Application of the Thorpe-Ziegler reaction for the synthesis of functionalized thiophenes, thienopyrimidines, and thienotriazines

Article abstract of DOI:10.1023/A:1016049204323

Approaches to the synthesis of 3-aminothiophene-2,4-dicarboxylic acid derivatives and to their conversions into thieno[3,4-d]pyrimidines, thieno[3,4-d]-1,2,3-triazines, and thieno[3,2-d]pyrimidines are developed.

Full text of DOI:10.1023/A:1016049204323

854
Russian Chemical Bulletin, International Edition, Vol. 51, No. 5, pp. 854—859, May, 2002
Application of the Thorpe—Ziegler reaction for the synthesis of
functionalized thiophenes, thienopyrimidines, and thienotriazines
S. A. Ryndina,a A. V. Kadushkin,a N. P. Solov´eva,b and V. G. Granika
ꢀ
aState Scientific Center of the Russian Federation
"Organic Intermediate Products and Dyes Institute" (NIOPIK),
1/4 ul. Bol´shaya Sadovaya, 103787 Moscow, Russian Federation.
Fax: +7 (095) 254 9724. Eꢀmail: alex111x@yandex.ru
bCenter of Drug Chemistry,
AllꢀRussian Research Chemical Pharmaceutical Institute,
7 Zubovskaya pl., 119815 Moscow, Russian Federation.
Fax: +7 (095) 246 7805
Approaches to the synthesis of 3ꢀaminothiopheneꢀ2,4ꢀdicarboxylic acid derivatives and
to their conversions into thieno[3,4ꢀd]pyrimidines, thieno[3,4ꢀd]ꢀ1,2,3ꢀtriazines, and
thieno[3,2ꢀd]pyrimidines are developed.
Key words: enamines, the Thorpe—Ziegler cyclization, thiophenes, pyrimidines, 1,2,3ꢀtriꢀ
azines.
Scheme 1
The Thorpe—Ziegler reaction is one of the most promꢀ
ising lines in the chemistry of fiveꢀmembered heteroꢀ
cycles, which makes it possible to obtain variously subꢀ
stituted 3ꢀaminofurans, ꢀpyrroles, and ꢀthiophenes.1,2
Recently,3 we have used this reaction to convert βꢀenamiꢀ
no nitriles into 3ꢀaminopyrrole derivatives. The goal of
the present work was the search for a general approach
to the synthesis of functionalized 3ꢀaminothiophenes and
studies of their transformations into fused heterocyclic
systems containing a thiophene fragment.
Results and Discussion
2ꢀCyanoꢀ3ꢀdimethylaminobutꢀ2ꢀenamide derivatives
1a—f were chosen as the starting compounds. These are
obtained by reactions of the corresponding cyanoꢀ
acetamides with N,Nꢀdimethylacetamide diethyl acetal.
There are some data indicating that (1ꢀethoxyethylꢀ
idene)malononitrile4 and enamino ketones of the 3ꢀ[(diꢀ
methylamino)methylidene]tetrahydrofuranꢀ2ꢀone series5
react with alkanethiols to give the corresponding substiꢀ
tuted 2ꢀalkylthio olefins. Based on these data, we studꢀ
ied the reactions of compounds 1a—f with ethyl thioꢀ
glycolate in the presence of K2CO3, which probably ocꢀ
cur via intermediates 2a—f. The latter undergo the
Thorpe—Ziegler cyclization into ethyl 3ꢀaminoꢀ4ꢀNꢀ
Rꢀcarbamoylꢀ5ꢀmethylthiopheneꢀ2ꢀcarboxylates 3a—f
(Scheme 1). The first member of this series, namely,
compound 3a, is smoothly dehydrated upon heating with
POCl3 in MeCN to form the known4 ethyl 3ꢀaminoꢀ4ꢀ
cyanoꢀ5ꢀmethylthiopheneꢀ2ꢀcarboxylate (4).
