Tridentate Nickel(II)-Catalyzed Chemodivergent C-H Functionalization and Cyclopropanation: Regioselective and Diastereoselective Access to Substituted Aromatic Heterocycles

Article abstract of DOI:10.1021/acs.orglett.0c02138

A Schiff-base nickel(II)-phosphene-catalyzed chemodivergent C-H functionalization and cyclopropanation of aromatic heterocycles is reported in moderate to excellent yields and very good regioselectivity and diastereoselectivity. The weak, noncovalent interaction between the phosphene ligand and Ni center facilitates the ligand dissociation, generating the electronically and coordinatively unsaturated active catalyst. The proposed mechanisms for the reported reactions are in good accord with the experimental results and theoretical calculations, providing a suitable model of stereocontrol for the cyclopropanation reaction.

Full text of DOI:10.1021/acs.orglett.0c02138

pubs.acs.org/OrgLett
Letter
Tridentate Nickel(II)-Catalyzed Chemodivergent C−H
Functionalization and Cyclopropanation: Regioselective and
Diastereoselective Access to Substituted Aromatic Heterocycles
Ekta Nag, Sai Manoj N. V. T. Gorantla, Selvakumar Arumugam, Aditya Kulkarni,
Kartik Chandra Mondal,* and Sudipta Roy*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c02138
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: A Schiff-base nickel(II)-phosphene-catalyzed chemodivergent C−H functionalization and cyclopropanation of
aromatic heterocycles is reported in moderate to excellent yields and very good regioselectivity and diastereoselectivity. The weak,
noncovalent interaction between the phosphene ligand and Ni center facilitates the ligand dissociation, generating the electronically
and coordinatively unsaturated active catalyst. The proposed mechanisms for the reported reactions are in good accord with the
experimental results and theoretical calculations, providing a suitable model of stereocontrol for the cyclopropanation reaction.
lation of the toxic heavy-metal wastes, especially for the large-
scale industrial applications, very often limit their usage as
catalysts. As a result, development of more abundant and cost-
effective first-row transition-metal-based catalysts are on high
demand.10 Herein, we report the syntheses, characterization of
a novel Schiff base-Ni(II)-phosphene complex 1 [(L-Me)Ni-
(PPh3); H2L = ((E)-2-((2-hydroxy-3-methoxybenzylidene)
amino)-4-methylphenol)] and its unprecedented catalytic
application for the chemodivergent C−H functionalization
and cyclopropanation of substituted indoles and pyrroles in the
presence of various diazoesters.
The air-stable, dark-brown block-shaped crystals of complex
1 (L-Me)Ni(PPh3) were synthesized in 85% yield. 1 was
characterized by single-crystal X-ray diffraction and various
spectroscopic techniques, both in solid state and in solution
(see the Supporting Information). The molecular structure of
Aromatic heterocycles, especially the functionalized indoles
and pyrroles, are the prevalent structural motifs of a broad
range of pharmaceutically active molecules.1 There are ample
examples of natural products and commercially available drugs
containing these heterocycles as their core structures (Figure
1).2 As a result, continuous efforts have been put forward to
develop various stereoselective methods3 for their syntheses,4
including the enzyme-catalyzed5 sustainable alternatives.
Late transition-metal phosphine complexes are well-known
for exhibiting diverse catalytic properties.6−8 However, their
applications in catalytic carbene transfer reactions9c to
heteroarenes are not documented so far.9 Moreover, the
harsh reaction conditions, and increased hazards of accumu-
Received: June 29, 2020
Figure 1. Representative bioactive molecules and natural products
containing functionalized indole and pyrrole cores.
