Synthesis of Unprotected and Highly Substituted Indoles by the Ruthenium(II)-Catalyzed Reaction of Phenyl Isocyanates with Diaryl/Diheteroaryl Alkynes/Ethyl-3-phenyl Propiolates

Article abstract of DOI:10.1021/acs.orglett.0c02793

A one-pot transformation has been developed for the synthesis of unprotected and highly substituted indoles by an in situ installed carbamide-directed Ru(II)-catalyzed intermolecular oxidative annulation of phenyl isocyanates with diaryl/diheteroaryl alkynes/ethyl phenyl propiolates in the presence of Cu(OAc)2·H2O as an oxidant and AgSbF6 as an additive at 120 °C within 3 h.

Full text of DOI:10.1021/acs.orglett.0c02793

pubs.acs.org/OrgLett
Letter
Synthesis of Unprotected and Highly Substituted Indoles by the
Ruthenium(II)-Catalyzed Reaction of Phenyl Isocyanates with Diaryl/
Diheteroaryl Alkynes/Ethyl-3-phenyl Propiolates
Amrendra Kumar and Narender Tadigoppula*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c02793
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: A one-pot transformation has been developed for
the synthesis of unprotected and highly substituted indoles by an in
situ installed carbamide-directed Ru(II)-catalyzed intermolecular
oxidative annulation of phenyl isocyanates with diaryl/diheteroaryl
alkynes/ethyl phenyl propiolates in the presence of Cu(OAc)2·
H2O as an oxidant and AgSbF6 as an additive at 120 °C within 3 h.
ndoles can be found in nature, in various commercial drugs,
Scheme 1. Previous Synthetic Protocols and Our Work on
the Substituted Indole Synthesis
I
as well as in molecules currently under clinical trials1
(Figure 1). The prevalence of the indole skeleton in bioactive
Figure 1. Indole skeleton containing commercial drugs/compounds
currently in clinical trials.
natural products has prompted organic and medicinal chemists
to develop new methods for their preparation.2 Various
transition-metal complexes involving Ru,3 Rh,4 Pd,5 Ir,6 and
Co7 have been effectively applied to indole synthesis by the
ortho-C−H functionalization of anilides. Despite advances,
most of these methods heavily rely on preactivated aniline
substrates, which can give N-substituted indoles.8 For example,
recently, Fagnou and coworkers developed NH-Ac-assisted
dehydrogenative cyclization between internal alkynes and
arenes using a Rh(III) catalyst to give N-acetylated indoles
(Scheme 1a).9 Zhu and coworkers explored the Rh(III)-
catalyzed cyclization of N-nitroso anilines with alkynes for the
synthesis of N-alkylated indoles.10 Su and coworkers disclosed
the Rh-catalyzed reaction between the N-nitroso group of N-
alkyl anilines and internal alkynes.11 Very limited methods are
reported in the literature, in which preactivated aniline
substrates directly provide unprotected (free NH) indoles.
The research group of Glorius and coworkers described the
cobalt-catalyzed unprotected indole synthesis from Boc-
phenylhydrazines (Scheme 1b).12 Similarly, Huang and
coworkers disclosed a Rh(III)-catalyzed unprotected indole
synthesis via triazene-directed annulation with alkynes.13
We desired to prepare unprotected and highly substituted
indoles without using preactivated substrates. We therefore
used commercial phenyl isocyanates, which can generate
carbamide in situ and subsequently act as a directing group.
Herein we disclose the synthesis of unprotected and highly
substituted indoles from phenyl isocyanates and diaryl/
diheteroaryl alkynes/ethyl-3-phenyl propiolates (Scheme 1c)
for the first time.
