Synthesis of triazolo[1,5-a]triazin-7-one derivatives and highly functionalized [1,2,4]triazoles

Article abstract of DOI:10.1002/hlca.200390261

The synthesis of novel triazolo[1,5-a]triazin-7-ones is presented. Starting from 3-amino-5-sulfanyl-1,2,4-triazole, the synthetic sequence involved alkylation with benzyl bromide, reaction with p-nitrophenyl chloroformate followed by treatment with a primary amine, and condensation with diethoxymethyl acetate. Final oxidation of the thioether moiety with 3-chloroperbenzoic acid provided 2-(benzylsulfonyl)[1,2,4]tri-azolo[1,5-a][1,3,5]triazin-7-ones 5a and 5b in good overall yields. Treatment of 5a and 5b with secondary amines provided highly functionalized [1,2,4]triazoles through an unexpected triazinone ring opening. A mechanism for this transformation is proposed.

Full text of DOI:10.1002/hlca.200390261

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Synthesis of Triazolo[1,5-a]triazin-7-one Derivatives and Highly
Functionalized [1,2,4]Triazoles
by Montserrat Heras*a), David Fonta), Anthony Lindenb), and Jose¬ M. Villalgordo*a)1)
a
¡
) Departament de QuÌmica, Facultat de Ciencies, Universitat de Girona, Campus de Montilivi,
E-17071 Girona
b) Organisch-Chemisches Institut der Universit‰t Z¸rich, Winterthurerstrasse 190, CH-8057Z¸rich
(phone: 34-972-418-274; fax: 34-972-418-150; e-mail: montserrat.heras@udg.es)
The synthesis of novel triazolo[1,5-a]triazin-7-ones is presented. Starting from 3-amino-5-sulfanyl-1,2,4-
triazole, the synthetic sequence involved alkylation with benzyl bromide, reaction with p-nitrophenyl
chloroformate followed by treatment with a primary amine, and condensation with diethoxymethyl acetate.
Final oxidation of the thioether moiety with 3-chloroperbenzoic acid provided 2-(benzylsulfonyl)[1,2,4]tri-
azolo[1,5-a][1,3,5]triazin-7-ones 5a and 5b in good overall yields. Treatment of 5a and 5b with secondary amines
provided highly functionalized [1,2,4]triazoles through an unexpected triazinone ring opening. A mechanism for
this transformation is proposed.
Introduction.
Heteroaromatic nucleophilic addition/elimination reactions are
commonly recognized in many electron-deficient heterocycles [1]. However, analogous
reactions with electron-rich heterocycles are rather uncommon [2]. On the other hand,
alkyl- or arylsulfinyl, or alkyl- or arylsulfonyl substituents as leaving groups in electron-
deficient heteroaromatic systems have been reported to have reactivities equivalent to
or greater than that of a Cl group, and many examples that demonstrate the reactivity
of electron-deficient azines bearing alkylsulfinyl and sulfonyl groups with a wide
variety of simple nucleophiles have been reported [3].
During the last few years, we have been engaged in a research program focused on
the development of efficient methodologies that could be readily adapted for the
combinatorial and/or parallel synthesis of relevant core structures in solution or on
solid support [4]. We have recently described the synthesis of novel 2,3-dihydroim-
idazo[2,1-b][1,3]oxazoles [5][6] and 2,6-disubstituted 3,4-dihydropyrimidin-4(3H)-ones
[7][8]. The method has a nucleophilic ipso-substitution of the corresponding activated
sulfones as one of the key steps for introducing molecular diversity (Scheme 1).
Scheme 1
1
¬
Present address: Roviall QuÌmica S.L., PolÌgono Industrial Oeste, Parcela 22/2 Modulo L, E-30169, San
)
¬
Gines, Murcia.

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Within this context, an investigation was undertaken to expand the scope of this
methodology and its potential application in the synthesis of more-elaborate hetero-
cyclic scaffolds based on the [1,2,4]triazole nucleus. Triazoles are important pharma-
cophores in different therapeutic areas, and many biologically active compounds have
this moiety incorporated into their structures. Particularly interesting are triazolo[1,5-
a]triazin-7-ones of type I, which are 5-aza analogues of hypoxanthine II with potential
therapeutic interest [9][10]. In particular, inhibition of xanthine oxidase [11] and
eosinophilia [12] has been studied. The results of this investigation are disclosed herein.
Results and Discussion. Our objective in this study was to develop a synthetic
protocol, which, starting from 3-amino-5-sulfanyl-1,2,4-triazole, would effectively
afford a variety of molecularly diverse triazolo[1,5-a]triazin-7-ones of type I with
different substitution patterns, especially at the C(2) position, which are the less studied
derivatives.
Several strategies have been reported for the synthesis of triazolo[1,5-a]triazin-7-
ones [13]. One of these approaches involves reaction of 1H-[1,2,4]triazol-3-amine with
an isocyanate followed by condensation with diethoxymethyl acetate (DEMA) [9].
