Efficient synthesis of functionalized furans and benzofurans based on a '[3+2] cyclization/oxidation' strategy

Article abstract of DOI:10.1016/j.tetlet.2005.02.040

Functionalized furans and benzofurans were prepared by DDQ oxidation of 2-alkylidenetetrahydrofurans, which are readily available by one-pot cyclizations of 1,3-dicarbonyl dianions or 1,3-bis-silyl enol ethers.

Full text of DOI:10.1016/j.tetlet.2005.02.040

Tetrahedron
Letters
Tetrahedron Letters 46(2005) 2185–2187
Efficient synthesis of functionalized furans and benzofurans
based on a Ô[3+2] cyclization/oxidationÕ strategy
a,b
Esen Bellur, Ilia Freifeld and Peter Langer
b
a,
*
a
Institut f u¨ r Chemie, Universit a¨ t Rostock, Albert-Einstein-Str. 3a, D-18051 Rostock, Germany
Institut f u¨ r Chemie und Biochemie, Universit a¨ t Greifswald, Soldmannstr. 16, D-17487 Greifswald, Germany
b
Received 9 January 2005; revised 6February 2005; accepted 8 February 2005
Abstract—Functionalized furans and benzofurans were prepared by DDQ oxidation of 2-alkylidenetetrahydrofurans, which are
readily available by one-pot cyclizations of 1,3-dicarbonyl dianions or 1,3-bis-silyl enol ethers.
Ó 2005 Elsevier Ltd. All rights reserved.
R2
O
Cl
Functionalized furans and benzofurans represent impor-
tant synthetic building blocks and are present in a vari-
ety of biologically relevant natural products, such as the
calicogorgins, furan fatty acids, cyctotoxic furanocem-
branes, gersolanes, pseudopteranes, rosefuran, agassi-
O
O
Br
O
R1
R1
R3 R2
i
R3
ref. 7
1a-k
2a-k
1
,2
zin, furodysin, mikanifuran or a-clausenan.
ii
R2
O
3
Although a variety of furan syntheses are known,
the development of new and convenient strategies is
of considerable interest. In the recent years, we
O
R1
R3
reported
a
-alkylidenetetrahydrofurans by [3+2] cyclization of free
number of one-pot syntheses of
3
a-k
2
and masked 1,3-dicarbonyl dianions with 1,2-dielectro-
Scheme 1. Synthesis of furans 3a–k. Reagents and conditions: (i): (1)
LDA (2.3 equiv), THF, 0 °C, 1 h, (2) ꢀ78 °C ! 20 °C, 14 h, (3) reflux,
4
philes. Herein, we wish to report a new and convenient
approach to functionalized furans and benzofurans
1
2 h; (ii): DDQ (2equiv), 1,4-dioxane, reflux, 48 h.
5
,6
based on a Ô[3+2] cyclization/oxidationÕ strategy.
Treatment of 2-alkylidenetetrahydrofuran 2a, prepared
by cyclization of the dianion 1a of methyl acetoacetate
Table 1. Optimization of the synthesis of 3b
a
7
a
Solvent
CH CN
THF
t [h]
Conditions
%
with 1-bromo-2-chloroethane, with 2,3-dichloro-5,6-
8
dicyano-1,4-quinone (DDQ) afforded the known furan
3
3
24
24
24
24
48
24
24
Reflux
Reflux
20 °C
0
17
0
a (Scheme 1). Optimal results were obtained when an
excess of DDQ was employed (2 equiv) and when the
reaction was carried out in 1,4-dioxane under reflux
Dioxane
Dioxane
Dioxane
Toluene
Reflux
Reflux
Reflux
Reflux
34
75
12
5
9
for 48 h. The use of other solvents, oxidizing agents
(
MnO ) and conditions proved less effective in terms
2
2 2
CH Cl
of yield (Table 1). The formation of 3a can be explained
by oxidation and subsequent aromatization by migra-
tion of the exocyclic double bond.
a
1
Conversion (by H NMR of the crude product).
The preparative scope of our methodology was studied
Table 2). The synthesis of 2-alkylidenetetrahydrofurans
(
Keywords: Benzofurans;
Tetrahydrofurans.
