Strategies Towards the Synthesis of N 2-Substituted 1 , 2 , 3-Triazoles

The chemistry of 1,2,3-triazoles gained much attention since the discovery of the copper catalyzed Alkyne-azide cycloaddition (CuAAC) reaction which delivers exclusively the 1,4-regioisomer in high yields. On the other hand there is still no universal methodology capable of delivering the N2 substituted regioisomer. The unique properties of these N2-substituted 1,2,3-triazoles have stimulated synthetic efforts on the developments of methodologies capable of delivering it in high yield and selectivity. These efforts are the subject of the presented review.

ring.The Nh bond can be on nitrogen 1 (1h) or in nitrogen 2 (2h) (those possible tautomers where h is attached to the carbon atom rather than the nitrogen atom is generally not considered as a function of its high energy).When the 1,2,3-triazole skeleton is substituted at the nitrogen and carbon atoms different regioisomers can be obtained according to figure 2. The structure of 1,2,3-triazoles,as presented in figure 1, may exist as two different tautomers, depending on the position of the N-h bond on the The 1,2,3-triazole have very distinct properties when compared to is isomeric 1,2,4 isomer, and more importantly the N 2 substituted has different properties then the N 1 as well as N 3 , despite structural similarity.An example of this difference can be found in specific applications of N 2 substituted triazoles, as for example its efficiency as binders in coordination polymers with impressive optical properties (Chen et al. 2015a, b).Differences in basicity between the N 1 and N 2 isomers can be responsible for their different behavior within biological systems; giving rise to new directions in pharmaceutical research.
Despite the increase interest in the 1,2,3-triazole core, there is still no universal methodology, except for the 1,4 regioisomer (see below) capable of deliver in the 2,4-and the 1,5 regioisomers in high yield and regioselectivity.however, advances the chemistry of the 2,4-regioisomer have been reported in recent years and are the subject of this review.

PROPERTIES OF 1,2,3-TRIAZOLES.
The discussion concerning the properties and the tautomeric equilibrium of 1,2,3-triazoles is a more complex subject then stated in the previous section.If one consider substitution at the 4 and 5 positions of the ring, as shown in figure 3, the structure with the hydrogen atoms at N 1 and N 3 become distinguishable since the N 1 -h -tautomer has C s symmetry and the N 2 -h tautomer C 2v symmetry.
The different tautomers present in figure 3 present distinct physical, chemical and biological properties.For example, according to Begtrupand co-workers (Begtrup et al. 1988), the dipole moment for the unsubistitutedN 1 -h tautomer is 4.38D, while that of the N 2 -h tautomer is only 0.218D.Katritzky and co-workers (Alan and Pozharskii 2000), based on the calculated charges for each carbon atom, attribute to the 1H-1,2,3-triazole π system an electron rich character, while for the N 2 -h tautomer an π electron deficient character.
Compared to others heteroaromatic compounds such as imidazole or pyrrole, the studies in the literature concerning the properties of 1,2,3-triazoles are scarce.Begtrup and co-workers studied by the use of microwave spectroscopy and gas phase electron diffraction on the properties of unsubstituted 1,2,3-triazoles (Begtrup et al. 1988).The experimental data pointed to a ratio of 1:1000 in favor of the N 2 -h tautomer in the gas phase.
lunazzi and co-workers, by means of solution Nuclear magnetic Resonance, studied the same unsubstituted 1,2,3-triazole observed the predominance of the N 1 -h tautomer at 175K in toluene solution (lunazzi et al. 1984).however, the tautomeric equilibrium is reported to be solvent, concentration and temperature dependent, where the relative amount of the other N 2 -h tautomer increases with decreasing solvent dipole moment, and concentration and increase with temperature.Thus the N 2 -h tautomer equals more than 97% at 300K at a concentration of 0.05m in toluene.Taylor and co-workers studied the tautomeric equilibrium of 1,2,3-triazoles in aqueous solution (Albert and Taylor 1989).According to the authors, the N 2 -htautomer is the dominant specie in the equilibrium in the aqueous phase by a factor of 2, being attributed the stability of this tautomer to the electronic repulsion between the pairs of electrons of the adjacent hydrogen atoms in the tautomer N 1 -h.Toernkivist and co-workers performed a theoretical study on the 1,2,3-triazoles tautomerism (Toernkvist et al. 1991).By these calculations (mP2 / 6-31G *) the authors determined that the N 2 -h tautomer is about 21 kJ mol -1 more stable than the N 1 -h tautomer.Oziminski and co-workers studied theoretically the properties of substituted 1,2,3-triazoles using the DFT theory level (B3PW91 / 6-311 ++ G **) (Ozimiński et al. 2003).
