Synthesis of thieno[3,4-d]pyrimidines by the reactions of 3-amino-4-carbamoylthiophene derivatives with 1,3-dicarbonyl compounds

Article abstract of DOI:10.1023/A:1021356603146

The reactions of ethyl 3-amino-4-carbamoyl-5-methylthiophene-2-carboxylate with 1,3-dicarbonyl compounds were studied. During the reactions, the corresponding ketone is eliminated to give ethyl 5-methyl-4-oxo-3,4-dihydrothieno[3,4-d]pyrimidine-7-carboxylates.

Full text of DOI:10.1023/A:1021356603146

Russian Chemical Bulletin, International Edition, Vol. 51, No. 10, pp. 1879—1885, October, 2002
1879
Synthesis of thieno[3,4ꢀd]pyrimidines by the reactions of
3ꢀaminoꢀ4ꢀcarbamoylthiophene derivatives with 1,3ꢀdicarbonyl compounds
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" ,
1 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
The reactions of ethyl 3ꢀaminoꢀ4ꢀcarbamoylꢀ5ꢀmethylthiopheneꢀ2ꢀcarboxylate with 1,3ꢀdiꢀ
carbonyl compounds were studied. During the reactions, the corresponding ketone is elimiꢀ
nated to give ethyl 5ꢀmethylꢀ4ꢀoxoꢀ3,4ꢀdihydrothieno[3,4ꢀd]pyrimidineꢀ7ꢀcarboxylates.
Key words: thiophenes, thieno[3,4ꢀd]pyrimidines, 1,3ꢀdicarbonyl compounds, cyclization,
alkylation.
Scheme 1
The present study is devoted to reactions of orthoꢀamiꢀ
noarenecarboxylates and ꢀcarboxamides 1a,b with 1,3ꢀdiꢀ
carbonyl compounds 2 (Scheme 1). These reactions beꢀ
gin with an acidꢀcatalyzed condensation of the carbonyl
group of compound 2 with the NH2 group of derivatives
1, giving the corresponding enamines 3.1,2 The condensaꢀ
tion is reversible under these conditions since water is
liberated and enamines are highly hydrolyzable.2 Subseꢀ
quent transformations of intermediate enamines 3a,b deꢀ
pend on the character of orthoꢀsubstituents.
In the reactions of oꢀamino esters 1a with βꢀdicarbonyl
compounds 2 under acid catalysis conditions, intermediꢀ
ates 3a undergo cyclization to give 1,4ꢀdihydropyridinꢀ4ꢀ
one derivatives 4.3,4 The reactions of βꢀdiketones 2 with
oꢀamino carbamoyl derivatives 1b such as anthranilamide
or 4ꢀaminoꢀ5ꢀcarbamoylthiazoles5,6 afford enaminones
3b, which are attacked by the carbamoyl NH2 group at the
αꢀposition to form 2ꢀacylmethylꢀ1,2,3,4ꢀtetrahydroꢀ
pyrimidinꢀ4ꢀones (5). Under the same conditions (heatꢀ
ing and acid catalysis), ketone can be eliminated, yielding
3,4ꢀdihydropyrimidinꢀ4ꢀone derivatives 6.7—10 The litꢀ
erature data for analogous reactions with compounds conꢀ
taining both functional groups (CONH2 and CO2Alk) are
lacking.
In the present work, we studied the reactions of ethyl
3ꢀaminoꢀ4ꢀcarbamoylꢀ5ꢀmethylthiopheneꢀ2ꢀcarboxylate
(7)11 with carbonyl compounds 2 (acetylacetone, benzoylꢀ
acetone, ethyl acetoacetate, acetoacetamide, ethyl benꢀ
zoylacetate, and αꢀcyanoacetophenone). The goal of this
study was to specify cyclization products of intermediate
enamine 8 between thieno[3,4ꢀd]pyrimidines 9 and
thieno[3,2ꢀb]pyridines 10 (Scheme 2).
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 1730—1735, October, 2002.
1066ꢀ5285/02/5110ꢀ1879 $27.00 © 2002 Plenum Publishing Corporation

1880
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 10, October, 2002
Ryndina et al.