R = H (a); CH2Ph (b); CH2CH2Ph (c); cycloꢀC6H11 (d);
CH2CMe2CH2NMe2 (e);
(f)
Derivatives of 3ꢀaminothiopheneꢀ2,4ꢀdicarboxylic
acid 3a—f are very interesting as precursors of fused hetꢀ
erocycles. Thus with HCO2H as a oneꢀcarbon compoꢀ
nent for the closure of the pyrimidine ring, one can
obtain substituted ethyl 3,4ꢀdihydrothieno[3,4ꢀd]pyrimꢀ
idineꢀ7ꢀcarboxylates 5a—d from thiophenes 3a,b,d,f
(Scheme 2). Compounds 5b,c,e were also synthesized by
alkylation of thienopyrimidine 5a. The structures of
Nꢀalkyl derivatives 5b,c were confirmed by their indeꢀ
pendent synthesis from compounds 3b,d and HCO2H.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 789—793, May, 2002.
1066ꢀ5285/02/5105ꢀ854 $27.00 © 2002 Plenum Publishing Corporation

Enamines in the synthesis of thiophenes
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 5, May, 2002
855
Scheme 2
Scheme 3
5: R = H (a); CH2Ph (b); cycloꢀC6H11 (c);
(d); CH2COPh (e)
6: R = H (a); CH2Ph (b); CH2CH2Ph (c); cycloꢀC6H11 (d);
CH2CMe2CH2NMe2 (e); CH2COꢀ1ꢀAd (f);
CH2COC6H4ꢀpꢀBr (g); CH2CONHC6H4ꢀpꢀMe (h)
Diazotization of thiophenes 3a—e (NaNO2, AcOH,
HCl, 20 °C) yielded thieno[3,4ꢀd]ꢀ1,2,3ꢀtriazines 6a—e
(Scheme 3). Bicyclic compound 6a was alkylated in DMF
in the presence of K2CO3 to give derivatives 6b,d,f—h.
Compounds 6b,d obtained by both methods are idenꢀ
tical, which suggests the selective Nꢀalkylation of thienoꢀ
triazine 6a.
The reaction of enamine 1a with thioglycolanilide in
the presence of EtONa afforded 3ꢀaminothiophene 7 conꢀ
taining two carbamoyl fragments (Scheme 4). To comꢀ
pare their reactivities in closing the pyrimidine ring, we
made to react compound 7 with HCO2H. The reaction
products were 6ꢀmethylꢀ4ꢀoxoꢀ3ꢀphenylꢀ3,4ꢀdihydroꢀ
thieno[3,2ꢀd]pyrimidineꢀ7ꢀcarboxamide (8) and 5ꢀmeꢀ
thylꢀ4ꢀoxoꢀ3,4ꢀdihydrothieno[3,4ꢀd]pyrimidineꢀ7ꢀcarbꢀ
oxanilide (9) in 81 and 7% yields, respectively. The
1H NMR spectrum of thieno[3,2ꢀd]pyrimidine 8 conꢀ
tains two symmetrically broadened singlets of equal inꢀ
tensity at δ 7.52 and 8.56 for the amido group, whereas
isomeric thieno[3,4ꢀd]pyrimidine 9 gives differently shaped
singlets at δ 10.98 (narrow signal) and 12.10 (strongly
broadened signal) for the NH protons of the pyrimidine
fragment and the CONHPh group, respectively.
The structures of compounds 8 and 9 were confirmed
by 13C NMR spectroscopy using heteronuclear resonance
technique. Signals for the C=O groups in isomers 8 and
9 differ in shape. Thus a signal at δ 163.4 for the C(7´)
atom in compound 8 is significantly broadened, probꢀ
ably, because of the conformational mobility of its amide
fragment. A signal for the C(4) atom appears at δ 155.5
3
(d, JC(4),C(2)H = 5.8 Hz). The 13C NMR spectrum of
compound 9 shows a narrow signal at δ 159.1 for the
C(7´) atom and a doublet at δ 158.4 for the C(4) atom
(3JC(4),C(2)H = 6.1 Hz).
Scheme 4

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Russ.Chem.Bull., Int.Ed., Vol. 51, No. 5, May, 2002
Ryndina et al.
Table 1. Yields, melting points, and elemental analysis data for
Nꢀalkylꢀ2ꢀcyanoꢀ3ꢀdimethylaminobutꢀ2ꢀenamides 1b—d,f and
ethyl 3ꢀaminoꢀ4ꢀNꢀRꢀcarbamoylꢀ5ꢀmethylthiopheneꢀ2ꢀcarꢀ
boxylates 3a—f
In the spectrum of compound 9, a signal for the
C atom of the methyl group is substantially shifted upfield
(δ 16.0) compared to the analogous signal for bicycle 8
(δ 26.9). This shift is due to a "steric compression" effect
in compound 9 (the soꢀcalled "γꢀgauche effect"6 between
the MeC(5) and C(4)=O groups), which is absent for the
analogous MeC(6) and C(7´)=O groups in compound 8.
