A green approach for highly regioselective syntheses of furo[3,2-h]quinolines in aqueous medium

Article abstract of DOI:10.1016/j.tetlet.2013.05.038

An environmentally benign, high yielding, and operationally simple protocol has been developed for the regioselective synthesis of furo[3,2-h]quinolines in aqueous micellar medium involving Cu-free domino Sonogashira reaction followed by 5-endo-dig-cyclization of substituted 8-hydroxyquinolines and terminal alkyne by using Pd(C₆H₅CN)Cl₂ as catalyst and 2-pyridinecarboxaldehyde methylphenyl hydrazone as ligand under aerobic condition.

Full text of DOI:10.1016/j.tetlet.2013.05.038

Accepted Manuscript
A green approach for highly regioselective syntheses of furo[3,2-h]quinolines
in aqueous medium
Swarbhanu Sarkar, Rammyani Pal, Nivedita Chatterjee, Samrat Dutta,
Subhendu Naskar, Asish Kumar Sen
PII:
S0040-4039(13)00795-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.05.038
TETL 42938
Reference:
To appear in:
Tetrahedron Letters
Please cite this article as: Sarkar, S., Pal, R., Chatterjee, N., Dutta, S., Naskar, S., Sen, A.K., A green approach for
highly regioselective syntheses of furo[3,2-h]quinolines in aqueous medium, Tetrahedron Letters (2013), doi: http://
dx.doi.org/10.1016/j.tetlet.2013.05.038
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GRAPHICAL ABSTRACT:
A green approach for highly regioselective syntheses of
furo[3,2-h]quinolines in aqueous medium
Swarbhanu Sarkar, Rammyani Pal, Nivedita Chatterjee,
Samrat Dutta, Subhendu Naskar, Asish Kumar Sen*
Cl
Cl
CH
CH3
Pd(C6H5CN)2Cl2
N
N
N
CTAB, H2O, 80 oC,
Base, Ligand
N
I
N
Ar
O
OH
Ligand
Ph

A green approach for highly regioselective syntheses of furo[3,2-h]quinolines in
aqueous medium
Swarbhanu Sarkar,a Rammyani Pal,a Nivedita Chatterjee,a Samrat Dutta,a Subhendu
Naskar,b Asish Kumar Sena,*
aChemistry Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road,
Jadavpur, Kolkata-700 032, India.
bDepartment of Science & Humanities, Bandwan Government Polytechnic, Madhupur, P.O.- Jitan,
Purulia-723129, West Bengal, India.
*Corresponding author. Fax: +91 33 24735197; Tel: +91 33 24995720.
E-Mail: aksen@iicb.res.in; asishksen@yahoo.com (A. K. Sen)
Abstract:
An environmentally benign, high yielding and operationally simple protocol has been developed for
the regioselective synthesis of furo[3,2-h]quinolines in aqueous micellar medium involving Cu-free
domino Sonogashira reaction followed by 5-endo-dig-cyclization of substituted 8-
hydroxyquinolines and terminal alkyne by using Pd(C6H5CN)Cl2 as catalyst and 2-
pyridinecarboxaldehyde methylphenyl hydrazone as ligand under aerobic condition.
Keywords: Furo[3,2-h]quinolines; Micelle; Reaction in water; Cu-free Sonogashira; 5-Exo-dig
cyclization; One-pot
In recent years substantial interest has been perceived among the scientists to execute organic
reactions in aqueous media1 that leads to environmentally benign chemical processes.2 But the
hydrophobicity of maximum organic compounds is in fact a thwart for the execution of these
reactions in aqueous environment. Introduction of aqueous surfactants, in the form of micelles, as
the reaction medium endowed a way around this limitation.3 In micellar catalysis, the surfactant
micelles accumulate reacting molecules within its small volume. The high concentration of
reactants with different orientations, often influence reaction mechanism and thus remarkable
differences with respect to reaction rate and selectivity has been observed compared to
homogeneous catalysis.4
Furoquinoline scaffold are present in many biologically and pharmacologically important
molecules5 and in the core structure of several natural products.6 These varied biological profiles
have attracted attentions of organic chemists for a long time and a number of synthetic

