Selective nucleophilic substitution reactions in 2,4,6-trisulfanyl- substituted pyrimidine-5-carbonitriles by secondary amines

Article abstract of DOI:10.1002/jhet.5570440402

(Chemical Equation Presented) The highly functionalized heterocycles 6-alkyl- respectively 6-aralkylsulfanyl-2,4-bis-(amidomethylsulfanyl)pyrimidine- 5-carbonitriles react selective in the 2-position with various secondary cyclic amines under mild conditi

Full text of DOI:10.1002/jhet.5570440402

Jul-Aug 2007
757
Selective Nucleophilic Substitution Reactions in 2,4,6-Trisulfanyl-
substituted Pyrimidine-5-carbonitriles by Secondary Amines
Simon Drescher1, Daniel Ramsbeck1¶, Detlef Briel2, Bodo Dobner1*
1 Fachbereich Pharmazie der Martin-Luther-Universität Halle/Wittenberg, Institut für Pharmazie, Wolfgang-
Langenbeck-Straße 4, 06120 Halle/Saale
¶ current address: Probiodrug AG, Weinbergweg 22, 06120 Halle/Saale
2 Fakultät für Biowissenschaften, Pharmazie und Psychologie der Universität Leipzig, Institut für Pharmazie,
Pharmazeutische Chemie, Brüderstraße 34, 04103 Leipzig
Received January 30, 2006
SR
SR
N
SR
N
CN
S
CN
S
CN
S
sec. amines
RT
ClCH2COR'
TEA
HN
N
N
S
N
H
R'OC
S
COR'
N
COR'
SR
NH2
cat. NaOCH3
N
COR'
S
N
N
The highly functionalized heterocycles 6-alkyl- respectively 6-aralkylsulfanyl-2,4-bis-(amidomethyl-
sulfanyl)pyrimidine-5-carbonitriles react selective in the 2-position with various secondary cyclic amines
under mild conditions. The resulting pyrimidines were finally transformed into the corresponding
thieno[2,3-d]pyrimidine-6-carboxylic acid amides which afford the synthesis of selective substituted
thienopyrimidines.
J. Heterocyclic Chem., 44, 757 (2007).
and 3 as shown in Scheme I. In contrast to triethyl amine
the reaction with Hünig’s base in the case of chloroacetic
acid pyrrolidide results in alkylation and cyclisation to the
corresponding thieno[2,3-d]pyrimidine [3].
INTRODUCTION
Pyrimidines are an interesting class of heterocycles
which possess numerous biological and pharmacological
effects. Therefore this ring system is found in many
pharmaceuticals, herbicides and fungicides [1]. Beside
these applications conveniently functionalised pyrimidines
are interesting initial compounds in heterocyclic synthesis.
Some time ago we published the synthesis of 6-methyl-
sulfanyl-2,4-dithioxo-1,2,3,4-tetrahydropyrimidine-5-carbo-
nitrile from simple starting compounds [2]. In that work we
have also reported some results of alkylation reaction with
electrophiles like alkyl halides, phenacyl bromides and
halogeno acetic acid derivatives. In the case of the 2,4,6-
trimethylsulfanylpyrimidine-5-carbonitrile some nucleophilic
substitution reactions were studied under drastic conditions
with low selectivity leading mainly to mixtures of products.
Now we report new results regarding to a selective
nucleophilic substitution reaction at 2,4,6-trisulfanyl-
substituted pyrimidine-5-carbonitriles under very mild
conditions. For that purpose more new alkylation products
of the 6-methylsulfanyl- and 6-benzylsulfanyl substituted
2,4-dithioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitriles
by reaction with aliphatic and aromatic 2-halogeno acetic
acid amides were prepared. Thus the reaction of
compound 1a and 1b with chloroacetic acid amides under
mild conditions (room temperature) and with triethyl
amine as base yielded the pyrimidine-5-carbonitriles 2
Scheme I
SR
SR
CN
S
CN
S
ClCH2COR'
HN
N
dry CH3OH, TEA
S
N
H
R'OC
S
N
COR'
2
1
Cl
CH
a: R = CH3
b: R = CH3
R' = NH2
a: R = CH3
b: R = CH2C6H5
2 C
ONHC
dr
y
C
H
N
R' =
3 OH,
6 H
4 p
T
R'
c: R = CH2C6H5 R' = NH2
E
A
N
d: R = CH2C6H5 R' =
SR
CN
N
H
H
N
N
S
N
S
O
O
3
R'
R'
a: R = CH3 R' = H
b: R = CH3 R' = CH3
c: R = CH3 R' = OCH3
d: R = CH2C6H5 R' = H
e: R = CH2C6H5 R' = CH3
f: R = CH2C6H5 R' = OCH3
We also found that the reaction of aromatic chloroacetic
acid amides (to products 3) was finished in shorter time

758
S. Drescher, D. Ramsbeck, D. Briel and B. Dobner
Vol 44
and in higher yields (53% to 80%) compared to the
reaction of non-aromatic chloroacetic acid amides. This is
due to the stronger electron withdrawing effect of the
aromatic amides compared to the aliphatic amides. An
influence of the 6-methylsulfanyl moiety compared to the
6-benzylsulfanyl moiety concerning alkylation reaction
behaviour could not be found.
Scheme II shows the results of the reaction of
compounds 2a-d and 3d-f with the secondary cyclic
amines pyrrolidine, piperidine and morpholine in a
suspension of 2-methoxyethanol under mild conditions at
room temperature. In the case of the aliphatic amine
residues in the amide structure of the substituents (2a-d)
we isolated only one main product. The mass spectra
indicate that one amidomethylsulfanyl residue was
substituted by the secondary amine. The position of the
substitution at the pyrimidine ring was determined by
cyclisation reaction. The formation of the thieno[2,3-d]-
pyrimidines 7 (see scheme III) is only possible if 2a-d and
3d-f react with the secondary cyclic amine in 2-position
Whereas the mono substitution reaction of compound 2
with secondary cyclic amines lead to pyrimidines 4 and 5 in
a straightforward manner the pyrimidines with the aromatic
amide residues (compounds 3d-f) show a different reaction
pattern. Only in the case of morpholine the mono substi-
tution products 6a-c could be isolated. The reaction of 3d-f
with pyrrolidine and piperidine results in a product mixture.
Beside the expected pyrimidine the corresponding thieno-
[2,3-d]pyrimidine and substitution products of the recent
compound were detected by mass spectrometry. This is due
to the higher basic strength of pyrrolidine and piperidine
compared to morpholine which trigger the cyclisation and
substitution reaction.
