An efficient synthetic method for 3-bromofuran derivatives via stereoselective cyclization of γ, δ-epoxy-(E)-α-bromoacrylates

Article abstract of DOI:10.3987/COM-08-S(F)25

A novel and efficient synthetic method for 3-bromofuran derivatives via stereoselective cyclization of γ,δ-epoxy-(E)-α-bromoacrylates is described. The reaction of a γ,δ-epoxy-(E)-α-bromoacrylate with MeAl₃,-H₂O gave rise to a 3-brom

Full text of DOI:10.3987/COM-08-S(F)25

HETEROCYCLES, Vol. 77, No. 1, 2009
201
HETEROCYCLES, Vol. 77, No. 1, 2009, pp. 201 - 206. © The Japan Institute of Heterocyclic Chemistry
Received, 9th June, 2008, Accepted, 22nd July, 2008, Published online, 24th July, 2008.
DOI: 10.3987/COM-08-S(F)25
AN EFFICIENT SYNTHETIC METHOD FOR 3-BROMOFURAN
DERIVATIVES
VIA
STEREOSELECTIVE
CYCLIZATION
OF
γ,δ-EPOXY-(E)-α-BROMOACRYLATES†
Fumihiko Yoshimura, Masaki Takahashi, Keiji Tanino, and Masaaki
Miyashita*,‡
Division of Chemistry, Graduate School of Science, Hokkaido University,
Sapporo 060-0810, Japan; E-mail: bt13149@ns.kogakuin.ac.jp
† Dedicated to Professor Emeritus Keiichiro Fukumoto on the occasion of his 75th
birthday.
‡ Current address: Department of Applied Chemistry, Kogakuin University,
Tokyo 192-0015, Japan
Abstract – A novel and efficient synthetic method for 3-bromofuran derivatives
via stereoselective cyclization of γ,δ-epoxy-(E)-α-bromoacrylates is described.
The reaction of a γ,δ-epoxy-(E)-α-bromoacrylate with MeAl3-H2O gave rise to a
3-bromo-2-methylfuran derivative, i.e., methylated bromofuran at the 2-position,
while the reaction with Me3Al-(CF3)2CHOH reagent produced
a
2-alkoxy-3-bromofuran derivative in high yield. The 3-bromofuran obtained
was transformed into various functionalized furan derivatives.
Substituted furans not only constitute an important class of five-membered heterocycles which have been
found in many natural products and important pharmaceuticals,1 but also they have been used as useful
building blocks in organic synthesis.2 Therefore, a large number of synthetic methods for substituted
furans have been reported so far,3 among which representatives include cyclocondensation of
1,4-dicarbonyl compounds (Paal-Knorr synthesis), the base-promoted condensation of 1,3-dicarbonyl
compounds with α-haloketones (Feist-Bénary synthesis), and various substitution reactions on a furan
ring. Recently, alternative synthetic strategies via cycloisomerization of alkynes and allenyl compounds
have been explored.4
Amongst furans, bromo-substituted ones have played particularly important roles as useful counterparts
for coupling reactions as well as versatile synthetic intermediates for functionalized furans.

