Reaction of 2-alkylidenetetrahydrofurans with boron tribromide: Chemo- and regioselective synthesis of 6-bromo-3-oxoalkanoates by application of a 'cyclization-ring-opening' strategy

Article abstract of DOI:10.1055/s-2004-830893

6-Bromo-3-oxoalkanoates, benzofurans and 1,7-dibromoheptan-4-ones were chemo- and regioselectively prepared by reaction of 2-alkylidenetetrahydrofurans with boron tribromide.

Full text of DOI:10.1055/s-2004-830893

2172
LETTER
Reaction of 2-Alkylidenetetrahydrofurans with Boron Tribromide:
Chemo- and Regioselective Synthesis of 6-Bromo-3-oxoalkanoates by
Application of a ‘Cyclization-Ring-Opening’ Strategy
R
eaction of 2-A
s
lkylidene
e
u
rans with Boron
T
B
ribromide ellur, Peter Langer*
Institut für Chemie und Biochemie, Ernst-Moritz-Arndt-Universität Greifswald, Soldmannstrasse 16, 17487 Greifswald, Germany
E-mail: peter.langer@uni-greifswald.de
Received 17 May 2004
O
O
Br
OLi OLi
OEt
Abstract: 6-Bromo-3-oxoalkanoates, benzofurans and 1,7-dibro-
moheptan-4-ones were chemo- and regioselectively prepared by
reaction of 2-alkylidenetetrahydrofurans with boron tribromide.
Br
OEt
1a
Br
2a
Key words: boron tribromide, domino reactions, nucleophilic sub-
stitution, halogenation, tetrahydrofurans
Cl
Br
O
O
4 BBr3
OEt
OEt
Boron tribromide (BBr3) has been widely used for the
demethylation of methylaryl ethers.1 The reaction of cy-
clic ethers with BBr3–MeOH has been reported to result in
ring opening and formation w-bromoalkanols.2 w-Halo-
carboxylic acids have been prepared by reaction of lac-
tones with BBr3.3 Herein, we wish to report what are, to
the best of our knowledge, the first reactions of BBr3 with
cyclic enol ethers, e.g. 2-alkylidenetetrahydrofurans. This
transformation allows a chemo- and regioselective ap-
proach to 6-bromo-3-oxoalkanoates, benzofurans and 1,7-
dibromoheptan-4-ones which all represent useful synthet-
ic building blocks. Our methodology relies on a ‘cycliza-
tion-ring-opening’ strategy: the starting materials, 2-
alkylidenetetrahydrofurans, are readily available by one-
pot cyclizations. In contrast, the ring-opening products are
in most cases not readily available by other methods.4
O
Br3B
O
A
3a
O
O
Br2B
O
O
OEt
H2O
OEt
Br
Br
B
2a (76%)
Scheme 1
The reaction of BBr3 with 2-alkylidenetetrahydrofurans
3b–h, containing a substituent located at the exocyclic
double bond, afforded the 2-alkyl- and 2-aryl-6-bromo-3-
oxoalkanoates 2b–h (Scheme 2, Table 1). During the for-
mation of 2h, the methylaryl ether of the starting material
was cleaved. The 4-alkyl-6-bromo-3-oxoalkanoates 2i–j
were prepared from 2-alkylidenetetrahydrofurans 3i–j
containing a substituent at carbon C-3. The reaction of
5,12-bicyclic 2-alkylidenetetrahydrofuran (3k), prepared
from ethyl cyclododecan-1-one-2-carboxylate, afforded
2k. The ring-opening of 5-alkyl-2-alkylidenetetrahydro-
furans, readily available by cyclization of 1,3-bis-silyl
enol ethers with epoxides,9 was studied next. Treatment of
3l–n with BBr3 afforded the 6-methyl-, 6-ethyl- and 6-bu-
tyl-6-bromo-3-oxoalkanoates 2l–n. The 6-bromo-7-chlo-
ro-3-oxoalkanoate (2o) was prepared in 80% yield from
3o. Starting with 4-phenyl-2-alkylidenetetrahydrofuran
(3p), 5-phenyl-6-bromo-3-oxoalkanoate (2p) was
prepared. Treatment of tetrahydrofuran 3q with BBr3
afforded the 1,3-diketone 2q. The reaction of 5-vinyl-2-
alkylidenetetrahydrofuran, readily available by cycliza-
tion of dilithiated methyl acetoacetate with 1,4-dibromo-
2-butene,10 afforded ethyl 8-bromo-3-oxooct-6-enoate. In
this reaction, the cleavage of the tetrahydrofuran moiety
proceeded by a SN¢ mechanism with migration of the dou-
ble bond. All reactions proceeded in good yield and with
The reaction of 1,3-dicarbonyl dianions with 1-bromo-2-
chloroethane has been reported to give 6-chloro-3-oxoal-
kanoates.5 These products readily undergo 5-exo-tet cy-
clizations under the basic conditions employed. In fact, 2-
alkylidenetetrahydrofurans 3 can be prepared in good
yields by one-pot cyclizations.6 Despite their synthetic
usefulness, 6-bromo-3-oxoalkanoates 2 are not directly
available by reaction of dianions with 1,2-dibromoethane,
due to reduction of the dielectrophile.7 We have found that
this problem could be successfully solved by sequential
treatment of 2-alkylidenetetrahydrofuran (3a) with BBr3
and water. During the optimization, the use of an excess
of BBr3 (4 equiv) proved to be important.8 A possible
mechanism could involve the activation of 3a (intermedi-
ate A), ring-opening (intermediate B) and subsequent pro-
tonation of the enolate. So far, we have no evidence for the
mechanism and for the configuration of B (Scheme 1).
