Bioorganic & Medicinal Chemistry 10 (2002) 3379–3393
`
`Review
`
`5-Substituted-1H-tetrazoles as Carboxylic Acid Isosteres:
`Medicinal Chemistry and Synthetic Methods
`
`Medicinal Chemistry Department, Albany Molecular Research, Inc., PO Box 15098, Albany, NY 12212-5098, USA
`
`R. Jason Herr*
`
`Received 25 February 2002; accepted 20 May 2002
`
`Abstract—5-Substituted-1H-tetrazoles (RCN4H) are often used as metabolism-resistant isosteric replacements for carboxylic acids
`(RCO2H) in SAR-driven medicinal chemistry analogue syntheses. This review provides a brief summary of the medicinal chemistry
`of tetrazolic acids and highlights some examples of tetrazole-containing drug substances in the current literature. A survey of
`representative literature procedures for the preparation of 5-substituted-1H-tetrazoles, focusing on preparations from aryl and alkyl
`nitriles, is presented in sections by generalized synthetic methods.
`# 2002 Elsevier Science Ltd. All rights reserved.
`
`Contents
`
`Introduction .............................................................................................................................................................3379
`
`Chemical and Pharmacological Properties ...............................................................................................................3380
`
`Three Medicinal Chemistry Case Histories .............................................................................................................. 3382
`
`Early Synthetic Procedures Using Hydrazoic Acid ..................................................................................................3384
`
`Metal Salt Methods Using Sodium Azide................................................................................................................ 3385
`
`Tin- and Silicon-Mediated Methods ........................................................................................................................ 3387
`
`Other Methods ......................................................................................................................................................... 3388
`
`Conclusion................................................................................................................................................................ 3390
`
`Acknowledgements...................................................................................................................................................3390
`
`Introduction
`
`the medicinal
`This review provides a summary of
`chemistry aspects of 5-substituted-1H-tetrazoles, which
`have found common usage as an isosteric replacement
`
`*Corresponding author. E-mail: rjasonh@ albmolecular.com
`
`for the carboxylic acid moiety in recent years. A discus-
`sion of the structural features of the tetrazolyl group
`which make it a suitable substitution for a carboxyl
`functionality in drug design will be presented, as well as
`a description of some of the metabolic liabilities of this
`surrogate moiety. An examination of some prominent
`examples of tetrazolic acid-containing drug substances
`from the literature will also be presented, focusing on
`
`0968-0896/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
`P I I : S 0 9 6 8 - 0 8 9 6 ( 0 2 ) 0 0 2 3 9 - 0
`
`

`
`3380
`
`R. J. Herr / Bioorg. Med. Chem. 10 (2002) 3379–3393
`
`two aryl and one aliphatic compound. Practicing med-
`icinal chemists who may be interested in an evaluation
`of more comprehensive tabular surveys may also con-
`sult some of the review materials listed in this biblio-
`graphy.15 Some representative literature procedures for
`the preparation of 5-substituted-1H-tetrazoles from aryl
`and alkyl nitriles will be presented, as well as some
`highlights from the very recent literature which involve
`carbon–carbon bond formations with 1-substituted-
`5-lithiotetrazoles.
`
`Chemical and Pharmacological Properties
`
`It has been long held that 5-substituted-1H-tetrazoles
`(RCN4H) may serve as a non-classical isostere for the
`carboxylic acid moiety (RCO2H) in biologically active
`molecules.17 The term non-classical
`isosterism (used
`interchangeably with the term bioisosterism) refers to
`the concept in which functional groups that have similar
`physicochemical properties may be interchangeable,
`resulting in similar biological properties. Furthermore, a
`non-classical isostere may or may not have the same
`steric or electronic characteristics, nor even the number
`of atoms, as the substituent for which it is used as a
`replacement.5,79 Other simple carboxylic acid surro-
`gates include carboxamides, sulfonamides, acyl sulfo-
`namides, sulfamides, sulfonates and phosphates. More
`complicated isosteres include isoxazol-3-ols, hydroxy-2-
`methylpyran-4-ones, 4H-[1,2,4]oxadiazol-5-ones, 4H-
`[1,2,4]thiadiazol-5-ones and 2,4-dihydro-[1,2,4]triazol-3-
`ones, to name a few.