methodologies have been developed for this system.7 However, most of the methods have
drawbacks like involvement of multistep process, longer reaction time and use of hazardous
chemicals/solvents etc. Moreover, 7-iodo-8-hydroxy-quinolines and terminal aryl acetylenes if
employed as precursors under Pd/Cu catalysis, probability for the formation of acyclic Sonogashira-
product cannot be neglected. The use of copper may also introduce Glaser-type homocoupling
product.8
The Sonogashira reaction of terminal acetylenes with aryl or vinyl halides has been proved to be a
powerful technique for C-C bond formation and has found wide applications in diverse areas such
as natural product synthesis and material science.9 A typical procedure requires utilization of
catalytic palladium with another metal salt as co-catalyst and a base under inert condition.10
Recently, palladium(II) salts, such as, Pd(dba)4, Pd(dtbpf)Cl2, PdCl2(PPh3)2, having bidentate N,N-
or N,P- ligands were used as efficient catalyst for this heteroannulation reaction but still required
amines as solvents or as co-solvents with CuI as co-catalyst.11 In general, palladium-mediated
reactions are highly sensitive to moisture, but methods utilizing water as reaction medium have also
been demonstrated.12 However, these reactions require higher amount of palladium or elevated
reaction temperature. Copper-free Sonogashira cross coupling reactions, using combination of at
least one phosphine ligand or an amine with tetra-butyl ammonium salts as activators appears to be
a suitable alternative.13 Similar reactions have also been carried out both in organic solvents or in
aqueous medium.14
We have developed a fast, efficient yet simple and green protocol which eliminates the use of
copper salts, phosphine ligands and also do not require quaternary ammonium salts as activators.
The method allows domino Sonogashira-cyclization of o-bromo or o-iodo-hydroxy-quinolines and
terminal alkynes using 2-pyridinecarboxaldehyde methylphenyl hydrazone (1i) as ligand (Figure 1)
in aqueous micellar medium under aerobic condition. Organic solvents are required only during
column chromatography. Additionally, since copper salts are not involved in our protocol, copper-
mediated oxidative homocoupling of acetylene can also be avoided. A library of furoquinolines
could thus be synthesized in high yield and in short reaction time. The uniqueness of the
methodology lies in its eco-friendly operation, short reaction time and excellent yield.

N
N
N
H
H
N
N
N
N N
N N
N
N
CH3
R
H3C
1e
1a
R = H
1d
1b R = Cl
1c R = OCH3
R
N
CH3
N N
N N
N
N
N N
N
1f
1g R = H
1h
1i
R = CH3
Figure 1. Ligands used in the study.
We envisaged 5-chloro-8-hydroxy-7-iodo-substituted quinolines and terminal alkynes to endow
substituted aryl and alkyl acetylenes that could subsequently be used in a one-pot, two-step
synthesis of furoquinoline (Scheme 1). We selected 7-iodo-8-hydroxyquinoline derivative (2a) and
phenylethyne (3a) as model reactants for the synthesis of 2-phenylfuro[3,2-h]quinoline (4a) and
evaluated the feasibility of a copper-free Sonogashira coupling-cycloisomerization domino strategy
in aqueous micellar medium using Pd(C6H5CN)2Cl2 (2 mol%) under aerobic condition. The effect
of different diimine, pyrazolyl-pyrimidine and hydrazone ligands15 (Figure 1) was also investigated
(Table 1). Diimine ligands, 1a-c, yielded fused furoquinolines derivative 4a in 64, 62 and 65%
respectively, showing eventually no effect of electron donating or electron withdrawing groups on
the benzene ring of the ligand. Use of ligand 1d or 1e, however, gave much less yield of 44% or
52% respectively. Similar observation was noted for bishydrazone ligand 1f with seven-membered
ring (found in repetitive experiments). Pyrazolyl-pyrimidine ligand 1g or 1h was not found to be
very effective for the particular reaction whereas introduction of pyridine type hydrazone ligand 1i
led to excellent yield of 91%.

