Synthesis of 1,2,4-triazolo[4,3-a]pyrimidine derivatives by cyclocondensation of a 2-thioxopyrimidin-4(3H)-one with hydrazonoyl halides

Article abstract of DOI:10.1002/hlca.200390073

The reaction of 1,2-dihydro-6-(phenylamino)-2-thioxopyrimidin-4(3H)one (16) with N-arylhydrazonoyl halides 15 in CHCl₃ in the presence of Et₃N under reflux afforded the corresponding 1,2,4-triazolo[4,3-a]-pyrimidin-5-ones of type 20 in good yields (Scheme 3). The structure of one of the derivatives, 20d, has been established by X-ray crystallography. Conceivable reaction mechanisms are discussed in Schemes 3 and 4. The products of type 20 easily undergo reactions with electrophiles such as benzenediazonium chloride, chloroacetyl chloride, and NaNO₂ in AcOH to give 6-phenylazo, 6-chloroacetyl, and 6-nitroso derivatives 21, 23, and 25, respectively (Scheme 5).

Full text of DOI:10.1002/hlca.200390073

Helvetica Chimica Acta Vol. 86 (2003)
739
Synthesis of 1,2,4-Triazolo[4,3-a]pyrimidine Derivatives by
Cyclocondensation of a 2-Thioxopyrimidin-4(3H)-one with Hydrazonoyl
Halides
by Nehal M. Elwan, Enas M. Awad1)2), and Hamdi M. Hassaneen*
Department of Chemistry, Faculty of Science, University of Cairo, Giza
and
Anthony Linden and Heinz Heimgartner*
Organisch-chemisches Institut der Universit‰t Z¸rich, Winterthurerstrasse 190, CH-8057 Z¸rich
The reaction of 1,2-dihydro-6-(phenylamino)-2-thioxopyrimidin-4(3H)one (16) with N-arylhydrazonoyl
halides 15 in CHCl3 in the presence of Et3N under reflux afforded the corresponding1,2,4-triazolo[4,3- a]-
pyrimidin-5-ones of type 20 in good yields (Scheme 3). The structure of one of the derivatives, 20d, has been
established by X-ray crystallography. Conceivable reaction mechanisms are discussed in Schemes 3 and 4. The
products of type 20 easily undergo reactions with electrophiles such as benzenediazonium chloride, chloroacetyl
chloride, and NaNO2 in AcOH to give 6-phenylazo, 6-chloroacetyl, and 6-nitroso derivatives 21, 23, and 25,
respectively (Scheme 5).
Introduction. Recently, the chemistry of 1,2,4-triazolo[4,3-a]pyrimidines 1 has
been reviewed comprehensively [1]. The other three isomeric 1,2,4-triazolopyrimidines
are 2 [2], 3 [3], and 4 [4] with [1,5-a], [4,3-c], and [1,5-c] fusions, respectively, of the two
heterocyclic systems. As with the other classes, derivatives of 1 have found broad
applications in biology and medicine as well as in photography [5].
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
1
2
3
4
Chemically, one of the most remarkable features of compounds of type 1 is their
tendency to rearrange to give [1,5-a] isomers 2 under acidic and basic conditions as well
as by heating[6]. This isomerization via ring-opening/ring-closure processes is well-
known as the Dimroth rearrangement [7] and appears often as a difficulty in the
preparation of 1. Another problem is the selectivity of the ringclosure process, e.g., in
the frequently used cyclizations of 2-hydrazinopyrimidines with C1 buildingblocks
(Scheme 1). For example, heating 5 in HCOOH to 50 608 for 1 h gave a mixture of the
isomeric 1,2,4-triazolo[4,3-a]pyrimidine derivatives 6 and 7, in addition to their
1
)
)
Part of the Ph.D. thesis of E.M.A., University of Cairo, 2001. Present address: National Research Centre,
Tahrir Street, Dokki, Giza, Egypt.
Swiss Federal Scholar (−Bundesstipendiatin×) at the University of Z¸rich, October 1998 June 2000.
2

