Orthoesters in heterocycle synthesis

Orthoesters have occupied an important niche in heterocycle synthesis since the mid-20 th century. They have found wide application in the synthesis of five-and six-membered nitrogen, oxygen-and sulfur-containing rings from precursors having an acyclic 1,3-or 1,4-arrangement of heteroatoms. Since orthoesters incorporate three geminal alkoxy groups on the central carbon, all of which can be lost, the central carbon of the orthoester [RC(OR) 3 ] is a synthetic equivalent for "RC 3+ " and can be introduced between the two heteroatoms by means of neutral or acid-catalyzed condensative processes. The current review surveys the literature on the use of orthoesters in heterocycle synthesis and presents numerous examples with mechanisms.


Introduction
There are many reasons for undertaking studies of synthetic processes involving new reagents.In some cases, a particular target is sought for medicinal evaluation or to prove a natural occurring structure.Alternatively, investigators may wish to develop a new methodology or strategy, or to improve the efficiency, purity or product yield in generating a valuable ring system.Other researchers are interested in testing the scope of a particular reaction or expanding the field by assembling new ring systems with varied substitution patterns which may find applications at a later time.Finally, there are also those chemists whose goal is to probe the mechanistic details of newly discovered transformations.
A number of orthoesters are commercially available, and these are the primary focus in the studies recorded to date.There are several reports detailing syntheses of these simple compounds. 1,2The key to future breakthroughs, however, will involve preparing derivatives bearing more functionality on the R group bound to the central carbon.This will permit further elaboration of the structure following installation of the reagent into a heterocyclic framework.
This review seeks to outline some of the uses of orthoesters in heterocycle synthesis.It is arranged according to the size of the ring being formed and the number of heteroatoms within that ring.Beyond this basic outline, each section begins with monocyclic systems and then proceeds to fused rings and finally to complex systems with multiple rings, and occasionally, rearranged products.The review focuses predominantly on reactions where the orthoester is directly installed into the heterocycle.Sequences where an orthoester is used to scavenge water or to prepare an isolable intermediate that is later converted to a heterocycle are generally not included.Most of the studies surveyed targeted nitrogen heterocycles, with some also containing oxygen and sulfur.Finally, several recent efforts have endeavored to prepare heterocycles incorporating only oxygen in the ring, and these are included at the end.
Phenylhydrazides 1 were prepared from (L)-α-amino acid ester hydrochlorides by treatment with phenylhydrazine in the presence of triethylamine.Heterocyclization with an orthoester (2 equiv) and acetic acid (AcOH, 0.1 equiv) under neat conditions at 80 o C led, via imino ether 2, to the chiral products 3 in 52-81% yields.Interestingly, in a system which could close to a five-or six-membered ring (3 or 4, respectively), the smaller ring was formed by addition of the less basic nitrogen to the carbon of the intermediate imino ether.Compound 3 closely resembles structures that have exhibited significant fungicidal properties.Scheme 1. Synthesis of 3,5-dihydro-4H-imidazol-4-ones from phenylhydrazide.
A family of drug candidates has also been designed to evaluate the interaction of (4RS,5SR)-4,5-bis(4hydroxyphenyl)-2-imidazolines with estrogen receptor models to identify potential drugs to treat breast cancer.In this project, Gust and co-workers prepared a series of racemic 4,5-diarylimidazolines. 4 The preparation of one of the more robust compounds is illustrated in Scheme 2. Treatment of meso diamine 5 with triethyl orthoformate afforded the imidazoline 6, also meso due to the delocalized π-bond between the nitrogen atoms.N-alkylation of 6 [1.n-BuLi, tetrahydrofuran (THF)-hexane; 2. EtI, -78 o C  20 o C], followed by ether cleavage [BBr 3 , dichloromethane (DCM), -60 o C  20 o C] gave the target compound 7 as a pair of enantiomers in 40% overall yield.Scheme 2. Synthesis of 4,5-diarylimidazolines from meso diamine 5.
Kim and co-workers 5 offered an efficient conversion of aroylnitromethanes 8 to 2,5-diaryloxazoles 9 by in situ reduction of the nitro function in the presence of trimethyl orthobenzoate (Scheme 3).The reduction was carried out using indium powder and AcOH in acetonitrile, and the yields were 45-75%.Lower recoveries and less pure products were noted when the aryl ring of the substrate was substituted by a halogen or an acid- A later paper by Bunce and co-workers 10 employed ammonium chloride as a catalyst in boiling ethanol (EtOH) to convert benzoic hydrazides 18 to 1,3,4-oxadiazoles 22.Most of these reactions were complete within 1 h, except for those employing triethyl orthobenzoate where 2-10 h were required.This procedure was found to require considerably less of the orthoester (1.1-1.2 equiv) compared with earlier methods.Yields were generally >75% except for substrates bearing strongly electron-withdrawing substituents.A proposed mechanism for this process is illustrated in Scheme 6.Initial loss of EtOH from the orthoester, and attack by hydrazide 18 on the stabilized carbocation, would give 19.Protonation of 19, followed by loss of a second molecule of EtOH, would yield 20. Cyclization to 21 and elimination of the third molecule of EtOH would then afford oxadiazole 22. Scheme 6. Synthesis of 1,3,4-oxadiazoles from benzoic hydrazides.
A fourth paper reported a synthesis of bis(1,3,4-oxadiazol-2-yl)phenylmethyl sulfides 32 from 1,1'diphenylthiodiacetic acid dihydrazide (31) and several triethyl orthoesters. 14This reaction led not only to the desired sulfide-linked heterocycles, but also resulted in cleavage of the carbon-sulfur bond in the substrate with formation of oxadiazoles 33 and 34.The results for two of the orthoesters are shown in Scheme 9.

