Selective nucleophilic replacement of the benzylsulfanyl group in 2,4-disulfanyl-substituted thieno[2,3-d]pyrimidin-6-carboxylic acid derivatives by secondary amines

Article abstract of DOI:10.1002/jhet.5570420514

Thieno[2,3-d]pyrimidines with benzylsulfanyl and allylsulfanyl group in the presence of other alkylsulfanyl substituents react selectively under mild conditions with secondary amines under replacement of the benzyl or allyl residue whereas the other subst

Full text of DOI:10.1002/jhet.5570420514

Selective Nucleophilic Replacement of the Benzylsulfanyl Group in
2,4-Disulfanyl-substituted Thieno[2,3-d]pyrimidin-6-carboxylic Acid
Derivatives by Secondary Amines
Jul-Aug 2005
841
Detlef Briel
Fakultät für Biowissenschaften, Pharmazie und Psychologie der Universität Leipzig, Institut für Pharmazie,
Pharmazeutische Chemie, Brüderstraße 34, 04103 Leipzig
Simon Drescher and Bodo Dobner*
Fachbereich Pharmazie der Martin-Luther-Universität Halle/Wittenberg, Institut für Pharmazeutische Chemie,
Wolfgang-Langenbeck-Straße 4, 06120 Halle/Saale
Received November 9, 2004
Thieno[2,3-d]pyrimidines with benzylsulfanyl and allylsulfanyl group in the presence of other alkylsul-
fanyl substituents react selectively under mild conditions with secondary amines under replacement of the
benzyl or allyl residue whereas the other substituents remain intact. This enables the synthesis of different
basic substituted derivatives with potentially biologically activity.
J. Heterocyclic Chem., 42, 841 (2005).
In a former publication [1] we have reported an effective
compounds 4a and 4b (Scheme 1). This is due to the
stronger electron withdrawing influence of the ester
group compared to the amide residue in the 6-position of
the thieno[2,3-d]pyrimidine. This was also found for
compound 2a [1].
But our aim was the selective replacement of only one
thiofunction by an amino substituent. A mono substitution
in the 4-position of the thieno[2,3-d]pyrimidine system
enables the selective variation of all three substituents to
deliver a broad substance pool for further biological tests.
The application of milder conditions led to mixtures in all
cases which could sometimes be separated with heavy
losses. So the methylsulfanyl function in position four was
not suitable. Several attempts to enhance the reactivity by
transforming the methylsulfanyl group into the corre-
and short synthesis of 6-methylsulfanyl-2,4-dithioxo-
1,2,3,4-tetrahydropyrimidin-5-carbonitrile 1 and some
reactions of this compound.
Whereas the reaction of the 2,4,6-trimethylsul-
fanylpyrimidin-5-carbonitrile resulting from the reaction
of 1 and methyl iodide with secondary amines gives amino
substituted pyrimidines, the alkylation reaction of 1 with
chloroacetic acid derivatives using sodium methoxide
and/or triethyl amine as base yield 2,4-disulfanyl substi-
tuted 5-aminothieno[2,3-d]pyrimidin-6-carboxylic acid
derivatives 2 [1].
Now we present our results regarding the selective
nucleophilic substitution of the benzylsulfanyl group in the
2,4-disulfanyl substituted thieno[2,3-d]pyrimidine system.
Since the thiophene ring is a bioisoster to benzene the
thieno[2,3-d]pyrimidines should have similar properties as
quinazolines which are interesting because of their known
biological activity. Basic substituted quinazolines were
found to be targets for tyrosin kinases [2]. The inhibition
of these kinases is of outstanding interest with regard to
cancer treatment. However there is a strong relationship
between structural variations and the selectivity on certain
tyrosinkinases of substances active in this regard.
Therefore the search for new compounds with potential
effect on tyrosinkinases is of great interest in this impor-
tant field of medical chemistry.
Starting from compound 1 we have synthesized two
new thieno[2,3-d]pyrimidin-6-carboxylic acid amides
2d and 2e. In a model reaction we have first investigated
the nucleophilic substitution by heating of 2b with the
secondary amines morpholine and pyrrolidine without
solvent. In this reaction compound 3a and 3b were iso-
lated in 77% and 85% yield, respectively. However the
reaction of 2d with morpholine under the same condi-
tions gives a mixture of the mono- and disubstituted

842
D. Briel, S. Drescher and B. Dobner
Vol. 42
sponding sulfoxide or sulfone which is a better leaving
group shown by some authors [3] failed. The reason for
that was that a selective oxidation was missing.
tives (8). The difference with respect to the products
which were isolated from 2a was that the side chain was
not separated during the reaction. Only the methoxy
group in the ester function in the 2-position of the
bicyclic system was transformed in the corresponding
amide structure. This was concluded from the analysis of
the mass spectra. So there was found a fragment peak
assigned to the fragmentation of the side chain in the 2-
position (m/z 277) including the sulfur atom of the heter-
obicyclic system. The corresponding fragment with a
methoxycarbonylmethylsulfanyl residue could not be
detected. The same situation was found in the reaction of
2a with piperidine indicating the higher stability of the
ester function bound directly to the thiophene ring sys-
tem. The separation of the mixtures is possible by recrys-
tallisation or chromatography.