Cl
Cl
Cl
3a, Pd(C6H5CN)2Cl2
N
I
N
Surfactant, H2O, 80 oC,
Base, Ligand
N
O
OH
OH
Ph
Ph
4a
2a
Scheme 1. Synthesis of 4a in aqueous miceller medium.
Table 1. Effect of different ligands
Entrya
Ligands
1a
Concentration (mol %)
4ab (Yield %)
1
2
-
12
64
62
65
44
52
42
51
48
91
82
91
1a
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.0
3.0
3
1b
1c
4
5
1d
1e
6
7
1f
8
1g
1h
1i
9
10
11
12
1i
1i
aAll reactions were performed using 2a (1.0 equiv.) and 3a (1.5 equiv.) in aqueous surfactant
medium (CTAB, 80 mM) at 80 °C for 1 h under aerobic condition and (i-pr)2EtN (2.0 equiv.);
catalyst used Pd(C6H5CN)2Cl2 (2 mol%).
bYield of isolated pure product; some loses during isolation is unavoidable in certain cases.
We also studied the outcomes of the reaction in aqueous solutions of various cationic, anionic and
non-ionic surfactants to examine the role of surfactant solutions (Table 2). Reactions carried out in
the absence of a surfactant remained ineffective even up to 12 h under aerobic condition. A drastic
change in the reaction yield was observed when cetyltrimethylammonium bromide (CTAB, 50 mM,
cmc 0.92 mM)16 was introduced in the system. Carrying out the reaction in water at 80 °C for 1 h
produced lower yield (32%; Table 2, entry 2) of 4a. An increase in the reaction yield was noticed

when surfactant of higher concentration is used. The most prominent result (91%) was obtained
when the reaction was performed using CTAB at 80 mM concentration (Table 2, entry 4); however,
no considerable increase in the product was noticed beyond its 80 mM concentration (Table 2, entry
5). Use of other surfactants resulted in decrease in the product formation. Sodium dodecylsulfate
(SDS: cmc 8.1 mM)17 produced 70% (Table 2, entry 7) where as tetradecyltrimethylammonium
bromide (TTAB: cmc 3.8 mM)18 produced 76% product (Table 2, entry 6) both at 80 mM
concentration. The use of a nonionic surface-active agent such as Triton X-114 (cmc 0.28 mM)19
was found to be less effective compared to CTAB or TTAB (Table 2, entry 8).
The effect of different bases, viz. Et3N, piperidine, tetramethyl piperidine, morpholine, DBU,
DABCO, (i-pr)2EtN, DMAP, K2CO3 and Cs2CO3 was also investigated (Table 3). (i-pr)2EtN
appeared to be the most effective when employed in 2.0 molar equivalent affording the product in
maximum yield (Table 3, entry 11). It is worth mentioning that other Pd-source [PdCl2, Pd(dba)2,
Pd(CH3CN)2Cl2, Pd2(dba)3, Pd(PPh3)4, Na2PdCl4, Pd(dtbpf)Cl2] provided either very poor or no
yield.
Table 2. Effect of different surfactants
Entrya
Surfactant
None
Concentration (mM)
4ab (Yield %)
1
2
3
4
5
6
7
8
-
-
CTAB
60
70
80
90
80
80
80
32
67
91
91
76
70
68
CTAB
CTAB
CTAB
TTAB
SDS
Triton X-114
aAll reactions were performed using 2a (1.0 equiv.) and 3a (1.5 equiv.) in water at 80 °C for 1 h
under aerobic condition and (i-pr)2EtN (2.0 equiv.); catalyst used Pd(C6H5CN)2Cl2 (2 mol%), ligand
1i (2.5 mol%).
bYield of isolated pure product; some loses during isolation is unavoidable in certain cases.

