Dehydration rearrangements of derivatives of methylenedihydro-benzofuran - A new path to substituted benzofurans

Article abstract of DOI:10.1023/A:1021721211363

When heated with acidic agents derivatives of 3-amino-2-(hydroxydialkylmethyl)methylene-2,3-dihydrobenzofuran undergo rapid dehyration and rearrangement to substituted 2-alkenyl-3-aminobenzofurans.

Full text of DOI:10.1023/A:1021721211363

Chemistry of Heterocyclic Compounds, Vol. 38, No. 10, 2002
DEHYDRATION REARRANGEMENTS
OF DERIVATIVES OF METHYLENEDIHYDRO-
BENZOFURAN – A NEW PATH TO
SUBSTITUTED BENZOFURANS
L. Yu. Ukhin, L. V. Belousova, Zh. I. Orlova, M. S. Korobov, and G. S. Borodkin
When heated with acidic agents derivatives of 3-amino-2-(hydroxydialkylmethyl)methylene-2,3-
dihydrobenzofuran undergo rapid dehydration and rearrangement to substituted 2-alkenyl-3-
aminobenzofurans.
Keywords: 2-alkenyl-3-aminobenzofurans, salicylaldehyde aminals, 2-alkylidene-3-amino-2,3-
dihydrobenzofuran acetylenes.
Earlier [1] we showed that the aminals of salicylaldehydes 1 in the presence of copper(I) iodide react
with terminal acetylenes, including the homologs of propargyl alcohol 2, and form propargylamines 3. The latter
undergo cyclization to derivatives of 3-amino-2-methylene-2,3-dihydrobenzofuran 4. [The synthesis of
compounds 4a,b was described in [1], and that of 4c is described in the present paper.]
OH
X
R
CH
OH
N
CuI
MeCN
CH2R3
HC
+
2
R2
2a,b
R1
1a–d
X
N
X
N
OH
R
H
CH2R3
C
H
R
OH
R2
CH2R3
R2
C
H
O
OH
R1
R1
3a
4a–c
1 a R = H, b R = NO2, c R = Cl, d R = Br; a, b R1 = H, c R1 = Cl, d R1 = Br; a X = CH2,
b-d X = O; 2 a R2 = Me, R3 = H, b R2+R3 = (CH2)4; 3 a R = R1 = H, R2 = Me, R3 = H;
4 a R = H, b, c R = NO2; a-c R1 = H, a, b R2 = Me, c R2+R3 = (CH2)4; a, b R3 = H; a X = CH2, b, c X = O
__________________________________________________________________________________________
Institute of Physical and Organic Chemistry, Rostov State University, Rostov-on-Don 344090, Russia;
e-mail: bell@ipoc.rsu.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1339-1344,
October, 2002. Original article submitted February 21, 2000.
1174
0009-3122/02/3810-1174$27.00©2002 Plenum Publishing Corporation

It can be concluded from the results in [1] that cuprous iodide catalyzes not only the Mannich reaction –
the formation of propargylamines 3 – but also cyclization of the latter to methylenedihydrobenzofurans 4.
However, further investigations showed that in individual cases the cyclization was caused by impurities present
in the samples of the employed CuI. In the absence of such impurities the reaction of the aminal 1a with the
acetylene 2a stops at the formation of propargylamine 3a. It was established that the rapid cyclization of 3a to
4a was caused by catalytic amounts of silver salts and also of the base. [Procedures for the synthesis of 4a using
silver nitrate and potassium hydroxide are described in the experimental section.]
It was suggested that further aromatization of compounds 4 does not occur on account of orbital
prohibition on the 1,3-migration of hydrogen [2], while the introduction of an additional double bond,
conjugated with the methylene group, would make the permitted 1,5-migration of hydrogen possible [2, 3]. Such
a conjugated system of double bonds must be formed during dehydration of the hydroxy derivatives 4.
