Synthesis of 1-benzofuran-2-carboxylates by reaction of 1-benzofuran with halomethanes and alcohols in the presence of iron compounds

Article abstract of DOI:10.1134/S1070428011030195

Alkyl 1-benzofuran-2-carboxylates were obtained in quantitative yield by reaction of 1-benzofuran with halomethanes and alcohols in the presence of iron-containing catalysts both in the presence and in the absence of radical initiators.

Full text of DOI:10.1134/S1070428011030195

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2011, Vol. 47, No. 3, pp. 437–441. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © R.I. Khusnutdinov, A.R. Baiguzina, R.R. Mukminov, 2011, published in Zhurnal Organicheskoi Khimii, 2011, Vol. 47, No. 3,
pp. 442–446.
Synthesis of 1-Benzofuran-2-carboxylates by Reaction
of 1-Benzofuran with Halomethanes and Alcohols
in the Presence of Iron Compounds
R. I. Khusnutdinov, A. R. Baiguzina, and R. R. Mukminov
Institute of Petroleum Chemistry and Catalysis, Russian Academy of Sciences,
pr. Oktyabrya 141, Ufa, 450075 Bashkortostan, Russia
e-mail: ink@anrb.ru
Received July 20, 2010
Abstract—Alkyl 1-benzofuran-2-carboxylates were obtained in quantitative yield by reaction of 1-benzofuran
with halomethanes and alcohols in the presence of iron-containing catalysts both in the presence and in the
absence of radical initiators.
DOI: 10.1134/S1070428011030195
1
-Benzofuran-2-carboxylic acid and its derivatives
with CCl
and methanol in the presence of iron catalyst
4
are widely used as starting compounds in the synthesis
of pharmaceuticals. For example, alkyl and aryl 1-ben-
zofuran-2-carboxylates are initial compounds for the
preparation of inhibitors of leukotriene biosynthesis
and are used for the treatment of asthma, allergy, and
cardiovascular and skin diseases [1, 2]. 3-Benzofuryl-
to give methyl 1-benzofuran-2-carboxylate (II)
(Scheme 1). Among the examined iron-containing
compounds, Fe(acac) , Fe(C H ) , FeBr , and Fe(OAc)
3 5 5 2 2 2
showed the highest catalytic activity. The reactions
were carried out at 140–160°C and were complete in
4–6 h (100% conversion of initial benzofuran I) with
selective formation of ester II (Table 1).
4
-phenyl(allyl)-1,2,4-triazole-5-thiols obtained by cy-
clization of substituted 1-benzofuran-2-carboxylic acid
thiosemicarbazides were found to exhibit antitumor
activity [3]. 1-Benzofuran-2-carboxylic acid was used
to synthesize cathepsin K inhibitors (azepanone and
methylazepanone) [4], neurokinin 2 (NK2) receptor
antagonist [5], dopamine (endogenous ligand for dopa-
mine receptors) [6], and chromans [7].
Scheme 1.
Catalyst
O
MeOH, Δ
+
CCl
4
O
O
OMe
I
II
3 2 2
Catalyst = Fc, Fe(acac) , FeBr , Fe(OAc) .
Most known methods for the synthesis of 1-benzo-
furan-2-carboxylic acid and its derivatives are based
on metalation of benzofuran, followed by carbonyla-
tion of intermediate metalated derivative [8–13]. The
goal of the present work was to obtain 1-benzofuran-2-
carboxylic acid esters according to a novel procedure,
which was successfully tested with 2-acetylfuran as
substrate [14]. Following this procedure, alkoxycar-
bonyl group is introduced into 2-acetylfuran molecule
via conjugate reaction with participation of the hetero-
cyclic substrate, carbon tetrachloride, and methanol in
the presence of iron-containing catalyst.
It is known [15] that carbon atoms in the benzene
and furan rings of benzofuran molecule are charac-
terized by similar reactivities; therefore, formation of
a mixture of regioisomeric benzofurancarboxylic acids
may be expected. The examined reaction ensures high
regioselectivity, and ester II is formed as the only
product. Its structure was determined by NMR spec-
1
13
troscopy using one- ( H, C) and two-dimensional
homo- (COSY) and heteronuclear correlation tech-
niques (HSQC, HMBC). The position of the ester
group in the benzofuran system was identified on the
2
basis of the chemical shift of the quaternary C atom
3
We have found that analogous transformation suc-
cessfully occurs with benzofuran I. Compound I reacts
(δ 145.37 ppm against δ 113.98 ppm for C H). The
C
C
1
3-H proton resonated in the H NMR spectrum as
4
37

4
38
KHUSNUTDINOV et al.
