Silver-catalyzed tandem 5- And 6-endo-cyclizationsviaconcomitant yne-ol-imine activation: selective entry to 2-aryldihydrofuroquinolines

Article abstract of DOI:10.1039/d1nj02643g

A silver(i) catalyzed domino imination-intramolecular biheterocyclization-aromatization cascade has been developed to construct 2-aryl/-heteroaryl dihydrofuroquinolines in moderate to good yield using an aldehyde and unprotected 4-(2-aminophenyl)but-3-yn-1-ol as precursors. Sequential Ag-(i)-induced 5-endo-digcyclization of the yne-ol part and 6-endo-trigcyclization of a proposed Ag-bound imine, followed by aromatization, furnish the furoquinoline derivatives.

Full text of DOI:10.1039/d1nj02643g

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Silver-catalyzed tandem 5- and 6-endo-
cyclizations via concomitant yne-ol-imine
Cite this: DOI: 10.1039/d1nj02643g
activation: selective entry to
2-aryldihydrofuroquinolines†
a
a
b
Swastik Karmakar, * Prasanta Das and Sandip Kundu
Received 29th May 2021,
Accepted 13th July 2021
A silver(I) catalyzed domino imination-intramolecular biheterocyclization-aromatization cascade has
been developed to construct 2-aryl/-heteroaryl dihydrofuroquinolines in moderate to good yield using
an aldehyde and unprotected 4-(2-aminophenyl)but-3-yn-1-ol as precursors. Sequential Ag-(I)-induced
DOI: 10.1039/d1nj02643g
5
-endo-dig cyclization of the yne-ol part and 6-endo-trig cyclization of a proposed Ag-bound imine,
rsc.li/njc
followed by aromatization, furnish the furoquinoline derivatives.
methodology could be developed to achieve poly-heterocyclization
putting a hydroxyl group on the alkyne chain of unprotected
Introduction
Indole and quinoline cores have been synthesized using numerous 2-alkynyl aniline along with in situ imination on it (Scheme 1).
popular strategies as these ring-systems are part of the structure of a Importantly, Huang et al. isolated 2,3-fused indoles from their silver-
7
wide array of pharmaceuticals, agrochemicals and important natural catalyzed reaction on N-protected 4-(2-aminophenyl)but-3-yn-1-ols
1
products. Cycloisomerizations involving 5- or 6-endo- or -exo-dig or and aldehydes, though their starting materials are similar to this
-
trig pathways are some of the most efficient and favourite cycliza- investigation. They could not find any furoquinoline derivative
2
tion processes for synthesizing these heterocyclic frameworks.
Though there are several examples of syntheses of heterocyclic cores
employing metal catalyzed activation of alkenes, alkynes and car- catalyzed (Pd(II)-acid) and Flynn’s iodonium-catalyzed
bon–heteroatom bonds via these cyclization processes, construc- approaches are noteworthy. Dihydrofuro-1,2-dihydroquinoline
tion of poly-hetero-cyclic scaffolds following the same strategy is derivatives were synthesized via Sc(OTf)3 catalysis using
somewhat less documented. Such approaches towards poly- N-protected o-alkynylanilines and aldehydes as precursors by
heterocyclic cores reduce chemical hazards of tedious multistep Ma et al. Youn and co-workers reported the formation of
synthesis and also enhance the efficacy of a chemical transforma- furoquinoline 3a (Table 1) in a Pd(OAc)
during their transformation.
8
a
In this context, Ma’s scandium(III)-catalyzed, Youn’s dual-
8
c
8b,d
2,3
4
8
a
4
2
-p-TsOH dual-catalysed
tion. Notably, poly-hetero-cyclic compounds with indole or/and process. They also showed that silver(I) did not catalyze the
8
c
quinoline moieties have proven their potent medicinal activity reaction to produce 3a under their reaction conditions. Inter-
1,4e
against various fatal diseases. Moreover, in the past two decades, estingly, Flynn’s group was able to furnish 3a in their metal-free
8
b,d
silver(I) has become an attractive catalyst for organic transformations iodonium-catalyzed approaches.
due to its efficacy, easy availability and low-cost. To date, its
5
alkynophilicity has influenced numerous elegant transformations.
5
Because of its s- and/or p-Lewis acid character, it can act as a
potential activator of double/triple bonds. Thus, based on our
6
experience on metal catalyzed cyclization and our recent success
in silver-catalyzed synthesis of bis-indolylarylmethane deriva-
6d
tives (BIAMs), we wondered whether a suitable silver-catalyzed
a
Department of Chemistry, Basirhat College, A/w West Bengal State University,
Basirhat-743412, West Bengal, India. E-mail: swastik.karmakar@gmail.com
b
CIF Division, Indian Institute of Chemical Biology (IICB), Jadavpur-700032,
West Bengal, India
†
Electronic supplementary information (ESI) available. CCDC 1952336. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
d1nj02643g
Scheme 1 Ag(I)-Catalyzed annulations under different reaction conditions.
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a
Table 1 Optimization of the bi-heterocyclization
b,c
Yield (%)
Entry
Catalyst (mol%)
Solvent
1a : 2a
Additives (DMA 20 mol% w.r.t 1a in all cases)
t (h)
3a
4
5
d
1
2
3
4
5
6
7
8
9
AgOTf (8)
AgOTf (3)
AgOTf (3)
AgOTf (3)
AgOTf (3)
AgOTf (3)
Toluene
Toluene
1 : 1
2 : 3
2 : 3
2 : 3
2 : 3
2 : 3
2 : 3
2 : 3
2 : 3
2 : 3
2 : 3
2 : 3
2 : 3
2 : 3
—
—
—
DMA
8
8
8
8
8
6
12
12
12
12
12
12
12
12
0
0
48
30
0
0
0
0
0
0
0
0
0
0
15
0
0
0
PhNMe
2
(DMA)
36
50
20
76
30
20
60
0
0
0
10
0
20
10
0
Toluene
Toluene
Toluene
Toluene
DMSO
TEA
DMA : TEA (2 : 1)
DMA : TEA (2 : 1)
DMA : TEA (2 : 1)
DMA : TEA (2 : 1)
DMA : TEA (2 : 1)
DMA : TEA (2 : 1)
DMA : TEA (2 : 1)
—
5
5
5
5
0
0
0
0
CF
3
2
CO Ag (3)
AgOTf (3)
AgOTf (3)
DMF
10
11
12
13
14
Ag
AgNO
2
CO
3
3
(3)
(3)
EtOH + H
EtOH + H
EtOH + H
Toluene
2
2
2
O
O
O
AgOAc (3)
AgOTf (3) + NaHCO
3
CF
3
SO
3
H
Toluene
—
0
a
d
b
c
Reaction conditions: 1 (0.1 mmol), 2a (0.1 or 0.15 mmol), catalyst (8 or 3 mol%), solvent (1 mL), at 120 1C. Isolated yield w.r.t. 1. Under argon.
