A one-pot approach to 10-(1H-1,2,3-triazol-1-yl)pyrimido[1,2-a]indoles via aryne-mediated transformations of 3-(pyrimidin-2-yl)-1,2,4-triazines

Article abstract of DOI:10.1016/j.tetlet.2016.07.052

An efficient synthetic approach toward 10-(1H-1,2,3-triazol-1-yl)pyrimido[1,2-a]indoles, including fluorinated derivatives, has been developed. The transformation of the 1,2,4-triazine ring of readily available 3-(pyrimidin-2-yl)-1,2,4-triazines proceeds

Full text of DOI:10.1016/j.tetlet.2016.07.052

Tetrahedron Letters 57 (2016) 3862–3865
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Tetrahedron Letters
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A one-pot approach to 10-(1H-1,2,3-triazol-1-yl)pyrimido[1,2-a]
indoles via aryne-mediated transformations of 3-(pyrimidin-2-yl)-
1,2,4-triazines
Dmitry S. Kopchuk a,b, Nikolay V. Chepchugov a, Albert F. Khasanov a, Igor S. Kovalev a, Sougata Santra a,
Emiliya V. Nosova a,b, Grigory V. Zyryanov a,b, , Adinath Majee c, Vladimir L. Rusinov a,b
,
⇑
Oleg N. Chupakhin a,b
a Ural Federal University, Mira St. 19, Ekaterinburg 620002, Russia
b Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, S. Kovalevskoy Str., 22, Ekaterinburg 620041, Russia
c Department of Chemistry, Visva-Bharati (A Central University), Santiniketan 731235, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthetic approach toward 10-(1H-1,2,3-triazol-1-yl)pyrimido[1,2-a]indoles, including
fluorinated derivatives, has been developed. The transformation of the 1,2,4-triazine ring of readily avail-
able 3-(pyrimidin-2-yl)-1,2,4-triazines proceeds via reaction with in situ generated aryne intermediates.
Improved methods have been developed for the synthesis of the starting 5,6-diaryl- and 6-aryl-3-(pyrim-
idin-2-yl)-1,2,4-triazines. The influence that the nature of the aryne intermediate has on the reaction
pathway was studied. The structure of the obtained pyrimido[1,2-a]indoles was confirmed by single
crystal X-ray crystallography.
Received 24 May 2016
Revised 12 July 2016
Accepted 14 July 2016
Available online 16 July 2016
Keywords:
1,2,4-Triazines
1,2-Dehydrobenzene
4,5-Difluoro-1,2-dehydrobenzene
Transformations
Ó 2016 Elsevier Ltd. All rights reserved.
10-(1H-1,2,3-Triazol-1-yl)pyrimido[1,2-a]
indoles
Introduction
propanedinitriles or ethyl phenylcyanoacetates with 2-cyanoani-
line derivatives19 or the Cu-catalyzed coupling of gem-
Pyrido[1,2-a]indoles and pyrimido[1,2-a]indoles are of wide
interest due to their presence in naturally occurring compounds
(Fig. 1). They exhibit a wide range of biological activities,1,2 in par-
ticular, against atherosclerosis,3 depression,4 and hypoglycemic
activity,4 as well as 5-HT4-receptor antagonists.1,5
So far, existing methods for the synthesis of these structures do
not always involve the use of readily available and/or inexpensive
reagents, or simple procedures. Thus, pyrimido[1,2-a]indoles can
be obtained by the intramolecular condensation of 2-((2-pyridyl)
methyl)pyridine N-oxide6 or diphenyl(pyrimidin-2-yl)methanol,7
or via the intermolecular heterocyclization reaction between
2-aminoindoles8–13 or their aza-analog, i.e., 1H-benzimidazol-2-
amine,2 with 1,2-diketones. In addition, the synthesis of pyrimido
[1,2-a]indoles can be performed via the transformations of 1-(2-
ethynylphenyl)-3,3-dialkyltriazenes,14 1-acetylamino-2-iodoben-
zenes,15 3-formylindole,16,17 or azidobenzylazide.18 Modern
synthetic methods involve the Pd-catalyzed reactions of phenyl-
dibromovinylanilides with sulfonamides.20
We have recently reported21–23 one-pot methods for the syn-
thesis of 1,2,3-triazole-substituted pyrido[1,2-a]indoles via the
rearrangement of 3-(2-pyridyl)-1,2,4-triazine during their reac-
tions with in situ generated aryne intermediates. Herein, we wish
to report a new approach toward the synthesis of pyrimido[1,2-a]
indoles via the transformations of 3-(pyrimidin-2-yl)-1,2,4-triazi-
nes when treated with arynes.
For the synthesis of the starting 3-(pyrimidine-2-yl)-1,2,4-tri-
azines 4, an improved procedure has been developed (ESI). The
most convenient method for obtaining the various 5,6-diaryl-3-
(het)aryl-1,2,4-triazines is the one-pot condensation reaction of
amidrazones with aromatic 1,2-diketones, most of which are com-
mercially available. However, for the synthesis of 3-pyrimidine-
substituted 1,2,4-triazines, this approach is reported only in very
few cases,24,25 while the less accessible pyrimidine–carboxylic acid
hydrazide is used as a starting material in other cases.26,27
We proposed an approach toward 3-(pyrimidine-2-yl)-1,2,4-
triazines
4 involving the reaction of commercially available
⇑
Corresponding author. Tel.: +7 343 375 4501.
E-mail address: gvzyryanov@gmail.com (G.V. Zyryanov).
2-cyanopyrimidine 1 with hydrazine hydrate. Reaction between
http://dx.doi.org/10.1016/j.tetlet.2016.07.052
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