It was in fact found that the action of heat on compounds 4a-c in formic acid led to rapid dehydration
and rearrangement to the respective benzofuran derivatives 5a-c (see the preliminary data in [4]):
X
N
X
N
R
R
HCOOH, ∆
–H2O
H
4a–c
CHR3
R2
CH2R3
R2
O
C
H
O
C
H
R1
R1
5a–e
a R = H, b,c R = NO2, d R = Cl, e R = Br; a-c R1 = H, d R1 = Cl, e R1 = Br; a, b R2 = Me,
c-e R2 + R3 = (CH2)4; a, b R3 = H; a X = CH2, b-e X = O
Compound 5b was also isolated after boiling from solutions of 4b in dimethoxyethane containing
catalytic amounts of sulfuric acid or p-nitrobenzoic acid. Dehydration and rearrangement under the same
conditions is also brought about by 2-formyl-4-nitrophenol, which is easily separated from the reaction products
on aluminum oxide.
It is not essential to start from previously isolated hydroxyl derivatives 4 to produce the benzofurans 5.
In certain cases "one-pot" syntheses from aminals 1, in which compounds 4 are formed in situ, are more
convenient. The benzofurans 5d,e were obtained by such a method. If, however, it is not possible to isolate even
the aminal 1, it is possible to attempt the reaction starting from the respective salicylaldehyde 6 with the
formation in situ of both the aminal 1 and the hydroxyl derivative 4:
NR42
R
CHO
OH
1. ∆, 30 min
R
2. HCOOH
4
Me
Me
2a
+
+ CuI
HNR2
+
MeCN
O
R1
R1
6
5f–h
5 f R = NO2, g, h R = Cl; f R1 = H, g, h R1 = Cl;
Me
4
4
, h –NR2
=
O
f, g –NR2
=
N
O
N
Me
Me
1175

In the last case (the benzofuran 5h) the crystalline product could only be isolated in the form of the
perchlorate.
1
The H NMR spectra of the benzofurans 5 show that the reaction results in the formation of one
geometric isomer (presumably the E-isomer). 2,6-Dimethylmorpholine from Fluka, which is a mixture of
configurational isomers, was used in the synthesis of compounds 5f, g. In these cases a mixture of compounds 5
with the two isomers of 2,6-dimethylmorpholine in approximately the same ratio (3:1) as in the initial amine
was formed. By a single recrystallization of 5f from ethanol it was possible to remove the minor isomer almost
completely. After a single recrystallization of 5g from methanol, according 1H NMR, the substance remained a
mixture of the isomers in a ratio of ~4:1.
EXPERIMENTAL
The IR spectra were recorded in vaseline oil on a Specord IR-75 instrument. The 1H NMR spectra were
recorded on a Varian UNITY-300 instrument at 300 MHz.
1-(2'-Hydroxyphenyl)-4-methyl-1-piperidino-2-pentyn-4-ol (3a). A mixture of the aminal 1a (2.74 g,
10 mmol) and the alcohol 2a (1 ml, 10.3 mmol) in acetonitrile (15 ml) was heated until the precipitate had
dissolved, and CuI (1.91 g, 10 mmol) was added. The mixture was boiled for 30 min and filtered while hot. The
filtrate was cooled, and concentrated NH4OH (20 ml) and water (40 ml) were added. The separated oil was
cooled with ice, rubbed with a rod, and left on ice for 2 h. The precipitate was filtered off and recrystallized
from hexane (25 ml). Yield 1.75 g (64%). The product formed pale-yellow crystals melting at 87-90°C (hexane).
IR spectrum, ν, cm-1: 3433, 3380 (OH); 1694 (w), 1607, 1587, 1494 (arom.); 1154 (C–O); 754 (o-disubstituted
1
benzene ring). H NMR spectrum, δ, ppm, J (Hz): 11.12 (1H, s, C(2')OH); 7.37 [1H, d, J = 7.5, C(6')H]; 7.10,
(1H, m, C(4')H); 6.74 (1H, m, C(5')H); 6.64 (1H, d, J = 8.0, C(3')H); 5.21 (1H, s, OH); 4.87 (1H, s, CH); 2.50
(4H, m, NCH2); 1.62-1.38 (12H, m, 3CH2, 2CH3). Found %: C 74.50; H 8.31; N 5.43. C17H23NO2. Calculated %:
C 74.73; H 8.42; N 5.13.
