Palladium complexes with an annellated mesoionic carbene (MIC) ligand: Catalytic sequential Sonogashira coupling/cyclization reaction for one-pot synthesis of benzofuran, indole, isocoumarin and isoquinolone derivatives

Article abstract of DOI:10.1039/d0dt02918a

Two Pd(ii) complexes (1 and 2) featuring a fused π-conjugated imidazo[1,2-a][1,8]naphthyridine-based mesoionic carbene ligand have been synthesized and structurally characterized. Both complexes effectively catalyze the one-pot synthesis of benzofuran starting from phenylacetylene and 2-iodophenol under mild conditions. Complex 1 is found to be an excellent catalyst for the straightforward access to a library of benzofuran, indole, isocoumarin and isoquinolone derivatives by the reaction of terminal alkynes with 2-iodo derivates of phenol, N-methyl aniline, benzoic acid and N-methyl benzamide, respectively. The general utility of the catalytic method is demonstrated using a variety of diversely substituted terminal alkynes and the corresponding desired products are obtained in good to excellent yields. On the basis of control experiments, a two-cycle mechanism is proposed which involves the Sonogashira coupling of 2-iodo derivatives with alkynes and the subsequent cyclization of the corresponding 2-alkynyl compounds.

Full text of DOI:10.1039/d0dt02918a

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DOI: 10.1039/D0DT02918A
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ARTICLE
Palladium Complexes with an Annellated Mesoionic Carbene
(MIC) Ligand: Catalytic Sequential Sonogashira
Coupling/Cyclization Reaction for One–Pot Synthesis of
Benzofuran, Indole, Isocoumarin and Isoquinolone Derivatives
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Akshi Tyagi,a Noor U Din Resi,a Prosenjit Daw,a,‡ and Jitendra K. Bera,*a
www.rsc.org/
Two Pd(II) complexes (1 and 2) featuring a fused π–conjugated imidazo[1,2–a][1,8]naphthyridine–based mesoionic
carbene ligand have been synthesized and structurally characterized. Both complexes effectively catalyze the one–pot
synthesis of benzofuran starting from phenylacetylene and 2–iodophenol under mild conditions. Catalyst 1 is found to be
an excellent catalyst for the straightforward access to a library of benzofuran, indole, isocoumarin and isoquinolone
derivatives by the reaction of terminal alkynes with 2–iodo derivates of phenol, N–methyl aniline, benzoic acid and N–
methyl benzamide, respectively. The general utility of the catalytic method is demonstrated using a variety of diversely
substituted terminal alkynes and the corresponding desired products are obtained in good to excellent yields. On the basis
of control experiments, a two-cycle mechanism is proposed which involves the Sonogashira coupling of 2–iodo derivatives
with alkynes and the subsequent cyclization of the corresponding 2–alkynyl compounds.
Bosiak reported [Pd(dppf)Cl2]/CuI (dppf
=
1,1′–
Introduction
bis(diphenylphosphino)ferrocene]) catalyzed one–pot, four–
step synthesis of 2–arylbenzofurans starting from aryl halides,
trimethylsilylacetylene and 2–halophenols.6a Wang and
Manabe employed an in situ generated Pd catalytic system
derived from PdCl2(CH3CN)2/HTP (hydroxyterphenylphosphine)
to access 2–substituted benzofurans via coupling/cyclization
pathway.6c Latter, the same group used DHTP
(dihydroxyterphenylphosphine) which improved the catalytic
efficiency as compared to the HTP ligand.6d,7g A [Pd(η3–
C3H5)Cl]2/tetraphosphine based system was reported by Li and
coworkers for the synthesis of benzofuran from 2–halophenols
and alkynes.7b A handful of Pd–based catalysts have also been
utilized under heterogeneous conditions for this tandem
process.6f–6j Bäckvall’s group employed Pd nanoparticles
immobilized on siliceous mesocellular foam to access
benzofuran and indole derivatives.6f Recently, Yang and
coworkers used supported Pd nanoparticles for the synthesis
of biologically active benzofurans.6j
Benzofused five or six membered O– and N–heterocyclic
compounds like benzofuran, indole, isocoumarin and
isoquinolone have ubiquitous presence in natural products1
and pharmaceuticals.2 Over the years, extensive efforts have
been directed to develop synthetic methodologies for this
class of compounds.3–5 Compared to multi–step traditional
methods, the transition–metal–catalyzed protocol that
involves Sonogashira coupling reaction between 2–haloaryl
heteroatom derivatives and terminal alkynes, followed by
intramolecular cyclization is an attractive option because of its
atom–economy, operational simplicity and environmental
benefits.6–10 Over the past years, several catalysts based on
Pd6c–6j,7, Cu8, Pd/Cu6a,6k-6n,9a–9f, Ni9g-9h, Zn9i, Ni/Zn9j and other
metals9k–9o have been employed for this tandem process. In
particular, Pd complexes bearing a variety of ligands including
phosphines6c–6e,6k,7a–7b,7g–7l and N–heterocyclic carbenes
(NHCs)7c–7f have shown promising results for the synthesis of
2–substituted benzofuran derivatives.