Cyclization;
Furans;
Oxidation;
7
2a,b and 2d–j has been previously reported. The furans
*
0
Corresponding author. Tel.: +49 381 4986410; fax: +49 381
986412; e-mail: peter.langer@uni-rostock.de
3b–d were prepared from 2b–d, containing ethyl, iso-
propyl and tert-butyl ester groups, respectively. The
4
040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.040

2186
E. Bellur et al. / Tetrahedron Letters 46 (2005) 2185–2187
Table 2. Products and yields
Me3SiO
OSiMe3
R1
OMe
O
O
1
R
2
R
3
a,b
a
MeO
2,3
R
% (2)
% (3)
Cl
R1
MeO
a
b
c
d
e
f
OMe
OEt
H
H
65
75
70
74
68
80
48
91
64
61
57
57
59
52
55
41
53
54
67
51
55
80
R4
R2
R4
R2
i, ii
H
H
R3
a-e
R3
OiPr
OtBu
OMe
OEt
H
H
ref. 10
H
H
7
8a-e
H
Me
Et
O
O
iii
H
R1
g
h
i
OtBu
OtBu
OEt
H
(CH
(CH
H
2
)
)
2
6
3 2
CH(CH )
Cl
H
2
R4
R2
Me
Et
–(CH
R3
9a-e
j
OEt
OEt
H
k
2 9
) –
a
Isolated yields.
See Ref. 7.
Scheme 3. Synthesis of benzofurans 9a–e. Reagents and conditions:
i): Me SiOTf (0.5 equiv), CH Cl
b
(
3
2
2
, ꢀ78 °C ! 20 °C; (ii): 2.0 equiv
DBU, THF, 20 °C; (iii): DDQ (2 equiv), 1,4-dioxane, reflux, 24 h.
oxidation of 2-alkylidenetetrahydrofurans 2e–g, pre-
pared by cyclization of the corresponding 1,3-dicarbonyl
dianions with 1-bromo-2-chloroethane, afforded the
furans 3e–g. The oxidation of chloro-substituted 2-
alkylidenetetrahydrofuran 2h, prepared from dilithiated
tert-butyl 10-chloro-3-oxodecanoate (1h), afforded the
corresponding furan 3h. The oxidation of 2-
alkylidenetetrahydrofurans 2i,j, prepared from ethyl 2-
methylacetoacetate and ethyl 2-ethylacetoacetate, gave
the methyl and ethyl substituted furans 3i,j. The cycliza-
tion of the dianion of ethyl 2-oxo-cyclododecanecarb-
oxylate with 1-bromo-2-chloroethane afforded the
novel 5,12-bicyclic 2-alkylidenetetrahydrofuran 2k.
Treatment of the latter with DDQ gave the furan 3k.
Table 3. Products and yields
1
R
2
R
3
4
a,b
a
8,9
R
R
% (8)
% (9)
a
b
c
d
e
OEt
OEt
OMe
OEt
OEt
H
H
H
38
71
90
85
60
53
c
Me
H
H
H
75
53
Me
Ph
H
H
c
H
H
Me
66
62
H
a
b
c
Isolated yields.
Yields over two steps (see Ref. 10).
Prepared in two steps: (1) dioxane, reflux, (2) DDQ, dioxane, reflux.
1
0
8a,d,e has been previously reported. Treatment of
the latter with DDQ resulted in formation of the 2,3-
unsubstituted benzofurans 9a–e by thermal elimination
of methanol and oxidation of the cyclohexene moiety
(Scheme 3, Table 3).
0
The 2,3 -bifuranylidenes 5a,b were prepared, according
7
to our recently reported methodology, by cyclization of
dilithiated a-acetyl-c-butyrolactones 4a,b with 1-bromo-
2
-chloroethane (Scheme 2). The synthesis of 5a has
7
been previously reported. Treatment of 5a,b with
DDQ afforded the furans 6a,b. The formation of 6a,b
can be explained by oxidation of both the tetrahydro-
furan and the lactone moiety. The employment of only
one (rather than two) equivalents of DDQ resulted in
the formation of a complex mixture.
A second approach was developed, which allows an effi-
cient synthesis of 2-substituted benzofurans: The cycli-
zation of 1,3-bis-silyl enol ethers 7a,c,d with propen-
oxide and epibromohydrin afforded the 5,6-bicyclic
2-alkylidenetetrahydrofurans 10a–d as a mixture of dia-
stereomers. These transformations represent the first
examples of cyclizations of cycloalkanone-derived 1,3-
bis-silyl enol ethers with epoxides. The oxidation of
10a–d with DDQ afforded the benzofurans 11a–d
(Scheme 4, Table 4).