According to the results obtained by the authors, when X= h, the 2h tautomer is 20,52kJ mol -1 more stable than the N 1 -h tautomer, in agreement with Toernkivist.The substitution of the triazole implies the study of the N 3 -h tautomer, in addition to the N 1 -h and N 2 -h.Table I summarizes some of the values obtained by the authors, on substituting the 1,2,3-triazole at carbon with different substituents.The authors observed that in all cases studied the N 2 -h tautomer to be the most stable.The relative energies of the N 3 -h and N 1 -htautomers compared to N 2 -H for different substituent are presented in Table I.It can be observed that the group X has a strong influence on the stabilization of the N 1 -h tautomer versus the N 3 -h.
As can be seen in the Table I, the electron withdrawing or donor behavior of different groups does not translate into differences in the stabilization of the tautomers.The steric interactions and hydrogen bonds between the substituent and the adjacent pyridine like nitrogen atom seem to be the preponderant factor in the stabilization of N 1 -h versus N 3 -h.
Wang and co-workers studied theoretically and experimentally the acidity and gas phase stability values of the three 4-phenyl-1,2,3-triazole tautomers (Wang et al. 2013).According to the authors, using the theoretical basis DFT B3lYP / 6-31 + G (d), the N 2 -htautomer was obtained as the more stable tautomer by about 16.317 kJ mol -1 compared to N 1 -h; the latter being only 3kJ mol -1 more stable than N 3 -h.As for acidity, in all cases, the most acidic site of the three tautomers is the N-h bond.Among these, the N 2 -h tautomer is the most acidic ∆h acid =1410 kJ mol -1 , followed by N 1 -h∆h acid =1393 kJ mol -1 and of N 3 -h ∆h acid =1389 kJ mol -1 .As for the proton affinity (PA), in the case of N 2 -h tautomer, the most basic site is N 3 -h with a PA=858 kJ mol -1 .In the case of the N 1 -h tautomer, N 3 -h is a rather basic center with PA=916kJ mol -1 .For the N 3 -h in its protonated form, it has the same structure as the conjugated acid of N 1 -h, which makes the proton affinity for N 3 -h 3kJ mol -1 greater than N 1 -h.The main strategy for the synthesis of 1,2,3-triazoles is the reaction between azides and acetylenes, originally described by huisgen in 1967 (Rolf et al. 1967, Rolf 1963).Originally, this reaction was performed in the presence of organic azides and acetylenes under reflux conditions in toluene, leading to a mixture of 1,4 and 1,5 regioisomers of 1,2,3-triazoles.In 2002, the Sharpless and medal groups (Tornøe et al. 2002(Tornøe et al. , haldón et al. 2015) ) independently reported that, in the presence of copper salts, this transformation occurs at room temperature and provides, in high yields and exclusively the 1,4 regioisomer.This highly selective reaction catalyzed by copper for the synthesis of this 1,2,3-triazoles regioisomer under very mild conditions has allowed its application in the most diverse areas of chemistry, as in the field of material chemistry (Zhou et al. 2005, li et al. 2010, Peng et al. 2004), medicinal chemistry (Cesare et al. 2008, Aher et al. 2009, Brockunier et al. 2000, Boechat et al. 2011, Dheer et al. 2017, Zhang et al. 2017), bio-conjugation among others (Agard et al. 2004, Wang et al. 2003).It is not the purpose of this paper to discuss the synthesis and properties of the 1,4 (or 1,4,5) substituted 1,2,3-triazoles.About this subject, many reviews are available and the interested reader can consult them (Sandip et al. 2011, Debets et al. 2013, Crowley and mcmorran 2012, Thirumurugan et al. 2013, Dheer et al. 2017).On the other hand, there is no strategy, or reaction that provides, in the same terms of the abovementioned reaction developed by Sharpless and medal (for the1,4, regioisomer) (Sharpless et al. 2001), 2,4-dissubtituted 1,2,3-triazoles.With this gap, there is evident lack of information on the properties of these substances, still being an unexplored chemical space in the most diverse areas.however, in the last decades, although timidly, some solutions to this question have appeared in the literature and are the subject of this review.