This effect is also observed for the C(4) atom in comꢀ
pound 9 (δ 158.4), as distinct from the C(7´) atom in
compound 8 (δ 163.4, ∆δ = δC(7´),8 – δC(4),9 = 5). These
data indicate that the C(4) atom of the carbonyl group in
thienopyrimidine 9 belongs to the cyclic fragment and is
close to the Me group in the thiophene ring, whereas it is
the C(6)Me and CONH2 groups that are close to each
other in bicycle 8. Hence, one can conclude that biꢀ
cycles 8 and 9 contain [3,2ꢀd]ꢀ and [3,4ꢀd]ꢀfused rings,
respectively.
Comꢀ Yield M.p.*
pound (%) /°C
Found
Calculated
Molecular
formula
(%)
С
H
N
S
1b
1c
1d
1f
79 108—111 69.23 7.21 17.18
69.11 7.04 17.27
75 95—98 70.23 7.31 16.51
70.01 7.44 16.33
81 131—133 66.19 8.75 17.76
66.35 8.99 17.86
81 93—95 60.11 8.71 19.77
59.98 8.63 19.98
—
C14H17N3O
C15H19N3O
C13H21N3O
C14H24N4O2
—
—
—
3а
3b
3c
3d
3e
3f
50 188—190 47.35 5.20 12.12 14.31 C9H12N2O3S
47.36 5.30 12.27 14.20
49 120—122 60.11 5.80 8.91 10.30 C16H18N2O3S
60.36 5.70 8.80 10.07
40 105—106 61.22 6.19 8.27 9.88 C17H20N2O3S
61.42 6.06 8.43 9.65
48 146—147 58.01 7.02 9.21 10.55 C15H22N2O3S
58.04 7.14 9.02 10.33
60 67—68 56.42 8.14 12.54 9.52 C16H27N3O3S
56.28 7.97 12.31 9.39
30 101—102 54.06 7.09 11.82 9.02 C16H25N3O4S
54.02 7.11 11.85 9.03
Thus, the cyclization of compound 7 mainly involves
the amide fragment in position 2 of the thiophene ring.
Such a tendency for heterocyclization with possible inꢀ
volvement of αꢀ and βꢀsubstituents has been found earꢀ
lier for thiophene4 and pyrrole derivatives.7
In this case, the Nꢀphenylcarbamoyl group in posiꢀ
tion 2 of the thiophene ring seems to be more basic,
which was confirmed by the diazotization of comꢀ
pound 7 resulting in thieno[3,2ꢀd]ꢀ1,2,3ꢀtriazine 10 (see
Scheme 4). The structure of compound 10 was deterꢀ
1
* Recrystallization from EtOH (1b—d,f and 3a—d), PriOH (3e),
or aqueous EtOH (3f).
mined using H NMR spectroscopy. The NH2 protons
of the amide fragment in compound 10 give two equally
broadened singlets at δ 7.85 and 8.10.
diluted with water, and cooled. The precipitate that formed
was filtered off and washed with water to give aminothiophenes
3a—d,f. The structure of compound 3a was proved by elemenꢀ
tal analysis data (see Table 1) and mass spectrum (m/z (Irel (%)):
228 [M]+ (74), 211 [M – NH3]+ (91), 183 [M – CO – NH3]+
(60), 166 [M – NH3 – OEt]+ (49)). The yields and physicoꢀ
chemical and spectroscopic characteristics of compounds 3b—d,f
are given in Tables 1 and 2.
