4′,x-Seco and 4′,x-4′,5′-Diseco C-Nucleosides from 2-Hydrazino-(3H)-thieno[2,3-d]pyrimidin-4-ones

Article abstract of DOI:10.1515/znb-2001-0817

Cyclization of 2-hydrazino-5,6-dimethyl-3H-thieno[2,3-d]pyrimidin-4-one (1) with acetic acid gave 3,6,7-trimethyl-1,2,4-triazolo[3,4-a]thieno[2,3-d] pyrimidin-5-one (5) whose Dimroth rearrangement gave 2,6,7-trimethyl-1,2,4-triazolo[3,4-a]thieno[2,3-d]pyrimidin-5-one (11). Alternatively, 5 was obtained from the dehydrogenative cyclization of acetaldehyde 5,6-dimethyl-4-3H-oxo-thieno[2,3-d]pyrimidin-2-yl hydrazone (7). Reaction of 1 and 2 with a number of sugars gave the respective hydrazones 19 and 20. Those of the D-glucose exist in the cyclic pyranosyl structure in addition to minor amounts of the acyclic structure. Dehydrogenative cyclization of the sugar hydrazones gave the respective fused tricyclic compounds 25 and 26.

Full text of DOI:10.1515/znb-2001-0817

4'^r-Seco and 4',*-4',5'-Diseco C-Nucleosides from 2-Hydrazino-(3/f)-
thieno[2,3-d]pyrimidin-4-ones
Atef A. Hamed3, Hesham F. Bader3, and El-Sayed H. El-Ashryb
a Department of Chemistry, Faculty of Science, Menoufia University, Shebin El-Koam, Egypt
b Department of Chemistry, Faculty of Science, Alexandria University, Alexandria, Egypt
Reprint requests to Prof. Dr. E. S. H. El Ashry.
Fax: +20-3-4271360. E-mail: eelashry@link.net
Dedicated to Prof. Dr. I. F. Zeid on the occasion o f his 60th birthday
Z. Naturforsch. 56b, 826-836 (2001); received January 18, 2001
Thieno[2,3-d]pyrimidinone, Triazolo[3,4-a]thieno[2,3-d] pyrimidinone, Sugar Hydrazones
Cyclization of 2-hydrazino-5,6-dimethyl-3//-thieno[2,3-d]pyrimidin-4-one (1) with acetic
acid gave 3,6,7-trimethyl-l,2,4-triazolo[3,4-a]thieno[2,3-d] pyrimidin-5-one (5) whose Dim-
roth rearrangement gave 2,6,7-trimethyl-l,2,4-triazolo[3,4-a]thieno[2,3-d]pyrimidin-5-one
(11). Alternatively, 5 was obtained from the dehydrogenative cyclization of acetaldehyde 5,6-
dimethyl-4-3//-oxo-thieno[2,3-c/]pyrimidin-2-yl hydrazone (7). Reaction of 1 and 2 with a
number of sugars gave the respective hydrazones 19 and 20. Those of the D-glucose exist in
the cyclic pyranosyl structure in addition to minor amounts of the acyclic structure. Dehydro-
genative cyclization of the sugar hydrazones gave the respective fused tricyclic compounds
25 and 26.
Introduction
and 9 at the early stage of the reaction was not
considered, since one of its components has been
transformed to the other one. Moreover, the struc-
ture of the product should not be 10 or 11 that
could be derived from the Dimroth rearrangement
[31] of either 5 or 9, because the product did not
change by alkali.
Methylation of 11 gave 13. The selection of the
linear structure 5 for the product from the dehy-
drative cyclization of 3 can be deduced from the
dissimilarity of compound 13 with the angularly
fused product 18 which was prepared from 14
whose methylation and subsequent hydrazinolysis
gave 16 via 15. In 16 N-3 cannot become involved
in the cyclization process; thus the angular struc-
ture 17 is the only possible product of cyclization
whose Dimroth rearrangement gave 18.
The biological importance of acyclonucleosides
[1-3] and C-nucleosides [4-14] attracted our at-
tention towards the synthesis of acyclo C-nucleo-
side analogues [15-25] of potential chemothera-
peutic interest. The acyclonucleosides have been
recently classified [1-3] according to the type of
the glycon rather than the aglycon part. Adapting
this classification, our targets in the present paper
are of the type 4'jc-seco and 4 ',x:4',5'-diseco-
nucleosides of thieno[2,3-d]pyrimido[3,4-a][1,2,4]-
triazoles. Our interest in this group of compounds
has arisen from the various biological activities re-
ported for compounds incorporating this ring sys-
tem [26-29].
Results and Discussion
The hydrazones 7 and 8 were prepared by the
The initial reaction of the hydrazine 1 [30] with reaction of
respectively. Dehydrogenative cyclization of the
and with time one of them was transformed into hydrazone 7 gave a product whose structure was
1
with acetaldehyde and benzaldehyde,
acetic acid gave two products as indicated by TLC
identical in all aspects with 5 that was obtained
the other. The transient product was considered to
be the hydrazide 3 which could be isolated after
10 min. On the other hand, upon prolonged heat- zone
from the cyclization of 1 with acetic acid. Hydra-
7 was formed as a mixture of syn and anti-
ing for 18 h, 3 underwent a dehydrative cyclization isomers as indicated by the XH NMR spectroscopy
(two quartets for the HC=N proton and two
was assigned, rather than the angular structure 9. doublets for the methyl protons). Monitoring of
the reaction of hydrazine with triethyl orthofor-
to give a product to which the linear structure 5
1
The assumption that the mixture is composed of 5
0932-0776/2001/0800-0826 $06.00 © 2001 Verlag der Zeitschrift für Naturforschung, Tübingen • www.znaturforsch.com
D
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827
A. A. Hamed et al. • 2-Hydrazino-(3//)-thieno[2,3-J]pyrimidin-4-ones
Me.