https://dx.doi.org/10.1021/acs.orglett.0c02138
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
complex 1 contains a dideprotonated, tridentate Schiff base
ligand (L-Me)2− coordinated to the Ni(II) center having a
distorted square planar geometry. The PPh3 moiety is
coordinated to the metal center in a trans fashion with a
Ni−P bond distance of 2.217(6) Å (see Figure 2, as well as
substrates to react at room temperature, using DCM as a
solvent in the presence of 5 mol % of complex 1 (see Table S2
in the Supporting Information, entry 1). To our delight, after
24 h, the C3-functionalized N-methylindole (4a) was obtained
as a single regioisomer in 15% isolated yield. Inspired by this
initial result, we moved to optimize the reaction condition (see
Table S2). Having the optimized reaction conditions in hand,
we turned our attention to probe the generality of the reaction
by varying the diazoesters 3 (Scheme 1). In all of the cases, the
Scheme 1. Complex 1-Catalyzed C3−H Functionalization of
a
Substituted Indoles
Figure 2. Molecular structure of complex 1 (top, left) and its solution
dynamics. Generation of nickel(II)-carbenoid intermediate (Int-n).
ΔG298 values are given in units of kcal/mol.
Figure S72 in the Supporting Information). The solution 31P
NMR spectrum of pure crystals of 1 exhibited two resonances:
one at +10.9 ppm, corresponding to the coordinated
phosphorus (Ni ← :PPh3), and the other at −5.5 ppm,
corresponding to the free PPh3 (see Figures S16−S17 in the
Supporting Information). The mass-spectrometric analysis of 1
in solution showed the presence of various oligomers [((L-
Me)Ni)n (Om-n), where n = 1−8] of the PPh3-dissociated
monomeric species 1′ [(L-Me)Ni], revealing the existence of
solution dynamics (see the Supporting Information). To
understand the bonding scenario of complex 1 and the reason
behind the spontaneous dissociation of PPh3 in solution,
geometry optimization and NBO analysis were performed (see
the Supporting Information for computational details). These
studies led to the conclusion that the Ni−P bond in 1 mostly
consists of noncovalent interaction (electrostatic, 61%), with a
minor contribution from the orbital overlap and mixing (39%),
resulting in a lower Ni−P bond dissociation energy (−De =
−29.8; 2ΔG = +29.4 kcal/mol), which is comparable in
magnitude with the dimerization energy (ΔG = −27.3 kcal/
mol) of 1′ to produce D-2 (Figure 2). This rationalizes the
spontaneous ligand (PPh3) dissociation from the nickel(II)
center of complex 1, creating the vacant coordination site in
active catalyst 1′ (Figure 2).
a
Isolated yields for 4 are shown for the reactions performed at 100 °C
for 24 h with 1 mmol of 2, 1.5 mmol of 3, and 5 mol % 1, using
toluene as the solvent. Mixture of regioisomers (see the Supporting
Information).
b
expected C3-functionalized N-methylindoles (4b−4d) were
obtained in moderate to good isolated yields (58%−88%) and
excellent regioselectivity. A much faster reaction with increased
yield of C3-functionalized product 4d (88%) was isolated
exclusively when dimethyl 2-diazomalonate (3e) was employed
(the corresponding nickel-carbenoid intermediate, Int-3e was
observed to have the highest computed electrophilicity indices
ω
11 of 5.08 eV, having the most electrophilic carbene center;12
see Figures S50−S69 and Table S5 in the Supporting
Information). Next, we moved to investigate the effect of
different substituents at the adjacent phenyl ring of N-
methylindole. Introduction of an electron-withdrawing Br-
group at the 5-position of N-methylindole (2b), yielded the
corresponding C3-functionalized product 4h exclusively with
an excellent yield of 93% when treated with 3e (Scheme 1).