SYNLETT 2004, No. 12, pp 2172–2174
0
1
.1
0
.2
0
0
4
Advanced online publication: 05.08.2004
DOI: 10.1055/s-2004-830893; Art ID: D12304ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Reaction of 2-Alkylidenetetrahydrofurans with Boron Tribromide
2173
1) 4 BBr3
2) H2O
R4
O
R2
O
O
1) 4 BBr3
R1
O
R5
Br
2) H2O
O
R5
O
O
OMe
OMe
R2
R1
R3
R4
R3
OMe
O
Br
2a–q
3a–q
4
5 (92%)
Scheme 2
_
H2O
BBr3
BBr3
Table 1 Products and Yields
2
a
b
c
R1
H
R2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
R3
R4
H
R5
(%)
76
95
96
84
84
89
77
72
96
86
87
80
91
75
80
83
98
BBr3
MeO
HO
H
OEt
OMe
OMe
H
H
Oct
Bn
OEt
O
O
O
O
Br
Br
BBr3
H
H
OMe
OMe
OMe
OMe
OMe
D
C
d
e
H
H
(CH2)3Cl
Ph
Scheme 3
H
H
f
H
H
4-MeC6H4
4-ClC6H4
O
g
h
i
H
H
O
H
H
4-HOC6H4 OMe
I
Amiodarone
CO2H
H
Pr
H
H
OEt
I
O
Figure 1
j
H
(CH2)3Cl
OMe
OEt
k
l
H
-(CH2)9-
O
1) 4 BBr3
2) H2O
O
R
Me
Et
Bu
H
H
H
H
H
H
H
H
H
H
H
H
OMe
OMe
OMe
OMe
OEt
O
Br
Br
m
n
o
p
q
O
R
R = H, CH2Cl
6a,b
7a,b (73–85%)
CH2Cl H
_
H2O
CO2
BBr3
H
H
Ph
Br2B
O
O
H
Ph
Br2BO
OBBr2
O
a Yields of isolated products.
BBr3
O
Br
Br
Br
R
very good chemo- and regioselectivity. As expected from
the chemistry of boron tribromide, alkyl esters remained
intact.1
R
E
F
Scheme 4
Treatment of 2-alkylidenetetrahydrofuran 4 with BBr3
afforded the functionalized benzofuran 5 (Scheme 3).11
The formation of 5 can be explained by ring-opening of 4
to give intermediate C, deprotection of the arylmethyl
ether (intermediate D) and subsequent BBr3 mediated cy-
clization by attack of the hydroxy onto the carbonyl
group. Functionalized benzofurans are of great pharmaco-
logical relevance and are used in the clinic.12 For example,
amiodarone represents a potent antiarrythmic drug
(Figure 1).12a,b Brominated benzofurans related to 5 repre-
sent useful synthetic building blocks. In addition, they are
interesting in their own right as metabolites of amio-
darone.12a
The reaction of BBr3 with dinuclear 2-alkylidenetetrahy-
drofuran (6a), available in one step from 2-acetyl-g-buty-
rolactone, afforded 1,7-dibromoheptan-4-one (7a) in 73%
yield (Scheme 4). The formation of 7a can be explained
by BBr3 mediated ring-opening of the cyclic enol, cleav-
age of the lactone, decarboxylation and protonation.13 The
unsymmetrical 1,7-dibromoheptan-4-one (7b) was pre-
pared in 85% yield from 2-alkylidenetetrahydrofuran (6b)
which is available in one step from epichlorohydrin.9 1,7-
Dibromoheptan-4-ones represent versatile synthetic
building blocks.14 For example, 7a has been used for the
synthesis of medium-sized carba- and heterocycles.14a,b
Unsymmetrical 1,7-dibromoheptan-4-ones are not readily
available by other methods.14f
Synlett 2004, No. 12, 2172–2174 © Thieme Stuttgart · New York

2174
E. Bellur, P. Langer
LETTER
(9) Langer, P.; Armbrust, H.; Eckardt, T.; Magull, J. Chem.–
Eur. J. 2002, 8, 1443; and references cited therein.