Ethyl 3ꢀaminoꢀ4ꢀ[Nꢀ(3ꢀdimethylaminoꢀ2,2ꢀdimethyl)propylꢀ
carbamoyl]ꢀ5ꢀmethylthiopheneꢀ2ꢀcarboxylate (3e). N,N,2,2ꢀTetꢀ
ramethylpropaneꢀ1,3ꢀdiamine (Aldrich) (6.35 g, 49 mmol) was
added to a solution of NCCH2CO2Et (5.52 g, 48.7 mmol) in
75 mL of EtOH. The reaction mixture was stirred for 2 h,
N,Nꢀdimethylacetamide diethyl acetal (8.9 mL, 49 mmol) was
added, and the mixture was left for 20 h. Then HSCH2CO2Et
(7.6 g, 58.8 mmol) and K2CO3 (2.0 g, 14 mmol) were added
and the resulting mixture was stirred at 75 °C for 16 h, cooled,
and poured into 100 mL of water. The reaction product was
extracted with 80 mL of AcOEt and the extract was dried with
CaCl2 and concentrated in vacuo. The residue was triturated
with water and the precipitate that formed was filtered off to
give compound 3e (see Tables 1 and 2).
Experimental
1
H and 13C NMR spectra were recorded on a Varian Unity
Plusꢀ400 spectrometer (400 MHz) in DMSOꢀd6 with Me4Si
as the internal standard. IR spectra were recorded on a
Perkin—Elmer 457 instrument (Nujol). Mass spectra (EI, 70 eV)
were recorded on a Finnigan SSQꢀ710 spectrometer (direct
inlet of a sample). The course of the reaction was monitored
and the purity of the products was checked by TLC on Kieselgel
60 F254 plates (Merck) in MeOH or MeOH—AcOEt. Melting
points were determined on a Boetius hot stage.
Compound 1a was prepared according to the known proꢀ
cedure.8
NꢀAlkylꢀ2ꢀcyanoꢀ3ꢀdimethylaminobutꢀ2ꢀenamides 1b—d,f
(general procedure). N,NꢀDimethylacetamide diethyl acetal
(21 mL, 120 mmol) was added at 60 °C to a solution of
Nꢀalkylcyanoacetamide9—11 (100 mmol) in 100 mL of anhydrous
EtOH. The reaction mixture was stirred for 30 min and cooled.
The precipitate that formed was filtered off to give compounds
1b—d,f. Their yields, melting points, and elemental analysis
data are given in Table 1.
Ethyl 3ꢀaminoꢀ4ꢀNꢀRꢀcarbamoylꢀ5ꢀmethylthiopheneꢀ2ꢀcarbꢀ
oxylates 3a—d,f (general procedure). The ester HSCH2CO2Et
(120 mmol) and K2CO3 (1 g, 7 mmol) were added to a suspenꢀ
sion of an enamine 1a—d,f (100 mmol) in 100 mL of anꢀ
hydrous EtOH. The reaction mixture was refluxed for 16 h,
Ethyl 3ꢀaminoꢀ4ꢀcyanoꢀ5ꢀmethylthiopheneꢀ2ꢀcarboxylate
(4). Phosphoryl chloride (2.0 g, 13 mmol) was added to a
solution of thiophene 3a (2.28 g, 10 mmol) in 20 mL of dry
MeCN. The reaction mixture was refluxed with stirring for 1 h
and poured into 200 mL of cold water. The precipitate that

Enamines in the synthesis of thiophenes
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 5, May, 2002
857
1
Table 2. Chemical shifts (δ) in the H NMR spectra of compounds 3b—f
Comꢀ
pound
δ (J/Hz)
CH2Me (t) C(5)Me (s) CH2Me (q) NH2 (s)
NH (t)
Other protons
3b
3c
1.22
(J = 7.2)
2.48
4.19
(J = 7.2)
6.41
8.61
(J = 6.0)
4.45 (d, 2 H, NHCH2,
JCH ,NH = 5.6); 7.22—7.38
(m,25 H, Ph)
1.22
(J = 7.2)
2.30
4.16
(J = 7.2)
6.34
8.13
(J = 6.0)
2.84 (t, 2 H, CH2Ph,
3JCH ,CH2 = 7.2); 3.53
(q, 22H, NHCH2,
3JCH ,NH = 7.3);
2
7.20—7.30 (m, 5 H, Ph)
1.23—1.80 (m, 13 H,
MeCH2 + 5 СH2);
3.70 (m, 1 H, CH)
3d
3e
—*
2.44
2.51
4.18
(J = 7.2)
6.31
6.42
7.97
(J = 5.6)**
1.24
(J = 7.2)
4.18
(J = 7.2)
8.09
(J = 6.0)
0.87 (s, 6 H, СMe2);
2.14 (s, 2 H, NCH2);
2.22 (s, 6 H, NMe2);
3.15 (d, 2 H, CH2NH,
3JCH ,NH = 5.6)
3f
1.23
(J = 6.8)
2.46
4.18
(J = 6.8)
6.37
8.09
(J = 5.6)
1.65 2(quint, 2 H, СН2);
2.32 (m, 6 H, 3 CH2);
3.24 (q, 2 H, CH2);
3.55 (t, 4 H, 2 СН2,
3JCH ,CH2 = 5.0)
2
* Overlap with signals for the CH2 groups of the cyclohexyl fragment.
