Microwave-assisted intramolecular reductive Heck in aqueous medium: Synthesis of 3,3′-Disubstituted heterocyclic compounds

Article abstract of DOI:10.1016/j.jorganchem.2019.120963

Heterocyclic products have been accomplished using microwave-assisted [Pd]-catalyzed intramolecular reductive Heck coupling. The protocol found suitable in delivering indolines, oxindoles, and dihydrobenzofurans. Notably, the process was successful in sol

Full text of DOI:10.1016/j.jorganchem.2019.120963

Journal Pre-proof
Microwave-assisted intramolecular reductive Heck in aqueous medium: Synthesis of
3,3′-Disubstituted heterocyclic compounds
Karu Ramesh, Gedu Satyanarayana
PII:
S0022-328X(19)30406-1
DOI:
https://doi.org/10.1016/j.jorganchem.2019.120963
JOM 120963
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 16 July 2019
Revised Date: 17 September 2019
Accepted Date: 28 September 2019
Please cite this article as: K. Ramesh, G. Satyanarayana, Microwave-assisted intramolecular reductive
Heck in aqueous medium: Synthesis of 3,3′-Disubstituted heterocyclic compounds, Journal of
Organometallic Chemistry (2019), doi: https://doi.org/10.1016/j.jorganchem.2019.120963.
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Microwave-Assisted Intramolecular Reductive Heck in Aqueous Medium:
Synthesis of 3,3’-Disubstituted Heterocyclic Compounds
Karu Ramesh and Gedu Satyanarayana*
Department of Chemistry, Indian Institute of Technology Hyderabad, Kandi – 502 285, Sangareddy, Telangana,
INDIA
Phone: (040) 2301 6033; Fax: (040) 2301 6003 / 32, E-mail: gvsatya@iith.ac.in
Abstract: Heterocyclic products have been accomplished using microwave-assisted [Pd]-catalyzed
intramolecular reductive Heck coupling. The protocol found suitable in delivering indolines, oxindoles,
and dihydrobenzofurans. Notably, the process was successful in sole aqueous medium and furnished the
products bearing a quaternary carbon center.
Keywords:
Introduction:
The synthesis of heterocyclic structures using ring-closing strategies is indispensable
[Pd]-Catalysis; Reductive Heck; Microwave; Water.
in organic synthesis.1 Whereas, the transition metal catalysis has proved to be a prominent
and powerful synthetic tool for obtaining the key cyclic compounds of natural as well as
unnatural products of biological significance.2 Among transition metals, palladium is the
most widely used metal that facilitates a variety of chemical reactions.3 Specifically,
palladium-catalyzed intramolecular reductive Heck coupling (or hydroarylation) of haloarene
moiety with a suitably substituted internal alkene is an important chemical process, for the
accomplishment of carbo-/hetero-cyclic compounds efficiently.4
The 3,3’-disubstituted dihydrobenzofurans5, indolines6, and oxindoles7 belongs to
ubiquitous structural cores of many heterocyclic natural products and also compounds with
interesting biological features.8 As a result, apart from classical synthetic routes,9 a notable
number of transition metal-catalyzed synthetic approaches have also been presented in the
literature for the construction of heterocyclic compounds.10 Particularly, 2,3-

dihydrobenzofurans have been achieved in their chiral11 or racemic12 forms using
intramolecular reductive Heck reactions. In addition, these products have also been
synthesized via radical-mediated conditions.13 Based on our interest in developing domino
transition metal-catalyzed strategies,14 Recently, our group presented a one-pot approach to
alkyne bearing 3,3’-disubstituted dihydrobenzofurans under microwave irradiation via
palladium catalysis.15 Later, this concept has been further elaborated to generate other
heterocyclic products possessing alkyne functionality, particularly, by making use of water as
the solvent, under microwave irradiation conditions.16 Herein, we report the preparation of
indolines, oxindoles and dihydrobenzofurans containing a quaternary center at 3-position,
catalyzed by palladium, under microwave assisting conditions in aqueous medium. Also, it
was observed that quaternary ammonium salt as an additive is necessary for this reductive
Heck coupling.17
Result and Discussions
The optimization study was initiated by taking ortho-iodophenyl allyl ether 1a, as
stating material. Our main intention was to perform the reactions, under microwave
irradiation conditions. Thus, initially, ortho-iodophenyl allyl ether 1a was treated using
Pd(OAc)2 (5 mol%), ligand BINAP (10 mol%), base K2CO3 (4 equiv), additive
tetrabutylammonium bromide (TBAB, 1 equiv) and solvent H2O (0.5 mL) for 10 min, at 100
°C, under microwave irradiation (Table 1, entry 1). However, there was no progress, and the
starting material was recovered back. Almost similar results were noted when the reaction
was conducted using different ligands (Table 1, entries 2 to 4). Even at elevated temperature
(120 °C), no betterment was noticed (Table 1, entry 5). Similar results were observed with
the catalyst Pd2(dba)3 for 10 min, at 100 °C, under microwave irradiation (Table 1, entry 6).
The expected product 4a was formed in trace amounts when the temperature was relatively
high, i.e. 110 °C (Table 1, entry 7). With these observations of temperature effect, 1a was
treated at 120 °C for 10 min, under microwave irradiation (Table 1, entry 8). Delightfully,
resulted the formation of 4a in 40% yield. Interestingly, when the irradiation time was
prolonged to 20 min, at 120 °C, the product 4a yield was raised to 80% (Table 1, entry 9).
The yield of 4a was dropped to 65% when the irradiation time was reduced to 15 min (Table
1, entry 10). While the product 4a yield was slightly decreased when tetrabutylammonium
iodide (TBAI) and benzyl triethylammonium chloride (BTEAC), were used as additives

