A convenient and efficient preparation of 2-acetyl-4,5-difluorothiophene

Article abstract of DOI:10.1080/00397910701649064

A convenient, five-step preparation of 2-acetyl-4,5-difluorothiophene from 2,3-dibromothiophene is described. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701649064

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A Convenient and Efficient Preparation of
2
‐Acetyl‐4,5‐difluorothiophene
a a
Gaifa Lai & Tao Guo
a
Pharmacopeia, Inc. , Princeton, New Jersey, USA
Published online: 25 Jan 2008.
To cite this article: Gaifa Lai & Tao Guo (2007) A Convenient and Efficient Preparation of
2‐Acetyl‐4,5‐difluorothiophene, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 38:1, 72-76, DOI: 10.1080/00397910701649064
To link to this article: http://dx.doi.org/10.1080/00397910701649064
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Synthetic Communications , 38: 72–76, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701649064
A Convenient and Efficient Preparation
of 2-Acetyl-4,5-difluorothiophene
Gaifa Lai and Tao Guo
Pharmacopeia, Inc., Princeton, New Jersey, USA
Abstract: A convenient, five-step preparation of 2-acetyl-4,5-difluorothiophene from
2
,3-dibromothiophene is described.
Keywords: 2-acetyl-4,5-difluorothiophene, fluorination, synthesis
The introduction of fluorine into organic compounds can have a profound
effect on their steric and electronic properties, often resulting in favorable
[1,2]
increased biological activities, lipophilicity, and metabolic stability.
In view of this, considerable effort has been devoted to develop facile prepara-
[3]
tive methods of fluorine-containing building blocks, to discover new and
[
4,5]
efficient fluorinating agents,
important organofluorine compounds.
and to design and synthesize biologically
Herein we describe a convenient,
[6,7]
five-step preparative route to 2-acetyl-4,5-difluorothiophene (1), a versatile
building block, from 2,3-dibromothiophene, as depicted in Scheme 1.
Thus, acetylation of 2,3-dibromothiophene with acetyl chloride and
aluminum chloride in carbon disulfide readily afforded the methyl ketone
[
8]
3
in 99% yield. Treatment of 3 with ethylene glycol in refluxing benzene
in the presence of a catalytic amount of p-toluenesulfonic acid (0.05 eq.)
smoothly gave the desired ketal 4 in 95% yield. Lithiation of 4 with n-BuLi
(
mide,
1.3 eq.) in THF and subsequent treatment with N-fluorobenzenesulfoni-
[
9,10]
(PhSO ) NF, furnished the monofluorinated compound 5 as
2 2
Received in the USA June 26, 2007
Address correspondence to Gaifa Lai, Pharmacopeia, Inc., P. O. Box 5350,
Princeton, NJ 08543, USA. E-mail: galai@pcop.com
7
2

2-Acetyl-4,5-difluorothiophene
73
.
OH p-TsOH H
Scheme 1. (i) AcCl, AlCl
3
, CS
iii) n-BuLi, THF, 2788C, then (PhSO
v) 3 N HCl, THF.
2
; (ii) HO(CH
2
)
2
2
O, benzene, reflux;
(
(
2 2
) NF, THF, 2788C; (iv) the same as (iii);
expected in 83% yield after column chromatography. The 4,5-difluorinated
thiophene 6 was prepared in 80% yield from 5 by repeating the aforementioned
lithiation-fluorination protocol. We tried to prepare the difluorinated compound
6
found that the monofluorinated compound 5 was predominantly formed with
directly from 4 by employing 2 equivalents of n-BuLi and (PhSO ) NF but
2 2
1
a small amount of 6 being detected by H NMR analysis. Deprotection of 6
was readily effected by treatment with 3 N HCl solution in THF to provide
the title compound 1 as a white solid in 85% yield.
It should be mentioned that a brief survey on the transformation of the
3
-bromo-5-fluorothiophene 7, prepared from 2,4-dibromothiophene in a
three-step route similar to that of 5, to the 3,5-difluorothiophene 8 was also
conducted in this laboratory. It was observed that lithiation of 7 with
n-BuLi (1.3 eq.) in THF and subsequent treatment with (PhSO ) NF
2
2
(1.3 eq.) led to a small amount of the desired compound 8 along with
several unidentified by-products in all cases. One of the reasons behind this
failed conversion could be the bulky ketal group at the neighboring position
disfavoring lithiation of the bromine atom in 7 or subsequent fluorination.
In summary, a convenient and practical preparation of 2-acetyl-4,5-
difluorothiophene (1) has been achieved in five steps from 2,3-dibromothio-
phene with good overall yield. This efficient route should prove useful in