Table 1. Reaction of 1-benzofuran (I) with carbon tetrachloride and methanol in the presence of iron-containing catalysts
a
Ratio catalyst–I–CCl
4
–MeOH
Catalyst
Fc
Temperature, °C Reaction time, h Conversion, % Yield of ester II, %
1
1
1
1
1
1
1
1
1
1
1
1
:100:200:800
140
150
150
150
150
150
150
150
160
160
160
160
6
6
6
6
6
6
6
6
4
4
4
4
080
090
098
098
098
100
100
100
100
100
100
100
93
95
96
97
97
98
98
98
98
99
99
99
:100:200:800
:100:700:1000
:100:800:1000
:100:750:1000
:100:750:1100
:100:750:1200
:100:750:1100
:100:750:1100
:100:750:1100
:100:750:1100
:100:750:1100
Fc
Fc
Fc
Fc
Fc
Fc
FeBr
Fc
2
Fe(acac)
FeBr
Fe(OAc)
3
2
2
a
Calculated on the reacted substrate.
a singlet at δ 7.52 ppm, and it showed correlations in
ment of methanol by ethanol or propan-1-ol leads to
the formation of, respectively, ethyl and propyl esters
III and IV (yield 92 and 95%). At a ferrocene–benzo-
3
a
2
the HMBC spectrum with C (δ 126.90 ppm) and C
C
7
a
(
δ 145.37 ppm), as well as with C (δ 155.69 ppm).
C
C
Alternative structure of methyl 1-benzofuran-3-carbox-
furan–CCl –ROH molar ratio of 1 :100 :750:1100
4
ylate (II′) should be characterized by upfield signal
(160°C, 8 h), the yields of the corresponding esters
ranged from 92 to 98%. Hydrogen chloride and ethers
ROR were formed as by-products.
3
from the quaternary carbon atom (C , δ 111.79 ppm)
C
2
and downfield signal from C H (δ 152.5 ppm) [16],
which are not observed in the experimental C NMR
spectrum.
C
1
3
With a view to elucidate whether the examined
reaction follows a radical mechanism or not, it was
carried out in the presence of galvinoxyl which is
known as an effective radical scavenger. However, the
inhibitory effect of galvinoxyl was insignificant; pre-
sumably, it undergoes deactivation at elevated tem-
perature. Replacement of carbon tetrachloride by more
active bromine-containing halomethanes, such as CBr4
O
H7.52 s
OMe
3
3
3
7
a
a
O
2
2
O
OMe
O
II
II'
and CBrCl allowed us to reduce the temperature to
3
It is known that reaction of ferrocene with carbon
tetrachloride generates trichloromethyl radical [17]
which can attack benzofuran molecule with formation
of trichloromethyl derivative (Scheme 2). The latter is
then converted into ester II via reaction with methanol.
This assumption is confirmed by the fact that replace-
1
30–140°C, the high yield of ester II being retained
(
Table 2). In the ferrocene-catalyzed reaction of
benzofuran I with CBr and MeOH in the presence of
4
galvinoxyl (molar ratio Fc–galvinoxyl–I–CBr –MeOH
4
1
:5:100:200:1100) the conversion of initial com-
pound I at 130°C in 4 h was 88%, and the yield of
methyl 1-benzofuran-2-carboxylate (II) decreased
from 95 to 87%. We then examined the effect of such
radical initiators as TEMPO, AIBN, (BzO) , and H O
2
Scheme 2.
·
+
Fc Cl–
Fc
+
CCl4
+
CCl
3
2
2
(
34% aqueous solution) on the process (Table 3). In the
·
CCl
3
CCl3
presence of radical initiators the optimal temperature
decreased to 100°C. Under these conditions, but in the
·
H
–
O
O
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 3 2011

SYNTHESIS OF 1-BENZOFURAN-2-CARBOXYLATES
439
Table 2. Reaction of 1-benzofuran (I) with bromomethanes and methanol in the presence of ferrocene (reaction time 4 h)
Ratio catalyst–I–
halomethane–MeOH
a
Halomethane
Temperature, °C
Conversion, %
Yield of ester II, %
1
1
1
:100:200:1100
:100:750:1100
:100:200:1100
CBr
CBrCl
CBr
4
140
140
130
100
096
096
98
89
98
3
4
a
Calculated on the reacted substrate.