(Table 1, entry 11 &12). In solvent DMF instead of H2O, 4a was obtained, in very good
yields (Table 1, entry 13). Nevertheless, our intension was to perform the reaction by using
non-toxic and environmentally benign H2O solvent; hence we decided to proceed further to
examine the generality of the process by employing optimal conditions of entry 9 of Table 1.
Table 1. Screening study to generate 4a.[a],[b],[c]
entry
ligand
(10 mol%)
catalyst
(5 mol%)
additive
(1 equiv) (0.5 mL)
solvent
temp
time
(min)
yield
4ab (%)
(°C)
c
1
2
BINAP
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAI
BTEAC
-
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
DMF
100
100
100
100
120
100
110
120
120
120
120
120
120
-
10 min (
10 min (
10 min (
10 min (
µ
w)
w)
w)
w)
c
Xantphos
-
µ
µ
µ
c
3
P(Cy)3
-
c
4
PPh3
-
c
5
PPh3
-
120 min (
µ
w)
w)
w)
w)
c
6
-
-
-
-
-
-
-
-
-
10 min (
10 min (
10 min (
20 min (
15 min (
20 min (
20 min (
20 min (
µ
7
trace
(40%)
(80%)
(62%)
(72%)
(68%)
(81%)
µ
µ
8
9
µ
w)
10
11
12
13
µw)
µw)
µw)
µw)
[a]Reaction conditions: 1-iodo-2-((2-methylallyl)oxy)benzene 1a (68.5 mg, 0.25 mmol), K2CO3 (138.6 mg, 1 mmol, 4
equiv), [Pd]-catalyst (5 mol%), ligand (10 mol%), additive (0.25 mmol, 1 equiv) and solvent (0.5 mL), microwave
irradiation (150 W, closed vessel). [b]Yields isolated of product 4a. [c] Starting material was recovered.
Thus, based on the standardized reaction conditions [i.e. catalyst (11.6 mg, 5 mol%),
K2CO3 (138.6 mg, 4 equiv), TBAB (80. 5 mg, 1 equiv), microwave irradiation for 20 min, at
120 °C (Table 1, entry 9)], next, to study the feasibility of the protocol, other ortho-
iodophenyl allyl ethers were examined. Significantly, the dihydrobenzofurans 4a-4i were
isolated in the range of 50 to 82% yields (Table 2). Particularly, the method was feasible on
ortho-iodophenyl allyl ethers 1b-1d wherein the aromatic ring has alkyl substituent (4b-4d,
Table 2). The method was also found suitable with phenyl substituent on the iodoaryl allyl
ether 1e and gave the product 4e. Gratifyingly, this method was tolerable with aromatic ring
connected to electron deactivating F, Cl, and Br functional groups (4f-4h, Table 2). Since in
the product 4h, the bromo moiety was intact, further transition metal-catalyzed cross-
coupling reactions would be feasible. Quite remarkably, this reductive Heck coupling was

also tolerable with electron-withdrawing aldehyde group on the aromatic ring of iodoarene 1i
(4i, Table 2). However, the hetero-iodoarene 1j was decomposed, under standard optimized
conditions.
Table 2: Scope of formation of dihydrobenzofurans 4a-4j from ortho-iodophenyl allyl ethers 1a-1j.[a],[b]
[a]Reaction conditions: ortho-iodophenyl allyl ethers 1a-1j (0.25 mmol), Pd2(dba)3 (5 mol%), TBAB (1 equiv), K2CO3
(4 equiv) and solvent H2O (0.5 mL), 120 C, 20 minutes, microwave irradiation (150 W, closed vessel). [b]Yields are
isolated yields of products 4a-4i.
After achieving the preparation of dihydrobenzofruans 4a-4i (Table 2), to emphasize
the utility of this protocol, the strategy was targeted to perform the reaction with nitrogen
analogues. Thus, various ortho-iodophenyl alkylallyl amines 2a-2f were subjected to reaction
using standard microwave irradiation conditions (i.e., Table 1, entry 9). Notably, the
methodology was smooth enough and afforded indolines 5a-5f, in good yields (Table 3).
Moreover, to signify generality of the method, it was also tested with ortho-iodophenyl
enamides 3a-3f. Remarkably the reaction was quite amenable and furnished oxindoles 6a-6f,
in the range of 50 to 82% yields (Table 3). Particularly, the allyl enamide 3f may pose a
chemoselective issue, as both olefins may compete in the initial intramolecular Heck step.
However, the reaction was found to be highly chemoselective, in which enamide double bond
has selectively underwent the Heck coupling and furnished oxindole 6f.

