IBD-mediated oxidative cyclization of pyrimidinylhydrazones and concurrent Dimroth rearrangement: Synthesis of [1,2,4]triazolo[1,5-c]pyrimidine derivatives

Article abstract of DOI:10.3762/bjoc.9.298

Oxidative cyclization of 6-chloro-4-pyrimidinylhydrazones 4 with iodobenzene diacetate (IBD) in dichloromethane gives rise to [1,2,4]triazolo[4,3-c]pyrimidine derivatives 5a-o. These incipient products undergo feasible Dimroth rearrangement to furnish the isolated [1,2,4]triazolo[1,5-c]pyrimidines 6a-o in moderate to high yields.

Full text of DOI:10.3762/bjoc.9.298

IBD-mediated oxidative cyclization of pyrimidinyl-
hydrazones and concurrent Dimroth rearrangement:
Synthesis of [1,2,4]triazolo[1,5-c]pyrimidine
derivatives
Caifei Tang, Zhiming Li and Quanrui Wang*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 2629–2634.
Department of Chemistry, Fudan University, 200433 Shanghai, P. R.
of China
doi:10.3762/bjoc.9.298
Received: 13 September 2013
Accepted: 04 November 2013
Published: 25 November 2013
Email:
Quanrui Wang* - qrwang@fudan.edu.cn
* Corresponding author
Associate Editor: J. P. Wolfe
Keywords:
© 2013 Tang et al; licensee Beilstein-Institut.
License and terms: see end of document.
cyclization; hydrazones; hypervalent iodine; oxidation; rearrangement;
[1,2,4]triazolo[1,5-c]pyrimidines
Abstract
Oxidative cyclization of 6-chloro-4-pyrimidinylhydrazones 4 with iodobenzene diacetate (IBD) in dichloromethane gives rise to
[1,2,4]triazolo[4,3-c]pyrimidine derivatives 5a–o. These incipient products undergo feasible Dimroth rearrangement to furnish the
isolated [1,2,4]triazolo[1,5-c]pyrimidines 6a–o in moderate to high yields.
Introduction
The pyrimidine moiety is an important pharmacophore [1]. a [1,2,4]triazolo[1,5-a]pyrimidine compound, which is the first
Especially, the fused bi- or tricyclic heterocyles containing a triazolopyrimidine registered as a drug possessing antiprolif-
pyrimidine motif have received considerable interest in the erative activity in glioma cells and vascular smooth muscle cells
design and discovery of new compounds for pharmaceutical and (VSMCs) and used as a coronary vasodilator in the therapy of
herbicidal applications [2,3]. For example, the pyrrolo[2,3- syndromes that may be influenced by immunomodulators [5,6].
d]pyrimidine derivative, ruxolitinib (INCB018424), was discov- Interestingly, the first [1,2,4]triazolo[1,5-a]pyrimidine antibi-
ered as a selective JAK1 and JAK2 inhibitor, which is currently otic essramycin has been isolated from natural sources
under clinical investigation [4]. To date, a number of fused (Figure 1) [7].
pyrimidine-type compounds have been successfully commer-
cialized, such as the pyrazolo[3,4-d]pyrimidine allopurinol and It has also been revealed that compounds carrying a [1,2,4]tria-
the pyrazolo[4,3-d]pyrimidine sildenafil. In addition, trapidil is zolo[1,5-c]pyrimidine nucleus behave as selective antagonists
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Results and Discussion
The investigation commenced with the preparation of 1-(6-
chloropyrimidin-4-yl)hydrazines 3. The required starting 4,6-di-
hydroxypyrimidines 1 can be prepared following the reported
procedure by condensation of dimethyl malonate either with
formamide (for 1a) or the respective formamidine salts (for 1b
and 1c) [15].
