Copper-catalyzed multicomponent coupling/cycloisomerization reaction between substituted 1-formyl-9H-β-carbolines, secondary amines, and substituted alkynes for the synthesis of substituted 3-aminoindolizino[8,7-b] indoles

Article abstract of DOI:10.1021/co300123y

A copper-catalyzed efficient one step three component strategy for preparing a library of aminoindolizino[8,7-b]indoles from N-substituted 1-formyl-9H-Β-carbolines, secondary amines, and substituted alkynes with high atom economy has been developed.

Full text of DOI:10.1021/co300123y

Research Article
pubs.acs.org/acscombsci
Copper-Catalyzed Multicomponent Coupling/Cycloisomerization
Reaction between Substituted 1‑Formyl‑9H‑β-carbolines, Secondary
Amines, and Substituted Alkynes for the Synthesis of Substituted
3‑Aminoindolizino[8,7‑b]indoles
Shashi U. Dighe, Samiran Hutait, and Sanjay Batra*
Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, P.O. Box 173, Lucknow 226 001, UP, India
S
* Supporting Information
ABSTRACT: A copper-catalyzed efficient one step three
component strategy for preparing a library of aminoindolizino-
[8,7-b]indoles from N-substituted 1-formyl-9H-β-carbolines,
secondary amines, and substituted alkynes with high atom
economy has been developed.
KEYWORDS: multicomponent reaction, copper, β-carbolines, aminoindolizino[8,7-b]indole
dary amine, and alkyne.8 Yan and Liu reported the synthesis of
aminoindolizines from 2-pyridinealdehyde, secondary amines,
and alkynes under solvent free conditions or in water in the
INTRODUCTION
Indolizino[8,7-b]indole is an interesting core represented in
■
alkaloids such as harmicine, fascaplysin, and bromofascaplysin
presence of gold catalyst.8a Later Liu and co-workers reported
the synthesis of a library of aminoindolizines from similar
substrates by employing silver catalyst instead of gold.8b
Conceptually, both these protocols proceeded via Grignard-
type direct addition of alkyne to imine involving C−H
activation to initially afford the NR1R2-propargylic amine,
which undergoes a metal-catalyzed cycloisomerization.
Although the literature revealed that formation of propargylic
amines via analogous coupling reaction has been reported to be
successful by a variety of metal catalysts,9 these reports8 showed
the success of their protocols essentially with either gold or
silver catalysts (Figure 2). More recently, however, Bobade and
co-workers succeeded in synthesizing similar 3-aminoindoli-
zines by the use of iron catalyst in the presence of
tetrabutylammonium hydroxide.8c
(Figure 1).1 This structural unit has been of significant interest
Figure 1. Natural products with an indolizino[8,7-b]indole core.
to the pharmaceutical industry also.2 Besides, the property of
the quaternized pyridine to undergo rapid nucleophilic attack
has been utilized to derive more complex structures from this
scaffold.3 There have been several elegant strategies which
successfully afford this scaffold, though some of them are
multistep or involve use of expensive reagents.4 Very recently,
we reported the synthesis of substituted indolizino[8,7-
b]indoles from N-substituted 1-formyl-9H-β-carbolines em-
ploying the Morita−Baylis−Hillman adducts (MBH).5 How-
ever, the diversity of this protocol is limited, which is an
impediment for building a chemical library based on this
scaffold. Therefore, we considered an alternative strategy for
developing a diversity-oriented library of compounds contain-
ing this core from the same starting substrates. Structural
analysis of indolizino[8,7-b]indole indicates it contains the
indole and the indolizine unit. It is widely reported that the
indolizine unit, which in itself is represented in several naturally
occurring alkaloids and compounds displaying a variety of
biological activities6 and electronic properties,7 can be rapidly
and directly synthesized through transition-metal based multi-
component reaction between 2-pyrdinecarbaldehyde, secon-
Since we had efficient access to 1-formyl-9H-β-carbolines, it
was anticipated that a multicomponent reaction (MCR)
between this substrate, secondary amines, and substituted
alkynes would lead to the synthesis of diverse 3-
aminoindolizino[8,7-b]indoles via a similar reaction pathway.