8
0 1C. DMA = N,N-dimethylaniline; TEA = triethylamine.
9
However, as our objective was to find an effective silver- Belmont’s obvervation, we envisioned that a polyheterocycliza-
9
catalyzed process for poly-heterocyclization, Belmont’s work
tion cascade might occur via Ag(I)-catalyzed domino activation of
motivated us to consider the role of nitrogenous additives to the yne-ol-imine unit, which could possibly be developed in situ,
8
a
afford Prins type cyclic-etherification in a silver-catalyzed in the presence of nitrogenous additives. Thus, the reaction was
method. Thus, we decided to carry out an investigation by conducted using N,N-dimethylaniline (DMA) as a solvent (Table 1,
treating unprotected 4-(2-aminophenyl)but-3-yn-1-ol and ben- entry 3). To our astonishment, bis-indolylbenzylmethane 4 was
zaldehyde with silver(I) in the absence or presence of some not formed and the desired tandem bi-cyclization was observed
0
nitrogenous bases/additives.
under these conditions. Relatively low polar 2-phenyl 2 ,
3
0
-dihydrofuroquiniline 3a was obtained in 36% yield, albeit an
unwanted adduct 5 was formed via condensation between DMA
and the aldehyde (20%). It reveals that Ag(I) shows different
activity in the presence of nitrogenous solvent/additives. To
Results and discussion
Initially, the reaction was conducted following our earlier increase the yield of 3a, we thought that DMA could be used as
6
d
conditions. AgOTf (8 mol%) was taken in toluene under argon an additive instead of using it as a solvent. Thus, the domino
and, subsequently, the substrates 4-(2-aminophenyl)but-3-yn-1- process was run with 20 mol% of N,N-dimethylaniline (DMA) in
ol and benzaldehyde were added in a 1 : 1 ratio (this ratio is toluene at 120 1C using AgOTf as a catalyst (3 mol%) (Table 1,
6
d
different from our previous report ). The reaction mixture was entry 4). The yield of tricyclic scaffold 3a increased dramatically
stirred for 8 hours at 80 1C (Table 1, entry 1). Under these (50%) along with a small amount of adduct 5 (10%). The use of a
conditions, substituted bis-indolylbenzylmethane 4 was the non-nucleophilic base triethylamine (TEA) instead of DMA did not
only product isolated along with some unreacted starting produce better results (Table 1, entry 5). 3a was formed only in
materials. We then re-investigated the reaction at elevated 20% yield. To reduce the formation of 5, it was decided to use TEA
temperature i.e. at 120 1C with low catalyst loading (3 mol%) in conjunction with DMA. Surprisingly, when the reaction was
by changing the mode of addition of the substrates and catalyst carried out with a combination of nitrogeneous bases N,N-
(
Table 1, entry 2). Thus, the substrates 4-(2-aminophenyl)but-3- dimethylaniline–triethylamine (DMA–TEA; 20 mol% : 10 mol%)
yn-1-ol and benzaldehyde (2 : 3) were stirred for 10 min in keeping the catalyst loading and other parameters the same, 3a
toluene at 120 1C in a sealed tube under argon.
was obtained in satisfactory yield (76%) and formation of adduct 5
After that, AgOTf was added to the stirred solution and it was observed only in a trace amount (E5%) (Table 1, entry 6).
was allowed to run for 8 hours with TLC monitoring. But However, silver trifluoroacetate did not show better catalytic
remarkable change was not found except formation of a activity under these conditions (Table 1; entry 7). Notably, polar
complex mixture. Moreover, formation of a small amount of aprotic solvent DMF was found to be another effective workable
bis-indolylbenzylmethane 4 was observed. Despite our unsuccess- medium compared to DMSO for this transformation (Table 1;
ful efforts under neutral conditions, we turned our attention to entries 9 and 8). Other silver catalysts (Ag
2 3 3
CO , AgNO , and
run this investigation under basic conditions. Inspired by AgOAc) did not catalyze the reaction in polar protic solvents
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(Table 1; entries 10–12). Furthermore, 3a was formed in a small aromatization transformed into 2-aryl/heteroaryl dihydrofuroqui-
amount with some bis-indolylbenzylmethane 4 when NaHCO nolines VII. A plausible explanation of this silver-catalyzed aroma-
3
was used as a base instead of DMA–TEA (Table 1; entry 13). tization could be given based on the usual captodative effect of
Trifluoromethane-sulfonic acid itself did not show any catalytic silver. Ag(I)-induced probable b-hydride elimination from VI
activity for this transformation (Table 1; entry 14). Thus, AgOTf followed by regeneration of Ag(I) from N-bound-silver might
proved to be an effective catalyst among others (Table 1, entry 4). develop aromatization in the presence of a nitrogenous base to
10
Finally, this optimization process led to the conclusion that furnish VII under an argon atmosphere (Scheme 2).
