CuSO4-Catalyzed Tandem C(sp3)-H Insertion Cyclization of Toluenes with Isonitriles to Form Indoles

Article abstract of DOI:10.1021/acs.orglett.9b03751

A CuSO₄-catalyzed tandem benzylic C-H insertion cyclization of toluene derivatives and isonitriles is described. The naturally abundant salt CuSO₄ serves as a low-cost ligand-free redox catalyst. This reaction provides a practical mo

Full text of DOI:10.1021/acs.orglett.9b03751

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
3
CuSO ‑Catalyzed Tandem C(sp )−H Insertion Cyclization of Toluenes
4
with Isonitriles to Form Indoles
Xiang-Huan Shan,† Mei-Mei Wang, Lin Tie, Jian-Ping Qu, and Yan-Biao Kang*,†
,§
†,§
†
‡
†
Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, China
‡
Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering, Nanjing Tech University, Nanjing 211816, China
*
S Supporting Information
ABSTRACT: A CuSO -catalyzed tandem benzylic C−H
4
insertion cyclization of toluene derivatives and isonitriles is
described. The naturally abundant salt CuSO serves as a low-
4
cost ligand-free redox catalyst. This reaction provides a
practical modular synthesis of N-aryl indoles from isonitriles.
he transition-metal-promoted cleavage of inert bonds
Table 1. Reaction Conditions
T
such as C−H and C−C bonds has been well-established
in recent years. The noble metals including Rh, Pd, Ru, Ir, and
so on have been widely used as catalysts with special strategies
using directing groups or Haller−Bauer-type cleavage for the
1
activation of these inert bonds. The cleavage of undirected
a
b
and unactivated C−H bonds remains a challenge in organic
synthesis. The base-assisted C−H cleaving [3 + 2] addition−
elimination has been a powerful method for the construction
entry
[Cu]
2a (equiv)
temp (°C)
3a (%)
1
2
3
4
5
6
7
8
9
Cu(OAc)2
CuI
3
3
3
3
3
3
3
3
3
2
2
2
2
90
90
90
90
90
90
70
60
75
70
70
70
6
10
24
28
36
44
61
45
56
80
81
0
2
,3
of five-membered heterocycles. In this work, isonitriles have
been found to be a remarkable C−N donor for N-aryl
CuCl
Cu(acac)
Cu(NCCH ) PF
3 4 6
2
2
4
,5
indoles. The combination of base-promoted benzylic C−H
6
7
cleavage and copper-catalyzed carbanion-radical redox relay
CuSO
CuSO
4
enables this reaction. Catalytic inexpensive naturally abundant
4
CuSO promotes the modular synthesis of N-aryl indoles from
CuSO4
CuSO4
CuSO4
4
toluene derivatives and isonitriles.
10
11
12
13
The reaction conditions have been explored by using the
conversion of 1a and 2a to 3a as the model reaction (Table 1).
Initially, various copper salts were screened as catalysts.
Cu(OAc) , CuI, CuCl , Cu(acac) , and Cu(NCCH ) PF
b
b
c
CuSO4
none
CuSO4
70
t
0
2
2
2
3
4
6
a
were all found to be less active in comparison with CuSO4,
an inexpensive naturally abundant copper salt (entries 1−6).
Further investigation shows that either a lower temperature or
a lower amount of isonitrile 2a can increase the reaction yields
Conditions: 1a (0.5 mmol), 2a (2− to 3 equiv), BuOK (5 equiv),
dioxane (2 mL), argon, 5 h, isolated yields. BuOK (3 equiv). No
BuOK.
b
t
c
t
(
entries 6−11). Dehalogenation and intramolecular cyclization
reactant (Scheme 1). Both arylthio- and alkylthio-substituted
toluenes were substrates for this reaction (3n−q and 3r−v).
Other substituents such as phenyl and heteroatom-containing
groups were found to be less reactive (3w−y). The
outstanding reactivity of arylthio- or alkylthio-substituted
toluenes is a reflection of the possible radical reaction pathway
due to the stability of the thio groups to adjacent radicals. The
gram-scale synthesis afforded 2.25 g of 3b in 84% yield.
The general scope for toluene derivatives and isonitriles is
demonstrated (Scheme 1). Toluenes bearing removable
protecting groups such as TIPSO (3z), MOMO (3B), and
side products were noticed at higher temperatures with more
base. No conversion was observed for reactions in the absence
of a base or CuSO4 (entries 12 and 13). The reaction
conditions identified in entry 11 were chosen as the standard
conditions for further investigations.
The isonitrile scope was explored using the reaction of 1 to 3
(Scheme 1). Several N-aryl isonitriles bearing representative
halo, alkyl, aryl, and hetero substituents were subjected to the