Initially, we carried out a test reaction between p-tolyl
isocyanate (1a, 1 mmol) and diaryl acetylene (2a, 1 mmol)
with 5 mol % of catalysts Pd(OAc)2/PtBr2/RuO2, additive
Received: August 22, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02793
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
a
Table 1. Screening of Reaction Conditions
e
entry
catalyst (5 mol %)
oxidant (0.5 mmol)
additive (20 mol %)
solvent
yield (%)
b
1
Pd(OAc)2
PtBr2
RuO2
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu2O
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
Ag2CO3
AgSO3CF3
AgBF4
ROH
ROH
ROH
MeOH
EtOH
n-PrOH
t-BuOH
t-AmOH
DCE
NR
NR
NR
49
53
57
b
2
b
3
c
4
[RuCl2(pcymene)]2
[RuCl2(pcymene)]2
[RuCl2(pcymene)]2
[RuCl2(pcymene)]2
[RuCl2(pcymene)]2
[RuCl2(pcymene)]2
[RuCl2(pcymene)]2
[RuCl2(pcymene)]2
[RuCl2(pcymene)]2
[RuCl2(pcymene)]2
[RuCl2(pcymene)]2
[RuCl2(pcymene)]2
[RuCl2(pcymene)]2
[RuCl2(pcymene)]2
[RuCl2(pcymene)]2
[RuCl2(pcymene)]2
c
5
c
6
c
7
67
91
c
8
d
9
NR
NR
NR
NR
NR
NR
NR
59
63
41
15
e
c
10
11
12
13
14
15
16
17
DMF
c
DMSO
toluene
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
c
b
b
AgOAc
c
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
c
c
c
18
19
Ag2O
AgNO3
c
a
b
c
d
Reaction conditions: 1a (1 mmol), 2a (1 mmol), at 120 °C. ROH = methyl/ethyl/isopropyl/t-butyl/t-amyl alcohol. 6 h. 3 h. 5 h. Isolated
yields. NR = no reaction.
AgSbF6 (20 mol %), and oxidant Cu(OAc)2·H2O (0.5 mmol)
at 120 °C for 6 h in various alcohols, which did not give the
anticipated product (Table 1, entries 1−3). Fortunately,
attempts with 5 mol % of the [(RuCl2(p-cymene)2] catalyst
in the place of other catalysts along with the above-described
reaction conditions resulted in the anticipated product 3aa in
49, 53, 57, 67, and 91% yield, respectively (Table 1, entries 4−
8). The formation of 3aa was determined by 2D-NMR spectral
data. Our attempts with other solvents such as DCE, DMF,
DMSO, and toluene in place of alcohols, however, failed to
give 3aa (Table 1, entries 9−12). The reaction with 5 mol % of
[RuCl2(p-cymene)]2 catalyst, Cu2O (0.5 mmol), or AgOAc
(0.5 mmol) as an oxidant at 120 °C for 6 h also did not give
the product 3aa (Table 1 entries 13 and 14). We then tested
the role of various additives. For this purpose, we screened a
few additives such as Ag2CO3 (0%), AgSO3CF3 (59%), AgBF4
(63%), Ag2O (41%), and AgNO3 (15%) (Table 1, entries 15−
19) and found that AgSbF6 (91%) gave the best results (Table
1, entry 8).
Scheme 2. Reaction between Substituted Phenyl
Isocyanates/Unsubstituted Phenyl Isocyanate 1b−k/1l and
Diaryl Acetylene/Substituted Diaryl Acetylenes 2a/2a−e
a
and Isolated Yields of Substituted Indoles 3ba−le
After developing the optimized conditions, we studied the
substrate scope of our method to find out the generality of the
reaction and the influence of substitution on the yield (Scheme
2). Various substituted phenyl isocyanates 1b−k were
investigated with the unsubstituted diaryl alkyne 2 and the
synthesized respective indoles 3ba−ka with yields ranging
from 62 to 86%. The phenyl isocyanate with electron-releasing
substituents such as p-OMe (1b, 86%) and m-OMe (1g, 79%)
gave good yields, whereas the electron-withdrawing groups
containing phenyl isocyanates such as p-CF3 (1c, 66%), p-
OCF3 (1d, 63%), p-chloro (1e, 67%), p-bromo (1f, 69%), m-
CF3 (1h, 62%), 3,4-dichloro (1i, 65%), 4-fluoro,3-methyl (1j,
67%), and 3-chloro, 4-methyl (1k, 72%) resulted in moderate
a
#
§, Regioisomer due to the influence of the steric factor.
Regioisomeric mixture formation determined by HPLC.
,
yields. The steric factors might be influencing the exclusive
formation of regioisomers 3ga−ka with symmetrical diaryl
alkynes. We next examined various substituted diaryl
acetylenes 2a−e with unsubstituted phenyl isocyanate 1l
under the optimized conditions, which also successfully
furnished the desired products 3la−le (Scheme 2) in moderate
to good yields (64−72%). Diaryl alkyne 2a without
substitution gave a moderate yield of 3la (64%). Symmetrical
diaryl alkynes 2b and 2c, which have electron-donating groups
B
https://dx.doi.org/10.1021/acs.orglett.0c02793
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
on the aromatic ring, gave improved yields (3lb, 71%; 3lc,
72%). In contrast, electron-withdrawing substituents contain-
ing symmetrical diary alkynes 2d and 2e furnished the
products 3ld (66%) and 3le (68%) in marginally low yields.