sequential 5-endo-dig and 6-endo-trig biheterocyclization could In this transformation, sequential s- and p-electronic rear-
0
0
be achieved to furnish 2-phenyl-2 ,3 -dihydrofuroquiniline 3a rangements occur in a tandem bond-making-bond-breaking
under basic conditions with low catalyst loading (3 mol%) and cascade under the influence of domino silver catalysis. In
high energy of activation (120 1C) (Table 1; entry 6), while bis- view of the wide applicability of quinoline derivatives in
1
indolylbenzylmethane 4 could be formed under neutral condi- pharmacology, the scope of the synthesis of 2-aryl dihydrofur-
tions with relatively high catalyst loading (8 mol%) and low energy oquinoline derivatives was explored based on the optimized
of activation (80 1C) (Table 1; entry 1) from the same substrate condition 4 (Table 1, entry 6). Thus, a set of 2-aryl/heteroaryl
combination.
dihydrofuroquinolines (3a–n) were synthesized in moderate to
Herein, to understand this silver-catalyzed domino biheter- good yield (47–78%) from unprotected 4-(2-aminoaryl)but-3-yn-
ocyclization, a plausible mechanistic manifold has been 1-ols 1 and various aldehydes 2 (Table 2). Benzaldehyde and its
proposed (Scheme 2) where Ag(I) is supposed to catalyze the p-Me and p-Cl analogues responded well to afford the corres-
intermolecular in situ imination selectively via condensation ponding products in good yield (71–76%; 3a–c; Table 2).
between the aldehyde (II) and amine (I) under basic conditions Whereas, the product yields from o-substituted benzaldehydes
to furnish a probable intermediate III, instead of promoting were comparatively low presumably due to steric hindrance
usually found intramolecular 5-endo-dig cyclization between the which may arise during 6-endo-trig cyclization (60–68%; 3d and
amine group (–NH ) and alkyne unit leading to a pyrrole core. e; Table 2). But this bicyclization worked well for o-hydroxy
2
Loosely bound Ag(I) of intermediate III may then induce Prins- benzaldehyde (3e, 68%) compared to o-chloro benzaldehyde
type 5-endo-dig cyclization via activation of the alkyne unit to (3d, 60%). This difference in yield could be explained by
afford a proposed Ag-bound intermediate IV.
reduced steric hindrance in the transition state arising due to
It is noteworthy that silver-catalyzed in situ imination and Prins- probable H-bonding between the hydroxyl group and the imine
type cyclization may occur simultaneously to produce intermediate nitrogen. When the reaction was carried out with vanillin, the
IV. At this stage, proto-deargentation may occur to produce the corresponding product was formed in 72% yield (3f). It is
dihydrofuran core. Ag(I) then coordinates to the imine nitrogen (V) noteworthy that m- and p-substituents on the benzene nucleus
and thus induces 6-endo-trig cyclization of the enol-substructure did not influence the product yield. Moreover, as various
to the electrophilic imine carbon of V to furnish Ag-bound heterocyclic cores like furan/thiophene or pyrrole in a molecule
1
bi-heterocyclic core VI, which on proto-deargentation followed by usually make it medicinally significant, an attempt was made
to tether these heterocycles to the dihydrofuroquinoline scaf-
fold. To our delight, the domino reaction proceeded smoothly
with furfural and thiophene-2-carbaldehyde to produce corres-
ponding products 3g (77%) and 3i (76%) in good yield.
But, unprotected pyrrole-2-aldehyde failed to produce the
expected product except a complex mixture. However, 3h was
isolated in moderate yield (55%) on executing the reaction with
benzyl protected pyrrole 2-aldehyde. We then tried to incorpo-
rate an indole core into this scaffold. Optimized condition 6
(Table 1, entry 6) did not work well for this transformation with
the substrate N-protected-indole-3-carbaldehydes. Following
these conditions, when the reaction was conducted at 120 1C
in toluene with additives DMA–TEA (2 : 1) and AgOTf (3 mol%),
2-indolyl dihydrofuroquinoline 3j was obtained only in 30%
yield. To modify the reaction conditions, it was allowed to run
in DMA using it as a solvent instead of toluene in conjunction
with 20 mol% of TEA at 140 1C. Surprisingly, the product yield
was improved and 3j was obtained in 65% yield along with
some aldehyde–DMA adduct (15% w.r.t aldehyde). Similarly, 3k
and 3l were obtained in moderate yields (52 and 60% respectively)
under these conditions. In view of the medicinal importance of
the chloro-substituted quinoline core embodied in chloroquine,
hydroxychloroquine etc., 3m and 3n were synthesized in moderate
Scheme 2 Proposed mechanism for bihererocyclization.
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Table 2 Scope of 2-aryl 2 ,3 -dihydrofuroquinoline 3
Conclusions
In conclusion, we have observed a unique behavior of a silver
catalyst to induce a domino biheterocyclization via tandem
5-endo-dig and 6-endo-trig cyclizations of the yne-ol-imine unit
followed by aromatization in the presence of nitrogenous
1
1
additives which may act as ligands for silver(I) under basic
conditions. We have also synthesized 2-indolyl, -pyrrolyl,
-
thiophenyl, -furanyl and -aryl substituted dihydrofuroquino-
line derivatives following this optimized domino process in
moderate to good yields. As all these heterocycles are part of the
structure of various medicinally significant molecules, these
newly derived 2-aryl/heteroaryl dihydrofuroquinolines may find
their use in the pharmaceutical industry. In a wider sense, the
domino process described herein might get decent entry to a
silver-mediated oxidative rearrangement of yne-ol-imine sys-
tems. The scope of this reaction and structural modifications of
some of the compounds are currently under investigation in
our laboratory.
Experimental section
General methods
Solvents were dried and distilled following standard proce-
dures. TLC analyses were carried out on aluminium sheets
coated with silica gel 60 F254. All chemical reactions were run
under an argon atmosphere in flame-dried glassware. Flash
chromatography was done using Merck silica gel 60 (partial size
1
13
0
.04–0.063 mm). H NMR and C NMR spectra were recorded
on a 400 MHz Bruker NMR spectrometer at 25 1C (100 MHz
1
3
13
for C). All C NMR spectra were proton decoupled. Chemical
shifts were quoted in parts per million (ppm) referenced to
1
0
.00 ppm for tetramethylsilane. Data for H NMR spectra are
provided as follows: chemical shift (d shift), multiplicity
s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet,
dd = doublet of doublets, brs = broad singlet), integration,
coupling constant ( J in Hz). A PerkinElmer FT-IR spectrometer
was used for recording infrared (IR) spectra.