As outlined in Scheme 1, the conversion of 4,6-dihydroxy-
pyrimidines 1 to the dichloro derivatives 2 was accomplished
by refluxing in phosphorus oxychloride for 4 h in the presence
of triethylamine in yields ranging from 75 to 90% [16,17]. After
screening a set of conditions, 1-(6-chloropyrimidin-4-
Figure 1: The structure of two representatives of [1,2,4]triazolopyrim-
idines.
for human A2A and A3 adenosine receptor sub-types which yl)hydrazines 3 were then obtained in 90–95% yield through the
offer great promise in the treatment of Parkinson’s disease, or reaction of compounds 2 with two equivalents of 50%
as Hsup90 modulators [8]. Clarkson and co-workers have hydrazine in ethanol at 45 °C for 2 h (Scheme 1).
prepared a range of benzothieno-fused 1,2,4-triazolo[4,3-
c]pyrimidines and 1,2,4-triazolo[1,5-c]pyrimidines by the
oxidative cyclisation of benzothieno[2,3-d]pyrimidine hydra-
zones. The investigation has also suggested the important
ability as inhibitors of Shiga toxin trafficking for protecting
HeLa cells [9].
The wide range of biological activities shown by various tria-
zolopyrimidines encouraged synthetic organic and medicinal
chemists to synthesize new members and to study their applica-
tions [10,11]. Several strategies for constructing triazolopyrimi-
dine rings are available. These include the pre-formation of
1-amino-6-imino-substituted pyrimidines followed by reaction
Scheme 1: Synthesis of 1-(6-chloropyrimidin-4-yl)hydrazines 3.
with carboxylic acids or derivatives as the one-carbon cyclizing
agent [12] and the dehydrative cyclization of carboxylic acid
N'-(pyrimidin-4-yl)-hydrazide and ring rearrangement [13]. We next examined the synthesis of the corresponding hydra-
Recently, Thiel and coworkers have also established an effi- zones of various aldehydes. After screening a set of conditions,
cient palladium-catalyzed intermolecular coupling of aldehyde- optimal conditions could be determined. Thus, 1-(6-chloropy-
derived hydrazones with chloro-substituted pyridines and rimidin-4-yl)hydrazine (3a) was condensed with 20% excess
related heterocycles, from which the triazolopyridines and other benzaldehyde to give 85% yield of the chloropyrimidinylhydra-
related fused heterocycles can be obtained after oxidative zone 4a in absolute ethanol at room temperature in about 1 h.
cyclization [14]. In accordance with the significance shown by As shown in Table 1, the reaction proceeded readily for most of
triazolopyrimidines, the development of complementary and the employed aldehydes, affording the corresponding hydra-
simple synthetic methods for the efficient preparation of novel zones 4. In general, aromatic aldehydes provided higher yields
triazolopyrimidines is needed.
than aliphatic aldehydes.
Recently, we have reported the synthesis of 8-bromo-7-chloro- In recent years, organo hypervalent iodine reagents have drawn
[1,2,4]triazolo[1,5-c]pyrimidines from the reaction of pyrim- considerable interests as versatile and environmentally benign
idinylhydrazones with bromine followed by Dimroth rearrange- oxidants with many applications in organic synthesis because of
ment [15]. In the present paper, we wish to report an efficient their low toxicity, stability, high reactivity, and availability.
synthesis of new [1,2,4]triazolo[1,5-c]pyrimidine derivatives Efficient formation of new carbon–heteroatom bonds as well as
from hypervalent iodine (IBD)-mediated oxidative cyclisation carbon–carbon bonds can be achieved typically under mild
of aldehyde pyrimidinylhydrazones and consecutive Dimroth reaction conditions with these metal-free reagents [18,19]. For
rearrangement in relatively good yields under very mild condi- example, Salgado has described the synthesis of novel
tions.
[1,2,4]triazolo[1,5-a]pyrimidine derivatives by iodobenzenedi-
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Beilstein J. Org. Chem. 2013, 9, 2629–2634.
acetate (IBD)-mediated oxidative cyclization of suitable
N-benzylidene-N′-pyrimidin-2-yl hydrazine precursors, fol-
lowed by a Dimroth rearrangement [20]. We envisioned that our
aldehyde chloropyrimidinylhydrazones 4 would undergo
feasible oxidative cyclisation to afford novel triazolopyrim-
idines.
Table 1: Synthesis of the chloropyrimidinylhydrazones 4a.
We initiated our investigation by examining the oxidative
cyclization of 4a with iodobenzenediacetate (IBD) as an oxidant
(Table 2). Thus, 4a was treated with one equivalent of freshly
prepared IBD in dichloromethane at room temperature. After
completion of the reaction, the solvent was removed and the
residue was dissolved in EtOH with a catalytic amount of conc.