To the best of our knowledge, the MCR route to 3-
aminoindolizino[8,7-b]indole remains unreported in the
literature. Working on the envisaged strategy, we discovered
that we could successfully accomplish the synthesis of desired
aminoindolizino[8,7-b]indoles via a one-pot copper-catalyzed
tandem process10 involving coupling/cycloisomerization reac-
tion without any elaborate reaction conditions. We found that
Received: May 29, 2012
Revised: November 7, 2012
Published: November 7, 2012
© 2012 American Chemical Society
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Research Article
Figure 2. Approaches to aminoindolizine core.
the presence of a slight excess of the amine facilitates the
formation of product and that copper salt in the Cu(I)
oxidation state is better suited for the reaction. Moreover, the
duration of the reaction was significantly reduced by perform-
ing the reaction under microwave heating. Results of our study
in this regard are presented herein.
yielded 4{1,1,1} in 96% yield (entry 9, Table 1). Further
titrating the amount of reagents, we discovered that increasing
the amount of phenyl acetylene from 1.1 to 1.5 equiv (ca. for
the synthesis of indolizines8) had no bearing on the outcome
but using 1.5 equiv of morpholine instead of 1.1 equiv reduced
the reaction time from 12 to 7 h without affecting the yields of
the product formed (entry 10, Table 1). It was realized that the
toluene was the best solvent for the reaction to furnish
4{1,1,1}. Inferior results were obtained when polar solvents
such as dioxane, DMSO, DMF, or MeCN were used as the
medium (compare entry 10 with entries 11−14, Table 1). As
indicated in Table 1, different Cu(I) and Cu(II) salts were also
examined and it was observed that the yields were better with
Cu(I) salts and the CuI was the most suited for the reaction
(compare entries 10 with 15−19, Table 1). Therefore, the
standardized conditions which worked best for us were
aldehyde (1.0 equiv), phenyl acetylene (1.1 equiv), and
morpholine (1.5 equiv) in the presence of 10 mol % of CuI
in toluene at 85 °C for 7 h.
RESULTS
■
To test the success of our strategy, we first screened various
metal catalysts for the coupling reaction of methyl N-allyl-1-
formyl-9H-β-carboline-3-carboxylate 1{1}, morpholine 2{1},
and phenyl acetylene 3{1} under different reaction conditions,
and the results are summarized in Table 1. Interestingly, during
the optimization we observed that, as compared to gold and
silver catalysts, the three components coupling/cycloisomeriza-
tion proceeded more efficiently in the presence of copper(I)
salts in toluene as medium to afford the desired methyl 11-allyl-
1-morpholino-3-phenyl-11H-indolizino[8,7-b]indole-5-carboxy-
late 4{1,1,1} after 12 h at 90 °C in 68% yields (entries 1−6,
Table 1). Lowering the catalyst load to less than 5 mol %
resulted in lowering of the yields of 4{1,1,1} (entry 7−8, Table
1). However, increasing the catalyst load to 10 mol % of CuI
With the optimized conditions, we investigated the scope of
this multicomponent strategy for the construction of a library of
3-amino indolizino[8,7-b]indoles. It may be noted that in our
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a
investigated for the protocol, we found trimethylsilyl acetylene
3{9} did not produced the required aminoindolizino[8,7-
b]indole 4{1,1,9}. On the basis of the work of Liu and co-
workers,8b it is likely that the TMS group is removed in the
presence of copper salt, leading to in situ generation of
acetylene which did not participate in the reaction. Moreover,
the aldehydes originating from tryptophan and tryptamine
reacted with similar efficiency, but the products generated from
the tryptamine have to be stored at lower temperature to
prevent them from decomposing.
The plausible mechanism for the formation of the 3-
aminoindolizino[8,7-b]indole is delineated in Figure 4. This
mechanism is analogous to Cu-catalyzed cycloisomerization of
alkynylimines to afford pyroles and Cu-catalyzed cyclo-
isomerisation of propargylic pyridines.11,9d It is assumed that
initially morpholine reacts with the aldehyde II, leading to the
formation of iminium ion III with the loss of a water molecule.