In the case of compounds 6b, c and e selective replace-
ment of the benzylsulfanyl group in the 4-position takes
place and the corresponding amino substituted derivatives
were isolated in good yields. The substances prepared after
that procedure are shown in Scheme 3. However our inves-
tigations failed in the case of primary amines like aniline.
On the other hand compounds 9 were transformed selec-
In some earlier attempts to synthesise thieno[2,3-
d]pyrimidin-6-carboxylic acid derivatives from 4-benzyl-
sulfanyl or 4-allylsulfanyl groups (5a, b) we found that
with strong alkoxide bases beside the cyclisation to com-
pounds 6a substitution by the alkoxide molecule has taken
place. This was not observed starting from compound 1.
Therefore we could assume the higher reactivity of benzyl-
sulfanyl or allylsulfanyl group. For studying these nucle-
ophilic replacements the synthesis of appropriate
thieno[2,3-d]pyrimidin-6-carboxylic acid derivatives was
necessary. Alkylation reaction proceeds smoothly at room
temperature using Hünig's base starting from 5a or b to get
thieno[2,3-d]pyrimidin-6-carboxylic acid derivatives 6a-d
in respectable yields between 56% and 87%. However no
cyclisation to this heterobicyclic system was observed in
the case when 5a was alkylated with chloroacetic acid
morpholide and chloroacetic acid piperidide using the
above discussed conditions. After heating the monocyclic
compounds 7 only 7a gives the bicyclic substance 6e
(Scheme 2).
For the investigation of the nucleophilic substitution
reaction we have used only 4-benzylsulfanyl substituted
thieno[2,3-d]pyrimidin-6-carboxylic acid derivatives.
This is due to the low to moderate yield obtained for the
synthesis of 5b [4]. Starting from compound 6a the reac-
tion with cyclic secondary amines gave a mixture of
monosubstituted (in position 4) and disubstituted deriva-
tively into substituted thieno[2,3-d]pyrimidin-6-carboxylic
acid derivatives (10) in high yields (about 90%) with three
different functions by heating with secondary amines.
Since the yields for these transformations are good the
method enables us to synthesize a broad spectrum of dif-
ferent functionalised thieno[2,3-d]pyrimidin-6-yl car-
boxylic acid derivatives.

Jul-Aug 2005
Selective Nucleophilic Replacement of the Benzylsulfanyl Group
843
13
–CH NCH –), 4.03 (s, 2H, –COCH S–), 6.74 (s, 2H, –NH );
C
2
2
2
2
nmr (100 MHz, deuteriochloroform): δ 12.75 (–SCH ), 34.87
3
+
(–COCH S–), 147.07 (–CNH ); ms: m/z 437 (M , 100%), 367
2
2
(30%), 326 (52%).
Anal. Calcd. for C
H N O S : C, 49.40; H, 5.30; N, 16.01;
18 23 5 2 3
S, 21.98. Found: C, 49.53; H, 5.27; N, 15.64; S, 21.88.
5-Amino-4-methylsulfanyl-2-(piperidinocarbonylmethylsul-
fanyl)thieno[2,3-d]pyrimidin-6-carboxylic Acid Piperidide (2e).
Compound 2e was obtained from compound 1 in reaction with
chloroacetic acid piperidide in 62% yield (1.44 g); mp: 161-162
°C; ir: 3447, 3424, 3242, 2938, 2925, 2856, 1639, 1557, 1511,
-1 1
1405, 1258 cm ; H nmr (500 MHz, deuteriochloroform): δ 1.6-
1.7 (m, 12H, 2x –CH (CH ) CH –), 2.69 (s, 3H, –SCH ), 3.5-3.6
2
2 3
2
3
(m, 8H, 2x –CH NCH –), 4.14 (s, 2H, –COCH S–), 6.00 (s, 2H,
2
2
2
13
–NH ); C nmr (125 MHz, deuteriochloroform): δ 12.67
2
(–SCH ), 34.11 (–COCH S–), 145.30 (–CNH ); ms: m/z 465
3
2
2
+
(M , 73%), 381 (20%), 340 (24%), 84 (100%).
Anal. Calcd. for C N O S : C, 51.59; H, 5.85; N, 15.04;
H
20 27
5 2 3
S, 20.66. Found: C, 51.58; H, 5.82; N, 15.10; S, 20.91.
Reaction of Compound 2b with Secondary Amines.
Compound 2b (0.21 g, 0.5 mmol) and 5 ml secondary amine
were heated 3 hours under reflux. After cooling to room tempera-
ture 10 ml methanol and 20 ml water were added. The precipitate
was collected by suction filtration, recrystallised from
2-methoxyethanol and dried in vacuo.
5-Amino-2,4-dimorpholinothieno[2,3-d]pyrimidin-6-carboxylic
Acid tert-Butylester (3a).