However, introduction of an electron-donating OMe group at
the 5-position of 2c led to the formation of a mixture of both
C3- and C2-functionalized products with various ratios in favor
of the C3 product. This can be attributed to the increased
electron density at both C3 and C2 positions (see the
Supporting Information for computed molecular electrostatic
potential (MEP) plot of 2c13a). The presence of a Me group at
the C7 and C2 positions of N-methylindoles afforded the
Having these results in hand, we envisioned that the
spontaneous dissociation (68%−75%, concluded by 31P NMR
studies) of PPh3 from complex 1 when dissolved in organic
solvents can create the vacant coordination site at the Ni
center in 1′, thereby facilitating the in situ generation of the
nickel-carbenoid intermediate (Int-n) in the presence of
diazoester 3, which can successively afford C−H functionaliza-
tion or cyclopropanation of electron-rich N-heterocycles. We
initiated the catalytic studies of complex 1, choosing N-
methylindole (2a) and ethyl diazoacetate (3a) as model
B
https://dx.doi.org/10.1021/acs.orglett.0c02138
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
corresponding C3-functionalized products exclusively (4r,
91%; 4s, 62%; 4t, 61%) when treated with the diazoester 3c.
Next, we probed our reaction with electronically varied
directing groups (DGs) attached to the N atom of indole in
the presence of the most electron-deficient diazoester,
dimethyl 2-diazomalonate (3e). Gratifyingly, in all of the
cases, we observed the formation of the corresponding C3
functionalized indoles (4l−4w) exclusively in good to excellent
yields (37%−96%). This regioselectivity can be attributed to
the nucleophilic attack14 of the indole derivatives (2) to the
most electron-deficient Ccarbene of Int-3e, predominantly
through the most electron-rich C3 center of 2 (see the
Supporting Information15a). The presence of electron-donating
DGs at the N atom of 2g and 2h afforded the corresponding
C3-functionalized products 4p and 4q in 88% and 96% yields,
respectively, when treated with 3e. The robustness of the
present method was established by conducting the reaction in
a larger scale of 1.59 g of N-acetyl indole (2l, 10 mmol) and 3c
(15 mmol, 2.64 g). The desired product 4u was isolated in
65% yield (see the Supporting Information).
group at the C5 position, leading to the reduced electron
densities around the C3−C2 positions (see the Supporting
Information15b) with more double-bond character (see the
Supporting Information15c). Overall, this result directed us
toward a possible chemodivergent route to synthesize the C2/
C3-cyclopropanated products by reducing the overall electron
density over the C2C3 double bond of the heteroarene 2
while reacting with diazoester 3 by introducing a suitable
electron-withdrawing DG at the N atom.
As anticipated, changing the DG, R2 of 2 from alkyl to the
ester group under similar reaction conditions dramatically
changed the course of the reaction (see the Supporting
Information15d), leading to the formation of the corresponding
C2/C3-cyclopropanated products 6 with excellent exo-
diastereoselectivity (Scheme 3). The relative stereochemistry
Scheme 3. Complex 1-Catalyzed C2/C3 Cyclopropanation
a
of Heteroarenes 2
Interestingly, under similar reaction conditions, N-methyl
pyrrole (2t) yielded the corresponding C2-functionalized
products (5a−5j) as the major products in the presence of
various diazoesters (3a−3e) in good yields and moderate
regioselectivity (see Scheme 2). Similar observation was found
Scheme 2. Complex 1-Catalyzed C2−H Functionalization of
a
Substituted Pyrroles and Indoles
a
Isolated yields of 6 are shown for the reactions performed at 100 °C
for 24 h with 1 mmol of 2, 1.5 mmol of 3, and 5 mol % 1, using
toluene as the solvent. bMixture of products (see the Supporting
Information).
a
Isolated yields for 5 are shown for the reactions performed at 100 °C
for 24 h with 1 mmol of 2, 1.5 mmol of 3, and 5 mol % 1, using
toluene as the solvent. Mixture of regioisomers (see the Supporting
b
Information).
