Synthesis of 8-Bromo-7-chloro[1,2,4]triazolo[4,3- C ]pyrimidines, Their Ring Rearrangement to [1,5- C ] Analogues, and Further Diversification

Article abstract of DOI:10.1055/s-0034-1378453

8-Bromo-7-chloro[1,2,4]triazolo[4,3-c]pyrimidines were prepared by bromine-mediated oxidative cyclization of the aldehyde-derived hydrazones. The structure of one such product was unambiguously confirmed by single-crystal X-ray analysis. While the C-5 unsubstituted 1,2,4-triazolo[4,3-c]pyrimidine chemotype is extremely susceptible to ring isomerization at ambient conditions, the C-5-substituted analogues were found to be quite stable, permitting isolation in pure form. Nevertheless, they can still be converted into the 1,2,4-triazolo[1,5-c]pyrimidines by base- or acid-promoted Dimroth rearrangement. The presence of halogen functionalities on the pyrimidine nucleus renders the products useful as versatile synthetic intermediates for the easy diversification, as evidenced by palladium-catalyzed Kumada cross-couplings and Buchwald-Hartwig amination, as well as direct aromatic substitution.

Full text of DOI:10.1055/s-0034-1378453

2734▌
PAPER
paper
Synthesis of 8-Bromo-7-chloro[1,2,4]triazolo[4,3-c]pyrimidines, Their Ring
Rearrangement to [1,5-c] Analogues, and Further Diversification
Triazolopyrimidines
Caifei Tang, Chao Wang, 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: 08.05.2014; Accepted after revision: 20.06.2014
lo[4,3-c]pyrimidin-3-ones behave likewise as the antago-
Abstract: 8-Bromo-7-chloro[1,2,4]triazolo[4,3-c]pyrimidines were
nists.9 A number of 3- and/or 5-substituted 7H-
prepared by bromine-mediated oxidative cyclization of the alde-
pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines
have
hyde-derived hydrazones. The structure of one such product was
unambiguously confirmed by single-crystal X-ray analysis. While
been reported to be potent xanthine oxidase (XO)
the C-5 unsubstituted 1,2,4-triazolo[4,3-c]pyrimidine chemotype is inhibitors.10 Moreover, triazolopyrimidine derivatives as
extremely susceptible to ring isomerization at ambient conditions,
the C-5-substituted analogues were found to be quite stable, permit-
ting isolation in pure form. Nevertheless, they can still be converted
N-donor heterocyclic ligands have also been well docu-
mented.11
The wide range of pharmacological properties demon-
strated by triazolopyrimidines stimulate the synthesis of
new members of this class of heterocycles.12 A number of
different strategies have been employed for the synthesis
of [1,2,4]triazolo[1,5-c]pyrimidines, and these can be cat-
egorized into two alternative disconnection strategies
(Scheme 1). The most frequently cited synthetic route in-
vokes the preformation of 1-amino-6-imino-substituted
pyrimidines, from which [1,2,4]triazolo[1,5-c]pyrimidine
ring is directly assembled through the annulation of a car-
bonyl compound like carboxylic acids or derivatives
(route A).13,14 The second most common route usually in-
volves the dehydrative cyclization of carboxylic acid N′-
(pyrimidin-4-yl)hydrazide to give [1,2,4]triazolo[4,3-
c]pyrimidines, and further ring rearrangement enables the
conversion into the [1,5-c] analogues (route B).15
into the 1,2,4-triazolo[1,5-c]pyrimidines by base- or acid-promoted
Dimroth rearrangement. The presence of halogen functionalities on
the pyrimidine nucleus renders the products useful as versatile syn-
thetic intermediates for the easy diversification, as evidenced by
palladium-catalyzed Kumada cross-couplings and Buchwald–
Hartwig amination, as well as direct aromatic substitution.
Key words: hydrazones, oxidation, nitrogen heterocycles, triazol-
opyrimidines, rearrangement
Due to the structural resemblance to purine nucleobases,
the triazolopyrimidine ring system has been extensively
explored as an important class of pharmacophore in drug
discovery process.1 So far, a great deal of diversified tri-
azolopyrimidine derivatives have been prepared possess-
ing a wide variety of biological activities.2 For example,
1,2,4-triazolo[1,5-a]pyrimidines are prevalent in many bi-
ologically active molecules and used as vasodilators, anti-
cancer agents with a unique mechanism of tubulin
inhibition,2 and spleen tyrosine kinase (SYK) inhibitors.3
In addition, they are also applied as herbicides.4 Interest-
ingly, the compound named essramycin has been isolated
as a natural product from the fermentation broth of a ma-
rine organism and assigned as the 1,2,4-triazolo[1,5-a]py-
rimidine. Two reports on its synthesis appeared in 2010 at
the same time, but with conflicting declaration on the an-
tibacterial activity.5,6
2
N
b
c
a
N
1
N
NH2
NH
route A
N
N
3
R
f
RCOCl
(RCO)2O
or RCO2H
5
N
e
d
4
isomerization
R
O
R
route B
a
N
b
4
N
N
N
5
N1
N
N
NH
c
f
RCONHNH2
N
X
3
N
e
d
H
2
Among all of the fused heterocycles containing a triazol-
opyrimidine core, [1,2,4]triazolo[1,5-c]pyrimidines and
[1,2,4]triazolo[4,3-c]pyrimidines have attracted consider-
able attention, mainly due to their important biological ac-
tivity displayed over a broad range of therapeutic classes.7
For example, compounds carrying a [1,2,4]triazolo[1,5-
c]pyrimidine nucleus behave as selective human A2A and
A3 adenosine receptor antagonists, which offers great
promise in the treatment of Parkinson’s disease, or as
Hsup90 modulators.8 Some derivatives of [1,2,4]triazo-
Scheme 1 Classical methods to generate [1,2,4]triazolo[1,5-c]py-
rimidines and [1,2,4]triazolo[4,3-c]pyrimidines
Each of these methods is capable of achieving the specific
triazolopyrimidines. There are, however, intrinsic limita-
tions to the existing methods, such as harsh conditions,
expensive reagents, low yields, and lack of easy availabil-
ity/preparation of the starting materials. As a result, devel-
opment of simple and efficient protocols to gain access to
novel triazolopyrimidines is still attracting significant at-
tention from organic community.10b,16,17
SYNTHESIS 2014, 46, 2734–2746
Advanced online publication: 21.07.2014
In an earlier publication, we described a facile access to 2-
substituted 8-bromo-7-chloro[1,2,4]triazolo[1,5-c]pyrim-
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0034-1378453; Art ID: ss-2014-h0286-op
© Georg Thieme Verlag Stuttgart · New York

PAPER
Triazolopyrimidines
2735
idines from the reaction of aldehyde-derived (6-chloro-4- aldehyde with 2a, which afforded hydrazone 3c in 66%
pyrimidinyl)hydrazones with bromine and ensuing yield (Table 1, entry 3).
Dimroth rearrangement.18 Because of the thermodynamic
Table 1 Synthesis of Aldehyde Chloropyrimidinylhydrazones 3a
instability of the incipient [1,2,4]triazolo[4,3-c]pyrimi-
dine products, only the [1,5-c] isomers devoid of C5-sub-
Entry
R1
R2
Time (h) Product Yield (%)b
stitution have been achieved. We wondered if the scope of
this method could be extended by the application to other
2-substituted 4,6-dichloropyrimidines. In this paper, we
report that the substitution at the C-2 position of the py-
rimidinylhydrazones dramatically enhance the stability of
the initial [1,2,4]triazolo[4,3-c]pyrimidine products, thus
ensuring routine isolation. Nevertheless, subsequent acid-
ic or basic treatment can convert them readily into the
[1,2,4]triazolo[1,5-c]pyrimidines. From a synthetic point
of view, this finding is quite profitable since it allows con-
struction of both [1,2,4]triazolo[4,3-c]pyrimidine and
[1,2,4]triazolo[1,5-c]pyrimidine counterparts, and the
halogen atoms offer the opportunity for feasible manipu-
lation of the products, thus being very beneficial for struc-
tural diversification.
1c
2c
H
Ph
0.5
0.5
1.0
0.5
0.5
0.5
0.5
0.5
1.0
1.0
1.0
0.5
0.5
0.5
0.5
1.0
1.0
3a
3b
3c
3d
3e
3f
85
84
66
81
85
90
84
88
84
78
81
89
87
90
93
96
82
H
2-MeC6H4
Et
3c
H
4d
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
5d
2-ClC6H4
2,4-Cl2C6H3
2-MeC6H4
3-MeC6H4
Et
6
7
3g
3h
3i
8
9d
10
11
12d
13d
14
15
16d
17
Me(Ph)CH
pyridin-4-yl
Ph
3j
We have demonstrated that the reaction of 6-chloro-4-hy-
drazinopyrimidines 2 with aldehydes followed by oxida-
tion with bromine and Dimroth rearrangement is an
efficient approach to access the title compounds.18 The
synthesis of the required aldehyde hydrazones was ac-
complished in the procedure as depicted in Scheme 2.
Usually, the hydrazinopyrimidines are prepared from
base-mediated Dimroth arrangement of 1-amino-6-imino-
pyrimidines.10b,14 The 6-chloro-4-hydrazinopyrimidines 2
were obtained by treatment of the dichlorides 1 with two
moles of 50% hydrazine in ethanol at 45 °C for two hours
in 90–95% yields. This aromatic nucleophilic substitution
route is obviously more straightforward. Next, the synthe-
3k
3l
2-ClC6H4
2-MeC6H4
3-MeC6H4
Et
3m
3n
3o
3p
3q
pyridin-4-yl
a The reaction was carried out using hydrazine 2 (3.0 mmol) and
R2CHO (3.6 mmol) in EtOH (20 mL) at r.t. for the time as indicated.
sis of the corresponding hydrazones of various aldehydes b Yield of isolated product.
was examined. Thus, the hydrazine 2a was condensed
with 1.2 equivalents of benzaldehyde to give 85% yield of
c See reference 18.
d See reference 19.
the hydrazone 3a in absolute ethanol at room temperature
in about 30 minutes. Using the same method, condensa-
tion of the hydrazine derivatives 2 with a set of appropri-
ate aldehydes provided other hydrazones 3b–q. All the
reactions proceeded with no difficulty (Table 1) and gave
uniformly satisfactory yields with exception for propion-
It is important to note that these reactions are applicable to
both aromatic and aliphatic aldehydes, thus, would allow
the production of chemical diversity at C-2 and C-3 of the
triazolo core of the title bicyclic heterocycles. Hydrazine
2c bearing a phenyl substituent at C-2 afforded generally
higher yields (Table 1, entries 12–17). Whilst some of
these hydrazones have been reported,18,19 several are hith-
erto unknown compounds. They were characterized by
their spectral data (1H, 13C NMR, IR, MS, and HRMS; see
the Supporting Information).
