Ruthenium(II)-Catalyzed Synthesis of Indolo[2,1-a]isoquinolines through Double Oxidative Annulation Reaction of Phenyl Isocyanates with Di(hetero)aryl Alkynes

Article abstract of DOI:10.1002/adsc.202000963

Indole-containing polycyclic hetero aromatic compounds are synthesized by multistep process, which have wide application in biological activities and organic semi-conductor materials. Herein we report the one-pot method for the synthesis of polysubstituted indolo[2,1-a]isoquinolines by Ru(II) catalyzed double aryl/hetero aryl C(sp²)?H activation through in-situ installed carbamide of phenyl isocyanate and di(hetero)aryl substituted alkynes in the presence of Cu(OAc)₂.H₂O as an oxidant and CsOAc as an additive at 120 °C for 3 h in good to excellent yields. (Figure presented.).

Full text of DOI:10.1002/adsc.202000963

Title: Ruthenium(II)-Catalyzed Synthesis of Indolo[2,1- a]isoquinolines
through double oxidative annulations reaction of Phenyl
isocyanates with Diaryl alkynes/Dihetero aryl alkynes
Authors: Tadigoppula Narender, Amrendra Kumar, and Ruchir Kant
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000963
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10.1002/adsc.202000963
Advanced Synthesis & Catalysis
COMMUNICATION
Ruthenium(II)-Catalyzed Synthesis of Indolo[2,1-
a]isoquinolines through Double Oxidative Annulation Reaction
of Phenyl Isocyanates with Di(hetero)aryl Alkynes
Amrendra Kumara Ruchir Kantb and Narender Tadigoppulaa*
a Medicinal and Process Chemistry Division
CSIR-Central Drug Research Institute, Lucknow - 226031, India.
Corresponding author E-mail: t_narendra@cdri.res.in
b Molecular and Structural Biology Division, CSIR-Central Drug Research Institute,
Lucknow - 226031, India
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201#####
metal-catalyzed double C(sp2)-H activation of the aryl
C(sp2)-H bond followed by alkyne annulation reactions is
very
helpful
for
synthesizing
heteroaromatic
compounds.[6] Although few double C-H bond activation
and subsequently C-C and C-N/O-H bond formation
reactions are reported by using diverse transition metals,
such as using Rhodium for the syntheses of
benzo[de](isoquinolino[2,1-a])[1,8]naphthyridines,[7]
using cobalt for the syntheses of dihydropyrroloindoles[8]
and using palladium for the syntheses of 11-methyl-5,6-
diphenyl-11H-benzo[a]carbazole,[9] very limited methods
are available in the literature for the synthesis of arylated
indolo[2,1-a]isoquinolines.[10]
Abstract Indole-containing polycyclic hetero aromatic
compounds are synthesized by multistep process, which
have wide application in biological activities and organic
semi-conductor materials. Herein we report the one-pot
method for the synthesis of polysubstituted indolo[2,1-
a]isoquinolines by Ru(II) catalyzed double aryl/hetero aryl
C(sp2)-H activation through in-situ installed carbamide of
phenyl isocyanate and di(hetero)aryl substituted alkynes
in the presence of Cu(OAc)2.H2O as an oxidant and
CsOAc as an additive at 120 °C for 3 h in good to
excellent yields.
Keywords: Phenyl isocyanate; Double C-H oxidative
cyclization; Ru(II) catalyst; Indolo[2,1-a]isoquinolines
The fused polycyclic heteroaromatic skeletons present in
various range of natural and biological molecules.[1]
Indolo[2,1-a]isoquinolines and their derivatives show
various biological activities such as tubulin-binding,[2]
acting as estrogen receptor modulators[3] (Figure 1).
Scheme 1. Examples of double C(sp2)-H activation and
alkyne annulation reactions for the synthesis of
polysubstituted indolo[2,1-a]isoquinolines
Figure 1. Indolo[2,1-a]isoquinoline containing Bioactive
and Luminescence compounds.