** Doublet.
formed was filtered off to give compound 4 (0.63 g, 30%), m.p.
139—140 °C (from aqueous MeCN). Found (%): C, 51.59;
H, 4.99; N, 13.20; S, 15.09. C9H10N2O2S. Calculated (%):
C, 51.41; H, 4.79; N, 13.32; S, 15.25.
Ethyl 5ꢀmethylꢀ4ꢀoxoꢀ3,4ꢀdihydrothieno[3,4ꢀd]pyrimidineꢀ
7ꢀcarboxylates 5a—e (general procedure A). A solution of
thiophene 3a (1.82 g, 8 mmol) in 40 mL of HCO2H was reꢀ
fluxed for 7—9 h (TLC). The reaction mixture was diluted with
water and the precipitate that formed was filtered off to give
compound 5a (1.52 g, 80%), m.p. >250 °C (from DMF).
Found (%): C, 50.67; H, 4.35; N, 11.82; S, 13.68. C10H10N2O3S.
Calculated (%): C, 50.41; H, 4.23; N, 11.76; S, 13.46. IR,
ν/cm–1: 1670 (C=O), 1570 (C=C).
3J = 6.9 Hz); 2.91 (s, 3 H, Me); 4.36 (q, 2 H, CH2Me); 14.60
(s, 1 H, NH).
Compounds 6b—e were obtained analogously from thioꢀ
phene derivatives 3b—e. Their yields and physicochemical and
spectroscopic characteristics are given in Tables 3 and 4.
General procedure B. Potassium carbonate (1.1 g, 8 mmol)
and an alkyl halide (PhCH2Cl, cycloꢀC6H11Cl, 1ꢀAdꢀCOCH2Br,
pꢀBrC6H4COCH2Br
(each
from
Aldrich),
and
pꢀMeꢀC6H4CONHCH2Br 12) (7.5 mmol) were added to a soꢀ
lution of thienotriazine 6a (6.3 mmol) in 40 mL of DMF. The
reaction mixture was stirred at 60 °C for 1.5 h and diluted with
water. The precipitate that formed was filtered off to give comꢀ
pounds 6b,d,f—h (see Tables 3 and 4).
Compounds 5b—d were obtained analogously from thioꢀ
phene derivatives 3b,d,f. Their yields and physicochemical and
spectroscopic characteristics are given in Tables 3 and 4.
General procedure B. Compounds 5b,c,e were synthesized
by alkylating compound 5a under the alkylation conditions for
bicycle 6a (see below) (see Tables 3 and 4).
Ethyl 5ꢀmethylꢀ4ꢀoxoꢀ3,4ꢀdihydrothieno[3,4ꢀd]ꢀ1,2,3ꢀtriꢀ
azineꢀ7ꢀcarboxylates 6a—h (general procedure A). Concentrated
HCl (5 mL) was added to a solution of thiophene 3a (2.28 g,
10 mmol) in a mixture of DMF (10 mL) and AcOH (15 mL).
Then a solution of NaNO2 (0.83 g, 12 mmol) in 3.0 mL of
water was added at 20 °C. The precipitate that formed was
filtered off to give compound 6a (2.0 g, 84%), m.p. 189—190 °C
(from EtOH—DMF, 3 : 1). Found (%): C, 45.53; H, 3.86;
N, 17.58; S, 13.56. C9H9N3O3S. Calculated (%): C, 45.18;
H, 3.79; N, 17.56; S, 13.40. 1H NMR, δ: 1.34 (t, 3 H, CH2Me,
3ꢀAminoꢀ4ꢀcarbamoylꢀ5ꢀmethylꢀ2ꢀ(Nꢀphenylcarbamoyl)thioꢀ
phene (7). A mixture of enamine 1a (2.0 g, 13 mmol),
HSCH2CONHPh (3.34 g, 20 mmol), and EtONa (1.36 g,
20 mmol) in 60 mL of anhydrous EtOH was refluxed with
stirring for 8 h and poured into water. The precipitate that
formed was filtered off to give compound 7 (0.75 g, 21%), m.p.