NHC ligands offer several advantages over phosphines in
many organometallic transformations.11 Mata and coworkers
introduced a bimetallic Pd complex bridged by a triazole–
based NHC ligand (Scheme 1a) as a catalyst for benzofuran
synthesis.7c
A
related mononuclear complex bearing
a Department of Chemistry and Centre for Environmental Sciences and Engineering,
Indian Institute of Technology Kanpur, Kanpur 208016, India. E-mail:
jbera@iitk.ac.in; Fax: +91-512-6796806; Tel: + 91-512-2597336
‡ Current address: Department of Chemical Sciences, Indian Institute of Science
Education and Research Berhampur, Govt. ITI (transit Campus), Berhampur
760010, India
imidazolylidene ligand afforded significantly lower yield of the
final product in the reaction between 2–iodophenol and
phenylacetylene. Ghosh group employed
a dipalladium
complex stabilized by a bis–NHC ligand (Scheme 1b)7d for the
sequential Sonogashira coupling/cyclization reaction of 2–
iodophenol with terminal alkynes. The related mononuclear
†
Electronic Supplementary Information (ESI) available: Experimental details,
supporting figures, spectroscopic and crystallographic data are provided. See DOI:
10.1039/x0xx00000x
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complexes were equally effective at the same palladium
loading. The same group later reported Pd-acyclic
diaminocarbene complex (Scheme 1c) for the tandem Hiyama
Results and discussion
Pd(I)(aPmic)(PPh3)2]I (1)
View Article Online
DOI: 10.1039/D0DT02918A
a
Among various synthetic methods to access metal–MIC
compounds,18 selective carbon–halogen oxidative addition to a
low–valent metal precursor is an efficient route.19 We
achieved regioselective metalation via oxidative addition of
C5–I in [aPmic.I]X (X = I, BF4) with metal–metal bonded
bimetallic precursors.16 The room temperature treatment of
alkynylation/cyclization
between
2–iodophenol
and
triethoxysilylalkynes.7e Recently, Dash group synthesized a
binuclear Pd-NHC complex (Scheme 1d) for catalytic
benzofuran synthesis.7f
Ar
N
Cl
iPr
Pd Py
Cl
N
N
N
N
PPh3
Pd Br
N
metal–metal
singly-bonded
dipalladium
complex
(H2C)2
(H2C)2
O
H
N
Br
CH2Ph
[Pd2(CH3CN)6](BF4)2 with [aPmic.I]BF4 afforded a mononuclear
compound [Pd(aPmic)(CH3CN)2](BF4)2 in high yield (Scheme
3a). Although the partially solvated complex was found to
catalyze several reactions including the peroxide–mediated
Wacker–type oxidation of terminal alkenes,20 being highly
hygroscopic, its use was a tedious endeavor. In order to obtain
an air and moisture stable compound, we sought to synthesize
Mes
N
N
N
Cl
Pd
Cl
(CH2)2
N
Cl
PPh3
Cl
Cl Pd
Cl
Pd
C
N
Mes
Py
N
N
Py
Br
Pd
Py
Pd
Cl
Br
N
N
Cl
N
iPr
Ar
(a)
(c)
(b)
(d)
Scheme
1
Pd–carbene complexes employed in C–C
coupling/cyclization reaction of 2–iodophenol with alkynes.
