On the bromination of methyl 2-methyl-3-furoate

Article abstract of DOI:10.1016/S0040-4039(01)00275-1

Methyl 2-methyl-3-furoate was subjected to bromination with N-bromosuccinimide (NBS), a milder brominating reagent, under different reaction conditions to obtain a variety of selective brominated products.

Full text of DOI:10.1016/S0040-4039(01)00275-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2643–2644
On the bromination of methyl 2-methyl-3-furoate†
Haripada Khatuya*
Department of Chemistry (0506), University of California-San Diego, La Jolla, CA 92093, USA
Received 2 June 1999; accepted 30 January 2001
Abstract—Methyl 2-methyl-3-furoate was subjected to bromination with N-bromosuccinimide (NBS), a milder brominating
reagent, under different reaction conditions to obtain a variety of selective brominated products. © 2001 Elsevier Science Ltd. All
rights reserved.
In connection with the synthesis of some terpenes it was
necessary to prepare compound 2. Hence compound 11
was subjected to bromination with NBS (1.05 equiv.),
using a radical initiator (benzoyl peroxide), and led to
the expected compound 22 in 93% yield, along with
minor amounts (ca. 5%) of the 5-bromo derivative 5. It
was reasoned that the use of more than 1.05 equiv. of
NBS would increase the percentage of 5. Hence the
present study was undertaken.3
When the above reaction was repeated without the
radical initiator, the 2/5 ratio remained nearly the same.
The use of excess NBS (2.2 equiv.) under the radical
conditions led to isolation of gem-dibromo compound
3 in 63% yield (vide Table 1) along with a trace amount
of 5-bromo derivative 6. Thus, the use of excess
NBS further substituted the side chain, in lieu of
the ring. Those two sets of experiments indicated
ring substitution might be possible. The use of 2.8
CO2Me
CO2Me
X
CO2Me
CO2Me
O
H
X
X
X
CO2Me
Br
O
O
O
O
O
Br
H
Br
3: X = H
4: X = Br
5: X = H
6: X = Br
1: X = H
2: X = Br
8: X = H
9: X = Br
7
Table 1. Bromination of 1 with NBS
Entry
Conditions, yield (%)
Product
1H NMR l (ppm)
13C NMR l (ppm)
1
2
3
4
5
NBS (1.05), Bz2O2 (cat.), CCl4, reflux,
14 h, 93%
NBS (2.2), Bz2O2 (cat.), CCl4, reflux,
24 h, 63%
NBS (2.8), Bz2O2 (cat.), CCl4, reflux,
20 h, 46%
NBS (1.2), DMF, 0°C; 40°C, 4 h, 82%
2
3
4
5
6
See Ref. 2
21.0, 51.6, 111.2, 115.6, 142.6, 155.2,
162.9
25.0, 52.1, 110.8, 112.4, 143.7, 154.9,
162.5
3.89 (s, 3H), 6.69 (d, 1H), 7.39 (s,
1H), 7.51 (d, 1H)
3.87 (s, 3H), 6.62 (s, 1H), 7.32 (s, 1H) 23.6, 52.4, 110.8, 112.4, 125.0, 143.7,
161.5
2.56 (s, 3H), 3.82 (s, 3H), 6.54 (s, 1H) 13.6, 51.4, 111.9, 115.7, 119.8, 160.5,
163.1
NBS (2.3), DMF, 0°C; rt, 3 h, 41%
3.88 (s, 3H), 4.76 (s, 2H), 6.34 (s, 1H) 20.3, 52.0, 112.8, 118.0, 123.2, 156.7,
161.9
Keywords: furans; halogenation; halocompounds; radicals and radical reactions.
* Present address: The R. W. Johnson P. R. I., 3210 Merryfield Row, San Diego, CA 92121, USA. Fax: (858) 784-3116; e-mail:
hkhatuya@prius.jnj.com
†
The author wishes to thank Professor E. Wenkert for his encouragement and support.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00275-1

