synthesis and functionalization of 5-substituted tetrazolesszolcsanyi/education/files... ·...

MICROREVIEW

DOI: 10.1002/ejoc.201200469

Synthesis and Functionalization of 5-Substituted Tetrazoles

Jaroslav Roh,*[a] Katerina 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-tions in organic chemistry, coordination chemistry, the photo-graphic industry, explosives, and, in particular, medicinalchemistry. In organic chemistry, 5-substituted tetrazoles areused as advantageous intermediates in the synthesis of otherheterocycles and as activators in oligonucleotide synthesis.In drug design, 5-monosubstituted tetrazoles are the mostimportant tetrazole derivatives because they represent non-classical bioisosteres of carboxylic acids, with similar acidi-ties but higher lipophilicities and metabolic resistance. In thisreview we focus on the preparation and further functionali-zation of these heterocycles. Firstly, the role of 5-substitutedtetrazoles in medicinal chemistry is described, including ex-amples of their effects on pharmacokinetics, pharmacodyn-

Introduction

Tetrazoles are synthetic compounds with the highest ni-trogen contents among the stable heterocycles. They playimportant roles in coordination chemistry, in the photo-graphic industry, or as components of special explosives.[1]

Moreover, the tetrazole ring is an important intermediate inthe synthesis of other more complex heterocycles, throughvarious rearrangements.[2] As a result of their acidities, 5-monosubstituted tetrazoles are also used as activators inoligonucleotide synthesis.[3] However, the most importantuse of tetrazoles is to be found in medicinal chemistry.

In the context of the natures of the tetrazole rings, thesystems can be classified into 1-, 2-, and 5-monosubstitutedtetrazoles, 1,5- and 2,5-disubstituted tetrazoles, and trisub-stituted tetrazolium salts. Other important tetrazole deriva-tives include 1,4-disubstituted 1H-tetrazol-5(4H)-ones, 1H-tetrazol-5(4H)-thiones, or 1H-tetrazol-5(4H)-imines.

The first compound containing a tetrazole ring to havebeen prepared is thought to be 2-phenyl-2H-tetrazole-5-car-bonitrile (1, Figure 1), which was prepared and charac-

[a] Department of Inorganic and Organic Chemistry, Faculty ofPharmacy, Charles University in Prague,Heyrovského 1203, 50005 Hradec Králové, Czech RepublicFax: +42-495-067-166E-mail: [email protected]: http://portal.faf.cuni.cz/Groups/Hrabalek-Group/

Eur. J. Org. Chem. 2012, 6101–6118 © 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 6101

amics, and metabolism of the associated drugs. Then, themain synthetic approaches to 5-substituted tetrazoles – con-sisting of methods based on acidic media/proton catalysis,Lewis acids, and organometallic or organosilicon azides – arepresented, from the early procedures to the most recent ones,with special attention paid to the reaction mechanisms. Func-tionalization of 5-substituted tetrazoles is a challenging taskbecause it usually leads to the formation of two isomers, 1,5-and 2,5-disubstituted tetrazoles, in various ratios. In thisoverview, reactions with high or unusual regioselectivitiesare described, with comments on the possible mechanisms.Microwave-assisted approaches to the synthesis and func-tionalization of 5-substituted tetrazoles are also included.

terized in 1885.[4,5] That compound was also used severalyears later for the first preparation of an unsubstituted 1H-tetrazole.[6]

Figure 1. 2-Phenyl-2H-tetrazole-5-carbonitrile: the first tetrazole-containing compound prepared.

The most interesting compounds containing tetrazolemoieties are 5-substituted tetrazoles (5-STs). The first partof this review briefly outlines the roles and uses of thesecompounds in medicinal chemistry. The next section dealswith the synthesis of 5-STs, from the early procedures torecent approaches, highlighting the most important meth-ods. Then, the functionalization of 5-STs, including alkyl-ation, arylation, and vinylation of this heterocycle system, ispresented, with focus on the reactions with high or unusualregioselectivities. Special attention is paid to the mecha-nisms of the presented reactions. Methods of synthesis andfunctionalization of 5-STs under microwave irradiation con-ditions, which have recently been widely explored, are alsopresented together with comments on the effects of micro-wave irradiation on these reactions.

J. Roh, K. Vávrová, A. HrabálekMICROREVIEW

5-STs in Medicinal Chemistry

5-STs are a typical bioisosteric replacement system forcarboxylic acids. Although these two functional groups arestructurally different and have different numbers of atoms,they display similar types of biological activity as a resultof their close physico-chemical properties.[7]

5-STs exist in two tautomeric states: 1H- and 2H-tauto-mers (Figure 2). Natural bond orbital analysis showed that2H-tautomers (3) were more stable than 1H-tautomers (2)in all of the ten 5-STs investigated in that study, due tohigher aromaticity indices and the greater electron delocal-ization in 2H-tautomers (for more details see the sectionAlkylation of 5-STs).[8] As a consequence of the abilities of5-STs to delocalize negative charges after deprotonation, 5-STs are relatively strong N–H acids, with their aciditiesstrongly dependent on the substituents in their 5-positions.The pKa values of 5-STs are very similar to those of thecorresponding carboxylic acids (Table 1),[9,10] which is im-portant for their bioisosteric interchangeability.

Figure 2. 1H- and 2H- tautomers of 5-STs.

The alkaline salts of 5-STs are highly soluble in waterand are better reactants than the non-ionized species for

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 workon synthesis and functionalization of 5-substituted tetrazoles. In 2007 he worked at the St. Petersburg State Institute ofTechnology (Russian Federation) in the group of Prof. G. I. Koldobskii. His research interests include chemistry ofnitrogen-containing heterocycles, microwave chemistry, and synthesis of iron chelators.

Katerina 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 workon transdermal permeation enhancers and ceramide analogues under the supervision of Prof. Alexandr Hrabálek. In2004–5 she investigated skin barrier repair agents in Prof. Humbert’s lab in Besançon, France. Since 2009 she has beenan associate professor in Medicinal Chemistry. Her research interests include skin barrier sphingolipids, cardioprotectiveiron 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 GoldMedal at the World Exhibition of Innovation, Research and New Technology in Brussels – Eureka 1997. In 2000 he wasappointed associate professor at the Department of Inorganic and Organic Chemistry at the Faculty of Pharmacy, CharlesUniversity, and in 2009 he become a full professor. The current research interests of his group include synthesis ofantimicrobial tetrazoles and amino-acid-based permeation enhancers.

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Table 1. Comparison of the acidities of selected carboxylic acidsand the corresponding 5-STs.

R pKa pKa

R–COOH R–CN4H

H 3.77 4.70CH3 4.76 5.50C2H5 4.88 5.59–CH2CH2– 4.19, 5.48 4.42, 5.74Ph 4.21 4.834-MeOC6H4– 4.25 4.754-NO2C6H4– 3.43 3.45

reactions with alkylation agents and other electrophiles (formore details see Functionalization of 5-STs).