However, this method has some limitations due to the lack of availability of the
corresponding isocyanates. This limitation prevents the introduction of a high degree of
molecular diversity over the C(2) position in these derivatives. To circumvent this
problem, an alternative approach would be the use of a chloroformate followed by
treatment with a primary amine. Moreover, the presence of the thiol group in 3-amino-
5-sulfanyl-1,2,4-triazole would also serve as an efficient means to introduce molecular
diversity through thioether formation, oxidation, and nucleophilic displacement of the
corresponding activated sulfone.
Thus, synthesis of triazolo[1,5-a]triazin-7-ones was carried out as depicted in
Schemes 2 and 3. Alkylation of 3-amino-5-sulfanyl-1,2,4-triazole 1 with PhCH2Br
bromide in DMF afforded 2. When 2 was allowed to react in 1,4-dioxane with p-
nitrophenyl chloroformate in the presence of pyridine followed by treatment with the
corresponding primary amine, carboxamides 3a and 3b were isolated in good yields
(70 87%). The structure elucidation of compounds 3 was accomplished by the usual
spectroscopic methods. In agreement with the literature [9][10], only one of the four
possible monosubstituted isomers was detected (Scheme 2). In addition, 3a was
subjected to an X-ray crystal-structure analysis, which unambiguously confirmed the
structure (Figure). Condensation of 3a and 3b with DEMA provided triazolo-
triazinones 4a and 4b, respectively in 65 67% yield (Scheme 3). Oxidation of the
thioether moiety with 3 equiv., of 3-chloroperbenzoic acid (m-CPBA) in CH2Cl2 led to
the sulfone derivatives 5a and 5b, respectively, in good yields (70 89%).

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Scheme 2
i) PhCH2Br (1.1 equiv.), Et3N (1.1 equiv.), DMF, r.t., 5 h. ii) p-Nitrophenyl chloroformate (1.1 equiv.), pyridine
(1.1 equiv.), 1,4-dioxane, r.t., 1 h. iii) R'NH2 (2.5 equiv.), 4 h.
Figure. ORTEPII [14] View of the molecular structure of compound 3a, showing the labelling of the non-H-
atoms (ellipsoids drawn at the 50% probability level)
We then examined the nucleophilic ipso-substitution of the PhCH2SO2 group
(Scheme 4). Unexpectedly, treatment of either sulfone 5a or 5b with 3 equiv. of the
corresponding secondary amine led to the formation of the same triazole derivatives
7a c, which were isolated in excellent yields (83 86%), together with ureas 8 (86
94%). The corresponding triazolotriazinones 6 were not obtained. The structure

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Scheme 3
i) DEMA (2 equiv.), DMF, 1208, 4 h. ii) m-CPBA (3 equiv.), CH2Cl2, r.t., overnight.
elucidation of the novel triazole derivatives 7a c was accomplished by the usual
spectroscopic methods.
Scheme 4
i) R2R3NH (3 equiv.), 1,4-dioxane, r.t.
Formation of triazoles 7 could be rationalized in terms of an initial attack of the
secondary amine at C(5) of the triazolo-triazinone 5 followed by triazinone ring
opening to give the triazole-carboxamide 9. It should be noted that this nucleophilic
attack is favored, since the negative charge formed at N(4) is stabilized by
delocalization in the triazole ring. Subsequent attack of a second molecule of amine

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at the carbonyl atom of 9, with ultimate loss of the corresponding urea 8, would afford
the triazole derivative 7 (Scheme 5).
Scheme 5
In good agreement with this mechanism, when sulfone 5a was treated with 1 equiv.
of pyrrolidine at room temperature, carboxamide 9 was obtained exclusively in 87%
yield (Scheme 6).
Scheme 6
i) Pyrrolidine (1 equiv.), 1,4-dioxane, r.t.
In addition, we examined whether triazolo-triazinones 4 behave similarly. Treat-
ment of 4a with 3 equiv. of pyrrolidine afforded carboxamide 10, triazole 11, and urea
8a in 67%, 14%, and 13% yields, respectively (Scheme 7).
Conclusions. An efficient synthetic strategy to prepare novel 2-(benzylsulfo-
nyl)[1,2,4]triazolo[1,5-a]triazin-7-ones has been described. Attempts to replace the
benzylsulfonyl group by treatment with secondary amines were unsuccessful, instead,
highly functionalized [1,2,4]triazoles were obtained in excellent yields. To the best of
our knowledge, there are no prior reports of this transformation performed under such
mild conditions.

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Scheme 7
i) Pyrrolidine (3 equiv.), 1,4-dioxane, r.t., 2 h.
Experimental Part
General. All commercially available chemicals were used as purchased. DMF and 1,4-dioxane were dried
over activated molecular sieves (4 ä). All reactions were carried out under dry N2. M.p.: Electrothermal digital
melting-point apparatus IA 91000, uncorrected. Anal. TLC: precoated TLC plates, silica gel 60 F254 (Merck).
Flash chromatography (FC): silica gel 60 (230 400 mesh, Merck). IR Spectra: Mattson-Galaxy Satellite FT-IR;
1
n in cmÀ1. H- and 13C-NMR (200 and 50 MHz, resp.): Bruker DPX-200 Advance instrument: d in ppm rel. to
SiMe4 as int. standard, J in Hz. MS: VG Quattro instrument in the pos. ion FAB mode, 3-NBA or 1-thioglycerol
as matrix, m/z (rel. %).
