First synthesis of 2-aminothiophen-3-ols

Full text of DOI:10.1134/S1070428009040289

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 4, pp. 626–628. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © N.A. Nedolya, O.A. Tarasova, L. Brandsma, B.A. Trofimov, 2009, published in Zhurnal Organicheskoi Khimii, 2009, Vol. 45, No. 4,
pp. 639–641.
SHORT
COMMUNICATIONS
First Synthesis of 2-Aminothiophen-3-ols
N. A. Nedolyaa, O. A. Tarasovaa, L. Brandsmab, and B. A. Trofimova
a Favorskii Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences,
ul. Favorskogo 1, Irkutsk, 664033 Russia
e-mail: nina@irioch.irk.ru
b Utrecht University, Utrecht, The Netherlands
Received July 16, 2008
DOI: 10.1134/S1070428009040289
Development of new improved procedures for the
synthesis of functionalized thiophene derivatives and
discovery of their new important applications, e.g., in
pharmacology (as medicines or their precursors), opto-
electronics, and molecular electronics (as dyes, liquid
crystalline photoswitches, organic transistors, conduct-
ing materials, etc.), continuously stimulate studies in
the field of thiophene chemistry [1].
Precursors of 2-aminothiophen-3-ols II, N-alkyl-
N-aryl-3-(1-ethoxyethoxy)thiophen-2-amines III (first
representatives of aminothienyl acetals), were formed
in a good yield (74%, Ar = Ph, R = Me) by reaction of
α-lithiated 1-(1-ethoxyethoxy)allene (IV) with aromat-
ic isothiocyanate (e.g., commercially available phenyl
isothiocyanate), followed by treatment of adduct V
first with tert-butyl alcohol and then with t-BuOK–
DMSO and alkylation of cyclic intermediate at the ni-
trogen atom. The acetal protection is removed from
thiophene III by methanolysis in the presence of
hydrogen chloride (45–50°C, 5 min) to give 95% of
2-aminothiophen-3-ol II.
We recently reported on novel reactions of lithiated
allenes and acetylenes with isothiocyanates, which
lead to the formation of fundamental nitrogen- and
sulfur-containing heterocycles [2], including 3- [2, 3]
and 5-substituted thiophen-2-amines [2, 4] and thio-
phen-2(5H)-imines [5]. While continuing studies in
this line, we found that the use of accessible 1-(1-eth-
oxyethoxy)allene (I) [6] as starting compound makes it
possible to readily obtain previously unknown 2-[alkyl-
(aryl)amino]thiophen-3-ols II which exist almost ex-
clusively as hydroxy tautomers [7]. In the present
communication we describe the first example of the
corresponding reaction sequence.
It should be noted that the alcoholysis process is not
inhibited despite the presence in molecule III of
an amino group capable of binding hydrogen chloride.
Presumably, unlike aliphatic amines, less basic aromat-
ic amines with mineral acids form considerably weaker
salts, so that some amount of free acid is always
present in equilibrium with the salt, and it is capable of
catalyzing electrophilic process. As we showed previ-
CH2
CH2
CH2
BuLi, THF–hexane
PhN=C=S
Me
·
Me
·
Me
·
SLi
Ph
EtO
O
EtO
O
Li
EtO
O
N
I
IV
V
OEt
(1) t-BuOH
O
OH
(2) t-BuOK–DMSO
(3) MeI
Me
Ph
H+, MeOH
Ph
N
N
S
S
Me
Me
III
II
626