Very recently Gogoi and co-workers reported a
straightforward method for the synthesis of
indolo[2,1-a]isoquinolines by Ru(II) catalyzed
double activation of C(sp2)-H bonds of preactivated
antipyrine and alkyne annulation reaction in the
presence of 20% phosphine ligand tricyclohexyl
phospine tetrafluoroborate (Scheme 1a).[11] Our
continuous interest in metal-catalyzed C-H
activation reactions for the synthesis of polycylic
hetero aromatic compounds, we explored
Indolo isoquinoline motif also has great importance as
semiconductor compounds because of their unique
property of π-conjugation.[4] The construction of highly
arylated indolo[2,1-
a]isoquinolines involves multistep synthesis and adverse
reaction conditions by conventional methods.[5] Transition
1
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10.1002/adsc.202000963
Advanced Synthesis & Catalysis
isopropanol, t-butanol and t-amyl alcohol, however, no
desired product was obtained. Fortunately, when we
examined the reaction with 5 mol% of [(RuCl2(p-
cymene)]2 catalyst, CsOAc (50 mol%) as additive and
Cu(OAc).H2O (50 mol%) as an oxidant in methanol,
ethanol, isopropanol, t-butanol and t-amyl alcohol
resulted in the formation of the desired product 3aa in
33%, 51%, 68%, 73% and 92% yield respectively (Table
1, entries 4-7). The chemical structure of 3aa has been
confirmed by spectral data and single crystal X-ray data
of 3ga (CCDC No. 1943183). Encouraged by these
results, we have screened with other solvents such as
DMF, DMSO, CH3CN, DCE and toluene, however, no
product was obtained (Table 1, entries 9-13). Next we
focused on to test few oxidants in t-amyl alcohol as a
solvent. The reaction with 5 mol% of [(RuCl2(p-
cymene)]2 as catalyst, CsOAc (0.5 equiv.) as an additive
and Cu(OTf)2, AgOAc and Zn(OAc)2 (50 mol%) as
commercially available phenyl isocyanates with an
anticipation that the in-situ generated carbamide
(urea derivative) from isocyanate group may act as a
directing group to provide desired polysubstituted
indolo[2,1-a]isoquinolines, which can avoid the
substrate preactivation. We herein report
polysubstituted indolo[2,1-a]isoquinolines synthesis
by Ru(II) catalyzed double C(sp2)-H bond activation
of commercially available phenyl isocyanates and
diaryl alkyne/dihetero aryl alkynes (Scheme 1b).
Table 1. Optimization of reaction conditions
0
oxidant in t-amyl alcohol at 120 C for 3 hours did not
give desired product 3aa (Table 1 entries 14-16).
Investigation with few bases such as NaOAc and KOAc
were also failed to give the desired product 3aa under
similar reaction condition (Table 1, entries 17 and 18).
Ent Oxidant
ry (50 mol %)
1a
2b
3c
4d
5d
6d
Additive
(50 mol %)
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
Solvent
Yield(%)e
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
ROH
ROH
ROH
MeOH
EtOH
Iso-
propanol
t-Butanol
t-AmOH
DMF
DMSO
CH3CN
DCE
Toluene
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
NR
NR
NR
33
51
68
With optimized reaction conditions in our hand, we
explored
the substrate scope of various substituted
phenyl isocyanates 1b-1h with diphenyl acetylene 2a,
which resulted in the formation of the desired product of
indolo[2,1- a]isoquinoline derivatives 3ba-3ha with
yields ranging from 74 to 89% (Scheme 2). The phenyl
isocyanates, which have electron withdrawing group such
as F (3ca:79%), Cl (3da:82%) and Br (3ea:86%) at para
position gave slightly less yield than the phenyl
isocyanates which have electron releasing groups
(3aa:92%; 3ba:89%). The substitution pattern has also
some influence in the yields. For example m-methyl
phenyl isocyanate 1f gave 86% yield of 3fa, whereas p-
methyl phenyl isocyante 1a gave respective product 3aa
in 92% yield. The reaction with disubstituted phenyl
isocyantes such as 1g and 1h also resulted in lower yields
of the respective products 3ga (74%) and 3ha (78%) with
standardized reaction conditions.
7d
8d
9d
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
CsOAc
CsOAc)
CsOAc
CsOAc
CsOAc)
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
NaOAc
KOAc
73
92
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
10d Cu(OAc)2.H2O
11d Cu(OAc)2.H2O
12d Cu(OAc)2.H2O
13d Cu(OAc)2.H2O
14d
15d
16d
Cu(OTf)2
AgOAc
Zn(OAc)2
17d Cu(OAc)2.H2O
18d Cu(OAc)2.H2O
Reaction Conditions: 1a (1.0 equiv), 2a (1.0 equiv.) in 2
ml of ROH at 120 °C for 3 h. R = ethyl, isopropyl, tert-
butyl and tert-amyl alcohol, NR = no reaction.
a Pd(OAc)2,
b PtBr2,
c RuO2,
d [RuCl2(pcymene)]2,
e Isolated yields.
