First synthesis of 5-(1-ethoxyethoxy)-N-methyl-N-phenylthiophen-2-amine and its unexpected alcoholysis

Full text of DOI:10.1134/S1070428009060244

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 6, pp. 939–941. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © O.A. Tarasova, N.A. Nedolya, A.I. Albanov, L.Brandsma, B.A. Trofimov, 2009, published in Zhurnal Organicheskoi Khimii, 2009,
Vol. 45, No. 6, pp. 951–953.
SHORT
COMMUNICATIONS
First Synthesis of 5-(1-Ethoxyethoxy)-N-methyl-
N-phenylthiophen-2-amine and Its Unexpected Alcoholysis
O. A. Tarasovaa, N. A. Nedolyaa, A. I. Albanova, L. Brandsmab, and B. A. Trofimova
a Favorskii Irkutsk Institute of Chemistry, Siberian Division, Russian Academy of Sciences,
ul. Favorskogo 1, Irkutsk, 664033 Russia
e-mail: olga@irioch.irk.ru
b Utrecht University, Utrecht, the Netherlands
Received July 28, 2008
DOI: 10.1134/S1070428009060244
2-Hydroxythiophenes have long been known and
studied in sufficient detail. They are usually prepared
from α-metalated thiophene derivatives through the
corresponding tert-butyl ethers or thienylboronic acids;
in some cases they are formed as intermediate products
in the synthesis of thiophene derivatives, e.g., via Paal
cyclocondensation [1]. However, 2-hydroxythiophenes
having a disubstituted amino group in position 5 were
not described previously.
[3]. We also briefly reported on the synthesis of
3-(1-ethoxyethoxy)-N-methyl-N-phenylthiophen-2-
amine by reaction of α-lithiated 1-(1-ethoxyethoxy)-
allene with phenyl isothiocyanate; alcoholysis of this
compound readily gives 3-hydroxy-N-methyl-N-phen-
ylthiophen-2-amine which exists exclusively in the
hydroxy form [4].
However, our attempt to obtain in a similar way
5-hydroxythiophen-2-amine I gave unexpected results
[4]. Previously unknown 5-(1-ethoxyethoxy)-N-meth-
yl-N-phenylthiophen-2-amine (II) was synthesized in
87% yield from lithiated 3-(1-ethoxyethoxy)prop-1-
yne (III), phenyl isothiocyanate, and methyl iodide ac-
cording to Scheme 1. Treatment of compound II with
methanol in the presence of hydrochloric acid (with
a view to remove acetal protection), instead of ex-
pected 2-[methyl(phenyl)amino]thiophen-2-ol (I) or its
oxo tautomer IV, led to the formation of 76% of
methyl 4-[methyl(phenyl)amino]-4-thioxobutanoate
(V) as the first representative of 4-amino-4-thioxobu-
We recently proposed a new general approach to
construction of thiophene ring on the basis of reaction
of lithiated allenes and alkynes with isothiocyanates. It
ensured synthesis of 3- or 5-substituted thiophen-2-
amines in one preparative step and in good yield [2, 3].
5-Substituted N,N-dialkyl- or N-alkyl-N-arylthiophen-
2-amines are formed by cyclization of adducts of
monolithiated terminal alkynes (HC≡CCH2R, R = Me,
t-Bu, OMe, NAlk2) with isothiocyanates by the action
of superbase (t-BuOH–t-BuOK–DMSO), followed by
alkylation of cyclic intermediate at the nitrogen atom
Scheme 1.
Li
EtO
CH
Me
BuLi, THF–hexane
PhN=C=S
Me
Me
O
N
Ph
O
OEt
O
OEt
SLi
III
(1) t-BuOH
Me
(2) t-BuOK–DMSO
Ph
(3) MeI
EtO
O
N
S
Me
II
939

