Reaction of 3-(2-nitrophenyl)-1-arylprop-2-en-1-ones with triethylphosphite in microwave revisited: One-pot synthesis of 2-aroylindoles and 2-arylquinolines

Article abstract of DOI:10.1080/00397911.2015.1116582

One-pot synthesis of 2-aroylindoles and 2-arylquinolines has been achieved by the reductive cyclization of 3-(2-nitrophenyl)-1-arylprop-2-en-1-ones with triethylphosphite [P(OEt)₃] under microwave irradiation. The formation of 2-arylquinolines by this method is unprecedented.

Full text of DOI:10.1080/00397911.2015.1116582

Synthetic Communications
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Reaction of 3-(2-Nitrophenyl)-1-arylprop-2-
en-1-ones with Triethylphosphite in Microwave
Revisited: One-Pot Synthesis of 2-Aroylindoles and
2-Arylquinolines
Annah Gupta, Rajni Khajuria & Kamal K. Kapoor
To cite this article: Annah Gupta, Rajni Khajuria & Kamal K. Kapoor (2015): Reaction of
3-(2-Nitrophenyl)-1-arylprop-2-en-1-ones with Triethylphosphite in Microwave Revisited:
One-Pot Synthesis of 2-Aroylindoles and 2-Arylquinolines, Synthetic Communications, DOI:
10.1080/00397911.2015.1116582
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Date: 03 December 2015, At: 10:00

Reaction of 3-(2-nitrophenyl)-1-arylprop-2-en-1-ones with triethylphosphite in
microwave revisited: One-pot synthesis of 2-aroylindoles and 2-arylquinolines
Annah Gupta1, Rajni Khajuria1, Kamal K. Kapoor1
1Department of Chemistry, University of Jammu, Jammu, India
Corresponding author Kamal K. Kapoor E-mail: k2kapoor@yahoo.com
Abstract
One-pot synthesis of 2-aroylindoles and 2-arylquinolines has been achieved by the
reductive cyclization of 3-(2-nitrophenyl)-1-arylprop-2-en-1-ones with triethylphosphite
[P(OEt)3] under microwave irradiation. The formation of 2-arylquinolines by this method
is unprecedented.
KEYWORDS: 3-(2-Nitrophenyl)-1-arylprop-2-en-1-ones, P(OEt)3, 2-aroylindoles, 2-
arylquinolines, microwave irradiation
INTRODUCTION
Indole is one of the most commonly encountered heterocyclic units in a variety of
biologically significant molecules [1]. C2–carbonyl indole derivatives have proven to be
important building blocks for the synthesis of natural and pharmacologically active
compounds [2]. In particular, C2–aroyl indole derivatives without any substituent at N1
and C3 positions have been identified as potent small molecular modulators for diverse
1

biological targets such as cell surface receptors (receptor tyrosine kinase) [3], histone
deacetylases [4] and controlling the polymerization of tubulin [5]. Quinoline, on the other
hand is another heterocyclic scaffold of paramount importance to human race. Quinoline
moiety is present in the framework of many natural products and pharmacologically
active compounds and have long been known for their wide range of biological [6] and
chemotherapeutic activities [7]. 2-arylquinolines are found to be biologically active and
found as substructure in many anti-malarial, anti-bacterial and anti-tumor agents [8]. In
addition to the medicinal importance, quinolines also find applications in dyestuffs,
photographic sensitizers [9] and are valuable precursors for the synthesis of nano and
mesostructures with enhanced electronic and photonic properties [10]. Due to their wide
range of applications, the synthesis of indole and quinoline derivatives has attracted the
attention of many organic chemists and biochemists. Some of the methods for the
synthesis of indole derivatives involves reductive cyclization of o-nitrochalcones using
triethylphosphite [11], Pd catalyzed synthesis from o-nitrochalcones [12], reductive N-
heterocyclization of 2-nitrovinylarenes catalyzed by ionic diamine rhodium complex [13]
and CuI-catalyzed SNAr reaction of o-bromochalcones with sodium azide [14]. For the
synthesis of 2-arylquinolines some of the reported methods are molecular iodine
catalyzed reaction between imines and aldehyde [15], one-pot Fe catalyzed synthesis from
o-nitroarylcarbaldehyde [16], base mediated cyclization reaction between 2-
aminobenzylalcohol and ketone [17], solid acid catalyzed microwave assisted reaction
between anilines and cinnamaldehydes [18], hydrotalcite-bound ruthenium catalyzed
reaction between 2-aminobenzyl alcohol and acetophenone [19]
.
2