7
4
G. Lai and T. Guo
the synthesis of other 2-acyl-4,5-difluorothiophene compounds, which may be
conveniently transformed to new building blocks such as amines and alcohols
containing these important functional groups.
EXPERIMENTAL
All reagents were purchased from Aldrich and used without further purifi-
1
13
19
cation. The H, C, and F NMR spectra were recorded on a Varian
Gemini 300 spectrometer. Melting points were taken in glass capillary tubes
on an EZ-Melt automated melting-point apparatus and are uncorrected.
Elemental analyses were performed by Atlantic Microlab, Inc., Atlanta, GA.
2
-Acetyl-4,5-dibromothiophene (3)
To a stirred solution of 2,3-dibromothiophene (3 g, 12.4 mmol) in carbon
disulfide (30 mL), aluminum chloride (2.48 g, 18.6 mmol, 1.5 eq.) was
added in one portion under argon. After the mixture was cooled to 08C,
acetyl chloride (1.32 mL, 18.56 mmol, 1.5 eq.) was added dropwise. The
resulting mixture was then agitated at room temperature under argon
overnight when thin-layer chromatographic (TLC) analysis (EtOAc–hexane,
1
:9) showed no presence of the starting material. The reaction mixture was
poured into 100 mL of ice water, followed by extraction with dichloromethane
2 Â 100 mL). The combined organic layers were washed with water (80 mL)
and 5% NaHCO solution (80 mL), dried over MgSO , and concentrated under
(
3
4
reduced pressure. Purification by column chromatography (EtOAc–hexane,
1:9) afforded 3.5 g (99%) of 2-acetyl-4,5-dibromothiophene (3) as an orange
[8]
solid: Rf 0.38 (EtOAc–hexane, 1:9); mp 84–858C (lit.
1
8
5–868C); H NMR (CDCl ) d 7.45 (s, 1H), 2.47 (s, 3H).
3
2-(4,5-Dibromo-2-thienyl)-2-methyl-1,3-dioxolane (4)
A mixture of 2-acetyl-4,5-dibromothiophene (3 g, 10.56 mmol), ethylene
glycol (2.36 mL, 42.32 mmol, 4 eq.), benzene (60 mL), and p-toluenesulfonic
acid monohydrate (100 mg, 0.53 mmol, 0.05 eq.) was heated at reflux under
argon overnight in a flask equipped with a Dean-Stark apparatus. TLC
analysis (EtOAc–hexane, 1:9) showed no presence of the starting material.
The reaction mixture was then cooled to room temperature, and EtOAc
(
washed with 5% NaHCO solution (80 mL) and brine (80 mL), dried over
160 mL) and water (80 mL) were added. The organic layer was separated,
3
MgSO , and concentrated under reduced pressure. Purification by column
4
chromatography (EtOAc–hexane, 1:15) afforded 3.31 g (95%) of 4 as a
1
yellow liquid: R 0.57 (EtOAc–hexane, 1:9); H NMR (CDCl ) d 6.84
f
3
(
s, 1H), 4.06–3.85 (m, 4H), 1.70 (s, 3H).