Table 3: Scope to give indolines 5a-5f and oxindoles 6a-6f.[a],[b]
H2O
X
X
Y
R
Y
H
R
Pd2(dba)3 (5 mol%)
I
CH3
TBAB (1 equiv)
5a-5f & 6a-6f
2a-2f & 3a-3f
K2CO3 (4 equiv)
MW, 120 C, 20 min
Me
Me
Me
N
NO2
N
N
H
N
H
N
H
H
H
CH3
CH3
CH3
CH3
CH3
5a (64%)
5b (63%)
5c (73%)
5d (62%)
5e (64%)
Me
Me
N
Me
N
N
N
O
N
O
H
O
O
H
H
H
H
Me
Me
Me
Me
Me
5f (60%)
6a (80%)
6b (78%)
6c (79%)
6d (77%)
Me
Me
N
N
O
H
O
H
Me
Me
6e (75%)
Me
6f (61%)
[a]Reaction conditions: 2-iodo-N-alkyl-(2-methylallyl)aniline 2a-2f (0.25 mmol), N-(2-iodophenyl)-N-
alkylmethacrylamide 3a-3f (0.25 mmol), Pd2(dba)3 (5 mol%), TBAB (1 equiv), K2CO3 (4 equiv) and solvent H2O (0.5
mL), 120 C, 20 minutes, microwave irradiation (150 W, closed vessel). [b]Yields are isolated yields of products 5a-
5f/6a-6f.
In order to probe the role of water and additive TBAB, we have carried out the
reactions by changing the reaction conditions with respect to solvent and additive. When the
reaction was performed on 1a under neat conditions (i.e. without solvent water), the reaction
was found to be very slow and the conversion of the desired product was only 15% (rest was
the starting material 1a). Whereas the reaction of 1a without additive (TBAB), there was, no
progress in the reaction except the starting material. This implies the importance TBAB as an
additive to drive the reaction. Moreover, according to the literature precedence, it was noted
that TBAB can acts as palladium nanoparticle stabilizer.18 Based on this and from our
observation, i.e. the reaction did not progress without the additive TBAB, it may be presumed
that TBAB can act as palladium nanoparticles stabilizer. To further understand whether or not

the palladium nanoparticles were present in the reaction mixture, the crude reaction was
subjected to Transmission Electron Microscopy (TEM) analysis. From the analysis of TEM
images and lattice fringes, it was realized the formation of palladium nanoparticles in the
chemical reaction (for details, see: supporting information).
The source of hydrogen required for this reductive Heck coupling is not clear yet. It
was hypothesized that the hydrogen might come from the H2O solvent. Thus, to further
understand the source of hydrogen, the reaction was conducted on enamide 3a by using D2O
1
in place of H2O, under established conditions (Scheme 1). However, H/13C{1H} NMR
spectra revealed that no deuterium was incorporated in the product 6a. Indeed, this
observation was in good agreement with established reports.12c,19 In addition, there are other
established reports, wherein tert-amines have been utilized as hydrogen sources instead of
hydride based reagents.20 Hydrogen source might be due to sacrificial agent that might be
oxidized or from the ligand species.
Scheme 1: Reductive Heck coupling in D2O solvent.
Though the exact reaction mechanism is not very much clear yet, a plausible path in
furnishing 4/5/6 is shown in Scheme 2. Initially, the organopalladium(II) species A could be
generated through the catalyst insertion across carbon-iodo bond of 1/2/3. Intramolecular
Heck cyclization of A, would furnish the bicyclic alkyl-Pd(II) intermediate B. Ultimately,
regeneration of the catalyst via reductive elimination of B and in the presence of hydrogen
source, gives the desired heterocyclic products 4/5/6.

Scheme 2: Plausible mechanism to generate the products 4/5/6.
Conclusions
In summary, a facile method affording heterocyclic products, is described. Palladium-
catalyzed intramolecular reductive Heck was employed as the key transformation of the
strategy. Moreover, unlike previous reports on reductive Heck reaction, the present
process was feasible in sole aqueous medium and accelerated by microwave irradiation
conditions. Indolines, oxindoles, and dihydrobenzofurans containing a quaternary center
have been accomplished. Moreover, TEM studies revealed the formation of palladium
nanoparticles and could serve as an active catalyst.
Experimental
1
General: IR spectra were recorded on a Bruker Tensor 37 (FTIR) spectrophotometer. H
NMR spectra were recorded on Bruker Avance 400 (400 MHz) spectrometer at 295 K in
CDCl3; chemical shifts (δ ppm) and coupling constants (Hz) are reported in standard fashion
with reference to either internal standard tetramethylsilane (TMS) (δH = 0.00 ppm) or CDCl3
(δH = 7.25 ppm). 13C{1H} NMR spectra were recorded on Bruker Avance 400 (100 MHz)
spectrometer at RT in CDCl3; chemical shifts (δ ppm) are reported relative to CDCl3 [δC =
13
77.00 ppm (central line of the triplet)]. In the C{1H} NMR, the nature of carbons (C, CH,
CH2 and CH3) was determined by recording the DEPT-135 spectra, and is given in
parentheses and noted as s = singlet (for C), d = doublet (for CH), t = triplet (for CH2) and q
1
= quartet (for CH3). In the H-NMR, the following abbreviations were used throughout: s =
singlet, d = doublet, t = triplet, q = quartet, qui =quintet, sept = septet, dd = doublet of
doublet, m = multiplet and br. s = broad singlet. The assignment of signals was confirmed by

