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

EFFICIENTDERIVATIVESSYNTHETICVIAMETHODFOR

STEREOSELECTIVE

3-BROMOFURANCYCLIZATIONOF

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 75thbirthday.
‡ 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,
whilethereactionwith

Me3Al-(CF3)2CHOH

2-alkoxy-3-bromofuran derivative in high yield.

reagent

producedaThe 3-bromofuran obtained

was transformed into various functionalized furan derivatives.

Substituted furans not only constitute an important class of five-membered heterocycles which have beenfound in many natural products and important pharmaceuticals,1 but also they have been used as usefulbuilding 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-dicarbonylcompounds with α-haloketones (Feist-Bénary synthesis), and various substitution reactions on a furanring.

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 counterpartsfor coupling reactions as well as versatile synthetic intermediates for functionalized furans.

202

HETEROCYCLES, Vol. 77, No. 1, 2009Bromo-substituted furans are generally prepared by an electrophilic substitution reaction of furan
derivatives

withbromineatom(s),halogen-induced

cyclization,andcyclocondensationor

cycloisomerization of halogenated precursors.5 However, these methods often suffer from the following
synthetic limitations: (1) inaccessibility to cyclization precursors having halogen-sensitive functionalgroups; (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 thatallows 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, thereaction 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 ofγ,δ-epoxy-(Z)-acrylate 3 with Me3Al-H2O produced 2-ethoxyfuran 4 as the major product along with asmall amount of γ-methylated compound 5.8
mechanism shown in Scheme 1.

We assumed that 4 was probably formed via the reaction

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.
MeO

Me3Al-H2O

BnO

CO2Et CH Cl , –30 °C
2 2OH

1
CO2Et

O
BnO

CO2Et

BnO

2 (96%, d.s.> 99:1)

OH
Me3Al-H2O

MeO

BnO

CH2Cl2, –30 °C
3BnO

O

OEt

O
6LnAlOBnO
H+ BnOOH

4 (60%)
Ln
AlOEt

CO2Et

O

5 (18%)

OEt
7Scheme 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 toinvestigate synthetic potential of the Lewis acid-mediated cyclization of γ,δ-epoxy-(Z)-acrylates, sinceHETEROCYCLES, Vol. 77, No. 1, 2009203

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 suchas 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 witha bromine atom might enhance the reactivity of the cyclization reaction which would culminate in thesynthesis of 3-bromofurans. In expectation for this idea, we prepared trans-γ,δ−epoxy-(E)-α-bromoacrylate 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 asingle product in 75% isolated yield.14

Apparently, 13 was produced by way of an oxonium ion 12 witha 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.
9/10 (5:1) mixture
t-BuOK
18-crown-6

O
BnO

CHO

THF, –78 °C

8

Me3Al-H2O
CO2Et

O
BnO

CH2Cl2–30 °C

O

311 (80%) (E/Z = 96:4)
LnAlO
BnO
H
12OOEt2CF3CH2O Br RBr

BnO

9: R=H, 10: R=BrOHOBnOOEtBrBr
11O
CF CH O PCO2EtMe AlMe2O13 (75%)

MeBrOH
Me3Al-(CF3)2CHOH (3:2)

BnOOhexane/CH2Cl2 (20:1)–30 °C14 (92%)OEt
BrScheme 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 thedesired 3-bromo-2-ethoxyfuran 14 as a single product in high yield (Scheme 2).

It should be noted that204

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 groupon the side chain did not afford any bromofurans and, instead, bromo-substituted butenolide 16 wasobtained in 40% yield.

These results clearly suggest that chelation of the aluminum reagent by theoxygen atoms of the epoxide and the ether moiety plays critical roles for the formation of bromofurans.

PrCO2Et

OBr

Pr

complex mixture

CH2Cl2, –30 °C

15O

Me3Al-H2O

CO2Et

Me3Al-(CF3)2CHOH (3:2)

Brhexane, –30 °C

OOPr

1516 (40%)

Br

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, thereaction 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 apromising entry to a variety of 3-substituted furans which are inaccessible by known methods.

BnOOTESO

171717OEt

BuLi, THF
–78 °CBr
BuLi, THF
–78 °C

then D2O(>99%)

BnO

then MeI(90%)
BuLi, THF
–78 °C
then allyl bromide
(66%)

OTES
O

BnOOEt18 (90%D) D
OTESO

17Me19

BnO

OEt

OTES
O
20OEt

17BuLi, THF–78 °C

OTES
O

BnO

then TsCN(70%)
BuLi, THF
–78 °C

21

BnO

then PhCHO(63%)

Scheme 4. Conversion of 3-bromofuran 17 to various 3-substituted furans (18–22).

OTES
OOEt
CNOEt

* OH
Ph22 (1:1 mixture)HETEROCYCLES, Vol. 77, No. 1, 2009205

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 (aGrant-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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HETEROCYCLES, Vol. 77, No. 1, 2009

11. K. Tago and H. Kogen, Org. Lett., 2000, 2, 1975.
12. Bromophosphonates

9/10(5:1mixture)

werepreparedbytreatment

ofethylbis(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 wasvigorously stirred at the same temperature for 30 min.

The reaction was quenched with aqueousHCl (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 byflash column chromatography on silica gel (hexane/EtOAc = 85:15) to give 13 (25.0 mg, 75%) as apale 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 obtainedin 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 inhexane, 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 withsaturated Rochelle’s salt (aq.) and extracted with Et2O.
over MgSO4 and concentrated.

The combined organic layers were dried

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.