Table 3. Reaction of 1-benzofuran (I) with tetrabromomethane and methanol in the presence of ferrocene and radical
initiators (100°C, 9 h)
a
Ratio catalyst–initiator–I–CBr
4
–MeOH
Initiator
Conversion of I, %
Yield of ester II, %
1
1
1
1
:5:100:200:1100
:5:100:200:1100
:5:100:200:1100
:5:100:200:1100
TEMPO
AIBN
98
94
86
88
95
92
98
98
98
99
(PhCOO)
2
H
H
2
2
O
O
2
2
1
:10:100:200:11000
a
Calculated on the reacted substrate.
absence of iron catalyst (molar ratio H O –I–CBr –
100.62 MHz, respectively, using CDCl as solvent; the
2
2
4
3
ROH 5:100:750:1100), the yield of ester II did not
exceed 5%.
chemical shifts were measured relative to tetramethyl-
silane. The mass spectra were obtained on a Shimadzu
GCMS-QP2010Plus instrument (SPB-5 capillary col-
umn, 30 m×0.25 mm; carrier gas helium; oven tem-
perature programming from 40 to 300°C at a rate of
An additional evidence in support of the radical
mechanism of the process is the presence in the reac-
tion mixture of Fe(II)/Fe(III) redox system. The oxida-
tion of Fe(II) to Fe(III) was detected by titration of the
reaction mixture with K [Fe(CN) ] and K [Fe(CN) ]
8
deg/min; injector temperature 280°C, ion source
temperature 200°C; electron impact, 70 eV). Chroma-
tographic analysis was performed on Shimadzu GC-9A
and GC-2014 instruments (2000×3-mm column, sta-
tionary phase 5% of SE-30 on Chromaton N-AW-
HMDS, oven temperature programming from 50 to
3
6
4
6
solutions. The redox couple Fe(II)/Fe(III) was also
formed when Fe(acac) was used as catalyst. Methanol
3
is likely to ensure the reduction of Fe(III) to Fe(II).
Examples of reduction of Fe(III) to Fe(II) with alco-
hols have been reported; the latter are thus oxidized to
aldehydes [18, 19].
2
70°C at a rate of 8 deg/min; carrier gas helium, flow
rate 47 ml/min). The elemental compositions were
determined on a Carlo Erba 1106 analyzer.
To conclude, we have proposed a procedure for the
synthesis of methyl, ethyl, and propyl 1-benzofuran-2-
carboxylates in quantitative yield by reaction of 1-ben-
zofuran with halomethanes and the corresponding
alcohols in the presence of iron catalysts. Addition of
radical initiators makes it possible to reduce the reac-
tion temperature, which suggests radical mechanism of
the process.
Commercially available 1-benzofuran, methanol,
ethanol, propan-1-ol, carbon tetrachloride, carbon
tetrabromide, and bromotrichloromethane were prelim-
inarily purified by distillation or recrystallization. Iron-
containing catalysts [Fe(acac) , Fe(OAc) , Fe(C H ) ,
3
2
5
5 2
and FeBr ], radical initiators [TEMPO, AIBN,
2
(
PhCOO) , and H O ], and galvinoxyl (radical scav-
2 2 2
enger) were commercial products.
EXPERIMENTAL
The reactions were carried out in a 10-ml glass
ampule placed into a 17-ml stainless-steel high-pres-
sure reactor under continuous stirring and controlled
heating.
1
13
The H and C NMR spectra were recorded on
a Bruker Avance-400 spectrometer at 400.13 and
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 3 2011

4
40
KHUSNUTDINOV et al.
4
5
3a
6
Alkyl 1-benzofuran-2-carboxylates II–IV (gen-
122.77 (C ), 123.74 (C ), 126.97 (C ), 127.53 (C ),
2
7a
eral procedure). An ampule was charged under argon
with 1 mmol of iron-containing catalyst, 0–10 mmol of
radical initiator, 100 mmol of 1-benzofuran, 750 mmol
of halomethane, and 1100 mmol of alcohol. The am-
pule was sealed and placed into a high-pressure re-
actor, and the reactor was sealed and heated for 4–9 h
at 100–160°C under continuous stirring. When the
reaction was complete, the reactor was cooled to room
temperature, the ampule was opened, the reaction mix-
ture was filtered through a layer of silica gel (2 g), and
the sorbent was washed with ethyl acetate. The solvent
was distilled off, and the residue was recrystallized
from aqueous methanol (compound II) or distilled
under reduced pressure (III, IV).