2-(2'-Hydroxy-2'-methylpropylidene)-3-piperidino-2,3-dihydrobenzofuran (4a). A. A mixture of
the aminal 1a (2.3 g, 8.4 mmol) and the alcohol 2a (0.9 ml, 9.3 mmol) in acetonitrile (15 ml) was heated until
the aminal had dissolved, and CuI (1.2 g, 6.3 mmol) was added. The mixture was boiled for 25 min, and silver
nitrate (0.2 g, 0.74 mmol) was added. It was boiled for a further 15 min and was then filtered from the red
precipitate. The filtrate was cooled, and concentrated NH4OH (20 ml) and water (40 ml) were added. The oil
that separated together with the precipitate soon began to crystallize on cooling and rubbing. The precipitate
was filtered off, washed with water, dried, and recrystallized from isooctane (40 ml) after being filtered hot
from the dark residue. Yield 1.55 g (67.7%); mp 100-103°C (twice from isooctane). IR spectrum, ν, cm-1: 3347
1
(OH); 1714 (sh); 1694 (=CH–); 1607, 1594 (arom.); 1154 (C–O); 747 (o-disubstituted benzene ring). H NMR
spectrum (deuterochloroform), δ, ppm, J (Hz): 7.37 (1H, d, J = 7.2, C(4)H); 7.23 (1H, m, C(6)H); 6.98 (1H, m,
C(5)H); 6.90 (1H, d, J = 8.0, C(7)H); 5.15 (1H, s, OH); 4.78 (1H, s, =CH; 3.05 (1H, s, CH); 2.58 (2H, m,
CH2N); 2.38 (2H, m, CH2N); 1.70-1.30 (12H, m, 3CH2, 2CH3). Found %: C 75.12; H 8.17; N 5.37. C17H23NO2.
Calculated %: C 74.73; H 8.42; N 5.13.
B. A mixture of compound 3a (0.27 g, 1 mmol) in acetonitrile (3 ml) was boiled with silver nitrate
(0.027 g, 0.1 mmol) for 15 min. A precipitate and an oil were separated with water, and the oil soon crystallized
when rubbed. It was filtered off, washed with water, and dried. Yield 0.17 g (63%). A mixed melting test on the
substance recrystallized from isooctane did not give a melting point depression with an authentic sample. The
IR spectra fully agreed.
C. A mixture of compound 3a (0.27 g, 1 mmol) in methanol (5 ml) with potassium hydroxide (0.2 g,
3 mmol) was boiled for 40 min. The oil that separated with water began to crystallize when rubbed with a rod
and was kept on ice for 1 h. The precipitate was filtered off, washed with water, and dried. Yield 0.2 g (74%).
The substance was identified by its IR spectrum and its melting point in a mixed melting test.
1176

2-[(1'-Hydroxycyclohexyl)methyl]-3-morpholino-5-nitro-2,3-dihydrobenzofuran (4c). A mixture of
the aminal 1c (1.62 g, 5 mmol) [1], 1-ethynylcyclohexanol 2b (0.9 g, 7 mmol), and cuprous iodide (1 g, 5 mmol)
in acetonitrile (10 ml) was boiled for 30 min and cooled, and concentrated NH4OH and water (50 ml) were
added. The oil that separated was removed and passed through a column of aluminum oxide (chloroform). The
solvent was evaporated, and the oil was boiled with petroleum ether and rubbed with a rod until it was
converted into a solid white precipitate. The product was cooled and filtered off. Yield 0.7 g (39%);
mp 115-117°C. IR spectrum, ν, cm-1: 3407 (OH); 1700 (C=C); 1614, 1594 (arom.); 1514, 1341 (NO2). 1H NMR
3
4
spectrum (deuterochloroform), δ, ppm, J (Hz): 8.27 (1H, d, J = 2.4, C(4)H); 8.23 (1H, dd, J = 8.8, J = 2.4,
C(6)H); 7.02 (1H, d, J = 8.8, C(7)H); 5.22 (1H, d, J = 1.5, =CH); 4.87 (1H, d, J = 1.5, C(3)H); 3.66 (4H, t,
J = 4.5, CH2O); 2.55 (1H, s, OH); 2.56 (4H, m, CH2N); 1.64 (6H, m, CH2); 1.44 (4H, m, CH2). Found %:
C 63.67; H 6.58; N 7.45. C19H24N2O5. Calculated %: C 63.33; H 6.66; N 7.77.