(
yield (47% and 51% respectively) from corresponding chloro-
substituted alkyne-amines 1b and 1c. Notably, 2-indolyl dihydro-
furoquinoline cannot be synthesized using unprotected 1H-
indole-3-carbaldehyde as a starting material. However, the thus
obtained N-protected-2-indolyl dihydrofuroquinolines have the
scope of further functionalization on their protecting groups.
On the contrary, when the reaction was run using aliphatic
aliphatic aldehydes as starting materials such as propionaldehyde
and acrolein, an inseparable complex mixture was obtained.
The structure of 3j was confirmed by X-ray crystallographic
analysis (Fig. 1). Detailed spectral analysis determined the
structures of all products.
General procedure for the synthesis of alkyne-amines 1a–c
Alkyne-amines (1a–c) were synthesized on a gram-scale from
2-iodoaniline and 3-butyn-1-ol employing a palladium-copper
catalyzed Sonogashira coupling reaction.
Synthesis of 4-(2-aminophenyl)but-3-yn-1-ol (1a)
PdCl (PPh ) (0.064 g, 0.09 mmol), CuI (0.036 g, 0.19 mmol)
2
3 2
and 2-iodoaniline (2 gm, 9.13 mmol) were taken in a round
bottom flask previously flushed with argon, and triethylamine
(15 mL) was added to it at room temperature. After that,
3-butyn-1-ol (0.645 gm, 9.2 mmol) was added dropwise. The
reaction mixture was stirred for 12 hours at room temperature.
After completion, Et O and water were added and the product
2
was extracted with Et
water and brine, dried over Na
The residue was purified by column chromatography on silica
2
O. The organic layer was washed with
2
SO , filtered and evaporated.
4
Fig. 1 Molecular structure of 3j by X-ray single crystal analysis.
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1
gel (hexane–ethylacetate; 6 : 1) to afford 1.24 gm (7.7 mmol) of 818, 749; H NMR (400 MHz, CDCl
-(2-aminophenyl)but-3-yn-1-ol in 84% yield.
3
) d 8.06 (d, J = 8.4 Hz, 1H),
4
7.87 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8 Hz, 2H), 7.61–7.57 (m, 1H),
7
2
.38 (t, J = 7.4 Hz, 1H), 7.24 (d, J = 8 Hz, 2H), 4.81 (t, J = 8.8 Hz,
H), 3.51 (t, J = 8.8 Hz, 2H), 2.36 (s, 3H); C NMR (100 MHz,
General procedure for the synthesis of the dihydrofuroquinoline
derivatives 3a–i: synthesis of 4-phenyl-2, 3-dihydrofuro[3,2-c]quinoline
(
13
CDCl ) d 164.4, 155.5, 149.0, 138.9, 137, 129.7, 129.3, 129.1,
3
3a)
A combination of DMA (15 mg, 0.12 mmol)–TEA (6 mg, analysis observed: C, 82.55; H, 5.62; N, 5.23; calcd for
.06 mmol) (20 mol% : 10 mol% w. r. t. alkyne) was taken in a 15NO:C, 82.73; H, 5.79; N, 5.36.
128.3, 125.3, 121.4, 115.9, 115.0, 73.1, 30.2, 21.4; elemental
0
18
C H
sealed tube at 25 1C. A mixture of 4-(2-aminophenyl)but-3-yn-1-
ol 1a (100 mg, 0.62 mmol) and benzalaldehyde 2a (99 mg,
4
-(4-chlorophenyl)-2, 3-dihydrofuro[3,2-c]quinoline (3c)
ꢀ1
0.93 mmol) in toluene (0.5 mL) was then added dropwise via a White crystalline solid, mp. 121–123 1C. IR (neat, cm ): 2961,
cannula into the sealed tube and the reaction mixture was 2920, 2854, 1629, 1589, 1572, 1548, 1488, 1410, 1390, 1337,
1
placed in a pre-heated oil bath at 120 1C and was stirred for 1261, 1086, 1012, 845, 812, 763; H NMR (400 MHz, CDCl3)
10 minutes. After that, AgOTf (6 mg, 0.02 mmol, 3 mol% with d 8.02 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.78 (d, J =
respect to alkyne 1) was taken in anhydrous toluene (0.5 mL) 8.8 Hz, 2H), 7.61–7.57 (m, 1H), 7.41–7.37 (m, 3H), 4.80 (t, J =
1
3
3
and was added dropwise into the reaction mixture by a syringe 9 Hz, 2H), 3.47 (t, J = 9 Hz, 2H); C NMR (100 MHz, CDCl )
under an argon atmosphere. It was monitored by TLC. Upon d 164.5, 154.2, 149.1, 138.3, 134.9, 129.9, 129.7, 129.2, 128.7,
completion, the solvent was removed under a vacuum and the 125.6, 121.4, 116.0, 114.9, 73.1, 30.1; elemental analysis
crude product was subjected to flash column chromatography observed: C, 72.29; H, 4.20; N, 4.85; calcd for C H ClNO: C,
1
7
12
(5% EA/hexane) to afford the pure product 3a (116 mg, 72.47; H, 4.29; N, 4.97.
0
.47 mmol) in 76% yield. The following products (3a–i) are
4
-(2-chlorophenyl)-2,3-dihydrofuro[3,2-c]quinoline (3d)
obtained from this study and their spectral data are included.