a
mixed aPmic/phosphine analog. The reaction of
[Pd2(CH3CN)6](BF4)2 with [aPmic.I]BF4 in the presence of two
equivalents of PPh3 in acetonitrile invariably gave the same
compound [Pd(aPmic)(CH3CN)2](BF4)2 (Scheme 3a). Direct
ligand exchange of [Pd(aPmic)(CH3CN)2](BF4)2 with PPh3 in
acetonitrile at room temperature was not successful (Scheme
3b). This is not surprising considering the kinetic inertness of
metal-bound acetonitriles in the same solvent. Switching the
solvent to dichloromethane, room temperature reaction of
Pd2(dba)3 (dba = dibenzylideneacetone) with [aPmic.I]I in the
presence of two equivalents of PPh3 afforded the desired
mixed aPmic/phosphine complex [Pd(aPmic)(PPh3)2(I)]I (1) in
85% yield (Scheme 3c). The 1H NMR spectrum of 1 in
dichloromethane–d2 suggested the composition of the
complex consisting of one aPmic ligand and two PPh3. The
carbene carbon resonance appeared as a triplet at  = 182.3
ppm (JCP = 8.35 Hz). The 31P{1H} NMR spectrum showed a
singlet at  = 18.8 ppm for two chemically equivalent
phosphines. The molecular structure of 1 (Figure 1(a)) revealed
a cationic unit with a central Pd in the square planar geometry
containing one aPmic (Pd–C10 = 2.033(6) Å), one iodide (Pd–I =
Mesoionic carbenes (MICs) is a subclass of NHCs that bind
the metal via imidazolium backbone carbon (C4/C5) instead of
C2.12 Owing to the higher electron donor ability of MICs,
metal-MIC complexes are known to catalyze several organic
transformations more efficiently than their metal–NHC
analogs.13 Furthermore, annellation of ring system(s) on the
basic framework of NHC or MIC has been shown to alter its
ligating properties significantly.14 The nature of the annellated
unit and the site of annellation on the parent scaffold
determine the stereoelectronic control of the ligand system.
We earlier designed a set of carbene ligands derived from N–
fused π–conjugated heterocycles and synthesized their
Rh(I),15,16 Ru(II)13b,16 and Pd(II)16 complexes. The Rh(I) complex
having a fused pyridyl–imidazole based NHC ligand with a di–
isopropylphenyl (Dipp) on the imidazole nitrogen was shown
to be an effective catalyst for accessing E–vinylsilanes via
hydrosilylation of terminal alkynes.15 A Ru(II)-COD (COD =
cyclooctadiene) complex bearing an annellated pyridyl-MIC
(aPmic) (Scheme 2a) catalyzes the selective oxidative scission
of a range of olefins to the corresponding aldehydes at room
temperature.13b A related Ru(CO)2I2 complex (Scheme 2b) was
recently shown to catalyze semihydrogenation of both internal
and terminal alkynes with high chemo- and stereoselectivity.17
In our ongoing efforts to explore the use of annellated
NHC/MIC ligands in a wider range of catalytic transformations,
we herein report a Pd(II)–aPmic complex (Scheme 2c) that
2.6625(6) Å), and two phosphines (Pd–P1/P2
=
2.3334(16)/2.3452(16) Å) in a cis arrangement relative to the
carbene center. The C10–Pd–P1, C10–Pd–P2 and P1–Pd–P2
bond angles are 88.81(17)˚, 88.18(17)˚ and 171.07(6),
respectively. The aPmic binds the metal through the carbene
carbon only and the naphthyridine nitrogen remains unbound.
The Pd–C10 bond is slightly longer than the corresponding
distance (1.962(4) Å) in [Pd(aPmic)(CH3CN)2](BF4)2.16. The ESI–
MS reveals a signal at m/z (z = 1) 1016.0917 which is assigned
for [1 – I]+.
efficiently
catalyzes
the
tandem
Sonogashira
coupling/cyclization reactions between alkynes and 2–iodo
derivatives of phenol, N–methyl aniline, benzoic acid and N–
methylbenzamide to afford a collection of benzofuran, indole,
isocoumarin and isoquinolone derivatives, respectively.
Ph
I
Ph
Ph
Pd(aPmic)(PPh3)2](PF6)2 (2)
In order to access chelate binding of the aPmic ligand to the
metal centre, compound 1 was treated with two equivalents of
AgPF6 in dichloromethane at room temperature, which
afforded [Pd(aPmic)(PPh3)2](PF6)2 (2) as an air–stable, yellow
solid in 84% yield (Scheme 3c). The carbene carbon resonance
appears at  = 180.5 ppm (JCP = 13.1, 11.7 Hz) as a doublet of
N
N
N
N
N
N
N
N
N
Ph
Br
Br
I
Ph3P
I
Ru
Ru
Pd
I
CO
OC
PPh3
(b)
Alkyne
semihydrogenation
(a)
(c)
Tandem C-C
coupling/Cyclization
(This work)
Olefin
oxidation
Scheme 2 aPmic complexes of Ru (a and b) and Pd (c).