Me
R1
R2
Me-
NH
NH
A
RCOOH
A
•g'
- y ;
NHNHCQR Me''
S
NHNHj
^
s
H
1
2
R1 = R2 = Me
R1, R2 — (CHj)^
5
6
R = Me
3
4
R = Me
R = H
R =
H
Fedj
EtCH
O
Me
Me
Me
NH
NH
NH
KOH
■ v
Me
x
s
NHN= CH
Me^
^ N ^ ^ N
iA
I
R
J— l
R = Me
7
8
R = Me
R = Ph
10
9
R = Me
Me.
Me
N
------ N
KOH
NaH/DMF
Mel
11
12
R = Me
R =
H
Scheme 1
mate by TLC showed the initial formation of two
Condensation of hydrazines 1 or 2 with the
products one of which was transformed into the monosaccharides D-arabinose, D-xylose, D-galac-
tose, and D-mannose, gave the corresponding hy-
other upon prolonged heating. Structure 12 was
19a-d and 20a-d. Their IR spectra
assigned to the final product because alkali had no drazones
showed absorption bands due to the OH, NH,
C(=0)N, and C=N groups. Their XH NMR spectra
showed the presence of a doublet in the ranges
effect on it. This means that the product was al-
ready a result of a Dimroth rearrangement of the
initially formed product
6
presumably due to the
presence of traces of formic acid as impurity pre- d = 7.44-7.67 ppm
(J =3.2 Hz) which corresponded to the 1-H of
the sugar residue. The spectra of the D-glucose
derivatives showed in addition to the minor
sent in the triethyl orthoformate; Dimroth re-
arrangement [31] can be catalyzed by acid, base or
heat. The negative result with alkali supported the
conclusion that the initially formed mixture con- doublet at 7.44 ppm, a major doublet at 5.79 ppm,
tained 6 and 12. This conclusion has been con- as well as two singlets at 11.07-11.12 and 11.34-
firmed by the
which did not show resonances due to the presum- also indicated that the D-glucose derivative exists
in the major pyranosyl form 22e which is accompa-
NMR spectrum of the mixture 11.37 for the NH proton. The 13C NMR spectra
ably formed intermediate 4 or its derivatives.
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828
Me
A. A. Hamed et al. • 2-Hydrazino-(3//)-thieno[2,3-ti]pyrimidin-4-ones
Me
Nn
NaH/DMF/Mel
16
17
R = Me
18
R= Me
Scheme 2
nied by the minor acyclic isomer 20e. On the other relationship to the anomeric C-l [33]. The identity
hand, its analogue is not accompanied by the of the product to be a- or /3-anomer cannot be
acyclic isomer 19 within the detection limits of the readily deduced from the chemical shift of the an-
omeric carbon as it appeared at 90.45 ppm, when
2
1
NMR method.
The 13C NMR spectra of the hydrazone deriva- compared to the C-l signal of a- and yS-D-gluco-
tives 19 and 20 showed resonances in the high field pyranose. However, it is almost close to that of 2'-
region corresponding to the sugar. The assignment (ß-D-glucopyranosyl) isonicotino hydrazide indi-
of carbons C-2 to C- 6 in the ranges <5 = 62.59-
cating its ^-configuration. Moreover, the shifts of
72.16 ppm for 19 and 20 was based on comparison C-3 and C-5 are much closes to those of the ß-
with the chemical shifts of open chain structures pyranosyl derivatives rather than to the a-pyra-
noses. The other possible cyclic structures were
signal was assigned to C- 6 in hexoses and C-5 in ruled out based on the pronounced effects on the
of the sugar hydrazones [9-11]. The highest field
chemical shifts of the carbon of the sugar part,
which agreed with a /3-glucopyranosyl type of
structure. In conclusion the cyclic and acyclic
structures are co-existing and the detection of the
minor one depends on its ratio. Thus, whereas
sugar hydrazones are mostly in the acyclic forms,
pentoses. The lowest field signals may be assigned
to C-4 or C-5 (C-4 or C-3 in pentoses). The reso-
nance at -71.0 ppm was assigned to C-2. Carbon
atom C-l appeared in the range d = 147.01 -
148.09 ppm for the acyclic structures 19 and 20.
The spectra of the D-glucose derivatives showed
the above resonances for the sugar carbons as a those of D-glucose exist mostly in the cyclic one
which is accompanied by minor amounts of the
acyclic form to the extent that could not be de-
tected in the respective 13C NMR spectrum.