D. S. Kopchuk et al. / Tetrahedron Letters 57 (2016) 3862–3865
3863
Cl
availability of these compounds by other methods, such yields
can be considered as acceptable.
HO
The structures of the compounds were determined by 1H and
13C NMR spectroscopy, mass spectrometry, and elemental analysis.
Thus, in the 1H NMR spectra of products 4a–c, signals in the range
of 7.30–9.40 ppm, ascribed to the proton resonance of the pyrim-
idine moiety (doublet of doublets and doublet with integrated
intensity of two protons) and aromatic substituents are observed.
In the case of triazine 4c the additional signal of the C-5 proton
of the 1,2,4-triazine ring is observed as a one-proton singlet at
9.53 ppm.
In the next step, in order to study the influence of the aryne
intermediate substituents on the reaction pathway, we investi-
gated the reactions of 3-(pyrimidin-2-yl)-1,2,4-triazines 4 with
in situ generated aryne intermediates.
OH
N
N
N
H
HN
(-)-Goniomitine
Ciclazindole (antidepressant,
hypoglycemic agent)
R'
N
O
R''
N
H
N
H
R4
O
H
R1
H
O
N
R2
R3
5-HT4-receptor antagonists
Thus, under typical conditions,21–23 the reaction of 3-(pyrim-
idin-2-yl)-1,2,4-triazines with the unsubstituted aryne, benzyne,
afforded 10-(1H-1,2,3-triazol-1-yl)pyrimido[1,2-a]indoles 5a–c as
the major products, i.e., the reaction proceeds by the same mecha-
nism as for 3-(2-pyridyl)-1,2,4-triazines (Scheme 2).21–23
However, compared to pyridine, the nucleophilicity of each of
the two pyridine-type nitrogen atoms in the pyrimidine moiety
is reduced. Therefore, the reaction also afforded the aza-Diels–
Alder reaction products, namely 1-(pyrimidin-2-yl)isoquinolines
6a–c, as minor products in 3–11% yields. The product ratios were
determined by 1H NMR of the crude products and ESI-MS. Product
6b was isolated as an analytically pure sample (see Scheme 1).
Due to the presence of two electron-donating methoxy-groups,
4,5-dimethoxy-1,2-dehydrobenzene is less susceptible to nucle-
ophilic attack by the nitrogen of the pyrimidine ring. For this rea-
son the reaction between 3-(pyrimidin-2-yl)-1,2,4-triazines 4 and
4,5-dimethoxy-1,2-dehydrobenzene under both typical21–23 and
harsh (boiling o-xylene) reaction conditions afforded neither the
desired products nor the aza-Diels–Alder reaction products, and
only starting compounds were isolated from the reaction mixture.
Finally, the reactions involving 3-(pyrimidin-2-yl)-1,2,4-triazi-
nes 4 with the most electrophilic aryne, 4,5-difluoro-1,2-dehy-
Strychnine
Figure 1. Representative examples of pyrido[1,2-a]- or pyrimido[1,2-a]indole
containing biologically important molecules.
the formed amidrazone 2 and aromatic 1,2-diketones afforded the
desired compounds (Scheme 1). It is noteworthy that purification
of amidrazone 2 is not needed, which makes our approach more
convenient than previously reported examples. In most reported
cases tedious purification and separation steps involving extrac-
tion28 or precipitation29 were required, thereby reducing the pro-
duct yield.
The 5-unsubstituted-6-aryl-3-(pyrimidin-2-yl)-1,2,4-triazines
have not been previously prepared in high yields. Only in a few
cases30,31 were these compounds isolated in very low yields as
side-products. On the other hand, the cyclocondensation reaction
of in situ generated iminoesters with iso-nitrosoacetophenone
hydrazones has been previously used to obtain 6-aryl-3-pyridyl-
1,2,4-triazines in moderate yields.32 This method was used to
obtain 3-(pyrimidin-2-yl)-1,2,4-triazine 4c in 45% yield. Due to
both the use of the one-step procedure and the extremely low
NC
N
i
ii
N
NH
1
N
Ar
O
O
N
HN
NH2
Ph
N
NH2
OMe
N
N
3
R
NOH
iv
2
NH
iii
Ar
R
N
N
(a) Ar, R = biphenyl-2,2'-diyl, X = H
(b) Ar = R = Ph, X = H
N
N
(c) Ar = Ph, R = H, X = H
4a
, 75%
4b, 71%
4c, 45%
N
(d) Ar = R = Ph, X = F
(e) Ar, R = biphenyl-2,2'-diyl, X = F
X
X
v
Ar
N
N
X
N
X
R
N
Ar
+
N
N
X
R
N
5a, 55%
5b, 58%
6a, <5%
N
X
6b, 11%
5c
6c
, <5%
, 51%
5d, 59%
5e, 62%
Scheme 1. Synthesis of 3-(pyrimidin-2-yl)-1,2,4-triazines and their reactions with arynes. Reagents and conditions: (i) Hydrazine hydrate, ethanol, 20 °C, 2 h, 100%;
(ii) NaOMe, methanol, 20 °C, 1 h, 100%; (iii) ethanol–THF (1:1), reflux, 10 h, 71–75%; (iv) methanol, 20 °C, 1 h, then AcOH, reflux, 30 min, 45%; (v) anthranilic acid, isoamyl
nitrite, dry toluene–dioxane (7:1), reflux, 1.5 h, 51–62%.

