Features of the behavior of 4-amino-5-carboxamido1,2,3-triazolein multicomponent heterocyclizations with carbonyl compounds

Article abstract of DOI:10.3762/bjoc.8.236

Multicomponent reactions involving polyfunctional 4-amino-5-carboxamido-l, 2,3-triazole and cyclic carbonyl-containing CH-acids were studied under conventional thermal heating, microwave and ultrasonic irradiation. The features of the reactions studied we

Full text of DOI:10.3762/bjoc.8.236

Features of the behavior of 4-amino-5-carboxamido-
1,2,3-triazole in multicomponent heterocyclizations
with carbonyl compounds
Eugene S. Gladkov*1,2, Katerina A. Gura2, Svetlana M. Sirko1,
Sergey M. Desenko1,3, Ulrich Groth2 and Valentin A. Chebanov1,3
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 2100–2105.
1Division of Chemistry of Functional Materials, State Scientific
Institution “Institute for Single Crystals” of National Academy of
Sciences of Ukraine, Lenin Ave. 60, 61158 Kharkiv, Ukraine,
2Fachbereich Chemie, Universität Konstanz, Fach M-720,
Universitätsstrasse 10, 78457 Konstanz, Germany and 3Chemistry
Faculty, Karazin Kharkiv National University, Svobody sq., 4, 61077
Kharkiv, Ukraine
doi:10.3762/bjoc.8.236
Received: 21 September 2012
Accepted: 13 November 2012
Published: 30 November 2012
Associate Editor: P. R. Hanson
Email:
© 2012 Gladkov et al; licensee Beilstein-Institut.
License and terms: see end of document.
Eugene S. Gladkov* - gladkov@isc.kharkov.com
* Corresponding author
Keywords:
4-amino-5-carboxamido-1,2,3-triazole; heterocycle;
microwave-assisted synthesis; multicomponent reaction;
ultrasound-assisted synthesis
Abstract
Multicomponent reactions involving polyfunctional 4-amino-5-carboxamido-1,2,3-triazole and cyclic carbonyl-containing
CH-acids were studied under conventional thermal heating, microwave and ultrasonic irradiation. The features of the
reactions studied were discussed and the optimized procedures for the synthesis of final triazolopyrimidines were elaborated.
In contrast to the similar MCRs of numerous other aminoazoles, a change of direction of the heterocyclizations in the case of
4-amino-5-carboxamido-1,2,3-triazole was not observed when microwave or thermal heating was substituted by ultrasonication at
ambient temperature.
Introduction
Multicomponent reactions (MCRs) [1-4] involving polyfunc- possibility of realization of several independent sequences of
tional aminazoles as a key reagent are challenging objectives in two-component stages of MCRs and the presence of alternative
the modern chemistry of heterocyclic compounds dealing with nucleophilic reaction centers in an aminazole molecule often
the synthesis of partially hydrogenated azoloazines [5-8]. The allows the synthesis of different final heterocyclic systems from
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Beilstein J. Org. Chem. 2012, 8, 2100–2105.
the same building blocks. However, one of the main problems Among the polyfunctional aminoazoles that have been studied
preventing efficient application of polyfunctional starting ma- in heterocyclization reactions [5-8,20], derivatives of 4-amino-
terials in MCRs is the existence of simultaneous competing 1,2,3-triazole have been less well investigated. There are only a
reactions leading to complicated mixtures of several com- few examples of their heterocyclizations with β-diketones [21],
pounds. Thereby, the development of a strategy for the control N-cyanomethaneimidates [22], isocyanates [23], chalcones [24]
of the MCR direction and the elaboration of synthetic methods and derivatives of carboxylic acids [25,26]. The only MCR
allowing tuning of their selectivity are the current objectives involving this type of aminoazole was described in our previous
that have attracted our attention and efforts over the past few publication [27].
years [5-8].
