Annulated 1,2,4-triazoles. A convenient synthesis of thieno[2,3-f][1,2,4]triazolo[1,5-a]azepines: A novel triheterocyclic ring system

Article abstract of DOI:10.1055/s-2003-39392

A synthetic approach to the previously unknown thieno[2,3-f][1,2,4]triazolo[1,5-a]azepine derivatives was efficiently accomplished by cycloaddition of the bicyclic 1-aza-2-azoniaallene salts 6, derived from 6,7-dihydrobenzo[b]thiophen-4(5H)-one hydrazones 4, to the triple bond of nitriles, followed by ring enlargement. The X-ray crystal diffraction analysis of the picrate 10a provided affirmative proof for the structural assignment made.

Full text of DOI:10.1055/s-2003-39392

PAPER
1231
Annulated 1,2,4-Triazoles. A Convenient Synthesis of Thieno[2,3-f][1,2,4]tria-
zolo[1,5-a]azepines: ANovel Triheterocyclic Ring System
A
nnulated1,2,4-T
u
riazoles anrui Wang,* Zheng Li, Haiyan Yang, Feng Li, Zongbiao Ding, Fenggang Tao
Department of Chemistry, Fudan University, 200433 Shanghai, P. R. China
Fax +86(21)65641740; E-mail: qrwangb@online.sh.cn
Received 7 January 2003; revised 31 March 2003
Two principle protocols are available in the literature for
Abstract: A synthetic approach to the previously unknown
thieno[2,3-f][1,2,4]triazolo[1,5-a]azepine derivatives was efficient-
ly accomplished by cycloaddition of the bicyclic 1-aza-2-azoniaal-
lene salts 6, derived from 6,7-dihydrobenzo[b]thiophen-4(5H)-one
the synthesis of 6,7-dihydrobenzo[b]thiophen-4(5H)-one
3, which serves as the key starting material in our pro-
gram. One involves the ring construction of 4-(2-thie-
hydrazones 4, to the triple bond of nitriles, followed by ring enlarge- nyl)butyric acid with either CH3SO3H/P2O5 (PPMA) or
CF3SO3H/P2O5 (PPTMA),11 via acid chloride formation
ment. The X-ray crystal diffraction analysis of the picrate 10a pro-
vided affirmative proof for the structural assignment made.
by Lewis acid catalysis.12 The other protocol calls for the
Key words: 1-aza-2-azoniaallene cations, cycloaddition, nitriles,
ring enlargement, thieno[2,3-f][1,2,4]triazolo[1,5-a]azepines
reaction of 3-mercaptocyclohexanone with aqueous gly-
oxal. The method we chose was based on the reagents
available. Thus, according to the literature procedure,11
thiophene was allowed to react with succinic anhydride
Many benzoazepine and benzoheteroazepine compounds under AlCl3 catalysis, giving 4-oxo-4-(2-thienyl)butanoic
with an additional triazolo ring fused on the seven-mem- acid (1). The Wolff–Kishner–Minlong reduction convert-
bered ring have been extensively investigated due to their ed the -oxo acid 1 to 4-(2-thienyl)butyric acid 2, from
wide spectrum of in vivo activities.1–7 Nowadays, efforts which 6,7-dihydrobenzo[b]thiophen-4(5H)-one 3 was
are still being devoted to the structural modification of prepared via intramolecular Friedel–Crafts acylation in
these pharmaceutically important molecules, for enhanc- the presence of PPMA in overall yield of 56%
ing the activity or modifying the activity profile. By far (Scheme 1).
the greatest attempts have been concentrated on thienotri-
azoloazepines, which differ from the benzo-fused ana-
Synthesis of the target heterocycles was started with the
hydrazones 4, which were prepared by condensation of
cyclic ketone 3 with the corresponding hydrazine in etha-
nolic solution in the presence of a catalytic amount of gla-
cial acetic acid. The hydrazones 4 were subjected to
chlorination by addition of a stoichiometric amount of
tert-butyl hypochlorite at low temperatures (–30 °C
–10 °C). Work-up afforded the -chloroazo compounds 5
logues by replacing the benzene ring with a thiophene
nucleus.3–5 These novel tricyclic compounds have been
described as having selective and potent blocking effects
on D4 receptor, antagonists for platelet activating factor,
as having antiallergic properties, and also act as antipsy-
chotic agents. However, to the best of our knowledge,
only a very few fusion patterns of thieno[1,2,4]tri-
as red oils in essentially quantitative yields.