3864
D. S. Kopchuk et al. / Tetrahedron Letters 57 (2016) 3862–3865
X
X
can be clearly detected. For example, the proton signals in the C4
X
X
and C6 positions of the isoquinoline moiety are observed as two
doublets with coupling constants of J = 4.8 Hz. Ultimately, the
structures of the representative compound 5c was confirmed by
single crystal X-ray crystallography (Fig. 2).33
X
X
Ar
R
N
N
Ar
R
N
N
N
N
Ar
R
N
N
N
N
N
N
N
N
N
In summary, we have developed an efficient synthetic approach
toward 10-(1H-1,2,3-triazol-1-yl)pyrimido[1,2-a]indoles by the
one-pot transformation of readily available 3-(pyrimidin-2-yl)-
1,2,4-triazines 4 using in situ generated arynes. It has been shown
that the reaction pathway and the product ratios depend strongly
on the nature of the substituents in the aryne core. In the case of a
less electrophilic aryne, benzyne addition to 3-(pyrimidin-2-yl)-
1,2,4-triazines resulted in the formation of 1-(pyrimidin-2-yl)iso-
quinolines 6 as minor products. The reaction of 4 with the least
electrophilic aryne, 4,5-dimethoxy-1,2-dehydrobenzene, did not
afford any products (see Scheme 3).
3
I
II
X
Ar
N
N
X
N
Ar
N
N
N
R
X
X
R
N
N
N
N
X = H, F
III
5
Scheme 2. Proposed mechanism for the formation of 10-(1H-1,2,3-triazol-1-yl)
pyrimido[1,2-a]indoles.
Acknowledgments
This work was supported by the Russian Science Foundation
(Grant # 15-13-10033), the Council for grants of the President of
the Russian Federation (grant no. MK-3079.2015.3), for A. Majee
by BRNS–DAE (Ref. No. 37(2)/14/35/2014-BRNS/563, June 10, 2014).
Supplementary data
Supplementary data (crystallographic data, 1H, 13C and 19F NMR
spectra of new compounds) associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.
2016.07.052.
Figure 2. Molecular structure of compound 5c.
drobenzene, afforded 2,3-difluoro-1H-1,2,3-triazol-1-yl)pyrimido-
[1,2-a]indoles 5d–e as the only products with no 6,7-difluoroiso-
quinolines detected.
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1,2,4-triazines 4a–c. Reagents and conditions: (i) isoamyl nitrite, o-xylene–dioxane
(7:1), reflux.

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