Scheme 2
ring. A second possible product 11b was not detected
either in the reaction mixture (1H NMR data) or in a
crude product (mass spectra). This indicates that the
acetyl group is more reactive than the benzoyl one,
in which the partial positive charge at the carbonyl
C atom is compensated by conjugation with the aroꢀ
matic ring.
The reactions of ethyl acetoacetate and acetoacetꢀ
anilide 2c,d with thiophene 7 occur in a different way; in
these cases, hydrogenated pyrimidine derivatives 9c,d can
both be isolated in ∼70% yield, which was impossible for
the reactions of βꢀdiketones 2a,b. Subsequent prolonged
heating of compounds 9c,d under the same conditions
(toluene, 110 °C, TsOH) results in elimination of ethyl
acetate and MeCONHPh to give thienopyrimidinone 11a
in 60 and 40% yields, respectively. Analogously, intermeꢀ
diate 9e was isolated in the reaction of compound 7 with
PhCOCH2CO2Et (2e); when heated, compound 9e reꢀ
leases ethyl acetate to form ethyl 5ꢀmethylꢀ4ꢀoxoꢀ2ꢀ
phenylꢀ3,4ꢀdihydrothieno[3,4ꢀd]pyrimidineꢀ7ꢀcarboxyꢀ
late (11b).
The reaction of thiophene 7 with αꢀcyanoacetoꢀ
phenone (2f) yields a cyanomethyl derivative 9f; under
these conditions, the C—C bond is mostly retained and,
consequently, MeCN is not eliminated.
Compound
2, 8, 9
R
R´
The structures of hydrogenated derivatives 9 was studꢀ
ied by 1H NMR (for 9c and 9f, see Table 1) and 13C NMR
spectroscopy (for 9c). Compounds 9 contain an asymꢀ
metric C(2) atom, which makes the methylene protons of
the CH2R´ fragment nonequivalent; as the result, two
doublets with 2JCH2 = 14.7 (9c) and 16.4 Hz (9f) appear in
a
b
c
d
e
f
Me
Me
Me
COMe
COPh
CO2Et
Me CONHPh
Ph
Ph
CO2Et
CN
1
their H NMR spectra. These spectra also show signals
for two NH protons with a weak spinꢀspin coupling
(4JNH,NH = 1.2 Hz). The 13C NMR spectrum of comꢀ
pound 9c contains a signal for the sp3ꢀhybridized C(2)
atom at δ 70.0.
Results and Discussion
The reaction of compound 7 with acetylacetone (2a)
(toluene, 110 °C, 6 h, TsOH) affords ethyl 2,5ꢀdimethylꢀ
4ꢀoxoꢀ3,4ꢀdihydrothieno[3,4ꢀd]pyrimidineꢀ7ꢀcarboxylate
(11a) in 86% yield; in this case, cyclization into a pyrimiꢀ
dine ring dominates clearly. Intermediate 9a is stabilized
by elimination of acetone (GLC). The structure of bicycle
11a was unambiguously proved by 1H and 13C NMR, IR,
and mass spectra, elemental analysis data (Tables 1—4),
and by an independent synthesis from thiophene 7 and
triethyl orthoacetate in the presence of Ac2O (the yield of
compound 11a was 40%).
According to quantumꢀchemical calculations,7 simiꢀ
lar reactions (e.g., the reaction of anthranilamide with
acetylacetone, which gives ethyl 2ꢀmethylꢀ4ꢀoxoꢀ1,2,3,4ꢀ
tetrahydroquinazolꢀ2ꢀylacetate and subsequently 2ꢀmeꢀ
thylꢀ3,4ꢀdihydroquinazolinꢀ4ꢀone), proceed with a sigꢀ
nificant gain in energy. However, data on mechanisms of
cyclization and ketone elimination following carbonꢀcarꢀ
bon bond cleavage are lacking; in addition, it remains
unclear how these processes depend on the structure of
starting βꢀdicarbonyl compounds.