Compound 3a was obtained from compound 2b and morpho-
line in 77% yield (0.16 g); mp: 187-189 °C; ir: 3456, 3341, 2970,
2881, 2843, 1656, 1250, 1113 cm ; H nmr (400 MHz, deuterio-
EXPERIMENTAL
Melting points were acquired with a Boetius apparatus and are
uncorrected. The H and C nmr spectra have been recorded on
a Varian Gemini 2000 or Varian Inova 500 using tetramethylsi-
lane as internal reference. Chemical shifts are given in ppm. Mass
spectrometric data were obtained on an AMD 402 (70eV) spec-
trometer (Intecta GmbH, Harpstedt). Elemental analyses were
performed with a CHNS-932 apparatus (LECO-Corporation, St.
Joseph, Michigan USA). Infrared spectra were obtained on a FT-
IR spectrometer IFS 28 (Bruker Optik, Ettlingen).
-1
1
chloroform): δ 1.54 (s, 9H, –C(CH ) ), 3.37, 3.74-3.75 and 3.84
3 3
13
(3m, 16H, 2x –N(C H ) O), 6.09 (s, 2H, –NH ); C nmr (100
MHz, deuteriochloroform): δ 146.98 (–CNH ); ms: m/z 421 (M ,
2
4 2
2
1
13
+
2
30%), 365 (100%).
Anal. Calcd. for C
H N O S: C, 54.14; H, 6.46; N, 16.62; S,
19 27 5 4
7.61. Found: C, 53.80; H, 6.29; N, 16.61; S, 7.80.
5-Amino-2,4-dipyrrolidinothieno[2,3-d]pyrimidin-6-carboxylic
Acid tert-Butylester (3b).
Compound 3b was obtained from compound 2b and pyrroli-
The chloroacetic acid amides were prepared according to liter-
ature [5]. Chloroacetic acid methylester and chloroacetic acid
tert-butylester were purchased from Aldrich.
dine in 85% yield (0.17g); mp: 173-174 °C; ir: 3417, 3314,
-1
1
2970, 2862, 1656, 1520 cm ; H nmr (200 MHz, deuterio-
chloroform): δ 1.53 (s, 9H, –C(CH ) ), 1.87-1.93 (m, 8H, 2x
3 3
–CH (CH ) CH –), 3.5-3.7 (m, 8H, 2x –CH NCH –), 5.96 (s,
2
2 2
2
2
2
New Thieno[2,3-d]pyrimidin-6-carboxylic Acid Amides (2d and e).
+
2H, –NH ); ms: m/z 389 (M , 35%), 333 (100%).
2
To 5 mmol of the pyrimidine 1 (1.08 g) in 20 ml dry methanol
were added 8 mmol (1.6 ml) sodium methoxide (5 M) and 8
mmol of the chloroacetic acid amides at room temperature. After
2 days the yellow precipitate was collected by suction filtration,
recrystallised from 2-methoxyethanol and dried in vacuo.
Anal. Calcd. for C
8.23. Found: C, 58.69; H 6.81; N, 17.78; S, 8.07.
H N O S: C, 58.59; H, 6.99; N, 17.98; S
19 27 5 2
Synthesis of 5-Amino-4-methylsulfanyl-2-morpholinoth-
ieno[2,3-d]pyrimidin-6-carboxylic Acid Pyrrolidide (4a) and 5-
Amino-2,4-dimorpholinothieno[2,3-d]pyrimidin-6-carboxylic
Acid Pyrrolidide (4b).
5-Amino-4-methylsulfanyl-2-(pyrrolidinocarbonylmethylsulfanyl)-
thieno[2,3-d]pyrimidin-6-carboxylic Acid Pyrrolidide (2d).
Compound 2d (0.22 g, 0.5 mmol) and 3 ml morpholine were
heated for 2 hours under reflux. After cooling to room tempera-
ture 10 ml dry methanol were added. The precipitate was col-
lected by suction filtration after one day. Compounds 4a and 4b
were separated by column chromatography (silica gel 60 Merck,
0.063-0.2 mm) with chloroform and methanol using gradient
Compound 2d was obtained from compound 1 in reaction with
chloroacetic acid pyrrolidide in 65% yield (1.42 g); mp: 221-222
°C; ir: 3432, 3233, 2980, 2960, 2880, 1633, 1563, 1514, 1394
-1
1
cm ; H nmr (400 MHz, deuteriochloroform): δ 1.8-2.0 (m, 8H,
2x –CH (CH ) CH –), 2.68 (s, 3H, –SCH ), 3.5-3.7 (m, 8H, 2x
2
2 2
2
3

844
D. Briel, S. Drescher and B. Dobner
Vol. 42
technique (starting with CHCl , final polarity CHCl /MeOH =
Anal. Calcd. for C H N O S : C, 55.47; H, 5.63; N, 8.09; S,
24 29 3 4 3
3
3
9:1).
18.51. Found: C, 55.67; H, 5.48; N, 8.07; S, 18.91.
5-Amino-4-methylsulfanyl-2-morpholinothieno[2,3-d]pyrim-
idin-6-carboxylic Acid Pyrrolidide (4a).
5-Amino-4-benzylsulfanyl-2-(pyrrolidinocarbonylmethylsulfanyl)-
thieno[2,3-d]pyrimidin-6-carboxylic Acid Pyrrolidide (6c).
