Na2S·9H2O mediated facile synthesis of 1,3-dihydrofuro[3,4-b]quinoline derivatives via domino reduction approach

Article abstract of DOI:10.1016/j.tet.2021.132447

A simple, highly efficient method for synthesis of 1,3-dihydrofuro[3,4-b]quinoline is described by the reaction of o-arylalkynyl quinoline aldehydes with Na₂S·9H₂O via domino reduction approach. The method is simple and proceeds under mild condition under an air atmosphere to give 1,3-dihydrofuro[3,4-b]quinoline in good to excellent yields. The beauty of the reaction is cyclization as well as reduction has been taken place in the same reaction pot. Also the conversion of aldehyde into primary alcohol has been discussed under the same reaction condition.

Full text of DOI:10.1016/j.tet.2021.132447

Tetrahedron xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Na2S$9H2O mediated facile synthesis of 1,3-dihydrofuro[3,4-b]
quinoline derivatives via domino reduction approach
,
**
Rashmi Singh a, Tanu Gupta b, Vishal Prasad Sharma a, Radhey M. Singh a
,
,
*
Ashish Kumar Tewari a
a Department of Chemistry, Centre of Advanced Study, Institute of Science, Banaras Hindu University, Varanasi, India
b Department of Chemistry, Rajendra College, Jai Prakash University, Chapra, Bihar, 841301, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple, highly efficient method for synthesis of 1,3-dihydrofuro[3,4-b]quinoline is described by the
reaction of o-arylalkynyl quinoline aldehydes with Na2S$9H2O via domino reduction approach. The
method is simple and proceeds under mild condition under an air atmosphere to give 1,3-dihydrofuro
[3,4-b]quinoline in good to excellent yields. The beauty of the reaction is cyclization as well as reduc-
tion has been taken place in the same reaction pot. Also the conversion of aldehyde into primary alcohol
has been discussed under the same reaction condition.
Received 9 May 2021
Received in revised form
24 August 2021
Accepted 8 September 2021
Available online xxx
© 2021 Published by Elsevier Ltd.
Keywords:
Organic synthesis
Heterocycles
Furoquinoline
Na2S$9H2O
Primary alcohol
1. Introduction
triggered by transition metal catalyst [6] such as Pd(II), Cu(I), Zn(II),
Au(III), Ag(I), W, Pt, Ru along with nucleophile such as ROH, NaOH
Oxygen annulated heterocycles, particularly furoquinoline, are
privileged class of skeletons present in bioactive alkaloids of
Rutaceae family [1]. This structural design is a ubiquitous core
structure of a large number of pharmaceutical agents such as Dic-
tamnine, Skimmianine, Aegelbine-A, Aegelbine-B and Dutadrupine
etc. (Fig. 1) [2] which are gifted with broad range of biological ac-
tivities such as anticancer, anticoagulant, anti platelet, antimalarial,
anti-inflammatory, antifungal, and antidiuretic [3]. A number of
novel furo[2,3-b]quinoline derivatives were designed and synthe-
sized from o-alkynyl-aromatic and heteroaromatic aldehydes, ke-
tones, alkynols and o-alkynylquinoline MBH (Morita-Baylis-
Hilman) adducts [4]. Among them, o-alkynyl aldehyde has emerged
as valuable synthon for the synthesis of furoquinoline due to the
presence of dual functional group in close proximity [5]. There are
two general strategies for the synthesis of furoquinoline from o-
alkynyl aldehyde reported in literature. One of this strategy,
or RSiMe3 and non metal catalyst [7] such as I2, ICl, NBS and BF4 via
intramolecular cyclization because of their ability to activate
p
electron system of alkyne act as primary electrophiles and another
functional group is set as the secondary electrophilic partner.
As our continued interest of exploring the reactivity and syn-
thetic applications of 2-chloroquinolinyl-3-carboxaldehydes [8],
we have synthesized number of quinoline annulated heterocyclic
compounds. In continuation to it, in our lab, Mishra et al. reported
synthesis of 1-trifluoromethyl-3-alkylidene-1,3-dihydrofuro[3,4-b]
quinolines from the reaction of o-arylalkynyl quinoline aldehydes
with trifluoromethyl trimethyl silane act as nucleophile using TBAB
as catalyst (Fig. 2a) [8b] and Kumar et al. reported synthesis of furo-
annulated quinoline from the reaction of o-ethynyl quinoline-3-
carbaldehydes with alcohol act as nucleophiles in presence of CuI
as a catalyst (Fig. 2b) [8a]. Further, here we are reporting the syn-
thesis of 3-benzylidene-1,3-dihydrofuro[3,4-b]quinoline by the
reaction of o-arylalkynyl quinoline aldehydes with Na2S$9H2O via
reduction of aldehyde within the same reaction pot at room tem-
perature in good to excellent yield (Fig. 2c). Where sodium sulphide
nonahydrate (Na2S$9H2O) used is an inexpensive and safe reducing
agent, which is previously reported for the reduction of aromatic
nitro group to the corresponding anilines and conversion of alkyne
* Corresponding author.
** Corresponding author.
E-mail addresses: rmohan@bhu.ac.in (R.M. Singh), ashishtewarichem@gmail.
com (A.K. Tewari).
https://doi.org/10.1016/j.tet.2021.132447
0040-4020/© 2021 Published by Elsevier Ltd.
Please cite this article as: R. Singh, T. Gupta, V.P. Sharma et al., Na2S$9H2O mediated facile synthesis of 1,3-dihydrofuro[3,4-b]quinoline
derivatives via domino reduction approach, Tetrahedron, https://doi.org/10.1016/j.tet.2021.132447