Furthermore we found that the thioether moiety in position
4 of the pyrimidine ring has no influence on the selectivity of
the nucleophilic substitution. This is contrary to the substi-
tution reaction at the 2,4-disulfanyl substituted thieno[2,3-d]-
pyrimidine-6-carboxylic acid derivatives published
previously [3]. In this case only the 4-benzylsulfanyl moiety
was selective substituted by secondary cyclic amines at these
Scheme II
H3C
N
SR
S
CN
S
CN
S
sec. amine
N
2-methoxyethanol, RT
R'OC
S
N
COR'
R''
N
COR'
(2a,b)
2a-d, 3d-f
4
N
N
N
N
N
N
N
N
N
a: R' = NH2 R'' =
b: R' = NH2 R'' =
c: R' = NH2 R'' =
d: R' =
e: R' =
f: R' =
R'' =
R'' =
R'' =
2-
s
m
ec.
e
thoxy
am
i
n
e
e
(
t
2c
hanol,
,
d
)
morpholine
2-methoxyethanol, RT
R
O
O
T
(3d-f)
S
S
CN
CN
S
N
N
N
N
S
COR'
R''
N
COR'
6
5
O
NH
NH
NH
N
N
N
N
N
N
N
a: R' =
b: R' =
c: R' =
a: R' = NH2 R'' =
b: R' = NH2 R'' =
c: R' = NH2 R'' =
d: R' =
e: R' =
R'' =
R'' =
CH3
OCH3
O
1
of the pyrimidine ring. Also a comparison of the H nmr
signals of the methylene groups in 2- and 4-position in the
pyrimidine system and the corresponding thieno[2,3-d]-
pyrimidine support this result to some extent.
compounds. The presence of a methylsulfanyl group instead
of the benzylsulfanyl residue leads to product mixtures. We
found a substitution of the methylsulfanyl moiety beside the
expected substitution of the substituent in 2-position [3].
The new pyrimidine-5-carbonitriles 4, 5 and 6 with
different functions were then suspended in 2-methoxy-
ethanol with catalytic amounts of sodium methoxide
yielding 5-amino-2-sec-amino-4-alkyl(aralkyl)sulfanyl-
thieno[2,3-d]pyrimidine-6-carboxylic acid amides [7a-k]
as shown in scheme III.
Furthermore the pyrimidines and thieno[2,3-d]-
pyrimidines differ in their photoelectronic properties.
Already during reaction monitoring of cyclisation using
thin layer chromatography the appearance of strong
fluorescence spots indicate the formation of the bicyclic
heterocyclic system.

Jul-Aug 2007
2,4,6-Trisulfanyl-substituted Pyrimidine-5-carbonitriles
759
Varian Gemini 2000 (400 MHz) using deuteriochloroform as
internal reference. Chemical shifts are given in ppm. Mass
spectrometric data were obtained on an AMD 402 (70 eV)
spectrometer (Intecta GmbH, Harpstedt). Static nanoES
experiments were conducted on a qTOF mass spectrometer Q-
TOF-2 (Waters/ Micromass, Manchester, UK) equipped with
a nanoES Z-Spray source. The nanoES glass capillaries were
obtained precoated from DNU-MS (Berlin, Germany). The
TOF analyzer was calibrated externally using a mixture of
sodium iodide and caesium iodide and internally using
metasulam (analytical standard) as lock mass. The typical
operating conditions for the qTOF mass spectrometer were as
follows: capillary voltage, 900 V; sample cone voltage, 35 V;
source temperature, 80°C. The instrument was operated in the
positive ion mode. Full scans were performed over the m/z
range of 50 to 1000. Elemental analyses were performed with
Due to the fact, that thieno[2,3-d]pyrimidines are bio-
isoster to quinazolines these compounds become more
important. It is known from this class of heterocycles that
they have become interesting with regard to tyrosin kinase
inhibitors [4]. The inhibition of these enzymes is now an
accepted strategy in cancer therapy.
Scheme III
SR
CN
N
R''
N
S
COR'
4a-e, 5a-d,
6a,b
2-methoxyethanol, RT
cat. NaOCH3
a
CHNS-932 apparatus (LECO-Corporation, St. Joseph,
a
Michigan USA). Infrared spectra were obtained on
Spektrum BX FT-IR-system (Perkin Elmer).
SR
NH2
The chloroacetic acid amides were prepared according to
literature [5].
N
COR'
S
R''
N
Reaction of Compound 1 with Various Chloroacetic Acid
Amides.
7
N
R'' =
a: R = CH3
b: R = CH3
c: R = CH3
d: R = CH3
e: R = CH3
R' = NH2
R' = NH2
General Procedure for the Preparation of Aliphatic
Substituted 2,4-Bis-(aminocarbonylmethylsulfanyl)pyrimi-
dine-5-carbonitriles (2a-d). To a suspension of 4.65 mmol of
compound 1a or 1b in 30 ml dry methanol were added 9.30
mmol (0.94 g) TEA and 9.30 mmol of the respective
chloroacetic acid amide. The reaction was allowed to stand over
night at room temperature. After that time the precipitate was
collected by suction filtration and recrystallized from
2-methoxyethanol.