Compound 4a was obtained in 38% yield (0.07 g); mp: 232-
Compound 6c was obtained from compound 5a in reaction
233 °C; ir: 3454, 3274, 2972, 2870, 1570, 1543, 1398, 1271, 1116
with chloroacetic acid pyrrolidide in 75% yield (3.85 g); ir: 3439,
3242, 3059, 3035, 2969, 2952, 2873, 1637, 1550, 1512 cm ; H
nmr (400 MHz, deuteriochloroform): δ 1.84-1.95 (m, 8H, 2x
-1
1
-1 1
cm ; H nmr (500 MHz, deuteriochloroform): δ 1.90-1.93 (m,
4H, –CH (CH ) CH –), 2.63 (s, 3H, –SCH ), 3.66-3.69 (m, 4H,
2
2 2
2
3
–CH NCH – from pyrrolidine), 3.74-3.76 and 3.85-3.87 (2t, 8H,
–CH (CH ) CH –), 3.5-3.7 (m, 8H 2x –CH NCH –), 4.04 (s,
2
2
2 2 2 2 2 2
13
–N(C H ) O), 6.77 (s, 2H, –NH ); C nmr (125 MHz, deuterio-
2H, –COCH S–), 4.60 (s, 2H, –SCH C H ), 7.23-7.42 (m, 5H,
2 2 6 5
2
4 2
2
+
chloroform): δ 12.51 (–SCH ), 148.02 (–CNH ); ms: m/z 379
–C H ); ms: m/z 513 (M , 77%), 401 (18%), 91 (100%).
3
2
6 5
+
(M , 100%), 309 (57%), 282 (44%).
Anal. Calcd. for C N O S : C, 50.64; H, 5.58; N, 18.46;
Anal. Calcd. for C
H N O S : C, 56.11; H, 5.30; N, 13.63;
24 27 5 2 3
H
S, 18.72. Found: C, 56.20; H, 5.28; N, 13.65; S, 18.93.
16 21
5 2 2
S, 16.90. Found: C, 50.53; H, 5.46; N, 18.42; S, 16.72.
4-Allylsulfanyl-5-amino-2-(pyrrolidinocarbonylmethylsulfanyl)-
5-Amino-2,4-dimorpholinothieno[2,3-d]pyrimidin-6-carboxylic
Acid Pyrrolidide (4b).
thieno[2,3-d]pyrimidin-6-carboxylic Acid Pyrrolidide (6d).
Compound 6d was obtained from compound 5b in reaction
with chloroacetic acid pyrrolidide in 56% yield (2.6 g); mp: 188
°C, dec.; ir: 3439, 3243, 3086, 2966, 2910, 2875, 1639, 1555,
Compound 4b was obtained in 24% yield (0.05 g); mp: 243-
244 °C; ir: 3445, 3300, 2962, 2924, 2854, 1557, 1422, 1261, 1117
-1
1
-1
1
1513 cm ; H nmr (200 MHz, deuteriochloroform): δ 1.91-1.97
(m, 8H, 2x –CH (CH ) CH –), 3.47-3,73 (m, 8H 2x
cm ; H nmr (200 MHz, deuteriochloroform): δ 1.88-1.95 (m,
4H, –CH (CH ) CH –), 3.34-3.38 and 3.64-3.85 (2m, 20H,
2
2 2
2
2
2 2
2
–CH NCH –), 4.01-4.04 (d, 2H, –SCH CH=), 4.04 (s, 2H,
–CH NCH – and 2x –N(C H ) O), 6.61 (s, 2H, –NH ); ms: m/z
2
2
2
2
2
2
4 2
2
+
–COCH S–), 5.16-5.40 (dd, 2H, =CH ), 5.88-6.02 (m, 1H,
418 (M , 100%), 348 (27%), 321 (36%).
Anal. Calcd. for C N O S: C, 54.53; H, 6.26; N, 20.08; S,
2
2
+
–CH=); ms: m/z 463 (M , 95%), 351 (100%).
Anal. Calcd. for C N O S : C, 51.81; H, 5.44; N, 15.11;
H
19 26
6 3
H
7.66. Found: C, 54.62; H, 6.12; N, 20.16; S, 7.52.
20 25
5 2 3
S, 20.75. Found: C, 51.67; H, 5.35; N, 15.11; S, 20.72.
General Procedure for the Synthesis of 4-Allylsulfanyl or 4-
Benzylsulfanyl Thieno[2,3-d]pyrimidin-6-carboxylic Acid
Derivatives (6a-d).
Synthesis of 2,4-disubstituted 6-Benzylsulfanylpyrimidin-5-car-
bonitrile (7a and 7b).
Compound 5a (10 mmol) was suspended in 50 ml dry
methanol. After addition of 20 mmol of Hünig's base and 20
mmol of the chloroacetic acid derivatives the mixture was
allowed to stand for 3 days at room temperature. The product was
collected by suction filtration and recrystallised from 2-
methoxyethanol.
To 10 mmol of the pyrimidine (5a or 5b) in 50 ml dry
methanol were added 20 mmol Hünig's base (2.58 g) and 20
mmol of the chloroacetic acid derivatives. After standing 3
days at room temperature the precipitate was collected by suc-
tion filtration, recrystallised from 2-methoxyethanol and dried
in vacuo.
