SbCl3-catalyzed solvent-free Friedel–Crafts reaction of phenols with mandelic acids to 3-aryl benzofuran-2(3H)-ones: Synthesis of spirocyclic 2,3-dihydrobenzofuran-2-ones

Article abstract of DOI:10.1080/00397911.2016.1226341

A facile, SbCl₃-catalyzed, one-pot, tandem Friedel–Crafts/lactonization reaction of phenols and mandelic acids has been developed under solvent-free conditions to afford 3-aryl benzofuran-2(3H)-ones in good to high yields (52–90%). Additionally

Full text of DOI:10.1080/00397911.2016.1226341

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
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SbCl3-catalyzed solvent-free Friedel–Crafts
reaction of phenols with mandelic acids to 3-aryl
benzofuran-2(3H)-ones: Synthesis of spirocyclic
2,3-dihydrobenzofuran-2-ones
Bhaskar B. Dhotare, Manoj K. Choudhary & Sandip K. Nayak
To cite this article: Bhaskar B. Dhotare, Manoj K. Choudhary & Sandip K. Nayak (2016)
SbCl3-catalyzed solvent-free Friedel–Crafts reaction of phenols with mandelic acids to 3-aryl
benzofuran-2(3H)-ones: Synthesis of spirocyclic 2,3-dihydrobenzofuran-2-ones, Synthetic
Communications, 46:21, 1772-1780, DOI: 10.1080/00397911.2016.1226341
To link to this article: http://dx.doi.org/10.1080/00397911.2016.1226341
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Date: 21 October 2016, At: 12:49

SYNTHETIC COMMUNICATIONS®
2016, VOL. 46, NO. 21, 1772–1780
http://dx.doi.org/10.1080/00397911.2016.1226341
SbCl3-catalyzed solvent-free Friedel–Crafts reaction of phenols
with mandelic acids to 3-aryl benzofuran-2(3H)-ones:
Synthesis of spirocyclic 2,3-dihydrobenzofuran-2-ones
Bhaskar B. Dhotare, Manoj K. Choudhary, and Sandip K. Nayak
Bio-organic Division, Bhabha Atomic Research Centre, Trombay, Mumbai, India
ABSTRACT
ARTICLE HISTORY
Received 13 July 2016
A facile, SbCl3-catalyzed, one-pot, tandem Friedel–Crafts/lactonization
reaction of phenols and mandelic acids has been developed under
solvent-free conditions to afford 3-aryl benzofuran-2(3H)-ones in good
to high yields (52–90%). Additionally, the utility of 3-aryl benzofuran-2
(3H)-ones is demonstrated by using them as precursors in the
synthesis of a new class of spirocyclic benzofuran-2-ones using
classical synthetic methodologies.
KEYWORDS
Antimony(III) chloride; 3-aryl
benzofuran-2(3H)-one;
Friedel–Crafts reaction;
mandelic acid; spirocyclic
benzofuran-2-one
GRAPHICAL ABSTRACT
Introduction
3,3-Disubstituted benzofuran-2(3H)-ones are important building blocks in organic synthesis
as they have been used in the total synthesis of a large number of biologically and pharma-
ceutically active natural products.[1] They display various activities including antihypoxic,[2a]
antispasmodic,[2b] and neurotropic activity.[2a] Classically, synthesis of 3,3-disubstituted
benzofuran-2(3H)-ones is achieved from 3-substituted benzofuran-2(3H)-ones through
carbanion-induced nucleophilic attack on the α-carbon atom with a variety of electrophiles.
This has been demonstrated in the synthesis of a large number of biologically active 3,3-
disubstituted benzofuran-2(3H)-ones[3] including anticancer compounds diazonamide
A,[4] hopeahainol A,[5] yuccaol A,[6] and radulifolin.[7] Also, 3-substituted benzofuran-2
(3H)-ones, namely 5,7-di-tert-butyl-3-(3,4-dimethylphenyl)benzofuran-2(3H)-one and its
analogs, are important carbon-centered radical antioxidants.[8] In spite of their importance
as precursors for the synthesis of 3,3-disubstituted benzofuran-2(3H)-ones, direct synthesis
of 3-substituted benzofuran-2(3H)-ones from readily available starting material in good
yields is limited. Therefore, development of an efficient and flexible method for 3-substituted
CONTACT Sandip K. Nayak
sknayak@barc.gov.in
Bio-organic Division, Bhabha Atomic Research Centre, Trombay,
Mumbai 400085, India.
Supplemental material (full experimental details and 1H and 13C NMR spectra) can be accessed on the publisher’s
website.
© 2016 Taylor & Francis

