Reduction of 3-acyl derivatives of oxindoles, benzo[b]furan-2-ones, and benzo[b]thiophen-2-ones to the corresponding alkyl derivatives by sodium borohydride-acetic acid

Article abstract of DOI:10.1080/00397910500449583

It was found that 3-acyl derivatives of oxindoles, benzo[b]furan-2-ones, and benzo[b]thiophen-2-ones could be efficiently and conveniently reduced to the corresponding alkyl derivatives by pelletized sodium borohydride in acetic acid. A typical procedure

Full text of DOI:10.1080/00397910500449583

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Reduction of 3‐Acyl Derivatives of
Oxindoles, Benzo[b]furan‐2‐ones,
and Benzo[b]thiophen‐2‐ones to the
Corresponding Alkyl Derivatives by Sodium
Borohydride–Acetic Acid
Francis X. Smith a , Brian D. Williams a , Eric Gelsleichter a , Judy A. Podcasy
a , John T. Sisko a & David M. Hrubowchak a
a Department of Chemistry, King's College, Wilkes‐Barre, Pennsylvania, USA
Published online: 16 Aug 2006.
To cite this article: Francis X. Smith , Brian D. Williams , Eric Gelsleichter , Judy A. Podcasy , John T. Sisko
& David M. Hrubowchak (2006): Reduction of 3‐Acyl Derivatives of Oxindoles, Benzo[b]furan‐2‐ones, and
Benzo[b]thiophen‐2‐ones to the Corresponding Alkyl Derivatives by Sodium Borohydride–Acetic Acid, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:6,
765-769
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Synthetic Communicationsw, 36: 765–769, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500449583
Reduction of 3-Acyl Derivatives of
Oxindoles, Benzo[b]furan-2-ones, and
Benzo[b]thiophen-2-ones to the
Corresponding Alkyl Derivatives by Sodium
Borohydride–Acetic Acid
Francis X. Smith, Brian D. Williams, Eric Gelsleichter,
Judy A. Podcasy, John T. Sisko, and David M. Hrubowchak
Department of Chemistry, King’s College, Wilkes-Barre,
Pennsylvania, USA
Abstract: It was found that 3-acyl derivatives of oxindoles, benzo[b]furan-2-ones, and
benzo[b]thiophen-2-ones could be efficiently and conveniently reduced to the corre-
sponding alkyl derivatives by pelletized sodium borohydride in acetic acid. A typical
procedure involves heating the acylated substrates for approximately 90 min in a
slurry of glacial acetic acid and sodium borohydride to provide the 3-alkyl product
in yields ranging from 62% to 96%. This synthetic methodology represents a con-
venient approach to the synthesis of the alkyl derivatives.
Keywords: Benzofuran-2-one, benzothiophen-2-one, borohydride, oxindole,
reduction
Several years ago, we reported that acylated derivatives of barbituric acid,
4-hydroxycoumarin, and Meldrum’s acid were easily reduced to the correspond-
ing alkyl derivatives by treatment with sodium cyanoborohydride–acetic acid.[1]
We now report that this transformation can be made to occur with 3-acyl
derivatives of oxindoles, benzo[b]furan-2-ones, and benzo[b]thiophen-2-ones,
Received in the USA September 15, 2005
Address correspondence to Francis X. Smith, Department of Chemistry, King’s
College, Wilkes-Barre, Pennsylvania 18711, USA. E-mail: fxsmith@kings.edu
765

766
F. X. Smith et al.
and that pelletized sodium borohydride in acetic acid is quite effective as a
reducing agent. Efforts to synthesize alkylated oxindoles directly from
oxindole often result in mixtures because of multiple alkylations and
N-alkylations.[2] Multiple alkylations can be avoided by an acylation
reaction followed by reduction. However, these reductions are typically
carried out using a metal catalyst and hydrogen gas under high pressures.
This method is inconvenient, and side products resulting from reduction of
the oxindole carbonyl have been reported.[3] The synthetic strategy under
investigation avoids the problem of multiple alkylations by replacing the
direct alkylation with an acylation. The inconvenience of reduction under
high pressure along with potential loss of the oxindole is eliminated by a
convenient reduction procedure involving acetic acid and pelletized sodium
borohydride at low temperatures and atmospheric pressures. Success with
this endeavor has led to an expansion of the methodology to include the
reduction of 3-acyl-benzo[b]furan-2-ones and 3-acyl-benzo[b]thiphen-2-ones
to the corresponding alkyl derivatives.
The general synthetic procedure that was developed is unique in its sim-
plicity (Figure 1). Briefly, a specific substrate is added to a magnetically
stirred slurry of glacial acetic acid and sodium borohydride. The reaction
mixture is subsequently heated at mild temperatures under atmospheric
pressure for about 90 min. After gradually cooling to room temperature, the
reaction mixture is diluted with distilled water, and the products are
extracted with diethyl ether. Table 1 lists the specific results for a variety of
the reductive transformations that were performed.
Removal of the extraction solvent under vacuum provided products 2a
and 2c–h with a high degree of purity as determined by GC/MS and
melting or boiling points. However, the extraction procedure consistently
yielded the product 2b as an oil, although it is known to exist as a crystalline
solid. It was found that 2b could be purified by column chromatography with
20% ethyl acetate (EtOAc/hexane) as the eluting solvent or by recrystalliza-
tion from ether/hexane, which provided the product as a yellow crystalline
solid with the appropriate melting point.
Figure 1. General reaction scheme for the reduction of the 3-acyl derivatives. Refer
to Table 1 for the empirical results pertaining to the reduction of specific substrates.

