Copper-Catalyzed Oxidative Dearomatization/Spirocyclization of Indole-2-Carboxamides: Synthesis of 2-Spiro-pseudoindoxyls

Article abstract of DOI:10.1021/acs.orglett.6b03131

A copper-catalyzed oxidative dearomatization/spirocyclization of indole-2-carboxamides using tert-butyl hydroperoxide (TBHP) as the oxidant has been developed that provides rapid and efficient access to C2-spiro-pseudoindoxyls. Two of the sp² C-H bonds are functionalized during the reaction process, and the reaction likely proceeds via the formation of a highly reactive 3H-indol-3-one intermediate followed by aromatic electrophilic substitution with the N-aryl ring of the amide moiety.

Full text of DOI:10.1021/acs.orglett.6b03131

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Oxidative Dearomatization/Spirocyclization of
Indole-2-Carboxamides: Synthesis of 2‑Spiro-pseudoindoxyls
Lingkai Kong, Mengdan Wang, Fangfang Zhang, Murong Xu, and Yanzhong Li*
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China
Normal University, 500 Dongchuan Road, Shanghai 200241, China
S
* Supporting Information
ABSTRACT: A copper-catalyzed oxidative dearomatization/
spirocyclization of indole-2-carboxamides using tert-butyl hydro-
peroxide (TBHP) as the oxidant has been developed that provides
rapid and efficient access to C2-spiro-pseudoindoxyls. Two of the
sp2 C−H bonds are functionalized during the reaction process,
and the reaction likely proceeds via the formation of a highly
reactive 3H-indol-3-one intermediate followed by aromatic
electrophilic substitution with the N-aryl ring of the amide moiety.
piro-pseudoindoxyls that contain a C2 spirocyclic quater-
nary carbon center are common structural subunits found
methodology for constructing C−C and C−heteroatom
bonds not only because of its low cost and low toxicity but
also because of its high efficiency in redox catalysis.11 During
the course of our ongoing program on copper-catalyzed
cyclization reactions to form nitrogen heterocycles, we found
that spiro-pseudoindoxyls can be conveniently formed under
copper redox conditions. Herein we report a new and efficient
route to spiro-pseudoindoxyls via copper-catalyzed oxidative
dearomatization/spirocyclization of indole-2-carboxamides
using TBHP as the oxidant (Scheme 1). It turned out that
both the C−H bond at C3 of the indole moiety and one of the
C−H bonds on the N-aryl ring were activated to allow
construction of the target products. Indoles are known to
undergo dearomatization under dioxygen, catalyzed by CuCl, to
S
in a variety of indole alkaloids such as fluorocurine,1
mitragynine pseudoindoxyl,2 and rauniticine pseudoindoxyl3
(Figure 1), and some of them are found to exhibit important
Figure 1. Representative indole alkaloids containing the spiro-
pseudoindoxyl core structure.
Scheme 1. Construction of C2 Quaternary Indolines
biological properties. For example, mitragynine pseudoindoxyl
has potent opioid agonistic activity in the guinea pig ileum and
in mouse vas deferens.2b Compared with the intensively studied
and biologically interesting spirooxindoles bearing a spiro
center at C3,4 the synthetic procedures for C2-spiro-
pseudoindoxyls are far less developed. The main approach to
these compounds is based on oxidative rearrangement of the
corresponding indole derivatives, which has been successfully
used in the synthesis of a series of indole alkaloids.5 Other
methods include Smalley cyclization,6 gold-catalyzed cyclo-
isomerization of 3-phenoxy alkynyl indoles7 or nitroalkynes,8
N-heterocyclic carbene (NHC)-catalyzed annulation of enals
with azaaurones,9 Ugi reactions,10 etc. However, these methods
usually suffer from multistep synthesis of substrates, utilization
of hazardous azide compounds, or limited reaction scope. Thus,
the development of straightforward and facile methods for the
synthesis of spiro-pseudoindoxyls from easily accessible starting
materials is highly desired.
