Cu(I)-catalyzed oxygen and nitrogen nucleophiles triggered regioselective synthesis of furo/pyrrolo-annulated quinolines

Article abstract of DOI:10.1021/acs.joc.9b00662

Cu(I)-catalyzed intramolecular annulation of o-ethynylquinoline-3-carbaldehydes leads to the synthesis of alkoxy/imidazole-substituted 1,3-dihydrofuro[3,4-b]quinolines via C-O and C-N bond formation. The scope of the reaction was further extended to o-eth

Full text of DOI:10.1021/acs.joc.9b00662

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Article
Cu(I)-Catalyzed Oxygen and Nitrogen Nucleophiles Triggered
Regioselective Synthesis of Furo/Pyrrolo Annulated-Quinolines
Ritush Kumar, Atish Chandra, Bilal Ahmad Mir, and Gaurav Shukla
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00662 • Publication Date (Web): 07 Aug 2019
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Cu(I)-Catalyzed Oxygen and Nitrogen Nucleophiles Triggered Regioselective
Synthesis of Furo/Pyrrolo Annulated-Quinolines
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8
9
Ritush Kumar,*a Atish Chandra,b Bilal Ahmad Mir,a Gaurav Shuklaa
aDepartment of Chemistry, Indian Institute of Technology Guwahati, Guwahati-781039, India
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bCentre of Biomedical Research, SGPGI Campus, Raibarely Road, Lucknow, Uttar Pradesh-226014
India
OR"
R"OH
O
R
Et3N
N
OR"
N
R'
N
CuI (2.5 %)
Ph3P (5 %)
CuI (2.5 %)
Ph3P (5 %)
FG
28 examples
R
R
FG = CHO
R'
N
N
K2CO3 , R"OH
FG = CN
N
R'
16 examples
N
N
H
5-exo-dig cyclization
O
C-O and C-N bond formation
Broad substrate scope
Good to excellent yields
Step economical reaction condition
R
t-BuOK
N
R'
9 examples
ABSTRACT
A Cu(I)-catalyzed intramolecular annulation of o-ethynylquinoline-3-carbaldehydes leads to
the synthesis of alkoxy/imidazole substituted 1,3-dihydrofuro[3,4-b]quinolines via C-O and
C-N bond formation. The scope of the reaction was further extended to o-ethynylquinoline-
3-carbonitriles for the synthesis of alkoxy substituted 3H-pyrrolo[3,4-b]quinolines using
alcohols as nucleophiles. These reactions are regioselectively favouring the 5-exo-dig
cyclizations in all the annulations processes.
INTRODUCTION
Transition metal-catalyzed reactions are powerful tool in organic synthesis for the
construction of various carbocycles and heterocyles.1 Among them metal-catalyzed
activation of alkynes2 has been an effective strategy for various bond forming and bond
breaking processes. One of the aspects of this chemistry is annulation reactions via the
intramolecular attack of appropriate nucleophiles onto alkynes.3 With the turn of century,
scope and utility of these reactions have seen further exploration with the introduction of
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dual electrophilic site skeletons using metal catalysis (Figure 1). These reactions are initiated
via nucleometalation of alkynes and quenched by 1,2-addition to carbon-heteroatom
multiple bonds for the synthesis of various carbocyles and heterocycles. In these
intramolecular reactions, the nucleophiles first attack at the metal-activated carbon-carbon
triple bond followed by the addition to carbon-heteroatom multiple bonds to form various
cyclized products (Figure 1, path a).4 In these type of annulation, the course of reaction
follows as same trend where alkynes acting as the primary electrophile and other
electrophile set as the secondary electrophile partner.
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XH
path a
X
R'
M
Nu
R'
Nu
Nu
X
Nu
M
path b
R
X
and/or
Nu
R
X
X = O, N
R
Figure 1. Modes of Annulations of ortho-Functionalized Alkyne using Nucleophile under
Metal catalysis.
However, an alternate path for the reaction is also delineated in the literature. The
carbon-carbon triple bonds of ortho functionalized acetylenic aldehydes/nitriles can be
activated by transition metals which undergo facile intramolecular attack by the first
electrophilic partner (i.e. aldehyde oxygen or nitrile nitrogen) triggered by a nucleophile
(oxygen, nitrogen, sulphur etc) (Figure 1, path b).5 Previously, The group of Yamamoto
reported an elegant and efficient Pd-catalyzed intramolecular cyclization of acetylenic
aldehydes using alcohols as the nucleophiles.6 Li et al. have also reported the gold catalysed
synthesis of 1-alkynyl-1H-isochromenes from ortho-alkynylarylaldehyde using terminal
alkynes as the nucleophile via a cascade addition/cyclization reactions.7 Singh et al. have
reported
a
Pd-catalyzed
synthesis
of
pyrano[4,3-b]quinolines
and
benzo[b][1,6]naphthyridines from ortho-ethynylquinoline-3-carbaldehydes/carbonitriles
using alcohols as nucleophiles (Scheme 1A).8 These reactions are generally reported via 6-
endo dig cyclization mode. However, Han et al. have described a Pd-catalyzed dihydro
isobenzofurans synthesis from ortho-electron-deficient alkynylarylaldehydes using
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carboxylic acid as the nucleophile via 5-exo dig cyclization.9 Most of the reported reactions
uses palladium10 and other expensive metals such as gold,7,11 rhodium,12 ruthenium13,
indium,14 cobalt15 and silver.16 However, copper catalysed synthesis of heterocycles using
nucleophiles are extremely rare.17 Previously, Patil et al. have been reported the synthesis
of isochromenes from o-alkynylbenzaldehydes via 6-endo dig cyclization using copper as
catalyst and alcohols as nucleophiles (Scheme 1B).18
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Scheme 1. Previous strategy of nucleophilic cyclization reactions
(A) Previous Work on 2-Ethynylquinoline-3-Carbaldehyde/Carbonitrile
OR"
O
Pd(OAc)2
PPh3
FG
N
N
R'
R'
R
R
OR"
N
N
R''OH
R
R'
FG = CHO, CN
(B) Patil's work
OR"
CHO
CuI (10 mol %)
O
DMF, R"OH
70 °C
R'
R
R
R'
(C) This work
OR"
O
R"OH
Et3N
R
N
R'
FG = CHO
N
N
N
CuI (2.5 %)
Ph3P (5 %)
FG
N
H
R
O
R
t-BuOK
N
N
R'
R'
FG = CHO, CN
OR"
N
FG = CN
R"OH
K2CO3
R
N
R'
Oxygen and nitrogen annulated polyheterocycles particularly furo/pyrrolo annulated
quinolines have drawn much attention due to their ubiquitous core structure, present in
numerous biologically active natural products and pharmaceutically important compounds,
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respectively (Figure 2).19, 20 The furoquinoline structural units present in bioactive alkaloids
of Rutaceae family. Some of known linearly fused natural occurring furoquinoline alkaloids
are 2-Acetylevolitrine (i) and Dictamnine (ii) represent the antimicrobial and mutagenic
activities, respectively. Further, furo[3,4-b]quinolin-8(5H)-one (iii) shows the antineoplastic
and anticancer activities. Next, pyrroloquinoline are present in numerous alkaloids such as
Camptothecin (iv), Lutonin A (v) and Mappicine (vi). In addition, these heterocyclic
compounds have also possessed a broad spectrum of biological activities such as antitumor,
anticancer, anti-proliferative, antiviral, antimicrobial, hypertensive, anti-inflammatory and
serotonergic.21, 22
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OH
H3CO
OCH3
OMe
N
OMe
O
R1
R2
R1
R2
O
O
O
O
O
O
N
N
R3
H
(i)
(ii)
(iii)
2-Acetylevolitrine (a): R1 = H; R2 = OMe
2-Acetylpteleine (b): R1 = OMe; R2 = H
Confusameline (a): R1 = R3 = H; R2 = OH
Antineoplastic and
anticancer agent
Dictamnine (b): R1 = R2 = R3 = H
O
N
O
N
O
N
N
N
N
N
O
(v)
H
(vi)
(iv)
HO
Camptothecin
Mappicine
Lutonin A
O
HO
Figure 2. Representative Examples of Furo/Pyrrolo Annulated-Quinolines Containing Natural
Products
Further, our own interest in this type of annulations reaction4a, 9,10a has prompted us
to investigate a boisterous catalytic system, which can tolerate terminal alkynes, for the
synthesis of heterocycles. These methods generally afford 6-endo-dig cyclized products
depending upon the reaction conditions and the type of substituent on the substrates.23
However, the best of our knowledge, there are only one previous report available of
alkoxy/imidazole-substituted furo/pyrrolo-annulated quinolines till date.23f Thus, herein we
report a novel, efficient and economic method for the synthesis of furo/pyrrolo annulated
quinolines
from
ortho-ethynylquinoline-3-carbaldehydes/carbonitriles
and
alcohol/imidazole as nucleophiles using CuI as the catalyst (Scheme 1C).
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RESULTS AND DISCUSSION
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Initially, 2-phenylethynylquinoline-3-carbaldehyde (1) was chosen as the model
substrate which can be easily obtained by Sonogashira coupling reaction of 2-
chloroquinoline-3-carbaldehyde.24 Thus, 2-phenylethynylquinoline-3-carbaldehyde (1) (0.20
mmol) was treated with 5 mol % of CuI using methanol as nucleophile and solvent both at
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o
80 C under an air atmosphere. The reaction did not proceed even after 12 h and the
starting material was recovered (Table 1, entry 1). However, adding 2 equiv of Et3N with
identical reaction condition promoted the intramolecular cyclization and completing the
reaction within 4 h (Table 1, entry 2). The isolated product was afforded in 79 % yield and
characterized to be 3-benzylidene-1-methoxy-1,3-dihydrofuro[3,4-b]quinoline (1a) from
various spectral analysis such as NMR, HRMS and was furthermore unambiguously
confirmed by single-crystal X-ray analysis (Figure S1, see in supporting information).
Interestingly, the use of Ph3P (10 mol %) as ligand to the above reaction condition, the
reaction was not only completed in 2 h but the yield also improved upto 91 % (Table 1, entry
3).