ꢀ1
White crystalline solid, mp. 117–119 1C. IR (neat, cm ): 3060,
2
1
General procedure for syntheses of the dihydrofuroquinoline derivatives
973, 2923, 2863, 1632, 1598, 1552, 1508, 1477, 1405, 1277,
3j–n: synthesis of 4-(1-benzyl-1H-indol-3-yl)-2, 3-dihydrofuro[3,2-c]quino-
1
3
260, 1088, 1059, 913, 760, 643; H NMR (400 MHz, CDCl )
line (3j)
d 8.03 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.62–7.57 (m,
-(2-Aminophenyl)but-3-yn-1-ol 1a (1 g, 6.2 mmol) and 1H), 7.44–7.38 (m, 3H), 7.32–7.27 (m, 2H), 4.79 (t, J = 9 Hz, 2H),
4
1
3
N-benzyl-indole-3-carbaldehyde 2j (2.18 g, 9.3 mmol) were 3.21 (t, J = 9 Hz, 2H); C NMR (100 MHz, CDCl ) d 163.6, 155.1,
3
added into a mixture of DMA (10 mL) and TEA (0.12 g, 148.9, 139.1, 132.3, 130.7, 129.8, 129.7, 129.3, 127.1, 125.8,
1.2 mmol, 20 mol% with respect to alkyne) in a sealed tube. 121.4, 117.2, 116.2, 73.4, 28.7; elemental analysis observed: C,
The reaction mixture was placed in a pre-heated oil bath at 72.32; H, 4.18; N, 4.83; calcd for C17 12ClNO:C, 72.47; H, 4.29;
H
140 1C and was stirred for 10 minutes. After that, AgOTf (60 mg, N, 4.97.
0
.2 mmol, 3 mol% with respect to alkyne 1) was added into the
2-(2,3-dihydrofuro[3,2-c]quinolin-4-yl)phenol (3e)
reaction mixture. It was monitored by TLC. Upon completion,
ꢀ1
the solvent was removed under a vacuum and the crude Yellow crystalline solid, mp. 142–144 1C. IR (neat, cm ): 3424,
product was subjected to flash column chromatography (10% 2923, 1635, 1609, 1584, 1500, 1418, 1251, 1090, 755, 737;
1
EA/hexane) to afford the pure product 3j (1.5 g, 4 mmol) in 65%
H NMR (400 MHz, CDCl ) d 7.91–7.85 (m, 2H), 7.69 (d, J = 8
3
yield. The following products 3k–n are obtained from this study Hz, 1H), 7.63–7.59 (m, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.26 (t, J = 7.6
and their spectral data are included. Some aldehyde–DMA Hz, 2H), 7.02 (d, J = 8.4 Hz, 1H), 6.82 (t, J = 7.6 Hz, 1H), 4.85
1
3
adduct (15–20% with respect to aldehyde) was formed during (t, J = 9 Hz, 2H), 3.69 (t, J = 9 Hz, 2H); C NMR (100 MHz,
each transformation. CDCl ) d 165.4, 161.3, 155.4, 145.4, 131.4, 130.6, 128.1, 126.7,
25.7, 121.5, 119.9, 118.6, 118, 115.6, 113.6, 73, 31.6; elemental
analysis observed: C, 77.29; H, 4.90; N, 5.16; calcd for
White crystalline solid, mp. 58–60 1C. IR (neat, cm ): 3056, C H NO : C, 77.55; H, 4.98; N, 5.32.
3
1
4-phenyl-2, 3-dihydrofuro[3,2-c]quinoline (3a)
ꢀ
1
1
7
13
2
2
1
960, 2916, 1630, 1588, 1551, 1506, 1493, 1411, 1342, 1267,
086, 918, 906, 760, 701. H NMR (400 MHz, CDCl ) d 8.04
3
1
4-(2,3-dihydrofuro[3,2-c]quinolin-4-yl)-2-methoxyphenol (3f)
ꢀ
1
(d, J = 8.8 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.83–7.79 (m, 2H), Greyish white crystalline solid, mp. 175–177 1C. IR (neat, cm ):
7
.60–7.56 (m, 1H), 7.44–7.33 (m, 4H), 4.78 (t, J = 9 Hz, 2H), 3.47 3444, 2921, 2853, 1626, 1587, 1538, 1495, 1387, 1368, 1291,
1
3
1
3 3
(t, J = 9 Hz, 2H); C NMR (100 MHz, CDCl ) d 164.3, 155.6, 1181, 1057, 971, 845, 733, 697; H NMR (400 MHz, CDCl ) d 8.05
1
1
49.2, 139.9, 129.7, 129.3, 128.8, 128.6, 128.3, 125.4, 121.4, (d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.61–7.56 (m, 2H),
16.0, 115.1, 73.1, 30.1; elemental analysis observed: C, 82.38; 7.38 (t, J = 7.4 Hz, 1H), 7.27 (dd, J = 2, J = 8 Hz, 1H), 6.93 (d, J = 8
H, 5.19; N, 5.51; calcd for C H NO: C, 82.57; H, 5.30; N, 5.66. Hz, 1H), 4.82 (t, J = 9 Hz, 2H), 3.94 (s, 3H), 3.52 (t, J = 9 Hz, 2H);
1
7
13
1
3
C NMR (100 MHz, (CD ) SO) d 164, 154.8, 148.6, 148.3, 147.9,
30.9, 130.2, 129.1, 125.6, 121.9, 121.6, 115.7, 115.6, 112.7, 73.6,
3
2
4
-p-tolyl-2, 3-dihydrofuro[3,2-c]quinoline (3b)
White crystalline solid, mp. 85–87 1C. IR (neat, cm ): 3085, 56.1, 30.3; elemental analysis observed: C, 73.57; H, 5.08; N,
994, 2905, 1631, 1588, 1549, 1498, 1425, 1340, 1272, 1085, 926, 4.66; calcd for C18 : C, 73.71; H, 5.15; N, 4.78.
1
ꢀ
1
2
H15NO
3
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NJC
1
4
-(furan-2-yl)-2,3-dihydrofuro[3,2-c]quinoline (3g)
1058, 943, 812, 744, 658; H NMR (400 MHz, CDCl
(brs, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.82 (d, J = 8 Hz, 1H), 7.61–7.55
m, 1H) 7.39 (s, 1H), 7.28–7.21 (m, 3H), 5.97–5.88 (m, 1H), 5.15
(d, J = 10.4 Hz, 1H), 5.04 (dd, J = 8 Hz, J = 1 Hz, 1H), 4.77 (t, J = 9
3
) d 8.80
ꢀ
1
Greyish white crystalline solid, mp. 77–79 1C. IR (neat, cm ):
(
2
8
1
1
961, 2924, 1632, 1590, 1504, 1424, 1345, 1248, 1088, 1034, 885,
08, 748, 657; H NMR (400 MHz, CDCl ) d 8.00 (d, J = 8.8 Hz,
3
1
1
3
Hz, 2H), 4.68–4.66 (m, 2H), 3.41 (t, J = 9 Hz, 2H); C NMR
100 MHz, CDCl ) d 163.5, 152.3, 149.2, 136.7, 132.9, 129.3,
128.8, 128.7, 127.3, 124.3, 123.4, 122.7, 121.2, 121.1, 117.7,
15.7, 115.4, 113.8, 109.5, 72.6, 49, 30.6; elemental analysis
observed: C, 80.79; H, 5.48; N, 8.41; calcd for C22 O: C,
0.96; H, 5.56; N, 8.58.