`
`5-Substituted tetrazoles that contain a free N–H bond
`are also frequently referred to as tetrazolic acids, and
`exist as a nearly 1:1 ratio of 1H- and 2H-tautomeric
`forms (Fig. 1, 1 and 2, respectively), although it is
`sometimes also convenient to describe them as imidoyl
`azides 3. It should be stated that tetrazolic acid struc-
`tures that appear throughout this article are assumed
`to be mixtures of both 1H- and 2H-tautomers. Pre-
`vious studies have shown that the two positional iso-
`mers 1 and 2 may be differentiated on the NMR
`timescale.10 Recently, Sadlej-Sosnowska has applied
`calculated natural bond orbital analysis to a series of
`5-substituted tetrazoles and determined that 2H-tau-
`tomers 2 are the more stable isomers, although they
`were found to have a larger degree of electron delo-
`calization than 1H tautomers 1.11 This consideration,
`in combination with steric factors, may have some
`bearing on the observation that N-alkylation of tetra-
`zolic acids often places the substituent on the N2
`position.12
`
`The free N–H bond of tetrazoles makes them acidic
`molecules, and not surprisingly it has been shown that
`both the aliphatic and aromatic heterocycles have pKa
`values that are similar to corresponding carboxylic acids
`(4.5–4.9 vs 4.2–4.4, respectively), due to the ability of
`the moiety to stabilize a negative charge by electron
`delocalization.6,1216 In general, tetrazolic acids exhibit
`physical characteristics similar to carboxylic acids and
`are strongly influenced by the effect of substituents at
`the C5-position.6 For example, many 5-aryl tetrazoles
`are highly soluble in water and are best crystallized from
`aqueous alcoholic solvents. However 5-aliphatic analo-
`gues, while still often soluble in water, are best crystal-
`lized from solvents such as ethyl acetate or toluene/
`pentane mixtures.6 The corresponding tetrazolate anio-
`nic species (RCN4Na or RCN4Li), which have a higher
`capacity for hydrogen bonding than the protic species,17
`are easily generated in hot alcohol or aqueous solutions
`and these intermediates are more reactive than the cor-
`responding neutral species toward a variety of electro-
`philes and alkylating agents.6 A recent review on the
`N-substitution of tetrazoles has appeared, which focuses
`on alkylation and electrophilic reactions at tetrazole
`nitrogen atoms.12 A recent review of transformations of
`heterocycles into tetrazoles, and conversions of tetra-
`zoles into other ring systems, also takes into considera-
`tion the physical properties of tetrazoles.18
`
`Like their carboxylic acid counterparts, tetrazoles are
`ionized at physiological pH (7.4), and both exhibit a
`planar structure. However, Hansch has shown that
`anionic tetrazoles are almost 10 times more lipophilic
`than the corresponding carboxylates,19 which is an
`important factor to bear in mind when designing a drug
`molecule to pass through cell membranes. Another
`important factor when considering a tetrazole as a
`replacement is the effect of delocalization of the nega-
`tive charge around the tetrazole ring. The distribution
`of charge over a greater molecular surface area may be
`favorable for a receptor–substrate interaction, or may
`complicate the contact, depending on the local charge
`density available at the interface.20 The larger size of the
`heterocycle (vs a carboxyl group) may also reduce the
`binding affinity at the active site, either by less favorable
`orientation of functional groups, or by steric hindering
`of an active conformational change of the receptor
`complex.21 An interesting comparison between the
`effective ‘length’ of carboxylic acid versus tetrazole
`pharmacophores was recently reported by Pellicciari
`and coworkers (Fig. 2).22 In a study designed to explore
`the SAR of propellane-derived analogues of l-glutamic
`acid as mGlu1 receptor agonists, the authors prepared the
`amino acids 4 and 5, which contained distal carboxylic
`
`Figure 1. Tetrazolic acids are bioisosteres of carboxylic acids.
