Facile one-pot synthesis of di- and tri-substituted furans from acyl isocyanates using trimethylsilyldiazomethane

Article abstract of DOI:10.1055/s-2004-822397

The Diels-Alder reaction of 2-substituted 4-(trimethylsilyloxy)oxazoles, which were prepared in situ from trimethylsilyldiazomethane and acyl isocyanates, with dimethyl acetylenedicarboxylate or ethyl propiolate gave furan-3,4-dicarboxylic or furan-3-carboxylic esters in good yields.

Full text of DOI:10.1055/s-2004-822397

PAPER
1359
Facile One-Pot Synthesis of Di- and Tri-Substituted Furans From Acyl Isocya-
nates Using Trimethylsilyldiazomethane
O
ne-Pot Synthesis
o
of Substitute
s
d
Furans hiyuki Hari, Tomoe Iguchi, Toyohiko Aoyama*
Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan
Fax +81(52)8363439; E-mail: aoyama@phar.nagoya-cu.ac.jp
Received 2 May 2004
TMSCHN2
(1.2 equiv)
O
Abstract: The Diels–Alder reaction of 2-substituted 4-(trimethyl-
silyloxy)oxazoles, which were prepared in situ from trimethylsilyl-
O
N
N
Solvent
Temperature
0.5 h
Ph
NCO
Ph
Ph
TMS
diazomethane
and
acyl
isocyanates,
with
dimethyl
O
2a
acetylenedicarboxylate or ethyl propiolate gave furan-3,4-dicarbox-
ylic or furan-3-carboxylic esters in good yields.
1a
Key words: acyl isocyanates, Diels–Alder reaction, furans, ox-
azoles, trimethylsilyldiazomethane
O
OTMS
H2O
N
Ph
O
O
4a
3a
2-Substituted oxazol-4-ones are useful not only as sub-
strates for the synthesis of multi-substituted oxazoles but
also as Diels–Alder heterodienes.1,2 They are generally
prepared by the reaction of acyl isocyanate with diazo-
methane (CH2N2)1,3 or the base-promoted cyclization of
N-chloroacetylamides,4 in which the former method
would be superior because of the generality of the meth-
od.1 However, CH2N2 is notorious as a highly toxic and
explosive gas.5
Scheme 1
Brook rearrangement to afford the 4-trimethylsiloxyox-
azole 3a. The oxazole 3a is very sensitive to moisture and
is hydrolyzed to the oxazolone 4a during work-up.
We thought that the oxazole 3a could be trapped by appro-
priate dienophiles if 3a acts as a heterodiene of the Diels–
Alder reaction.8 In fact, treatment of 3a, generated in situ,
with dimethyl acetylenedicarboxylate (DMAD) in MeCN
at room temperature gave the desired trisubstituted furan
6a in moderate yield (Scheme 2 and entry 1 in Table 2).
Raising the reaction temperature to reflux showed a re-
markable increase in the yield (84%) (entry 2). The obvi-
ous intermediate will be the cycloaddact 5 which will
spontaneously lose trimethylsilyl cyanate to give the furan
6. Under the same conditions, various aliphatic acyl iso-
cyanates 1 bearing a primary, secondary, and tertiary alkyl
We have already demonstrated that trimethylsilyldiazo-
methane (TMSCHN2), as a safe reagent for hazardous
CH2N2, is quite useful as a reagent for introducing a C1
unit, a [C–N–N]azole synthon, and an alkylidene carbene
generator.6,7 Our continued interest in the use of
TMSCHN2 in organic synthesis has led us to investigate
the reaction of TMSCHN2 with acyl isocyanates.
Initially, TMSCHN2 was allowed to react with benzoyl
isocyanate (1a) in THF at room temperature for 30 min-
utes, as shown in Scheme 1 and Table 1. Purification of
the crude product by silica gel column chromatography
gave the oxazolone 4a3 in 61% yield, and no 5-trimethyl-
silyloxazolone 2a or 4-trimethylsiloxyoxazole 3a could
be detected (entry 1). After screening of the reaction sol-
vent under similar reaction conditions, both Et2O and
MeCN gave good results in 72% yield, respectively (en-
tries 1–5 and 7). Furthermore, the reaction was carried out
at 0 °C in MeCN to afford 4a in 93% yield (entry 8). In
this reaction, the 1H NMR spectrum of the reaction mix-
ture showed the signal of the methyl protons of the TMSO
group at 0.31 ppm as a singlet in addition to the signal of
an olefinic proton at 7.31 ppm, characteristic of the 4-tri-
methylsiloxyoxazole structure. These data indicated the
reaction of TMSCHN2 with 1a would first give the 5-tri-
methylsilyloxazolone 4a, which immediately undergoes
Table 1 Synthesis of 2-Phenyl-4-oxazolone (4a)
Entry
Solvent
THF
Temperature
Yield (%)a
1
r.t.
61
33
65
65
72
51
72
93
74
2
AcOEt
CH2Cl2
Toluene
Et2O
r.t.
3
r.t.
4
r.t.
5
r.t.
6
Et2O
0 °C
r.t.
7
MeCN
MeCN
MeCN
8
0 °C
–20 °C
9
SYNTHESIS 2004, No. 9, pp 1359–1362
x
x
.
x
x
.2
0
0
4
a Isolated yield.
Advanced online publication: 08.06.2004
DOI: 10.1055/s-2004-822397; Art ID: C03604SS
© Georg Thieme Verlag Stuttgart · New York

