Piperidine-mediated annulation of 2-acylphenols with 4-nitrobenzaldehyde to 3-benzofuranones

Article abstract of DOI:10.1016/j.tetlet.2015.05.023

Piperidine - mediated reactions of 2-acylphenols and 4-nitrobenzaldehydes afforded 3-benzofuranones in high yield (82-95%) at reflux temperature in ethanol. The electron density calculation of HOMO-LUMO energy in the chalcone intermediates by DFT showed t

Full text of DOI:10.1016/j.tetlet.2015.05.023

Tetrahedron Letters 56 (2015) 4175–4179
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Piperidine-mediated annulation of 2-acylphenols with
4-nitrobenzaldehyde to 3-benzofuranones
⇑
Nishant Verma, Varun Kundi, Naseem Ahmed
Department of Chemistry, Indian Institute of Technology Roorkee, Roorkee 247 667, Uttarakhand, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Piperidine—mediated reactions of 2-acylphenols and 4-nitrobenzaldehydes afforded 3-benzofuranones
in high yield (82–95%) at reflux temperature in ethanol. The electron density calculation of HOMO–
LUMO energy in the chalcone intermediates by DFT showed the influence of the 4-nitro group and alkyl
chain at C-2 position for the regioselective products. However, the reaction of 2- and 3-nitrobenzaldehy-
des with 2-acylphenols afforded flavones and flavanones, respectively, under the same reaction condi-
tions. The substituent position effects were further studied in respect of 2-, 3- and 4-nitro substituted
benzaldehydes and 2-acylphenols in the product formation.
Received 9 March 2015
Revised 6 May 2015
Accepted 7 May 2015
Available online 25 May 2015
Keywords:
3-Benzofuranones
Piperidine (organocatalyst)
Knoevenagel reaction
Regioselective cyclization
HOMO–LUMO & DFT calculations
Ó 2015 Elsevier Ltd. All rights reserved.
Introduction
(a-addition), followed by rearomatization of the 4-nitroaryl ring.
The reason was supported by the DFT calculation which gave more
electrophilic character at C-2 position in the chalcone intermedi-
ates (Fig. 1). However, the reactions of 2- and 3-nitrobenzaldehy-
des with 2-acylphenols afforded flavones and flavanones,
respectively, under the same reaction conditions. It indicated that
the 2- and 3-nitro groups have less electron-withdrawing nature
as compared to the carbonyl group which might be due to the
steric factor which causes a non-planar geometry in the chalcone
intermediates. This was further supported by the DFT calculations.
The substituent position effects were further studied with respect
to 2-, 3- and 4-nitro substituted benzaldehydes and 2-acylphenols
in the product formation.
In continuation of our interest to develop new methods in the
organic synthesis and acid/base catalysis reactions,11 we report
herein an unprecedented one-pot facile and efficient method for
the synthesis of 2-alkyl-2-(4-nitrobenzyl)-3-benzofuranones in
excellent yield (82–95%) using 2-acylphenols, 4-nitrobenzaldehy-
des in the presence of piperidine base in ethanol at reflux
temperature.
3-Benzofuranone and 4-benzopyranone moieties are widely
present in the natural products. They are used as versatile interme-
diates in various organic and natural product transformations.1 For
example, 3-benzofuranones are used in the synthesis of important
molecules like flavaglines, rocaglamide and rocaglaol which are
used as anticancer, cytoprotective agents2 and insecticides respec-
tively.3 Therefore, a number of efforts have been made for their
efficient synthesis using aurones as precursor.4–6 In some cases,
toxic metals7 and organometallic catalysts5,6 were used in the mul-
ti-step synthesis under harsh reaction condition.8 Similarly, differ-
ent organocatalysts in sub-stoichiometric amount were also used
for the synthesis of 3-benzofuranones under metal-free conditions.
Recently, piperidine was used as organocatalyst in the carbonyl
transformations via iminium ion and enamine intermediates in
various organic syntheses.9,10
Serendipitously, we observed a fascinating competitive reaction
between carbonyl and 4-substituted nitro groups in the presence
of piperidine base under Knoevenagel reaction condition, where
the 4-nitro group has changed the path of cyclization around
the conjugated double bond of chalcone intermediate to afford
3-benzofuranones. This showed that the 4-nitro substituted
aromatic ring has stronger electron-withdrawing character relative
to the carbonyl group which led in cyclization at C-2 position
O
O
O
O
3
2
R
O
R
O
N
O
N
O
⇑
Corresponding author. Fax: +91 1332 285745.
E-mail address: nasemfcy@iitr.ac.in (N. Ahmed).
Figure 1. Influence of 4-nitro group in cyclization.
http://dx.doi.org/10.1016/j.tetlet.2015.05.023
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