1
1
The cyclization of cyclic 1,3-bis-silyl enol ethers 7a–e
with 1-chloro-2,2-dimethoxyethane afforded, following
1
0
our recently reported methodology, the 5,6-bicyclic
-alkylidenetetrahydrofurans 8a–e. The synthesis of
2
R3
Me3SiO
OSiMe3
R1
O
O
O
O
O
R
Br
R3
Cl
O
R1
O
R
O
i
i
R2
O
R2
ref. 7
4
a,b
5
5
a (R = H): 58%
b (R = Me): 60%
7
a,c,d
R3
10a-d
ii
ii
R
O
O
O
R1
O
O
R2
11a-d
6
6
a (R = H): 56%
b (R = Me): 48%
˚
4
(2 equiv), 4 A
Scheme 2. Synthesis of furans 6a,b. Reagents and conditions: (i): (1)
LDA (2.3 equiv), THF, 0 °C, 1 h, (2) ꢀ78 °C ! 20 °C, 14 h, (3) reflux,
Scheme 4. Synthesis of benzofurans 11a–d. (i): TiCl
MS, CH Cl
, ꢀ78 °C ! 20 °C, 14 h, 20 °C, 2 h; (ii): DDQ (2 equiv),
1,4-dioxane, reflux, 24–48 h.
2
2
1
2 h; (ii): DDQ (2 equiv), 1,4-dioxane, reflux, 48 h.

E. Bellur et al. / Tetrahedron Letters 46 (2005) 2185–2187
2187
Table 4. Products and yields
Schnapper, M.; Powers, M.; Woodward, R.; Rodriguez,
W.; Golec, S.; Studt, W.; Dodson, S. A.; Fitzpatrick, L.
R.; Pendley, C. E.; Martin, G. E. J. Med. Chem. 1992, 35,
1
R
2
R
3
a
a
10,11
R
% (10)
% (11)
a
b
c
OEt
H
Me
Me
Me
CH
28
30
32
37
60
65
63
9
03; for the oxidation of tetrahydrofurans to furans and
hexahydrobenzofurans to benzofurans, see for example:
b) B u¨ chi, G.; Chu, P.-S. J. Org. Chem. 1978, 43, 3717; (c)
OMe
OMe
OMe
Me
Ph
Ph
(
b
d
2
Br
31
Brewer, J. D.; Elix, J. A. Aust. J. Chem. 1975, 28, 1059.
. For isomerizations of bis-enol ethers into furans, see: (a)
Babidge, P. J.; Massy-Westropp, R. A. Aust. J. Chem.
1977, 30, 1629; (b) Carvalho, C. F.; Sargent, M. V. J.
Chem. Soc., Perkin 1 1984, 1605.
a
6
Isolated yields.
Besides, the corresponding 2,3-dihydrobenzofuran was isolated in
0% yield.
b
4
7
. (a) Langer, P.; Holtz, E.; Karim e´ , I.; Saleh, N. N. R. J.
Org. Chem. 2001, 66, 6057; (b) Langer, P.; Bellur, E. J.
Org. Chem. 2003, 68, 9742.
In summary, we have reported a new and efficient ap-
proach to a variety of furans and benzofurans based
on a [3+2] cyclization/oxidation strategy.
8
. (a) Kawano, T.; Ogawa, T.; Islam, S.; Ueda, I. Hetero-
cycles 2000, 52, 1279; (b) Wenkert, E.; Guo, M.; Lavilla,
R.; Porter, B.; Ramachandran, K.; Sheu, J.-H. J. Org.
Chem. 1990, 55, 6203; (c) Al-Awadi, N. A.; Al-Bashin, R.
F.; El-Dusouqui, O. M. E. Tetrahedron Lett. 1989, 30,
Acknowledgements
Financial support from the DAAD (scholarship for
E.B.) and the Deutsche Forschungsgemeinschaft is
gratefully acknowledged.
1
699; (d) Piotti, M. E.; Alper, H. J. Org. Chem. 1997, 62,
8484; (e) Kozikowski, A. P.; Li, C.-S. J. Org. Chem. 1985,
59, 778; (f) Ryan, J. F.; Plucker, J., III. J. Am. Chem. Soc.
1
. Representative experimental procedure: To a 1,4-dioxane
940, 62, 2037.
9
References and notes
solution (10 mL) of 2d (0.100 g, 0.54 mmol) was added
2
,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) (0.246g,
1
. (a) R o¨ mpp Lexikon Naturstoffe; Steglich, W., Fugmann,
B., Lang-Fugmann, S., Eds.; Thieme: Stuttgart, 1997; for
furan natural products, see Refs. 1–11 in: (b) Bach, T.;
Kr u¨ ger, L. Eur. J. Org. Chem. 1999, 2045.