5-(Benzylsulfanyl)-1H-[1,2,4]-triazol-3-amine (2). Et3N (4.39 ml, 34.1 mmol) was added dropwise to a
suspension of 3-amino-5-sulfanyl-1,2,4-triazole 1 (3.6 g, 31.0 mmol) in dry DMF (50 ml), and the mixture was
stirred under N2 at r.t. for 15 20 min. Next, benzyl bromide (4.05 ml, 34.1 mmol) was added, and the mixture
was stirred under N2 at r.t. for 4 h. The soln. was evaporated to dryness, and the resulting residue was partitioned
between AcOEt (150 ml) and H2O (100 ml). The org. layer was washed with brine (50 ml), dried (MgSO4), and
concentrated under reduced pressure. FC (AcOEt) provided 2 (5.69 g, 89%). Colorless solid. M.p. 107 108 8.
TLC (hexane/AcOEt 1:3): Rf 0.26. IR (KBr): 3412s, 3323m, 3227m, 3206m, 3174w, 3061m, 2981m, 2882m,
2767m, 2730m, 2579m, 2366m, 2340w, 1622s, 1546s, 1495m, 1452m, 1339m, 1294m, 1238m, 1140w, 1086m, 1022m,
920w, 857w, 7 51m, 7 04m, 659w. 1H-NMR (CDCl3, 508): 7.38 7.22 (m, 5 arom. H); 5.8 (br. s, 3 H, NH2, NH);
4.32 (s, CH2S). 13C-NMR (CDCl3, 508): 158.8 (s, C(5)); 155.5 (s, C(3)); 137.3 (s); 128.8, 128.7, 127.5 (3d), 37.5 (t).
Synthesis of Carboxamides 3a and 3b. General Procedure 1 (GP 1). A mixture containing 2 (619 mg,
3.0 mmol, 1 equiv.), p-nitrophenyl chloroformate (665 mg, 3.3 mmol, 1.1 equiv.), and pyridine (0.26 ml,
3.3 mmol, 1.1 equiv.) in dry 1,4-dioxane was stirred under N2 at r.t. for 1 h. Next, the corresponding amine
(7.5 mmol, 2.5 equiv.) was added in one portion, and the resulting mixture was stirred under N at r.t. Upon
2
completion of the reaction (TLC monitoring), the solvent was removed under reduced pressure and the residue
was dissolved in CH2Cl2 (50 ml), washed with aq. sat. NaHCO3 soln. (3 Â 10 ml) and brine (10 ml). The org.
layer was dried (MgSO4), filtered, and concentrated. The resulting crude material was purified by FC (hexane/
AcOEt).
5-Amino-N-3-(benzylsulfanyl)-butyl-1H-[1,2,4]triazole-1-carboxamide (3a). According to GP 1, the re-
action between 2 and butylamine (0.4 ml, 7.5 mmol, 2.5 equiv.) afforded3a (796 mg, 87%). Colorless solid. M.p.
52 538. TLC (hexane/AcOEt 2 :1): Rf 0.38. IR (KBr): 3415m, 3355m, 2957m, 2989m, 2869w, 1715s, 1626s,
1530s, 1487s, 1307s, 1274s, 1187m, 1073w, 989w, 857w, 7 52m, 7 00m. 1H-NMR (CDCl3): 7.32 7.18 (m, 5 arom. H);

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6.65 (t, J ˆ 5.8, NH); 6.5 (br. s, NH2); 4.2 (s, CH2S); 3.25 (q, J ˆ 6.6, CH2NH); 1.53 1.18 (m, 4 H); 0.85 (t, J ˆ
7.2, Me). 13C-NMR (CDCl3): 159.4 (s, CˆO); 156.5 (s, C(5)); 150.6 (s, C(3)); 136.9 (s, 1 arom. C); 128.8, 128.5,
127.4 (3d, 5 arom. CÀH); 39.6 (t, CH2NH); 35.5 (t, CH2S); 31.5, 19.8 (t, 2 CH2); 13.6 (q, Me). FAB-MS: 306 (45,
‡
‡
[M ‡ 1] ), 305 (14, M ), 208 (12), 207(100), 206 (37).
5-Amino-N-3-(benzylsulfanyl)-(4-methylphenyl)-1H-[1,2,4]-triazole-1-carboxamide (3b). According to
GP 1, the reaction between 2 and p-toluidine (810 mg, 7.5 mmol, 2.5 equiv) afforded 3b (712 mg, 70%).
