New One-Pot Synthesis of Polysubstituted Benzofurans and Benzo-1,4-dioxines

Article abstract of DOI:10.1134/S0012500818100051

It has been revealed that the copper(II) triflate catalyzed reaction of ethyl-2-diazo-3-oxobutanoate with phenols followed by cyclization of the intermediate enol in the presence of polyphosphoric acid is a simple and efficient method of synthesis of polysubstituted benzofurans. The use of pyrocatechol leads to the corresponding substituted 1,4-benzodioxine-2-carboxylates as major products.

Full text of DOI:10.1134/S0012500818100051

ISSN 0012-5008, Doklady Chemistry, 2018, Vol. 482, Part 2, pp. 233–236. © Pleiades Publishing, Ltd., 2018.
Original Russian Text © G.N. Sakhabutdinova, G.Z. Raskil’dina, S.S. Zlotskii, R.M. Sultanova, 2018, published in Doklady Akademii Nauk, 2018, Vol. 482, No. 5.
CHEMISTRY
New One-Pot Synthesis of Polysubstituted Benzofurans
and Benzo-1,4-dioxines
G. N. Sakhabutdinovaa, G. Z. Raskil’dinaa, S. S. Zlotskiia, and R. M. Sultanovaa,b,*
Presented by Academician A.A. Berlin June 4, 2018
Received June 4, 2018
Abstract—It has been revealed that the copper(II) triflate catalyzed reaction of ethyl-2-diazo-3-oxobuta-
noate with phenols followed by cyclization of the intermediate enol in the presence of polyphosphoric acid is
a simple and efficient method of synthesis of polysubstituted benzofurans. The use of pyrocatechol leads to
the corresponding substituted 1,4-benzodioxine-2-carboxylates as major products.
DOI: 10.1134/S0012500818100051
Benzofuran and benzo-1,4-dioxine derivatives
exhibit diverse biological activity, in particular, anti-
bacterial, antifungal, and anti-inflammatory, and thus
attract attention as candidates for use in the synthesis
of drugs [1–4].
With 4-tert-butylpyrocathechol 2, the reaction
involves two hydroxyl groups (Scheme 3), not disturb-
ing the aromatic nucleus, to give a mixture of isomeric
ethyl tert-butyl-3-methyl-1,4-benzodioxine-2-car-
boxylates 6a and 6b.
It is evident that when treated with PPA, the inter-
mediate enols undergo intramolecular dehydration to
give heterocycles 6a and 6b.
The tert-butyl substituent distant from the hydroxyl
groups has no effect on their reaction with alkoxycar-
bonyl carbene, which explains the formation of the
equimolar mixture of benzoheterocycles 6a and 6b
(Table 1).
In this paper, we report a new route of synthesis of
polyfunctional benzofurans and benzo-1,4-dioxines
through the reaction of substituted phenols 1a–1f and
pyrocatechol 2 with ethyl-2-diazo-3-oxobutanoate 3
in the presence of Cu(OTf)2, where the key stage is the
insertion of a carbene intermediate obtained from α-
diazo-β-keto ether into the О–Н bond of phenols
(Scheme 1). The resulting О-arylalkoxycarbonyl
ketones were further cyclized to form benzofurans.
The structures of compounds 4a–4e, 5a, 5b, 6a,
and 6b were proved by 1H and 13C NMR and chroma-
tography/mass spectrometry.
In the presence of 2 mol % Cu(OTf)2 in toluene at
110°С, nearly complete conversion of the reagents was
observed within 2 h. The subsequent treatment of the
reaction mixture with polyphosphoric acid (PPA)
under stirring for 8 h led to the formation of benzofu-
rans 4a–4е in 35–70% yields (Table 1).
The signals of substituted benzofurans 4a–4e, 5a,
and 5b were assigned by analyzing the chemical shifts
and spin coupling constants of the benzoheterocyclic
protons.
1
The Н NMR spectrum of a mixture of 5a and 5b
In the case of m-chlorophenol 1f, the reaction mix-
ture contains both benzofuran isomers 5a and 5b
(Scheme 2). Judging from their ratio (5a : 5b = 1.5 : 1),
the cyclization of the intermediate enol in the p-posi-
tion to the Cl atom is more preferable than in the о-
position.
showed a set of signals characteristic for the ester –CH2–
protons as a quartet at 4.42 ppm and a singlet corre-
sponding to the methyl proton in the range 2.56–
2.80 ppm. In the 13С NMR spectrum of these com-
pounds, the signals of the C4, C4' and C9, C9' carbon
atoms of fused nuclei were observed at 141.16 and
127.65 ppm, respectively. The ratio of benzofuran iso-
mers 5a and 5b was 1.5 : 1 according to the integrated
a Ufa State Petroleum Technological University, Ufa,
Bashkortostan, 450105 Russia
1
intensities of methyl protons in the Н NMR spec-
trum.
b Ufa Institute of Chemistry, Russian Academy of Sciences,
Ufa, Bashkortostan, 450054 Russia
The 1Н NMR spectrum of the mixture of 6a and 6b
showed a double set of proton signals. In the 13С NMR
*e-mail: sultanova_rm@anrb.ru
233

