Efficient procedure for the preparation of 2-bromo-5-ethylfuran and its unexpected isomerization

Full text of DOI:10.1134/S107042801409022X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 9, pp. 1369–1371. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © V.A. Pal’chikov, J. Robertson, 2014, published in Zhurnal Organicheskoi Khimii, 2014, Vol. 50, No. 9, pp. 1384–1386.
SHORT
COMMUNICATIONS
Efficient Procedure for the Preparation of 2-Bromo-5-ethylfuran
and Its Unexpected Isomerization*
V. A. Pal’chikov and J. Robertsonb
a
a
Department of Organic Chemistry, Oles Honchar Dnipropetrovsk National University,
Dnipropetrovsk, 49010 Ukraine
e-mail: palchikoff@mail.ru
b
Department of Chemistry, Chemistry Research Laboratory, University of Oxford,
Mansfield Road, Oxford OX13TA, UK
e-mail: jeremy.robertson@chem.ox.ac.uk
Received May 14, 2014
DOI: 10.1134/S107042801409022X
Furans, one of the most important classes of five-
membered heterocyclic compounds, are key structural
units in many natural products and various therapeutic
agents [1]. Much attention has been paid to the syn-
thesis and study of 2,5-disubstituted furans, as these
have been shown to possess antibacterial and antiviral
activities [2]. Some substituted 2-alkylfurans isolated
from natural sources exhibit antiplasmodial and anti-
viral activities, as well as tonic effects (e.g. Bilo-
banone) [3]. Many halogenated furans are useful tools
in drug design and synthetic organic chemistry [4], as
they participate in halogen dance (HD) reactions [5]
and palladium-catalyzed arylation of (hetero)aromatics
application, we screened a number of routes toward II
starting from commercially available 2-ethylfuran (I).
First, we attempted bromination of the starting
furan I with molecular bromine (see similar methods
[
5, 6, 9]), but invariably recovered only 2-vinylfuran
(
III) in low yields (up to 9%). The use of NBS under
different conditions [10] led to a mixture of products II
and IV (Scheme 1). In addition to the products shown,
use of NBS in THF (conditions iii) also generated
4
-bromobutan-1-ol (yields up to 6%) arising from
cleavage of the tetrahydrofuran ring by liberated HBr
11]. The identity of 2-(1-hydroxyethyl)furan (IV)
[
was reliably established by NMR spectroscopy. The
[
6] (Suzuki or Stille cross coupling) as well as other
1
13
H and C nuclei of the CH(OH) group exhibited
halogen exchange processes [7].
characteristic resonances at δ 4.90 and 63.7 ppm,
respectively [12]. However, all the described methods
led to the formation of significant amounts of side
products. Eventually, we were able to perform the
synthesis as a one-pot operation under low-temperature
The title 2-bromo-5-ethylfuran (II) was sought as
a starting material in a projected synthesis of 5-ethyl-2-
hexylfuran-3-sulfonic acid, a natural product isolated
from the earthworm Eisenia veneta [8]. For this
Scheme 1.
i–iv
Me
Me
CH
2
Me
OH
+
+
Br
O
O
O
O
I
II
III
IV
i:
ii:
iii:
iv:
29%
25%
12%
54%
9%
–
–
–
17%
4%
–
–
Reagents and conditions: i: Br
2
(1 equiv), DMF, 20°C, 1 h; ii: NBS (1 equiv), AIBN (5 mol %), Et O, reflux, 4 h; iii: NBS (1 equiv),
2
THF, 0°C to room temperature, 24 h; iv: (1) n-BuLi (1 equiv), THF, –78 to –10°C, 2 h; (2) DBDMH (1 equiv), –78 to 0 °C, 12 h.
*
The article was translated by the authors.
1
369