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HETEROCYCLES, Vol. 77, No. 1, 2009
Bromo-substituted furans are generally prepared by an electrophilic substitution reaction of furan
derivatives with bromine atom(s), halogen-induced cyclization, and cyclocondensation or
cycloisomerization of halogenated precursors.5 However, these methods often suffer from the following
synthetic limitations: (1) inaccessibility to cyclization precursors having halogen-sensitive functional
groups; (2) a furan ring essentially undergoes an electrophilic substitution reaction mainly at the 2- or
5-position rather than at the 3- or 4-position.6 Thus, development of an alternative synthetic method that
allows the regioselective synthesis of bromofurans including 3- and 4-bromo derivatives has remained as
an important subject. We report herein an efficient synthetic method for 3-bromofuran derivatives via
the Me3Al-mediated stereoselective 5-exo cyclization of γ,δ-epoxy-(E)-α-bromoacrylates.
As a program of new acyclic stereocontrol based on the stereospecific methylation reaction of epoxides,
we previously reported that the reaction of trans-γ,δ-epoxy-(E)-acrylate 1 with Me3Al-H2O produced
anti-δ-hydroxy-γ-methyl-(E)-acrylate 2 stereospecifically in high yield (Scheme 1).7 Similarly, the
reaction of various γ,δ-epoxy-(E)-acrylates with the Me3Al-H2O system occurred highly stereoselectively
giving rise to γ-methylated compounds with inversion of configuration. On the contrary, the reaction of
γ,δ-epoxy-(Z)-acrylate 3 with Me3Al-H2O produced 2-ethoxyfuran 4 as the major product along with a
small amount of γ-methylated compound 5.8 We assumed that 4 was probably formed via the reaction
mechanism shown in Scheme 1. Namely, the reaction would be initiated by activation of the oxygen
atom of the epoxide by an aluminum reagent as shown in 6 and subsequent attack of the carbonyl oxygen
would lead to oxonium ion 7, which was then aromatized by elimination of a proton to afford the furan 4.
Me
O
Me3Al-H2O
BnO
BnO
CO2Et
BnO
CO2Et
CO2Et
CH2Cl2, –30 °C
OH
OH
1
2 (96%, d.s.> 99:1)
Me CO2Et
Me3Al-H2O
O
O
OEt
+
BnO
BnO
CH2Cl2, –30 °C
OH
3
4 (60%)
5 (18%)
Ln
Al
LnAlO
O
OEt
O
BnO
OEt
BnO
O
H
6
7
Scheme 1. The reactions of γ,δ-epoxy-(E)-acrylate 1 and (Z)-acrylate 3 with Me3Al-H2O.
Although formation of 4 was unexpected, this particular furan-forming reaction prompted us to
investigate synthetic potential of the Lewis acid-mediated cyclization of γ,δ-epoxy-(Z)-acrylates, since

HETEROCYCLES, Vol. 77, No. 1, 2009
203
various γ,δ-epoxy-(Z)-acrylates including the optically active ones are easily obtainable by the Z-selective
Honer-Emmons reaction using the Ando reagent.9
Initially, a number of Lewis acids were surveyed to optimize conversion from 3 to 4. Lewis acids such
as Me3Al,10 Me2AlCl, i-Pr3Al, ZnCl2, Ti(Oi-Pr)4, TiCl(Oi-Pr)3, Ti(OEt)4, and BF3·OEt2 were found,
however, to be totally fruitless, probably due to instability of both 3 and 4 under the reaction conditions.
Then, we hypothesized that replacement of a hydrogen atom at the α-position of the acrylate moiety with
a bromine atom might enhance the reactivity of the cyclization reaction which would culminate in the
synthesis of 3-bromofurans. In expectation for this idea, we prepared trans-γ,δ−epoxy-(E)-α-bromo-
acrylate 11 as a model substrate. The α-bromoacrylate 11 was readily prepared from aldehyde 8
according to the procedure of Tago and Kogen11 in high yield (Scheme 2).12,13 With the model substrate
11 in hand, the key cyclization reaction was examined. Thus, upon treatment of 11 with Me3Al-H2O at
–30 °C, not the expected 3-bromo-2-ethoxyfuran 14, but 3-bromo-2-methylfuran 13 was obtained as a
single product in 75% isolated yield.14 Apparently, 13 was produced by way of an oxonium ion 12 with
a methyl group transfer from Me3Al as shown in Scheme 2. In order to synthesize 3-bromo-2-ethoxy
furan 14, we assumed that addition of an appropriate alcohol bearing electron-withdrawing substituent(s)
might prevent transfer of a methyl group from Me3Al, so 14 might be obtainable.
O
P
O
9/10 (5:1) mixture
t-BuOK
18-crown-6
CO2Et
CF3CH2O
CF3CH2O
O
O
OEt
Br R
BnO
CHO
BnO
Br
THF, –78 °C
(E/Z = 96:4)
11 (80%)
8
9: R=H, 10: R=Br
LnAlO
OH
O
O
Me3Al-H2O
BnO
BnO
OEt
Me
H
CH2Cl2
–30 °C
Me AlMe2
CO2Et
Br
Br
Br
13 (75%)
12
O
BnO
OH
11
Me3Al-(CF3)2CHOH (3:2)
O
BnO
OEt
hexane/CH2Cl2 (20:1)
–30 °C
Br
14 (92%)
Scheme 2. Synthesis of two types of 3-bromofuran derivatives from (E)-α-bromoacrylate 11.
To this end, several alcohol additives were examined and finally we found that addition of
1,1,1,3,3,3-hexafluoro-2-propanol [(CF3)2CHOH] gave the satisfactory results. Namely, treatment of 11
with Me3Al-(CF3)2CHOH reagent15 in a mixed solvent of hexane and CH2Cl2 at –30 °C produced the
desired 3-bromo-2-ethoxyfuran 14 as a single product in high yield (Scheme 2). It should be noted that