740
Helvetica Chimica Acta Vol. 86 (2003)
Scheme 1
H
N
H
H
H
N
O
N
Me
N
O
N
N
NH2
HCOOH
N
N
[8]
N
N
N
50-60°, 1 h
Me
O
Me
5
6 (42%)
7 (14.5%)
O
H
N
H
O
+
N
N
H
H
N
Me
8 (43.5%)
precursor 8 [8]. Cyclization of 8 by ringclosure via N(1) or N(3) of the pyrimidine ring
and dehydration leads to 7 or 6, respectively.
A different synthetic approach to the ringskeleton 1 is the heterocyclization of a
pyrimidine 9 with a CÀNÀN buildingblock, e.g., the chemo- and regioselective 1,3-
dipolar cycloaddition of diaryl-nitrile imines generated in situ from 10, leadingto 11 [9]
(Scheme 2). An intramolecular variant via 1,5-dipolar electrocyclization of a nitrile
imine is also known [10]. On the other hand, pyrimidines bearinga leavinggroup at
C(2) react with acid hydrazides [11], semicarbazide [12], thiosemicarbazide [13], and
hydrazonoyl bromides [14]. For example, the reaction of pyrimidine derivative 12 with
hydrazide 13 (R ˆ alkyl) gave, after heating the intermediate 2-hydrazinopyrimidine in
the presence of phenol, 3-alkyl-7-methyl-1,2,4-triazolo[4,3-a]pyrimidin-5-one 14 [15]
(Scheme 2), whereas, with benzohydrazide under the same conditions, 5-methyl-3-
phenyl-1,2,4-triazolo[4,3-a]pyrimidin-7-one was formed [16]. Recently, 5-substituted
1,2,4-triazolo[4,3-a]pyrimidines of type 1 have been prepared by the reaction of a 3-
(dimethylamino)prop-2-en-1-one with 3-amino-1H-1,2,4-triazole [17].
One of us has a long-lasting interest in using heterocyclic compounds containing a
thiourea moiety in the synthesis of fused heterocycles (cf. [18][19]). For example, it has
been shown that hydrazonoyl halides 15 react with such heterocycles to give, in general,
only one of the two possible isomers of the fused products. This selectivity has been
explained by the assumption that one of the two ring-N-atoms is more basic and more
nucleophilic (cf. [20][21]). Therefore, in the case of 2-thioxopyrimidin-4-one
derivatives of type 16, the ringclosure is expected to occur at N(1), as N(3) is more
desactivated by the neighboring CˆO group. On the other hand, the dehydrocycliza-
tion of intermediate 8 (Scheme 1) yielded 6 as the major product, and the expected
isomer 7 was obtained as the minor one.
Recently, first examples of the reaction of 6-(phenylamino)-2-thioxopyrimidin-
4(3H)-one (16) and C-(ethoxycarbonyl)hydrazonoyl chlorides leadingto 5-oxo-1,2,4-
triazolo[4,3-a]pyrimidine-3-carboxylates have been described [22]. In the present

Helvetica Chimica Acta Vol. 86 (2003)
741
Scheme 2
Ar'
R
N
R
N
Cl
N
Et3N
-HCl
NHAr'
N
[9]
N
N
Ar
N
Ar
9
10
11
H
H
N
O
N
SEt
O
Me
N
NH2
N
[15]
N
R
N
H
N
Me
R
O
12
13
14
O
X
NH
NHAr
R
N
PhHN
N
H
S
16
15 (X = Cl, Br)
study, we report the generalization of the reaction of 16 with different hydrazonoyl
halides of type 15. The latter are known as very useful CÀNÀN buildingblocks that can
react either via substitution by nucleophiles followed by cyclization (cf. [18][19][23])
or via intermediate nitrile imines by 1,3-dipolar cycloaddition (cf. [9][24 27]).
Results and Discussion.
The reactions of 16 with equimolar amounts of
hydrazonoyl halides 15a 15h were carried out in refluxingCHCl in the presence of
3
Et3N. When all 15 had disappeared (4 6 h, TLC), the mixture was worked up by
evaporatingthe solvent and treatingthe residue with MeOH. In all cases, a single
product was obtained, which was recrystallized from a suitable solvent to give orange to
yellow crystals. Both mass spectrometry and elemental analyses confirmed the absence
of sulfur in all products (cf. [18][19]). Therefore, structures 17 and 18 (Scheme 3),
which are the products of a nucleophilic substitution of X of 15 by the S-atom of 16 and
the cyclization product of the intermediate3), respectively, were ruled out.
3
)
Formally, 18 is the product of the 1,3-dipolar cycloaddition of the correspondingnitrile imine, generated in
situ from 15 by elimination of HX, onto the CˆS group. Although nonenolizable CˆS groups belong to
the most reactive dipolarophiles known, and, therefore, thioketones are called −superdipolarophiles× [28],
it is rather unlikely that 18 is formed by this mechanism as nitrile imines like other 1,3-dipoles are
easily protonated by OH, SH, and NH compounds (cf. [26]). For this reason, a nitrile imine and 16 would
react to give the 1,3-adduct 17.