(10) Langer, P.; Holtz, E.; Saleh, N. N. R. Chem.–Eur. J. 2002, 8,
917.
Acknowledgment
Financial support from the DAAD (scholarship for E. B.) and from
the Deutsche Forschungsgemeinschaft is gratefully acknowledged.
(11) Typical Experimental Procedure for 5: To a CH2Cl2
solution (10 mL) of 4 (0.150 g, 0.6 mmol) was added BBr3
(0.605 g, 2.4 mmol) at 0 °C. The reaction mixture was
allowed to warm to 20 °C and was stirred for 24 h. Water (15
mL) was slowly added to the reaction mixture and the
organic layer was separated. The aqueous layer was
extracted with EtOAc (4 × 30 mL). The combined organic
extracts were dried (Na2SO4), filtered and the filtrate was
concentrated in vacuo. The residue was purified by
chromatography (silica gel, n-hexane–EtOAc, 100:1 to 1:1)
to give 5 (0.163 g, 92%) as a yellow oil. 1H NMR (300 MHz,
CDCl3): d = 2.34 (quint, J = 7.2 Hz, 2 H, CH2), 3.35 (t,
J = 7.5 Hz, 2 H, CH2), 3.47 (t, J = 6.9 Hz, 2 H, CH2-Br),
3.95 (s, 3 H, OCH3), 7.28–7.33 (m, 2 H, 2 × CH), 7.42–7.45
(m, 1 H, CH), 7.95–7.98 (m, 1 H, CH). 13C NMR (75 MHz,
CDCl3): d = 26.83, 30.80 (CH2), 32.41 (CH2-Br), 51.44
(OCH3), 109.17 (C=C-O), 110.88, 121.87, 123.86, 124.58
(CH), 125.82, 153.62 (C), 164.52 (O=C-O), 165.17 (O-
C=C). IR (neat): 2952 (m, C-H), 1714 (s, O=C-O), 1593 (s),
1478 (m), 1451 (s), 1437 (s), 1386 (m), 1342 (w), 1284 (m),
1235 (s), 1174 (s), 1127 (w), 1106 (m), 1073 (s), 1010 (w),
959 (w), 935 (w), 861 (w), 790 (m), 752 (s) cm–1. MS (EI, 70
eV): m/z (%) = 297 (38) [M+], 266 (7), 217 (16), 203 (10),
188 (100), 174 (5), 170 (29), 158 (47), 144 (4). Anal. Calcd
for C13H13O3Br (297.148): C, 52.55; H, 4.41. Found: C,
52.84; H, 4.74.
(12) (a) Wendt, B.; Ha, H. R.; Hesse, M. Helv. Chim. Acta 2002,
85, 2990. (b) Carlsson, B.; Singh, B. N.; Temciuc, M.;
Nilsson, S.; Li, Y.-L.; Mellin, C.; Malm, J. J. Med. Chem.
2002, 45, 623; and references cited therein. (c) Kwiecien,
H.; Baumann, E. J. Heterocycl. Chem. 1997, 1587.
(d) Larock, R. C.; Harrison, L. W. J. Am. Chem. Soc. 1984,
106, 4218.
(13) The reaction of 2-acetyl-g-butyrolactone with HBr has been
reported to give 1-bromopentan-4-one by ring-opening and
subsequent decarboxylation. See: (a) Cornish, C. A.;
Warren, S. J. Chem. Soc., Perkin Trans. 1 1985, 2585.
(b) Baldwin, J. E.; Li, C.-S. J. Chem. Soc., Chem. Commun.
1988, 261. (c) Wu, J.-M.; Li, Y. Tetrahedron Lett. 2001, 42,
6737.
References
(1) Review: (a) Bhatt, M. V.; Kulkarni, S. U. Synthesis 1983,
249. (b) See also: McOmie, J. F. W.; Watts, M. L.; West, D.