R'' = N
R'' = N
O
R' = NH2
N
N
N
R'' =
R' =
R' =
R'' = N
R'' = N
2,4-Bis(aminocarbonylmethylsulfanyl)-6-methylsulfanyl-
pyrimidine-5-carbonitrile (2a). Compound 2a was obtained
from compound 1a in reaction with chloroacetic acid amide in
56% yield (0.86 g); mp: 252-255 °C; ir: 2972, 2923, 2212, 1665
f: R = CH2C6H5 R' = NH2
g: R = CH2C6H5 R' = NH2
h: R = CH2C6H5 R' = NH2
i: R = CH2C6H5 R' =N
N
N
N
R'' =
R'' =
R'' =
1
cm-1; H nmr (DMSO-d6): ꢀ 2.60 (s, 3H, -SCH3), 3.90 (s, 2H,
-SCH2CO-), 3.99 (s, 2H, -COCH2S-), 7.23-7.28 (d, 2H,
H2NCO-), 7.58-7.64 (d, 2H, -CONH2); ms: m/z 329 (M+, 100%),
312 (64%), 285 (65%). Anal. Calcd. for C10H11N5O2S3: C, 36.46;
H, 3.37; N, 21.26; S, 29.20. Found: C, 36.61; H, 3.50; N, 21.05;
S, 29.58
6-Methylsulfanyl-2,4-bis(pyrrolidinocarbonylmethylsul-
fanyl)pyrimidine-5-carbonitrile (2b). Compound 2b was
obtained from compound 1a in reaction with chloroacetic acid
pyrrolidide in 68% yield (1.38 g); mp: 184-186 °C; ir: 2977,
2930, 2210, 1640 cm-1; 1H nmr (deuteriochloroform): ꢀ 1.82-
2.04 (m, 8H, 2x -CH2(CH2)CH2-), 2.53 (s, 3H, -SCH3), 3.44-
3.62 (m, 8H, 2x -CH2NCH2-), 3.99 (s, 2H, -SCH2CO-), 4.02 (s,
2H, -COCH2S-); ms: m/z 437 (M+, 50%) Anal. Calcd. for
C18H23N5O2S3: C, 49.40; H, 5.30; N, 16.01; S, 21.98. Found: C,
49.53; H, 5.27; N, 15.64; S, 21.88
O
j: R = CH2C6H5 R' =NH
k: R = CH2C6H5 R' =NH
R'' = N
O
O
CH3
N
R'' =
The results presented here enable not only the synthesis
of highly functionalised pyrimidines with different
substituents but also the synthesis of the corresponding
thieno[2,3-d]pyrimidines. Moreover in connection with
the selective substitution of the benzylsulfanyl group at
the bicyclic system published previously [3] broad
synthesis of new heterocyclic compounds with basic
substituents are possible.
2,4-Bis(aminocarbonylmethylsulfanyl)-6-benzylsulfanyl-
pyrimidine-5-carbonitrile (2c). Compound 2c was obtained
from compound 1b in reaction with chloroacetic acid amide in
43% yield (0.81 g); mp: 239-241 °C; ir: 2976, 2925, 2213, 1673
1
cm-1; H nmr (DMSO-d6): ꢀ 3.92 (s, 2H, -SCH2CO-), 3.99 (s,
EXPERIMENTAL
2H, -COCH2S-), 4.55 (s, 2H, -SCH2C6H5), 7.26-7,61 (m, 5H,
phenyl protons); ms: m/z 405 (M+, 39%), 388 (38%), 347 (32%).
Anal. Calcd. for C16H15N5O2S3: C, 47.39; H, 3.73; N, 17.27; S,
23.72. Found: C, 47.38; H, 3.76; N, 17.30; S, 23.74.
Melting points were taken with a Boetius apparatus and are
uncorrected. The 1H nmr spectra have been recorded on a

760
S. Drescher, D. Ramsbeck, D. Briel and B. Dobner
Vol 44
6-Benzylsulfanyl-2,4-bis(pyrrolidinocarbonylmethylsul-
2,4-Bis(anilinocarbonylmethylsulfanyl)-6-benzylsulfanyl-
pyrimidine-5-carbonitrile (3d). Compound 3d was obtained
from compound 1b in reaction with chloroacetic acid anilide in
53% yield (1.02 g); mp: 228-230 °C; ir: 3061, 2985, 2918, 2211,
1658 cm-1; 1H nmr (deuteriochloroform): ꢀ 3.85 (s, 2H,
-SCH2CO-), 3.91 (s, 2H, -COCH2S-), 4.42 (s, 2H, -SCH2C6H5),
7.13-7.59 (m, 15H, phenyl protons); ms: m/z 557 (M+, 7%), 465
(18%), 438 (4%). Anal. Calcd. for C28H23N5O2S3: C, 60.30; H,
4.16; N, 12.56; S, 17.25. Found: C, 60.21; H, 4.07; N, 12.66; S,
16.98.
fanyl)pyrimidine-5-carbonitrile (2d). Compound 2d was
obtained from compound 1b in reaction with chloroacetic acid
pyrrolidide in 51% yield (1.22 g); mp: 191-194 °C; ir: 2921, 2854,
1
2206, 1668 cm-1; H nmr (deuteriochloroform): ꢀ 1.77-2.03 (m,
8H, 2x -CH2(CH2)CH2-), 3.33-3.62 (m, 8H, 2x -CH2NCH2-), 3.96
(s, 2H, -SCH2CO-), 4.00 (s, 2H, -COCH2S-), 4.43 (s, 2H,
-SCH2C6H5), 7.24-7.31 (m, 5H, phenyl protons); ms: m/z 513 (M+,
5%). Anal. Calcd. for C24H27N5O2S3: C, 56.11; H, 5.30; N, 13.63;
S, 18.73. Found: C, 56.20; H, 5.28; N, 13.65; S, 18.93.
General Procedure for the Preparation of Aromatic
Substituted 2,4-Bis-(aminocarbonylmethylsulfanyl)-6-methyl-
sulfanylpyrimidine-5-carbonitriles (3a-c). To a suspension of
4.65 mmol (1.0 g) of compound 1a in 30 ml dry methanol were
added 9.30 mmol (0.94 g) TEA and 9.30 mmol of the respective
chloroacetic acid amide. After 3-4 hours standing at room
temperature the precipitate was collected by suction filtration
and recrystallized from 2-methoxyethanol.
6-Benzylsulfanyl-2,4-bis[(4-methylanilino)carbonylmethyl-
sulfanyl]pyrimidine-5-carbonitrile (3e). Compound 3e was
obtained from compound 1b in reaction with chloroacetic acid
4-methylanilide in 56% yield (1.13 g); mp: 231-233 °C; ir: 2921,
2214, 1660 cm-1; 1H nmr (deuteriochloroform): ꢀ 2.24 (s, 6H, 2x
-C6H4CH3), 3.88 (s, 2H, -SCH2CO-), 3.93 (s, 2H, -COCH2S-),
4.38 (s, 2H, -SCH2C6H5), 7.03-7.38 (m, 13H, phenyl protons);
ms: m/z 585 (M+, 7%), 479 (21%), 452 (6%). Anal. Calcd. for
C30H27N5O2S3: C, 61.51; H, 4.65; N, 11.96; S, 16.42. Found: C,
61.25; H, 4.58; N, 12.06; S, 16.34.