H), 7.81 (d, J = 8 Hz, 1H), 7.58–7.54 (m, 2H), 7.34 (t, J = 7.4 Hz,
H), 7.06 (d, J = 3.2 Hz, 1H), 6.51 (t, J = 1.6 Hz, 1H), 4.82 (t, J = 9
(
3
1
3
Hz, 2H), 3.57 (t, J = 9 Hz, 2H); C NMR (100 MHz, CDCl3)
d 164.5, 153.6, 149.0, 145.9, 143.9, 129.8, 128.9, 125.2, 121.3,
1
18 2
H N
115.9, 113.3, 111.9, 111.1, 73.2, 29.9; elemental analysis
8
observed: C, 75.86; H, 4.59; N, 5.79; calcd for C15 : C,
H11NO
2
75.94; H, 4.67; N, 5.90.
4-(1-(prop-2-ynyl)-1H-indol-2-yl)-2,3-dihydrofuro[3,2-c]-quinoline (3l)
ꢀ
1
4-(1-benzyl-1H-pyrrol-2-yl)-2, 3-dihydrofuro[3,2-c]quino-line
Pale yellow crystalline solid, mp. 148–150 1C. IR (neat, cm ):
(
3h)
3271, 2962, 2909, 2123, 1628, 1587, 1542, 1504, 1390, 1296,
1
ꢀ
1
1191, 1059, 895, 735, 655; H NMR (400 MHz, CDCl ) d 8.78
3
Pale yellow crystalline solid, mp. 68–70 1C. IR (neat, cm ):
3
1
(
d, J = 7.2 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 8 Hz, 1H),
7.59 (d, J = 7.2 Hz, 1H), 7.56 (s, 1H), 7.36–7.32 (m, 2H), 7.30–7.23
m, 2H), 4.84 (d, J = 2.4, 2H), 4.81 (t, J = 9 Hz, 2H), 3.46 (t, J = 9
060, 2921, 2850, 1630, 1591, 1501, 1476, 1438, 1420, 1327,
262, 1087, 1043, 906, 764, 720; H NMR (400 MHz, CDCl )
3
1
(
d 7.86 (d, J = 4.8 Hz, 1H), 7.79 (d, J = 8 Hz, 1H), 7.52 (t, J = 7.6 Hz,
H), 7.32 (t, J = 7.6 Hz, 1H), 7.14–7.05 (m, 3H), 6.96 (d, J = 7.2
Hz, 2H), 6.82 (s, 1H), 6.58–6.56 (m, 1H), 6.22 (t, J = 3.2 Hz, 1H),
1
3
Hz, 2H), 2.39 (t, J = 2.2 Hz, 1H); C NMR (100 MHz, CDCl3)
d 163.4, 151.9, 149.1, 136.2, 129.3, 128.8, 128.1, 127.5, 124.4,
123.7, 122.9, 121.3, 121.2, 116.1, 115.4, 113.8, 109.1, 74.1, 72.6,
1
1
3
5
.82 (s, 2H), 4.77 (t, J = 9 Hz, 2H), 3.41 (t, J = 9 Hz, 2H); C NMR
3
8
5.9, 30.4; elemental analysis observed: C, 81.22; H, 4.88; N,
.48; calcd for C22 O: C, 81.46; H, 4.97; N, 8.64.
(100 MHz, CDCl ) d 163.7, 149.2, 148.5, 139.8, 130.7, 129.4,
3
16 2
H N
1
1
8
28.7, 128.4, 126.9, 126.8, 126.2, 124.8, 121.3, 115.5, 114.8,
12.8, 108.1, 72.9, 52.4, 30.6; elemental analysis observed: C,
0.73; H, 5.47; N, 8.44; calcd for C22H N O: C, 80.96; H, 5.56;
18 2
8-chloro-4-(1-(prop-2-ynyl)-1H-indol-3-yl)-2, 3-dihydro-furo[3,2-c]quinoline
(3m)
N, 8.58.
ꢀ1
Yellow crystalline solid, mp. 163–165 1C. IR (neat, cm ): 3096,
4
-(thiophen-2-yl)-2, 3-dihydrofuro[3,2-c]quinoline (3i)
2922, 2817, 1652, 1526, 1468, 1401, 1386, 1175, 1136, 1038, 990,
1
ꢀ
1
928, 747; H NMR (400 MHz, CDCl ) d 8.81 (d, J = 6.8 Hz, 1H),
3
Greyish white crystalline solid, mp. 114–116 1C. IR (neat, cm ):
7.99 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 2.4 Hz, 1H), 7.54 (s, 1H), 7.49
2
1
961, 2922, 2855, 1628, 1587, 1552, 1503, 1370, 1344, 1261,
080, 1024, 804, 761, 700; H NMR (400 MHz, CDCl ) d 7.95
3
1
(dd, J = 2 Hz, J = 8.8 Hz, 1H), 7.35 (d, J = 6.8 Hz, 1H), 7.30–7.24
(
(
m, 2H), 4.85 (d, J = 2.4 Hz, 2H), 4.81 (t, J = 9 Hz, 2H), 3.45
t, J = 9 Hz, 2H), 2.39 (t, J = 2.4 Hz, 1H); C NMR (100 MHz,
(
(
d, J = 8.8 Hz, 1H), 7.78 (d, J = 8 Hz, 1H), 7.57–7.53 (m, 1H),7.47
brs, 1H), 7.38 (dd, J = 2, J = 4.8 Hz, 1H), 7.34–7.30 (m, 1H),
1
3
CDCl ) d 162.9, 152.4, 146.3, 132.3, 136.5, 130.5, 130.4, 130.1,
3
7
.08–7.05 (m, 1H), 4.84–4.78 (m, 2H), 3.54–3.48 (m, 2H);
1
3
128.4, 127.6, 123.8, 123.3, 121.7, 120.5, 116.1, 114.7, 109.4, 74.5,
C NMR (100 MHz, CDCl
3
) d 164.4, 149.3, 148.9, 144.8, 129.8,
72.9, 36.3, 30.7; elemental analysis observed: C, 73.31; H, 4.12;
1
28.8, 128.3, 127.9, 126.7, 125.1, 121.3, 115.9, 113.1, 72.9, 30.3;
N, 7.65; calcd for C22 15ClN O: C, 73.64; H, 4.21; N, 7.81.