The strategy for the synthesis of 1,2,3-triazole derivatives substituted in N 2 can be divided, in order to facilitate their discussion, in two different strategies: a) the construction of the 1,2,3-triazole skeleton already functionalized in N 2 and b) the N 2 functionalization of the 1,2,3-triazole skeleton a posteriori.
The two most important methodologies for the construction of the triazole skeleton already substituted in N 2 are the Boulton-Katritzky rearrangement and hydrazine oxidative cyclization reactions, as represented schematically in Figure 4.The BOUlTON-KATRITZKY ReARRANGemeNT The rearrangement observed by Boulton and Katritzky in 1962 involves what is also known as monocyclic rearrangement of heterocycles, which occurs in the presence of both acids or bases (Boulton et al. 1966).In general the rearrangement can be represented according to Figure 5 ("Boulton-Katritzky Rearrangement,"): In the case of the synthesis of N 2 -substituted 1,2,3-triazoles, this rearrangement involves the reaction of hydrazones derived from oxadiazoles.This reaction has not found many applications as a tool to construct the N 2 substituted 1,2,3-triazole skeleton, propably due to difficulties in synthesizing the corresponding oxadiazoles.Some examples of molecules obtained through this approach are presented in Figure 6 (Vincenzo et al. 2014, D'Anna et al. 2005, 2010, Cosimelli et al. 2001).
OXIDATIVe CYClIZATION OF hYDRAZONeS: The synthesis of N 2 -substituted 1,2,3-triazoles from the cyclization of bis-arylhydrazones were first reported by Stollè in 1926(Stollè 1926).Thus, the heating of phenylhydrazones, bis-hydrazones, bis-aroylhydrazones or bis-semicarbazones derived from 1,2-dicarbonyl compounds in the presence of oxidizing agents, has been the most commonly used methodology for the synthesis of the N 2substituted 1,2,3-triazolic skeleton.however, this methodology has, as the main disadvantage, the low to moderate yields (hegarty et al. 1974).The use of copper as catalyst in these cyclizations leads to cleaner and better yielding reactions.Reviews of this reaction can be found in the literature (Shaban et al. 1977, Shaban 1976, Nassr et al. 1985, el Sekily et al. 1977), and for this reason only the recent advances will be discussed in this section.Punniyamurthy and co-workers reported recently the oxidative cyclization of hydrazones in the presence of a copper catalyst and molecular oxygen as final oxidant (Punniyamurthy and Guru 2012) for the synthesis of symmetric N 2 substituted 1,2,3-triazoles in good yields, Figure 7.
Wu and co-workers, also using copper catalysis, explored the oxidative intramolecular cyclization of β-ketohydrazones in the presence of ammonium acetate (Wu et al. 2015).In this approach, presented in figure 8, the imine is initially formed, followed by oxidative cyclization to the 1,2,3-triazole skeleton.Thus, in this reaction there is no aniline formation as a by-product, which occurs when oxidative cyclization of bis-arylhidrazones takes place.
The synthesis of 2-aryl-5-amino-1,2,3triazoles was recently reported by Kseniya and co-workers (Kseniya et al. 2016).The authors also make use of copper salts as catalyst for the oxidative cyclization, and used, as substrate, α-hydrazono-nitriles to obtain the 1,2,3-triazoles.These nitriles, in the presence of aliphatic amines, lead to the in situ formation of 2-(aryl-azo)-ethene-1,1-diamines, which in the presence of copper salts cyclizes to the triazole skeleton.examples of this approach are found in Figure 9.As can be seen in the Figure this methodology leads to complex structures in moderate to good yields.
