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DOI: 10.1039/c8nj02312c
rsc.li/njc
An improved ultrasound assisted green synthesis of 1-substituted provide high yields.4 In this context, 1,3-dipolar cycloaddition
1H-1,2,3,4-tetrazoles via a novel isocyanide based multicomponent offers a convenient and straightforward approach for the
click reaction (IMCCR) under mild, solvent, catalyst and column-free synthesis of a wide range of five-membered ring nitrogen
conditions has been developed. This new, green and sustainable heterocycles. Among them, [3+2] cycloaddition has attracted
IMCCR methodology resulted in good to excellent yields (71–97%) in great interest due to its status as the best click reaction to date.5
shorter reaction times. From the green chemistry point of view, the development of
green, solvent and catalyst-free IMCRs under mild conditions is a
Isocyanide based multicomponent reactions (IMCRs) have been hot topic in organic synthesis. In this context, ultrasound irradia-
widely known as a useful tool toward a facile synthesis and tion (USI), a convenient energy source with several advantages,
functionalization of diverse nitrogen heterocycles.1 Despite this, produces the formation, growth and implosive collapse of bubbles,
the design and development of more green and eco-friendly IMCRs resulting in strong shock waves which cause high velocity collisions
for the synthesis of nitrogen heterocycles is an unexplored field. between reactants.6 These collisions create strong heating, leading
Water, one of the cheapest and abundant sources of green- to the melting of the reactants particularly in solvent-free reactions
nucleophiles, has been rarely used as a component in IMCRs and form the expected products in short times with minimal
to synthesize heterocycles. To our knowledge, three IMCR by-products.7 Also, in recent years solvent-free multicomponent
methodologies are known, among which two methods2 need reactions have gained great importance in organic synthesis.8
palladium catalysts and heating conditions, while the third In spite of this, the synthesis of heterocycles via IMCR strategies
method3 describes the use of ten times excess isocyanide in a or methodologies based on mild, catalyst and solvent-free con-
non-eco-friendly solvent with a very limited substrate scope. ditions is still rare.9
However, mild and green IMCRs using water as a component 1-Substituted tetrazoles (1-STs) have attracted much attention
towards the synthesis of nitrogen heterocycles or polyhetero- because of their various applications, mainly in the fields of
cycles have not yet been reported. medicinal and coordination chemistry. For instance, compound
IMCRs and click reactions share various common features 1 is anti-inflammatory,10a 2 is anticoagulant,10b 3 is strongly
and often considered as ideal reactions. The concept of click phytocidally active10c and 4 is used as an aluminum10d and
chemistry is mainly focused on the construction of carbon– copper10e corrosion inhibitor. Additionally, compound 5 is an
heteroatom bonds using spring-loaded reactants under mild reac- antibacterial and antitumor agent10f and 6 is a coordination
tion conditions. A click reaction must fulfill a set of stringent polymer ligand (Fig. 1).10g
criteria, particularly, the starting materials should be easily The synthesis of 1-STs from isocyanide has been less
available, the reaction should proceed under mild neat condi- explored, though the first method was reported in 1910 using
tions or in green solvents and form non-harmful by-products, a large excess amount of hydrazoic acid (HN3).11 However, HN3
and the purification should be non-chromatographic and is a very toxic and harmful compound and its excess content in
the reaction can lead to violent explosions.12 Further, in 2004
Yamamoto et al. reported a methodology utilizing trimethylsilyl
Departamento de Quı́mica, División de Ciencias Naturales y Exactas,
azide (TMSN3) instead of toxic HN3 to afford 1-STs, under catalytic
Universidad de Guanajuato, Noria Alta S/N, Col. Noria Alta, Guanajuato,
C.P. 36050, Gto., Mexico. E-mail: rociogm@ugto.mx
conditions at 60 1C.13 Few more methodologies are known in the
† Electronic supplementary information (ESI) available. See DOI: 10.1039/ literature wherein cat. HCl,14a,b ZnBr214c and supramolecular
c8nj02312c self-assembled catalysts14d were used to synthesize 1-STs from
11294 | New J. Chem., 2018, 42, 11294--11298 This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2018
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Letter NJC
Equiv.
Entry TMSN3 H2O Time (h) Yielda (%)
1 1 1 2 42
2 1 1 4 48
3 1.5 1.5 2 67
4 2 2 1 94
5b 2 2 3 90
Scheme 1 Previously reported MCR methodologies vs. IMCCR strategy
a b
towards 1-STs. Isolated product. Reaction without USI, with stirring at RT.