R. Singh, T. Gupta, V.P. Sharma et al.
Tetrahedron xxx (xxxx) xxx
absence of benzyl chloride, reaction was completed in 0.5 h and
isolated product was new and characterized as 1,3-dihydrofuro[3,4-
b]quinoline 2a in 50% yield which is also further confirmed by
crystal structure of 2j [9]. Inspired by these results, we focused on
finding the optimal conditions for getting better yield of 2a.
Lowering the reaction temperature to 50 ꢀC led to the isolation of
product 2a after 1 h with an improved yield of 59% (Table 1, Entry
2). When the transformation was carried out at room temperature,
reaction was completed in 2.5 h with yield of 2a increased to 70%
(Table 1, Entry 3). The subsequent reactions were conducted at
room temperature in the absence of ligand, but timing and yield
both are unaffected (Table 1, Entry 4). Next we explored the reac-
tion in absence of catalyst, the reaction time and yield were unaf-
fected (Table 1, Entry 5). Then, reaction was explored with different
equiv. Of Na2S$9H2O and with different solvents to achieve the best
yield of 2a. On using one equiv. Of Na2S$9H2O, reaction was
completed in 3 h and yield was decreased to 40% (Table 1, Entry 6).
On increasing equiv. Of Na2S$9H2O to 3 equiv., reaction was
completed in 2.5 h with better yield to 78% (Table 1, Entry 7).
Further increasing the equiv. Of Na2S$9H2O to 4 equiv. Led to
decreasing of yield to 50% (Table 1, Entry 8). Then reaction was
further screened with different solvents such as DMSO, methanol,
acetonitrile and THF with 3 equiv. Of Na2S$9H2O (Table 1, Entries
9e12) and it was found that none of these solvents gave better
results that those obtained in DMF (Table 1, Entry 7). Thus, the
combination of 0.5 mmol of 1a along with 3 equiv. Of Na2S$9H2O in
2 mL of DMF at room temperature was determined as the optimal
reaction conditions to afford 2a in best yield.
Fig. 1. Biologically active core of furo-quinoline.
With the best optimized reaction condition in hand, varieties of
furofused quinoline were synthesized. Several electron-
withdrawing groups (EWGs) and electron-donating groups
(EDGs) at the quinoline ring as well as at the phenyl ring of the
alkynyl part of substrate 1 were studied, and the results are sum-
marized in Table 2. Similarly, o-Arylalkynylquinoline that contain
different groups such as 6-Me, 7-Me, 8-Me, 6-OMe, 7-OMe, 8-OMe,
8-Et on the quinoline moiety subjected to optimized reaction
condition and gave respective product i.e. furofused quinoline de-
rivatives 2be2h in good to better yield (72e86% yield). o-Ary-
lalkynylquinoline aldehydes that contain EDG such as 3-Me, 4-Me,
Fig. 2. Previous work and current work.
into the alkene [6].
2. Results and discussion
Initially, we reported the Pd-catalyzed facile synthesis of
cyclopenta[b]-quinolin-1-one by using of Pd(OAc)2, 5 mol% of Ph3P,
2 equiv. Of Na2S$9H2O and benzyl chloride in DMF at 80 ꢀC [8c].
When we explored same reaction condition (Table 1, Entry 1) in
Table 1
Optimization of Reaction condition.
.
Entry
Catalyst (mol%)
Ligand (mol%)
Na2S$9H2O
Temp. (0C)
Solvent
Time (h)
Yield (%)
1.
2.
3.
4.
5.
6.
7.
8.
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
e
e
e
e
e
e
e
e
Ph3P (10)
Ph3P (10)
Ph3P (10)
2 Equiv
2 Equiv
2 Equiv
2 Equiv
2 Equiv
1 Equiv
3 Equiv
4 Equiv
3 Equiv
3 Equiv
3 Equiv
3 Equiv
80
50
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
Methanol
ACN
0.5
1.0
2.5
2.5
2.5
3.0
2.5
2.5
3.0
3.5
3.5
3.0
50
59
70
70
70
40
78
50
60
49
35
44
e
e
e
e
e
e
e
e
e
9.
10.
11.
12
THF
2