Like carboxylic acids, 5-STs are ionized at physiologicalpH values. However, tetrazole anions are nearly 10 timesmore lipophilic than the corresponding carboxylates.[11]

This fact is important for the pharmacokinetics of the tetra-zole analogues of carboxylic acids. From the point of viewof the pharmacodynamics, the effect of the replacement ofa carboxylic acid by a 5-ST is more complex. The delocal-ization of the negative charge in the tetrazole ring can eitherenhance or reduce the interaction with an appropriate re-ceptor, depending on the electron distribution in the recep-tor site.[12] The size of the tetrazole ring might decrease theaffinity towards the receptor site relative to a carboxylategroup as a result either of steric hindrance or of an inconve-nient orientation of the functional groups of the activesite.[13] The main difference between the carboxylate andthe tetrazole anion lies in the ability of all of the nitrogen


atoms, which act as acceptors of hydrogen bonds, to inter-act with a receptor. Examples of this are the interaction ofthe tetrazole anion with protonated lysine and hystidine inthe receptor for angiotensin II[14] and the interaction of allfour nitrogen atoms of the tetrazole fragment of the HIV-1integrase inhibitor 5ClTEP with its receptor.[15] Despite allthe previously identified differences in the pharmacodyn-amic effects of the carboxylic and tetrazole analogues, it isdifficult accurately to predict the pharmacodynamic re-sponse to the replacement of a carboxylic acid by a 5-ST.Various examples from the literature show that the pharma-codynamic effect can increase, decrease, or completely dis-appear.[16]

The main advantage of 5-STs is their resistance to meta-bolic degradation. One of the first in vivo studies foundthat the tetrazole analogue of nicotinic acid was excretedunchanged, whereas nicotinic acid itself was quickly metab-olized.[17] Nonetheless, the main metabolic transformationof 5-STs, as in the cases of many other xenobiotics, wasfound to involve glucuronidation of one of their nitrogenatoms. Glucuronidation is mediated by the enzyme UDP-glucuronosyltransferase, and involves the transfer of gluc-uronic acid from the cofactor uridine-5-diphospho-α-d-glucuronic acid to a xenobiotic. It is interesting to note thatboth N1 (compounds 4) and N2 glucuronides (compounds5) were detected (Figure 3). During the administration ofcompound AA-344 [6-ethyl-3-(1H-tetrazol-5-yl)chromone]to laboratory animals the N1 isomer was primarilyfound,[18] whereas the group of compounds derived from 5-(biphenyl-2-yl)-1H-tetrazoles (antagonists of the receptorfor angiotensin II)[19] or the potential antidiabetic drugRG 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-STsis thus not strictly regioselective. It was also suggested thatenterohepatal circulation was responsible for the long bio-logical half-lives of tetrazole drugs.[19]

Figure 3. Structures of the main metabolites of 5-STs.

The most important group of biologically active com-pounds based on 5-STs are the selective antagonists of thereceptor for angiotensin II. The first representative, Losar-tan (6, Figure 4), has been in clinical use since 1994.[21] Los-artan is a good example of a drug in which the optimalratio of antihypertensive activity and per os bioavailabilitywas achieved. Carboxylic acid analogues of this drug alsohave antihypertensive properties but are less active, evenwhen they are administered intravenously. Other bioiso-steric replacements of carboxylic acid were examined dur-ing the development of this drug, but none had better prop-erties than the 5-ST.[16]

Eur. J. Org. Chem. 2012, 6101–6118 © 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org 6103

Figure 4. Structure of Losartan.

Other important compounds in which 5-STs play a no-table role are antileukotriene antiasthmatics.[22,23] Com-pound LY171883, later known as the drug Tomelukast (7,Figure 5), is one example.[24] Through the substitution of acarboxylic acid by a 5-ST, its in vitro activity was increasedby approximately thirty times, probably due to a better in-teraction between the delocalized negative charge on thetetrazole ring and the arginine residue in the active site ofthe cysLT1 receptor for LTD4.[25] In addition, in vivo ac-tivity after oral administration was increased, due to thehigher lipophilicity of the tetrazole analogue. Because ofthe great success of Losartan and its analogues, 5-STs werewidely explored as bioisosteric replacements for carboxylicacid groups. Other examples of the successful use of 5-STsare tetrazolic analogues of the HCV NS3 protease inhibi-tor,[26] the tetrazolic ligand for the mutant thyroid hormonereceptor TRβ(R320H),[27] and the tetrazolic inhibitor of theprotein tyrosine phosphatase 1B as potential antidiabet-ics.[28]

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 abioisosteric replacement for thiazolidin-2,4-dione (com-pounds 9) was synthesized.[29] A similar derivative (com-pound 10) was also reported in 2002.[30] The results of thesestudies showed that tetrazolic analogues had the samemechanism of action as thiazolidin-2,4-dione insulin sensi-tizers and established that these two structural fragmentswere, in this case, bioisosteres. In 2005 a series of com-pounds with the 5-[(1H-pyrazol-3-yl)methyl]-1H-tetrazolicstructural base was synthesized. They also showed antidia-betic activity.[31]

Furthermore, the 5-ST fragment can also be found inthe receptor antagonists of the excitatory amino acids 11{Figure 7, antagonist of AMPA [2-amino-3-(5-methyl-3-hy-droxyisoxazol-4-yl)propionic acid]} and 12 [antagonist ofNMDA (N-methyl-d-aspartate)], which are potential drugsagainst schizophrenia and cerebral ischemia.[32]


Figure 6. The antidiabetic Ciglitazone (8) and its tetrazole ana-logues.

Figure 7. Selective antagonists of AMPA and NMDA receptors.

Interestingly, the 5-ST fragment has also been used as astabilizing structural moiety, as a result of its high crystal-linity. In one example, a potent inhibitor of NO synthase,l-6-N-(1-iminoethyl)lysine, which is hygroscopic and un-stable in air, was stabilized by the addition of a 5-ST frag-ment to afford 13 (Figure 8). In vivo metabolism then re-sulted in the active l-6-N-(1-iminoethyl)lysine.[33–35]

Figure 8. Tetrazole-based prodrug of l-6-N-(1-iminoethyl)lysine.

Synthesis of 5-STs

The first specific and widely used methods for 5-ST syn-thesis consisted of the diazotization of polynitrogen com-pounds, especially hydrazidines (imidohydrazides) such as14 (Scheme 1), which are prepared primarily from imino-ethers (imidates) and hydrazine.[36]

Scheme 1. Synthesis of 5-phenyl-1H-tetrazole from benzimido-hydrazide.


The currently favored approach to 5-ST synthesis lies inthe interaction of nitrile moieties with azide groups. A reac-tion of this type was successfully accomplished for the firsttime in 1901, when 5-amino-1H-tetrazole, known at thetime as diazoguanidine, was prepared from cyanamide andazoimide.[37] In 1910, 1H-tetrazole itself was synthesized bya similar reaction, which involved the cycloaddition of azo-imide to hydrogen cyanide.[38] Azoimide, a toxic and explos-ive gas, prepared either in advance or in situ, was used as amajor reactant for 5-ST preparation until the end of the1950s.[39] During this period, hundreds of 5-STs were pre-pared.[36]

In 1958, Finnegan et al. published their fundamentalwork utilizing sodium azide and ammonium chloride inN,N-dimethylformamide (DMF) in the synthesis of 5-STs(Scheme 2). Although azoimide could also be detected inthe reaction mixture, this method completely changed thesynthetic approaches to 5-STs. Since then, the processeshave become much safer, the reaction times have been sig-nificantly 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 thepreparation of 5-STs and has completely displaced the pro-cesses utilizing azoimide.[40] Many new methods and modi-fications of existing processes have appeared since Finne-gan’s invention. The principle of most of them is a reactionbetween a nitrile and an azide moiety, although they can bedivided into three main groups: a) using acidic media (pro-ton-catalyzed), b) using Lewis acids, and c) using organo-metallic and organosilicon azides. There is no clear distinc-tion between these approaches and many of the latest meth-ods combine their advantages.