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2018 New J. Chem., 2018, 42, 11294--11298 | 11295
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11296 | New J. Chem., 2018, 42, 11294--11298 This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2018
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Letter NJC
solvent and catalyst-free room temperature conditions to give 3 J. Ruiz, M. P. Gonzalo, M. Vivanco, M. R. Diez and S. Garcia-
1-STs in high yields, (b) as the reactions are solvent-free, at the Granda, Chem. Commun., 2011, 47, 4270.
end liquid mixtures are formed, which are purified via pre- 4 H. C. Kolb, M. G. Finn and K. B. Sharpless, Angew. Chem.,
cipitation (except a few, such as 7g, 7j, and 7l), thus avoiding Int. Ed., 2001, 40, 2004.
chromatographic purification and (c) while performing the 5 R. Huisgen, in 1,3-Dipolar cycloaddition chemistry, ed. A. Padwa,
reactions, there is no need to take specific precautions as Wiley, New York, 1984, pp. 1–176.
reactants are compatible with air or water. Although Ugi IMCR 6 To see reviews: (a) G. Cravotto and P. Cintas, Chem. Soc. Rev.,
Published on 12 June 2018. Downloaded by UNIVERISDAD DE GUANAJUATO on 1/18/2019 6:22:50 PM.
is considered to be a multicomponent click reaction due to its 2006, 35, 180; (b) B. Banerjee, Ultrason. Sonochem., 2017,
significantly similar features to the click reaction,22 the mild, 35, 1.
green and solvent-free IMCR involving click [3+2] cycloaddition 7 S. J. Doktycz and K. S. Suslick, Science, 1990, 247, 1067.
has not yet been reported. Thus, to the best of our knowledge, 8 M. S. Singh and S. Chowdhury, RSC Adv., 2012, 2, 4547.
this protocol reported here is the first mild, green and solvent- 9 (a) T. A. Shah, Z. Ahmad, N. P. Rath and M. Muneer, Tetrahedron
free strategy so far of an IMCCR to synthesize heterocycles. Lett., 2016, 57, 2638; (b) G. Keykha, M. R. Hosseini-Tabatabaei
Moreover, for this study we used an ultrasonic cleaning bath and A. Hassanabadi, J. Chem. Res., 2017, 41, 85; (c) M. Kumar,
(45 kHz) which is an excellent alternative non-conventional L. K. Kumwat, V. K. Gupta and A. Sharma, ChemistryOpen, 2015,
source of energy, with very good sound distribution throughout 4, 626.
liquid bath and is inexpensive. 10 (a) S.-J. Park, S.-G. Han, F. M. Ahsan, K. Lee, J. Y. Lee, J.-S.
All synthesized compounds were characterized using 1H, Shin, K.-T. Lee, N.-S. Kang and Y. G. Yu, Bioorg. Med. Chem.
13
C, FT-IR and HRMS. Lett., 2012, 22, 7335; (b) N. Howard, C. Abell, W. Blakemore,
In conclusion, we have developed an efficient USI assisted G. Chessari, M. Congreve, S. Howard, H. Jhoti, C. W.
strategy to improve the synthesis of 1-STs via a novel IMCCR Murray, L. C. A. Seavers and R. L. M. van Montfort, J. Med.
approach involving [3+2] cycloaddition. To our knowledge, this Chem., 2006, 49, 1346; (c) W.-K. Su, Z. Hong, W.-G. San and
is the first protocol for mild and green synthesis of 1-STs via X.-X. Zhang, Eur. J. Org. Chem., 2006, 2723; (d) K. F. Khaled
MCR and the first IMCR to do so. Also, this is the first solvent and M. M. Al-Qahtani, Mater. Chem. Phys., 2009, 113, 150;
and catalyst-free, mild and green IMCR strategy using water as (e) M. Mihit, K. Laarej, H. A. El Makarim, L. Bazzi, R. Salghi
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over the previously reported MCR strategy such as solvent, 11 E. Oliver-Mandela and B. Alagna, Gazz. Chim. Ital., 1910,
catalyst and column-free synthesis, short reaction times, mild 40, 442.
reaction conditions, high yields, environmental friendliness and 12 B. Gutmann, D. Obermayer, J.-P. Roduit, D. M. Roberge and
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ogy completely meets the click and green chemistry criteria. 14 (a) H.-P. Fang, C.-C. Fu, C.-K. Tai, K.-H. Chang, R.-H. Yang,
R. G.-M. thanks CONACYT for financial support through M.-J. Wu, H.-C. Chen, C.-J. Li, S.-Q. Huang, W.-H. Lien,
CONACYT CB-2016-285622 and DAIP-UG 193/2018 projects. C.-H. Chen, C.-H. Hsieh, B.-C. Wang, S.-F. Cheung and
S. G. P. (636753/573230) and M. A. R.-G. (707974/585367) thank P.-S. Pan, RSC Adv., 2016, 6, 30362; (b) A. Zajdlik, Z. Wang,
CONACYT-México for a scholarship and Laboratorio Nacional J. L. Hickey, A. Aman, A. D. Schimmer and A. K. Yudin,
de Caracterización de Propiedades Fisicoquı́mı́cas y Estructura Angew. Chem., Int. Ed., 2013, 52, 8411; (c) V. V. Sureshbabu,
Molecular (CONACYT-México, Project: 123732). N. Narendra and G. Nagendra, J. Org. Chem., 2009, 74, 153;
(d) S. Giust, G. La Sorella, L. Sperni, F. Fabris, G. Strukul and
A. Scarso, Asian J. Org. Chem., 2015, 4, 217.
Conflicts of interest 15 Y. Wang, P. Patil and A. Domling, Synthesis, 2016, 3701.
16 M. Esmaeilpour, J. Javidi and S. Zahmatkesh, Appl. Organo-
There are no conflicts to declare.
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11298 | New J. Chem., 2018, 42, 11294--11298 This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2018