2 | Dalton Trans., 2020, XX, X-X
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ARTICLE
doublets. The 31P{1H} NMR spectrum revealed two signals at 
= 34.8 ppm and  = 27.6 ppm confirming the presence of two
chemically non–equivalent phosphines. Molecular structure of
2 (Figure 1(b)) confirms the chelate binding of aPmic through
View Article Online
DOI: 10.1039/D0DT02918A
the carbene carbon (Pd–C10
= 2.037(3) Å) and the
naphthyridine nitrogen (Pd–N1 = 2.169(2) Å). The C10–Pd–N1
bite–angle is 80.58(10)˚ which is similar to that in
[Pd(aPmic)(CH3CN)2](BF4)2 (82.06(14˚)). Two mutually cis
phosphines complete the square planar geometry around the
metal center. The Pd–C10 bond distance is similar to the
precursor complex 1. The phosphine trans to the carbene
carbon reveals
a longer Pd–P2 distance (2.3659(8) Å)
compared to the one trans to the naphthyridine nitrogen (Pd–
P1 = 2.2543(8) Å).
(a)
Scheme 3 Syntheses of 1 and 2.
Catalytic Studies
(b)
Figure 1. Molecular structures of the cationic unit in 1 (a) and 2 (b) with
selected atoms labeled. Hydrogen atoms are omitted for clarity. Thermal
ellipsoids are drawn at 40% probability.
To evaluate the catalytic efficacy of compound 1 for the
tandem Sonogashira coupling/cyclization reaction, initial
experiments were carried out using 2–iodophenol (1 mmol),
t
phenylacetylene (1.2 mmol), BuOK (1 mmol) and catalyst 1
(0.02 mmol) in dimethylsulphoxide (DMSO) at 100 ˚C. Under
these conditions, the corresponding benzofuran was obtained
in 70% yield (entry 1, Table 1). A variety of other bases (entries
2–6) and solvents (entries 8–11) were screened, and the use of
K2CO3 in DMSO proved optimal (entry 6). Notably, the reaction
did not proceed in the absence of a base (entry 7). Whereas
performing the reaction at 90 ˚C gave the quantitative yield of
the product (entry 12), reducing the temperature further led
to a decrease in the product yield to 83% (entry 13). Not
surprisingly, the yield decreased by lowering the catalyst
loading (entry 14) and the product was not obtained in the
absence of the catalyst (entry 15). Under the optimized
conditions given in entry 12, the reaction of the bromo–
derivative (2–bromophenol) with phenylacetylene gave the
corresponding product in moderate yield (55%), whereas in
case of 2-chlorophenol, no product was detected (Scheme 4b).
Catalyst screening was conducted with different Pd salts
for the model reaction under the optimized conditions and the
results are summarized in Table S2. Both catalysts 1 and 2 gave
quantitative yields of the bezofuran product under additive-
free condition. Performing the reaction with Pd(OAc)2 and
Pd(PPh3)2Cl2 led to a very poor yield of the cyclized product
(<12%) but the C–C coupled product was formed in moderate
yield (48 and 57%, respectively). The use of PdCl2, PdI2 and
PdCl2(CH3CN)2 afforded only the coupled product in low yields.
Although we believe that using a different combination of
base/solvent might improve the yield of the coupled products,
the readily available Pd precursors exhibit poor activity under
the additive-free optimized reaction conditions.6m, 7j-k, 8j, 9e-f
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The methodology was then applied to a varietVyieowfAartricolemOanltinice
DOI: 10.1039/D0DT02918A
and aliphatic alkynes to establish the scope, and the results are
summarized in Table 2. The presence of either electron–
Table 1: Optimization studies.a
OH
Ph
I
O
1
, Base
Ph
H
Solvent, Temp °C,
2 h
donating (entries
2
and 3) or electron–withdrawing
substituents on the phenylacetylene derivatives (entries 4 and
5) had no significant effect on the yields of the products. 2–
ethynylpyridine gave the corresponding product in 33% yield
(entry 6); which probably is a result of coordination of the
nitrogen atom of 2-ethynylpyridine to the metal center. The
transformation of sterically bulky alkynes (2–ethynyl–6–
Entry
1.
