Synthesis and Functionalization of 5-Substituted Tetrazoles

MICROREVIEW

DOI: 10.1002/ejoc.201200469

Jaroslav Roh,*[a] Katerˇina Vávrová,[a] and Alexandr Hrabálek[a]

Dedicated to the memory of Professor Grigorii I. Koldobskii

Keywords: Synthetic methods / Medicinal chemistry / Nitrogen heterocycles / Reaction mechanisms / Regioselectivity

Tetrazoles are synthetic heterocycles with numerous applica- amics, and metabolism of the associated drugs. Then, the tions in organic chemistry, coordination chemistry, the photo- main synthetic approaches to 5-substituted tetrazoles – con- graphic industry, explosives, and, in particular, medicinal sisting of methods based on acidic media/proton catalysis, chemistry. In organic chemistry, 5-substituted tetrazoles are Lewis acids, and organometallic or organosilicon azides – are used as advantageous intermediates in the synthesis of other presented, from the early procedures to the most recent ones, heterocycles and as activators in oligonucleotide synthesis. with special attention paid to the reaction mechanisms. Func- In drug design, 5-monosubstituted tetrazoles are the most tionalization of 5-substituted tetrazoles is a challenging task important tetrazole derivatives because they represent non- because it usually leads to the formation of two isomers, 1,5- classical bioisosteres of carboxylic acids, with similar acidi- and 2,5-disubstituted tetrazoles, in various ratios. In this ties but higher lipophilicities and metabolic resistance. In this overview, reactions with high or unusual regioselectivities review we focus on the preparation and further functionali- are described, with comments on the possible mechanisms. zation of these heterocycles. Firstly, the role of 5-substituted Microwave-assisted approaches to the synthesis and func- tetrazoles in medicinal chemistry is described, including ex- tionalization of 5-substituted tetrazoles are also included. amples of their effects on pharmacokinetics, pharmacodyn-

Introduction terized in 1885.[4,5] That compound was also used several years later for the first preparation of an unsubstituted 1H- Tetrazoles are synthetic compounds with the highest ni- tetrazole.[6] trogen contents among the stable heterocycles. They play important roles in coordination chemistry, in the photo- graphic industry, or as components of special explosives.[1] Moreover, the tetrazole ring is an important intermediate in the synthesis of other more complex heterocycles, through various rearrangements.[2] As a result of their acidities, 5- monosubstituted tetrazoles are also used as activators in Figure 1. 2-Phenyl-2H-tetrazole-5-carbonitrile: the first tetrazole- [3] oligonucleotide synthesis. However, the most important containing compound prepared. use of tetrazoles is to be found in medicinal chemistry. In the context of the natures of the tetrazole rings, the The most interesting compounds containing tetrazole systems can be classified into 1-, 2-, and 5-monosubstituted moieties are 5-substituted tetrazoles (5-STs). The first part tetrazoles, 1,5- and 2,5-disubstituted tetrazoles, and trisub- of this review briefly outlines the roles and uses of these stituted tetrazolium salts. Other important tetrazole deriva- compounds in medicinal chemistry. The next section deals tives include 1,4-disubstituted 1H-tetrazol-5(4H)-ones, 1H- with the synthesis of 5-STs, from the early procedures to tetrazol-5(4H)-thiones, or 1H-tetrazol-5(4H)-imines. recent approaches, highlighting the most important meth- The first compound containing a tetrazole ring to have ods. Then, the functionalization of 5-STs, including alkyl- been prepared is thought to be 2-phenyl-2H-tetrazole-5-car- ation, arylation, and vinylation of this heterocycle system, is bonitrile (1, Figure 1), which was prepared and charac- presented, with focus on the reactions with high or unusual regioselectivities. Special attention is paid to the mecha- [a] Department of Inorganic and Organic Chemistry, Faculty of nisms of the presented reactions. Methods of synthesis and Pharmacy, Charles University in Prague, functionalization of 5-STs under microwave irradiation con- Heyrovského 1203, 50005 Hradec Králové, Czech Republic ditions, which have recently been widely explored, are also Fax: +42-495-067-166 E-mail: [email protected] presented together with comments on the effects of micro- Homepage: http://portal.faf.cuni.cz/Groups/Hrabalek-Group/ wave irradiation on these reactions.

5-STs in Medicinal Chemistry Table 1. Comparison of the acidities of selected carboxylic acids and the corresponding 5-STs. 5-STs are a typical bioisosteric replacement system for RpK pK carboxylic acids. Although these two functional groups are a a R–COOH R–CN4H structurally different and have different numbers of atoms, H 3.77 4.70 they display similar types of biological activity as a result CH 4.76 5.50 [7] 3 of their close physico-chemical properties. C2H5 4.88 5.59 5-STs exist in two tautomeric states: 1H- and 2H-tauto- –CH2CH2– 4.19, 5.48 4.42, 5.74 mers (Figure 2). Natural bond orbital analysis showed that Ph 4.21 4.83 2H-tautomers (3) were more stable than 1H-tautomers (2) 4-MeOC6H4– 4.25 4.75 4-NO C H – 3.43 3.45 in all of the ten 5-STs investigated in that study, due to 2 6 4 higher aromaticity indices and the greater electron delocal- ization in 2H-tautomers (for more details see the section Alkylation of 5-STs).[8] As a consequence of the abilities of reactions with alkylation agents and other electrophiles (for 5-STs to delocalize negative charges after deprotonation, 5- more details see Functionalization of 5-STs). STs are relatively strong N–H acids, with their acidities Like carboxylic acids, 5-STs are ionized at physiological strongly dependent on the substituents in their 5-positions. pH values. However, tetrazole anions are nearly 10 times more lipophilic than the corresponding carboxylates.[11] The pKa values of 5-STs are very similar to those of the corresponding carboxylic acids (Table 1),[9,10] which is im- This fact is important for the pharmacokinetics of the tetra- portant for their bioisosteric interchangeability. zole analogues of carboxylic acids. From the point of view of the pharmacodynamics, the effect of the replacement of a carboxylic acid by a 5-ST is more complex. The delocal- ization of the negative charge in the tetrazole ring can either enhance or reduce the interaction with an appropriate receptor, depending on the electron distribution in the receptor site.[12] The size of the tetrazole ring might decrease the affinity towards the receptor site relative to a carboxylate Figure 2. 1H-and2H- tautomers of 5-STs. group as a result either of steric hindrance or of an inconve- nient orientation of the functional groups of the active The alkaline salts of 5-STs are highly soluble in water site.[13] The main difference between the carboxylate and and are better reactants than the non-ionized species for the tetrazole anion lies in the ability of all of the nitrogen

Jaroslav Roh received his M.Sc. degree at the Charles University in Prague, Faculty of Pharmacy in Hradec Králové (Czech Republic) in 2006. Under the supervision of Prof. Alexandr Hrabálek he received his Ph.D. in 2010 for his work on synthesis and functionalization of 5-substituted tetrazoles. In 2007 he worked at the St. Petersburg State Institute of Technology (Russian Federation) in the group of Prof. G. I. Koldobskii. His research interests include chemistry of nitrogen-containing heterocycles, microwave chemistry, and synthesis of iron chelators.