6-Benzylsulfanyl-2,4-bis(morpholinocarbonylmethylsulfanyl)-
5-Amino-4-benzylsulfanyl-2-(methoxycarbonylmethylsulfanyl)-
pyrimidin-5-carbonitrile (7a)
thieno[2,3-d]pyrimidin-6-carboxylic Acid Methylester (6a).
Compound 7a was obtained from compound 5a in reaction
Compound 6a was obtained from compound 5a in reaction
with chloroacetic acid methylester in 71% yield (3.09 g); mp:
176-177 °C; ir: 3453, 3344, 2983, 2929, 2853, 1745, 1667, 1530,
with chloroacetic acid morpholide in 62% yield (3.4 g); mp: 194-
-1
1
195 °C; ir: 3017, 2935, 2862, 2215, 1662, 1587, 1503 cm ; H
nmr (400 MHz, deuteriochloroform): δ 3.40-3.72 (m, 16H, 2x
–N(C H ) O), 4.06 and 4.15 (2s, 4H, 2x –COCH S–), 4.44 (s,
-1
1
1277 cm ; H nmr (400 MHz, deuteriochloroform): δ 3.73 and
3.84 (2s, 6H, 2x –OCH ), 3.98 (s, 2H, –COCH S_), 4.62 (s, 2H,
2
4 2
2
3
2
+
2H, –SCH C H ), 7.25-7.34 (m, 5H, –C H ); ms: m/z 545 (M ,
–SCH C H ), 6.42 (s, 2H, –NH ), 7.26-7.42 (m, 5H, –C H );
2
6
5
6 5
2
6
5
2
6 5
+
21%), 417 (38%), 91 (100%).
Anal. Calcd. for C N O S : C, 52.82; H, 4.99; N, 12.83;
ms: m/z 435 (M , 100%), 362 (38%).
Anal. Calcd. for C N O S : C, 49.64; H, 3.94; N, 9.65; S,
H
H
24 27
5 4 3
18 17
3 4 3
S, 17.63. Found: C, 52.89; H, 5.07; N, 12.86; S, 18.18.
22.08. Found: C, 49.80; H, 4.00; N, 9.67; S, 22.70.
6-Benzylsulfanyl-2,4-bis(piperidinocarbonylmethylsulfanyl)-
pyrimidin-5-carbonitrile (7b)
5-Amino-4-benzylsulfanyl-2-(tert-butoxycarbonylmethylsul-
fanyl)thieno[2,3-d]pyrimidin-6-carboxylic Acid tert-Butylester
(6b).
Compound 7b was obtained from compound 5a in reaction
with chloroacetic acid piperidide in 58% yield (3.1 g); mp: 147-
Compound 6b was obtained from compound 5a in reaction
with chloroacetic acid tert-butylester in 87% yield (4.5 g); mp:
-1
1
148 °C; ir: 3017, 2937, 2857, 2214, 1663, 1580, 1502 cm ; H
nmr (500 MHz, deuteriochloroform): δ 1.53-1.64 (m, 12H, 2x
–CH (CH ) CH –), 3.35-3.54 (m, 8H, 2x –CH NCH –), 4.07
-1
158-160 °C; ir: 3459, 3339, 2978, 2936, 1730, 1667, 1525 cm ;
1
H nmr (500 MHz, deuteriochloroform): δ 1.45 and 1.54 (2s,
2
2 3
2
2
2
and 4.15 (2s, 4H, 2x –COCH S–), 4.44 (s, 2H, –SCH C H ),
18H, 2x –C(CH ) ), 3.86 (s, 2H, –COCH S–), 4.62 (s, 2H,
2
2 6 5
3 3
2
+
13
7.25-7.34 (m, 5H, –C H ); ms: m/z 541 (M , 35%), 415 (26%),
–SCH C H ), 7.27-7.42 (m, 5H, –C H ); C nmr (125 MHz,
6
5
2
6
5
6 5
91 (100%).
Anal. Calcd. for C
deuteriochloroform): δ 34.13 and 34.76 (2x –SCH –), 81.73 and
2
+
H N O S : C, 57.64; H, 5.77; N, 12.93;
82.11 (2x –C(CH ) ); ms: m/z 519 (M , 56%), 463 (62%), 407
26 31 5 2 3
3 3
(100%).
S, 17.75. Found: C, 57.60; H, 5.85; N, 13.01; S, 17.48.

Jul-Aug 2005
Selective Nucleophilic Replacement of the Benzylsulfanyl Group
845
Procedure for the Conversion of Compound 7a into 6e.
a clear solution in most cases. After 2 h for the reaction with
pyrrolidine and 20 h for piperidine and morpholine the mixture
was cooled down to -20 °C. Than 10 ml methanol were added
and the mixture was brought to room temperature. Subsequent
adding of 20 ml water yields a precipitate which was collected by
suction filtration, recrystallised from methanol/glycol mono
methylether and dried in vacou.
Compound 7a (3.0 g, 5.5 mmol) was suspended in 40 ml 2-
methoxyethanol. After addition of 10 drops of Hünig's base the
mixture was heated for 10 hours under reflux. After cooling to
room temperature the precipitate was collected by suction filtra-
tion and recrystallised two times from methanol.
5-Amino-4-benzylsulfanyl-2-(morpholinocarbonylmethylsul-
fanyl)thieno[2,3-d]pyrimidin-6-carboxylic Acid Morpholide
(6e).
