Benzo[b]furan in the povarov reaction

Article abstract of DOI:10.1016/j.mencom.2012.06.010

The Povarov-type condensation of ethyl 2-(arylimino)acetates, 1-aryl-2-aryliminoethanones or N-benzylideneanilines with benzo[b]-furan affords 5,6,6a,11b-tetrahydrobenzofuro[2,3-c]quinolines and/or related benzofuro[2,3-c]quinolines.

Full text of DOI:10.1016/j.mencom.2012.06.010

Mendeleev
Communications
Mendeleev Commun., 2012, 22, 201–202
Benzo[b]furan in the Povarov reaction
Gulnaz F. Krainova,a Yulia O. Chudinova,a Alexey A. Gorbunov,a
Olga A. Mayorovaa and Vladimir A. Glushkov*a,b
a Institute of Technical Chemistry, Ural Branch of the Russian Academy of Sciences, 614013 Perm,
Russian Federation. Fax:+7 342 237 8262; e-mail: glusha55@gmail.com
b Department of Chemistry, Perm State National Research University, 614990 Perm, Russian Federation
DOI: 10.1016/j.mencom.2012.06.010
The Povarov-type condensation of ethyl 2-(arylimino)acetates, 1-aryl-2-aryliminoethanones or N-benzylideneanilines with benzo[b]-
furan affords 5,6,6a,11b-tetrahydrobenzofuro[2,3-c]quinolines and/or related benzofuro[2,3-c]quinolines.
Interaction of the Schiff bases with activated olefins (the Povarov
reaction1) is recognized as a versatile method for the synthesis
of 1,2,3,4-tetrahydroquinolines annulated to tetrahydrofuran and
tetrahydropyran,2 pyrrolidine,3 indole,4 oxazole and thiazole5
moieties. In contrast to 2,3-dihydrofuran and 3,4-dihydro-2H-
pyran,2 only one example is known of the use of benzo[b]furan
in the Povarov reaction, namely, a three-component condensa-
tion with substituted anilines and glyoxylic acid.6 In the course
of our synthetic studies,7 we have explored condensation of
benzo[b]furan with ethyl 2-(arylimino)acetates 1, 1-aryl-2-aryl-
iminoethanones 2 and arylideneanilines 3 (Schemes 1 and 2).
account the results obtained, we used further MeCN as a solvent
and BF3·OEt2 as a catalyst (see Scheme 1).
This protocol provides a straightforward route to substituted
5,6,6a,11b-tetrahydrobenzofuro[2,3-c]quinolines which are pro-
mising subjects for medicinal chemistry.6 General synthetic
approaches to benzofuro[2,3-c]quinolines are scarce. In 1990,
Yamaguchi had reported two methods for the synthesis of benzo-
furo[2,3-c]quinolines: condensation of 2-amino-2'-hydroxybenzo-
phenone with chloroacetone10 or photocyclization of N-benzyl-
N-phenyl-2-benzofurancarboxamides.11
It is interesting to note that regioselectivity of benzo[b]furan in th
e
reaction resembles that of indene:12 the electrophilic attack of imine
is aimed at C(2) atom rather than C(3) (as in 2,3-dihydrofuran).2,13
Compounds 4 and 5 were isolated in yields of 58–96%.†
R1
9
10
1
8
R2
11
According to the structure of compound 4a, its H NMR spec-
N
1, 2
trum exhibits signals of C6aH proton at d 5.62 ppm (dd, J 9.6 Hz,
J 2.4 Hz), C6Hax at d 3.98 ppm (d, J 2.4 Hz) and HC11b at d 4.65 ppm
(d, J 9.6 Hz). For an alternative structure of benzofuro[3,2-c]-
H
BF3·OEt2
MeCN
1
4
R1
6a
6
O
2
+
11b
H
R2
5
3
N
H
†
All new compounds have correct analytical and spectral data. Some
O
experimental details and selected spectral characteristics [1H (300 MHz),
4, 5
13C (75 MHz) NMR, GC-MS] are as follows.
1, 4: a R1 = Br, R2 = C(O)OEt
b R1 = Me, R2 = C(O)OEt
c R1 = R2 = C(O)OEt