Monocyclic: four heteroatoms
Two studies have enlisted orthoesters for the synthesis of tetrazoles.Tetrazoles are potentially valuable as they can be used in drugs as isosteres of the carboxylic acid function.Isosteres are molecular fragments with similar shapes and electronic properties to other groups that are sometimes introduced into potential drug molecules to modify solubility, toxicity or metabolism.The classic synthesis of these systems requires treatment of nitriles with azide salts in polar aprotic solvents. 17This strategy involves a concerted 1,3-dipolar addition to the nitrile, while orthoester-based syntheses proceed by stepwise mechanisms.Aridoss and Laali 18 contributed a tetrazole synthesis involving reaction of an amine 41 with trimethylsilyl azide (42) and triethyl orthoformate catalyzed by a Brønsted acid ionic liquid (Scheme 12).In this account, the amines 41 were generally aniline derivatives, but benzylamine and 2-furylamine were also examined.Best results were obtained using the orthoester as the solvent with a catalytic amount of 1-methyl-3-(3-sulfopropyl)-1H-imidazol-3-ium triflate at 50-60 o C for 0.5-3 h.Yields were in the range of 77-95% and did not appear to be sensitive to the electronic nature of substituents on the aromatic rings.Several mechanistic pathways were evaluated and discussed based on density functional theory calculated energies of the possible intermediates.
Scheme 12. Synthesis of tetrazoles promoted by a Brønsted acid ionic liquid.
A second study evaluated this same transformation promoted by AcOH. 19The optimum ratio of RNH 2 : HC(OEt) 3 : NaN 3 : AcOH was 1:3:1.1:8 at 80-100 o C for 2-3 h.Yields were generally greater than 70% for a wide selection of aliphatic and aromatic amines.The proposed mechanism involved condensation of the aliphatic or aromatic primary amine and triethyl orthoformate to generate imino ether 44, or amidine 45, followed by azide addition-elimination to give 46, which cyclized to tetrazole 47 (Scheme 13).