2,4-Bis(anilinocarbonylmethylsulfanyl)-6-methylsulfanyl-
pyrimidine-5-carbonitrile (3a). Compound 3a was obtained
from compound 1a in reaction with chloroacetic acid anilide in
62% yield (1.39 g); mp: 234-237 °C; ir: 3061, 2928, 2214, 1665
6-Benzylsulfanyl-2,4-bis[(4-methoxyanilino)carbonyl-
methylsulfanyl]pyrimidine-5-carbonitrile (3f). Compound 3f
was obtained from compound 1b in reaction with chloroacetic
acid 4-methoxyanilide in 59% yield(1.25 g); mp: 241-243 °C; ir:
1
cm-1; H nmr (deuterio-chloroform): ꢀ 2.57 (s, 3H, -SCH3), 3.85
(s, 2H, -SCH2CO-), 3.93 (s, 2H, -COCH2S-), 7.12-7.60 (m, 10H,
phenyl protons); ms: m/z 481 (M+, 25%), 389 (100%), 362
(19%). Anal. Calcd. for C22H19N5O2S3: C, 54.86; H, 3.98; N,
14.54; S, 19.97. Found: C, 54.87, H, 3.78, N; 14.33; S, 19.47.
HRMS: calcd. for C22H19N5O2S3 (M+H)+ 481.0701, found
481.0722.
2,4-Bis[(4-methylanilino)carbonylmethylsulfanyl]-6-methyl-
sulfanylyrimidine-5-carbonitrile (3b). Compound 3b was
obtained from compound 1a in reaction with chloroacetic
acid 4-methylanilide in 71% yield (1.68 g); mp: 157-159 °C;
ir: 3037, 2928, 2829, 2213, 1660 cm-1; 1H nmr (deuterio-
chloroform): ꢀ 2.20 (s, 6H, 2x -CH3), 2.58 (s, 3H, -SCH3),
3.86 (s, 2H, -SCH2CO-), 3.94 (s, 2H, -COCH2S-), 6.96-7.29
(m, 8H, phenyl protons); ms: m/z 509 (M+, 28%), 403
(100%), 376 (18%). Anal. Calcd. for C24H23N5O2S3: C, 56.56;
H, 4.55; N, 13.74; S, 18.87. Found: C, 56.83; H, 4.39; N,
14.07; S 18.41. HRMS: calcd for C24H23N5O2S3 (M+H)+
509.1014, found 509.1029.
1
2924, 2857, 2207, 1655 cm-1; H nmr (deuteriochloroform): ꢀ
3.68 (s, 6H, 2x -OCH3), 3.83 (s, 2H, -SCH2CO-), 3.88 (s, 2H,
-COCH2S-), 4.34 (s, 2H, -SCH2C6H5), 6.72-7.35 (m, 13H,
phenyl protons); ms: m/z 617 (M+, 2%), 495 (4%). Anal. Calcd.
for C30H27N5O4S3: C, 58.33; H, 4.41; N, 11.34, S, 15.57. Found:
C, 58.33; H, 4.34; N, 11.23; S, 15.34.
General Procedure for the Reaction of the Bisalkylated
Compounds with Various Secondary Amines. The respective
bisalkylated compound (2a-d, 3d-f) (0.1 g) were suspended in
10 ml 2-methoxyethanol. After adding 0.1 g of the corre-
sponding secondary amine the reaction was stirred at room
temperature for 3 hours in the case of pyrrolidine or piperidine
and 30 hours in case the of morpholine. After addition of 30 ml
water the precipitate was filtered of and recrystallized from 2-
methoxyethanol.
4-(Aminocarbonylmethylsulfanyl)-6-methylsulfanyl-2-pyr-
rolidinopyrimidine-5-carbonitrile (4a). Compound 4a was
obtained from compound 2a and pyrrolidine in 46% yield (43
2,4-Bis[(4-methoxyanilino)carbonylmethylsulfanyl]-6-
methylsulfanylpyrimidine-5-carbonitrile (3c). Compound 3c
was obtained from compound 1a in reaction with chloroacetic
acid 4-methoxyanilide in 80% yield (2.01 g); mp: 254-256 °C;
1
mg); mp: 263-265 °C; ir: 2930, 2875, 2203, 1674 cm-1; H nmr
(deuteriochloroform/methanol-d4):
ꢀ 1.98-2.00 (m, 4H,
-CH2(CH2)2CH2-), 2.52 (s, 3H, -SCH3), 3.61-3.64 (m, 4H,
-CH2NCH2-), 3.79 (s, 2H, -SCH2CO-); ms: m/z 309 (M+, 33%),
265 (14%), 251 (100%). Anal. Calcd. for C12H15N5OS2: C,
46.58; H, 4.89; N, 22.63; S, 20.73. Found: C, 46.53; H, 5.01; N,
22.19; S, 20.18. HRMS: calcd. for C12H15N5OS2 (M+H)+
309.0718, found 309.0718.
1
ir: 3070, 3003, 2933, 2835, 2214, 1664 cm-1; H nmr (deuterio-
chloroform): ꢀ 2.58 (s, 3H, -SCH3), 3.77 (s, 6H, 2X -OCH3),
3.88 (s, 2H, -SCH2CO-), 3.91 (s, 2H, -COCH2S-), 6.83-7.48 (m,
8H, phenyl protons); ms: m/z 541 (M+, 25%), 419 (55%), 392
(4%). Anal. Calcd. for C24H23N5O4S3: C, 53.22; H, 4.28; N,
12.93; S, 17.76. Found: C, 53.42; H, 4.22; N, 13.05; S, 18.26.
HRMS: calcd. for C24H23N5O4S3 (M+H)+ 541.0912, found
541.0935.
4-(Aminocarbonylmethylsulfanyl)-6-methylsulfanyl-2-
piperidinopyrimidine-5-carbonitrile (4b). Compound 4b was
obtained from compound 2a and piperidine in 49% yield (48
1
General Procedure for the Preparation of Aromatic
Substituted 2,4-Bis-(aminocarbonylmethylsulfanyl)-6-benzyl-
sulfanylpyrimidine-5-carbonitriles (3d-f). Compound 1b (3.44
mmol, 1.0 g) was suspended in 30 ml dry methanol. After
addition of 6.88 mmol (0.69 g) TEA and 6.9 mmol of the
respective chloroacetic acid amide the reaction was allowed to
stand for 3-4 hours. After that time the precipitate was collected
by suction filtration and recrystallized from 2-methoxyethanol.
mg); mp: 231-233 °C; ir: 2937, 2856, 2202, 1668 cm-1; H nmr
(deuterio-chloroform/methanol-d4):
ꢀ
1.68-1.69 (m, 6H,
-CH2(CH2)3CH2-), 2.51 (s, 3H, -SCH3), 3.75 (s, 2H, -SCH2CO-),
3.82-3.86 (m, 4H, -CH2NCH2-); ms: m/z 323 (M+, 29%), 279
(9%), 265 (100%). Anal. Calcd. for C13H17N5OS2: C, 48.27; H,
5.30; N, 21.65; S, 19.83. Found: C, 48.27; H, 5.21; N, 20.98; S,
19.67. HRMS: calcd. for C13H17N5OS2 (M+H)+ 323.0875, found
323.0870.