1360
Y. Hari et al.
PAPER
group were also smoothly converted to the corresponding Finally, the synthesis of disubstituted furans using ethyl
furans 6 in good yields (entries 3–6). Moreover, 2-furoyl propiolate was examined as shown in Scheme 4 and
isocyanate (1f), a heteroaromatic one, also underwent the Table 3. Under the same conditions as the reaction using
reaction to give the 2,2¢-bifuryl derivative 6f in high yield DMAD (Table 2, entry 2), treatment of 3a, generated in
(entry 7).
situ, with ethyl propiolate gave a mixture of the furan 8a
and its regioisomer 9a with high regioselectivity (8a:9a >
20:1), though the yield was low (entry 1). Changing the
reaction solvent from MeCN to toluene or xylene led to a
significant improvement in the yield without loss of the
selectivity (entries 2 and 3). Other substrates 1b,c,e also
gave the corresponding furans 8b,c,e and 9b,c,e in moder-
ate yields with good selectivity (entries 4–6). In contrast
to DMAD and ethyl propiolate, phenylacetylene was inac-
tive under the reaction conditions. The observed high se-
lectivity of the addition would be explained by interaction
between a nucleophilic C-5 of 3 and an electrophilic ter-
minal carbon of ethyl propiolate.
OTMS
TMSCHN2
(1.2 equiv)
O
N
MeCN
0 °C, 0.5 h
R
NCO
R
O
1
3
DMAD (2.0 equiv)
see Table 2
MeO2C
R
CO2Me
O
TMSO
N
CO2Me
CO2Me
–TMSOCN
O
R
5
6
Scheme 2
EtO2C
i) TMSCHN2 (1.2 equiv), MeCN
0 °C, 0.5 h
O
Table 2 Diels–Alder Reaction with Dimethyl Acetylenedicarboxy-
late
8
R
R
NCO
O
ii) ethyl propiolate (2.0 equiv), reflux
see Table 3
1
and
Entry
R
Temperature Time (h)
Yield (%)a
6a (68)
6a (84)
6b (76)
6c (73)
6d (77)
6e (65)
6f (83)
CO2Et
1
2
3
4
5
6
7
Ph (1a)
r.t.
24
11
11
11
14
11
11
9
R
O
Ph (1a)
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Scheme 4
Table 3 Diels–Alder Reaction with Ethyl Propiolate
t-Bu (1b)
Cyclohexyl (1c)
Bn (1d)
Entry Substrate Solvent
Time (h)
11
Yield (%)a 8:9b
n-Pentyl (1e)
2-Furyl (1f)
1
2
3
4
5
6
1a
1a
1a
1b
1c
1e
MeCN
38
81
79
57
60
64
> 20:1
Toluene
Xylene
Toluene
Toluene
Toluene
12
> 20:1
20:1
6:1
a Isolated yield.
12
12
Next, we examined the one-pot synthesis of 6 from
amides, precursor of acyl isocyanates. As shown in
Scheme 3, successive treatment of p-methoxybenzamide
(7g) with oxalyl chloride (preparation of acyl isocyanate),
followed with TMSCHN2, and then with DMAD in one-
pot gave the furan 6g in good yield. The presence of an
electron-withdrawing group, such as a chlorine atom, on
the benzene ring of 7 did not affect the reaction and the de-
sired 6h was obtained in good yield.
13
13:1
11:1
12
a Isolated yield.
b The ratio of regiomers 8 and 9 was determined by 1H NMR measure-
ments.
In conclusion, we have succeeded in a facile one-pot syn-
thesis of di- and tri-substituted furans from acyl isocyan-
ates using TMSCHN2.
O
R = p-MeOPh (7g)
p-ClPh (7h)
R
NH2
i) (COCl)2 (excess), (CH2Cl)2, reflux, 24 h
ii) evaporation
iii) TMSCHN2 (1.2 equiv), MeCN, 0 °C, 0.5 h
iv) DMAD (2.0 equiv), reflux, 11-14 h
Synthesis of 2-Phenyl-4-oxazolone 4a: The Synthetic Procedure
Shown in Entry 8 of Table 1
To a solution of benzoyl isocyanate (1a) (108 mg, 0.73 mmol) in
MeCN (5 mL), TMSCHN2 (2.40 M in hexane solution, 0.37 mL,
0.89 mmol) was added at 0 °C under Ar. After being stirred for 0.5
h, the reaction solvent was removed in vacuo. The residue was pu-
rified by flash column chromatography (Fuji Silysia PSQ 60B, hex-
ane–EtOAc, 5:1) to give 2-phenyl-4-oxazolone (4a,3 109 mg, 93%).
MeO2C
R
CO2Me
R = p-MeOPh (6g), 62%
p-ClPh (6h), 75%
O
Scheme 3
Synthesis 2004, No. 9, 1359–1362 © Thieme Stuttgart · New York