Table1. Optimization of Reaction Conditions for Intramoecular Cylcizationa
OMe
CHO
Catalyst, Ligand
O
Base , Solvent, 80 oC
N
N
Ph
Ph
1)
1a
)
(
(
entry
catalyst
(mol %)
CuI (5)
ligand
(mol %)
-
base
(equiv)
-
time
(h)
12
yield
(%)b
Nr
1
2
CuI (5)
CuI (5)
-
Et3N (2)
Et3N (2)
Et3N (2)
Et3N (2)
Et3N (2)
Et3N (2)
4
2
2
6
2
2
79
91
3
Ph3P (10)
Ph3P (5)
Ph3P (2)
Ph3P (5)
Ph3P (5)
4
CuI (2.5)
CuI (1)
95
5
43
6d
7e
CuI (2.5)
CuI (2.5)
Trace
85
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8f
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CuI (2.5)
CuBr (2.5)
CuCl (2.5)
CuCl2 (2.5)
Ph3P (5)
Ph3P (5)
Ph3P (5)
Ph3P (5)
Ph3P (5)
Et3N (2)
Et3N (2)
Et3N (2)
Et3N (2)
Et3N (2)
2
4
5
3
5
64
80
70
55
65
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Cu(OTf)2
(2.5)
13
14
15
CuI (2.5)
CuI (2.5)
CuI (2.5)
Cy3P (5)
Et3N (2)
Et3N (2)
Et3N (2)
3
67
54
69
BINAP (5)
1.5
2.5
1, 10
Phen. (5)
16
17
18
19
20
CuI (2.5) TMEDA (5)
Et3N (2)
3.5
2
47
73
87
93
81
CuI (2.5)
CuI (2.5)
CuI (2.5)
CuI (2.5)
Ph3P (5) DABCO (2)
Ph3P (5)
Ph3P (5)
Ph3P (5)
Cs2CO3 (2)
K2CO3 (2)
K3PO4 (2)
2
2
2
aAll reactions were carried out using 0.20 mmol of 1. b Isolated yield.
cNr = no reaction Reaction at room temp. eReaction at 60 °C. Reaction at 100 °C.
d
f
Encouraged by this result, we next considered finding optimal reaction conditions by
varying catalysts, ligands, base and temperature for the best yield of (1a). On decreasing the
catalyst and ligand loading to 2.5 mol % and 5 mol % respectively, surprisingly the yield of
(1a) was enhanced to 95% yield (entry 4). The yield of product (1a) (43%) was decreased
when catalyst and ligand loading was further reduced to 1 mol % and 2 mol % respectively
(entry 5). Performing the reactions at room temperature (trace), lower (60 °C) (85%) or
higher (100 °C) (64%) temperature was detrimental to product formation (entries 6, 7 and
8). Other Cu(I) and Cu(II) catalysts such as CuBr (80%), CuCl (70%) CuCl2 (55%) and Cu(OTf)2
(65%) (entries 9-12) were also found less effective as compared to CuI (95%) catalyst (entry
4). Monodentate ligand Cy3P (67%), bidentate ligand BINAP (54%) and nitrogen based
ligands 1,10 phenanthroline (69%), TMEDA (47%) (entries 13-16) were found to be less
effective than PPh3 (95%) (entry 4). With CuI as the suitable catalyst and Ph3P as ligand,
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other organic (DABCO) and inorganic (Cs2CO3, K2CO3 and K3PO4) bases were screened. The
organic base DABCO (73%) (Table 1, entry 17) gave a yield lower than that of Et3N. No
encouraging results could be obtained using inorganic bases such as Cs2CO3 (87%) and K3PO4
(81%) (Table 1, entries 18, 20). However, the use of K2CO3 was found almost equally
effective (Table 1, entry 19) to that of Et3N (Table 1, entry 4). Thus, the combination of 2-
phenylethynylquinoline-3-carbaldehyde (1) (0.2 mmol) with 2.5 mol % CuI, 5 mol % Ph3P, 2
equiv Et3N in methanol as solvent cum nucleophile at 80 °C under air atmosphere is the best
optimal reaction condition providing the best yield (95%) of 3-benzylidene-1-methoxy-1,3-
dihydrofuro[3,4-b]quinoline (1a) (entry 4).
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With these promising findings in hand, we next explored the scope of the annulation
to construction furo-annulated quinolines with a variety of substituted substrate 2-
ethynylquinoline-3-carbaldehydes (1) under the optimal reaction condition (Table 2). The
substrate (1) having different substituents on phenylacetylene ring such as 3-Me (2), 4-Me
(3), 4-tBu (4), 2-MeO (5), 4-MeO (6), 3-Cl (7), 3-F (8), 4-F (9) and all (2a-9a) proceeded
smoothly giving annulated products in 1–4 h. The corresponding annulated products 2a-9a
were obtained in yield ranging (84-93%). No significant variations in the product yields were
found with phenylacetylene ring bearing either electron-donating (2a, 92%; 3a, 92%; 4a,
87%; 5a, 91%; 6a, 93%) or electron withdrawing groups (7a, 84%; 8a, 89%; 9a, 91%;).
However, the rate of reaction in electron withdrawing group is faster than electron donating
group (Table 2, etntry 2-9). Furhter, this observation has been supported by controlled
experiment on substrate bearing p-dimethyl amino group at phenyl acetylene moiety (a
strong electron donating group) afforded the cyclized product in 3 hours (27aa, 89%).
However, in presence of strong electron withdraing group p-nitro at phenyl acetylene
moiety, reaction proceeded very fast ( 15 min) with inseperable mixture of products.25
Similarly, heterocyclic alkyne such as 3-ethynylthiophene (10) afforded the cyclized product
(10a) in 88% yield. The reaction with alkyl acetylenes such as oct-1-yne failed to provide the
cyclized product (11a), as a complex TLC was observed.
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Table 2. Reaction Scope for the Synthesis of 1,3-Dihydrofuro[3,4-b]quinolinesa
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8
OR'
O
CuI (2.5%)
Ph3P (5%)
O
R
R
Et3N (2 equiv)
R'OH, 80 oC, 1-7 h
N
N
9
1-27
R'
1a-27a
)
(
)
(
R'
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OCH3
OCH3
O
OCH3
O
OCH3
O
O
N
N
N
N
CH3
4a
(
, 87 %), 3 h
OCH3
3a
(
, 92 %), 3 h
OCH3
2a
(
, 92 %), 3 h
OCH3
1a
5a
(
, 95 %), 2 h
CH3
OCH3
O
O
O
O
OCH3
N
N
N
N
F
Cl
8a
(
, 89%), 1 h
7a
(
, 84 %), 1 h
OCH3
(
, 91 %), 4 h
OCH3
6a
(
, 93 %), 4 h
OCH3
OCH3
OCH3
O
H3C
O
O
O
N
N
N
N
C6H13
, 00 %), 12 h
10a
9a
(
, 88 %), 2 h
OCH3
11a
12a
(
(
, 91 %), 1 h
(
, 90 %), 3 h
OCH3
S
F
OCH3
OCH3
O
O
H3C
O
O
O
H3C
N
O
N
N
H3C
N
CH3
15a
(
, 91 %), 4 h
O
13a
14a
(
, 89 %), 3 h
(
, 83 %), 3 h
16a
(
, 89 %), 4 h
O
OCH3
O
OCH3
CH3
CH3
Ph
O
O
O
N
Cl
N
N
N
20a
(
, 79 %), 6 h
O
19a
18a
(
, 86 %), 4 h
O
(
, 90 %), 3 h
17a
(
, 87 %), 1 h
CH3
CH3
O
O
O
O
O
O
N
N
N
N
21a
(
, 81 %), 6 h
O
24a
(
, 83%), 3 h
O
22a
(
, 00%), 12 h
OCH2CF3
23a
(
, 87 %), 2 h
O
CF3
CF3
O
O
O
O
N
N
N
N
N
27a
(
, 83 %), 7 h
26a
(
, 87 %), 4 h
27aa
25a
(
, 89 %), 3 h
(
, 77 %), 5 h
Conditions: aAnnulation: 2.5 mol % CuI, 5 mol % Ph3P, 2 equiv Et3N, R“OH as nucleophile and solvent, 80 °C, air.
b isolated yields.
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The generality of the reaction was further examined with various substitution (6-Me,
7-Me, 8-Me, 6-MeO, 7-MeO and 7-Cl) on quinoline part of substrate 2-
phenylethynylquinoline-3-carbaldehyde (12-18) under the optimized reaction conditions. All
substrates proceeded smoothly and completed in 1-4 h affording the corresponding
annulated products (12a-18a) in yield ranging (83-91%) (Table 2). The presence of electron-
donating groups on phenyl ring in quinolines (12a, 90%; 13a, 89%; 14a, 83%; 15a, 91%; 16a,
89%). were completed in longer reaction time than electron withdrawing group (17a, 87%).
The reaction also worked well with 5-phenyl-2-(phenylethynyl)nicotinaldehyde (18)
derivative affording the annulated product 7-Benzylidene-5-methoxy-3-phenyl-5,7-
dihydrofuro[3,4-b]pyridine (18a) in 90% yield.
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14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
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41
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43
44
45
46
47
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53
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To further explore the generality and scope of this annulation, various alcohols as
nucleophiles cum solvents were tested with substrate (1) under the optimized reaction
conditions (Table 2). Alcohols, such as EtOH, n-BuOH, i-PrOH, allyl alcohol and propargyl
alcohol reacted well and provided excellent yields of their desired annulated products (19a,
86%; 20a, 79%; 21a, 81%; 23a, 87%; 24a, 83%). However, t-BuOH failed to provide the
cyclized product (22a), which could be attributed to steric hindrance in t-BuOH. Alicyclic
alcohol such as cyclohexanol also afforded the cyclized product (25a) in 77% yield in 5 h.
Fluorinated alcohol such as trifluroethanol and hexafluro iso-propanol (HFIP) were also used
as nucleophiles and solvents both under optimized reaction condition, the reaction works
well and afforded the cyclized product (26a) and (27a) in 87 and 83% yield respectively.
Notably the robustness of chemistry was examined in large-scale reaction; this
cyclization proceeded smoothly in gram scale (1, 5 mmol, 1.285 g) to deliver 1a in good yield
(1.315 g, 91%).
After establishing the reaction condition using oxygen nucleophile, we became
interested to see if nitrogen nucleophiles such as imidazole can undergo similar annulation.
It is well documented that imidazole derivatives are of particular interest for drug discovery
and reported to have biological activities such as antivirals, antitumor, antifungals etc.26
Imidazole was selected as the nucleophile and attempt were made to optimize the reaction
conditions (Table 3).
In pursuit to accomplish an appropriate reaction condition for this annulation
reaction using imidazole as nucleophile with numerous parameters such as catalyst, ligand,
base and solvents were screened using 2-phenylethynylquinoline-3-carbaldehyde (1) as the
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reacting partner. Thus, 2-phenylethynylquinoline-3-carbaldehyde (1) (0.20 mmol) was
o
treated with 2.5 mol % CuI, 5 mol % Ph3P along with 2 equiv imidazole in CH3CN at 80 C
7
8
9
under an air atmosphere. The reaction did not proceed even after 12 h and the starting
material (1) was recovered (Table 3, entry 1). Next, we changed the base from Et3N to K2CO3
in CH3CN solvent keeping all the parameter fixed, trace amount of cyclized product was
observed after 12 h (entry 2). Further, by changing the base from K2CO3 to 2 equiv t-BuOK
under other identical reaction condition, the reaction was completed in 9 h (entry 3). The
isolated product (1b) was afforded in 57% yield and characterized to be the anticipated 3-
benzylidene-1-(1H-imidazol-1-yl)-1,3-dihydrofuro[3,4-b]quinoline from various spectral and
analytical data. Further on increasing the amount of t-BuOK from 2 equiv to 3 equiv did not
improve the yield of annulated product (1b) (entry 4). Other inorganic bases such as Cs2CO3,
K3PO4 were also screened. K3PO4 afforded the 27 % yield (entry 5). However, Cs2CO3 found
totally ineffective for the cyclization of reaction (entry 6).
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17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
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41
42
43
44
45
46
47
48
49
50
51
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Table 3. Optimization of Reaction Conditions for the Synthesis of 1ba
N
Cu- source (mol %)
ligand (mol %)
Base (equiv)
N
O
O
N
(2 equiv)
NH
N
N
Ph
solvent, 80 oC, air
Ph
1)
(
1b)
(
entry catalyst
(mol %)
ligand
(mol %)
Ph3P (5)
base
(equiv)
Et3N (2)
solvent
time
(h)
12
yield
(%)b
1
2
3
4
5
6
7
8
9
CuI (2.5)
CuI (2.5)
CuI (2.5)
CuI (2.5)
CuI (2.5)
CuI (2.5)
CuI (2.5)
CuI (2.5)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
S.M.c
Ph3P (5)
Ph3P (5)
Ph3P (5)
Ph3P (5)
Ph3P (5)
Cy3P (5)
TMEDA (5)
1, 10
K2CO3 (2)
t-BuOK (2)
t -BuOK (3)
K3PO4 (2)
12
9
Trace
57
7
52
12
12
10
7.5
6
27
Cs2CO3 (2)
t -BuOK (2)
t -BuOK (2)
t-BuOK (2)
S.M.