Recently, the copper-catalyzed oxidative C−H bond
functionalization reaction has emerged as an attractive
Received: October 19, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03131
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Organic Letters
Letter
give 2,3-dioxygenated cleavage products12 or 3-oxo-3H-
indoles13 via the intermediacy of 3H-indol-3-one. Recently,
Jia’s group disclosed a Pd-catalyzed construction of C2
quaternary indoline for the synthesis of fused-ring com-
pounds.14a A Pd-catalyzed oxidation of indoles to C2 noncyclic
quaternary indolin-3-ones has been reported by Guchhait’s
group.14b Oxidative di- or trimerization of indoles catalyzed by
copper salts15a,b or copper oxidase15c has also been described.15
However, to the best of our knowledge, transition-metal-
catalyzed oxidative dearomatization of indole followed by
spirocyclization by means of intramolecular nucleophilic attack
of the reactive intermediates has not been established.
in a high yield of 85% (entry 6). Interestingly, the reaction
could also proceed in the presence of 10 mol % FeCl3, and 2a
was formed in 47% yield (entry 7). The catalyst loading of
Cu(OTf)2 could be reduced to 5 mol %, in which case 2a was
isolated in 86% yield (entry 8). Decreasing the amount of
TBHP to 2.0 equiv resulted in a lower product yield (65%;
entry 9). Changing the substrate concentration from 0.05 to 0.1
or 0.03 M afforded 2a in slightly lower yields (entries 11 and
12). Only a trace amount of 2a was observed when the reaction
was carried out at the lower temperature of 40 °C (entry 13).
Other solvents such as toluene, THF, DMF, DMAc, CH3CN,
and 1,4-dioxane were also tested. However, they are not
effective for this reaction (entries 15−20). The use of 3.0 equiv
of TBHP in a decane solution (5−6 M) was also found to be
effective for this reaction, leading to 2a in 84% yield (entry 21).
In the absence of copper catalyst or TBHP, no reaction was
observed (entries 22 and 23).
Initially, we investigated the copper-catalyzed reactions of
1H-indole-2-carboxamide 1a bearing an N-phenyl ring (Table
1). When 1a was treated with 10 mol % CuCl and 3.0 equiv of
a
Table 1. Optimization Studies for the Formation of 2a
Encouraged by the above results, we next examined the
substrate scope for accessing diversely substituted spiro-
pseudoindoxyls by varying the substituents on the indole and
amide moieties under the conditions shown in Table 1, entry 8
(Figure 2). First, we investigated the effect of different N-alkyl
equiv
of
temp time
yield
b
entry catalyst (mol %) TBHP
solvent
DCE
(°C)
(h)
(%)
1
2
CuCl (10)
3
3
3
3
3
3
3
3
2
4
3
3
3
3
3
3
3
3
3
3
3
3
−
60
60
60
60
60
60
60
60
60
60
60
60
40
80
60
60
60
60
60
60
60
60
60
6
6
5
5
6
3
4
4
8
4
4
4
6
2
6
6
3
4
6
6
3
4
4
27
CuCl2 (10)
DCE
21
3
CuBr2 (10)
DCE
38
4
Cu(OAc)2 (10)
Cu(acac)2 (10)
Cu(OTf)2 (10)
FeCl3 (10)
DCE
24
5
DCE
messy
85
6
DCE
7
DCE
47
8
Cu(OTf)2 (5)
Cu(OTf)2 (5)
Cu(OTf)2 (5)
Cu(OTf)2 (5)
Cu(OTf)2 (5)
Cu(OTf)2 (5)
Cu(OTf)2 (5)
Cu(OTf)2 (5)
Cu(OTf)2 (5)
Cu(OTf)2 (5)
Cu(OTf)2 (5)
Cu(OTf)2 (5)
Cu(OTf)2 (5)
Cu(OTf)2 (5)
−
DCE
86
9
DCE
65
10
11
12
13
14
15
16
17
18
19
20
21
22
23
DCE
79
c
DCE
78
d
DCE
84
DCE
trace
80
DCE
toluene
THF
27
trace
DMF
DMAc
CH3CN
1,4-dioxane
DCE
−
−
34
NR
84
e
DCE
NR
NR
Cu(OTf)2 (5)
DCE
a
b
e
Reactions were run on a 0.2 mmol scale using 4 mL of solvent.