of 6 was unambiguously established by the single-crystal XRD
studies of 6f and 6r (see the Supporting Information). When
N-Boc pyrrole was separately treated with ethyl diazoacetate
and methyl-2-diazo-2-phenylacetate, the corresponding cyclo-
propanated products 6a (39%) and 6c (25%) were isolated,
along with the C2-functionalized products as the minor
products (6a′, 12%; 6c′, 10%). However, in the case of tert-
butyl diazoacetate, the exo-cyclopropanated product 6b (50%)
was formed exclusively because of the increased steric bulk
offered by the tert-butyl group. On the other hand, when N-
Boc indole (2q) was treated with methyl-2-diazo-2-phenyl-
acetate, the expected cyclopropanated product 6g was isolated
in 46% yield along with the corresponding C3-functionalized
product (6g′) as the minor product (10%). This can be
attributed to the more sterically hindered C2 position of 2q,
while coordinated to the Ni center with the carbonyl oxygen
in the case of the 1,3-dimethylindole (2k), giving rise to the
corresponding C2-functionalized products (5f−5j) in moder-
ate to good yields (26%−82%).
Surprisingly, introduction of a stronger electron-withdrawing
NO2 group at the C5 position of N-methylindole (2d)
produced the corresponding C3-functionalized product 4f in
58% yield, along with the C2−C3 cyclopropanated product 4f′
as the minor product in 14% yield (see the Supporting
Information). This result indicated that a relatively electron-
poor C2−C3 π-system, as in 2d, attributed by the negative
mesomeric effect of the NO2 group, may open up the
possibility of cyclopropanation across the C2−C3 bond. The
computed MEP plot of 2d revealed the maximum electron
density accumulation over the electron-withdrawing −NO2
C
https://dx.doi.org/10.1021/acs.orglett.0c02138
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
available for the nickel-carbenoid to attack. Under similar
reaction conditions, benzofuran (2s) and methyl 2- and 3-
furoates (2u and 2v, respectively) afforded the corresponding
cyclopropanated products 6n−6s in moderate yields and
diastereoselectivity.
It is noteworthy to mention that the reactivity of N-acetyl
and N-pivaloyl indoles (2g, 2h) was observed to be largely
dependent on the specific diazoesters used as the reaction
partner that decides the final products.16
The intermolecular competition experiment performed by
treating 2a with an equimolar mixture of the diazoesters 3b
and 3e under similar reaction conditions led to the selective
formation of 4d (23%, Scheme 4). This result furnishes strong
a
Scheme 4. Competition Experiments
Figure 3. Proposed mechanism for the C3 functionalization of 2.
ΔG298 values are given in units of kcal/mol and calculated for R = H,
R1 = Et, R3 = H, n = 3a, Int-3a.
the next step, migratory insertion of the carbenoid (:C(R)-
CO2R1) occurs from the Ni center to the C3 atom of 2, leading
to the formation of intermediate B. This process was
determined to be highly exergonic. Finally, the decoordination
of product 4 from the Ni center occurs, releasing the expected
C3-functionalized product 4 and the monomeric intermediate
1′. 1′ further reacts with diazoester 3 to regenerate the Int-n
and participate in the next catalytic cycle.
a
Isolated yields are shown.
The proposed mechanism for cyclopropanation is depicted
in Figure 4. Once the Int-3a is generated in situ, the formation
support in favor of the higher reactivity of 3e over 3b toward
C3-H functionalization of 2a. This can be attributed to the low
lying LUMO of Int-3e (see the Supporting Information15e).
Moreover, when an equimolar mixture of 2a and 2m was
treated with 1.5 equiv of 3e, the corresponding C3-function-
alized product 4d was isolated with only a trace amount of the
C3-functionalized N-Boc derivative, showing the preference of
the more-electrophilic nickel-carbenoid intermediate, Int-3e,
toward the comparatively more electron-rich C3 position (see
the Supporting Information15f) of 2a than 2m, producing 4d in
38% yield.
To have an insight into the reaction mechanisms and origin
for the present chemodivergence, NBO analysis were
performed on 1′ and Int-n (see the Supporting Information).
The Ni−Ccarbene bond of Int-n has been found to be of a
donor−acceptor-type partial double bond (Ni → C and Ni ←
C), which is slightly stronger (∼10 kcal/mol) than the Ni−P
bond in 1. Accordingly, the computed bond dissociation
energy (De) for Ni−Ccarbene bonds in Int-n was found to be
higher, compared to that of the Ni−P bond in 1, which favors
the formation of Int-n (Figure 3).