Scheme 2. Finnegan’s method for preparation of 5-STs.

In addition, there are also methods for 5-ST preparationthat do not utilize nitriles as the main reactants. 5-STs canalso 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-posi-tion.[41]

The general disadvantage in preparations of 5-STs is longreaction times. Microwave (MW) irradiation has beenwidely explored in attempts to overcome this limitation gen-erally. The first work dealing with microwave-irradiated or-ganic reactions was published in 1986. Since then, micro-wave chemistry has been the subject of intense investi-gations, and around 4000 papers have been published todate. Most of these declared microwave irradiation to besuperior to conventional heating, and to result in decreasedreaction times and increased yields or selectivities of reac-tions.[42] These benefits have been suggested to be the resultsof thermal effects and so-called “specific microwave ef-fects”. It is of note that the existence of the previously as-sumed non-thermal effects of microwave irradiation was re-cently rejected.[43]


Microwave-assisted methods for preparation of 5-STs arepresented in each section according to the reagents in-volved.

Methods Using Acidic Media – Proton-Catalyzed

All of the above methods utilize azoimide[37–39] and Fin-negan’s method also falls into this class.[40] In 1987 Finne-gan’s method was modified by the use of N-methylpyrroli-din-2-one (NMP) as the solvent. This change allowed thereaction temperature to be increased, which led to higheryields and shorter reaction times.[44]

In 2000, the first microwave-assisted preparation of 5-STs based on Finnegan’s work[40] was published. Thismethod again utilized treatment of nitriles with sodium az-ide and ammonium chloride in DMF. Reaction times weresignificantly reduced, with the obtained yields remaininghigh. Reactions were carried out in closed vessels withoutmonitoring of the reaction temperature (Scheme 3).[45]

Scheme 3. Microwave-assisted Finnegan’s reaction.

Two significant modifications of Finnegan’s method ap-peared in 1998, when Koguro et al. carried out reactions ofnitriles with sodium azide and triethylammonium chloridein toluene (Scheme 4). The main advantage of this processis the simplicity of the product isolation: the 5-ST can beextracted straight from the reaction mixture into water oran alkaline aqueous solution. Another possibility is fil-tration of triethylammonium tetrazolate from the reactionmixture, together with inorganic salts.[46,47]

Scheme 4. Koguro’s method for preparation of 5-STs.

The principle of the second modification is the utilizationof tensides in aqueous media. 5-STs were prepared fromnitriles in water in the presence of sodium azide, ammo-nium chloride, and dodecyltrimethylammonium or hexa-decyltrimethylammonium bromides (Scheme 5).[48]

Scheme 5. Preparation of 5-STs in micellar media.

Koguro’s method[46] was also modified and improvedthrough the use of microwave irradiation. 5-STs were pre-pared by treatment of nitriles with sodium azide and trieth-ylammonium chloride in nitrobenzene in a microwave reac-tor (Scheme 6). This practical method combines the advan-tages of the previous procedures, including good to excel-lent yields, short reaction times, and easy isolation of theproducts.[49]


Scheme 6. Preparation of 5-STs by use of in situ generation of tri-ethylammonium azide in nitrobenzene.

Another microwave-assisted method consisted of treat-ment of nitriles in ionic liquids with azoimide generated insitu from sodium azide in the presence of acetic acid. Reac-tion times were shortened from 24 h to 30 min at reactiontemperatures of around 170 °C.[50]

A rapid and effective method for the synthesis of 5-STsby a high-temperature/high-pressure microreactor approachhas recently been published (Scheme 7).[51]

Scheme 7. Synthesis of 5-STs by a high-temperature microreactorapproach.

With regard to the preferred mechanism of the reactionsin acidic media (proton-catalyzed), the following threehypotheses have been discussed: 1) concerted dipolar [2+3]cycloaddition, 2) anionic two-step [2+3] cycloaddition, and3) activation of the nitrile by protons – via an intermediateimidoyl azide.

In 1892 Thiele claimed that he had prepared guanyl azideby diazotization of aminoguanidine. Its heating in an aque-ous solution led to its cyclization to 5-amino-1H-tetra-zole.[52] Dimroth and Fester then suggested that reactionsbetween nitriles and azoimide proceeded through the inter-mediate imidoyl azides.[38] However, this hypothesis was notconfirmed for almost one hundred years.[53]

Although Finnegan’s group formulated the role of theacid catalysis in the preparation of 5-STs, they proposedthat the principle step of the reaction is the attack of theazide anion on the nitrile carbon, followed by ring closure(hypothesis 2).[40] Several reactions with use of azoimideand ammonium azide were performed, with better resultsseen in the case of the ammonium salt.

This hypothesis was confirmed in work by Jursic andZdravkovski in 1994, in which a two-step [2+3] cycload-dition, involving nucleophilic attack of the azide ion on thecarbon of the nitrile group, followed by tetrazole ring clo-sure, was shown to be the preferred mechanism (Scheme 8).Interestingly, only two mechanisms, corresponding tohypotheses 1 and 2, were considered, with the role of acidcatalysis in these reactions not being mentioned.[54]

On the other hand, data supporting the concerted di-polar [2+3] cycloaddition (hypothesis 1) were presented byscientists from the St. Petersburg Technological Institute.[55]

They discovered that dimethylammonium azide is generallynot ionized in DMF and undergoes the reaction as the hy-drogen-bonded complex (CH3)2NH·HN3, and not as azideanion and dimethylammonium cation. The azide part ofthis complex has a structure and distribution of electron


Scheme 8. Mechanism of formation of 5-STs through two-step[2+3] cycloadditions of azide anion; intermediates 16 could befound 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 az-ides (RN3). Because azoimide and organic azides are typical1,3-dipoles in dipolar cycloaddition reactions, the authorssuggested that the reaction mechanism is a concerted di-polar [2+3] cycloaddition (Scheme 9). At the same time,they also discovered that tetraalkylammonium azides donot react with nitriles under certain conditions. These az-ides only release azide anion, which is not a 1,3-dipole andcannot react by 1,3-dipolar cycloaddition. The fact that tet-raalkylammonium azides do not react also rules out theanionic two-step [2+3] cycloaddition mechanism.

Scheme 9. Mechanism of formation of 5-STs through concerted di-polar [2+3] cycloadditions.

It was shown that organic azides react at elevated tem-peratures only with highly reactive nitriles (through con-certed dipolar [2+3] cycloadditions), whereas ammoniumazides react readily with a wide range of nitriles under theseconditions.[56] As already mentioned, the electronic struc-tures of organic azides and ammonium azides are very sim-ilar, but their reactivities are significantly different. Thisclearly demonstrates that the actual mechanism of 5-ST for-mation must be different from those proposed in hypothe-ses 1 and 2.