Fused rings: two heteroatoms
An intense effort has been devoted to optimizing protocols for the synthesis of benzimidazoles, benzoxazoles and benzothiazines using orthoesters.Classical routes required dehydrative ring closure of 2-amino-, 2hydroxy-or 2-mercaptoanilides under relatively harsh conditions. 20More recently, numerous approaches have employed orthoesters as a source of "RC 3+ " to position a carbon between two aryl-bound heteroatoms to form the benzo-fused azole rings.Today, these three scaffolds are considered priviledged ring systems as they are core structures found in many drugs.Over the past 10 years, many different strategies and catalysts have been evaluated and the major contributions are highlighted below.
One of the first reports on the use orthoesters to generate heterocycles was a serendipitous synthesis of benzothiazoles and benzoxazoles that appeared in 1961. 21In a study aimed at preparing 2-(N- alkylamino)benzenethiols from 2-aminobenzenethiol and ethyl orthoformate, Jenkins and co-workers instead isolated benzothiazole.The method was extended to the synthesis of benzoxazoles as well, with yields for both systems in the 75-85% range.A later study by Kaboudin et al. applied this strategy to the preparation of benzimidazoles by simple heating of o-phenylenediamine derivatives with orthoesters to afford the target heterocycles in 50-85%. 22lthough initial investigations utilized no catalyst, subsequent studies focused on the use of different agents to promote the reaction and methods that could be exploited to prepare all three of these benzo-fused heterocycles from commercial orthoesters.Aridoss and Laali 18 explored the use of Brønsted acid ionic liquids as catalyts under neat conditions with sonication.Villemin and co-workers 23 utilized montmorillonite KSF clay in refluxing toluene.The Bunce group 24  A project in the Jeffries-El group examined functionalized orthesters in a novel preparation of 2,6disubstituted benzobisthiazoles as potential organic semiconductors. 25The synthesis involved treatment of 2,5-diamino-1,4-benzenedithiol dihydrochloride (53)    Beyond this, 1,3-dibromo-5,5-dimethylhydantoin 26 and mildly acidic solvents, such as 1,1,1,3,3,3hexafluoro-2-propanol, 27 were shown to accelerate the formation of benzimidazoles while Brønsted acids, such as silica-supported tin exchanged silicotungstic acid 28 and silica sulfuric acid, 29 were employed to prepare benzoxazoles.Finally, Marko and co-workers 30 reported the use of boron trifluoride etherate (BF 3 •OEt 2 ) in DCM at 23 o C to promote reactions of complex orthoesters which permitted some interesting post-cyclization transformations such as those shown in Scheme 16.All three benzazoles were prepared and all of the yields were high.Two of these processes are outlined for the conversion of 56 to 59 and 62.This publication also cited references to milder variants of the Pinner reaction to prepare the required orthoesters.Two additional studies have appeared wherein the fused heterocycle was generated from an ophenylenediamine or 2-aminophenol created in situ by reduction of the corresponding nitro compound (Scheme 18).The Shen team catalytically reduced 2-nitroanilines 66 in the presence of an orthoester to prepare 1,2-disubstituted benzimidazoles 67. 32These authors reported 36 examples with yields in the 45-95% range.In this sequence, chloroaromatic substrates failed to react cleanly, and this likely resulted from competitive dehalogenation under catalytic reduction with Pd/C.Kim and co-workers used dissolving metal conditions to reduce 2-nitrophenols 68 with indium metal and AcOH in benzene to produce 2-substituted Cl benzoxazoles 69. 5 This protocol permitted the preparation of 30 derivatives in 50-98% yields and aryl-bound halogens presented no problems.
Scheme 18. Domino syntheses of benzimidazoles and benzoxazoles initiated by reduction of nitro precursors.
Chorvat and colleagues prepared and studied a series of 2,6,8,9-tetrasubstituted purines as corticotropin-releasing factor binding agents in an effort to enhance immune response to various types of stress. 33S N Ar conversion of the symmetrical dichloroaminopyrimidine 70 to the arylamino-substituted derivative 71, followed by heating with a series of orthoesters, afforded imidazopyrimidine 72.Intermediate 72 was then reacted with a series of amines to produce the target compounds 73 (Scheme 19).Several of these purines exhibited good pharmaceutical properties.Scheme 19.Synthesis of 2,6,8,9-tetrasubstituted purines.
A team led by Smith adapted the synthesis of similarly substituted purines to a solid-phase protocol. 34tarting with commercial ArgoGel-MB-CHO, several primary amines were loaded onto the gel by reductive amination.S N Ar reaction of resin-bound secondary amine 74 with 4,6-dichloro-2-(methylthio)-5nitropyrimidine (75) linked the aromatic heterocycle to the resin to give 76.Similar replacement of the C-6 chlorine by an alkylamino moiety was followed by oxidation of the C-2 thioether to a sulfone.A third S N Ar process served to install the final alkylamino unit at C-2 via displacement of the sulfone.Reduction of the nitro function using chromium(II) chloride in DMF/methanol (MeOH) gave 77 and heterocyclization with a triethyl orthoester then led to the resin-bound purine derivative 78.The target compound 79 was released from the resin bead by treatment with aqueous TFA at 23 o C. The purines were cleaved with good to excellent yields and purities, but the cyclization step was sensitive to steric hindrance when R 2 and R 4 were large.The reaction sequence for the assembly of purines 79 by this strategy, as well as number schemes for reactants and products, are summarized in Scheme 20.Scheme 20.Solid-phase protocol for the synthesis of tetrasubstitued purines.Finally, a further example of this ring forming strategy was reported by Portilla et al. 35 who applied MW heating to promote an annulation reaction to form pyrazolo [