234
SAKHABUTDINOVA et al.
O
O
O
Me
N2
O
Cu(OTf)2
EtO
R
+
OH
R
PhMe
110°C, 2 h
COOEt
Me
3
1a−1e
Me
HO Me
COOEt
PPA
R
COOEt
R
−H2O
85°C, 8 h
O
O
4a−4e
R = H (1a, 4a), o-Me (1b, 4b), p-Me (1c, 4c), p-tBu (1d, 4d), o-Cl (1e, 4e)
Scheme 1.
Me
COOEt
Cl
O
Cl
O
O
Cl
5a
Cl
N2
O
Cu(OTf)2
PPA
OH
EtO
+
PhMe
110°C, 2 h
85°C, 8 h
−H2O
Cl
Me
O
O
Me
COOEt
Me
Me
3
OH
1f
COOEt
EtOOC
O
5b
Scheme 2.
O
O
Me
HO Me
COOEt
OH
O
COOEt
OH
COOEt
Me
O
PPA
85°C, 8 h
−H2O
OH
O
tBu
O
OH
N2
O
Cu(OTf)2
EtO
tBu
OH
tBu
6a
+
PhMe
110°C, 2 h
Me
tBu
OH
OH
Me
O
2
3
Me
O
O
O
PPA
Me
85°C, 8 h
−H2O
COOEt
COOEt
COOEt
tBu
O
tBu
tBu
6b
Scheme 3.
spectrum of the mixture of compounds 6a and 6b, the
chemical shifts of carbon atoms in the 9- and 8'-posi-
tions were noticeably different being 147.36 and
148.09 ppm, respectively.
Thus, the reaction of ethyl-2-diazo-3-oxobuta-
noate with substituted mono- and diphenols is a con-
venient route of synthesis of polyfunctional benzofu-
rans and 1,4-benzodioxine-2-carboxylates.
EXPERIMENTAL
The NMR spectra of solutions in CDCl3 were
recorded on a Bruker Avance III 500 radiospectrome-
ter operating at 500 (1H) and 125.76 MHz (13С) (TMS
as an internal reference). GLC analysis was performed
on a Kristall-2000M chromatograph (“Khromatek,”
Russia, column length 2.0 m, stationary phase SE-30
DOKLADY CHEMISTRY
Vol. 482
Part 2
2018