Jul-Aug 2007
2,4,6-Trisulfanyl-substituted Pyrimidine-5-carbonitriles
761
4-(Aminocarbonylmethylsulfanyl)-6-methylsulfanyl-2-
morpholinopyrimidine-5-carbonitrile (4c). Compound 4c was
obtained from compound 2a and morpholine in 45% yield (44
17.53; S, 16.05. Found: C, 56.79; H, 5.13; N, 17.01; S, 15.27.
HRMS: calcd. for C19H21N5OS2 (M+H)+ 399.1188, found
399.1197.
1
mg); mp: 262-264 °C; ir: 2927, 2857, 2205, 1674 cm-1; H nmr
4-(Aminocarbonylmethylsulfanyl)-6-benzylsulfanyl-2-mor-
pholinopyrimidine-5-carbonitrile (5c). Compound 5c was
obtained from compound 2c and morpholine in 48% yield (47
mg); mp: 233-236 °C; ir: 3029, 2924, 2855, 2212, 1675 cm-1; 1H
nmr (DMSO-d6): ꢀ 3.61-3.62 (t, 4H, -CH2NCH2-), 3.84-3.86 (t,
4H, -CH2OCH2-), 3.92 (s, 2H, -SCH2CO-), 4.54 (s, 2H,
-SCH2C6H5), 7.14-7.63 (m, 5H, phenyl protons); ms: m/z 401
(M+, 96%), 394 (8%), 357 (36%), 343 (39%). Anal. Calcd. for
C18H19N5O2S2: C, 53.85; H, 4.77; N, 17.44; S, 15.97. Found: C,
54.11; H, 4.65; N, 17.52; S, 15.69.
6-Benzylsulfanyl-4-(pyrrolidinocarbonylsulfanyl)-2-pyrro-
lidinopyrimidine-5-carbonitrile (5d). Compound 5d was
obtained from compound 2d an pyrrolidine in 49% yield (85
mg); mp: 191-196 °C; ir: 2873, 2200, 1645 cm-1; 1H nmr
(deuteriochloroform): ꢀ 1.83-1.99 (m, 8H, 2x -CH2(CH2)2CH2-),
3.45-3.62 (m, 8H, 2x -CH2NCH2-), 3.98 (s, 2H, -SCH2CO-),
4.40 (s, 2H, -SCH2C6H5), 7.19-7.35 (m, 5H, phenyl protons);
ms: m/z 439 (M+, 21%), 341 (6%), 327 (100%). Anal. Calcd. for
C22H25N5OS2: C, 60.11; H, 5.73; N, 15.93; S, 14.59. Found: C,
59.97; H, 5.84; N, 16.48; S, 14.10. HRMS: calcd. for
C22H25N5OS2 (M+H)+ 439.1501, found 439.1501.
6-Benzylsulfanyl-2-piperidino-4-(pyrrolidinocarbonylsul-
fanyl)-pyrimidine-5-carbonitrile (5e). Compound 5e was
obtained from compound 2d and piperidine in 30% yield (26
mg); mp: 155-157 °C; ir: 3061, 2937, 2870, 2202, 1645 cm-1; 1H
nmr (deuteriochloroform): ꢀ 1.55-1.67 (m, 6H, -CH2(CH2)3-
CH2-), 1.85-1.98 (m, 4H, -CH2(CH2)2CH2-), 3.47-3.49 (m, 4H,
-CH2NCH2- from pyrrolidine), 3.80 (s, 4H, -CH2NCH2- from
morpholine), 3.92 (s, 2H, -SCH2CO-), 4.36 (s, 2H, -SCH2C6H5),
7.24-7.32 (m, 5H, phenyl protons); ms: m/z 453 (M+, 16%), 362
(15%), 355 (6%). Anal. Calcd. for C23H27N5OS2: C, 60.90; H,
6.00; N, 15.44; S, 14.14. Found: C, 60.45; H, 5.94; N, 15.43; S,
14.11. HRMS: calcd. for C23H27N5OS2 (M+H)+ 453.1657, found
453.1664.
4-(Anilinocarbonylmethylsulfanyl)-6-benzylsulfanyl-2-
morpholinopyrimidine-5-carbonitrile (6a). Compound 6a was
obtained from compound 3d and morpholine in 44% yield (38
mg); mp: 248-250 °C; ir: 3061, 2921, 2857, 2206, 1665 cm-1; 1H
nmr (deuteriochloroform): ꢀ 3.61 (m, 4H, -CH2NCH2-), 3.81-
3.83 (m, 4H, -CH2OCH2-), 3.84 (s, 2H, -SCH2CO-), 4.37 (s, 2H,
-SCH2C6H5), 7.11-7.45 (m, 10H, phenyl protons); ms: m/z 477
(M+, 100%), 385 (16%), 358 (42%), 343 (68%). Anal. Calcd. for
C24H23N5O2S2: C, 60.36; H, 4.85; N, 14.66, S, 13.43. Found: C,
60.52; H, 4.92; N, 14.63; S, 13.25.
(deuteriochloroform/methanol-d4): ꢀ 2.51 (s, 3H, -SCH3), 3.73-
3.75 (m, 4H, -CH2NCH2-), 3.76 (s, 2H, -SCH2CO-), 3.86-3.91
(m, 4H, -CH2OCH2-); ms: m/z 325 (M+, 43%), 281 (11%), 267
(100%). Anal. Calcd. for C12H15N5O2S2: C, 44.29; H, 4.65; N,
21.52; S, 19.71. Found: C, 44.36; H, 4.66; N, 21.11; S, 20.10.
6-Methylsulfanyl-4-(pyrrolidinocarbonylmethylsulfanyl)-
2-pyrrolidinopyrimidine-5-carbonitrile (4d). Compound 4d
was obtained from compound 2b and pyrrolidine in 51% yield
(42 mg); mp: 210-213 °C; ir: 2926, 2876, 2200, 1648 cm-1;
1H nmr (deuteriochloroform): ꢀ 1.82-2.01 (m, 8H, 2x
-CH2(CH2)2CH2-), 2.51 (s, 3H, -SCH3), 3.46-3.64 (m,8H, 2x
-CH2NCH2-), 3.99 (s, 2H, -SCH2CO-); ms: m/z 363 (M+, 54%),
293 (7%), 265 (9%), 251 (100%). Anal. Calcd. for C16H21N5OS2:
C, 52.87; H, 5.82; N, 19.27; S, 17.64. Found: C, 53.12; H, 5.81;
N, 19.20; S, 17.72.