H
2
elemental analysis observed: C, 70.95; H, 4.30; N, 5.41; calcd for
11NOS: C, 71.12; H, 4.38; N, 5.53.
15
C H
4
(
-(1-allyl-1H-indol-3-yl)-7-chloro-2,3-dihydrofuro[3,2-c]-quinoline
3n)
Greyish white crystalline solid, mp. 160–162 1C IR (neat, cm ):
941, 1624, 1585, 1537, 1494, 1417, 1306, 1286, 1213, 1054, 909,
4
-(1-benzyl-1H-indol-3-yl)-2, 3-dihydrofuro[3,2-c]quino-line (3j)
ꢀ
1
ꢀ1
White crystalline solid, mp. 180–182 1C. IR (neat, cm ): 3137,
2
2
8
1
964, 2920, 1629, 1593, 1540, 1504, 1393, 1366, 1297, 1058, 921,
1
1
748; H NMR (400 MHz, CDCl ) d 8.84 (brs, 1H), 8.07 (brs, 1H),
3
94, 772, 731; H NMR (400 MHz, CDCl
3
) d 8.81 (d, J = 5.6 Hz,
7.76–7.72 (m, 1H), 7.39 (s, 1H), 7.26–7.19 (m, 4H), 5.99–5.89
H), 8.11 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.60–7.56
(m, 1H), 5.17 (d, J = 10.4 Hz, 1H), 5.06 (d, J = 16.8 Hz, 1H),
(m, 1H) 7.49 (s, 1H), 7.36–7.32 (m, 1H), 7.26–7.19 (m, 6H), 7.08
4
.81–4.76 (m, 2H), 4.69 (d, J = 1.2 Hz, 2H), 3.43–3.38 (m, 2H);
(d, J = 2 Hz, 1H), 7.07 (s, 1H), 5.32 (s, 2H), 4.81 (t, J = 9 Hz, 2H),
1
3
1
3
C NMR (100 MHz, CDCl ) d 163.6, 153.5, 149.7, 136.9, 135.3,
3
3
1
1
.43 (t, J = 9 Hz, 2H); C NMR (100 MHz, CDCl ) d 163.6, 152.4,
3
132.9, 129.3, 127.8, 127.4, 125.3, 123.8, 123, 122.8, 121.4, 117.9, 114.1,
49.4, 137.1, 129.4, 129.3, 129, 128.9, 127.9, 127.6, 126.8, 124.5,
23.7, 123.1, 121.3, 116.2, 115.6, 113.9, 109.7, 72.8, 50.4, 30.7;
113.9, 109.7, 72.9, 49.2, 30.8; elemental analysis observed: C, 73.11; H,
4
.66; N, 7.81; calcd for C H ClN O: C, 73.23; H, 4.75; N, 7.76.
22
17
2
elemental analysis observed: C, 82.76; H, 5.27; N, 7.29; calcd for
O: C, 82.95; H, 5.35; N, 7.44.
26 20 2
C H N
Author contributions
4-(1-allyl-1H-indol-2-yl)-2,3-dihydrofuro[3,2-c]quinoline (3k)
ꢀ
1
Greyish white crystalline solid, mp. 159–161 1C. IR (neat, cm ): The project was conceived and supervised by S. Karmakar. All
285, 2923, 2851, 1610, 1519, 1461, 1344, 1185, 1162, 1121, experiments were conducted by S. Karmakar and P. Das. The
3
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Paper
manuscript and ESI were prepared by S. Karmakar, and
S. Kundu carried out X-ray single crystal structure analysis.
All authors have given approval to the final version of the
manuscript.
4 (a) L. F. Tietze, Chem. Rev., 1996, 96, 115–136;
(b) K. C. Nicolaou and J. S. Chen, Chem. Soc. Rev., 2009,
38, 2993–3009; (c) A. Furstner, Chem. Soc. Rev., 2009, 38,
3208–3221; (d) F. A. Tsao, A. J. Lougha and D. W. Stephan,
Chem. Commun., 2015, 51, 4287–4289; (e) M. Garcia-Castro,
S. Zimmermann, M. G. Sankar and K. Kumar, Angew. Chem.,
Int. Ed., 2016, 55, 7586–7605; ( f ) A. R. Vaidya, V. N. Gogte
and B. D. Tilak, Indian J. Chem., Sect. B: Org. Chem. Incl. Med.
Chem., 1977, 15B(5), 403–407; (g) H. Su, M. Bao, J. Huang,
L. Qiu and X. Xu, Adv. Synth. Catal., 2019, 361, 826–831;
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
(h) S. J. Gharpure, S. K. Nanda, P. A. Adate and Y. G. Shelke,
J. Org. Chem., 2017, 82, 2067–2080.
(a) C. J. Li and X. Bi, Silver Catalysis in Organic Synthesis,
We gratefully acknowledge the ‘‘Science and Engineering
Research Board (SERB), Department of Science and Technology
5
Wiley-VCH, Weinheim, Volumes
1
and 2, 2018;
(DST), Government of India’’ (Grant No. SERB/F/4912/2013-14)
˜
oz, Chem. Soc. Rev., 2014, 43, 3164–3183;
for the financial support of this research.