E. Tetrahedron 1968, 24, 2289.
(2) Cleavage of cyclic ethers: Kulkarni, S. U.; Patil, V. D.
Heterocycles 1982, 18, 163.
(3) Cleavage of lactones: Olah, G. A.; Karpeles, R.; Narang, S.
C. Synthesis 1982, 963.
(4) 7-Bromoheptane-2,4-dione has been prepared by reaction of
5-bromopent-1-yne with acetic anhydride: Tanabe, Y.;
Mukaiyama, T. Chem. Lett. 1985, 673.
(5) Lambert, P. H.; Vaultier, M.; Carrié, R. J. Org. Chem. 1985,
50, 5352.
(6) (a) Langer, P.; Holtz, E.; Karimé, I.; Saleh, N. N. R. J. Org.
Chem. 2001, 66, 6057. (b) Langer, P.; Bellur, E. J. Org.
Chem. 2003, 68, 9742. (c) For Suzuki reactions of 2-
alkylidenetetrahydrofurans, see: Bellur, E.; Langer, P.
Synlett, preceeding paper.
(7) Hampton, K. G.; Light, R. J.; Hauser, C. R. J. Org. Chem.
1965, 30, 1413.
(8) Typical Experimental Procedure for 2h: To a CH2Cl2
solution (5 mL) of 3h (0.130 g, 0.5 mmol) was added BBr3
(0.525 g, 2.1 mmol) at 0 °C. The reaction mixture was
allowed to warm to 20 °C during 12 h. Water (2 mL) was
added and the solution was stirred for 3 h at 20 °C. The
solvent was removed in vacuo and the residue was purified
by column chromatography (silica gel, n-hexane–EtOAc,
30:1 to 1:1) to give 2h as a brownish solid (0.118 g, 72%).
The product mainly resides in the keto tautomeric form
(keto–enol = 10:1). 1H NMR (300 MHz, CDCl3): d = 2.09
(quint, J = 6.6 Hz, 2 H, CH2), 2.68 (t, J = 6.9 Hz, 2 H, CH2),
3.35 (t, J = 6.9 Hz, 2 H, CH2-Br), 3.76 (s, 3 H, OCH3), 4.70
(s, 1 H, CH), 5.65 (br, 1 H, OH), 6.83 (d, J = 8.7 Hz, 2 H,
Ar), 7.20 (d, J = 8.7 Hz, 2 H, Ar), 13.03 (br, 1 H, enol from,
OH). 13C NMR (75 MHz, CDCl3): d = 26.33, 32.69 (CH2),
39.44 (CH2-Br), 52.76 (OCH3), 63.92 (CH), 103.92 (C=C-O,
enol), 115.96 (CH), 123.71 (C), 130.55 (CH), 156.08 (C),
169.64 (O=C-O), 175.04 (O-C=C, enol), 203.55 (C=O). IR
(KBr): 3396 (m, OH), 3184 (w), 2957 (w, C-H), 1735 (s,
O=C-O), 1703 (s, C=O), 1614 (w), 1594 (w), 1516 (s), 1439
(m), 1359 (m), 1335 (w), 1302 (w), 1274 (m), 1249 (m),
1213 (s), 1161 (m), 1095 (w), 991 (w), 832 (w), 557 (w), 528
(w) cm–1. MS (EI, 70 eV): m/z (%) = 315 (1) [M+], 284 (14),
234 (5), 203 (1), 175 (5), 165 (85), 150 (29), 118 (3), 109
(100), 106 (55). Anal. Calcd for C13H15O4Br (315.163): C,
49.54; H, 4.80. Found: C, 49.63; H, 5.03. All products gave
satisfactory spectroscopic and analytical and/or high-
resolution mass data.
(14) For syntheses and reactions of 7a, see: (a) Almirante, N.;
Forti, L. J. Heterocycl. Chem. 1984, 21, 1121.
(b) Schuhmacher, H.; Meier, H. Z. Naturforsch. B 1992, 47,
563. (c) Fittig, F.; Stroem, A. Liebigs Ann. Chem. 1892,
267, 192. (d) Burdick, H. E.; Adkins, H. J. Am. Chem. Soc.
1934, 56, 438. (e) Farlow, M.; Burdick, H. E.; Adkins, H. J.
Am. Chem. Soc. 1934, 56, 2498. (f) For an unsymmetrical
derivative, see: Ponomarew, M.; Monachowa, M. J. Gen.
Chem. USSR 1964, 34, 1242.
Synlett 2004, No. 12, 2172–2174 © Thieme Stuttgart · New York