Fused rings: three heteroatoms
Numerous other methods for fusing five-membered rings with multiple heteroatoms to pre-existing rings have also been documented.Most of these have sought to generate compounds of medicinal value.A paper by

72-82%
The Davoodnia group published a preparation of 1,2,4-triazolo[4,3-a]perimidine, the tetraaza analog of 91, but no further studies were described for this compound. 41ther related examples have appeared in the literature [42][43][44][45][46][47][48] and are summarized in Figure 1.All reactions were performed neat or as solutions in the indicated solvent and at the reported temperature (room temperature was assumed to be 23 o C).The subunit derived from the orthoester is highlighted in red for each molecule.

Figure 1.
Other examples of fused 5-membered rings with three heteroatoms.

Complex rings and systems that rearrange
Many reactions that form five-membered rings undergo a rearrangement following the initial cyclization process.This bond reorganization is known as the Dimroth rearrangement, 49 and several versions of the process have been cataloged.The process is detailed in Scheme 25 for 1,2,4-triazolo[4,3-a]pyridine (98) under basic conditions. 49,50At moderate temperatures (100-120 o C), cyclization of 2-hydrazinopyridine with an orthoester initially gave 98 as the kinetic product, and this slowly rearranged to the more stable thermodynamic [1,5-a] product 100.When the reaction was repeated at higher temperature (≥150 o C), 100 was isolated as the major product.Under basic conditions, a ring bond in 98 is cleaved to generate the stabilized cyclic anion 99, which undergoes bond rotation and reclosure to the 1,2,4-triazolo[1,5-a]pyrimidine 100. 51This process, however, is also observed in acid and in neutral solvents with heat where an anionic intermediate is unlikely.
The generation of fused rings from orthoesters has been directed primarily towards the formation of quinoxalines and benzoxazines.These are both highly coveted templates found in many drug molecules.The process to assemble these structures from 2-(aminomethyl)-or 2-(hydroxymethyl)anilines is usually quite facile since both reactive centers are held in close proximity by the aromatic ring.In 2-(aminomethyl)aniline, the two nitrogens have sufficient nucleophilicity to rapidly react with the orthoester as it sequentially loses alcohol molecules.In 2-(hydroxymethyl)aniline, the analogous cyclization is expected to be more difficult due the decreased nucleophilicity of oxygen and the shorter C-O bond length.Additionally, in products with a ]-benzoxazin-4-ones, the greater reactivity of the ester versus the amide linkage would make the heterocycle less stable.One of the earliest disclosures of a cyclization involving insertion of an orthoester between two nitrogens to form a six-membered ring was advanced in 1960 by Partridge and co-workers (Scheme 30). 59hese investigators found that refluxing 2-(2-aminophenyl)-4-hydroxyquinoline (113a) with triethyl orthoformate for 2 h led to clean formation of 114a (86%).The authors asserted that triethyl orthoformate promoted a more efficient ring closure than an earlier cyclization with formic acid, 60 but no yield was recorded in the cited work.A similar conversion was documented by these same researchers from the corresponding 4-(phenylamino) derivative 113b to generate the 4-(phenylimino) product 114b in 76% yield. 61heme 30.Synthesis of tetracycles 114a and 114b.
The Bunce group has published an improved procedure for the preparation of quinazolin-4(3H)-ones. 62his method examined cyclizations of 2-aminobenzamide (115) with a series of orthoesters promoted by AcOH.Best results were observed when the reaction was performed in EtOH with AcOH (2-3 equiv) at 110 o C in a sealed tube.Under these conditions, steric factors seemed to pose less of a problem, and very high yields were achieved with minimal purification requirements.Although the study was focused on procedure rather than scope, the reaction was found to be tolerant of a small selection of substituents on the aromatic ring and the amide nitrogen of the substrate.The ring formation is illustrated with a mechanism in Scheme 31 and follows a path parallel to that described for the formation of benzimidazoles. 24Initial loss of EtOH from the orthoester and attack by the aromatic amino function of 115 on the stabilized carbonium ion would give 116.Protonation of 116, followed by loss of a second molecule of EtOH, should give 117, which can cyclize to 118.Elimination of a third molecule of EtOH would then furnish the quinazolin-4(3H)-one 119.This account also described an extension of this process to the preparation of 5,6-dihydropyrimidin-4(3H)-ones, but the yields were modest for all examples except when R was Ph. 62 El-Gaby et al. utilized orthoesters in a novel approach to pyrimidothienopyridazines. 63 Synthesis of the cyclization substrate 5-amino-3-methyl-4-styryl-6-carbamoylthienyl[2,3-c]pyridazine (120) was achieved in five steps (57%) from 5,6-dimethyl-3-oxo-2,3-dihydropyridazine-4-carbonitrile. 