2-(2'-Methyl-1'-propenyl)-3-piperidinobenzofuran (5a). A 0.55-g sample of compound 4a (2 mmol)
was dissolved by heating in formic acid (3 ml). The solution was cooled, and a precipitate and an oil were
separated with water. The oil began to crystallize when cooled with ice and rubbed with a rod. The precipitate
was filtered off, washed with water, and dried. The yield of the impure product was 0.38 g (74.5%). After
recrystallization from a small amount of methanol 0.19 g of the analytically pure product was obtained; mp
100-103°C. IR spectrum, ν, cm-1: 1654 (C=C); 1607, 1581, 1560 (arom.); 741 (o-disubstituted benzene ring).
1H NMR spectrum (deuterochloroform), δ, ppm, J (Hz): 7.63 (1H, d, J = 8.5, C(7)H); 7.35 (1H, d, J = 8.5,
C(4)H); 7.14 (2H, m, C(5)H, C(6)H); 6.30 (1H, s, CH=); 3.15 (4H, m, CH2N); 2.14 (3H, s, CH3); 1.95 (3H, s,
CH3); 1.4-1.8 (6H, m, CH2). Found %: C 80.12; H 8.31; N 5.17. C17H21NO. Calculated %: C 80.00; H 8.24; N 5.49.
2-(2'-Methyl-1'-propenyl)-3-morpholino-5-nitrobenzofuran (5b). A 0.1-g sample (0.3 mmol) of
compound 4b [2] was dissolved by heating in formic acid (2 ml). The solution was boiled for 20 min and
cooled. The precipitate that separated with the addition of water (5 ml) was filtered off and dried. The yield of
the impure product was 0.076 g (85%). The product formed yellow crystals, which melted at 150-153°C
1
(methanol). IR spectrum, ν, cm-1: 1650, 1627, 1567 (C=C, arom.); 1521, 1341 (NO2); 1114 (C–O–C). H NMR
3
4
spectrum (deuterochloroform), δ, ppm, J (Hz): 8.53 (1H, d, J = 2.3, C(4)H); 8.13 (1H, dd, J = 8.9, J = 2.3,
C(6)H); 7.44 (1H, d, J = 8.9, C(7)H); 6.28 (1H, s, CH=); 3.88 (4H, m, CH2O); 3.20 (4H, m, CH2N); 2.18 (3H, s,
CH3); 2.00 (3H, s, CH3). Found %: C 63.85; H 5.97; N 9.60. C16H18N2O4. Calculated %: C 63.58; H 5.96;
N 9.27.
2-(Cyclohexylidenemethyl)-3-morpholino-5-nitrobenzofuran (5c). A mixture of the carbinol 4c
(0.2 g, 0.55 mmol) in formic acid (2 ml) was heated to boiling and cooled. The precipitate and tar that were
separated with water (5 ml) were recrystallized from ethanol. Yield 0.1 g (53%). The product formed yellow
crystals melting at 134-136°C (ethanol). IR spectrum, ν, cm-1: 1647, 1621, 1581, 1560 (C=C, arom.); 1514, 1341
1
(NO2). H NMR spectrum (deuterochloroform), δ, ppm, J (Hz): 8.50 (1H, d, J = 2.3, C(4)); 8.11 (1H, dd,
4
3J = 9.0, J = 2.3, C(6)H); 7.42 (1H, d, J = 9.0, C(7)H); 6.20 (1H, s, CH=); 3.85 (4H, m, CH2O); 3.20 (4H, m,
CH2); 2.70 (2H, m, CH2N); 2.30 (2H, m, CH2N); 1.64 (6H, m, CH2). Found %: C 66.76; H 6.73; N 8.27.
C19H22N2O4. Calculated %: C 66.66; H 6.43; N 8.19.