In an acidic medium, the preparation of a 5-ST actuallyproceeds preferentially through an imidoyl azide intermedi-ate such as 19 (Scheme 10), which spontaneously cyclizes tothe 5-ST under the reaction conditions (hypothesis 3). Asin the case of Pinner synthesis[57] or the acid hydrolysis ofnitriles,[58] protonation of the nitrile increases its reactivityand susceptibility to attack by azide anions. The transitionstate of this process has an energy significantly lower thanthose of concerted or anionic two-step [2+3] cycloadditions.In the reaction, the ammonium cation acts as the mediatorof proton transfer, even in cases in which ammonium saltis not ionized in the reaction medium. The conversion ofacetonitrile into 5-methyl-1H-tetrazole is an example ofthis. In the case of proton activation by the ammonium partof the salt, the energy barrier, either ionized (NH4

+) or notionized (NH3), was calculated to be approx. 21 kcalmol–1,whereas all other discussed mechanisms showed higher


energetic barriers, with values of 35 kcalmol–1 for concerteddipolar [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 10. Mechanism of formation of 5-STs via imidoyl azideintermediates 19.

In the context of the anionic two-step mechanism, inter-mediates 16 could be found only in the cases of nitriles withvery strongly electron-withdrawing groups such as F orCH3SO2. They are weakly bound, however, and have al-most the same energy as the free reactants, with the ener-getic barriers to their formation less than 4 kcal mol–1. Theactual transition states (17) for the ring closing steps there-fore turn out to be almost identical to the concerted [2+3]transition states 18. From these findings it can be statedthat hypotheses 1 and 2 are essentially the same.[53]

The role of the partial positive charge on the nitrile car-bon is essential. The presence of electron-withdrawing sub-stituents on the nitrile decreases the activation energy andincreases the reactivity of the nitrile towards azide anions.In the cases of the strongest electron acceptors, the energiesof the transition states of anionic [2+3] cycloaddition areclose to the energies of the ammonium-activated transitionstates, which is why the anionic mechanism cannot be com-pletely rejected. Moreover, the most electron-poor nitrilesreact with sodium azide without any additional reactantsunder very mild conditions.[59]

Methods using acidic media are widely used both insmall laboratories and on industrial scales. The main draw-backs are the presence of the highly toxic and explosiveazoimide in the reaction mixtures and the use of the ther-mally unstable (generated in situ) ammonium azides, whichreadily sublimate from the reaction mixtures.

Methods Using Lewis Acids

The principle of the second group of methods for thepreparation of 5-STs is close to that of the first one, becauseLewis acids also coordinate nitriles and activate themtowards attack by azide anion.

The first Lewis acid used for the preparation of 5-STswas aluminum azide, which was prepared from aluminumhydride and azoimide in 1954.[60] Later, this Lewis acid was


prepared in a safer way by treatment of aluminum chloridewith sodium azide in THF. The same reactant was used forthe preparation both of 5-(2-aminoethyl)-1H-tetrazole[61]

and of a series of 5-(chloroalkyl)-1H-tetrazoles(Scheme 11).[62] The main drawbacks were the water sensi-tivity, the release of two equivalents of azoimide during iso-lation, and the instability of the azides of elements ofgroup IIIa. Interestingly, the conversion of all three azideanions of Al(N3)3 to afford aluminum tetrazolate has notbeen described to date.

Scheme 11. Preparation of 5-STs utilizing Al(N3)3, showing thepossible reaction mechanism.

Finnegan et al. also used boron trifluoride as a Lewisacid in their work. They postulated that Lewis acids shouldactivate the nitrile group towards reaction with azide ions.However, boron trifluoride was the only Lewis acid used inthat study and the results were actually worse than thosefor ammonium azide.[40] Nonetheless, treatment of nitrileswith sodium azide and boron trifluoride in DMF was suc-cessfully used to synthesize 5-(hydroxyphenyl)tetrazoles in1996.[63]

In 1993, interest in Lewis acids was reopened by the utili-zation of trimethylaluminum in the synthesis of a series of5-STs under relatively mild reaction conditions(Scheme 12).[64] In these reactions, trimethylsilyl azide(TMSN3) served as the azide donor.

Scheme 12. Preparation of 5-STs utilizing trimethylaluminum.

The main disadvantage of all the reactions mentionedabove lies in their water sensitivity. They should thereforebe carried out under inert atmosphere. A major break-through in this field came with the publication of Sharpless’work.[65] This method consisted of treatment of a nitrilewith sodium azide and zinc bromide in water (Scheme 13).Isolation of the product was carried out by simple acidifica-


tion of the reaction mixture and filtration of the precipi-tated 5-ST. The main drawback is the need to use high pres-sure and temperatures of up to 170 °C for the conversionof less reactive nitriles.

Scheme 13. Sharpless’ method for preparation of 5-STs.

This reactions proceeded through complex structures,each with a central zinc atom coordinated with tetrazolateligands. These intermediates were studied by use of pyr-idine-2-, -3-, and -4-carbonitriles as the reactants. Withouttreatment of the reaction mixtures with alkalis or acids, theisolated solids contained zinc complexes with pyridyl-tetrazolate, water, and surprisingly also hydroxide ligands.Water thus played two roles in these reactions: as a solventand as a reactant.[66]

In 2009, a series of 5-aryl-1H-tetrazoles was prepared bySharpless’ method, except that the conditions were solvent-free. As a result of this modification, the reaction timeswere shortened, but larger amounts of sodium azide andzinc 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 wereprepared in yields of 75–91 % after 20 minutes under micro-wave heating to 185 °C.[68] In the second study, 5-STs wereprepared in 15–30 minutes at 80 °C in an average yield of75%.[69] The main difference lies in the presence of iodineresidues in the second study; it probably played the role ofan effective catalyst, like in the case described below.[70] Inthe third study, nitriles of diverse structures reacted withNaN3 in water in the presence of ZnCl2 under microwaveirradiation conditions to give good yields of 5-STs. The es-sential fact was that the reaction times under microwaveirradiation conditions were two to three times shorter thanin the inactivated process, with 5-STs being obtained inyields of 60–86% in 2–14 hours at 92–95 °C (Scheme 14).[71]

Scheme 14. MW-based version of Sharpless’ protocol.

As in the case of acid-catalyzed synthesis, the mechanismof this type of 5-ST preparation involved a significant de-crease in activation energy when a nitrile nitrogen was coor-dinated to a Lewis acid. For the binding of azide ion toLewis acid, the activation energy remained untouched: theconversion of acetonitrile into 5-methyl-1H-tetrazole orinto 1,5-dimethyl-1H-tetrazole through reaction withmethyl azide are examples of this. Activation energies ofreactions in which zinc ions were bonded only to azideanions was calculated to be 34 and 36 kcalmol–1 for tetra-hedral and octahedral coordination of zinc ions, respec-tively. When a zinc cation was bonded either to a nitrile orto a nitrile together with an azide ion, the activation ener-gies decreased to 25–30 kcalmol–1, again depending on the

J. Roh, K. Vávrová, A. HrabálekMICROREVIEWnumbers and types of ligands. The activation energies of theuncatalyzed reactions were 32 kcal mol–1 for the reactionwith methyl azide and 34 kcal mol–1 with azide anions. Thisstudy confirmed that the Lewis acid coordinates with thenitrile nitrogen (Figure 9). This coordination increased thepolarization of the nitrile moiety and decreased the acti-vation energy of the entire reaction. In the case of zinc cat-ions, for example, the activation energies were around 5–6 kcalmol–1 lower.[72]

Figure 9. Potential intermediates with the nitrile coordinated tozinc.