standard reaction conditions, and the corresponding indoles
were obtained.
Bromo and iodo groups were found to be tolerant of the
reaction conditions (3c, 3g, 3j, and 3m). The structure of
indole product was confirmed by the X-ray analysis of 3m. The
scope of 2-iodotoluenes was examined using isonitrile 2a as the
MeSCH O (3C) were converted to corresponding indoles
2
Received: October 23, 2019
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03751
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Reaction Scope
a
t
b
c
Conditions: 1 (0.5 mmol), 2 (1 mmol), BuOK (1.5 mmol), dioxane (2 mL), isolated yield. Isonitrile (1.25 mmol). [Cu] (20 mol %).
B
DOI: 10.1021/acs.orglett.9b03751
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
without altering these protecting groups. Carboxylic acid is also
tolerated (3A). Other substituents including iodo, bromo, and
chloro groups were also tolerated (3D−J). The structure of the
representative indole 3G was confirmed by X-ray analysis.
The thio groups are removable in most indole products. For
example, the alkylthio group in indole 3s is reduced to C3−H
indole 4 in 73% (Scheme 2). In another case, 3a was oxidized
to 3-sulfonyl indole 5. 3-Alkylthioindoles can be directly used
Scheme 3. Proposed Mechanism
8
for cross-coupling.
a
Scheme 2. Synthetic Applications
derivatives and isonitriles. The combination of the base-
promoted benzylic C−H cleavage and the copper-catalyzed
carbanion−radical redox relay enables this reaction. Catalytic
a
Conditions A: NiCl (6.8 equiv), NaBH (6.8 equiv), EtOH, reflux,
2 h. Conditions B: mCPBA (3 equiv), CH Cl , r.t., 5 h.
2 2
2
4
1
amount of inexpensive naturally abundant CuSO ensure the
4
modular synthesis of N-aryl indoles from abundant toluene
derivatives and isonitriles.
To explore the reaction mechanism, control experiments
were performed. In the radical trapping experiment, 1a-
OTEMP adduct 6 was isolated in 49% yield (eq 1), indicating
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b03751.
Experimental procedures, full analysis data for com-
pounds, and copies of nuclear magnetic resonance
spectra (PDF)
that a benzylic radical might be involved. Benzyl radical
addition to nitriles and carbonyls has been proposed. The
isotope labeling experiment shows 88% D-incorporation at C2
2
,3
Accession Codes
CCDC 1877064−1877065 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.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.
(eq 2).
AUTHOR INFORMATION
Corresponding Author
■
The reaction mechanism is proposed in Scheme 3. The
*
E-mail: ybkang@ustc.edu.cn.
t
BuOK-promoted C−H cleavage affords carbanion A, which
can possibly pass either an anionic addition to isonitrile or a
redox anion-radical relay to radical B. The control experiment
is consistent with this reaction passing through a radical
ORCID
Jian-Ping Qu: 0000-0002-5002-5594
Yan-Biao Kang: 0000-0002-7537-4627
Author Contributions
3
pathway (eq 1). The detailed mechanism for the redox anion-
radical relay has been previously reported. The oxidation of A
by Cu(II) affords radical B, followed by the addition to
isonitrile to form C, followed by the 1,2-D-shift to D (eq 2).
The D-shift step should not be involved with the transfer of the
§
X.-H.S. and M.-M.W. contributed equally to this work.
Notes
The authors declare no competing financial interest.
t
deuterium atom by BuOD because the formation of a more
ACKNOWLEDGMENTS
active oxygen radical from carbon radical C is not allowed. The
addition−elimination via either D affords 3. The detailed
reaction mechanism is unclear and still underway.
■
We thank the National Natural Science Foundation of China
(21602001, 21922109, 21672196, 21831007) and the
Fundamental Research Funds for the Central Universities of
China (WK2060190086) for financial support.
In conclusion, we have developed a CuSO -catalyzed indole
4
3
synthesis from the C(sp )−H cleaving cyclization of toluene
C
DOI: 10.1021/acs.orglett.9b03751
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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of (1R)-(+)-verbenone with Fe(III) and Cu(II) salts. Two modes of
conjoining this bicyclic ketone across a benzene ring. J. Org. Chem.
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