In the case of 4-amino-5-carboxamido-1,2,3-triazole, hetero-
In some of our recent publications it was demonstrated that the cyclizations can proceed in two main ways: “classical” for
direction of MCRs involving aminazoles, carbonyls and active α-aminoazole direction with participation of the NH2-group and
methylene compounds can be effectively controlled by varia- endocyclic NH (Figure 2, compound VII or its position isomer
tion of such reaction parameters as temperature, solvent type, VIII), or an alternative pathway involving the NH2-group and
catalytic system, method of activation, etc. [9-17]. Changing carboxamide fragment [25,26] (compound IX).
these parameters gives us the opportunity to synthesize different
types of heterocyclic systems, with a high level of selectivity,
from the same starting materials. For example, MCRs or
5-aminopyrazoles containing several nonequivalent nucle-
ophilic reaction centers with aromatic aldehydes and deriva-
tives of 1,3-cyclohexanedione [10,11] or pyruvic acids [12-14]
can be selectively directed to the formation of one of the com-
pounds I–III or IV–VI (Figure 1). Such an approach is in good
correspondence with the “ideal synthesis” concept [18,19] and
Figure 2: Some possible products of MCRs involving 4-amino-5-
carboxamido-1,2,3-triazole and carbonyl compounds.
allows significant increasing of the molecular diversity of target
azoloazine systems.
Thus, there are several alternative directions for reactions
between 4-amino-5-carboxamido-1,2,3-triazole, carbonyls and
active methylene compounds. In the present article we disclose
our recent results of a study of such MCRs and analyze the
influence of some of the reaction parameters on their develop-
ment and outcome.
Results and Discussion
It was found that reaction between one equivalent of aminotria-
zole 1 and two equivalents of cycloalkanones 2a,b (n = 1–2) in
boiling dry ethanol for 3 h (Method A) proceeded as ABB’-type
[28] MCR with chemodifferentiation of cyclic ketone and
yielded spiroheterocycles 4a,b (31–37%, Scheme 1, Table 1) as
the sole reaction products. However, better yields and purity of
compounds 4a,b were observed when the starting materials 1
and 2a,b were treated in methanol under microwave (MW) ir-
radiation at 120 °C for 30 min (Method B). At the same time,
the reaction involving cycloheptanone (n = 3) did not allow the
synthesis of compound 4c, which was not found in the reaction
mixture even in trace amounts by TLC, while aminotriazole 1
was isolated unchanged from the reaction mixture.
Figure 1: Some MCRs of aminoazoles with controlled switching of the
direction.
Positional-isomeric compounds 3, whose formation had been
expected according to the data published earlier for the similar
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Beilstein J. Org. Chem. 2012, 8, 2100–2105.
Scheme 1: Multicomponent and sequential reactions of 4-amino-5-carboxamido-1,2,3-triazole with cyclic ketones.
Table 1: Multicomponent synthesis of 4,5,6,7,8,9-hexahydro[1,2,3]triazolo[5,1-b]quinazoline-3-carboxamides 4a–c, 7 and 9a–j.
Aldehyde Ketone
Entry
Product
Methoda
Yield, %
No
R
No
R1
1
2
–
–
–
5a
5b
5c
2b
8a
8a
8a
8a
8a
8b
8b
8b
8b
8b
–
–
4a
4b
4c
7
A (D)
A (B,C,D)
D
31 (67)
37 (45,27,81)
45
–
3
–
–
–
4
6a
6a
6b
6c
6d
6e
6a
6b
6c
6d
6e
C6H5
C6H5
–
A (B,C,D)
A (B,C)
B (C)
21 (41,60,71)
35 (80,61)
90 (43)
5
H
9a
9b
9c
9d
9e
9f
6
4-CH3OC6H4
2-CH3OC6H4
4-BrC6H4
H
7
H
B (C)
55 (51)
8
H
B (C)
70 (75)
9
4-ClC6H4
H
B (C)
61 (69)
10
11
12
13
14
C6H5
CH3
CH3
CH3
CH3
CH3
A (B,C)
B (C)
37 (52,78)
66 (86)
4-CH3OC6H4
2-CH3OC6H4
4-BrC6H4
9g
9h
9i
B (C)
51 (88)
B (C)
90 (91)
4-ClC6H4
9j
B (C)
85 (77)
aMethod A: three-component reaction, EtOH, Δ; Method B: three-component reaction, MeOH, MW; Method C: three-component reaction, HOAc,
ultrasonification (US); Method D: sequential reaction, MeOH, MW.
reactions of 3-amino-1,2,4-triazole [29], was not isolated or temperature ultrasonication. However, treatment of the starting
even chromatographically detected in either of the procedures compounds 1 and 2a,b under ultrasonication at ambient
applied.
temperature in acetic acid, which was selected instead of
methanol due to solubility problems, also yielded only hetero-
cycles 4a,b (Method C). The yields and purity of the com-
pounds obtained under ultrasonication were slightly lower than
in the case of Methods A and B.