Isolated yields. Using 2 mL of solvent. Using 6 mL of solvent.
Using 5−6 M TBHP in decane.
c
d
Figure 2. Substrate scope of the dearomatization/spirocyclization
reaction. Unless otherwise noted, the reactions were carried out using
3.0 equiv of TBHP and 5 mol % Cu(OTf)2 in DCE at 60 °C under N2
on a 0.3 mmol scale. Isolated yields are shown. aThe reaction was run
on a 0.2 mmol scale.
TBHP in DCE at 60 °C for 6 h, the spirocyclized product,
spiro-pseudoindoxyl 2a, was obtained in 27% yield (entry 1).
Structural identification of 2a was carried out by X-ray
crystallography. Although the yield was low, the result was
highly attractive since it revealed that two of the sp2 C−H
bonds were functionalized during the reaction process. Inspired
by these initial results, we next screened various Cu(II) salts. It
was found that CuCl2, CuBr2, and Cu(OAc)2 all could catalyze
the reaction. However, the yields of 2a were in the range of
21−38% (entries 2−4). To our delight, when Cu(OTf)2 was
employed as the catalyst, the desired product 2a was obtained
substituents (R1) on the amide group. It was found that in
addition to an N-methyl substituent, N-ethyl- or N-benzyl-
substituted substrates also underwent the reaction smoothly to
afford 2b and 2c in 89% and 72% yield, respectively. Next, the
electronic effects of different N-aryl substituents (R2) were
studied. With an electron-donating group at the para position
of the N-phenyl ring, such as p-CH3, p-nBu, or p-MeO, the
corresponding products 2d−f were obtained in 63−71% yield.
B
DOI: 10.1021/acs.orglett.6b03131
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An electron-withdrawing p-Cl substitution afforded 2g in a
lower yield of 47%, possibly becausse of the lower
nucleophilicity of the N-aryl ring in this case (compare 2f
with 2g). An N-methyl,N-(o-methylphenyl)-substituted sub-
strate was transformed into 2h in a good yield of 70%. With a
methyl group at the meta position of the N-phenyl ring, two
spirocyclized products 2i and 2i′ were obtained in a combined
yield of 81% in a ratio of 1:1.2. The results indicated that both
of the ortho C−H bonds on the N-aryl ring could be
competitively functionalized. With methyl groups at the 3-
and 5-positions of the N-phenyl ring, the desired product 2j
could be obtained in a moderate yield. Interestingly, indole-2-
carboxamide bearing a tetrahydroquinoline moiety on the
amide moiety cyclized readily under the standard reaction
conditions to afford the highly strained polycyclic spiroindole
2k in 45% yield, demonstrating the synthetic potential for the
construction of complex organic molecules by this method. A
chlorine or fluorine substituent on the indole moiety was
tolerated well during the reaction, and the corresponding
products 2l−n were obtained in 46−57% yield.
Scheme 3. Possible Reaction Mechanism
To understand the reaction mechanism, we carried out the
following control experiments (Scheme 2). It was found that
Scheme 2. Control Experiments
product 2a. Alternatively, in path b, indolylcopper(II)
intermediate E might be formed in the presence of
Cu(OTf)2.19 E could react with tert-butylperoxy radical to
give the Cu(III) intermediate F.20 Reductive elimination
followed by elimination of t-BuOH would deliver the same
intermediate D as in path a. The produced Cu(I) would
subsequently be oxidized by TBHP to regenerate the Cu(II)
catalyst for the next catalytic cycle.