HCl. Usual workup afforded the [1,2,4]triazolo[1,5-c]pyrimi-
dine 6a in 57% yield (Table 2, entry 1).
Entry R1
R2
Product
Yield [%]b
1
H
Ph
4a
4b
4c
4d
4e
4f
85
84
75
80
66
81
85
83
85
84
89
87
90
85
96
2
H
2-ClC6H4
2-furanyl
4-(MeO)C6H4
Et
3
H
4
H
5
H
6
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
7
2-ClC6H4
2-furanyl
4-(MeO)C6H4
Et
4g
4h
4i
8
With this promising result in hand, the reaction efficiency was
improved by optimizing the conditions, such as the amount of
IBD, solvent, reaction time and purification method. Gratify-
ingly, 6a was formed in 81% yield when 1.3 equiv of IBD were
used in dichloromethane for 6 h (Table 2, entry 5). Further
extension of the reaction time to 24 h did not provide superior
results (Table 2, entry 6). Meanwhile, reactions in THF or ethyl
acetate resulted in marginally lower yields (Table 2, entries 8
and 9). Switching to water with assistance by microwave irradi-
ation or performing the reaction in ethanol provided even unac-
9
10
11
12
13
14
15
4j
Ph
4k
4l
2-ClC6H4
2-furanyl
4-(MeO)C6H4
Et
4m
4n
4o
aReagents and conditions: chloropyriminylhydrazine 3 (3.0 mmol),
EtOH (15 mL), aldehyde (3.6 mmol, 1.2 equiv), rt, 30–60 min. bIsolated
yield after column chromatography.
Table 2: Selected results of screening the optimal conditions.
Entry
IBD (equiv)
Additive
T (°C)
Time (h)
Solvent
Yield [%]a
1
1.0
1.1
1.2
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
–
25
25
25
25
25
25
40
25
25
25
25
25
25
25
4
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
57
66
75
75
81
79
72
70
70
12b
25
c
2
–
4
3
–
4
4
–
4
5
–
6
6
–
24
10
6
7
–
8
–
9
–
6
EtOAc
H2O
10
11
12
13
14
–
6
–
6
EtOH
–
6
DMF
Bu4NId
I2d
6
CH2Cl2
CH2Cl2
75
75
6
aIsolated yields of 6a. bPerformed under microwave irradiation. cComplex mixture of products. dAn amount of 10 mol % was used.
2631

Beilstein J. Org. Chem. 2013, 9, 2629–2634.
ceptable yields (Table 2, entries 10 and 11). Further, when functional group on the para position of the aromatic ring
replacing the solvent by DMF, a complex mixture of products seems to afford slightly lower yields (Table 3, entries 4, 9, 14).
was produced, and no pure desired product could be isolated
(Table 2, entry 12). Employment of 10 mol % Bu4NI or I2 as an On the other hand, the reaction is less sensitive to substitution
additive did not improve the result (Table 2, entries 13 and 14). of 4 at the C-2 position. Although both aromatic and aliphatic
It has also been observed that temperature elevation did not aldehyde-derived hydrazones 4 participated well in the reaction,
benefit the transformation (Table 2, entry 7). Thus, the use of the latter furnished only low to moderate yields (Table 3, entries
IBD (1.3 equiv) at room temperature in dichloromethane for 6 h 5, 10 and 15).
was found to be most efficient and therefore used as the stan-
dard conditions.
Although the employed procedure was believed to afford
initially [1,2,4]triazolo[4,3-c]pyrimidines 5, a formal Dimroth
To probe the generality of the IBD-oxidative cyclization rearrangement occurred readily to give the isolated products
protocol, all of the other pyrimidinylhydrazones 4 with different that belong to the [1,5-c] series 6. This kind of rearrangement
R1 and R2 groups were examined under optimal conditions. As has been described previously [10,11,21]. The accepted mecha-
shown in Table 3, the protocol appeared to be quite general. In nism of the Dimroth rearrangement might involve protonation
all cases studied, the respective [1,2,4]triazolo[1,5-c]pyrim- of 5 to give I (5-H+), ring opening (II), tautomerization by
idines 6 could be obtained. Various aryl substituents on the tria- H-shift (III) of the 1,2,4-triazole ring, ring closure (IV) and
zole ring (R2), including phenyl, electron-rich and electron-poor deprotonation to isomeric 1,2,4-triazolo[1,5-c] pyrimidine 6
aryls, were compatible with this reaction, and high yields of the (Scheme 2).
triazolopyrimidines 6 could generally be obtained. Substrates
carrying a heteroaromatic group such as 2-furanyl also Indeed, small quantities of the triazole 6 can be observed by 1H
proceeded smoothly to give a good yield of the product. NMR and thin-layer chromatography in our original attempts to
Aromatic aldehyde hydrazones bearing an electron-donating isolate pure 5. Although very slow, the rearrangement of the
Table 3: Synthesis of the triazolopyrimidines 6a.