Subsequently, Cu-coordinated alkyne I formed in situ reacts
with III, wherein a nucleophilic attack of pyridyl nitrogen on
the Cu-coordinated allenyl double bond occurs, resulting in
formation of cationic intermediate IV. The morpholine captures
a proton from IV to furnish the intermediate V, which upon
protonolysis yields the product VI.
Since the intermediate species were ionic, we were prompted
to test the reaction under microwave conditions to potentially
decrease the reaction time. An optimization study under
microwave (MW) conditions was performed via coupling
reaction of methyl N-allyl-1-formyl-9H-β-carboline-3-carboxy-
late 1{1}, morpholine 2{1}, and phenylacetylene 3{1}. We
were delighted to note that at 90 °C under MW the reaction
was complete in 45 min to afford the product 4{1,1,1} in 94%
yields. Hence, a few more reactions were investigated under
MW conditions, and the results are presented in Table 3. As
evident, all reactions successfully gave the products but the
yields were relatively less as compared to the conventional
route.
Since we were unable to include the N-unsubstituted 1-
formyl-9H-β-carboline for the study, we decided to unmask the
N-allyl or N-benzyl groups in representative products using
literature strategies. Initially, in order to remove the allyl group,
compound 4{1,1,1} was treated with RhCl(PPh3)3 in a MeCN/
H2O mixture under reflux, as reported earlier.12 However, the
reaction resulted in a complex mixture of products which could
not be purified. On the other hand, debenzylation in 4{6,1,1},
which was attempted either by hydrogenation13 or via different
chemical methods,14 also failed to give the desired results.
The successful use of copper salts for the coupling/
cycloisomerization reaction in β-carboline inspired us to
reinvestigate the three component reaction between of
pyridine-2-carbaldehyde, secondary amine, and alkyne under
the optimized conditions of our study. Accordingly, pyridine-2-
carbaldehyde was treated with phenyl acetylene (1.1 equiv) and
morpholine or piperidine (1.5 equiv) in toluene at 85 °C
(Scheme 1). It was gratifying to note that both reactions were
successful and gave the respective products in 82 and 74%
yields.
Table 1. Results of the Study for Optimization of the
Catalyst and Reaction Conditions for the MCR
b
entry mol %
catalyst
AuCl3
solvent
temp time (h)
yield (%)
1
2
5
5
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
dioxane
DMSO
MeCN
DMF
85
85
85
85
85
85
85
85
85
85
85
85
85
85
85
85
85
85
85
12
12
12
12
12
12
12
12
12
7
21
34
64
68
65
54
60
55
96
96
47
58
36
42
90
53
15
79
Ag2O
AgBF4
CuI
3
5
4
5
5
5
CuBr
CuCl
CuI
6
5
7
4
8
3
CuI
9
10
10
10
10
10
10
10
10
10
10
10
CuI
10
11
12
13
14
15
16
17
18
19
CuI
CuI
7
CuI
7
CuI
7
CuI
7
CuBr
CuCl
Cu2O
CuBr2
Cu(OAc)2
toluene
toluene
toluene
toluene
toluene
7
7
7
7
7
22
a
b
All reactions were performed with 0.13 mmol of aldehyde. Entries
1−9: 1.1 equiv of sec amine was employed. Entries 10−17: 1.5 equiv
of sec amine was employed.