64This precursor was boiled in triethyl orthoformate containing catalytic AcOH for 1 h to afford 3-methyl-4-styryl-7,8-dihydro-8oxopyrimido[4',5':4,5]thieno[2,3-c]pyridazine (121) in 96% yield (Scheme 32).Two other derivatives bearing aryl substitution on the amide nitrogen were also prepared, each in 90% yield.Two research groups have also documented several other 6-ring cyclizations from orthoesters (Figure 2).In the first case, Hazarkhani and Karimi 65 cyclized a series of orthoesters with 2-amino-Nbenzimidazolylbenzamide in DMA using catalytic p-toluenesulfonic acid (p-TsOH) under MW conditions to produce 3-(2-benzimidazolyl)-4(3H)-quinazolinones 122 in 70-95% yields.Davoodnia 66 exploited MW heating to promote the cyclization of 2-(1H-benzimidazol-2-yl)aniline to the benzimidazo[1,2-c]quinazolines 123 in 82-88% yields.Experimental and spectral details in this report were minimal.This same group 67 further examined the ring closure of thieno [2,3-d]pyrimidin-4(3H)-ones 124 (73-82%) promoted by phosphotungstic acid.The catalyst was shown to be recyclable, with a slight decrease in yield for a single subsequent cyclization.Davoodnia and co-workers also reported synthesis of pyrazolo [3,4-d]pyrimidin-4-ones 125 from 5-amino-1-phenyl-1H-pyrazole-4-carboxamides and orthoesters without solvent using catalytic Brønsted acid ionic liquids (84-93%) 68 and montmorillonite K10 (78-89%). 69Again, the catalysts were touted as being reusable, but it was not clear how many cycles could be performed with the same charge of catalyst.Additionally, a tedious extraction procedure was necessary to recycle the ionic liquid catalyst.The final products are depicted below, once again showing the fragment derived from the orthoester in red.On rare occasions, unexpected reactions are observed in cyclizations with orthoesters.One such example was noted by Okamoto, et al. in the ring closure of 2-alkoxy-5-(benzimidazol-2-ylidene)-3-cyano-6imino-5,6-dihydropyridines 126 with triethyl orthoesters at reflux to produce 6-alkyl-3-alkoxy-2-cyano-4,5,6a,11-tetraazabenzo[a]fluorene derivatives 127 (Scheme 33). 70While 127 was obtained cleanly from reaction with triethyl orthoformate, cyclizations from the orthoacetate and orthopropionate were complicated by the unexpected transfer of an ethyl group from an orthoester oxygen to C-1 of the heterocycle to give 128 upon prolonged heating.Furthermore, it was observed that product 127 from triethyl orthoformate was ethylated when boiled with triethyl orthoacetate.The authors rationalized these observations in terms of the increased reactivity of the C-alkylated orthoesters and an initial ipso ethylation at C-2, followed by migration of the ethyl substituent to C-1.
A paper by Shi and co-workers 71 delineated a versatile domino reaction for the formation of quinazoline derivatives.In this procedure, a pre-formed low-valent titanium reagent, prepared from titanium(IV) chloride and zinc dust in THF, was treated with N-aryl-2-nitrobenzylamines 129 or N-aryl-2nitrobenzamides 131 and an orthoester.This process, performed in refluxing THF, involved the in situ reduction of the nitro function to the amino group, followed by condensation with the orthoester to give 3,4dihydroquinazolines 130 and quinazolin-4(3H)-ones 132, respectively (Scheme 34).These products were isolated in good to excellent yields.The procedure to prepare 133 was not described or referenced.However, the presence of a nitro group on the phenyl ring could potentially simplify the synthesis of many precursors since it would allow engagement of the S N Ar reaction.
Annor-Gyamfi and Bunce 75 recently disclosed the application of this reaction to aromatic amino acids.In this study, several anthranilic acids 141 were reacted with orthoesters (2.7 equiv) under neat conditions in the presence of stoichiometric AcOH at 100 o C (4-48 h) to generate 4H-benzo[d] [1,3]oxazin-4-ones 142.Interestingly, not all of the substrates explored afforded the desired targets.It was noted that anthranilic acids with electron-rich aromatic rings produced 4H-benzo[d] [1,3]oxazin-4-ones, while those bearing electronwithdrawing substituents tended to stop at the dihydro derivatives 143, wherein the final elimination of EtOH did not occur.Reaction of 2-aminonicotinic acid also produced the dihydro product.The reaction was further explored using microwave conditions [400 W, 100 o C] with nearly identical results, although reaction times were significantly shorter (0.75-3 h) (Scheme 38).The formation of the dihydro derivative was linked to the availability of the electron pair on nitrogen.In electron-deficient aromatic rings, these electrons would be less available to assist in the elimination of the final molecule of EtOH.In several substrates, it was possible to isolate either product by modification of the reaction conditions.Similar dihydro derivatives were previously observed in a synthesis of highly substituted 2,3,4,5-tetrahydro-1,2,4-triazines from 2arylhydrazonoacetamides and the same rationale can be applied.In 1973, Fujii and co-workers 77 communicated an early orthoester-based approach to an adenine derivative (Scheme 39).In this work, imidazole 144 78 was cyclized with boiling triethyl orthoformate to produce 145 in 73% yield. 77Hydrogenolysis of the N-methoxy group from the perchlorate salt of 145 [H 2 , 10% Pd/C] then afforded 3,9-dimethyladenine perchlorate in 26% yield.Scheme 39.Synthesis of an adenine derivative.