Katerˇina Vávrová received her M.Sc. degree at the Charles University in Prague, Faculty of Pharmacy in Hradec Králové (Czech Republic) in 1999. At the same university, she received her Ph.D. in Bioorganic Chemistry in 2003 for her work on transdermal permeation enhancers and ceramide analogues under the supervision of Prof. Alexandr Hrabálek. In 2004–5 she investigated skin barrier repair agents in Prof. Humbert’s lab in Besançon, France. Since 2009 she has been an associate professor in Medicinal Chemistry. Her research interests include skin barrier sphingolipids, cardioprotective iron chelators, and antimycobacterial tetrazoles.

Alexandr Hrabálek obtained his M.Sc. degree in Pharmacy in 1980 at the Charles University in Prague (Czech Republic). His doctorate (1992) involved synthesis of transdermal permeation enhancers. For this work he was awarded a Gold Medal at the World Exhibition of Innovation, Research and New Technology in Brussels – Eureka 1997. In 2000 he was appointed associate professor at the Department of Inorganic and Organic Chemistry at the Faculty of Pharmacy, Charles University, and in 2009 he become a full professor. The current research interests of his group include synthesis of antimicrobial tetrazoles and amino-acid-based permeation enhancers.

6102 www.eurjoc.org © 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 2012, 6101–6118 Synthesis and Functionalization of 5-Substituted Tetrazoles atoms, which act as acceptors of hydrogen bonds, to inter- act with a receptor. Examples of this are the interaction of the tetrazole anion with protonated lysine and hystidine in the receptor for angiotensin II[14] and the interaction of all four nitrogen atoms of the tetrazole fragment of the HIV-1 integrase inhibitor 5ClTEP with its receptor.[15] Despite all the previously identified differences in the pharmacodynamic effects of the carboxylic and tetrazole analogues, it is difficult accurately to predict the pharmacodynamic re- sponse to the replacement of a carboxylic acid by a 5-ST. Figure 4. Structure of Losartan. Various examples from the literature show that the pharmacodynamic effect can increase, decrease, or completely dis- Other important compounds in which 5-STs play a no- [16] appear. table role are antileukotriene antiasthmatics.[22,23] Com- The main advantage of 5-STs is their resistance to meta- pound LY171883, later known as the drug Tomelukast (7, bolic degradation. One of the first in vivo studies found Figure 5), is one example.[24] Through the substitution of a that the tetrazole analogue of nicotinic acid was excreted carboxylic acid by a 5-ST, its in vitro activity was increased unchanged, whereas nicotinic acid itself was quickly metab- by approximately thirty times, probably due to a better in- [17] olized. Nonetheless, the main metabolic transformation teraction between the delocalized negative charge on the of 5-STs, as in the cases of many other xenobiotics, was tetrazole ring and the arginine residue in the active site of found to involve glucuronidation of one of their nitrogen [25] the cysLT1 receptor for LTD4. In addition, in vivo ac- atoms. Glucuronidation is mediated by the enzyme UDP- tivity after oral administration was increased, due to the glucuronosyltransferase, and involves the transfer of gluc- higher lipophilicity of the tetrazole analogue. Because of d uronic acid from the cofactor uridine-5-diphospho-α- - the great success of Losartan and its analogues, 5-STs were glucuronic acid to a xenobiotic. It is interesting to note that widely explored as bioisosteric replacements for carboxylic both N1 (compounds 4) and N2 glucuronides (compounds acid groups. Other examples of the successful use of 5-STs 5) were detected (Figure 3). During the administration of are tetrazolic analogues of the HCV NS3 protease inhibi- compound AA-344 [6-ethyl-3-(1H-tetrazol-5-yl)chromone] tor,[26] the tetrazolic ligand for the mutant thyroid hormone to laboratory animals the N1 isomer was primarily receptor TRβ(R320H),[27] and the tetrazolic inhibitor of the [18] found, whereas the group of compounds derived from 5- protein tyrosine phosphatase 1B as potential antidiabet- (biphenyl-2-yl)-1H-tetrazoles (antagonists of the receptor ics.[28] for angiotensin II)[19] or the potential antidiabetic drug RG 12525 {2-[(4-{[2-(1H-tetrazol-5-ylmethyl)phenyl]meth- oxy}phenoxy)methyl]quinoline}[20] were predominantly me- tabolized to the N2 isomers. The functionalization of 5-STs is thus not strictly regioselective. It was also suggested that enterohepatal circulation was responsible for the long biological half-lives of tetrazole drugs.[19]

Figure 5. Structure of Tomelukast.

In 1989, a series of analogues of the antidiabetic Ciglita- zone (8, Figure 6) in which the 5-ST system served as a bioisosteric replacement for thiazolidin-2,4-dione (compounds 9) was synthesized.[29] A similar derivative (com- Figure 3. Structures of the main metabolites of 5-STs. pound 10) was also reported in 2002.[30] The results of these studies showed that tetrazolic analogues had the same The most important group of biologically active com- mechanism of action as thiazolidin-2,4-dione insulin sensi- pounds based on 5-STs are the selective antagonists of the tizers and established that these two structural fragments receptor for angiotensin II. The first representative, Losar- were, in this case, bioisosteres. In 2005 a series of com- tan (6, Figure 4), has been in clinical use since 1994.[21] Los- pounds with the 5-[(1H-pyrazol-3-yl)methyl]-1H-tetrazolic artan is a good example of a drug in which the optimal structural base was synthesized. They also showed antidia- ratio of antihypertensive activity and per os bioavailability betic activity.[31] was achieved. Carboxylic acid analogues of this drug also Furthermore, the 5-ST fragment can also be found in have antihypertensive properties but are less active, even the receptor antagonists of the excitatory amino acids 11 when they are administered intravenously. Other bioiso- {Figure 7, antagonist of AMPA [2-amino-3-(5-methyl-3-hy- steric replacements of carboxylic acid were examined dur- droxyisoxazol-4-yl)propionic acid]} and 12 [antagonist of ing the development of this drug, but none had better prop- NMDA (N-methyl-d-aspartate)], which are potential drugs erties than the 5-ST.[16] against schizophrenia and cerebral ischemia.[32]

The currently favored approach to 5-ST synthesis lies in the interaction of nitrile moieties with azide groups. A reaction of this type was successfully accomplished for the first time in 1901, when 5-amino-1H-tetrazole, known at the time as diazoguanidine, was prepared from cyanamide and azoimide.[37] In 1910, 1H-tetrazole itself was synthesized by a similar reaction, which involved the cycloaddition of azoimide to hydrogen cyanide.[38] Azoimide, a toxic and explosive gas, prepared either in advance or in situ, was used as a major reactant for 5-ST preparation until the end of the 1950s.[39] During this period, hundreds of 5-STs were prepared.[36] In 1958, Finnegan et al. published their fundamental work utilizing sodium azide and ammonium chloride in Figure 6. The antidiabetic Ciglitazone (8) and its tetrazole analogues. N,N-dimethylformamide (DMF) in the synthesis of 5-STs (Scheme 2). Although azoimide could also be detected in the reaction mixture, this method completely changed the synthetic approaches to 5-STs. Since then, the processes have become much safer, the reaction times have been significantly reduced, and the yields of 5-STs have increased (for more details, see Methods Using Acidic Media – Pro- ton-Catalyzed). This method is used to this day for the preparation of 5-STs and has completely displaced the processes utilizing azoimide.[40] Many new methods and modi- Figure 7. Selective antagonists of AMPA and NMDA receptors. fications of existing processes have appeared since Finne- gan’s invention. The principle of most of them is a reaction Interestingly, the 5-ST fragment has also been used as a between a nitrile and an azide moiety, although they can be stabilizing structural moiety, as a result of its high crystal- divided into three main groups: a) using acidic media (pro- linity. In one example, a potent inhibitor of NO synthase, ton-catalyzed), b) using Lewis acids, and c) using organo- l-6-N-(1-iminoethyl)lysine, which is hygroscopic and un- metallic and organosilicon azides. There is no clear distinc- stable in air, was stabilized by the addition of a 5-ST frag- tion between these approaches and many of the latest meth- ment to afford 13 (Figure 8). In vivo metabolism then re- ods combine their advantages. sulted in the active l-6-N-(1-iminoethyl)lysine.[33–35]

