A convenient synthesis of highly substituted furans by microwave irradiation of ring-fused alkylidenecyclopropanes

Article abstract of DOI:10.1055/s-2004-830857

Microwave irradiation of ring-fused alkylidenecyclopropanes under solvent-free conditions afforded highly substituted furans in good yields.

Full text of DOI:10.1055/s-2004-830857

LETTER
1933
A Convenient Synthesis of Highly Substituted Furans by Microwave
Irradiation of Ring-Fused Alkylidenecyclopropanes
A
Convenient
S
ynthes
o
r
ubstitut
s
ed
F
uranshed Alam Chowdhury, Hisanori Senboku, Masao Tokuda*
Laboratory of Organic Synthesis, Division of Molecular Chemistry, Graduate School of Engineering, Hokkaido University,
Sapporo 060-8628, Japan
Fax +81(11)7064889; E-mail: tokuda@org-mc.eng.hokudai.ac.jp
Received 21 April 2004
ring-fused alkylidenecyclopropanes (bicyclo[n.1.0] alkyl-
idene derivatives)15 and their transformation to various
useful compounds.16 We also reported a stereoselective
preparation of 7-exo-amino-7-endo-substituted bicyc-
lo[4.1.0]heptanes.17 In this study, we attempted to prepare
highly substituted ring-fused furans 2 and 4 by microwave
irradiation of either ring-fused alkylidenecyclopropanes
1, 3 or 7-exo-morpholino-7-endo-substituted bicyc-
Abstract: Microwave irradiation of ring-fused alkylidenecyclopro-
panes under solvent-free conditions afforded highly substituted
furans in good yields.
Key words: microwave reaction, solvent-free, substituted furan,
ring-fused alkylidenecyclopropane, bicyclo[4.1.0]heptane deriva-
tive
lo[4.1.0]heptanes
(Scheme 1).
5
under solvent-free conditions
Furans can be found in many naturally occurring
compounds.1 Polysubstituted furans are present as a key
structural unit in many natural products and pharmaceuti-
cals.1b,2 Substituted furans are important intermediates
and building blocks in organic synthesis. There are many
strategies developed for the preparation of a multi-substi-
tuted furan ring.3,4 One of the simplest involves starting
with either furan itself or a mono-substituted furan fol-
lowed by the introduction of functional groups at various
positions around the furan ring. The introduction of func-
tional groups into the 3- and 4-positions is, however,
sometimes difficult since the direct lithiation of furan
rings followed by the reaction with electrophiles preferen-
tially occurs at the 2- or 5-position. Many synthetic meth-
ods for the preparation of substituted furans5 and one
mechanistic study on thermolysis of 1-cyclopropylidene-
2-propanone to give 2,4-dimethylfuran6 have been report-
ed. However, further synthetic development on thermo-
lysis of methylenecyclopropanes and solvent-free
approaches using microwave irradiation affording highly
substituted furans still remain unknown. Microwave-as-
sisted organic syntheses have attracted chemists recently7
because chemical transformations can be accelerated both
in solution and in solid phases. High yields of highly pure
products are reached within a short time. There is an in-
creasing interest in the use of environmentally benign
conditions, particularly solvent-free procedures.8 Avoid-
ing organic solvents during the reaction in organic synthe-
sis provides a clean, efficient and economical procedure,
and easy workup process. In addition, methylene- and
alkylidenecyclopropanes are highly strained but readily
accessible molecules that have served as useful building
blocks in organic synthesis.9–13 They have also been wide-
ly used for the syntheses of various heterocycles.14 Re-
cently, we reported a facile method for the preparation of
O
R1
R2
R1
MW, 5 min
R2
neat
( )n
1, 3
( )n
O
2, 4
neat
MW, 9 min
1-2 (n=1)
3-4 (n=2)
R2
R1
O
R2COCH2
a
b
c
d
e
H
H
CH3
C6H5
N
CH3 CH3
CH3 C6H5
H
p-Br-C6H4
5a; R2=CH3
5b; R2=C6H5
Scheme 1
The results of the transformations of 1a into furan 2a un-
der various conditions, including microwave irradiation,
are summarized in Table 1. Conventional heating of 1a in
o-xylene for five hours gave furan 2a only in 33% yield,
and 60% of 1a was recovered (entry 1). On the other hand,
ten minutes microwave irradiation of 1a in o-xylene re-
sulted in a quantitative recovery of 1a (entry 2), while a
similar microwave reaction in DMSO instead of o-xylene
gave 2a in 20% yield, along with 75% of 1a (entry 3). We
next tried to use a solid support such as acidic alumina,18
silica gel19 or bentonite.20 Microwave irradiation of 1a im-
pregnated onto the solid support for five minutes yielded
no products and most of the substrate 1a was recovered
(entries 4–6). Next, we carried out microwave irradiation
of the substrate 1a under a solvent-free condition for three
minutes at 200 °C and surprisingly obtained the furan de-
rivative 2a in 60% isolated yield along with 35% recovery
of 1a (entry 7). When the irradiation time was increased
SYNLETT 2004, No. 11, pp 1933–1936
0
6
.0
9
.2
0
0
4
Advanced online publication: 28.07.2004
DOI: 10.1055/s-2004-830857; Art ID: U11704ST
© Georg Thieme Verlag Stuttgart · New York