azoloazepines have been reported as compared to the mul-
More recently it came to our attention that BTMA+ICl4
–
titude of their benzo annulated counterparts. Included
(benzyltrimethylammonium tetrachloroiodate) has been
among these are derivates of the parent heterocycles
1H-thieno[3,4-c][1,2,4]triazolo[4,3-a]azepine,3 1H-thieno-
[3,2-c][1,2,4]triazolo[4,3-a]azepine,3 and 1H-thieno[3,2-
succinic anhydride
d][1,2,4]triazolo[1,5-a]azepine.4
AlCl3/CH2Cl2
r.t., 1h
CO2H
We have previously described the synthesis of various
1,2,4-triazolo[3,2-d][1,5]benzoxazepine8,9 as well as
1,2,4-triazolo[3,2-d][1,5]benzothiazepine9,10 compounds
via reaction of the allenium ions derived from chroman-4-
ones and respectively thiochroman-4-ones, with nitriles.
Mechanistically, the reaction involves an initial cycload-
dition followed by a ring enlargement. The present work
is aimed at broadening the range of thieno[1,2,4]tri-
azoloazepine heterocycles.
91%
S
S
O
1
(HOCH2CH2)2O
NH2NH2 H2O/KOH
200 °C, 3 h
PPMA
100 °C, 30 min
CO2H
82%
75%
S
2
O
S
Synthesis 2003, No. 8, Print: 05 06 2003.
3
Art Id.1437-210X,E;2003,0,08,1231,1235,ftx,en;F00503SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
Scheme 1

1232
Q. Wang et al.
PAPER
frequently used as an easy-to-prepare chlorination
agent.14 However, tert-butyl hypochlorite gave superior
results. This reagent is readily availabile, offers mild reac-
tion conditions, and is also convenient to use. Compounds
5a,b, which are susceptible to thermal or photodecompo-
sition, were employed for further transformation as de-
scribed below.
The synthesis of the title compounds is outlined in
Scheme 2. Thus, for example, a solution of the -chloroa-
zo compound 5a in anhydrous dichloromethane was al-
lowed to react with antimony pentachloride at low
temperature (–60 °C), generating the allene-like cation 6a
upon departure of the chloride ion. In general, the salts 6
are highly reactive intermediates, thus precluding their
isolation.
In the presence of a slight excess amount of acetonitrile,
cycloaddition of 6a to the triple bond of acetonitrile oc-
curred smoothly leading to the formation of the 3-spiro
substituted 3H-1,2,4-triazolium salt 7a. On elevation of
the temperature to about 35 °C, 7a underwent spontane-
ous rearrangement with insertion of the nitrogen atom into
the carbon skeleton providing the tricyclic product 8a as
white crystals in 87% yield. The other two thieno[2,3-f]
[1,2,4]triazolo[1,5-a]azepinium salts 8b and 8c were syn-
thesized in high yields under comparable conditions.
With the aim of conducting physiological evaluations, we
next considered expanding this reaction to the synthesis of
the N(3) unsubstituted neutral free bases. To this end, the
N-ester group substituted chloroazo compound 5b was
prepared and employed as the reactant. In a similar way as
described for 8a–c, the N(3)-carbethoxy substituted 8d–f
were produced. Since salts 8d–f are extremely moisture-
sensitive, they were treated directly in the same reaction
vessel with a cold solution of aqueous sodium hydroxide.
The neutral products 9a–c were obtained after usual work-
up as brown oils, which were transformed to the picrates
10a–c for characterization (Scheme 2).
Mechanistically, the reaction begins with the cycloaddi-
tion of the allene-like ions 6 to the triple bond. The five-
membered heterocyclic ring of the initial spiro adducts 7
contains, as a characteristic feature, a diazenium function,
in which the nitrogen atom in the -position to the aryl or
ester substituent exhibits a latent nitrenium character.