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N. Verma et al. / Tetrahedron Letters 56 (2015) 4175–4179
Table 1
Different bases and solvents in the optimization of 5a reaction conditiona
O
O
Br
CHO
C4H9
Br
C4H9
piperidine
O
+
solvent, temp
OH
NO2
4a
5a
O2N
3a
Entry
Solvent
Base
Base (equiv)
Temp (°C)
Time (h)
Yieldb (%)
1
2
3
4
5.
6
7
8
9
10
11
12
13
15
16
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
Pyrrolidine
Pyrrolidine
Pyrrolidine
Pyrrolidine
Pyrrolidine
Pyridine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
1.0
3.0
3.5
3.5
4
1 to 4
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
RT
80
85
85
98
24
24
24
30
24
48
14
12
72
12
16
16
16
48
48
20
60
78
75
78
10-20
78
95
20
75
60
69
40
n.d
n.d
EtOH
Propan-2-ol
EtOH/H2O
t-BuOH
sec-BuOH
Toluene
THF
110
70
a
Reaction condition: 1-(2-hydroxyphenyl) hexanones 3a (1 mmol), 4-nitrobenzaldehydes 4a (1 mmol), piperidine (1–4.0 equiv), EtOH (3 mL).
Isolated yield of 5a; no product obtained with NaOH, KOH, t-BuOK, DBU, triethylamine and in solvents toluene, THF.
b
O
O
O
O
Br
OH
O
Br
nBu
nBu
Br
nBu
A
B
CHO
nBu
R1
O
A
Piperidine (3.5 eq)
EtOH, reflux, 12h
+
O
C
R1
C
R3
R2
O2N
Br
5(a,f)
NO2
R3
6(a-c)
3a
7a
4
O2N
entry
R1
R2
H
R3
5b
%
6c %
7d
-
%
1
2
3
4
5
6
H
NO2
NO2
H
5a (95)
-
OCH3
H
5f (84)
-
-
H
NO2
H
-
-
-
-
6a(46)
-
-
NO2
H
H
7a(85)
H
OCH3
NMe2
6b(85)
6c(82)
-
H
H
-
a Reaction condition: 3a (1 mmol), 4 (1 mmol), piperidine (3.5 equiv.),
ethanol (3-4 mL), reflux, 12 h. b,c,d Isolated yield of products 5, 6 and 7 at 80
°C.
Scheme 1. Effect of nitro group position as 2-, 3- and 4-nitroaryl derivativesa.
Initially, the reaction was performed in equimolar ratio of 1-(5-
bromo-2-hydroxyphenyl)hexanone 3a, 4-nitrobenzaldehyde 4a
and pyrrolidine in MeOH at reflux temperature which gave the
product 5a in 20% yields. Then, we increased pyrrolidine ratio
(up to 4 equiv), and the yield increased up to 78% (Table 1, entries
1–5). In order to obtain optimal conditions, we performed the reac-
tion by changing the base, solvents and temperature (Table 1).
Among the bases (pyrolidine, pyridine, piperidine, TEA, NaOH,
KOH, t-BuOK, DBU) used varying the concentration (1–4 equiv),
pyrrolidine, pyridine and piperidine at 3.5 equiv gave the desired
product 5a in maximum yield 82%, 20% and 95% respectively
(Table 1, entries 5, 6 and 8). The pKa values of DBU and TEA are
close to piperidine however they failed to give similar results.
We also examined the solvent effects using MeOH, propan-2-ol,
sec-BuOH, t-BuOH, EtOH (polar protic solvents), THF (polar aprotic
solvent) and toluene (non-polar solvents) (Table 1, entries 7–15).
Among them, the polar protic solvents were found as the desired
solvents where EtOH gave the maximum yields (Table 1, entry 8)
which might be due to the protonation of piperidine that increases
the polarity of the nitro group. Further, in order to investigate the
temperature effects, the reaction was performed varying from
room temperature to reflux temperature (Table 1, entries 1–10).
Therefore, the optimal reaction condition for the maximum yields
and minimum reaction time was obtained as substrates (1 equiv),
piperidine (3.5 equiv) and EtOH as solvent at reflux temperature
for the one-pot condensation and cyclization reactions (Table 1,
entry 8) (non-polar solvents) (Table 1, entries 7–15).17 Among
them, the polar protic solvents were found as the desired solvents
where EtOH gave the maximum yields (Table 1, entry 8) which
might be due to the protonation of piperidine that increases the
polarity of the nitro group. Further, in order to investigate the tem-
perature effects, the reaction was performed varying from room
temperature to reflux temperature (Table 1, entries 1–10).
Therefore, the optimal reaction condition for the maximum yields