1H, 13C{1H} CPD, and DEPT spectra. High-resolution mass spectra (HR-MS) were recorded
on an Agilent 6538 UHD Q-TOF electron spray ionization (ESI) mode and atmospheric
pressure chemical ionization (APCI) modes. The microwave irradiation experiments were
carried out in a dedicated CEM-Discover monomode microwave apparatus, operating at a
frequency of 2.45 GHz with continuous irradiation power from 0 to 300 W. The reactions
were carried out in 10 mL glass tubes, sealed with Teflon septum and placed in the
microwave cavity. The reactions were irradiated at the required set temperature for the
stipulated time and then cooled to ambient temperature with air-jet cooling. Reactions were
monitored by TLC on silica gel using a combination of hexane and ethyl acetate as eluents.
Solvents were distilled prior to use; petroleum ether with a boiling range of 60 to 80 °C was
used. Pd2(dba)3, TBAB (tetrabutylammonium bromide) and K2CO3 were purchased from
Sigma-Aldrich and used as received. Methacryloyl bromide and phenols were purchased
from local sources and used as received. ortho-Iodoaniline and 3-chloro-2-methylpropene
were purchased from TCI and used as received. Acme’s silica gel (60–120 mesh) was used
for column chromatography (approximately 20 g per one gram of crude material). It is worth
noting that these sort of experimental procedures have already been published elsewhere.14b &
14c, 15, 16
GP (General Procedure for the Synthesis of 3,3’-Disubstituted Heterocyclic Compounds
4/5/6): To an oven dried 10 mL glass tube sealed with teflon septum was equipped with a
magnetic stir bar, were added ortho-iodoaryl allyl ether 1/ortho-iodophenyl allylic amines
2/ortho-iodophenyl enamide 3 (68 to 88 mg, 0.25 mmol), followed by Pd2(dba)3 (11.4 mg, 5
mol%), K2CO3 (138.6 mg, 1 mmol), TBAB (80.5 mg, 0.25 mmol) and solvent water (0.5 mL)
at room temperature. The resultant reaction mixture was subjected to microwave irradiation
at 120 °C for 20 min, 150 W, closed vessel. The progress of the reaction was monitored by
TLC till the reaction is completed. The reaction mixture was cooled to room temperature,
quenched with an aqueous NaHCO3 solution and extracted with ethyl acetate (3 × 10 mL).
The organic layers were washed with saturated NaCl solution, dried (Na2SO4) and filtered.
Evaporation of the solvent(s) under reduced pressure and purification of the crude mixture by
silica gel column chromatography (petroleum ether/ethyl acetate), furnished the 3,3’-
disubstituted heterocyclic compounds 4/5/6 (50 to 82%) as oil/solid.

5-ethyl-3,3-dimethyl-2,3-dihydro-1-benzofuran (4c): GP was carried out with 4-ethyl-2-
iodo-1-[(2-methylprop-2-enyl)oxy]benzene 1c (75 mg, 0.25 mmol), Pd2(dba)3 (11.4 mg, 5
mol%), TBAB (80.5 mg, 0.25 mmol), K2CO3 (138.6 mg, 1 mmol) and water (0.5 mL).
Purification of the crude material by silica gel column chromatography (petroleum ether/ethyl
acetate, 100:0 to 99:1) furnished the benzofuran 4c (33.5 mg, 78%) as light yellow liquid,
[TLC control (petroleum ether/ethyl acetate 100:0), Rf(1c)=0.9, Rf(4c)=0.8, UV detection]. IR
(MIR-ATR, 4000–600 cm-1): νmax=3031, 2960, 2875, 1607, 1473, 1247, 1193, 983, 759, 697,
1
642 cm-1. H NMR (CDCl3, 400 MHz): δ=6.95 (dd, 1H, J = 8.3 and 2.0 Hz, A−H), 6.92 (s,
1H, Ar–H), 6.70 (d, 1H, J = 8.3 Hz, Ar–H), 4.20 (s, 2H, Ar–O−CH2), 2.59 (q, 2H, J = 7.3 Hz,
A−H), 1.33 (s, 6H, 2 × CH3), 1.21 (t, 3H, J = 7.3 Hz, A−H) ppm. 13C{1H} NMR (CDCl3, 100
MHz): δ=157.2 (s, Ar–C), 136.5 (s, 2 × Ar–C), 127.1 (d, Ar–CH), 121.6 (d, Ar–CH), 109.2
(d, Ar–CH), 84.5 (t, CH2), 41.9 (s, C), 28.4 (t, CH2), 27.5 (q, 2 × CH3), 16.0 (q, CH3) ppm.
HR-MS m/z calculated for [C12H20NO]+=[M+NH4]+: 194.1539; found 194.1533.
5-tert-butyl-3,3-dimethyl-2,3-dihydro-1-benzofuran (4d): GP was carried out with 4-tert-
butyl-2-iodo-1-[(2-methylprop-2-enyl)oxy]benzene 1d (82 mg, 0.25 mmol), Pd2(dba)3 (11.4
mg, 5 mol%), TBAB (80.5 mg, 0.25 mmol), K2CO3 (138.6 mg, 1 mmol) and water (0.5 mL).
Purification of the crude material by silica gel column chromatography (petroleum ether/ethyl
acetate, 100:0 to 99:1) furnished the benzofuran 4d (38.4 mg, 76%) as light yellow liquid,
[TLC control (petroleum ether/ethyl acetate 100:0), Rf(1d)=0.9, Rf(4d)=0.8, UV detection].
IR (MIR-ATR, 4000–600 cm-1): νmax=2959, 2875, 1605, 1487, 1365, 1223, 1127, 980, 818,
750, 691 cm-1. 1H NMR (CDCl3, 400 MHz): δ=7.14 (dd, 1H, J = 8.3 and 2.1 Hz A−H), 7.11
(d, 1H, J = 2.1 Hz, Ar–H), 6.71 (d, 1H, Ar–H, J = 8.3 Hz), 4.21 (s, 2H, Ar–O−CH2), 1.34 (s,
6H, 2 × CH3), 1.34 (s, 9H, 3 × CH3) ppm. 13C{1H} NMR (CDCl3, 100 MHz): δ=156.9 (s, Ar–
C), 143.6 (s, Ar–C), 136.0 (s, Ar–C), 124.7 (d, Ar–CH), 119.0 (d, Ar–CH), 108.7 (d, Ar–
CH), 84.6 (t, CH2), 42.0 (s, C), 34.4 (s, C), 31.8 (q, 3 × CH3), 27.5 (q, 2 × CH3) ppm. HR-MS
m/z calculated for [C14H20O]+=M+: 204.1509; found 204.1575.
3,3-dimethyl-5-phenyl-2,3-dihydro-1-benzofuran (4e): GP was carried out with 3-iodo-
1,1'-biphenyl-4-yl 2-methylprop-2-enyl ether 1e (87.5 mg, 0.25 mmol), Pd2(dba)3 (11.4 mg, 5
mol%), TBAB (80.5 mg, 0.25 mmol), K2CO3 (138.6 mg, 1 mmol) and water (0.5 mL).
Purification of the crude material by silica gel column chromatography (petroleum ether/ethyl
acetate, 100:0 to 99:1) furnished the benzofuran 4e (45.5 mg, 82%) as light yellow liquid,