6-Methylsulfanyl-4-(pyrrolidinocarbonylmethylsulfanyl)-
2-piperidinopyrimidine-5-carbonitrile (4e). Compound 4e was
obtained from compound 2b and piperidine in 44% yield (38
1
mg); mp: 179-182 °C; ir: 2934, 2871, 2203, 1644 cm-1; H nmr
(deuteriochloroform): ꢀ 1.55-1.69 (m, 6H, -CH2(CH2)3CH2-),
1.84-1.99 (m, 4H, -CH2(CH2)2CH2-), 2.49 (s, 3H, -SCH3), 3.46-
3.53 (m, 4H, -CH2NCH2- from pyrrolidine), 3.82 (m, 4H,
-CH2NCH2- from piperidine), 3.94 (s, 2H, -SCH2CO-); ms: m/z
377 (M+, 38%), 307 (5%), 279 (7%), 265 (100%). Anal. Calcd.
for C17H23N5OS2: C, 54.08; H, 6.14; N, 18.55; S, 16.99. Found:
C, 54.26; H, 6.29; N, 18.67, S, 16.96.
6-Methylsulfanyl-2-morpholino-4-(pyrrolidinocarbonyl-
methylsulfanyl)pyrimidine-5-carbonitrile (4f). Compound 4f
was obtained from compound 2b and morpholine in 40% yield
1
(35 mg); mp: 186-188 °C; ir: 2920, 2861, 2209, 1668 cm-1; H
nmr (deuteriochloroform): ꢀ 1.83-2.01 (m, 4H, -CH2(CH2)2-
CH2-), 2.49 (s, 3H, -SCH3), 3.45-3.52 (m, 4H, -CH2NCH2- from
pyrrolidine), 3.72-3.75 (m, 4H, -CH2NCH2- from morpholine),
3.87-3.88 (m, 4H, -CH2OCH2-), 3.94 (s, 2H, -SCH2CO-); ms:
m/z 379 (M+, 57%), 309 (7%), 281 (9%), 267 (100%). Anal.
Calcd. for C16H21N5O2S2: C, 50.64; H, 5.58; N, 18.45; S, 16.90.
Found: C, 50.47; H, 5.62; N, 18.01; S, 16.19. HRMS: calcd. for
C16H21N5O2S2 (M+H)+ 379.1137, found 379.1129.
4-(Aminocarbonylmethylsulfanyl)-6-benzylsulfanyl-2-pyrrol-
idinopyrimidine-5-carbonitrile (5a). Compound 5a was
obtained from compound 2c and pyrrolidine in 47% yield (45
mg); mp: 226-228 °C; ir: 3028, 2936, 2872, 2204, 1666 cm-1; 1H
nmr (deuteriochloroform): ꢀ 1.95-1.98 (m, 4H, -CH2(CH2)2-
CH2-), 3.57-3.63 (m, 4H, -CH2NCH2-), 3.78 (s, 2H, -SCH2CO-),
4.41 (s, 2H, -SCH2C6H5), 7.20-7.39 (m, 5H, phenyl protons);
ms: m/z 385 (M+, 100%), 341 (43%), 327 (69%). Anal. Calcd.
for C18H19N5OS2: C, 56.08; H, 4.97; N, 18.17; S, 16.64. Found:
C, 55.73; H, 5.05; N, 17.89; S, 16.05. HRMS: calcd. for
C18H19N5OS2 (M+H)+ 385.1031, found 385.1029.
4-(Aminocarbonylmethylsulfanyl)-6-benzylsulfanyl-2-
piperidinopyrimidine-5-carbonitrile (5b). Compound 5b was
obtained from compound 2c and piperidine in 45% yield (44
mg); mp: 228-231 °C; ir: 3028, 2931, 2854, 2204, 1664 cm-1; 1H
nmr (deuteriochloroform/methanol-d4): ꢀ 1.39-1.50 (m, 6H,
-CH2(CH2)3CH2-), 3.58 (s, 2H, -SCH2CO-), 3.64 (m, 4H,
-CH2NCH2-), 4.20 (s, 2H, -SCH2C6H5), 7.03-7.16 (m, 5H,
phenyl protons); ms: m/z 399 (100% M+), 355 (30%), 341
(96%). Anal. Calcd. for C19H21N5OS2: C, 57.12; H, 5.30; N,
6-Benzylsulfanyl-4-[(4-methylanilino)carbonylmethylsul-
fanyl]-2-morpholinopyrimidine-5-carbonitrile (6b). Compound
6b was obtained from compound 3e and morpholine in 46%
yield (39 mg); mp: 250-253 °C; ir: 3030, 2916, 2858, 2205,
1
1669 cm-1; H nmr (deuteriochloroform): ꢀ 2.29 (s, 3H, -CH3),
3.60 (m, 4H, -CH2NCH2-), 3.81-3.82 (m, 4H, -CH2OCH2-), 3.83
(s, 2H, -SCH2CO-), 4.37 (s, 2H, -SCH2C6H5), 7.09-7.33 (m, 9H,
phenyl protons); ms: m/z 491 (M+, 63%), 385 (33%), 358
(100%), 343 (43%). Anal. Calcd. for C25H25N5O2S2: C, 61.08; H,
5.13; N, 14.25; S, 13.04. Found: C, 61.13; H, 5.14; N, 14.01; S,
12.54. HRMS: calcd. for C25H25N5O2S2 (M+H)+ 491.1450, found
491.1465.
6-Benzylsulfanyl-4-[(4-methoxyanilino)carbonylmethylsul-
fanyl]-2-morpholinopyrimidine-5-carbonitrile (6c). Compound
6c was obtained from compound 3f and morpholine in 43%

762
S. Drescher, D. Ramsbeck, D. Briel and B. Dobner
Vol 44
yield (35 mg); mp: 251-253 °C; ir: 2923, 2856, 2207, 1656 cm-1;
1H nmr (deuteriochloroform): ꢀ 3.62 (m, 4H, -CH2NCH2-), 3.76
(s, 3H, -OCH3), 3.81-3.83 (m, 4H, -CH2OCH2-), 3.84 (s, 2H,
-SCH2CO-), 4.37 (s, 2H, -SCH2C6H5), 6.82-7.34 (s, 9H, phenyl
protons); ms: m/z 507 (M+, 55%), 385 (36%), 358 (100%), 343
(19%). Anal. Calcd. for C25H25N5O3S2: C, 59.15; H, 4.96; N,
13.80; S, 12.63. Found: C, 59.42; H, 5.04; N, 13.71; S, 12.38.