`
`Figure 2. The size of tetrazole 5 extends the distance between the two
`acidic pharmacophores relative to the analogous dicarboxylic acid 4.
`
`LUPIN0069308
`
`Page 2
`
`

`
`R. J. Herr / Bioorg. Med. Chem. 10 (2002) 3379–3393
`
`3381
`
`acid and tetrazole units, respectively. Models suggested
`that the distance between the acidic functional groups
`were such that the 2H-tetrazole moiety increases the
`distance between the pharmacophores by about 1 A˚ . In
`vitro evaluation revealed that
`the tetrazole 5 was
`2.5-fold less potent versus 4, which was attributed to the
`increased distance between the two acidic sites, indicat-
`ing an unfavorable fit between two important synergis-
`tic positions.
`
`Hydrogen bonding capability of tetrazolic anions with
`receptor recognition sites has recently been shown to be
`the key interaction for enhanced binding affinity. The
`finding that tetrazole substrates may form two hydrogen
`bonds with peptide residues in a biological target site
`may well explain the stronger binding interaction. For
`example, mutagenesis studies have indicated that the
`tetrazolate moiety of several nonpeptide antagonists
`interact with a protonated lysine and a histidine in the
`active site of the angiotensin II receptor.23 A short time
`ago an X-ray crystal structure has revealed the ionic
`interaction of the N1 and N2 tetrazole nitrogens of an
`HIV-1 integrase inhibitor with two lysine residues
`within the enzyme active site.24 Lately it has been shown
`that a tetrazole can form two hydrogen bonds to an
`N,N’-disubstituted benzamidine, although with a con-
`siderably smaller association constant versus the corre-
`sponding carboxylate-amidine interaction.25
`
`In the design of drug molecules, one advantage of
`tetrazolic acids over carboxylic acids is that they are
`resistant
`to many biological metabolic degradation
`pathways. Some of the earliest findings showed that
`tetrazole-derived nicotinic acid analogues that were
`administered to dogs were excreted essentially unchan-
`ged over a 24-h period, whereas nicotinic acid itself was
`rapidly metabolized.26 As in these cases, it is often seen
`that the resistance of tetrazolic drug substances to
`metabolism may result in a longer duration of action
`versus carboxylic acids, although just as often a corre-
`sponding lack of potency is also observed.
`
`When drug substances enter the body, a host of pro-
`cesses take action in order to render these xenobiotics
`into more polar substrates for elimination. While both
`carboxylic acids and tetrazoles may act as ligand bind-
`ing functionality for CYP450-derived oxidative meta-
`bolic processes, tetrazoles may exhibit an advantage
`over carboxylic acids in terms of escaping most bio-
`transformations by Phase II (a.k.a. conjugation) reac-
`tion pathways. Benzoic acid substrates often undergo
`covalent bond formation with transferase enzymes such
`as Coenzyme-A to form activated acyl (thio)esters,
`which then undergo subsequent conjugation transfor-
`mations by a variety of pathways.8 However, the ana-
`logous activation process does not occur with aromatic
`or aliphatic tetrazoles,7 and so this moiety will not
`undergo glycine conjugation, incorporation into lipids,
`or degradation by b-oxidation.27
`
`On the other hand, tetrazolic acids have been shown to
`undergo conjugation reactions to form b-N-glucuronides,
`a metabolic fate that often befalls aliphatic carboxylic
`
`acids to form O-b-glucuronic acid conjugates (Fig. 3).28
`Glucuronidation of xenobiotics is an important path-
`way for the biological clearance of drug compounds,
`and involves the transfer of the glucuronic acid func-
`tionality of the cofactor uridine-50-diphospho-a-d-glu-
`curonic acid (UDPGA) to the nucleophilic atom of a
`substrate (e.g., carboxylate or tetrazolic anion). This
`transformation is mediated by an isoform of the enzyme
`UDP-glucuronosyltransferase (UDPGT), and the resul-
`tant inversion of the a-stereochemistry at the pyranose
`anomeric center by a nucleophile results in a b-product.8
`Both tetrazole tautomers may serve as substrates for
`N-glucuronidation, and indeed both structural varia-
`tions are known. In 1980, Nohara identified the first
`tetrazole N1 glucuronide 8 in the urine stream of several
`animals orally dosed with a chromone-derived tetra-
`zole,29 which was identified as the exclusive isomer by
`synthesis and NMR studies. Several more recent studies
`have shown that the N2-product 7 is the preferred
`metabolite of biphenyltetrazole substrates, as deter-
`mined by NMR and X-ray crystal structures,30,31 and
`the N2-glucuronide of an aliphatic drug candidate has
`also recently been reported.32 Some authors have
`attributed the long half-life of a number of orally
`administered tetrazolic acid drugs to enterohepatic
`recirculation mechanisms.31 While N-glucuronide for-
`mation and subsequent biliary excretion of a tetrazolic
`acid may remove the drug from circulation, reabsorp-
`tion of the metabolite may result in hydrolysis by
`microflora in the intestinal mucosa, thereby allowing
`additional assimilation of the parent drug in a second
`pass. Indeed similar reprocessing phenomena have long
`been implicated as a mechanism for unexpectedly long
`drug half-lives of other drug substances.
