Palladium-catalyzed cyclization of 2-alkynyl-N-ethanoyl anilines to indoles: Synthesis, structural, spectroscopic, and mechanistic study

Article abstract of DOI:10.1002/poc.3477

This study reports a facial regio-selective synthesis of 2-alkyl-N-ethanoyl indoles from substituted-N-ethanoyl anilines employing palladium (II) chloride, which acts as a cyclization catalyst. The mechanistic trait of palladium-based cyclization is also explored by employing density functional theory. In a two-step mechanism, the palladium, which attaches to the ethylene carbons, promotes the proton transfer and cyclization. The gas-phase barrier height of the first transition state is 37kcal/mol, indicating the rate-determining step of this reaction. Incorporating acetonitrile through the solvation model on density solvation model reduces the barrier height to 31kcal/mol. In the presence of solvent, the electron-releasing (-CH₃) group has a greater influence on the reduction of the barrier height compared with the electron-withdrawing group (-Cl). These results further confirm that solvent plays an important role on palladium-catalyzed proton transfer and cyclization. For unveiling structural, spectroscopic, and photophysical properties, experimental and computational studies are also performed. Thermodynamic analysis discloses that these reactions are exothermic. The highest occupied molecular orbital-lowest unoccupied molecular orbital gap (4.9-5.0eV) confirms that these compounds are more chemically reactive than indole. The calculated UV-Vis spectra by time-dependent density functional theory exhibit strong peaks at 290, 246, and 232nm, in good agreement with the experimental results. Moreover, experimental and computed ¹H and ¹³C NMR chemical shifts of the indole derivatives are well correlated.

Full text of DOI:10.1002/poc.3477

Research article
Received: 8 February 2015,
Revised: 6 May 2015,
Accepted: 26 June 2015,
Published online in Wiley Online Library: 4 August 2015
(wileyonlinelibrary.com) DOI: 10.1002/poc.3477
Palladium-catalyzed cyclization of 2-alkynyl-N-
ethanoyl anilines to indoles: synthesis,
structural, spectroscopic, and mechanistic
study
Mohammad Mazharol Hoquea,b, Mohammad A. Halimb*,
Mohammed G. Sarwarc and Md. Wahab Khana**
This study reports a facial regio-selective synthesis of 2-alkyl-N-ethanoyl indoles from substituted-N-ethanoyl anilines
employing palladium (II) chloride, which acts as a cyclization catalyst. The mechanistic trait of palladium-based cyclization
is also explored by employing density functional theory. In a two-step mechanism, the palladium, which attaches to the
ethylene carbons, promotes the proton transfer and cyclization. The gas-phase barrier height of the first transition state is
37 kcal/mol, indicating the rate-determining step of this reaction. Incorporating acetonitrile through the solvation model
on density solvation model reduces the barrier height to 31 kcal/mol. In the presence of solvent, the electron-releasing
(–CH3) group has a greater influence on the reduction of the barrier height compared with the electron-withdrawing group
(–Cl). These results further confirm that solvent plays an important role on palladium-catalyzed proton transfer and cycliza-
tion. For unveiling structural, spectroscopic, and photophysical properties, experimental and computational studies are also
performed. Thermodynamic analysis discloses that these reactions are exothermic. The highest occupied molecular orbital–
lowest unoccupied molecular orbital gap (4.9–5.0 eV) confirms that these compounds are more chemically reactive than in-
dole. The calculated UV–Vis spectra by time-dependent density functional theory exhibit strong peaks at 290, 246, and
232 nm, in good agreement with the experimental results. Moreover, experimental and computed 1H and 13C NMR chemical
shifts of the indole derivatives are well correlated. Copyright © 2015 John Wiley & Sons, Ltd.
Keywords: cross-coupling; density functional theory (DFT); indole derivatives; palladium catalysis; time-dependent density functional
theory (TD-DFT); transition states
of H2O2 upon light exposure and is capable of protecting trypto-
phan from oxidation in mAb1 against diverse reactive oxygen
INTRODUCTION
species, which may lead to formulation of applications in protec-
tion of proteins against degradation via oxidation.[17] Nowadays,
dye-sensitizing solar cells (DSSCs) have attracted common
interest as a new renewable energy source because of their
low cost and high efficiency.[18–22] A recent investigation on
The substituted indoles, both naturally occurring and synthetic,
exhibit a wide range of biological activity.[1–5] They have been re-
ferred to as a “privileged structure” because of their excellent
binding ability with various receptors.[6,7] This is a reason why in-
dole derivatives have become structural motifs in many pharma-
ceuticals and agrochemical products.[8] Serotonin, a simple
indole derivative, acts as a neurotransmitter,[9] and vinblastine,
a complex alkaloid therapeutic agent, is used clinically as an an-
ticancer agent.[10–12] Moreover, a number of important synthetic
drugs contain an indole motif. For example, fluvastatin is used to
treat hypercholesterolemia as well as to prevent cardiovascular
disease[13]; 5-chloro-3-{(3, 5-dimethylphenyl)sulfunyl}-4-fluoro-
1H-indole-2-carboximate[14] and methyl (2-carbamoyl-5-chloro-
1H-indol-3yl) (phenyl) phosphinate are potent inhibitors of
HIV-1.[15] Furthermore, Indole-3-Carbinol, a simple molecule
present in wide range of plants, has modest activity against the
glioma cell lines 132N1 and U87MG.[16]
* Correspondence to: Mohammad A. Halim, Bangladesh Institute of Computa-
tional Chemistry and Biochemistry, 38 Green Road West, Dhaka 1205,
Bangladesh.
E-mail: bdcomputchem@gmail.com
**Correspondence to: Md. Wahab Khan, Department of Chemistry, Bangladesh
University of Engineering and Technology, Dhaka 1000, Bangladesh.
E-mail: mwkhan@chem.buet.ac.bd
a M. M. Hoque, M. W. Khan
Department of Chemistry, Bangladesh University of Engineering and Technol-
ogy, Dhaka 1000, Bangladesh
Besides medicinal or therapeutic activities, many proteins con-
tain indole skeletons; for example, tryptophan – an essential aro-
matic amino acid in the human diet – is a component of many
structural or enzyme proteins. It has been reported that indole
and tryptophan with hydroxyl groups on the six-member aro-
matic ring were found to have lower oxidation potentials than
their parent compounds. Hence, it produces the least amount
b M. M. Hoque, M. A. Halim
Bangladesh Institute of Computational Chemistry and Biochemistry, 38 Green
Road West, Dhaka 1205, Bangladesh
c M. G. Sarwar
Department of Chemistry, The Scripps Research Institute, La Jolla, CA, 92037,
USA
J. Phys. Org. Chem. 2015, 28 732–742
Copyright © 2015 John Wiley & Sons, Ltd.