In the preceding paper,18 we reported that the C-2 unsub-
stituted hydrazones 3 afforded the [1,2,4]triazolo[1,5-
c]pyrimidine products 5a–c when they are subjected to
oxidation with bromine (Scheme 3). We presumed that
the 1,2,4-triazolo[4,3-c]pyrimidines 4a–c are intermedi-
ates, which then quickly undergo the Dimroth ring rear-
rangement. In fact, small quantities of the triazoles 4a–c
were observable from 1H NMR spectra and TLC analysis
as the reaction proceeded.
Cl
Cl
NH2NH2•H2O (50%)
N
N
45 °C, 2 h
90–95%
R1
N
Cl
R1
R2
N
NHNH2
1a–c
2a–c
Cl
R2CHO
H
N
r.t., 30–60 min
66–96%
N
R1
N
N
H
3a–q
R
2 = alkyl, aryl, heteroaryl
1a, 2a: R1 = H
1b, 2b: R1 = Me
1c, 2c: R1 = Ph
Scheme 2 Synthesis of the aldehyde pyrimidinylhydrazones 3
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2734–2746

2736
C. Tang et al.
PAPER
R1
R2
N
3a–c
N
N
R1 = H
2 h
N
Cl
R1
65–83%
Br
4a–c
not isolable
H
R2
Br2 (3.0 equiv)
N
N
N
AcOH, NaOAc
r.t.
Cl
N
H
R1
R1
R2
N
3a–q
3d–q
N
N
N
N
Et3N
N
N
R2
reflux, 5–24 h
75–98%
N
R
1 = Me, Ph
24–72 h
52–94%
Cl
Cl
Br
4d–q
Br
5a–q
Scheme 3 Bromine-mediated oxidative cyclization of hydrazones 3 and subsequent Dimroth rearrangement
To examine the effect of the C-2 substituent of hydra- dine 4d′ carrying no bromo substituent. Further treatment
zones 3 on the reactivity, the methyl-substituted 3d was of 4d′ with three additional equivalents of bromine under
taken as the model substrate to explore the reaction with the same conditions resulted in the formation of the 8-bro-
three equivalents of bromine in glacial acetic acid in the mo-substituted product 4d in 85% yield (Scheme 4). This
presence of sodium acetate, according to our previously observation provided clear evidence that the bromination
established conditions.18 The reaction proceeded smooth- takes place after completion of the oxidative cyclization.
ly and reached completion after 24 hours. Usual basic
workup afforded 94% yield of the 8-bromo-7-
chloro[1,2,4]triazolo[4,3-c]pyrimidine 4d as the sole
product.
Table 2 Oxidative Cyclization of Aldehyde Chloropyrimidinyl-
hydrazones 3 Leading to Triazolopyrimidines 4 or 5a
Entry R1
R2
Time (h) Product Yield (%)b
The protocol was extended to other 2-substituted pyrim-
idinylhydrazones 3e–q and the respective [1,2,4]triazo-
lo[4,3-c]pyrimidine 4e–q were successfully isolated
(Scheme 3) in generally high yields (Table 2). For com-
parison, the results with C-2 unsubstituted 3a–c to afford
5a–c are also presented.
1c
2c
3c
4
H
Ph
2
2
5a
5b
5c
4d
4e
4f
83
70
65
94
91
93
90
89
91
86
60
84
82
81
83
86
52
H
2-MeC6H4
Et
H
2
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
24
24
24
24
24
24
24
48
72
72
72
72
72
72
Exceptions were found when the isonicotinaldehyde-
derived hydrazones 3k and 3q were subjected to the same
conditions. In these cases, only moderate yields of the cor-
responding [1,2,4]triazolo[4,3-c]pyrimidines 4 were pro-
duced, even after a much longer reaction time (Table 2,
entries 11 and 17). This may be attributed to the electron-
withdrawing effect of the 4-pyridyl group, inhibiting the
oxidization of the hydrazones.
5
2-ClC6H4
2,4-Cl2C6H3
2-MeC6H4
3-MeC6H4
Et
6
7
4g
4h
4i
8
9
It has also been observed that 2-phenyl-substituted sub-
strates 3l–q underwent the oxidative cyclization smoothly
to give the respective 5-phenyl-substituted [1,2,4]triazo-
lo[4,3-c]pyrimidines 4l–q (Table 2, entries 12–17), de-
spite that the rate became very slow and 72 hours were
required for full conversion, plausibly due to the steric
hindrance.
10
Me(Ph)CH
pyridin-4-yl
Ph
4j
11
12
13
14
15
16
17
4k
4l
2-ClC6H4
2-MeC6H4
3-MeC6H4
Et
4m
4n
4o
4p
4q
Although it is very interesting that the protocol afforded
products bearing two different halogens in this process,
the mechanistic aspect seems to be unclear. To get some
evidence on the mechanism, substrate 3d was allowed to
react with only slightly excessive amount of bromine
(Scheme 4).
pyridin-4-yl
a The reaction was carried out using hydrazone 3 (1.0 mmol), Br2
(0.48 g, 3.0 mmol), and NaOAc (0.74 g, 9.0 mmol) in AcOH (10 mL)
at r.t. for the specified time.
To our delight, the reaction resulted in 81% yield of the
corresponding chloro-substituted triazolo[4,3-c]pyrimi-
b Yield of isolated product.
c See reference 18.
Synthesis 2014, 46, 2734–2746
© Georg Thieme Verlag Stuttgart · New York

PAPER
Triazolopyrimidines
2737
Table 3 Base-Catalyzed Dimroth Rearrangement of 4 to 5a
Ph
N
Br2 (1.1 equiv)
AcOH, NaOAc
H
Ph
N
N
N
N
N
Entry
R1
R2
Time (h) Product Yield (%)b
N
N
r.t., 2 h
81%
Cl
Cl
Cl
N
H
1
2
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Ph
5
5
5d
5e
5f
98
96
95
98
96
94
91
80
86
88
85
88
86
75
H
3d
4d'
2-ClC6H4
2,4-Cl2C6H3
2-MeC6H4
3-MeC6H4
Et
Ph
Ph
N
Br2 (3.0 equiv)
AcOH, NaOAc
3
5
N
N
N
N
4
5
5g
5h
5i
Cl
AcO
r.t., 12 h
85%
N
N
H
Br
5
5
Br
A
4d
6
5
Scheme 4 Verifying the sequential oxidative cyclization and bromi-
nation using 3d
7
Me(Ph)CH
pyridin-4-yl
Ph
5
5j
8
5
5k
5l
In addition, because the bromination occurs exclusively at
the electron-deficient pyrimidine ring, the reaction pre-
sumably goes by way of addition/elimination via an inter-
mediate like A rather than an electrophilic process in
nature.20
9
24
24
24
24
24
24
10
11
12
13
14
Ph
2-ClC6H4
2-MeC6H4
3-MeC6H4
Et
5m
5n
5o
5p
5q
Ph
Ph
Literature work has revealed that [1,2,4]triazolo[1,5-c]py-
rimidine ring system like 5 is thermodynamically more
stable than its [1,2,4]triazolo[4,3-c]pyrimidine isomers
4.21 Taking this inherent driving force in mind, the Dim-
roth rearrangement of the incipient [4,3-c] products 4d–q
was next examined. Both acidic and basic conditions were
employed. We were pleased to find that, by treatment with
catalytic amount of concentrated hydrochloric acid or an-
hydrous triethylamine in refluxing ethanol, compounds
4d–q underwent the expected Dimroth ring isomerization
to yield cleanly the [1,5-c] heterocylces 5d–q in high to
excellent yields (Scheme 3). While the reaction reached
completion in five hours for the C-5 methyl-substituted 4,
a much longer time (24 h) was required for the phenyl-
substituted analogues. In addition, the latter furnished
somewhat diminished yields. Table 3 summarizes the
base-catalyzed ring isomerization.
Ph
Ph
pyridin-4-yl
a The reaction was carried out using 4 (0.5 mmol) and one drop of
Et3N in EtOH (20 mL) at reflux.
b Yield of isolated product.
species nitrilimines II would be generated by the action of
the attendant sodium acetate. Intermediates II are as-
sumed to undergo in situ symmetry-allowed 6π-disrotato-
ry 1,5-electrocyclization to furnish, after a concomitant
bromination via III, the bicyclic heterocycles 4. The cy-
clization of 3 to 4 recalls the related oxidative cyclization
of a number of N-heteroarylaldehyde hydrazones with
chloramine-T, FeCl3, Br2, I2, iodobenzene diacetate, and
many other oxidizing agents.7a,10,16,19
As mentioned above, when R1 is not a hydrogen atom,
heterocycles 4 are isolable and are proved to be stable un-
der ambient conditions. However, they are capable of un-
dergoing Dimroth rearrangement to give the
thermodynamically more stable 1,2,4-triazolo[1,5-c]py-
rimidines 5. The HCl-catalyzed rearrangement of 4 to
their isomeric derivatives 5 is in accord with our pub-
lished work under similar conditions.18
The progress of the rearrangement can be monitored eas-
ily by TLC analysis. The structures of the [4,3-c] products
4 and the ring-isomerized [1,5-c] products 5 are distin-
guishable by careful comparison of their NMR spectra.