hands the reaction of unsubstituted 1-formyl-9H-β-carboline
with phenyl acetylene and morpholine resulted in a complex
mixture of products; therefore, it was out of the scope. In all 13
N-substituted 1-formyl-9H-β-carbolines (1), seven secondary
amines (2) and 9 alkynes (3) (Figure 3) were employed for
preparing the library, and different products synthesized during
the present study are illustrated in Table 2. It is worthwhile to
mention that all products were obtained by initially passing the
reaction mixture (without any workup) through a small band of
silica gel using hexane as eluent to remove the excess alkyne,
followed by elution with hexane/EtOAc (97:3, v/v). In general,
different aldehydes whose reactions were performed in toluene
furnished the products in excellent yields. But as a few
aldehydes 1{3 & 4} were insoluble in toluene, their reactions
were carried out in DMSO as the medium, which led to the
formation of the respective products 4{3,1,1} and 4{4,1,1} in
low yields. It was interesting to note that different substitutions
present on the indole nitrogen do not have any influence on the
outcome of the reaction. In the case of substrates having the
benzyl substitution 1{6−11, 13}, the electronic character of the
substitution (donating or withdrawing) on the phenyl ring of
the benzyl group also does not affect the formation of product.
It was observed that, among all the secondary amines examined
during the study, the diphenylamine 2{7} failed to produce the
required product 4{1,7,1}. On the other hand since diethyl
amine 2{6} was able to afford the respective aminoindolizino-
[8,7-b]indole 4{6,6,1}, we speculate that the presence of
diphenyl rings attached to the amino group induces steric
hindrance unsuited for the reaction. Of the nine alkynes
In summary, we have developed a Cu-mediated multi-
component route involving coupling/cycloisomerization for the
synthesis of 3-aminoindolizino[8,7-b]indoles. As illustrated, the
methodology is efficient and amenable to library development.
The protocol is amenable to microwave conditions, thereby
reducing the reaction time significantly. Further work is
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Figure 3. Diversity of reagents.
underway to develop the chemistry of these 3-aminoindolizino-
[8,7-b]indoles for obtaining new fused β-carbolines.
aldehydes were prepared following the method reported
earlier.5
General Procedure for the multicomponent reaction
as exemplified for the synthesis of methyl 11-allyl-1-
morpholino-3-phenyl-11H-indolizino[8,7-b]indole-5-
carboxylate 4{1,1,1}. . To a reaction vessel in 10 mL of
toluene were added 1{1} (150 mg, 0.51 mmol), morpholine
(67.0 μL, 0.76 mmol), phenylacetylene (61.0 μL, 0.56 mmol),
and CuI (10 mg, 0.05 mmol) and then nitrogen was bubbled
for 10 min to deoxygenate the reaction mixture. Thereafter, the
resulting solution was stirred at 85 °C for 7 h. On completion,
the reaction mixture was cooled to room temperature and was
purified by silica gel column chromatography (hexanes/EtOAc,
97:3, v/v) to obtain pure 4{1,1,1} as a yellow solid (228 mg,
96%). Mp: 116−118 °C; Rf = 0.54 (hexanes/EtOAc, 80:20); IR
EXPERIMENTAL PROCEDURES
■
Melting points are uncorrected and were determined in
capillary tubes on a Precision melting point apparatus
containing silicon oil. IR spectra were recorded using a
1
Perkin-Elmer’s RX I FTIR spectrophotometer. H NMR and
13C NMR spectra were recorded either on a Bruker DPX-200
or Bruker Avance DRX-300 spectrometer, using TMS as an
internal standard (chemical shifts in δ). The ESMS were
recorded on a Thermo Finnigan LCQ Advantage, Ion Trap
Mass spectrometer. The HRMS spectra were recorded as EI-
HRMS on an Agilent 6520 Q-TOF, LC-MS/MS mass
spectrometer. The reactions under microwave heating were
carried out in a Biotage initiator 2.5 microwave system. All
1
(KBr) ν: 1500, 1629, 1715 2384, 2855 cm−1. H NMR (300
MHz, CDCl3): δ (ppm) = 3.02−3.16 (m, 4H), 3.24 (s, 3H),
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a
Table 2. Copper-Catalyzed Three-Component Reactions To Synthesize a Library of Aminoindolizino[8,7-b]indoles
a
All reactions were performed by using 1.0 equiv of aldehyde, 1.5 equiv of sec amine, and 1.1 equiv of alkyne, 10 mol % of CuI in toluene at 85 °C;
the yields included in the table are the isolated yields of compounds.