The oxidative cyclization between oximes and diazo compounds catalyzed by copper has recently been reported by Jiang and co-workers (Zhu et al. 2018).Important examples of this methodology are highlighted in Figure 10.Some aspects of this methodology deserved some comments.The first is the possibility of efficiently obtaining 1,2,3-triazole skeletons substituted at the 4 and 2 positions only (R 2 =h) or at the 4 and 5 positions.The oxidative cyclization of phenylhydrazones, bis-hydrazones, bis-aroylhydrazones or bis-semicarbazones derived from 1,2-dicarbonyl compounds produces efficiently only 1,2,3-triazoles substituted in the 2,4 and 5-positions.Another highlight is the small scope with regard to the diazonium salt.Of all those studied by the author only that derived from 4-methoxy-benzene (PmB) provides satisfactory results.

POST-CYClOADDITION FUNCTIONAlIZATION
As shown in the previous sections, the methodologies available for the synthesis of N 2 substituted 1,2,3-triazoles through the construction of the triazole skeleton involves multiple steps,  An Acad Bras Cienc (2019) 91(Suppl.1) e20180751 9 | 24 which reduces the efficiency of its production; since the synthesis and purification of the precursors are necessary and it is limited by the availability of the hydrazines, which in many cases are also prepared.In this way, another strategy was developed, in which the 1,2,3-triazole skeleton is prepared prior to its selective functionalization.In general, in this strategy, the synthesis of the triazole skeletons occurs easily and in high yields through the aforementioned copper catalyzed reaction between azides and acetylenes.Once constructed, the triazole skeleton is then functionalized.The functionalization of N 2 through this strategy is described in the literature for alkylation, acylation and arylation reactions, which may or may not be catalyzed by transition metals such as copper or palladium.The challenge in this approach is derived from the fact that, the 1,2,3-triazole skeleton formed has all three nitrogen atoms as potential nucleophiles which can lead to a mixture of N 2 and N 1 regioisomers (or N 3 when the case).In these cases it is observed that the regioselectivity is a multivariable matter being influenced by the electrophile, solvent, base, catalyst (when present) and temperature.Generally speaking, N 1 alkylation occurs first, due to the higher electron density in this atom.On the other hand, the 1,2,3-triazoles substituted in N 2 are thermodynamically more stable.Additionally substituent at positions 4 and 5 facilitate N 2 functionalization.Thus, in general, it is not uncommon in these1,2,3-triazoles functionalization reactions to observe a mixture of regioisomers (Blass et al. 2006, estelle et al. 2008, Calderone et al. 2005), and the development of highly selective reactions is still a challenge to be overcome.

AlKYlATION AND ARYlATION (SN AR ) ReACTIONS
Miller and co-workers conducted the first systematic study on regioselectivity (N 2 vs N 1 ) on the alkylation of 1,2,3-triazoles through the reaction with alkyl halides and michael acceptors (Tanaka and miller 1973).In this study, the reaction of 4-phenyl-1,2,3-triazole with ethyl chloroacetate showed a selectivity of 5:1 in favor of N 2 regioisomer, using triethylamineas base and dimethylformamide as solvent.In the case of the michael addition to ethyl propiolate only the product of N 2 addition was observed, using the same reaction conditions for the reaction with ethyl chloropropiolate.Sharpless and co-workers reported the synthesis of isomeric hydroxymethyl-1,2,3triazoles from the reaction, in a single pot,of acetylenes, sodium azide and formaldehyde in the presence of copper and sodium ascorbate (Kalisiak et al. 2008).In this reaction the formed triazole reacts with formaldehyde yielding the product.The selectivity and yields varies from good to excellent as exemplified in Figure 11.