For example, the 1H NMR spectrum of 4d revealed the C-
5 methyl protons as a singlet at δ = 2.35, whereas this ab-
sorption in 5d was observed obviously downfield at δ =
3.00. Similar downfield shift for the C-5 phenyl groups in
the 1H NMR spectra is also discernible for the isomeriza-
tion 4l–q → 5l–q. The downfield shift can be attributed to
proximity of the two nitrogen atoms in the rearranged tri-
azole ring. To get an unambiguous structural assignment,
a single crystal of 4d was grown and subjected to X-ray
diffraction analysis. The result ascertained the spectral de-
termination.22
In the presence of triethylamine, the Dimroth rearrange-
ment is presumed to occur via tandem ring opening and
ring closure (Scheme 5). Thus, the electrophilic C-5 of 4
would be attacked, resulting in the ring opening to give
the heterodienyl-substituted triazole anions IV, which
could give rise to tautomeric IV′ by 180° turn along the
single bond between the triazole C-4 and the C–Br fol-
lowed by resonance. The intramolecular ring closure by
triazole anion attack on the imine bond, with release of the
base, leads to the formation of the triazolo[1,5-c]pyrimi-
dines 5. The experimental findings are aligned with this
proposed mechanism: the substitution by methyl or phe-
The proposed reaction mechanism for the present protocol
is shown in Scheme 5. In the oxidative cyclization to form
[1,2,4]triazolo[4,3-c]pyrimidines 4, the first step is the ad-
dition and elimination reaction of hydrazones 3 with bro-
mine to produce hydrazonyl chlorides I. From these
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2734–2746

2738
C. Tang et al.
PAPER
R1
R2
N
N
N
••
••
Cl
N
••
II'
oxidative cyclization:
R1
R1
R1
R1
R2
C
R2
N
R2
Br
R2
H
Br2
N
N
base
N
N
N
N
N
N
N
N
••
N
− HBr
Cl
N
Cl
N
H
N
Cl
N
Cl
••
H
R3
3
I
II
III R3 = H
4 R3 = Br
Br2
basic Dimroth rearrangement:
B
R1
R1
R1
R1
R2
R2
N
N
N
N
B
N
B
N
N
N
N
N
B
R2
N
R2
N
N
N
N
Cl
N
Cl
Cl
Cl
Br
IV'
Br
Br
Br
4
IV
R1
R1
B
N
N
N
N
N
N
N
R2
R2
− B
Cl
N
Cl
Br
Br
5
V
Scheme 5 Proposed mechanism for the present approach to [1,2,4]triazolo[1,5-c]pyrimidines 5
nyl significantly suppresses the base/nucleophilic attack was achieved for 5l in six hours, furnishing better yields
on the electrophilic C-5 of 4, hence dramatically enhances (Table 4, entry 1 vs 4, entry 3 vs 5).
their thermodynamic stability.
Since the products still bear a chlorine substituent, we
Finally, we paid efforts to exploit the halogen atoms pres- wondered if additional modification was possible. Thus,
ent in the pyrimidine nucleus of triazolo[1,5-c]pyrimi- the reaction was performed in refluxing toluene by apply-
dines 5 for plausible elaboration. It was presumed that ing 2.2 equivalents of p-toluidine. To our delight, the 7,8-
substitution pattern at C-5 could influence in the reaction di(p-toluidino)-substituted product 6f was produced in
pattern, thus it was decided to examine the reaction over 60% yield after two hours (Table 4, entry 6).
three substrates, that is, 5a, 5d, and 5l, respectively, hav-
ing no substitution and with methyl and phenyl at C-5.
In the absence of a palladium catalyst, direct aromatic nu-
cleophilic substitution (SNAr process) could be performed
To our delight, the halogen atoms are practically useful on 5a, as evidenced by the reaction with benzylamine and
functional group in the common palladium-catalyzed pro- p-toluidine as the nucleophiles. Both halogen moieties
cesses. The selected three compounds were treated under showed reactivity and the corresponding C7/C8-diamino-
typical Buchwald–Hartwig aromatic amination23 or triazolopyrimidines 6g and 6h were prepared in good
Kumada cross-coupling conditions.24
yields through sequential displacement with the requisite
amine (Table 4, entries 7 and 8).
For the Buchwald–Hartwig aromatic aminations, it has
transpired that using 10 mol% Pd2(dba)3 as the catalyst, 10 Finally, the Kumada coupling of the selected substrates 5
mol% xantphos as the ancillary ligand, and three equiva- with vinylmagnesium bromide using 10 mol%
lents of Cs2CO3 in toluene, the substrates 5d and 5l bear- Pd(PPh3)2Cl2 as catalyst was also successful. It is worth
ing a substituent at C-5 participate satisfactorily in the mentioning that different chemoselectivity was observed
cross-coupling reaction (Table 4). p-Toluidine, the cyclic for the above Buchwald–Hartwig aromatic amination.
electron-rich amine morpholine, and benzylamine worked The Kumada cross-coupling took place at C-7 affording
equally well to furnish the chemoselective coupling prod- the 7-vinyl-substituted and C-8 debrominated product 8 in
ucts 6a–e. The methyl-substituted substrate 5d required acceptable yields. An initial magnesium–bromine ex-
20 hours for full conversion and afforded moderate to change process and subsequent protonation of the inter-
good yields (Table 4, entries 1–3), while full conversion vening species 7 tentatively accounted for the observed
debromination (Scheme 6).
Synthesis 2014, 46, 2734–2746
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Triazolopyrimidines
2739
Table 4 Palladium-Catalyzed Coupling of 5d and 5l with Amines and Direct Aromatic Nucleophilic Substitution of 5a with Aminesa
R
R
Pd2(dba)3 (10 mol%)
Xantphos (10 mol%)
Cs2CO3 (3 equiv), toluene, 90 °C
R1
N
N
N
N
N
N
N
N
N
Ph
Ph
+
H
R2
Cl
Cl
Br
N
R1
R2
5
6
Entry
Substrate 5
5d R = Me
Amine (equiv)
Time (h)
Product 6
Yield (%)b
N
N
N
N
H
Ph
1
4-MeC6H4NH2 (2.2)
20
6a
56
Cl
N
N
N
N
Ph
N
Cl
2
3
4
5
5dR = Me
5d R = Me
5l R = Ph
5l R = Ph
morpholine (2.2)
20
20
6
6b
6c
6d
6e
43
86
85
90
N
O
N
N
N
Bn
N
N
Ph
BnNH2 (2.2)
Cl
NH
Ph
N
N
N
Ph
4-MeC6H4NH2 (1.2)
Cl
HN
Ph
N
N
N
N
Ph
BnNH2 (2.2)
6
Cl
HN
Bn
Ph
N
N
N
N
Ph
6
5l R = Ph
4-MeC6H4NH2 (2.2)
2
6f
60
72
N
H
HN
N
N
N
N
Ph
N
H
7c
5a R = H
4-MeC6H4NH2 (3.0)
24
6g
HN
© Georg Thieme Verlag Stuttgart · New York
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Table 4 Palladium-Catalyzed Coupling of 5d and 5l with Amines and Direct Aromatic Nucleophilic Substitution of 5a with Aminesa (continued)
R
R
Pd2(dba)3 (10 mol%)
Xantphos (10 mol%)
Cs2CO3 (3 equiv), toluene, 90 °C
R1
N
N
N
N
N
N
N
N
N
Ph
Ph
+
H
R2
Cl
Cl
Br
N
R1
R2
5
6
Entry
8c
Substrate 5
5a R = H
Amine (equiv)
BnNH2 (3)
Time (h)
24
Product 6
Yield (%)b
N
N
N
N
Ph
Bn
N
6h
65
H
HN
Bn
a General procedure: 8-bromo-7-chloro[1,2,4]triazolo[1,5-c]pyrimidine 5 (0.5 mmol), amine, Pd2(dba)3 (0.05 mmol), and xantphos (0.05 mmol)
in toluene (8 mL) were allowed to react at 90 °C until no unreacted material was detected by TLC.
b Isolated yields.
c Condition: 5a (0.5 mmol), amine (1.5 mmol), and Et3N (5 mmol) in MeOH (15 mL) were allowed to react at reflux for 24 h.
reaction products were carried out by column chromatography on
silica gel eluting with petroleum ether (PE, bp 60–90 °C) and
EtOAc. 1H NMR and 13C NMR spectra were recorded on a Bruker
Avance 400 spectrometer. Chemical shifts are given in ppm relative
to TMS (1H, δ = 0.00), or with the solvent resonance of CDCl3 (13C,
δ = 77.16) as the internal standard. Coupling constant (J) values are
given in Hz. IR spectra were recorded as KBr discs on a FT-IR spec-
trometer, and absorptions are given in wavenumbers (cm–1). Mass
spectra were measured on an Agilent 5973N mass spectrometer op-
erating in electrospray mode. The HRMS data were obtained on a
Bruker Compass (microTOF II) with electron ionization.
R
R
CH2=CHMgBr
(0.7 M in THF)
N
N
N
N
N
N
N
N
Ph
Ph
Pd(PPh3)2Cl2
(10 mol%)
THF, 70 °C
N2, 2 h
Cl
Br
5a,d,l
MgBr
7
R
H2O
N
N
N
N
Ph
All commercially available compounds were used without further
purification. 4,6-Dichloropyrimidine25 and 4,6-dichloro-2-methyl-
pyrimidine26 were prepared according to literature procedure.
8a: R = H, 30%
8b: R = Me, 33%
8c: R = Ph, 36%
Bromine-Mediated Synthesis of 8-Bromo-7-chloro[1,2,4]triazo-
lo[4,3-c]pyrimidines 4d–q; General Procedure
Scheme 6 Palladium-catalyzed Kumada coupling of 5 with vinyl-
magnesium bromide
The hydrazone 3 (1 mmol) was dissolved in glacial AcOH (10 mL),
and NaOAc (0.74 g, 9.0 mmol) was added. To the mixture was add-
ed Br2 (0.48 g, 3.0 mmol) dropwise with vigorous stirring at r.t. The
progress of the reaction was monitored by TLC analysis (eluent:
PE–EtOAc, 2:1). After the specified time (Table 2), the reaction
mixture was cooled to r.t., and aq NaOH (1 M, 25 mL) was added.
The precipitate was isolated by filtration and subjected to silica gel
column chromatography, eluting with PE–EtOAc (2:1) to obtain 4
in the yields shown in Table 2.