N. Verma et al. / Tetrahedron Letters 56 (2015) 4175–4179
4177
and minimum reaction time was obtained as substrates (1 equiv),
piperidine (3.5 equiv) and EtOH as solvent at reflux temperature
for the one-pot condensation and cyclization reactions (Table 1,
entry 8).
chain (acetophenone) and 4-nitrobenzaldehyde failed to give the
products. The chemical structure of 5a was further supported by
the single crystal X-ray analysis (Fig. 2).
In order to investigate the highest occupied molecular orbital
(HOMO) and lowest unoccupied molecular orbital (LUMO) of chal-
cone intermediate for the molecular structure was optimized by
density functional theory (DFT) calculations using B3LYP level14
with 6-311+G* using Gaussian 09, Revision A.02. SMP15 and
Avogadro 1.1.1 (Fig. 3).16 For example, in molecules I5a, I6a, I7a
and I5f, the HOMO delocalisation covers mainly towards ring A
and slightly towards the carbonyl group which reflected that the
position of the nitro group does not have significant effects on
HOMO. While in molecule I6b, the HOMO delocalisation covers
mainly towards ring C due to the presence of electron rich OCH3
group. However, in the LUMOs of I5a, I5f is delocalized towards
the ring C and spread towards C–C double bond and the carbonyl
We also observed the nitro group position effects at 2- and 3-ni-
troaryl derivatives. When, 2-nitrobenzaldehyde was treated with
3a, flavone (Michael addition product) was the major product 7
which might be an oxidative product of flavanone.12 The structure
of the products was confirmed by the spectral analysis (Supporting
information). Similarly, 3-nitrobenzaldehyde and electron-donat-
ing substituted 2- and 3-nitrobenzaldehyde such as methoxy,
N,N-dimethyl amine were treated with 3a, flavanone (Michael
addition product) was the major product 6 (Scheme 1, entries
3,5,6). Products 6a, 6b and 6c were obtained in good yield as
trans-products (Supporting information).8d,13
These observations suggested that the cyclization depends on
nitro group position. It was supported by the formation of different
products after changing the nitro group position. The reaction of 3a
with 4-nitro-2-methoxybenzaldehyde gave the low yield. This
might be due to the slightly higher electron density on the phenyl
ring as compared to 4-nitrobenzaldehyde (Scheme 1 entry 2 and
Scheme 2 product 5f). We also observed the substituent effects
on the product formation (Scheme 2, products 5a–p). The elec-
tron-withdrawing (EWG) or electron donating group (EDG) sub-
stituents on ring-A have less significant effects (Scheme 2,
products 5a, 5c, 5d, 5h) but substituent position on ring-C demon-
strated substantial effects on the reaction path and the product for-
mation. In case of strong electron-withdrawing nitro-group at 4-
O
O2N
O
5a
position, only product
5
was obtained (Scheme 2, 5a–
Br
e and 5m, 5n, 5o; Scheme 1, entry 1). In the case of alkyl substitu-
tion at C-2 position, for example, butyl chain containing 2-acylphe-
nols 3a gave a better product 5a yield as compared to methyl chain
containing 2-acylphenols 5n. However, in the absence of alkyl
Figure 2. ORTEP plot of product 5a (CCDC 994386).
O
R4
OH
O
CHO
R6
R5
R6
R1
Piperidine (3.5 equiv.)
Ethanol, 80 oC, 12h
O
+
R5
R1
R4
NO2
5(a-n)
3
4
O2N
O
O
O
O
O
Br
Br
Br
Cl
I
O
O
O
O
O
Br
I
O
CH3
5d
yield-94%
O2N
O2N
O2N
O2N
yield-92%
O
O2N
yield-92%
O
5c
5b
5e
5f
yield-92%
O
yield-84%
O
O
Ph
Br
Br
Cl
O
O
O
O
O
I
Br
O
O
O
O
O
CH3
CH3
CH3
CH3
CH3
O2N
O2N
O2N
O2N
yield-86%
O2N
5k
5g
5j
yield-84%
5i
5h
yield-82%
yield-82%
yield-84%
O
O
O
O
O
I
Br
Br
Br
CH3
O
O
O
O
O
I
O
CH3
O
CH3
O2N
5l
yield-88%
O2N
yield-78%
O2N
yield-84%
5n
O2N
5o
yield-0%
5m
5p
yield-0%
O2N
Scheme 2. Example of 3-benzofuranones.