At the beginning, we tested the reaction between
phenyl isocyanate (1a, 1.0 equiv.) and diphenyl acetylene
(2a, 1.0 equiv.) in the presence of 5 mol% of Pd(OAc)2,
PtBr2 and RuO2 at 120 ºC for 7 h (Table 1, entries 1-3),
CsOAc (0.5 equiv.) as additive and Cu(OAc).H2O (50
mol%) as oxidant in solvents such as methanol, ethanol,
2
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10.1002/adsc.202000963
Advanced Synthesis & Catalysis
Scheme 2. Substrate scope of the reaction between
Substituted Phenyl isocyanates (1b-1h) and Unsubstituted
diaryl alkyne (2a).
We then shifted our focus on to investigate with various
symmetrically substituted diaryl alkynes. Initially, a
reaction was carried out between unsubstituted phenyl
isocyanate 1i and substituted alkynes such as 2a-2e with
standardized reaction conditions, which also gave their
respective products 3ia-3ie in yields ranging from 72-
85% (Scheme 3). Further investigations with various
substituted phenyl isocynates (1a, 1c-1e and 1g) and
substituted alkynes (2a-2e) also resulted in highly
substituted indolo[2,1- a]isoquinolines in the yield range
of 58 to 84%. Electron releasing groups on diaryl alkynes
playing important role in enhancement of the product
yields (3cb:73%, 3cc:75%, 3cd:77% and 3db:74%;
3dc:75%; 3dd:79%), whereas electron withdrawing
groups on phenyl isocyanate gave marginally decreased
yields (3cb:73% vs 3db:74%; 3cc 71% vs 3dc:75% vs
3ec:77%; 3cd:77% vs 3dd:79%). The electron
withdrawing groups on both phenyl isocyanates and
alkynes have further impact on the yields (3ce:69% and
3ge:58%). The reaction between disubstituted phenyl
isocyanates and para substituted diaryl alkynes gave
product with the yields in the range of 71-73% (3gc:72%;
3hb:71% and 3hc:73%). We then tried to carry out few
reactions with heteroaryl alkynes in place of diaryl
alkynes to verify the scope of the reaction.
We tested a reaction between phenyl isocyanate 1a/1b
and
1,2-di(thiophen-3-yl)ethyne
(2f)
with
the
Scheme 3. Substrate scope of the reaction between
Unsubstituted and Substituted Phenyl isocyanates (1a-1c,
1e and 1g-1i) and Substituted Symmetrical Diaryls (2a-
2e) and Dihetero aryl acetylene (2f).
standardized reaction conditions, which also, fortunately,
gave respective thiophene substituted indolo[2,1-
a]isoquinolines (3af and 3cf) in moderate yields (68% and
66%) (Scheme 3).
We further investigated the reaction between
phenylisocyanate 1a with unsymmetrical diaryl alkyne 2g
and phenyl isocyanates 1d and 1h with unsymmetrical
3
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10.1002/adsc.202000963
Advanced Synthesis & Catalysis
alkynes 2g and 2h. The reactions resulted an unresolvable
mixture of regioisomers (see SI for spectra).
On the basis of our results, possible reaction mechanism
for the indoles synthesis via oxidative annulations of
phenylisocyanate 1a with diarylalkyne 2a is proposed in
(Scheme 4). Initially, the nucleophilic attack of t-AmOH
on the carbonyl group of 1a generates a carbamate
intermediate B followed by benzyl amine species D by
elimination of di-tert-pentyl carbomate C. Reaction
between benzyl amine species D and phenyl isocyanate
might have led to formation of urea derivative E.[12]
Fortunately, we could isolate the intermediate B and E
and characterize them by 1 and 2 D-NMR spectral data
respectively. The in-situ generated intermediate E might
have converted into
F by Ru(II) catalyzed C–H
activation via concerted metalation-deprotonation
a
(CMD) mechanism assisted by the acetate ion and
subsequent removal of acetic acid might led to G. Then
coordinative insertion of diarylalkyne 2a into the Ru-
carbon bond of intermediate
G in tandem with
elimination of phenyl isocyanate might provide H and I
respectively.[13] In the next step, J might have generated
from I by reacting with Cu(OAc2). The second molecule
of diaryl alkyne insertion between Ru-Carbon bond by
Ru(II) catalyzed C–H activation of J might have led to K
and further reductive elimination of the Ru resulted 3aa.
