Tandem aldehyde-alkyne-amine coupling/cycloisomerization: A new synthesis of coumarins

Article abstract of DOI:10.3762/bjoc.9.21

Cu-catalyzed A³ coupling of ethoxyacetylene, pyrrolidine and salicylaldehydes led to a concomitant cycloisomerization followed by hydrolysis of the resultant vinyl ether to afford coumarins in a cascade process. The reaction proceeded through exclusive 6-endo-dig cyclization and is compatible with halo and keto groups giving coumarins in good to moderate yields.

Full text of DOI:10.3762/bjoc.9.21

Tandem aldehyde–alkyne–amine coupling/cyclo-
isomerization: A new synthesis of coumarins
Maddi Sridhar Reddy*, Nuligonda Thirupathi and Madala Haribabu
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 180–184.
Medicinal & Process Chemistry Division, CSIR-Central Drug
Research Institute, Lucknow-226 001, India, Fax: +91-(522)-2623405,
Tel: +91–(522)–2612 411, Extn: 4379
doi:10.3762/bjoc.9.21
Received: 23 October 2012
Accepted: 28 December 2012
Published: 28 January 2013
Email:
Maddi Sridhar Reddy* - msreddy@cdri.res.in
Associate Editor: P. R. Hanson
* Corresponding author
© 2013 Reddy et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
A3 coupling; cooperative catalysis; coumarin synthesis;
cycloisomerization; transition-metal catalysts
Abstract
Cu-catalyzed A3 coupling of ethoxyacetylene, pyrrolidine and salicylaldehydes led to a concomitant cycloisomerization followed
by hydrolysis of the resultant vinyl ether to afford coumarins in a cascade process. The reaction proceeded through exclusive
6-endo-dig cyclization and is compatible with halo and keto groups giving coumarins in good to moderate yields.
Introduction
An alkyne, an aldehyde and an amine coupling, referred to as If one of the partners in A3 coupling has any nucleophile for
A3 coupling [1], has been found as an efficient method for C–N concomitant electrophilic cyclization on the alkyne group in the
and C–C bond formation that results in equivalence of reduc- A3 product, this may result in an interesting reaction sequence
tive alkylation of amines while at the same time appending an to produce various heterocycles. Recently, Gevorgyan and
alkyne, i.e., a highly useful moiety for further functionlization. co-workers [23] used these two processes (A3/5-exo-dig cyclo-
This three-component coupling has been accomplished with a isomerization) in tandem to obtain indolines, which were then
very broad range of transition metals, including copper, silver, converted to useful substituted indole derivatives (Scheme 1,
gold, ruthenium/copper, cobalt, iridium and iron. Similarly, (a)). Similarly, Patil and Raut [24] reported an elegant method
cycloisomerization of alkynols and alkynamines has also been for the synthesis of 2-substituted quinolines from 2-amino-
an attractive approach for the synthesis of various known and benzaldehydes and terminal alkynes by a tandem A3/6-endo-
new heterocyclic frameworks [2-22]. Various alkynophilic cata- dig-cycloisomerization (Scheme 1, (b)) using a cooperative
lysts such as transition-metal catalysts (based on gold, mercury, catalytic system consisting of CuI and pyrrolidine. Prior to these
platinum, silver, etc.), Brønsted acids and electrophilic iodine two findings, Sakai et al. [25] reported a facile synthesis of
sources (I2, ICl, NIS) have been used for the transformation.
3-aminobenzofurans through an A3 coupling and an exclusive
180

Beilstein J. Org. Chem. 2013, 9, 180–184.
Scheme 1: Synthesis of various heterocycles by a tandem A3 coupling/cycloisomerization strategy.
5-exo-dig-cycloisomerization (Scheme 1, (c)). Similarly, Yan gated the reaction with various Cu-, Au- and Pd-based catalysts
and Liu [26], Fujii et al. [27,28], Chernyk and Gevorgyan [29], in the presence of pyrrolidine in MeCN at room temperature
Ji et al. [30], and Wu et al. [31] reported the synthesis of amino- (Table 1).
indolizines, 2-(aminomethyl)indoles, imidazopyridines, buteno-
lides and 1,2-dihydroisoquinoline derivatives, respectively, The required product was obtained but in very low yield, and
combining these two approaches successfully. Along the same the reaction time was prolonged to more than 24 h. When the
lines, we investigated a reaction between ethoxyacetylene,
pyrrolidine and salicylaldehyde in the presence of a transition-
Table 1: Catalyst and condition screening.
metal catalyst. That, after consecutive A3 coupling, cyclo-
isomerization and hydrolysis of the resultant vinyl ether inter-
mediate, should produce coumarins (Scheme 1, (d)). The reason
for the selective 6-endo-dig cyclization of such a cooperative-
catalysis reaction has been well documented through
DFT computational studies by Patil et al. in their recent
entry catalyst
solvent/temp
CH3CN/rt
base
Time yield
publication [32].
(h)
(%)
Results and Discussion
1
2
3
4
5
6
7
8
9
10
CuI
pyrrolidine 24
pyrrolidine 24
pyrrolidine 24
pyrrolidine 24
pyrrolidine 24
pyrrolidine 24
pyrrolidine 24
58
24
35
48
50
30
25
65
—
—
Coumarins [33-46] have been attractive targets [47-53] for syn-
thetic chemists due to their frequent occurrence in nature and
for their interesting biological and pharmaceutical applications.
In continuation of our interest in the cycloisomerization of
alkynols and alkynamines for the synthesis of various hetero-
cycles [17-22], we herein report the synthesis of coumarins
from salicylaldehydes by a Cu-catalyzed exclusive 6-endo-dig
electrophilic cyclization of the intermediate hydroxyphenyl-
propargylamine as shown in Scheme 1 (d). We initially investi-
Cu(OTf)2 CH3CN/rt
AuCl
CH3CN/rt
CH3CN/rt
CH3CN/rt
AuCl3
HAuCl4
PPh3AuCl CH3CN/rt
PdCl2
CuI
—
CH3CN/rt
CH3CN/100 °C pyrrolidine
CH3CN/100 °C pyrrolidine
CH3CN/100 °C pyrrolidine
2
3
3
CuI
181