5-Amino-2-(tert-butoxycarbonylmethylsulfanyl)-4-morpholino-
thieno[2,3-d]pyrimidin-6-carboxylic Acid tert-Butylester (9a).
Compound 9a was obtained from compound 6b and morpho-
Compound 6e was obtained in 40% yield (1.2 g); mp: 185 °C;
line in 73% yield (0.10 g); mp: 175-176 °C; ir: 3458, 3347, 3204,
ir: 3348, 3201, 3048, 3013, 2929, 2862, 1662, 1501, 1397, 1316,
-1
1
2977, 2932, 2859, 1734, 1668, 1590, 1540, 1324, 1114 cm ; H
-1
1
1114 cm ; H nmr (400MHz, deuteriochloroform): δ 3.58-3.71
(m, 16H, 2x –N(C H ) O), 4.10 (s, 2H, –COCH S–), 4.61 (s, 2H,
nmr (400 MHz, deuteriochloroform): δ 1.45 and 1.56 (2s, 18H,
2
4 2
2
2x –C(CH ) ), 3.44 (m, 4H, –CH NCH –), 3.82 (m, 4H,
3 3
2
2
–SCH C H ), 6.15 (s, 2H, –NH ), 7.26-7.50 (m, 5H, –C H );
2
6
5
2
6 5
13
–CH OCH –), 3.84 (s, 2H,–COCH S–), 6.09 (s, 2H, –NH );
C
+
2
2
2
2
ms: m/z 545 (M , 100%), 458 (21%).
Anal. Calcd. for C N O S : C, 52.82; H, 4.99; N, 12.83;
nmr (100 MHz, deuteriochloroform): δ 34.81 (–COCH S–),
2
H
24 27
5 4 3
+
81.59 and 81.93 (2x –C(CH ) ); ms: m/z 482 (M , 53%), 426
3 3
S, 17.63. Found: C, 52.64; H, 4.83; N, 12.67; S, 17.91.
(100%), 370 (39%).
General Procedure for the Reaction of 6a with Secondary
Amines.
Anal. Calcd. for C
H N O S : C, 52.26; H, 6.27; N, 11.61;
21 30 4 5 2
S, 13.29. Found: C, 52.32; H, 6.43; N, 11.61; S, 13.24.
In a flask 1 mmol of compound 6a (0.44 g) were suspended in
20 ml of the corresponding secondary amine with occasionally
stirring at room temperature. After 1 h for the reaction with
pyrrolidine 2 h for piperidine and 6 h for morpholine, respively
the reaction mixture was cooled down to -20 °C. At this tempera-
ture 20 ml methanol were added and the temperature was than
allowed to come to room temperature. After addition of 20 to 30
ml water the precipitate was collected by suction filtration,
recrystallised two times from methanol and dried in vacuo.
5-Amino-2-(tert-butoxycarbonylmethylsulfanyl)-4-pyrrolidino-
thieno[2,3-d]pyrimidin-6-carboxylic Acid tert-Butylester (9b).
Compound 9b was obtained from compound 6b and pyrroli-
dine in 84% yield (0.11 g); mp: 149-150 °C; ir: 3335, 3200, 2977,
-1
1
2935, 1731, 1666, 1599, 1535, 1320, 1139 cm ; H nmr (400
MHz, deuteriochloroform): δ 1.45 and 1.55 (2s, 18H, 2x
–C(CH ) ), 1.90 (m, 4H, –CH (CH ) CH –), 3.66 (m, 4H,
3 3
2
2 2
2
–CH NCH –), 3.82 (s, 2H, –COCH S–), 5.90 (s, 2H, –NH ); ms:
2
2
2
2
+
m/z 466 (M , 58%). 410 (100%), 354 (50%).
5-Amino-4-pyrrolidino-2-(pyrrolidinocarbonylmethylsulfanyl)-
thieno[2,3-d]pyrimidin-6-carboxylic Acid Methylester (8a).
Anal. Calcd. for C N O S : C, 54.05; H, 6.48; N, 12.01;
H
21 30
4 4 2
S, 13.74. Found: C, 54.08; H, 6.76; N, 12.07; S, 13.71.
Compound 8a was obtained from 6a and pyrrolidine in 63%
5-Amino-2-(tert-butoxycarbonylmethylsulfanyl)-4-piperidino-
thieno[2,3-d]pyrimidin-6-carboxylic Acid tert-Butylester (9c).
yield (0.27 g); mp: 225-227 °C; ir: 3399, 3339, 3203, 2971, 2952,
-1
1
2876, 1671, 1643, 1605, 1535, 1312 cm ; H nmr (500 MHz,
Compound 9c was obtained from compound 6b and piperidine
in 71% yield (0.10 g); mp: 162-163°C; ir: 3463, 3348, 3209,
deuteriochloroform): δ 1.82-1.88 and 1.98-2.01 (2m, 8H, 2x
–CH (CH ) CH –), 3.45-3.47 and 3.61-3.64 (2m, 8H, 2x
2
2 2
2
-
2978, 2936, 2856, 1736, 1667, 1590, 1539, 1324, 1285, 1141 cm
–CH NCH –), 3.80 (s, 3H, –OCH ), 3.94 (s, 2H, –COCH S–),
2
2
3
2
1
1
13
; H nmr (400 MHz, deuteriochloroform): δ 1.45 and 1.55 (2s,
18H, 2x –C(CH ) ), 1.71 (m, 6H, –CH (CH ) CH –), 3.34 (m,
6.00 (s, 2H, –NH ); C nmr (125 MHz, deuteriochloroform): δ
34.51 (–COCH S–); ms: m/z 421 (M , 100%), 335 (60%).
