Cs2CO3 as a source of carbonyl and ethereal oxygen in a Cu-catalysed cascade synthesis of benzofuran [3,2-: C] quinolin-6[5- H] ones

Article abstract of DOI:10.1039/c6ob01029f

The simultaneous construction of C-C, C-O, and C-N bonds utilizing Cs₂CO₃ as a source of both carbonyl (CO) and ethereal oxygen and a cascade synthesis of benzofuro[3,2-c]quinolin-6(5H)-one have been achieved using a combination of C

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Cs2CO3 as source of carbonyl and ethereal oxygen in
Cu-catalysed cascade synthesis of benzofuran
[3,2-c] quinolin-6[5-H]ones
Wajid Ali, Anju Modi, Ahalya Behera, Prakash Ranjan Mohanta and Bhisma K.
Patel*
viz. the incorporation of carbonyl as well as a ethereal oxygen
functionality in the resultant heterocycle and their origin. The unique
feature of this heterocycle (1a) is the simultaneous formation of
three types of bonds viz. two CO and one each of CC and CN
bonds.
Benzofuro[3,2-c]quinolin-6(5H)-one derivatives are reported to
show activity against osteoporosis and malaria.8 Some derivatives of
benzofuro[3,2-c]quinolin-6(5H)-one having potential antimalarial
activity are shown in Figure 1. Surprisingly, literature contains only
few reports describing the synthesis of benzofuro[3,2-c]quinolin-
6(5H)-ones.8,9
Simultaneous construction of CC, CO, and CN bonds
utilizing Cs2CO3 as the source of both carbonyl (CO) and
ethereal oxygen; a cascade synthesis of benzofuro[3,2-c]quinolin-
6(5H)-one has been achieved using a combination of Cu(OAc)2
and Ag2CO3. A plausible mechanism has been proposed for this
unprecedented transformation.
In modern era of organic chemistry, synthesis of highly
functionalised and structurally diverse heterocycles is a challenging
task. In this regard, domino reactions are most promising approach
for the synthesis of complex organic molecules.1 Formation of
multiple CC and Cheteroatom bonds for the rapid access to fused
and complex polycyclic skeleton is the attractive feature of any
domino reaction. Recently, the strategy has emerged as a powerful
“Synthetic Avenue” for the conversion of internal alkynes into
biologically interesting polycycles2 or spiro heterocycles.3 Alkynes
tethered substrates possessing nucleophilic groups at appropriate
positions are often utilised as substrates for metal-catalysed cascade
transformations.4 Such substrates may be prefunctionalised with a
nucleophile or the desired functionality may be introduced into the
substrate via Ullmann type cross-coupling reactions in situ. Copper
as a catalyst has a great potential in initiating both Ullmann coupling
as well as triggering cascade reactions.5 Hence, of late copper
catalysed domino synthesis of cyclic compounds in combination
with Ullmann coupling is receiving much attention.6
Figure 1 Molecules showing antimalarial activity.
To ensure the origin of the carbonyl group in product (1a) some
control reactions were carried out. The probable sources of carbonyl
functionality are either the carboxyl group of L-alanine or the
Cs2CO3. A control reaction carried out under otherwise identical
condition, but in the absence of L-alanine gave the same product
(1a) in similar yield confirming L-alanine not to be the source of the
carbonyl group. This suggests, Cs2CO3 to be the possible source of
the carbonyl group in (1a) (Table S1, entry 2, see ESI†). To check,
whether other inorganic carbonates or bicarbonates could be the
possible replacement for Cs2CO3, reactions were performed with
other inorganic bases (Table S1, entries 36, see ESI†) such as
K2CO3, Na2CO3, KHCO3, and NaHCO3. While K2CO3 gave product
in < 8%, all other basic salts were completely unproductive
suggesting Cs2CO3 to be the ideal source of the carbonyl group for
(1a).