Treatment of compounds 19 and 20 with acetic
anhydride in pyridine gave crystalline derivatives,
whose analysis indicated that peracetylation had
taken place on both the polyol residue and one
NH group to give 23 and 24, respectively. Their IR
spectra showed absorptions indicating the pres-
minor set of resonances whereas the major set cor-
responded to the cyclic structures 21 and 22. This
conclusion was reached by comparing their 13C
NMR resonances with those of a- and /5-D-gluco-
pyranose [32] as well as 2'-(/?-D-glucopyranosyl)-
isonicotinohydrazide [33,34] and the respective
derivative from 3-hydrazinophenanthro[9,10-e]-
[l,2,4]triazine [25]. Since the derivatization at C-l
has a minimal effect on C-4 and C- , the signal of
6
C-4 and C- 6 in 21 and 22 can be readily identified ence of OAc and C (=0)N groups. The :H NMR
at d = 70.50 and 62.10 ppm, respectively, carbon spectrum of 23 g showed the presence of four OAc
atoms C-3 and C-5 have the same stereochemical and one NAc groups. The two quartets at 3.99 and
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A. A. Hamed et al. • 2-Hydrazino-(3//)-thieno[2,3-^]pyrimidin-4-ones
829
N— N=
CH
(CHOHV
I
I
Ac
(CHOAc^
a^oH
I
CHjOAc
23
24
R1 = R2
R1,R2
= Me
25
26
R1 = R2
= Me
R !,R 2 «-(CHaJj-
-----OH HO------
HO-----
|
HO-----
-----OH HO-----
HO-----
(CHOH)n
-----OH HO------
-----OH
HO-----
-----OH
-----OH
-----OH
j
---
ch2cm
-----OH
-----OH
-----OH
-----OH
-----OH
a
C
b
d
OAc
AcO-
AcO-
AcO-
■OAc AcO■
AcO
(CHOAc)n
-----OAc AcO
—OAc
OAc
OAc
OAc
I
CHjOAc
OAc
OAc
OAc
-O A c
OAc
f
g
Scheme 3
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830
A. A. Hamed et al. • 2-Hydrazino-(3//)-thieno[2,3-^]pyrimidin-4-ones
Table 1. ’H NMR spectral data.
Compd.
19a
Chemical shifts [ö] and assignments
2.27 (s, 3 H, Me), 2.34 (s, 3 H, Me), 3.50 (m, 4 H, 5, 5'-H + 2 OH), 4.40, 4.50, 4.60 (m, 2 H, 2, 3, 4-H
+ OH), 5.11 (d, I H, OH) 7.45 (d, I H , / 12 3.2 Hz, 1-H), 11.09 (bs, I H, NH), 11.34 (bs, I H, NH).
2.24 (s, 3 H, Me), 2.31 (s, 3 H, Me), 3.50 (m, 4 H, 5,5'-H + 2 OH), 4.30 (m, 2 H, 3,4-H + OH), 4.50
(dd, 1 H, / = 5.6 Hz, 2-H), 5.31 (d, 1 H, OH), 7.48 (d, 1 H , / 12 3.0 Hz, 1-H), 11.13 (s, 1 H, NH) 11.36
(s, 1 H, NH).
19b
19c
19d
20a
2.25 (s, 3 H, Me) 2.32 (s, 3 H, Me), 3.45 and 3.55 (2 m 6 H, 5, 6,6'-H + 3 OH), 4.20, 4.40, 4.50, (m, 5
H, 2, 3,4-H + 2 OH), 5.09 (d, 1 H, OH), 7.44 (d, 1 H , / 12 3.2 Hz, 1-H), 11.07 (bs, 1 H, NH), 11.33 (bs,
1 H, NH).
2.26 (s, 3 H, Me), 2.33 (s, 3 H, Me), 3.50 and 3.60 (2 m, 5 H, 5, 6,6'-H + 2 OH), 4.20, 4.40, 4.50 (m, 5
H, 2-H, 3,4 +2 OH), 5.25 (d, 1 H, OH), 7.67 (d, 1 H , / 12 3.2 Hz, 1-H), 11.14 (s, 1 H, NH), 11.37 (s, 1
H, NH).
1.75 (bs, 4 H, 2 CH2), 2.62 and 2.80 (2 bs, 4 H, 2 CH2), 3.50 (m, 6 H, 5,6,6'-H + 3 OH), 4.50 (m, 3 H,
3,4-H + OH) 5.11 (d, 1 H, OH), 5.79 (d, 0.2 H, 1-H) 7.44 (d, 0.8 H, 1-H), 8.63 (s, 0.2 H, NH), 10.40 (s,
> 0.2 H, NH), 11.12 (bs, < 1 H, NH), 11.35 (bs, < 1 H, NH).
20b
20c
1.76 (bs, 4 H, 2 CH2), 2.62 and 2.80 (2 bs, 4 H, CH2), 3.50 (m, 4 H, 5,6,6'-H + OH) 4.40 (m, 4 H, 2,3,4-
H + OH), 5.30 (d, 1 H, OH), 7.49 (d, 1 H, 1-H), 11.10 (s, 1 H, NH), 11.35 (s, 1 H, NH).
1.76 (bs, 4 H, 2 CH2), 2.50 and 2.51 (bs, 4 H, 2 CH2), 3.42 (bt, 2 H, 6,6'-H), 3.57, 3.75 (2 m, 1 H, 4, 5-
H + OH), 4.15, 4.45 (m, 5 H, 2,3-H + 3 OH), 5.04 (d, 1 H, OH), 7.45 (d, 1 H, 1-H), 11.10 (s, 1 H, NH),
11.35 (s, 1 H, NH).