General procedure for the preparation of compounds 4–6. BF3·OEt2
(7 ml, 7.9 mg, 0.15 mmol) was added to Shiff base 1–3 (1 mmol) in 10 ml of
MeCN with stirring, and after 10 min benzofuran (0.21 ml, 0.23 g, 2 mmol)
was added. After 1 h of stirring at 25°C the mixture was poured into water
(50 ml), extracted with ethyl acetate (2×25 ml), washed with NaHCO3
solution (15 ml), brine (20 ml), dried over MgSO4 and concentrated. The
residue was purified by column chromatography on silica gel (EtOAc–light
petroleum, 19:1) and crystallized from ethanol.
2, 5: a R1 = H, R2 = C(O)C6H4OMe-4
b R1 = F, R2 = C(O)C6H4OMe-4
c R1 = F, R2 = C(O)C6H4Cl-4
Scheme 1
Ethyl (6R*S*,6aR*,11bR*)-2-bromo-5,6,6a,11b-tetrahydrobenzo-
furo[2,3-c]quinoline-6-carboxylate 4a. Yield 89%, colourless needles,
1
mp 172.3°C. H NMR, d: 1.38 (t, 3H, Me, J 7.2 Hz), 3.98 (d, 1H, H6,
Initially, we found that the three-component condensation
gives low conversion, so we chose the traditional approach involv-
ing preliminary synthesis of imines 1 and 2. Also, it seemed
reasonable to use the Schiff bases from ethyl glyoxylates and
arylglyoxals, which, according to the literature, are the good
candidates for this purpose.8
Optimization of a solvent and a catalyst was performed for
compound 4a obtained from ethyl 4-bromophenyliminoacetate.9
The following solvents were tested: acetonitrile (89% yield),
2,2,2-trifluoroethanol (94% yield), 1,1,1,3,3,3-hexafluoropropan-
2-ol. In the last case, aromatization of 1,2,3,4-tetrahydroquinoline
core takes place giving rise to the respective benzofuro[2,3-c]-
quinoline in 55% yield along with 10% of 4a. The appropriability
of 2,2,2-trifluoroethanol as a solvent for the Povarov condensa-
tion was mentioned earlier.2(g),7(b) Catalysts [BF3·OEt2, InCl3,
Dy(OTf)3] were tested in acetonitrile. All the above mentioned
catalysts showed high activity (~89–92% yields). So, taking into
J 2.4 Hz), 4.39 (q, 3H, OCH2 + NH, J 7.2 Hz), 4.65 (d, 1H, H11b, J 9.3 Hz),
5.62 (dd, 1H, H6a, 3J 9.3 Hz, 3J 2.4 Hz), 6.53 (d, 1H, H4, J 8.4 Hz), 6.78 (m,
2 Harom), 7.06 (d, 1Harom, J 7.5 Hz), 7.11 (dd, 1H, H3, 3J 8.4 Hz, 4J 2.4 Hz),
7.16 (d, 1Harom, J 7.5 Hz), 7.41 (d, 1H, H1, 4J 2.4 Hz). 13C NMR, d: 14.2
(Me), 43.2 (C11b), 58.2 (OCH2), 62.0 (C6), 83.4 (C6a), 109.8 (C2), 111.8
(C8), 117.7 (C4), 121.0, 124.7, 126.7, 128.8, 129.1, 130.2, 130.4, 143.1 (C4a),
7a
+
·
159.1 (C ), 168.9 (C=O). GC-MS, m/z: 373 [M ]. Found (%): C, 57.49;
H, 4.45; N, 3.67. Calc. for C18H16BrNO3 (%): C, 57.77; H, 4.31; N, 3.74.
Ethyl (6R*S*,6aR*,11bR*)-2-methyl-5,6,6a,11b-tetrahydrobenzofuro-
[2,3-c]quinoline-6-carboxylate 4b, ethanol solvate. Yield 61%, colour-
less crystals, mp 144.8°C. 1H NMR, d (a mixture of two diastereomers at
C6, R:S ~ 1:1): 1.07 (t, 3H, Me, J 7.2 Hz), 1.21 (t, 3H, J 7.2 Hz, Me), 1.37
(t, 3H, Me, J 7.2 Hz), 2.23 (s, 3H, Ar–Me), 2.27 (s, 3H, Ar–Me), 3.97 (d,
1H, H6, J 2.1 Hz), 4.09 (q, 3H, OCH2, J 7.2 Hz), 4.16 (q, 3H, OCH2,
J 7.2 Hz), 4.67 (d, 1H, H11b, J 9.3 Hz), 5.63 (dd, 1H, H6a, J 9.3 and 2.1 Hz),
6.59 (d, 1Harom, J 8.7 Hz), 6.73–6.87 (m, 3Harom), 7.00–7.17 (m, 3Harom).
+
·
GC-MS, m/z: 309 [M ]. Found (%): C, 70.88; H, 6.40; N, 3.79. Calc. for
C19H19NO3·C2H5OH (%): C, 70.96; H, 7.09; N, 3.94.
© 2012 Mendeleev Communications. All rights reserved.
– 201 –

