A convenient route for the synthesis of novel 2-substituted [1,2,4]triazolo[1,5- C ]pyrimidine derivatives

Article abstract of DOI:10.1055/s-0030-1258514

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.

Full text of DOI:10.1055/s-0030-1258514

LETTER
2179
A Convenient Route for the Synthesis of Novel 2-Substituted
[1,2,4]Triazolo[1,5-c]pyrimidine Derivatives
2
-Substituted [1,2
h
,4]Triazolo[
a
1,5-
c
]pyrim
o
idine
D
erivatives Li, Zhiming Li, Quanrui Wang*
Department of Chemistry, Fudan University, Shanghai 200433, P. R. of China
Fax +86(21)65641740; E-mail: qrwang@fudan.edu.cn
Received 15 April 2010
they are plagued by the limitations of complex pathways,
harsh conditions, difficult workup aside from the forma-
tion of side products. In view of the emerging importance
of [1,2,4]triazolo[1,5-c]pyrimidine nucleus as a fertile
Abstract: Reactions of easily accessible chloropyrimidinyl hydra-
zones with bromine were investigated. Oxidative cyclization fol-
lowed 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-substitut- source of biologically important molecules we wish to re-
ed [1,2,4]triazolo[1,5-c]pyrimidines.
port our recent findings in this connection.
Key words: 4,6-dichloropyrimidine,
Dimroth rearrangement, [1,2,4]triazolo[1,5-c]pyrimidine
hydrazones,
bromine,
The required starting material, 4,6-dichloropyrimidine (2)
was easily prepared using a two-step patent method as de-
picted in Scheme 1.8 Thus, dimethyl malonate and two
equivalents of formamide, both commercially available,
reacted in the presence of sodium methoxide in methanol
under reflux to give the intermediate 4,6-dihydroxypyrim-
idine (1) in 85% yield. The transformation into 2 was
achieved in 80% yield by chlorination with POCl3 under
catalysis by N,N-dimethylaniline at refluxing temperature
for 12 hours. Compound 2 was employed for the synthesis
of 1-(6-chloropyrimidin-4-yl)hydrazine (3). After screen-
ing a set of conditions, an optimal condition could be de-
termined. Thus, 2 was allowed to react with two-mole
amount of 50% hydrazine in ethanol at 45 °C for two
hours and stirred overnight at room temperature to furnish
3 in 88% yield (Scheme 1).
Pyrimidines and fused bi- or tricyclic analogues are priv-
ileged heterocycles that are of immense importance in the
design and discovery of new compounds for pharmaceu-
tical and herbicide applications.1 In particular, compounds
carrying a [1,2,4]triazolo[1,5-c]pyrimidine nucleus have
received considerable attention due to their remarkable