`
`Tetrazole compounds which also contain an additional
`basic functionality in the molecule may exist as zwitter-
`ions, which can result in poor absorption properties for
`a potential drug candidate. In some cases a prodrug
`approach has been developed, similar to the strategy
`developed for carboxylic acids to enhance oral bio-
`availability.33 Derivatization of polar molecules into
`compounds in which the acidic tetrazole N–H bond has
`been masked (protected by a moiety that can be
`removed under physiological conditions) results in a
`more lipophilic molecule of neutral charge that can
`exhibit greater biomembrane transport ability. This
`tactic has been used to improve the physicochemical
`
`Figure 3. N-Glucuronidation is the major metabolic pathway for
`physiological clearance of aryl tetrazolic acids.
`
`LUPIN0069309
`
`Page 3
`
`

`
`3382
`
`R. J. Herr / Bioorg. Med. Chem. 10 (2002) 3379–3393
`
`Figure 4. A tetrazole prodrug approach to mask BMS-183920 (9) as
`10 increased bioavailability (% F) by better than 3-fold.
`
`properties of the angiotensin II receptor antagonist
`BMS-183920 (diacidic structure 9) as the prodrug 10
`(Fig. 4).34 By N-‘bioreversible’ protection of the poorly
`absorbed tetrazole with a pivaloylisobutyl moiety, the
`bioavailability in rats was increased from 11% for 9 to
`37% for 10. Interestingly, prodrug protection of the
`carboxylic acid instead of the tetrazole moiety (11) did
`not increase oral availability to better than 26%.
`
`A word of caution: the pharmacological effects of bio-
`isosteric replacement of carboxylates with tetrazoles in a
`potential drug candidate are not necessarily predictable,
`as the wealth of medicinal chemistry literature points
`out. In fact, diverse examples from the literature show
`that
`the pharmacological effects can be enhanced,
`reduced or eliminated completely when compared to
`carboxylic acid analogues. The next section will show-
`case a few examples in which the application of the
`surrogate strategy has advanced research toward both
`aromatic and aliphatic tetrazole-containing commercial
`drugs and drug contenders.
`
`Before moving onto some case histories, it is also worth
`noting that an emerging field of research has begun to
`accumulate evidence that 1,5-disubstituted tetrazoles are
`effective bioisosteres for cis-amide bonds in peptidomi-
`metics (Fig. 5). Marshall and Zabrocki have shown that
`peptides which contain a 1,5-disubstituted tetrazole
`unit, as in 13, may be effective conformational mimics
`for the corresponding peptides that prefer to adopt a
`cis-amide bond conformation, or which need to pre-
`organize the amide bonds to act as enzyme substrates,
`as in 12.35,36 A synthetic probe of this type can be
`important when investigating the role of peptide bond
`cis–trans
`isomerism in the geometry of molecular
`recognition. Through synthesis and conformational
`study of an analogue of bradykinin, it was shown that
`peptides containing a tetrazole in place of an amide
`bond were able to adopt most of the conformations
`available to the parent compound.35,36 This applies to
`peptides that contain a free N–H bond, as well as for
`
`Figure 5. 1,5-Disubstituted tetrazoles as cis-amide surrogates.