Colorless solid. M.p. 165 1668. TLC (hexane/AcOEt 2 :1): Rf 0.44. IR (KBr): 3429m, 3360m, 3288w, 3122w
1732s, 1640m, 1597m, 1539s, 1491s, 1312m, 1098w, 811w, 624w. 1H-NMR ((D6)DMSO): 9.82 (s, NH); 7.56 7.06
(m, 9 arom. H, NH2); 4.42 (s, CH2S); 2.29 (s, Me). 13C-NMR ((D6)DMSO): 158.8 (s, C(5)); 157.1 (s, CˆO);
152.6 (s, C(3)); 137.9, 134.5, 133.5 (s, 3 arom. C); 129, 128.8, 128.3, 127.2, 121.2 (5d, 9 arom. CH); 34.4 (t, CH2S);
‡
‡
13.6 (q, Me). FAB-MS: 340 (40, [M ‡ 1] ), 339 (9, M ), 241 (22), 242 (15), 207(100).
Synthesis of Triazolo-triazinones 4a and 4b. General Procedure 2 (GP 2). Diethoxymethyl acetate (0.65 ml,
4 mmol, 2 equiv.) was added in one portion to a soln. of the corresponding carboxamide (2 mmol, 1 equiv.) 3a, b
in dry DMF (6 ml). The resulting mixture was then stirred under N2 at 1208. Upon completion of the reaction
(TLC monitoring), the solvent was removed under reduced pressure, and the resulting residue was purified by
FC (hexane/AcOEt).
2-(Benzylsulfanyl)-6-butyl-6,7-dihydro[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-one (4a). According to GP 2,
starting with carboxamide 3a (610 mg, 2 mmol, 1 equiv.), 4a (422 mg, 67%) was obtained as a colorless solid.
M.p. 94 958. TLC (hexane/AcOEt 1:1): Rf 0.35. IR (KBr): 3060w, 2958w, 2929w, 2865w, 1735s, 1595s, 1545s,
1454w, 1429m, 1388m, 1333w, 1270m, 1246s, 1194w, 1152w, 7 3w6, 7 0m8 . 1H-NMR ((D6)DMSO): 8.64
(s, HÀC(7 )); 7.5 7.24 (m, 5 arom. H); 4.49 (s, CH2S); 3.98 (t, J ˆ 7.2, CH N); 1.78 1.27 (m, 4 H); 0.93 (t, J ˆ
2
7.0, Me). 13C-NMR ((D6)DMSO): 164.9 (s, CˆO); 157.7 (s, C(3a)); 153.5 (d, C(5)); 143.1 (s, C(2)); 137.3
(s, 1 arom. C); 128.8, 128.4, 127.3 (3d, 5 arom. CH); 46.9 (t, CH2N); 34.4 (t, CH2S); 30.2, 18.9 (t, 2 aliph. CH2);
‡
13.4 (q, Me). FAB-MS: 316 (100, [M ‡ 1] ).
2-(Benzylsulfanyl)-6,7-dihydro-6-(4-methylphenyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-one (4b). Accord-
ing to GP 2, starting with carboxamide 3b (679 mg, 2 mmol, 1 equiv.), 4b (454 mg, 65%) was obtained as a
colorless solid. M.p. 192 1938. TLC (hexane/AcOEt 1:1): Rf 0.48. IR (KBr): 3067w, 2926w 1762s, 1640m, 1590s,
1503w, 1441w, 1334s, 1268w, 1222w, 1144m, 1025w, 7 7 1m, 639w. 1H-NMR ((D6)DMSO): 8.62 (s, HÀC(5)); 7.51
7.31 (m, 9 arom. H); 4.52 (s, CH2S); 2.42 (s, Me). 13C-NMR ((D6)DMSO): 165.1 (s, CˆO); 157.7 (s, C(3a));
153.2 (d, C(5)); 142.9 (s, C(2)); 139.4, 137.3, 133.1 (s, 3 arom. C); 129.8, 129.1, 128.8, 127.3, 127.2 (5d, 9 ar-
‡
‡
om. CH); 34.4 (t, CH2S); 20.7( q, Me). FAB-MS: 350 (100, [M ‡ 1] ); 349 (9, M ).
Oxidation of 2-(Benzylsulfanyl)triazolo-triazinones 4a and 4b to the Corresponding Sulfones 5a and 5b.
General Procedure 3 (GP 3). m-CPBA (1.4 g, 4.5 mmol, 3 equiv.) was added in small portions to cooled solns.
(08) of 4a and 4b (1.5 mmol, 1 equiv.) in CH2Cl2 (15 ml). The resulting mixture was then stirred overnight as the
temp. was increased from 08 to r.t. Upon completion of the reaction (TLC monitoring), the solvent was removed
under reduced pressure and the resulting residue was purified by FC (hexane/AcOEt).
2-(Benzylsulfonyl)-6-butyl-6,7-dihydro[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-one (5a). According to GP 3,
starting with 4a (473 mg, 1.5 mmol, 1 equiv.), 5a (364 mg, 70%) was obtained as a colorless solid. M.p. 152 1538.