Based on the experimental and theoretical investigations, we
proposed that, upon dissociation of PPh3 from 1, the
monomeric species 1′ (active catalyst) forms in the reaction
mixture, which then generates Int-n in situ by reacting with the
diazoester employed upon removal of the dinitrogen. Next, in
the presence of the heteroarene containing electron-donating
groups at the N atom (alkyl, aryl), Int-n forms a π-complex, A
(Figure 3) through N1−C2−C3 delocalized π-cloud, with the
highest contribution coming from the C3 atom of 2 (Ni−
Cindole = 2.49 Å; see Figure S49 in the Supporting
Information). Successful geometry optimization of intermedi-
ate A showed a significant elongation of the Ni−Ccarbene bond
by 0.8 Å (Ni−Ccarbene = 1.87 Å; see the Supporting
Information15g), when compared to that in Int-3a (1.79 Å),
providing evidence for weakening of the Ni−Ccarbene bond. In
Figure 4. Proposed mechanism and model for stereocontrol of
cyclopropanation. R = H, R1 = Et. ΔG298 values are given in units of
kcal/mol.
of intermediate A (see the Supporting Information15h) occurs
upon coordination of the lone pair of Oco of the Boc group.
However, this intermediate could not be optimized theoret-
ically. In the next step, the Ccarbene of the Ni−Ccarbene bond of A
accepts the nucleophilic attack14 (to its LUMO) from the C2
carbon of 2 (see the Supporting Information15i) to produce
the six-membered metallacycle B, for which the geometry
could be successfully optimized (see the Supporting
Information15j). This zwitterionic intermediate B with a longer
D
https://dx.doi.org/10.1021/acs.orglett.0c02138
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Ni−Ccarbene bond (2.00 Å; see the Supporting Information15j
)
Sai Manoj N. V. T. Gorantla − Department of Chemistry,
Indian Institute of Technology Madras, Chennai 600036,
India; orcid.org/0000-0001-7315-6354
Selvakumar Arumugam − Department of Chemistry, Indian
Institute of Technology Madras, Chennai 600036, India
Aditya Kulkarni − Department of Chemistry, Indian Institute of
Science Education and Research (IISER), Tirupati 517507,
India; orcid.org/0000-0002-0735-4851
either can form the cyclopropane ring (isolated as the major
product) from the same surface by attacking back at the C3
atom or can collapse into the C2−H bond functionalization
product (in a few cases, isolated as the minor product). We
assume that the formation of this zwitterionic intermediate,
having only the top phase available, because of the sterically
crowded bottle phase, is crucial for the observed exo-
diastereoselectivity of the cyclopropanated products. Finally,
dissociation of the weakly bonded product (6) from the Ni
center of C occurs, regenerating the monomeric active catalyst
1′, followed by the binding of the diazoester to produce Int-3a
for the next catalytic cycle.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02138
Notes
The authors declare no competing financial interest.
In conclusion, we have developed an efficient, cost-effective
Ni(II)-phosphene (1)-catalyzed chemodivergent C−H func-
tionalization and cyclopropanation of aromatic heterocycles
with excellent regioselectivity and diastereoselectivity. The
overall process is atom-economic, highly functional-group-
tolerant, and provides an efficient route to generate function-
alized indoles, pyrroles, and furans in good yields and
selectivity. On the basis of experimental results and theoretical
calculations, we have proposed that, mechanistically, the
inherent inductive nature of the DG attached to the
heteroatom of the aromatic heterocycle plays a crucial role
in the unique chemodivergence.
ACKNOWLEDGMENTS
■
S.R. and K.C.M. gratefully acknowledge SERB, New Delhi for
their respective ECR grants (No. ECR/2016/000733 for S.R.;
No. ECR/2016/000890 for K.C.M.). E.N. thanks IISER,
Tirupati and A.K. thanks KYPY for financial support.