[TLC control (petroleum ether/ethyl acetate 100:0), Rf(1e)=0.8, Rf(4e)=0.7, UV detection]. IR
(MIR-ATR, 4000–600 cm-1): νmax=3032, 2960, 2875, 1607, 1472, 1249, 1192, 981, 819, 757,
1
696 cm-1. H NMR (CDCl3, 400 MHz): δ=7.60–7.50 (m, 2H, Ar–H), 7.50–7.35 (m, 2H, Ar–
H), 7.37 (dd, 1H, J = 8.2 and 2.0 Hz, Ar–H), 7.35–7.25 (m, 1H, Ar–H), 7.33 (d, 1H, J = 2.0
Hz, Ar–H), 6.87 (d, 1H, J = 8.2 Hz, Ar–H), 4.29 (s, 2H, Ar–O−CH2), 1.39 (s, 6H, 2 × CH3)
13
ppm. C{1H} NMR (CDCl3, 100 MHz): δ=158.8 (s, Ar–C), 141.4 (s, Ar–C), 137.2 (s, Ar–
C), 134.2 (s, Ar–C), 128.7 (d, 2 × Ar–CH), 127.0 (d, Ar–CH), 126.8 (d, 2 × Ar–CH), 126.5
(d, Ar–CH), 121.2 (d, Ar–CH), 109.8 (d, Ar–CH), 84.8 (t, CH2), 41.9 (s, C), 27.5 (q, 2 ×
CH3) ppm. HR-MS m/z calculated for [C16H17O]+=[M+H]+: 225.1274; found 225.1269.
5-fluoro-3,3-dimethyl-2,3-dihydro-1-benzofuran (4f): GP was carried out with 4-fluoro-2-
iodo-1-[(2-methylprop-2-enyl)oxy]benzene 1f (73 mg, 0.25 mmol), Pd2(dba)3 (11.4 mg, 5
mol%), TBAB (80.5 mg, 0.25 mmol), K2CO3 (138.6 mg, 1 mmol) and water (0.5 mL).
Purification of the crude material by silica gel column chromatography (petroleum ether/ethyl
acetate, 100:0 to 99:1) furnished the benzofuran 4f (29.8 mg, 72%) as light yellow liquid,
[TLC control (petroleum ether/ethyl acetate 100:0), Rf(1f)=0.9, Rf(4f)=0.8, UV detection]. IR
(MIR-ATR, 4000–600 cm-1): νmax=2957, 2868, 1612, 1488, 1363, 1263, 1195, 1109, 1028,
1
887, 817 cm-1. H NMR (CDCl3, 400 MHz): δ=6.83–6.73 (m, 2H, Ar–H), 6.68 (dd, 1H, J =
13
9.3 and 3.9 Hz, Ar–H), 4.23 (s, 2H, Ar–O–CH2), 1.32 (s, 6H, 2 × CH3) ppm. C{1H} NMR
(CDCl3, 100 MHz): δ=158.9 (s, Ar–C), 155.5 (d, Jc-f = 161.0 Hz, Ar–C−F), 138.1 (d, Jc-f =
7.0 Hz, Ar–C), 114.0 (d, Jc-f = 24.0 Hz, Ar–CH), 109.7 (d, J = 8.0 Hz, Ar–CH), 109.4 (d, J =
24.0 Hz, Ar–CH), 84.8 (t, CH2), 42.3 (s, C), 27.2 (q, 2 × CH3) ppm. HR-MS m/z calculated
for [C10H12FO]+=[M+H]+: 166.0867; found 166.0859.
5-bromo-3,3-dimethyl-2,3-dihydro-1-benzofuran (4h): GP was carried out with 4-bromo-
2-iodo-1-[(2-methylprop-2-enyl)oxy]benzene 1h (88.2 mg, 0.25 mmol), Pd2(dba)3 (11.4 mg,
5 mol%), TBAB (80.5 mg, 0.25 mmol), K2CO3 (138.6 mg, 1 mmol) and water (0.5 mL).
Purification of the crude material by silica gel column chromatography (petroleum ether/ethyl
acetate, 100:0 to 99:1) furnished the benzofuran 4h (38.5 mg, 68%) as colorless liquid, [TLC
control (petroleum ether/ethyl acetate 100:0), Rf(1h)=0.9, Rf(4h)=0.8, UV detection]. IR
(MIR-ATR, 4000–600 cm-1): νmax=2923, 2859, 1602, 1458, 1374, 1230, 1032, 980, 755 cm-1.
1H NMR (CDCl3, 400 MHz): δ=7.20 (dd, J = 8.8 and 2.4 Hz 1H, Ar–H), 7.17 (d, 1H, J = 2.0
Hz, Ar–H), 6.65 (d, 1H, J = 8.3 Hz, Ar–H), 4.22 (s, 2H, Ar–O–CH2), 1.32 (s, 6H, 2 × CH3)