Scheme 2. Finnegan’s method for preparation of 5-STs. In addition, there are also methods for 5-ST preparation that do not utilize nitriles as the main reactants. 5-STs can Figure 8. Tetrazole-based prodrug of l-6-N-(1-iminoethyl)lysine. also be prepared, for example, from the corresponding N- monosubstituted amides via 1,5-disubstituted tetrazoles, followed by the cleavage of the substituent in the 1-position.[41] Synthesis of 5-STs The general disadvantage in preparations of 5-STs is long The first specific and widely used methods for 5-ST syn- reaction times. Microwave (MW) irradiation has been thesis consisted of the diazotization of polynitrogen com- widely explored in attempts to overcome this limitation gen- pounds, especially hydrazidines (imidohydrazides) such as erally. The first work dealing with microwave-irradiated or- 14 (Scheme 1), which are prepared primarily from imino- ganic reactions was published in 1986. Since then, micro- ethers (imidates) and hydrazine.[36] wave chemistry has been the subject of intense investi- gations, and around 4000 papers have been published to date. Most of these declared microwave irradiation to be superior to conventional heating, and to result in decreased reaction times and increased yields or selectivities of reactions.[42] These benefits have been suggested to be the results of thermal effects and so-called “specific microwave effects”. It is of note that the existence of the previously as- Scheme 1. Synthesis of 5-phenyl-1H-tetrazole from benzimido- sumed non-thermal effects of microwave irradiation was re- hydrazide. cently rejected.[43]

Microwave-assisted methods for preparation of 5-STs are presented in each section according to the reagents involved. Scheme 6. Preparation of 5-STs by use of in situ generation of triethylammonium azide in nitrobenzene. Methods Using Acidic Media – Proton-Catalyzed

All of the above methods utilize azoimide[37–39] and Fin- Another microwave-assisted method consisted of treat- negan’s method also falls into this class.[40] In 1987 Finne- ment of nitriles in ionic liquids with azoimide generated in gan’s method was modified by the use of N-methylpyrroli- situ from sodium azide in the presence of acetic acid. Reac- din-2-one (NMP) as the solvent. This change allowed the tion times were shortened from 24 h to 30 min at reaction reaction temperature to be increased, which led to higher temperatures of around 170 °C.[50] yields and shorter reaction times.[44] A rapid and effective method for the synthesis of 5-STs In 2000, the first microwave-assisted preparation of 5- by a high-temperature/high-pressure microreactor approach STs based on Finnegan’s work[40] was published. This has recently been published (Scheme 7).[51] method again utilized treatment of nitriles with sodium azide and ammonium chloride in DMF. Reaction times were significantly reduced, with the obtained yields remaining high. Reactions were carried out in closed vessels without monitoring of the reaction temperature (Scheme 3).[45] Scheme 7. Synthesis of 5-STs by a high-temperature microreactor approach.

With regard to the preferred mechanism of the reactions Scheme 3. Microwave-assisted Finnegan’s reaction. in acidic media (proton-catalyzed), the following three hypotheses have been discussed: 1) concerted dipolar [2+3] Two significant modifications of Finnegan’s method ap- cycloaddition, 2) anionic two-step [2+3] cycloaddition, and peared in 1998, when Koguro et al. carried out reactions of 3) activation of the nitrile by protons – via an intermediate nitriles with sodium azide and triethylammonium chloride imidoyl azide. in toluene (Scheme 4). The main advantage of this process In 1892 Thiele claimed that he had prepared guanyl azide is the simplicity of the product isolation: the 5-ST can be by diazotization of aminoguanidine. Its heating in an aque- extracted straight from the reaction mixture into water or ous solution led to its cyclization to 5-amino-1H-tetra- an alkaline aqueous solution. Another possibility is fil- zole.[52] Dimroth and Fester then suggested that reactions tration of triethylammonium tetrazolate from the reaction between nitriles and azoimide proceeded through the inter- mixture, together with inorganic salts.[46,47] mediate imidoyl azides.[38] However, this hypothesis was not confirmed for almost one hundred years.[53] Although Finnegan’s group formulated the role of the acid catalysis in the preparation of 5-STs, they proposed that the principle step of the reaction is the attack of the Scheme 4. Koguro’s method for preparation of 5-STs. azide anion on the nitrile carbon, followed by ring closure (hypothesis 2).[40] Several reactions with use of azoimide The principle of the second modification is the utilization and ammonium azide were performed, with better results of tensides in aqueous media. 5-STs were prepared from seen in the case of the ammonium salt. nitriles in water in the presence of sodium azide, ammo- This hypothesis was confirmed in work by Jursic and nium chloride, and dodecyltrimethylammonium or hexa- Zdravkovski in 1994, in which a two-step [2+3] cycload- decyltrimethylammonium bromides (Scheme 5).[48] dition, involving nucleophilic attack of the azide ion on the carbon of the nitrile group, followed by tetrazole ring closure, was shown to be the preferred mechanism (Scheme 8). Interestingly, only two mechanisms, corresponding to Scheme 5. Preparation of 5-STs in micellar media. hypotheses 1 and 2, were considered, with the role of acid catalysis in these reactions not being mentioned.[54] Koguro’s method[46] was also modified and improved On the other hand, data supporting the concerted di- through the use of microwave irradiation. 5-STs were pre- polar [2+3] cycloaddition (hypothesis 1) were presented by pared by treatment of nitriles with sodium azide and trieth- scientists from the St. Petersburg Technological Institute.[55] ylammonium chloride in nitrobenzene in a microwave reac- They discovered that dimethylammonium azide is generally tor (Scheme 6). This practical method combines the advan- not ionized in DMF and undergoes the reaction as the hy- tages of the previous procedures, including good to excel- drogen-bonded complex (CH3)2NH·HN3, and not as azide lent yields, short reaction times, and easy isolation of the anion and dimethylammonium cation. The azide part of products.[49] this complex has a structure and distribution of electron

energetic barriers, with values of 35 kcalmol–1 for concerted dipolar [2+3] cycloaddition, 34 kcalmol–1 for anionic [2+3] cycloaddition, and 31 kcalmol–1 for reaction with azoimide (six-membered transition state).[53]

Scheme 8. Mechanism of formation of 5-STs through two-step [2+3] cycloadditions of azide anion; intermediates 16 could be found only in cases of nitriles containing very strongly electron- withdrawing groups such as F or CH3SO2.