TLC (hexane/AcOEt 1 :2): Rf 0.49. IR (KBr): 3058w, 2963w, 2927w, 2862w, 1766s, 1601s, 1548m, 1459w, 1432m,
1390m, 1340m, 1234w, 1200w, 1148m, 1107w, 836w, 7 7 1m, 696m. 1H-NMR ((D6)DMSO): 8.82 (s, HÀC(5)); 7.39
(s, 5 arom. H); ); 4.97( s, CH2SO2); 4.05 (t, J ˆ 7.0, CH N); 1.81 1.29 (m, 4 H); 0.94 (t, J ˆ 7.0, Me). 13C-NMR
2
((D6)DMSO): 163.2 (s, CˆO); 158.5 (s, C(3a)); 155.4 (d, C(5)); 144.2 (s, C(2)); 131.9, 129.2, 128.9
(3d, 5 arom. CH); 127.1 (s, 1 arom. C); 59.5 (t, CH2SO2); 47.9 (t, CH2N); 30.5, 19.4 (t, 2 CH2); 13.9 (q, Me).
‡
FAB-MS: 348 (100, [M ‡ 1] ); 155 (16); 154 (53); 138 (20); 137(41); 136 (39).
2-(Benzylsulfonyl)-6-(4-methylphenyl)-6,7-dihydro[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-one (5b). Accord-
ing to GP 3, starting with 4b (524 mg, 1.5 mmol, 1 equiv.), 5b (509 mg, 89%) was obtained as a colorless solid.
M.p. 191 1928. TLC (hexane/AcOEt 1:1): Rf 0.13. IR (KBr): 3054w, 3041w, 2967w, 2906w, 1777s, 1595s, 1555m,
1521m, 1434m, 1360s, 1326s, 1272m, 1232m, 1144s, 1077w, 929w, 828w, 7 6m8 , 7 0m0 , 633m. 1H-NMR
((D6)DMSO): 8.84 (s, HÀC(5)); 7.47 7.41 (m, 9 arom. H); 5.03 (s, CH2SO2); 2.43 (s, Me). 13C-NMR
((D6)DMSO): 163.0 (s, CˆO); 158.0 (s, C(3a)); 154.8 (d, C(5)); 143.6 (s, C(2)); 139.7, 132.8 (s, 2 arom. C);
131.4, 129.9, 128.7, 128.5, 127.1 (5d, 9 arom. CH); 126.7( s, 1 arom. C); 58.9 (t, CH2SO2); 20.7( q, Me). FAB-MS:
‡
382 (100, [M ‡ 1] ); 228 (15); 201 (18).
Reaction of Sulfone Derivatives 5a and 5b with Amines. Synthesis of Triazoles 7 and 9. General Procedure 4
(GP 4). To a soln. of 5a and 5b (0.5 mmol, 1 equiv.) in dry 1,4-dioxane (2 ml), the corresponding amine
(1.5 mmol, 3 equiv.) was added at r.t. The mixture was stirred under N2 at r.t. Upon completion of the reaction

Helvetica Chimica Acta Vol. 86 (2003)
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(TLC monitoring), the solvent was removed under reduced pressure and the resulting residue was purified by
FC (hexane/AcOEt) to provide triazoles 7 together with the corresponding ureas 8 or the triazoles 9.
3-(Benzylsulfonyl)-5-{[(pyrrolidin-1-yl)methylidene]amino}-1H-[1,2,4]triazole (7a). According to GP 4,
treatment of 5a (187mg, 0.5 mmol, 1 equiv.) or 5b (190 mg, 0.5 mmol, 1 equiv.) with pyrrolidine (0.12 ml,
1.5 mmol, 3 equiv.) afforded 7a (130 mg, 84%) as a colorless solid. M.p. 194 1958. TLC (hexane/AcOEt 1:5): Rf
0.21. IR (KBr): 3198w, 3081w, 2969w, 2926w, 2870w, 1618s, 1566s, 1461w, 1408m, 1324m, 1244w, 1127m, 1051w,
1
729w, 7 01w. H-NMR ((D6)DMSO): 13.76 (s, NH); 8.66 (s, CH); 7.38 7.25 (m, 5 arom. H); 4.70 (s, CH2SO2);
3.36 (t, J ˆ 6.0, CH2N); 3.44 (t, J ˆ 6.0, CH2N); 2.01 1.79 (m, 4 H). 13C-NMR ((D6)DMSO): 161.9 (s, triaz. C);
158.2 (s, triaz. C); 155.2 (d, CH); 131.1, 128.4, 128.3 (3d, 5 arom. CH); 127.7 (s, 1 arom. C); 59.2 (t, CH2SO2);
‡
48.9 (t, CH2N); 45.5 (t, CH2N); 24.5, 24.0 (t, 2 CH2). FAB-MS: 320 (73, [M ‡ 1] ), 171 (100), 154 (32), 149 (21),
147(28), 138 (25), 137(52), 136 (59), 135 (25), 133 (23), 125 (26).