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Scheme 1. SbCl3 catalyzed Friedel–Crafts alkylation of phenols with benzylic alcohols.
benzofuran-2(3H)-one skeletons using inexpensive starting materials/reagents remains a
challenging task to synthetic organic chemists.
Although Friedel–Crafts (F-C) reaction of phenols with mandelic acids is the most con-
venient approach to the synthesis of 3-aryl benzofuran-2(3H)-ones, only a few reports are
available so far on this transformation, possibly due to the formation of destabilized
benzylic carbocation attached to carboxylic acid function[3f] (Scheme 1). So far F-C alky-
lation of phenols/aryl alkyl ethers with mandelic acid has been accomplished in poor to
moderate yields using strong acid catalysts (HClO4, H2SO4, and MeSO3H).[9] However,
to the best of our knowledge, no systematic study on this reaction using mild Lewis acids
has been reported to date. Herein, we report an efficient one-pot synthesis of 3-aryl
benzofuran-2(3H)-ones from SbCl3-catalyzed F-C alkylation/lactonization of phenols with
mandelic acids and their utility in the synthesis of spirocyclic benzofuran-2-one derivatives.
Results and discussion
In recent years F-C alkylation of electron-rich aromatic/heteroaromatic compounds with
alcohols using Brønsted acids/Lewis acids as catalyst has emerged as an important envir-
onmentally friendly protocol as water is the only by-product formed.[10a] Earlier, we have
developed an efficient protocol for F-C alkylation of phenols/alkyl aryl ethers with benzylic
alcohols using SbCl3 as catalyst.[10b] To explore its catalytic potential further, we wanted to
evaluate its efficacy in the F-C reaction of phenols with less stabilized benzylic cation such
as carbocation derived from mandelic acid. Mechanistically, F-C alkylation of 4-substituted
phenol with mandelic acid is expected to form the intermediate 2-(2-hydroxyaryl)-2-
phenylacetic acid, which in turn is likely to undergo in situ lactonization to form 3-phenyl
2,3-dihydrobenzofuran-2-one skeleton (Scheme 1).
At the outset, a model reaction of 4-methylphenol (1a) with mandelic acid (2a) was
chosen for optimization of reaction conditions. Thus, reaction of 1a (5 mmol) with 2a

1774
B. B. DHOTARE ET AL.
(6 mmol) in acetonitrile (2 mL/mmol) using a catalytic amount of SbCl3 (0.5 mmol,
10 mol%) was carried out both at ambient temperature (25 °C) as well as under refluxing
conditions (90 °C). Disappointingly, in both the cases, no reaction occurred to get
5-methyl-3-phenyl benzofuran-2(3H)-ones (3aa). Also, increase in catalyst loading up to
30 mol% could not initiate the reaction for the formation of 3aa (Scheme 2).
During the course of our previous work on microwave-assisted SbCl3-catalyzed F-C
reaction of phenols with benzylic alcohols,[10] it was noticed that the reaction rate is dras-
tically reduced on dilution with solvent. Keeping this in view as well as the requirement of
green synthesis for environmental concern, we planned to carry out the reaction under
solvent-free conditions. Initially, reaction of 1a (5 mmol) and 2a (6 mmol) with SbCl3
(1.0 mmol, 20 mol%) was carried out at 100 °C without any solvent when no reaction
was observed. Increase in reaction temperature to 120 °C also could not initiate the
reaction. To our surprise, when the reaction temperature was increased to 140 °C, a smooth
reaction took place to afford 3aa in good yield (70%) in 10 h. Moreover, increase in catalyst
loading to 30 mol% helped in increasing the reaction rate, leading to completion of the
reaction in 6 h to afford 3aa[11] as sole product in 86% yield (Scheme 2). However, during
the entire course of the reaction we could not detect the formation of the intermediate,
2-(2-hydroxy-5-methylphenyl)-2-phenylacetic acid (Scheme 1). The compound 3aa was
1
fully characterized by H NMR, 13C NMR, and DEPT (Distortionless Enhancement by
Polarization Transfer in NMR) and compared with the reported values. Further increase
in catalyst loading (50 mol%) did not reduce the reaction time significantly and therefore
use of 30 mol% of catalyst without using any solvent was considered as optimized reaction
conditions and used for subsequent studies.
To see the generality of the solvent-free F-C reaction, alkylation of a various substituted
phenol derivatives (1b–e) with both 2a and 4-methoxymandelic acid (2b) was explored. As
revealed in Table 1, reaction of p-substituted phenols with both electron-donating as well
as electron-withdrawing substituents reacted smoothly with 2a/2b to afford the corre-
sponding 3-aryl benzofuran-2(3H)-ones in good to high yields. Reaction of phenol (1g)
with mandelic acid, however, afforded the expected 3-phenyl benzofuran-2(3H)-one 3ga,
albeit in moderate yield (52%), possibly due to alkylation at the electron-rich para-position
as a side reaction. Similarly, reaction of 3,5-dimethoxyphenol and 3-methoxyphenol with
2a and 2b respectively yielded corresponding benzofuranones 4 and 5 respectively in good
Scheme 2. Condition optimization.