PALLADIUM-CATALYZED CYCLIZATION
the photovoltaic performance of LI-3 and LI-4 in DSSCs demon-
strated the overall efficiency of 4.31%, compared with the stan-
dard cell from N719 (7.88%) under the same condition.[23]
Because of the great importance and diverse applications,
the continued development of routes toward indoles has been
a central theme in organic synthesis over the last century.[24–27]
Palladium-catalyzed protocols have played significant role for
the synthesis of functionalized indole from simple and com-
mercially accessible starting materials.[28–34] The most com-
monly used palladium (II) salts in indole chemistry are PdCl2
and Pd(OAc)2, generally employed as PdCl2(PPh3)2, Pd(OAc)2
(PPh3)2, and PdCl2(MeCN)2. In numerous transformations, aryl io-
dide has widely been used as a synthetic intermediate. A
microwave-assisted two-step reaction was carried out under
Sonogashira coupling conditions from N-substituted/N,N-disubsti-
tuted iodo anilines and terminal alkynes followed by the addition
of acetonitrile and aryl iodide to synthesize polysubstituted in-
doles.[35] In addition, the direct synthesis of indole from anilines
and ketones has been carried out, employing Pd(OAc)2 with Cu
(OAc)2 as a stoichiometric co-oxidant.[36] In recent years, our group
has developed methods for the synthesis of benzo-fused heterocy-
clic compounds including isoindolines, isoquinolinone,[37] benz[b]
furans,[38] and indoles,[39] by palladium-catalyzed reactions of aryl
iodide with terminal alkynes.[40]
2-Iodo-4-methylacetanilide 1
Brown crystal; Mp. 125–128 °C; IR (KBr): νmax 3265.3, 1654.8,
1523.7, 1290.3 cmꢀ1; UV (EtOH): λmax 401.85, 199.99 nm; 1H
NMR (400 MHz, CDCl3): δH 7.99 (d, 1H, J = 8.0 Hz), 7.59 (s, 1H),
7.32 (br s, 1H), 7.12 (d, 1H, J = 8.0 Hz), 2.26 (s, 3H), 2.10 (s, 3H);
13C NMR (100 MHz, CDCl3): δc 168.15, 145.98, 138.96, 135.79,
129.92, 122.12, 90.29, 24.67, 20.30.
4-Chloro-2-iodoacetanilide 2
White crystal; IR (KBr): νmax 3274.9, 1658.7, 1577.7, 1568.0, 1521.7,
1463.9 1375.2, 1288.4 cmꢀ1; 1H NMR (400 MHz, CDCl3): δH 8.15 (d,
1H, J = 8.0 Hz), 7.74 (d, 1H, J = 2.0 Hz), 7.36 (br s, 1H), 7.30 (dd, 1H,
J = 8.0 and 2.0 Hz, H-5), 2.22 (s, 3H); UV (EtOH): λmax 240.65,
200.15 nm.
General procedure for the synthesis of substituted-2-(1-
alkynyl)acetanilides, 5–7
In a 50-mL round bottom flask equipped with a reflux condenser,
a
mixture of 2-iodo-4-methyl-N-ethanoyl aniline 1 (0.5 g,
1.818 mmol), bis(triphenylphosphine) palladium (ІІ) chloride
(0.044 g, 0.063 mmol), copper (І) iodide (0.027 g, 0.145 mmol),
and triethylamine (0.734 g, 7.272 mmol) was stirred in 7-ml
dimethylformamide (DMF) under a nitrogen atmosphere for 1 h
at room temperature. Then, 1-heptyne 3 (0.178 g, 2.181 mmol)
was added, and the solution was heated at 60 °C for 48 h. The
mixture was then evaporated to dryness under reduced pres-
sure. The residue was extracted with chloroform (3 × 50 mL),
and the combined chloroform extracts were washed with dis-
tilled water (3 × 50 mL), dried over anhydrous Na2SO4, filtered,
and concentrated under reduced pressure. The residue was puri-
fied by column chromatography on silica gel using n-hexane/
ethyl acetate (8:1) to yield the pure 2-(1-heptynyl)-4-methyl-N-
ethanoyl aniline 5 (Scheme 1).
As the substituted indole nucleus is a structural component of
a vast number of biologically active and functional materials and
natural and synthetic compounds, we are therefore interested in
developing a convenient method for the synthesis. For exploring
detail structural, spectroscopic, and photophysical properties,
density functional theory (DFT) and time-dependent DFT
(TD-DFT) are employed. The mechanistic feature of palladium
(II) chloride-based cyclization to form 2-alkyl-N-ethanoyl indole
is also investigated by locating transition states.
EXPERIMENTAL AND COMPUTATIONAL
METHODS
2-(1-Heptynyl)-4-methyl-N-ethanoyl aniline, 5
Brown crystalline solid; Mp. 64–65 °C; IR (KBr): νmax 3274.9,
2933.5, 2219.9, 1662.5, 1522.5 cmꢀ1; UV (EtOH): λmax 365.5,
284 nm; 1H NMR (400 MHz, CDCl3): δH 8.21 (d, 1H, J = 8.4 Hz),
7.84 (br s, 1H), 7.16 (s, 1H), 7.07 (d, 1H, J = 8.0 Hz), 2.48 (t, 2H,
J = 6.8 Hz), 2.25 (s, 3H), 2.18 (s, 3H), 1.64 (quint, 2H, J = 7.2 and
6.8 Hz), 1.49–1.24 (m, 4H), 0.92 (t, J = 7.2 Hz); 13C NMR (100 MHz,
CDCl3): δc 167.94, 136.48, 132.73, 131.80, 129.59, 118.91 and
112.38, 97.42, 76.09, 31.18, 28.47, 24.90, 22.24, 20.64, 19.55, 14.01.
General experimental
Melting points were determined in open capillary tubes on
Gallenkamp (London, England) melting point apparatus and
are uncorrected. Infrared (IR) spectra were recorded on a
Shimadzu (Kyoto, Japan) Fourier transform infrared (FTIR) spectro-
photometer (range: 4000–400/cm and number of scans: 45), and
UV spectra were recorded in dry EtOH with a Shimadzu (Kyoto,
Japan) visible spectrophotometer. H NMR and 13C NMR spectra
1
were recorded on a Bruker (Billerica, MA, USA) DPX-400 spectro-
photometer (400 MHz) using tetramethylsilane as an internal refer-
ence. Analytical thin layer chromatography (TLC) was performed
on pre-coated silica gel 60 F254 (E. Merck, Darmstadt, Germany),
and the spots were visualized with UV light. Column chromatogra-
phy was performed on silica gel (60–120mesh). Reagents were
purchased from E. Merck and Fluka (St Gallen, Switzerland).
2-(1-Hexynyl)-4-methyl-N-ethanoyl aniline, 6
Brown crystalline solid; Mp. 84–86 °C; IR (KBr): νmax 3274.9, 2956.7,
2933.5, 2223.8, 1664.5, 1587.3, 1525.6, 1488.9, 1363.6, 1301.9,
829.3 cmꢀ1; UV (EtOH): λmax 308, 265.2, 263.6, 260.4 nm; 1H NMR
Synthesis of starting materials
substituted-2-iodoacetanilides 1 and 2
In our recent study, we developed a method of one-pot synthe-
sizing 2-iodoacetanilide, which has been employed to prepare
the required starting materials 1 and 2 of our present study
using iodine–copper (ІІ) acetate in acetic acid from their parent
substituted anilines.