20d
21
1.77 (bs, 4 H, 2 CH2), 2.63 and 2.81 (2 bs, 4 H, 2 CH2), 3.45 (m, 2 H, 6, 6'-H) 3.60, 4.15, 4.35 (m, 1 H,
2-H), 4.45 (m, 7 H, 2,3,4-H +4 OH), 5.24 (d, 1 H, OH), 7.66 (d, 1 H, 1-H), 11.19 (s, 1 H, NH), 11.40 (s,
1 H, NH).
2.23 (s, 3 H, Me), 2.30 (s, 3 H, Me), 3.20 (m, 5 H, 5,6,6'-H + 2 OH) 3.70 (m, 2 H, 4-H + OH), 4.25 (bd,
1 H, 3-H), 4.43 (bd, 1 H, 2-H) 4.90 (bd, 1 H, OH), 5.30 (bs, 1 H, OH), 5.30 (bs, 1 H, OH), 5.78 and
7.44 (d, 1 H, 1-H), 8.78, 10.59 (2 s, 1 H, NH), 11.02, 11.10, 11.32 (3 s, 1 H, NH).
1.75 (bs, 4 H, 2 CH2), 2.62 and 2.80 (2 bs, 4 H, 2 CH2), 3.10 (m, 2 H, 6, 6'-H), 3.70 (m, 2 H, 5-H +
OH), 4.30 (bd, 2 H, 4-H +OH), 4.48 (bd, 1 H, 3-H), 4.60 (bd, 1 H, 2-H), 4.95 (bd, 1 H, OH), 5.35 (bs,
1 H, OH), 5.80 (d, < 1 H, 1-H), 7.50 (s, < 1 H, 1-H), 8.81, 10.60 (bs, 1 H, NH), 11.09 (bs, 1 H, NH),
11.35 (bs, 1 H, NH).
22
23g
2.04, 2.09, 2.11, 2.13, 2.40, 2.44 (7 s, 21 H, 7 Me), 3.99 (dd, 1 H, J45 6.2 Hz, J55 11.8 Hz, 5'-H), 4.34 (dd,
1 H, J45 4.65 Hz, 5-H) 5.39 (m, 1 H, 4-H), 5.55 (dd, 1 H, 3-H), 5.63 (t, 1 H, / 23 1.5 Hz, 2-H), 7.20 (d,
1 H, / 12 4.3 Hz, 1-H).
23h
23i
2.01, 2.05, 2.19, 2.13, 2.39, 2.44, (6 s, 24 H, 8 Me), 3.85 and 4.26 (2 dd, 2 H, 6,6'-H), 5.32 (m, 1 H, 5-H),
5.47 (m, 2 H, 4-H), 5.70 (bdd, 1 H, 3-H), 5.54 (bdd, 1 H, 2-H), 7.17 (d, 1 H, 1-H).
2.03, 2.04, 2.10, 2.14, 2.32, 2.34, 2.39, 2.41, (8 s, 24 H, 8 Me), 4.06 and 4.22 (2 dd, 2 H, 6,6'-H), 5.14 (m,
1 H, 5-H), 5.40 (m, 1 H, 3,4-H), and 7.15) (d, 1 H, 1-H).
24f
1.80 (bs, 2 H, 2 CH2), 1.91,1.97, 1.99, 2.06, 2.08, 2.24 (5 s, 15 H, 5 Me), 2.78 and 2.90 (2 bs, 4 H, 2 CH2),
4.12 and 4.17 (2 bdd, 2 H, 5,5'-H), 5.20 (bm, 1 H, 4-H), 5.48 (bdd, 1 H, 3-H), 5.61 (bd, 1 H, 2-H) 6.91
(s, 1 H, 1-H), 8.60 (bs, 1 H, NH).
24g
24i
1.81 (bs, H, 2 CH2), 2.00, 2.04, 2.08, 2.12, 2.27 (5 s, 15 H, 5 Me), 2.80 (2 bs, 4 H, 2 CH2), 4.08 and 4.19
(2 bdd, 2 H, 5,5'-H), 5.27 (bm, 1 H, 4-H), 5.50 (bt, 1 H, 3-H), 5.58 (bd, 1 H, 2-H), 6.94 (bd, 1 H, 1-H),
8.60 (bs, 1 H, NH), 12.86.
1.80 (bs, 4 H, 2 CH2), 1.96, 1.97, 2.01, 2.06, 2.08, 2.23, 2.78, and 2.90 (8 s, 24 H, 8 Me), 3.90 and 4.20
(2 dd, 2 H, 6,6'-H), 5.20 (bm, 1 H, 5-H) 5.38 (q, 2 H, 3,4-H), 5.50 (s, 1 H, 2-H), 6.84 (d, 1H , / 12 4.0 Hz,
1-H), 7.4 and 8.60 (bs, 1 H, NH).
25a
25d
26c
26d
2.28 and 2.37 (2 s, 6 H, 2 Me), 3.50 (bm, 4 H, 4,4'-H + 20H ), 4.5 (bm, 3 H, 2,3-H +OH), 5.50 (m, 2 H,
1-H +OH).
2.31 and 2.40 (2 s, 6 H, 2 Me), 3.45 and 3.65 (2 bm, 4 H, 4-H, 5,5'+OH), 4.18, 4.30 and 4.40 (3 m, 5 H,
2, 3-H +3 OH), 5.29 (t, 1 H, 1-H), 5.50 (d, 1 H, OH).