63
69
CuI (2.5)
78
phenanthroline (5)
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CuI (2.5)
CuI (2.5)
CuI (2.5)
1, 10
phenanthroline (5)
t-BuOK (2)
t -BuOK (2)
DMF
5
6
7
57
49
64
1, 10
phenanthroline (5)
DMSO
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27
28
29
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31
32
33
34
35
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1, 10
t -BuOK (2) Toluene
phenanthroline (5)
aAll reactions were carried out using 0.20 mmol of (1a). bIsolated yield. cS.M. = starting material
Next, we examined various monodentate ligand Cy3P and nitrogen based bidentate
ligands 1,10-phenanthroline and TMEDA along with Cu(I) metal salt. Cy3P and TMEDA
afforded the product in 63% and 69% yield individually with Cu(I) salt (entry 7-8). However,
in the presence of 1,10-phenanthroline, the reaction was completed in 6 h and yield of (1b)
enhanced upto 78 % (entry 9). The use of polar aprotic solvents such as DMF (57%), DMSO
(49%) and nonpolar solvent toluene (64%) (entries 10- 12) were found to be less effective as
compared to CH3CN (78%) (entry 10). Thus, the combination of 2-phenylethynylquinoline-3-
carbaldehyde (1) 0.2 mmol with CuI (2.5 mol %), 1,10 phenanthroline (5 mol %), imidazole (2
equiv) along with t-BuOK (2 equiv) in CH3CN (1 mL) at 80 °C under aerobic atmosphere is an
optimal reaction condition providing the best yield 78% of 3-benzylidene-1-(1H-imidazol-1-
yl)-1,3-dihydrofuro[3,4-b]quinoline (1b) (entry 9).
With the optimized conditions in hand (Table 3, entry 10), the scope of reaction with
various substitutions on phenyl group of alkynes such as 3-Me (2), 2-MeO (5), 3-Cl (7) and 3-
F (8) were examined. These results are summarized in Table 4. The reactions proceeded
smoothly and completed in 2-8 h affording the corresponding cyclized products 2b-8b in 67-
84 % yields (Table 4). Electron-withdrawing groups (7b, 84%; 8b, 79%) attached on the
phenyl ring of alkynes afforded higher yields as compared to electron donating groups (2b,
67%; 5b, 76%) in shorter reaction time. The reaction with alkyl acetylenes such as oct-1-yne
failed to provide the cyclized product (11b), as inseparable mixture was observed on TLC
plate. Other substituted imidazole moiety such as 2-methyl-1H-imidazole was also used as
nucleophile under the optimized condition, the reaction works well and afforded the
product (1b') in 77 % yield in 5 h. Other azoles such as pyrazole and triazole was also
examined under the optimized reaction condition, Pyrazole provided the cyclized product
(1b'') in 79 % yield in 5 h, however triazole did not afford any cyclized product (1b''') due to
unclean and inseparable mixture on TLC plate.
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Table 4. Reaction Scope for the Synthesis of 1,3-Dihydrofuro[3,4-b]quinolinesa
5
6
7
8
NR1R2
CuI (2.5%)
Ph3P (5%)
O
O
t-BuOK (2 equiv)
R1R2NH, (2 equiv)
CH3CN, 80 oC, air
N
N
9
R'
R'
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
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56
57
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59
60
1-11)
1b-11b
)
(
(
N
N
N
N
N
N
O
O
O
OMe
N
N
N
CH3
2b
(
, 67 %), 7 h
1b
, 78 %), 6 h
(
5b
, 76 %), 8 h
(
N
N
N
N
N
N
O
O
O
N
N
N
F
Cl
C6H13
, 00 %), 12 h
11b
(
7b
(
, 84 %), 2 h
8b
, 79 %), 2 h
(
N
N
N
N
N
N
N
CH3
O
O
O
N
N
N
1b"
(
, 79 %), 4 h
1b'
(
1b'''
, 00 %), 12 h
, 77 %), 5 h
(
Conditions: aAnnulation: 2.5 mol % CuI, 5 mol % Ph3P, 2 equiv R1R2NH, 2 equiv t-BuOK,
CH3CN, 80 °C, air. b isolated yields.
Owing to the importance of pyrrolo annulated-quinoline framework in various natural
products and biological systems (Figure 2), we next attempted the synthesis of this class of
compound using o-ethynylquinoline-3-carbonitrile. Thus, 2-phenylethynylquinoline-3-
carbonitrile (28) (0.20 mmol) was treated under our optimized reaction condition i.e. CuI
(2.5 mol %), Ph3P (5 mol %), Et3N (2 equiv) in methanol as solvent cum nucleophile at 80 oC
under aerobic atmosphere, the reaction did not proceed and starting material was observed
till 12 h (Table 5, entry 1). Next, we changed the base from Et3N (2 equiv) to K2CO3 (2 equiv)
keeping all the parameter fixed, the reaction was completed in 3 h affording the cyclized
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product (28a) in 87% yield (entry 2). This result could be explained by considering that
methoxide ion acts as a nucleophile in annulation process.
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Among other inorganic bases, K3PO4 and Cs2CO3 tested. K3PO4 afforded the product
(28a) in 82 % yield (entry 3) whereas Cs2CO3 was found ineffective (entry 4). Other Cu(I) and
Cu(II) salts such as CuCl (68%), CuBr (73%), CuCl2 (56%), Cu(OTf)2 (61%) provided lower
yields (entries 5-8) compared to CuI (87%) (entry 2). Thus, the combination of 28 (0.2 mmol)
with CuI (2.5 mol %), Ph3P (5 mol %), along with K2CO3 (2 equiv) in methanol as solvent cum
nucleophile at 80 °C under air atmosphere is found to be optimal reaction condition
affording the best yield of (28a) (87%) (entry 2).
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29
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36
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42
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Table 5. Optimization Reaction Conditions for Intramoecular Cylcizationa
OMe
Cu- source (mol %)
CN
ligand (mol %)
N
Base (equiv), MeOH
N
N
80 oC, air
Ph
Ph
28)
28a)
(
(
entry
catalyst
(mol %)
CuI (2.5)
ligand
(mol %)
Ph3P (5)
base
(equiv)
Et3N (2)
time
(h)
2
yield
(%)b
Nrc
1
2
3
4
5
6
7
8
CuI (2.5)
CuI (2.5)
CuI (2.5)
Ph3P (5)
Ph3P (5)
Ph3P (5)
Ph3P (5)
Ph3P (5)
Ph3P (5)
K2CO3 (2)
K3PO4 (2)
Cs2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
3
3
87
82
Nr
68
73
68
65
12
5.5
4
CuCl (2.5)
CuBr (2.5)
CuCl2 (2.5)
7
Cu(OTf)2 (2.5) Ph3P (5)
9
aAll reactions were carried out using 0.20 mmol of 1a. bIsolated yield. cNr = no reaction
With the optimum conditions in hand, the generality of reaction with various
substitutions on phenylacetylene ring such as 3-Me (29), 4-Me (30), 4-MeO (31) and 3-F (32)
(Table 6) was examined. All reactions proceeded smoothly and completed in 2-6 h. The
corresponding cyclized products (29a, 84%; 30a, 88%; 31a, 89%; 32a, 83%) were obtained in
excellent yields. Substrate having heterocyclic alkyne (33) such as 3-ethynylthiophene
afforded the cyclized product (33a) in 79% yields in 4 h. However, alkyl alkyne such as oct-1-
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yne failed to provide the annulated product (34a) due to uncleaned and inseparable mixture
in TLC plate. The scope of the reaction was further examined with various quinoline
derivatives. All the reactions proceeded smoothly and completed in 2.5-6 h affording the
annulated products (35a, 88%; 36a, 89%; 37a, 76%; 38a, 87%; 39a, 91%; 40a, 81%) in good
to excellent yields.
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19
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21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
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Table 6. Reaction Scope for the Synthesis of Pyrrolo[3,4-b]quinolinea
OR'
N
CuI (2.5 %)
Ph3P (5 %)
R
N
R
K2CO3 (2 equiv)
N
N
R'OH, 80 oC
air
R1
28a-43a
(
)
28-43
R1
(
)
OCH3
N
OCH3
N
OCH3
N
OCH3
N
N
N
N
N
CH3
31a
, 89 %), 6 h
28a
(
(
, 87 %), 3 h
OCH3
30a
29a
(
, 88 %), 5 h
OCH3
(
, 84 %), 5 h
OCH3
CH3
OCH3
OCH3
N
H3C
N
N
N
N
N
N
N
C6H13
, 00 %), 12 h
34a
(
32a
33a
(
, 83 %), 2 h
OCH3
(
, 79 %), 4 h
35a
(
, 88 %), 5 h
S
F
OCH3
N
OCH3
OCH3
H3C
N
O
N
N
H3C
O
N
N
N
H3C
N
CH3
37a
(
, 76 %), 4 h
38a
(
, 87 %), 6 h
OC4H9
36a
39a
(
, 89 %), 5 h
OCH3
(
, 91 %), 6 h
OCH3
OC2H5
Ph
N
N
N
N
N
N
N
Cl
N
42a
41a
(
, 71 %), 6 h
43a
, 83 %), 7 h
40a
(
, 83 %), 4 h
(
(
, 81 %), 2.5 h
Conditions: aAnnulation: 2.5 mol % CuI, 5 mol % Ph3P, 2 equiv Et3N, R“OH as nucleophile and solvent,
80 °C, air. b isolated yields.
Primary aliphatic alcohols such as EtOH, n-BuOH also served as nucleophiles under the
optimized reaction condition. The reactions proceeded smoothly and provided the desired
cyclized products (41a- 42a) in 83% and 71% yields in 4-6 h respectively. The reaction also
worked well with 5-phenyl-2-(phenylethynyl)nicotinonitrile (43) derivative affording the
cyclized product 7-benzylidene-5-methoxy-3-phenyl-7H-pyrrolo[3,4-b]pyridine (43a) in 83%
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yield. Finally, the structure of products was also confirmed by single crystal X-ray analysis of
compound (29a) (Figure S2, see in supporting information).
7
8
9
Encouraged by the above results, we further check, whether this nucleophilic strategy
for the synthesis of exclusively five-membered heterocycles is applicable to other
nucleophile such as dimethyl phosphite as phosphorous nucleophile, secondary amine as
nitrogen nucleophile, sodium sulphide as sulphur nucleophile with 2-
phenylethynylquinoline-3-carbaldehyde/carbonitrile under standard reaction condition
(Scheme 2). Thus, initially, we examined the reaction of 2-phenylethynylquinoline-3-
carbaldehyde (1) using dimethylphosphite as nucleophile under standard reaction condition
i.e. the combination of 2-phenylethynylquinoline-3-carbaldehyde (1) 0.2 mmol with CuI (2.5
mol %), Ph3P (5 mol %), Et3N (2 equiv) along with dimethyl phosphite as nucleophile (2
equiv) in CH3CN (1 mL) at 80 °C under aerobic atmosphere. The reaction was completed in
1h and afforded the product in 87 % yield. The isolated product was characterized to be
dimethyl-(3-benzylidene-1,3-dihydrofuro[3,4-b]quinolin-1-yl)phosphonate (44) from various
spectral and analytical data (Scheme 2, i). The structure of compound was also confirmed by
the single crystal analysis of (44) (Figure S3, see in supporting information). Next, we
examined the reaction with pyrrolidine as nitrogen nucleophile. Under the standard
reaction condition with slight modification i.e. the combination of 2-
phenylethynylquinoline-3-carbaldehyde (1) (0.2 mmol) with 2.5 mol % CuI, 5 mol % Ph3P, 2
equiv K2CO3 along with pyrrolidine as nucleophile (2 equiv) in CH3CN (1 mL) at 80 °C under
air atmosphere afforded the product 2-Phenyl-3-(pyrrolidin-1-yl)-1H-cyclopenta[b]quinolin-
1-one (45) in 77% yield (Scheme 2, ii). The structure of product was confirmed by the
spectroscopic (1H, 13C, IR and HRMS) analysis. The structure of product (45) was also
confirmed by the single crystal analysis (Figure S4, see in supporting information). The
reaction was further investigated with sodium sulphide as sulphur nucleophile. Under the
standard reaction condition, the reaction proceeded smoothly and completed in 10 min.