In conclusion, an efficient and straightforward approach
was developed for the construction of novel 8-bromo-7-
chloro[1,2,4]triazolo[4,3-c]pyrimidines 4 and the isomer-
ic 8-bromo-7-chloro[1,2,4]triazolo[1,5-c]pyrimidines 5;
both are biologically significant heterocycles. The reac-
tion involves the bromine-mediated oxidative cyclization
of the easily accessible pyrimidinyl hydrazones 3 via in
situ generated nitrilimine 1,5-electrocyclization, followed
by a Dimroth rearrangement. A variety of commercially
available aromatic, heteroaromatic, and aliphatic alde-
hydes permit the facial chemical diversification at posi-
tions C-2 and C-3 of the heterocyclic nucleus. The
usefulness of the present halogen atoms was demonstrated
representatively by the palladium-catalyzed Buchwald–
8-Bromo-7-chloro-5-methyl-3-phenyl[1,2,4]triazolo[4,3-c]py-
rimidine (4d)
Yield: 0.30 g (94%); white powder; mp 220–221 °C; Rf = 0.62 (PE–
EtOAc, 2:1).
IR (KBr): 3019, 1607, 1499, 1335, 1211, 1104 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.63–7.60 (m, 1 H, ArH), 7.57–
7.52 (m, 4 H, ArH), 2.35 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 150.4, 147.9, 146.6, 143.8, 131.3,
Hartwig aromatic aminations and Kumada coupling, pro- 131.0, 128.8, 127.1, 104.1, 23.0.
viding further diversified products.
MS (EI, 70 eV): m/z (%) = 321.0 (39), 321.9 (80), 323.0 (62), 323.9
(100), 324.9 (27), 325.9 (25).
HRMS (ESI): m/z [M + H]+ calcd for C12H8BrClN4: 322.9699;
found: 322.9691.
Melting points are uncorrected. All reactions were run under air at-
mosphere, unless otherwise stated. Commercially available sol-
vents were dried by standard methods prior to use. Purification of
Synthesis 2014, 46, 2734–2746
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Triazolopyrimidines
2741
8-Bromo-7-chloro-3-(2-chlorophenyl)-5-methyl[1,2,4]triazo-
lo[4,3-c]pyrimidine (4e)
Yield: 0.33 g (91%); white powder; mp 224–225 °C; Rf = 0.60 (PE–
EtOAc, 2:1).
IR (KBr): 3055, 1617, 1504, 1345, 1222, 1109 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.63–7.55 (m, 3 H, ArH), 7.49–
7.45 (m, 1 H, ArH), 2.37 (s, 3 H, CH3).
1H NMR (400 MHz, CDCl3): δ = 3.30 (q, J = 7.2 Hz, 2 H, CH2), 2.97
(s, 3 H, CH3), 1.54 (t, J = 7.2 Hz, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 150.5, 149.7, 146.0, 143.3, 104.1,
22.2, 21.8, 12.7.
MS (EI, 70 eV): m/z (%) = 273.0 (73), 273.9 (62), 274.9 (100),
275.9 (79), 276.9 (31), 277.9 (19).
HRMS (ESI): m/z [M + H]+ calcd for C8H8BrClN4: 274.9699;
found: 274.9704.
13C NMR (100 MHz, CDCl3): δ = 150.5, 146.3, 145.1, 144.1, 135.6,
133.2, 133.1, 129.9, 127.4, 127.1, 104.2, 21.1.
8-Bromo-7-chloro-5-methyl-3-(1-phenylethyl)[1,2,4]triazo-
lo[4,3-c]pyrimidine (4j)
Yield: 0.30 g (86%); white powder; mp 156–157 °C; Rf = 0.52 (PE–
EtOAc, 2:1).
MS (EI, 70 eV): m/z (%) = 355.9 (63), 356.9 (30), 357.9 (100),
358.9 (26), 359.9 (44).
HRMS (ESI): m/z [M + H]+ calcd for C12H7BrCl2N4: 356.9309;
found: 356.9311.
IR (KBr): 2983, 1607, 1520, 1345, 1196, 1104 cm–1.
8-Bromo-7-chloro-3-(2,4-dichlorophenyl)-5-methyl[1,2,4]tri-
azolo[4,3-c]pyrimidine (4f)
Yield: 0.37 g (93%); white powder; mp 244–245 °C; Rf = 0.55 (PE–
EtOAc, 2:1).
1H NMR (400 MHz, CDCl3): δ = 7.33–7.29 (m, 2 H, ArH), 7.26–
7.23 (m, 1 H, ArH), 7.05–7.03 (m, 2 H, ArH), 4.76 (q, J = 7.2 Hz, 1
H, CH), 2.74 (s, 3 H, CH3), 1.96 (d, J = 7.2 Hz, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 151.0, 150.5, 146.2, 143.4, 143.0,
129.6, 127.6, 127.0, 104.1, 39.6, 23.5, 22.6.
IR (KBr): 3060, 1607, 1509, 1443, 1335, 1217 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.60–7.58 (m, 2 H, ArH), 7.49–
7.47 (m, 1 H, ArH), 2.41 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 150.7, 146.1, 144.3, 144.1, 138.9,
136.5, 133.9, 130.0, 128.0, 125.7, 104.2, 21.3.
MS (EI, 70 eV): m/z (%) = 105.1 (100), 271.0 (26), 334.9 (59),
336.9 (76), 349.0 (43), 350.0 (72), 351.0 (66), 352.0 (91), 353.0
(29), 354.0 (23).
HRMS (ESI): m/z [M + H]+ calcd for C14H12BrClN4: 351.0012;
found: 351.0012.
MS (EI, 70 eV): m/z (%) = 389.9 (54), 390.9 (26), 391.9 (100),
392.9 (29), 393.9 (62).
HRMS (ESI): m/z [M + H]+ calcd for C12H6BrCl3N4: 390.8920;
found: 390.8918.
8-Bromo-7-chloro-5-methyl-3-(4′-pyridyl)[1,2,4]triazolo[4,3-
c]pyrimidine (4k)
Yield: 0.20 g (60%); yellow powder; mp 276–277 °C; Rf = 0.35
(PE–EtOAc, 2:1).
IR (KBr): 3060, 1602, 1504, 1340, 1227, 1109 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.85–8.84 (m, 2 H, ArH), 7.56–
7.55 (m, 2 H, ArH), 2.43 (s, 3 H, CH3).
8-Bromo-7-chloro-5-methyl-3-(o-tolyl)[1,2,4]triazolo[4,3-c]py-
rimidine (4g)
Yield: 0.31 g (90%); white powder; mp 191–192 °C; Rf = 0.65 (PE–
EtOAc, 2:1).
IR (KBr): 2921, 1612, 1499, 1335, 1109, 944, 841 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.51 (t, J = 7.2 Hz, 1 H, ArH),
13C NMR (100 MHz, CDCl3): δ = 150.8, 150.3, 145.8, 145.5, 144.2,
135.3, 125.1, 104.2, 23.3.
7.41–7.33 (m, 3 H, ArH), 2.23 (s, 3 H, ArH), 2.12 (s, 3 H, ArH).
MS (EI, 70 eV): m/z (%) = 321.9 (41), 322.9 (76), 323.9 (60), 324.9
13C NMR (100 MHz, CDCl3): δ = 150.3, 147.1, 146.5, 143.9, 139.1,
131.7, 131.4, 130.6, 126.9, 126.2, 104.3, 21.7, 20.0.
(100), 325.9 (29), 326.9 (22).
HRMS (ESI): m/z [M + H]+ calcd for C11H7BrClN5: 323.9652;
found: 323.9646.
MS (EI, 70 eV): m/z (%) = 320.9 (75), 321.9 (19), 322.9 (100),
323.9 (17), 324.9 (24), 336.0 (11), 338.0 (13).
HRMS (ESI): m/z [M + H]+ calcd for C13H10BrClN4: 336.9856;
found: 336.9852.
8-Bromo-7-chloro-3,5-diphenyl[1,2,4]triazolo[4,3-c]pyrimi-
dine (4l)
Yield: 0.32 g (84%); white powder; mp 300–302 °C; Rf = 0.70 (PE–
EtOAc, 2:1).
8-Bromo-7-chloro-5-methyl-3-(m-tolyl)[1,2,4]triazolo[4,3-c]py-
IR (KBr): 3055, 1597, 1514, 1484, 1448, 1335 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.32–7.23 (m, 4 H, ArH), 7.11–
7.07 (m, 6 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 151.2, 148.5, 147.0, 143.9, 131.6,
130.2, 129.9, 129.6, 129.0, 128.0, 126.7, 104.4.
rimidine (4h)
Yield: 0.30 g (89%); white powder; mp 228–229 °C; Rf = 0.63 (PE–
EtOAc, 2:1).
IR (KBr): 3019, 1611, 1509, 1345, 1196, 1114, 939 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.44–7.33 (m, 4 H, ArH), 2.43 (s,
3 H, CH3), 2.36 (s, 3 H, CH3).
MS (EI, 70 eV): m/z (%) = 383.0 (24), 383.9 (77), 385.0 (48), 386.0
13C NMR (100 MHz, CDCl3): δ = 150.3, 148.1, 146.7, 143.7, 138.8,
132.0, 131.5, 128.6, 128.0, 126.9, 104.1, 23.0, 21.5.
(100), 387.0 (27), 388.0 (27).
HRMS (ESI): m/z [M + H]+ calcd for C17H10BrClN4: 384.9856;
found: 384.9844.
MS (EI, 70 eV): m/z (%) = 335.0 (23), 335.9 (77), 337.0 (41), 337.9
(100), 339.0 (23), 339.9 (24).
HRMS (ESI): m/z [M + H]+ calcd for C13H10BrClN4: 336.9856;
found: 336.9860.
8-Bromo-7-chloro-3-(2-chlorophenyl)-5-phenyl[1,2,4]triazo-
lo[4,3-c]pyrimidine (4m)
Yield: 0.34 g (82%); white powder; mp 231–232 °C; Rf = 0.68 (PE–
EtOAc, 2:1).
8-Bromo-7-chloro-3-ethyl-5-methyl[1,2,4]triazolo[4,3-c]pyrim-
IR (KBr): 3060, 1607, 1586, 1484, 1345, 1232 cm–1.
idine (4i)
1H NMR (400 MHz, CDCl3): δ = 7.58–7.55 (m, 1 H, ArH), 7.35–
7.26 (m, 5 H, ArH), 7.13 (t, J = 7.2 Hz, 2 H, ArH), 7.04–7.02 (m, 1
H, ArH).