13
ppm. C{1H} NMR (CDCl3, 100 MHz): δ=158.3 (s, Ar–C), 139.1 (s, Ar–C), 130.6 (d, Ar–
CH), 125.5 (d, Ar–CH), 112.3 (s, Ar–C), 111.3 (d, Ar–CH), 84.8 (t, CH2), 42.2 (s, C), 27.4
(q, 2 × CH3) ppm. HR-MS m/z calculated for [C10H11BrO]+=M+: 225.9988; found 225.9853.
7-methoxy-3,3-dimethyl-2,3-dihydro-1-benzofuran-5-carbaldehyde (4i): GP was carried
out with 3-iodo-5-methoxy-4-[(2-methylprop-2-enyl)oxy]benzaldehyde 1i (82.7 mg, 0.25
mmol), Pd2(dba)3 (11.4 mg, 5 mol%), TBAB (80.5 mg, 0.25 mmol), K2CO3 (138.6 mg, 1
mmol) and water (0.5 mL). Purification of the crude material by silica gel column
chromatography (petroleum ether/ethyl acetate, 100:0 to 99:1) furnished the benzofuran 4i
(25.0 mg, 50%) as colorless liquid, [TLC control (petroleum ether/ethyl acetate 60:40),
Rf(1i)=0.7, Rf(4i)=0.6, UV detection]. IR (MIR-ATR, 4000–600 cm-1): νmax=2959, 2750,
1
1682, 1590, 1459, 1314, 1220, 1129, 1056, 949, 854, 755, 709 cm-1. H NMR (CDCl3, 400
MHz): δ=9.82 (s, 1H, Ar–CHO), 7.31 (d, 1H, J = 1.5 Hz, Ar–H), 7.30 (d, 1H, J = 1.5 Hz, Ar–
13
H), 4.42 (s, 2H, Ar–O–CH2), 3.93 (s, 3H, Ar–OCH3), 1.38 (s, 6H, 2 × CH3) ppm. C{1H}
NMR (CDCl3, 100 MHz): δ=190.6 (s, Ar–CO), 153.3 (s, Ar–C), 145.1 (s, Ar–C), 138.2 (s,
Ar–C), 131.5 (s, Ar–C), 118.8 (d, Ar–CH), 111.4 (d, Ar–CH), 86.2 (t, CH2), 56.1 (q, OCH3),
42.1 (s, C), 27.6 (q, 2 × CH3) ppm. HR-MS m/z calculated for [C12H15O3]+=[M+H]+:
207.1016; found 207.1110.
1-ethyl-3,3-dimethylindoline (5b): GP was carried out with 2-iodo-N-ethyl-2-iodo-N-(2-
methylallyl)aniline 2b (75.2 mg, 0.25 mmol) Pd2(dba)3 (11.4 mg, 5 mol%), TBAB (80.5 mg,
0.25 mmol), K2CO3 (138.6 mg, 1 mmol) and water (0.5 mL). Purification of the crude
material by silica gel column chromatography (petroleum ether/ethyl acetate, 100:0 to 98:2)
furnished the indoline 5b (27.4 mg, 63%) as light yellow liquid, [TLC control (petroleum
ether/ethyl acetate 100:0), Rf(2b)=0.9, Rf(5b)=0.8, UV detection]. IR (MIR-ATR, 4000–600
1
cm-1): νmax=3051, 2957, 2809, 1718, 1605, 1489, 1376, 1299, 1248, 749 cm-1. H NMR
(CDCl3, 400 MHz): δ=7.06 (ddd, 1H, J = 7.8, 7.8 and 1.0 Hz, Ar–H), 7.00 (dd, 1H, J = 7.3
and 1.0 Hz, Ar–H), 6.67 (ddd, 1H, J = 7.3, 7.3 and 1.4 Hz, Ar–H), 6.45 (d, 1H, J = 7.8 Hz,
Ar–H), 3.14 (q, 2H, J = 7.3 Hz, CH2), 3.09 (s, 2H, CH2), 1.29 (s, 6H, 2 × CH3), 1.16 (t, 3H, J
= 7.3 Hz, CH3) ppm. 13C{1H} NMR (CDCl3, 100 MHz): δ=150.9 (s, Ar–C), 139.2 (s, Ar–C),
127.3 (d, Ar–CH), 121.6 (d, Ar–CH), 117.4 (d, Ar–CH), 107.1 (d, Ar–CH), 66.5 (t, CH2),
42.6 (t, CH2), 40.0 (s, C), 27.6 (q, 2 × CH3), 11.8 (q, CH3) ppm. HR-MS m/z calculated for
[C12H17N]+=M+: 175.1361; found 175.1251.