Mendeleev Commun., 2012, 22, 201–202
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a R = F
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Scheme 2
quinoline, we should have observed a dublet HC6a at downfield
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To our regret, all our attempts to produce a crystal suitable for
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annulated R*/S* diastereomers at C6 atom.
The condensation of the Schiff bases 3a,b with benzo[b]furan
required higher temperatures (70–90°C) due to the lower electro-
philicity of their imine entity; moreover, in the course of pro-
cessing such 1,2,3,4-tetrahydroquinolines underwent aromatiza-
tion affording the respective benzofuro[2,3-c]quinolines 6a,b in
moderate yields (58–60%) (see Scheme 2).‡
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6-(4-Methoxybenzoyl)-5,6,6a,11b-tetrahydrobenzofuro[2,3-c]quinoline
5a.Yield 58%, colourless crystals, mp 177.7°C. 1H NMR, d: 3.87 (s, 3H,
OMe), 4.77 (d, 1H, H11b, J 9.0 Hz), 4.86 (d, 1H, H6, J 2.1 Hz), 5.71 (dd,
1H, H6a, 3J 9.0 Hz, 3J 2.1 Hz), 6.63 (d, 1Harom, J 8.1 Hz,), 6.71 (m, 2Harom),
6.84 (m, 1Harom), 6.98 (d, 2H, H3', H5', 3J 8.7 Hz), 7.03 (m, 1Harom), 7.12
(d, 1Harom, 3J 7.8 Hz), 7.32 (d, 1Harom, 3J 7.8 Hz), 7.98 (d, 2H, H2', H6',
1
3J 8.7 Hz), NH group is not observed in the H NMR spectrum due to
+
·
proton exchange. GC-MS, m/z: 355 [M – 2]. Found (%): C, 77.18; H, 5.32;
N, 3.75. Calc. for C23H19NO3 (%): C, 77.29; H, 5.36; N, 3.92.
6-(4-Methoxybenzoyl)-2-fluoro-5,6,6a,11b-tetrahydrobenzofuro[2,3-c]-
1
quinoline 5b. Yield 75%, colourless crystals, mp 156.0°C. H NMR, d:
3.88 (s, 3H, OMe), 4.72 (d, 1H, H11b, J 9.3 Hz), 4.83 (d, 1H, H6, J 2.1 Hz),
5.67 (dd, 1H, H6a, 3J 9.3 and 2.1 Hz), 6.65 (m, 2Harom), 6.77 (m, 2Harom),
6.98–7.06 (m, 4Harom), 7.13 (d, 1Harom, J 7.2 Hz), 7.98 (d, 2H, H2', H6',
1379; (g) Z. Zhou, F. Xu, X. Han, J. Zhou and Q. Shen,
Chem., 2007, 5265; (h) E. Vicente-García, R. Ramon and R. Lavilla,
Synthesis, 2011, 2237.
Eur. J. Org.
1
J 8.7 Hz); NH group is not observed in the H NMR spectrum due to
+
·
proton exchange. GC-MS, m/z: 373 [M – 2]. Found (%): C, 73.42;
H, 4.84; N, 3.77. Calc. for C23H18FNO3 (%): C, 73.59; H, 4.83; N, 3.73.
16 (a) M. J. Alves, N. G. Azoia and A. G. Fortes, Tetrahedron, 2007, 63,
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and A. Whiting, Org. Biomol. Chem., 2004, 2, 2451; (b) D. B. Damon,
R. W. Dugger, G. Magnus-Aryitey, R. B. Ruggeri, R. T. Wester, M. Tu
and Yu. Abramov, Org. Process Res. Dev., 2006, 10, 464.
‡
2-Fluoro-6-phenylbenzofuro[2,3-c]quinoline 6a.Yield 60%, colourless
crystals, mp 164.7°C. 1H NMR, d: 7.45–7.66 (m, 6Harom), 7.78 (d, 1Harom
,
J 7.8 Hz), 8.09 (dd, 1Harom, J 9.0 and 3.0 Hz), 8.32 (m, 2Harom), 8.51 (m,
+
·
2 Harom). GC-MS, m/z: 313 [M ]. Found (%): C, 79.50; H, 3.46; N, 4.26.
Calc. for C21H12FNO (%): C, 80.50; H, 3.86; N, 4.47.
2-Bromo-6-phenylbenzofuro[2,3-c]quinoline 6b. Yield 58%, colourless
crystals, mp 178.9°C. 1H NMR, d: 7.50–7.66 (m, 5Harom), 7.78 (m, 2Harom),
8.16 (d, 1Harom, 3J 9.0 Hz), 8.35 (d, 1Harom, 3J 7.8 Hz), 8.51 (m, 1Harom),
8.61 (d, 1Harom, 4J 2.1 Hz). 13C NMR, d: 112.85, 121.27, 122.77, 122.84,
124.10, 124.65, 124.86, 124.49, 128.70, 128.90, 129.23, 130.04, 131.05,
+
·
132.18, 135.98, 143.07, 145.60, 148.35, 156.14. GC-MS, m/z: 373 [M ].
Found (%): C, 67.30; H, 3.14; N, 3.66. Calc. for C21H12BrNO (%): C, 67.40;
H, 3.23; N, 3.74.
Received: 9th February 2012; Com. 12/3875
– 202 –