In continuation to our effort towards copper catalysed synthesis of
heterocycles,7 when 2-((2-bromophenyl)ethynyl)aniline (1) was
treated with L-alanine in the presence of Cu(OAc)2 and Cs2CO3 in
o
dimethyl sulphoxide (DMSO) at 130 C a product was isolated in
57% yield (Table S1, entry 1, see ESI†). Spectroscopic analysis
(NMR, IR and HRMS) and subsequent crystal structure
determination of one of its derivative confirms its structure to be
benzofuro[3,2-c]quinolin-6(5H)-one (1a) (Scheme 1). The product
structure brings about few interesting facets of this transformation
It is well established that metal carbonates and bicarbonates act
as CO2 source. However, until now Cs2CO3 has been reported to
serves as CO2 source for the synthesis of cyclic or acyclic
carbonates.10 Recently, Cs2CO3 as oxygen source for the synthesis of
ester by the coupling of acid chloride and alkyl halide has been
reported.11 So far synthesis of biologically active heterocycles using
_____________________________________________
Department of Chemistry, Indian Institute of Technology Guwahati, 781 039,
Assam, India. Fax no. +91-3612690762; E-mail: patel@iitg.ernet.in
†Electronic supplementary information (ESI) available: Optimization table,
1H and 13C NMR spectra. CCDC 1453512. For ESI or other electronic
format see DOI: 10.1039/xxxxxx.
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CO2 generated from metal carbonates is unfamiliar. On the other observed for both electron-donating and electron-withdrawing
hand, gaseous CO2 have been extensively utilised for the synthesis substituents when present in the other ring. The presence of electron-
of carbonates, acid, ester and lactone etc.12 Silver catalysed donating groups such as p-Me (12), p-Bu (13) on the halogen
incorporation of gaseous CO2 in a variety of internal and terminal bearing aromatic ring gave products (12a) and (13a) in 60% and
alkynes, allenes, o-alkynylacetophenone, and allysilane as well as 61% yields respectively. Here again, when electron-donating -Me
carboxylation of terminal alkynes are summarized by Yamada et group is present at C3, C4 positions as in (14) its product (14a) was
al.13 in his recent review. This inserted CO2 undergo various kind of isolated in 54% yield. However, when the -Me group is present at
rearangements to afford various heterocycles.13 Similarily, Cu(II)- C2, C4 positions as in (15) the yield of the corresponding product
catalysed incorporation of CO2 into alkene, alkyne, allene and other (15a) dropped to 48% which is due to both steric and electronic
systems have been reported by various other groups.14 To the best of factors. Further, moderately electron-withdrawing groups such as p-
knowledge a cascade synthesis of benzofuro[3,2-c]quinolin-6(5H)- Cl (16), p-F (17) in the halogen bearing aromatic ring gave
ones has been reported for the first time utilising CO2 from Cs2CO3.
marginally better yields of the product [(16a, 73%) and (17a, 76%)]
Intrigued by this unprecedented outcome, further screening of the to that of amine bearing ring (7a and 8a). Coincidently, similar
reaction parameters were carried out to enhance the efficacy of this inferior yield of the product (18a, 55%) was observed even when the
cascade cyclisation using 2-((2-bromophenyl)ethynyl)aniline (1) as electron-withdrawing -CN (18) group is present on the other ring. In
the model substrate. Initially, various copper salts such as Cu(OAc)2 any cascade reaction several bond making and bond breaking
(62%), Cu(OTf)2 (61%), Cu(C5HF6O2)2 (57%), CuBr2 (52%), CuCl2 process takes place from multiple directions bearing substituents at
(58%), CuI (60%), CuBr (56%) and CuCl (51%), were scrutinised various sites. Thus, it is difficult to correlate the true electronic
factor and ascertain the exact rate determining step in the reaction on
the basis of final yields. When the bromo substituent was replaced
with an iodo group the yields of their products were marginally
better than their bromo analogues as demonstrated during the
synthesis of (1a), (2a) and (8a) (Scheme 1).
(Table S2, entries 19, see ESI†). As can be seen from Table S2 all
the copper salts tested gave product (1a) in comparable yields.
However, the reaction was cleaner with few side products using
Cu(OAc)2 (Table S2, entry 1, see ESI†). The use of Ag2CO3 as an
additive enhanced the yield of the cyclised product by further 6%
(Table S2, entry 10, see ESI†). The incremental improvement in the
product yield using Ag2CO3 leaves a question, whether it is also
acting as a carbonyl source similar to Cs2CO3. To find an answer to
this, a reaction was performed under otherwise identical conditions
but using Ag2CO3 (4 equiv.) in lieu of Cs2CO3 (Table S2, entry 11,
see ESI†). Complete failure of product (1a) formation reconfirms
Cs2CO3 as the sole source of carbonyl functionality and Ag2CO3
might be helping during the cyclisation step. Using Cu(OAc)2 as the
catalyst and Cs2CO3 as the carbonyl source other silver salts like
Ag(OCOCF3) and Ag(OSO2CF3) were examined (Table S2, entries
1213, see ESI†); however Ag2CO3 turned out to be the most
effective (Table S2, entry 10, see ESI†). Increasing the catalyst
loading to 20 mol% was not beneficial in giving better yield (Table
S2, entry 14, see ESI†). A lower catalyst loading (5 mol%) was
equally effective to that of higher catalyst loading (10 mol%) (Table
S2, entry 15, see ESI†). An identical reaction carried out in the
absence of Cu(OAc)2 gave lower yield of the product (< 10)
suggesting the active role of copper in the overall transformation
(Table S2, entry 16, see ESI†). Finally, the optimized conditions for
this transformation is the use of Cu(OAc)2 (5 mol%), Cs2CO3 (4
equiv.), Ag2CO3 (1 equiv.) in DMSO (3 mL) at 130 oC.