A very interesting solution toward a high yielding and regioselective synthesis of 4-substituted 2-Alkyl-1,2,3-triazoles was described by Wipf and co-workers (Wipf et al. 2010, Wang et al. 2009a, 2010).As previously stated, the potential nucleophilicity of the 3 nitrogen atoms at the triazole core renders a regioselective reaction a very tricky issue.On the other hand, 1,2,3-triazoles substituted at both 4 and 5 positions direct the reaction at the N 2 position due to disfavored steric interactions at the N 1 or N 3 positions with the ligands present at the carbon atoms.With this in mind, the authors developed an alkylation reaction with a 1,2,3-triazole containing bromine atoms at the 4,5 positions, which direct reaction at the N 2 .These bromine atoms can be readily transformed into different groups, allowing the selective synthesis of 4-substituted 2-Alkyl-1,2,3-triazoles.This strategy is present in Figure 12.In the Figure 12I are examples of the structures obtained by such reaction, and in Figure 12II how this bromine atoms can be manipulated to the desired 2,4,5 and 2,4-substitued 1,2,3-triazoles.A similar strategy was studied by the same authors concerning the arylation of 4,5-dibromo-1,2,3-triazole with electron deficient arenes and heteroarenes (Wang et al. 2009b).In this approach according to the authors complete selectivity is observed in all cases depicted in Figure 13.
The arylation of 4,5-dissubstitued 1,2,3-triazoles was also studied by Chen and coworkers.In this case chloro-nitro benzene were studied, and complete selectivity was also reported for N 2 , probably due to the presence of substituents at the 4 and 5 positions (li et al. 2009), Figure 14.
Nenajdenko and co-workers studied the regioselective alkylation of 5-aryl-4-fluoro-1,2,3triazole (Nenajdenko et al. 2017).In this case also complete N 2 selectivity was observed (only the use of methyl iodide as alkylating agent yields detectable amounts of the N 1 regioisomer, Figure 15.
The interesting point in the present case is that, while in the abovementioned examples the use of bromine atom can exert steric hindrance to the adjacent nitrogen atom, such effect is not expected for fluorine.Its influence may be exerted by lowering the nucleophilicity of the neighbor nitrogen atom, increasing the N 2 selectivity.
An asymmetric aza-michael reaction of 4-aryl-Nh-1,2,3-triazoles to cyclic enones under the catalytic influence of chiral bifunctional thiourea organocatalysts for the enantioselective generation of 2,4-disubstituted 1,2,3-triazoles was reported by Bhagat and co-workers (Bhagat and Peddinti 2018).The cinchonine derived thiourea catalyst 91 produce the N 2 -functionalized 1,2,3-triazoles as major products in good and excellent optical yields, Figure 16.The use of six membered cyclic conjugate ketones furnishes better yields and optical purity then the corresponding five membered rings.
An efficient copper-catalyzed C−N bond formation by N−H/C−H cross-dehydrogenative coupling (CDC) between Nh-1,2,3-triazoles   are presented in Figure 18.All reactions reported by the authors lead to good yields irrespective the substitution pattern on the triazole and cyclopropenone.
The mechanistic studies conducted by the authors suggest an autocatalytic cycle as the one presented in Figure 19.In this mechanism, the ionization of the N 1-sulfonyl-1,2,3-triazole leads to specie 124, which reacts with the cyclopropenone to furnish aromatic cation such as 126.This cation reacts with a second equivalent of the N 1-sulfonyl-1,2,3-triazolesyielding the isolated product and the corresponding sulfonyl anhydride.The reaction of the sulfonyl anhydride with another equivalent of the cyclopropenone leads to intermediate 127, which upon reaction with N 1-sulfonyl-1,2,3-triazole leads again to cation 126andsulfonyl anhydride, closing then the autocatalytic cycle.
Theoretical calculations show that the selectivity in favor of N 2 occurs in the reductive elimination step where the transition state for the formation of the arylated product for N 2 is 3.3 kcal.mol - lower than the transition state for the formation of N 1 .
The methodology described by Buchwald represented a major advance in triazole chemistry.This methodology enabled a series of subsequent studies, by several authors, where they were able to explore the 2-aryl-1,2,3-triazole skeleton.An important example of these studies is that developed by Tian and co-workers concerning the selective halogenation reaction of N 2 -substituted 1,3,2-triazoles by activation of C sp2 -h bond (Tian et al. 2013).