. For reviews of furan syntheses, see: (a) Friedrichsen, W. In
Comprehensive Heterocyclic Chemistry; Katritzky, A. R.,
Rees, C. W., Scriven, E. F. V., Eds.; Elsevier: Oxford,
1.09 mmol) under Argon atmosphere at 20 °C. The
mixture was heated for 48 h at reflux and, after cooling,
the solvent was removed in vacuo. To the residue was
added diethylether to give a precipitate which was filtered
off. The filtrate was concentrated in vacuo and the residue
was purified by column chromatography (silica gel, n-
hexane/EtOAc = 100:1 ! 50:1) to give 3d as a slight
2
1
996; Vol. 2, pp 359–363, and references cited therein; (b)
yellow oil (0.054 g, 55%); R = 0.77 (n-hexane/
f
1
K o¨ nig, B. In Science of Synthesis; Thieme: Stuttgart, 2001;
Vol. 9, pp 183–285.
. (a) Marshall, J. A.; Robinson, E. D. J. Org. Chem. 1990,
EtOAc = 5:1). H NMR (CDCl , 300 MHz): d = 1.46(s,
3
9H, OtBu), 3.59 (s, 2H, CH ), 6.20 (dt, J = 3.3, 0.9 Hz, 1H,
CH), 6.33 (dd, J = 3.3, 1.8 Hz, 1H, CH), 7.36(dd, J = 1.8,
2
3
1
3
55, 3450; (b) Marshall, J. A.; Wang, X. J. Org. Chem.
1991, 56, 960; (c) Marshall, J. A.; Wang, X. J. Org. Chem.
1992, 57, 3387; (d) Marshall, J. A.; DuBay, W. J. J. Org.
0.9 Hz, 1H, CH).
C NMR (CDCl3, 150 MHz):
d = 28.21 (CH ), 35.49 (CH ), 81.54 (C), 107.86, 110.63,
c
3
2
142.06 (CH), 148.64 (C), 168.90 (O@C–O). IR (neat,
ꢀ
1
Chem. 1993, 58, 3602; (e) Marshall, J. A.; Bartley, G. S. J.
Org. Chem. 1994, 59, 7169; (f) Marshall, J. A.; Sehon, C.
A. J. Org. Chem. 1995, 60, 5966; (g) Hashmi, A. S. K.;
Ruppero, T. L.; Kn o¨ fel, T.; Bats, J. W. J. Org. Chem.
cm ): ~m ¼ 2980 (w, C–H), 1739 (s, O@C–O), 1394 (w),
1370 (m), 1340 (w), 1279 (w), 1255 (w), 1234 (m), 1152 (s),
1096(w), 1013 (w), 734 (w). MS (EI, 70 eV): m/z (%) = 183
+
(M , 13), 123 (20), 116(100), 108 (8), 101 (48), 81 (65). The
exact molecular mass m/z = 182.0943 ± 2 ppm [M ] for
+
1
997, 62, 7295; (h) Gabriele, B.; Salerno, G.; De Pascali,
F.; Costa, M.; Chiusoli, G. P. J. Org. Chem. 1999, 64,
693; (i) Sperry, J. B.; Whitehead, C. R.; Ghiviriga, I.;
Walczak, R. M.; Wright, D. L. J. Org. Chem. 2004, 69,
726; (j) Aso, M.; Ojida, A.; Yang, G.; Cha, O.-J.; Osawa,
C H O was confirmed by HRMS (EI, 70 eV). All
3
1
0
14
7
products gave satisfactory spectroscopic data and correct
elemental analyses and/or high resolution mass data.
3
10. (a) Langer, P.; Krummel, T. Chem. Eur. J. 2001, 7, 1720;
for the formation of furans by elimination of methanol
from 2-alkylidene-4-methoxytetrahydrofurans, see: (b)
Bellur, E.; G o¨ rls, H.; Langer, P. Eur. J. Org. Chem., in
press.
11. For reactions of 1,3-bis-silyl enol ethers with epoxides, see:
Langer, P.; Armbrust, H.; Eckardt, T.; Magull, J. Chem.
Eur. J. 2002, 8, 1443.
E.; Kanematsu, K. J. Org. Chem. 1993, 58, 3960.
. For reviews of cyclization reactions of free and masked
dianions, see: (a) Langer, P. Chem. Eur. J. 2001, 7, 3858;
4
5
(b) Langer, P. Synthesis 2002, 441; (c) Langer, P.;
Freiberg, W. Chem. Rev. 2004, 104, 4125.
. For oxidations of benzo-2,3-dihydrofurans, see: (a) You-
ssefyeh, R. D.; Campbell, H. F.; Airey, J. E.; Klein, S.;