1.79 (bs, 4 H, 2 CH2), 2.66 and 2.87 (2 bs, 4 H, 2 CH2), 3.30, 4.10 (m, H, 2,3,4,5,5'-H +5 OH), 5.40 (d,
1 H, 1-H), 5.55 (d, 1 H, OH), 11.35 (s, 1 H, NH).
1.80 (bs, 4 H, 2 CH2), 2.67 and 2.89 (2 bs, 4 H, 2 CH2), 3.35 and 3.70 (2 bm, 4 H, 4,5,5'-H +OH), 4.20
and 4.30 (2 bm, 5 H, 2,3-H + 3 OH), 5.28 (t, 1 H, 1-H), 5.50 (d, 1 H, OH).
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831
A. A. Hamed et al. • 2-Hydrazino-(3//)-thieno[2,3-*i]pyrimidin-4-ones
Merck silica gel 60-F254 precoated plastic plates.
Microanalyses were performed in the unit of mi-
croanalysis at the Universities of Cairo, Odense
(Denmark) and Konstanz (Germany).
4.34 ppm were assigned to 5'-H and 5-H, respec-
tively. The multiplet at 5.39 ppm was due to 4-H.
The doublet of doublets at 5.55 ppm and the trip-
let at 5.63 were due to 3-H and 2-H, respectively.
The doublet at 7.20 ppm was due to 1-H. The *H
NMR spectra of the other acetates showed a sim-
ilar pattern (Table 1).
2-Acetylhydrazino-5,6-dimethyl-(3H)-thieno-
[2,3-d]pyrimidin-4-one (3)
Reaction of the hydrazones 19 and 20 with a
solution of iron chloride gave the triazolopyrimid-
ines 25 and 26, respectively. The assignment of
their structures was based on the model study dis-
cussed above.
A
mixture of 2-hydrazino-5,6-dimethyl-(3H)-
thieno[2,3-<i]pyrimidin-4-one (2.12 g, 10 mmol)
and acetic acid (30.0 ml) was heated under reflux
for 10 min. The yellow product, that separated out
on cooling, was filtered and recrystallized from
ethanol to give yellow crystals (1.06 g, 50% yield),
m.p. 255-257° C. - IR (KBr): v = 1625 (C=N and
C=C), 1677 (C=0) cm -1.
Experimental
-
XH NMR (250 MHz, DMSO-d6): (5= 1.90 (s, 3
Melting points were determined with a Kofler
block apparatus and are uncorrected. IR spectra
were recorded with Perkin-Elmer Model 1720
FTIR spectrometer. *H and 13C NMR spectra
were determined with Varian EM-390 and Bruker
AC-250 spectrometers. The chemical shifts in ppm
are expressed on the d scale using tetramethylsi-
lane as internal standard. Coupling constants are
given in Hz. Mass spectra were recorded on an
AEIMS 30 spectrometer. TLC was performed on
H, Me), 2.27 (s, 3 H, Me), 2.30 (s, 3 H, Me), 8.70,
9.80 and 11.25 (3 s, 3 H, 3 NH). - 13C NMR: (5 =
169.44 (C=0), 164.62 (C-4), 158.56 (C-2), 127.78
(C-
12.11 (Me), 12.71 (Me), 20.70 (Me).
2S (252.3): calcd. C47.60, H 4.79, N
6
), 122.72 (C-4a), 152.69 (C-7a), 115.94 (C-5),
-
CioH1 2
N
4 0
22.21; found C 47.2, H 4.8, N 22.41.
Table 2. 13C NMR spectral data of 17 and 18.
Chemical shifts [d]a
Chemical shifts [<3];
19d
20d
20eb
Assignment
19c
Assignment
19a
19b
20a
Alditolyl carbons
153.65
72.33
71.39
71.11
70.49
62.11
147.01
72.12
71.68
71.12
62.59
147.73
72.12
70.93
70.00
63.42
147.70
72.15
70.93
70.00
67.92
63.41
148.41
72.11
70.99
69.80
69.53
63.79
148.09
72.08
70.92
69.73
69.46
63.75
147.69
C-l
C-5
C-2
C-3
C-4
C-6
C-l
C-4
C-2
C-3
C-5
72.14
70.93
70.00
63.40
Heterocyclic carbons
164.71
158.43
127.98
115.93
122.60
149.94
164.31
153.56
130.22
114.98
125.63
148.42
166.31
158.06
130.03
113.97
124.61
149.98
165.40
158.12
130.23
114.97
125.65
149.98
164.67
158.35
127.94
115.89
122.56
149.87
164.66
158.33
127.94
115.88
122.55
149.85
164.73
158.42
128.01
115.94
122.63
149.92
C-4
C-2
C-6
C-5
C-4a
C-7a
Substituents
12.16
12.79
12.18
12.81
12.22
12.86
Me
Me
CH2
c h 2
c h 2
CH,
12.14
12.77
21.82
22.61
24.14
25.24
21.83
22.63
24.16
25.26
a DMSO-d6 was used as a solvent; b minor isomer with 22 (Table 3).
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832
A. A. Hamed et al. • 2-Hydrazino-(3//)-thieno[2,3-<i]pyrimidin-4-ones
Table 3. 13C NMR spectral data of 21, 23, 25 and 26.