`
`N-methyl amino acids. In a recent report, Rodziewicz-
`Motowidlo and coworkers conducted a two-dimen-
`sional NMR study of the conformational constraint
`imparted to scyliorhinin I when a 1,5-tetrazole ring was
`introduced between positions 7 and 8.37 Much more can
`be said of this interesting field of study, and readers
`should refer to the citations listed here.
`
`Three Medicinal Chemistry Case Histories
`
`The following examples were taken from the literature
`to represent the various classes of aryl and aliphatic
`tetrazole-containing analogues
`that
`emerged from
`research efforts. Often clinically advanced or commer-
`cial tetrazolic acid drugs were identified as isosteres
`prepared to investigate the binding energy of carboxylic
`acid lead compounds. In addition to these examples,
`several reviews have appeared which evaluate tetrazolic
`acid by disease state in tabular formats.15 Readers are
`also encouraged to peruse publications of other current
`research efforts38 as well as to review some lead articles
`for the preparation of tetrazole analogues of amino
`acids and peptides.39
`
`A comprehensive search of the patent literature shows
`that the majority of tetrazolic acid-based drug sub-
`stances are aryl tetrazoles. In fact, a great part of these
`structures contain the biphenyl tetrazole motif, many of
`which are structural derivations of DuPont’s non-pep-
`tidic
`selective angiotensin II
`receptor antagonist
`Losartan (16, Fig. 6), a drug launched in 1994 to treat
`
`Figure 6. Comparison of Losartan (16) data with early 2- and 3-car-
`boxybiphenyl analogue leads.
`
`LUPIN0069310
`
`Page 4
`
`

`
`3383
`
`R. J. Herr / Bioorg. Med. Chem. 10 (2002) 3379–3393
`hypertension.4042 While investigating a new series of
`analogues derived from a biphenyl scaffold,
`it was
`found that compound isomers 14 and 15 were both
`active by intravenous injection into renal hypertensive
`rats. Unfortunately, the effect was minimized upon oral
`administration. In an effort by the research team to find
`compounds of greater potency and bioavailability, a
`series of carboxylic acid isosteres were prepared. Inter-
`estingly, no carboxamide or sulfonamide compounds
`were found to improve the oral activity, but when
`tetrazole was introduced at the C2-position, a dramatic
`enhancement in binding affinity and oral potency were
`observed. The authors felt that the increase in receptor
`binding was due to the greater ability of the heterocycle
`to distribute a negative charge at physiological pH,
`allowing for better interaction (vs carboxylate) with the
`positive charge at the receptor.23a This early hypothesis
`has more recently been borne out by conformational
`analysis utilizing theoretical calculations and NMR
`spectroscopy.43 As well, the longer spatial distance of
`the N–H bond into the receptor may be the optimal
`depth for receptor binding. Better oral bioavailability
`(33% for Losartan) may be due to the greater lipophi-
`licity of tetrazole 16 versus 14 and 15, a property which
`can be evaluated by a comparison of log P values. The
`major metabolite of Losartan has been identified as the
`N2-glucuronide,30 which has also been implicated in
`the long duration of action, perhaps by an enter-
`ohepatic reprocessing mechanism.31 Since the intro-
`duction of Losartan to the literature, a great number
`of papers have been published regarding potential
`analogues of Losartan (16), as well as a variety of
`other biphenyl
`tetrazolic acid structures for other
`indications.23a,44
`
`Figure 7. The role of l-692,429 (19) as a mid-stream success early in
`the development of MK-0677 (24).