PAPER
One-Pot Synthesis of Substituted Furans
1361
Synthesis of 2-Substituted Dimethyl Furan-3,4-dicarboxylates:
The Synthetic Procedure Shown in Entry 2 of Table 2
Synthesis of Ethyl 2-Substituted Furan-3-carboxylates and
Their Regioisomers; Typical Procedure; The Synthetic Proce-
dure Shown in Entry 2 of Table 3
To a solution of benzoyl isocyanate (1a) (135 mg, 0.91 mmol) in
MeCN (5 mL), TMSCHN2 (1.67 M in hexane solution, 0.66 mL,
1.10 mmol) was added at 0 °C under Ar. After being stirred for 0.5
h, DMAD (0.13 mL, 1.09 mmol) was added and the mixture was re-
fluxed for 11 h. After the reaction solvent was removed in vacuo,
the residue was purified by flash column chromatography (Fuji Sil-
ysia PSQ 60B, hexane–EtOAc, 10:1) to give dimethyl 2-phenylfu-
ran-3,4-dicarboxylate (6a,2a 200 mg, 84%).
To a solution of benzoyl isocyanate (1a) (149 mg, 1.01 mmol) in
MeCN (5 mL), TMSCHN2 (1.67 M in hexane solution, 0.73 mL,
1.21 mmol) was added at 0 °C under Ar. After stirring for 0.5 h,
MeCN was removed in vacuo under moisture-free conditions.
Then, toluene (5 mL) and ethyl propiolate (0.20 mL, 2.02 mmol)
were added under argon and the mixture was refluxed for 12 h. Af-
ter the reaction solvent was removed in vacuo, the residue was pu-
rified by flash column chromatography (Fuji Silysia BW 200,
hexane–EtOAc, 30:1) to give a mixture of ethyl 2-phenylfuran-3-
carboxylate (8a)10 and its regioisomer 9a11 (176 mg, 81%, 8a:9a
>20:1).
Dimethyl 2-tert-Butylfuran-3,4-dicarboxylate (6b)
1H NMR (CDCl3, TMS): d = 1.32 (s, 9 H), 3.80 (s, 3 H), 3.88 (s, 3
H), 7.79 (s, 1 H).
MS (EI): m/z (%) = 240 (11) [M+], 193 (100).
HRMS (EI): m/z [M+] calcd for C12H16O5: 240.0998; found:
Ethyl 2-tert-Butylfuran-3-carboxylate (8b) and Its Regioisomer
9b
Signals of characteristic protons.
240.0986.
Dimethyl 2-Cyclohexylfuran-3,4-dicarboxylate (6c)
1H NMR (CDCl3, TMS): d = 1.85–1.22 (m, 10 H), 3.13 (tt, J = 11.7,
3.1 Hz, 1 H), 3.82 (s, 3 H), 3.86 (s, 3 H), 7.74 (s, 1 H).
MS (EI): m/z (%) = 266 (18) [M+], 234 (100).
HRMS (EI): m/z [M+] calcd for C14H18O5: 266.1154; found:
266.1151.
8b
1H NMR (CDCl3, TMS): d = 6.67 (d, J = 1.9 Hz, 1 H), 7.17 (d, J =
1.9 Hz, 1 H).
9b
1H NMR (CDCl3, TMS): d = 6.30 (d, J = 0.7 Hz, 1 H), 7.88 (d, J =
0.7 Hz, 1 H).
MS (EI): m/z (%) = 196 (18) [M+], 135 (100).
HRMS (EI): m/z [M+] calcd for C11H16O3: 196.1099; found:
Dimethyl 2-Benzylfuran-3,4-dicarboxylate (6d)9
Dimethyl 2-n-Pentylfuran-3,4-dicarboxylate (6e)
1H NMR (CDCl3, TMS): d = 0.89 (t, J = 6.9 Hz, 3 H), 1.23–1.33 (m,
4 H), 1.66 (tt, J = 7.4, 7.4 Hz, 2 H), 2.87 (t, J = 7.4 Hz, 2 H), 3.83
(s, 3 H), 3.85 (s, 3 H), 7.75 (s, 1 H).