249—251 °C (from EtOH—acetone, 2 : 1). Found (%): C, 56.80;
H, 4.65; N, 15.35; S, 11.40. C13H13N3O2S. Calculated (%):
C, 56.71; H, 4.76; N, 15.26; S, 11.65. MS, m/z (Irel (%)): 275
[M]+ (54), 258 [M – NH2]+ (33), 183 [M – PhNH – NH3]+
(100), 166 [M – PhNH – 2 NH3]+ (59).
6ꢀMethylꢀ4ꢀoxoꢀ3ꢀphenylꢀ3,4ꢀdihydrothieno[3,2ꢀd]pyrimꢀ
idineꢀ7ꢀcarboxamide (8) and 5ꢀmethylꢀ4ꢀoxoꢀ3,4ꢀdihydroꢀ
thieno[3,4ꢀd]pyrimidineꢀ7ꢀcarboxanilide (9). Thiophene 7 (2.0 g,
7.3 mmol) was added to a DMF—HCOOH—HCONH2 mixꢀ
ture (15 : 5 : 2, 70 mL). The reaction mixture was refluxed for

858
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 5, May, 2002
Ryndina et al.
Table 3. Yields, melting points, and elemental analysis data for ethyl 5ꢀmethylꢀ4ꢀoxoꢀ
3,4ꢀdihydrothieno[3,4ꢀd]pyrimidineꢀ7ꢀcarboxylates 5b—e and ethyl 5ꢀmethylꢀ4ꢀoxoꢀ3,4ꢀ
dihydrothieno[3,4ꢀd]ꢀ1,2,3ꢀtriazineꢀ7ꢀcarboxylates 6b—h
Comꢀ Yield
pound (%)
(method)
M.p./°C
(solvent)
Found
Calculated
Molecular
formula
(%)
С
H
N
S
5b
5c
78 (A)
56 (B)
219—220
(toluene—DMF,
3 : 1)
204—205
(MeCN—DMF,
2 : 1)
62.21 4.72
62.18 4.91
8.81 9.67
8.53 9.76
C17H16N2O3S
C16H20N2O3S
84 (A)
69 (B)
60.00 6.19
59.98 6.29
8.92 9.98
8.74 10.01
5d
5e
6b
6c
75 (B)
65 (A)
171—173
(aqueous DMF)
>260
(aqueous DMF)
150—151
(EtOH)
149—150
(EtOH—DMF,
2 : 1)
59.21 6.48
59.32 6.64
60.85 4.65
60.66 4.53
58.19 4.48 12.51 9.59
58.35 4.59 12.76 9.73
59.43 5.01 12.22 9.37
59.46 4.99 12.24 9.34
7.57 8.69
7.69 8.80
7.96 9.31
7.86 9.00
C18H24N2O4S
C18H16N2O4S
C16H15N3O3S
C17H17N3O3S
62 (A)
90 (B)
83 (A)
6d
6e
6f
71(A)
82 (B)
51 (B)
206—207
(DMF)
84—85
56.08 6.00 13.03 9.96
56.06 5.96 13.07 9.98
54.35 6.76 15.97 9.10
54.53 6.86 15.90 9.10
60.61 6.18 10.07 7.45
60.70 6.06 10.11 7.72
C15H19N3O3S
C16H24N4O3S
C21H25N3O4S
(aqueous PriOH)
151—153
51 (A)
57 (A)
82 (A)
(PriOH—acetone,
1 : 1)
6g
6h
171—173
(PriOH—acetone,
1 : 1)
>260
(DMF—water,
2 : 1)
47.05 3.31
46.80 3.23
9.84 7.60
9.63 7.35
C17H14BrN3O4S
C18H18N4O4S
56.11 4.59 14.63 8.20
55.95 4.70 14.50 8.30
1
Table 4. Chemical shifts (δ) in the H NMR spectra of compounds 5c,e and 6b—e,g,h
Comꢀ
pound
δ (J/Hz)
Comꢀ
pound
δ (J/Hz)
СH2Me С(5)Me СН2Me
Other
СH2Me С(5)Me СН2Me
Other
(t)
(s)
(q)
protons
(t)
(s)
(q)
protons
5e
1.28
(J = 7.2)
2.88
4.28
5.09 (s, 2 H, CH2Ph);
6d
6e
—*
2.95
4.39
1.20—1.98 (m, 13 H,
(J = 7.2) 7.25—7.38 (m, 5 H, Ph);