Base
1 (mol%)
Solvent
DMSO
Temp (°C)
100
Yield (%)b
70
tBuOK
2
2
2
2
2
2
2
2
2
2
2
2
2
1
—
2.
3.
KH
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
100
100
100
100
100
100
100
100
100
70
60
70
KOH
4.
Et3N
56
methoxynaphthalene,
3,3–dimethylbutyne
and
1,1–
diphenylprop–2–yn–1–ol) proceeded smoothly to give the
corresponding products in 87–98% yields (entries 7–9).
Different aliphatic alkynes, such as 4–phenyl–1–butyne, 1–
hexyne, cyclohexyl–acetylene, 3–butyne–1–ol, 4–pentyne–1–
ol, and 3–methylpent–1–en–4–yn–3–ol, furnished the
corresponding benzofurans in 90–98% yields (entries 10–15).
1,7–dioctyne gave 99% yield of the respective benzofuran
derivative (entry 16).
The optimized reaction protocol was then extended to the
syntheses of indole derivatives. The reaction of 2–iodoaniline
and phenylacetylene afforded only the coupled product (95%)
and no cyclized product was obtained (Scheme 4c). However,
performing the reaction with N–methyl–2–iodoaniline
furnished the corresponding indole in 95% yield (entry 17). The
indole formation proceeded smoothly with both electron–rich
(entry 18) and electron–deficient aromatic alkynes (entry 19)
giving the product in 93–96% yields. Aliphatic alkyne 1–hexyne
afforded the corresponding indole in 92% yield (entry 20).
5.
Cs2CO3
K2CO3
—
100
100
<5
6.
7.
8.
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
75
1,4–
Dioxane
9.
85
10.
11.
12.
13.
14.
Toluene
THF
85
48
DMSO
DMSO
DMSO
DMSO
90
100
83
80
90
85
15.
K2CO3
90
ndc
aReaction
conditions:
2–iodophenol/phenylacetylene/base/catalyst
=
1/1.2/1/0.02 mmol), solvent (2 mL). bDetermined by GC–MS using p–xylene as an
internal standard. cnot detected.
Table 2. Table 3. Synthesis of 2–substituted benzofurans and 1,2–
disubstituted indoles via Pd–catalyzed coupling/cyclization reaction a.
To compare the catalytic efficacy of 1 and 2, the progress
of the reactions was monitored by GC–MS under the
optimized conditions (Figure 2). Initially, catalyst 2 showed
higher activity and gave 38% conversion within 15 minutes as
compared to catalyst 1 which gave only 20% conversion at the
same time. The removal of iodide from 1 to generate the
catalytically active species is likely to be the reason for the
initial delay. However, catalyst 1 achieved saturation slightly
faster than 2. Further catalytic studies were conducted using
compound 1 owing to its easier synthetic accessibility.
XH
X
1 (2 mol%), K2CO3
R
+
R
H
DMSO, 90 o
C
I
R = aryl, alkyl
X = O, NMe
Entry
Substrate
Product
Yield %b
1.
2.
3.
4.
5.
100
100
100
98
O
O
H3CO
OCH3
F
F
95
O
6.
7.
33
98
N
O
8.
9.
92
87
Figure 2. Time–conversion profile of heteroannelation reactions
catalyzed by catalysts 1 and 2.
HO
Ph
Ph
OH
Ph
Ph
O
4 | Dalton Trans., 2020, XX, X-X
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Table 3. Synthesis of isocumarins and isoquinolones via Pd–catalyzed
View Article Online
10.
11.
12.
13.
14.
15.
16.
17.
18.
98
coupling/cyclization reactions.a
DOI: 10.1039/D0DT02918A
O
O
97
90
98
98
97
99
95
96
XH
X
1 (2 mol%), K2CO3
DMSO, 90 o
R
H
+
I
C
R
O
R = aryl, alkyl
X = O, NMe
Entry
1.
Substrate
Product
Yield %b
O
O
97
98
O
O
O
OH
HO
2.
H3CO
3.
4.
5.
98
95
94
N
O
O
F
N
N
O
O
F
Br
F
19.
93
F
Br
6.
7.
8.
94
94
92
N
20.
92
aReaction conditions: 2–iodo derivative of phenol or N–
methylaniline/phenylacetylene/base/1 = 1/1.2/1/0.02 mmol), DMSO (2
mL), 2 h bDetermined by GC–MS using p–xylene as internal standard.