However, the reaction of 1l with the monosubstituted diaryl
alkyne 2b (unsymmetrical) resulted in the formation of a 6:4
mixture of regioisomers 3lb and 3lb′ (determined by HPLC).
In further testing, we carried out a few reactions with both
substituted phenyl isocyanates 1a, 1i, and 1k and substituted
diaryl alkynes 2b and 2d−i using our standardized reaction
conditions, which resulted in 63−71% of yields of highly
substituted indoles 3af, 3ib, 3id,ie, 3ig−ii, and 3kd, which
supports the generality and wide applicability of the reaction
(Scheme 3). Here regiomeric mixtures 3af (62:38), 3ib
Scheme 4. Reaction between Substituted Phenyl Isocyanates
1a, 1e, and 1k−n and Phenyl Propiolate 4a and Isolated
a
Yields of Substituted Indoles 5aa, 5ea, and 5ka−na
Scheme 3. Reaction between Substituted Phenyl Isocyanates
1a, 1k, and 1i and Substituted Diaryl/Diheteroaryl
Acetylenes 2b, 2d−i, and 2j and Isolated Yields of
a
§, Regioisomer due to the substitution pattern of phenylisocyanate. #,
Regioisomer due to electronic factors.
a
Substituted Indoles 3af, 3ib, 3id,ie, 3ig−ii, 3kd, and 3aj
alkyne or phenyl propiolate system to obtain the indole
products.
To find out the rate-determining step, a few deuterium
labeling experiments were carried out. A reaction with phenyl
isocyanate 1l in CD3OD in the absence of alkyne 2a under the
optimized conditions did not give the deuterium−hydrogen
exchanged compound 1l-D2 (Scheme 5, eq 1). The
Scheme 5. Isotopically Labeled Experiments
a
§, Regioisomer due to steric factors. #, Regioisomeric mixture
formation determined by HPLC.
(51:49), 3ig (74:26), and 3ii were also formed from the
respective unsymmetrical diaryl alkynes 2a, 2b, 2g, and 2i due
to electronic factors (ratio determined by HPLC; see the SI).
Interestingly, attempts with heteroaryl alkyne 2j also
successfully gave the respective indole 3aj under the
standardized reaction conditions.
To test the further application of the method, we carried out
a reaction between phenyl propiolate 4a, instead of diaryl
acetylene 2a, and various substituted phenyl isocyanates 1a, 1e,
and 1k−n, which also successfully resulted in the formation of
ester-containing indoles 5aa, 5ea, and 5ka−na regioselectively
(>90%) in 65−73% yield (Scheme 4) due to the conjugated
electronic system.
However, an attempt at a reaction between aliphatic internal
alkyne/phenyl acetylene/3-phenylprop-2-yn-1ol/trimethyl-
(phenylethynyl)silane/4-phenyl-3-butyn-2-one and phenyl iso-
cyanate 1a did not give the respective indole product under the
optimized conditions (Scheme S1 of the Supporting
Information), which indicates the requirement of the diaryl
competitive (Scheme 5, eq 2) and intermolecular (Scheme 5,
eq 3) kinetic isotope effect experiments resulted in a kH/kD of
4.9 and 3.6, respectively. These experiments indicated that the
rate-limiting step could be the metal-catalyzed C(sp2)−H bond
activation.