Scheme 1. Synthesis of substituted-2-(1-alkynyl)acetanilides
J. Phys. Org. Chem. 2015, 28 732–742
Copyright © 2015 John Wiley & Sons, Ltd.
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M. M. HOQUE ET AL.
(400 MHz, CDCl3): δH 8.21 (d, 1H, J = 8.4 Hz), 7.84 (br s, 1H), 7.15
(s, 1H), 7.07 (d, 1H, J = 8.4 Hz), 2.49 (t, 2H, J = 7.2 Hz), 2.25 (s, 3H),
2.17 (s, 3H), 1.63 (quint, 2H, J = 7.2 and 6.8 Hz), 1.50 (sex, 2H,
J = 7.2 and 6.8 Hz), 0.96 (t, 3H, J = 7.2 Hz); 13C NMR (100 MHz,
CDCl3): δc 167.91, 136.54, 132.74, 131.81, 129.59, 118.99, 112.46,
97.33, 76.17, 30.83, 24.83, 22.08, 20.63, 19.25, 13.59.
(s, 1H), 2.98 (t, 2H, J = 7.6 Hz), 2.72 (s, 3H), 2.41 (s, 3H), 1.68 (quint,
2H, J = 7.2 and 7.6 Hz), 1.44 (sex, 2H), 0.95 (t, 3H, J = 7.2 Hz);
13C NMR (100 MHz, CDCl3): δc 170.19, 143.18, 134.60, 132.49,
130.31, 124.59, 120.20, 114.48, 108.03, 31.07, 30.30, 27.57, 22.56,
21.11, 13.97; anal. calcd. for C15H19NO: C, 78.56; H, 8.35. Found:
78.48; H, 8.39.
4-Chloro-2-(1-hexynyl)-N-ethanoyl aniline, 7
2-Butyl-5-chloro-N-ethanoyl indole, 10
White crystalline solid; Mp. 80–82 °C; IR (KBr): 3294.2, 2956.7, 2927.7,
2223.8, 1662.5, 1598.9, 1473.5 cmꢀ1; UV (EtOH): λmax 300.5, 284 nm;
1H NMR (400 MHz, CDCl3): δH 8.31 (d, 1H J = 8.8 Hz), 7.85 (br s, 1H,
7.31 (d, 1H, J = 2.0 Hz), 7.21 (dd, 1H, J =8.8 and 2.0 Hz), 2.49 (t, 2H,
J= 6.8 Hz), 2.18 (s, 3H), 1.62 (quint, 2H, J = 6.8 and 7.2 Hz), 1.50
(sex, 2H, J = 7.2 and 7.6 Hz), 0.96 (t, 3H, J= 7.6 Hz); 13C NMR
(100 MHz, CDCl3): δc 168.01), 137.50, 131.05, 128.87, 127.98,
120.12, 114.09, 99.07, 74.94, 30.63, 24.82, 22.06, 19.22, 13.55.
White crystalline solid; Mp. 51–52 °C; IR (KBr): νmax 2937.4, 1685.7,
1591.2, 1448.4, 1371.3, 1317.3, 829.3 cmꢀ1; UV (EtOH): λmax 352.5,
305.0, 291.0 nm; 1H NMR (400 MHz, CDCl3): δH 7.80 (d, 1H,
J = 9.2 Hz), 7.42 (d, 1H, J = 2.0Hz), 7.17(dd, 1H, J = 9.2 and 2.0 Hz),
6.34 (s, 1H), 2.96 (t, 2H, J = 7.2 Hz), 2.72 (s, 3H), 1.69 (quint, 2H,
J = 7.2 and 7.6 Hz), 1.44 (sex, 2H, J = 7.2 and 7.6 Hz), 0.96 (t, 3H,
J = 7.6 Hz); 13C NMR (100 MHz, CDCl3): δc 170.05, 144.13, 134.90,
131.20, 128.63, 123.47, 119.63, 115.94, 107.52, 30.96, 30.22,
27.48, 22.55, 13.93; anal. calcd. for C14H16ClNO: C, 67.33; H,
6.46. Found: 67.10; H, 6.45.
General methods for PdCl2-catalyzed synthesis of
2,5-disubstituted-N-ethanoyl indoles 8–10
General procedure for the synthesis of substituted-1H
indoles, 9a and 10a, by base-catalyzed reaction.
In a 50-mL round bottom flask equipped with a reflux condenser, a
mixture of palladium (ІІ) chloride (0.006 g, 0.032 mmol) and aceto-
nitrile (5mL) was refluxed at 80 °C with constant stirring. The solid
dissolved after 20 min, and the reaction mixture was allowed to
cool at room temperature. In this solution (0.076 g, 0.315 mmol)
of 2-(1-heptynyl)-4-methyl-N-ethanoyl aniline 5 was added and
the mixture was refluxed at 80 °C. The progress of the reaction
was monitored by TLC. The starting material disappeared after
40 min, and the reaction mixture was evaporated to dryness under
reduced pressure. The product was purified by column chroma-
tography on silica gel using n-hexane/ethyl acetate (5:1) to yield
0.056 g of the pure 5-methyl-2-pentyl-N-ethanoylindole 8.
A mixture of substituted 2-alkynylacetanilides, 21–24 (1 mmol),
and sodium ethoxide (1.2–1.5 mmol) in 20-mL ethanol was
stirred under a nitrogen atmosphere for 4 h at 80 °C. The reaction
mixture was evaporated to dryness under reduced pressure. Af-
ter usual workup, the residue was purified by column chroma-
tography on silica gel using n-hexane/ethylacetate as eluant to
yield substituted-1H-indoles 9a and 10a (Scheme 2).
2-Butyl-5-methyl-1H-indole, 9a
Pale yellow liquid; IR (KBr): νmax 3408.0, 2956.7, 2929.7, 1618.2,
1502.4, 1458.1 cmꢀ1; H NMR (400 MHz, CDCl3): δ 7.75 (br s, 1H),
7.29 (s, 1H), 7.16 (d, 1H, J = 8.0 Hz), 6.91 (d, 1H, J = 8.0 Hz), 6.45
(s, 1H), 2.72 (t, 2H, J = 7.6 Hz), 2.41 (s, 3H), 1.68 (quint, 2H, J = 7.6,
7.2 Hz, H-2′), 1.39 (sex, 2H, J = 7.2, 7.6 Hz), 0.87 (t, 3H, J = 7.2 Hz).
1
2-Pentyl-5-methyl-N-ethanoyl indole, 8
White crystalline solid; Mp. 50–51 °C; IR (KBr): νmax 2921.9, 1687.6,
1591.2, 1460.70, 1373.2, 1315.4, 815.8 cmꢀ1; UV (EtOH): λmax
371.4, 304.0, 293.5 nm; 1H NMR (400 MHz, CDCl3): δH 7.68
(d, 1H, J = 8.4 Hz), 7.25 (s, 1H), 7.04 (d, 1H, J = 8.4 Hz), 6.32
(s, 1H), 2.97 (t, 2H, J = 7.6 Hz), 2.72 (s, 3H), 2.41 (s, 3H), 1.69 (quint,
2H, J = 7.2 and 7.6 Hz′), 1.42–1.28 (m, 4H), 0.96 (t, J = 7.2 Hz);
13C NMR (100 MHz, CDCl3): δc 170.19, 143.21, 134.61, 132.49,
130.31, 124.59, 120.20, 114.48, 108.03, 31.67, 30.55, 28.62, 27.57,
22.56, 21.12, 14.05; anal. calcd. for C16H21NO: C, 78.97; H, 8.70.