It is worth noting that in our previous works [9-17] we also
showed a possibility to change the direction of similar MCRs by
replacement of conventional thermal or MW heating with room
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Beilstein J. Org. Chem. 2012, 8, 2100–2105.
Spirocompound 4c was obtained by linear reaction via prelimi- Multicomponent heterocyclizations of aminotriazole 1 with
nary synthesis and isolation of cyclic α,β-unsaturated ketone 5c aromatic aldehydes 6a–e and cyclohexanediones 8a,b carried
and its further treatment with 4-amino-5-carboxamido-1,2,3- out according to Method A, B or C yielded tricyclic com-
triazole (1) in acetic acid under ultrasonication at ambient pounds 9a–j in 51–91% (Scheme 2, Table 1). The most effi-
temperature, in boiling dry ethanol or under MW heating in cient synthetic procedure was the treatment of the starting ma-
methanol. The same procedure also allowed us to obtain com- terials in methanol under ultrasonication at ambient tempera-
pounds 5a,b. The best results in this case were observed when ture. Very similar results were observed for MW-assisted
the microwave-assisted procedure (Method D) was applied.
syntheses.
It should be noted that for similar treatments involving The structures of the compounds synthesized were established
3-amino-1,2,4-triazole [7,29,30] the structures of the final prod- by MS and NMR spectroscopy in combination with elemental
ucts were different depending on whether a multicomponent or analyses. However, MS data obtained for the reaction product
sequential procedure was used, while in our case both pro- isolated from the MCR between aminoazole 1 and cycloalka-
cedures gave the same compounds.
none 2 may correspond to both structure 3 and 4. Moreover, 1H
and 13C NMR spectra of these compounds should contain very
ABC-type MCR of aminoazole 1, cyclohexaneone 2b and similar signals, and we thus used the position of the signal of
benzaldehyde 6a was carried out in dry ethanol by conven- pyrimidine NH in the 1H NMR spectra, which strongly depends
tional heating under reflux (Method A), in methanol under on type of the structure: for angular compounds such as 3 its
microwave irradiation at 120 °C (Method B), or by ultrasonica- signal appears at 5–6 ppm while for heterocycles 4 it should be
tion at ambient temperature in acetic acid (Method C). In all at 7–8 ppm [8,29,31,32], as was observed in our case. Ad-
these cases triazolopyrimidine 7 was isolated as the sole reac- ditionally, the HMBC spectrum of the heterocycles obtained
tion product (Scheme 2, Table 1). In most cases the best results does not contain cross-peaks between pyrimidine NH and spiro-
from the viewpoint of yields and purity of the target com- carbon, which is also in good correlation with structure 4.
pounds were observed when ultrasound-assisted method C was Analogous elucidations allowed the structures of compounds 7
applied.
and 9 to be established.
Conclusion
In summary, two types of heterocyclization reactions involving
4-amino-5-carboxamido-1,2,3-triazole and cyclic ketones
were studied under conventional thermal heating, and
microwave and ultrasonic irradiation. ABB’-type MCR
proceeding with chemodifferentiation of cyclopentanone or
cyclohexanone molecules yields 4,5,6,7-tetrahydrospiro{cyclo-
penta[d][1,2,3]triazolo[1,5-a]pyrimidine-8,1'-cyclopentane}-3-
carboxamide (4a) or 5,6,7,8-tetrahydro-4H-spiro{[1,2,3]tri-
azolo[5,1-b]quinazoline-9,1'-cyclohexane}-3-carboxamide (4b)
under all the conditions tested. The best results were observed
in the case of microwave-assisted synthesis in methanol at
120 °C. Spirocompound 4c may be obtained by a sequential
procedure via the preliminary synthesis of 2-cycloheptylidene-
cycloheptanone but not by a three-component reaction
involving cycloheptanone. ABC-type MCR between 4-amino-5-
carboxamido-1,2,3-triazole, aldehydes and cyclohexanone or
1,3-cyclohexandiones leads to the formation of 4,5,6,7,8,9-
hexahydro[1,2,3]triazolo[5,1-b]quinazoline-3-carboxamides 7
or 9 under all the reactions conditions studied; however, the
ultrasound-assisted procedure is the method of choice for this
Scheme 2: Multicomponent and sequential reactions of 4-amino-5-
carboxamido-1,2,3-triazole with aldehydes and cyclic ketones.