Sharpless’ work increased the interest in methods utiliz-ing Lewis acids. Yamamoto et al., for example, prepared 5-STs by treatment of aromatic or aliphatic nitriles withTMSN3 in the presence of catalytic amounts of Cu2O inDMF/MeOH mixtures (Scheme 15). It was shown that theTMSN3 released azoimide in the presence of methanol. Thereaction between azoimide and Cu2O was assumed to formcopper azide, a main reactant with catalytic activity. Thereaction product, copper tetrazolate, then attracted a pro-ton from azoimide, leading to the regeneration of copperazide.

Scheme 15. Preferential mechanism of Cu2O-catalyzed preparationof 5-STs.

The actual mechanism was thought to be a combinationof several procedures, because the reactions proceeded to30–50 % yields without methanol, as well as without a cop-per catalyst. The authors also described another interestingexample of copper catalysis with use of stoichiometricamounts of NaN3 and catalytic amounts of CuI in DMF/MeOH. However, this procedure was illustrated by only oneexample: the preparation of 5-(4-methoxyphenyl)-1H-tetrazole from 4-methoxybenzonitrile in a yield of 92%.[73]

One year later, Bonnamour and Bolm utilized FeII salts,Fe(OAc)2 in particular, instead of copper catalysts. With analmost identical experimental procedure the authors pre-pared several aromatic 5-STs, but in lower yields after reac-tion times twice as long. Moreover, aliphatic nitriles did notreact under these conditions.[74]


One of the latest studies from this group used iodine asa catalyst. Treatment of nitriles with sodium azide in thepresence of catalytic amounts of iodine led to the pro-duction of 5-STs in high yields even in cases of stericallyhindered nitriles. The simple workup and easily availablereactants are the main benefits of this method(Scheme 16).[70]

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

An important approach to the preparation of 5-STs bytreatment of nitriles with sodium azide in DMF can befound in studies utilizing heterogeneous catalysts such asZnO,[75] ZnS[76] and other ZnII minerals,[77,78] natrolite zeo-lite,[79] FeCl3/SiO2,[80] MIIWO4,[81] or magnetically recovera-ble CuFe2O4 nanoparticles.[82] The main advantages are thesimple filtration of catalysts and the ability to reuse them.

Those methods, however, suffer from substantial draw-backs. All of them were performed in DMF and neededlong reaction times with temperatures around 120 °C andproducts had to be chromatographically purified. More-over, aliphatic nitriles either were converted into 5-STs invery low yields or were not included at all.

Methods Using Organometallic and Organosilicon Azides

The ability of TMSN3 to react with organic nitriles toyield 5-STs was described for the first time in 1968.[83] Thiscompound had convenient properties, such as stability, sol-ubility in organic solvents, and a relatively high boilingpoint (95–96 °C). However, reactions of nitriles withTMSN3 alone led to low levels of conversion, and less reac-tive nitriles remained untouched. A recent study showedthat calculated energy barriers for the cycloaddition ofTMSN3 to acetonitrile were higher than for the cycload-dition 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-wave reactor with 2 equivalents of sodium azide led tohigher conversion rates (17%) than treatment with 2 equiv-alents of TMSN3 (4%).[84]

Another notable class of azide donors is that of trialkyl-tin azides, usually in the form of trimethyltin azide or tri(n-butyl)tin azide (Scheme 17).[41,85] The use of tris(2-perfluoro-hexylethyl)tin azide allowed the isolation of a stannylatedproduct from the reaction mixture by liquid/liquid extrac-tion into a fluorous solvent. In addition, tris(2-perfluoro-hexylethyl)tin chloride, a byproduct formed after acid hy-drolysis of the stannylated tetrazole, could be separatedanalogously.[86] Reactions between these tin reactants andnitriles produced 5-STs in high yields, even from stericallyhindered and electron-rich nitriles. The main drawback,however, is the use of toxic reactants in high amounts. Thepotential for recycling of the tin reactants is achieved onlyin 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-alkyltin chlorides (trialkyltin azide precursors) and to de-crease the amounts of organotin reagents necessary whilemaintaining their advantages, a 5-ST synthesis based onTMSN3 in the presence of catalytic amounts of dibutyltinoxide was developed. The authors suggested that dibutyl-(trimethylsilyloxy)tin azide (21, Scheme 18) was formed insitu during this reaction and further reacted with the corre-sponding nitrile to yield complex 22. This intermediate de-composed to N-(trimethylsilyl)tetrazole and regenerated di-butyltin oxide (20) or dibutyl(trimethylsilyloxy)tin azide(21).[87]

The actual mechanism was revealed later, and confirmedthat the dialkyl(trimethylsilyloxy)tin azide complex is in-deed the catalyst. The calculated free energy barrier for theformation of the intermediate dimethyl(trimethylsilyloxy)tinazide (23, Scheme 19) is low (13.2 kcal mol–1) and these pro-cesses are highly exothermic (–48.8 kcalmol–1), so the re-generation of dialkyltin oxide seems improbable. Complex23 does not react with nitriles through concerted 1,3-di-polar cycloadditions, because the calculated energy barriersfor these reactions are almost the same as for uncatalyzedreactions (+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 firstbinds to the acidic tin atom, which activates the nitrile car-bon for the attack of the azide group. The open-chain inter-mediate 24 than cyclizes to the 1-[dimethyl(trimethyl-silyloxy)stannyl]-5-ST 25 (Scheme 19). The calculated en-ergy barrier to this process is more than 5 kcal mol–1 lowerthan in the case of uncatalyzed cycloaddition.[84]

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


Scheme 19. Reaction between nitriles and catalytic complex 23.

The catalytic complex 23 is then regenerated through thesimple SN2 reaction between 25 and TMSN3 via transitionstate 26 (Scheme 20). It has recently been shown that cata-lyst 23 can be recovered from the complex 25 by treatmentwith azide anions (Scheme 21). This meant that only cata-lytic amounts of TMSN3 (or TMSCl) and Bu2SnO, to-gether with stoichiometric amounts of inexpensive sodiumazide, could be used in this new protocol (Scheme 22).[84]

In a recent study, bis(tributyltin) oxide was used instead ofdibutyltin oxide.[88]

Scheme 20. Mechanism of recovery of catalytic complex 23 withuse of TMSN3.

Reactions between nitriles and TMSN3 in the presenceof catalytic amounts of dibutyltin oxide under microwaveirradiation conditions were performed in 1,4-dioxane[89]


Scheme 21. Mechanism of recovery of the catalytic complex 23 bytreatment with azide.

