A Convenient Route for the Synthesis of Novel 2-Substituted [1,2,4]Triazolo[1,5-c]pyrimidine Derivatives

Abstract

Reactions of easily accessible chloropyrimidinyl hydrazones with bromine were investigated. Oxidative cyclization followed by concomitant bromination led to the formation of [1,2,4]triazolo[4,3-c]pyrimidines, which then underwent the ­Dimroth rearrangement to afford highly functionalized 2-substituted [1,2,4]triazolo[1,5-c]pyrimidines.

Key words

4,6-dichloropyrimidine - hydrazones - bromine - ­Dimroth rearrangement - [1,2,4]triazolo[1,5-c]pyrimidine

References and Notes

• For reviews, see:
• 1a Hurst DT. An Introduction to the Chemistry and Biochemistry of Pyrimidines, Purines and Pteridines   Wiley; Chichester: 1980. 
• 1b Brown DJ. The Pyrimidines   Wiley; New York: 1994. 
• 1c Katrizky AR. Rees CW. Scriven EFV. Comprehensive Heterocyclic Chemistry II   Pergamon; Oxford: 1996. 
• 1d Gribble G. Joule J. Progress in Heterocyclic Chemistry   Vol. 18:  Elsevier; Oxford: 2007. 
• For reviews on the synthesis of pyrimidine triazoles, see:
• 2a Shaban MAE. Morgaan AEA. Adv. Heterocycl. Chem.  1999,  75:  131 
• 2b Shaban MAE. Morgaan AEA. Adv. Heterocycl. Chem.  1999,  75:  243 
• 3 Nagamatsu T. Fujita T. Chem. Commun.  1999,  1461 
• 4a Pastorin G. Da Ros T. Spalluto G. Deflorian F. Moro S. Cacciari B. Baraldi PG. Gessi S. Varani K. Borea PA. J. Med. Chem.  2003,  46:  4287 
• 4b Neustadt BR. Hao JS. Lindo N. Greenlee WJ. Stamford AW. Tulshian D. Ongini E. Hunter J. Monopoli A. Bertorelli R. Foster C. Arik L. Lachowicz J. Ng K. Feng KI. Bioorg. Med. Chem. Lett.  2007,  17:  1376 
• 4c Neustadt BR. Liu H. Hao JS. Greenlee WJ. Stamford AW. Foster C. Arik L. Lachowicz J. Zhang HT. Bertorelli R. Fredduzzi S. Varty G. Cohen-Williams M. Ng K. Bioorg. Med. Chem. Lett.  2009,  19:  967 
• 4d Shawali AS. Hassaneen HM. Shurrab NK. Tetrahedron  2008,  64:  10339 
• 5 Guetzoyan LJ. Spooner RA. Lord JM. Roberts LM. Clarkson GJ. Eur. J. Med. Chem.  2010,  45:  275 
• 6 Baraldi P. Gioanni C. Cacciari B. Romagnoli R. Spalluto G. Varani K. Gessi S. Merighi S. Borea P. Drug. Dev. Rev.  2001,  52:  406 
• 7 Mezheritsky VV. Minkin VI. Minyaeva LG. Tyurin RG. Krasnikov VV. Vorobyev EV. Starikova ZA. ARKIVOC  2005,  (x):  9 
• 8 Andreas K, and Hunds A. inventors; Eur. Pat. Appl., EP  1284261.  ; Chem. Abstr. 2003, 138, 170252
• 10 Nasyr IA. Ovchinnikov VG. Bobrova OB. Cherkasov VM. Ukr. Khim. Zh. (Russ. Ed.)  1987,  53:  198 ; Chem. Abstr. 1987, 108, 112366
• 13a Subbotina OJ. Fabian W. Tarasov VE. Volkova NN. Bakulev AV. Eur. J. Org. Chem.  2005,  2914 
• 13b Widyan K. Kurz T. Synthesis  2005,  1340 
• 13c Sako M. Kawada H. J. Org. Chem.  2004,  69:  8148 
• 14 Fischer G. Adv. Heterocycl. Chem.  1993,  57:  81 

9

General Procedure for the Preparation of the Aldehyde Chloropyrimidinyl Hydrazones 4a-l: To the suspension of 1-(6-chloropyridin-4-yl)hydrazine (3) (0.289 g, 2.00 mmol) in EtOH (15 mL) was added dropwise with vigorous stirring an aldehyde (2.20 mmol, 1.1 equiv) at r.t. over 30-40 min. During this period, a white precipitate was produced. The mixture was stirred further for a couple of hours and then filtrated. The crude products were recrystallized from an appropriate solvent (Table  [¹] ) to furnish pure hydrazones 4 as white powders or crystals. The yields ranged from 63% to 85%. Data for Benzaldehyde (6-Chloro-4-pyrimidinyl)-hydrazone (4a): Yield: 0.339 g (73%); off-white powder; mp 208-210 ˚C. IR (KBr): 3456, 3203, 1608, 1589, 685
cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 8.98 (s, 1 H), 8.46 (s, 1 H), 7.86 (s, 1 H), 7.68-7.70 (m, 2 H), 7.42-7.44 (m, 3 H), 7.30 (s, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 162.0, 160.9, 158.1, 144.1, 133.6, 130.4, 129.0, 127.2, 103.4. GC-MS (EI): m/z = 232 [M]⁺ (100.00), 234 (37.10), 233 (8.23). HRMS (ESI): m/z [M]⁺ calcd for C₁₁H₉ClN₄: 232.0516; found: 232.0528.

11

A single crystal of 6a suitable for X-ray diffraction analysis was obtained by recrystallization from CH₂Cl₂-n-hexane. CCDC 768081 contains the supplementary crystallographic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk, or by emailing [e-mail], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: [phone].

12

General Procedure for the Preparation of 2-Substituted 8-Bromo-7-chloro[1,2,4]triazolo[1,5- c ]pyrimidine 6a-l: A soln of Br₂ (0.71 g, 4.4 mmol, 2.2 equiv) in glacial AcOH (0.57 mL) was slowly added to a suspension of anhyd NaOAc (1.53 g) and the appropriate hydrazone 4 (2.00 mmol, 1.0 equiv) in glacial AcOH (6.33 mL), and the mixture was stirred at r.t. for additional 30-60 min. The progress of the reaction was monitored by TLC. The reaction was quenched by pouring into ice-cooled 0.5 N aq NaOH soln (25-33 mL). With vigorous stirring, the mixture was agitated for 30-60 min. The product was collected by filtration, washed several times with H₂O, and dried. The product was recrystallized from an appropriate solvent (Table  [²] ). Pure products 6 were obtained as off-white powders or crystals in yields ranging from 40% to 83%. All are previously unknown products and were fully characterized by IR, NMR and mass spectra. Selected Data for 8-Bromo-7-chloro-2-phenyl[1,2,4]triazolo[1,5- c ]-pyrimidine (6a): Yield: 0.52 g (83%); off-white powder; mp 240-242 ˚C. IR (KBr): 3404, 1606, 1486, 1364, 715 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 9.18 (s, 1 H), 8.32-8.34 (m, 2 H), 7.52-7.54 (m, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 166.1, 153.8, 146.7, 140.1, 131.9, 130.4, 129.5, 127.9, 106.3. GC-MS (EI): m/z = 311 [M + H]⁺ (100.00), 309 (78.21), 274 (38.13). HRMS (ESI): m/z [M + H]⁺ calcd for C₁₁H₇BrClN₄: 310.9522; found: 310.9519.