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HETEROCYCLES, Vol. 77, No. 1, 2009
the yield of 14 varied depending on a ratio of Me3Al and (CF3)2CHOH16 and the best result was obtained
when the reaction was carried out at –30 °C using a 3:2 molar ratio of Me3Al and (CF3)2CHOH in a 20:1
mixed solvent of hexane and CH2Cl2.17
On the other hand, the Lewis acid-mediated reaction of (E)-α-bromoacrylate 15 bearing no alkoxy group
on the side chain did not afford any bromofurans and, instead, bromo-substituted butenolide 16 was
obtained in 40% yield. These results clearly suggest that chelation of the aluminum reagent by the
oxygen atoms of the epoxide and the ether moiety plays critical roles for the formation of bromofurans.
CO2Et
Me3Al-H2O
O
complex mixture
Pr
Br
CH2Cl2, –30 °C
15
O
CO2Et
Br
O
Me3Al-(CF3)2CHOH (3:2)
hexane, –30 °C
O
Pr
Pr
Br
15
16 (40%)
Scheme 3. The reaction of (E)-α-bromoacrylate 15 bearing no alkoxy group on the side chain.
In order to demonstrate the synthetic potential of the new method, a number of 3-substituted furans
(18–22) were synthesized using the silylated 3-bromofuran 1718 as shown in Scheme 4. Thus, the
reaction of 17 with butyllithium in THF at −78 °C generated the corresponding 3-lithiofuran
quantitatively,19 which smoothly reacted with a variety of electrophiles in a one-pot operation to afford
various functionalized 3-substituted furans in 63-90% isolated yield. These reactions demonstrate a
promising entry to a variety of 3-substituted furans which are inaccessible by known methods.
BuLi, THF
–78 °C
OTES
OTES
O
O
BnO
BnO
OEt
OEt
then D2O
(>99%)
Br
D
17
17
18 (90%D)
OTES
OTES
O
BuLi, THF
–78 °C
BuLi, THF
–78 °C
O
BnO
BnO
OEt
CN
BnO
OEt
Me
17
17
then MeI
(90%)
then TsCN
(70%)
21
OTES
19
OTES
BuLi, THF
–78 °C
BuLi, THF
–78 °C
O
OEt
OH
O
BnO
OEt
17
then PhCHO
(63%)
then allyl bromide
(66%)
*
Ph
20
22 (1:1 mixture)
Scheme 4. Conversion of 3-bromofuran 17 to various 3-substituted furans (18–22).

HETEROCYCLES, Vol. 77, No. 1, 2009
205
In conclusion, we developed a new synthetic method for 3-bromofurans, which involves a novel
Me3Al-mediated 5-exo cyclization of γ,δ-epoxy-(E)-α-bromoacrylates. Two types of 3-bromofuran
derivatives were obtainable from the same starting material by the use of Me3Al-H2O and
Me3Al-(CF3)2CHOH reagents.
The 3-bromofuran 17 was efficiently transformed into various
3-substituted furans by the substitution reactions with a variety of nucleophiles. Since it is well known
that the substitution reaction of a furan ring at the 3- or 4-position is difficult, the present method provides
useful tools in organic synthesis including natural product synthesis and pharmaceutical synthesis.
ACKNOWLEDGEMENTS
Financial support from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (a
Grant-in-Aid for Scientific Research (B) (No. 16350049)) is gratefully acknowledged.
REFERENCES AND NOTES
1. B. A. Keay, P. W. Dibble, ‘Comprehensive Heterocyclic Chemistry II,’ Vol. 2, ed., by A. R.
Katritzky, C. W. Ress, and E. F. V. Scriven, Pergamon, Oxford, 1997, pp. 395-436.
2. For reviews, see: (a) B. H. Lipshutz, Chem. Rev., 1986, 86, 795. (b) C. O. Kappe, S. S. Murphree,
and A. Padwa, Tetrahedron, 1997, 53, 14179.
3. For recent reviews of furan synthesis, see: (a) X. L. Hou, H. Y. Cheung, T. Y. Hon, P. L. Kwan, T. H.
Lo, S. Y. Tong, and H. N. C. Wong, Tetrahedron, 1998, 54, 1955. (b) S. F. Kirsch, Org. Biomol.
Chem., 2006, 4, 2076. (c) N. T. Patil and Y. Yamamoto, ARKIVOC, 2007, 121.
4. For selected examples of cycloisomerization approaches to furans, see: (a) A. V. Kel’in and V.
Gevorgyan, J. Org. Chem., 2002, 67, 95. (b) A. S. K. Hashmi, L. Schwarz, J. Choi, and T. M. Frost,
Angew. Chem. Int. Ed., 2000, 39, 2285. (c) J. A. Marshall and C. A. Sehon, J. Org. Chem., 1995, 60,
5966.
5. For recent examples of bromofuran synthesis, see: (a) A. W. Sromek, M. Rubina, and V. Gevorgyan,
J. Am. Chem. Soc., 2005, 127, 10500. (b) A. Sniady, K. A. Wheeler, and R. Dembinski, Org. Lett.,
2005, 7, 1769. (c) Y. Tanabe, K. Wakimura, Y. Nishii, and Y. Muroya, Synthesis, 1996, 388.
6. T. Eicher, S. Hauptmann, and A. Speicher, ‘The Chemistry of Heterocycles,’ 2nd ed., Wiley-VCH,
Weinheim, 2003, pp. 52-62.
7. M. Miyashita, M. Hoshino, and A. Yoshikoshi, J. Org. Chem., 1991, 56, 6483.
8. Recently, we found that the correct structure of the product formed by the reaction of 3 with
Me3Al-H2O is not originally assigned 5-hydroxy allenic ester,7 but the furan 4.
9. K. Ando, J. Org. Chem., 1997, 62, 1934.
10. The reaction without addition of water resulted in lower yield (<51%).