S.M.N.V.T.G. and S.A. thank CSIR for SRF. We thank Prof.
K. N. Ganesh (Director, IISER Tirupati) and Prof. M. S.
Krishnan (IIT Madras) for their support to complete this
work.
REFERENCES
■
(1) Mizuno, A.; Matsui, K.; Shuto, S. A Strategy Based on the
Structural Features of Cyclopropane. Chem. - Eur. J. 2017, 23, 14394.
(2) (a) Bhardwaj, V.; Gumber, D.; Abbot, V.; Dhiman, S.; Sharma,
P. A Resourceful Small Molecule in Key Medicinal Hetero-aromatics.
RSC Adv. 2015, 5, 15233. (b) Kirillova, M. S.; Muratore, M. E.; Dorel,
R.; Echavarren, A. M. Concise Total Synthesis of Lundurines A-C
Enabled by Gold Catalysis and a Homodienyl Retro-Ene/Ene
Isomerization. J. Am. Chem. Soc. 2016, 138, 3671. (c) Xu, H.; Li, Y.
P.; Cai, Y.; Wang, G. P.; Zhu, S. F.; Zhou, Q. L. Highly
Enantioselective Copper- and Iron-Catalyzed Intramolecular Cyclo-
propanation of Indoles. J. Am. Chem. Soc. 2017, 139, 7697.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02138.
Syntheses of complex 1, compounds 2−6; NMR; UV-
vis; mass spectrometric analysis; single-crystal X-ray
diffraction of complex 1 and representatives of
compounds 4, 5, and 6; computational details; spectral
1
data for 1−6; copies of H, 13C, and 31P NMR spectra
(3) (a) Joucla, L.; Djakovitch, L. Transition Metal-Catalyzed, Direct
and Site-Selective N1-, C2- or C3-Arylation of the Indole Nucleus: 20
Years of Improvements. Adv. Synth. Catal. 2009, 351, 673. (b) Gao,
X.; Wu, B.; Huang, W.-X.; Chen, M.-W.; Zhou, Y.-G. Enantioselective
Palladium-Catalyzed C-H Functionalization of Indoles Using an
Axially Chiral 2,2′-Bipyridine Ligand. Angew. Chem., Int. Ed. 2015, 54,
11956. (c) Loup, J.; Zell, D.; Oliveira, J. C. A.; Keil, H.; Stalke, D.;
Ackermann, L. Asymmetric Iron-Catalyzed C−H Alkylation Enabled
by Remote Ligand meta-Substitution. Angew. Chem. 2017, 129, 14385.
(d) Pilsl, L. K. A.; Ertl, T.; Reiser, O. Enantioselective Three-Step
Synthesis of Homo-β-proline: A Donor-Acceptor Cyclopropane as
Key Intermediate. Org. Lett. 2017, 19, 2754. (e) Pesciaioli, F.; Dhawa,
U.; Oliveira, J. C. A.; Yin, R.; John, M.; Ackermann, L.
Enantioselective Cobalt(III)-Catalyzed C−H Activation Enabled by
Chiral Carboxylic Acid Cooperation. Angew. Chem., Int. Ed. 2018, 57,
(PDF)
Accession Codes
CCDC 1896711−1896714, 1922563, 1922565, and 1922566
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge via www.ccdc.ca-
m.ac.uk/data_request/cif, or by emailing data_request@ccdc.
cam.ac.uk, or by contacting The Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
+44 1223 336033.
AUTHOR INFORMATION
■
̈
15425. (f) Ozuduru, G.; Schubach, T.; Boysen, M. M. K.
̈
Corresponding Authors
Enantioselective Cyclopropanation of Indoles: Construction of All-
Carbon Quaternary Stereocenters. Org. Lett. 2012, 14, 4990. (g) Li, Y.