Scheme 3
Ar
H
H
N
N N
PhHN
N
S
N
PhHN
N
PhHN
S
Et3N
-HX
NHAr
R
15a-h
S
H
NH
R
N
NH
O
O
O
16
17
18
R
HS
N
N
NH
N
R
N
N
PhHN
PhHN
Ar
Ar
a)
b)
-H2S
a)
N
N
Ar
S
H
PhHN
N
N
O
O
N
H
R
19
B
N
b)
Ar
Ar
O
PhHN
N
PhHN
N
N
N
NH
SH
N
-H2S
A
N
N
R
R
O
O
20a-h
C
15, 20 R / Ar
________________________
15, 20 R / Ar
________________________
a
b
c
d
MeOCO / Ph
e
f
g
h
PhCH=CH / Ph
MeCO / Ph
MeOCO / 4-MeC6H4
MeOCO / 4-ClC6H4
EtOCO / 4-MeOC6H4
PhNHCO / Ph
2-thienyl / 4-NO2C6H4

Helvetica Chimica Acta Vol. 86 (2003)
743
However, the analytical and spectroscopic data of the isolated products were in
accordance with structures 19 or 20 formed via a cyclocondensation of 15 and 16 by
elimination of H2S. For example, the product from the reaction with 15a showed two
intense IR absorptions (in KBr) at 1744 and 1692 cmÀ1, which are characteristic for an
acetate and a pyrimidinone. In the 1H-NMR spectrum (CDCl3), three singlets appeared
at 7.05 (NH), 5.45 (HÀC(5) of pyrimidin-4-one), and 4.06 ppm (MeOCO), in addition
to a multiplet at 8.15 7.3 ppm (10 arom. H). In Scheme 3, reaction mechanisms leading
to 19 and 20 are proposed. The common intermediate A can be generated from the
initially formed thiohydrazonate derivative 17 by an S ! N migration of the pyrimidine
ring via the spirocyclic intermediate 18. Cyclization of A via nucleophilic attack of N(1)
(Route a) or N(3) (Route b) of the pyrimidin-4-one onto the thioamide C-atom leads to
B and C, respectively. Elimination of H2S then yields either 19 or 20.
A different reaction mechanism via nucleophilic attack of N(1) or N(3) of 16 at the
hydrazonoyl halide 15 to give the substitution products D and F, respectively, is
formulated in Scheme 4. Cyclization of these intermediates could lead to E and G,
which, by elimination of H2S, could give 19 and 20, respectively. Although it is difficult
to distinguish between the mechanisms in Scheme 3 and 4, those via D/Fare unlikely for
the followingreasons: a) although amidrazones of type D and F are known to be stable
(cf. [29 31]), all attempts to isolate them from the reaction mixture failed; b) reactions
of 2-thiouracil derivatives with various halogen compounds gave, in all reported cases,
only the S-substituted products (cf. [32 34]). Therefore, we strongly favor the
mechanism depicted in Scheme 3.
Unfortunately, neither the spectroscopic data4) of the products nor the proposed
reaction mechanisms allowed discrimination between structures 19 and 20. For this
Scheme 4
R
R
N
NHAr
S
N
PhHN
N
N
N
PhHN
Ar
SH
19
NH
N
-H2S
H
O
O
D
E
15 + 16
H
H
N
Ar
SH
PhHN
S
R
PhHN
N
O
N
NHAr
N
20
N
N
N
-H2S
O
R
G
F
All products showed a singlet at ca. 5.5 ppm in the 1H-NMR spectrum, assignable to HÀC(5) of the
pyrimidin-4-one moiety and, in the IR spectrum, absorption bands near 3280 and 1700 cmÀ1 for an NH and
amide CO group, respectively.
4
)