It is pertinent to mention here, that Creencia et al. obtained 2-benzoylindole from 3-(2-
nitrophenyl)-1-phenylprop-2-en-1-one in good yield using triphenylphosphine (PPh3) in
microwave (MW) and observed poor yields of the product with P(OEt)3 in MW [20]. We
have successfully synthesised pyrrole derivatives by P(OEt)3 mediated reductive
cyclization of ethyl 2-nitro-5-oxo-3,5-diarylpentanoates in MW [21]. Therefore, we wished
to revisit the Creencia’s protocol, which, surprisingly has not been successful for the
synthesis of 2-benzoylindole from 3-(2-nitrophenyl)-1-phenylprop-2-en-1-one while
using P(OEt)3 in MW.
RESULTS AND DISCUSSION
3-(2-Nitrophenyl)-1-phenylprop-2-en-1-one (1a) upon MW irradiation with P(OEt)3 (6
eq.) at 90 ˚C resulted in the formation of two products which were isolated in 42% and
20% respective yields. The major product was characterized as 2-benzoylindole, while
the minor product was found to be 2-phenylquinoline. This result is in variance to those
reported in the literature [11,20] where the formation of 2-phenylquinoline has not been
noticed. Raising the temperature of the above reaction to 110 ˚C, resulted in the overall
improvement of the yields of 2-benzoylindole and 2-phenylquinoline to 62% and 28%
respectively. No improvement in the yields of products (2a) and (3a) as well as their ratio
(~ 2 : 1) was noticed by further raising the temperature of the reaction to 120 ˚C, 130 ˚C
and 140 ˚C. Thus, the optimized reaction condition involves the MW irradiation of 3-(2-
nitrophenyl)-1-phenylprop-2-en-1-one with 6 eq. of P(OEt)3 at 110 ˚C for 60 min
(Scheme 1).
3

To check the versatility of this reaction, various 3-(2-nitrophenyl)-1-arylprop-2-en-1-ones
(1a-i) bearing various electron-withdrawing and electron-releasing groups in 1-aryl were
examined and found to yield the desired products viz. 2-aroylindoles (2a-i) and 2-
arylquinolines (3a-i) in satisfactory yields (Scheme 2, Table 1). Heterocyclic ring at 1-
position (Table 1, entry 9) also gave the expected products in good yields. The requisite
starting propenones (1a-i) were, in turn prepared by an aldol/dehydration reaction of 2-
nitrobenzaldehyde and various substituted ketones under basic conditions [22]
.
In order to have a mechanistic insight into the formation of 2-aroylindoles and 2-
arylquinolines, 31P NMR was recorded on the aliquots of the reaction at time 0 min and
30 min. In 31P NMR of the aliquot at 30 min, appearance of a singlet at δ: -0.87 ppm and
disappearance of singlet at δ: 138.7 ppm spoke in favour of formation of
triethylphosphate from triethylphosphite (Figure 1). Based on this information coupled
with that reported in literature[23,24], following mechanism is proposed for the formation
of 2-aroylindoles (2) and 2-arylquinolines (3) (Scheme 3). Formation of (2) and (3)
occurs via a nitrene intermediate (4 and 6) formed by deoxygenation of nitro group with
2 eq. of P(OEt)3. Following path A, nitrene intermediate (4) rearranges to cyclic
zwitterion (5), which undergoes proton transfer to give 2-aroylindoles (2). Nitrene (4) on
isomerisation gives cis-nitrene which eventually collapses to 2-arylquinoline (3) via path
B. Phosphorimidate (7) formed by the reaction of (6) with P(OEt)3 undergoes [2+2]
cycloaddition to produce four-membered heterocycle (8) which disproportionates to 2-
arylquinolines (3) owing to the strong affinity of phosphorus for oxygen. The synthesis of
4

2-arylquinolines (3) via path B is in line with the mechanism proposed by Ogasawara et
al. [24]
.
EXPERIMENTAL
General
All the commercially available reagents were purchased from Aldrich and were used
without further purification. The reactions were performed with a Discover™ single
mode cavity MW synthesizer (CEM Corporation). Melting points (°C) were measured in
open glass capillaries using Perfit melting point apparatus and are uncorrected. The
progress of the reaction was monitored by thin layer chromatography (TLC) using silica
gel pre-coated aluminium sheets (60 F254, Merck). Visualization of spots was effected
by exposure to ultraviolet light (UV) at 254 nm, iodine vapours, 2% 2,4-
dinitrophenylhydrazine in methanol containing few drops of H2SO4 and draggendroff
reagent. Column chromatography was performed on silica gel (60-120 mesh). IR spectra
(ν, cm-1) were recorded on Perkin-Elmer FTIR spectrophotometer using KBr discs. 1 H
NMR and 13C NMR spectra in CDCl3 as solvents were recorded on Burker AC-400
spectrometer operating at 400 MHz for 1H and 100 MHz for 13C, with tetramethylsilane
(TMS) as internal standard. Electron impact mass spectra (EIMS) were recorded on
Micro Mass VG-7070 H mass spectrometer at 70 ev. Elemental analysis were performed
on Leco CHNS-932 analyzer.
General Procedure For The Synthesis Of 2-Aroyl Indoles (2a-I) And 2-
Arylquinoline (3a-I)
5