Table 3. Effect of different bases
Entrya
Base
Et3N
Amount (mmol) 4ab (Yield %)
1
1.0
1.0
1.0
1.0
80
74
75
75
2
3
4
piperidine,
tetramethyl piperidine
morpholine
5
6
DBU
DABCO
DMAP
1.0
1.0
1.0
1.0
1.0
1.0
2.0
2.5
82
78
73
72
74
86
91
91
7
8
K2CO3
9
Cs2CO3
10
11
12
(i-pr)2EtN
(i-pr)2EtN
(i-pr)2EtN
aReactions performed using 2a (1.0 equiv.) and 3a (1.5 equiv.) in water at 80 °C for 1 h under
aerobic condition in presence of CTAB (80 mM), Pd(C6H5CN)2Cl2 (2 mol%) and ligand 1i (2.5
mol%).
bYield of isolated pure product; some loses during isolation is unavoidable in certain cases.
To establish the scope and applicability of this protocol, various aryl or heteroaryl alkynes was used
in the study (Table 4). All reactions yielded only 5-endo-cyclized products and no acyclic
Sonogashira product, or product due to 4-exo-dig cycloisomerization was noticed regardless of the
electronic properties of the electrophilic substituents on both quinoline and acetylene compounds.
Another major advantage of the procedure is that no dimerized product, which normally occurs
during heteroannulation reaction, was observed. Moreover, corresponding bromides 2c, which are
less prone to participate in such reaction, gave equal yield in particular reaction condition (Table 4,
entry 11).
The protocol was also found to be equally good for aliphatic alkynes. Compound 4j was formed in
good yield when cyclopropyl acetylene 3j was reacted with quinoline 2a under the same condition
(Table 4, entry 10). It is interesting to note that the same reaction yielded furoquinoline 520 (Scheme
2) when performed with trimethylsilyl acetylene 3k in presence of tetra-butylammonium fluoride
(50 mol%). This may be due to the presence of fluoride ion in the immediate vicinity of the cationic

surfactant and thus acted as desilylating agent.
Table 4. Reactions of 7-halo-8-hydroxyquinolines (2a-c) with terminal alkynes (3a-j) leading to
furoquinolines (4a-k) in aqueous micellar medium
Entry Quinoline
Acetylene
Producta
Yieldb(%) Ref
X1
X1
Y2
Y1
Y1
Y2
Y3
X2
N
Y3
O
N
OH
7a
1
2
3
4
5
6
7
8
2a: X1=Cl, X2=I
3a: Y1=Y2=Y3=H
3b: Y1=Y2=H, Y3=OMe
3c: Y1=Y2=H, Y3=OPh
4a: X1=Cl, Y1=Y2=Y3=H
4b: X1= Cl, Y1=Y2=H, Y3=OMe
4c: X1=Cl, Y1=Y2=H, Y3=OPh
91
89
87
90
91
88
92
87
-
-
2a
2a
2a
2a
2a
2a
3d: Y1=Y2=H, Y3=n-pentyl 4d: X1=Cl, Y1=Y2=H, Y3=n-pentyl
-
3e: Y1=F, Y2=Y3=H
3f: Y2=Cl, Y1=Y3=H
3g: Y1=Y2=H, Y3=NO2
4e: X1=Cl, Y1=F, Y2=Y3=H
4f: X1=Cl, Y2=Cl, Y1=Y3=H
4g: X1=Cl, Y1=Y2=H, Y3=NO2
7a
7a
-
2b: X1=NO2, X2=I 3h: Y1=Y2=Y3=H
4h: X1=NO2, Y1=Y2=Y3=H
7a
Cl
N
N
7a
9
83
52
2a
O
N
3i
4i
Cl
10
-
2a
O
N
3j
4j