3-(Benzylsulfonyl)-5-{[(morpholin-4-yl)methylidene]amino}-1H-[1,2,4]triazole (7b). According to GP 4,
treatment of 5a (187mg, 0.5 mmol, 1 equiv.) or 5b (190 mg, 0.5 mmol, 1 equiv.) with morpholine (0.13 ml,
1.5 mmol, 3 equiv.) afforded 7b (139 mg, 83%). Colorless solid. M.p. 154 1558. TLC (hexane/AcOEt 1 :2): Rf
0.10. IR (KBr): 3167w, 3077w, 2970w, 2924w, 2861w, 1614s, 1569s, 1437m, 1412m, 1356m, 1321m, 1263w, 1236w,
1152m, 1115m, 1068w, 997w, 87 5w, 7 85w, 697w. 1H-NMR ((D6)DMSO): 13.81 (s, NH); 8.56 (s, CH); 7.39 7.25
(m, 5 arom. H); 4.70 (s, CH2SO2); 3.69 3.60 (m, 8 H). 13C-NMR ((D6)DMSO): 162.1, 158.7(2 s, triaz. C); 157.6
(d, CH); 131.6, 128.9, 128.7(3 d, 5 arom. CH); 127.1 (s, 1 arom. C); 66.9 (t, CH2O); 65.8 (t, CH2O); 59.7
‡
(t, CH2SO2); 49.5 (t, CH2N); 43.3 (t, CH2N). FAB-MS: 336 (100, [M ‡ 1] ), 187(18), 154 (38), 149 (48), 141
(26), 140 (72), 139 (19), 138 (32), 137 (52), 136 (65), 135 (19), 125 (18).
3-(Benzylsulfonyl)-5-[({4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}methylidene)amino]-1H-[1,2,4]tri-
azole (7c). According to GP 4, treatment of 5a (187mg, 0.5 mmol, 1 equiv.) or 5b (190 mg, 0.5 mmol, 1 equiv.)
with 1-(3-trifluoromethylphenyl) piperazine (0.28 ml, 1.5 mmol, 3 equiv.) afforded 7c (205 mg, 86%) as a
colorless solid. M.p. 198 1998. TLC (hexane/AcOEt 1:2): Rf 0.30. IR (KBr): 3246w, 3067w, 2972w, 2860w,
1625s, 1560s, 1445m, 1324m, 1237w, 1123m, 944w, 865w, 7 83w, 696w. 1H-NMR ((D6)DMSO): 13.82 (s, NH); 8.63
(s, CH); 7.51 7.12 (m, 9 arom. H); 4.72 (s, CH2SO2); 3.81 3.75 (m, 4 H, CH2N); 3.38 (br. s, 4 H, CH2N).
13C-NMR ((D6)DMSO): 162.1, 158.7(2 s, triaz. C); 157.5 (d, CH); 151.2 (s, 1 arom. C); 131.6, (d, 2 arom. CH);
130.5 (q, J(C,F) ˆ 31, 1 arom. C); 130.4, 128.7, 128.9 (3d, 4 arom. CH); 128.1 (s, 1 arom. C); 124.8 (q, J(C,F) ˆ
270, CF3); 119.7, 115.7, 112.1 (3d, 3 arom. CH); 59.7( t, CH2SO2); 48.8 (t, CH2N); 48.7( t, CH2N); 47.5 (t, CH2N);
‡
42.4 (t, CH2N).FAB-MS: 479 (100, [M ‡ 1] ), 213 (52), 200 (60), 172 (48), 154 (40), 147 (40), 145 (45), 137 (64),
137(52), 136 (77), 135 (38), 133 (47).
N-Butylpyrrolidine-1-carboxamide (8a). From 5a: 80 mg (94%) colorless solid. M.p. 65 668. TLC (hexane/
AcOEt 1:5): Rf 0.25. IR (KBr): 3341w, 2948w, 2922m, 2857m, 1620s, 1534s, 1482m, 1462m, 1436m, 1397m,
1362m, 1255m, 1228m, 1191m, 1147m, 7 65m. 1H-NMR ((D6)DMSO): 6.04 (br. s, NH); 3.31 3.24 (m, 4 H); 3.08
(t, J ˆ 6.7, CH N); 1.93 1.83 (m, 4 H); 1.51 1.29 (m, 4 H); 0.96 (t, J ˆ 6.7, Me). 13C-NMR ((D6)DMSO): 156.5
2
(s, CˆO); 45.2 (t, CH2N); 39.5 (t, CH2N); 32.3, 24.9, 19.5 (3t, 3 CH2); 13.7( q, Me). FAB-MS: 171 (100, [M ‡
‡
1] ), 169 (14).
N-(4-Methylphenyl)pyrrolidine-1-carboxamide (8b). From 5b: 92 mg (90%) colorless solid. M.p. 140 1418.
TLC (hexane/AcOEt 1 :5): Rf 0.38. IR (KBr): 3316w, 3032m, 2969m, 2867m, 1645s, 1592s, 1525s, 1477m, 1447m,
1409m, 1380m, 1288m, 1245m, 1199m, 1115m, 809m, 754m. 1H-NMR ((D6)DMSO): 7.97 (br.s, NH); 7.39 (d, J ˆ
8.3, 2 arom. H); 7.03 (d, J ˆ 8.3, 2 arom. H); 3.39 3.34 (m, 4 H); 2.24 (s, Me); 1.92 1.83 (m, 4 H). 13C-NMR
((D6)DMSO): 153.9 (s, CˆO); 138.0, 130.1 (2s, 2 arom. C); 128.6, 119.6 (2d, 4 arom. CH); 45.6 (t, CH2N); 24.9
‡
‡
(t, 2 CH2); 20.3 (q, Me). FAB-MS: 205 (100, [M ‡ 1] ), 204 (38, M ), 203 (13).