Scheme 22. New protocol for 5-ST formation with use of catalyst23 formed in situ.

and dimethoxyethane.[90] Again, the microwave irradiationreduced the reaction times while maintaining high yields ofthe products.

Another synthesis of 5-STs based on the use of TMSN3

without the organotin reagents (Scheme 23) was developedin 2004. Tetrabutylammonium fluoride (TBAF) trihydratewas found to be a suitable catalyst for this synthesis. Undersolvent-free conditions, a series of 5-STs was prepared.[91]

The principle of this reaction took advantage of the anionicactivation of the silicon-nitrogen bond by fluorideanions.[92]

Scheme 23. Preparation of 5-STs by use of TMSN3 and TBAF.

The most universal method from this group, providinghigh yields of 5-STs under mild reaction conditions, waspublished in 2007. Dialkylaluminum azides were the crucialreactants for this procedure and the main source of azideanions, and were prepared in situ from the dialkylaluminumchlorides and sodium azide (Scheme 24). Their structurescombine several advantages: high solubility in organic sol-vents, 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 theuse of highly toxic organometallic reactants, the residues ofwhich are often present in the products, thus necessitatingvery careful separation. The price of these substances couldalso play an important role.

Other Methods

The previously mentioned diazotization of polynitrogencompounds is one of the methods that does not use a reac-tion between an azide and a nitrile.[36] Diazotization ofamidrazone 26 (Scheme 25) by N2O4, followed by the cleav-


age of a cyanoethyl group, can be offered as an example ofthe newer methods.[41] Alternatively, the reaction betweenthe corresponding N-(2-cyanoethyl)amide and TMSN3 un-der Mitsunobu conditions can be used to synthesize 1-(2-cyanoethyl)-5-substituted tetrazoles, which leads to 5-STformation upon cleavage of the cyanoethyl group.[41,94] Thecyanoethyl group can be replaced by another protectivegroup, such as benzyl.[95]

Scheme 25. Two methods for the preparation of 5-STs, either underMitsunobu conditions or by diazotization of amidrazone 26.

Straight conversions of carboxamides into 5-STs were re-ported in 1997. Triazidochlorosilane was presented as themain reactant, although it was actually a mixture of tetra-chlorosilane with sodium azide in a 1:3 ratio in acetonitrile(Scheme 26). The authors hypothesized that bis-silylatedimidoyl ether 27 was formed during the reaction, preventingthe conversion of amide to nitrile.[96]

Scheme 26. The suggested mechanism of straight conversions ofamides to 5-STs.

Finally, 5-STs can also be prepared by the substitutionof 1- or 2-protected tetrazoles on their C5 carbon atoms(Scheme 27). Cleavage of the protective groups in the 1- or2-positions then leads to 5-STs. The substitution was car-ried out conventionally by lithiation of the 1- or 2-protectedtetrazole followed by treatment with an electrophile.[97]


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

The lithiated tetrazole can also react with tributyltinchloride and then undergo a Stille coupling to form a disub-stituted tetrazole. Cleavage of the protective group in the 1-or 2-position yields a 5-ST (Scheme 28).[98]

Scheme 28. Preparation of 5-aryl-1H-tetrazoles by the Stille reac-tion.

Recently, the first organocatalyst for cycloadditions ofazides and nitriles was described. Addition of catalyticamounts of TMSCl to the reaction mixture when NMP wasused as the solvent led to the formation of 5-azido-1-methyl-3,4-dihydro-2H-pyrrolium azide (28, Scheme 29).[84]

Scheme 29. Formation of the 5-azido-1-methyl-3,4-dihydro-2H-pyrrolium azide (28) catalyst.

This Vilsmeier–Haack-type compound was successfullyused as a catalyst for reactions between various nitriles andsodium azide under microwave irradiation conditions(Scheme 30).

Scheme 30. First method for preparation of 5-STs by use of or-ganocatalysis.

In the first step (Scheme 31), the nitrile nitrogen attacksthe Lewis acidic carbon adjacent to the dihydropyrroliumnitrogen, which activates the nitrile for the approach of theazide anion. After the formation of the tetrazole, the cata-lyst is recovered through nucleophilic substitution with anazide anion.


Scheme 31. Mechanism of action of the organocatalyst 28.

The calculated barrier to the formation of the tetrazolering is lower than the barrier to the tin-catalyzed pathwayby more than 3 kcalmol–1.[84]

Functionalization of 5-Substituted Tetrazoles

5-STs are valuable intermediates in the synthesis of morecomplex compounds. During these reactions, tetrazole ringscan variously be preserved, transformed into other cycles,or completely eliminated. As a result of their π electron sys-tems and the presence of a lone pair on each nitrogen, 5-STs react with a wide range of electrophiles. 5-STs can beprotonated, functionalized, or coordinated. Substitution of5-STs is the most common and effective method for thepreparation of 1,5- and 2,5-disubstituted tetrazoles.[99]

There are many alternative ways to prepare 1,5-disubsti-tuted tetrazoles,[100] usually from the correspondingamides,[101] but for the preparation of 2,5-disubstitutedtetrazoles, substitution on the 5-ST is the only possiblemethod. As well as a wide range of alkyl substituents, aryl,acyl, silyl, vinyl, sulfonyl, phosphoryl, and other similargroups can be introduced onto the tetrazole ring.[102]

Reactions between 5-STs and electrophiles have beenwidely investigated, with special attention paid to theunderlying mechanisms. Substitutions of 5-STs are usuallycarried out in aqueous or alcoholic alkaline solutions, inaprotic organic solutions in the presence of a base, or underphase-transfer catalysis conditions. Depending on the reac-tion conditions, 5-STs can act as free tetrazolate anions, ionpairs, or hydrogen-bonded complexes with nitrogen bases.

The main problem of 5-ST substitution lies in its low andhardly influenceable regioselectivity. Alkylation of a tetraz-olate 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 32. Alkylation of 5-STs.

J. Roh, K. Vávrová, A. HrabálekMICROREVIEWfunctionalizations, such as arylation and acylation, proceedin the same manner.[99,102,103]

The ratio of isomers formed during the reaction dependson the reaction temperature and the properties of the sub-stituent at the 5-position, in particular with regard to sterichindrance. Higher reaction temperatures lead to increasedamounts of 1-isomers, whereas electron-accepting proper-ties of substituents at the 5-position increase the amountsof 2-isomers. Bulky substituents, either R or R� or theircombination, direct the substitution to the 2-position of thetetrazole ring.

The mechanism of these reactions involves a bimolecularprocess leading to the formation of an unstable intermedi-ate of type 29 (Scheme 33) in the first, rate-limiting step. Inthe second step, isomeric products are formed. The reactionrate is influenced by the properties of substituent R, by thereactivity of the electrophile R�X, and by the reaction me-dium. Formation of the isomeric products is controlled bythe properties of the reaction intermediate 29.[102]

Scheme 33. Bimolecular mechanism of a reaction between atetrazolate anion and an alkyl halide.