Yield: 0.25 g (91%); white powder; mp 226–227 °C; Rf = 0.50 (PE–
EtOAc, 2:1).
IR (KBr): 2978, 1602, 1525, 1443, 1391, 1186 cm–1.
© Georg Thieme Verlag Stuttgart · New York
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13C NMR (100 MHz, CDCl3): δ = 151.2, 147.3, 145.7, 144.4, 134.6,
132.2, 132.0, 131.4, 129.3, 129.2, 127.4, 127.2, 127.0, 104.4.
MS (EI, 70 eV): m/z (%) = 383.9 (17), 385.0 (77), 385.9 (38), 386.9
(100), 387.9 (24), 388.9 (24).
MS (EI, 70 eV): m/z (%) = 417.9 (61), 418.9 (25), 419.9 (100),
420.9 (26), 421.9 (48).
HRMS (ESI): m/z [M + H]+ calcd for C16H9BrClN5: 385.9808;
found: 385.9812.
HRMS (ESI): m/z [M + H]+ calcd for C17H9BrCl2N4: 418.9466;
found: 418.9465.
7-Chloro-5-methyl-3-phenyl[1,2,4]triazolo[4,3-c]pyrimidine
(4d′)
A solution of Br2 (0.18 g, 1.1 mmol) in glacial AcOH (2 mL) was
slowly added to a mixture of anhydrous NaOAc (0.76 g, 9.0 mmol)
and hydrazone 3d (0.25 g, 1.0 mmol) in glacial AcOH (6 mL). The
reaction mixture was stirred at r.t. for 2 h. The progress of the reac-
tion was monitored by TLC (eluent: PE–EtOAc, 2:1). The reaction
was quenched by pouring the mixture into 1 M aq NaOH (30 mL).
The product was extracted with EtOAc (3 × 50 mL) and the com-
bined organic extracts were concentrated under reduce pressure.
The residue was directly subjected to column chromatography on
silica gel using PE–EtOAc (2:1) as the eluent (Rf = 0.50) to afford
the desired product 4d′; yield: 0.22 g (81%); white powder; mp
130–132 °C.
IR (KBr): 3070, 3035, 1614, 1529, 1422, 1266 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.62–7.58 (m, 2 H, ArH), 7.57–
7.51 (m, 4 H, ArH), 2.39 (m, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 151.1, 148.5, 146.5, 144.2, 131.1,
130.9, 128.7, 127.6, 107.5, 23.4.
8-Bromo-7-chloro-5-phenyl-3-(o-tolyl)[1,2,4]triazolo[4,3-c]py-
rimidine (4n)
Yield: 0.32 g (81%); white powder; mp 285–286 °C; Rf = 0.65 (PE–
EtOAc, 2:1).
IR (KBr): 3065, 1612, 1597, 1499, 1340, 1242 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.29 (d, J = 6.8 Hz, 1 H, ArH),
7.23–7.16 (m, 3 H, ArH), 7.08 (t, J = 7.6 Hz, 2 H, ArH), 7.00–6.96
(m, 3 H, ArH), 2.04 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 150.9, 147.5, 147.2, 144.0, 137.7,
131.3, 130.8, 130.5, 130.2, 129.6, 128.8, 127.6, 126.7, 125.6, 104.6,
20.2.
MS (EI, 70 eV): m/z (%) = 322.9 (90), 321.0 (100), 398.0 (30),
400.0 (36).
HRMS (ESI): m/z [M + H]+ calcd for C18H12BrClN4: 399.0012;
found: 399.0011.
8-Bromo-7-chloro-5-phenyl-3-(m-tolyl)[1,2,4]triazolo[4,3-c]py-
HRMS (ESI): m/z [M + H]+ calcd for C12H9ClN4: 245.0594; found:
245.0592.
rimidine (4o)
Yield: 0.33 g (83%); white powder; mp 232–233 °C; Rf = 0.62 (PE–
EtOAc, 2:1).
Dimroth Rearrangement of 4d–q to 8-Bromo-7-chlo-
ro[1,2,4]triazolo[1,5-c]pyrimidines 5d–q; General Procedure
To a solution of the appropriate [1,2,4]triazolo[4,3-c]pyrimidine 4
(0.5 mmol) in EtOH (20 mL) was added one drop Et3N and the re-
action mixture was stirred and heated at reflux for the time indicated
in Table 3. On cooling, the solvent was evaporated in vacuo, and the
residue was crystallized from an appropriate solvent or chromato-
graphed (silica gel, PE–EtOAc, 10:1) to furnish 5d–q in yields
shown in Table 3.
IR (KBr): 3035, 1591, 1494, 1443, 1335, 1253 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.34–7.29 (m, 1 H, ArH), 7.27–
7.25 (m, 2 H, ArH), 7.12 (t, J = 8.0 Hz, 2 H, ArH), 7.07–7.00 (m, 3
H, ArH), 6.83 (s, 1 H, ArH), 2.11 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 151.2, 148.6, 147.0, 143.9, 137.9,
131.5, 130.7, 130.4, 128.9, 128.1, 127.9, 126.8, 126.5, 104.5, 21.1.
MS (EI, 70 eV): m/z (%) = 397.0 (24), 398.0 (78), 399.0 (45), 400.0
(100), 400.9 (28), 402.0 (26).
HRMS (ESI): m/z [M + H]+ calcd for C18H12BrClN4: 399.0012;
found: 399.0012.
8-Bromo-7-chloro-5-methyl-2-phenyl[1,2,4]triazolo[1,5-c]py-
rimidine (5d)
Yield: 0.16 g (98%); white powder; mp 182–183 °C; Rf = 0.60 (PE–
EtOAc, 5:1).
8-Bromo-7-chloro-3-ethyl-5-phenyl[1,2,4]triazolo[4,3-c]pyrim-
IR (KBr): 2922, 1607, 1514, 1448, 1427, 1329 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.35–8.33 (m, 2 H, ArH), 7.51 (d,
idine (4p)
Yield: 0.29 g (86%); white powder; mp 280–281 °C; Rf = 0.55 (PE–
EtOAc, 2:1).
J = 4.8 Hz, 3 H, ArH), 3.00 (s, 3 H, CH3).
IR (KBr): 2973, 1617, 1602, 1514, 1438, 1360 cm–1.
13C NMR (100 MHz, CDCl3): δ = 166.6, 153.4, 149.1, 146.7, 131.4,
129.3, 128.9, 128.1, 103.9, 19.5.
1H NMR (400 MHz, CDCl3): δ = 7.68–7.64 (m, 1 H, ArH), 7.61–
7.56 (m, 4 H, ArH), 2.46 (q, J = 7.2 Hz, 2 H, CH2), 1.12 (t, J = 7.2
Hz, 3 H, CH3).
MS (EI, 70 eV): m/z (%) = 321.0 (33), 322.0 (79), 323.0 (54), 324.0
(100), 325.0 (24).
13C NMR (100 MHz, CDCl3): δ = 150.7, 150.1, 146.8, 143.3, 132.0,
131.3, 128.9, 128.8, 105.0, 22.0, 11.7.
HRMS (ESI): m/z [M + H]+ calcd for C12H8BrClN4: 322.9699;
found: 322.9691.
MS (EI, 70 eV): m/z (%) = 335.0 (70), 335.9 (69), 337.0 (100),
337.9 (84), 338.9 (36), 339.9 (22).
HRMS (ESI): m/z [M + H]+ calcd for C13H10BrClN4: 336.9856;
found: 336.9848.
8-Bromo-7-chloro-2-(2-chlorophenyl)-5-methyl[1,2,4]triazo-
lo[1,5-c]pyrimidine (5e)
Yield: 0.17 g (96%); white powder; mp 170–172 °C; Rf = 0.61 (PE–
EtOAc, 5:1).
IR (KBr): 3085, 1612, 1591, 1514, 1422, 1294 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.05–8.03 (m, 1 H, ArH), 7.56–
7.53 (m, 1 H, ArH), 7.46–7.38 (m, 2 H, ArH), 3.02 (s, 3 H, CH3).
8-Bromo-7-chloro-5-phenyl-3-(4′-pyridyl)[1,2,4]triazolo[4,3-
c]pyrimidine (4q)
Yield: 0.20 g (52%); white powder; mp >310 °C (dec.); Rf = 0.38
(PE–EtOAc, 2:1).
13C NMR (100 MHz, CDCl3): δ = 165.2, 152.8, 149.4, 147.0, 133.8,
132.6, 131.7, 131.1, 128.7, 127.0, 104.2, 19.5.
IR (KBr): 3050, 1591, 1504, 1478, 1401, 1330 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.41 (d, J = 5.6 Hz, 2 H, ArH),
7.41 (t, J = 7.6 Hz, 1 H, ArH), 7.31–7.29 (m, 2 H, ArH), 7.20 (t, J =
7.6 Hz, 2 H, ArH), 7.08 (d, J = 6.0 Hz, 2 H, ArH).
MS (EI, 70 eV): m/z (%) = 321.0 (21), 323.0 (27), 356.0 (64), 357.0
(25), 358.0 (100), 359.0 (22), 360.0 (47).
HRMS (ESI): m/z [M + H]+ calcd for C12H7BrCl2N4: 356.9309;
found: 356.9308.
Synthesis 2014, 46, 2734–2746
© Georg Thieme Verlag Stuttgart · New York

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Triazolopyrimidines
2743
8-Bromo-7-chloro-2-(2,4-dichlorophenyl)-5-methyl[1,2,4]tri-
azolo[1,5-c]pyrimidine (5f)
Yield: 0.19 g (95%); white powder; mp 198–199 °C; Rf = 0.60 (PE–
EtOAc, 5:1).
IR (KBr): 2978, 1612, 1520, 1268, 1165, 955, 862 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.44–7.42 (m, 2 H, ArH), 7.31 (t,
J = 7.6 Hz, 2 H, ArH), 7.22 (t, J = 7.6 Hz, 1 H, ArH), 4.50 (q, J =
7.2 Hz, 1 H, CH), 2.92 (s, 3 H, CH3), 1.81 (d, J = 7.6 Hz, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 172.9, 153.0, 149.1, 146.6, 142.8,
128.7, 127.8, 127.0, 103.8, 40.3, 21.1, 19.5.