744
Helvetica Chimica Acta Vol. 86 (2003)
Figure. ORTEP Plot [35] of the molecular structure of 20d: disordered conformation A (arbitrary numberingof
the atoms; 50% probability ellipsoids)
reason, the molecular structure of the product obtained with 15d has been established
by X-ray crystallography as the 1,2,4-triazolo[4,3-a]pyrimidin-5-one derivative 20d (Fig.).
In the structure of 20d, the EtO atoms of the ethyl ester group are disordered over
two positions that are related by a ca. 1808 rotation about the O(11)ÀC(12) bond, with
relative site occupation factors of 0.542 :0.458. The plane of the OˆCÀO moiety is
almost orthogonal to the ring plane (torsion angle O(10)ÀC(10)ÀC(1)ÀN(2)
76.6(3)8). The six-membered heterocyclic ringshows evidence for strongbond
delocalization in that the CˆO bond is slightly elongated (1.248(2) ä), and most of the
lengths of the ring bonds approach those normally found in Ph rings. Neither the
aromatic residue at N(3) nor PhNH at C(6) is coplanar with the heterocyclic system;
the angles between the planes are 44.59(8) and 13.70(7)8, respectively. The amine
group (N(6)H) of the molecule forms an intermolecular H-bond with O(8) of the

Helvetica Chimica Acta Vol. 86 (2003)
745
amide CˆO group of a neighboring molecule. The interactions link the molecules into
infinite one-dimensional chains that run parallel to the y-axis and have a graph-set
motif of C(6) [36].
In analogy to [22], the prepared 7-(phenylamino)-1,2,4-triazolo[4,3-a]pyrimidin-5-
ones 20 undergo smooth reactions with electrophiles leading to C(6)-functionalized
derivatives. For example, 20f was readily coupled with an equimolar amount of
benzenediazonium chloride to give the corresponding 6-(phenylazenyl) derivative 21
as the only product (Scheme 5). The structure of 21 was established on the basis of the
1
elemental analysis and spectroscopic data (IR, H-NMR, MS). Furthermore, the
structure was confirmed by an independent synthesis via the reaction of 1,2-dihydro-6-
(phenylamino)-5-(phenyldiazenyl)-2-thioxopyrimidin-4(3H)-one [37] with 15f.
Scheme 5
Ph
PhHN
N
N
N
N
R
O
20a, f
NaNO2
AcOH
PhN2Cl
Ph
Ph
ClCH2COCl
Ph
PhHN
N
O
PhHN
N
O
N
N
N
N
N
N
N
N
Ph
N
O
PhHN
ClH2C
N
N
R
R
N
N
23 (R = MeOCO)
21 (R = MeCO)
R
O
O
22 (R = MeOCO)
Acylation of 20a with ClCH2COCl furnished the corresponding6-(chloroacetyl)
derivative 22, and nitrosation with NaNO2 in AcOH gave the corresponding 6-nitroso-
1,2,4-triazolo[4,3-a]pyrimidine derivative 23 in excellent yield. The same compound
was obtained after treatment of 16 with NaNO2 in AcOH (cf. [37]) and reaction of the
intermediate with hydrazonoyl chloride 15a (Scheme 5).
In conclusion, we have shown that the reaction of 16 with differently substituted
hydrazonoyl halides 15 is a general approach to 1,2,4-triazolo[4,3-a]pyrimidin-5-ones of
type 20, which can be further substituted at C(6) by reactions with electrophiles. The
initial reaction in the formation of 20 is a nucleophilic substitution of the halide of 15
rather than a 1,3-dipolar cycloaddition of an intermediate nitrile imine, in contrast to
reactions with N-substituted 1H-pyrimidinethiones [9]. The structure of 20d was
established by X-ray crystallography. The other structures of type 20 have been
assigned on the basis of the similarity of spectroscopic data and under the assumption

