New approach to the formation of azepine ring: Synthesis of 2-methyl-6-(5-methyl-2-thienyl)-3H-azepine from 2-methyl-5-propargylthiophene and isothiocyanate

Article abstract of DOI:10.1007/s10593-008-0161-y

The first representative of thienyl-substituted 3H-azepines has been synthesized starting from dilithiated 2-methyl-5-propargylthiophene and isopropyl isothiocyanate. It was shown that N-(1-methylethylidene)-2-(5-methyl- 2-thienyl)-1-(methylthio)-1,3-butadiene-1-amine (2-aza-1,3,5-triene) formed as a result of this reaction is readily converted into 2-methyl-6-(5-methyl-2- thienyl)-3H-azepine under the action of super bases.

Full text of DOI:10.1007/s10593-008-0161-y

Chemistry of Heterocyclic Compounds, Vol. 44, No. 9, 2008
NEW APPROACH TO THE FORMATION
OF AZEPINE RING: SYNTHESIS OF 2-METHYL-
6-(5-METHYL-2-THIENYL)-3H-AZEPINE
FROM 2-METHYL-5-PROPARGYLTHIOPHENE
AND ISOTHIOCYANATE*
N. A. Nedolya, O. A. Tarasova, O. G. Volostnykh, and A. I. Albanov
The first representative of thienyl-substituted 3H-azepines has been synthesized starting from dilithiated
2-methyl-5-propargylthiophene and isopropyl isothiocyanate. It was shown that N-(1-methylethylidene)-
2-(5-methyl-2-thienyl)-1-(methylthio)-1,3-butadiene-1-amine (2-aza-1,3,5-triene) formed as a result of
this reaction is readily converted into 2-methyl-6-(5-methyl-2-thienyl)-3H-azepine under the action of
super bases.
Keywords: azatrienes, 3H-azepines, deprotonation, isothiocyanates, propargylthiophene,
electrocyclization.
The reaction of dilithiated 2-methyl-5-propargylthiophene 1 with isothiocyanates leads, depending on
the structure of the latter, with a high degree of selectivity to an exotic bicyclic systems, viz. poly-substituted
2,3'-bithiophenes 2, 1-(2-thienyl)cyclobutenes 3, and 3-(2-thienyl)thietane 4 [1].
While continuing these investigations we have found that the conjugated 2-aza-1,3,5-triene 5, readily
obtained from the adduct of dilithiated 2-methyl-5-propargylthiophene with isopropyl isothiocyanate
(intermediate 6, R = i-Pr), interacts with potassium tert-butoxide (THF–DMSO, 4.5:1, -30°C, 30 min) with the
formation of the previously unknown and unavailable 2-methyl-6-(5-methyl-2-thienyl)-3H-azepine (7), the
nonoptimized yield of which was 45%.
1
The structure of azepine 7 was established on the basis of data of elemental analysis and H and 13C
NMR spectra. Heteronuclear (HSQC and HMBC) two-dimensional correlation methods were used to assign the
carbon atom signals in the 13C NMR spectra.
The whole process, from lithiation of the available 2-methyl-5-propargylthiophene [2] to formylation of
the azepine nucleus, was carried out in three preparative stages: 1) one-pot synthesis of 1-aza-1,3,4-triene 8; 2)
thermally induced isomerization of 1-aza-1,3,4-triene 8 into 2-aza-1,3,5-triene 5 (through a [1,5]-H sigmatropic
shift); 3) rapid transformation of 2-aza-1,3,5-triene 5 into azepine 7 under the action of t-BuOK (through
intermediates 9 and 10).
_______
* Dedicated to Academician B. A. Trofimov of the Russian Academy of Sciences on his 70th jubilee.
__________________________________________________________________________________________
A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences, Irkutsk
664033; e-mail: nina@irioch.irk.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1380-
1383, September, 2008. Original article submitted July 3, 2008.
0009-3122/08/4409-1113©2008 Springer Science+Business Media, Inc.
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2-Aza-1,3,5-trienes, obtained from monolithiated allenic acetals, are subject to highly selective
reorganization under the action of superbases into structural isomers of the azacycloheptadiene series, viz.
2-(methylsulfanyl)-4,5-dihydro-3H-azepines [3].
It is evident that the implication into this reaction of other isothiocyanates containing sec-alkyl and
cycloalkyl substituents like other propargylthiophenes offers an effective synthetic approach to previously
unknown azepine–thiophene ensembles as promising basic compounds for the construction of new medicinal
agents and materials for critical technology [4-8].
EXPERIMENTAL
1
The H and 13C NMR spectra (400 and 100 MHz respectively) and the experiments on heteronuclear