density similar to those of azoimide (HN3) and organic azides (RN3). Because azoimide and organic azides are typical 1,3-dipoles in dipolar cycloaddition reactions, the authors suggested that the reaction mechanism is a concerted dipolar [2+3] cycloaddition (Scheme 9). At the same time, they also discovered that tetraalkylammonium azides do not react with nitriles under certain conditions. These azides only release azide anion, which is not a 1,3-dipole and cannot react by 1,3-dipolar cycloaddition. The fact that tet- Scheme 10. Mechanism of formation of 5-STs via imidoyl azide raalkylammonium azides do not react also rules out the intermediates 19. anionic two-step [2+3] cycloaddition mechanism. In the context of the anionic two-step mechanism, intermediates 16 could be found only in the cases of nitriles with very strongly electron-withdrawing groups such as F or

CH3SO2. They are weakly bound, however, and have almost the same energy as the free reactants, with the energetic barriers to their formation less than 4 kcal mol–1. The actual transition states (17) for the ring closing steps therefore turn out to be almost identical to the concerted [2+3] Scheme 9. Mechanism of formation of 5-STs through concerted di- transition states 18. From these findings it can be stated polar [2+3] cycloadditions. that hypotheses 1 and 2 are essentially the same.[53] The role of the partial positive charge on the nitrile car- It was shown that organic azides react at elevated tem- bon is essential. The presence of electron-withdrawing sub- peratures only with highly reactive nitriles (through con- stituents on the nitrile decreases the activation energy and certed dipolar [2+3] cycloadditions), whereas ammonium increases the reactivity of the nitrile towards azide anions. azides react readily with a wide range of nitriles under these In the cases of the strongest electron acceptors, the energies [56] conditions. As already mentioned, the electronic struc- of the transition states of anionic [2+3] cycloaddition are tures of organic azides and ammonium azides are very sim- close to the energies of the ammonium-activated transition ilar, but their reactivities are significantly different. This states, which is why the anionic mechanism cannot be com- clearly demonstrates that the actual mechanism of 5-ST for- pletely rejected. Moreover, the most electron-poor nitriles mation must be different from those proposed in hypothe- react with sodium azide without any additional reactants ses 1 and 2. under very mild conditions.[59] In an acidic medium, the preparation of a 5-ST actually Methods using acidic media are widely used both in proceeds preferentially through an imidoyl azide intermedi- small laboratories and on industrial scales. The main draw- ate such as 19 (Scheme 10), which spontaneously cyclizes to backs are the presence of the highly toxic and explosive the 5-ST under the reaction conditions (hypothesis 3). As azoimide in the reaction mixtures and the use of the ther- [57] in the case of Pinner synthesis or the acid hydrolysis of mally unstable (generated in situ) ammonium azides, which [58] nitriles, protonation of the nitrile increases its reactivity readily sublimate from the reaction mixtures. and susceptibility to attack by azide anions. The transition state of this process has an energy significantly lower than those of concerted or anionic two-step [2+3] cycloadditions. Methods Using Lewis Acids In the reaction, the ammonium cation acts as the mediator of proton transfer, even in cases in which ammonium salt The principle of the second group of methods for the is not ionized in the reaction medium. The conversion of preparation of 5-STs is close to that of the first one, because acetonitrile into 5-methyl-1H-tetrazole is an example of Lewis acids also coordinate nitriles and activate them this. In the case of proton activation by the ammonium part towards attack by azide anion. + of the salt, the energy barrier, either ionized (NH4 )ornot The first Lewis acid used for the preparation of 5-STs –1 ionized (NH3), was calculated to be approx. 21 kcalmol , was aluminum azide, which was prepared from aluminum whereas all other discussed mechanisms showed higher hydride and azoimide in 1954.[60] Later, this Lewis acid was

6106 www.eurjoc.org © 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 2012, 6101–6118 Synthesis and Functionalization of 5-Substituted Tetrazoles prepared in a safer way by treatment of aluminum chloride tion of the reaction mixture and filtration of the precipi- with sodium azide in THF. The same reactant was used for tated 5-ST. The main drawback is the need to use high pres- the preparation both of 5-(2-aminoethyl)-1H-tetrazole[61] sure and temperatures of up to 170 °C for the conversion and of a series of 5-(chloroalkyl)-1H-tetrazoles of less reactive nitriles. (Scheme 11).[62] The main drawbacks were the water sensitivity, the release of two equivalents of azoimide during isolation, and the instability of the azides of elements of group IIIa. Interestingly, the conversion of all three azide Scheme 13. Sharpless’ method for preparation of 5-STs. anions of Al(N3)3 to afford aluminum tetrazolate has not been described to date. This reactions proceeded through complex structures, each with a central zinc atom coordinated with tetrazolate ligands. These intermediates were studied by use of pyr- idine-2-, -3-, and -4-carbonitriles as the reactants. Without treatment of the reaction mixtures with alkalis or acids, the isolated solids contained zinc complexes with pyridyl- tetrazolate, water, and surprisingly also hydroxide ligands. Water thus played two roles in these reactions: as a solvent and as a reactant.[66] In 2009, a series of 5-aryl-1H-tetrazoles was prepared by Sharpless’ method, except that the conditions were solvent- free. As a result of this modification, the reaction times were shortened, but larger amounts of sodium azide and zinc salts were used than in the original procedure.[67] Three microwave-assisted methods based on Sharpless’ work[65] have been published since 2005. Specific 5-STs were Scheme 11. Preparation of 5-STs utilizing Al(N ) , showing the prepared in yields of 75–91 % after 20 minutes under micro- 3 3 [68] possible reaction mechanism. wave heating to 185 °C. In the second study, 5-STs were prepared in 15–30 minutes at 80 °C in an average yield of 75%.[69] The main difference lies in the presence of iodine Finnegan et al. also used boron trifluoride as a Lewis residues in the second study; it probably played the role of acid in their work. They postulated that Lewis acids should an effective catalyst, like in the case described below.[70] In activate the nitrile group towards reaction with azide ions. the third study, nitriles of diverse structures reacted with

However, boron trifluoride was the only Lewis acid used in NaN3 in water in the presence of ZnCl2 under microwave that study and the results were actually worse than those irradiation conditions to give good yields of 5-STs. The es- for ammonium azide.[40] Nonetheless, treatment of nitriles sential fact was that the reaction times under microwave with sodium azide and boron trifluoride in DMF was suc- irradiation conditions were two to three times shorter than cessfully used to synthesize 5-(hydroxyphenyl)tetrazoles in in the inactivated process, with 5-STs being obtained in 1996.[63] yields of 60–86% in 2–14 hours at 92–95 °C (Scheme 14).[71] In 1993, interest in Lewis acids was reopened by the utilization of trimethylaluminum in the synthesis of a series of 5-STs under relatively mild reaction conditions (Scheme 12).[64] In these reactions, trimethylsilyl azide Scheme 14. MW-based version of Sharpless’ protocol. (TMSN3) served as the azide donor. As in the case of acid-catalyzed synthesis, the mechanism of this type of 5-ST preparation involved a significant decrease in activation energy when a nitrile nitrogen was coordinated to a Lewis acid. For the binding of azide ion to Scheme 12. Preparation of 5-STs utilizing trimethylaluminum. Lewis acid, the activation energy remained untouched: the conversion of acetonitrile into 5-methyl-1H-tetrazole or into 1,5-dimethyl-1H-tetrazole through reaction with The main disadvantage of all the reactions mentioned methyl azide are examples of this. Activation energies of above lies in their water sensitivity. They should therefore reactions in which zinc ions were bonded only to azide be carried out under inert atmosphere. A major break- anions was calculated to be 34 and 36 kcalmol–1 for tetra- through in this field came with the publication of Sharpless’ hedral and octahedral coordination of zinc ions, respec- work.[65] This method consisted of treatment of a nitrile tively. When a zinc cation was bonded either to a nitrile or with sodium azide and zinc bromide in water (Scheme 13). to a nitrile together with an azide ion, the activation ener- Isolation of the product was carried out by simple acidifica- gies decreased to 25–30 kcalmol–1, again depending on the