We then examined the protocol for accessing six–
membered heterocyclic compounds. The reaction of 2–
iodobenzoic acid with alkynes can afford either phthalides via
5–exo–dig cyclization or isocoumarins via 6–endo–dig
cyclization. Complex 1 catalyzed the reaction between 2–
iodobenzoic acid and phenylacetylene furnishing exclusively
the corresponding 6–endo–dig product in 97% yield (entry 1,
Table 3). Subsequently, a variety of terminal alkynes were used
to access isocoumarin derivatives. Phenylacetylenes bearing
electron–donating (entries 2 and 3) and electron–withdrawing
substituents (entries 4 and 5) furnished the products in 94–
98% yields. Aliphatic alkynes 1–hexyne, 1–heptyne and 3–
butyne–1–ol produced the corresponding isocumarin
derivatives in 92–94% yields (entries 6–8).
9.
95
96
95
92
10.
11.
12.
H3CO
F
13.
92
The reaction of N–methyl–2–iodobenzamide with
phenylacetylene resulted in the selective formation of
corresponding 6-endo-dig cyclized product (isoquinolone) in
95% yield (entry 9). The formation of isoquinolones proceeded
smoothly with both electron–rich (entries 10 and 11) and
electron–deficient alkynes (entry 12) furnishing the products in
excellent yields. Aliphatic alkyne 1–hexyne afforded the
corresponding isoquinolone in 92% yield (entry 13).
aReaction
conditions:
2–iodobenzoic
acid
or
N–methyl–2–
iodobenzamide/phenylacetylene/base/1 = 1/1.2/1/0.02 mmol), DMSO (2
mL), 2 h. bDetermined by GC–MS using p–xylene as internal standard.
A
comparison of the performances of reported Pd-NHC
catalysts7c-f (see SI, Table S3) reveals the better catalytic efficacy of
1 in terms of lower base loading, shorter reaction time and wider
scope.
Proposed mechanism
Control experiments were conducted to shed light on the
mechanism of this transformation. Under the optimized
catalytic conditions, the reaction of iodobenzene with 4–
methyl phenylacetylene in the presence of
1 afforded
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quantitative yield of the C-C coupled product (Scheme 4a). The of the alkyne unit to the Pd0 centre affording an ViniewteArrmticleedOinalitnee
DOI: 10.1039/D0DT02918A
cyclized product benzofuran was isolated when 2–iodophenol D. Base-assisted deprotonation, followed by nucleophilic
(or 2–bromophenol) was reacted with phenylacetylene, attack of the heteroatom to the Pd-bound alkyne gives the
however, the coupled product was not detected (Scheme 4b). metallated product E.7b,9p Oxidative addition of X-H bond to
Though N–methyl–2–iodoaniline afforded the corresponding Pd(0) centre is a potential alternative pathway.7d However, in a
indole in high yield, use of 2–iodoaniline gave the coupled stoichiometric reaction of 2–(phenylethynyl)phenol, K2CO3 and
product (Scheme 4c). This result insinuates the coupled 1 (equimolar) in DMSO-d6 at 90 oC, we failed to identify a Pd-H
product as the intermediate in the formation of the benzo- intermediate by 1H NMR spectroscopy, which does not support
fused N/O-heterocycles. To support this hypothesis, the an oxidative pathway.22 Protonolysis of E gives the final
presumed intermediate 2–(phenylethynyl)phenol was cyclized product regenerating the catalytic species A, thus
synthesized5i and employed for the intramolecular cyclization closing the second cycle.
reaction (Scheme 4d). The expected 2–substituted benzofuran
was obtained quantitatively under the optimized reaction
conditions supporting the intermediacy of the ortho–alkynyl
derivative. In the absence of 1, only 17% of the cyclized
product was obtained (Scheme 4e).
1 (2 mol%)
(a)
I
K2CO3
DMSO, 90 °C
100%
O
X
1 (2 mol%)
K2CO3
DMSO, 90 °C
(b)
On the basis of these control experiments and literature
precedents,7b,7d,7e a probable reaction mechanism is proposed
in which two consecutive metal–catalysed cycles are involved:
the Sonogashira coupling (Cycle A), followed by an
intramolecular cyclization reaction (Cycle B) (Scheme 5).