The reaction of compound 7 with PhCOCH2COMe
(2b) follows the same scheme as described for acetylꢀ
acetone (2a); however, prolonged heating is required for
the process to be completed (32 h, TLC). According to
the TLC data, the reaction mixture contains the starting
reagents 7 and 2b, thienopyrimidine 11a, and the deꢀ
tached acetophenone only; i.e., intermediate 9b is rapidly
transformed into compound 11a. Hence, the rateꢀlimitꢀ
ing step of the process is the cyclization into a pyrimidine
Hence, one can assume that the synthesis under study
of thieno[3,4ꢀd]pyrimidines includes (1) reversible conꢀ
densation of thiophene 7 with ketones to give enamꢀ
ines of type 8, (2) cyclization involving the enamine
αꢀC atom and the amide NH2 group, and (3) C—C bond
cleavage with elimination of the carbonylꢀcontaining molꢀ
ecule.
1. Reversible condensation of thiophene 7 with ketones
into enamines of type 8. Enamines 8 were found7 to be

Synthesis of thieno[3,4ꢀd]pyrimidines
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 10, October, 2002
1881
Table 1. 1H NMR spectra of the compounds obtained (DMSOꢀd6, δ)
Comꢀ
pound
CH2CH3, t, C(2)Me, s C(5)Me, s
CH2CH3, q
Other groups
9c
1.24
1.27
1.49
—
2.65
2.59
4.20 (3J = 6.8)
1.13 (t, 3 Н, СН2СН3); 2.76 (q, 2 Н, CH2CO2Et, 2J = 4.8);
3.98 (q, 2 Н, СН2СН3, 3J = 5.2); 7.30 (br.d, 1 Н, N(1)H);
8.26 (br.d, 1 Н, N(3)H, 4JNH,NH = 1.2)
9f
4.29 (3J = 6.8)
3.04 and 3.69 (both q, 2 H each, CH2CN; J = 16.4);
7.28—7.45 (m, 5 H, Ph); 8.07 (br.d, 1 H, N(1)H);
9.25 (br.d, 1 H, N(3)H, 4JNH,NH = 1.2)
11а
12а
12b
1.27
1.28
1.29
2.27
2.40
2.50
2.83
2.88
2.86
4.25 (3J = 7.0)
4.26 (3J = 7.2)
4.28
11.84 (br.s, 1 Н, NH)
5.25 (s, 2 Н, CH2Ph); 7.20—7.38 (m, 5 Н, Ph)
1.22 (t, 3 Н, СН2СН3); 4.18 (q, 2 Н, СН2СН3, 3J = 7.6);
4.82 (s, 2 Н, СН2СО2Et)
12c
12d
1.27
1.28
2.56
2.41
2.85
2.88
4.25 (3J = 7.2)
4.27 (3J = 6.8)
5.07 (s, 2 H, NCH2)
5.24 (s, 2 H, NCH2); 7.24, 7.39 (both d, 2 H each,
ClC6H4)
12е
16b
1.31
—
2.48
2.62
2.87
2.87
4.29 (3J = 7.2)
2.25 (s, 3 H, CH3C6H4); 7.11, 7.45 (both d, 2 H each,
CH3C6H4); 10.22 (br.s, 1 Н, NH)
—
4.05, 4.35 (both d, 2 H each, 2 NHCH2,
3JСН,NH = 5.2, 3JСН,NH = 6.0); 5.41 (s, 2 H, CH2CO);
2 C5H5N: 7.32 (m, 2 Н); 7.60 (d, 1 Н); 7.67 (d, 1 Н);
8.44 (d, 1 Н); 8.50 (m, 2 Н); 8.54 (d, 1 Н); 8.62, 9.91
(both t, 1 H each, 2 NHCH2)
metastable systems, and some energy is required for their
formation (∆H = +11—19 kJ mol–1).
our conditions (nonpolar solvent, catalytic amount of an
acid), the protonation of enamines has not been studied.
However, a nucleophilic attack at the αꢀposition of an
enamine is known13 to be hindered for an Nꢀprotonated
form (A), be possible for an Oꢀprotonated form (B), and
occur most easily for immonium cations (C). However, it
is not always possible to determine, under reaction condiꢀ
tions, the ratio between protonated forms for a particular
βꢀsubstituent in an enamine.