Eur. J. Org. Chem. 2012, 6101–6118 © 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org 6107 MICROREVIEW J. Roh, K. Vávrová, A. Hrabálek numbers and types of ligands. The activation energies of the One of the latest studies from this group used iodine as uncatalyzed reactions were 32 kcal mol–1 for the reaction a catalyst. Treatment of nitriles with sodium azide in the with methyl azide and 34 kcal mol–1 with azide anions. This presence of catalytic amounts of iodine led to the pro- study confirmed that the Lewis acid coordinates with the duction of 5-STs in high yields even in cases of sterically nitrile nitrogen (Figure 9). This coordination increased the hindered nitriles. The simple workup and easily available polarization of the nitrile moiety and decreased the acti- reactants are the main benefits of this method vation energy of the entire reaction. In the case of zinc cat- (Scheme 16).[70] ions, for example, the activation energies were around 5– 6 kcalmol–1 lower.[72]

Scheme 16. Preparation of 5-STs with iodine catalysis.

An important approach to the preparation of 5-STs by treatment of nitriles with sodium azide in DMF can be Figure 9. Potential intermediates with the nitrile coordinated to found in studies utilizing heterogeneous catalysts such as zinc. ZnO,[75] ZnS[76] and other ZnII minerals,[77,78] natrolite zeo- lite,[79] FeCl /SiO ,[80] MIIWO ,[81] or magnetically recovera- Sharpless’ work increased the interest in methods utiliz- 3 2 4 ble CuFe O nanoparticles.[82] The main advantages are the ing Lewis acids. Yamamoto et al., for example, prepared 5- 2 4 simple filtration of catalysts and the ability to reuse them. STs by treatment of aromatic or aliphatic nitriles with Those methods, however, suffer from substantial draw- TMSN in the presence of catalytic amounts of Cu Oin 3 2 backs. All of them were performed in DMF and needed DMF/MeOH mixtures (Scheme 15). It was shown that the long reaction times with temperatures around 120 °C and TMSN released azoimide in the presence of methanol. The 3 products had to be chromatographically purified. More- reaction between azoimide and Cu O was assumed to form 2 over, aliphatic nitriles either were converted into 5-STs in copper azide, a main reactant with catalytic activity. The very low yields or were not included at all. reaction product, copper tetrazolate, then attracted a proton from azoimide, leading to the regeneration of copper azide. Methods Using Organometallic and Organosilicon Azides

The ability of TMSN3 to react with organic nitriles to yield 5-STs was described for the first time in 1968.[83] This compound had convenient properties, such as stability, solubility in organic solvents, and a relatively high boiling point (95–96 °C). However, reactions of nitriles with

TMSN3 alone led to low levels of conversion, and less reactive nitriles remained untouched. A recent study showed that calculated energy barriers for the cycloaddition of

TMSN3 to acetonitrile were higher than for the cycloaddition of the azide anion itself. These calculations were cor- roborated experimentally: treatment of a solution of benzo- nitrile in NMP (1 m) at 200 °C for 15 minutes in a micro- Scheme 15. Preferential mechanism of Cu2O-catalyzed preparation of 5-STs. wave reactor with 2 equivalents of sodium azide led to higher conversion rates (17%) than treatment with 2 equiv- [84] The actual mechanism was thought to be a combination alents of TMSN3 (4%). of several procedures, because the reactions proceeded to Another notable class of azide donors is that of trialkyl- 30–50 % yields without methanol, as well as without a cop- tin azides, usually in the form of trimethyltin azide or tri(n- per catalyst. The authors also described another interesting butyl)tin azide (Scheme 17).[41,85] The use of tris(2-perfluoro- example of copper catalysis with use of stoichiometric hexylethyl)tin azide allowed the isolation of a stannylated amounts of NaN3 and catalytic amounts of CuI in DMF/ product from the reaction mixture by liquid/liquid extrac- MeOH. However, this procedure was illustrated by only one tion into a fluorous solvent. In addition, tris(2-perfluoro- example: the preparation of 5-(4-methoxyphenyl)-1H- hexylethyl)tin chloride, a byproduct formed after acid hy- tetrazole from 4-methoxybenzonitrile in a yield of 92%.[73] drolysis of the stannylated tetrazole, could be separated One year later, Bonnamour and Bolm utilized FeII salts, analogously.[86] Reactions between these tin reactants and

Fe(OAc)2 in particular, instead of copper catalysts. With an nitriles produced 5-STs in high yields, even from sterically almost identical experimental procedure the authors pre- hindered and electron-rich nitriles. The main drawback, pared several aromatic 5-STs, but in lower yields after reac- however, is the use of toxic reactants in high amounts. The tion times twice as long. Moreover, aliphatic nitriles did not potential for recycling of the tin reactants is achieved only react under these conditions.[74] in the case of perfluorinated reactants.[86]

Scheme 17. Preparation of 5-STs by use of trialkyltin azides.

In order to avoid the utilization of toxic and volatile tri- Scheme 19. Reaction between nitriles and catalytic complex 23. alkyltin chlorides (trialkyltin azide precursors) and to decrease the amounts of organotin reagents necessary while The catalytic complex 23 is then regenerated through the maintaining their advantages, a 5-ST synthesis based on simple SN2 reaction between 25 and TMSN3 via transition TMSN3 in the presence of catalytic amounts of dibutyltin state 26 (Scheme 20). It has recently been shown that cata- oxide was developed. The authors suggested that dibutyl- lyst 23 can be recovered from the complex 25 by treatment (trimethylsilyloxy)tin azide (21, Scheme 18) was formed in with azide anions (Scheme 21). This meant that only cata- situ during this reaction and further reacted with the corre- lytic amounts of TMSN3 (or TMSCl) and Bu2SnO, to- sponding nitrile to yield complex 22. This intermediate de- gether with stoichiometric amounts of inexpensive sodium composed to N-(trimethylsilyl)tetrazole and regenerated di- azide, could be used in this new protocol (Scheme 22).[84] butyltin oxide (20) or dibutyl(trimethylsilyloxy)tin azide In a recent study, bis(tributyltin) oxide was used instead of (21).[87] dibutyltin oxide.[88] The actual mechanism was revealed later, and confirmed that the dialkyl(trimethylsilyloxy)tin azide complex is in- deed the catalyst. The calculated free energy barrier for the formation of the intermediate dimethyl(trimethylsilyloxy)tin azide (23, Scheme 19) is low (13.2 kcal mol–1) and these processes are highly exothermic (–48.8 kcalmol–1), so the regeneration of dialkyltin oxide seems improbable. Complex 23 does not react with nitriles through concerted 1,3-dipolar cycloadditions, because the calculated energy barriers for these reactions are almost the same as for uncatalyzed reactions (+44 and +49.5 kcalmol–1 for the 1,5- and the 2,5- approaches, respectively, to cycloaddition with acetonitrile). This reactions proceed stepwise: the nitrile nitrogen first binds to the acidic tin atom, which activates the nitrile car- Scheme 20. Mechanism of recovery of catalytic complex 23 with bon for the attack of the azide group. The open-chain inter- use of TMSN3. mediate 24 than cyclizes to the 1-[dimethyl(trimethylsilyloxy)stannyl]-5-ST 25 (Scheme 19). The calculated en- Reactions between nitriles and TMSN3 in the presence ergy barrier to this process is more than 5 kcal mol–1 lower of catalytic amounts of dibutyltin oxide under microwave than in the case of uncatalyzed cycloaddition.[84] irradiation conditions were performed in 1,4-dioxane[89]