`
`An interesting tetrazole semi-success story can be told
`about Merck & Company’s non-peptidyl growth hor-
`mone secretagogue l-692,429 (19, Fig. 7). In 1988, a
`program was started to identify small molecule pepti-
`domimetics of the growth hormone releasing hexapeptide
`His-d-Trp-Ala-Trp-d-Phe-Lys-NH2
`(GHRP-6),
`from
`which the biphenyltetrazole 17 was designated as a lead
`the 20-carboxylic acid
`compound.45 Replacement of
`group with a series of isosteric replacements singled out
`primary carboxamide 18 and tetrazole 19 (l-692,429),
`which provided an increased in vitro potency from the
`micromolar range to low nanomolar concentrations. On
`the other hand, acidic isosteres such as sulfonamides
`and acyl sulfonamides were found to be only micro-
`molar in potency.46 At this point l-692,429 (19) was
`nominated for participation in clinical trial studies, and
`has progressed as far as Phase I.47 (Note: ED50 is
`defined as the effective dose at which a 50% maximal
`growth hormone response was achieved in vitro. EC50 is
`defined as the effective concentration at which 50% of
`maximal growth hormone release was induced.) A short
`time later, SAR studies conducted by chemists at Novo-
`Nordisk determined that other heterocycles without an
`acidic functionality were even more potent than 19 (e.g.,
`21, 22 and N-methyltetrazole 20), leading the research-
`ers to conclude that the relevant ionic interaction with
`the receptor involved a hydrogen bond acceptor func-
`tionality on the drug molecule.48 This makes intuitive
`
`sense that tetrazole 19, being slightly less acidic than
`carboxylic functionality of 17, would conversely be a
`better hydrogen bond acceptor. It was around this time
`that Merck researchers became aware of some serious
`problems with the oral bioavailability of candidate 19,
`which was determined to be about 2% as studied in
`beagle dogs.49 The acidic tetrazolic functionality in pre-
`sence of a basic primary amine causes 19 to be zwitter-
`ionic in nature, resulting in poor oral absorption
`properties that contribute to low oral efficacy. Based on
`this complicating factor, ongoing work to develop
`appropriate functional group compatibility had con-
`currently identified the N-methylurea candidate 23
`(l-739,943). This neutral compound was even more
`potent at 1 nM (GHRP-6 has a potency of 10 nM) and
`was found to have a greatly enhanced oral bioavail-
`ability of 24% (hexapeptide GHPR-6 has an availability
`by oral dose at less than 1%).50 Ultimately, however,
`Merck has progressed the candidate MK-0677 (24;
`l-163,191; Ibutamoren Mesylate) into Phase II clinical
`studies for the treatment of growth hormone defi-
`ciency.51 Based on the ‘privileged structure’ approach52
`to discover leads for G-protein coupled receptors, the
`researchers grafted the spiroindane moiety onto the
`peptide portion of 19, resulting in the potent growth
`hormone secretagogue 24. Oral dosing with MK-0677
`was shown to elevate levels of growth hormone in dogs
`as low as 0.125 mg/kg, and its oral bioavailability was
`
`LUPIN0069311
`
`Page 5
`
`

`
`3384
`
`R. J. Herr / Bioorg. Med. Chem. 10 (2002) 3379–3393
`
`estimated to be greater than 60%. Merck researchers
`attributed the excellent oral absorption of 24 to its
`lipophilicity (log P=3.0 for 24 vs 2.5 for 19) in combi-
`nation with the good aqueous solubility of the mesylate
`salt.53
`
`The next example will serve to showcase a representa-
`tive pharmaceutical substance that contains an aliphatic
`tetrazolic acid. In the early 1970s, the pharmaceutical
`division of Fisons Limited published the discovery of
`FPL 55712 (25, Fig. 8),54 a prototypical selective cystei-
`nyl leukotriene D4 (LTD4) receptor antagonist. While
`the short half-life and poor bioavailability of 25 kept it
`from reaching clinical trials, it nevertheless set the stage
`for the ensuing flood of research efforts focused on the
`development of peptidomimetic antagonists as anti-