R. Singh, T. Gupta, V.P. Sharma et al.
Tetrahedron xxx (xxxx) xxx
Table 2
Substrate Scope for synthesis of 1,3-dihydrofuro[3,4-b]quinoline derivatives..
3

R. Singh, T. Gupta, V.P. Sharma et al.
Tetrahedron xxx (xxxx) xxx
Table 3
Synthesis of Primary Alcohol derivatives.
2-OMe, on alkylphenyl were also gave respective product under
similar reaction condition i.e. furofused quinoline derivatives
2ie2k (83e89%). And those having EWG such as 4-F, also afforded
respective product 2l (70% yield). To generalize the scope of the
reaction, alkynylaryl moiety of the substrate was replaced with
alkynylheteroaryl moiety such as 2-thienyl, this substrate was
subjected to the optimization reaction condition and afforded the
corresponding products in good yields (2m, 75%). Substrates
bearing substituents at both quinoline and alkyne moieties of
substrate 2 were also applied under the optimized reaction con-
ditions. EDG on both moieties of substrate 2 gave very good yield of
products (2n, 82% and 2o, 84%). The scope of the reaction was also
examined with phenyl substituted pyridine under optimized con-
ditions, and good yield of the product (2p, 78%) was obtained
(Table 2).
After discussing the plausible mechanism for the formation of
product, it was presumed that synthesis of 1,3-dihydrofuro[3,4-b]
quinoline was taken place through the formation of primary
alcohol. For confirming the formation of primary alcohol, next we
focused our attention at the conversion of aldehyde 3 into primary
alcohol 4 on using the same reaction condition (Table 3), we got the
respective product 4a in 96% and 4b in 94% yield. On applying the
same reaction condition on pyridine derivative also gave the
respective product 4c in 88% yield.
All reactions were carried out on 0.5 mmol scale of 3 using 3.0
equiv. Na2S.9H2O in DMF solvent (2 mL) at room temperature.
Reaction times and yields of isolated products are given.
3. Conclusions
All reactions were carried out on 0.5 mmol scale of 1 using 3.0
equiv. Na2S.9H2O in DMF solvent (2 mL) at room temperature.
Reaction times and yields of isolated products are given.
It is found that on using sodium sulphide nonahydrate
(Na2S$9H2O), sulphide ion attack on electrophilic carbon of alde-
hydic group and tends to form intermediate A which further react
with environmental oxygen and forms the intermediate B which
further undergo the release of sulphur oxide and take the proton
from hydrated reagent i. e. Na2S$9H2O and form the intermediate C
having aryloxy ion which attack on triple bond and form the in-
termediate D which take the hydrogen ion and tends to formation
of final product i. e. 1,3-dihydrofuro[3,4-b]quinoline.
In conclusion, we have developed one-pot, mild reaction con-
ditions for the synthesis of 1,3-dihydrofuro[3,4-b]quinoline by the
reaction of o-arylalkynyl quionoline-aldehydes with Na2S$9H2O at
room temperature through the formation of primary alcohol within
the same reaction pot at room temperature in good to better yield.
The protocol avoids the use of metal and is very safe and
convenient.
Declaration of competing interest
The authors declare the following financial interests/personal
relationships which may be considered as potential competing
interests: Dr. Ashish Tewari reports financial support was provided
by DST-SERB.
Plausible Mechanism for synthesis of 1,3-dihydrofuro[3,4-b]
quinoline:
Acknowledgements
The author gratefully acknowledges the DST-SERB, New Delhi
for a fellowship. TG is thankful to Jai Prakash University, Chapra,
Bihar. VPS is thankful to CSIR, New Delhi for JRF and SRF. We are
thankful to DST-SERB project EMR/2016/000706 for funding.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2021.132447.
4

R. Singh, T. Gupta, V.P. Sharma et al.
Tetrahedron xxx (xxxx) xxx
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