Subsequent migration of a substituent adjacent to the ni-
trogen atom mentioned above takes place with simulta-
neous ring enlarging annulation. We have previously
shown that the 1,2-rearrangement of carbon to electron-
deficient nitrogen in 3H-1,2,4-triazolium ions occurs with
exclusive selectivity. Although the precise factors that
govern migratory aptitude are not completely understood,
given two different substituents, the migratory aptitude
seems to parallel their ability to accommodate the respec-
tive carbocation. Studies of other substituents have shown
that the migratory aptituide of groups is H > phenyl (aryl)
> 3° alkyl > 2° alkyl > 1° alkyl > methyl approx. = cyclo-
propyl.15,16 This behavior is just what we would expect in
the present circumstances. We found that the ring enlarge-
Scheme 2
ment proceeded smoothly under mild conditions with mi-
gration of the thiophene side of the spiro compounds 7,
leading to the formation of the tricyclic compounds 8 as
the sole isolated products. Otherwise isomer 8 would
have formed through migration of the aliphatic side of the
ring (Figure 1).
R2
N
R1
N
+
N
-
SbCl6
S
8'
Figure 1
Synthesis 2003, No. 8, 1231–1235 ISSN 1234-567-89 © Thieme Stuttgart · New York

PAPER
Annulated 1,2,4-Triazoles
1233
On the other hand, it has been revealed that an electron- cantly shorter in comparison to that found in structurally
withdrawing group at N(1) in the 3H-triazolium rings ac- closely related systems.16,19 From these bond lengths it
celerates the rearrangement dramatically.15,16 In the can be surmised that there is a delocalization of electron
present examination, we chose 4a and 4b bearing a density in the 5-membered ring. Finally, all the bond
trichlorophenyl group as the starting material in order to lengths and bond angles in the two aryl rings are normal.
facilitate the final rearrangement 7 8. However, the em-
Table 1 Selected Bond Lengths (Å) and Bond Angles (deg) for 10a
ployment of the substrate 5c derived from pentafluo-
rophenyl hydrazone 4c (R1 = C6F5) failed to furnish the
Bond
Bond Length
(Deg)
Bond
Bond Length
(Deg)
expected tricyclic compounds 8 in practically useful
yields, even if other Lewis acids such as AlCl3, TiCl4,
CF3CO2Ag, etc. were used instead of SbCl5.
S1–C10
1.705(4)
1.332(4)
1.423(4)
1.323(4)
1.485(5)
1.516(6)
1.499(6)
1.426(4)
92.81(16)
130.8(3)
104.5(2))
110.6(3)
123.9(3)
124.2(3)
115.5(3)
115.1(4)
109.2(2)
126.0(3)
119.7(3)
S1–C7
1.727(3)
1.379(3)
1.300(4)
1.353(4)
1.480(5)
1.495(6)
1.359(4)
1.346(5)
110.5(2)
118.6(2)
108.4(3)
125.6(3)
106.1(3)
129.7(3)
114.9(3)
132.0(3)
118.8(3)
114.3(3)
111.9(3)
The structures of compounds 8 and 10 were principally
N1–C3
N1–N2
1
assigned by H NMR and 13C NMR spectroscopy along
N1–C8
N2–C2
with microanalyses (see experimental). For each com-
pound, the chemical shifts around 2.50–3.10 ppm arise
from the CH2CH2CH2 group and at 8.30 ppm is due to the
aryl group (R1). In the 13C NMR spectra of compounds 8
and 10 the two C=N signals are found between 155 and
164 ppm. The IR absorption at about 1560 cm–1 can be ac-
counted for by the triazole ring.
N3–C3
N3–C2
C1–C2
C3–C4
C4–C5
C6–C7
C6–C5
C7–C8
C8–C9
C9–C10
C10–S1–C7
C3–N1–C8
C2–N2–N1
N2–C2–N3
N3–C2–C1
N3–C3–C4
C3–C4–C5
C6–C5–C4
C8–C7–S1
C7–C8–N1
N1–C8–C9
C3–N1–N2
N2–N1–C8
C3–N3–C2
N2–C2–C1
N3–C3–N1
N1–C3–C4
C7–C6–C5
C8–C7–C6
C6–C7–S1
C7–C8–C9
C10–C9–C8
Crystal Structure of Compound 10a
To finally distinguish compounds 8 and the plausible iso-
mers 8 , a crystal of 10a was developed and submitted for
X-ray diffraction analysis. The results provided clear
proof of the structural assignment. The X-ray structure for
10a is shown in Figure 2 and some significant metric pa-
rameters are listed in Table 1.