The effect of the solvent can be illustrated by the alkyl-ation of 5-phenyltetrazolate anion with dimethylsulfate inacetonitrile, in which increasing amounts of water in aceto-nitrile led to decreased reaction rates as a result of greatersolvation of the substrate by water molecules.[104]

Several substitutions on the tetrazole ring that displayhigh or nonstandard regioselectivity are outlined below.

Alkylation of 5-STs

Tritylation of a 5-ST is one of the most valuable substitu-tions on the tetrazole ring. The triphenylmethyl group is thefundamental protecting group of 5-STs and is used in thesynthesis of more complex structures such as Losartan andits analogues.[105,106] Alkylation of 5-STs with tri-phenylmethyl chloride (30, Scheme 34) resulted in the for-mation only of the 2-isomers (compounds 31), regardless ofthe substituents at the 5-position. Phase-transfer catalysis isoften used for these reactions.[107,108]

Scheme 34. Tritylation of 5-STs under phase-transfer catalysis con-ditions.


In view of the size of the triphenylmethyl moiety, it is notsurprising that tritylation of 5-STs proceeded only at the 2-position of the tetrazole ring. However, in the case of un-substituted tetrazole this reaction still displayed a high re-gioselectivity even without steric control of the process.[107]

Tritylation of a 5-ST or of unsubstituted tetrazole shouldprobably proceed through the SN1 mechanism. In this case,the limiting stage consists of triphenylmethyl chloride ion-ization to provide a triphenylmethyl cation, characterizedby high thermodynamic stability. At the same time, themore stable the carbocation is, the higher its selectivity to-ward one of the two competing nucleophilic centers willbe.[109] This is most likely the reason why these reactionsproceeded with high regioselectivity, even in the case of un-substituted tetrazole.[99]

In many cases, the existence of ionic pairs, associated togreater or lesser extents, in the reaction medium must beconsidered. However, the influence of these associates onthe reaction rates or regioselectivity is not still clearlyunderstood, although many examples have shown that theregioselectivity is controlled in the same manner as in thecase of the tetrazolate anion.[102]

In substitution reactions, 5-STs are often employed asammonium salts. It was found that in aprotic solvents, thesesalts existed in the form of hydrogen-bonded complexessuch as 32 (Figure 10).[110] These complexes had lower aro-maticities than highly aromatic tetrazolate anions due tothe hydrogen-bonded nitrogen in the 1-position of thetetrazole ring. It was argued that the existence of such acomplex would orient the electrophile towards doublebonding between N2 and N3 of the tetrazole ring, and notto the plane of the tetrazole, as in the case of the tetrazolateanion.

Figure 10. Structure of an ammonium salt of a 5-ST and a possibleattack by an electrophile.

These findings, along with the higher steric hindrance atthe N1 nitrogen atom, led to the hypothesis that ammoniumsalts of 5-STs facilitate the selective formation of 2,5-disub-stituted tetrazoles. In 1987, the reaction between the trieth-ylammonium salt of 5-phenyl-1H-tetrazole and methylvinyl ketone (33, Scheme 35) was found to lead predomi-nantly to the formation of the 2-isomer 34.[111] However,the reaction between a 5-ST with a more compact substitu-ent at the 5-position yielded the two isomers 34 and 35 incomparable amounts, putting the major role of the abovehypothesis into question.[102]

Another highly regioselective reaction producing strictlythe 2-isomer involved the alkylation of 5-STs with 5�-O-benzoyl-2,3�-anhydrothymidine (36, Scheme 36) in the pres-ence of triethylamine.[112] It was again demonstrated that


Scheme 35. Reactions between triethylammonium tetrazolates andmethyl vinyl ketone.

the triethylammonium salt played only a minor role in theregioselectivity, because the 2-isomer 37 was exclusivelyformed, even in reactions with sodium salts of 5-STs.[113]

The regioselectivity was again directed by steric aspects.

Scheme 36. Reactions between triethylammonium salts of 5-STsand 5�-O-benzoyl-2,3�-anhydrothymidine (36).

As previously mentioned, 2H-tautomers are thought tobe more stable than 1H-tautomers. In the gas phase, 2H-tautomers of 5-STs were 1.5–4 kcal mol–1 more thermody-namically stable than the 1H-forms.[8] In the crystallinestate, however, the majority of 5-STs exist in the 1H-formstabilized by hydrogen bonds to the neighboring molecules,which results in dimers and larger agglomerates. In mediaof high dielectric constant, 1H-tautomers are preferred dueto their higher polarities. A 15N NMR study of tetrazole ina dimethyl sulfoxide (DMSO) revealed that 90–99% of thetetrazole exists in the 1H-form.[114] However, there are sev-eral situations in which the relative proportions of the 2H-tautomers strongly increase. This is seen especially in sol-vents with lower polarities, in which the less polar 2H-formis better solvated and both the 1H- and 2H-forms are pre-dicted to exist in comparable amounts. The free energies oftautomerization of 1H-tetrazole in the gas phase (ε = 1)and in nonpolar (ε = 2) and polar media (ε = 40) are pre-dicted to be –7, 1, and 12 kJmol–1, respectively.[115] Thepresence of an electron-withdrawing substituent at the 5-position increases the polarity of the 2H-tautomer and alsothe relative proportion of the 2H-form in polar solvents. Inaddition, the presence of a bulky substituent on the tetra-zole carbon or in the ortho-position of the phenyl ring in a5-aryltetrazole can increase the relative proportion of the2H-form.[10]

The ratio of tetrazole tautomers in a reaction mixturecould significantly influence the regioselectivity of substitu-tion on the tetrazole ring, but only in the case of a non-ionized 5-ST species. The following two reactions can beshown as examples, although the true state of the tetrazole


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

Scheme 37. Reactions between 5-STs and O-tert-butyl-N,N�-dicy-clohexylisourea.

Although the incorporation of a bulky tert-butyl moietyinto the tetrazole ring by conventional alkylation led to theformation of the 2-isomers 39, in this case the relative pro-portions of 1-isomers 40 were substantially higher, indicat-ing an unusual reaction mechanism.[116]

Other highly regioselective reactions are acid-catalyzedadditions of 5-STs to vinyl ethers 41 (Scheme 38). Consist-ently with the Markovnikov rule, the 5-STs are directed tothe α-carbon atoms, predominantly yielding the 2-isomers42.[117]

Scheme 38. Reactions between 5-STs and vinyl ethers.

The highly regioselective methylation[118] and benz-ylation[119] of 5-phenyl-1H-tetrazole (43, Scheme 39) werecarried out with O-alkyl S-propargyl dithiocarbonates.

Scheme 39. Benzylation of 5-phenyl-1H-tetrazole with O-benzyl S-propargyl dithiocarbonate (44).

In the first step in each case, the tetrazole was deproton-ated by the alkylation agent, resulting in a tetrazolate anion,which was further alkylated. Surprisingly, the reactionspreferentially yielded 2-methyl-5-phenyl-2H-tetrazole andgave 2-benzyl-5-phenyl-2H-tetrazole (45, Scheme 40) exclu-sively.

This reaction mechanism showed a certain analogy withthe reactions between 5-STs and alcohols under Mitsunobuconditions. In the case of the Mitsunobu conditions, how-ever, lower yields of the 2-isomers were produced.[120]

A completely different mechanism of substitution oc-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-enes[122,123] in sulfuric acid produced only 2-alkylated prod-ucts. No 1-isomers were detected in the reaction mixtures,regardless of the substituents at the 5-position in the tetra-zole ring (Scheme 41).