2. Cyclization involving the enamine αꢀC atom and the
amide NH2 group. This process is favored by protonation
of enamines (Scheme 3). Enamine protonation is known
to occur at the Nꢀ and βꢀC atoms, while enaminones are
protonated at the N, βꢀC, and O(C=O) atoms.12 Under
Scheme 3
3. C—C bond cleavage with elimination of a carbonylꢀ
containing molecule. On the assumption that the transiꢀ
tion state (TS) of this process for carbonylꢀcontaining
compounds 9a—e in the presence of TsOH as an acid
agent can be represented as shown in Scheme 4, the elimiꢀ
nation of the enol fragment will be hindered by any group
R´ capable of conjugating with the C=O+H group; the
stronger the conjugation the stronger this effect of R´
Scheme 4
R´ = COR″

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Russ.Chem.Bull., Int.Ed., Vol. 51, No. 10, October, 2002
Ryndina et al.
Table 2. Yields, properties, and elemental analysis data for the compounds obtained
Comꢀ
pound
Yield
(%)
M.p./°C
(solvent)
Molecular
formula
Found
Calculated
(%)
N
C
H
S
9c
70
70
50
55
131—133
(acetone—DMF)
220—222
(acetone—DMF)
175—176
(EtOH—DMF)
>255
(aqueous DMF)
276—278
(CH3CN—DMF)
>255
(DMF)
137—139
(aqueous CH3CN)
133—135
C2H5OH
73—74
(EtOH)
136—138
(acetone)
>255
(PriOH : DMF, 1 : 2)
133—134
C15H20N2O5S
C19H21N3O4S
C20H22N2O5S
C18H17N3O3S
C11H12N2O3S
C16H14N2O3S
C18H18N2O3S
C15H18N2O5S
C13H13N3O3S
C18H17ClN2O3S
C20H21N3O4S
C15H22N2O4
52.87
52.93
58.76
58.90
59.44
59.69
60.73
60.83
52.45
52.37
60.98
61.13
62.98
63.14
53.18
53.24
53.85
53.60
57.18
57.37
60.01
60.14
61.39
61.21
66.56
66.37
59.57
59.73
6.00
5.92
5.55
5.46
5.39
5.51
4.73
4.82
4.69
4.79
4.56
4.49
5.18
5.30
5.42
5.36
4.56
4.50
4.43
4.55
5.23
5.30
7.45
7.53
5.59
5.78
4.68
4.79
8.36
8.23
10.99
10.84
7.12
9.27
9.42
8.07
8.28
7.91
7.97
8.88
9.02
12.59
12.71
10.02
10.20
9.19
9.36
9.29
9.48
10.87
11.01
8.45
8.51
7.87
8.03
3—
9d
9e
6.96
9f
12.08
11.82
11.12
11.10
8.80
8.91
8.03
8.18
8.09
11а
11b
12a
12b
12c
12d*
12e
15
86
(А)
20
65
71
64
56
61
63
72
69
8.28
14.49
14.42
7.61
7.43
10.68
10.52
9.38
(EtOH)
206—207
(acetone—DMF)
224—225
(EtOH—DMF)
9.52
16а
16b
C27H28N4O3S
C23H22N6O3S
11.31
11.47
18.39
18.17
6.51
6.56
6.81
6.93
* Found (%): Cl, 9.27. Calculated (%): Cl, 9.41.
since its interaction with the charged carbonyl group is
significantly more intense than with the C=C bond.