Scheme 1 Substrate scope of cascade cyclisation.ab
With the above optimized condition in hand, we set out to explore
the generality and scope of this protocol and the experimental results
are summarised in Scheme 1. Initially, the effect of substituents on
the amine bearing ring was explored. The presence of electron-
donating groups such as p-Me (2), p-Bu (3), p-iPr (4), and p-tBu (5)
on the aromatic ring produce their corresponding products (2a5a)
in the yields ranging between 6264%. The yields so obtained were
lower than the un-substituted analogue (1a). The yield plunge
further, when the electron-donating -Me group is present at C3, C4
position of the amine bearing ring as in (6a). Presence of moderately
electron-withdrawing groups such as p-Cl (7), p-F (8) gave identical
yields of their products (7a, 70%) and (8a, 73%) to that of un-
substituted analogue (1a). The structure of the product (8a) has been
unequivocally established by single crystal X-ray crystallography
(Figure 2). The presence of strongly electron-withdrawing group p-
CN (9) provided inferior yield (54%) of product (9a). Position of
substitution of moderately electron-withdrawing groups i.e. m-Cl
(10), m-F (11) have no significant effect on their yields [(10a, 68%)
and (11a, 69%)] to that of their para analogues (7a) and (8a) as
depicted in Scheme 1. Similar trend in electronic effect was
aReaction conditions: 118 (0.2 mmol), Cu(OAc)2 (5 mol%), Cs2CO3 (0.8
o
mmol, 4 equiv.), Ag2CO3 (0.2 mmol, 1 equiv.), DMSO (3 mL) at 130 C for
b
24 h. Isolated pure product. cReaction performed with iodo substrate.
Next, variation in the nature of substituents on both the aryl rings
were explored (Scheme 2). When both the rings possess sets of
electron-donating groups such as p-Me/p-Me (19), p-Me/p-Bu (20),
p-iPr/p-Me (21) and p-tBu/p-Me (22) lesser yields (57%59%) of
their cyclised products (19a22a) were obtained. On the other hand,
when the amine bearing ring is substituted with electron-donating
and the other ring with electron-withdrawing groups such as p-Me/p-
Cl (23), p-Me/p-F (24), p-Bu/p-Cl (25), p-Bu/p-F (26), p-tBu/p-F
2 | J. Name., 2012, 00, 1-3
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(27) and 3,4-diMe/p-F (28), the yield of the cascade products mechanism, further investigations were carried out (Scheme 3). The
source of carbonyl in the quinolone part has already been accounted
for; however the source of ethereal oxygen in the benzofuran ring is
yet to be ascertained. Previously, we envisaged that the possible
source of ethereal oxygen could be either the aerial oxygen or the
traces of water present in the commercial grade DMSO. Comparable
yield of (1a) was obtained when the reaction was performed under
an argon atmosphere, suggesting aerial oxygen not to be the source
of benzofuran oxygen. Another reaction performed using anhydrous
DMSO under an inert atmosphere in an otherwise identical
conditions, gave the desired product (1a) in 59% yield. This result
ruled out moisture/H2O in commercial grade DMSO not to be the
source of ethereal oxygen in (1a). This leaves Cs2CO3 as the only
possible source of oxygen in benzofuran moiety.11 There are reports
where aryl halides undergo hydroxylation in the presence of base
and copper catalyst.15 During this cascade cyclisation, the ortho
bromo group is replaced with an oxygen atom therefore, initial ortho
hydroxylation via copper catalysis with an appropriate oxygen
source (possibly Cs2CO3) cannot be completely ruled out.