SYNTHETIC COMMUNICATIONS®
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Table 1. Scope of the reaction.
yields. Importantly, the rate of the reactions with 2b as electrophile was faster, as exempli-
fied by the completion of the reactions within 2–2.5 h as compared to that with 2a (4–6 h).
Spirocyclic benzofuran-2-one units are privileged structural skeletons found in many
natural and pharmaceutically important compounds with a broad range of biological
activities[12] (Fig. 1). For example, spirocyclic indeno-benzofuran-2-one 9c was used as
specific inhibitor for (PO3H2)Ser/(PO3H2)Thr-Pro-specific peptidyl-prolyl- cis/trans-
isomerases.[13] Also, both abiesinol E (10) and rosmadial (11) have displayed promising
cytotoxic activity against human cancer cell lines.[14] Although few methods are reported
on the synthesis of spirocyclic benzofuran-2-ones,[15] more efficient strategies for the
synthesis of those are still in high demand. Because of their intriguing biological profile,
the possibility of developing an efficient route to the synthesis of spirocyclic benzofuranone
using 3-aryl benzofuran-2-(3H)-ones as synthon appeared interesting to us.
From a retrosynthetic perspective, we felt that synthesis of spirocyclic benzofuran-2-
ones (9) could be accomplished through alkylation of 3-aryl benzofuran-2(3H)-ones at
3-position at the first step. Accordingly, 3aa was alkylated at 3-position with tert-butyl

1776
B. B. DHOTARE ET AL.
Figure 1. Representative biologically active spiro-cyclic benzofuran-2-ones.
bromoacetate[3m] to afford corresponding lactone ester 6a in 90% yield, which was
subsequently hydrolyzed with trifluoroacetic acid[16] to get 5-methyl dihydrobenzofuran-
2-one-3-acetic acid (7a) in high yield (82%). Intramolecular cyclo-dehydration of 7a with
polyphosphoric acid[17] (PPA) at 120 °C led to smooth conversion to spiro-cyclic benzofur-
andione 8a (65%). Finally, catalytic hydrogenation of 8a with Pd-C/H2 in acetic acid as
solvent led to reductive deoxygenation of ketone to methylene unit,[18] affording 9a as
the only product in excellent yield (Scheme 3). In a similar way benzofuran-2-one 3ca
was converted to corresponding carboxy benzofuran-2-one 7b in good yield. However,
treatment of 7b with PPA under identical reaction conditions as that of 7a led to
Scheme 3. Elaboration of 3-aryl benzofuran-2(3H)-ones to the syntheses of spirocyclic benzofuran-2-
ones.