Found: 78.91; H, 8.71.
2-Butyl-5-chloro-1H-indole, 10a
Pale brown liquid, yield; IR (KBr): νmax 3421.5, 2958.6, 2929.7,
1488.9 cmꢀ1 1H NMR (400 MHz, CDCl3): δ 7.87 (s, 1H), 7.46
;
(s, 1H), 7.17 (d, 1H, J = 8.4 Hz), 7.04 (d, 1H, J = 8.4 Hz), 6.13
(s, 1H), 2.73 (t, 2H, J = 7.6 Hz), 1.69 (quint, 2H, J = 7.2 and 7.6 Hz),
1.39 (sex, 2H, J = 7.2, 7.6 Hz), 0.95 (t, 3H, J = 7.2 Hz).
2-Butyl-5-methyl-N-ethanoyl indole, 9
Computational details
White crystalline solid; Mp. 68–69 °C; IR (KBr): νmax 2958.6, 2935.5,
1679.9, 1591.2, 1469.7 1379.4, 1317.3 cmꢀ1; UV (EtOH): λmax
366.5, 304.0, 295.5 nm; 1H NMR (400 MHz, CDCl3): δH 7.68
(d, 1H, J = 8.4 Hz), 7.25 (s, 1H), 7.04 (d, 1H, J = 8.4 Hz), 6.32
All calculations were carried out using the Gaussian 09 program
package (Gaussian Inc., Wallingford, CT, USA).[41] The equilibrium
geometry of compounds 5–10 were optimized at the B3LYP/6-
31+G(d, p) level of theory, and subsequently vibrational frequen-
cies were calculated. A scaling factor of 0.9648
was applied to the computed vibrational frequen-
cies in order to compare with experimental re-
sults.[42,43] The optimized structures 8–10 were
used to compute the lowest 10 singlet → singlet
spin-allowed electronic vertical excitation
energies by TD-DFT using B3LYP/6-31+G(d, p),
CAM-B3LYP/6-31+G(d, p), M06/6-31+G(d, p), and
X3LYP/6-31+G(d, p) level of theories. However,
Scheme 2. Synthesis of 2,5-disubstituted-N-ethanoyl indoles and substituted-1H indoles
X3LYP/6-31+G(d, p) showed the best agreement
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PALLADIUM-CATALYZED CYCLIZATION
with the experimental UV–Vis results. Chemical shift values of hydro-
gen and carbon were performed, employing the gauge-including
atomic orbital approach and using 6-311+G(2d) basis set in CHCl3.
The transition states related to the palladium (II) chloride-catalyzed
cyclization of 2-alkynal-4-substituted-N-ethanoyl acetanilides to 2-al-
kyl-5-substituted-N-ethanoyl indoles were optimized at the B3LYP/
SDD level of theory. All transition states have a single imaginary fre-
quency. An intrinsic reaction coordinate calculation has been per-
formed to connect the transition states with their corresponding
reactant, intermediates, and product. Single-point calculation with
B3LYP/SDD level of theory was performed to test the solvent effect
on this reaction mechanism employing conductor-like polarizable
continuum model (CPCM)[44,45] and solvation model on density
(SMD)[46] solvation models, where acetonitrile has been used as the
solvent. SMD provides the best result on stabilizing the transition
state, intermediate, and product.
(4mol equiv.) under nitrogen atmosphere in DMF (5–8 mL) at
60–80 °C for 24–48 h. This reaction produces 2-alkynal-4-
substituted-N-ethanoyl anilines 5–7 with good yield (60–72%).
To explore the generality of the coupling reaction, different 1-
alkynes can be employed. It is observed that 1-hexyne 4 has rel-
atively short reaction time (36 h) and high yield (72%), whereas
1-heptyne 3 takes a longer time (48 h) and produces a compara-
tively low yield (60%). The result indicates that the short-chain
terminal alkynes are more reactive than the long-chain terminal
alkynes. In addition, the substituent (X) groups in 2-
iodoacetanilide (Scheme 1) also have significant impact. In the
coupling reaction, acetanilide 1 with substituent p-CH3 resulted
in higher yields and greater kinetic reactivity than acetanilide 2
with substituent p-Cl in same reaction conditions.
The cyclization of 2-alkynyl-N-ethanoyl anilines were usually
carried out by heating a mixture of palladium (ІІ) chloride
(10 mol%) in acetonitrile. In order to optimize the cyclization re-
action, various catalysts along with solvents were employed
(Scheme 2 and Table 1b).
RESULTS AND DISCUSSION
Heating a mixture of 2-alkynyl-N-ethanoyl anilines 5–7 with
palladium (ІІ) chloride (10 mol%) in acetonitrile at 80 °C for 0.5–
2 h produced 2,5-disubstituted-N-ethanoyl indoles 8, 9, and 10.
Other palladium catalysts such as bis(triphenylphosphine) palla-
dium (ІІ) with co-catalyst copper (І) iodide, in the presence of
base triethylamine in DMF under nitrogen atmosphere at 80 °C,
were not able to yield an indole compound for 2-alkynyl-N-
ethanoyl aniline 6. However, sodium ethoxide (1.2 mol equiv.)
in ethanol under a nitrogen atmosphere at 80 °C for 4–12 h was
found to be a potential catalytic system for annulations of
2-alkynyl-N-ethanoyl anilines 6 and 7 to give in 9a and 10a,
but this protocol provides an inadequate yield percent.
Synthesis and related discussion of 2-alkyl-5-substituted-N-
ethanoyl indoles
Here, we report a new approach for the regio-selective synthesis of
2-alkyl-4-substituted-N-ethanoyl indoles 8–10 by palladium-
catalyzed reaction (Table 1a). Recently, we described a facile and
efficient one-pot iodination of aryl amines synthesizing substituted
2-iodoacetanilides.[47] In this study, 2-iodoacetanilides 1 and 2,
which contain an N-acetyl as a protecting group of the amine func-
tion, have been used as intermediates for coupling with 1-alkynes
3 and 4 in the presence of bis(triphenylphosphine) palladium (ІІ)
chloride (3.5 mol%), copper (І) iodide (8mol%), and triethylamine
Table 1a. Synthesis of substituted-2-alkynyl-N-ethanoyl anilines and substituted indoles
Substituted-
2-iodoacetanilide
Alkyne-1
Substituted 2-alkynyl-
Substituted indoleb
% yield
a(b)
N-ethanoyl anilinea
HC≡C ꢀ (CH2)4CH3 3
60(74)
HC≡C ꢀ (CH2)3CH3 4
72(71)
68(68)
HC≡C ꢀ (CH2)3CH3 4
aIsolated yield out of bracket based on substituted-2-iodoacetanilide.
bIsolated yield in bracket based on substituted 2-alkynyl-N-ethanoyl aniline.