746
Helvetica Chimica Acta Vol. 86 (2003)
that the regioselectivity of the cyclization in intermediate A (Scheme 3) is not
influenced by the variation of the substituents (cf. also [22]).
We thank the analytical units of our institutes for spectra and analyses. E.M.A. thanks the Swiss Federal
Government for the provision of a National Scholarship for Foreign Students.
Experimental Part
1
1. General. See [23]. IR Spectra: in KBr. H-NMR Spectra: in CDCl3. Hydrazonoyl halides (chlorides or
bromides) 15a 15c, [38], 15d [39], 15e [40], 15f [41], 15g [42], and 15h [43], and 1,2-dihydro-6-(phenylamino)-
2-thioxopyrimidin-4(3H)-one (16) [37] were prepared accordingto the procedures indicated in the literature.
2. Synthesis of 1,2,4-Triazolo[4,3-a]pyrimidin-5-ones 20. General Procedure. To a stirred soln. of 16 (1.1 g,
5 mmol) and the appropriate hydrazonoyl halide 15 (5 mmol) in CHCl3 (40 ml), Et3N (0.7 ml, 5 mmol)
was added at r.t. The mixture was refluxed until 16 disappeared (4 6 h; TLC). The solvent was evapo-
rated under reduced pressure, and the residue was treated with MeOH (10 ml). The solid formed was collected
and crystallized from a suitable solvent to give the corresponding 1,2,4-triazolo[4,3-a]pyrimidine derivative
20.
Methyl 5-Oxo-1-phenyl-7-(phenylamino)-1,2,4-triazolo[4,3-a]pyrimidine-3-carboxylate (20a). Yield 1.26 g
(70%). M.p. 1968 (AcOH). IR: 3287 (NH), 1744 (CO), 1692 (CO). 1H-NMR: 4.06 (s, MeO); 5.45 (s, HÀC(6));
.
‡
7.05 (s, NH); 7.3 8.15 (m, 10 arom. H). EI-MS: 361 (100, M ), 303 (16), 213 (46), 193 (23), 144 (73), 117 (46),
77 (76). Anal. calc. for C19H15N5O3 (361.35): C 63.15, H 4.18, N 19.38; found: C 63.21, H 4.35, N 19.30.
Methyl 1-(4-Methylphenyl)-5-oxo-7-(phenylamino)-1,2,4-triazolo[4,3-a]pyrimidine-3-carboxylate (20b).
Yield 1.41 g(75%). M.p. 225 8 (EtOH/DMF). IR: 3281(NH), 1746 (CO), 1691 (CO). 1H-NMR: 2.45 (s,
.
‡
Me); 4.10 (s, MeO); 5.49 (s, HÀC(6)); 6.80 (s, NH); 7.2 8.0 (m, 9 arom. H). EI-MS: 375 (100, M ), 316 (8),
259 (14), 227 (62), 207 (43), 144 (59), 105 (37), 73 (85). Anal. calc. for C20H17N5O3 (375.38): C 63.99, H 4.57, N
18.66; found: C 64.20, H 4.25, N 18.59.
Methyl 1-(4-Chlorophenyl)-5-oxo-7-(phenylamino)-1,2,4-triazolo[4,3-a]pyrimidine-3-carboxylate (20c).
Yield 1.39 g(70%). M.p. 232 8 (AcOH). IR: 3284 (NH), 1755 (CO), 1693 (CO). 1H-NMR: 4.10 (s, MeO);
.
‡
5.45 (s, HÀC(6)); 6.82 (s, NH); 7.2 8.2 (m, 9 arom. H). EI-MS: 395 (0.4, M ), 368 (1), 313 (1), 271 (2), 236 (9),
185 (7), 149 (11), 97 (52), 57 (100). Anal. calc. for C19H14N5O3Cl (395.81): C 57.66, H 3.57, N 17.69; found: C
57.36, H 3.29, N 17.57.
Ethyl 1-(4-Methoxyphenyl)-5-oxo-7-(phenylamino)-1,2,4-triazolo[4,3-a]pyrimidine-3-carboxylate (20d).
Yield 1.62 g(80%). M.p. 186 8 (EtOH). IR: 3280 (NH), 1740 (CO), 1690 (CO). 1H-NMR: 1.45 (t, J ˆ 7,
Me); 3.85 (s, MeO); 4.55 (q, J ˆ 7, CH2O); 5.45 (s, HÀC(6)); 6.91 (s, NH); 7.05 8.0 (m, 9 arom. H). EI-MS: 406
.
‡
(43), 405 (100, M ), 333 (4), 262 (5) 243 (7), 223 (8), 148 (4), 144 (9), 77 (7). Anal. calc. for C21H19N5O4
(405.42): C 62.21, H 4.72, N 17.28; found: C 62.12, H 4.65, N 17.21.
1-Phenyl-7-(phenylamino)-3-(2-phenylethenyl)-1,2,4-triazolo[4,3-a]pyrimidin-5-one (20e). Yield 1.58 g
.
‡
(78%) M.p. 2658 (AcOH). IR: 3315 (NH), 1668 (CO). EI-MS: 406 (24), 405 (100, M ), 328 (48), 289 (18),
261 (24), 219 (16), 144 (19), 129 (18), 91 (53). Anal. calc. for C25H19N5O (405.46): C 74.06, H 4.72, N 17.28;
found: C 74.35, H 4.54, N 17.10.
3-Acetyl-1-phenyl-7-(phenylamino)-1,2,4-triazolo[4,3-a]pyrimidin-5-one (20f). Yield 1.30 g(75%). M.p.
.
‡
2698 (EtOH/DMF). IR: 3282 (NH), 1731 (CO), 1682 (CO). EI-MS: 345 (100, M ), 229 (22), 193 (13), 144
(40), 117 (17), 77 (41). Anal. calc. for C19H15N5O2 (345.35): C 66.07, H 4.38, N 20.28; found: C 66.00, H 4.21, N
20.05.
N-Phenyl 5-Oxo-1-phenyl-7-(phenylamino)-1,2,4-triazolo[4,3-a]pyrimidine-3-carboxamide (20g). Yield
1.48 g(70%). M.p. 285 8 (DMF). IR: 3250 (NH), 3214 (NH), 1703 (CO), 1645 (CO). EI-MS: 423 (7, [M ‡
‡
1] ), 408 (15), 338 (19), 297 (13), 251 (21) 193 (33), 152 (27), 97 (72), 57 (100). Anal. calc. for C24H18N6O2
(422.43): C 68.23, H 4.29, N 19.90; found: C 68.15, H 4.25, N 19.77.
1-(4-Nitrophenyl)-7-(phenylamino)-3-(thiophen-2-yl)-1,2,4-triazolo[4,3-a]pyrimidin-5-one (20h). Yield
.
‡
1.61 g(75%). M.p. 290 8 (EtOH/DMF). IR: 3285 (NH), 1687 (CO). EI-MS: 430 (100, M ), 314 (26), 287
(45), 144 (44), 77 (29). Anal. calc. for C21H14N6O3S (430.43): C 58.59, H 3.28, N 19.53, S 7.45; found: C 58.55, H
3.12, N 19.20, S 7.30.
3. Synthesis of 3-Aceytyl-1-phenyl-7-(phenylamino)-6-(phenylazenyl)-1,2,4-triazolo[4,3-a]pyrimidin-5-one
(21). Method A. To a soln. of 20f (5 mmol) in EtOH (100 ml), NaOH (0.2 g, 5 mmol) was added. A soln. of
benzenediazonium chloride (prepared from aniline (0.5 ml, 5 mmol) and the appropriate quantities of aq. HCl

