With Ortho Esters

Triethyl orthoformate was introduced by Cook and Smith in 1949 to cyclize 5-amino-2-methylthiothiazole-4-carboxamide to 6-methylthio[5,4-rf]pyrimidin-4-one (148) in excellent yield.201 Usually, the starting material is vigorously refluxed with equal volumes of this reagent and acetic anhydride for 2 hr in a bath at 150°C. In some cases, when the acetic anhydride was omitted, ethoxymethyleneamino derivatives, such as 149, accumulated, thus 

Other successful uses of triethyl orthoformate include formation of pteri-din-4-ones from 2-aminopyrazine-3-carboxamide (see 9) and its derivatives127,229 233 234 cis- and trans-4a,5,6,7,8,8a-hexahydroquinazolin-4-ones from the related 2-aminocyclohexanecarboxamides61,65 pyrido[2,3-d]pyri-midin-4-ones (see 3) from 2-aminopyridine-3-carboxamide235 thiazolo[5,4-d]pyrimidin-4-one (see 148) from 5-aminothiazole-4-carboxamide236 and purin-6-ones (see 19) from 4-aminoimidazole-5-carboxamide.232,237 Any partial acetylation of 7c-excessive products can be reversed by a final alkaline treatment.238 

Dimethylformamide has been used in place of acetic anhydride, as when 2-methyl-4-aminoimidazole-5-carboxamide hydrochloride was quantititively converted to 8-methylpurin-6-one after only 5 min of boiling.239 Treated similarly, 4-aminopyridazine-5-carboxamide gave an excellent yield of 

Secondary amines, debarred from the normal pathway, which requires primary amines, can present difficulties. 1-Methyl-5-methylaminoimidazole- 

6- one (151) and its 9-benzyl derivative were obtained by stirring the triazole with a mixture of 10 N hydrochloric acid and triethyl orthoformate for 1 hr at 100°C or 24 hr at 25°C.64 The mechanism of this surprising reaction is thought to be an electrophilic attack by the diethoxycarbenium ion [HC+(OEt)2] to give the acetal 152, which loses two molecules of ethanol to furnish the isolated products.64 

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Biphenyl-2,2 -diamine and ring-substituted biphenyl-2,2 -diamines are transformed into dibenzo[rf,/][l JJdiazepines 1 in various ways by reaction with ortho esters (Method A),169 with hydrochlorides of imido acid esters (Method B)170 or with the benzenesulfonates of pro-tonated nitriles (Method C).171 Selected examples are given. 

Salicylohydrazide (1) reacts with acyl chlorides or acid anhydrides in the presence of meth-anesulfonic acid to give 1,3,4-benzoxadiazepin-5(4//)-ones 2 (Method A).317 A modification (Method B) consists of the condensation of the hydrazide 1 with ortho esters.317... 

The reaction of 2-aminobenzoic acid hydrazidcs with ortho esters gives 4-methyl-3//-1,3,4-benzotriazepin-5(4//)-ones 17 or 4-methyl-l//-l, 3,4-benzotriazepin-5(4//)-ones 18, depending on the structure of the hydrazide. Selected examples are given.359 11 360 361... 

Condensation of 2-Aminobenzoic Acid Hydrazides with Ortho Esters General Procedure 361... 

The required acid sensitivity can be achieved by preparing polymers with ortho ester linkages in their backbone. The first poly-(ortho ester) has been described in a series of patents by Choi and Heller (3-6), assigned to the ALZA corporation. These proprietary materials were first designated with the trade name Chronomer and later Alzamer. They are prepared by a transesterification as follows ... 

Furo[2, 3 4,5]pyrrolo[l,2-d][l,2,4]triazolo[3,4-/][l,2,4]triazines 667 were prepared by reaction of 664 with phosphorus pentasulfide to give 665 followed by conversion to the hydrazino derivative 666 and subsequent cyclization with ortho-esters (84CCC65, 84M13). Similarly, the indolo analogue 670 was prepared from 668 by sulfurization and hydrazinolysis to give 669, which cyclized with ortho-esters (84CCC1529). 

Cyclization of 776 with ortho-esters gave (83JOC1628) [l,2,4]triazolo-[4,3-fc]pyrimido[5,4-< ][ 1,2,4]triazines 777, whereas reaction with sodium nitrite afforded the corresponding tetrazolopyrimidotriazine 778.3-Azido-pyrimido[4,5-e][l, 2,4]triazine 779 exists in a cyclic form as tetrazolo derivative 780, as shown by X-ray analysis (86KGS114). In solution the position of the 779 780 equilibrium depended on temperature and solvent. Higher temperatures favored 779. Azido compound 779 predominated in water, and tetrazolo compound 780 predominated in pyridine. Addition of sodium azide to the aqueous solution shifted the equilibrium toward 780. The... 

Alcohols react with ortho esters by exchange of their alkoxy groups to form new ortho esters. The equilibrium is shifted to the right by removal of the vola-... 

Enol Ethers and Esters 0-15 O-Alkylation of carbonyl compounds with diazo alkanes 0-17 Transetherification 0-20 Reaction between acyl halides and active hydrogen compounds 0-23 Transesterification 0-24 Acylation of vinylic halides 0-94 Alkylation with ortho esters 0-107 O-Acylation of 1,3-dicarbonyl compounds... 