Scheme 4. Plausible Reaction Mechanism for formation
of Indolo[2,1-a]isoquinolines
To gain insight into the reaction mechanism, some
control experiments were conducted as shown in
(Scheme 5). A reaction between 5-methyl-2,3-
diphenyl-1H-indole (1) in t-amyl alcohol without
catalyst resulted in the formation of intermediate B
in 96% of yield, which was isolated and
characterized by spectral data. Intermediate E was
also isolated from the reaction mixture while
carrying out a reaction with phenyl isocyanate and
Cu(OAc)2.H2O/CsOAc in t-amyl alcohol without
adding diaryl alkyne 2a in 96% of yield (Scheme 5,
II). Treatment of isolated intermediate E (1.0 equiv.)
with 2a (1.0 equiv) in the presence of standardized
reaction conditions [RuCl2(p-cymene)]2 (5 mol%),
CsOAc (50 mol%) and Cu(OAc)2.H2O (0.5 equiv) in
t-AmOH at 120 °C for 3 h provided substituted
indole 3aa in 93% of isolated yield (Scheme 5, III).
All these control experiments strongly support the
proposed reaction mechanism.
4
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10.1002/adsc.202000963
Advanced Synthesis & Catalysis
obtained free of charge from The Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
We thank the Director, CSIR-CDRI, for financial support,
the SAIF Division for spectral data, Dr. Tejendar Thankur
for X-ray crystal data and CSIR, New Delhi, for
fellowship to Amrendra. This is CDRI communication
number XXXX.
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In conclusion, we have developed a new one-pot method
for the synthesis of polysubstituted indolo[2,1-
a]isoquinolines by Ru(II) catalyzed and in-situ installed
carbamide directed double aryl C(sp2)-H activation
between various phenyl isocyanates and internal aryl
alkynes/hetero aryl alkynes in the presence of [RuCl2(p-
cymene)]2 (5 mol%), Cu(OAc)2.H2O (50 mol%) and
additive CsOAc (50 mol%) at 120 °C. To our knowledge,
this is the first report on the use of in-situ generated
carbamide (urea derivative) from isocyanate group as a
directing group in C-H activation of the C(sp2)-H bond.
Further exploration on the synthetic utilities of this in-situ
installed carbamide group from isocyanate and its
directing chemistry is currently progress in our lab and
the results will be reported in due course of time.
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Experimental Section
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General procedure for synthesis of substituted
indolo[2,1-a]isoquinolines: In an oven dried 50 ml R.B
flask charged with stir bar, phenylisocyanate (1.0 equiv.),
diarylalkyne (1.0 equiv.), [RuCl2(pcymene)]2 (5 mol%),
Cu(OAc)2.H2O (0.5 equiv) and CsOAc (0.5 equiv) in 2 ml
of t-AmOH resulting mixture was stirred at 120 °C for 3h.
Completion of reaction was monitored by TLC (1:7 Ethyl
acetate and Hexane). Reaction mixture was cooled down
to room temperature and diluted with 10 mL of H2O. The
resultant mixture was extracted with ethyl acetate (3 × 15
mL). The combined organic phase was dried over
anhydrous Na2SO4. After removal of the solvent under
reduced pressure, the crude product was purified by
column chromatography on silica gel (60-120 mesh) by
using hexane/ethylacetate solvent system to give desired
poly substituted indolo[2,1-a]isoquinolines compounds.
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CCDC-1943183
crystallographic data for this paper. These data can be
contains
the
supplementary
2352-2356.
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000963
Advanced Synthesis & Catalysis
COMMUNICATION
Ruthenium(II)-Catalyzed
Synthesis
of
Indolo[2,1- a]isoquinolines through double
oxidative annulations reaction of Phenyl
isocyanates with Diaryl alkynes/Dihetero aryl
alkynes
Amrendra Kumar Ruchir Kant and Narender
Tadigoppula*
Adv. Synth. Catal. Year, Volume, Page – Page
6
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