2
+
3 3
2
2 3
2
2
4H, –CH NCH –), 3.84 (s, 2H, –COCH S–), 6.15 (s, 2H, –NH );
Anal. Calcd. for C
H N O S : C, 51.29; H, 5.50; N, 16.62;
2
2
2
2
18 23 5 3 2
+
ms: m/z 480 (M , 79%), 424 (100%), 368 (40%).
S, 15.21. Found: C, 51.06; H, 5.54; N, 16.59; S, 15.05.
Anal. Calcd. for C N O S : C, 54.97; H, 6.71; N, 11.66;
S, 13.34. Found: C, 54.98; H, 6.84; N, 11.63; S, 13.28.
H
22 32
4 4 2
5-Amino-4-piperidino-2-(piperidinocarbonylmethylsulfanyl)-
thieno[2,3-d]pyrimidin-6-carboxylic Acid Methylester (8b).
5-Amino-4-pyrrolidino-2-(pyrrolidinocarbonylmethylsulfanyl)-
thieno[2,3-d]pyrimidin-6-carboxylic Acid Pyrrolidide (9d)
Compound 8b was obtained from 6a and piperidine in 24%
yield (0.11 g); mp: 195-197°C; ir: 3461, 3344, 3195, 2938, 2856,
-1
1
Compound 9d was obtained from compound 6c and pyrroli-
1672, 1646, 1593, 1540, 1280 cm ; H nmr (400 MHz, deuterio-
chloroform): δ 1.55-1.72 (m, 12H, 2x –CH (CH ) CH –), 3.36
dine in 68% yield (0.09 g); mp: 213-215 °C; ir: 3334, 3205, 2971,
2
2 3
2
-1
1
2875, 1671, 1642, 1567, 1387 cm ; H nmr (500 MHz, deuterio-
and 3.54-3.58 (m, 8H, 2x –CH NCH –), 3.84 (s, 3H, –OCH ),
2
2
3
+
chloroform): δ 1.84-2.01 (m, 12H, 3x –CH (CH ) CH –), 3.48-
4.11 (s, 2H, –COCH S–), 6.24 (s, 2H, –NH ); ms: m/z 449 (M ,
2
2 2
2
2
2
3.69 (m, 12H, 3x –CH NCH –), 4.01 (s, 2H, –COCH S–), 6.35
97%), 349 (100%).
Anal. Calcd. for C
2
2
2
+
(s, 2H, –NH ); ms: m/z 460 (M , 66%), 348 (100%), 277 (59%).
H
N O S : C, 53.43; H, 6.05; N, 15.59;
2
20 27
5 3 2
S, 14.26. Found: C, 53.43; H, 6.36; N, 15.56; S, 14.31.
Anal. Calcd. for C H N O S : C, 54.76; H, 6.13; N, 18.25;
21 28 6 2 2
S, 13.92. Found: C, 54.57; H, 6.27; N, 17.77; S, 13.62.
Reaction of the 4-Benzylsulfanylthieno[2,3-d]pyrimidin-6-car-
boxylic Acid Derivatives 6b,c and e with Secondary Amines.
5-Amino-4-piperidino-2-(pyrrolidinocarbonylmethylsulfanyl)-
thieno[2,3-d]pyrimidin-6-carboxylic Acid Pyrrolidide (9e)
In an Erlenmeyer flask 150 mg of the compounds 6b,c or e
were suspended in 6 ml of the respective secondary amine with
occasionally stirring of the slurry at room temperature leading to
Compound 9e was obtained from compound 6c and piperidine
in 56% yield (0.08 g); mp: 165 °C dec.; ir: 3346, 3195, 2985,

846
D. Briel, S. Drescher and B. Dobner
Vol. 42
-1
1
dine), 3.82-3,84 (m, 4H, –CH OCH –), 6.13 (s, 2H, –NH ); ms:
2 2 2
m/z 405 (M , 27%), 349 (100%).
2956, 2880, 1662, 1572, 1391 cm ; H nmr (500MHz, deuterio-
chloroform): δ 1.65-1.99 (m, 14H, 2x –CH (CH ) CH – and
+
2
2 2
2
Anal. Calcd. for C N O S: C, 56.27; H, 6.71; N, 17.27; S,
H
–CH (CH ) CH –), 3.40-3.69 (m, 12H, 3x –CH NCH –), 4.05
(s, 2H, –COCH S–); ms: m/z 474 (M , 53%), 362 (100%), 291
19 27
5 3
2
2 3
2
2
2
+
7.91. Found: C, 56.03; H, 6.72; N, 17.57; S, 8.02.
2
(71%).
Anal. Calcd. for C
S, 13.51. Found: C, 55.23; H, 6.18; N, 17.62; S, 13.60.