3,3-dimethyl-1-propylindoline (5c): GP was carried out with 2-iodo-N-(2-methylallyl)-N-
propylaniline 2c (78.7mg, 0.25 mmol), Pd2(dba)3 (11.4 mg, 5 mol%), TBAB (80.5 mg, 0.25
mmol), K2CO3 (138.6 mg, 1 mmol) and water (0.5 mL). Purification of the crude material by
silica gel column chromatography petroleum ether/ethyl acetate, 100:0 to 96:4) furnished the
indoline 5c (34.1 mg, 73%) as light yellow liquid, [TLC control (petroleum ether/ethyl
acetate 100:0), Rf(2c)=0.9, Rf(5c)=0.8, UV detection]. IR (MIR-ATR, 4000–600 cm-1):
1
νmax=2959, 2925, 1670, 1601, 1484, 1371, 1262, 1093, 1034, 804, 752 cm-1. H NMR
(CDCl3, 400 MHz): δ=7.06 (ddd, J = 7.3, 7.3 and 1.0 Hz, 1H, Ar–H), 7.00–6.98 (dd, 1H, J =
7.3 and 1.0 Hz, Ar–H), 6.63 (ddd, 1H, J = 7.3, 7.3 and 1.0 Hz, Ar–H), 6.45 (d, 1H, J = 7.8
Hz, Ar–H), 3.09 (s, 2H, CH2), 3.00 (t, 2H, J = 7.3 Hz, CH2), 1.60 (m, 2H,), 1.28 (s, 6H, 2 ×
CH3), 0.96 (t, 3H, J = 7.3 Hz, CH3) ppm. 13C{1H} NMR (CDCl3, 100 MHz): δ=151.3 (s, Ar–
C), 138.8 (s, Ar–C), 127.4 (d, Ar–CH), 121.6 (d, Ar–CH), 117.1 (d, Ar–CH), 106.7 (d, Ar–
CH), 67.3 (t, CH2), 50.4 (t, CH2), 40.1 (s, C), 27.6 (q, 2 × CH3), 20.6 (t, CH2), 11.7 (q, CH3)
ppm. HR-MS m/z calculated for [C13H19N]+=M+: 189.1512; found 189.1656.
3,3-dimethyl-1-(2-nitrophenyl)indoline (5e): GP was carried out with N-(2-iodophenyl)-N-
(2-methylprop-2-enyl)-N-(2-nitrophenyl)amine 2e (76 mg, 0.25 mmol), Pd2(dba)3 (11.4 mg, 5
mol%), TBAB (80.5 mg, 0.25 mmol), K2CO3 (138.6 mg, 1 mmol) and water (0.5 mL).
Purification of the crude material by silica gel column chromatography (petroleum ether/ethyl
acetate, 100:0 to 92:8) furnished the indoline 5e (42.6 mg, 64%) as liquid, [TLC control
(petroleum ether/ethyl acetate 100:0), Rf(2e)=0.9, Rf(5e)=0.8, UV detection]. IR (MIR-ATR,
1
4000–600 cm-1): νmax=2959, 2861, 1595, 1517, 1484, 1339, 1284, 1030, 801, 740 cm-1. H
NMR (CDCl3, 400 MHz): δ=7.93 (dd, 1H, J = 7.8 and 1.0 Hz, Ar–H), 7.54–7.50 (m, 2H, Ar–
H), 7.15–7.04 (m, 3H, Ar–H), 6.87 (ddd, 1H, J = 7.3, 7.3 and 1.0 Hz, Ar–H), 6.62 (d, 1H, J =
13
7.8 Hz, Ar–H), 3.61 (s, 2H, CH2), 1.37 (s, 6H, 2 × CH3) ppm. C{1H} NMR (CDCl3, 100
MHz): δ=144.9 (s, Ar–C), 142.1 (s, Ar–C), 140.5 (s, Ar–C), 138.8 (s, Ar–C), 133.7 (d, Ar–
CH), 127.1 (d, Ar–CH), 126.3 (d, Ar–CH), 122.5 (d, Ar–CH), 122.4 (d, Ar–CH), 122.3 (s,
Ar–C), 120.9 (s, Ar–C), 109.4 (d, Ar–CH), 67.8 (t, CH2), 41.2 (s, C), 27.3 (q, 2 × CH3) ppm.
HR-MS m/z calculated for [C16H16N2NaO2]+=[M+Na]+: 291.1104; found 291.1096.
3,3-dimethyl-1-(2-methylprop-2-enyl)indoline (5f): GP was carried out with N-(2-
iodophenyl)-N,N-bis(2-methylprop-2-enyl)amine 2f (81.7 mg, 0.25 mmol), Pd2(dba)3 (11.4
mg, 5 mol%), TBAB (80.5 mg, 0.25 mmol), K2CO3 (138.6 mg, 1 mmol) and water (0.5 mL).