SYNTHETIC COMMUNICATIONS®
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cyclo-dehydration with concomitant de-tert-butylation to afford spirocyclic benzofuran-
dione 8c as the only product instead of expected product 8b. As in the case of 9a, 8c
was smoothly converted to 9b under catalytic hydrogenation conditions. Also, compound
3fa was converted to 9c following a similar procedure adopted for 9a. Incidentally, this is
the first report on synthesis of spirocyclic benzofuran-2-ones from 3-aryl benzofuran-2
(3H)-ones.
Conclusion
In summary we have developed an easy and efficient SbCl3-catalyzed synthesis of 3-aryl
benzofuran-2(3H)-ones in good to high yields from inexpensive and readily available start-
ing materials such as mandelic acid and substituted phenols under solvent-free conditions.
The synthetic utility of these molecules has been demonstrated by the synthesis of a new
class of potential bio-active spirocyclic benzofuran-2-ones through alkylation of 3-aryl
benzofuran-2(3H)-ones at 3-position with tert-butyl bromoacetate as a key step. To the
best of our knowledge, this is the first report on synthesis of spirocyclic benzofuran-2-ones
from 3-aryl benzofuran-2(3H)-ones.
Experimental
General procedure for SbCl3-catalyzed Friedel–Crafts reaction/lactonization of
phenols with mandelic acids to 3-aryl benzofuran-2-ones
In a flame-dried, three-necked, round-bottom flask, a mixture of phenol/substituted phe-
nol (1) (5 mmol), mandelic acid/4-methoxymandelic acid (2) (6 mmol), and SbCl3 (1.5
mmol) was taken and the mixture was heated at 50 °C with stirring under a nitrogen
atmosphere when the mixture turned into a viscous oil. In the case of high-melting phe-
nols, a little amount of acetonitrile (∼0.2 mL/mmol) was used to make a paste. The viscous
oil/paste heated at 140 °C under stirring. The progress of the reaction was monitored by
thin-layer chromatography (TLC). After completion of the reaction (4–6 h for mandelic
acid and 2–2.5 h for 4-methoxymandelic acid), the mixture was cooled to ambient tem-
perature and quenched with cold 10% aqueous NaHCO3 solution. The reaction mixture
was diluted with ethyl acetate passed through a Celite bed to remove antimony salts.
The filtrate was extracted with ethyl acetate (3 � 40 mL) and the combined organic layer
was washed with water and brine and dried (Na2SO4). Removal of solvent afforded a thick
mass, which was purified by silica-gel column chromatography to afford pure 3-aryl
benzofuran-2(3H)-ones.
5-Methyl-3-phenyl-benzofuran-2(3H)-one[11] (3aa)
Yield: 965 mg (86%); colorless solid; mp 78–79 °C; IR (CHCl3): 2899, 1790, 1620, 1597,
1292 cmÀ 1
.
1H NMR (200 MHz, CDCl3): δ ¼ 7.37–7.05 (m, 8H), 4.90 (s, 1H), 2.38
(s, 3H); 13C NMR (50 MHz, CDCl3): δ ¼ 175.29, 151.70, 135.27, 134.05, 129.62, 128.97,
128.16, 128.01, 126.92, 125.61, 110.27, 49.74, 20.93. Anal. calcd. for C15H12O2: C, 80.34;
H, 5.39. Found: C, 80.37; H, 5.37.

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B. B. DHOTARE ET AL.
Typical procedure for the synthesis of tert-butyl 2-(2,3-dihydro-5-methyl-
2-oxo-3-phenylbenzofuran-3-yl)acetate (6a)
To an ice-cooled solution of potassium tert-butoxide (1.50 g, 13.37 mmol) in dry tetrahy-
drofuran (THF, 30 mL) under argon, a solution of 3aa (2.0 g, 8.92 mmol) in THF (20 mL)
was added. The reaction mixture was stirred at 0 °C for 2 h and then a solution of tert-butyl
bromoacetate (2.60 g, 13.37 mmol) in THF (20 mL) was added to the reaction mixture
dropwise. Stirring was continued at 0 °C. After completion of the reaction (cf. TLC, 2 h),
the reaction mixture was quenched with ice-cooled water (20 mL) and extracted with ethyl
acetate (3 � 40 mL). The combined organic extracts were washed with H2O and brine and
then dried (Na2SO4). Removal of solvent in vacuo followed by column chromatography
(silica gel, using petroleum ether–ethyl acetate as eluent) afforded pure 6a. Yield: 2.720 g
(90%); colorless solid; mp 100–101 °C; IR (CHCl3): 3022, 2981, 1803, 1729, 1486 cmÀ 1
;
1H NMR (500 MHz, CDCl3): δ ¼ 7.28–7.33 (m, 5H), 7.17 (d, J ¼ 8.5 Hz, 1H), 7.12 (s,
1H), 7.08 (d, J ¼ 7.5 Hz, 1H), 3.62 (d, J ¼ 15.5 Hz, 1H), 3.08 (d, J ¼ 16.0 Hz, 1H), 2.38
(s, 3H), 1.17 (s, 9H); 13C NMR (50 MHz, CDCl3): δ ¼ 177.46, 167.84, 151.65, 138.11,
133.85, 129.71, 129.15, 128.86, 128.04, 126.39, 125.15, 110.46, 82.02, 52.72, 44.25, 27.29,
21.07. HRMS (ESI): Calcd for C21H22NaO4 (M þ Na)þ: 361.1410; found: 361.1412.
Typical procedure for the synthesis of 2-(2,3-dihydro-5-methyl-2-oxo-3-
phenylbenzofuran-3-yl)acetic acid (7a)
To an ice-cooled solution of 6a (2.5 g 7.39 mmol) in dichloromethane was added 10 mL
aqueous solution of TFA (TFA/H2O ¼ 9:1) and the mixture was stirred at 0 °C. After com-
pletion of reaction (cf. TLC, 3 h) a saturated aqueous solution of NaHCO3 was added to the
reaction mixture to neutralize acid. The organic layer was separated and the aqueous layer
was extracted with CHCl3 (2 � 50 mL). The combined organic extracts were washed with
H2O and brine, and dried (Na2SO4). Removal of solvent in vacuo followed by column
chromatography (silica gel, using CHCl3/MeOH as eluent) afforded pure 7a. Yield: 82%;
colorless solid; mp 169–170 °C; IR (CHCl3): 3400, 2926, 1796, 1743, 1487 cmÀ 1 1H
;
NMR (200 MHz, CDCl3): δ ¼ 8.46 (bs, 1H), 7.22–7.50 (m, 8H), 3.82 (d, J ¼ 17.2 Hz,
1H), 3.47 (d, J ¼ 17.2 Hz, 1H), 2.57 (s, 3H); 13C NMR (50 MHz, CDCl3): δ ¼ 177.56,
174.88, 151.60, 137.48, 133.99, 129.99, 128.96, 128.80, 128.21, 126.35, 124.75, 110.65,
52.08, 42.11, 21.16. HRMS (ESI): calcd. for C17H14NaO4 (M þ Na)þ: 305.0784; found:
305.0796.
Typical procedure for the synthesis of 5-methyl-2H-spiro[benzofuran-
3,10-indene]-2,30(20H)-dione (8a)
A mixture of 7a (1.0 g, 3.54 mmol) and polyphosphoric acid (10 mL) was heated overnight
(16 h) at 120 °C under argon when the reaction completed. The reaction mixture was
cooled in ice; water (100 mL) was added slowly and then extracted with CHCl3. The
organic layer was washed with water (2 � 50 mL) and brine and then dried (Na2SO4).
Removal of solvent in vacuo followed by column chromatography (silica gel, using pet-
roleum ether–ethyl acetate as eluent) afforded pure 8a. Yield: 65%; colorless solid; mp
106–107 °C; IR (CHCl3): 3020, 1804, 1722, 1487 cmÀ 1 1H NMR (500 MHz, CDCl3):
;