In summary, we report in this paper a practical methodol-
ogy for the synthesis of novel thieno[1,2,4]triaz-
oloazepine derivatives. Full characterization data, along
with an X-ray crystallographic analysis for 10a have es-
tablished the structure. The obvious advantages of this
method include (i) the annulation mode of the products is
unprecedented in the literature and this would offer us the
opportunity to enhance the activity or modify the profile;
(ii) the reagents employed are readily accessible; (iii) the
route is short and the work-up procedure is simple; and
(iv) the overall yields are from good to excellent. To pro-
vide additional synthetic scope, we are currently testing
the possibility of incorporating a diverse range of substit-
uents on the thiophene ring. We are also exploring the ex-
tension of the strategy to other interesting analogues with
different fusion pattern of the thiophene ring, e.g.,
thieno[3,4-f]- as well as thieno[3,2-f]triazoloazepines by
employing 2,3,6,7-tetrahydro-2-thiainden-4-ones and re-
spectively 4,5-dihydrobenzo[b]thiophen-7(6H)-ones.
Figure 2 Molecular structure of compound 10a.
The molecular skeleton is a [5-7-5] tricyclic system with
a thiophene ring, an azepine ring, which adopts a twist-
boat configuration, and an essentially planar triazole ring.
The triazolo ring contains an apparently long N(1)–N(2)
distance of 1.379 (3) Å, which is typical for a single N–N
bond; however, it is slightly shorter than a N–N single
bond with a value of 1.401 Å as given by Allen.17 On the
other hand, the bonds N(3)–C(2), N(3)–C(3) and N(1)–
C(3) in the triazole ring are nearly equally long with val-
ues ranging from 1.323(4) to 1.353(4) Å which refer to a
partial double bond length and are in accordance with
those of delocalized systems such as 1.338 Å in pyri-
dine,18 whereas the bond length of N(2)–C(2) is signifi-
Synthesis 2003, No. 8, 1231–1235 ISSN 1234-567-89 © Thieme Stuttgart · New York

1234
Q. Wang et al.
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Melting points are uncorrected. Commercially available solvents
were dried by standard methods prior to use. IR spectra were record-
ed using a Mattson Alpha-centauri FT-IR spectrometer, for solids in
KBr discs and for liquids by placing a thin layer of the CCl4 soln be-
tween two KBr discs, and absorptions are given in wavenumbers
1H NMR (CDCl3): = 2.10–2.81 (m, 6 H, 3 × CH2), 6.77 (d, J = 5.5
Hz, 1 H), 7.00 (d, J = 5.5 Hz, 1 H, SC4H2), 7.10 (s, 2 H, ArH).
4-Chloro-4-(ethoxycarbonylazo)-6,7-dihydrobenzo[b]-thio-
phene (5b)
Yield: 92%; orange oil.
1
(cm–1). H and 13C NMR spectra were measured in DMSO-d6, or
CDCl3 solns on a Bruker 500 or Varian 400 spectrometer with TMS
as internal reference. Coupling constant (J) values are given in Hz.
The elemental analyses for C, H, N were obtained on a Carlo Erba
1106 elemental analyzer. Satisfactory microanalysis (C 0.20, H
0.20, N 0.30) was obtained for all new compounds. X-ray diffrac-
tion analysis of 7a was measured with a Rigaku AFC7R diffracto-
meter.
6,7-dihydrobenzo[b]thiophen-4(5H)-one,11–13 tert-butyl hypochlor-
ite20 were prepared according to literature procedures. All non-aq
reactions were performed with exclusion of moisture.
IR (neat): 1236, 1576, 1764, 2935 cm–1.
1H NMR (CDCl3): = 1.26 (t, J = 6.0 Hz, 3 H, CH3), 2.03–2.77 (m,
6 H, 3 × CH2), 4.10 (q, J = 6.0 Hz, 2 H, OCH2), 6.76 (d, J = 5.5 Hz,
1 H), 7.28 (d, J = 5.5 Hz, 1 H, SC4H2).
1,2-Disubstituted-5,6-dihydro-4H-thieno[2,3-f][1,2,4]triazo-
lo[1,5-a]azepinium Salts 8; General Procedure
The reaction was carried out in a nitrogen atmosphere. To a soln of
5 (2 mmol) and the appropriate nitrile (3 mmol) in anhyd CH2Cl2
(10 mL) was added dropwise a soln of SbCl5 (0.73 g, 2.4 mmol) in
CH2Cl2 (10 mL) at about –60 °C. The mixture was stirred at this
temperature for 2 h, then allowed gradually to warm to 30 °C (bath
temperature) and was stirred further for 1 h. The crude product was
precipitated by slow addition of Et2O. Recrystallization from
MeOH–MeCN gave pure 1,2-disubstituted-5,6-dihydro-4H-thieno-
[2,3-f][1,2,4]triazolo[1,5-a]azepinium hexachloroantimonate 8 as
crystals.