General Procedure for the Cyclization to Thieno[2,3-d]-
pyrimidines. The respective 6-Alkylsulfanyl-2-sec-amino-
4-aminocarbonylmethylsulfanylpyrimidin-5-carbonitrile
(100 mg) were suspended in 10 ml of 2-methoxyethanol.
After addition of 1-2 drops of a 5 M solution of sodium
methoxide the suspension was stirred at room temperature.
After 1-3 hours the reaction was cooled down and 30 ml
water were added. The resulting yellow precipitate was
extracted three times with 15 ml chloroform. The organic
layer was dried over sodium sulfate and the solvent was
removed under vacuum. The resulting residue was purified
by recrystallization from a small amount of 2-methoxy-
ethanol.
ꢀ 1.55-1.67 (m, 6H, -CH2(CH2)3CH2-), 1.89-1.93 (m, 4H,
-CH2(CH2)2CH2-), 2.63 (s, 3H -SCH3), 3.66-3.85 (m, 8H, 2x
-CH2NCH2-); ms: m/z 377 (M+, 100%), 307 (75%), 280 (88%).
Anal. Calcd. for C17H23N5OS2: C, 54.08; H, 6.14; N, 18.55; S,
16.99. Found: C, 53.79; H, 5.76; N, 18.41; S, 16.98.
5-Amino-4-benzylsulfanyl-2-pyrrolidinothieno[2,3-d]pyrim-
idine-6-carboxylic Acid Amide (7f). Compound 7f was
obtained from compound 5a in 39% yield (39 mg); mp: 202-
204 °C; ir: 2968, 2871, 1640 cm-1; 1H nmr (deuterio-
chloroform/methanol-d4): 1.98-2.03 (m, 4H, -CH2(CH2)2-
CH2-), 3.57-3.69 (m, 4H, -CH2NCH2-), 4.61 (s, 2H,
-SCH2C6H5), 7.08-7.39 (m, 5H, phenyl protons); ms: m/z 385
(M+, 100%), 368 (37%), 340 (18%). Anal. Calcd. for
C18H19N5OS2: C, 56.08; H, 4.97; N, 18.17; S, 16.64. Found:
C, 55.74; H, 4.92; N, 17.64; S, 16.35. HRMS: calcd. for
C18H19N5OS2 (M+H)+ 385.1031, found 385.1020.
5-Amino-4-benzylsulfanyl-2-piperidinothieno[2,3-d]pyrim-
idine-6-carboxylic Acid Amide (7g). Compound 7g was
obtained from compound 5b in 41% yield (41 mg); mp: 223-
226 °C; ir: 2930, 2851, 1644 cm-1; 1H nmr (deuterio-
chloroform/methanol-d4): ꢀ 1.54-1.67 (m, 6H, -CH2(CH2)3-
CH2-), 3.79-3.87 (m, 4H, -CH2NCH2-), 4.56 (s, 2H,
-SCH2C6H5), 7.24-7.41 (m, 5H, phenyl protons); ms: m/z
399 (M+, 100%), 382 (26%), 354 (9%), 308 (16%). Anal.
Calcd. for C19H21N5OS2: C, 57.12; H, 5.30; N, 17.53; S,
16.05. Found: C, 56.92; H, 5.25; N, 17.45; S, 15.83.
5-Amino-4-methylsulfanyl-2-pyrrolidinothieno[2,3-d]-
pyrimidine-6-carboxylic Acid Amide (7a). Compound 7a was
obtained from compound 4a in 42% yield (42 mg); mp: 229-
1
231 °C; ir: 2971, 2872, 1646 cm-1, H nmr (deuteriochloro-
form/methanol-d4): ꢀ 1.97-2.00 (m, 4H, -CH2(CH2)2CH2-),
2.66 (s, 3H, -SCH3), 3.61-3.70 (m, 4H, -CH2NCH2-); ms:
m/z 323 (M+, 100%), 306 (10%), 278 (11%). Anal. Calcd. for
C12H15N5OS2: C, 46.58; H, 4.89; N, 22.63; S, 20.73. Found:
C, 46.30; H, 4.92; N, 22.47; S, 20.84.
5-Amino-4-benzylsulfanyl-2-morpholinothieno-[2,3-d]-
pyrimidine-6-carboxylic Acid Amide (7h). Compound 7h was
obtained from compound 5c in 37% yield (37 mg); mp: 207-
1
5-Amino-4-methylsulfanyl-2-piperidinothieno[2,3-d]-
pyrimidine-6-carboxylic Acid Amide (7b). Compound 7b was
obtained from compound 4b in 45% yield (45 mg); mp: 203-
210 °C; ir: 2914, 2854, 1644 cm-1; H nmr (deuteriochloro-
form/methanol-d4): ꢀ 3.71-3.74 (m, 4H, -CH2NCH2-), 3.83-
3.87 (m, 4H, -CH2OCH2-), 4.55 (s, 2H, -SCH2C6H5), 7.23-
7.37 (m, 5H, phenyl protons); ms: m/z 401 (M+, 100%), 384
(23%), 358 (22%). Anal. Calcd. for C18H19N5O2S2: C, 53.85;
H, 4.77; N, 17.44; S, 15.97. Found: C; 53.41; H, 4.76; N,
17.08; S, 15.39. HRMS: calcd. for C18H19N5O2S2 (M+H)+
401.0980, found 401.0983.
5-Amino-4-benzylsulfanyl-2-pyrrolidinothieno[2,3-d]-
pyrimidine-6-carboxylic Acid Pyrrolidide (7i). Compound 7i
was obtained from compound 5d in 35% yield (35 mg); mp:
197-201 °C; ir: 2968, 2872, 1634 cm-1; 1H nmr (deuterio-
chloroform): ꢀ 1.84-1.99 (m, 8H, -CH2(CH2)2CH2-), 3.46-
3.69 (m, 8H, -CH2NCH2-), 4.41 (s, 2H, -SCH2C6H5), 7.19-
7.41 (m, 5H, phenyl protons); ms: m/z 439 (M+, 100%), 369
(41%), 342 (34%). Anal. Calcd. for C22H25N5OS2: C, 61.08;
H, 5.13; N, 14.25; S, 13.04. Found: C, 60.93; H 5.16; N,
14.13; S, 12.89.