MS (EI): m/z (%) = 254 (23 ) [M+], 179 (100).
HRMS (EI): m/z [M+] calcd for C13H18O5: 254.1154; found:
196.1122.
Ethyl 2-Cyclohexylfuran-3-carboxylate (8c) and Its Regioiso-
mer 9c
Signals of characteristic protons.
254.1162.
8c
1H NMR (CDCl3, TMS): d = 6.62 (d, J = 1.8 Hz, 1 H), 7.22 (d, J =
Dimethyl 2-Furylfuran-3,4-dicarboxylate (6f)
1H NMR (CDCl3, TMS): d = 3.86 (s, 3 H), 3.93 (s, 3 H), 6.51 (dd,
J = 3.5, 1.7 Hz, 1 H), 6.99 (d, J = 3.5 Hz, 1 H), 7.52 (d, J = 1.7 Hz,
1 H), 7.90 (s, 1 H).
1.8 Hz, 1 H).
9c
1H NMR (CDCl3, TMS): d = 6.30 (s, 1 H), 7.86 (s, 1 H).
MS (EI): m/z (%) = 250 (100) [M+].
MS (EI): m/z (%) = 222 (100) [M+].
Anal. Calcd for C12H10O6: C, 57.60; H, 4.03. Found: C, 57.58; H,
4.09.
HRMS (EI): m/z [M+] calcd for C13H18O3: 222.1256; found:
222.1232.
One-Pot Synthesis of 2-Substituted Dimethyl Furan-3,4-dicar-
boxylates from Amides: The Synthesis of 6h
Ethyl 2-n-Pentylfuran-3-carboxylate (8e) and Its Regioisomer
9e
To a solution of p-chlorobenzamide (7h) (229 mg, 1.26 mmol) in
1,2-dichloroethane (3 mL), oxalyl chloride (0.13 mL, 1.51 mmol)
was added. After being stirred under reflux for 24 h, the reaction
solvent was removed in vacuo under moisture-free conditions. The
residue (p-chlorobenzoyl isocyanate) was dissolved in MeCN (5
mL) and TMSCHN2 (1.67 M in hexane solution, 0.90 mL, 1.51
mmol) was added at 0 °C under Ar. After stirring for 0.5 h, DMAD
(0.31 mL, 2.52 mmol) was added and the mixture was refluxed for
11 h. After the reaction solvent was removed in vacuo, the residue
was purified by flash column chromatography (Fuji Silysia BW
200, hexane–EtOAC, 8:1) to give dimethyl 2-(4-chlorophenyl)fu-
ran-3,4-dicarboxylate (6h,2a 280 mg, 75%).
Signals of characteristic protons.
8e
1H NMR (CDCl3, TMS): d = 6.64 (d, J = 1.8 Hz, 1 H), 7.23 (d, J =
1.8 Hz, 1 H).
9e
1H NMR (CDCl3, TMS): d = 6.33 (s, 1 H), 7.86 (s, 1 H).
MS (EI): m/z (%) = 210 (23) [M+], 125 (100).
HRMS (EI): m/z [M+] calcd for C12H18O3: 210.1256; found:
210.1252.
Dimethyl 2-(4-Methoxyphenyl)furan-3,4-dicarboxylate (6g)
1H NMR (CDCl3, TMS): d = 3.84 (s, 3 H), 3.85 (s, 3 H), 3.90 (s, 3
H), 6.94 (d, J = 9.1 Hz, 2 H), 7.67 (d, J = 9.1 Hz, 2 H), 7.92 (s, 1 H).
MS (EI): m/z (%) = 290 (100) [M+].
Acknowledgment
This work was financially supported by a Grant-in-Aid from The
Fujisawa Foundation (to Y. H.).
HRMS (EI): m/z [M+] calcd for C15H14O6: 290.0790; found:
290.0791.
Synthesis 2004, No. 9, 1359–1362 © Thieme Stuttgart · New York

1362
Y. Hari et al.
PAPER
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Synthesis 2004, No. 9, 1359–1362 © Thieme Stuttgart · New York