SYNTHETIC COMMUNICATIONS®
1779
δ ¼ 7.87 (d, J ¼ 8.0 Hz, 1H), 7.58–7.61 (m, 1H), 7.52 (t, J ¼ 7.0 Hz, 1H), 7.13–7.19 (m, 2H),
7.07 (d, J ¼ 7.0 Hz, 1H), 6.80 (s, 1H), 3.33 (d, J ¼ 18.5 Hz, 1H), 2.99 (d, J ¼ 18.5 Hz, 1H),
2.29 (s, 3H); 13C NMR (50 MHz, CDCl3): δ ¼ 201.90, 177.48, 153.25, 151.15, 135.96,
135.15, 130.32, 130.24, 129.71, 124.89, 124.30, 123.88, 110.77, 52.61, 48.24, 21.02. HRMS
(ESI): calcd. for C17H13O3 (M þ H)þ: 265.0859; found: 265.0860.
Typical procedure for the synthesis of 5-methyl-20,30-dihydro-2H-spiro
[benzofuran-3,1′-inden]-2-one (9a)
To a solution of 8a (0.265 g, 1.0 mmol) in glacial acetic (10 mL) under a hydrogen atmos-
phere, 10% Pd-C (0.050 g) was added, and the mixture was stirred overnight (16 h) at
ambient temperature. The reaction mixture was passed through a small pad of silica and
the pad was washed with ethyl acetate. Solvent was removed in vacuo and the residue
was purified by preparative TLC to afford pure 9a. Yield: 92%; thick oil; IR (CHCl3):
1
3020, 1801, 1486 cmÀ 1; H NMR (500 MHz, CDCl3): δ ¼ 7.38 (d, J ¼ 7.0 Hz, 1H), 7.27–
7.30 (m, 1H), 7.13–7.16 (m, 2H), 7.08 (d, J ¼ 8.0 Hz, 1H), 6.90 (s, 1H), 6.78 (d, J ¼ 7.5 Hz,
1H), 3.43–3.50 (m, 1H), 3.19–3.25 (m, 1H), 2.76–2.81 (m, 1H), 2.46–2.52 (m, 1H), 2.31 (s,
3H); 13C NMR (125 MHz, CDCl3): δ ¼ 178.96, 151.14, 144.59, 143.08, 134.38, 132.17,
129.46, 128.55, 127.20, 125.12, 124.18, 123.67, 110.24, 58.53, 39.04, 31.43, 21.08. HRMS
(ESI): calcd. for C17H14NaO2 (M þ Na)þ: 273.0886; found: 273.0881.
Acknowledgment
The authors gratefully thank Professor I. N. N. Namboothiri (IIT, Mumbai, India) for HRMS data.
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