(23a28a) isolated were marginally better (in the range of 6270%).
Further, when the amine bearing ring is substituted with electron-
withdrawing and the other ring with electron-donating groups p-
Cl/p-Me (29), p-F/p-Me (30), p-F/p-Bu (31) their products (29a),
(30a) and (31a) were obtain in 59%, 65% and 66% yields
respectively. Coincidently, this trend in the yields observed follows
the similar pattern when substituents were swapped across the rings
(Scheme 2). Better yields of the products were obtained when both
the rings were substituted with electron-withdrawing groups such as
p-Cl/p-F (32a, 74%), p-F/p-Cl (33a, 72%), p-F/p-F (34a, 76%).
Scheme 3 Mechanistic investigations.
Figure 2 Ortep view of (8a).
Scheme 2 Substrate scope of cascade cyclisation.ab
To check the possibility of hydroxylation path when
a
presynthesized 2-((2-aminophenyl)ethynyl)phenol (1′) was subjected
to the present reaction condition failed to give the expected product
(1a) even after 36 h. This ruled out any possibility of initial
hydroxylation via Ullmann coupling path [Scheme 3, eq. (i)]. During
the synthesis of 4-hydroxyquinolin-2(1H)-ones the carbonyl and
oxygen both originated from CO2 via the intermediacy of isocyanate
as demonstrated by Yamada et al.13g Thus, a reaction was carried out
in an atmosphere of CO2 using DBU as the base but in the absence
of Cs2CO3 under similar reaction conditions [Scheme 3, eq. (ii)].
Formation of product (1a) in 42% yield suggests that both ethereal
oxygen and the carbonyl groups originate from CO2 (i.e. Cs2CO3).
Scheme 4 Plausible mechanism for Cs2CO3 acting as both carbonyl
and oxygen source.
aReaction conditions: 1934 (0.2 mmol), Cu(OAc)2 (5 mol%), Cs2CO3 (0.8
Based on the above experimental results, a probable reaction
pathway is illustrated in Scheme 4. The process starts with the initial
N-carboxylation with Cs2CO3 to give species (A), which undergo 6-
exo-dig cyclisation that is assisted by Cu/Ag salts giving a cyclic
carbamate intermediate (B). A base mediated ring opening of
mmol, 4 equiv.), Ag2CO3 (0.2 mmol, 1 equiv.), DMSO (3 mL) at 130 oC for
24 h. bIsolated pure product.
To understand the nature of this unprecedented carbonylation-
etherification process and to gain insight into the reaction intermediate (B) gave intermediate isocyanate (C). Intermediate C
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undergo intramolecular cyclisation (CC bond formation) to
generate a 1,3-diketone intermediate (D). Enolisation of (D) to (E)
followed by an intramolecular Ullmann coupling (CO bond
formation) produces benzofuro[3,2-c]quinolin-6(5H)-one (1a)
(Scheme 4). Formations of intermediates (B), (C), (D) and (E) in the
reaction have been detected by HRMS analysis of the reaction
mixture at various time intervals (See ESI†).
In conclusion, we have developed a novel protocol for the
synthesis of benzofuro[3,2-c]quinolin-6(5H)-one derivatives
catalysed by Cu(II). Concomitant installation of three types of bonds
viz. two CO and one each of CC and CN achieved in a tandem
process. In this carbonylation-etherification cascade process both
carbonyl and ethereal oxygen originates from Cs2CO3.
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B. K. P acknowledges the support of this research by the
Department of Science and Technology (DST) (SB/S1/OC-53/2013),
New Delhi, the Council of Scientific and Industrial Research (CSIR)
(02(0096)/12/EMR-II) and MHRD: 5-5/2014-TS-VII. W.A. and
A.M. thank CSIR for fellowships.
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4
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Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C6OB01029F
Cs2CO3 as source of carbonyl and ethereal oxygen in Cu-catalysed cascade synthesis
of benzofuran [3,2-c] quinolin[5-H]ones
Wajid Ali, Anju Modi, Ahalya Behera, Prakash Ranjan Mohanta and Bhisma K. Patel*
Simultaneous construction of C−C, C−O, and C−N bonds utilizing Cs2CO3 as the source of both carbonyl (CO) and ethereal oxygen; a cascade
synthesis of benzofuro[3,2-c]quinolin-6(5H)-one has been achieved using a combination of Cu(OAc)2 and Ag2CO3. A plausible mechanism
has been proposed for this unprecedented transformation.