145.71 (C ), 155.71 (C ), 159.67 (C=O). Found, %:
C 70.50; H 5.92; O 23.58. C H O . Calculated, %:
1
2
12
3
C 70.57; H 5.93; O 23.50.
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 09-03-00472).
REFERENCES
1. Atkinson, J.G., Guindon, Y., and Lau, C.K., US Patent
no. 4663347, 1987.
. Atkinson, J.G., Guindon, Y., and Lau, C.K., US Patent
no. 4745127, 1988.
. Kaldrikyan, M.A., Grigoryan, L.A., Melik-Ogandzha-
nyan, R.G., and Arsenyan, F.G., Khim.-Farm. Zh., 2009,
vol. 43, no. 5, p. 11.
. Yamashita, D.E., Marquis, R., Xie, R., Nidamarthy, S.,
Oh, H., Jeong, J., Erhard, K., Ward, K., Roethke, T.,
Smith, B., Cheng, H., Geng, X., Lin, F., Offen, P.,
Wang, B., Nevins, N., Head, M., Haltiwanger, R.,
Sarjeant, A., Liable-Sands, L., Zhao, B., Smith, W.,
Janson, C., Gao, E., Tomaszek, T., McQueney, M.,
James, I., Gress, C., Zembryki, D., Lark, M.W., and
Veber, D., J. Med. Chem., 2006, vol. 49, p. 1597.
. Fattori, D., Porcelloni, M., D’Andreat, P., Catali-
oto, R.-M., Ettorret, A., Giuliani, S., Marastoni, E.,
Maurot, S., Meini, S., Rossi, C., Altamura, M., and
Maggi, C.A., J. Med. Chem., 2010, vol. 53, p. 4148.
. Bettinetti, L., Schlotter, K., Hubner, H., and Gmeiner, P.,
J. Med. Chem., 2002, vol. 45, p. 4594.
. Banerji, K.D. and Poddar, D., J. Indian Chem. Soc.,
976, vol. 53, p. 1119.
. Fuson, R.C. and Jackson, H.L, J. Am. Chem. Soc., 1948,
vol. 70, p. 1655.
. Costa, A., Dean, F., Jones, M., and Varma, R., J. Chem.
Soc., Perkin Trans. 1, 1985, p. 799.
2
3
The structure of esters II–IV was proved by NMR
and mass spectrometry, as well as by comparing with
authentic samples and reference data.
4
Methyl 1-benzofuran-2-carboxylate (II). Yield
9
5
9%, mp 49.5–50°C; published data: mp 52°C [20],
1
2–53°C [21]. H NMR spectrum, δ, ppm: 3.96 s (3H,
OCH ), 7.30 t (1H, J = 8 Hz), 7.44 t (1H, J = 7.6 Hz),
3
7
1
1
1
1
.52 s (1H), 7.58 d (1H, J = 8 Hz), 7.67 d (1H, J =
1
3
0.4 Hz). C NMR spectrum, δ , ppm: 52.35 (CH ),
C
3
5
5
7
3
4
12.32 (C ), 113.98 (C ), 122.83 (C ), 123.8 (C ),
3
a
6
2
7a
26.9 (C ), 127.66 (C ), 145.37 (C ), 155.69 (C ),
59.95 (C=O). Mass spectrum, m/z (I , %): 176 (63)
rel
+
[
M] , 145 (100), 118 (11), 89 (41), 63 (15), 44 (2).
6
7
8
9
Found, %: C 68.20; H 4.57; O 27.23. C H O . Cal-
1
0
8
3
culated, %: C 68.18; H 4.55; O 27.27. M 176.13.
1
Ethyl 1-benzofuran-2-carboxylate (III). Yield
9
2%, bp 106–107°C (2 mm); published data [22]:
1
bp 274°C (720 mm). H NMR spectrum, δ, ppm: 1.40 t
(
7
7
3H, CH CH , J = 7.2 Hz), 4.40 q (2H, OCH , J =
2
3
2
.2 Hz), 7.29 t (1H, J = 7.2 Hz), 7.44 t (1H, J =
.2 Hz), 7.52 s (1H), 7.59 d (1H, J = 8 Hz), 7.67 d (1H,
1
0. Gissot, A., Becht, J., Desmurs, J., Pevere, V.,
Wagner, A., and Mioskowski, C., Angew. Chem., Int.
