Hoshimoto, Y.;
Ohashi, M.; Ogoshi, S. Catalytic Transformation of Aldehydes with
Nickel Complexes through η2 Coordination and Oxidative Cyclization.
Acc. Chem. Res. 2015, 48, 1746−1755. (b) Jackson, E. P.; Malik, H. A.;
Sormunen, G. J.; Baxter, R. D.; Liu, P.; Wang, H.; Shareef, A.-R.;
Montgomery, J. Mechanistic Basis for Regioselection and Regiodi-
vergence in Nickel-Catalyzed Reductive Couplings. Acc. Chem. Res.
2015, 48, 1736−1745. (c) Standley, E. A.; Tasker, S. Z.; Jensen, K. L.;
Jamison, T. F. Nickel Catalysis: Synergy between Method Develop-
ment and Total Synthesis. Acc. Chem. Res. 2015, 48, 1503−1514.
(8) (a) Huggins, J. M.; Bergman, R. G. Reaction of alkynes with a
methylnickel complex: observation of a cis insertion mechanism
capable of giving kinetically controlled trans products. J. Am. Chem. Soc.
1979, 101, 4410−4412. (b) Huggins, J. M.; Bergman, R. G.
Mechanism, regiochemistry, and stereochemistry of the insertion
reaction of alkynes with methyl(2,4-pentanedionato)-
(triphenylphosphine)nickel. A cis insertion that leads to trans kinetic
products. J. Am. Chem. Soc. 1981, 103, 3002−3011. (c) Clarke, C.;
Incerti-Pradillos, C. A.; Lam, H. W. Enantioselective Nickel-Catalyzed
anti-Carbometallative Cyclizations of Alkynyl Electrophiles Enabled by
Reversible Alkenylnickel E/Z Isomerization. J. Am. Chem. Soc. 2016,
138, 8068−8071. (d) Shimkin, K. W.; Montgomery, J. Synthesis of
Tetrasubstituted Alkenes by Tandem Metallacycle Formation/Cross-
Electrophile Coupling. J. Am. Chem. Soc. 2018, 140, 7074−7078.
(e) Koeritz, M. T.; Burgett, R. W.; Kadam, A. A.; Stanley, L. M. Ni-
Catalyzed Intermolecular Carboacylation of Internal Alkynes via Amide
C−N Bond Activation. Org. Lett. 2020, 22, 5731−5736.
(9) During the revision process, the indole synthesis was tried under
the conditions used for benzofuran synthesis reported by the Arisawa
group with tridentate TerPy ligand (ref 6b), but 2a was not generated,
indicating the ligand effect and different reactivity of N and O
analogues.
(10) Iqbal, N.; Iqbal, N.; Maiti, D.; Cho, E. J. Access to
Multifunctionalized Benzofurans by Aryl Nickelation of Alkynes:
Efficient Synthesis of the Anti-Arrhythmic Drug Amiodarone. Angew.
Chem., Int. Ed. 2019, 58, 15808−15812.
̀
̀
(11) Canellas, S.; Montgomery, J.; Pericas, M. A. Nickel-Catalyzed
̃
Reductive [2 + 2] Cycloaddition of Alkynes. J. Am. Chem. Soc. 2018,
140, 17349−17355.
(12) (a) Barber, E. R.; Hynds, H. M.; Stephens, C. P.; Lemons, H. E.;
Fredrickson, E. T.; Wilger, D. J. Nickel-Catalyzed Hydroarylation of
Alkynes under Reductive Conditions with Aryl Bromides and Water. J.
E
https://dx.doi.org/10.1021/acs.orglett.0c03148
Org. Lett. XXXX, XXX, XXX−XXX