IR (KBr): 3086, 1617, 1586, 1520, 1396, 1299 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.06 (d, J = 8.4 Hz, 1 H, ArH),
7.57 (d, J = 1.6 Hz, 1 H, ArH), 7.39 (dd, J = 1.6, 8.4 Hz, 1 H, ArH),
3.01 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 164.3, 152.8, 149.4, 147.1, 137.3,
134.6, 133.4, 131.0, 127.5, 127.2, 104.2, 19.5.
MS (EI, 70 eV): m/z (%) = 271.0 (88), 273.0 (55), 350.0 (77), 351.0
(60), 352.0 (100).
HRMS (ESI): m/z [M + H]+ calcd for C14H12BrClN4: 351.0012;
found: 351.0008.
MS (EI, 70 eV): m/z (%) = 338.0 (100), 336.0 (79), 337.0 (32),
392.0 (6).
8-Bromo-7-chloro-5-methyl-2-(4′-pyridyl)[1,2,4]triazolo[1,5-
c]pyrimidine (5k)
Yield: 0.13 g (80%); white powder; mp 227–228 °C; Rf = 0.45 (PE–
EtOAc, 5:1).
HRMS (ESI): m/z [M + H]+ calcd for C12H6BrCl3N4: 390.8920;
found: 390.8874.
8-Bromo-7-chloro-5-methyl-2-(o-tolyl)[1,2,4]triazolo[1,5-c]py-
IR (KBr): 3035, 1612, 1509, 1422, 1283, 1134 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.79 (d, J = 4.8 Hz, 2 H, ArH),
8.18 (d, J = 5.6 Hz, 2 H, ArH), 3.00 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 164.5, 153.6, 150.7, 149.4, 147.3,
136.8, 121.9, 104.4, 19.5.
rimidine (5g)
Yield: 0.17 g (98%); white powder; mp 178–179 °C; Rf = 0.66 (PE–
EtOAc, 5:1).
IR (KBr): 2973, 1612, 1520, 1453, 1304, 1263 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.17 (d, J = 7.6 Hz, 1 H, ArH),
7.39 (t, J = 7.2 Hz, 1 H, ArH), 7.33 (s, 2 H, ArH), 2.98 (s, 3 H, CH3),
2.72 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 167.5, 152.6, 149.1, 146.6, 138.5,
131.6, 130.9, 130.7, 128.5, 126.2, 103.9, 22.1, 19.5.
MS (EI, 70 eV): m/z (%) = 322.0 (34), 323.0 (77), 324.0 (54), 325.0
(100), 326.0 (25).
HRMS (ESI): m/z [M + H]+ calcd for C11H7BrClN5: 323.9652;
found: 323.9651.
MS (EI, 70 eV): m/z (%) = 131.0 (24), 257.0 (100), 259.0 (34),
336.0 (19), 337.0 (4), 338.0 (25).
HRMS (ESI): m/z [M + H]+ calcd for C13H10BrClN4: 336.9856;
found: 336.9834.
8-Bromo-7-chloro-2,5-diphenyl[1,2,4]triazolo[1,5-c]pyrimi-
dine (5l)
Yield: 0.16 g (86%); white powder; mp 200–201 °C; Rf = 0.75 (PE–
EtOAc, 5:1).
IR (KBr): 3060, 1607, 1530, 1468, 1437, 1283 cm–1.
8-Bromo-7-chloro-5-methyl-3-(m-tolyl)[1,2,4]triazolo[1,5-c]py-
1H NMR (400 MHz, CDCl3): δ = 8.73 (t, J = 7.2 Hz, 2 H, ArH),
8.36–8.34 (m, 2 H, ArH), 7.67–7.58 (m, 3 H, ArH), 7.52–7.48 (m,
3 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 166.6, 155.0, 147.1, 146.9, 132.9,
131.4, 130.9, 129.7, 129.3, 128.9, 128.8, 128.2, 104.1.
rimidine (5h)
Yield: 0.16 g (96%); white powder; mp 203–204 °C; Rf = 0.65 (PE–
EtOAc, 5:1).
IR (KBr): 2922, 1612, 1520, 1422, 1309, 1278 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.12 (d, J = 14.8 Hz, 2 H, ArH),
7.41–7.31 (m, 2 H, ArH), 2.98 (s, 3 H, CH3), 2.45 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 166.8, 153.4, 149.1, 146.7, 138.7,
132.2, 129.2, 128.8, 128.6, 125.3, 103.8, 21.5, 19.5.
MS (EI, 70 eV): m/z (%) = 384.0 (73), 385.0 (35), 386.0 (100),
386.9 (23), 388.0 (24).
HRMS (ESI): m/z [M + H]+ calcd for C17H10BrClN4: 384.9856;
found: 384.9845.
MS (EI, 70 eV): m/z (%) = 335.0 (19), 336.0 (81), 337.0 (33), 338.0
(100), 339.0 (21), 340.0 (26).
HRMS (ESI): m/z [M + H]+ calcd for C13H10BrClN4: 336.9856;
found: 336.9849.
8-Bromo-7-chloro-2-(2-chlorophenyl)-5-phenyl[1,2,4]triazo-
lo[1,5-c]pyrimidine (5m)
Yield: 0.18 g (88%); white powder; mp 198–199 °C; Rf = 0.72 (PE–
EtOAc, 5:1).
8-Bromo-7-chloro-2-ethyl-5-methyl[1,2,4]triazolo[1,5-c]pyrim-
IR (KBr): 3045, 1591, 1571, 1504, 1478, 1160 cm–1.
idine (5i)
1H NMR (400 MHz, CDCl3): δ = 8.79 (d, J = 7.6 Hz, 2 H, ArH),
8.19–8.17 (m, 1 H, ArH), 7.66–7.56 (m, 4 H, ArH), 7.47–7.40 (m,
2 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 164.9, 154.3, 147.3, 147.1, 133.7,
133.1, 132.7, 131.7, 131.2, 131.0, 129.5, 128.8, 128.6, 127.1, 104.2.
Yield: 0.13 g (94%); white powder; mp 94–95 °C; Rf = 0.72 (PE–
EtOAc, 5:1).
IR (KBr): 2978, 1607, 1520, 1324, 1242, 1124 cm–1.
1H NMR (400 MHz, CDCl3): δ = 2.97 (q, J = 7.6 Hz, 2 H, CH2), 2.91
(s, 3 H, CH3), 1.41 (t, J = 7.6 Hz, 3 H, CH3).
MS (EI, 70 eV): m/z (%) = 281.0 (27), 283.0 (33), 418.0 (67), 419.0
(23), 420.0 (100), 422.0 (47).
HRMS (ESI): m/z [M + H]+ calcd for C17H9BrCl2N4: 418.9466;
found: 418.9463.
13C NMR (100 MHz, CDCl3): δ = 171.7, 153.0, 148.9, 146.6, 103.5,
22.6, 19.4, 12.5.
MS (EI, 70 eV): m/z (%) = 335.0 (19), 273.0 (74), 275.0 (100),
276.0 (60), 277.0 (30).
8-Bromo-7-chloro-5-phenyl-2-(o-tolyl)[1,2,4]triazolo[1,5-c]py-
HRMS (ESI): m/z [M + H]+ calcd for C8H8BrClN4: 274.9699;
found: 274.9676.
rimidine (5n)
Yield: 0.17 g (85%); white powder; mp 225–226 °C; Rf = 0.76 (PE–
EtOAc, 5:1).
8-Bromo-7-chloro-5-methyl-2-(1-phenylethyl)[1,2,4]triazo-
lo[1,5-c]pyrimidine (5j)
Yield: 0.16 g (91%); white powder; mp 90–91 °C; Rf = 0.70 (PE–
EtOAc, 5:1).
IR (KBr): 2968, 1612, 1566, 1514, 1478, 1453 cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2734–2746

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C. Tang et al.
PAPER
1H NMR (400 MHz, CDCl3): δ = 8.74 (d, J = 7.2 Hz, 2 H, ArH),
8.26 (d, J = 8.0 Hz, 1 H, ArH), 7.66–7.57 (m, 3 H, ArH), 7.41 (t, J =
7.0 Hz, 1 H, ArH), 7.35 (t, J = 6.2 Hz, 2 H, ArH), 2.77 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 167.4, 154.2, 147.0, 146.9, 138.4,
132.9, 131.7, 131.1, 130.9, 130.7, 129.8, 128.8, 128.6, 126.2, 104.1,
22.4.
at 90 °C under N2 atmosphere for 20 h. The progress of the reaction
was monitored by TLC (eluent: PE–EtOAc, 3:1). Then, the mixture
was concentrated under educed pressure. The residue was directly
subjected to column chromatography on silica gel using PE–EtOAc
(8:1) as the eluent to afford the desired product 6a. Other C-7/C-8
amino-substituted derivatives 6b–f were similarly prepared by
slightly varied conditions as detailed in Table 4 (entries 2–6); yield:
0.10 g (56%), yellow powder; mp 166–168 °C; Rf = 0.45 (PE–
EtOAc, 3:1).
MS (EI, 70 eV): m/z (%) = 283.0 (26), 319.0 (100), 320.0 (24),
321.0 (38), 400.0 (26).
HRMS (ESI): m/z [M + H]+ calcd for C18H12BrClN4 399.0012;
found: 398.9980.
IR (KBr): 3373, 3024, 2916, 1612, 1509, 1448 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.23–8.21 (m, 2 H, ArH), 7.47–
7.46 (m, 3 H, ArH), 7.10 (d, J = 8.0 Hz, 2 H, ArH), 6.88 (d, J = 8.0
Hz, 2 H, ArH), 6.28 (s, 1 H, NH), 2.97 (s, 3 H, CH3), 2.34 (s, 3 H,
CH3).
8-Bromo-7-chloro-5-phenyl-3-(m-tolyl)[1,2,4]triazolo[1,5-c]py-
rimidine (5o)
Yield: 0.18 g (88%); white powder; mp 196–197 °C; Rf = 0.75 (PE–
EtOAc, 5:1).
13C NMR (100 MHz, CDCl3): δ = 165.2, 149.9, 142.9, 138.4, 132.9,
132.3, 130.9, 130.0, 129.4, 128.8, 127.9, 123.6, 119.7, 20.9, 19.2.