adenosine and benzodiazepine receptor affinity.2 For
example, 3- and/or 5-substituted 7H-pyrazolo[4,3-
e][1,2,4]triazolo[4,3-c]pyrimidines have been reported to
be potent xanthine oxidase (XO) inhibitors.3 Many 1,2,4-
triazolo[1,5-c]pyrimidines as well as pyrazolo[4,3-
e][1,2,4]triazolo[4,3-c]pyrimidines have recently been
prepared and investigated for use as selective antagonists
at the A2a receptor, which offers great promise in the
treatment of Parkinson’s disease.4 A recent paper by
Clarkson and co-workers also predicted the potential use
of triazolopyrimidines as inhibitors of Shiga toxin traf-
ficking.5 In addition, various triazolopyrimidines have
been used as the new pharmacological tool for the charac-
terization of human A3 adenosine receptor.6
OMe
+ 2 H
OH
O
C
O
O
MeONa, MeOH
N
NH2
reflux, 3 h
85%
N
1
OH
Cl
OMe
Cl
POCl3
N,N-dimethylaniline
50% NH2NH2⋅H2O
N
N
In contrast to the significance of this class of heterocycles,
a literature survey revealed that methods available for the
construction of the [1,2,4]triazolo[1,5-c]pyrimidine moi-
ety are not plentiful. The frequently employed route in-
volves the preformation of 1-amino-6-imino-substituted
pyrimidines, from which [1,2,4]triazolo[1,5-c]pyrimidine
can be assembled by reaction with carboxylic acids or de-
rivatives as the one-carbon cyclizing agent.4 Alternative-
ly, dehydrative cyclization of the 4-acyl-hydrazino-
pyrimidines was reported to afford, after ring rearrange-
ment, [1,2,4]triazolo[1,5-c]pyrimidines instead of the iso-
meric [1,2,4]triazolo[4,3-c]pyrimidines.7 Each of the
existing methods has its own merits, while sometimes
reflux, 12 h
80%
45 °C, 2 h
88%
N
NHNH2
N
Cl
3
2
Scheme 1 Synthesis of the chloropyrimidinyl hydrazine 3
With compound 3 in hand, we started out the preparation
of the corresponding hydrazones of various aldehydes.
Thus, the chloropyrimidinyl hydrazone 4a was firstly pre-
pared by condensation of hydrazine 3 with slightly exces-
sive benzaldehyde at room temperature in about half an
hour as an off-white solid in 73% yield. Analogously, a set
of different aldehyde hydrazones 4b–l was prepared under
the same conditions except that appropriate recrystalliza-
tion solvent has to be selected to achieve an optimal puri-
fication. The yields ranged from good to excellent
(Table 1).9
SYNLETT 2010, No. 14, pp 2179–2183
x
x
.x
x
.2
0
1
0
Advanced online publication: 27.07.2010
DOI: 10.1055/s-0030-1258514; Art ID: W06110ST
© Georg Thieme Verlag Stuttgart · New York