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M. M. HOQUE ET AL.
Table 1b. Effect of catalyst on cyclization of 2-alkynyl-N-ethanoyl anilines to indoles
2-Alkynyl-N-ethanoyl anilines
Conditions
Indoles
Compounds
R
X
Compounds
Yield (%)
5
6
6
6
6
n-C5H11
n-C4H9
n-C4H9
n-C4H9
n-C4H9
CH3
CH3
CH3
CH3
CH3
PdCl2 (10 mol%), CH3CN, 80 °C, 0.75 h
PdCl2 (10 mol%), CH3CN, 80 °C, 0.5 h
PdCl2 (5 mol%), CH3CN, 80 °C, 0.5 h
NaOEt (120 mol%), EtOH, 80 °C, 6 h
(PPh3)2PdCl2 (3.5 mol%), CuI (8 mol%), Et3N (4 mol equiv.)
DMF, N2, 80 °C, 24 h
8
9
9
9a
—
68
74
40
51
—
7
7
n-C4H9
n-C4H9
Cl
Cl
PdCl2 (10 mol%), CH3CN, 80 °C, 2 h
NaOEt (120 mol%), EtOH, 80 °C, 12 h
10
10a
71
53
DMF, dimethylformamide.
Still et al.[48] reported that o-bromo acetanilide exhibited a smooth
intermolecular cross-coupling reaction with alkynylstannanes to
yield 2-alkyl indoles using organostannaes; however, this also pro-
duced toxic metal-containing by-products.[27] Therefore, instead of
alkynylstannanes, we use free terminal alkynes, which are environ-
mentally friendly. Another key feature of this procedure is that
iodoacetanilides 1 and 2 are employed in the reaction, as Ar–I dom-
inates over Ar–Br or Ar–Cl in reactivity in coupling reaction.[49]
results are summarized in Table 2. In the first reaction, the hetero
annulations of 2-(1-heptynyl)-4-methyl-N-ethanoyl aniline 5 have
been carried out in the presence of palladium (II) chloride in ace-
tonitrile to yield 2-pentyl-5-methyl-N-ethanoyl indole 8. The
change of electronic energy, enthalpy, and Gibbs free energies
of this reaction are ꢀ28.67, ꢀ28.67, and ꢀ25.91 kcal/mol, respec-
tively. Similar values are observed for the second and third reac-
tions. Overall, all cyclization reactions are found to be
exothermic.
Equilibrium geometries
Frontier molecular orbitals
The optimized structures of compounds 8, 9, and 10 are com-
puted at the B3LYP/6-31+G(d, p) level of theory (Fig. 1). The
bond distance (Å), bond angle (°), and dihedral angle (°) of com-
pounds 8, 9, and 10 are presented in the Supporting Information
(Tables S1–S3).
Energies (eV) of the highest occupied molecular orbital (HOMO)
and lowest unoccupied molecular orbital (LUMO) and of the
HOMO–LUMO gaps are calculated at the X3LYP/6-31G+(d, p)
level of theory for compounds 8–10. The energy outline of the
HOMO, LUMO, and HOMO–LUMO gaps of compounds 8–10 is
listed in Table 3. The pictographic presentation of the HOMO
and LUMO is illustrated in Fig. 2. The HOMO and LUMO energies
of entry 8 are ꢀ6.01263 and ꢀ1.08216 eV, respectively, with a
HOMO–LUMO gap of 4.93047 eV. Entry 9 has almost the same
HOMO–LUMO gap of 4.95261 eV as it possesses nearly the same
structural feature. The HOMO–LUMO gap of indole is reasonably
higher than these compounds, which indicates that these
compounds are more chemically reactive than indole.[52] In com-
parison with entry 8, the one electron-withdrawing chlorine
atom in compound 10 slightly decreases the LUMO energy
to ꢀ1.24065 eV whereas the HOMO energy is lowered to
ꢀ6.24321 eV. The HOMO–LUMO gap of entry 10 is 5.00256 eV.
The HOMO–LUMO energy gap can be utilized as a simple indica-
tor of kinetic stability. This implies that electron-withdrawing
group has a great influence on indole moiety and stabilized
the molecular system, thus in turn making compound 10 less
reactive. However, electron-releasing groups destabilize the
HOMO and LUMO of compounds 8 and 9, thus promoting
greater reactivity.
In each indole skeleton, the hetero N forms bonds with three
carbon atoms. Among these bonds, N–CO is found to have the
lowest values of 1.406 Å in 8 and 9, which is a direct conse-
quence of the electron-withdrawing tendency of the electroneg-
ative oxygen atom. The C1–N28 bond distance (1.424 Å) in 8 and
C2–N13 bond distance (1.423 Å) in 9 are consistent with the
X-ray structure of indole derivatives reported earlier.[50] However,
in indole, this bond distance is shorter, 1.37 Å, indicating that
substituent has an impact on the geometry of the indole moi-
ety.[51] On the other hand, the bond distance is slightly longer
for entry 10. Interestingly, the C¼O bond distance is 1.222 Å,
which is similar for all compounds. Surprisingly, the distance be-
tween the two vinyl carbon atoms has the same value of 1.363 Å,
and this is also the same for the C–H (1.08 Å) of vinyl group. The
distance between the two carbon atoms of benzo-fused rings is
1.411 Å for entries 8 and 9, whereas it is 1.413 Å for entry 10.
The hydrogen attached to carbon of benzene ring appears to
have the C–H distance between 1.079 and 1.087 Å.
The estimated dipole moments of compounds 8, 9, and 10 are
3.7288, 3.7077, and 5.6166 Debye, respectively, and the highest
negative charges, on the C4 carbon atom of indole nucleus, are
ꢀ0.726, ꢀ0.808, and ꢀ0.549 Mulliken, respectively. The
electron-withdrawing group in 10 increases the dipole moment
and thus makes it more polar.
Vibrational frequencies
For compounds 8, 9, and 10, the experimental and computed vi-
brational frequencies with their relative intensities are given in
Table 4 (IR spectra are included in the Supporting Information
(Figs S1–S3)). A characteristic feature of the IR spectra of aro-
matic compounds is usually observed near 3030 cmꢀ1 because
of the sp2 C–H stretching vibration. Bands are usually found near
Thermochemistry
The thermodynamic properties of the isomerization reactions are
also computed at the B3LYP/6-31G+(d, p) level of theory, and the
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PALLADIUM-CATALYZED CYCLIZATION
at 1600, 1580, 1500, and 1450 cmꢀ1 for in-
plane skeletal vibration of aromatic ring.[53]
For the entries 8 and 9, weak bands are ob-
served at 3013 and 3045 cmꢀ1, respectively,
which are slightly higher than the computed
(scaled) vibrational frequencies 3063 and
3064 cmꢀ1
.