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H. Khatuya / Tetrahedron Letters 42 (2001) 2643–2644
equiv. of NBS afforded the ring brominated product 4
revealed the expected product 4 to be contaminated
with minor amounts of 5 and 6 [4:(5+6)=90:10]. SiO2
chromatography (1% EtOAc in light petroleum ether)
afforded compound 4 (2.11 g, 46%).
(46%).
The structure of gem-dibromo compound 3 was estab-
lished from the chemical shift of the methine proton
(vide Table 1) and by a chemical transformation. Thus,
when compound 3 was warmed at 50°C in wet DMF,
solvolysis occurred and a new compound was obtained,
Compound 6: NBS (33.4 g, 0.30 mol) was added in
portions to a solution of furan 1 (15.0 g, 0.11 mol) in
anhyd. DMF (20 mL) at 0°C. After an additional 1 h
the reaction mixture was allowed to warm to rt and
stirred for 3 h more. Water (100 mL) was added and
extracted with ether. The combined extracts were
washed with water, brine, and then dried. Distillation
of the crude material under reduced pressure (110°C/
0.2 mmHg) gave 12.97 g (41%) of 6.
1
whose H NMR spectrum [l (ppm): 3.89 (s, 3H), 6.90
(d, 1H, J=1.5 Hz), 7.65 (br.s, 1H) and 10.24 (s, 1H)]
supported the aldehyde 7.
In search of a selective ring bromination, a non-protic
polar solvent (viz. DMF) was considered. When furan 1
was reacted with NBS (1.2 equiv.), a clean 5-bromin-
ated product (5) was obtained in 82% yield. On the
other hand, with 2.3 equiv. of NBS, the side chain as
well as ring brominated product (6) was obtained.
References
Encouraged by these results, the bromination of furan 8
was carried out employing NBS, invariably a mixture
of furans 8 and 94 was isolated. The conversion was
found to be most effective when Br2 (1.8 equiv.) was
added at 40–45°C and the solution then heated at
50°C.4a As the ester group at the 2-position deactivates
both the double bonds in furan 8, a stronger brominat-
ing agent was required. A 3-carboethoxy group (i.e. 1)
deactivates predominantly its conjugated double bond,
permitting a milder brominating agent to be effective.
1. (a) Adapted from the literature procedure: Winberg, H. E.;
Fawcett, F. W.; Mochel, W. E.; Theobald, C. W. J. Am.
Chem. Soc. 1960, 82, 1428; (b) For NMR data, see:
Padwa, A.; Zhi, L.; Fryxell, G. E. J. Org. Chem. 1991, 56,
1077.
2. (a) Khatuya, H., Taken from Ph.D. Dissertation, Univer-
sity of California-San Diego, 1995; (b) After completion of
this work there appeared a paper on the preparation and
use of 2: Salimbeni, A.; Canevotti, R.; Paleari, F.; Poma,
D.; Caliari, S.; Fici, F.; Cirillo, R.; Renzetti, A. R.;
Subissi, A.; Belvisi, L.; Bravi, G.; Scolastico, C.; Giachetti,
A. J. Med. Chem. 1995, 38, 4806.
Experimental:
3. For a study on 3-methylindoles, see: Zhang, P.; Liu, R.;
Compound 4: A mixture of furan 1 (1.70 g, 12.1 mmol),
NBS (6.10 g, 33.9 mmol) and (PhCO)2O2 (0.030 g) was
refluxed in CCl4 (25 mL) for 20 h. After the usual
Cook, J. M. Tetrahedron Lett. 1995, 36, 3103.
4. (a) Wenkert, E.; Khatuya, H.; Klein, P. S. Tetrahedron
Lett. 1999, 40, 5171; (b) Grigg, R.; Knight, J. A.; Sargent,
M. V. J. Chem. Soc. (C) 1966, 976.
1
work-up, the H NMR spectrum of the crude material
.
.