NEW ONE-POT SYNTHESIS OF POLYSUBSTITUTED BENZOFURANS
Table 1. 1H and 13C NMR spectra of products 4a–4e, 5a, 5b, 6a, and 6b
235
Compound
(yield, %)
1H, ppm
13C, ppm
m/e, (Irel, %)
4a (70)
4b (40)
4c (40)
4d (35)
1.46 (t, 3H, CH3, J 7.2), 2.59 (s,
3Н, CH3), 4.45 (q, 2Н, CH2, J
4.5), 7.29 (t, 1H, CH), 7.42 (t, 1H,
CH), 7.53 (d, 1H, CH), 7.62 (d,
1H, CH)
1.45 (t, 3H, CH3, J 7.1), 2.56 (s,
3Н, CH3), 2.58 (s, 3Н, CH3), 4.46
(q, 2Н, CH2, J 4.0), 7.20 (t, 1H,
CH), 7.25 (t, 1H, CH), 7.43 (d,
1H, CH)
1.44 (t, 3H, CH3, J 7.2), 2.47 (s,
3Н, CH3), 2.57 (s, 3Н, CH3), 4.42
(q, 2Н, CH2, J 4.2), 7.08 (d, 1H,
CH), 7.21 (d, 1H, CH), 7.40 (t,
1H, CH)
1.32 (t, 9H, 3CH3), 1.45 (t, 3Н,
CH3, J 7.1), 2.60 (s, 3Н, CH3),
4.45 (q, 2Н, CH2, J 7.1), 7.00 (d,
1H, CH), 7.39 (dd, 1H, CH), 7.52
(d, 1H, CH)
160.38 (C), 154.29 (C), 140.85
(C), 129.02 (C), 127.64 (CH),
125.50 (C), 123.03 (CH), 120.95 159 (64), 176 (70), 204 (100)
(CH), 112.14 (CH), 60.96 (CH2),
36 (16), 51 (10), 63 (8), 77 (38), 91
(10), 103 (40), 131 (72), 147 (9),
14.41 (CH3), 9.35 (CH3)
160.70 (C), 153.51(C), 140.77 (C), 39 (8), 51 (8), 65 (9), 77 (8), 91
128.59 (C), 128.34 (CH), 123.74 (28), 115 (64), 145 (54), 173 (48),
(С), 123.09 (CH), 122.41 (C),
118.36 (CH), 60.95 (CH2), 15.03
(CH3), 14.36 (CH3), 9.54 (CH3)
189 (74), 218 (100)
160.58 (C), 152.80 (C), 140.96
(C), 136.49 (C), 132.63(C), 129.20 (24), 115 (58), 45 (62), 173 (52),
(CH), 129.08 (C), 120.56 (CH),
111.66 (CH), 61.00 (CH2), 21.30
(CH3), 14.38 (CH3), 9.34 (CH3)
39 (8), 51 (8), 65 (9), 77 (8), 91
189 (84), 218 (100)
160.55 (C), 154.35 (C), 140.90
(C), 130.90 (C), 128.80 (C),
120.80 (CH), 116.70 (CH), 111.53 (9.0), 172 (7.0), 189 (16.5), 217
(CH), 61.02 (CH2), 29.68 (С),
31.71 (3CH3), 14.30 (CH3), 9.20
(CH3)
44 (12.5), 57 (5.8), 86 (6.0), 91
(5.0), 115 (8.5), 128 (11.5), 143
(13.5), 245 (100), 260 (5.5)
4e (45)
1.43 (t, 3H, CH3, J 7.1), 2.56 (s,
3Н, CH3), 4.44 (q, 2Н, CH2, J
7.1), 7.18 (t, 1H, CH), 7.23 (t, 1H,
CH), 7.45 (t, 1H, CH)
160.59 (C), 153.51 (C), 140.77
(C), 128.61 (C), 128.35 (CH),
125.71 (C), 123.11 (CH), 122.37
(С), 118.35 (CH), 60.87 (CH2),
15.08 (CH3), 9.56 (CH3)
39 (2), 51 (4), 65 (5), 77 (4), 91
(18), 115 (48), 145 (44), 179 (45),
189 (67), 218 (100)
5a + 5b (51) 1.43 (t, 3H, CH3, J 5.5), 2.56 (s, 160.08(C), 154.22(C), 141.39(C), 44 (12), 51 (6), 75 (12), 102 (28),
133.65(C), 128.52(C), 125.83(C), 136 (20), 165 (42), 193 (52), 210
124.20(CH), 124.07 (CH), 112.53 (84), 238 (100)
(CH), 61.16 (CH2), 14.16 (CH3),
3H, CH3), 4.42 (q, 2H, CH2, J
2.7), 7.26 (t, 1H, CH), 7.40 (d,
1H, CH), 7.50 (d, 1H, CH)
9.26 (CH3)
1.43 (t, 3H, CH3, J 5.5), 2.80 (s, 160.08 (C), 154.99 (C), 127.84
(CН), 127.65 (C), 126.06 (C),
125.20 (C), 125.20 (C), 121.57
(CH), 110.88 (CH), 61.16 (CH2),
14.16 (CH3), 10.99 (CH3)
3H, CH3), 4.42 (q, 2H, CH2, J
2.7), 7.21 (d, 1H, CH), 7.29 (t,
1H, CH), 7.50 (d, 1H, CH)
6a + 6b (35) 1.27 (s, 9Н, 3CH3, J 7.1), 1.36 (t, 162.50 (C), 147.29 (C), 148.09
43 (8), 55 (6), 67 (4), 77 (7), 91
(C), 141.76 (C), 139.97 (C), 125.27 (10), 105 (6), 115 (12), 131 (6), 159
3H, CH3), 2.25 (s, 3Н, CH3), 4.32
(q, 2Н, CH2, J 6.9), 6.63 (d, 1H,
CH), 6.75 (d, 1H, CH), 7.21(d,
1H, CH)
(C), 120.25 (CH), 115.39 (CH),
(5), 187 (12), 233 (24), 261 (100),
112.95 (CH), 61.13 (CH2), 34.40 276 (58)
(CH3), 31.35 (3CH3), 16.86
(CH3), 14.23 (CH3)
162.50 (C), 148.50 (C), 147.36
43 (16), 55 (6), 67 (9), 77 (9), 91
(C), 140.42 (C), 138.60 (C), 125.14 (14), 103 (6), 115 (12), 131 (8), 159
(C), 121.48 (CH), 114.91 (CH),
(19), 187 (14), 233 (16), 261 (100),
113.55 (CH), 61.13 (CH2), 34.40 276 (66)
(CH3), 31.35 (3CH3), 16.86
(CH3), 14.23 (CH3)
DOKLADY CHEMISTRY Vol. 482 Part 2 2018