This study by Tian presented an important advance to the previous approach reported by morin on the halogenation of the N 2 -Phenyl-1,2,3triazoles where poor selectivities were originally observed, Figure 21A.In this study the palladiumcatalyzed halogenation of 2-aryl-1,2,3-triazoles was reported using N-halosuccinimides as a source of halogen.It is important to highlight the wide scope of the reaction regarding the use of aromatic systems with the most diverse substituents.Some examples are present in Figure 21A.In this study, the observed regioselectivity results from the ability of the triazole skeleton to guide ortho-palatation of the 2'-position, as summarized in Figure 21B.The constructed frameworks found application in the synthesis the core present in Suvorexant, as shown in Figure 21C.
The ability of the 1,2,3-triazole to orient orthopalatation of the 2'-position of the aromatic system bond to N 2 also stimulated Wu and co-workers to carry out studies for the ethoxy carbonylation of the 2-Aryl-1,2,3-triazole C2' position, Figure 22.In this reaction, ethyl diazocarboxylate is used as the source of carbamoyl, with the concomitant evolution of N 2 .Such reaction was also applied to the synthesis of Suvorexant.
The methodology developed by Buchwald was also used in the synthesis of novel triazolic C-nucleoside (lopes et al. 2016).In this work, the use of the same phosphine ligand reported by Buchwald and co-workers led to selectivities lower than originally reported.The use of an even more sterically hindered ligand such as AdBrettPhos was able to rescue the selectivity in the cases studied, as shown in Figure 23.In this work, because of the use of an even more sterically hindered ligand, a reduction in scope has been imposed where halo ortho-substituted arenes are not capable of leading to the desired arylated product.The first report on the regioselectivity of copper-catalyzed 1,2,3-triazoles arylation was that described by liu and co-workers.In their study, the reaction was conducted under microwaves, in the presence of proline as ligand and in DmSO as the solvent (liu et al. 2008).As shown in Figure 24, the selectivity was studied fundamentally in 4,5-substituted 1,2,3-triazoles which leads to complete regioselectivity for the N 2 isomer.As described in the previous sections, the selectivity in these cases is facilitated since the presence of these substituents (other than h) exert a steric effect leading to a preferential N 2 reaction.In the study reported by liu, in the only example where the reaction is performed on mono substituted triazole the selectivity is 80:20 favoring the N 2 -Arylated regioisomer.
The first systematic study on the coppercatalyzed of N 2 -selective arylation reaction of mono substituted triazoles was reported recently by our group (lopes et al. 2017).In a model reaction using 4-Phenyl-1,2,3-triazole 182, the different classes of ligands used in copper catalyzed Ullmann coupling were screened in the reaction, and the yield and regioselectivity is present Figure 25.
In this study it was observed that among the different class of ligands screened, amino acids (186,188,(190)(191)(192)(193)(194)(195)(196)(197)(198)(199)(200)(201)(202)(203)(206)(207)(208) gave the best results in terms of yield and selectivity.Among them secondary amino acids are better than primary amino acids.It was also observed that the group alkylating the nitrogen atom has also profound impact in the outcome of the reaction.The scope was evaluated under the optimized conditions  and selectivities up to 92:8 for the N 2 -regioisomer could be observed under much smoother conditions the one reported by Shi and co-workers (liu et al. 2008).

CONCLUSIONS
As can be observed in the previous sections, there have been an increased interest in developing new approaches towards the synthesis of the N 2substituted 1,2,3-triazoles.The developments so far achieved represent important advances in the area of the 1,2,3-triazole chemistry, especially those reactions that allow the functionalization of the triazolea posteri, which enable the synthesis of 2; 2,4 and 2,4,5-substituted 1,2,3-triazole libraries and then to study their properties.however,it is an area where much is still to be done since those reactions are far from achieving the goals obtained by the CuAAC reaction, i.e high yielding and selective under smooth and even aqueous condition, allowing its application in areas where the properties of the N 2 -regioisomers is still unknown such as the bioconjugation of biomolecules such as proteins and polyssacharides.

Figure 4
Figure 4 -major approaches toward the -Synthesis of the 1,2,3-triazole skeleton already functionalized in N 2

Figure 19 -
Figure 19 -Proposed autocatalytic mechanism for the ditriazolylation reaction of cyclopropenones.