Helvetica Chimica Acta Vol. 86 (2003)
747
and NaNO2) was then added to the stirred mixture at r.t. The product precipitated on standingand was collected
by filtration and crystallized from DMF to give 21. Yield 1.75 g(78%). M.p. 248 8 (AcOH). IR: 3363 (NH), 1726
(CO), 1695 (CO). 1H-NMR: 2.88 (s; Me): 7.18 8.18 (m, 15 arom. H); 13.90 (s, NH). Anal. calc. for C25H19N7O2
(449.46): C 66.80, H 4.26, N 21.82; found: C 66.65, H 4.10, N 21.64.
Method B. Compound 21 was prepared by the same method described for the synthesis of 20 with 1,2-
dihydro-6-(phenylamino)-5-(phenylazenyl-2-thioxopyrimidin-4(3H)-one [37] in place of 16. The product was
identical to that obtained by Method A.
4. Synthesis of 6-(Chloroacetyl)-5-oxo-1-phenyl-7-(phenylamino)-1,2,4-triazolo[4,3-a]pyrimidine-3-carbox-
ylate (22). A soln. of 20a (5 mmol) in ClCH2COCl (10 ml) was heated to reflux for 3 h. Then, the mixture was
cooled to r.t., the precipitate was collected and crystallized from AcOH to give 22. Yield 1.64 g(75%). M.p. 232 8
(AcOH). IR: 3062 (NH), 1766 (CO), 1700 (CO), 1689 (CO). 1H-NMR: 4.10 (s, MeO); 5.05 (s, CH2Cl); 7.2 8.1
(m, 10 arom. H); 12.80 (s, NH). EI-MS: 439 (8), 402 (63), 388 (100), 328 (21), 288 (7), 213 (13), 170 (4), 144
(14), 77 (30). Anal. calc. for C21H16N5O4Cl (437.83): C 57.60, H 3.68, N 16.00; found: C 57.50, H 3.52, N 16.21.
5. Synthesis of Methyl 6-Nitroso-5-oxo-1-phenyl-7-(phenylamino)-1,2,4-triazolo[4,3-a]pyrimidine-3-carbox-
ylate (23). Method A. To a stirred soln. of 20a (5 mmol) in AcOH (10 ml), a conc. soln. of NaNO2 (2 gin 5 ml
H2O) was added. The solid formed was collected and crystallized from EtOH to give 23. Yield 1.37 g(70%).
.
‡
M.p. 1738 (AcOH). 1H-NMR: 4.00 (s, MeO); 7.3 8.1 (m, 10 arom. H); 11.90 (s, NH). EI-MS: 391 (0.6, M ),
359 (1), 346 (41), 288 (10), 244 (3), 213 (2), 144 (17), 129 (20), 91 (100). Anal. calc. for. C19H14N6O4 (390.35): C
58.46, H 3.61, N 21.53; found: C 58.30, H 3.55, N 21.31.
Method B. Compound 23 was prepared by the same method described for the synthesis of 20 with 1,2-
dihydro-5-nitroso-6-(phenylamino)-2-thioxopyrimidin-4(3H)-one [37] in place of 16. The product was identical
to that obtained by Method A.
Table. Crystallographic Data of Compound 20d
Crystallized from
CHCl3/i-PrOH
C21H19N5O4
405.41
orange, prism
0.32 Â 0.45 Â 0.50
173(1)
Empirical formula
Formula weight [g molÀ1
Crystal color, habit
Crystal dimensions [mm]
Temp. [K]
]
Crystal system
Space group
monoclinic
P21/c
Z
4
Reflections for cell determination
25
2q Range for cell determination [8]
38 40
Unit-cell parameters a [ä]
13.150(1)
8.057(1)
19.165(1)
107.155(7)
1940.2(3)
1.388
b [ä]
c [ä]
b [8]
V [ä3]
Dx [gcm À3
]
m(MoKa) [mmÀ1
Scan type
]
0.0992
w/2q
2q(max) [8]
55
Total reflections measured
Symmetry-independent reflections
Reflections used [I > 2s(I)]
Parameters refined
4969
4450
3324
299
Final R
0.0438
0.0429
2.104
wR (w ˆ [s2(Fo) ‡ (0.005Fo)2]À1
)
Goodness-of-fit
Secondary extinction coefficient
Final Dmax/s
1.50(9) Â 10À6
0.0003
D1(max; min) [e äÀ3
]
0.23; À0.21