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SAKHABUTDINOVA et al.
5%), Khromaton N-AW carrier (“Ekolan,” Russia, The organic layer was dried by MgSO4, which was fil-
working temperature 50–250°C, carrier gas—helium).
Mass spectra were recorded on a ThermoFisher Sci-
entific ThermoFinnigan MAT 95 XP high-resolution
chromatograph/mass spectrometer at an ionizing
voltage of 70 eV (ionizing chamber temperature
250°C, direct inlet temperature 50–270°C, heating
rate 10 K/min). The reaction was monitored by TLC
on a Sorbfil silica gel (“IMID,” Russia). Silica gel with
dispersion 70–230 mesh (Lancaster, Great Britain)
was used for column chromatography.
tered off, and the solvent (benzene) was
removed under reduced pressure. The residue was
chromatographed on silica gel (elution with petroleum
ether : ethyl acetate = 100 : 1).
Quantum-chemical calculations justifying the
reaction mechanisms and biological activity of the
synthesized compounds will be addressed in our future
research.
The yields and spectral characteristics of com-
pounds 4a–4e, 5a, 5b, 6a, and 6b are summarized in
Table 1. The properties of compound 4a were consis-
tent with the literature data [5].
REFERENCES
1. Khanova, M.D., Sultanova, R.M., Khursan, S.L.,
Dokichev, V.A., and Tomilov, Yu.V., Izv. Akad. Nauk,
Ser. Khim., 2006, vol. 8, p. 1411.
General procedure of synthesis of benzoheterocycles
4a–4e, 5a, 5b, 6a, and 6b. To a mixture of 1.2 mmol
(200 mg) of ethyl-2-diazo-3-oxobutanoate (3) and
1.1 mmol of phenol (1a–1f, 2) in toluene, 2.4 ×
10–5 mmol (8 mg) of the Cu(OTf)2 catalyst was added.
The reaction mixture was heated to 110°C for 2 h.
Then, the reaction mixture was cooled to room tem-
perature, and the solvent (toluene) was removed under
reduced pressure. Polyphosphoric acid (300 mg) was
preheated to 85°C and added to the crude reaction
mixture. The viscous mixture was stirred at 85°C for 8 h.
After the reaction completion, the reaction mixture
was cooled to 0°C; then, water (20 mL) was added,
and the mixture was extracted with benzene (30 mL × 3).
2. Sultanova, R.M., Khanova, M.D., and Dokichev, V.A.,
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3. Shaikhullina, G.N., Sultanova, R.M., Baikova, I.P.,
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Translated by G. Kirakosyan
DOKLADY CHEMISTRY
Vol. 482
Part 2
2018