correlation were carried out on Bruker DPX 400 and AV-400 instruments in CDCl3, internal standard was
HMDS.
N-(1-Methylethylidene)-2-(5-methyl-2-thienyl)-1-(methylsulfanyl)-1,3-butadienylamine
(2-Aza-
1,3,5-triene 5). A solution of BuLi (102 mmol) in hexane (64 ml) was added with vigorous stirring at –100°C in
an atmosphere of argon to a solution of 2-methyl-5-propargylthiophene (6.81 g, 50 mmol) in dry THF (110 ml).
The mixture was stirred for 10 min at 10-12°C, then cooled to -90oC, and isopropyl isothiocyanate (5.05 g,
50 mmol) added. The mixture was stirred for 15 min at about -30oC, cooled to -55°C, and t-BuOH (3.7 g,
50 mmol) added. The temperature was allowed to rise to -40oC, the mixture cooled to -80°C, MeI (23 g,
16 mmol) was added, and the cooling removed. The mixture was stirred for 2 h at ~20°C, cooled to -80°C,
saturated aqueous NH4Cl solution (100 ml) was added, and the organic layer separated. The products from the
aqueous fraction were extracted with ether (4×30 ml), the combined organic fraction was washed with water
(2×50 ml), and dried over MgSO4. The solvents were removed at ~20°C under reduced pressure. The residue
(15.57 g) was chromatographed on a column of neutral Al2O3 [eluent petroleum ether (40-70°C)], methyl
N-isopropyl-2-(5-methyl-2-thienyl)-2,3-butadieneimidothioate (1-aza-1,3,4-triene 8, mixture of syn and anti
isomers) mixed with 2-aza-1,3,5-triene 5 in a ratio of 88:12 was obtained (7.41 g, 59%) . 1H NMR spectrum, δ,
3
ppm (J, Hz): 1.08 (6H, d, J = 6.24, (CH3)2CH); 2.35 (3H, s, SCH3); 2.41 (3H, s, 5'-CH3); 3.86 (1H, hept,
3
3J = 6.24, Me2CH); 5.21 (2H, s, CH2=); 6.62, 6.58 (2H, two d, J = 2.68, H-3',4' thienyl) – major isomer; 1.23
(6H, d, 3J = 6.24, (CH3)2CH); 2.33 (3H, s, SCH3); 2.41 (3H, s, 5'-CH3); 3.92 (1H, hept, 3J = 6.24, Me2CH); 5.31
(2H, s, CH2=); 6.78, 6.58 (2H, two d, 3J = 2.68, H-3',4' thienyl) – minor isomer; ratio 61:39.
The quantitative isomerization of 1-aza-1,3,4-triene 8 into 2-aza-1,3,5-triene 5 was effected by rotating a
1
sample in a rotary evaporator at 74-82°C (bath temperature) for 10 min. H NMR spectrum, δ, ppm (J, Hz):
1.94, 2.01 (6H, two s, (CH3)2C=): 2.22 (3H, s, SCH3); 2.48 (3H, s, 5'-CH3); 4.77 (1H, dd, Jtrans = 17.05,
J
gem = 1.4, CH2=); 4.84 (1H, dd, Jcis = 10.64, Jgem = 1.4, CH2=); 6.36 (1H, dd, Jcis = 10.64, Jtrans = 17.05, CH=);
6.68 (2H, s, H-3',4' thienyl). 13C NMR spectrum, δ, ppm: 13.94 (SCH3); 15.44 (5'-CH3); 21.60, 27.57
((CH3)2C=)); 112.13 (CH2=); 113.41 (C-2); 124.82, 133.74 (C-3', C-4' thienyl); 128.66 (CH=); 135.81 (C-1);
140.24 (C-2' thienyl); 145.61 (C-5' thienyl); 172.47 (C=N).
2-Methyl-6-(5-methyl-2-thienyl)-3H-azepine (7). A mixture of DMSO (10 ml) and THF (10 ml) and
then t-BuOK (3.81 g, 34 mmol) were added to a solution of 2-aza-1,3,5-triene 5 (7.13 g, 28 mml) in THF
(35 ml) at -65°C. The mixture was stirred at ~-30°C for 30 min, cooled to -60oC and water (100 ml) added. After
separating the layers the products of the aqueous fraction were extracted with ether (4×40 ml), the combined
organic fraction was washed with water (3 times), dried over MgSO4, and the solvents removed under reduced
pressure. The residue was purified by column chromatography [through a 3-4 cm layer of neutral Al2O3, eluent
was petroleum ether (40-70°C)–Et2O, 10:1]. Azepine 7 (2.59 g, 45%) was obtained as fine, light- brown
1
crystals, mp 56°C. H NMR spectrum, δ, ppm (J, Hz): 2.15 (3H, s, 2-CH3); 2.44 (3H, s, 5'-CH3); 5.39 (1H, dt,
3
3
4
3
3J4,5 = 8.83, J4-CH2-3 = 6.91, H-4); 6.45 (1H, dd, J5,4 = 8.83, J5,7 = 1.66, H-5); 6.64 (1H, dq, J4',3' = 3.58,
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4J4',Me = 1.02, H-4' thienyl); 6.81 (1H, d, 3J3',4' = 3.58, H-3' thienyl); 7.65 (1H, br. s, H-7). 13C NMR spectrum, δ,
ppm: 15.31 (5'-CH3); 26.21 (2-CH3); 38.35 (C-3); 116.61 (C-4); 123.14 (C-6); 123.62 (C-3' thienyl); 125.83
(C-4' thienyl); 127.0 (C-5); 136.69 (C-7); 138.76 (C-5' thienyl); 141.76 (C-2' thienyl); 149.90 (C-2). Found, %:
C 71.36; H 6.55; N 6.94; S 16.49. C12H13NS. Calculated, %: C 70.89; H 6.45; N 6.86; S 15.77.
The work was carried out with the financial supportof the Russian Foundation for Fundamental
Investigations (RFFI) (grant No. 05-03-32578a).
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