Purification of the crude material by silica gel column chromatography (petroleum ether/ethyl
acetate, 100:0 to 98:2) furnished the indoline 5f (29.8 mg, 60%) as liquid, [TLC control
(petroleum ether/ethyl acetate 100:0), Rf(2f)=0.9, Rf(5f)=0.8, UV detection]. IR (MIR-ATR,
1
4000–600 cm-1): νmax=2956, 2860, 2808, 1604, 1489, 1454, 1376, 1156, 1068, 749 cm-1. H
NMR (CDCl3, 400 MHz): δ=7.05 (ddd, 1H, J = 7.3, 7.3 and 1.0 Hz, Ar–H), 7.00 (dd, 1H, J =
7.3 and 1.0 Hz, Ar–H), 6.66 (ddd, 1H, J = 7.3, 7.3 and 1.0 Hz, Ar–H), 6.46 (d, 1H, J = 7.8
Hz, Ar–H), 4.94 (s, 1H, CHaHb=C), 4.87 (s, 1H, CHaHb=C), 3.56 (s, 2H, CH2), 3.07 (s, 2H,
13
CH2), 1.76 (s, 2H,), 1.29 (s, 6H, 2 × CH3) ppm. C{1H} NMR (CDCl3, 100 MHz): δ=151.1
(s, Ar–C), 142.4 (s, Ar–C), 138.8 (s, Ar–C), 127.3 (d, Ar–CH), 121.6 (d, Ar–CH), 117.3 (d,
Ar–CH), 111.9 (t, CH2), 106.6 (d, Ar–CH), 67.8 (t, CH2), 55.3 (t, CH2), 40.0 (s, C), 27.6 (q, 2
× CH3), 20.3 (q, CH3) ppm. HR-MS m/z calculated for [C14H20N]+=[M+H]+: 202.1590; found
202.1512.
3,3-dimethyl-1-propyl-1,3-dihydro-2H-indol-2-one (6c): GP was carried out with N-(2-
iodophenyl)-2-methyl-N-propylacrylamide 3c (82.2 mg, 0.25 mmol), Pd2(dba)3 (11.4 mg, 5
mol%), TBAB (80.5 mg, 0.25 mmol), K2CO3 (138.6 mg, 1 mmol) and water (0.5 mL).
Purification of the crude material by silica gel column chromatography (petroleum ether/ethyl
acetate, 100:0 to 90:10) furnished the oxindole 6c (39.8 mg, 79%) as liquid, [TLC control
(petroleum ether/ethyl acetate 100:0), Rf(3c)=0.8\4, Rf(6c)=0.5, UV detection]. IR (MIR-
ATR, 4000–600 cm-1): νmax=2969, 2929, 2869, 1707, 1611, 1487, 1460, 1361, 1215, 1129,
1
750 cm-1. H NMR (CDCl3, 400 MHz): δ=7.25–7.18 (m, 2H, Ar–H), 7.03 (ddd, 1H, J = 7.3,
7.3 and 1.0 Hz, Ar–H), 6.84 (d, 1H, J = 7.8 Hz, Ar–H), 3.67 (t, 2H, J = 7.3 Hz, CH2), 1.70
13
(m, 2H), 1.36 (s, 6H, 2 × CH3), 0.94 (t, 3H, J = 7.3 Hz, CH3) ppm. C{1H} NMR (CDCl3,
100 MHz): δ=181.4 (s, Ar–CO), 142.1 (s, Ar–C), 136.0 (s, Ar–C), 127.5 (d, Ar–CH), 122.4
(d, Ar–CH), 122.2 (d, Ar–CH), 108.3 (d, Ar–CH), 44.1 (s, C), 41.3 (t, CH2), 24.5 (q, 2 ×
CH3), 20.7 (t, CH2), 11.3 (q, CH3) ppm. HR-MS m/z calculated for [C13H18NO]+=[M+H]+:
204.1383; found 204.1370.
3,3-dimethyl-1-(2-methylprop-2-enyl)-1,3-dihydro-2H-indol-2-one (6f): GP was carried
out with N-(2-iodophenyl)-2-methyl-N-(2-methylprop-2-enyl)acrylamide 3f (85.2 mg, 0.25
mmol), Pd2(dba)3 (11.4 mg, 5 mol%), TBAB (80.5 mg, 0.25 mmol), K2CO3 (138.6 mg, 1
mmol) and water (0.5 mL). Purification of the crude material by silica gel column
chromatography (petroleum ether/ethyl acetate, 100:0 to 85:15) furnished the oxindole 6f

(32.6 mg, 61%) as liquid, [TLC control (petroleum ether/ethyl acetate 100:0), Rf(3f)=0.6,
Rf(6f)=0.7, UV detection]. IR (MIR-ATR, 4000–600 cm-1): νmax=2963, 2927, 2868, 1711,
1
1611, 1462, 1368, 1202, 1133, 802 cm-1. H NMR (CDCl3, 400 MHz): δ=7.25–7.16 (m, 2H,
Ar–H), 7.04 (ddd, 1H, J = 7.3, 7.3 and 1.0 Hz, Ar–H), 6.82 (dd, 1H, J = 7.3 and 1.0 Hz, Ar–
CH), 4.91 (s, 1H, CHaHb=C), 4.82 (s, 1H, CHaHb=C), 4.26 (s, 2H, CH2), 1.71 (s, 3H, CH3),
1.39 (s, 6H, 2 × CH3) ppm. 13C{1H} NMR (CDCl3, 100 MHz): δ=181.2 (s, Ar–CO), 141.9 (s,
Ar–C), 139.2 (s, Ar–C), 135.7 (s, Ar–C), 127.5 (d, Ar–CH), 122.4 (d, Ar–CH), 122.2 (d, Ar–
CH), 112.2 (t, CH2), 109.1 (d, Ar–CH), 45.5 (t, CH2), 44.1 (s, C), 24.5 (q, 2 × CH3), 19.8 (q,
CH3) ppm. HR-MS m/z calculated for [C14H18NO]+=[M+H]+: 216.1383; found 216.1366.
Acknowledgement
We are grateful to the Department of Science and Technology-Science and Engineering
Research Board (DST-SERB) [NO.:EMR/2017/005312], New Delhi, for financial support.
K.R. thanks MHRD, New Delhi, for the award of a research fellowship.
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‹ Reductive Heck Coupling
‹ [Pd]-catalysis
‹ Synthesis of heterocyclic compounds
‹ Environmentally benign process
‹ Water as the sole green solvent
‹ Microwave-assisted synthesis
‹ Short reaction times