(J = 7.2) 5 СH2 + MeCH2);
8.42 (s, 1 H, CH)
1.17—1.90 (m, 13 H,
4.80 (m, 1 H, CH)
0.87 (s, 6 H, СMe2);
2.21 (s, 2 H, Me2NCH2);
2.27 (s, 6 H, NMe2);
4.22 (s, 2 H, CH2CMe2)
5.95 (s, 2 H, CH2CO);
5c
—*
2.88
4.28
1.33
1.35
2.94
4.37
4.39
(J = 7.2) MeСH2 + 5 СH2);
4.50 (m, 1 H, СНN);
8.24 (s, 1 H, С(2)Н)
5.48 (s, 2 H, CH2);
6b
6c
1.37
(J = 7.2)
1.33
2.91
2.94
4.38
(J = 7.2) 7.25—7.40 (m, 5 H, Ph)
4.37 3.11 (t, 2 H, CH2CH2,
(J = 7.2) J = 7.2); 4.51 (t, 2 H,
CH2CH2, J = 7.2);
6g
2.93
2.94
(J = 7.2)
(J = 7.2) 7.82, 8.05 (both d,
2 H each, BrC6H4)
2.24 (s, 3 H, MeC6H4);
(J = 6.8)
6h
1.33
(J = 7.2)
4.39
(J = 7.2) 5.12 (s, 2 H, CH2CO);
7.10, 7.42 (both d,
7.18—7.28 (m, 5 H, Ph)
2 H each, MeC6H4)
* Overlap with signals for the CH2 groups of the cyclohexyl fragment.

Enamines in the synthesis of thiophenes
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 5, May, 2002
859
5 h and cooled. The precipitate that formed was filtered off to
give compound 8 (1.68 g, 81%), m.p. 326—328 °C (from DMF).
Found (%): C, 58.87; H, 3.78; N, 14.59; S, 11.00. C14H11N3O2S.
Calculated (%): C, 58.93; H, 3.89; N, 14.73; S, 11.24. MS,
m/z (Irel (%)): 285 [M]+ (31), 268 [M – NH3]+ (100), 240
[M – CO – NH3]+ (23). 1H NMR, δ: 2.89 (s, 3 H, Me);
References
1. F. S. Babichev, Yu. A. Sharanin, V. P. Litvinov, V. K.
Promonenkov, and Yu. M. Volovenko, Vnutrimolekulyarnoe
vzaimodeistvie nitril´noi i CHꢀ, OHꢀ i SHꢀgrupp [Intramoꢀ
lecular Interactions of a Nitrile Group with CH, OH, and SH
Groups], Naukova Dumka, Kiev, 1985, 200 pp. (in Russian).
2. V. G. Granik, A. V. Kadushkin, and J. Liebscher, Adv.
Heterocycl. Chem., 1998, 72, 79.
3. S. A. Ryndina, A. V. Kadushkin, N. P. Solov´eva, and
V. G. Granik, Khim. Geterotsikl. Soedinenii, 2000, 1643
[Chem. Heterocycl. Compd., 2000, 26, 1409 (Engl. Transl.)].
4. K. Saito, S. Kambe, A. Sakurai, and H. Midorikawa, Synꢀ
thesis, 1982, 1056.
5. S. F. Martin and D. R. Moore, Tetrahedron Lett., 1976, 4459.
6. F. W. Wehrli and T. Wirthlin, Interpretation of Carbon
13C NMRꢀspectra, Reine Heyden and Son, Ltd, Lonꢀ
don—New York, 1976, p. 37.
7. A. V. Kadushkin, I. N. Nesterova, T. V. Golovko, I. S.
Nikolaeva, T. V. Pushkina, A. N. Fomina, A. S. Sokolova,
V. N. Chernov, and V. G. Granik, Khim.ꢀFarm. Zhurn.,
1990, 24, 18 [Pharm. Chem. J., 1990, 24, 875 (Engl. Transl.)].