1934
M. A. Chowdhury et al.
LETTER
to five minutes at the same temperature, 2a was isolated Table 2 Microwave Irradiation of Bicyclo[4.1.0]heptylidene
Derivativesa
in 78% yield and a trace of 1a was observed (entry 8).
However, upon further increase of irradiation time to six
minutes at the same temperature, there remained no sub-
O
R1
R2
strate 1a but the product yield was lower (75%), presum-
ably due to the decomposition of 2a (entry 9). On the other
hand, conventional heating of 1a at 200 °C under solvent-
free conditions resulted in a quantitative recovery of 1a
(entry 10). These results indicate that five minutes micro-
wave irradiation of 1a under solvent-free conditions was
required to obtain the maximum product yield. Therefore,
we decided to carry out the microwave irradiation of all
ring-fused alkylidenecyclopropanes (bicyclo[n.1.0]alkyl-
idene derivatives) 1 and 3 for five minutes under solvent-
free conditions.21
R1
MW, 5 min
neat
R2
O
2
1
Entry
Substrate
R1
H
R2
Product yield (%)b
1c
2c
3
1a
1b
1c
1d
1e
CH3
C6H5
CH3
C6H5
2a (78)
2b (61)
2c (63)
2d (80)
H
CH3
CH3
H
Table 1 Optimization of Reaction Conditions under Microwave
4
Irradiationa
5
p-Br-C6H4 2e (63)
Entry Condition
Reaction time Yield of 2a Recovery of 1a
a Compound 1 (300 mg) was used in all the reactions. General
experiment is given in ref.21
(min)
300
10
10
5
(%)b
33
–
(%)
b Isolated yields are shown in parentheses.
c Irradiation was carried out at 200 °C.
1
2
o-Xylenec
60
o-Xylened
100
75
nyl-5,6,7,8-tetrahydro-4H-cyclohepta[b]furan (2d) in
63% and 80% isolated yields, respectively (entries 3, 4).
We also succeeded to prepare 2-(p-bromophenyl)-5,6,7,8-
tetrahydro-4H-cyclohepta[b]furan (2e) in good isolated
yield (entry 5). When 1a or 1b was irradiated under mi-
crowave without temperature control, the yield of 2a or 2b
was decreased, probably due to the decomposition of the
product. Microwave irradiation of alkylidenecyclopro-
panes 1c–e required no temperature control to obtain the
products 2c–e.
3
DMSOd
20
–
4
Acidic aluminae
Silica gele
95
5
5
–
98
6
Bentonitee
5
–
94
7
Solvent-freef
Solvent-freef
Solvent-freef
Solvent-freeg
3
60
78
75
0
35
8
5
Trace
–
9
6
We also carried out the microwave irradiation of bicyc-
lo[5.1.0]octylidene derivatives 3 in a similar fashion and
isolated ring-fused furans 4 in good yields. The results are
summarized in Table 3. Irradiation of 3a and 3b at 200 °C
for five minutes afforded 2-methyl-4,5,6,7,8,9-hexahy-
drocycloocta[b]furan (4a) and 2-phenyl-4,5,6,7,8,9-
hexahydrocycloocta[b]furan (4b) in 55% and 59% isolat-
ed yields, respectively (entries 1, 2). Similarly, 3c and 3d
10
300
100
a Compound 1a (300 mg) was used in all the reactions. The general
experimental procedure is given in ref.21
b Isolated yields.
c Solvent (5 mL) was used and heated under reflux temperature using
an oil bath.
d Solvent (5 mL) was used and irradiated under microwave at reflux
temperature.
e Solid support (100 mg), 1 (300 mg) and CH2Cl2 (5 mL) was stirred
for few minutes at r.t. and then evaporated the solvent thoroughly in
vacuo prior to microwave irradiation.
afforded
2,3-dimethyl-4,5,6,7,8,9-hexahydrocyclo-
octa[b]furan (4c) and 3-methyl-2-phenyl-4,5,6,7,8,9-
hexahydrocycloocta[b]furan (4d) in 61% and 73% isolat-
ed yields, respectively (entries 3 and 4).
f Irradiated at 200 °C.
g Heated at 200 °C without microwave irradiation.
Irradiation of 3e also afforded 2-(p-bromophenyl)-
4,5,6,7,8,9-hexahydrocycloocta[b]furan (4e) in good iso-
lated yield (entry 5). Microwave irradiation of alkyl-
idenecyclopropanes 3c–e required no temperature control
to obtain the furan derivatives 4c–e.
Microwave irradiation of bicyclo[4.1.0]heptylidene de-
rivatives 1 under solvent-free conditions for five minutes
afforded ring-fused furans 2 in good yields. The results
are summarized in Table 2.
We were also able to prepare furans by using 7-exo-mor-
pholino-7-endo-substituted bicyclo[4.1.0]heptanes 5.
Alkylidenecyclopropanes were formed as an intermediate
products during the synthesis of 7-exo-amino-7-endo-sub-
stituted bicyclo[4.1.0]heptanes 5.15,17 Therefore, under
microwave irradiation, 7-exo-morpholino-7-endo-substi-
tuted bicyclo[4.1.0]heptanes 5 also gave ring-fused furans
Methyl- and phenyl ketones 1a and 1b under microwave
irradiation at 200 °C for five minutes afforded 2-methyl-
5,6,7,8-tetrahydro-4H-cyclohepta[b]furan (2a) and 2-
phenyl-5,6,7,8-tetrahydro-4H-cyclohepta[b]furan (2b) in
78% and 61% isolated yields, respectively (entries 1 and
2). Similarly, 1c and 1d afforded 2,3-dimethyl-5,6,7,8-tet-
rahydro-4H-cyclohepta[b]furan (2c) and 3-methyl-2-phe-
Synlett 2004, No. 11, 1933–1936 © Thieme Stuttgart · New York