Hydrazones (4); General Procedure
A mixture of 6,7-dihydrobenzo[b]thiophen-4(5H)-one (3.05 g, 20
mmol) and the appropriate hydrazine (20 mmol) in EtOH (30 mL)
containing a catalytic amount of HOAc (ca. 1 mL) was refluxed for
3 h. After removal of solvent in vacuo, the residual solids were re-
crystallized from a suitable solvent to afford pure hydrazone 4.
6,7-Dihydrobenzo[b]thiophen-4(5H)-one (2,4,6-Trichlorophe-
nyl)hydrazone (4a)
From 6,7-dihydrobenzo[b]thiophen-4(5H)-one and (2,4,6-trichlo-
rophenyl)hydrazine. Crystallization from EtOH (95%) afforded 4a
as white-needles.
5,6-Dihydro-2-methyl-1-(2,4,6-trichlorophenyl)-4H-thieno[2,3-
f][1,2,4]triazolo[1,5-a]azepinium Hexachloroantimonate (8a)
Yield: 87%; white crystals (MeOH–MeCN, 1:1); mp 192–194 °C
(decomp).
IR (KBr): 1455, 1564, 2931, 3084 cm–1.
Yield: 90%; mp 127–129 °C.
IR (KBr): 1122, 1470, 1556, 3298 cm–1.
1H NMR (CDCl3): = 2.10–2.81 (m, 6 H, 3 × CH2), 6.77 (d, J = 5.5
Hz, 1 H), 7.00 (d, J = 5.5 Hz, 1 H, SC4H2), 7.10 (2 H, s, ArH), 7.20
(1 H, s, NH).
1H NMR (DMSO-d6): = 2.70 (s, 3 H, CH3), 2.53–3.14 (m, 6 H, 3
× CH2), 6.58 (d, 1 H, J = 5.6 Hz), 7.57 (d, 1 H, J = 5.6 Hz, SC4H2),
8.27 (s, 2 H, Cl3C6H2).
13C NMR (DMSO-d6): = 164.1, 161.1 (C=N), 141.8, 141.0, 135.7,
131.0, 127.5, 124.4, 123.9, 120.8 (aryl), 31.9, 24.9, 23.9 (CH2), 12.8
(CH3).
Anal. Calcd for C14H11Cl3N2S: C, 48.64; H, 3.21; N, 8.10. Found:
C, 48.68; H, 3.20; N, 8.16.
Anal. Calcd for C16H13Cl9N3SSb: C, 26.68; H, 1.82; N, 5.84. Found:
C, 26.56; H, 1.78; N, 5.85.
6,7-Dihydrobenzo[b]thiophen-4(5H)-one Ethoxy Carbonylhy-
drazone (4b)
From 6,7-dihydrobenzo[b]thiophen-4(5H)-one and ethyl carbazate.
Crystallization from petroleum ether (bp 60–90 °C) afforded 4b as
a white solid.
5,6-Dihydro-2-ethyl-1-(2,4,6-trichlorophenyl)-4H-thieno[2,3-
f][1,2,4]triazolo[1,5-a]azepinium Hexachloroantimonate (8b)
Yield 89%; brown solid (MeOH–MeCN, 1:1); mp 180–183 °C (de-
comp).
Yield: 90%; mp 112–114 °C.
IR (KBr): 1328, 1540, 1692, 3249 cm–1.
1H NMR (CDCl3): = 1.26 (t, J = 6.0 Hz, 3 H, CH3), 2.03–2.77 (m,
J = 6.0 Hz, 6 H, 3 × CH2), 4.10 (q, J = 6.0 Hz, 2 H, OCH2), 6.76 (d,
J = 5.5 Hz, 1 H), 7.28 (d, J = 5.5 Hz, 1 H, SC4H2), 8.33 (s, 1 H, NH).
IR (KBr): 1478, 1566, 2924, 3111 cm–1.
1H NMR (DMSO-d6): = 1.35 (t, 3 H, J = 7.5 Hz, CH3), 2.93 (q, 2
H, J = 7.5 Hz, CH2), 2.54, 3.01, 3.16 (m, 6 H, 3 × CH2), 6.58, 7.57
(d, 2 H, J = 5.6 Hz, SC4H2), 8.26 (2 H, s, Cl3C6H2).