2180
C. Li et al.
LETTER
Cl
N
Cl
N
H
R
RCHO, EtOH
r.t., 30–40 min
N
N
N
H
N
NHNH2
3
4
Br
Br
i. Br2, AcHO, r.t., 30–60 min
ii. 0.5 N NaOH, 30–60 min
Cl
N
N
Cl
N
R
N
N
N
N
N
6
R
5
Figure 1 Perspective view and atom labeling of the X-ray crystal
structure of 6a. The bond lengths in the bicyclic system are the follo-
wing: N(1)–C(2) 1.354, C(2)–C(3) 1.358, C(3)–C(4) 1.417, N(2)–
C(4) 1.373, N(2)–C(1) 1.366, N(1)–C(1) 1.289, N(2)–N(3) 1.360,
N(3)–C(5) 1.345, N(4)–C(5) 1.368, N(4)–C(4) 1.325, C(5)–C(6)
1.461, Cl(1)–C(2) 1.729, Br(1)–C(3) 1.864 Å. The dihedral angles:
C(1)–N(2)–N(3)–C(5), C(4)–N(2)–N(3)–C(5), C(2)–C(3)–C(4)–
N(4) and N(2)–N(3)–C(5)–C(6) are –179.6°, –0.7°, 179.2° and
–179.9°, respectively.
Scheme 2 Synthesis of the [1,2,4]triazolo[1,5-c]pyrimidines 6
As can be seem from Table 1, aromatic aldehydes gener-
ally afforded satisfactory isolated yields of the corre-
sponding hydrazones 4, while aliphatic ones gave inferior
results (Table 1, entries 1–9 vs. 10–12). For unsaturated
aliphatic aldehydes, the hydrazone preparation failed
completely under the same and variable conditions
(Table 1, entries 13 and 14).
Table 1 Synthesis of the Chloropyrimidinyl Hydrazones 4a
Since most of the attained chloro-substituted pyrimidinyl
hydrazones 4 have not been reported hitherto,10 they were
characterized by means of spectral (MS, IR and NMR)
Entry
R
Productb Solventc
Yield
(%)d
1
1
2
Ph
4a
4b
4c
4d
4e
4f
EtOH
73
80
63
85
74
tools (see supporting information). For example, the H
NMR spectra of all such hydrazones showed a character-
istic signal in the downfield region, d = 8.32–9.85, assign-
able to the C-2 pyrimidine proton. The absorptions around
3400 cm–1 can be attributed to the N–H stretching vibra-
tions of the hydrazone group.
2-ClC6H4
4-ClC6H4
2,4-Cl2C6H3
2-BrC6H4
4-BrC6H4
EtOH
3
DMF
4
DMF–H2O (2:8)
EtOH
5
Our initial oxidative cyclization study was attempted us-
ing 4a as the model substrate. Thus, 4a was treated with
2.2 equivalents of bromine in glacial acetic acid contain-
ing a small amount of anhydrous sodium acetate at ambi-
ent conditions for one hour. After stirring with 0.5 N
aqueous NaOH for 30 minutes, a single off-white solid
product was isolated. Based on NMR spectroscopy and
mass spectroscopy analysis, this was assigned to be the 2-
phenyl-substituted [1,2,4]triazolo[1,5-c]pyrimidine 6a
bearing an additional bromo substituent at the pyrimidine 11
ring (Scheme 2). Thus, the mass spectrum revealed that
the product has two hydrogen atoms less than the starting
hydrazone 4a. The proton NMR spectrum indicated also
6
EtOH–DMF (2:1) 66
7
2-Br-4,5-(MeO)2C6H2 4g
DMF
EtOH
EtOH
PE
85
84
74
65
8
4-MeOC6H4
2-MeC6H4
Et
4h
4i
9
10
4j
4k
4l
i-Pr
EtOH–PE (1:19) 68
12
Me(Ph)CH
– (1:19)
–
78
e
13
4m
4n
–
the absence of the signals from the N=CH and the NH pro-
tons on the hydrazone moiety along with the disappear-
ance of the pyrimidine C(5)-H of 4a.
e
14
–
–
The formation of 6a can be accounted for by the initial ox-
idative cyclization with concomitant monobromination of
the pyrimidine ring at the position next to the chloro-bear-
ing carbon followed by ring isomerization.
a Reaction performed using the chloropyrimidinyl hydrazine 2 (0.30
g, 2.08 mmol, 1 equiv), absolute EtOH (15 mL), aldehyde (2.29
mmol, 1.1 equiv), at r.t. for 30–40 min.
b For general procedure and selected characterization data, see ref. 9.
c Used for recrystallization.
This result deviated somewhat from our original expecta-
tion that the product was the isomeric [1,2,4]triazolo[4,3-
c]pyrimidine 5a. To unambiguously confirm the structur-
al establishment, an X-ray crystallography analysis was
performed, providing unequivocal evidence for the struc-
ture 6a (Figure 1).11
d Yields refer to isolated product by recrystallization.
e Complex mixture of products.
This result was quite promising to us and drew our atten-
tion considerably in view of the significance of this class
of heterocyclic compounds. Therefore, the generality of
Synlett 2010, No. 14, 2179–2183 © Thieme Stuttgart · New York