Chemical shifts [<3]a
Chemical shifts [(3]a
Assignment
21
22
Assignment
23i
25d
26d
23g
Alditolyl carbons
major
C-l
C-5
C-3
C-2
C-4
C-6
90.66
90.64
77.55
76.89
71.21
70.18
63.30
C-l
C-2
C-3
C-4
C-5
C-6
143.89
70.93
69.70
68.90
61.73
142.64
69.59
68.05
67.65
66.97
61.35
70.85
70.90
77.61
76.91
71.14
70.50
62.10
70.58
96.08
66.57
63.85
70.64
69.11
66.62
63.89
Heterocyclic carbons
C-4
C-2
C-6
C-5
C-5a
C-7a
158.31
153.56
127.73
115.00
121.53
143.86
165.40
158.12
130.21
114.93
125.63
146.95
161.01
159.99
132.26
122.88
129.64
141.82
160.14
159.21
131.43
123.01
128.58
140.73
C-8
169.20
153.80
127.28
112.50
123.31
147.43
149.02
167.26
153.55
129.60
111.90
126.52
147.43
149.12
C-9a
C-6
C -l
C-7a
C-4a
C-3
Substituents
12.84
13.00
12.58
12.58
Me
Me
12.13
12.82
12.45
13.19
c h 2
c h 2
c h 2
c h 2
Me
Me
Me
Me
21.82
22.63
24.12
25.26
21.85
22.52
24.40
25.52
20.33
20.33
20.43
21.04
20.57
20.63
20.67
20.77
22.13
Me
169.51
169.70
169.93
170.46
172.55
168.88
169.12
169.25
169.25
169.93
171.36
CO
CO
CO
CO
CO
CO
a DMSO-d6 was used as a solvent except for 23 (CDC13).
0
0
and washed with ethanol. It was recrystallized
from ethanol in colorless crystals (1.7 g, 80%
yield), m.p. 280-282° C. It is identical to the pro-
duct from method B.
3,6,7-Trimethyl-l,2,4-triazolo[3,4-a]thieno-
[2,3-d]pyrimidin-5-one (5)
Method A
A mixture of 3 (2.12 g, 10 mmol) and acetic acid
(30.0 ml) was heated under reflux for 18 h. The
product that separated out on cooling was filtered
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A. A. Hamed et al. • 2-Hydrazino-(3//)-thieno[2,3-^]pyrimidin-4-ones
833
Method B
for 2 h. The product that separated out on cooling
was filtered, washed with ethanol and dried. It was
recrystallized from ethanol to give white crystals
(0.13 g, 60% yield), m.p. 262-264° C. - IR (KBr):
v = 1608 (C=N and C=C), 1670 (C=0) cm -1. - XH
NMR (250 MHz, DMSO-d6): Ö = 1.98 and 1.93 (2
d, 3 H, J = 5.4 Hz) Me, 2.24 (s, 3 H, Me), 2.30 (s,
3 H, Me), 6.85 and 7.39 (2 q, ratio 1:10, 1 H, HC=
), 10.28 (bs, 1 H, NH), 11.15 (bs, 1 H, NH). - 13C
NMR: d = 164.79 (C-4), 157.82 (C-2), 149.63 (C-
A solution of ferric chloride (0.4 g) in ethanol
(5 ml) was added dropwise to a boiling solution of
7 (0.46 g, 2 mmol) in ethanol (200 ml). Heating
was continued for 5 h and the mixture was then
kept overnight at r.t. The product that separated
out on cooling was filtered, washed with water and
recrystallized from ethanol to give colorless crys-
tals (0.28 g, 62% yield), m.p. 280-282° C. - IR
(KBr): v = 1615 (C=N and C=C), 1680 (C =0)
cm“1. - XH NMR (250 MHz, DMSO-d6): (3 = 2.26
(s, 3 H, Me), 2.34 (s, 3 H, Me), 2.75 (s, 3 H, Me),
13.55 (bs, 1 H, NH). - 13C NMR: 0= 173.92 (C-
4a), 143.83 (HC=N), 127.94 (C-
115.91 (C-5), 12.16 (Me), 12.76 (Me), 18.15 (Me).
Ci 1 2 N4OS (236.3): calcd. C 50.83, H 5.11, N
6
), 122.53 (C-5a),
0
H
23.71; found C 51.2 H 4.8, N 23.4.
8
), 153.74 (C-9a), 149.25 (C-4a), 142.65 (HC=N),
127.38 (C- ), 122.27 (C-7a), 112.7 (C-7), 13.98
(Me), 13.03 (Me), 12.23 (Me).
6
C1 0 H 1 0 N4OS
Benzaldehyde[5,6-dimethy1-4(3H)-oxo-thieno-
(234.3): calcd. C 51.27, H 4.30, N 23.91; found C
[2,3-d]pyrmidin-2-yl]hydrazone (8)
51.3, H 4.3, N 23.5.
A suspension of 1 (0.25 g, 1 mmol) in ethanol
(80 ml) was treated with benzaldehyde (0.45 ml,
4.2 mmol) and a few drops of acetic acid. The reac-
tion mixture was processed as above and the pro-
duct was recrystallized from DMF/EtOH to give
yellow crystals (0.18 g, 50% yield). m.p.>300° C. -
IR(KBr): v = 1608 (C=N and C=C), 1657 (C=0),
3203 (NH) cm -1. - lH NMR (250 MHz, DMSO-
d6): Ö = 2.27 (s, 3 H, Me), 2.34 (s, 3 H, Me), 7.40
(m, 3 H, ph), 7.95 (d, 2 H, Ph), 6.03 (s, 1 H, -CH=
N), 11.25 (bs, 1 H, NH), 11,60 (bs, 1 H, NH). -
13C NMR: <3 = 164.50 (C-4), 158.35 (C-2), 149.61
(C-7a), 142.81 (HC=N)2, 127.25, 128.37, 129.38
Dimroth rearrangement o f 5
A solution of 5 (0.23 g, 1 mmol) in absolute eth-
anol (15.0 ml) was treated with potassium hydrox-
ide (0.25 g). The mixture was heated under reflux
for 4 h. The product that separated out on cooling
was filtered and recrystallized from ethanol to give
11 (0.12 g, 52% yield), m.p. >300° C. - IR (KBr):
v = 1575 (C=C and C=N), 1686 (C =0) cm "1. -
XH NMR (250 MHz, DMSO-d6): Ö = 2.33 (s, 3 H,
Me), 2.44 (s, 3 H, Me), 2.54 (s, 3 H, Me).