Some control experiments were also carried out to
understand the reaction mechanism (Scheme S2 of the
Supporting Information). A reaction with p-tolyl isocyanate
1a in t-amyl alcohol in the absence of a catalyst gave the
isolable intermediate B, which was confirmed by the spectral
C
https://dx.doi.org/10.1021/acs.orglett.0c02793
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
data (Supporting Information). The reaction of p-tolyl
isocyanate 1a with Cu(OAc)2·H2O or AgSbF6 in t-amyl
alcohol in the absence of 2a and a catalyst [(RuCl2(p-
cymene)2] gave intermediate E in 96% yield.14 A reaction of E
(1 mmol) with 2a (1 mmol) using the optimized reaction
conditions resulted in intermediate J, and a further extension of
the reaction time gave 3aa in 93% isolated yield. The isolated
intermediate J was subjected to the optimized reaction
conditions, which also gave the final product 3aa.15
On the basis of control experiments and isolated
intermediates (see the Supporting Information), a plausible
reaction mechanism for the indole synthesis is proposed as an
oxidative annulation of p-tolyl isocyanate 1a with diaryl alkyne
2a/phenyl propiolates 4a. First, the carbamate B might have
formed due to the nucleophilic attack of t-AmOH on the
carbonyl group followed by aniline intermediate D due to the
elimination of di-tert-pentyl carbamate C. Carbamide inter-
mediate E might have been generated due to a reaction
between intermediate D and p-tolyl isocyanate.14 Both the
intermediates B and E were isolated from the reaction mixture,
and they were characterized by 2D-NMR spectral data
(Supporting Information). The intermediate E might have
transformed to F due to the Ru(II)-catalyzed C−H activation
via an MD mechanism with acetate ion assistance and
subsequently transformed to G (Scheme 6) by the loss of
acetic acid. Diaryl-alkyne 2a’s coordinative insertion into the
Ru−carbon bond of G might have given species H, and the
subsequent removal of p-tolyl isocyanate with the assistance of
an acetate ion might have led to species I.16 The intermediate J
might have been afforded due to the reductive elimination in
the presence of Cu(OAc)2·H2O and regenerated the active Ru
species for the next catalytic cycle. The intermediate J was also
purified from the reaction mixture and characterized by 2D-
NMR spectral data. Furthermore, the cleavage of the C−N
bond of indole-1-carboxamide intermediate J in the presence
of the optimized reaction conditions might have resulted in the
desired unprotected and highly substituted indole 3aa.15 The
electron-releasing groups on 2b, 2f, 2g, and 2i might have
influenced the alkyne insertion into the Ru−N bond in
producing major regioisomers 3af, 3ib, 3ig, and 3ii. The
regioselective formation of ester-containing indoles 5aa, 5ea,
5ka−na from phenyl propiolate 4a also accounted for the
electronic factors of the extended conjugation system upon the
alkyne insertion into the Ru−N bond (Schemes 4 and 6, path
B).17 Further studies, however, are essential to support the
exact reaction mechanism.
In summary, we have developed a new method for the
synthesis of unprotected indoles by a Ru(II)-catalyzed and in
situ generated carbamide (urea derivative)-directed oxidative
annulation reaction between phenyl isocyanates and diaryl/
diheteroaryl alkynes/phenyl propiolates for the first time in the
presence of Cu(OAc)2·H2O and additive AgSbF6 and have
demonstrated its wide application. This method can avoid the
synthesis of preactivated aniline surrogates and the depro-
tection of N-alkyl or N-acyl groups of final products. Further
work is in progress to use the in situ installed carbamide group
from isocyanate and its directing chemistry to make privileged
structures of biological importance at our lab.
Scheme 6. Plausible Reaction Mechanism for the Synthesis
of Unprotected Substituted Indoles
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02793.
General information, general procedure for the synthesis
of substituted indoles, general procedure for the
preparation of alkynes, control experiments, isotopically
labelled experiments, spectral data of internal alkynes,
references, spectral data of isolated intermediates B, E,
and J, spectral data of the obtained compounds, copies
of NMR spectra, and HPLC data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
Narender Tadigoppula − Medicinal and Process Chemistry
Division, CSIR-Central Drug Research Institute, Lucknow
226 031, India; orcid.org/0000-0002-2290-2764;
Email: t_narendra@cdri.res.in
Author
Amrendra Kumar − Medicinal and Process Chemistry
Division, CSIR-Central Drug Research Institute, Lucknow
226 031, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02793
Notes
The authors declare no competing financial interest.
D
https://dx.doi.org/10.1021/acs.orglett.0c02793
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
ACKNOWLEDGMENTS
■
We thank the Director, CSIR-CDRI, for financial support, the
SAIF Division for spectral data, and CSIR, New Delhi for the
fellowship to Amrendra. This is CDRI communication number
10166.
REFERENCES
■
(1) Zhang, Z.; Chen, Q.; Yang, G. F. Eur. J. Med. Chem. 2015, 89,
421−441.
(2) (a) A Beilstein search for indoles with biological activity yielded
>45 000 results. (b) Richter, J. M.; Ishihara, Y.; Masuda, T.;
Whitefield, B. W.; Llamas, T.; Pohjakallio, A.; Baran, P. S. J. Am.