5,7-Dichloro-2-(cyclohexylidenemethyl)-3-morpholinobenzofuran (5d). To a solution of the aminal
1c (1.74 g, 5 mmol) and the alcohol 2b (1 ml, 7.8 mmol) in acetonitrile (10 ml), heated to boiling, we added
cuprous iodide (0.5 g, 2.5 mmol). The mixture was boiled for 30 min, and formic acid (1.5 ml) was added. It
was boiled for a further 2 min and filtered while hot. The filtrate was cooled with ice, and the precipitate was
filtered off and washed with cold acetonitrile. Yield 1 g (54%). The product formed colorless crystals melting at
158-160°C (acetonitrile). IR spectrum, ν, cm-1: 1647, 1601, 1560, 1541 (C=C, arom.); 1107 (C–O–C). 1H NMR
spectrum (deuterochloroform), δ, ppm, J (Hz): 7.50 (1H, d, J = 1.8, C(6)H; 7.20 (1H, d, J = 1.8, C(4)H); 6.29
(1H, s, CH=C); 3.90 (4H, m, CH2O); 3.19 (4H, m, CH2); 2.76 (2H, m, CH2N); 2.31 (2H, m, CH2N); 1.65 (6H, m,
CH2). Found %: C 62.27; H 6.08; Cl 19.22; N 4.12. C19H21Cl2NO2. Calculated %: C 62.29; H 5.74; Cl 19.40;
N 3.83.
1177

5,7-Dibromo-2-(cyclohexylidenemethyl)-3-morpholinobenzofuran (5e). To a boiling mixture of the
aminal 1d (1.45 g, 3.3 mmol) and the alcohol 2b (1 ml, 7.8 mmol) in acetonitrile (10 ml) we added cuprous
iodide (0.5 g, 2.5 mmol). The mixture was boiled for 30 min, and formic acid (1.5 ml) was added. The mixture
was boiled for a further 2 min and filtered while hot. The precipitate was washed with hot acetonitrile. The
colorless crystalline precipitate that separated when the filtrate was cooled with ice was filtered off and washed
with cold acetonitrile. Yield 0.8 g (53%); mp 138-140°C (ethanol). IR spectrum, ν, cm-1: 1647, 1601, 1554,
1
1541 (C=C, arom.); 1107 (C–O–C). H NMR spectrum (deuterochloroform), δ, ppm, J (Hz): 7.68 (1H, d,
J = 1.8, C(6)H); 7.47 (1H, d, J = 1.8, C(4)H); 6.25 (1H, s, CH=C); 3.87 (4H, m, CH2O); 3.16 (4H, m, CH2); 2.78
(2H, m, CH2N); 2.29 (2H, m, CH2N); 1.64 (6H, m, CH2). Found %: C 49.73; H 4.89; Br 35.47; N 3.45.
C19H21Br2NO2. Calculated %: C 50.11; H 4.62; Br 35.16; N 3.08.
3-(2',6'-Dimethylmorpholino)-2-(2'-methyl-1'-propenyl)-5-nitrobenzofuran (5f). A mixture of
5-nitrosalicylaldehyde (1.2 g, 7.2 mmol) and 2,6-dimethylmorpholine (1.75 ml, 15 mmol) in acetonitrile (10 ml)
was heated to boiling, and the alcohol 2a (1 ml, 10.3 mmol) was added. The mixture was boiled for 5 min, and
cuprous iodide (0.3 g, 1.5 mmol) was added. The mixture was boiled for 30 min, formic acid (1.5 ml) was
added, and the mixture was filtered while hot. The filtrate was cooled with ice, and the yellow crystalline
precipitate that separated was filtered off and washed with cold ethanol. Yield 1.15 g (49%) (ethanol). IR
1
spectrum, ν, cm-1: 1654, 1621, 1567 (C=C, arom.); 1527, 1341 (NO2); 1081 (C–O–C). H NMR spectrum
(deuterochloroform), δ, ppm, J (Hz): 8.48 (1H, d, J = 2.3, C(4)H); 8.11 (1H, dd, 3J = 9.0, 4J = 2.3, C(6)H); 7.42
(1H, d, J = 9.0, C(7)H); 6.24 (1H, t, J = 1.3, CH=C); 3.84 (2H, m, CHO); 2.94 (4H, m, CH2N); 2.15 (3H, s,
CH3); 1.98 (3H, s, CH3); 1.23 (3H, s, CH3); 1.21 (3H, s, CH3). Found %: C 65.98; H 7.00; N 8.73. C18H22N2O4.
Calculated %: C 66.26; H 6.75; N 8.59.