Beilstein J. Org. Chem. 2013, 9, 180–184.
Table 2: Synthesis of coumarins 2 from salicylaldehydes 1 by A3 coupling/cycloisomerization.
entry
substrate 1a
product 2
yield
(%)b
entry
substrate 1a
product 2
yield
(%)b
1
62
68
9
62
62
1a
2a
1i
1j
2i
2j
2
3
10
11
1b
1c
2b
2c
78
60
1k
2k
4
5
75
80
12
13
65
76
1d
1e
2d
2e
1l
2l
1m
2m
6
82
14
15
65
84
1f
2f
1n
1o
2n
2o
7
8
50
80
1g
1h
2g
2h
aAll reactions were conducted with 1 mmol substrate in 0.25 M concentration. bIsolated yields.
reaction temperature was raised to 100 °C in the presence of Encouraged by this promising result, the scope of the reaction
CuI and pyrrolidine in CH3CN, the desired product was ob- was tested with a number of salicylaldehydes. As is apparent
tained in 65% in 2 h.
from Table 2, the reaction is highly versatile, working effi-
182

Beilstein J. Org. Chem. 2013, 9, 180–184.
ciently with both electron-rich and -poor substrates. Substrates Conclusion
1b–h with various alkyl substituents produced the corres- In summary, a facile synthesis of coumarins is reported from
ponding coumarins 2b–h in 50–82% yield.
readily available starting materials, i.e., salicylaldehydes and
ethoxyacetylene, through a tandem A3 coupling and cyclo-
A slight reduction in yield was observed in the cases of halogen isomerization cascade. The reaction was catalyzed by a pyrroli-
containing substrates. Thus, substrates 1i–l gave the required dine and copper iodide cooperative catalytic system, and the
products 2i–l in 62–65% yield. Substrates 1m and 1n with reaction was not observed in the absence of either of the cata-
extended conjugation also reacted well under the standardized lysts. The yields are good to moderate and the reaction has a
conditions to give the corresponding products 2m and 2n in good substrate scope being compatible with halogen and keto
good yields (65–76%). The reaction is highly compatible with groups. The process constitutes an easy and efficient access to
keto functionality, as is evident from the conversion of 1o to 2o highly valuable building blocks of natural products or bio-
in 84% yield. It should be noted that the reaction is limited to logically active compounds.
aldehydes and not to ketones, which do not undergo A3
coupling.
Supporting Information
A plausible mechanism via a cooperative catalysis by Cu and
Supporting Information File 1
pyrrolidine is described in Scheme 2 (with the assistance of the
work reported by Patil et al. [24,32]). Initial condensation of
pyrrolidine with salicylaldehyde 1 produced iminium intermedi-
ate A. The addition of copper ethoxyacetylide, formed on the
reaction of ethoxyacetylene with Cu, to the iminium intermedi-
ate A yielded propargylamine intermediate B. Copper being co-
ordinated with the amine group immediately activated the
alkyne group to facilitate cycloisomerization with the phenoxy
group, to produce vinyl ether C, which, being susceptible to
hydrolysis, underwent water addition followed by an extrusion
of the pyrrolidine molecule for further catalysis. The resulted
intermediate D lost an EtOH molecule to furnish the required
product 2.
Experimental procedures and product characterization for
compounds 2a–o.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-9-21-S1.pdf]
Acknowledgments
We thank CSIR for the financial aid and Prof. Pierre
Deslongchamps, emeritus professor at University of Laval,
Canada, and Dr. T. K. Chakraborty, Director CSIR-CDRI for
their constant encouragement. We thank SAIF division CDRI
for the analytical data support. Generous financial aid from
CSIR Network project "BSC0102" (CSIR-CDRI-THUNDER)
is acknowledged. CDRI Communication NO. 8371.
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