In summary, we have developed a novel copper-catalyzed
oxidative dearomatization/spirocyclization of indole-2-carbox-
amides using TBHP as the oxidant. The method provides rapid
and efficient access to C2-spiro-pseudoindoxyls, which are
common structural units prevalent in indole alkaloids but are
usually difficult to prepare. Two of the sp2 C−H bonds are
functionalized during the reaction process, and the reaction
likely proceeds via the formation of a highly reactive 3H-indol-
3-one intermediate followed by aromatic electrophilic sub-
stitution with N-aryl ring of the amide moiety. This method
offers several advantages such as easily accessible starting
materials, good functional group tolerance, and mild reaction
conditions. Further studies to elucidate the reaction mechanism
and extend this chemistry are in progress.
when N-Me-protected indole 3 or substrate 4 containing a
−CO2(4-MePh) group was employed under the standard
reaction conditions, no reaction occurred, indicating that the
presence of the free N-H indole and amide moiety in 1 are
crucial for the success of this reaction. Substrate 5 bearing an N-
H amide group resulted in a complex reaction mixture. When
the reaction was performed in the presence of a radical
scavenger such as TEMPO, the yield of 2a was decreased
significantly to 27%. Increasing the amount of TEMPO to 4.0
equiv resulted in only traces of the desired product of 2a. The
results implied that radical species might be involved in the
reaction process.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03131.
On the basis of the above results and literature reports, we
propose the following reaction mechanism involving two
possible pathways for this novel transformation (Scheme 3).
In path a, N-centered indole radical A might be generated in
the presence of Cu(OTf)2/TBHP,16 and it could isomerize to
form C3 radical B. Intermediate B would couple with tert-
butylperoxy radical (t-BuOO·) produced through the reaction
of Cu(II) and TBHP according to the study by Sasson et al.17
to afford indole 3-tert-butylperoxide C. Elimination of t-BuOH
from C would furnish 2-substituted 3H-indol-3-one D,14,18
which would then undergo aromatic electrophilic substitution
with the N-aryl ring of the amide moiety to produce the
X-ray crystallographic data for 2a (CIF)
Experimental details and spectroscopic characterization
of all new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yzli@chem.ecnu.edu.cn.
ORCID
Mengdan Wang: 0000-0002-2898-3075
Yanzhong Li: 0000-0002-2898-3075
C
DOI: 10.1021/acs.orglett.6b03131
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(16) For oxidation of indoles to N-centered indole radicals by
Cu(II)/base, see: Deng, X.; Liang, K. J.; Tong, X. G.; Ding, M.; Li, D.
S.; Xia, C. F. Org. Lett. 2014, 16, 3276.
Notes
The authors declare no competing financial interest.
(17) Rothenberg, G.; Feldberg, L.; Wiener, H.; Sasson, Y. J. Chem.
Soc., Perkin Trans. 2 1998, 2429.
ACKNOWLEDGMENTS
■
(18) Kornblum, N.; Delamare, H. E. J. Am. Chem. Soc. 1951, 73, 880.
(19) For C−H activation of indole-2-carboxamides at C3, possibly
involving a C3-cuprated indole intermediate, see: (a) Ban, I.; Sudo, T.;
Taniguchi, T.; Itami, K. Org. Lett. 2008, 10, 3607. (b) Shang, M.; Sun,
S.-Z.; Dai, H.-X.; Yu, J.-Q. Org. Lett. 2014, 16, 5666.
(20) Rout, S. K.; Guin, S.; Gogoi, A.; Majji, G.; Patel, B. K. Org. Lett.
2014, 16, 1614.
We thank the National Natural Science Foundation of China
(Grant 21272074) and the Program for Changjiang Scholars
and Innovative Research Team in University (PCSIRT) for
financial support.
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