Scheme 18. Two discussed mechanisms for reactions between nitriles and TMSN3 in the presence of dialkyltin oxide.

age of a cyanoethyl group, can be offered as an example of the newer methods.[41] Alternatively, the reaction between

the corresponding N-(2-cyanoethyl)amide and TMSN3 under Mitsunobu conditions can be used to synthesize 1-(2- cyanoethyl)-5-substituted tetrazoles, which leads to 5-ST formation upon cleavage of the cyanoethyl group.[41,94] The cyanoethyl group can be replaced by another protective Scheme 21. Mechanism of recovery of the catalytic complex 23 by group, such as benzyl.[95] treatment with azide.

Scheme 22. New protocol for 5-ST formation with use of catalyst 23 formed in situ. and dimethoxyethane.[90] Again, the microwave irradiation reduced the reaction times while maintaining high yields of the products.

Another synthesis of 5-STs based on the use of TMSN3 without the organotin reagents (Scheme 23) was developed in 2004. Tetrabutylammonium fluoride (TBAF) trihydrate was found to be a suitable catalyst for this synthesis. Under solvent-free conditions, a series of 5-STs was prepared.[91] The principle of this reaction took advantage of the anionic activation of the silicon-nitrogen bond by fluoride Scheme 25. Two methods for the preparation of 5-STs, either under anions.[92] Mitsunobu conditions or by diazotization of amidrazone 26.

Straight conversions of carboxamides into 5-STs were reported in 1997. Triazidochlorosilane was presented as the main reactant, although it was actually a mixture of tetra- Scheme 23. Preparation of 5-STs by use of TMSN and TBAF. 3 chlorosilane with sodium azide in a 1:3 ratio in acetonitrile The most universal method from this group, providing (Scheme 26). The authors hypothesized that bis-silylated high yields of 5-STs under mild reaction conditions, was imidoyl ether 27 was formed during the reaction, preventing published in 2007. Dialkylaluminum azides were the crucial the conversion of amide to nitrile.[96] reactants for this procedure and the main source of azide anions, and were prepared in situ from the dialkylaluminum chlorides and sodium azide (Scheme 24). Their structures combine several advantages: high solubility in organic solvents, a suitable azide donor, and typical Lewis acids.[93]

Scheme 24. Synthesis of 5-STs by use of dialkylaluminum azides. The general disadvantage of these procedures lies in the use of highly toxic organometallic reactants, the residues of which are often present in the products, thus necessitating very careful separation. The price of these substances could Scheme 26. The suggested mechanism of straight conversions of also play an important role. amides to 5-STs.

Finally, 5-STs can also be prepared by the substitution Other Methods of 1- or 2-protected tetrazoles on their C5 carbon atoms The previously mentioned diazotization of polynitrogen (Scheme 27). Cleavage of the protective groups in the 1- or compounds is one of the methods that does not use a reac- 2-positions then leads to 5-STs. The substitution was car- tion between an azide and a nitrile.[36] Diazotization of ried out conventionally by lithiation of the 1- or 2-protected [97] amidrazone 26 (Scheme 25) by N2O4, followed by the cleav- tetrazole followed by treatment with an electrophile.

Scheme 27. Synthesis of a 5-ST from a 1-protected tetrazole.

The lithiated tetrazole can also react with tributyltin chloride and then undergo a Stille coupling to form a disub- Scheme 31. Mechanism of action of the organocatalyst 28. stituted tetrazole. Cleavage of the protective group in the 1- or 2-position yields a 5-ST (Scheme 28).[98] The calculated barrier to the formation of the tetrazole ring is lower than the barrier to the tin-catalyzed pathway by more than 3 kcalmol–1.[84]

Functionalization of 5-Substituted Tetrazoles 5-STs are valuable intermediates in the synthesis of more complex compounds. During these reactions, tetrazole rings can variously be preserved, transformed into other cycles, or completely eliminated. As a result of their π electron sys- Scheme 28. Preparation of 5-aryl-1H-tetrazoles by the Stille reac- tems and the presence of a lone pair on each nitrogen, 5- tion. STs react with a wide range of electrophiles. 5-STs can be protonated, functionalized, or coordinated. Substitution of Recently, the first organocatalyst for cycloadditions of 5-STs is the most common and effective method for the azides and nitriles was described. Addition of catalytic preparation of 1,5- and 2,5-disubstituted tetrazoles.[99] amounts of TMSCl to the reaction mixture when NMP was There are many alternative ways to prepare 1,5-disubsti- used as the solvent led to the formation of 5-azido-1- tuted tetrazoles,[100] usually from the corresponding methyl-3,4-dihydro-2H-pyrrolium azide (28, Scheme 29).[84] amides,[101] but for the preparation of 2,5-disubstituted tetrazoles, substitution on the 5-ST is the only possible method. As well as a wide range of alkyl substituents, aryl, acyl, silyl, vinyl, sulfonyl, phosphoryl, and other similar groups can be introduced onto the tetrazole ring.[102] Reactions between 5-STs and electrophiles have been Scheme 29. Formation of the 5-azido-1-methyl-3,4-dihydro-2H- widely investigated, with special attention paid to the pyrrolium azide (28) catalyst. underlying mechanisms. Substitutions of 5-STs are usually carried out in aqueous or alcoholic alkaline solutions, in This Vilsmeier–Haack-type compound was successfully aprotic organic solutions in the presence of a base, or under used as a catalyst for reactions between various nitriles and phase-transfer catalysis conditions. Depending on the reac- sodium azide under microwave irradiation conditions tion conditions, 5-STs can act as free tetrazolate anions, ion (Scheme 30). pairs, or hydrogen-bonded complexes with nitrogen bases. The main problem of 5-ST substitution lies in its low and hardly influenceable regioselectivity. Alkylation of a tetrazolate anion, either with or without a substituent in the 5- position, almost always leads to a mixture of both 1- and 2- alkyltetrazole isomers in various ratios (Scheme 32). Other Scheme 30. First method for preparation of 5-STs by use of or- ganocatalysis.

In the first step (Scheme 31), the nitrile nitrogen attacks the Lewis acidic carbon adjacent to the dihydropyrrolium nitrogen, which activates the nitrile for the approach of the azide anion. After the formation of the tetrazole, the catalyst is recovered through nucleophilic substitution with an azide anion. Scheme 32. Alkylation of 5-STs.