2-Acetyl-4,5-difluorothiophene
75
2
-(4-Bromo-5-fluoro-2-thienyl)-2-methyl-1,3-dioxolane (5)
To a solution of 4 (9 g, 27.44 mmol) in THF (60 mL) at 2788C, n-BuLi
solution (2.5 M in hexanes, 14 mL, 35 mmol, 1.3 eq.) was added dropwise
with stirring under argon. After addition, the mixture was stirred at 2788C
for 1 h. A solution of N-fluorobenzenesulfonimide (11.2 g, 35.51 mmol,
1
.3 eq.) in THF (30 mL) was added dropwise, and the resulting mixture was
1
stirred at 2788C to –708C for 2 h when a miniworkup and H NMR
analysis showed no presence of the starting material. The mixture was
slowly poured into cold saturated NH Cl solution (100 mL), followed by
4
extraction with EtOAc (2 Â 150 mL). The combined organic layers were
washed with brine (100 mL) and water (100 mL), dried over MgSO , and con-
4
centrated under reduced pressure. Purification by column chromatography
(EtOAc–hexane, 1:15) afforded 6.1 g (83%) of 5 as a pale yellow liquid: R
f
1
0
.52 (EtOAc–hexane, 1:10); H NMR (CDCl ) d 6.65 (d, J ¼ 3.48 Hz, 1H),
3
1
.04–3.92 (m, 4H), 1.69 (s, 3H); F NMR (CDCl ) d2130.2.
9
4
3
2
-(4,5-Difluoro-2-thienyl)-2-methyl-1,3-dioxolane (6)
To a stirred solution of 5 (6.7 g, 25.08 mmol) in THF (55 mL) at 2788C,
n-BuLi solution (2.5 M in hexanes, 13 mL, 32.5 mmol, 1.3 eq.) was added
dropwise under argon. After addition, the mixture was stirred at 2788C for
1
in THF (30 mL) was then added dropwise. The resulting mixture was
h. A solution of N-fluorobenzenesulfonimide (11.2 g, 35.51 mmol, 1.3 eq)
1
stirred at 2788C to –708C for 2 h when a miniworkup and H NMR
analysis showed that the reaction was complete. The mixture was slowly
poured into cold saturated NH Cl solution (100 mL), followed by extraction
4
with EtOAc (2 Â 130 mL). The combined organic layers were washed with
brine (100 mL) and water (100 mL), dried over MgSO , and concentrated
4
under reduced pressure. Purification by column chromatography (EtOAc–
hexane, 1:20) gave 4.15 g (80%) of 6 as a pale yellow liquid: R 0.47
f
1
(
EtOAc–hexane, 1:10); H NMR (CDCl ) d 6.61 (d, J ¼ 3.63 Hz, 1H),
3
1
.02–3.91 (m, 4H), 1.68 (s, 3H); F NMR (CDCl ) d2146.3, 2154.0.
9
4
3
2
-Acetyl-4,5-difluorothiophene (1)
To a stirred solution of 6 (4.15 g, 20.13 mmol) in THF (40 mL) at 08C, 3 N
HCl solution (20 mL, 60 mmol) was added dropwise. The resulting mixture
was stirred at room temperature for 4 h when TLC analysis (EtOAc–
hexane, 1:9) showed no presence of the starting material. EtOAc (100 mL)
and water (100 mL) were added. The organic layer was separated, and the
aqueous layer was extracted with EtOAc (100 mL). The combined organic
layers were washed with brine (80 mL) and 5% NaHCO solution (80 mL),
3

7
6
G. Lai and T. Guo
dried over MgSO , and concentrated under reduced pressure. Purification by
4
column chromatography (EtOAc–hexane, 1:8) afforded 2.77 g (85%) of
2
-acetyl-4,5-difluorothiophene (1) as a white solid: R 0.32 (EtOAc–hexane,
f
1
1
:10); mp 48–498C; H NMR (CDCl ) d 7.29 (d, J ¼ 3.30 Hz, 1H), 2.46
3
1
9
13
(
s, 3H); F NMR (CDCl ) d2140.9, 2143.7; C NMR (CDCl ) d 189.86,
3 3
1
55.93, 142.61, 132.62, 120.97, 25.45. Anal. calcd. for C H F OS1/4H O:
6 4 2 2
C, 43.24; H, 2.72; F, 22.80; S, 19.24. Found: C, 43.60; H, 2.44; F, 22.88;
S, 19.26.
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