After completion of reaction and quenching with methyl iodide (2 equiv), the product 3-
(methylthio)-2-phenyl-1H-cyclopenta[b]quinolin-1-one (46) in afforded in 79% yield, after
workup and column chromatography (Scheme 2, iii).4a These results (Scheme 2, ii, iii) could
be attributed that the nucleophile first attack at the metal-activated carbon-carbon triple
bond followed by the addition to carbon-heteroatom multiple bond to form the carbocycles
(path A).
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9
OMe
OMe
O
P
CuI (2.5%)/ Ph3P (5%)
Et3N (2 equiv)
80 oC,CH3CN, 1 h
O
O
O
(i)
O
N
N
OMe
(2 equiv)
Ph
Ph
H
O
Ph
P OMe
(44, 87%)
(1)
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29
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32
33
34
35
36
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45
46
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O
CuI (2.5%)/ Ph3P (5%)
K2CO3 (2 equiv)
80 oC, CH3CN, 1 h
(ii)
Ph
N
N
N
O
(2 equiv)
NH
(1)
(45, 77%)
CuI (2.5%)/ Ph3P (5%)
(iii)
(iv)
Ph
SMe
Na2S/MeI (2 equiv)
80 oC, CH3CN, 10 min
N
N
Ph
Ph
(46, 79%)
(1)
SMe
N
CN
CuI (2.5%)/ Ph3P (5%)
Na2S/MeI (2 equiv)
80 oC, CH3CN, 10 min
N
N
Ph
(28)
(47, 68%)
N
CuI (2.5%)/ Ph3P (5%)
K2CO3 (2 equiv)
80 oC, CH3CN, 3 h
CN
(v)
N
N
N
Ph
Ph
(2 equiv)
NH
(28)
(48, 59%)
Scheme 2. Reaction with Other Nucleophiles
Amftbpd5sSoihc-r]yehiohesbirhornemiycr]pemwnzdiohdonmyyonlairfldoslo-laen-e5io2[3inri2dmsH6-ls,e,4m.a3-fi-doan-swardzta3ohs-[e4,
Further, the reaction was also extended with 2-phenylethynylquinoline-3-
carbonitrile (28) with sodium sulphide and pyrrolidine as nucleophile under standard
reaction condition.10a With sodium sulphide as nucleophile and 2-phenylethynylquinoline-3-
carbonitrile (28) as substrate under standard reaction condition afforded the product in 68%
yield and characterized as 1-(methylthio)-3-phenylbenzo[b][1,6]naphthyridine (47) with
various spectral data (Scheme 2, iv). The reaction was also works well with pyrrole as
nucleophile and afforded the product in 59% yield and characterized as 3-phenyl-1-
(pyrrolidin-1-yl)benzo[b][1,6]naphthyridine (48) (Scheme 2, v). These results suggested that
the formation of product proceeded via path b via six membered heterocyclization.
A similar mechanism was proposed for the formation of 1,3-dihydrofuro[3,4-b]quinoline
and 3H-pyrrolo[3,4-b]quinoline as shown in Scheme 3.6b,9b,16 In this reaction CuI plays dual
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role: (1) as a Lewis acid, which forms complex (A) with the oxygen atom of the aldehyde
group, facilitating the nucleophilic attack of methoxide ion on to the carbon atom of
aldehyde group and (2) act as a transition metal catalyst, which forms complex (B) with pi-
electrons of alkyne. Complex (B) undergoes cyclization to give organocopper intermediate
(C), which on protonation with regeneration of the Cu(I) catalyst gives the cyclized product
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45
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(1a).
OMe
O
CuI
N
Ln = PPh3
O
Ph
H
N
CuILn
2a
1a
Ph
:Base
HI
MeO H
O
OMe
CuILn
N
O
Ph
A
N
CuI Ln
C
Ph
OMe
OH
HI
N
Ph
B
CuILn
Scheme 3. Plausible Mechanism for the Synthesis of Furo[3,4-b]quinoline.
CONCLUSIONS
In conclusion, we have developed a novel, efficient and cost-effective Cu-catalyzed
synthesis of furo[3,4-b]quinoline via intramolecular cyclization of o-ethynylquinoline-3-
carbaldehyde using alcohol and imidazole as nucleophiles. The reaction was further
extended with o-ethynylquinoline-3-carbonitriles for the synthesis of pyrrolo[3,4-
b]quinoline. Further, the presence of the PPh3 and 1,10 phenanthroline ligand with CuI
facilitates the cyclization reaction by reducing the reaction time and increasing the yield of
cyclized product. The yields of product are excellent and regioselectivity was always 100%
favouring the 5-exo-dig cyclization.
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EXPERIMENTAL SECTION
General Methods
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Unless otherwise stated, all reactions were performed under nitrogen atmosphere and air
successively. Solvents were purified following standard literature procedures. Melting points
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were measured in an open capillary tube and are uncorrected. H (300, 400, 500 and 600
MHz) and 13C (75, 100, 125 and 150 MHz) NMR (proton decoupled) spectra were recorded
300 MHz, 400 MHz, 500 MHz and 600 MHz spectrometer. Multiplicities are given as: s
(singlet), brs (broad singlet), d (doublet), t (triplet), dd (doublet of doublets) or m (multiplet).
The chemical shifts (δ ppm) and coupling constants (J Hz) are reported in the standard
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fashion with reference to either internal tetramethylsilane (for H) or the central line (77.0
ppm) of CDCl3 (for 13C). Moisture and residual peak of CDCl3 appear at δ 1.5 and 7.2
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respectively in H NMR. High resolution mass spectra (HRMS) were obtained on TOF/6500
SRIES QTOF B.05.00 (B5042.0). Thin-layer chromatographies (TLC) were performed on glass
plates (7.5 x 2.5 and 7.5 x 5.0 cm) coated with silica gel GF 254 and various combinations of
ethyl acetate and hexane were used as eluent. Visualisation of spots was accomplished by
exposure to UV light. Silica gel (60-120 mesh) was used for column chromatography
(approximately 15-20 g per 1g of the crude product). All the heating reactions were done in
controlled heating oil bath. All compounds are recrystallized in variable ratio of DCM and
methanol for melting point observation.
Procedure for the synthesis of starting material (1—27) and (28—43). 16a, 16d, 16e, 24a-d
The starting materials for final products were synthesized by the known literature
procedures which was cited in reference. Individually, 2-arylethynylquinoline-3-
carbaldehyde (1—27) and 2-arylethynylquinoline-3-carbonitrile (28—43) was prepared
accordingly know literatures 16a, 16d, 16e, 24a-d.
General procedure for Copper-catalyzed synthesis of 1,3-dihydro-furo[3,4-b]quinoline
using alcohol as nucleophiles (1a−27a).
A mixture of 2-arylethynylquinolin-3-carbaldehyde (1−27) (0.20 mmol), 2.5 mol% of CuI, 5
mol% of PPh3 and 2 equiv Et3N were added in appropriate alcohols as nucleophile cum
solvent and reaction was heated at 80°C under aerobic atmosphere. After completion of
reaction, the mixture was diluted with water, extracted with ethyl acetate, washed with
brine solution and dried over anhydrous Na2SO4. The solvent was evaporated and the
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residue was purified by column chromatography on silica gel using EtOAc/hexane to afford
the annulated product (1a−27a).
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3-Benzylidene-1-methoxy-1,3-dihydro-furo[3,4-b]quinoline (1a).
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green solid; yield 54.9 mg, 95%; mp 142−143 °C; Rf = 0.70 (05:95 EtOAc/hexane); H NMR
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(300 MHz, CDCl3)  3.64 (s, 3H), 6.68 (s, 1H), 6.77 (s, 1H), 7.25 (t, J = 7.5 Hz, 2H, merged with
CDCl3), 7.40 (t, J = 7.5 Hz, 2H), 7.56 (t, J = 7.8 Hz, 1H), 7.78 (t, J = 8.1 Hz, 1H), 7.88 (t, J = 6.9
Hz, 3H), 8.17 (d, J = 8.7 Hz, 1H), 8.23 (s, 1H); 13C{1H} NMR (75 MHz, CDCl3)  54.8, 101.0,
105.2, 126.7, 126.7, 127.6, 128.4, 128.5, 129.2, 129,3, 130.6, 131.4, 131.4, 135.2, 150.0,
150.6, 154.5 ppm; HRMS (ESI) m/z calcd for C19H16NO2 [M+H]+ 290.1176, found 290.1184
1-Methoxy-3-(3-methyl-benzylidene)-1,3-dihydro-furo[3,4-b]quinoline (2a).
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light green solid; yield: 55.7 mg, 92%; mp 185−187 °C; Rf = 0.65 (05:95 EtOAc/hexane); H
NMR (300 MHz, CDCl3)  2.40 (s, 3H), 3.61 (s, 3H), 6.68 (s, 1H), 6.74 (s, 1H), 7.07 (d, J = 7.2
Hz, 1H), 7.31 (d, J = 7.5 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.70−7.80 (m, 3H), 7.87 (d, J = 7.8 Hz,
1H), 8.17 (d, J = 8.4 Hz, 1H), 8.20 (s, 1H); 13C{1H} NMR (75 MHz, CDCl3)  21.4, 54.7, 101.2,
105.0, 126.4, 126.7, 127.7, 128.4, 128.5, 129.3, 129.9, 130.6, 131.4, 135.1, 137.9, 150.0,
150.5, 154.6 ppm; HRMS (ESI) m/z calcd for C20H18NO2 [M+H]+ 304.1332, found 304.1338.
1-Methoxy-3-(4-methyl-benzylidene)-1,3-dihydro-furo[3,4-b]quinoline (3a).
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light green solid; yield: 55.7 mg, 92%; mp 118−119 °C; Rf = 0.65 (05:95 EtOAc/hexane); H
NMR (400 MHz, CDCl3)  2.41 (s, 3H), 3.61 (s, 3H), 6.69 (s, 1H), 6.74 (s, 1H), 7.08 (d, J = 7.6
Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.56 (t, J = 7.2 Hz, 1H), 7.72 (d, J = 8.8 Hz, 2H), 7.78 (t, J = 7.2
Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H), 8.17 (d, J = 8.8 Hz, 1H), 8.23 (s, 1H); 13C{1H} NMR (150 MHz,
CDCl3)  21.5, 54.8, 101.2, 105.0, 126.3, 126.6, 127.6, 128.3, 128.4, 129.3, 129.8, 130.6,
131.4, 135.0, 137.8, 149.9, 150.4, 154.6 ppm; HRMS (ESI) m/z calcd for C20H18NO2 [M+H]+
304.1332, found 304.1342.
3-(4-(tert-Butyl)benzylidene)-1-methoxy-1,3-dihydrofuro[3,4-b]quinoline (4a).