As a result, the conjugation energy is partially lost
upon the bond cleavage, the TS energy increases, and the
process decelerates. In the case of 9a (R´ = Me), the TS
Table 3. Mass spectra (EI, 70 eV) of the compounds obtained
Comꢀ
pound
m/z
Table 4. IR spectra of the compounds obtained
Comꢀ
pound
ν/cm–1
9c
340 [M]+ (57), 325 [M – NH]+ (46),
295 [M – OEt]+ (29), 279 [M + H – Me –
OEt]+ (100), 253 [M – Me – CO2Et]+ (78)
252 [M]+ (43), 207 [M — OEt]+ (69),
180 [M + H – CO2Et]+ (100)
9c
9d
9e
3363, 3167 (NH), 1723, 1682, 1771 (CO),
1595 (C=C)
3350, 3308, 3258, 3197, 3134 (NH), 1685,
1660, 1648 (CO)
3341, 3167, 3060 (NH); 1734, 1682, 1660 (CO);
1600 (С=С)
11а
12e
399 [M]+ (7), 354 [M – OEt]+ (4), 293
[M – NH – C6H4 – CH3 + H]+ (100), 265
[M – NH – C6H4 – CH3 + H – CO]+ (58)
310 [M]+ (98), 295 [M – Me]+ (10), 265
[M – OEt]+ (43), 237 [M – CO2Et]+ (100)
488 [M]+ (45), 368 [M – NHCH2CH2Ph]+ (37),
340 [M – CONHCH2CH2Ph]+ (70), 311 [M +
H – NCH2CONHCH2CH2Ph]+ (100)
462 [M]+ (18), 370 [M – CH2Py]+ (20),
327 [M – NHCOCH2Py]+ (13), 298 [M +
H – NCH2NHCH2CH2Ph]+ (100)
15
9f
3284, 3305 (NH); 2247 (CN); 1658 (CO)
3140 (NH); 1665 (СО); 1610 (С=С)
3168 (NH), 1680 (СО)
11a
11b
12a
12b
12c
12e
15
16а
1714, 1672 (CO)
1742, 1714 (CO); 1674 (C=C)
2256 (CN), 1723, 1686 (CO), 1646 (C=C)
3285 (NH); 1714, 1685 (CO), 1667 (C=C)
1710, 1725 (СО); 1655 (С=С)
16b

Synthesis of thieno[3,4ꢀd]pyrimidines
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 10, October, 2002
1883
energy increases insignificantly since the Me group weakly
interacts with the double bonds. For R´ = Ph and espeꢀ
cially electronꢀdonating OEt and NHPh groups capable
of conjugating with the C=O+H group, the TS energy
becomes substantially higher. For this reason, the reacꢀ
tion of thiophene 7 with acetylacetone (2a) proceeds most
easily. Benzoylacetone (2b) reacts with more difficulty,
although intermediate 9b cannot be isolated in this case.
In contrast, intermediates 9c—e were isolated, and a corꢀ
responding carbonyl compound was eliminated only on
prolonged heating. In the reaction of thiophene 7 with
α−cyanoacetophenone (2f), no intermediate alleneꢀ
immonium TS was formed for thermodynamic reasons,
and acetonitrile was not liberated. Hindrances to the elimiꢀ
nation of ethyl acetate from derivative 9e (heating for
more than 100 h) are due to the presence of a bulky
phenyl group in position 2 of the tetrahydropyrimidine
ring, which causes the ethoxycarbonylmethyl group to
deflect from the bicycle plane, thus increasing the TS
energy. Although the mechanism proposed above explains
the experimental data qualitatively and consistently, it
is only tentative and calls for extensive kinetic investiꢀ
gation.
3.9 Hz) for the C(2) atom (in the case of Oꢀalkylation, a
signal for the C(2) atom would appear as a quartet beꢀ
cause of a spinꢀspin coupling between C(2) and the CH3
protons). Apparently, the reaction regioselectivity is enꢀ
sured by the shielding effect of the C(5)ꢀbound Me group
on the amide CO group.14—16
Scheme 6
Thienopyrimidine 11a obtained was a starting reagent
for the synthesis of some derivatives of this system. Alkyꢀ
lation of 11a smoothly proceeds in acetone or DMF in
the presence of K2CO3 (Scheme 5).