Sequential reaction via synthesis of arylidenecyclohexanone 10 heterocyclization.
also gave as sole reaction product compound 7 under all the
methods of activation applied. However, microwave heating For all the MCRs studied, changes in the directions of the
(Method D) was the procedure of choice in this case as well. heterocyclizations were not observed when microwave or
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Beilstein J. Org. Chem. 2012, 8, 2100–2105.
15.Sakhno, Y. I.; Desenko, S. M.; Shishkina, S. V.; Shishkin, O. V.;
Musatov, V. I.; Chebanov, V. A. Synthesis 2011, 1120.
doi:10.1055/s-0030-1258468
thermal heating was substituted by ultrasonication at ambient
temperature or when the three-component reaction was replaced
by a sequential protocol via the preliminary synthesis of cyclic
α,β-unsaturated ketones.
16.Muravyova, E. A.; Desenko, S. M.; Rudenko, R. V.; Shishkina, S. V.;
Shishkin, O. V.; Sen’ko, Y. V.; Vashchenko, E. V.; Chebanov, V. A.
Tetrahedron 2011, 67, 9389. doi:10.1016/j.tet.2011.09.138
17.Chebanov, V. A.; Saraev, V. E.; Shishkina, S. V.; Shishkin, O. V.;
Musatov, V. I.; Desenko, S. M. Eur. J. Org. Chem. 2012, 5515.
doi:10.1002/ejoc.201200669
Supporting Information
Supporting Information File 1
Experimental details and characterization data for all new
compounds.
18.Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3168.
doi:10.1002/1521-3773(20000915)39:18<3168::AID-ANIE3168>3.0.CO
;2-U
19.Wender, P. A.; Handy, S. T.; Wright, D. L. Chem. Ind. (London) 1997,
765.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-236-S1.pdf]
20.Chebanov, V. A.; Desenko, S. M. Curr. Org. Chem. 2006, 10, 297.
doi:10.2174/138527206775473904
21.Okabe, T.; Bhooshan, B.; Novinson, T.; Hillyard, I. W.; Garner, G. E.;
Robins, R. K. J. Heterocycl. Chem. 1983, 20, 735.
doi:10.1002/jhet.5570200345
Acknowledgments
ESG is grateful for financial support to DAAD (scholarship
A/09/02523). We thank Dr. Vataliy Polovinko (Enamine Ltd.)
for measuring HMBC spectra.
22.Oakes, F. T.; Leonard, N. J. J. Org. Chem. 1985, 50, 4986.
doi:10.1021/jo00224a074
23.Ege, G.; Gilbert, K.; Maurer, K. Chem. Ber. 1987, 120, 1375.
doi:10.1002/cber.19871200816
References
1. Zhu, J.; Bienaymé, H., Eds. Multicomponent Reactions; Wiley-VCH:
24.Desenko, S. M.; Gladkov, E. S.; Shishkina, S. V.; Shishkin, O. V.;
Komykhov, S. A.; Orlov, V. D.; Meier, H. J. Heterocycl. Chem. 2006,
43, 1563. doi:10.1002/jhet.5570430620
Weinheim, Germany, 2005.
2. Biggs-Houck, J. E.; Younai, A.; Shaw, J. T. Curr. Opin. Chem. Biol.
2010, 14, 371. doi:10.1016/j.cbpa.2010.03.003
25.Biagi, G.; Giorgi, I.; Livi, O.; Scartoni, V.; Lucacchini, A. Farmaco 1989,
44, 843.
3. Ganem, B. Acc. Chem. Res. 2009, 42, 463. doi:10.1021/ar800214s
4. Isambert, N.; Lavilla, R. Chem.–Eur. J. 2008, 14, 8444.
doi:10.1002/chem.200800473
26.Biagi, G.; Giorgi, I.; Livi, O.; Scartoni, V.; Tonetti, I.; Lucacchini, A.
