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LETTER
H. T.; Bertorelli, R.; Fredduzzi, S.; Varty, G.; Cohen-
Williams, M.; Ng, K. Bioorg. Med. Chem. Lett. 2009, 19,
967. (d) Shawali, A. S.; Hassaneen, H. M.; Shurrab, N. K.
Tetrahedron 2008, 64, 10339.
protonated to generate ammonium salts I, which facilitate
the ring opening to give the iminium salts II (in resonance
with the nitrilium salts II¢). Subsequently, hydrogen shift
results in the formation of the triazole-tethered vinylimin-
ium salts III. Recyclization by intramolecular nucleo-
philic attack at another nitrogen atom of the triazole ring
affords, after deprotonation of IV, the isolated [1,2,4]tri-
azolo[1,5-c]pyrimidines 6. The driving force for the ob-
served rearrangement relies on the fact that
[1,2,4]triazolo[1,5-c]pyrimidine ring system is thermody-
namically more stable than its isomer, namely, [1,2,4]tri-
azolo[4,3-c]pyrimidine.14
(5) Guetzoyan, L. J.; Spooner, R. A.; Lord, J. M.; Roberts,
L. M.; Clarkson, G. J. 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, V. V.; Minkin, V. I.; Minyaeva, L. G.; Tyurin,
R. G.; Krasnikov, V. V.; Vorobyev, E. V.; Starikova, Z. A.
ARKIVOC 2005, (x), 9.
(8) Andreas, K.; Hunds, A. Eur. Pat. Appl., EP 1284261, 2003;
Chem. Abstr. 2003, 138, 170252.
(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): d = 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): d = 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.
In conclusion, a mild and simple condition has been dis-
covered to induce the conversion of the aldehyde chloro-
pyrimidinyl hydrazones
4
into 1,2,4-triazolo[1,5-
c]pyrimidines 6 simply by treating with bromine followed
by a basic workup. The condition allows concurrent ring-
bromination and Dimroth rearrangement taking place via
temporary ring opening of the pyrimidine moiety fol-
lowed by a repeated ring closure. The present methodolo-
gy carries very attractive features such as good yields,
simple reaction conditions and easy workup. Moreover,
the two halogen atoms in the products offer great promise
for easy elaboration by, for example, nucleophilic dis-
placement and coupling reactions. This investigation is
underway in our laboratory.
Supporting Information for this article is available online at
(10) Nasyr, I. A.; Ovchinnikov, V. G.; Bobrova, O. B.;
Cherkasov, V. M. Ukr. Khim. Zh. (Russ. Ed.) 1987, 53, 198;
Chem. Abstr. 1987, 108, 112366.
(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
Acknowledgment
We thank Ms. Jingmei Wang for her assistance with analyzing the
X-ray diffraction. Mr. Shanyong Ma from Shanghai ChemPartner
Co., Ltd. is acknowledged for his generous help with the preparati-
on of 4,6-dichloropyrimidine.
data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 (1223)336033.
(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
References and Notes
(1) For reviews, see: (a) Hurst, D. T. An Introduction to the
Chemistry and Biochemistry of Pyrimidines, Purines and
Pteridines; Wiley: Chichester, 1980. (b) Brown, D. J. The
Pyrimidines; Wiley: New York, 1994. (c) Katrizky, A. R.;
Rees, C. W.; Scriven, E. F. V. Comprehensive Heterocyclic
Chemistry II; Pergamon: Oxford, 1996. (d) Gribble, G.;
Joule, J. Progress in Heterocyclic Chemistry, Vol. 18;
Elsevier: Oxford, 2007.
(2) For reviews on the synthesis of pyrimidine triazoles, see:
(a) Shaban, M. A. E.; Morgaan, A. E. A. Adv. Heterocycl.
Chem. 1999, 75, 131. (b) Shaban, M. A. E.; Morgaan,
A. E. A. Adv. Heterocycl. Chem. 1999, 75, 243.
(3) Nagamatsu, T.; Fujita, T. Chem. Commun. 1999, 1461.
(4) (a) Pastorin, G.; Da Ros, T.; Spalluto, G.; Deflorian, F.;
Moro, S.; Cacciari, B.; Baraldi, P. G.; Gessi, S.; Varani, K.;
Borea, P. A. J. Med. Chem. 2003, 46, 4287. (b) Neustadt,
B. R.; Hao, J. S.; Lindo, N.; Greenlee, W. J.; Stamford,
A. W.; Tulshian, D.; Ongini, E.; Hunter, J.; Monopoli, A.;
Bertorelli, R.; Foster, C.; Arik, L.; Lachowicz, J.; Ng, K.;
Feng, K. I. Bioorg. Med. Chem. Lett. 2007, 17, 1376.
(c) Neustadt, B. R.; Liu, H.; Hao, J. S.; Greenlee, W. J.;
Stamford, A. W.; Foster, C.; Arik, L.; Lachowicz, J.; Zhang,
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): d = 9.18 (s, 1 H), 8.32–8.34 (m,
2 H), 7.52–7.54 (m, 3 H). 13C NMR (100 MHz, CDCl3): d =
Synlett 2010, No. 14, 2179–2183 © Thieme Stuttgart · New York