LETTER
A Convenient Synthesis of Highly Substituted Furans
1935
Table 3 Microwave Irradiation of Bicyclo[5.1.0]octylidene
O
O
Derivativesa
H
R2COCH2
R2
N
O
R1
O
MW, 9 min
neat
R2
R1
N
H
MW, 5 min
5a; R2=CH3
5b; R2=C6H5
neat
R2
O
(65–70%)
3
4
Entry Substrate
R1
R2
Product yield (%)b
4a (55)
o-xylene
5a or 5b
1c
2c
3
3a
3b
3c
3d
3e
H
CH3
reflux, 12 h
(35–37%)
R2
O
H
C6H5
4b (59)
2a; R2=CH3
2b; R2=C6H5
CH3
CH3
H
CH3
4c (61)
Scheme 2
4
C6H5
4d (73)
5
p-Br-C6H4
4e (62)
a Compound 3 (300 mg) was used in all the reactions. The general
experimental procedure is given in ref.21
N
b Isolated yields are shown in parentheses.
O
c Irradiation was carried out at 200 °C.
toluene
reflux
6
in good yields (Scheme 2). Conventional heating of both
1-(7-morpholinobicyclo[4.1.0]hept-7-yl)-2-propanone
(5a) and 2-(7-morpholinobicyclo[4.1.0]hept-7-yl)ace-
tophenone (5b) required 12 hours reflux in o-xylene to
give 2a and 2b in 35% and 37% yields, respectively.
Whereas microwave irradiation of solid substrates 5a and
5b under solvent-free conditions required only nine min-
utes to obtain 2a and 2b in 65% and 70% isolated yields,
respectively. 7-exo-Morpholino-7-endo-substituted bicy-
clo[4.1.0]heptanes 5 required a little longer irradiation
time (nine minutes) compared to that of alkylidenecyclo-
propanes 1, 3 (five minutes) because in this case, 5 first
converted to alkylidenecyclopropanes by the elimination
of free morpholine and then formed furans. The elimina-
tion of morpholine is proven by the 1H NMR spectrum of
the irradiated crude reaction mixture, which shows two
peaks at d = 2.88 ppm (t, J = 4.62 Hz, 4 H) and d = 3.85
ppm (t, J = 4.62 Hz, 4 H), indicating the liberation of free
morpholine from 5.
O
BrCH2COCH3
8
7
CH3
10% H2SO4
heat
(10%)
H
O
MW, 5 min
CH3
200 °C, neat
(78%)
O
1a
2a
Scheme 3
lo[4.1.0]heptanes F under microwave irradiation elimi-
nates morpholine to give A which follows the same
pathways to furnish E (Scheme 4).
Acknowledgment
The structure of the furan derivatives 2 and 4 obtained by
microwave irradiation were confirmed by comparison
with an authentic sample 2a which was prepared in 10%
yield by using an independent route22 as shown in
Scheme 3. Enamine 6 was reacted with mono-bromoace-
tone 7 in refluxing toluene to give 8. Acidification with
10% H2SO4 and heating afforded furan 2a. NMR spectra
of authentic 2a were identical with that obtained by mi-
crowave irradiation.
This work was supported by a Grant-in-Aid for Scientific Research
from the Japan Society for the Promotion of Science (JSPS) (No.
02169). A JSPS postdoctoral fellowship to M. A. C. is gratefully
acknowledged.
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Microwave irradiation of ring-fused alkylidenecyclopro-
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inherent strain to give allyl type radical B which is reso-
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other hand, 7-exo-morpholino-7-endo-substituted bicyc-
Synlett 2004, No. 11, 1933–1936 © Thieme Stuttgart · New York