LETTER
2-Substituted [1,2,4]Triazolo[1,5-c]pyrimidine Derivatives
2181
this facile transformation was established by converting terms of yield and reaction rate. All the new products were
all of the prepared hydrazones 4b–l into the corresponding fully characterized by IR, NMR and mass spectra.
[1,2,4]triazolo[1,5-c]pyrimidines 6b–l.12 As indicated in
Although we were unable to elucidate the mechanism in
Table 2, the reactions were all successful leading to the
detail, the reactions investigated above allow a convenient
formation of 6 without detection of any intermediates 5.
methodology to access specific triazolopyrimidine iso-
The protocol showed a good substrate scope. The reaction
mers from readily accessible precursors by simple oxida-
of substrates 4a–i derived from aromatic aldehydes went
tion.
to completion in one hour to provide the corresponding
product 6 in moderate to high yields, except with the
trisubstituted 4g which required slightly longer reaction
time. Substrates bearing electron-withdrawing group(s)
The presence of acidic species was assumed to catalyze
the Dimroth-type rearrangement of the intermediate
1,2,4-triazolo[4,3-c]pyrimidines 5 to the isomeric 1,2,4-
triazolo[1,5-c]pyrimidines 6 in a similar manner to other
seemed to be beneficial in achieving a better yield
acid-catalyzed Dimroth rearrangements (Scheme 3).13 In
(Table 2, entries 2–7) than those bearing electron-releas-
the first step, the hydrazones undergo oxidative ring clo-
ing groups (Table 2, entries 9–12). Similarly, substrates
sure and concurrent bromination by reaction with Br2 to
from aliphatic aldehydes such as isobutyraldehyde and 2-
produce 1,2,4-triazolo[4,3-c]pyrimidines 5, which have
phenylpropanal (4k, 4l) worked smoothly to furnish 6k
and 6l, respectively, with the latter one more promising in
been reported to be unstable under both acidic and basic
conditions.4d In our case, compounds 5 are assumed to be
Table 2 Synthesis of the Triazolopyrimidines 6a
Entry
1
R
Productb
6a
Time (min)
Solventc
EtOH–H2O (8:2)
EtOH
Yield (%)d
Ph
60
60
60
60
60
60
80
60
60
80
120
60
83
75
73
74
68
56
53
45
70
65
40
73
2
2-ClC6H4
4-ClC6H4
2,4-Cl2C6H3
2-BrC6H4
4-BrC6H4
2-Br-4,5-(MeO)2C6H2
4-MeOC6H4
2-MeC6H4
Et
6b
6c
3
EtOH
4
6d
6e
EtOH
5
EtOH
6
6f
EtOH
7
6g
EtOH
8
6h
6i
EtOH
9
EtOH
10
11
12
6j
EtOH–PE (2:3)
e
i-Pr
6k
–
Me(Ph)CH
6l
EtOH–PE (1:19)
a Reaction performed using hydrazone 4 (0.6 mmol), Br2 (2.2 equiv), AcOH (1.9 mL), at r.t.; then NaOH (0.5 N, 10 mL), 0 °C, 30–60 min.
b For general procedure and selected characterization data, see ref. 12.
c Used for recrystallization.
d Yields refer to isolated product by recrystallization.
e Separated by chromatography with PE–EtOAc as eluent (2:1).
Br
Br
N
Br
Br
N
N
N
N
N
N
N
H+
[1,3]-H shift
Cl
N
N
N
Cl
N
Cl
Cl
R
R
R
R
N
H
H
N
N
N
H
5
I
II
II'
Br
Br
Br
H
Br
N
N
Cl
Cl
Cl
N
N
N
N
R
R
R
N
Cl
N
N
R
N
N
H
N
N
– H+
N
N
N
H
III
III'
IV
6
Scheme 3 Postulated mechanism for the Dimroth rearrangement 5 → 6
Synlett 2010, No. 14, 2179–2183 © Thieme Stuttgart · New York

2182
C. Li et al.
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
http://www.thieme-connect.com/ejournals/toc/synlett.
(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
charge via www.ccdc.cam.ac.uk, or by emailing
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

LETTER
2-Substituted [1,2,4]Triazolo[1,5-c]pyrimidine Derivatives
2183
166.1, 153.8, 146.7, 140.1, 131.9, 130.4, 129.5, 127.9,
(13) (a) Subbotina, O. J.; Fabian, W.; Tarasov, V. E.; Volkova,
N. N.; Bakulev, A. V. Eur. J. Org. Chem. 2005, 2914.
(b) Widyan, K.; Kurz, T. Synthesis 2005, 1340. (c) Sako,
M.; Kawada, H. J. Org. Chem. 2004, 69, 8148.
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.
(14) Fischer, G. Adv. Heterocycl. Chem. 1993, 57, 81.
Synlett 2010, No. 14, 2179–2183 © Thieme Stuttgart · New York