Scheme 5
R´ = CH2CH2Ph (a), 2ꢀPyCH2 (b)
It was illustrated with compound 12b that desulfurꢀ
ization is possible under the action of Raney nickel
(Scheme 6). Intermediate 14 is subsequently reduced with
the catalystꢀabsorbed hydrogen to give diethyl 5ꢀethylꢀ
2ꢀmethylꢀ6ꢀoxoꢀ1,6ꢀdihydropyrimidineꢀ1,4ꢀdiaceꢀ
1
tate (15); its structure was proved by H and 13C NMR
spectra.
Compound 12b smoothly reacts with amines to give
bis(carbamoyl) derivatives (16a,b).
Experimental
Comꢀ
pound 12
R
a
b
c
d
e
1
Ph
CO2Et
CN
C6H4ꢀClꢀp CONHC6H4Meꢀp
H NMR spectra were recorded on a Varian Unity plus
400 MHz spectrometer in DMSOꢀd6 with SiMe4 as the internal
standard. IR spectra were recorded on a PerkinꢀElmer 457 specꢀ
trometer (Nujol). The course of the reactions were monitored
and the purity of the products were checked by TLC on Kieselgel
60 F254 plates (Merck Co.). Melting points were determined on
The process can involve both the endocyclic N(3) atom
to give derivatives 12a—e and the exocyclic O atom to
form compounds 13 (Scheme 5). Based on the 13C NMR
data, we assigned structure 12 to the products obtained.
Thus, the 13C NMR spectrum of compound 12a, recorded
without total but selective proton decoupling for C(2)CH3
a Boetius hot stage at a heating rate of 2 to 3 K min–1
Characteristics of the compounds obtained are given in
Tables 1—4.
.
(δ 2.40) and NHCH2Ph groups (δ 5.26), shows a multiꢀ
Ethyl 2,5ꢀdimethylꢀ4ꢀoxoꢀ3,4ꢀdihydrothieno[3,4ꢀd]pyrimidiꢀ
neꢀ7ꢀcarboxylate (11a). A. Thiophene 7 (15.0 g, 66 mmol) and
3
plet at δ 151.7 (2JC(2),CH = 6.6 Hz and JC(2),NHCH
=
3
2

1884
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 10, October, 2002
Ryndina et al.
TsOH (0.1 g) were added to a solution of acetylacetone (70 mL)
in 80 mL of toluene. The reaction mixture was refluxed for 9 h.
The precipitate that formed was filtered off and washed with
EtOH. The yield of compound 11a was 13.3 g (86%).
B. A mixture of thiophene 7 (1.02 g, 4.4 mmol), MeC(OEt)3
(10 mL), and Ac2O (10 mL) was refluxed for 20 h. The precipiꢀ
tate that formed was filtered off. The yield of compound 11a was
0.44 g (40%).
Ethyl 2ꢀcyanomethylꢀ5ꢀmethylꢀ4ꢀoxoꢀ2ꢀphenylꢀ1,2,3,4ꢀ
tetrahydrothieno[3,4ꢀd]pyrimidineꢀ7ꢀcarboxylate (9f). A mixture
of thiophene 7 (1.6 g, 7 mmol), NCCH2COPh (3.05 g, 21 mmol),
and TsOH (0.1 g) in 40 mL of toluene was refluxed for 48 h
and then cooled. The precipitate that formed was filtered
off and washed with EtOH. The yield of compound 9f was
1.37 g (55%).
Ethyl
3ꢀalkylꢀ2,5ꢀdimethylꢀ4ꢀoxoꢀ3,4ꢀdihydrothieꢀ
C. A mixture of thiophene 7 (1.02 g, 4.4 mmol), benzoylꢀ
acetone (2.0 g, 12.3 mmol), and TsOH (0.1 g) in 50 mL of
toluene was refluxed for 32 h. The precipitate that formed was
filtered off. The yield of product 11a was 0.67 g (60%).
D. A mixture of tetrahydropyrimidine 9c (1.02 g, 3 mmol)
and TsOH (0.1 g) in 40.0 mL of toluene was refluxed for 48 h.