Ed., 2002, vol. 41, p. 340.
11. Wagner, A., Mioskovski, C., Desmurs, J.-R., and
Jost, S., WO Patent Appl. no. 064905, 2000.
2. Jaouhari, R., Dixneuf, P.H., and Lecolier, S., Tetra-
hedron Lett., 1986, vol. 27, no. 52, p. 6315.
3. Babin, P., Bourgeois, P., and Dunogues, J., C. R. Acad.
Sci., Ser. C, 1976, vol. 283, no. 4, p. 149.
1
3
J = 7.6 Hz) [23, 24]. C NMR spectrum, δ , ppm:
C
7
3
1
1
1
4.32 (CH ), 61.48 (CH ), 112.33 (C ), 113.76 (C ),
3 2
4
5
3a
6
22.78 (C ), 123.74 (C ), 126.96 (C ), 127.54 (C ),
2
7a
45.71 (C ), 155.68 (C ), 159.57 (C=O). Found, %:
1
1
1
C 69.60; H 5.04; O 25.36. C H O . Calculated, %:
11
10
3
C 69.40; H 5.26; O 25.24.
Propyl 1-benzofuran-2-carboxylate (IV). Yield
1
9
5%, bp 80–82°C (0.2 mm). H NMR spectrum, δ,
4. Khusnutdinov, R.I., Baiguzina, A.R., Mukminov, R.R.,
and Dzhemilev, U.M., Zh. Prikl. Khim., 2009, vol. 82,
p. 346.
ppm: 1.05 t (3H, CH CH , J = 7.6 Hz), 1.70–1.90 m
2
3
(
(
2H, CH CH ), 4.35 t (2H, OCH , J = 6.8 Hz), 7.30 t
2 3 2
1H, J = 7.2 Hz), 7.44 t (1H, J = 7.2 Hz), 7.53 s (1H),
15. Joule, J.A. and Mills, K., Heterocyclic Chemistry,
7
.61 d (1H, J = 8.4 Hz), 7.68 d (1H, J = 7.6 Hz).
C NMR spectrum, δ , ppm: 10.37 (CH ), 22.08
Malden, MA: Blackwell Science, 2000, 4th ed.
16. Chou, C.-H. and Trahanovsky, W.S., J. Org. Chem.,
1
3
C
3
7
3
(CH CH ), 66.97 (OCH ), 112.34 (C ), 113.70 (C ),
1986, vol. 51, p. 4208.
2
3
2
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 3 2011

SYNTHESIS OF 1-BENZOFURAN-2-CARBOXYLATES
441
1
1
1
2
2
7. Brand, J.C.D. and Snedden, W., Trans. Faraday Soc.,
957, vol. 53, p. 894.
8. Potekhin, V.V., Matsura, V.A., Solov’eva, S.N., and
Potekhin, V.M., Kinet. Katal., 2004, vol. 45, p. 407.
9. Potekhin, V.V., Solov’eva, S.N., and Potekhin, V.M., Izv.
Ross. Akad. Nauk, Ser. Khim., 2003, p. 2525.
0. Feinstein, A., Gore, P.H., and Reed, G.L., J. Chem.
Soc. B, 1969, p. 205.
1. Suzuki, T., Horaguchi, T., and Shimizu, T., Bull. Chem.
Soc. Jpn., 1983, vol. 56, p. 2762.
22. Dictionary of Organic Compounds, Heilbron, J. and
Bunbury, H.M., Eds., London: Eyre and Spottswoode,
1953, vols. 1–3. Translated under the title Slovar’
organicheskikh soedinenii, Moscow: Inostrannaya Lite-
ratura, 1949, vol. 1, p. 574.
1
23. Guo, H., Shao, H., Yang, Z., Xue, S., Li, X., Liu, Z.,
He, X., Jing, J., Zhang, Y., Si, S., and Li, Z., J. Med.
Chem., 2010, vol. 53, p. 1819.
24. Shiotani, S. and Morita, H., J. Heterocycl. Chem., 1991,
vol. 28, p. 1469.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 3 2011