`asthmatic agents.55 In the late 1980s, the then-ICI
`Pharmaceuticals group proposed the similarity between
`the endogenous ligand LTD4 (26) and FPL 55712 was
`such that the chromone acid portion of 25 corresponded
`to the glycine terminus of 26 (rather than the aliphatic
`C1 carboxyl group),56 an assertion which has more
`recently been confirmed experimentally.57 This led to
`the development of several leukotriene antagonist ana-
`logues in which the hydroxyacetophenone moiety was
`tethered to terminal carboxylic acids,
`including 27,
`which exhibited a much longer duration of action in
`vivo versus 25. Researchers at the Lilly Research Labs
`synthesized 27 and had come to the same finding inde-
`pendently,58 and took their SAR one step further to
`examine carboxylic isosteres, eventually identifying tet-
`razole l-171883 (28) as a potent antagonist in vitro and
`with excellent oral activity in vivo with guinea pigs.59
`The authors attributed the better activity of 28 in vitro
`(30 times more potent than 27) to the better ability of
`the delocalized tetrazolic anion to interact with the
`arginine residue in the LTD4 active site (vs the carbox-
`ylate). It is also interesting to compare the lipophilicities
`of the isosteric analogues, in which the log P of tetrazole
`28 (2.8) is higher than the corresponding carboxylic acid
`27 (2.4). This may have some bearing when keeping in
`mind that the pharmacophoric models built over the
`last decade have reflected both the importance of the
`
`acidic component of LTD4 antagonists as well as the
`need for an overall lipophilic character.57,60 Ultimately
`l-171883 (28) was chosen for clinical evaluation, and
`under the drug name Tomelukast it is currently in Phase
`III studies as an anti-asthmatic.61,62 It is worth men-
`tioning that the tetrazolic replacement approach has
`also been successful in at least one other LTD4 antago-
`nist research effort.63
`
`The text throughout the rest of this review will attempt
`to provide a representative survey of the most often-
`used literature procedures for the preparation of 5-sub-
`stituted-1H-tetrazoles, focusing on preparations of tet-
`razolic acids from aryl and alkyl nitriles. A few other
`synthetic methods will be presented,
`including some
`very recent procedures involving carbon–carbon bond
`formations with 1-substituted 5-lithiotetrazoles, which
`show useful alternatives to the standard cycloaddition
`chemistry protocols.
`
`Early Synthetic Procedures Using Hydrazoic Acid
`
`The earliest published methods for the preparation of
`5-substituted tetrazoles were reactions of nitriles with
`azides.64 In fact, the first method to appear in the lit-
`erature was the reaction of hydrazoic acid (HN3) with
`organic cyanides in 1932 (Scheme 1).65 This process is
`generally thought to occur by a concerted 1,3-dipolar
`cycloaddition mechanism, in which nitrile 29 acts as the
`dipolarophile toward the azide, which serves as the
`1,3-dipolar species (which may or may not be hydrogen-
`bonded with the amine).66 Cycloaddition through 30
`leads to the tautomeric tetrazolium anions 31 and 32,
`which can simply be drawn as the delocalized resonance
`form 33. Protonation of 33 upon workup provides the
`tetrazolic acid 1. It should be mentioned that some evi-
`dence to support a two-step mechanism has also been
`reported.67
`
`A great disadvantage to this procedure is that hydrazoic
`acid in organic solution is toxic and extremely explosive.
`Not many organic solvents are stable at the high tem-
`peratures that are necessary for this cycloaddition
`(sometimes as high as 130 C), and for this reason DMF
`is most commonly used for this purpose.4,6,66
`
`Figure 8. The tetrazole moiety of Tomelukast (28) mimics the cystein-
`ylglycine terminus of growth hormone LTD4 (26).
`
`Scheme 1.
`
`LUPIN0069312
`
`Page 6
`
`

`
`R. J. Herr / Bioorg. Med. Chem. 10 (2002) 3379–3393
`
`3385
`
`Scheme 2.
`
`Metal Salt Methods Using Sodium Azide
`
`Scheme 4.