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light green solid; yield: 60.0 mg, 87%; mp 117−118 °C; Rf = 0.70 (05:95 EtOAc/hexane); H
NMR (400 MHz, CDCl3)  1.35 (s, 9H), 3.60 (s, 3H), 6.66 (s, 1H), 6.76 (s, 1H), 7.43−7.45 (m,
2H), 7.52−7.56 (m, 1H), 7.74−7.78 (m, 1H), 7.85 (t, J = 8.4 Hz, 3H), 8.16 (d, J = 8.4 Hz, 1H),
8.21 (s, 1H); 13C{1H} NMR (150 MHz, CDCl3)  31.2, 34.5, 54.7, 101.1, 104.9, 125.4, 126.5,
127.5, 128.4, 128.4, 128.9, 129.2, 130.5, 131.4, 132.3, 149.8, 149.9, 150.1, 154.6 ppm;
HRMS (ESI) m/z calcd for C23H24NO2 [M+H]+ 346.1802, found 346.1814.
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1-Methoxy-3-(2-methoxybenzylidene)-1,3-dihydrofuro[3,4-b]quinoline (5a).
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green solid; yield: 58.0 mg, 91%; mp 160−161°C; Rf = 0.60 (05:95 EtOAc/hexane); H NMR
(400 MHz, CDCl3)  3.59 (s,3H), 3.92 (s, 3H), 6.66 (s, 1H), 6.92 (d, J = 8.4 Hz, 1H), 7.03 (t, J =
7.6 Hz, 1H), 7.21−7.25 (m, 2H), 7.54 (t, J = 6.8 Hz, 1H), 7.76 (t, J = 6.8 Hz, 1H), 7.85 (d, J = 8.8
Hz, 1H), 8.17 (s, 1H), 8.20 (s, 1H), 8.34 (d, J = 8.0 Hz, 1H); 13C{1H} NMR (150 MHz, CDCl3) 
54.7, 55.4, 94.6, 104.9, 110.2, 120.4, 124.0, 126.4, 127.4, 127.9, 128.2, 128.3, 129.4, 129.8,
130.4, 131.2, 150.0, 150.4, 154.7, 156.8 ppm; HRMS calcd for C20H18NO3 [M+H]+ 320.1281,
found 320.1285.
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1-Methoxy-3-(4-methoxy-benzylidene)-1,3-dihydro-furo[3,4-b]quinoline (6a).
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light green solid; yield: 59.3 mg, 93%; mp 181−182 °C; Rf = 0.60 (05:95 EtOAc/hexane); H
NMR (300 MHz, CDCl3)  3.60 (s, 3H), 3.84 (s, 3H), 6.66 (s, 1H), 6.73 (s, 1H), 6.95 (d, J = 8.7
Hz, 2H), 7.54 (t, J = 7.5 Hz, 1H), 7.76 (d, J = 7.2 Hz, 1H), 7.85 (d, J = 8.7 Hz, 3H), 8.15 (d, J = 8.7
Hz, 1H), 8.20 (s, 1H); 13C{1H} NMR (75 MHz, CDCl3)  54.7, 55.1, 101.0, 104.9, 114.0, 126.5,
127.5, 128.0, 128.3, 128.5 129.3, 130.6, 131.4, 131.4, 149.1, 150.0, 154.8, 158.6 ppm; HRMS
(ESI) m/z calcd for C20H18NO3 [M+H]+ 320.1281, found 320.1295.
3-(3-Chlorobenzylidene)-1-methoxy-1,3-dihydrofuro[3,4-b]quinoline (7a).
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light green solid; yield: 54.2 mg, 84%; mp 129−130 °C; Rf = 0.80 (05:95 EtOAc/hexane); H
NMR (600 MHz, CDCl3)  3.64 (s, 3H), 6.65 (s, 1H), 6.69 (s, 1H), 7.21−7.23 (m, 1H), 7.32 (t, J =
7.8 Hz, 1H), 7.56 (t, J = 7.2 Hz, 1H), 7.69 (d, J = 7.2 Hz, 1H), 7.77−7.80 (m, 1H), 7.86 (d, J = 8.4
Hz, 1H), 7.95 (t, J = 1.8 Hz, 1H), 8.17 (d, J = 9.0 Hz, 1H), 8.21 (s, 1H); 13C{1H} NMR (150 MHz,
CDCl3)  55.1, 99.5, 105.4, 126.5, 126.9, 127.2, 127.6, 128.3, 128.5, 128.7, 129.3, 129.5,
130.7, 131.5, 134.2, 136.9, 149.3, 151.5, 154.0 ppm; HRMS (ESI) m/z calcd for C19H15ClNO2
[M+H]+ 324.0786, found 324.0782.
3-(3-Fluorobenzylidene)-1-methoxy-1,3-dihydrofuro[3,4-b]quinoline (8a).
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light yellow solid; yield: 54.6 mg, 89%; mp 177−179 °C; Rf = 0.80 (05:95 EtOAc/hexane); H
NMR (400 MHz, CDCl3)  3.63 (s, 3H), 6.66 (s, 1H), 6.72 (s, 1H), 6.92−6.96 (m, 1H), 7.30−736
(m, 1H), 7.54−7.58 (m, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.78 (t, J = 7.2 Hz, 1H), 7.87 (d, J = 8.4 Hz,
1H), 8.16 (d, J = 8.4 Hz, 1H), 8.23 (s, 1H); 13C{1H} NMR (100 MHz, CDCl3)  55.2, 99.9 (d, J =
1.9 Hz), 105.4, 113.5 (d, J = 14.3 Hz), 115.3 (d, J = 15.0 Hz), 124.9 (d, J = 1.7 Hz), 126.9, 127.6,
128.4, 128.5, 129.3, 129.6 (d, J = 5.6 Hz), 130.8, 131.6, 137.3 (d, J = 5.6 Hz), 149.9, 151.4,
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154.1, 162.0, 163.7 ppm; HRMS (ESI) m/z calcd for C19H15FNO2 [M+H]+ 308.1081, found
308.1085.
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3-(4-Fluoro-benzylidene)-1-methoxy-1,3-dihydro-furo[3,4-b]quinoline (9a).
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light yellow solid; yield: 55.8 g, 91%; mp 166−167 °C; Rf = 0.80 (05:95 EtOAc/hexane); H
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NMR (600 MHz, CDCl3)  3.64 (s, 3H), 6.70 (s, 1H), 6.75 (s, 1H), 7.11 (t, J = 8.4 Hz, 2H), 7.59 (t,
J = 7.2 Hz, 1H), 7.80 (t, J = 7.2 Hz, 1H), 7.88−791 (m, 3H), 8.19 (d, J = 8.4 Hz, 1H), 8.26 (s, 1H)
13C{1H} NMR (150 MHz, CDCl3)  54.9, 99.9, 105.2, 115.3 (d, J = 21.3 Hz), 126.7, 127.6, 128.2,
128.5, 129.3, 130.7 (d, J = 1.65 Hz), 130.7, 131.3 (d, J = 3.34 Hz), 131.5, 149.9, 150.1 (t, J =
2.4 Hz), 154.3, 160.6, 162.3 ppm HRMS (ESI) m/z calcd for C19H15FNO2 [M+H]+ 308.1081,
found 308.1079.
1-Methoxy-3-thiophen-3-ylmethylene-1,3-dihydro-furo[3,4-b]quinoline (10a).
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yellow solid; yield: 51.9 mg, 88%; mp 122−123 °C; Rf = 0.75 (05:95 EtOAc/hexane); H NMR
(300 MHz, CDCl3)  3.58 (s, 3H), 6.60 (s, 1H), 6.83 (s, 1H), 7.32 (s, 1H), 7.49−7.54 (m, 2H),
7.70−7.76 (m, 2H), 7.81 (t, J = 3.3 Hz, 1H), 8.11 (s, 1H), 8.16 (t, J = 4.2 Hz, 1H); 13C{1H} NMR
(75 MHz, CDCl3)  54.8, 95.8, 105.0, 123.8, 125.0, 126.6, 127.6, 128.5, 128.7, 128.8, 129.3,
130.6, 131.4, 136.1, 149.9, 150.0, 154.4 ppm; HRMS (ESI) m/z calcd for C17H14NO2S [M+H]+
296.0740, found 296.0749.
3-Benzylidene-1-methoxy-7-methyl-1,3-dihydro-furo[3,4-b]quinoline (12a).
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light yellow solid; yield: 54.5 mg, 90%; mp 171−172 °C; Rf = 0.70 (05:95 EtOAc/hexane); H
NMR (300 MHz, CDCl3)  2.56 (s, 3H), 3.64 (s, 3H), 6.70 (s, 1H), 7.28 (d, J = 7.2 Hz, 2H), 7.39
(t, J = 7.2, 2H), 7.67 (s, 2H), 7.90 (d, J = 7.5, 2H), 8.29 (s, 1H), 8.42 (s, 1H); 13C{1H} NMR (75
MHz, CDCl3)  21.4, 55.4, 105.4, 126.3, 127.5, 127.6, 127.7, 128.4, 129.3, 129.6, 133.8,
134.6, 138.0, 144.9, 148.2, 151.8 ppm; HRMS (ESI) m/z calcd for C20H18NO2 [M+H]+
304.1332, found 304.1339.
3-Benzylidene-1-methoxy-6-methyl-1,3-dihydrofuro[3,4-b]quinoline (13a).
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yellow solid; yield: 53.9 mg, 89%; mp 111−112 °C; Rf = 0.70 (05:95 EtOAc/hexane); H NMR
(400 MHz, CDCl3)  2.58 (s, 3H), 3.61 (s, 3H), 6.66 (s, 1H), 6.74 (s, 1H), 7.23−7.27 (m, 1H),
7.40 (t, J = 8.0 Hz, 3H), 7.76 (d, J = 8.4, 1H), 7.89 (d, J = 7.2, 2H), 7.95 (s, 1H), 8.17 (s, 1H);
13C{1H} NMR (125 MHz, CDCl3)  21.8, 54.7, 100.7, 105.2, 125.6, 126.6, 127.5, 128.0, 128.3,
128.4, 128.9, 129.1, 131.0, 135.2, 141.1, 150.1, 150.7, 154.3 ppm; HRMS (ESI) m/z calcd for
C20H18NO2 [M+H]+ 304.1332, found 304.1336.
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3-Benzylidene-5-ethyl-1-methoxy-1,3-dihydro-furo[3,4-b]quinoline (14a).
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green solid; yield: 52.6 mg, 83%; mp 129−131 °C; Rf = 0.90 (05:95 EtOAc/hexane); H NMR
(300 MHz, CDCl3)  1.43 (t, J = 7.5, 3H), 3.40 (q, J = 7.5, 2H), 3.60 (s, 3H), 6.68 (s, 1H), 6.75 (s,
1H), 7.25 (t, J = 7.2 Hz, 2H, one proton merged with CDCl3), 7.38−7.44 (m, 2H), 7.48 (d, J =
7.5, 1H), 7.62 (d, J = 6.9 Hz, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.90 (d, J = 7.5 Hz, 2H), 8.18 (s, 1H);
13C{1H} NMR (75 MHz, CDCl3)  14.9, 24.4, 54.6, 100.2, 105.3, 126.4, 126.5, 127.6, 127.7,
128.4, 128.9, 129.1, 131.5, 131.5, 135.4, 143.3, 148.5, 151.3, 153.3 ppm; HRMS (ESI) m/z
calcd for C21H20NO2 [M+H]+ 318.1489, found 318.1485.
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3-Benzylidene-1,7-dimethoxy-1,3-dihydro-furo[3,4-b]quinoline (15a).