IR (KBr): 3098, 1602, 1509, 1473, 1448, 1258 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.74–8.71 (m, 2 H, ArH), 8.14 (d,
J = 10.0 Hz, 2 H, ArH), 7.67–7.59 (m, 3 H, ArH), 7.38 (t, J = 7.6
Hz, 1 H, ArH), 7.32 (d, J = 7.6 Hz, 1 H, ArH), 2.46 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 166.8, 155.0, 147.1, 146.9, 138.7,
132.9, 132.2, 130.9, 129.8, 129.2, 128.8, 128.7, 125.4, 104.0, 21.5.
MS (EI, 70 eV): m/z (%) = 349.1 (100), 350.1 (27), 351.1 (35).
HRMS (ESI): m/z [M + H]+ calcd for C19H16ClN5: 350.1172; found:
350.1193.
7-Chloro-5-methyl-8-morpholino-2-phenyl[1,2,4]triazolo[1,5-
c]pyrimidine (6b)
Prepared from 5d and morpholine; yield: 0.07 g (43%); white pow-
der; mp 250–251 °C; Rf = 0.38 (PE–EtOAc, 3:1).
MS (EI, 70 eV): m/z (%) = 319.0 (27), 398.0 (75), 399.0 (35), 400.0
(100), 401.0 (26), 402.0 (25).
HRMS (ESI): m/z [M + H]+ calcd for C18H12BrClN4: 399.0012;
found: 398.9988.
IR (KBr): 2973, 2911, 2855, 1597, 1504, 1443 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.32–8.31 (m, 2 H, ArH), 7.50–
7.49 (m, 3 H, ArH), 3.92 (t, J = 4.0 Hz, 4 H, 2 CH2), 3.55 (t, J = 4.0
Hz, 4 H, 2 CH2), 2.95 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 165.3, 152.0, 145.0, 139.2, 130.9,
130.4, 130.1, 128.9, 127.9, 67.6, 50.9, 19.4.
8-Bromo-7-chloro-2-ethyl-5-phenyl[1,2,4]triazolo[1,5-c]pyrim-
idine (5p)
Yield: 0.14 g (86%); white powder; mp 132–133 °C; Rf = 0.78 (PE–
EtOAc, 5:1).
IR (KBr): 2968, 1602, 1509, 1468, 1443, 1335 cm–1.
MS (EI, 70 eV): m/z (%) = 244.0 (72), 258.1 (100), 264.1 (40),
299.1 (64), 329.1 (20).
HRMS (ESI): m/z [M + H]+ calcd for C16H16ClN5O: 330.1122;
found: 330.1118.
1H NMR (400 MHz, CDCl3): δ = 8.64 (d, J = 7.2 Hz, 2 H, ArH),
7.64–7.55 (m, 3 H, ArH), 3.03 (q, J = 7.6 Hz, 2 H, CH2), 1.46 (t, J =
7.6 Hz, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 171.7, 154.6, 146.9, 146.8, 132.9,
130.8, 129.7, 128.7, 103.7, 22.7, 12.5.
8-Benzylamino-7-chloro-5-methyl-2-phenyl[1,2,4]triazolo[1,5-
c]pyrimidine (6c)
Prepared from 5d and benzylamine; yield: 0.14 g (86%); white
powder; mp 117–118 °C; Rf = 0.60 (PE–EtOAc, 3:1).
MS (EI, 70 eV): m/z (%) = 335.0 (65), 336.0 (77), 337.0 (98), 338.0
(100), 340.0 (24).
HRMS (ESI): m/z [M + H]+ calcd for C13H10BrClN4: 336.9856;
found: 336.9836.
IR (KBr): 3412, 2851, 1610, 1557, 1516, 1469 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.33–8.31 (m, 2 H, ArH), 7.50–
7.49 (m, 3 H, ArH), 7.41 (d, J = 7.6 Hz, 2 H, ArH), 7.34 (t, J = 7.6
Hz, 2 H, ArH), 7.28–7.25 (m, 1 H, ArH), 5.30 (s, 2 H, CH2), 4.77 (s,
1 H, NH), 2.88 (s, 3 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 164.4, 147.3, 140.0, 139.0, 130.7,
130.3, 128.2, 128.1, 127.7, 127.6, 126.0, 49.1, 19.0.
8-Bromo-7-chloro-5-phenyl-2-(4′-pyridyl)[1,2,4]triazolo[1,5-
c]pyrimidine (5q)
Yield: 0.14 g (75%); white powder; mp 232–233 °C; Rf = 0.45 (PE–
EtOAc, 5:1).
IR (KBr): 2988, 1602, 1514, 1468, 1448, 1422 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.81 (d, J = 4.8 Hz, 2 H, ArH),
8.70 (d, J = 7.6 Hz, 2 H, ArH), 8.21 (d, J = 5.6 Hz, 2 H, ArH), 7.68
(t, J = 7.2 Hz, 1 H, ArH), 7.62 (t, J = 7.4 Hz, 2 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 164.5, 155.2, 150.7, 147.7, 147.2,
136.9, 133.2, 130.9, 129.4, 128.9, 122.0, 104.6.
MS (EI, 70 eV): m/z (%) = 91.1 (100), 272.0 (54), 274.1 (17), 349.1
(45), 351.1 (16).
HRMS (ESI): m/z [M + H]+ calcd for C19H16ClN5: 350.1172; found:
350.1140.
7-Chloro-2,5-diphenyl-8-(p-toluidino)[1,2,4]triazolo[1,5-c]py-
rimidine (6d)
Prepared from 5l and p-toluidine; yield: 0.18 g (85%); white pow-
der; mp 202–204 °C; Rf = 0.65 (PE–EtOAc, 3:1).
MS (EI, 70 eV): m/z (%) = 283.0 (27), 306.0 (21), 385.0 (74), 386.0
(32), 387.0 (100), 388.0 (24).
HRMS (ESI): m/z [M + H]+ calcd for C16H9BrClN5: 385.9808;
found: 385.9794.
IR (KBr): 3370, 2918, 1599, 1533, 1521, 1474 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.73–8.70 (m, 2 H, ArH), 8.29–
8.26 (m, 2 H, ArH), 7.60–7.58 (m, 3 H, ArH), 7.49–7.47 (m, 3 H,
ArH), 7.14 (d, J = 8.0 Hz, 2 H, ArH), 6.97 (d, J = 8.0 Hz, 2 H, ArH)
6.48 (s, 1 H, NH), 2.36 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 165.0, 150.9, 140.8, 138.0, 132.8,
132.4, 131.5, 130.9, 130.7, 130.0, 129.4, 128.8, 128.6, 128.0, 124.0,
120.5, 21.0.
Palladium-Catalyzed Amination; 7-Chloro-5-methyl-2-phenyl-
8-(p-toluidino)[1,2,4]triazolo[1,5-c]pyrimidine (6a); Typical
Procedure
A sealed round-bottomed flask was charged with 5d (0.16 g, 0.5
mmol), p-toluidine (0.11 g, 1.0 mmol, 2.2 equiv), Pd2(dba)3 (0.05
mmol, 0.1 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethylxan-
thene (xantphos, 289 mg, 0.05 mmol, 0.1 equiv), Cs2CO3 (0.49 g,
1.5 mmol, 3.0 equiv), and toluene (8 mL). The mixture was stirred
Synthesis 2014, 46, 2734–2746
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PAPER
Triazolopyrimidines
2745
MS (EI, 70 eV): m/z (%) = 410.2 (13), 411.1 (100), 412.1 (33),
413.1 (37).
HRMS (ESI): m/z [M + Na]+ calcd for C24H18ClN5: 434.1148;
found: 434.1120.
7,8-Dibenzylamino-2-phenyl[1,2,4]triazolo[1,5-c]pyrimidine
(6h)
Prepared from 5a and benzylamine; yield: 0.15 g (65%); red pow-
der; mp 163–164 °C; Rf = 0.65 (PE–EtOAc, 3:1).
IR (KBr): 3300, 2879, 2756, 1611, 1550, 1351 cm–1.
8-Benzylamino-7-chloro-2,5-diphenyl[1,2,4]triazolo[1,5-c]py-
rimidine (6e)
Prepared from 5l and benzylamine; yield: 0.19 g (90%); yellow
powder; mp 149–150 °C; Rf = 0.62 (PE–EtOAc, 3:1).
1H NMR (400 MHz, CDCl3): δ = 7.90–7.88 (m, 2 H, ArH), 7.44–
7.33 (m, 6 H, ArH), 7.30–7.24 (m, 7 H, ArH, 2 × NH), 7.20–7.17
(m, 3 H, ArH), 5.60 (s, 2 H, CH2), 4.68 (s, 2 H, CH2).
13C NMR (100 MHz, CDCl3): δ = 155.6, 155.4, 150.3, 140.8, 137.1,
135.6, 130.1, 129.0, 128.9, 128.7, 128.5, 127.9, 127.4, 127.3, 126.8,
126.5, 103.1, 50.5, 48.2.
IR (KBr): 3389, 2920, 1602, 1551, 1477, 1452 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.64–8.62 (m, 2 H, ArH), 8.37–
8.35 (m, 2 H, ArH), 7.58–7.45 (m, 8 H, ArH), 7.37 (t, J = 7.2 Hz, 2
H, ArH), 7.32–7.28 (m, 1 H, ArH), 5.40 (d, J = 5.6 Hz, 2 H, CH2),
4.91 (t, J = 5.6 Hz, 1 H, NH).
MS (EI, 70 eV): m/z (%) = 405.3 (9), 406.2 (100), 407.2 (31).
HRMS (ESI): m/z [M + H]+ calcd for C25H22N6: 407.1984; found:
407.1953.
13C NMR (100 MHz, CDCl3): δ = 164.2, 148.0, 139.8, 137.6, 131.1,
130.7, 130.6, 130.3, 129.5, 128.9, 128.8, 128.4, 127.8, 127.6, 126.4,
48.2.