However,
experimental
(3108 cmꢀ1) and calculated (3102 cmꢀ1) vi-
brational frequencies are almost the same
for compound 10. In the case of compounds
8, 9, and 10, a pair of bands at 1591 and 1460,
1591 and 1469, and 1591 and 1487 cmꢀ1, re-
spectively, is observed for the in-plane skeletal
vibration of the aromatic ring, which shows a
good agreement with computed frequencies
of 1603 and 1460, 1603 and 1460, and 1587
and 1547 cmꢀ1. Symmetric and asymmetric
C–H stretching vibrational bands are found
between 3000 and 2840 cmꢀ1 for methyl and
methylene groups,[54] and their corresponding
computed (scaled) vibrations of compounds 8,
9, and 10 are observed at 2926, 2929, and
2929 cmꢀ1, respectively.
The emergence of strong bands in the IR
around 1800–1650 cmꢀ1 in aromatic com-
pounds is the most salient feature of the ex-
istence of the C¼O stretching vibration. A
comparison of the experimental and com-
puted C¼O vibrational frequencies of 8, 9,
and 10 reveals that the computed (scaled)
values (coupled with CH3) (1688, 1689, and
1693 cmꢀ1, respectively) are almost the
same as the experimental values (1688,
1680, and 1686 cmꢀ1, respectively).
Photophysical properties
The electronic absorption spectra of entries
8, 9, and 10 are recorded in ethanol, and
spectra are shown in the Supporting Infor-
mation (Figs S4–S6). Experimental and com-
puted absorption properties are presented
in Tables 5 and 6.
The absorption properties of indole deriv-
atives are highly sensitive to the indole nu-
cleus.[55] The bands in the UV absorption
spectrum of indole in 95% ethanol occur at
287, 266, and 216 nm, and a recent study of
N-acyl indole demonstrated absorption at
297, 288, and 238 nm.[56] The experimental
absorptions (strong) of compound 8 are
found at 304, 300, and 294 nm. The
computed absorptions calculated at the
X3LYP/6-31+G(d, p) level of theory are found
at 290, 271, 246, and 232 nm, which shows
good agreement with the experimental re-
sults. The most intense peak is contributed
from excitation of electrons from HOMO to
LUMO (75.01%). For compound 9, peaks of
weaker intensity are found at 304 and
296 nm. The corresponding calculated peaks
are observed at 288, 270, 245, and 232 nm.
Figure 1. Optimized structures of compounds 8, 9, and 10 calculated at the B3LYP/6-31+G(d, p)
level of theory
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M. M. HOQUE ET AL.
increases the intensity. The maximum wavelength observes at
237 nm contributed from HOMO ꢀ1 to LUMO +1 (83.21%) transition.
It is evident from Table 5 that a small increment of the alkyl chain
(–CH2–) also causes red shift along with a substantial hyperchromic
effect for compound 8. However, removal of one alkyl chains at 2-
position exhibits a large bathochromic shift for compound 9.
Table 2. Thermodynamic properties (change of energy, en-
thalpy, and Gibbs free energy in kcal/mol) of all cyclization
reactions
Entry
1
2
3
ΔE
ΔH
ΔG
ꢀ28.67
ꢀ28.67
ꢀ25.91
ꢀ28.70
ꢀ28.70
ꢀ25.07
ꢀ28.80
ꢀ28.80
ꢀ25.94
NMR
The experimental and calculated NMR at B3LYP/6-311+G(2d, p)
is presented in the Supporting Information (Figs S7–S13 and
Tables S4–S6, NMR atom numbering is indicated in the Fig S7).
The computed values of the singlet signals found at 8.91, 8.90,
and 8.99 ppm for compounds 8, 9, and 10 are assigned to H27,
H9, and H17, respectively. However, experimental values 7.685,
7.6825, and 7.8045 ppm are slightly lower than the computed re-
sults. Similar trends for experimental and computed chemical
shifts are observed for the remaining proton present in the ben-
zene ring. The experimental δ values (6.327, 6.325, and
6.343 ppm) of vinyl proton (H35, H13, and H21) present in the
pyrrole ring of entries 8, 9, and 10, whereas the calculated values
of those protons are found to resonate at 6.5891, 6.6004, and
6.6911 ppm, respectively. The methylene protons in the vicinity
of indole nucleolus of compounds 8, 9, and 10 are resonated be-
tween 2.99 and 2.97 ppm, which shows a good correlation to the
calculated chemical shift. Overall, the recorded 1H NMR chemical
shifts of compounds 8, 9, and 10 demonstrate a very good cor-
respondence with the calculated chemical shifts.
Nevertheless, the carbonyl carbon C¼O has a low-lying excited
state involving the movement of electrons from the oxygen lone
pair to the anti-bonding p orbital that
Table 3. The energy (eV) of HOMO, LUMO, and HOMO–
LUMO gaps of compounds 8–10
Molecular
orbital
8
9
10
Indole
LUMO +2
LUMO +1
LUMO
0.36126
0.10692
0.04563
0.392388
ꢀ0.39474 ꢀ0.37341 ꢀ0.71982 ꢀ0.12871
ꢀ1.08216 ꢀ1.05813 ꢀ1.24065 ꢀ0.47266
ꢀ6.01263 ꢀ6.01074 ꢀ6.24321 ꢀ5.76446
ꢀ6.35877 ꢀ6.36012 ꢀ6.56019 ꢀ6.21944
ꢀ7.62642 ꢀ7.6383 ꢀ7.75764 ꢀ7.73375
HOMO
HOMO ꢀ1
HOMO ꢀ2
Gap
4.93047
4.95261
5.00256
5.29179
HOMO, highest occupied molecular orbital; LUMO, lowest
unoccupied molecular orbital.
Absorption at 245 nm arises from excitation of electrons from HOMO
to LUMO +1 (74.01%) transition. The replacement of methyl group
by chlorine at 5-position exerts a negative inductive effect and
generates a paramagnetic current. This
n→π* transition causes the large shift
to high frequency, and thus, the car-
bonyl carbon has a smaller intensity
and appears in a characteristic field,
150–220 ppm,[57,58] making it easier to
recognize the carbonyl absorption from
the other resonances. In this study, low-
field shift of carbonyl carbons C29, C27,
and C11 was recorded in 13C NMR spec-
trum at 170.19, 170.195, and 170.052 for
compounds 8, 9, and 10, respectively.