1
205 °C; ir: 2928, 2852, 1646 cm-1; H nmr (deuteriochloro-
form/methanol-d4): ꢀ 1.59-1.68 (m, 6H, -CH2(CH2)3CH2-),
2.64 (s, 3H, -SCH3), 3.83-3.86 (t, 4H, -CH2NCH2-); ms: m/z
323 (M+, 100%), 306 (10%), 278 (11%). Anal. Calcd. for
C13H17N5OS2: C, 48.27; H, 5.30; N, 21.65; S, 19.83. Found:
C, 48.15; H, 5.27; N, 21.02; S, 19.39. HRMS: calcd. for
C13H17N5OS2 (M+H)+ 323.0875, found 323.0882.
5-Amino-4-methylsulfanyl-2-morpholinothieno[2,3-d]-
pyrimidine-6-carboxylic Acid Amide (7c). Compound 7c was
obtained from compound 4c in 40% yield (40 mg); mp: 232-
1
235 °C; ir: 2923, 2854, 1638 cm-1, H nmr (deuteriochloro-
form/methanol-d4): ꢀ 2.64 (s, 3H, -SCH3), 3.75-3.77 (t, 4H,
-CH2NCH2-), 3.87-3.89 (t, 4H, -CH2OCH2-); ms: m/z 325
(M+, 100%), 308 (7%), 280 (9%). Anal. Calcd. for
C12H15N5O2S2: C, 44.29; H, 4.65; N, 21.53; S, 19.71. Found:
C, 43.87; H, 4.61; N, 21.31; S, 19.54. HRMS: calcd. for
C12H15N5O2S2 (M+H)+ 325.0667, found 325.0675.
5-Amino-4-benzylsulfanyl-2-morholinothieno[2,3-d]pyrim-
idine-6-carboxylic Acid Anilide (7j). Compound 7j was
obtained from compound 6a in 46% yield (46 mg); mp: 205-
5-Amino-4-methylsulfanyl-2-pyrrolidinothieno[2,3-d]-
pyrimidine-6-carboxylic Acid Pyrrolidide (7d). Compound 7d
was obtained from compound 4d in 39% yield (39 mg); mp:
1
207 °C; ir: 3028, 2921, 2855, 1637 cm-1; H nmr (deuterio-
chloroform): ꢀ 3.73-3.76 (t, 4H -CH2NCH2-), 3.86-3.89 (t,
4H, -CH2OCH2-), 4.57 (s, 2H, -SCH2C6H5), 7.07-7.51 (m,
10H, phenyl protons); ms: m/z 477 (M+, 76%), 385 (100%),
358 (18%). Anal. Calcd. for C24H23N5O2S2: C, 60.36; H,
4.85; N, 14.66; S, 13.43. Found: C, 59.82; H 4.83; N,
14.49; S, 13.16. HRMS: calcd. for C24H23N5O2S2 (M+H)+
477.1293, found 477.1291.
1
199-202 °C; ir: 2969, 2874, 1636 cm-1; H nmr (deuterio-
chloroform): ꢀ 1.84-1.99 (m, 8H, -CH2(CH2)2CH2-), 2.65 (s,
3H -SCH3), 3.46-3.68 (m, 8H, -CH2NCH2-); ms: m/z 363
(M+, 64%), 293 (41%), 266 (40%). Anal. Calcd. for
C16H21N5OS2: C, 52.87; N, 5.82; H, 19.27; S, 17.64. Found:
C, 52.75; H, 5.58; N, 19.04; S, 17.52.
5-Amino-4-benzylsulfanyl-2-morholinothieno[2,3-d]pyrim-
idine-6-carboxylic Acid 4-Methylanilide (7k). Compound 7k
was obtained from compound 6b in 42% yield (42 mg); mp:
231-233 C; ir: 3028, 2918, 2856, 1632 cm-1; 1H nmr
5-Amino-4-methylsulfanyl-2-piperidinothieno[2,3-d]pyrimi-
dine-6-carboxylic Acid Pyrrolidide (7e). Compound 7e was
obtained from compound 4e in 42% yield (42 mg); mp: 230-
233 °C; ir: 2939, 2854 cm-1; 1H nmr (deuteriochloroform):

Jul-Aug 2007
2,4,6-Trisulfanyl-substituted Pyrimidine-5-carbonitriles
763
J.; Hawking, F.; Ed.; Chemotherapy of Malaria Part 2. The Antimalarial
Drugs.; Academic Press Inc. New York, 1963; Vol. 1, pp 417-441; [d]
The Pesticide Manual 11th Ed. British Crop Protection Council 1997.
[2] Briel, D.; Franz, T.; Dobner, B. J. Heterocyc. Chem. 2002,
39, 863-868.
(deuteriochloroform): ꢀ 2.31 (s, 3H, -CH3), 3.73-3.75 (t, 4H
-CH2NCH2-), 3.86-3.88 (t, 4H, -CH2OCH2-), 4.56 (s, 2H,
-SCH2C6H5), 7.11-7.39 (m, 9H, phenyl protons); ms: m/z
491 (M+, 86%), 385 (100%), 358 (23%). Anal. Calcd. for
C25H25N5O2S2: C, 61.08; H, 5.13; N, 14.25; S, 13.04. Found:
C, 60.93; H 5.16; N, 14.13; S, 12.89.
[3] Briel, D.; Drescher, S.; Dobner, B. J. Heterocyc. Chem. 2005,
42, 841-846.
[4] See, for example, [a] Barker, A. J.; Johnstone, C. World Pat.
Appl. WO 97/30034 A1, 1997; [b] Brown, D. S.; Morris, J. J.; Thomas,
A. P. World Pat. Appl. WO 96/15118 A1, 1996; [c] Fry, D. W.; Kraker,
A. J.; McMichael, A.; Ambroso, L. A.; Nelson, J. M.; Leopold, W. R.;
Connors, R. W.; Bridges, A. J. Science 1994, 265, 1093-1095; [d] Ward,
W. H. J.; Cook, P. N.; Slater, A. M.; Davies, D. H.; Holdgate, G. A.;
Green, L. R. Biochem. Pharmacol. 1994, 48, 659-666.
Acknowledgement. We are grateful to Mr. Chr. Schmelzer,
Martin-Luther-University, for recording HRMS data of the
compounds published in this paper.
REFERENCES
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S.; Engbersen, J. F. J.; Reinhoudt, D. N. J. Am. Chem. Soc. 1994, 116,
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1984, 23, 417; [b] Wormser, G. P.; Keusch, G. T.; Heel, R. C. Drugs
1982, 24, 459; [c] Hill, J. In Experimental Chemotherapy; Schnitzer, R.