3-(Benzylsulfonyl)-N-butyl-5-{[(pyrrolidin-1-yl)methylidene]amino}-1H-[1,2,4]triazole-1-carboxamide
(9a). According to GP 4, treatment of 5a (187mg, 0.5 mmol, 1 equiv.) with pyrrolidine (41 ml, 0.5 mmol,
1 equiv.) afforded 9a (178 mg, 85%) as a colorless solid. M.p. 135 1368. TLC (hexane/AcOEt 1:5): Rf 0.28. IR
(KBr): 3463w, 3218w, 3082w, 2963w, 2876w, 1745s, 1634s, 1535s, 1464w, 1420w, 1340m, 1233w, 1140m, 917w, 7 04w.
1H-NMR ((D6)DMSO): 9.27( t, J ˆ 5.2, NH); 8.82 (s, CH); 7.40 7.35 (s, 5 arom. H); 4.79 (s, CH2SO2); 3.76
(t, J ˆ 6.4, CH2N); 3.53 (t, J ˆ 6.2, CH2N); 3.39 3.30 (m, CH2N); 2.52 1.89 (m, 4 H); 1.63 1.25 (m, 4 H); 0.92
(t, J ˆ 7.0, Me). 13C-NMR ((D6)DMSO): 155.5 (s, CˆO); 153.2 (s, triaz. C); 151.2 (d, CH); 143.4 (s, triaz. C);
126.8, 124.1, 123.9 (3d, 5 arom. CH); 122.6 (s, 1 arom. C); 54.4 (t, CH2SO2); 45.3 (t, CH2N); 41.6 (t, CH2N); 36.2
‡
(t, CH2N); 26.3, 20.0, 19.3, 14.9 (4t, 4 CH2); 8.9 (q, Me). FAB-MS: 419 (10, [M ‡ 1] ), 321 (18), 320 (100), 154
(19), 137(26), 136 (36), 125 (18).
Reaction of Triazolo-triazinones 4a and 4b with Pyrrolidine. Synthesis of 10 and 11. Pyrrolidine (0.12 ml,
1.5 mmol, 3 equiv.) was added to a soln. of triazolotriazinone 4a (0.5 mmol, 1 equiv.) in dry 1,4-dioxane (2 ml).
The mixture was stirred under N2 at r.t. Upon completion of the reaction (TLC monitoring), the solvent was

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Helvetica Chimica Acta Vol. 86 (2003)
removed under reduced pressure. FC of the resulting residue (hexane/AcOEt) provided 10 (124 mg, 67%), 11
(24 mg, 14%), and urea 8a (11 mg, 13%) as colorless solids.
3-(Benzylsulfanyl)-N-butyl-5-{[(pyrrolidin-1-yl)methylidene]amino}-1H-[1,2,4]triazole-1-carboxamide
(10). M.p. 106 1078. TLC (hexane/AcOEt 1 :5): Rf 0.38. IR (KBr): 3437w, 3217w, 3051w, 2932w, 2870w, 1725m,
1630s, 1533s, 1462m, 1337w, 1277m, 7 04w. 1H-NMR ((D6)DMSO): 9.23 (t, J ˆ 5.4, NH); 8.83 (s, CH); 7.52 7.34
(s, 5 arom. H); 4.42 (s, CH2S); 3.79 (t, J ˆ 6.4, CH2N); 3.56 (t, J ˆ 6.4, CH2N); 3.43 3.34 (m, CH2N); 2.08 1.95
(m, 4 H); 1.66 1.33 (m, 4 H); 1.02 (t, J ˆ 7.2, Me). 13C-NMR ((D6)DMSO): 159.6 (s, CˆO); 157.7 (s, triaz. C);
155.5 (d, CH); 148.7( s, triaz. C); 138.2 (s, 1 arom. C); 129.2, 128.7, 127.5 (3d, 5 arom. CH); 49.9 (t, CH2N); 46.3
(t, CH2N); 39.6 (t, CH2N); 34.7( t, CH2S); 31.4, 24.9, 24.2, 19.9 (t, 4 CH2); 13.9 (q, Me). FAB-MS: 387(13, [ M ‡
‡
1] ), 289 (18), 288 (100), 198 (37), 197 (19), 149 (11), 133 (18), 124 (26).
5-(Benzylsulfanyl)-5-{[(pyrrolidin-1-yl)methylidene]amino}-1H-[1,2,4]triazole (11). M.p. 163 1648. TLC
(hexane/AcOEt 1:5): Rf 0.18. IR (KBr): 3217w, 3061w, 2923w, 2871w, 1619s, 1564s, 1455w, 1402w, 1324m, 1260w,
1056w, 87 w7, 698w. 1H-NMR ((D6)DMSO): 12.86 (s, NH); 8.66 (s, CH); 7.48 7.32 (s, 5 arom. H); 4.35
(s, CH2S); 3.36 (t, J ˆ 6.0, CH2N); 3.47( t, J ˆ 6.4, CH2N); 2.03 1.91 (m, 4 H). 13C-NMR ((D6)DMSO): 161.5
(s, triaz. C); 154.7( d, CH); 144.7( s, triaz. C); 138.7( s, 1 arom. C); 129.1, 128.7, 127.3 (3d, 5 arom. CH); 49.1
‡
(t, CH2N); 45.7( t, CH2N); 35.2 (t, CH2S); 24.9, 24.5 (t, 2 CH2). FAB-MS: 289 (18), 288 (100, [M ‡ 1] ), 198
(23), 197(13), 171 (21), 149 (23), 133 (19), 124 (13).