Methylene groups of pyrylium cations also react under mild conditions with nitrosoben-zenes in the presence of acetic anhydride and an alkali metal salt, which plays an essential role in the formation of Schiff s bases (116). The latter are hydrolyzed to the carbonyl compound (117) (71BSF3603). It is possible to form potential dyes by treatment of pyrylium salts with ortho esters such as triethyl orthoformate. The reactants are heated together in acetic anhydride or pyridine and trimethine dyes of type (118) and (119) are formed (70JHC1395, 71JOC600, 59CB2309). 

Dihydrazones of cyclic 1,2-diketones react with ortho esters and similar reagents to form aza macrocycles, which coordinate as for (31). 

Eliel, E. L. Nader, F. W. Conformational analysis. XX. The stereochemistry of reaction of Grignard reagents with ortho esters. Synthesis of 1,3-dioxanes with axial substituents at C-2.]. Am. Chem. Soc. 1970, 92, 584-590. 

Another important synthesis involves the reductive cyclization of 4-ethoxyalkylidinehydrazino-5-nitropyrimidines of type (372), which are obtained readily by reaction of 4-hydrazino-5-nitro-pyrimidines (371) with ortho esters. Catalytic reduction of the nitro group in (372) affords the 5-aminopyrimidine intermediate (373), which cyclizes in situ to the dihydro product (374). This may be oxidized without isolation to give the fully aromatic product (375). These reactions are shown in... 

Heating 2-aminobenzenesulfinamides 69 with ortho esters or the acetal of DMF affords heterocyclic sulfinimines such as 70 48... 

An alternative to the imidazolium salts as starting materials is the elimination of an alcohol from 2-alkoxy-l,2-dihydro-l f-imidazoles that are accessible by reaction of vicinal diamines with ortho-esters of formic acid [59-61] (see Figure 1.9). 

The most efficient method of preparation of (31) and its alkyl derivatives was reported (62JOC3243) to be via ring closure of 2-hydrazinopyrazines with ortho esters (Scheme 58). 

Cyclization of 2-hydrazinoquinoxalines occurs very readily with carboxylic acids and esters and ortho esters. This is in contrast to the pyrazines which could only be cyclized with ortho esters (60JA4044,68JHC485). Pyrolysis of the hydrazones derived from 2-hydrazinoquinoxalipe have led to various compounds of this series (60JA4044>. 

Cyclization of 2-aminobenzamides or 2-aminothiobenzamides 3 with ortho esters to form 2-substituted quinazolin-4(3f/)-ones or quinazoline-4(3//)-thiones 5 is a general although little studied cyclization process which can be applied also to hetarenic 2-aminocarboxamides. The isolation of intermediate 4 (R = H = Me X = CH = CH Y = O) from the reaction of 2-aminobenzamide with triethyl orthoacetate and the demonstration of its facile cyclization to 2-methylquinazolin-4(3//)-one on heating in ethanolic solution strongly supports the intermediacy of compounds of type 4 in the formation of 5. ° ... 

The reaction of aminomalonodiimidamide dihydrochloride with ortho esters in dimethyl-formamide gives 2,8-disubstituted adenines 7. ... 

Regiochemical synthesis of 1-substituted imidazole-4-carboxylates can be achieved by treatment of a (Z)-)3-dimethylamino-of-isocyanoacrylate with an alkyl or acyl halide (see Section 2.1.1 and Scheme 2.1.8), by cyclization of 3-alkylamino-2-aminopropanoic acids with triethyl orthoformate followed by dehydrogenation of the initially formed imidazoline (see Section 3.1.1 and Scheme 3.1.2), by condensation of 3-arylamino-2-nitro-2-enones with ortho esters in the presence of reducing agents (see Section 3.1.1 and Scheme 3.1.4), by reaction of an alkyl A -cyanoalkylimidate with a primary amine (see Section 3.2 and Scheme 3.2.1), the poor-yielding acid-catalysed cyclization of a 2-azabutadiene with a primary amine (see Section 3.2 and Scheme 3.2.3), the cyclocondensation of an isothiourea with the enolate form of ethyl isocyanoacetate (see Section 4.2 and Scheme 4.2.5), and from the interaction of of-aminonitrile, primary tunine and triethyl orthoformate (see Chapter 5, Scheme 5.1.5, and Tables 5.1.1 and 5.1.2). 

For a review of the reaction with ortho esters, see DeWolfe, R.H. Carboxylic Ortho Acid Derivatives, Academic Press, NY, 1970, pp. 44-45, 224-230. 

A-Alkyl-2-methyl-l, 3-benzotellurazolium tetrafluoroborates condense with ortho esters of acetic or propionic acid at 140° to yield A-alkyl-2-(2 -ethoxyalk-r-en-r-yl)-l,3-benzo-tellurazolium tetrafluoroborates, that are converted upon boiling with concentrated hydrochloric acid to A-alkyl-2-(2 -oxo-r,T-alkylidene)-2,3-dihydro-l,3-benzotellurazoles. On heating with phosphorus oxychloride and subsequent treatment with tetrafluoroboric acid these compounds formed 77-alkyl-2-(2 -chloroalk-r-en-T-yl)-l,3-benzotellurazolium tetrafluoroborates. ... 

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