Eur. J. Org. Chem. 2012, 6101–6118 © 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org 6111 MICROREVIEW J. Roh, K. Vávrová, A. Hrabálek functionalizations, such as arylation and acylation, proceed In view of the size of the triphenylmethyl moiety, it is not in the same manner.[99,102,103] surprising that tritylation of 5-STs proceeded only at the 2- The ratio of isomers formed during the reaction depends position of the tetrazole ring. However, in the case of un- on the reaction temperature and the properties of the sub- substituted tetrazole this reaction still displayed a high re- stituent at the 5-position, in particular with regard to steric gioselectivity even without steric control of the process.[107] hindrance. Higher reaction temperatures lead to increased Tritylation of a 5-ST or of unsubstituted tetrazole should amounts of 1-isomers, whereas electron-accepting proper- probably proceed through the SN1 mechanism. In this case, ties of substituents at the 5-position increase the amounts the limiting stage consists of triphenylmethyl chloride ion- of 2-isomers. Bulky substituents, either R or RЈ or their ization to provide a triphenylmethyl cation, characterized combination, direct the substitution to the 2-position of the by high thermodynamic stability. At the same time, the tetrazole ring. more stable the carbocation is, the higher its selectivity to- The mechanism of these reactions involves a bimolecular ward one of the two competing nucleophilic centers will process leading to the formation of an unstable intermedi- be.[109] This is most likely the reason why these reactions ate of type 29 (Scheme 33) in the first, rate-limiting step. In proceeded with high regioselectivity, even in the case of un- the second step, isomeric products are formed. The reaction substituted tetrazole.[99] rate is influenced by the properties of substituent R, by the In many cases, the existence of ionic pairs, associated to reactivity of the electrophile RЈX, and by the reaction me- greater or lesser extents, in the reaction medium must be dium. Formation of the isomeric products is controlled by considered. However, the influence of these associates on the properties of the reaction intermediate 29.[102] the reaction rates or regioselectivity is not still clearly understood, although many examples have shown that the regioselectivity is controlled in the same manner as in the case of the tetrazolate anion.[102] In substitution reactions, 5-STs are often employed as ammonium salts. It was found that in aprotic solvents, these salts existed in the form of hydrogen-bonded complexes such as 32 (Figure 10).[110] These complexes had lower aro- maticities than highly aromatic tetrazolate anions due to the hydrogen-bonded nitrogen in the 1-position of the tetrazole ring. It was argued that the existence of such a Scheme 33. Bimolecular mechanism of a reaction between a complex would orient the electrophile towards double tetrazolate anion and an alkyl halide. bonding between N2 and N3 of the tetrazole ring, and not The effect of the solvent can be illustrated by the alkyl- to the plane of the tetrazole, as in the case of the tetrazolate ation of 5-phenyltetrazolate anion with dimethylsulfate in anion. acetonitrile, in which increasing amounts of water in acetonitrile led to decreased reaction rates as a result of greater solvation of the substrate by water molecules.[104] Several substitutions on the tetrazole ring that display high or nonstandard regioselectivity are outlined below.

Alkylation of 5-STs Figure 10. Structure of an ammonium salt of a 5-ST and a possible Tritylation of a 5-ST is one of the most valuable substitu- attack by an electrophile. tions on the tetrazole ring. The triphenylmethyl group is the fundamental protecting group of 5-STs and is used in the These findings, along with the higher steric hindrance at synthesis of more complex structures such as Losartan and the N1 nitrogen atom, led to the hypothesis that ammonium its analogues.[105,106] Alkylation of 5-STs with tri- salts of 5-STs facilitate the selective formation of 2,5-disub- phenylmethyl chloride (30, Scheme 34) resulted in the for- stituted tetrazoles. In 1987, the reaction between the trieth- mation only of the 2-isomers (compounds 31), regardless of ylammonium salt of 5-phenyl-1H-tetrazole and methyl the substituents at the 5-position. Phase-transfer catalysis is vinyl ketone (33, Scheme 35) was found to lead predomi- [111] often used for these reactions.[107,108] nantly to the formation of the 2-isomer 34. However, the reaction between a 5-ST with a more compact substituent at the 5-position yielded the two isomers 34 and 35 in comparable amounts, putting the major role of the above hypothesis into question.[102] Another highly regioselective reaction producing strictly the 2-isomer involved the alkylation of 5-STs with 5Ј-O- Scheme 34. Tritylation of 5-STs under phase-transfer catalysis con- benzoyl-2,3Ј-anhydrothymidine (36, Scheme 36) in the pres- ditions. ence of triethylamine.[112] It was again demonstrated that

on entering into the reaction is not clear. The first example is found in reactions between 5-STs and O-tert-butyl-N,NЈ- dicyclohexylisourea (38, Scheme 37).

Scheme 35. Reactions between triethylammonium tetrazolates and methyl vinyl ketone.

Scheme 37. Reactions between 5-STs and O-tert-butyl-N,NЈ-dicy- the triethylammonium salt played only a minor role in the clohexylisourea. regioselectivity, because the 2-isomer 37 was exclusively tert formed, even in reactions with sodium salts of 5-STs.[113] Although the incorporation of a bulky -butyl moiety into the tetrazole ring by conventional alkylation led to the The regioselectivity was again directed by steric aspects. formation of the 2-isomers 39, in this case the relative proportions of 1-isomers 40 were substantially higher, indicat- ing an unusual reaction mechanism.[116] Other highly regioselective reactions are acid-catalyzed additions of 5-STs to vinyl ethers 41 (Scheme 38). Consist- ently with the Markovnikov rule, the 5-STs are directed to the α-carbon atoms, predominantly yielding the 2-isomers 42.[117]

Scheme 36. Reactions between triethylammonium salts of 5-STs and 5Ј-O-benzoyl-2,3Ј-anhydrothymidine (36).

As previously mentioned, 2H-tautomers are thought to Scheme 38. Reactions between 5-STs and vinyl ethers. be more stable than 1H-tautomers. In the gas phase, 2H- tautomers of 5-STs were 1.5–4 kcal mol–1 more thermody- The highly regioselective methylation[118] and benz- namically stable than the 1H-forms.[8] In the crystalline ylation[119] of 5-phenyl-1H-tetrazole (43, Scheme 39) were state, however, the majority of 5-STs exist in the 1H-form carried out with O-alkyl S-propargyl dithiocarbonates. stabilized by hydrogen bonds to the neighboring molecules, which results in dimers and larger agglomerates. In media of high dielectric constant, 1H-tautomers are preferred due to their higher polarities. A 15N NMR study of tetrazole in a dimethyl sulfoxide (DMSO) revealed that 90–99% of the tetrazole exists in the 1H-form.[114] However, there are several situations in which the relative proportions of the 2H- tautomers strongly increase. This is seen especially in solvents with lower polarities, in which the less polar 2H-form is better solvated and both the 1H- and 2H-forms are pre- dicted to exist in comparable amounts. The free energies of tautomerization of 1H-tetrazole in the gas phase (ε =1) Scheme 39. Benzylation of 5-phenyl-1H-tetrazole with O-benzyl S- and in nonpolar (ε = 2) and polar media (ε = 40) are pre- propargyl dithiocarbonate (44). dicted to be –7, 1, and 12 kJmol–1, respectively.[115] The presence of an electron-withdrawing substituent at the 5- In the first step in each case, the tetrazole was deproton- position increases the polarity of the 2H-tautomer and also ated by the alkylation agent, resulting in a tetrazolate anion, the relative proportion of the 2H-form in polar solvents. In which was further alkylated. Surprisingly, the reactions addition, the presence of a bulky substituent on the tetra- preferentially yielded 2-methyl-5-phenyl-2H-tetrazole and zole carbon or in the ortho-position of the phenyl ring in a gave 2-benzyl-5-phenyl-2H-tetrazole (45, Scheme 40) exclu- 5-aryltetrazole can increase the relative proportion of the sively. 2H-form.[10] This reaction mechanism showed a certain analogy with The ratio of tetrazole tautomers in a reaction mixture the reactions between 5-STs and alcohols under Mitsunobu could significantly influence the regioselectivity of substitu- conditions. In the case of the Mitsunobu conditions, how- tion on the tetrazole ring, but only in the case of a non- ever, lower yields of the 2-isomers were produced.[120] ionized 5-ST species. The following two reactions can be A completely different mechanism of substitution oc- shown as examples, although the true state of the tetrazole curred in strongly acidic media. Reactions between 5-STs