`
`Although many groups reported improved syntheses of
`5-substituted tetrazolic acids from nitriles, it was really
`the work of Robert Lofquist that led to a practical
`procedure by in situ generation of hydrazoic acid from
`ammonium chloride and sodium azide (Scheme 2).68 A
`process chemistry approach to the problem led these US
`Navy chemists to find that DMF and DMSO were the
`best solvents for the cyclization reaction. A host of
`other amine
`salts were
`investigated,
`leading the
`researchers to conclude that reaction temperatures
`lower than 130 C at atmospheric pressure could be
`achieved when hydrazoic acid was generated from an
`ammonium azide. This ‘gentle’ acidic media procedure
`was more efficient than the older methods in which
`hydrazoic acid was used directly, and where high-pres-
`sure equipment or heating from four to seven days to
`reach completion were common.68
`
`More recently, Bernstein and Vacek showed that a
`combination of sodium azide and triethylamine hydro-
`chloride is useful when N-methylpyrrolidinone is used
`as a solvent.69 Use of this higher-boiling solvent allowed
`the cycloaddition reaction for one particular substrate
`to be complete in 76% isolated yield after 3 h at 150 C.
`
`This is in comparison to the use of ammonium chloride
`in DMF, which provided only a 35% yield of the same
`product after heating at 125 C for 96 h. A very recent
`paper has shown that aqueous micellar media may also
`serve as a method for preparation of aryl tetrazoles.70
`
`Recent examples of the ammonium azide method for
`the preparation of drug targets include the synthesis of
`38 and 41, which are analogues of AstraZeneca’s
`Tomudex (39, Scheme 3).71 These compounds were
`prepared in a program effort to identify peptide-based
`inhibitors of thymidylate synthase, and include replace-
`ment of the g-carboxylic acid of the l-glutamate portion
`of 39 by a tetrazolic acid moiety (Scheme 3).71 In this
`case, the conditions described by Grzonka and co-
`workers for tetrazole formation from nitrile 36 (90 C in
`DMF for 16 h)39c were responsible for the complete
`racemization of the a-amino acid stereochemistry lead-
`ing to a mixture of enantiomers 37. In the end, the bio-
`logical activity of this homologue was not interesting
`enough to justify a chiral resynthesis of 38, or even to
`optimize the reaction yield. The l-glutamate-derived
`(S)-tetrazole analogue 40 was prepared by a similar
`method, but in this case the conditions used for tetra-
`zole formation (reflux in THF for 72 h) did not racemize
`the amino acid stereochemistry. It is interesting to note
`that the enantiopure analogue ZD9331 (41), prepared
`from (S)-amino acid 40, was found to have increased
`potency versus Tomudex (39) and is currently undergoing
`Phase II clinical development trials. The epimeric ana-
`logue of 41, prepared from the antipode of 40, was
`found to have diminished activity versus 39 and 41.
`
`Another example of the metal azide/ammonium salt
`combination method was published by chemists at the
`Dr. Karl Thomae GmbH in Germany. This synthesis
`required heating of the aryl nitrile 42 in DMF at 140 C
`to provide synthetically useful amounts of the benzimi-
`dazole-based Losartan derivative 43 (Scheme 4).72
`
`A recent paper by Jursic and LeBlanc has shown that the
`addition of a phase transfer catalyst improves the synthesis
`of 5-benzylthiotetrazoles 45 from benzyl thiocyanates 44
`(Scheme 5).73 In this case, hexadecyltrimethylammonium
`
`Scheme 3.
`
`Scheme 5.
`
`LUPIN0069313
`
`Page 7
`
`

`
`3386
`
`R. J. Herr / Bioorg. Med. Chem. 10 (2002) 3379–3393
`
`Scheme 6.
`
`Scheme 8.
`
`bromide was found to be the most useful catalyst. The
`authors point out that 5-alkylthio- and 5-arylthiotetra-
`zoles are significantly better activators for RNA and
`DNA synthesis than the corresponding 5-aryltetrazoles,
`presumably due to the fact that the alkylsulfur moiety
`increases the acidity of the tetrazole proton.74
`
`Alterman and Hallberg recently disclosed a report in
`which aryl and vinyl tetrazoles were prepared from
`nitriles using ammonium azide conditions in which
`microwaves were used as the energy source (Scheme
`6).75 A microwave-assisted palladium-catalyzed cross-
`coupling reaction between several aryl bromides and an
`organozinc reagent provided a series of aryl nitriles.
`Cycloaddition using sodium azide and ammonium
`chloride smoothly converted all of the aryl nitriles to the
`correspon