Table. Crystallographic Data of Compound 3a
Crystallized from
Et2O/pentane
C14H19N5OS
305.40
Colorless, prism
0.23 Â 0.42 Â 0.43
173 (1)
Monoclinic
P21/c
Empirical formula
Formula weight [g molÀ1
Crystal color, habit
Crystal dimensions [mm]
Temperature [K]
]
Crystal system
Space group
Z
4
Reflections for cell determination
25
2q range for cell determination [8]
37
Unit-cell parameters a [ä]
8.801 (2)
10.309 (2)
16.753 (2)
99.49 (1)
1499.2 (5)
648
1.353
0.223
55
b [ä]
c [ä]
b [8]
V [ä3]
F(000)
Dx [g cmÀ3
]
m(MoKa) [mmÀ1
2q(max) [8]
]
Total reflections measured
Symmetry-independent reflections
Reflections used [I > 2s(I)]
Parameters refined
Final R (F)
3875
3449
2818
203
0.0409
wR(F)
0.0405
Goodness-of-fit
1.892
Secondary extinction coefficient
Final Dmax/s
D1 (max; min) [e äÀ3
1.18 (9) Â 10À6
0.0004
0.30; À 0.33
]

Helvetica Chimica Acta Vol. 86 (2003)
3213
X-Ray Crystal-Structure Determination of 3a (see Table and Fig.)2). All measurements were conducted at
low temp. on a Rigaku AFC5R diffractometer with graphite-monochromated MoKa radiation (l ˆ 0.71073 ä)
and a 12-kW rotating-anode generator. The w/2q scan mode was employed for data collection. The intensities
were corrected for Lorentz and polarization effects, but not for absorption. The space group was uniquely
determined by the systematic absences. Equivalent reflections were merged. Data collection and refinement
parameters are given in the Table, and a view of the molecule is shown in the Figure. The structure was solved by
direct methods with SHELXS97[15], which revealed the positions of all non-H-atoms. The non-H-atoms were
refined anisotropically. The amine and amide H-atoms were placed in the positions indicated by a difference
electron-density map, and their positions were allowed to refine together with individual isotropic displacement
parameters. All of the remaining H-atoms were fixed in geometrically calculated positions [d(CÀH) ˆ 0.95 ä),
and each was assigned a fixed isotropic displacement parameter with a value equal to 1.2Ueq of its parent C-
atom. Refinement of the structure was carried out on F by means of full-matrix least-squares procedures, which
minimized the function Sw(j Fo jÀj Fc j )2, where w ˆ [s (Fo) ‡ (0.005Fo)2]À1. A correction for secondary
extinction was applied. Neutral- atom scattering factors for non-H-atoms were taken from [16a], and the
scattering factors for H-atoms were taken from [17]. Anomalous dispersion effects were included in Fc [18]; the
values for f ' and f '' were those of [16b]. The values of the mass-attenuation coefficients are those found in [16c].
All calculations were performed with the teXsan crystallographic software package [19].
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Germany, 1997.
[16] a) E. N. Maslen, A. G. Fox, M. A. O×Keefe, in −International Tables for Crystallography×, Ed. A. J. C.
Wilson, Kluwer Academic Publishers, Dordrecht, 1992, Vol. C, Table 6.1.1.1, p. 477; b) D. C. Creagh, W. J.
McAuley, in −International Tables for Crystallography×, Ed. A. J. C. Wilson, Kluwer Academic Publishers,
Dordrecht, 1992, Vol. C, Table 4.2.6.8, p. 219; c) D. C. Creagh, J. H. Hubbell, in −International Tables for
Crystallography×, Ed. A. J. C. Wilson, Kluwer Academic Publishers, Dordrecht, 1992, Vol. C, Table 4.2.4.3,
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2
)
Crystallographic data for this paper have been deposited with the Cambridge Crystallographic Data Centre
(CCDC-202952). These data can be obtained, free of charge, via www.ccdc.cam.ac.uk/conts/retrieving.html
(or from the CCDC, 12 Union Road, Cambridge CB21EZ, UK; fax: ‡441223336033; e-mail:
deposit@ccdc.cam.ac.uk).

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Helvetica Chimica Acta Vol. 86 (2003)
[17] R. F. Stewart, E. R. Davidson, W. T. Simpson, J. Chem. Phys. 1965, 42, 3175.
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[19] teXsan: Single Crystal Structure Analysis Software, Version 1.10, Molecular Structure Corporation, The
Woodlands, TX, 1999.
Received May 19, 2003