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11. K. Tago and H. Kogen, Org. Lett., 2000, 2, 1975.
12. Bromophosphonates 9/10 (5:1 mixture) were prepared by treatment of ethyl
bis(2,2,2-trifluoroethoxy)phosphonoacetate with NaH and Br(CH2)2Br in THF.
13. Preparation of 11 from 8 by the Olpp and Brückner method with diphenoxybromophosphonoacetate
resulted in lower E-selectivity of 11 (E/Z = 77:23); T. Olpp and R. Brückner, Synthesis, 2004, 2135.
14. To a solution of 11 (36.4 mg, 0.11 mmol) in CH2Cl2 (1.1 mL) were added H2O (1.2 µL, 0.66 mmol)
and then Me3Al (2.0 M solution in hexane, 0.55 mL, 1.1 mmol) at –30 °C, and the mixture was
vigorously stirred at the same temperature for 30 min. The reaction was quenched with aqueous
HCl (0.05 M) and the mixture was thoroughly extracted with Et2O. The combined organic layers
were washed with water, dried over MgSO4 and concentrated. The crude product was purified by
flash column chromatography on silica gel (hexane/EtOAc = 85:15) to give 13 (25.0 mg, 75%) as a
pale yellow oil.
15. The reactive species generated from Me3Al and (CF3)2CHOH is probably Me2AlOCH(CF3)2
(dimethyl(1,1,1,3,3,3-hexafluoro-2-propanolato)aluminum.
16. When the ratio of Me3Al and (CF3)2CHOH was changed in 3:1, 3:2, 1:1, and 1:2, 14 was obtained
in 76%, 92%, 77%, and <20% yield, respectively.
17. (CF3)2CHOH (21 µL, 0.20 mmol) was added dropwise to a solution of Me3Al (a 2.0 M solution in
hexane, 0.15 mL, 0.30 mmol) in hexane (0.3 mL) at 0 °C. After being stirred at the same
temperature for 10 min, a solution of 11 (35.5 mg, 0.10 mmol) in hexane-CH2Cl2 (14:1, 0.75 mL)
was added. After stirring was continued at 0 °C for 15 min, the reaction mixture was treated with
saturated Rochelle’s salt (aq.) and extracted with Et2O. The combined organic layers were dried
over MgSO4 and concentrated. The crude product was purified by flash column chromatography
on silica gel (hexane/EtOAc = 8:2) to give 14 (32.7 mg, 92%) as a pale yellow oil.
18. 17 was prepared in 92% yield from 14 (TESOTf, 2,6-lutidine, CH2Cl2, 0 °C).
19. Y. Fukuyama, Y. Kawashima, T. Miwa, and T. Tokoroyama, Synthesis, 1974, 443.