Farmaco 1990, 45, 979.
27.Gladkov, E. S.; Sirko, S. N.; Shishkina, S. V.; Shishkin, O. V.;
Knyazeva, I. V.; Desenko, S. M.; Chebanov, V. A. Monatsh. Chem.
2010, 141, 773. doi:10.1007/s00706-010-0326-0
28.Tejedor, D.; García-Tellado, F. Chem. Soc. Rev. 2007, 36, 484.
doi:10.1039/b608164a
5. Chebanov, V. A.; Gura, K. A.; Desenko, S. M. Top. Heterocycl. Chem.
2010, 23, 41. doi:10.1007/7081_2009_21
6. Chebanov, V. A.; Desenko, S. M.; Gurley, T. W. Azaheterocycles
Based on α,β-Unsaturated Carbonyls; Springer: Meppel, 2008.
7. Chebanov, V. A.; Desenko, S. M. Chem. Heterocycl. Compd. 2012, 48,
566. doi:10.1007/s10593-012-1030-2
29.Desenko, S. M.; Orlov, V. D.; Éstrada, K. Chem. Hetetocycl. Compd.
1990, 26, 839. doi:10.1007/BF00509729
8. Sedash, Y. V.; Gorobets, N. Yu.; Chebanov, V. A.; Konovalova, I. S.;
Shishkin, O. V.; Desenko, S. M. RSC Adv. 2012, 2, 6719.
doi:10.1039/c2ra20195j
30.Chernyshev, V. M.; Khoroshkin, D. A.; Sokolov, A. N.;
Taranushich, V. A.; Gladkov, E. S.; Shishkina, S. V.; Shishkin, O. V.;
Desenko, S. M. J. Heterocycl. Chem. 2008, 45, 1419.
doi:10.1002/jhet.5570450527
9. Chebanov, V. A.; Sakhno, Ya. I.; Desenko, S. M.; Chernenko, V. N.;
Musatov, V. I.; Shishkina, S. V.; Shishkin, O. V.; Kappe, C. O.
Tetrahedron 2007, 63, 1229. doi:10.1016/j.tet.2006.11.048
10.Chebanov, V. A.; Saraev, V. E.; Desenko, S. M.; Chernenko, V. N.;
Shishkina, S. V.; Shishkin, O. V.; Kobzar, K. M.; Kappe, C. O. Org. Lett.
2007, 9, 1691. doi:10.1021/ol070411l
31.Lipson, V. V.; Desenko, S. M.; Shirobokova, M. G.; Borodina, V. V.
Chem. Heterocycl. Compd. 2003, 39, 1213.
doi:10.1023/B:COHC.0000008269.69460.ac
32.Desenko, S. M.; Orlov, V. D.; Getmanskii, N. V.; Shishkin, O. V.;
Lindeman, S. V.; Struchkov, Yu. T. Chem. Heterocycl. Compd. 1993,
29, 406. doi:10.1007/BF00529878
11.Chebanov, V. A.; Saraev, V. E.; Desenko, S. M.; Chernenko, V. N.;
Knyazeva, I. V.; Groth, U.; Glasnov, T. N.; Kappe, C. O. J. Org. Chem.
2008, 73, 5110. doi:10.1021/jo800825c
12.Sakhno, Ya. I.; Desenko, S. M.; Shishkina, S. V.; Shishkin, O. V.;
Sysoyev, D. O.; Groth, U.; Kappe, C. O.; Chebanov, V. A. Tetrahedron
2008, 64, 11041. doi:10.1016/j.tet.2008.09.089
13.Muravyova, E. A.; Shishkina, S. V.; Musatov, V. I.; Knyazeva, I. V.;
Shishkin, O. V.; Desenko, S. M.; Chebanov, V. A. Synthesis 2009,
1375. doi:10.1055/s-0028-1088024
14.Sakhno, Ya. I.; Shishkina, S. V.; Shishkin, O. V.; Musatov, V. I.;
Vashchenko, E. V.; Desenko, S. M.; Chebanov, V. A. Mol. Diversity
2010, 14, 523. doi:10.1007/s11030-010-9226-9
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