P.; Li, Z. Q.; Zhu, S. F. Recent Advances in Transition-Metal-
Catalyzed Asymmetric Reactions of Diazo Compounds with Electron-
Rich (Hetero-) Arenes. Tetrahedron Lett. 2018, 59, 2307.
Sudipta Roy − Department of Chemistry, Indian Institute of
Science Education and Research (IISER), Tirupati 517507,
India; orcid.org/0000-0002-5883-4329;
Email: roy.sudipta@iisertirupati.ac.in
(4) (a) Gogoi, A.; Guin, S.; Rout, S. K.; Patel, B. K. Copper-
Catalyzed Synthesis of 3-Aroylindoles via a sp3 C-H Bond Activation
Followed by C-C and C-O Bond Formation. Org. Lett. 2013, 15,
1802. (b) Dutta, P. K.; Chauhan, J.; Ravva, M. K.; Sen, S. Directing
Group-Assisted Manganese-Catalyzed Cyclopropanation of Indoles.
Org. Lett. 2019, 21, 2025. (c) Ghorai, J.; Chaitanya, M.; Anbarasan, P.
Cp*Co(III)-Catalyzed Selective Alkylation of C-H Bonds of Arenes
and Heteroarenes with α-diazocarbonyl compounds. Org. Biomol.
Chem. 2018, 16, 7346. (d) Li, Z.; Shi, Z.; He, C. Addition of
Kartik Chandra Mondal − Department of Chemistry, Indian
Institute of Technology Madras, Chennai 600036, India;
Email: csdkartik@iitm.ac.in
Authors
Ekta Nag − Department of Chemistry, Indian Institute of Science
Education and Research (IISER), Tirupati 517507, India;
orcid.org/0000-0003-4490-4207
E
https://dx.doi.org/10.1021/acs.orglett.0c02138
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Heterocycles to Electron Deficient Olefins and Alkynes Catalyzed by
Gold(III). J. Organomet. Chem. 2005, 690, 5049. (e) Jackson, R. W.;
Manske, R. H. The Reaction Products of Indoles with Diazoesters.
Can. J. Res. 1935, 13b, 170. (f) Gibe, R.; Kerr, M. A. Convenient
Preparation of Indolyl Malonates via Carbenoid Insertion. J. Org.
Chem. 2002, 67, 6247.
Supporting Information. (j) Figure S50 in the Supporting
Information.
(16) See page S77, Table S5, and Figures S53 and S64 in the
Supporting Information.
(5) For enzyme-catalyzed cyclopropanation, see: (a) Coelho, P. S.;
Brustad, E. M.; Kannan, A.; Arnold, F. H. Olefin Cyclopropanation
via Carbene Transfer Catalyzed by Engineered Cytochrome P450
Enzymes. Science 2013, 339, 307. (b) Carminati, D. M.; Fasan, R.
Stereoselective Cyclopropanation of Electron-Deficient Olefins with a
Cofactor Redesigned Carbene Transferase Featuring Radical Re-
activity. ACS Catal. 2019, 9, 9683. For enzyme-catalyzed C-H
functionalization of indoles, see: (c) Brandenberg, O. F.; Chen, K.;
Arnold, F. H. Directed Evolution of a Cytochrome P450 Carbene
Transferase for Selective Functionalization of Cyclic Compounds. J.
Am. Chem. Soc. 2019, 141, 8989.
(6) (a) Ji, Y.; Plata, R. E.; Regens, C. S.; Hay, M.; Schmidt, M.;
Razler, T.; Qiu, Y.; Geng, P.; Hsiao, Y.; Rosner, T.; Eastgate, M. D.;
Blackmond, D. G. Mono-Oxidation of Bidentate Bis-phosphines in
Catalyst Activation: Kinetic and Mechanistic Studies of a Pd/
Xantphos-Catalyzed C-H Functionalization. J. Am. Chem. Soc. 2015,
́
137, 13272. (b) Rull, S. G.; Alvarez, E.; Fructos, M. R.; Belderrain, T.