FIRST SYNTHESIS OF 2-AMINOTHIOPHEN-3-OLS
627
ously [8], N-benzyl- and N,N-dimethylaniline hydro-
chlorides catalyze addition of propan-2-ol to butoxy-
ethene with formation of the corresponding acetal.
N-Aryl-N-hetarylamines are expected to give even
weaker hydrochlorides; therefore, protolysis of acetal
III was successful under fairly mild conditions. On the
other hand, the acetal moiety in N,N-dialkyl-3-(1-eth-
oxyethoxy)thiophen-2-amines obtained from allene I
and alkyl isothiocyanates remained unchanged under
analogous conditions, whereas more severe conditions
promoted profound decomposition.
cooled to –10°C, and the mixture was heated for 5 min
at 45–50°C. A few drops of a saturated aqueous solu-
tion of potassium carbonate were added, and methanol
and volatile alcoholysis products were removed on
a rotary evaporator. The residue was a brown liquid
which was treated with 30 ml of water and extracted
with two portions of diethyl ether. The extracts were
washed with water, dried over MgSO4, and evaporated
under reduced pressure to isolate 2.45 g (95%) of com-
pound II containing 96% of the main substance
(GLC). IR spectrum, ν, cm–1: 3462 s (OH), 3104 v.w,
3063 v.w, 3036 v.w, 2993 v.w, 2939 v.w, 2879 v.w,
2813 v.w, 1598 v.s, 1580 v.s, 1498 v.s, 1474, 1449,
1421, 1399, 1336, 1322, 1295, 1282, 1253, 1182 s,
1169, 1121, 1088, 1042, 979 s, 875, 843, 814, 753 s,
3-(1-Ethoxyethoxy)-N-methyl-N-phenylthio-
phen-2-amine (III). (1-Ethoxyethoxy)allene (I), 16 g
(125 mmol), was added in one portion to a solution
of 112 mmol of butyllithium in a mixture of 70 ml
of hexane and 90 ml of tetrahydrofuran, cooled to
–100°C. The mixture warmed up to –55°C and was
stirred for 10 min at −65 to −60°C and cooled to
–90°C, 13.5 g (100 mmol) of phenyl isothiocyanate
was added, and the mixture was stirred for 20 min at
−65 to −60°C. A solution of 10 ml of tert-butyl alcohol
in 15 ml of diethyl ether was added, and a suspension
of 14 g (125 mmol) of potassium tert-butoxide in 50 g
of DMSO was then added. When the temperature
reached –13°C (~10 min), 40 g (282 mmol) of methyl
iodide was added, and the mixture was heated for
20 min at 35–45°C, cooled to 20°C, treated with a sat-
urated aqueous solution of NH4Cl, and extracted with
diethyl ether (2×50 ml). The extracts were combined,
washed with five portions of water, and dried over
potassium carbonate, the solvent was removed under
reduced pressure, and the residue (30.07 g) was
distilled in the presence of ~2 ml of diethylamine.
Yield 20.41 g (74%), purity 100% (GLC), bp ~160°C
1
728 s, 693 s, 669, 645, 569, 547, 514, 452. H NMR
3
spectrum, δ, ppm: 7.22 t (2H, m-H, J = 8.73 Hz),
3
6.98 d and 6.70 d (1H each, 4-H, 5-H, J = 6.0 Hz),
3
6.83 t (1H, p-H, J = 8.16 Hz), 6.75 m (2H, o-H),
4.90 br.s (1H, OH), 3.21 s (3H, NMe). 13C NMR spec-
trum, δC, ppm: 148.94 (C3), 148.15 (Ci), 129.27 (Cm),
125.94 (C2), 120.84 (C5), 119.22 (C4), 118.10 (Cp),
113.94 (Co), 40.86 (NMe). Found, %: C 64.55; H 5.31;
N 6.74; S 15.33. C11H11NOS. Calculated, %: C 64.36;
H 5.40; N 6.82; S 15.62.
The IR spectra were recorded on a Bruker IFS-25
spectrometer from samples prepared as thin films. The
13
1H and C NMR spectra were measured on a Bruker
DPX-400 spectrometer at 400.13 and 100.61 MHz, re-
spectively, using CDCl3 as solvent and hexamethyldi-
13
siloxane as internal reference. Signals in the C NMR
spectra were assigned using HSQC two-dimensional
heteronuclear correlation technique; two-dimensional
NMR experiments were performed on a Bruker AV-
400 instrument. Gas–liquid chromatography was per-
formed on a Varian 3400 chromatograph equipped
with a flame ionization detector and a DB-5 capillary
column, 15 m×0.53 mm, film thickness 1.5 μm; car-
rier gas nitrogen.
(0.8 mm), nD20 = 1.5700. H NMR spectrum, δ, ppm:
1
7.17 t (2H, m-H, 3J = 8.06 Hz), 6.94 d (1H, 4-H, 3J4,5
=
3
6.04 Hz), 6.83 d (1H, 5-H, J5,4 = 6.04 Hz), 6.76 m
3
(3H, o-H, p-H), 5.13 q (1H, OCHO, J = 5.27 Hz),
3.71 d.q and 3.42 d.q (1H each, OCH2, 2JAB = 9.27 Hz),
3
3.22 s (3H, NMe), 1.31 d (3H, CHCH3, J = 5.27 Hz),
3
1.12 t (3H, CH2CH3, J = 7.07 Hz). 13C NMR spec-
All operations were carried out under nitrogen.
Liquid nitrogen was used as cooling agent. Tetrahydro-
furan was purified by treatment with finely dispersed
potassium hydroxide (~50 g/l), followed by distillation
over LiAlH4 in the presence of benzophenone under
nitrogen. 1-(1-Ethoxyethoxy)allene (I) was prepared
according to the procedure described in [6]. Butyl-
lithium (a ~1.6 M solution in hexane) and the other
reagents and solvents used in this work were com-
mercial products.
trum, δC, ppm: 149.84 (C3), 147.29 (C2), 132.93 (Ci),
128.70 (Cm), 120.60 (C5), 119.62 (C4), 118.19 (Cp),
113.54 (Co), 101.50 (OCHO), 62.25 (OCH2), 40.32
(NMe), 20.45 (CHCH3), 15.00 (CH2CH3). Found, %:
C 65.03; H 6.74; N 5.13; S 11.40. C15H19NO2S. Cal-
culated, %: C 64.95; H 6.90; N 5.05; S 11.56.
2-[Methyl(phenyl)amino]thiophen-3-ol (II). One
drop of 30% hydrochloric acid and 3.5 g (12.6 mmol)
of thiophene III were added to 50 ml of methanol
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NEDOLYA et al.
lya, N.A., and Dmitrieva, G.V., Abstracts of Papers,
628
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