3-(2',6'-Dimethylmorpholino)-5,7-dichloro-2-(2'-methyl-1'-propenyl)benzofuran (5g). A mixture of
0.8 g (4.2 mmol) of 3,5-dichlorosalicylaldehyde and 1.25 ml (11 mmol) of 2,6-dimethylmorpholine in 10 ml of
acetonitrile was heated to boiling, 1 ml (10.3 ml) of the alcohol (2a) was added, 0.25 g (1.25 mmol) of cuprous
iodide was added, and the mixture was boiled for 30 min. Formic acid (1.5 ml) was added, and the mixture was
filtered while hot and cooled with ice. The crystalline precipitate that separated after rubbing with a glass rod
was filtered and washed with cold methanol. Yield 0.77 g (52%). The product formed colorless crystals melting
1
-1
at 110-116°C (from methanol). IR spectrum, ν, cm : 1654, 1601, 1560 (C=C, arom.); 1081 (C–O–C). H NMR
spectrum, δ, ppm, J (Hz): 7.45 (1H, d, J = 2.1, C(6)H); 7.18 (1H, d, J = 2.1, C(4)H); 6.23 (1H, s, CH=); 4.12
(0.4H, m, CH2O); 3.80 (1.6H, m, CH2O); 3.18 (0.8H, m, CH2N); 2.88 (3.2H, m, CH2N); 2.19 (3H, s, CH3); 1.97
(3H, s, CH3); 1.34 (0.6H, s, CH3); 1.31 (0.6H, s, CH3); 1.21 (2.4H, s, CH3); 1.11 (2.4H, s, CH3). Found %: C
60.78; H 6.21; Cl 19.70; N 4.12. C18H21Cl2NO2. Calculated %: C 61.02; H 5.93; Cl 20.06; N 3.95.
5,7-Dichloro-3-(N-methylpiperazino)-2-(2'-methyl-1'-propenyl)benzofuran Perchlorate (5h). A
mixture of 3,5-dichlorosalicylaldehyde (0.8 g, 4.2 mmol) and N-methylpiperazine (1.1 ml, 7.6 mmol) in
acetonitrile (10 ml) was heated to boiling, the alcohol 2a (1 ml, 10.3 mmol) was added, cuprous iodide (0.25 g,
1.25 mmol) was added, and the mixture was boiled for 30 min. Formic acid (1.5 ml) was added to the boiling
mixture, the solution was filtered while hot, the filtrate was cooled, water (30 ml) was added, the precipitate was
filtered off, and concentrated NH4OH (10 ml) was added to the filtrate. The released dark oil was separated and
passed through a column of aluminum oxide (chloroform). The solvent was evaporated, the light oil was
dissolved in ether, and 70% perchloric acid (0.5 ml) was added. The crystalline precipitate was filtered off
(0.7 g) and recrystallized from 2-propanol (30 ml). The yield of the pure product was 0.52 g (28%);
mp 225-230°C (decomp.). IR spectrum, ν, cm-1: 3080 (NH+); 1647, 1600, 1567 (C=C, arom.); 1100 (ClO4).
1H NMR spectrum (deuterochloroform), δ, ppm, J (Hz): 8.96 (1H, s, NH+); 7.45 (1H, s, C(6)H); 7.17 (1H, s,
C(4)H); 6.16 (1H, s, CH=C); 3.80 (4H, m, CH2N); 3.20 (1H, m, CH2N); 3.08 (3H, s, NCH3); 2.19 (3H, s, CH3);
1.90 (3H, s, CH3). Found %: C 46.20; H 5.08; Cl 24.25; N 6.23. C17H20Cl2N2O·HClO4. Calculated %: C 46.42;
H 4.78; Cl 24.23; N 6.37.
1178

The work was carried out with financial support from the Russian Fund of Fundamental Research
(Grant No. 97-0332894a).
REFERENCES
1.
2.
3.
4.
L. Yu. Ukhin, V. N. Komissarov, S. V. Lindeman, V. N. Khrustalev, and Yu. T. Struchkov, Izv. Akad.
Nauk, Ser. Khim., 455 (1994).
T. I. Temnikova and S. N. Semenova, Molecular Rearrangements in Organic Chemistry [in Russian],
Khimiya, Leningrad (1983), p. 49.
L. Yu. Ukhin, Zh. I. Orlova, O. V. Shishkin, and Yu. T. Struchkov, Izv. Akad. Nauk, Ser. Khim., 1222
(1996).
L. Yu. Ukhin and L. V. Belousova, in: IV All-Russian Seminar on Magnetic Resonance. Abstracts
[in Russian], Rostov-on-Don (1998), p. 104.
1179