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

One possible explanation for this is that although 5-STsare weak bases (e.g., pKBH+ = –1.8 for 5-methyl-1H-tetra-zole and pKBH+ = –9.3 for 5-nitro-1H-tetrazole),[9] they areprotonated in strong mineral acid solutions. The nitrogenat the 4-position is protonized preferentially, resulting in a1H,4H-tetrazolium cation of type 46 (Scheme 42).[124] Theelectrophilic attack of a carbocation, formed from alcoholor olefin, could be directed only to N2 or N3 of the tetraz-olium cation, leading exclusively to 2,5-disubstitutedtetrazoles (48).

Scheme 42. Mechanism of 5-ST alkylation in strongly acidic media.

The interaction of the two cations seems to be very un-usual, but NMDO quantum chemical calculations showeda high electron density localized on nitrogen atoms N2 andN3 of the 1H,4H-tetrazolium cation 46.[125] Moreover,decreasing the acidity of the reaction medium led to an in-creased yield of the 1-isomer, which is in agreement withthe proposed mechanism.[122]

The alkylation of 5-STs under microwave irradiation con-ditions has been the subject of only a few studies. Notably,no significant effects of microwave irradiation on the re-gioselectivity 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-tri-O-benzyl-4-O-triflyl-α-d-glucopyranoside (50) in boiling


acetone were performed. As previously discussed, micro-waves did not influence the regioselectivity, but did increasethe reaction rates.[126]

Scheme 43. Reactions between potassium salts of 5-STs and gluc-ose derivatives under microwave irradiation.

It should be mentioned that during the reaction between5-phenyl-1H-tetrazole and 2,3,4,6-tetra-O-acetyl-α-d-gluco-pyranosyl bromide (49), a mixture of both 1- and 2-isomerson the tetrazole ring was formed. This contrasts with thereaction 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-tetrazolecould approach a more accessible equatorial site, facilita-ting the formation of both isomers. In the second case, 5-phenyl-1H-tetrazole had to approach a sterically inconve-nient axial site, which allowed the formation only of the 2-isomer.

Scheme 44. Sterically controlled formation of a 2,5-disubstitutedtetrazole.


A study of the influence of microwave irradiation on 5-ST alkylation showed that the reactions proceeded with thesame regioselectivity regardless of the heating method orsolvent used (Scheme 45).[127,128]

Scheme 45. Alkylation of 5-benzyl-1H-tetrazole with 4-bromo-benzyl bromide.

Arylation of 5-STs

Arylations of 5-STs are described less frequently in theliterature than alkylations. The reaction between sodium 5-methylsulfanyl-1H-tetrazolate and 4-nitrofluorobenzene isone example, however. This reaction resulted in the forma-tion of both isomers – 5-methylsulfanyl-1-(4-nitrophenyl)-1H-tetrazole and 5-methylsulfanyl-2-(4-nitrophenyl)-2H-tetrazole – in a 1:3 ratio. 5-Aryltetrazoles did not react un-der these conditions.[129] On the other hand, in the case of2,4-dinitrofluorobenzene (52, Scheme 46) the reactions pro-ceeded under mild reaction conditions even with 5-aryl-tetrazoles.[130]

Scheme 46. Arylation of 5-STs with 2,4-dinitrofluorobenzene (52).

In 2002, regioselective arylations leading to the selectivepreparation of 5-substituted 2-aryltetrazoles 54 (Scheme 47)in high yields were reported. They involved treatment ofsalts of 5-STs with diaryliodonium salts 53 in tert-butylalcohol in the presence of palladium(0) and copper(II) cata-lysts.[131]

Scheme 47. Regioselective arylations of 5-STs with diaryliodoniumtetrafluoroborates 53.

Microwave-assisted arylations of 5-STs by treatment oftheir sodium salts with 4-nitrofluorobenzene in DMSOhave recently been described (Scheme 48). With 5-aryl-1H-


tetrazoles the reactions led regioselectively to the formationof 2,5-diaryl-2H-tetrazoles. In cases of more compact sub-stituents such as 5-alkyl-1H-tetrazoles, however, the reac-tions yielded mixtures of both regioisomers.[132]

Scheme 48. Arylations of 5-STs with 4-nitrofluorobenzene undermicrowave irradiation conditions.

Vinylation of 5-STs

The first direct vinylations of 5-STs, utilizing vinyl acet-ate, were published in 1986. The main drawbacks of thismethod lie in the need for mercury(II) catalysts and themoderate yields (Scheme 49).[133]

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

The analogous reaction of 5-phenyl-1H-tetrazole, in thepresence of palladium(0) catalysts, led to low yields (17%)with a high tendency to polymerization.[134]

We have recently described a one-pot, regioselectivemethod for the preparation of 5-substituted 2-vinyl-2H-tetrazoles 55 (Scheme 50) through a simple procedure with-out a metal catalyst or organocatalyst.

Scheme 50. Regioselective vinylations of 5-STs.

The mechanism of this reaction was also investigated. Inthe first step, triethylamine could react with 1,2-dibromo-ethane to form (2-bromoethyl)triethylammonium bromide(56, Scheme 51), which could react with the 5-ST to pro-duce compound 57. Under these reaction conditions, 57could undergo spontaneous elimination to produce a vinylderivative.[135]


Scheme 51. Mechanism of regioselective vinylation.

Conclusions

The chemistry of 5-STs has widely been explored sincethe discovery of these compounds. Currently, there are nu-merous approaches to the preparation of 5-STs in the litera-ture, and their number is still increasing because theseheterocycles can be found in many applications in variousfields of science, especially in medicinal chemistry as meta-bolically stable surrogates for the carboxylic acid group.Here, the major approaches to the preparation of 5-STs,based variously on acidic media/proton catalysis, Lewis ac-ids, and organometallic or organosilicon azides, have beensummarized, from the early procedures to the most recentones, including those under microwave irradiation condi-tions. Although the newer procedures have brought sub-stantial improvements on the previously known methods,the optimal protocol for the synthesis of 5-STs, whichshould combine high yields, versatility, low cost, and scal-ability, remains elusive.

The main problem with further 5-ST functionalizationlies in the poor regioselectivity of this process. It is commonfor both 1- and 2-isomers in various ratios to occur in thereaction mixture. The search for highly regioselective pro-cedures resulting in the formation of only one isomer, eithera 1,5- or 2,5-disubstituted tetrazole, is therefore currentlyan intensely investigated research topic. This is especiallytrue for 2,5-disubstituted tetrazoles, which can be preparedalmost solely by these methods. In this review examples ofalkylation, arylation, and vinylation of 5-STs with unusualregioselectivity have been presented, with special attentionpaid to the reaction mechanisms.

It is this group’s belief that tetrazoles, with their uniquephysicochemical properties, will find more applications invarious fields of chemistry in the near future, in particularin drug discovery.

Acknowledgments

This work was supported by the Charles University in Prague (Pro-ject UNCE 33/2012), by the Grant Agency of Charles University


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

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