Chem. Soc. 2008, 130, 17938−17954. (c) Furstner, A. Angew. Chem.,
Int. Ed. 2003, 42, 3582−3603.
(3) (a) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev.
2012, 112, 5879−5918. (b) Chinnagolla, R.-K.; Jeganmohan, M.
Chem. Commun. 2014, 50, 2442−2444. (c) Ackermann, L.; Lygin, A.
V. Org. Lett. 2012, 14, 764−767.
(4) (a) Haridharan, R.; Muralirajan, K.; Cheng, C.-H. Adv. Synth.
Catal. 2015, 357, 366−6607. (b) Fukui, M.; Shibata, Y.; Hoshino, Y.;
Sugiyama, H.; Teraoka, K.; Uekusa, H.; Noguchi, K.; Tanaka, K.
Chem. - Asian J. 2016, 11, 2260−2264.
(5) (a) Yang, S.; Li, B.; Wan, X.; Shi, Z. J. Am. Chem. Soc. 2007, 129,
6066−6607. (b) Boele, M. D. K.; van Strijdonck, G. P. F.; de Vries, A.
H. M.; Kamer, P. C. J.; de Vries, J. G.; van Leeuwen, P. W. N. M. J.
Am. Chem. Soc. 2002, 124, 1586−1587.
(6) (a) Ryu, J.; Kwak, J.; Shin, K.; Lee, D.; Chang, S. J. Am. Chem.
Soc. 2013, 135, 12861−12868. (b) Phatake, S.; Patel, R. P.; Ramana,
C. V. Org. Lett. 2016, 18, 292−295.
(7) Moselage, M.; Li, J.; Ackermann, L. ACS Catal. 2016, 6, 498−
525.
(8) (a) Inman, M.; Moody, C. J. Chem. Sci. 2013, 4, 29−41.
(b) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875−
2911. For a recent review, see: (c) Zeni, G.; Larock, R. C. Chem. Rev.
2006, 106, 4644−4680. (d) Larock, R. C.; Yum, E. K. J. Am. Chem.
Soc. 1991, 113, 6689−6690. (e) Larock, R. C.; Yum, E. K.; Refvik, M.
D. J. Org. Chem. 1998, 63, 7652−7662. (f) Ackermann, L.; Kaspar, L.
T.; Gschrei, C. J. Chem. Commun. 2004, 2, 2824−2825.
(9) Stuart, D. R.; Bertrand-Laperle, M.; Burgess, K. M. N.; Fagnou,
K. J. Am. Chem. Soc. 2008, 130, 16474−16475.
(10) Liu, B.; Song, C.; Sun, C.; Zhou, S.; Zhu, J. J. Am. Chem. Soc.
2013, 135, 16625−16631.
(11) Shang, Y.; Jonnada, K.; Yedage, S. L.; Tu, H.; Zhang, X.; Lou,
X.; Huang, S.; Su, W. Chem. Commun. 2019, 55, 9547−9550.
́
́
(12) Lerchen, A.; Vasquez-Cespedes, S.; Glorius, F. Angew. Chem.,
Int. Ed. 2016, 55, 3208−3211.
(13) Wang, C.; Sun, H.; Fang, Y.; Huang, Y. Angew. Chem., Int. Ed.
2013, 52, 5795−5798.
(14) Wu, X.; Niu, Q.; Li, T. Synth. Commun. 2016, 46, 1364−1369.
(15) (a) Sharma, S.; Han, S.; Kim, M.; Mishra, N. K.; Park, J.; Shin,
Y.; Ha, J.; Kwak, J. H.; Jung, Y. H.; Kim, I. S. Org. Biomol. Chem. 2014,
12, 1703−1706. (b) Schipper, D. J.; Hutchinson, M.; Fagnou, K. J.
Am. Chem. Soc. 2010, 132, 6910−6911. (c) Hartung, C. G.; Fecher,
A.; Chapell, B.; Snieckus, V. Org. Lett. 2003, 5, 1899−1902.
(16) Zheng, L.; Hua, R. Chem. - Eur. J. 2014, 20, 2352−2356.
(17) (a) Muralirajan, K.; Cheng, C. H. Adv. Synth. Catal. 2014, 356,
1571−1576. (b) Korivi, R. P.; Cheng, C. H. Org. Lett. 2005, 7, 5179−
5182.
E
https://dx.doi.org/10.1021/acs.orglett.0c02793
Org. Lett. XXXX, XXX, XXX−XXX