748
Helvetica Chimica Acta Vol. 86 (2003)
6. Crystal-Structure Determination of 20d (see the Table and Fig.5). All measurements were performed on a
Rigaku AFC5R diffractometer with graphite-monochromated MoKa radiation (l ˆ 0.71069 ä) and a 12-kW
rotatinganode generator. The intensities were corrected for Lorentz and polarization effects, but not for
absorption. The structure was solved by direct methods with SHELXS86 [44], which revealed the position of all
non-H-atoms. The EtO atoms of the ethyl ester group are disordered over two orientations with relative site-
occupation factors of 0.542 :0.458. All of the H-atoms bonded to C-atoms were fixed in geometrically calculated
positions (d(CÀH) ˆ 0.95 ä). The amine H-atom was fixed in the position indicated by a difference-electron-
density map. Each H-atom was assigned a fixed isotropic displacement parameters with a value equal to 1.2 Ueq
of its parent atom. Refinement of the structure was carried out on F by full-matrix least-squares procedures,
which minimized the function Sw(j Fo jÀj Fc j)2. A correction for secondary extinction was applied. Neutral atom
scatteringfactors for non-H-atoms were taken from [45a], and the scatteringfactors for H-atoms were taken
from [46]. Anomalous dispersion effects were included in Fcalc [47]; the values for f' and f'' were those of [45b].
All calculations were performed with the TEXSAN crystallographic software package [48].
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5
)
CCDC-181576 contains the supplementary crystallographic data for this paper. These data can be
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lographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, U.K.: fax: ‡ 441223336033; e-mail:
deposit@ccdc.cam.ac.uk).

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Received November 12, 2002