C H 1 0 N4OS (234.3): calcd. C 51.27, H 4.30, N
1 0
23.91; found C 51.4, H 4.6, N 24.2.
and 134.18 (ph), 128.06 (C-
6
), 122.88 (C-4a),
116.50 (C-5), 12.18 (Me), 12.80 (Me). C1 5
H
1 4 N4OS
(298.3): calcd. C 60.38, H 4.72, N 18.78; found C
60.1, H 4.9, N 19.1.
6,7-Dimethyl-l,2,4-triazolo[3,4-aJthieno[2,3-d]-
pyrimidin-5(4H)-one ( )
6
A mixture of 1 (0.4 g, 2 mmol) and triethyl or-
thoformate (30.0 ml) was heated under reflux for
10 min. TLC showed the presence of two products
with Rf - 0.4 and 0.7 (ethanol). Further heating
2,6,7,9-Tetramethyl-l,2,4-triazolo[3,4-a]-
thieno[2,3,d]pyrimidin-8-one (13)
for
2
h led to the disappearance of the fast moving
A stirred solution of 11 (0.46 g, 2 mmol) in dry
DMF (10.0 ml) was treated with sodium hydride
(0.1 g, 5 mmol) and then heated under reflux on a
water bath for 1 h. Methyl iodide (3.0 g) was
added and the mixture was heated for further 5 h.
The product that separated out on cooling was fil-
tered and recrystallized from ethanol to give or-
ange crystals (0.35 g, 70% yield), m.p. 218-
221° C. - IR (KBr): v = 1610 (C=C and C=N),
1680 (C=0) cm“1. - lH NMR (250 MHz, CDCU):
(5 = 2.32 (s, 3 H, Me), 2.44 (s, 3 H, Me), 2.90 (s, 3
spot. The mixture was cooled and the separated
product was filtered and recrystallized from etha-
nol to give yellow crystals (0.3 g, 76% yield), m.p.
270° C. - IR (KBr): v = 1572 (C=N, C=C), 1692
(C=0) cm -1. C
H, 3.65, N 25.4; found C 50.2, H 3.8, N 25.8.
9
H 8 N4OS (220.2): calcd. C 49.08,
Acetaldehyde[5,6-dimethyl-4(3H)-oxo-thieno-
[2,3-d]pyrimidin-2-yl]hydrazone (7)
A suspension of 1 (0.25 g, 1 mmol), acetalde- H, Me), 3.80 (s, 3 H, Me). - Cn H 1 2 N4OS (248.3):
hyde (0.3 ml, mmol) and a few drops of acetic calcd. C 53.21, H 4.86, N 22.56; found C 53.5, H
acid in ethanol ( 1 ml) was heated under reflux 5.1, N 22.3.
6
0
0
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834
A. A. Hamed et al. • 2-Hydrazino-(3//)-thieno[2,3-<i]pyrimidin-4-ones
(10 mmol) in ethanol (150 ml) and a few drops of
acetic acid. The mixture was boiled under reflux
for 2 h. The product that separated out on cooling
was filtered, washed with water followed by etha-
nol and dried. The product was recrystallized from
DMF to give colorless crystals.
3.6.7.9-Tetramethyl-l,2,4-triazolo[4,3-a]thieno-
[2,3-d]pyrimidin-8-one (17)
A mixture of 14 (0.5 g) and acetic acid (10 ml)
was heated under reflux for 18 h. The product that
separated out on cooling was filtered and washed
with ethanol, it was recrystallized from ethanol to
give colorless crystals (0.42 g, 70% yield), m.p.
240-242° C. - IR(KBr): v = 1612 (C=C and C=
N), 1675 (C =0) cm -1. - *H NMR (250 MHz,
Acetylation o f sugar hydrazones
A cold solution of the sugar hydrazone 19 or 20
CDC13): d = 2.33 (s, 3 H, Me), 2.43 (s, 3 H, Me), (0.25 g, 1 mmol) in dry pyridine (5.0 ml) was
treated with acetic anhydride (5.0 ml). The mix-
ture was kept at r.t. for 15 h with stirring. It was
poured onto crushed ice and the product that sep-
arated out was filtered, washed repeatedly with
water, dried and recrystallized from ethanol to
give yellow crystals of 23 and 24, respectively (see
Tables 1, 3, 5).
2.88 (s, 3 H, Me), 3.79 (s, 3 H, Me).
2.6.7.9-Tetramethyl-l,2,4-triazolo[2,3-a]thieno-
[2,3-d]pyrimidin-8-one (18)
A solution of 17 (0.24 g) in absolute ethanol
(15 ml) was treated with KOH (0.25 g). The mix-
ture was heated under reflux for 4 h. The product
that separated out on cooling was filtered and
recrystalized from ethanol to give colorless crys-
Cyclization o f sugar hydrazones
tals (0.16 g, 65% yield), m.p. 258-260° C.