Reduction of 3-Acyl Derivatives
Table 1. Results for a variety of reductive transformations
767
Substrate
Product
X
R
Yield (%)
1a
1b
1c
1d
1e
1f
2a
2b
2c
2d
2e
2f
N22H
N22H
N22H
N22H
O
H
CH3
72
74
84
82
96
72
62
74
CH2Ph
CH2OPh
CH3
O
CH2CH3
H
CH3
1g
1h
2g
2h
S
S
Representative compounds from three classes (oxindoles, benzo[b]furan-
2-ones, and bezo[b]thiophen-2-ones) have been subjected to the general
reduction procedure with good to excellent yields (62–96%), and conse-
quently, it is envisioned that the procedure could be applied to a large
variety of acylated compounds of these types.
EXPERIMENTAL
All commercially available reagents were used without further purification.
Each substrate was prepared according to literature procedures; the starting
materials used for the preparation of the substrates were reacted under a
nitrogen atmosphere in a round-bottomed flask of the appropriate size
1
equipped with a reflux condenser. H and 13C NMR spectra were recorded
in CDCl3 on a Varian EM360L CW 60-MHz spectrometer upgraded with
an Anasazi Instruments, Inc. EFT FT NMR upgrade with carbon-13
accessory. Carbon-type assignments were made from 13C NMR DEPT data.
Quantitative Technologies, Inc. (Whitehouse, NJ) and Atlantic Microlab,
Inc. (Norcross, GA) performed analyses. For the general reduction
procedure, the appropriate mass of pelletized sodium borohydride was
achieved by shaving the pellets with a razor blade. It should be noted that
although less hazardous than the powder form, pelletized sodium borohydride
creates a possible ignition hazard.
General Reduction Procedure
In a 100-mL round-bottomed flask equipped with a water-cooled reflux
condenser, 3.32 mmol of the acylated substrate were magnetically stirred in
6.5 mL of glacial acetic acid. To the resulting suspension was added
10.2 mmol of sodium borohydride in the form of a pellet. Gas evolved upon
the addition. The reaction mixture was gradually warmed to 758C over a

768
F. X. Smith et al.
30-min period. Another 10.2 mmol of pelletized sodium borohydride was
added to the transparent reaction mixture that resulted. The temperature was
maintained at ca. 758C for an additional 60 min. After a total reaction time
of 90 min, the reaction mixture was gradually cooled to room temperature,
diluted with 50 mL of distilled water, and extracted with three 20-mL
portions of diethyl ether. The combined organic layers were washed with
three 45-mL portions of 5% sodium bicarbonate, thoroughly dried over
anhydrous magnesium sulfate, filtered by gravity, and concentrated in vacuo.
The following 3-acyl and 3-alkyl derivatives of oxindoles, benzo[b]furan-
2-ones, and benzo[b]thiophen-2-ones are known compounds that have spectral
data in accord with the literature data: 1a,[4] 2a,[2] 1b,[5] 2b,[6] 1c,[5] 2c,[5]
1d,[6] 2d,[6] 1e,[7] 2e,[8] 1f,[9] 1g,[10] 2g,[11] and 1h.[10] Purity was verified by
melting point and/or elemental analysis as follows:
2a: Mp 120–1218C (heptane), lit. mp 123–1248C. 2b: Mp 97–998C
(ether/hexane), lit. mp 1048C. 2c: Anal. calcd. for C16H15NO: C, 80.98; H,
6.37: N, 5.90. Found: C, 80.93; H, 6.40; N, 5.89. 2d: Mp 106–1078C
(ether/hexane), lit. mp 1088C 2e: Anal. calcd. for C10H10O2: C, 74.09; H,
6.17. Found: C, 74.18; H, 6.24. 2g: Anal. calcd. for C9H8OS: C, 65.84; H,
4.92; S, 19.49. Found: C, 65.71; H, 4.98; S, 19.38. Products 2f and 2h are
new compounds with the following characterization data.
3-Propyl-2(3H)-benzofuranone (2f): The colorless oil boiled at 165–
1
1668C (33 mm). 72% yield. H NMR (60 MHz, CDCl3) d 7.2 (m, 4H), 3.7
(t, 1H), 1.9 (m, 2H), 1.5 (m, 2H), 0.95 (t, 3H). Anal. calcd. for C11H12O2:
C, 74.97; H, 6.86. Found: C, 75.00; H, 6.87. 3-Ethyl-benzo[b]thiophen-
2(3H)-one (2h): The colorless oil boiled at 143–1448C (14 mm). 74% yield.
1H NMR (60 MHz, CDCl3) d 7.4 (m, 4H), 3.85 (t, 1H), 2.1 (m, 2H), 0.85
(t, 3H). Anal. calcd. for C10H10OS: C, 67.43; H, 5.61; S, 17.97. Found: C,
67.27; H, 5.68; S, 17.85.
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Reduction of 3-Acyl Derivatives
769
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