Initially, complex 1 is reduced to Pd(0) species A in the
presence of PPh3 and K2CO3.21 It is reasonable to assume
chelate coordination of the ligand in the reduced species A
obtained upon base treatment. Oxidative addition of halo–
aromatic compound to Pd(0) center leads to the formation of
species B. Alkyne coordination to B with concomitant release
of HI in the presence of base furnishes the Pd-alkynyl
intermediate C. Reductive elimination of 2–alkynyl derivative
from C completes the first catalytic cycle. The so-obtained 2–
alkynyl derivative enters the catalytic cycle B by coordination
OH
X = I, 100%
X = Br, 55%
X= Cl, nd
I
1 (2 mol%)
K2CO3
DMSO, 90 °C
(c)
NH2
NH2
95%
OH
O
1 (2 mol%)
K2CO3
DMSO, 90 °C
(d)
(e)
100%
OH
O
K2CO3
DMSO, 90 °C
17%
Scheme 4. Control experiments
Scheme 5. Proposed mechanism for the tandem coupling/cyclization reaction.
6 | Dalton Trans., 2020, XX, X-X
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DOI: 10.1039/D0DT02918A
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ARTICLE
23
Pd2(dba)3
were synthesized following the literature
procedures.
Conclusion
Synthesis of 1
In this study, we have synthesized two well–defined mixed-
ligand Pd compounds via C–I oxidative addition of an iodo-
functionalized aPmic precursor salt to Pd2(dba)3 in the
presence of phosphine. Both compounds are effective
catalysts for the synthesis of benzofuran via Sonogashira
Pd2(dba)3 (0.045 g, 0.077 mmol) was added to a suspension of
[aPmic.I]I (0.080 g, 0.155 mmol) in 10 mL dry DCM. The
reaction mixture was allowed to stir at room temperature for 3
h under the exclusion of light in N2 atmosphere. PPh3 (0.081,
0.310 mmol) was then added and the resulting solution was
stirred for 30 min. The mixture was subsequently filtered over
a pad of celite. The solution was concentrated under reduced
pressure and 10 mL diethyl ether was added while stirring to
get a yellow precipitate. Repeated washing followed by
prolonged drying under vacuum provided a yellow crystalline
solid in 85% yield. Needle shaped yellow crystals suitable for
X–ray diffraction were grown by layering petroleum ether over
a concentrated dichloromethane solution of 1 inside a
vacuum-sealed glass tube. ESI–MS, m/z=1016.0917 (z = 1) for
coupling/cyclization
between
2–iodophenol
and
phenylacetylene. The catalyst 1 is also used for the synthesis of
a variety of benzofuran, indole, isocumarin and isoquinolone
derivatives by the same protocol. A diverse array of terminal
alkynes is converted to the corresponding benzo-fused N/O-
heterocycles with high yield and selectivity. The control
experiments reveal that the formation of the product proceeds
via a tandem process involving Sonogashira coupling followed
by metal-assisted cyclization. This work underlines the wider
use of annellated mesoionic carbene ligand scaffold in catalytic
organometallic transformations.
1
[1 – I]+; H–NMR (500 MHz, CDCl3): δ 9.30 (s, 1H, NP), 8.64 (s,
1H, Im), 7.86 (s, 1H, NP), 7.84 – 7.871 (m, 1H, NP), 7.75–7.71
(m, 6H, NP), 7.62 – 7.43 (m, 30H, Ar), 3.15 (s, 3H, CH3); 13C
NMR (125 MHz, CDCl3): 182.3, 150.8, 142.7, 138.6, 138.1,
134.4, 134.2, 34.1, 132.9, 130.6, 130.1, 129.3, 129.1, 128.0,
127.2, 125.9, 124.3, 118.5, 37.82 (Me); Anal. Calcd for
PdC53H43I2N3P2: C, 55.64; H, 3.79; N, 3.67; Found: C, 55.23; H,
3.40; N, 3.41.
Experimental Section
General Procedures
All reactions with metal complexes were carried out under an
atmosphere of purified nitrogen using standard Schlenk–vessel
and vacuum line techniques. Glassware was flame–dried under
1
vacuum prior to use. H and 13C NMR spectra were obtained
Synthesis of 2
on JEOL JNM–LA 400 MHz and JEOL JNM–LA 500 MHz
AgPF6 (0.028 g, 0.126 mmol) was added to the CH2Cl2 solution
(10 mL) of 1 (0.060 g, 0.056 mmol). Resultant solution was
allowed to stir at room temperature for 2 h and then filtered
over a pad of celite. The filtrate was concentrated under
reduced pressure, followed by the addition of 15 mL of diethyl
ether with stirring to induce precipitation. The precipitate was
washed with diethyl ether (3 × 10 mL) and dried under vacuum
to afford 2 as yellow powder in 82% yield. Crystals suitable for
X–ray diffraction were grown by layering petroleum ether over
a concentrated dichloromethane solution of compound inside
1
spectrometers. H NMR chemical shifts are referenced to the
residual hydrogen signal of the deuterated solvents. The
chemical shift is given as dimensionless δ values and frequency
referenced relative to TMS for H and 13C NMR spectroscopy.