The precipitate that formed was filtered off. The yield of product
11a was 0.45 g (60%).
no[3,4ꢀd]pyrimidineꢀ7ꢀcarboxylates (12a—e) (general proceꢀ
dure). A mixture of compound 11a (0.45 g, 1.8 mmol), an alkyl
halide (2.1 mmol), and K2CO3 (0.35 g, 2.5 mmol) in 30 mL of
acetone was refluxed with stirring for 6 h (reaction conditions:
DMF, 70 °C, 2 h (12b); DMF, 50 °C, 5 h (12c,d); and DMF,
100 °C, 1 h (12e)). The reaction mixture was poured into water,
and the precipitate that formed was filtered off. Compound 12a:
13C NMR, δ: 14.5 (CH2Me, 1JCH = 126.7 Hz); 16.3 (q, C(5)Me,
1JCH2 = 132.0 Hz); 23.7 (q, C(2)Me, 1JCH = 128.9 Hz); 45.7 (tt,
E. A mixture of thiophene 7 (1.02 g, 4.4 mmol),
MeCOCH2CONHPh (23.4 g, 13.2 mmol), and TsOH (0.1 g) in
50 mL of toluene was refluxed for 20 h. The precipitate that
formed was filtered off. The yield of compound 11a was 0.44 g
1
1
N(3)CH2, JCH = 140.4 Hz); 60.7 (OCH2, JCH = 148.0 Hz);
3
115.9 (br.s, C(7)); 121.1 (q, C(4a), JCH = 3.8 Hz); signals for
the aromatic carbon atoms, δ: 126.4 (2 C); 127.5 (1 C); 129.1
1
2
(40%). 13C NMR, δ: 14.6 (q, CH2Me, JCH = 127.1 Hz); 16.1
(2 C); 136.8 (m); 149.6 (br.s, C(7a)); 152.2 (q, C(5), JCH
=
=
1
1
2
3
(q, C(5)Me, JCH = 131.2 Hz); 21.9 (q, C(2)Me, JCH
=
7.6 Hz); 157.1 (m, C(2), JC(2),CH = 6.6 Hz, JC(2),NCH
2
128.9 Hz); 60.5 (t, CH2Me, JCH = 148.0 Hz); 115.8 (br.s,
C(7)); 122.0 (q, C(4a), JCH = 3.8 Hz); 151.4 (q, C(5), JCH
7.6 Hz); 151.8 (br.s, C(7a)); 156.6 (q, C(2), JCH = 7.8 Hz);
159.3 (br.s, C(4)); 161.2 (t, C(7)CO, JCO,CH2 = 3.9 Hz).
3.9 Hz); 158.9 (t, C(4), JC(4),CH2 = 33.5 Hz); 160.5 (t, C(7)CO,
1
3
3
2
=
3JCO,CH2 = 3.8 Hz).
2
Ethyl 4ꢀ(ethoxycarbonylmethyl)ꢀ5ꢀethylꢀ2ꢀmethylꢀ6ꢀoxoꢀ
1,6ꢀdihydropyrimidinꢀ1ꢀylacetate (15). A 50% suspension of
Ni/Ra (7.5 g) was carefully added in portions to a boiling soluꢀ
tion of compound 12b (1.5 g, 4.4 mmol) in 40 mL of ethanol.
The reaction mixture was refluxed for 4 h then filtered. The
filtrate was concentrated in vacuo, and the residue was crystalꢀ
lized from EtOH. The yield of compound 15 was 0.86 g (63%).
1H NMR, δ: 0.96 (t, 3 H, CH2CH3); 1.17, 1.20 (both t, 3 H each,
2 CH2CH3); 2.38 (m, 5 H, CH2CH3 + C(2)Me); 3.61 (s, 2 H,
CH2C(4)); 4.08 and 4.15 (both q, 2 H each, 2 CH2CH3); 4.78
(s, 2 H, CH2N(1)). 13C NMR, δ: 13.0 (CH3CH2); 14.3 and
14.4 (2 CO2CH2Me); 19.4 (CH3CH2); 22.5 (C(2)Me); 40.3
(C(4)CH2); 46.0 (N(1)CH2); 60.8 and 61.7 (2 CO2CH2Me);
124.4 (C(5)); 154.0 (C(4)); 161.8 (CO); 168.0 (CO); 169.0 (CO).