8. V. G. Granik, A. M. Zhidkova, I. S. Zhivotovskaya, N. P.
Solov´eva, and M. K. Polievktov, Zhurn. Org. Khim.,
1981, 2421 [J. Org. Chem. USSR, 1981, 17, 2163 (Engl.
Transl.)].
7.50—7.60 (m, 5 H, Ph); 7.62, 8.60 (both br.s, each 1 H,
1
NH2); 8.52 (s, 1 H, C(2)H). 13C NMR, δ: 26.9 (CH3, JC,H
=
132.6 Hz); 119.8 (s, C(4a)); 125.6 (m, C(7)); 127.5 (2 C);
1
129.1, 129.3 (2 C); 136.8 (Ph); 149.1 (d, C(2), JC(2),H
=
3
210 Hz); 153.8 (d, C(7a), JC(7a),C(2)H = 12.7 Hz); 155.5 (d,
C(4), 3JC(4),C(2)H = 5.8 Hz); 156.6 (q, C(6), 2JC(6),CH3 = 6.9 Hz);
163.4 (br.s, C(7´)).
The mother liquor was diluted with water (100 mL) and the
precipitate (0.2 g) that formed was filtered off and dissolved in
10% NaOH. The solution was filtered and neutralized with
conc. HCl to pH 7. The precipitate that formed was filtered off
to give compound 9 (0.15 g, 7%), m.p. >260 °C. Found (%):
C, 58.81; H, 3.72; N, 14.51; S, 11.01. C14H11N3O2S. Calcuꢀ
1
lated (%): C, 58.93; H, 3.89; N, 14.73; S, 11.24. H NMR, δ:
2.88 (s, 3 H, Me); 7.10 (t, 1 H, C(4´)H, Ph); 7.36 (t, 2 H,
C(3´)H, Ph); 7.63 (d, 2 H, C(2´)H, Ph); 8.07 (s, 1 H, CH);
10.98 (s, 1 H, NH); 12.10 (br.s, 1 H, NH). 13C NMR, δ: 16.0
1
3
(q, CH3, JC,H = 132.0 Hz); 122.7 (q, C(4a), JC(4a),CH
=
3
3.8 Hz); 122.9 (s, C(7)); 119.6 (2 C); 124.0, 129.3 (2 C);
3
138.4 (Ph); 147.0 (d, C(7a), JC(7a),C(2)H = 12.9 Hz); 147.5
1
2
(d, C(2), JC(2),H = 205.3 Hz); 150.7 (q, C(5), JC(5),CH
=
6.8 Hz); 158.4 (d, C(4), 3JC(4),C(2)H = 6.1 Hz); 159.1 (s, C(73´)).
7ꢀCarbamoylꢀ6ꢀmethylꢀ3ꢀphenylꢀ3,4ꢀdihydrothieno[3,2ꢀd]ꢀ
1,2,3ꢀtriazinꢀ4ꢀone (10) was obtained by the diazotization of
thiophene 7 as described for compound 6a. The yield was 62%,
m.p. 286—288 °C (from DMF). Found (%): C, 54.69; H, 3.71;
N, 19.32; S, 11.09. C13H10N4O2S. Calculated (%): C, 54.54;
H, 3.52; N, 19.57; S, 11.20. MS, m/z (Irel (%)): 286 [M]+ (91),
9. A. P. Tamiz, S. X. Cai, Z.ꢀL. Zhou, P.ꢀW. Yuen, R. M.
Schelkun, E. R. Whittemore, E. Weber, R. M. Woodward,
and J. F. W. Keana, J. Med. Chem., 1999, 42, 3412.
10. B. Leonard, J. Am. Chem. Soc., 1950, 72, 2980.
11. T. Whitehead, J. Am. Chem. Soc., 1955, 77, 5867.
12. A. Bellotti, E. Cogni, A. Baruffuni, G. Pagani, and
P. Borgna, Farmaco, Ed. Sci., 1968, 23, 591.
258 [M – CO]+ (100), 241 [M – CO – NH3]+ (17). H NMR,
1
δ: 2.86 (s, 3 H, Me); 7.52—7.68 (m, 5 H, Ph); 7.85, 8.10
Received April 24, 2001;
(both br.s, each 1 H, NH2).
in revised form August 14, 2001