1936
M. A. Chowdhury et al.
LETTER
R2
R2
R1
R1
R1
R1
R2
R2
O
O
R1
O
O
MW, neat
R2
A
O
D
A
B
C
H
+
HN
HN
O
O
O
aromatization
R1
H
O
R2COCH2
R2COCH
N
N
R2
O
MW, neat
E
F
F
Scheme 4
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reaction apparatus, Model No. SMW-05, 650 W, Shikoku
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carried out with stirring for 5 min. After cooling to r.t., the
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Selected data of 3-methyl-2-phenyl-5,6,7,8-tetrahydro-4H-
cyclohepta[b]furan (2d): 1H NMR (270 MHz, CDCl3): d =
1.65–1.85 (m, 6 H), 2.13 (s, 3 H), 2.41 (t, J = 5.9 Hz, 2 H),
2.80 (t, J = 5.9 Hz, 2 H), 7.18 (t, J = 7.6 Hz, 1 H), 7.36 (t,
J = 7.6 Hz, 2 H), 7.57 (d, J = 8.3 Hz, 2 H). 13C NMR (67.5
MHz): d = 9.83, 23.67, 26.53, 28.49, 28.93, 30.82, 117.32,
123.24, 125.11, 125.94, 128.35, 132.26, 145.14, 152.22.
EIMS: m/z (rel. intensity) = 226 (100) [M+], 211 (11), 197
(18), 184 (11), 172 (28), 155 (6), 141 (6), 105 (7), 77 (8).
HRMS: m/z calcd for C16H18O: 226.1358. Found: 226.1351.
Selected data of 3-methyl-2-phenyl-4,5,6,7,8,9-
hexahydrocycloocta[b]furan (4d): 1H NMR (270 MHz,
CDCl3): d = 1.40–1.60 (m, 4 H), 1.60–1.80 (m, 4 H), 2.14 (s,
3 H), 2.50 (t, J = 6.3 Hz, 2 H), 2.79 (t, J = 6.3 Hz, 2 H), 7.18
(t, J = 7.6 Hz, 1 H), 7.36 (t, J = 7.6 Hz, 2 H), 7.59 (d, J = 7.3
Hz, 2 H). 13C NMR (67.5 MHz): d = 9.70, 21.53, 25.60,
25.81, 26.15, 27.97, 28.21, 116.92, 120.97, 124.89, 125.83,
128.35, 132.38, 145.76, 150.61. EIMS: m/z (rel. intensity) =
240 (100) [M+], 212 (58), 197 (30), 185 (42), 172 (23), 155
(11), 141 (14), 105 (21), 77 (26). HRMS: m/z calcd for
C17H20O: 240.1514. Found: 240.1511. Anal. Calcd for
C17H20O: C, 84.96; H, 8.39. Found: C, 85.02; H, 8.39.
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Synlett 2004, No. 11, 1933–1936 © Thieme Stuttgart · New York