13C NMR (DMSO-d6): = 164.7, 164.3 (C=N), 141.9, 141.1, 135.8,
131.0, 127.5, 124.2, 123.9, 120.8 (aryl), 32.0, 24.9, 23.9 (3 × CH2),
19.9 (CH2), 10.8 (CH3).
-Chloroazo Compounds (5); General Procedure
The reaction was carried out in the dark. To a soln of hydrazone 4
(10 mmol) in CH2Cl2 (10 mL) cooled between –30 °C and –10 °C
in an ice-salt bath was added dropwise over 10 min a soln of t-
BuOCl (1.25 g, 10 mmol) in CH2Cl2 (10 mL). After the mixture was
stirred for about 1 h, the resulting soln was dried (CaCl2). Thorough
removal of volatiles by rotary evaporation left the -chloroazo com-
pound 5 as a red oil, which can be stored under air at low
temperatures for prolonged times and was used without further pu-
rification.
Anal. Calcd for C17H15Cl9N3SSb: C, 27.81; H, 2.06; N, 5.72. Found:
C, 27.68; H, 2.07; N, 5.74.
5,6-Dihydro-2-propyl-1-(2,4,6-trichlorophenyl)-4H-thieno[2,3-
f][1,2,4]triazolo[1,5-a] azepinium Hexachloroantimonate (8c)
Yield 85%; brown crystals (MeOH–MeCN, 1:1); mp 172–174 °C
(decomp)
IR (KBr): 1480, 1566, 2959, 3072 cm–1.
1H NMR (DMSO-d6): = 0.99 (t, 3 H, J = 7.3 Hz, CH3), 1.83 (m, 2
H, CH2), 2.89 (2 H, t, J = 7.3 Hz, CH2), 2.55, 3.01, 3.16 (m, 6 H, 3
× CH2), 6.58, 7.56 (d, 2 H, J = 5.6 Hz, SC4H2), 8.26 (s, 2 H,
Cl3C6H2).
4-Chloro-4-(2,4,6-trichlorophenylazo)-6,7-dihydrobenzo[b]-
thiophene (5a)
Yield: 90%; deep-red oil.
IR (neat): 1141, 1551, 1571, 2968 cm–1.
Synthesis 2003, No. 8, 1231–1235 ISSN 1234-567-89 © Thieme Stuttgart · New York

PAPER
Annulated 1,2,4-Triazoles
1235
13C NMR (DMSO-d6): = 164.2, 163.8 (C=N), 141.9, 141.0, 135.8,
131.0, 127.4, 124.2, 123.9, 120.8 (aryl), 32.0, 24.9, 23.9 (3 × CH2),
27.5, 19.7 (CH2), 13.7 (CH3).
Anal. Calcd for C22H18N6O7S: C, 51.76; H, 3.55; N, 16.46. Found:
C, 51.14; H, 3.50; N, 16.11.
X-Ray Crystallographic Data for Compound 10a
Anal. Calcd for C18H17Cl9N3SSb: C, 28.89; H, 2.29; N, 5.62. Found:
C, 28.83; H, 2.29; N, 5.67.
Suitable crystals for an X-ray diffraction analysis were grown from
CHCl3–MeOH. [C16H14N6O7S], yellow prisms, FW = 434.39; tri-
clinic, space group P–1, a = 8.136 (7), b = 8.692 (7), c = 14.158
Neutral 2-Substituted-5,6-dihydro-4H-thieno[2,3-f][1,2,4]triaz-
olo[1,5-a]azepines 9 and their Picrates 10; Typical Procedure
The N-ethoxycarbonyl substituted -chloroazo compound 5b was
employed as the substrate. Instead of precipitating the heterocycles
8d–f by adding Et2O upon completion of the reaction, the resulting
mixture was chilled to 0 °C, and an aq soln of NaOH (2 N, 10 mL)
was added dropwise with vigorous stirring. Stirring was continued
for 20 min, and then the mixture was filtered. The filtrate was ex-
tracted with CH2Cl2 (3 × 20 mL), the combined extracts were
washed with H2O (2 × 20 mL) and dried over Na2SO4. Removal of
the solvent under reduced pressure afforded the neutral tricyclic
compounds 9a–c as brownish oily residues, which were trans-
formed to the picrates by addition of a sat. soln of picric acid in
MeOH. The crystals formed were filtered and recrystallized from
MeOH–CHCl3 to furnish the analytically pure 10a–c as yellow nee-
dles.