The ring carbon atom of compounds 8,
9, and 10 attached to hydrogen atoms
is resonated from 124.599 to
104.037 ppm, similar to the computed
values. In the experimental 13C spec-
trum of compounds 8, 9, and 10, the
peak intensities of the methyl carbon
are similar to or slightly smaller than
those of the methylene carbon. The ex-
perimental values of carbon of three
methyl groups C30, C22, and C4 are
found at 27.573, 21.122, and
14.045 ppm, and their corresponding
computed values are observed at
29.225, 22.0473, and 15.8026 ppm. On
the other hand, the experimental values
of methylene carbon are 31.678, 30.553,
28.626, and 22.56 ppm whereas the cal-
Figure 2. Selected HOMO and LUMO of compounds 8, 9, and 10
culated values are 35.682, 33.665,
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PALLADIUM-CATALYZED CYCLIZATION
Table 4. Selected experimental and calculated (without and with scaling) vibrational frequencies (cmꢀ1) of compounds 8–10
Experimental
Frequencies without scaling (intensity)
Frequencies with scalinga
Assignmentsb
Compound 8
3014
2922
1688
1591
1460
1373
1315
816
3175 (21)
3033 (49)
1750 (256)
1661 (14)
1514 (22)
1420 (2)
3063
2926
1688
1603
1460
1370
1291
801
ѵ sp2C–H
ѵsym sp3C–H
ѵ C¼O + ωCH3
ѵ C¼C + β sp2C–H
ѵ C¼C + β sp2C–H + s CH2
ω CH3
1338 (336)
830 (46)
ѵ C–N + ω CH3 + β sp2C–H
γ sp2C–H
737
745 (2)
719
r CH2
Compound 9
3046
2959
2936
1680
1591
1469
1369
1317
824
3176 (21)
3073 (8)
3064
2965
2929
1689
1603
1460
1373
1292
805
ѵ sp2C–H
ѵsym CH3
3035 (71)
1751 (259)
1661 (14)
1513 (41)
1424 (7)
ѵsym CH3 + ѵsym CH2
ѵ C¼O + ω CH3
ѵ C¼C + β sp2C–H
ѵ C¼C + β sp2C–H + ω CH3
ω CH3
1339 (248)
834 (26)
ѵ C–N + β sp2C–H + ω CH3
γ sp2C–H + r CH2
Compound 10
3108
2937
1686
1591
1487
1371
1317
829
3215 (5)
3102
2929
1693
1587
1547
1372
1306
799
ѵ sp2C–H
ѵsym CH3
3036 (76)
1755 (250)
1645 (44)
1603 (3)
1422 (7)
1335 (354)
829 (36)
ѵ C¼O + ω CH3
ѵ C¼C + β sp2C–H
ѵ C¼C + β sp2C–H
ω CH3
ѵ C–N + β sp2C–H+ ω CH3
γ sp2C–H + r CH2
aScaling factor for B3LYP/6-31G+(d, p) is 0.9648.
bν, stretching; νsym, symmetric stretching; β, in-plane bending; γ, out-plane bending; r, rocking; ω, bending.
the qualitative proton and carbon NMR chemical shifts of the
Table 5. Experimental absorption properties of compounds
8, 9, and 10
studied indole derivatives are described fairly well by the se-
lected method along with the basis set. The correlation between
the experimental and calculated chemical shifts is obtained by
B3LYP/6-311+G(2d, p), which is depicted in Fig. 3.
Compound
Substituent on indoles nucleus λ nm(Abs)
1
2
5
Mechanistic study
8
–CO–CH3 –(CH2)4CH3 –CH3 304.0(0.352),
300.3(0.323),
293.5(0.364)
–CO–CH3 –(CH2)3CH3 –CH3 366.5(0.005),
304.0(0.204),
The distinctive palladium-catalyzed reactions start with the for-
mation of a π-complex between Pd(II) salt and the alkenes or al-
kynes. The Pd–π complex significantly diminished the electron
density at the C¼C or C≡C bonds, which eventually promotes cy-
clization and proton transfer by facilitating the intermolecular or
intramolecular nucleophilic attack.[27,59,60] In this mechanistic
study, we focus on the cyclization and subsequent proton
transfer. Palladium (II) chloride-based cyclization proceeds via a
two-step reaction. In the first transition state, one proton is trans-
ferred from the –NH group to the alkyne carbon. The breaking
N–H bond distance is 1.37 Å, and the forming ¼C–H bond dis-
tance is 1.25 Å (Fig. 4). Moreover, the amino nitrogen simulta-
neously approaches to the ethylene carbon for cyclization with
a C–N bond distance of 2.26 Å. The palladium is attached to
the other ethylene carbon and promotes the overall proton trans-
fer and cyclization. In this concerted mechanism, both proton
9
295.5(0.208)
10
–CO–CH3 –(CH2)3CH3 –Cl
352.5(0.005),
305.0(0.350),
291.0(0.436)
31.027, and 26.276 ppm, which implies that the calculated values
are slightly higher than the experimental ones. However, com-
pounds 9 and 10 exhibit a similar correlation with the calculated
and experimental results for both methyl and methylene carbons.
Based on the H and 13C chemical shift data presented in the
1
Supporting Information (Tables S4–S6), it can be deduced that
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M. M. HOQUE ET AL.
Table 6. Calculated absorption properties of compounds 8, 9, and 10 at X3LYP/6-31+G(d, p) level of theory including ethanol as a
solvent
Wavelength
(nm)
Excitation
energies (eV) strengths
Oscillator
Molecular orbital contribution
Compound 8
289.97
271.48
248.7
246.17
233.4
4.2757
4.5669
4.9852
5.0364
5.3121
5.3257
5.7003
5.7046
5.7789
5.8986
0.1454
0.0814
0.0044
0.3185
0.0737
0.1806
0.0033
0.0001
0.0021
0.0198
H-1 → L + 1 (3.02%), H → L (91.15%), H → L + 1 (5.1%)
H-1 → L (81.41%), H → L + 1 (11.97%), H → L + 7 (2.08%)
H-3 → L (2.72%), H-2 → L (83.16), H-2 → L + 1 (7.21%), H-2 → L + 7 (2.21%)
H-1 → L (12.14%), H-1 → L + 7 (2.99%), H → L (3.31%), H → L (75.16%)
H-1 → L + 1 (18.72%), H → L + 2 (69.85%), H → L + 3 (2.71%)
H-1 → L + 1 (63.2%), H → L + 2 (21.01%), H → L + 7 (4.73%)
H-1 → L + 2 (75.5%), H-1 → L + 3 (6.35%), H-1 → L + 4 (5.06%), H → L + 3 (8.58%)
H-1 → L + 2 (7.82%), H → L + 2 (2.65%), H → L + 3 (84.02%)
H → L + 4 (80.08%), H → L + 5 (6.27%), H → L + 6 (6.06%)
232.8
217.51
217.34
214.55
210.19
H-3 → L (40.79%), H → L + 6 (6.99%), H → L + 7 (44.45%)
Compound 9
288.19
270.16
246.75
245.18
231.97
231.58
217.12
216.69
212.14
209.35
4.3021
4.5893
5.0247
5.0568
5.3449
5.3538
5.7105
5.7218
5.8444
5.9223
0.146
H-1 → L + 1 (3.09%), H → L (90.74%), H → L + 1 (5.36%)
H-1 → L (80.19%), H → L + 1 (12.88%), H → L + 8 (2.66%)
H-2 → L (84.24%), H-2 → L + 1 (7.41%), H-2 → L + 5 (3.58%)
H-1 → L (13.08%), H-1 → L + 5 (3.43%), H → L (3.19%), H → L + 1 (74.01%)
H → L + 2 (90.68%), H → L + 3 (3.22%), H → L + 6 (2.44%)
H-1 → L (2.17%), H → L (81.04%), H-1 → L (2.36%), H → L + 5 (7.15%)
H → L + 2 (3.06%), H → L + 3 (93.21%)
H-1 → L + 2 (85.33%), H-1 → L + 3 (8.71%)
H → L + 4 (74.85%), H → L + 6 (13.68%), H → L + 8 (6.76%)
H-3 → L (44.88%), H → L + 5 (34.64%), H → L + 7 (13.58%)
0.0809
0.0048
0.3115
0.0103
0.2585
0.0012
0.0022
0.002
0.0328
Compound 10
285.17
270.54
250.66