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light yellow solid; yield: 58.0 mg, 91%; mp 123−124 °C; Rf = 0.60 (05:95 EtOAc/hexane); H
NMR (300 MHz, CDCl3)  3.60 (s, 3H), 3.94 (s, 3H), 6.65 (s, 1H), 6.69 (s, 1H), 7.11 (d, J = 2.1
Hz, 1 H), 7.22 (d, J = 6.9, 1H), 7.36-7.45 (m, 3H), 7.87 (d, J = 7.5, 2H), 8.05 (s, 1H), 8.09 (d, J =
3.9 Hz, 1H); 13C{1H} NMR (75 MHz, CDCl3)  54.7, 55.4, 100.2, 105.1, 105.9, 123.5, 126.5,
128.4, 128.7, 128.8, 129.0, 130.0, 130.4, 135.3, 145.8, 150.7, 152.1, 158.0 ppm; HRMS (ESI)
m/z calcd for C20H18NO3 [M+H]+ 320.1281, found 320.1282.
3-Benzylidene-1,6-dimethoxy-1,3-dihydrofuro[3,4-b]quinoline (16a).
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yellow solid; yield: 56.7 mg, 89%; mp 156−157 °C; Rf = 0.60 (05:95 EtOAc/hexane); H NMR
(400 MHz, CDCl3)  3.60 (s, 1H), 3.98 (s, 3H), 6.65 (s, 1H), 6.71 (s, 1H), 720−7.24 (m, 2H), 7.40
(t, J = 8.0 Hz, 1 H), 7.48 (d, J = 2.4, 1H), 7.74 (d, J = 9.2, 1H), 7.89 (d, J = 7.2 Hz, 1H), 8.14 (s,
1H); 13C{1H} NMR (150 MHz, CDCl3)  54.7, 55.5, 1007, 105.3, 107.1, 120.1, 122.9, 126.4,
126.6, 128.4, 129.1, 129.3 131.0, 135.2, 150.8, 151.8, 154.6, 161.6 ppm; HRMS (ESI) m/z
calcd for C20H18NO3 [M+H]+ 320.1281, found 320.1290.
3-Benzylidene-6-chloro-1-methoxy-1,3-dihydro-furo[3,4-b]quinoline (17a).
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light yellow solid; yield: 56.2 mg, 87%; mp 131−132 °C; Rf = 0.75 (05:95 EtOAc/hexane); H
NMR (300 MHz, CDCl3)  3.63 (s, 1H), 6.64 (s, 1H), 6.75 (s, 1H), 7.23 (t, J = 5.7 Hz, 2 H, 1 H
merged with CdCl3), 7.40 (t, J = 7.5 HZ, 2H), 7.50 (d, J = 7.5 Hz, 1H), 7.79 (d, J = 8.7 Hz, 1H),
7.88 (d, J = 7.5 Hz, 2H), 8.16 (s, 1H), 8.19 (s, 1H); 13C{1H} NMR (75 MHz, CDCl3)  55.1, 101.8,
105.1, 126.0, 127.0, 127.7, 128.4, 128.5, 128.7, 129.3, 129.5, 131.3, 132.4, 135.0, 136.7,
150.3, 155.6 ppm; HRMS (ESI) m/z calcd for C19H15ClNO2 [M+H]+ 324.0786, found 324.0798.
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7-Benzylidene-5-methoxy-3-phenyl-5,7-dihydrofuro[3,4-b]pyridine (18a).
white solid; yield: 56.7 mg, 90%; mp 92−93 °C; Rf = 0.70 (05:95 EtOAc/hexane); 1H NMR (300
MHz, CDCl3)  3.62 (s, 3H), 6.54 (s, 1H), 6.61 (s, 1H), 7.22 (d, J = 7.2 Hz, 1H), 7.38 (t, J = 7.5,
2H), 7.43−7.53 (m, 3H), 7.61 (d, J = 7.2, 2H), 7.84 (d, J = 7.8, 2H), 7.95 (s, 1H), 8.90 (s, 1H);
13C{1H} NMR (75 MHz, CDCl3)  54.9, 100.1, 105.6, 105.6, 126.5, 127.1, 128.4, 128.1, 129.1,
129.6, 129.6, 130.5, 135.2, 136.4, 137.1, 150.7, 151.0, 151.0, 153.0 ppm; HRMS (ESI) m/z
calcd for C21H18NO2 [M+H]+ 316.1332, found 316.1341.
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3-Benzylidene-1-ethoxy-1,3-dihydro-furo[3,4-b]quinoline (19a).
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light yellow solid; yield: 52.1 mg, 86%; mp 107−108 °C; Rf = 0.75 (05:95 EtOAc/hexane); H
NMR (600 MHz, CDCl3)  1.35 ( t, J = 7.2 Hz, 3H), 3.86−3.91 (m, 1H), 3.99−4.05 (m, 1H), 6.74
(s, 1H), 6.76 (s, 1H), 7.24 (d, J = 7.2 Hz, 1H), 7.40 (t, J = 7.8 Hz, 2H), 7.56 (t, J = 7.8, 1H), 7.77
(t, J = 8.4, 1H), 7.87−7. 90 (m, 3H), 8.17 (d, J = 8.4, 1H), 8.24 (s, 1H); 13C{1H} NMR (125 MHz,
CDCl3)  15.2, 64.1, 101.0, 104.4, 126.7, 127.7, 128.4, 128.4, 128.9, 129.1, 129.3, 130.6,
131.4, 133.4, 135.2, 149.9, 150.6, 154.5 ppm; HRMS (ESI) m/z calcd for C20H18NO2 [M+H]+
304.1332, found 304.1337.
3-Benzylidene-1-butoxy-1,3-dihydrofuro[3,4-b]quinoline (20a).
green solid; yield: 52.2 mg, 79%; mp 93−94 °C; Rf = 0.80 (05:95 EtOAc/hexane); 1H NMR (300
MHz, CDCl3)  0.94 ( t, J = 7.2 Hz, 3H),1.41−1.48 (m, 2H), 1.65−1.72 (m, 2H), 3.77−3.92 (m,
2H), 6.73 (s, 1H), 6.76 (s, 1H), 7.21 (s, 1H), 7.39 (t, J = 7.5 Hz, 2H), 7.55 (t, J = 7.5 Hz, 1H), 7.77
(t, J = 8.1, 1H), 7.88 (t, J = 5.1, 3H), 8.17 (d, J = 8.7, 1H), 8.22 (s, 1H); 13C{1H} NMR (75 MHz,
CDCl3)  13.7, 19.1, 31.6, 68.2, 101.0, 104.7, 126.7, 127.8, 128.5, 128.5, 128.8, 129.0, 129.2,
129.4, 130.6, 131.5, 135.4, 150.0, 150.8, 154.7 ppm; HRMS calcd for C22H22NO2 [M+H]+
332.1645, found 332.1643.
3-Benzylidene-1-isopropoxy-1,3-dihydro-furo[3,4-b]quinoline (21a).
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white solid; yield: 51.3 mg, 81%; mp 165−166 °C; Rf = 0.65 (05:95 EtOAc/hexane); H NMR
(600 MHz, CDCl3)  1.43 ( t, J = 6.0 Hz, 6H), 4.33−4.37 (m, 1H), 6.77 (s, 1H), 6.81 (s, 1H), 7.27
(d, J = 9.0 Hz, 1H), 7.42 (t, J = 7.8 Hz, 2H), 7.57 (t, J = 6.6 Hz, 1H), 7.78 (t, J = 8.4 Hz, 1H), 7.88
(d, J = 8.4 Hz, 1H), 7.92 (d, J = 7.2Hz, 2H), 8.18 (d, J = 9.0 Hz, 1H), 8.22 (s, 1H); 13C{1H} NMR
(150 MHz, CDCl3)  22.5, 23.6, 72.3, 100.8, 103.6, 126.6, 126.6, 127.7, 128.4, 128.4, 129.0,
1292, 129.4, 130.5, 131.3, 135.3, 149.8, 150.5, 154.5 ppm; HRMS calcd for C21H20NO2
[M+H]+ 318.1489, found 318.1497.
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1-(allyloxy)-3-benzylidene-1,3-dihydrofuro[3,4-b]quinoline (23a).
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yellow solid; yield: 54.8 mg, 87%; mp 79−80 °C; Rf = 0.70 (05:95 EtOAc/hexane); H NMR
(600 MHz, CDCl3)  4.38−4.41 ( m, 1H), 4.44−4.47 (m, 1H), 5.30−5.32 (m, 1H), 5.42−5.45 (m,
1H), 6.03−6.10 (m, 1H), 6.75 (s, 1H), 6.80 (s, 1H), 7.29 (d, J = 7.2 Hz, 1H), 7.44 (t, J = 7.8 Hz,
2H), 7.55 (t, J = 7.8 Hz, 1H), 7.78 (t, J = 8.4 Hz, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 7.8 Hz,
2H), 8.19 (d, J = 9.0 Hz, 1H), 8.22 (m, 1H); 13C{1H} NMR (150 MHz, CDCl3)  69.2, 101.2, 103.9,
118.2, 126.7, 126.8, 127.6, 128.5, 128.5, 128.7, 129.2, 129.3, 130.6, 131.5, 133.5, 135.2,
149.9, 150.6, 154.5 ppm; HRMS calcd for C21H18NO2 [M+H]+ 316.1332, found 316.1340.
3-Benzylidene-1-(prop-2-yn-1-yloxy)-1,3-dihydrofuro[3,4-b]quinoline (24a).
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green solid; yield: 51.9 mg, 83%; mp 124−126 °C; Rf = 0.55 (05:95 EtOAc/hexane) H NMR
(400 MHz, CDCl3)  2.58 ( s, 1H), 4.49−4.54 (m, 1H), 4.62−4.66 (m, 1H), 6.78 (s, 1H), 6.90 (s,
1H), 7.26 (t, J = 6.0 Hz, 1H, merged with CDCl3), 7.41 (t, J = 7.6 Hz, 2H), 7.57 (t, J = 8.0 Hz,
1H), 7.78 (t, J = 8.0 Hz, 1H), 7.88 (d, J = 7.6 Hz, 3H), 8.17 (d, J = 7.6 Hz, 1H), 8.27 (s, 1H);
13C{1H} NMR (150 MHz, CDCl3)  55.3, 75.6, 78.5, 101.5, 102.5, 126.6, 126.8, 127.4, 128.1,
128.4, 128.4, 129.1, 129.2, 130.6, 131.6, 134.9, 149.9, 150.2, 154.1 HRMS calcd for
C21H16NO2 [M+H]+ 314.1176, found 314.1180.
3-benzylidene-1-(cyclohexyloxy)-1,3-dihydrofuro[3,4-b]quinoline (25a).
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green solid; yield: 54.9 mg, 77%; mp 149−151 °C; Rf = 0.75 (05:95 EtOAc/hexane) H NMR
(400 MHz, CDCl3)  1.29−1.38 (m, 3H), 1.53−1.61 (m, 3H), 1.78−1.80 (m, 2H), 2.05−2.08 (m,
2H), 3.93−4.02 (m, 1H), 6.72 (s, 1H), 6.76 (s, 1H), 7.21−7.24 (m, 1H), 7.38 (t, J = 8.0 Hz, 2H),
7.50 (t, J = 7.2 Hz, 1H), 7.72 (t, J = 8.4 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 7.6 Hz, 2H),
8.12 (s, 1H), 8.14 (s, 1H); 13C{1H} NMR (100 MHz, CDCl3)  239, 25.4, 32.4, 33.5, 77.9, 100.6,
103.6, 126.5, 127.6, 128.3, 128.4, 129.0, 129.3, 129.4, 130.4, 131.2, 135.4, 149.8, 150.6,
154.6; HRMS calcd for C24H24NO2 [M+H]+ 358.1802, found 358.1806.