3.83−3.98 (m, 4H,), 4.92 (d, 1H, J = 17.2 Hz), 5.10 (d, 1H, J =
10.1 Hz), 5.95−6.04 (m, 1H), 6.25 (s, 2H), 6.88 (s, 1H), 7.26−
7.49 (m, 8H), 7.81 (s, 1H), 7.88 (d, 1H, J = 7.4 Hz). 13C NMR
(50 MHz, CDCl3): δ (ppm) = 49.5, 51.6, 55.6, 67.3, 109.5,
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Figure 4. Plausible mechanism for the formation of the aminoindolizino[8,7-b]indole.
a
Table 3. Copper-Catalyzed Three-Component Reactions To Synthesize Aminoindolizino[8,7-b]indoles under Microwave
Conditions
a
All reactions were performed by using 1.0 equiv of aldehyde, 1.5 equiv of sec amine, and 1.1 equiv of alkyne, 10 mol % of CuI in toluene at 85 °C;
the yields included in the table are the isolated yields of compounds.
Methyl 11-Benzyl-1-morpholino-3-phenyl-11H-
indolizino[8,7-b]indole-5-carboxylate 4{6,1,1}. The com-
pound was prepared following a similar procedure as described
above. Yield: 96% (0.197 g from 0.15 g); yellow solid; mp:
166−168 °C; Rf = 0.52 (hexanes/EtOAc, 80:20); IR (KBr) ν:
1220, 1630, 1713 cm−1. 1H NMR (300 MHz, CDCl3): δ (ppm)
= 2.86 (d, 2H, J = 11.2 Hz), 3.00 (dd, 2H, J1 = 9.5 Hz, J2 = 11.4
Hz), 3.26−3.31 (m, 5H), 3.71 (d, 2H, J = 10.2 Hz), 6.84 (s,
2H), 6.88 (s, 1H), 7.09 (d, 2H, J = 6.7 Hz), 7.19−7.31 (m,
7H), 7.40−7.50 (m, 4H), 7.86−7.89 (m, 2H). 13C NMR (50
MHz, CDCl3): δ (ppm) = 51.1, 51.6, 55.9, 66.8, 109.8, 111.2,
114.3, 118.6, 119.8, 121.2, 124.1, 124.7, 125.2, 126.1, 127.2,
128.8, 129.2, 130.5, 132.0, 135.7, 138.9, 139.7, 164.7. MS (ESI
+) m/z: = 516.2 (M + H)+. ESI-HR-MS calculated for
C33H30N3O3 [MH]+: 516.2287, found: 516.2281.
Scheme 1. Copper Catalyzed Three-Component Reactions
To Synthesize Aminoindolizines
111.1, 114.3, 116.0, 118.7, 121.2, 123.9, 124.6, 125.2, 127.2,
129.2, 132.0, 134.6, 139.9, 164.7. MS (ESI+) m/z: = 466.2 (M
+ H)+. ESI-HR-MS calculated for C29H28N3O3 [MH]+:
466.2131, found: 466.2121.
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and related compounds. German Patent 2,033,631, 1971; Chem. Abstr.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Spectral and analytical data along with copies of H- and 13C-
NMR for all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
1
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AUTHOR INFORMATION
Corresponding Author
*Tel.: +91-522-2612411-18. Extn. 4234, 4368. Fax: +91-0522-
2623405, 2623938. E-mail: batra_san@yahoo.co.uk.
Author Contributions
SD, SH and SB conceived and designed the experiments, SD
and SH performed the experiments, SD and SB co-wrote the
manuscript.
■
Funding
Two of the authors (S.D. and S.H.) acknowledge the financial
support from CSIR, N. Delhi, in the form of a fellowship. This
work was carried out under a grant from DST, N. Delhi.
Notes
The authors declare no competing financial interest.
This paper is CDRI Communication No. 8349.
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ACKNOWLEDGMENTS
■
The authors acknowledge the SAIF Division of CDRI for
providing the spectroscopic and analytical data. The authors
acknowledge the comments of the anonymous reviewers, which
helped to improve the manuscript.
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