(b) M. P. Mun
(c) M. Liu, F. Zhou, Z. Jia and C. J. Li, A silver-catalyzed
transfer hydrogenation of aldehyde in air and water,
Org. Chem. Front., 2014, 1, 161–166; (d) G. Fang and X. Bi,
Chem. Soc. Rev., 2015, 44, 8124–8173; (e) H. Pellissier, Chem.
Rev., 2016, 116, 14868–14917; ( f ) Q.-Z. Zheng and N. Jiao,
Chem. Soc. Rev., 2016, 45, 4590–4627; (g) F. Chen and
A. S. K. Hashmi, Org. Lett., 2016, 18, 2880–2882;
References
1
(a) G. W. Gribble, Indole Ring Synthesis: From Natural
Products to Drug Discovery, Wiley, 2016; (b) G. Zeni and
R. C. Larock, Chem. Rev., 2006, 106, 4644–4680;
(
3
c) N. T. Patil and Y. Yamamoto, Chem. Rev., 2008, 108,
395–3442; (d) M. Beller, O. R. Thiel, H. Trauthwein and
C. G. Hartung, Chem. – Eur. J., 2000, 6, 2513–2522;
e) G. Collin and H. H o¨ ke, Quinoline and Isoquinoline,
Ullmann’s Encyclopedia of Industrial Chemistry’, Weinheim,
(h) A. Ahrens, N. F. Heinrich, S. R. Kohl, M. Hokamp,
M. Rudolph, F. Rominger and A. S. K. Hashmi, Adv. Synth.
Catal., 2019, 361, 5605–5615; (i) R. R. Annapureddy, F. Burg,
J. Gram u¨ ller, T. P. Golub, C. Merten, S. M. Huber and
T. Bach, Angew. Chem., Int. Ed., 2021, 60, 7920–7926;
( j) T. Dalton, S. Greßies, M. Das, M. Niehues,
M. L. Schrader, C. Gutheil, B. J. Ravoo and F. Glorius,
Angew. Chem., Int. Ed., 2021, 60, 8537–8541.
6 (a) S. Karmakar, A. Kim and C. H. Oh, Synthesis, 2009,
0194–0198; (b) C. H. Oh and S. Karmakar, J. Org. Chem.,
2009, 74, 370–374; (c) C. H. Oh, S. Karmakar, H. S. Park,
Y. C. Ahn and J. W. Kim, J. Am. Chem. Soc., 2010, 132,
1792–1793; (d) S. Karmakar, P. Das, D. Ray, S. Ghosh and
S. K. Chattopadhyay, Org. Lett., 2016, 18, 5200–5203.
7 Y. Huang, Y. Yang, H. Song, Y. Liu and Q. Wang, Sci. Rep.,
2015, 5, 13516.
(
‘
Wiley-VCH, 2000; ( f ) X.-F. Shang, S. L. Morris-Natschke,
Y.-Q. Liu, X. Guo, X.-S. Xu, M. Goto, J.-C. Li, G.-Z. Yang and
K.-H. Lee, Med. Res. Rev., 2018, 38, 775–828; (g) X.-F. Shanga,
S. L. Morris-Natschkec, G.-Z. Yangb, Y.-Q. Liub, X. Guoe,
X.-S. Xub, M. Gotoc, J.-C. Lib, J.-Y. Zhanga and K.-H. Lee,
Med. Res. Rev., 2018, 38, 1614–1660; (h) B. S. Matada,
R. Pattanashettar and N. G. Yernale, Bioorg. Med. Chem.,
2
021, 32, 115973.
(a) B. M. Trost, Angew. Chem., Int. Ed. Engl., 1989, 28, 1173;
b) D. J. Gorin, B. D. Sherry and F. D. Toste, Chem. Rev.,
008, 108, 3351–3378; (c) K. Gilmore and I. V. Alabugin,
2
(
2
Chem. Rev., 2011, 111, 6513–6556; (d) A. V. Gulevich,
A. S. Dudnik, N. Chernyak and V. Gevorgyan, Chem. Rev.,
8 (a) C. Zhu and S. Ma, Angew. Chem., Int. Ed., 2014, 53,
13532–13535; (b) R. Halim, L. Aurelio, P. J. Scammells and
B. L. Flynn, J. Org. Chem., 2013, 78, 4708–4718; (c) S. K. Ock
and S. W. Youn, Bull. Korean Chem. Soc., 2010, 31, 704–707;
(d) R. Halim, P. J. Scammells and B. L. Flynn, Org. Lett.,
2008, 10, 1967–1970.
2013, 113, 3084–3213; (e) M. Rudolph and A. S. K. Hashmi,
Chem. Commun., 2011, 47, 6536–6544; ( f ) Y.-C. Lee,
K. Kumar and H. Waldmann, Angew. Chem., Int. Ed., 2018,
57, 5212–5226.
3
(a) M. Beller and C. Bolm, Transition Metals for Organic
Synthesis, Wiley-VCH, Weinheim, 2004; (b) L. Ackermann,
Modern Arylation Methods, Wiley-VCH, Weinheim, 2009;
9 E. Parker, N. Leconte, T. Godet and P. Belmont,
Chem. Commun., 2011, 47, 343–345.
(
c) B. M. Trost and C. Li, Modern Alkyne Chemistry, Wiley- 10 B. K. Tate, C. M. Wyss, J. Bacsa, K. Kluge, L. Gelbaum and
VCH, Weinheim, 2014; (d) A. M. Asiri and A. S. K. Hashmi,
J. P. Sadighi, Chem. Sci., 2013, 4, 3068–3074.
Chem. Soc. Rev., 2016, 45, 4471–4503; (e) P. Querard, 11 M. D. Acqua, B. Castano, C. Cecchini, T. Pedrazzini,
S. A. Girard, N. Uhlig and C.-J. Li, Chem. Sci., 2015, 6,
332–7335.
V. Pirovano, E. Rossi, A. Caselli and G. Abbiati, J. Org. Chem.,
2014, 79, 3494–3505.
7
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New J. Chem.