1
370
PAL’CHIKOV, ROBERTSON
Scheme 2.
CDCl , 20°C, 48 h
Me
Br
3
O
Me
V
Br
O
Br
LDA (1.2 equiv), t-BuOK (1.2 equiv), THF
(1) –78 to 20°C (2 h); (2) –20 to 20°C (30 min)
II
Me
6
0%
O
VI
conditions, obtaining the desired furan II in 54% yield
slowly to 0°C (~12 h) while stirring rapidly. The
reaction mixture was diluted with brine (100 mL) and
the product was extracted with petrol (3×150 mL).
The combined organic layers were dried (Na SO ) and
(
conditions iv).
Interestingly, solutions of 2-bromo-5-ethylfuran
II) in CDCl stored at room temperature under am-
2
4
(
3
concentrated in vacuo (25°C, 70 mm). Purification
bient light for about 48 hours underwent unexpected
rearrangement to the product assigned as 2-(1-bromo-
ethyl)furan (V) (Scheme 2). The formation of V was
indicated by the appearance of new signals in the
by flash chromatography (petroleum ether, 30–40°C;
SiO , 40–63 μm; 30 × 85 mm) afforded the title
2
compound as a colorless oil (2.22 g, 54%), R 0.76
f
−
1
1
(
petrol). IR spectrum, ν, cm : 2975 m, 1598 m, 1510
H NMR spectrum; notably, a doublet at δ 2.06 ppm
s, 1202 m, 1128 s, 1006 m, 972 w, 932 m, 776 s.
(
7
3H, J = 7.0 Hz) and a quartet at δ 5.28 ppm (1H, J =
1
H NMR spectrum (400 MHz, CDCl ), δ, ppm: 1.22 t
.0 Hz). Only trace amounts of starting bromide II
3
were detected by NMR in these solutions after two
days. This isomerization is presumably catalyzed by
(3H, CH
3
, J = 7.6 Hz), 2.63 q.d (2H, CH
2
, J = 7.6,
1.0 Hz), 5.96 dt (1H, Harom, J = 3.2, 1.0 Hz), 6.18 d
1
3
adventitious acid (HCl or DCl) present in the CDCl .
(1H, Harom, J = 3.2 Hz). C NMR spectrum (100 MHz,
4
3
The title bromide II was easily converted into
CDCl
3
), δ
C
, ppm: 12.1 (CH
3
), 21.7 (CH ), 106.9 (C ),
2
3
2
5
+
4
-bromo-2-ethylfuran (VI) under halogen dance con-
111.7 (C ), 119.1 (C ), 160.0 (C ). HRMS (FI ):
+
ditions [5]. Compounds II–IV and VI could all be
purified by flash column chromatography on silica.
NMR spectra of known compounds III, IV, and VI
were identical to those described [12, 13].
Found: 173.9678, 175.9661. C
6
H BrO [M] . Calculat-
7
ed: 173.9680, 175.9660. The product can be stored up
to 3–4 weeks in the dark at –20 °C.
All reactions were carried out in oven-dried glass-
ware and under an atmosphere of argon. Commercially
available reagents, including 2-ethylfuran, 1,3-di-
bromo-5,5-dimethylhydantoin, and n-BuLi were used
as purchased (Sigma–Aldrich Co.). Analytical thin-
layer chromatography was carried out on Merck
In summary, we have screened a variety of routes
for the synthesis of 2-bromo-5-ethylfuran (II) and
developed a simple scalable one-pot protocol with
good overall yield. The structure of the product II was
1
13
investigated using H, C NMR, COSY, and HSQC
methods. The present paper describes the first use of
DBDMH in the synthesis of bromofurans, this method
opens broad prospects for the synthesis of many
similar brominated furans.
aluminum backed DC 60 F
0.2-mm precoated
2
54
plates. The developed chromatograms were visualized
by potassium permanganate stain. Flash chromatog-
raphy was performed with Merck silica gel 60 (40–
6
3 μm). The NMR spectroscopic data were measured
2
-Bromo-5-ethylfuran (II). To a stirring solution
in the indicated solvent with either 200 or 400 MHz
Bruker spectrometers. The IR spectroscopic data were
recorded using Bruker Tensor-27 spectrometer with
diamond ATR module. High resolution mass spectra
of 2-ethylfuran (2.27 g, 2.5 mL, 23.6 mmol) in 20 mL
of dry THF was added n-BuLi (2.5 M in hexane,
9
.4 mL, 23.6 mmol) at –78°C dropwise over 20 min.
The reaction mixture was then slowly warmed up to
(
HRMS) were recorded using a Waters GC-TOF spec-
–
0
(
10°C (~2 h) then recooled to –78°C. A pre-cooled (to
°C) solution of 1,3-dibromo-5,5-dimethylhydantoin
trometer (EI/FI).
DBDMH, 6.75 g, 23.6 mmol) in 35 mL of dry THF
This work was financially supported by the
Ukrainian Ministry of Education and Science interna-
tional internship program.
was added to the reaction mixture (~5 min). The result-
ing heterogeneous reaction mixture was warmed
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 9 2014

EFFICIENT PROCEDURE FOR THE PREPARATION OF 2-BROMO-5-ETHYLFURAN
1371
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