Monocyclic/fused: three heteroatoms
In the late 1980's, Piskala 79 led a project to obtain 5-azacytosines as potential antisecretory agents for the mitigation of ulcers.The preparation involved the treatment of amidinourea hydrochloride (146) with ethyl orthobenzoate in DMF at 100 o C for 1.5 h to give a 52% conversion to the drug candidate 147 (Scheme 40).As this was part of a patent, few details were available.

Complex Ring Systems
A study by Sun and co-workers 87 employed orthoesters in an electrocyclic ring closure-elimination sequence to obtain non-steroidal anti-inflammatory drug candidates (Scheme 46).Treatment of the 3aminobenzofuranylcoumarin 167 with triethyl orthoesters at reflux initially gave imino ether 168, followed by a 6π electrocyclic ring closure and elimination of EtOH to give the fused coumarins 169 (70-80%).Several of the products showed significant anti-inflammatory properties.
One last report detailed a complementary approach to prepare Tenofovir, an HIV/AIDs and hepatitis B drug. 96In this application, the imidazole ring of the purine was assembled first followed by annulation of the aromatic ring to give the adenine nucleus.Thus, reaction of diaminomaleonitrile (193) was condensed with trimethyl orthoformate in DMF containing catalytic TFA to give formidate 194 (93%).Addition of (R)-1-aminopropan-2-ol to 194 in acetonitrile at