1
Elemental analyses were performed on a Thermoquest EA1110
CHNS/O analyzer. The crystallized compounds were powdered,
washed several times with dry petroleum ether, and dried in
vacuum for at least 48 h prior to elemental analyses. ESI–MS
measurements were recorded on a Waters Micromass Quattro
Micro triple–quadrupole mass spectrometer. The GC–MS
experiments were performed using an Agilent 7890A GC and
5975C MS system.
1
a vacuum-sealed glass tube. Yield: 85%. H–NMR (500 MHz,
CDCl3): δ 9.04 (s, NP), 8.64 (s, 1H, Im), 7.86 (s, 1H, NP), 7.84 –
7.871 (m, 1H, NP), 7.75–7.71 (m, 6H, NP), 7.62 – 7.43 (m, 30H,
Ar), 3.15(s, 3H, CH3); 13C NMR (125 MHz, CDCl3): 180.5, 157.0,
143.5, 141.9, 138.4, 135.6, 134.4, 132.9, 132.8, 132.7, 132.6,
Materials
All solvents were purified and dried by conventional methods 132.5, 132.4, 132.3, 132.1, 130.9, 130.7, 130.2, 129.7, 129.6,
prior to use. PdCl2 was purchased from Arora Matthey, India. 129.2, 129.1, 128.2, 127.7, 125.3, 119.0, 37.7 (Me); Anal.
All other chemicals were purchased from Sigma–Aldrich. The Calcd. for PdC53H43N3P4F12: C 53.94; H, 3.67; N, 3.56; Found: C,
ligand
precursor
5′–iodo–3–phenylimidazo[1,2– 53.43; H, 3.28; N, 3.45.
a][1,8]naphthyridine-imidazolium iodide [aPmic.I]I16 and
This journal is © The Royal Society of Chemistry 20xx
Dalton Trans., 2020, XX, X-X | 7
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Dalton Transactions
Anzini, L. Mennuni, F. Ferrari, F. Makovec, E. MV.ieKwleAirnticrlaetOhn,linTe.
General Procedure for the Coupling/Cyclization Reaction
Langer, M. Valoti, G. Giorgi, S. Vomero, J. Med. Chem. 2006,
DOI: 10.1039/D0DT02918A
An oven–dried reaction vessel was charged with catalyst 1
(0.02 mmol), alkyne (1.2 mmol), 2–iodoarenes (1 mmol), K2CO3
(1 mmol) and p–xylene (1 mmol) in 2 mL of DMSO and the
reaction mixture was heated at 90 °C for 2 h. The reaction
mixture was cooled to room temperature and water (ca. 12
mL) was added. The resulting mixture was extracted with
EtOAc (ca. 50 mL). The aqueous layer was further extracted
with EtOAc (3 × 20 mL). The organic layers were combined and
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vacuum–dried to obtain
a
crude product that was
subsequently purified by column chromatography using silica
gel as a stationary phase and eluting it with a mixed medium of
petroleum ether/EtOAc to give the desired product.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
Financial support from the Science and Engineering Research
Board (SERB) and the Department of Atomic Energy (DAE) are
gratefully acknowledged. J.K.B. thanks SERB, India, for a J. C.
Bose fellowship. A.T. thanks the UGC, India, for fellowship.
N.U.D.R. thanks IIT Kanpur for a post–doctoral fellowship.
3
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TOC Graphic
Palladium Complexes with an Annellated Mesoionic
Carbene (aPmic) Ligand: Catalytic Sequential
Sonogashira Coupling/Cyclization Reaction for One–
Pot Synthesis of Benzofuran, Indole, Isocoumarin and
Isoquinolone Derivatives
Dalton Trans Year, Volume, Page – Page
Akshi Tyagi, Noor U Din Reshi, Prosenjit Daw and
Jitendra K. Bera*
A Pd(II) complex containing a mesoionic carbene and
phosphine ligands is an efficient catalyst for tandem
coupling/cyclization reaction.
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