A solution of 3-(2-nitrophenyl)-1-arylprop-2-en-1-ones (1 mmol) in P(OEt)3 (6 mmol) in
a capped vial was exposed to MW irradiation at 110 °C (80 W). After the completion of
the reaction (TLC), the reaction mixture was cooled to room temperature, transferred to a
10 mL round-bottomed flask and concentrated under vacuum at 80 °C in a rotary
evaporator. The residue so obtained upon column chromatography yield pure products
2(a-i; 57-62% yield) and 3(a-i; 27-30% yield).
Spectral Characterization Of (2a) And (3a)
Compound (1H-indol-2-yl)(phenyl)methanone (2a) was obtained as yellow solid, yield:
62%, m.pt. 145-147 °C ( lit. 150-151 °C) [25], 1H NMR (400 MHz, CDCl3): δ 9.65 (br s,
1H, NH), 8.04 (d, J = 7.8 Hz, 2H), 7.76 (d, J = 8.1 Hz, 1H), 7.66 (t, J = 7.0 Hz, 1H), 7.60
– 7.52 (m, 3H), 7.41 (t, J = 7.6 Hz, 1H), 7.20 (t, J = 7.4 Hz, 2H). 13C NMR (100 MHz,
CDCl3): δ 187.3, 138.0, 137.6, 134.3, 132.4, 129.2, 128.5, 127.7, 126.5, 123.2, 121.0,
112.9, 112.2. IR (KBr, υmax cm-1): 3315, 1618, 1577, 1512, 1328, 1261, 1132, 734.
MS(ESI) (m/z) : 222. Anal. calcd. for C15H11NO : C, 81.43; H, 5.01; N, 6.33%. Found: C,
81.52; H, 5.02; N, 6.31% and compound 2-phenylquinoline (3a) was separated as oil,
yield: 28%, 1H NMR (400 MHz, CDCl3): δ 8.44 – 8.08 (m, 4H), 7.89 (dd, J = 18.8, 8.3
Hz, 2H), 7.77 (t, J = 7.6 Hz, 1H), 7.59 – 7.51 (m, 4H). 13C NMR (100 MHz, CDCl3): δ
157.4, 148.2, 139.7, 136.8, 129.7, 129.3, 128.8, 128.3, 127.6, 127.4, 127.2, 126.3, 119.0.
IR (KBr, υmax cm-1): 3053, 2958, 1710, 1596, 1551, 1446, 1282, 1074, 828, 765. MS(ESI)
(m/z) : 206. Anal. calcd. for C15H11N : C, 87.77; H, 5.40; N, 6.82%. Found: C, 87.65; H,
5.38; N, 6.81.
6

CONCLUSION
In summary, we have successfully developed a strategy for the one-pot synthesis of 2-
aroylindoles and 2-arylquinolines from 3-(2-nitrophenyl)-1-arylprop-2-en-1-ones and
P(OEt)3 under microwave irradiation. Formation of 2-arylquinolines has been reported
for the first time using 3-(2-nitrophenyl)-1-arylprop-2-en-1-ones and P(OEt)3.
SUPPLEMENTAL MATERIAL
Experimental data, 1H NMR and 13C NMR spectra of all the synthesized compounds can
be accessed on the publisher’s website.
ACKNOWLEDGEMENTS
The authors are grateful to the Department of Chemistry, University of Jammu for
providing necessary facilities and Department of Science and Technology, GOI, New
Delhi for NMR facility under PURSE. A. G. and R. K. are thankful respectively to DST,
GOI, New Delhi for INSPIRE fellowship and UGC, New Delhi for SRF.
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9

Table 1 Triethylphosphite mediated synthesis of 2-aroylindoles and 2-arylquinolines.
S.
R
2-aroylindoles (yield
%)
2-arylquinolines (yield
%)
Time
(min)
60
No.
1
C6H5
2
3
4-CH3C6H4
50
45
4-OCH3C6H4
4
5
3-OCH3C6H4
55
45
4-ClC6H4
6
4-BrC6H4
40
10

7
8
9
4-FC6H4
50
60
45
3,4-
(OCH3)2C6H3
2-Furyl
11

Scheme 1. Triethylphosphite mediated one-pot synthesis of 2-benzoylindole (2a) and 2-
phenylquinoline (3a).
12

Scheme 2. Triethylphosphite mediated one-pot synthesis of 2-aroylindoles (2a-i) and 2-
arylquinolines (3a-i).
13

Scheme 3. Plausible mechanism for the synthesis of 2-aroylindoles (2) and 2-
arylquinolines (3)
14

Figure 1. 31P NMR study of reaction mixture at 0.0 min and 30 min for mechanistic
proof.
15