(11) Å;
= 75.171(10),
= 84.314(9), = 72.098(11)°; V =
920.7(13) Å ; Z = 2; Dcalc = 1.567 g cm–3, F(000) = 448; (Mo–
K ) = 0.71073 Å; T = 193 (2) K. A total of 4556 reflections were
measured on a Rigaku AFC7R diffractometer by employing graph-
ite-monochromated Mo–K radiation and a 12 kW rotating anode
generator; 3819 unique [Rint = 0.1033]. The structure was solved by
direct methods and expanded using Fourier techniques. The refine-
ment converged at R1 = 0.0884 and wR2 = 0.2086 for all data.
3
Acknowledgments
This work was carried out with the financial assistance of Founda-
tion for University Key Teacher by the Ministry of Education in
conjunction with the Key Organic Synthesis Laboratory of Jiangsu
Province.
5,6-Dihydro-2-methyl-4H-thieno[2,3-f][1,2,4]triazolo[1,5-a]-
azepine Picrate (10a)
References
Yield 81%; yellow needles; mp 178–182 °C (decomp).
IR (KBr): 1313, 1530, 1608, 3057 cm–1.
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1H NMR (DMSO-d6): = 2.31 (s, 3 H, CH3), 2.06, 3.13, 3.17 (m, 6
H, 3 × CH2), 4.46 (NH), 7.41, 7.47 (d, J = 5.5 Hz, 2 H, SC4H2), 8.59
[s, 2 H, (NO2)3C6H2].
13C NMR (DMSO-d6): = 160.6, 155.5 (C=N), 154.0, 141.8, 131.8,
128.8, 125.1, 124.2, 124.0, 122.3 (aryl), 27.9, 26.4, 20.8 (3 × CH2),
12.2 (CH3).
Anal. Calcd for C16H14N6O7S: C, 44.12; H, 3.22; N, 19.26. Found:
C, 44.24; H, 3.25; N, 19.35.
5,6-Dihydro-2-ethyl-4H-thieno[2,3-f][1,2,4]triazolo[1,5-a]-
azepine Picrate (10b)
Yield 79%; yellow solid; mp 204–206 °C (decomp).
IR (KBr): 1318, 1547, 1634, 3081 cm–1.
1H NMR (DMSO-d6): = 1.25 (t, J = 7.6 Hz, 3 H, CH3), 2.70 (q,
J = 7.6 Hz, 2 H, CH2), 2.07, 3.14, 3.20 (m, 6 H, 3 × CH2), 4.75
(NH), 7.43, 7.47 (d, J = 5.5 Hz, 2 H, SC4H2), 8.59 [s, 2 H,
(NO2)3C6H2].
13C NMR (DMSO-d6): = 161.1, 159.8 (C=N), 154.4, 142.3, 132.2,
129.8, 125.6, 124.7, 124.6, 122.9 (aryl), 28.4, 26.8, 21.2 (3 × CH2),
20.2 (CH2), 12.1 (CH3).
Anal. Calcd for C17H16N6O7S: C, 45.54; H, 3.60; N, 18.74. Found:
C, 45.22; H, 3.54; N, 18.51.
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2-Benzyl-5,6-dihydro-4H-thieno[2,3-f][1,2,4]triazolo[1,5-a]-
azepine Picrate (10c)
Yield 76%; yellow solid; mp 146–148 °C (decomp).
IR (KBr): 1320, 1536, 1619, 2998 cm–1.
1H NMR (DMSO-d6): = 2.06, 3.13, 3.19 (m, 6 H, 3 × CH2), 4.06
(s, 2 H, ArCH2), 7.25–7.48 (m, 7 H, ArH), 8.00 (NH), 8.60 [s, 2 H,
(NO2)3C6H2].
13C NMR (DMSO-d6): = 161.1, 158.7 (C=N), 155.1, 142.3, 137.3,
132.4, 129.4, 129.3, 128.9, 127.1, 125.6, 124.8, 124.5, 123.0 (aryl),
33.1 (CH2), 28.5, 27.2, 21.4 (3 × CH2).
Synthesis 2003, No. 8, 1231–1235 ISSN 1234-567-89 © Thieme Stuttgart · New York