2c: X1=Br, X2=Br
89
7a
11
3a
O
N
4k
a
Reactions were performed using 2a-c (10 mmol), alkyne (15 mmol), Pd(C6H5CN)2Cl2 (2 mol%),
ligand 1i (2.5 mol%), (i-pr)2EtN (20 mmol) in water at 80 °C for 1 h under aerobic condition in
presence of CTAB. Products were characterized by spectroscopic and analytical data.
b Isolated yield; some loses during isolation is unavoidable in certain cases.
Cl
2a
Pd-catalysis
N
TBAF, CTAB
SiMe
3
O
3k
5
Scheme 2. Synthesis of disilylated furoquinoline 5.
Sonogashira coupling reaction is generally inefficient when aryl chlorides are used as coupling
partners. The catalytic systems that can perform domino Sonogashira-cyclization more efficiently
with aryl chlorides in short time is still in high demand. We applied our protocol to dichloro
derivative 6 (Scheme 3). Compound 4k and 77a was formed in good yield. However, 10 mol% of
ligand (8) was required to perform these reactions. Increase in the amount of the ligand/catalyst
beyond 10 mol% lead to dechlorination of 6, and thus desired product was obtained in low yield.
Ar
Cl
P(Cy)2
O-iPr
Ar
O
Pri-O
Ar
Pd-catalysis (2 mol%)
CTAB, (i-pr)2EtN
80 oC, 2h
N
Cl
N
OH
iPr
4k Ar = Ph (83 %)
7 Ar = o-Pyridyl (80 %)
6
Ligand 8
(10 mol%)
Scheme 3. Synthesis of disubstituted furoquinolines

In summary, an efficient, economical and environmentally benign process21,22 for the synthesis of
furoquinolines scaffold in aqueous miceller medium has been demonstrated under aerobic
condition. We established that, 2-pyridinecarboxaldehyde methylphenyl hydrazone was useful as
phosphine-free ligand for this protocol. Future work will be focused on probing the role and
reaction mechanism of the ligands used in this study for Sonogashira reaction in aqueous micellar
medium.
Acknowledgment
The authors express their gratitude to the Director, IICB for laboratory facilities, the Council of
Scientific and Industrial Research (CSIR) for providing the funding and fellowships to S.S, R.P,
N.C and S.D.
Supplementary data
13
Supplementary data (1H and C NMR spectra of all new compounds) associated with this article
can be found in the online version, at doi…...
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21. General reaction procedure for the synthesis of furo[3,2-h]quinolines (4a-4k): In an open
round-bottomed flask filled with 50 mL of water, hydroxy quinolines (2a-c, 1.0 equiv.), alkyne
(3a-j, 1.5 equiv.), Pd(C6H5CN)2Cl2 (0.02 equiv.), ligand 1i (0.025 equiv.), (i-pr)2EtN (2.0
equiv.) was stirred vigorously for 1 h at 80 °C with CTAB (4 mmol). When TLC indicated
completion of the reaction, the mixture was extracted with ethyl acetate (4 x 30 mL) and the
organic layer was washed thoroughly with water. The crude mass was purified by column
chromatography using silica gel and petroleum ether: ethyl acetate (4:1) as eluent.
22. Spectral data of 5-Chloro-2-(4-methoxyphenyl)furo[3,2-h]quinoline (4b): White solid (yield:
89%); 1H NMR (DMSO-d6, 600 MHz):  3.84 (s, 3H, OCH3), 7.12 (d, J = 8.7 Hz, 1H), 7.48
(s, 1H), 7.71 (dd, J = 4.3, 8.5 Hz, 1H), 7.96-7.97 (m, 2H), 8.10 (s, 1H), 8.64 (d, J = 8.5 Hz,
13
1H), 9.04-9.05 (m, 1H); C NMR (DMSO-d6, 150 MHz): 55.79, 101.63, 115.13, 121.02,
121.95, 122.38, 123.17, 125.46, 126.96, 129.01, 133.74, 136.48, 147.77, 151.57, 157.52,

160.57; HRMS (ESI): m/z calcd for C18H12O2NCl [M+H]+310.0635; found: 310.0622.