3ꢀ(NꢀAlkylcarbamoylmethyl)ꢀ2,5ꢀdimethylꢀ4ꢀoxoꢀ3,4ꢀdiꢀ
hydrothieno[3,4ꢀd]pyrimidineꢀ7ꢀcarboxamides (16a,b) (general
procedure). A mixture of compound 12b (2.3 g, 7 mmol) and an
amine (30 mmol) in 40 mL of anhydrous EtOH was reꢀ
fluxed for 9 h. The precipitate that formed on cooling was filꢀ
tered off.
3
Ethyl 2ꢀmethylꢀ4ꢀoxoꢀ5ꢀphenylꢀ3,4ꢀdihydrothieno[3,4ꢀd]pyꢀ
rimidineꢀ7ꢀcarboxylate (11b). Thiophene 7 (1.02 g, 4.4 mmol)
was added to a solution of PhCOCH2CO2Et (30 mL) in 30 mL
of toluene. The reaction mixture was refluxed for 105 h and then
cooled. The precipitate that formed was filtered off and washed
with EtOH to give product 11b (0.28 g, 20%).
Ethyl 2ꢀ(ethoxycarbonylmethyl)ꢀ2,5ꢀdimethylꢀ4ꢀoxoꢀ1,2,3,4ꢀ
tetrahydrothieno[3,4ꢀd]pyrimidineꢀ7ꢀcarboxylate (9c). A mixture
of thiophene 7 (8.0 g, 35 mmol), MeCOCH2CO2Et (50 mL),
and TsOH (0.1 g) in 60 mL of toluene was refluxed for 6 h and
then cooled. The precipitate that formed was filtered off and
washed with EtOH. The yield of compound 9c was 8.3 g (70%).
13C NMR, δ: 14.12 and 14.68 (2 CH21Me, 1JCH = 127.4 Hz and
1JCH = 127.7 Hz); 15.6 (C(5)Me, JCH = 131.2 Hz); 28.6
(C(2)Me, JCH = 127.4 Hz); 46.5 (CH22, JCH = 131.2 Hz);
1
1
2
1
1
60.17 and 60.70 (2 OCH2, JCH = 148.0 Hz and JCH
=
148.0 Hz); 70.0 (br.s, C(2)); 95.8 (br.s, C(7)); 117.6 (m, C(4a));
2
150.7 (br.s, C(7a)); 153.0 (q, C(5), JCH = 7.4 Hz); 160.0 (br.s,
3
C(4)); 162.9 (t, C(7)CO, JCH = 3.6 Hz); 169.9 (m, C(2)CO).
Ethyl 2,5ꢀdimethylꢀ4ꢀoxoꢀ2ꢀ(Nꢀphenylcarbamoylmethyl)ꢀ
1,2,3,4ꢀtetrahydrothieno[3,4ꢀd]pyrimidineꢀ7ꢀcarboxylate (9d). A
mixture of thiophene 7 (1.6 g, 7 mmol), MeCOCH2CONHPh
(4.9 g, 21 mmol), and TsOH (0.1 g) in 60 mL of toluene was
refluxed for 4 h and then cooled. Compound 11a (0.2 g, 10%)
was filtered off. The mother liquor was concentrated in vacuo.
The residue was recrystallized from acetone—DMF to give prodꢀ
uct 9d (1.9 g, 70%).
Ethyl 2ꢀ(ethoxycarbonylmethyl)ꢀ5ꢀmethylꢀ4ꢀoxoꢀ2ꢀphenylꢀ
1,2,3,4ꢀtetrahydrothieno[3,4ꢀd]pyrimidineꢀ7ꢀcarboxylate (9e). A
mixture of thiophene 7 (1.6 g, 7 mmol), PhCOCH2CO2Et
(40.3 g, 21 mmol), and TsOH (0.1 g) in 40 mL of toluene was
refluxed for 5 h and then cooled. The precipitate that formed
was filtered off and washed with EtOH. The yield of compound
9e was 1.4 g (50%).
References
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Received March 27, 2002;
in revised form June 5, 2002