́
R.; Perez, P. J. The Elusive Palladium-Diazo Adduct Captured:
Synthesis, Isolation and Structural Characterization of [(ArNHC-
PPh2)Pd(η2-N2C(Ph)CO2Et)]. Chem. - Eur. J. 2017, 23, 7667.
(7) Carlsen, R.; Wohlgemuth, N.; Carlson, L.; Ess, D. H. Dynamical
Mechanism may Avoid High-Oxidation State Ir(V)-H Intermediate
and Coordination Complex in Alkane and Arene C-H Activation by
Cationic Ir(III) Phosphine. J. Am. Chem. Soc. 2018, 140, 11039.
(8) For Group-VI-phosphene complexes, see: (a) Fu
Furstner, A.; Picquet, M.; Bruneau, C.; Dixneuf, P. H. Cationic
̈
rstner, A.;
̈
Ruthenium Allenylidene Complexes as a New Class of Performing
Catalysts for Ring Closing Metathesis. Chem. Commun. 1998, 12,
1315. (b) Dorta, R.; Kelly, R. A., III; Nolan, S. P. Cross Metathesis
Allowing the Conversion of a Ruthenium Indenylidene Complex into
Grubbs’ Catalyst. Adv. Synth. Catal. 2004, 346, 917.
(9) (a) Liu, K.; Xu, G.; Sun, J. Gold-Catalyzed Stereoselective
Dearomatization/Metal-Free Aerobic Oxidation: Access to 3-Sub-
stituted Indolines/Oxindoles. Chem. Sci. 2018, 9, 634 and ref 3
therein. (b) Ciszewski, Ł. W.; Durka, J.; Gryko, D. Photocatalytic
Alkylation of Pyrroles and Indoles with α-Diazo Esters. Org. Lett.
2019, 21, 7028. (c) Jurberg, I. D.; Davies, H. M. L. Blue Light-
Promoted Photolysis of Aryldiazoacetates. Chem. Sci. 2018, 9, 5112.
(d) Huang, X.; Webster, R. D.; Harms, K.; Meggers, E. Asymmetric
Catalysis with Organic Azides and Diazo Compounds Initiated by
Photoinduced Electron Transfer. J. Am. Chem. Soc. 2016, 138, 12636.
(10) Saha, S.; Jana, S.; Gupta, S.; Ghosh, A.; Nayek, H. P. Syntheses,
Structures and Biological Activities of Square Planar Ni(II), Cu(II)
Complexes. Polyhedron 2016, 107, 183.
́
(11) Parr, R. G.; Szentpaly, L. v.; Liu, S. Electrophilicity Index. J. Am.
Chem. Soc. 1999, 121, 1922.
(12) Khade, R. L.; Zhang, Y. Catalytic and Biocatalytic Iron
Porphyrin Carbene Formation: Effects of Binding Mode, Carbene
Substituent, Porphyrin Substituent, and Protein Axial Ligand. J. Am.
Chem. Soc. 2015, 137, 7560.
(13) See: (a) Figure S41 in the Supporting Information.
(14) Vargas, D. A.; Tinoco, A.; Tyagi, V.; Fasan, R. Myoglobin-
Catalyzed C-H Functionalization of Unprotected Indoles. Angew.
Chem., Int. Ed. 2018, 57, 9911.
(15) See: (a) Tables S5 and S6; and Figure S40 and 43 in the
Supporting Information. (b) Figure S41 in the Supporting
Information, indicated by green color. (c) Table S7 and Figure
S53 in the Supporting Information. (d) Figures S40, S42 and S44 in
the Supporting Information. (e) Table S8; Figures S64 and S65 in
the Supporting Information. (f) Figure S40 in the Supporting
Information. (g) Figure S49 in the Supporting Information.
(h) Figure S44 in the Supporting Information. (i) Table S7 in the
F
https://dx.doi.org/10.1021/acs.orglett.0c02138
Org. Lett. XXXX, XXX, XXX−XXX