TARASOVA et al.
940
Scheme 2.
H+/MeOH
40°C, 5 min
Ph
Ph
Ph
MeO
HO
MeOH
HO
N
O
S
N
N
II
S
S
Me
Me
Me
I
IV
A
OH
Ph
O
Ph
N
N
MeO
Me
MeO
Me
SH
S
B
V
tanoic acid esters (Scheme 2). Neither hydroxy- (I)
nor ketothiophene (IV) was detected in the reaction
mixture.
chloride, and extracted with three portions of diethyl
ether. The extracts were combined, washed with water,
and dried over potassium carbonate, the solvent was
removed under reduced pressure, and the residue was
distilled in a vacuum. Yield 12.0 g (87%), bp 180–
185°C (~0.8 mm), nD23 = 1.5660. 1H NMR spectrum, δ,
ppm: 1.23 t (3H, CH2Me, 3J = 7.09 Hz), 1.46 d (3H,
Presumably, acid-catalyzed hydrolysis of the acetal
moiety in compound II does not stop at the stage of
formation of hydroxythiophene I but is followed by
further transformations. The driving force of these
transformations is the ability of more stable and reac-
tive thiophen-2(5H)-one IV to take up methanol mole-
cule at the carbonyl group; this process is accompanied
by opening of the thiophene ring in intermediate A and
tautomerization of open-chain intermediate B.
3
CHMe, J = 5.38 Hz), 3.24 s (3H, NMe), 3.59 d.q and
3.87 d.q (1H each, OCH2, 3JAB = 9.29 Hz), 5.16 q (1H,
3
3
OCHO, J = 5.38 Hz), 6.14 d (1H, 3-H, J3, 4
=
3
3.91 Hz), 6.39 d (1H, 4-H, J4,3 = 3.91 Hz), 6.79 m
(1H, p-H), 6.82 m (2H, o-H), 7.19 m (2H, m-H).
13C NMR spectrum, δC, ppm: 15.11 (CH2Me), 20.03
(CHMe), 41.71 (NMe), 63.27 (OCH2), 103.96
(OCHO), 108.71 (C3), 114.46 (Co), 118.82 (Cp), 119.85
(C4), 128.89 (Cm), 142.07 (Ci), 149.52 (C2), 155.62
(C5). Found, %: C 64.98; H 6.81; N 5.03; S 11.51.
C15H19NO2S. Calculated, %: C 64.95; H 6.90; N 5.05;
S 11.56.
It should be noted that acid methanolysis [5] or
hydrolysis [6] of analogous acetals of the pyrrole
series, e.g., 2-(1-ethoxyethoxy)-5-methylsulfanyl)-1H-
pyrroles obtained according to the above scheme from
1-(1-ethoxyethoxy)hept-2-yne and isothiocyanate (by
alkylation of the corresponding adduct and cyclization
of the resulting 1-aza-1,3,4-triene in the presence of
CuBr), smoothly affords 5-methylsulfanyl-1H-pyrrol-
2-ols which exist as tautomeric 2,5-dihydro-1H-pyrrol-
2-ones.
Methyl 4-[methyl(phenyl)amino]-4-thioxobutan-
oate (V). Compound II, 11 g (40 mmol), was added to
a solution of 1 ml of 30% hydrochloric acid in 30 ml of
methanol. The mixture warmed up to 40°C. After
5 min, excess methanol and volatile products were
distilled off under reduced pressure. The residue was
dissolved in diethyl ether, the solution was washed
with an aqueous solution of potassium carbonate, dried
over K2CO3, and evaporated, and the residue was dis-
tilled in a vacuum. Yield 7.24 g (76%), greenish–
yellow viscous liquid which rapidly crystallized,
bp ~160°C (0.8 mm), mp 40–42°C. IR spectrum
(KBr), ν, cm–1: 3060 w, 3043 w, 2997 w, 2944, 2935,
2910, 1737 s (C=O), 1594, 1494 s, 1472, 1454, 1435,
1404, 1386, 1362, 1335 w, 1283, 1242, 1222, 1193,
1175, 1158, 1109, 1073 w, 1018, 998 w, 982, 951, 921,
836, 810 w, 778, 703 s, 654, 609 w, 566 w, 524 w.
1H NMR spectrum, δ, ppm: 2.49 m (2H, CH2C=O),
2.69 m (2H, CH2C=S), 3.44 s (3H, OMe), 3.60 s
(NMe), 7.10 m (2H, o-H), 7.25 m (1H, p-H), 7.53 m
5-(1-Ethoxyethoxy)-N-methyl-N-phenylthiophen-
2-amine (II). A solution of 7.68 g (60 mmol) of
alkoxypropyne III in 45 ml of THF was cooled to
–30°C, a solution of 56 mmol of butyllithium in 35 ml
of hexane was added over a period of ~5 min (the mix-
ture warmed up to 8°C), the mixture was cooled to
0°C, and 6.75 g (50 mmol) of phenyl isothiocyanate
was added. The mixture was allowed to warm up to
18°C, and the subsequent reaction was accompanied
by heat evolution (the temperature rose to 35°C). The
mixture was stirred for 20 min at 28–35°C and cooled
to –30°C, and a solution of 5 g of tert-butyl alcohol
and 6 g of potassium tert-butoxide in 30 ml of DMSO
was added. The mixture was heated for 10 min at 35°C
and cooled to –10°C, 20 g of methyl iodide was added,
and the mixture was heated for 20 min at 40°C, treated
with a saturated aqueous solution of ammonium
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 6 2009

FIRST SYNTHESIS OF 5-(1-ETHOXYETHOXY)-N-METHYL-...
(2H, m-H). 13C NMR spectrum, δC, ppm: 34.76
941
REFERENCES
(CH2C=S), 38.48 (CH2C=O), 46.98 (NMe), 52.78
(OMe), 126.95 (Co), 129.84 (Cp), 131.36 (Cm), 146.61
(Ci), 174.10 (C=O), 204.57 (C=S). Signals in the NMR
spectra were assigned using two-dimensional HSQC
and HMBC techniques. Found, %: C 60.58; H 6.51;
N 5.77; S 13.51. C12H15NO2S. Calculated, %: C 60.73;
H 6.37; N 5.90; S 13.51.
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yne (III) was obtained in quantitative yield from
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trifluoroacetic acid. Butyllithium (a ~1.6 M solution in
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 6 2009