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N. Verma et al. / Tetrahedron Letters 56 (2015) 4175–4179
Figure 3. Calculated HOMOs and LUMOs of intermediate I5a, I6a, I7a, I5f and I6b.
3. Ribeiro, N.; Thuaud, F. D. R.; Bernard, Y.; Gaiddon, C.; Cresteil, T.; Hild, A.;
Hirsch, E. C.; Michel, P. P.; Nebigil, C. G.; Saubry, L. D. J. Med. Chem. 2012, 55,
10064.
4. Mak, M.; Nogradi, M.; Szollosy, A. Tetrahedron 2006, 62, 8425.
5. (a) Harkat, H.; Blanc, A.; Weibel, J. M.; Pale, P. J. Org. Chem. 2008, 73, 1620; (b)
Miao, H.; Yang, Z. Org. Lett. 2000, 2, 1765; (c) Yu, M.; Skouta, R.; Zhou, L.; Jiang,
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Org. Chem. 2014, 79, 4218.
group. While in the case of I7a LUMO is localized mainly on ring C
with slight delocalized over C–C double bond and the carbonyl
group. In molecule I6a LUMO is localized on ring C. Therefore,
we speculated that the effective overlapping between HOMO and
LUMO may play a major role in regioselective cyclization which
results in 3-benzofuranone formation. Similarly, flavanone forma-
tion in I6b is explained on the basis of effective overlap between
the HOMO and LUMO where LUMO is present on ring A. This is fur-
ther supported from the orbital distribution of I5f in which the
electron rich methoxy group is present on ring C even though it
gives 3-benzofuranone formation. This is attributed to the position
of LUMO on ring C.
In conclusion, we have reported a one-pot facile and efficient
synthetic method of 3-benzofuranones under mild reaction condi-
tion in excellent yield (82–95%) using 2-acylphenols and 4-ni-
trobenzaldehydes mediated by piperidine at reflux temperature
in EtOH. The electron density at C-2 and C-3 positions in the chal-
cone intermediate was determined by HOMO-LUMO energy calcu-
lation by DFT calculations which supported the regioselective
products formation. The substituent position effects were further
studied in respect of 2-, 3- and 4-nitro substituted benzaldehydes
and 2-acylphenols in the product formation.
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Acknowledgments
Authors are grateful to BRNS, Mumbai and DST, New Delhi for
the financial support and CSIR for fellowship for N.V. Mr.
Abhishek Baheti for valuable discussion and Mr. Dinesh Kumar
Shukla for X-ray analysis. The reviewers are acknowledged for
their valuable comments.
Supplementary data
Supplementary data (synthetic procedures and spectral data 1H
and 13C NMR, HRMS, IR is provided) associated with this article can
be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.
2015.05.023.
14. (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648; (b) Lee, C.; Yang, W.; Parr, R. G.
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Hutchison, G. R. J. Cheminfo. 2012, 4, 17.
17. General procedure for the synthesis of 3-benzofuranone, 5a–n, 6a–c, 7a and 8a: To
a stirred solution of compound 3 (1 mmol, 270 mg) in ethanol was added
piperidine (3.5 equiv) and 4-nitrobenzaldehyde 4 (1 mmol, 151 mg, 1 equiv).
The resulting solution was stirred at 80 °C for 12 h. TLC monitoring, the
reaction mixture was cooled to room temperature and neutralized with dilute
aqueous HCl, a semi-solid precipitate obtained. It was filtered and dissolved in
CH2Cl2 and purified by silica gel column chromatography by using ethyl
References and notes
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Soc. 2013, 135, 7553; (b) Ward, M. D.; Raithby, P. R. Chem. Soc. Rev. 2013, 42,
1619.

N. Verma et al. / Tetrahedron Letters 56 (2015) 4175–4179
4179
acetate (5%) in hexane as an eluent to give the 3-benzofuranone in 82–95%
yields. For example, 5-bromo-2-butyl-2-(4-nitrobenzyl)benzofuran-3(2H)-one
5a: Light yellow solid, yield: 95%, 1H NMR (500 MHz, CDCl3) d ppm: 0.78 (t,
J = 7 Hz, 3H), 1.04–1.09 (m, 1H), 1.19–1.23 (m, 3H), 1.81–1.84 (m, 1H), 1.89–
1.94 (m, 1H), 3.18 (s, 2H), 6.90 (d, J = 9.5 Hz, 1H), 7.29 (d, J = 8.5 Hz, 2H), 7.53–
7.55 (m, 2H), 7.95 (d, J = 9 Hz, 2H),). 13C NMR (125 MHz, CDCl3) d ppm: 13.6,
22.5, 24.8, 36.07, 41.6, 93.0, 114.2, 114.6, 122.9, 123.0, 126.4, 131.0, 140.8,
141.8, 146.9, 170.2, 201.4. FTIR (v = cmÀ1):829, 1343, 1464, 1519, 1610, 1718,
2856, 2923, 2965.HRMS (ESI+): m/z calcd for
426.0317, found: 426.0314.
C
19H18BrNO4Na [M+Na]+: