Synthesis and Dimroth rearrangement of 6-cyano-1,2,4-triazolo-[4,3-a]pyrimidin-5- and 7-ones. A novel alkylation with orthoesters and a new participation of the cyano group in the rearrangement

Article abstract of DOI:10.1515/znb-1998-1017

The cyclization products of 5-cyano-2-hydrazino-6-phenyl-3,4-dihydropyrimidin-4-one (6) with one carbon inserting agents have been confirmed to be of the 1,2,4-triazolo[4,3-a]pyrimidin-5(8H)-ones type and not the respective 7-ones, by comparing their alkylated derivatives 10a, 11a, 27 and 28 with the product from the cyclization of the 3-methyl and 3-benzyl derivatives of 6. A novel alkylation process was found when triethyl orthoformate was used as a cyclizing agent. Dimroth rearrangement of 8, 14, 15, 24, 34 and 36 with 2% ethanolic KOH gave the respective triazolo[1,5-a]pyrimidinone 13, 18, 19, 25, 38 and 40, respectively. Using 10% ethanolic KOH led to a novel participation of the cyano group in the rearrangement whereby 8a gave 7-imino-5-phenyl-1,2,4-triazolo[1,5-a]pyrimidine 22.

Full text of DOI:10.1515/znb-1998-1017

Synthesis and Dimroth Rearrangement of 6-Cyano-l,2,4-triazolo-
[4,3-fl]pyrimidin-5- and 7-ones. A Novel Alkylation with Orthoesters and
a New Participation of the Cyano Group in the Rearrangement
E. S. H. El Ashry*, Y. El Kilany, N. Rashed, A. Mousaad, H. Assafir
Chemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt
Z. Naturforsch. 53b, 1203-1212 (1998); received June 3, 1998
Dimroth Rearrangment, Alkylation with Orthoesters, Cyano Group, Pyrimidine,
Triazolopyrimidine
The cyclization products of 5-cyano-2-hydrazino-6-phenyl-3,4-dihydropyrimidin-4-one (6)
with one carbon inserting agents have been confirmed to be of the l,2,4-triazolo[4,3-a]pyri-
midin-5(8//)-ones type and not the respective 7-ones, by comparing their alkylated deriva-
tives 10a, 11a, 27 and 28 with the product from the cyclization of the 3-methyl and 3-benzyl
derivatives of 6. A novel alkylation process was found when triethyl orthoformate was used
as a cyclizing agent. Dimroth rearrangement of 8, 14, 15, 24, 34 and 36 with 2% ethanolic
KOH gave the respective triazolo[l,5-a]pyrimidinone 13, 18, 19, 25, 38 and 40, respectively.
Using 10% ethanolic KOH led to a novel participation of the cyano group in the rearrange-
ment whereby 8a gave 7-imino-5-phenyl-l,2,4-triazolo[l,5-a]pyrimidine 22.
Introduction
zolo-heterocycles and their acyclonucleoside ana-
logues [17-27], the synthesis of 1,2,4-triazolotria-
zines, quinolines and quinoxalines has been
reported. In the present work, the regioselective
form ation and Dim roth rearrangem ent of the an-
The Dimroth rearrangem ent with certain types
of compounds gives rise to unexpected products
[I], Thus, l,2,4-triazolo[4,3-fl]-pyrimidines undergo
rearrangem ent to give [1,5-a] analogues [1,2].
There is an increasing interest in the pharm acolog-
ical activity of such annelated systems. Com -
pounds having this skeleton with a [4,3-fl] fusion
are useful as calcium channel blocking vasodila-
tors, and have antihypertensive [3], cardiovascu-
lar[4,5] and anxiolytic [6] activities as well as a
component in photographic materials [7], The [1,5-
a] analogues have much more biological activities.
They are used as herbicides [8], fungicides [9], an-
giotensin II receptors antagonist [10], antianginal
[I I ], and useful for prevention of cardiovascular
diseases [12] and treatm ent of atherosclerosis [13],
Individuals of this class slow down the growth of
Lactobacillus casei and Streptococcus faecalis and
are also active against experimental tum ors [14-
16].
nelated
6-cyano-l,2,4-triazolo[4,3-a]pyrimidines
has been investigated. N-alkylation with triethyl
orthoform ate and a new rearrangem ent involving
the participation of the nitrile group in the a-ami-
donitrile system have been found during this study.
Cyclization of the hydrazine derivative A may
provide l,2,4-triazolo[4,3-a]pyrimidines (C) or (D)
or a mixture of both [2]. A possible Dim roth re-
arrangem ent of C and D would give 1,2,4-tria-
zolo[l,5-a]pyrimidines (E) and (F), respectively.
On the other hand, the cyclization of the hydra-
zine B can afford only C and/or its rearranged pro-
duct E. M oreover, the products C and E from B
can be used for deducing the site of cyclization by
their comparison with the alkylated derivatives of
the products from A. Consequently, the hydra-
zines 4, 5 and 6 were selected for the present study.
They were prepared [28] by the nucleophilic dis-
placem ent of the SH or SR groups at C-2 of 1-3.
The displacement from 2 and 3 was more facile
than that from 1. The thioethers 2 and 3 were pre-
pared by the alkylation of 1. It has to be confirmed
which nitrogen of the pyrimidine is the site of al-
kylation. The mono- and dimethylation of 1 has
been reported [28]. The structure of the former
Results and Discussion
Continuing our work on the use of heterocyclic
hydrazine derivatives as precursors for 1,2,4-tria-
* Reprint requests to Prof. Dr. E. S. H. El Ashry.
0932-0776/98/1000-1203 $06.00 © 1998 Verlag der Zeitschrift für Naturforschung, Tübingen • www.znaturforsch.com
D
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1204
E. S. H. El Ashry et al. • Dim roth Rearrangem ent
u
N' H
Ph
NHNHj
XX"
R2
N
NHNHj
R*'
4
5
R = Me
R = Bn
2
3
R = Me
R = Bn
R 3 ^
A
B
R = H
R = Alkyl
0
" s A ,
d, e
orf
I 9.
'N -------
N
:xY
1
R2" ^N ^^N ^R 3
n^
H^(
n
R
6
7
R = H
R = CHO
9
R = Et
10 R = Me
11 R = Bn
d, e
orf
f
N
was based on the spectroscopic methods as well
as its synthesis by an unambiguous m ethod. The
second methyl group has been introduced on N-3.
This assignment was based [28] on a comparison
of its NM R spectrum with that of the m onomethy-
lated derivative. The deshielding of the ortho phe-
nyl protons in both derivatives by about 0.5 ppm
relative to the meta and para protons indicated
that the phenyl group is coplanar with the pyrimi-
dine ring leading to the conclusion that N -l is un-
substituted. Otherwise, the phenyl protons may
give a compact signals indicating that the phenyl
group is twisted out of plane of the pyrimidine
nucleus because of the steric interaction resulting
from the substituent at N -l.
XX?
XX
i
H
^=-N
14 R = Me
^=-N
13
15 R = Bn
i3
I'
0
N° y ^ H
P»AnA
n
PiA nA
n
N-=/
Me
17
l^=/
16
18 R = Me
19 R = Bn
a, Mel/ K2C 03; b, BnCI/NaOH; c, NH2NH2.H20/Et0H; d, heat;
e, HCOOH/heat; f, HC(OEtfe; g, Etl/NaH; h, KOH/EtOH
a, Ar=Ph; b, Ar = C 6H4OMe-p; c, Ar= C6H4CI-p
Reaction of the hydrazine 6 with formic acid in
ethanol gave the formyl derivative 7 whose ring
closure gave the triazole 8a [29]. Alternatively, the
latter triazole can be obtained by heating of 6 with
formic acid. Moreover, the triazolopyrimidine 8a
has been also prepared by the reaction of 6 with
The reaction was found to be
whereby 8a-c gave 9a-c.
The form ation of 8a utilizing triethyl orthofor-
m ate indicated that the product did not undergo
the D im roth rearrangem ent either thermally or
a general one
triethyl orthoformate. Prolonged reaction of
6
with triethyl orthoformate led to the form ation of under the influence of formic acid (formic acid is
a byproduct 9a which with time became the sole
product accompanied by the disappearance of 8a.
The new product was analyzed for Ci4H n N50 . Its
mass spectrum showed a molecular ion peak at ml
z 265 i.e an increase of 28 from the anticipated
product 8a. Its 'H NM R spectrum showed the
presence of a pattern corresponding to an ethyl
group as a triplet and quartet at 1.70 and 4.40 ppm,
respectively. Moreover, synthesis of 9a was
achieved by the ethylation of 8a. These data led
to the conclusion that alkylation has taken place
by the triethyl orthoform ate to give 9a. Alkylation
with H C (O R )3 have been reported before [30],
known to induce the Dimroth rearrangem ent [2]).
However, in our hands no such rearrangem ent
took place even when 10% HC1 in AcOH was
used. To confirm this finding, the triazolopyrimid-
ine 8a was subjected to the action of 2 % ethanolic
KOH whereby compound 13 was formed. Treat-
m ent of 8a or 13 with a more concentrated alkali
(1 0 % ) gave a product whose elemental analysis
and mass spectrum led to the molecular formula
C n H 9N5, indicating the loss of a carbonyl group.
Its IR spectrum showed no band around 2224 cm -1
(C =N ). Its mass spectrum showed a peak at m lz
184 due to the loss of C=NH.
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E. S. H. El Ashry et al. • D im roth Rearrangem ent
1205
The 'H NM R spectrum of this new product
different confirmed the assignment for the pro-
showed the presence of a new proton signal at ducts.
Oxidative cyclization of the benzylidene deriva-
6.80 ppm. Consequently, the product has been as-
signed the structure 22. The mechanism of its for- tive 23 with ferric chloride gave 24 and not 26 or
m ation may be depicted in the following scheme.
It involves the attack of the hydroxide ion on the
25 as indicated by the susceptibility of 24 to the
action of alkali to give 25 via a D im roth rearrange-
carbonyl amide of 8a to give a Dimroth like inter- ment.
mediate 20. Migration of the charge from N-4 to
W hen the cyclization of 23 was carried out with
N -l and rotation around the C-N bond gave 13, bromine in acetic acid, it gave a major product
when dilute alkali was used. A simultaneous isom- identified as 25 in addition to two minor products
erization of the double bond of 20 may have taken
place under the strong alkalinity of the medium to
give 21, which cyclized and then decarboxylated to
give 22. Although, the addition on a nitrile group
one of which was identified as 24. The absence of
the methine proton of the hydrazone 23 in the 'H
NM R spectrum of 24 confirmed the structure.
M ethylation of 24 and 25 gave 27 and 29, respec-
in other systems was known [31], the possible hy- tively. Benzylation of 24 gave 28. The 'H NM R
drolysis of the nitrile to an amide followed by cycl- spectra of the alkylated derivatives showed the
ization can not be roled out.
This new rearrangem ent confirms indirectly that
the site of cyclization of 6 involves N-3 to give 8a
presence of an alkyl group in each. The hydra-
zones 30-33 were cyclized to give 34-37, respec-
tively as the major isolated products by the action
rather than 12 or its rearranged product 16. Com- of thionyl chloride. Partial Dim roth rearrange-
parison of the cyclized products 14 and 15 ob- ment has taken place during this cyclization
tained from 4 and 5 (blocked at the N-3), respec- whereby 38-40, respectively were formed as by-
tively with 10a and 1 1 a obtained by the
u
rn
derivatization of 8a by the same blocking agents
indicated which N atom of the pyrimidine is in-
volved in the cyclization step. In order to confirm
that no Dim roth rearrangem ent has taken place
during the methylation or benzylation of 8, meth-
ylation of the rearranged products 13 was carried
out to give 17, whereas 18 and 19 were prepared
by the action of the alkali on 14 and 15, respec-
tively. The susceptibility of 14 and 15 for the action
of alkali as well as the finding that 14 and 17 are
J k 'N
N^N
Ph
N N H N = C H P h
i
H
25
f*
O
1‘
O
Ncy ^ H
P h ^ N ^ N
c'A » A
'N
I
Me
R = Me
R = Bn
O. OH
/
\
o
O
C N-'A
w
Ncy V
R
nc- A n"R _<l
X
Ph
N
I
r * *
' M
H
P h ^ ^ N ^ N H N = C H A r
P h ^ N ^ N
n
Ar
Ar
O v OH
30 Ar = Ph, R = Me
34 Ar = Ph, R = Me
38 Ar = Ph, R = Me
31 Ar = C6H4N02-p, R = Me
35 Ar = C6H4N02-p, R = Me 39 Ar = C6H4N02-p, R = Me
36 Ar = Ph, R = Bn
40 Ar = Ph, R = Bn
32 Ar = Ph, R = Bn
33 Ar = C6H4N02-p, R = Bn
37 Ar = C6H4N02-p, R = Bn
X o
PIT
N
I
H
J
13
NM
NH
, FeClj/EtOH; b, KOH/EtOH; c, Mel/K2C03;
ho2c ^ ^ n_n
v s r *
, SOCI2; e, Ac20/C5H5N; f, Br2/AcOH
r r >
Ph/ ^N^^NN=CHPh
41 R = Me
42 R = Bn
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1206
E. S. H. El Ashry et al. • D im roth Rearrangem ent
Table I. Mass spectral data.
Compound No.
m/z (%)
8a
237(100, M t), 209(88, M t-CO), 182(7, M t-(CO. HCN)), 171 (11), 155(8), 127(20,
PhC=CCN+), 103(26, PhCN+), and 77(38, Ph+).
237(54,
H C=CCN+).
M
t), 209(27, M t-CO), 127(100. PhC^CCN+), 77(21, Ph+), and 51(25,
13
14
18
22
25
38
251(100, M t), 222(31, M t-NM e), 154(12), 141(5), 127(89, PhC=CCN+), 77(14. Ph+) and
51(15, HC=CCN+).
251(100, M t), 222(18, M t-NM e), 196(16), 169(12), 154(15), 141(7), 127(17, PhC=CCN+),
77(22, Ph+), and 51(28, HC=CCN+).
211(100, M t), 184(15, M t-HCN), 171(24), 128(18), 104(19), 77(24, Ph+), and 51(22,
H C=CCN+).
313(100, M t), 285(54, M t CO), 181(5), 153(8), 127(89, PhC=CCN+), 104(52) and 77(31,
Ph+).
327(100, M t), 289(9, M t-NM e), 225(4), 169(7), 141(10), 127 (22, PhC=CCN+), 103(43,
PhCN+), 77(37, Ph+), and 51(21, HC=CCN+).
ethanol-chloroform mixture as colorless crystals
(0.41 g, 46% yield); m.p. 138-140 °C. IR (KBr):
2216 (C =N ), 1657 cm “ 1 (CON). ]H NM R
(CDC13): (3 = 4.50 (s, 2 H, SCH2), 5.40 (s, 2 H,
N CH2), 7.40 (m, 13 H, A rH ), 7.90 (m, 2 H, A rH ).
products. On the other hand, the cyclization with
Br2/AcO H gave the D im roth rearranged products
38-40.
The rearrangem ent of 34-36 to 38-40 was
achieved with alkali. Acetylation of 30 and 32 gave
41 and 42, respectively. The *H NM R spectra of
the acetyl derivatives confirmed the assigned
structures by the presence of a singlet correspond-
ing to the acetyl group in addition to the presence
of the methine proton of the hydrazone residue.
C25H 19N3OS (409.5)
Calcd
C 73.32 H 4.68 N 10.26%,
Found C 73.30 H 4.70 N 10.50%.
3-Benzyl-5-cyano-2-hydrazino-6-pheny 1-3,4-
dihydropyrim idin-4-one (5)
Experimental
A suspension of 3 (1.0 g, 2.44 mmol) in ethanol
(20 ml) and hydrazine hydrate (4 ml) was heated
under reflux for 1 h. The reaction mixture was
cooled and the separated product was filtered, and
crystallized from ethanol as orange crystals (0.62 g,
80% yield); m.p. 230-232 °C. IR (KBr): 3304, 3187
(NH2 and NH), 2204 (C =N ), 1661 cm “ 1 (CON).
'H NMR (DM SO-d6): (3 = 5.10 (s, 2 H, N C H 2),
7.50 (m, 5 H, A rH ), 7.90 (m, 5 H, A rH ), 8.80 (s, 3
Melting points were determ ined on a Meltemp
apparatus and are uncorrected. IR spectra were
recorded with a Unicam SP 1025 Spectrometer. ]H
NMR spectra were recorded with Varian EM-390
spectrom eter at 200 MHz. The chemical shifts are
expressed in the d scale using tetramethylsilane as
a reference. Mass spectra were carried out on Tin-
nigan MAT 312. TLC was perform ed on Baker-
Flex silica gel 1B-F (2 .1 -1 .5 cm) plates. Micro- H, 3 NH).
analyses were perform ed in the unit of M icroanal-
ysis at Cairo University.
C 18H 15N50 (317.3)
Calcd C 68.12 H 4.67 N 22.07%,
Found C 68.40 H 4.80 N 22.10%.
3-Benzy l-2-benzylthio-5-cyano-6-pheny 1-3,4-
dihydropyrim idin-4-one (3)
5-Cyano-2-(N-form ylhydrazino)-6-phenyl-3,4-
dihydropyrim idin-4-one (1)
A suspension of 1 [32] (0.50 g, 2.18 mmol) and
potassium hydroxide (0.28 g, 5.0 mmol) in N,N-di-
methylformamide (10 ml) was cooled to 0 °C and
then benzyl chloride (3.50 ml, 27.64 mmol) was
added. The mixture was refluxed for 4 h, cooled
and poured onto crushed ice. The product was fil-
tered off, washed with water and crystallized from
A mixture of compound 6 (0.45 g, 1.98 mmol)
and formic acid (30 ml) in ethanol (20 ml) was
heated under reflux for 3 h. The solid product that
separated out on cooling was filtered, washed with
ethanol and then crystallized from ethanol as col-
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E. S. H. El Ashry et al. • Dim roth Rearrangem ent
1207
orless crystals (0.35 g, 69% yield); m.p. 244-
245 °C, [Lit.[29] m.p. 243 °C].
filtered and crystallized from ethanol as colorless
crystals (0.38 g, 69% yield); m.p. 219-220 °C. IR
(KBr): 2220 (C =N ), 1680 cm " 1 (CON).
6-Cyano-7-phenyl-l,2,4-triazolo[4,3-a]-
pyrimidin-5 (8H)-one (8a)
C15H 13N50 2 (295.3)
Calcd
C 61.01 H 4.44 N 23.72%,
(a) Compound 7 (0.47 g, 1.84 mmol) was fused
at 260 °C for 1 h. The solidified product was tritu-
rated with ethanol, filtered off and crystallized
from ethanol into colorless crystals (0.35 g, 80%
yield); m.p. 236-239 °C, [Lit.[29] m.p. 236 °C].
Found C 61.40 H 4.20 N 23.60%.
(b)
A stirred solution of 8b (0.50 g, 1.87 mmol)
in AfN-dimethylformamide (10 ml) was treated
with sodium hydride (0.43 g, 17.92 mmol) for
20 min. Then, ethyl iodide (10 ml) was added and
the mixture was processed as above, colorless crys-
tals (0.39 g, 71% yield); m.p. 219-220 °C. It is
identical with that obtained from a.
(b)
A
mixture of compound
6
(0.47 g,
2.07 mmol) and (20 ml) formic acid was heated
under reflux for 4 h. The reaction mixture was
cooled and the product that separated out was fil-
tered, and crystallized from ethanol as colorless
crystals (0.37 g, 75% yield); m.p. 236-239 °C. It is
identical with the product from m ethod a.
(c) A mixture of 6 (0.47 g, 2.07 mmol) and tri-
ethyl orthoform ate (30 ml) was heated under re-
flux for 1 h. The product that separated out on
cooling, was filtered, and crystallized from ethanol
as colorless crystals (0.31 g, 63% yield); m.p. 236-
239 °C. It is identical with the product from
m ethod a.
6-Cyano-8-ethyl-7-p-chlorophenyl-1,2,4-
triazolo[4,3-a]pyrimidin-5-one (9c)
A mixture of 8c (0.50 g, 1.84 mmol) and triethyl
orthoform ate (10 ml) was heated under reflux for
4 h. The product was crystallized from ethanol as
pale yellow crystals (0.39 g, 71% yield); m.p. 160-
163 °C. IR (KBr): 2222 (C =N ), 1683 cm “ 1 (CON).
C 14H 10N,OC1 (299.8)
Calcd
C 56.09 H 3.36 N 23.35%,
6-Cyano-8-ethyl-7-pheny1-1,2,4-triazolo[4,3-a]-
pyrimidin-5-one (9a)
Found C 56.30 H 3.60 N 23.60%.
6-Cyano-8-methyl-7-phenyl-1,2,4-triazolo[4,3-a]-
pyrimidin-5-one (10a)
(a) A mixture of 8a (0.47 g, 1.98 mmol) and tri-
ethyl orthoform ate ( 10 ml) was heated under re-
flux for 4 h. The product that separated out was
filtered and crystallized from ethanol as colorless
crystals (0.30 g, 57% yield); m.p. 182-183 °C. IR
(KBr): 2220 (C =N ), 1682 cm “ 1 (CON).
A suspension of 8a (0.47 g, 1.98 mmol) and po-
tassium carbonate (1.0 g, 7.24 mmol) in N,N-d\-
methylformamide (20 ml) was treated with methyl
iodide (1.0 ml). The reaction mixture was stirred
for 4 h at room tem perature, and then processed
as before. The product was crystallized from etha-
nol as colorless crystals (0.36 g, 72% yield); m.p.
230-232 °C. IR (KBr): 2218 (C =N ), 1669 cm “ 1
C 14H n N sO (265.3)
Calcd
C 63.38 H 4.18 N 26.40%,
Found C 63.40 H 4.20 N 26.00%.
(CON).
NM R (DM SO-d6): <5 = 3.95 (s, 3 H,
(b) A stirred solution of 8a (0.47 g, 1.98 mmol)
in A^A^-dimethylformamide (10 ml) was treated
with sodium hydride (0.43 g, 17.92 mmol) for
20 min. Then, ethyl iodide (10 ml) was added and
the mixture was stirred at room tem perature for 4
h. Then, it was diluted with cold water, and the
product that separated out was filtered, washed
with water, and crystallized from ethanol as color-
NMe), 7.60 (m, 3 H, A rH ), 7.90 (m, 2 H, A rH ),
9.47 (s, 1 H, CH).
C 13H 9N50 (251.2)
Calcd
C 62.14 H 3.61 N 27.88%,
Found C 62.30 H 3.80 N 27.50%.
6-Cyano-8-benzyl-7-pheny1-1,2,4-triazolo[4,3-a]-
less crystals (0.39 g, 74% yield); m.p. 182-183 °C. pyrimidin-5-one (11a)
It is identical with that obtained from a.
A suspension of 8a (0.47 g, 1.98 mmol) and po-
tassium hydroxide (0.50 g, 8.93 mmol) in A^N-di-
methylformamide (10 ml) was cooled and treated
with benzyl chloride (3.5 ml). The reaction mix-
6-Cyano-8-ethyl-7-p-methoxyphenyl-1,2,4-
triazolo[4,3-a]pyrimidin-5-one (9b)
(a)
ethyl orthoform ate (10 ml) was heated under re- poured onto crushed ice. The product that sepa-
flux for 4 h. The product that separated out was
A mixture of 8b (0.50 g, 1.87 mmol) and tri- ture was heated under reflux for 4 h, cooled and
rated was filtered, washed with water and crystal-
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1208
E. S. H. El Ashry et al. • D im roth Rearrangem ent
8-Benzyl-6-cyano-5-phenyl-1,2,4-triazolo[4,3-a]-
pyrimidin-7-one (15)
lized from ethanol as white crystals (0.30 g, 46%
yield); m.p. 213-215 °C. IR (KBr): 2212 (C =N ),
1641 cm “ 1 (CON). ’H NM R (DM SO-d6): d = 2.51
(s, 2 H, NCH 2), 7.19-7.40 (m, 6 H, A rH ), 7.52 (m,
2 H, A rH ), 7.83 (m, 2 H, A rH ), 8.91 (s, 1 H, CH).
(a) A mixture of 5 (0.60 g, 1.89 mmol) and tri-
ethyl orthoform ate (6 ml) was heated under reflux
for 1 h. The product was crystallized from ethanol
as colorless crystals (0.45 g, 73% yield); m.p. 217-
218 °C. IR (KBr): 2231 (C =N ), 1681 (CON), 1622
cm “ 1 (C=N).
C 19H n N sO (327.3)
Calcd
C 69.71 H 4.00 N 21.40%,
Found C 69.90 H 3.80 N 21.60%.
C 19H n N ,0 (327.3)
6-Cyano-5-phenyl-l,2,4-triazolo[1,5-a]-
pyrimidin-7(4H)-one (13)
Calcd
C 69.71 H 4.00 N 21.40%,
Found C 69.80 H 4.10 N 21.30%.
(a) A mixture of 8a (0.47 g, 1.98 mmol) and po-
tassium hydroxide (0.50 g, 8.93 mmol) in ethanol
(25 ml) was heated under reflux for 3 h. The reac-
tion mixture was cooled and neutralized with di-
lute HC1. The product that separated out was fil-
tered, and crystallized from ethanol as colorless
crystals (0.32 g, 68% yield); m.p. 325-328 °C. IR
(KBr): 3114 (NH), 2230 (C =N ), 1671 (CON), 1606
cm-1 (C=N).
(b) A mixture of 5 (0.60 g, 1.89 mmol) and for-
mic acid (6 ml) was heated under reflux for 1 h.
The product was crystallized from ethanol (0.46 g,
74% yield); m.p. 217-219 °C. It is identical with
that obtained by method a.
6-Cyano-4-methyl-5-phenyl-l,2,4-triazolo[1,5-a]-
pyrimidin-7-one (17)
C 12H 7N ,0 (237.2)
A suspension of 13 (0.47 g, 1.98 mmol) and po-
tassium carbonate (1.0 g, 7.24 mmol) in N,N-d\-
methylformamide (20 ml) was treated with methyl
iodide (1.0 ml). The reaction mixture was stirred
for 6 h, and then processed as for 10. The product
was crystallized from ethanol as colorless crystals
(0.31 g, 62% yield); m.p. 157-160 °C. IR (KBr):
2239 (C =N ), 1690 (CON), 1603 cm " 1 (C=N).
Calcd
C 60.75 H 2.97 N 29.53%,
Found C 60.50 H 3.10 N 29.60%.
(b) Compound 8a (0.47 g, 1.98 mmol) was fused
above its melting point for 1 h. The solidified pro-
duct was triturated with ethanol, filtered off and
recrystallized from ethanol (0.32 g, 68% yield);
m.p. 325-327 °C. It is identical with the product
from m ethod a.
C 13H 9N50 (251.2)
Calcd
C 62.14 H 3.61 N 27.88%,
Found C 62.40 H 3.80 N 27.60%.
6-Cyano-8-methyl-5-phenyl-l,2,4-triazolo[4,3-a]-
pyrimidin-7-one (14)
6-Cyano-4-methyl-7-phenyl-l,2,4-triazolo[1,5-a]-
pyrimidin-5-one (18)
(a) A mixture of 4 [28] (0.48 g, 1.99 mmol) in
DMF (3 ml) and triethyl orthoform ate (6 ml) was
heated under reflux for 1 h, whereby the product
precipitated out during the heating. The product
was crystallized from ethanol as pale yellow crys-
tals (0.31 g, 62% yield); m.p. 287-289 °C. IR
(KBr): 2231 (C =N ), 1677 (CON), 1621 cm " 1 (C=
N). 'H NM R (CDC1,): (5 = 3.70 (s, 3 H, NMe), 7.60
(s, 5 H, A rH ), 8.10 (s, 1 H, CH).
A mixture of 14 (0.50 g, 1.99 mmol) and potas-
sium hydroxide (0.50 g, 8.92 mmol) in absolute
ethanol (25 ml) was heated under reflux for 2 h.
The reaction mixture was processed as for 13 and
the product was crystallized from ethanol as color-
less crystals (0.33 g, 66% yield); m.p. 227-228 °C.
IR (KBr): 2234 (C =N ), 1674 (CO N ), 1620 c ir r 1
(C=N).
C 13H 9N ,0 (251.2)
Calcd
C 62.14 H 3.61 N 27.88%,
C n H 9NsO (251.2)
Found C 62.40 H 3.80 N 27.50%.
Calcd
C 62.14 H 3.61 N 27.88%,
Found C 62.00 H 3.60 N 28.20%.
(b) A mixture of 4 (0.48 g, 1.99 mmol) and for-
mic acid (60 ml) was heated under reflux for 4
h. The product that separated out on cooling was
crystallized from ethanol (0.36 g, 72% yield); m.p.
287-289 °C. It is identical with the product from
method a.
4-Benzyl-6-cyano-7-phenyl-1,2,4-triazolo[1,5-a]-
pyrimidin-5-one (19)
A mixture of 15 (0.30 g, 0.92 mmol) and potas-
sium hydroxide (0.50 g, 8.92 mmol) in absolute
ethanol (25 ml) was heated under reflux for 1 h.
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E. S. H. El Ashry et al. ■D im roth Rearrangem ent
1209
The reaction mixture was processed as before and
the product was crystallized from ethanol as color-
less crystals (0.23 g, 77% yield); m.p. 190 °C. IR
(KBr): 2228 ( O N ) , 1670 (CON), 1619 cm “ 1 (C=
N).
(0.40 g, 65% yield); m.p. 237-239 °C [Lit.[29]
m.p. 235 °C],
6-Cyano-2,5-diphenyl-l,2,4-triazolo[1,5-a]-
pyrimidin-7(4H)-one (25)
C 19H 13N50 (327.3)
(a) A suspension of 23 (0.62 g, 1.97 mmol) in
acetic acid (10 ml), was treated with bromine (5
ml) in acetic acid (2 ml) dropwise and the reaction
mixture was stirred for 4 h. Then, it was diluted
with water and the product was filtered and crys-
tallized from ethanol. TLC showed the presence
of a major spot and two minor ones. One of the
m inor spots was identified to be for compound 24.
The major product was separated by fractional
crystallization as colorless crystals (0.45 g, 73%
yield); m.p. > 300 °C. IR (KBr); 3225 (NH), 2227
(C =N ), 1666 (CON), 1615 cm “ 1 (C=N). lH NM R
(DM SO-d6): (3 = 7.62 (m, 6 H, A rH ), 7.66 (s, 1 H,
NH), 7.84 (m, 2 H, A rH ), 8.16 (m, 2 H, A rH ).
Calcd
C 69.71 H 4.00 N 21.40%,
Found C 69.60 H 4.00 N 21.20%.
7-Imino-5-phenyl-1,2,4-triazolo[1,5-a]pyrimidine
(22)
A mixture of 8a (0.47 g, 1.89 mmol) and potas-
sium hydroxide (2.0 g, 35.71 mmol) in ethanol (20
ml) was heated under reflux for 2 h. The reaction
mixture was cooled and neutralized with dilute
HC1. The product that separated out was filtered,
and crystallized from ethanol as colorless crystals
(0.35 g, 84% yield); m.p. 303-306 °C. IR (KBr):
3314 (NH), 1606 cm “ 1 (C=N). *H NM R (DMSO-
d6): (3 = 6.80 (s, 1 H, CH), 7.54 (m, 3 H, A rH ), 8.06
(m, 2 H, A rH ), 8.20 (s, 2 H, NH), 8.48 (s, 1 H, CH).
C 18H „ N 50 (313.3)
Calcd
C 69.00 H 3.54 N 22.35%,
Found C 68.60 H 3.80 N 22.10%.
C n H 9N 5 (211.2)
Calcd
C 62.55 H 4.30 N 33.16%,
(b) A mixture of 24 (0.30 g, 0.96 mmol) and po-
tassium hydroxide (0.50 g, 8.93 mmol) in absolute
ethanol (25 ml) was heated under reflux for 2 h.
The reaction mixture was processed as for 13. The
product was crystallized from ethanol (0.20 g, 67%
Found C 62.50 H 4.30 N 33.30%.
Attempted Dimroth rearrangement with acid
W hen compound 15 (0.20 g, 0.61 mmol) in acetic
acid (10 ml) and HCl (1 ml) were boiled under yield); m.p. > 300 °C. It is identical with the pro-
reflux for 4 h, then diluted with water, the product
formed was recovered unchanged.
duct from method a.
6-Cyano-8-methy1-3,7-diphenyl-l,2,4-triazolo-
[4,3-a]pyrimidin-5-one (21)
Benzaldehyde 5-cyano-4-oxo-6-phenyl-3,4-
dihydropyrimidin-2-yl)hydrazone (23)
A suspension of 24 (0.62 g, 1.98 mmol) and po-
tassium carbonate (0.50 g, 3.62 mmol) in N,N-&\-
methylformamide (10 ml), was treated with
methyl iodide (3 ml). The reaction mixture was
processed as before and the product was crystal-
lized from ethanol as colorless crystals (0.40 g,
62% yield); m.p. 175-178 °C. IR (KBr): 2216
(C =N ), 1680 cm“ 1 (OCN). ’H NM R (CDC13): (3 =
4.08 (s, 3 H, NMe), 7.55 (m, 6 H, A rH ), 7.84 (m,
2 H, A rH ), 8.02 (m, 2 H, Ar-H).
A suspension of 6 [28] (0.45 g, 1.98 mmol) in
ethanol (10 ml), benzaldehyde (1 ml) and 2 drops
of acetic acid was heated under reflux for 1 h. D ur-
ing the reaction period the hydrazine dissolved
with the precipitation of the hydrazone. The pro-
duct was filtered and crystallized from ethanol as
pale yellow crystals (0.41 g, 66% yield); m.p. 299-
301 °C [Lit.[28] m.p. 299 °C].
C 19H 13NsO (327.3)
6-Cyano-3,7-dipheny1-1,2,4-triazolo[4,3-a]-
Calcd
C 69.71 H 4.00 N 21.40%,
pyrimidin-5(8H)-one (24)
Found C 69.40 H 4.10 N 21.10%.
A solution of 2
m
solution of ferric chloride in
ethanol (50 ml) was added dropwise to a boiling
solution of 23 (0.62 g, 1.97 mmol) in ethanol (10
ml), and heating was continued for 15 min. The
reaction mixture was cooled and diluted with
water. The product that separated out was filtered
and crystallized from ethanol as colorless crystals
8-Benzyl-6-cyano-3,7-dipheny1-1,2,4-triazolo-
[4,3-a]pyrimidin-5-one (28)
A suspension of 24 (0.62 g, 1.98 mmol) and po-
tassium hydroxide (0.28 g, 5.0 mmol) in N,N-di-
methylformamide (10 ml), was cooled and treated
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1210
E. S. H. El Ashry et al. ■Dimroth Rearrangem ent
with benzyl chloride (3.5 ml). The reaction mix- Benzaldehyde (3-benzyl-5-cyano-4-oxo-6-phenyl-
3,4-dihydropy rim idin-2-yI)hydrazone (32)
ture was processed as before and the product was
crystallized from ethanol as colorless crystals
(0.46 g, 58% yield); m.p. 213-215 °C. IR (KBr):
2213 ( O N ) , 1698 c ir r 1 (CON).
A suspension of 5 (0.60 g, 1.89 mmol) in ethanol
(10 ml) and benzaldehyde (1 ml) with 2 drops of
acetic acid was heated under reflux for 1 h. The
reaction was processed as before. The product was
crystallized from ethanol as yellow needles (0.56 g,
73% yield); m.p. 220-222 °C. IR (KBr): 3311
(NH), 2222 (C = N ), 1684 (CON), 1623 cm “ 1 (C=
N).
C2SH 17N ,0 (403.4)
Calcd
C 74.43 H 4.25 N 17.35%,
Found C 74.10 H 4.30 N 17.00%.
6-Cyano-4-m ethy 1-2,5-dipheny 1-1,2,4-triazolo-
[1,5-a]pyrim idin-7-one (29)
C2sH 19NsO (405.4)
Caicd
C 74.06 H 4.72 N 17.28%,
A suspension of 25 (0.62 g, 1.98 mmol) and po-
tassium carbonate (0.50 g, 3.62 mmol) in N,7V-di-
m ethylformamide (10 ml), was treated with
methyl iodide (3 ml). The reaction mixture was
processed as before and the product was crystal-
lized from ethanol as colorless crystals (0.40 g,
62% yield); m.p. 299-301 °C. IR (KBr): 2210
(C =N ), 1697 cm “ 1 (CON). 'H NMR (CDC1,): 6 =
3.77 (s, 3 H, NMe), 7.52 (m, 6 H, A rH ), 7.70 (m,
2 H, ArH ), 8.40 (m, 2 H, A rH).
Found C 74.30 H 4.80 N 17.00%.
p-N itrobenzaldehyde (3-benzyl-5-cyano-4-oxo-6-
pheny 1-3,4-dihydropyrim idin-2-yI)hydrazone (33)
A suspension of 5 (0.60 g, 1.89 mmol) in ethanol
(10
ml)
and
p-nitrobenzaldehyde
(0.30 g,
1.99 mmol) with 2 drops of acetic acid was heated
under reflux for 1 h. The product was crystallized
from ethanol as yellow crystals (0.52 g, 61% yield);
m.p. 289-292 °C. IR (KBr): 3310 (NH), 2223
(C =N ), 1685 (CON), 1625 cm “ 1 (C=N).
C 19H n N ,0 (327.3)
Calcd
C 69.71 H 4.00 N 21.40%,
C25H 18N60 3 (450.4)
Found C 69.50 H 4.20 N 21.20%.
Calcd
C 66.66 H 4.03 N 18.66%,
Found C 66.80 H 4.20 N 18.40%.
Benzaldehyde (5-cyano-3-methyl-4-oxo-6-phenyl-
3,4-dihydropyrim idin-2-yl) hydrazone (30)
6-Cyano-8-methy1-3,5-dipheny 1-1,2,4-triazolo-
[4,3-a]pyrim idin-7-one (34)
A suspension of 4 [28] (0.48 g, 2.11 mmol) in
ethanol (10 ml) and benzaldehyde (1 ml) with 2
drops of acetic acid was heated under reflux for 1
h. During the reaction period the hydrazine dis-
solved with the formation of the hydrazone. The
product was filtered and crystallized from ethanol
as yellow crystals (0.42 g, 60% yield); m.p. 220-
221 °C [Lit.[28] m.p. 220 °C],
A mixture of 30 (0.50 g, 1.52 mmol) and thionyl
chloride (0.5 ml) was heated under reflux for 3 h.
The reaction mixture was cooled and poured onto
crushed ice. The product separated was filtered,
washed with water and crystallized from ethanol
as colorless crystals (0.30 g, 60% yield); m.p. 181 —
183 °C. IR (KBr): 2237 (C =N ), 1698 (CON), 1630
cm “ 1 (C=N). ’H NM R (CDC13): <3 = 3.85 (s, 3 H,
NMe), 6.96-7.30 (m, 10 H, A rH).
p-N itrobenzaldehyde (5-cyano-3-methyl-4-oxo-6-
phenyl-3,4-dihydropyrim idin-2-yl)hydrazone (31)
C 19H n NsO (327.3)
Calcd
C 69.71 H 4.00 N 21.40%,
Found C 69.70 H 4.10 N 21.00%.
A suspension of 4 (0.48 g, 2.11 mmol) in ethanol
(10
ml)
and
p-nitrobenzaldehyde
(0.30 g,
1.99 mmol) with 2 drops of acetic acid was heated
under reflux for 1 h. The mixture was processed
as before. The product was crystallized from etha-
nol as yellow crystals (0.42 g, 53% yield); m.p.
253-254 °C. IR (KBr): 2220 (C =N ), 1678 (CON),
1620 cm " 1 (C=N).
6-Cyano-8-m ethyl-3-p-nitrophenyl-l,2,4-
triazolo[4,3-a]pyrim idin-7-one (35)
A mixture of 31 (0.55 g, 1.47 mmol) in thionyl
chloride (5 ml) was heated under reflux for 3 h.
The reaction mixture was processed as above and
the product was crystallized from ethanol as pale
yellow crystals (0.30 g, 55% yield); m.p. 264-
265 °C. IR (KBr): 2238 (C =N ), 1682 (CON), 1624
cm -1 (C=N).
C 19H 14N60 3 (374.4)
Calcd
C 60.96 H 3.77 N 22.45%,
Found C 60.80 H 3.90 N 22.70%.
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E. S. H. El Ashry et al. • Dim roth Rearrangement
C19H 12N60 3 (372.3)
1211
288 °C. IR (KBr): 2234 (C=N), 1684 (CON), 1631
Calcd
C 61.29 H 3.25 N 22.56%,
cm-1 (C=N).
Found C 61.10 H 3.30 N 22.30%.
6-Cyano-4-methyl-2-p-nitrophenyl-7-phenyl-l,2,4-
triazolofl,5-a]pyrimidin-5-one (39)
8-Benzyl-6-cyano-3,5-dipheny1-1,2,4-triazolo-
[4,3-a]pyrimidin-7-one (36)
(a) A suspension of 31 (0.37 g, 1.0 mmol) in ace-
tic acid (10 ml), was treated with bromine (5 ml)
in acetic acid (20 ml) dropwise addition and the
reaction mixture was stirred for 4 h. Then, it was
processed as before. The product was crystallized
from ethanol as pale yellow crystals, m.p. 260 °C
(0.29 g, 78% yield). IR (KBr): 2234 (C=N), 1689
(CON), 1629 cm“ 1 (C=N).
A mixture of 32 (0.60 g, 1.48 mmol) in thionyl
chloride (5 ml) was heated under reflux for 3 h.
The reaction mixture was processed as before. The
product was crystallized from ethanol as colorless
crystals (0.35 g, 58% yield); m.p. 140-143 °C. IR
(KBr): 2235 (C=N), 1683 (CON), 1621 cm' 1 (C=
N).
C19H 12N60 3 (372.3)
C2SH 17NS0 (403.4)
Calcd
C 61.29 H 3.25 N 22.56%,
Calcd
C 74.42 H 4.25 N 17.36%,
Found C 61.40 H 3.20 N 22.80%.
Found C 74.50 H 4.20 N 17.40%.
(b) A mixture of 35 (0.74 g, 1.99 mmol) and po-
tassium hydroxide (0.50 g, 8.93 mmol) in absolute
ethanol (25 ml) was heated under reflux for 2 h.
The reaction mixture was processed as before. The
product crystallized from ethanol as colorless crys-
tals; m.p. 260 °C. It was found to be identical with
the product from method a.
8-Benzyl-6-cyano-3-p-nitrophenyl-5-phenyl-l,2,4-
triazolo[4,3-a]pyrimidin-7-one (37)
A suspension of 33 (0.60 g, 1.33 mmol) in thio-
nyl chloride (5 ml) was heated under reflux for 3
h. The reaction mixture was processed as before.
The product was crystallized from ethanol as col-
orless crystals (0.38 g, 64% yield); m.p. 210-
212 °C. IR (KBr): 2240 (C=N), 1694 (CON), 1627
cm-1 (C=N).
4-Benzyl-6-cyano-2,7-diphenyl-l ,2,4-triazolo-
[1,5-a]pyrimidin-5-one (40)
C25H 16N60 3 (448.4)
(a) A suspension of 32 (0.60 g, 1.48 mmol) in
acetic acid (10 ml), was treated with bromine (5
ml) in acetic acid (20 ml) dropwise addition and
the reaction mixture was processed as before. The
product was crystallized from ethanol as colorless
crystals (0.45 g, 75% yield); m.p. 245-247 °C. IR
(KBr): 2226 (C=N), 1674 (CON), 1620 c irr1 (C=
N).
Calcd
C 66.96 H 3.60 N 18.73%,
Found C 67.10 H 3.70 N 18.30%.
6-Cyano-4-methyl-2,7-diphenyl-l ,2,4-triazolo-
[1,5-a]pyrimidin-5-one (38)
(a)
A suspension of 30 (0.50 g, 1.52 mmol) in
acetic acid (10 ml), was treated with bromine (5
ml) in acetic acid (20 ml) dropwise addition and
the reaction mixture was stirred for 4 h. Then, it
was diluted with water and the product formed
was filtered and crystallized from ethanol as color-
less crystals, m.p. 286-288 °C (0.35 g, 70% yield).
IR (KBr): 2235 (C=N), 1684 (CON), 1631 cm“ 1
(C=N).
C25H 17N50 (403.4)
Calcd
C 74.42 H 4.25 N 17.36%,
Found C 74.20 H 4.00 N 17.40%.
(b) A mixture of 36 (0.40 g, 0.99 mmol) and po-
tassium hydroxide (0.50 g, 0.93 mmol) in absolute
ethanol (25 ml) was heated under reflux for 2 h.
The reaction mixture was processed as before;
m.p. 245-247 °C. IR (KBr): 2226 (C=N), 1674
(CON), 1620 cm-1 (C=N). The product was found
to be identical with that obtained by method a.
C 19H n N.O (327.3)
Calcd
C 69.71 H 4.00 N 21.40%,
Found C 69.90 H 3.80 N 21.00%.
(b) A mixture of 34 (0.60 g, 1.83 mmol) and po-
tassium hydroxide (0.50 g, 8.93 mmol) in absolute
ethanol (25 ml) was heated under reflux for 2 h.
The reaction mixture was processed as for 13. The
2-(N-Acetylbenzylidenehydrazino)-5-cyano-3-
methyl-6-phenyl-3,4-dihydropyrimidin-4-one (41)
A cold solution of 30 (0.50 g, 1.52 mmol) in dry
product was filtered crystallized from ethanol as pyridine (5 ml), was treated with acetic anhydride
colorless crystals (0.43 g, 72% yield); m.p. 286-
(4 ml). The reaction mixture was kept overnight
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1212
E. S. H. El Ashry et al. ■Dimroth Rearrangement
at 20 °C with occasional stirring and then poured
onto crushed ice. The product that separated was
yellow crystals (0.32 g, 72% yield); m.p. 131 —
134 °C. IR (KBr): 2226 (O N ), 1696 and 1650
filtered, washed with water and dried. It was crys- cm- 1 (CON).
tallized from ethanol as yellow crystals (0.46 g,
C27H21N ,0 2 (447.5)
Calcd C 72.47 H 4.73 N 15.65%,
82% yield); m.p. 222 °C. IR (KBr): 2228 (O N ),
1697 and 1640 cm“ 1 (CON). 'H NMR (CDC13):
(3 = 2.20 (s, 3 H, COMe), 3.47 (s, 3 H, NMe), 6.81
(m, 2 H, ArH), 6.90 (s, 1 H, N=CH), 7.20 (m, 5 H,
ArH), 7.52 (m, 3 H, ArH).
Found C 72.20 H 5.00 N 15.40%.
(b)
A suspension of 32 (0.40 g, 0.99 mmol) in
acetic anhydride (4 ml) was heated under reflux
on a boiling water bath for 3 h. The reaction mix-
ture was cooled and poured onto crushed ice. The
product that separated was filtered, washed, dried
and crystallized from ethanol as yellow crystals,
m.p. 131-134 °C. It was found to be identical
with 42.
C21H 17N50 2 (371.4)
Calcd
C 67.91 H 4.61 N 18.86%,
Found C 67.90 H 5.00 N 18.50%.
2-(N-Acetylbenzylidenehydrazino)-3-benzyl-5-
cyano-6-phenyl-3,4-dihydropyrimidin-4-one (42)
A cold solution of 32 (0.40 g, 0.99 mmol) in dry
pyridine (5 ml), was treated with acetic anhydride
(4 ml). The reaction mixture was processed as be-
Acknowledgment
Thanks are due to Klaus Hagele, Universität
fore. The product was crystallized from ethanol as Konstanz for making available the mass spectra.
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