Scheme 40. Mechanism of benzylation of 5-phenyl-1H-tetrazole (43) with O-benzyl S-propargyl dithiocarbonate (44). and secondary or tertiary aliphatic alcohols[121] or alk- acetone were performed. As previously discussed, micro- enes[122,123] in sulfuric acid produced only 2-alkylated prod- waves did not influence the regioselectivity, but did increase ucts. No 1-isomers were detected in the reaction mixtures, the reaction rates.[126] regardless of the substituents at the 5-position in the tetrazole ring (Scheme 41).

Scheme 41. Alkylation of 5-STs in acidic media.

One possible explanation for this is that although 5-STs are weak bases (e.g., pKBH+ = –1.8 for 5-methyl-1H-tetra- [9] zole and pKBH+ = –9.3 for 5-nitro-1H-tetrazole), they are protonated in strong mineral acid solutions. The nitrogen at the 4-position is protonized preferentially, resulting in a 1H,4H-tetrazolium cation of type 46 (Scheme 42).[124] The electrophilic attack of a carbocation, formed from alcohol Scheme 43. Reactions between potassium salts of 5-STs and gluc- or olefin, could be directed only to N2 or N3 of the tetraz- ose derivatives under microwave irradiation. olium cation, leading exclusively to 2,5-disubstituted tetrazoles (48). It should be mentioned that during the reaction between 5-phenyl-1H-tetrazole and 2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl bromide (49), a mixture of both 1- and 2-isomers on the tetrazole ring was formed. This contrasts with the reaction with methyl 2,3,6-tri-O-benzyl-4-O-triflyl-α-d- glucopyranoside (50), which yielded only the 2-isomer 51 (Scheme 44). In the first example, 5-phenyl-1H-tetrazole could approach a more accessible equatorial site, facilita- ting the formation of both isomers. In the second case, 5- Scheme 42. Mechanism of 5-ST alkylation in strongly acidic media. phenyl-1H-tetrazole had to approach a sterically inconve- The interaction of the two cations seems to be very un- nient axial site, which allowed the formation only of the 2- usual, but NMDO quantum chemical calculations showed isomer. a high electron density localized on nitrogen atoms N2 and N3 of the 1H,4H-tetrazolium cation 46.[125] Moreover, decreasing the acidity of the reaction medium led to an increased yield of the 1-isomer, which is in agreement with the proposed mechanism.[122] The alkylation of 5-STs under microwave irradiation conditions has been the subject of only a few studies. Notably, no significant effects of microwave irradiation on the regioselectivity of 5-ST alkylation were observed. In 2007, reactions of 5-phenyl-1H-tetrazole and 1H- tetrazole potassium salts with 2,3,4,6-tetra-O-acetyl-α-d- glucopyranosyl bromide (49, Scheme 43) and methyl 2,3,6- Scheme 44. Sterically controlled formation of a 2,5-disubstituted tri-O-benzyl-4-O-triflyl-α-d-glucopyranoside (50) in boiling tetrazole.

A study of the influence of microwave irradiation on 5- tetrazoles the reactions led regioselectively to the formation ST alkylation showed that the reactions proceeded with the of 2,5-diaryl-2H-tetrazoles. In cases of more compact sub- same regioselectivity regardless of the heating method or stituents such as 5-alkyl-1H-tetrazoles, however, the reac- solvent used (Scheme 45).[127,128] tions yielded mixtures of both regioisomers.[132]

Scheme 45. Alkylation of 5-benzyl-1H-tetrazole with 4-bromo- benzyl bromide. Scheme 48. Arylations of 5-STs with 4-nitrofluorobenzene under microwave irradiation conditions.

Arylation of 5-STs Arylations of 5-STs are described less frequently in the literature than alkylations. The reaction between sodium 5- Vinylation of 5-STs methylsulfanyl-1H-tetrazolate and 4-nitrofluorobenzene is one example, however. This reaction resulted in the forma- The first direct vinylations of 5-STs, utilizing vinyl acet- tion of both isomers – 5-methylsulfanyl-1-(4-nitrophenyl)- ate, were published in 1986. The main drawbacks of this 1H-tetrazole and 5-methylsulfanyl-2-(4-nitrophenyl)-2H- method lie in the need for mercury(II) catalysts and the [133] tetrazole – in a 1:3 ratio. 5-Aryltetrazoles did not react un- moderate yields (Scheme 49). der these conditions.[129] On the other hand, in the case of 2,4-dinitrofluorobenzene (52, Scheme 46) the reactions proceeded under mild reaction conditions even with 5-aryltetrazoles.[130]

Scheme 49. Direct vinylation of 5-ST with vinyl acetate.

The analogous reaction of 5-phenyl-1H-tetrazole, in the presence of palladium(0) catalysts, led to low yields (17%) with a high tendency to polymerization.[134] We have recently described a one-pot, regioselective method for the preparation of 5-substituted 2-vinyl-2H- Scheme 46. Arylation of 5-STs with 2,4-dinitrofluorobenzene (52). tetrazoles 55 (Scheme 50) through a simple procedure without a metal catalyst or organocatalyst. In 2002, regioselective arylations leading to the selective preparation of 5-substituted 2-aryltetrazoles 54 (Scheme 47) in high yields were reported. They involved treatment of salts of 5-STs with diaryliodonium salts 53 in tert-butyl alcohol in the presence of palladium(0) and copper(II) catalysts.[131]

Scheme 50. Regioselective vinylations of 5-STs.

The mechanism of this reaction was also investigated. In Scheme 47. Regioselective arylations of 5-STs with diaryliodonium the first step, triethylamine could react with 1,2-dibromo- tetrafluoroborates 53. ethane to form (2-bromoethyl)triethylammonium bromide (56, Scheme 51), which could react with the 5-ST to pro- Microwave-assisted arylations of 5-STs by treatment of duce compound 57. Under these reaction conditions, 57 their sodium salts with 4-nitrofluorobenzene in DMSO could undergo spontaneous elimination to produce a vinyl have recently been described (Scheme 48). With 5-aryl-1H- derivative.[135]

(Project GAUK 55610/2010) and by the Czech Science Foundation (Project No. P207/10/2048).

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