3-benzylidene-1-(2,2,2-trifluoroethoxy)-1,3-dihydrofuro[3,4-b]quinoline (26a).
yellow solid; yield: 60.6 mg, 85%; mp 159−160 °C; 1H NMR (600 MHz, CDCl3)  4.08−4.15 (m,
1H), 4.17−4.23 (m, 1H), 6.79 (s, 1H), 6.82 (s, 1H), 7.31 (t, J = 7.2 Hz, 1H), 7.45 (t, J = 7.8 Hz,
2H), 7.56−7.58 (m, 1H), 7.78−7.81 (m, 1H), 7.86−7.89 (m, 3H), 8.19 (d, J = 9.0, 1H), 8.24 (s,
1H); 13C{1H} NMR (150 MHz, CDCl3):  64.28 (q, J = 34.9 Hz), 102.07, 103.97, 123.50 (q, J =
276.3 Hz), 126.92, 126.99, 127.13, 127.49, 128.52, 128.59, 129.26, 129.35, 130.99, 131.86,
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134.61, 149.91. 150.15, 153.92 ppm; HRMS (ESI) m/z calcd for C20H15F3NO2 [M+H]+
358.1049, found 358.1054.
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3-benzylidene-1-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)-1,3-dihydrofuro[3,4-b]quinoline
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(27a). light yellow solid; yield: 68.8 mg, 81%; mp 169−170 °C; H NMR (400 MHz, CDCl3) 
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4.89−4.95 (m, 1H), 6.70 (s, 1H), 708 (s, 1H), 7.43−7.48 (m, 3H), 7.51 (t, J = 8.0 Hz, 1H), 7.75 (t,
J = 7.2 Hz, 1H), 7.81−7.85 (m, 3H), 8.08 (t, J = 4.4, 2H); 13C{1H} NMR (100 MHz, CDCl3):  71.5
(t, J = 32.3 Hz), 99.4, 102.8, 119.7, 125.1, 126.1, 126.8, 128.1, 128.6, 128.8, 130.1, 130.9,
132.7, 134.2, 148.6, 149.4, 154.6 ppm; HRMS (ESI) m/z calcd for C21H14F6NO2 [M+H]+
426.0923, found 426.0932.
4-((1-methoxyfuro[3,4-b]quinolin-3(1H)-ylidene)methyl)-N,N-dimethylaniline (27aa).
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yellow solid; yield 73.9 mg, 89%; mp 156−157 °C; Rf = 0.70 (05:95 EtOAc/hexane); H NMR
(300 MHz, CDCl3)  3.00 (s, 6H), 3.58 (s, 3H), 6.66 (s, 1H), 6.72 (s, 1H), 6.77 (d, J = 8.4 Hz, 2H),
7.53 (d, J = 7.2 Hz, 1H), 7.74−785 (m, 4H), 8.13 (d, J = 8.4 Hz, 1H), 8.18 (s, 1H); 13C{1H} NMR
(75 MHz, CDCl3)  21.5, 55.9, 120.1, 121.4, 126.4, 126.9, 128.0, 128.5, 128.8, 129.5, 130.8,
132.3, 135.6, 138.0, 143.6, 149.0, 160.4, 170.3 ppm; HRMS (ESI) m/z calcd for C21H21N2O2
[M+H]+ 333.1598, found 333.1603.
General procedure for Copper-catalyzed synthesis of 1,3-dihydro-furo[3,4-b]quinoline
using imidazole as nucleophiles (1b).
A mixture of 2-phenylethynylquinolin-3-carbaldehyde (1) (0.20 mmol), 2.5 mol% of CuI, 5
mol% of PPh3, 2 equiv t-BuOK and 2 equiv imidazole as nucleophile were added in CH3CN
solvent and reaction was heated at 80°C under aerobic atmosphere. After completion of
reaction, the mixture was diluted with water, extracted with ethyl acetate, washed with
brine solution and dried over anhydrous Na2SO4. The solvent was evaporated and the
residue was purified by column chromatography on silica gel using EtOAc/hexane to afford
the annulated product (1b).
3-Benzylidene-1-(1H-imidazol-1-yl)-1,3-dihydrofuro[3,4-b]quinoline (1b).
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light brown solid; yield 50.7 mg, 78%; mp 166−168 °C; Rf = 0.40 (05:95 EtOAc/hexane); H
NMR (600 MHz, CDCl3)  6.87 (s, 1H), 6.89 (s, 1H), 7.14 (s, 1H), 7.27 (d, J = 6.0 Hz, 1H), 7.38
(t, J = 7.8 Hz, 2H), 7.51 (s, 1H), 7.63 (t, J = 7.2 Hz, 1H), 7.82 (t, J = 7.8 Hz, 3H), 7.88 (d, J = 7.8
Hz, 2H), 8.15 (s, 1H), 8.25 (d, J = 8.4 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3)  86.8, 102.5,
117.1, 127.0, 127.3, 127.6, 128.1, 128.5, 129.3, 129.5, 130.4, 130.6, 131.4, 131.5, 134.2,
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136.8, 149.5, 150.3, 153.6 ppm; HRMS (ESI) m/z calcd for C21H16N3O [M+H]+ 326.1288, found
326.1312.
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1-(1H-Imidazol-1-yl)-3-(3-methylbenzylidene)-1,3-dihydrofuro[3,4-b]quinoline (2b).
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green solid; yield 45.4 mg, 67%; mp 176−177 °C; Rf = 0.35 (05:95 EtOAc/hexane); H NMR
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(600 MHz, CDCl3)  2.37 (s, 3H), 6.85 (s, 1H), 6.88 (s, 1H), 7.14 (s, 1H), 7.19 (d, J = 7.8 Hz,
2H), 7.50 (s, 1H), 7.61 (t, J = 7.2 Hz, 1H), 7.70 (d, J = 7.8 Hz, 2H), 7.82 (s, 1H), 7.85 (d, J = 7.2
Hz, 2H), 8.13 (s, 1H), 8.23 (d, J = 8.4 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3)  21.2, 86.6,
102.4, 110.6, 126.9, 127.1, 127.3, 127.5, 128.4, 128.6, 129.1, 129.2, 129.3, 130.1, 130.8,
130.9, 131.2, 131.3, 137.2, 148.9, 150.1, 153.6 ppm; HRMS (ESI) m/z calcd for C22H18N3O
[M+H]+ 340.1444, found 340.1463.
1-(1H-Imidazol-1-yl)-3-(2-methoxybenzylidene)-1,3-dihydrofuro[3,4-b]quinoline (5b).
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light yellow solid; yield 53.9 mg, 76%; mp 185−187 °C; Rf = 0.30 (05:95 EtOAc/hexane); H
NMR (600 MHz, CDCl3)  3.85 (s, 3H), 6.78 (s, 1H), 6.83 (d, J = 8.4 Hz, 1H), 6.88 (t, J = 7.8 Hz,
1H), 7.04 (s, 1H), 7.15 (t, J = 7.2 Hz, 1H), 7.19 (s, 1H), 7.39 (s, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.74
(t, J = 7.2 Hz, 3H), 8.02 (s, 1H), 8.04 (s, 1H), 8.15 (d, J = 8.4 Hz, 1H); 13C{1H} NMR (150 MHz,
CDCl3)  55.4, 86.6, 96.1, 110.3, 120.5, 123.1, 126.9, 127.0, 127.3, 128.4, 128.5, 129.5, 130.0,
130.5, 131.1, 131.3, 136.8, 149.5, 150.2, 153.7, 156.8 ppm; HRMS (ESI) m/z calcd for
C22H18N3O2 [M+H]+ 356.1139, found 356.1147.
3-(3-Chlorobenzylidene)-1-(1H-imidazol-1-yl)-1,3-dihydrofuro[3,4-b]quinoline (7b).
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light yellow; yield 60.3 mg, 84%; mp 227−229 °C; Rf = 0.45 (05:95 EtOAc/hexane); H NMR
(500 MHz, CDCl3)  6.78 (s, 1H), 6.87 (s, 1H), 7.13 (s, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.28 (d, J =
8.0 Hz, 1H), 7.50k (s, 1H), 7.62 (d, J = 7.0 Hz, 2H), 7.79 (d, J = 5.0 Hz, 2H), 7.85 (t, J = 7.5 Hz,
2H), 8.14 (s, 1H), 8.22 (d, J = 8.5 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3)  86.9, 100.9, 117.1,
127.0, 127.2, 127.4, 127.6, 128.5, 128.9, 129.6, 129.6, 131.9, 131.5, 131.5, 134.3, 136.1,
136.8, 150.3, 150.5, 153.3 ppm; HRMS (ESI) m/z calcd for C21H15ClN3O [M+H]+ 360.0898,
found 360.0911.
3-(3-Fluorobenzylidene)-1-(1H-imidazol-1-yl)-1,3-dihydrofuro[3,4-b]quinoline (8b).
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white solid; yield 54.1 mg, 79%; mp 197−199 °C; Rf = 0.45 (05:95 EtOAc/hexane); H NMR
(600 MHz, CDCl3)  6.83 (s, 1H), 6.96 (t, J = 8.4 Hz, 1H), 7.33 (q, J = 8.4 Hz, 2H), 7.52 (t, J = 7.8
Hz, 2H), 7.57 (d, J = 10.8 Hz, 1H), 7.65 (t, J = 7.8 Hz, 2H), 7.88 (t, J = 7.8 Hz, 3H), 8.17 (s, 1H),
8.24 (d, J = 8.4 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3)  87.0, 101.2, 114.1 (d, J = 21.3 Hz),
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115.5 (d, J = 22.2 Hz), 125.1, 127.0, 127.5, 128.5, 129.5, 129.7, 129.8, 131.5 (d, J = 7.3 Hz),
136.3 (d, J = 8.5 Hz), 150.3 (d, J = 18 Hz), 153.3, 161.8, 163.8 ppm; HRMS (ESI) m/z calcd for
C21H15FN3O [M+H]+ 344.1194, found 344.1203.
3-Benzylidene-1-(2-methyl-1H-imidazol-1-yl)-1,3-dihydrofuro[3,4-b]quinoline (1b’).
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green solid; yield: 52.2 mg, 77%; mp 167−169 °C; Rf = 0.55 (05:95 EtOAc/hexane); H NMR
(600 MHz, CDCl3)  2.53 (s, 3H), 6.52 (s, 1H), 6.77 (s, 1H), 6.84 (s, 1H), 7.17 (d, J = 7.2 Hz, 1H),
7.29 (t, J = 7.8 Hz, 2H), 7.38 (s, 1H), 7.53 (t, J = 8.4 Hz, 1H), 7.70 (d, J = 7.2 Hz, 2H), 7.75−7.79
(m, 2H), 8.04 (s, 1H), 8.14 (d, J = 9.0 Hz, 1H); 13C{1H} NMR (150 MHz, CDCl3);  13.2, 86.0,
102.3, 117.0, 126.9, 127.3, 127.3, 127.3, 128.1, 128.4, 128.5, 129.2, 129.4, 131.3, 131.4,
134.2, 145.6, 149.5, 150.1, 153.6 ppm; HRMS (ESI) m/z calcd for C22H18N3O [M+H]+
340.1444, found 340.1454.
3-Benzylidene-1-(1H-imidazol-1-yl)-1,3-dihydrofuro[3,4-b]quinoline (1b”).