5-Amino-4-piperidino-2-pyrrolidinothieno[2.3-d]pyrimidine-6-
carboxylic Acid tert-Butylester (10b)
H N O S : C, 55.67; H, 6.37; N, 17.71;
22 30 6 2 2
Compound 10b was obtained from compound 9c and pyrroli-
5-Amino-2-(morpholinocarbonylmethylsulfanyl)-4-pyrrolidino-
thieno[2,3-d]pyrimidin-6-carboxylic Acid Morpholide (9f)
dine in 92% yield (0.07 g); mp: 187-188 °C; ir: 3459, 3341, 3193,
-1
1
2975, 2936, 2870, 1660, 1586, 1553, 1320 cm ; H nmr (400
MHz, deuteriochloroform): δ 1.54 (s, 9H, –C(CH ) ), 1.61 and
Compound 9f was obtained from compound 6e and pyrrolidine
3 3
1.69-1.71 (m, 6H, –CH (CH ) CH –), 1.93-1.96 (m, 4H,
in 85% yield (0.11 g); mp: 124-126 °C; ir: 3349, 3197, 2942,
2866, 1653, 1617, 1559, 1397 cm ; H nmr (500 MHz, deuterio-
2
2 3
2
-1
1
–CH (CH ) CH –), 3.25 (m, 4H, –CH NCH – from piperidine),
2
2 2
2
2
2
3.58-3.61 (m, 4H, –CH NCH – from pyrrolidine), 6.20 (s, 2H,
chloroform): δ 1.91-1.93 (m, 4H, –CH (CH ) CH –), 3.63-3.72
2
2
2
2 2
2
+
–NH ); ms: m/z 403 (M , 46%), 347 (100%).
(m, 20H, –CH NCH – and 2x –N(C H ) O), 4.08 (s, 2H,
2
2
2
2 4 2
+
–COCH S–), 5.96 (s, 2H, –NH ); ms: m/z 492 (M , 100%), 364
Anal. Calcd. for C
H N O S: C, 59.53; H, 7.24; N, 17.36; S,
2
2
19 27 5 3
(62%).
Anal. Calcd. for C
S, 13.02. Found: C, 51.14; H, 5.82; N, 16.91; S, 12.77.
7.94. Found: C, 59.04; H, 7.24; N, 17.62; S, 7.87.
REFERENCES AND NOTES
H
N O S : C, 51.20; H, 5.73; N, 17.06;
6 4 2
21 28
Reaction of the 2,4-Disubstituted 5-Aminothieno[2,3-d]pyrim-
idin-6-carboxylic Acid tert-Butylester Derivatives 9a and c with
Pyrrolidine.
[1] D. Briel, T. Franz and B. Dobner: J. Heterocyclic Chem., 39,
863 (2002)
[2] See, for example, [a] A. J. Barker and C. Johnstone, World
Pat. Appl. WO 97/30044 A1 (1997); Chem. Abstr., 127, 220671
(1997); [b] D. S. Brown, J. J. Morris and A. P. Thomas, World Pat.
Appl. WO 96/15118 A1 (1996); Chem. Abstr., 125, 142741 (1996); [c]
D. W. Fry, A. J. Kraker, A. McMichael, L. A. Ambroso, J. M. Nelson,
W. R. Leopold, R. W. Connors and A. J. Bridges, Science, 265, 1093
(1994); [d] W. H. J. Ward, P. N. Cook, A. M. Slater, D. H. Davies, G. A.
Holdgate and L. R. Green, Biochem. Pharmacol., 48, 659 (1994).
[3] See, for example, [a] D. Spinelli, G. Consiglio and R. Noto,
J. Chem. Soc. Perkin Trans II, 1495 (1976); [b] D. Briel, D. Pohlers, M.
Uhlig, S. Vieweg, G. H. Scholz, M. Thormann and H. J. Hofmann, J.
Med. Chem., 42, 1849 (1999).
In a flask 100 mg of the compounds 9a or 9c were suspended
in 5 ml pyrrolidine and were heated for 2 hours under reflux.
After cooling to room temperature 5 ml methanol and 20 ml
water were added, the precipitates were collected by suction fil-
tration, recrystallised from methanol and dried in vacou.
5-Amino-4-morpholino-2-pyrrolidinolthieno[2,3-d]pyrimidine-
6-carboxylic Acid tert-Butylester (10a)
Compound 10a was obtained from compound 9a and pyrroli-
dine in 90% yield (0.07 g); mp: 205.5-206.5 °C; ir: 3460, 3343,
-1
1
3205, 2973, 2870, 1659, 1587, 1557, 1532, 1302, 1118 cm ; H
nmr (400 MHz, deuteriochloroform): δ 1.54 (s, 9H, –C(CH ) ),
[4] S. Drescher and B. Dobner, unpublished results
3 3
1.94-1.97 (m, 4H, –CH (CH ) CH –), 3.35 (m, 4H, –CH NCH –
[5] N. L. Drake, C. M. Eaker and W. Shenk, J. Am. Chem. Soc.,
70, 677 (1948).
2
2 2
2
2
2
from morpholine), 3.58-3.61 (m, 4H, –CH NCH – from pyrroli-
2
2