4.3477
4.5828
4.9464
0.1413
0.0585
0.2043
H-1 → L + 1 (4.48%), H → L (84.86%), H → L + 1 (8.67%)
H-1 → L (70.33%), H → L (6.09%), H → L + 1 (18.78%), H → L + 5 (2.33%)
H-2 → L (13.11%), H-2 → L + 1 (2.37%), H-1 → L (16.05%), H-1 → L + 5 (2.14%),
H → L (3.03%), H → L + 1 (56.76%)
249.49
4.9695
0.0449
H-2 → L (70.03%), H-2 → L + 1 (6.68%), H-2 → L + 5 (3.48%), H-1 → L (4.88%),
H → L + 1 (10.27%)
237.13
224.62
215.04
212.97
210.5
5.2285
5.5197
5.7655
5.8216
5.89
0.4024
0.0052
0.0003
0.0022
0.0028
0.0028
H-1 → L (3.05%), H-1 → L + 1 (83.21%), H → L (3.92%), H → L + 5 (4.37%)
H → L + 2 (93.45%)
H-1 → L + 4 (2.55%), H → L + 4 (90.27%)
H-1 → L + 2 (45.09%), H-1 → L + 4 (46.85%), H → L + 4 (2.53%)
H-1 → L + 2 (32.93%), H-1 → L + 3 (10.18%), H-1 → L + 4 (27.53%), H → L + 3 (24.72%)
H-1 → L + 2 (32.93%), H-1 → L + 3 (10.18%), H-1 → L + 4 (27.53%), H → L + 3 (24.72%)
209.94
5.9056
1.40 Å, and forming C–H bond distance is 1.35 Å. The gas-phase
activation barrier of the first transition state is 37 kcal/mol, which
appears to be the rate-determining step (Fig. 5). The barrier
height of the second transition state is 28 kcal/mol, which indi-
cates that proton transfer between the two carbon atoms occurs
faster as compared with the proton transfer between nitrogen
and carbon. Incorporation of a solvent (acetonitrile) by the SMD
solvation model further reduces the barrier height of the rate-
determining step to 31 kcal/mol. However, the CPCM solvation
model fails to lower the barrier height. Overall, the palladium-
based cyclization reaction of anilines to indoles is exothermic.
The effect of substitution on the transition states of this reac-
tion is also considered by replacing the –CH3 group (9) with an
electron-withdrawing –Cl group (10). The gas-phase barrier height
of the first transition state is slightly higher (ꢀ38 kcal/mol)
than the –CH3 substituent pathway. Solvent (acetonitrile) has
little influence on the barrier height (37 kcal/mol) of the rate-
determining step contrary to the –CH3 substituent pathway
Figure 3. Correlation between experimental (red) and calculated (blue)
chemical shift 13C NMR of compound 8
transfer and cyclization occur synchronously, which is also a com-
mon feature in various concerted reactions.[61] In the second tran-
sition state, one proton is transferred from one of the ethylene
carbon atoms to the other. The breaking C–H bond distance is
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PALLADIUM-CATALYZED CYCLIZATION
reaction, free terminal alkynes and
substituted 2-iodoacetanilides, which
form distinct halogen bonding, have
been used for synthesis of substituted
anilines 5–7. Overall, the strategy al-
lows the facile preparation of 5-
substituted-2-alkyl-N-ethanoyl indoles,
which may be applied to prepare other
N-alkanoyl indoles. The calculated en-
ergy and enthalpy of these reactions
related to products 8–10 are nearly
the same as ꢀ28.67 kcal/mol. The opti-
mized geometries of 8–10 demon-
strate that the substituents attached
to an indole framework have an influ-
ence on their structure. Introduction
of a Cl group at the 5-position in 10
slightly increases the HOMO–LUMO
gap as compared with the gaps of 8
and 9. The lower HOMO–LUMO gaps
in 8 and 9 suggest that they are more
chemically reactive than 10. Reduction
of one –CH2– group in 9 decreases the
absorption compared with 8; however,
the replacement of methyl group by
chlorine at the 5-position increases
the absorption. Experimental IR and
NMR studies are in good agreement
Figure 4. Two-step concerted mechanism of palladium-catalyzed cyclization of 2-alkynyl-4-substituted-
N-ethanoyl anilines to indoles, computed at B3LYP/SDD level of theory
with the DFT calculations. Cyclization of 2-alkynyl-4-
substituted-N-ethanoyl anilines to indole 9 by the palladium
catalyst follows a two-step concerted mechanism in which the
gas-phase activation energies of TS1 and TS2 are 37 and
28 kcal/mol, respectively. Solvent (acetonitrile) further decreases
the activation energy of the rate-determining step to 31 kcal/mol.
The relative energy profile reveals that cyclization and proton
transfer occur synchronously in step one, which is assumed to
be the rate-limiting step. Moreover, an electron-withdrawing
group has a smaller influence on the barrier height of this reac-
tion compared with the electron-releasing group.
Acknowledgements
Figure 5. Relative energy (kcal/mol) diagram of palladium-catalyzed cy-
clization computed at B3LYP/SDD level of theory. Blue and orange lines
represent the gas and solvent phase barrier heights, respectively
We acknowledge the financial assistance of Ministry of National Sci-
ence Information and Communication Technology, Bangladesh. We
are thankful to Bangladesh Council of Scientific and Industrial Re-
search (BCSIR), Dhaka, for taking NMR spectra. We are also grateful
to our donors who are helping to build a computational platform in
Bangladesh http://computchembiochem.com/1_8_Donate.html.
We are also thankful to Professor Raymond Poirier, Department of
Chemistry, Memorial University, Canada, and the Atlantic Computa-
tional Excellence Network for allocating computational resource to
NMR calculation. Authors like to thank Dr Steven Daly, Institut
Lumière Matière, CNRS et Université Lyon 1, Villeurbanne 69100,
France, for reading this manuscript.
(Fig. S14). The gas-phase and solvent-mediated barrier heights of
the second transition state are 26 and 27 kcal/mol, respectively.
These results suggest that the electron-releasing –CH3 group pro-
motes the Pd-catalyzed C–N cyclization to indoles compared with
the electron-withdrawing –Cl group in the presence of acetoni-
trile, which is in complete agreement with our experimental find-
ing. Although the main driving force of Pd-catalyzed reactions
depends on several factors including solvent, temperature, and
substitutes, these results show that solvent has great influence
on C–N coupling and proton transfer.
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J. Phys. Org. Chem. 2015, 28 732–742
Copyright © 2015 John Wiley & Sons, Ltd.
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