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green solid; yield 51.3 mg, 79%; mp 180−182 °C; H NMR (600 MHz, CDCl3)  6.38 (s, 1H),
6.87 (s, 1H), 7.25 (t, J = 7.2 Hz 1H), 7.38 (t, J = 7.8 Hz, 3H), 7.60 (t, J = 7.8 Hz, 1H), 7.71 (s,
1H), 7.73 (s, 1H), 7.82-7.87 (m, 4H), 8.19 (s, 1H), 8.23 (d, J = 9.0 Hz, 1H); 13C{1H} NMR (125
MHz, CDCl3)  90.8, 102.2, 107.9, 127.1, 127.2, 127.7, 128.1, 128.5, 128.6, 129.4, 129.5,
131.2, 131.7, 134.6, 141.2, 150.1, 150.3, 154.0 ppm; HRMS (ESI) m/z calcd for C21H16N3O
[M+H]+ 326.1288, found 326.1298.
General procedure for Copper-catalyzed synthesis of Pyrrolo[3,4-b]quinoline using alcohol
as nucleophiles (28a−43a).
A mixture of 2-arylethynylquinolin-3-carbonitrile (28−43) (0.20 mmol), 2.5 mol% of CuI, 5
mol% of PPh3 and 2 equiv K2CO3 were added in appropriate alcohols as nucleophile cum
solvent and reaction was heated at 80°C under aerobic atmosphere. After completion of
reaction, the mixture was diluted with water, extracted with ethyl acetate, washed with
brine solution and dried over anhydrous Na2SO4. The solvent was evaporated and the
residue was purified by column chromatography on silica gel using EtOAc/hexane to afford
the annulated product (28a−43a).
3-benzylidene-1-methoxy-3H-pyrrolo[3,4-b]quinoline (28a).
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light green solid; yield 49.7 mg, 87%; mp 121−122 °C; Rf = 0.65 (05:95 EtOAc/hexane); H
NMR (300 MHz, CDCl3)  4.21 (s, 3H), 7.26 (t, J = 7.2 Hz, 1H), 7.37 (t, J = 7.5 Hz, 2H), 7.45 (t, J
= 7.2 Hz, 2H), 7.70 (t, J = 7.5 Hz, 1H), 7.80 (d, J = 8.7 Hz, 1H), 8.13 (d, J = 4.8 Hz, 2H), 8.23 (d, J
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= 7.5 Hz, 2H); 13C{1H} NMR (75 JMHz, CDCl3)  55.8, 119.8, 121.3, 126.4, 126.8, 127.8, 128.5,
129.4, 19.7, 130.7, 131.6, 132.6, 135.7, 143.7, 148.9, 160.3, 170.3 ppm; HRMS (ESI) m/z
calcd for C19H15N2O [M+H]+ 287.1179, found 287.1174.
1-methoxy-3-(3-methylbenzylidene)-3H-pyrrolo[3,4-b]quinoline (29a).
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white solid; yield 50.4 mg, 84%; mp 133−135 °C; Rf = 0.65 (05:95 EtOAc/hexane); H NMR
(600 MHz, CDCl3)  2.45 (s, 3H), 4.34 (s, 3H), 7.18 (d, J = 7.8 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H),
7.55 (s, 1H), 7.58 (t, J = 7.2 Hz, 1H), 7.81 (t, J = 7.2 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 8.12 (s,
1H), 8.17 (d, J = 7.8 Hz, 1H), 8.24 (d, J = 8.4 Hz, 1H), 8.29 (d, J = 3.6 Hz, 1H); 13C{1H} NMR
(150 MHz, CDCl3)  21.5, 55.9, 120.0, 121.3, 126.3, 126.8, 127.8, 128.4, 128.7, 129.3, 129.4,
129.7, 130.7, 132.2, 135.5, 137.9, 143.5, 148.9, 160.3, 170.2 ppm; HRMS (ESI) m/z calcd for
C20H17N2O [M+H]+ 301.1335, found 301.1343.
1-methoxy-3-(4-methylbenzylidene)-3H-pyrrolo[3,4-b]quinoline (30a).
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yellow solid; yield 52.8 mg, 88%; mp 153−154 °C; Rf = 0.65 (05:95 EtOAc/hexane); H NMR
(600 MHz, CDCl3)  2.43 (s, 3H), 4.34 (s, 3H), 7.28 (t, J = 5.4 Hz, 2H), 7.56 (s, 1H), 7.58 (t, J =
7.2 Hz, 1H), 7.81 (t, J = 7.8 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 8.23 (d, J = 8.4 Hz, 2H), 8.25 (s,
1H), 8.30 (s, 1H); 13C{1H} NMR (150 MHz, CDCl3)  21.5, 55.9, 120.0, 121.3, 126.2, 126.8,
127.8, 129.3, 129.4, 129.6, 130.7, 131.5, 132.9, 138.7, 142.9, 148.9, 160.3, 169.2 ppm;
HRMS (ESI) m/z calcd for C20H17N2O [M+H]+ 301.1335, found 301.1353.
1-methoxy-3-(4-methoxybenzylidene)-3H-pyrrolo[3,4-b]quinoline (31a).
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light yellow solid; yield 56.2 mg, 89%; mp 181−182 °C; Rf = 0.60 (05:95 EtOAc/hexane); H
NMR (300 MHz, CDCl3)  3.87 (s, 3H), 4.33 (s, 3H), 6.99 (d, J = 7.2 Hz, 2H), 7.53 (s, 1H), 7.58
(d, J = 7.2 Hz, 1H), 7.80 (t, J = 7.2 Hz, 1H), 7.95 (d, J = 7.8 Hz, 2H), 8.22 (d, J = 8.7 Hz, 1H), 8.27
(s, 1H), 8.30 (d, J = 3.0 Hz, 2H); 13C{1H} NMR (75 MHz, CDCl3)  55.2, 58.8, 114.1, 119.8,
121.2, 126.2, 126.8, 127.9, 128.6, 129.5, 129.6, 130.7, 132.8, 133.2, 141.8, 148.9, 160.0,
160.3, 169.7 ppm; HRMS (ESI) m/z calcd for C20H17N2O2 [M+H]+ 317.1285, found 317.1291.
3-(4-fluorobenzylidene)-1-methoxy-3H-pyrrolo[3,4-b]quinoline (32a).
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yellow solid; yield 50.4 mg, 83%; mp 176−177 °C; Rf = 0.70 (05:95 EtOAc/hexane); H NMR
(300 MHz, CDCl3)  4.31 (s, 3H), 7.12 (t, J = 8.4 Hz, 1H), 7.49 (s, 1H), 7.57 (t, J = 7.2 Hz, 1H),
7.80 (t, J = 7.5 Hz, 2H), 7.93 (d, J = 8.1 Hz, 1H), 8.22 (d, J = 8.4 Hz, 1H), 8.29 (s, 2H), 8.32 (s,
1H); 13C{1H} NMR (75 MHz, CDCl3)  56.0, 115.62 (d, J = 21.3 Hz), 118.5, 121.4, 126.5, 126.9,
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128.1, 129.68 (d, J = 15.5 Hz), 130.9, 132.1, 133.44 (d, J = 7.7 Hz), 143.4, 149.0, 160.3, 161.2,
164.5, 170.5 ppm; HRMS (ESI) m/z calcd for C19H14FN2O [M+H]+ 305.1085, found 305.1093.
1-methoxy-3-(thiophen-3-ylmethylene)-3H-pyrrolo[3,4-b]quinoline (33a).
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yellow solid; yield 46.1 mg, 79%; mp 149−150 °C; Rf = 0.65 (05:95 EtOAc/hexane); H NMR
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(300 MHz, CDCl3)  4.33 (s, 3H), 7.25 (t, J = 3.9 Hz, 1H, 1proton merged with CdCl3), 7.54 (s,
1H), 7.58 (d, J = 7.8 Hz, 1H), 7.80 (t, J = 7.2 Hz, 1H), 7.95 (d, J = 8.1 Hz, 1H), 8.22 (d, J = 7.8
Hz, 2H), 8.24 (s, 1H), 8.30 (s, 1H); 13C{1H} NMR (75 MHz, CDCl3)  55.8, 104.7, 107.5, 117.1,
120.3, 121.7, 121.9, 127.2, 128.5, 128.9, 130.0, 137.9, 140.3, 141.7, 150.5, 154.2, 163.5
ppm; HRMS (ESI) m/z calcd for C17H13N2OS [M+H]+ 293.0743, found 293.0753.
3-benzylidene-1-methoxy-7-methyl-3H-pyrrolo[3,4-b]quinoline (35a).
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white solid; yield 52.8 mg, 88%; mp 143−144 °C; Rf = 0.65 (05:95 EtOAc/hexane); H NMR
(600 MHz, CDCl3)  2.57 (s, 3H), 4.34 (s, 3H), 7.35 (t, J = 7.2 Hz, 1H), 7.46 (t, J = 7.8 Hz, 2H),
7.53 (s, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.69 (s, 1H), 8.13 (d, J = 9.0 Hz, 1H), 8.19 (s, 1H), 8.32
(d, J = 7.8 Hz, 2H); 13C{1H} NMR (150 MHz, CDCl3)  21.5, 55.9, 119.4, 121.4, 126.9, 127.1,
128.3, 128.3, 129.3, 131.5, 133.1, 135.8, 136.4, 143.8, 147.5, 159.5, 170.4 ppm; HRMS (ESI)
m/z calcd for C20H17N2O [M+H]+ 301.1335, found 301.1351.
3-benzylidene-1-methoxy-6-methyl-3H-pyrrolo[3,4-b]quinoline (36a).
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white solid; yield 53.4 mg, 89%; mp 178−180 °C; Rf = 0.65 (05:95 EtOAc/hexane); H NMR
(600 MHz, CDCl3)  2.62 (s, 3H), 4.33 (s, 3H), 7.35 (t, J = 7.2 Hz, 1H), 7.40 (d, J = 7.2 Hz, 1H),
7.46 (t, J = 7.8 Hz, 2H), 7.54 (s, 1H), 7.82 (d, J = 8.4 Hz, 1H), 8.02 (s, 1H), 8.23 (s, 1H), 8.32 (d,
J = 7.2 Hz, 2H); 13C{1H} NMR (150 MHz, CDCl3)  22.0, 55.9, 119.5, 120.8, 124.9, 127.6, 128.3,
128.4, 128.7, 128.7, 129.0, 131.5, 135.7, 141.4, 143.8, 149.1, 160.3, 170.5 ppm; HRMS (ESI)
m/z calcd for C20H17N2O [M+H]+ 301.1335, found 301.1352.
3-Benzylidene-1-methoxy-5-methyl-3H-pyrrolo[3,4-b]quinoline (37a).
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brown solid; yield 45.6 mg, 76%; mp 190−191 °C; Rf = 0.80 (05:95 EtOAc/hexane); H NMR
(300 MHz, CDCl3)  2.93 (s, 3H), 4.33 (s, 3H), 7.34 (d, J = 6.9 Hz, 1H), 7.45 (t, J = 7.5 Hz, 3H),
7.56 (s, 1H), 7.64 (d, J = 6.9 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H), 8.25 (s, 1H), 8.31 (d, J = 7.8 Hz,
2H); 13C{1H} NMR (75 MHz, CDCl3)  18.0, 55.8, 119.9, 120.9, 125.8, 126.1, 127.4, 127.9,
128.5, 130.9, 131.6, 133.0, 135.9, 137.9, 144.3, 148.0, 159.3, 170.7 ppm; HRMS (ESI) m/z
calcd for C20H17N2O [M+H]+ 301.1335, found 301.1347.
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