Entry
R1
R2
Product
Yield [%]b
1
H
Ph
6a
6b
6c
6d
6e
6f
81
80
81
69
64
81
86
86
71
34
84
87
87
71
36
2
H
2-ClC6H4
2-furanyl
4-(MeO)C6H4
Et
3
H
4
H
5
H
6
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
7
2-ClC6H4
2-furanyl
4-(MeO)C6H4
Et
6g
6h
6i
8
9
10
11
12
13
14
15
6j
Ph
6k
6l
2-ClC6H4
2-furanyl
4-(MeO)C6H4
Et
6m
6n
6o
aReagents and conditions: hydrazone 4 (1.0 mmol), IBD (1.3 mmol), DCM (6 mL) at rt, then refluxed in abs. EtOH for 1–3 h. bIsolated yield after
column chromatography.
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Beilstein J. Org. Chem. 2013, 9, 2629–2634.
Scheme 2: Plausible mechanism for the transformation of [1,2,4]triazolo[4,3-c]pyrimidines 5 to the [1,5-c] series 6.
triazole 5 to 6 was found to occur spontaneously. The process strate scope, which make it a useful and attractive process for
can be catalyzed under catalytic amount of HCl. In one case, the synthesis of structurally diverse triazolopyrimidines. More-
pure 1,2,4-triazolo[4,3-c]pyrimidine 5f was isolated and charac- over, the 7-chloro-substitution would allow further manipula-
terized (see Supporting Information File 1 for full experimental tions through nucleophilic substitution [23] and metal-catalyzed
data), which was dissolved in ethanol and allowed to be stirred cross-coupling reactions, which are under investigation in our
at room temperature. After one day, formation of 6f was group.
observed. The isomerization was completed after 10 days as
evidenced by the disappearance of the methyl signal at 2.39
Supporting Information
ppm in 5f and fully shifting to downfield absorption at 3.04
ppm in 6f.
Supporting Information File 1
Experimental procedures and analytical data for new
Since compounds 5 are generally unstable as compared with
their [1,5-c]-counterparts, isolation of the initial
[1,2,4]triazolo[4,3-c]pyrimidine intermediates proved to be of
no preparative value. Instead, they were allowed directly to
isomerize under HCl catalysis to provide the thermodynami-
cally more stable title compounds through tandem ring opening
and ring closing Dimroth reactions.
compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-9-298-S1.pdf]
Supporting Information File 2
NMR spectral data for unknown compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-9-298-S2.pdf]
The structure of bicycles 6a–o was principally assigned from
their spectral evidence and mass spectrometry analysis (see
Supporting Information File 2 for full data). To confirm the Acknowledgements
structure of the regio-isomer of the cyclization rearrangement, This work was financially supported by the National Science
colorless single crystals of compound 6h were obtained from Foundation of China (No. 21372045) and the Scientific Study
CH2Cl2/n-hexane and its molecular structure was determined by Fund for Distinguished Doctor Candidates at Fudan University.
X-ray crystallography, providing unequivocal evidence for the Wang is grateful to the Hangzhou Government for Qian-Jiang
assignments [22].
scholar assistance. We are also indebted to Dr. Z. Chen for
X-ray measurements and G. Tang for acquiring high-resolution
mass spectrometry data.
Conclusion
In conclusion, we report herein a general and convenient
method for the synthesis of novel [1,2,4]triazolo[1,5-c]pyrimi-
dine derivatives with moderate to excellent yields. The protocol
features initial oxidative cyclization of readily available
chloropyrimidinylhydrazones followed by feasible Dimroth
rearrangement. The procedure offers several advantages
including good yields, operational simplicity, environmental
friendliness and shorter reaction time along with broad sub-
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