Seven-Membered Rings
The formation of seven-membered rings is rare and has only been reported one time. 97In this disclosure, Peet and co-workers initially reacted isatoic anhydride (198) with methylhydrazine in DMF to give 2-amino-Nmethylbenzoic hydrazide (199).Subsequent treatment of 199 with a series of orthoesters in ethanol then led to the isolation of 3,4-dihydro-5H-1,3,4-benzotriazepin-5-ones 200a-d in 46-63% yields (Scheme 56).The success of this transformation was likely facilitated by the rigid planar structure which positioned the reactive centers in close proximity.Scheme 56.Condensative closure of a seven-membered ring.

Oxygen Heterocycles
Warren and co-workers advanced an interesting synthesis of highly functionalized tetrahydrofurans (THF) and tetrahydropyrans (THP) involving an acid-catalyzed reaction of a series of triols with trimethyl orthoacetate (Scheme 57). 98The Sharpless asymmetric dihydroxylation was used to fashion a series of enantiomerically enriched 1,2,4-triols such as 201.Exposure of triol 201 to trimethyl orthoacetate and pyridinium ptoluenesulfonate (PPTS, 25 mol%) in DCM for 2 min resulted in quantitative conversion to the bicyclic orthoester 202.Extending the reaction time to 24 h with this mild acid catalyst, however, resulted in further conversion to a 23:73 mixture of the rearranged THF 203 and THP 204 derivatives in 98% yield.These products derived from the two possible ring openings of a bridged episulfonium ion intermediate formed when a phenylthioether substituent assisted in the ring opening of an adjacent 5,6-dihydro-4H-1,3-dioxin-1ium ion.Further treatment of this mixture with p-TsOH in the same solvent resulted in isolation of THP 204 as the exclusive product (91%).Following several control experiments, it was concluded that the THF compound was the kinetic product, while the THP was the thermodynamic product.A number of related triols were investigated 99 with similar, although slightly varying, outcomes.EtOH, reflux Scheme 57.An approach to highly functionalized tetrahydrofurans and tetrahydropyrans.

Conclusions
The research cited above clearly establishes the high potential of orthoesters in heterocycle synthesis.Since most of the studies delineated have employed simple commercial orthoester derivatives, it is clear that only the surface of this field has been explored.Future work should strive to prepare and evaluate new orthoester derivatives with additional functionality on the carbon group bound to the central oxygenated carbon.This would permit additional substitution patterns on the basic ring structures and invite further transformations of the initially formed products.These advancements would assure an expanding variety of new drug candidates and other derivatives for natural product and materials synthesis.

Scheme 48 .
Scheme 48.Synthesis of 176 and 177 via divergent pathways through the same intermediate.

Scheme 55 .
Scheme 55.Synthesis of HPI (195) and its conversion to the HIV/AIDS and hepatitis B drug Tenofovir (197).

52. Scheme 14. Synthesis of benzazoles promoted by ammonium chloride.
employed catalytic ammonium chloride in boiling EtOH to facilitate the process.A mechanism for this last entry is shown in Scheme 14.Initial loss of EtOH from the orthoester and attack by the aromatic amino function of 48 on the stabilized carbonium ion would give 49.Protonation of 49, followed by loss of a second molecule of EtOH, would give 50.Cyclization of 50 to 51 and release of a third molecule of EtOH would then furnish benzazole ) with sulfamide (159) in acetonitrile at 0-20 o C for 48 h.Reaction of 160 with bisnucleophiles such as ethylenediamine, 2-aminoethanol and 2-aminoethanethiol afforded imid-, ox-and thiazolidines 161a-c, respectively, in 77-89% yields.Reaction of 161a-c furnished the bicyclic thiatriazines 162a-c in 71-92% yields.In an alternative sequence, 160 was reacted with various primary and secondary amines, followed by ammonia, to give sulfamoylguanidines 163.Refluxing 163 with triethyl orthoformate or orthoacetate containing p-TsOH gave the 1,2,4,6-thiatriazine-1,1-dioxides 164 in 54-96% yields.These compounds were evaluted as potential anti-ulcer drugs.