-
A solution of iron(III) chloride (0.49 g) in etha-
nol ( . 0 ml) was added dropwise to a boiling solu-
2
IR(KBr): v = 1615 (C=C and C=N), 1685 (C=0)
cm "1. - XH NMR (250 MHz, CDC13): (5 = 2.31 (s,
3 H, Me), 2.46 (s, 3 H, Me), 2.91 (s, 3 H, Me), 3.81
(s, 3 H, Me).
tion of sugar hydrazones 19 and 20 (3 mmol) in
ethanol (200 ml). Heating was continued for
30 min, and the mixture was kept at r.t. for 15 h.
The product that separated out on cooling was fil-
tered, washed with water and recrystallized from
ethanol to give pale yellow crystals of 25 and 26
Sugar[5,6-disubstituted-4(3H)-oxo-thieno-
[2,3-d]pyrimidin-2-yl]hydrazones (19-22)
(see Tables 1, 3, ).
6
A solution of the respective sugar (10 mmol) in
water (5 ml) was treated with a solution of 1 or 2
Table 4. Elemental analyses and IR spectral data for 19 and 20.
v (KBr) [cm
1
']
Analysis calcd/found
Compd.
Yield
[%]
67
M.p.
Formula
(M.W.)
C=N
1617
1612
1620
1608
1620
1610
1590
1620
1622
1610
C
H
N
OH/NH
NCO
1665
1650
1680
1670
1650
1660
1650
1670
1652
1660
[°C]
240-243
230-232
222-225
250-252
2 10 -2 12
225-227
215-218
222-225
228-230
230-232
45.61
45.7
45.61
46.1
45.16
45.4
45.16
45.1
48.90
48.7
5.46
5.4
5.29
4.8
5.29
5.6
5.40
5.4
5.40
5.7
5.46
5.3
5.46
5.4
14.36
14.9
16.36
16.7
15.04
15.1
15.0
14.9
15.20
15.5
15.20
15.6
3220
3230
3200
3220
3300
3330
3315
3220
3220
3320
19a
19b
19c
19d
20a
20b
20c
20d
21
Ci3H 18N40 5S
(342.3)
C13H 18N4O5S
(342.3)
Ci4H2oN40 6S
(372.3)
70
55
78
c 14h 20n 4o 6s
(372.3)
65
Ci5H20N4O5S
(368.4)
c 15h 20n 4o 5s
(368.4)
63
5.56
5.3
14.06
14.4
5.56
5.3
60
C)6H22N4Of,S
(398.3)
14.06
13.6
5.56
5.2
5.56
5.2
75
c 16h 22n 4o 6s
(398.3)
c 14h 2„n4o 6s
(372.3)
15.04
15.4
5.40
5.1
5.40
5.1
70
5.56
5.5
5.56
5.5
14.06
14.2
22
73
c , 6h 22n 4o 6s
(398.3)
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A. A. Hamed et al. • 2-Hydrazino-(3//)-thieno[2,3-^]pyrimidin-4-ones
835
Table 5. Elemental analyses and IR spectral data for 23 and 24.
Compd.
Yield
[%]
60
M.p.
[°C]
Formula
(M.W.)
Analysis calcd/found
v (KBr) [cm 1
']
C=N
C
H
N
oco
NCO
1680
1675
1680
1670
1690
1690
23f
78-81
50.00
49.8
50.00
50.1
50.00
49.7
5.10
5.2
5.10
5.3
5.16
5.5
10.14
10.3
10.14
10.5
8.97
9.3
1760
1750
1740
1750
1740
1750
1588
1592
1580
1590
1582
1580
C23H28N4O 10S
(552.5)
75
100-102
80-82
C23H28N4O 10S
23g
23h
24f
24g
24h
(552.5)
70
C26H32N4O 10S
(624.5)
68
107-110
115-118
112-115
C25H30N4 0 10S
51.90
51.6
5.22
5.1
9.68
9.9
(578.5)
72
C25H30N4O k)S
(578.5)
51.90
51.7
5.22
5.1
9.68
9.3
70
C2HH34N4O ]2S
51.69
51.9
5.26
5.6
8.61
9.3
(650.5)
Table 6. Elemental analyses and IR spectral data for 25 and 26.
Compd.
Yield
[%]
52
M.p.
Formula
(M.W.)
Analysis calcd/found
v (KBr) [cm
']
OH/NH
[°C]
C
H
N
NCO
1675
1678
1680
1680
C=N
1610
1600
1612
1600
25a
25d
26c
26d
220-222
255-258
220-223
218-220
45.88
48.9
c 13h 16n 4o 5s
(340.3)
4.73
4.8
16.46
16.8
3215
3230
3210
3220
63
c 14h 18n 4o 6s
45.40
45.2
4.89
5.3
15.12
15.2
(370.3)
60
Ci6H2()N4Of,S
(396.3)
48.48
48.5
5.08
4.8
14.13
13.7
64
C16H20N4O6S
48.48
48.1
5.08
5.2
14.13
14.3
(396.3)
Acknowledgement
The authors thank DANIDA for the support of
this work.
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836
A. A. Hamed et al. • 2-Hydrazino-(3//)-thieno[2,3-<i]pyrimidin-4-ones
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