2-Phenyl-7-vinyl[1,2,4]triazolo[1,5-c]pyrimidines 8; General
Procedure
A sealed round-bottomed flask was charged with 5 (0.5 mmol),
Pd(PPh3)2Cl2 (0.035 g, 0.05 mmol, 0.1 equiv), vinylmagnesium
chloride (0.7 M in THF, 1.1 mmol, 1.5 mL), and THF (6 mL). The
mixture was stirred at 70 °C under N2 atmosphere for 2 h. The prog-
ress of the reaction was monitored by TLC (eluent: PE–EtOAc,
8:1). After completion of the reaction, sat. aq NH4Cl (5 mL) was
added, and extracted with EtOAc (3 × 50 mL). After removal of the
solvent under reduced pressure, the residue was subjected to col-
umn chromatography on silica gel (eluent: PE–EtOAc, 12:1) to af-
ford products 8.
MS (EI, 70 eV): m/z (%) = 91.1 (100), 106.1 (20), 334.1 (66), 335.0
(16), 336.1 (24).
HRMS (ESI): m/z [M + Na]+ calcd for C24H18ClN5: 434.1148;
found: 434.1133.
2,5-Diphenyl-7,8-di(p-toluidino)[1,2,4]triazolo[1,5-c]pyrimi-
dine (6f)
Prepared from 5l and p-toluidine; yield: 0.14 g (60%); yellow pow-
der; mp 220–222 °C; Rf = 0.68 (PE–EtOAc, 3:1).
IR (KBr): 3403, 2923, 2852, 1603, 1563, 1511 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.81–8.79 (m, 2 H, ArH), 8.33–
8.31 (m, 2 H, ArH), 7.61–7.59 (m, 3 H, ArH), 7.45–7.43 (m, 5 H,
ArH), 7.16 (d, J = 8.0 Hz, 2 H, ArH), 7.01 (d, J = 8.0 Hz, 2 H, ArH),
6.74–6.72 (m, 3 H, ArH, NH), 6.49 (s, 1 H, NH), 2.36 (s, 3 H, CH3),
2.27 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 165.3, 154.2, 145.9, 144.0, 141.0,
137.0, 132.4, 131.7, 131.4, 130.6, 130.4, 130.3, 129.9, 129.8, 129.4,
128.6, 128.4, 127.9, 120.5, 115.4, 104.6, 20.9, 20.6.
2-Phenyl-7-vinyl[1,2,4]triazolo[1,5-c]pyrimidine (8a)
Yield: 0.04 g (30%); white powder; mp 199–200 °C; Rf = 0.45 (PE–
EtOAc, 8:1).
IR (KBr): 3055, 3009, 1622, 1525, 1448, 1417 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.29 (s, 1 H, ArH), 8.27 (s, 2 H,
ArH), 7.49 (s, 3 H, ArH), 7.45 (s, 1 H, ArH), 6.78 (dd, J = 10.4, 16.8
Hz, 1 H, CH), 6.48 (d, J = 16.8 Hz, 1 H, CH2), 5.65 (d, J = 10.4 Hz,
1 H, CH2).
13C NMR (100 MHz, CDCl3): δ = 166.4, 153.5, 151.5, 139.9, 134.1,
131.0, 129.9, 128.9, 127.8, 121.8, 108.0.
MS (EI, 70 eV): m/z (%) = 288.1 (40), 482.3 (100), 483.3 (37).
HRMS (ESI): m/z [M + H]+ calcd for C31H26N6: 483.2297; found:
483.2267.
MS (EI, 70 eV): m/z (%) = 221.1 (33), 222.1 (100), 223.0 (15).
HRMS (ESI): m/z [M + H]+ calcd for C13H10N4: 223.0984; found:
223.0992.
7,8-Bis(amino)-Substituted Products 6g and 6h
A mixture of 5a (0.16 g, 0.5 mmol), the appropriate amine (1.5
mmol, 3.0 equiv), and Et3N (0.51 g, 5 mmol) in anhydrous MeOH
(15 mL) was stirred under reflux for 24 h until full consumption of
the substrates. The progress of the reaction was monitored by TLC
(eluent: PE–EtOAc, 3:1). Then, the mixture was concentrated under
reduced pressure. The residue was directly subjected to column
chromatography on silica gel using PE–EtOAc (8:1) as the eluent to
afford, respectively, the desired 7,8-bis(amino)-substituted
[1,2,4]triazolo[1,5-c]pyrimidines 6g and 6h.
5-Methyl-2-phenyl-7-vinyl[1,2,4]triazolo[1,5-c]pyrimidine (8b)
Yield: 0.04 g (33%); white powder; mp 184–185 °C; Rf = 0.40 (PE–
EtOAc, 8:1).
IR (KBr): 3060, 3015, 1624, 1542, 1428, 1320 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.30–8.28 (m, 2 H, ArH), 7.49–
7.48 (m, 3 H, ArH), 7.35 (s, 1 H, ArH), 6.76 (dd, J = 10.4, 17.2 Hz,
1 H, CH), 6.45 (d, J = 17.2 Hz, 1 H, CH2), 5.60 (d, J = 10.4 Hz, 1
H, CH2), 3.01 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 165.4, 153.7, 150.8, 150.2, 134.6,
130.7, 130.3, 128.8, 127.8, 121.2, 106.0, 20.0.
2-Phenyl-7,8-di(p-toluidino)[1,2,4]triazolo[1,5-c]pyrimidine
(6g)
Prepared from 5a and p-toluidine; yield: 0.17 g (72%); red powder;
mp 246–247 °C; Rf = 0.70 (PE–EtOAc, 3:1).
MS (EI, 70 eV): m/z (%) = 235.1 (47), 236.1 (100), 237.1 (17).
HRMS (ESI): m/z [M + H]+ calcd for C14H12N4: 237.1140; found:
237.1158.
IR (KBr): 3289, 2915, 2853, 1614, 1511, 1465 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.89 (s, 1 H, ArH), 8.07 (d, J = 5.6
Hz, 2 H, ArH), 7.55 (d, J = 8.0 Hz, 2 H, ArH), 7.49–7.43 (m, 3 H,
ArH), 7.42 (s, 2 H, 2NH), 7.30 (s, 4 H, ArH), 7.13 (d, J = 8.0 Hz, 2
H, ArH), 2.41 (s, 3 H, CH3), 2.31 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 148.0, 140.2, 139.5, 136.6, 133.4,
130.9, 129.9, 129.7, 128.8, 126.5, 126.0, 117.5, 21.3, 20.8.
2,5-Diphenyl-7-vinyl[1,2,4]triazolo[1,5-c]pyrimidine (8c)
Yield: 0.05 g (36%); white powder; mp 191–192 °C; Rf = 0.42 (PE–
EtOAc, 8:1).
IR (KBr): 3060, 1622, 1520, 1478, 1452, 1330 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.76 (d, J = 6.4 Hz, 2 H, ArH),
8.35 (d, J = 4.4 Hz, 2 H, ArH), 7.62 (d, J = 4.4 Hz, 3 H, ArH), 7.51
(s, 3 H, ArH), 7.46 (s, 1 H, ArH), 6.86 (dd, J = 10.4, 16.8 Hz, 1 H,
MS (EI, 70 eV): m/z (%) = 405.2 (9), 406.2 (100), 407.2 (28).
HRMS (ESI): m/z [M + H]+ calcd for C25H22N6: 407.1984; found:
407.1957.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2734–2746

2746
C. Tang et al.
PAPER
CH), 6.60 (d, J = 16.8 Hz, 1 H, CH2), 5.68 (d, J = 10.4 Hz, 1 H,
CH2).
13C NMR (100 MHz, CDCl3): δ = 165.3, 155.3, 150.9, 148.2, 134.5,
132.0, 131.6, 130.8, 130.7, 130.2, 128.8, 128.5, 127.9, 121.5, 106.3.
5380. (c) Federico, S.; Ciancetta, A.; Sabbadin, D. J. Med.
Chem. 2012, 55, 9654. (d) Kyoichiro, I.; Takamasa, S.
Patent EP1544200, 2005; Chem. Abstr. 2004, 140, 321375.
(9) Harris, J. M.; Neustadt, B. R.; Zhang, H. Bioorg. Med.
Chem. Lett. 2011, 21, 2497.
(10) (a) Nagamatsu, T.; Fujita, T. Chem. Commun. 1999, 1461.
(b) Shurrab, N. K.; El-Louh, A. K.; Al-Meghari, I. M.
J. Chem. Res. 2013, 37, 91.
MS (EI, 70 eV): m/z (%) = 297.1 (29), 298.1 (100), 299.1 (22),
195.0 (27).
HRMS (ESI): m/z [M + H]+ calcd for C19H14N4: 299.1297; found:
299.1294.
(11) For reviews, see: (a) Salas, J. M.; Romero, M. A.; Sanchez,
M. P.; Quiros, M. Coord. Chem. Rev. 1999, 193, 1119.
(b) Haasnoot, J. G. Coord. Chem. Rev. 2000, 200–202, 131.
(12) 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.
(13) For examples by using orthoformates, see: (a) Brown, D. J.;
Nagamatsu, T. Aust. J. Chem. 1978, 31, 2505. (b) Rashad, A.
E.; Heikal, O. A.; El-Nezhawy, A. O.; Abdel-Megeid, H. F.
M. E. Heteroat. Chem. 2005, 16, 226.
Acknowledgment
This work was financially supported by the National Natural Sci-
ence Foundation of China (No. 21102019). Q.-R. Wang is grateful
to Hangzhou Government for a Qian-Jiang scholar assistance. We
thank G. Tang for acquiring high-resolution mass spectrometry data
and Dr. Z. Chen for X-ray crystal structure measurements.
(14) For examples by using activated acids or derivatives, see:
Shawali, A. S.; Hassaneen, H. M.; Shurrab, N. K.
Tetrahedron 2008, 64, 10339.
Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
10.1055/s-00000084.SunpfgIpi
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o
nr
i
(15) Neustadt, B. R.; Liu, H.; Hao, J.; Greenlee, W. J.; Stamford,
A. W.; Foster, C.; Arik, L.; Lachowicz, J.; Zhang, H.;
Bertorelli, R.; Fredduzzi, S.; Varty, G.; Cohen-Williams,
M.; Ng, K. Bioorg. Med. Chem. Lett. 2009, 19, 967.
(16) Thiel, O. R.; Achmatowicz, M. M.; Reichelt, A.; Larsen, R.
D. Angew. Chem. Int. Ed. 2010, 49, 8395; Angew. Chem.
2010, 122, 8573.
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Synthesis 2014, 46, 2734–2746
© Georg Thieme Verlag Stuttgart · New York