Triethyl orthoformate

As with malonate, the two strong electron-withdrawing functional groups of cyanoacetate significantly enhance the acidity of the methylene group. Accordingly, it can be readily deprotonated and the anion reacts with abroad spectrum of electrophiles, such as alkyl and activated aryl halides, carbonyl compounds, a,/3-unsaturated carbonyl or carboxyl derivatives, and nitrous acid. 

Under analogous conditions to the first example, ethyl [ C]cyanoacetate reacted with quinuclidin-3-one to afford the corresponding a-cyanoacrylate. Catalytic reduction followed by mild saponification and decarboxylation of the ester function converted this 

Reaction conditions 1. NH4OAC, HOAc, benzene reflux, 2 h 2. NaBH4, MeOH/CHjCIs 1 1 0 °C 3. NaCI/OMSO/HjO, 170 °C 4. NH4OAC, HOAc, toluene reflux 5. Hj, 10 % Pd/C, EtOH r.t. 6. EtONa, EtOH A 7. AamylONO 40-50 °C  

Classically, [ CJcyanoacetates have been used in the synthesis of pyrimidine derivatives 

The functional groups, as well as the methylene, undergo a number of transformations, either sequentially or simultaneously in which either the carboxyl and cyano groups, or the methylene and cyano groups, participate in cyclocondensation reactions. These two synthetic approaches are distinct tactically, but can both be utilized to produce cyclic products. 

Keisuke Suzuki Tetsuya Nagasawa Keio University, Yokohama, Japan 

Form Supplied in clear liquid widely available. 

Handling, Storage, and Precautions highly moisture sensitive flammable irritant with high volatility. Use in a fume hood. 

Cyclic Orthoformates. When the above strategy is applied to polyols, cyclic orthoformates can be isolated. Most common are the cyclization of 1,3-diols (eq 2) and 1,2-diols, as well as the formation of caged structures from the use of polyols (eq 3). Those orthoformates obtained from 1,2-diols (eq 4) can undergo cycloelimination upon pyrolysis to afford alkenes in high yield. There are a variety of methods for carrying out this overall 

Elsterification. In a related process, orthoformates are good esterification agents they operate on carboxylic acids (eq 8), sulfonic acids, and carboxyboranes, often without the need for acid catalysis. 

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Otherwise, the main reactions at the methylene group are the dialkylation with alkyl haUdes (77), the acetylation with acetyl chloride which yields acetylma1 ononitrile [1187-11-7] (78), the Knoevenagel condensation, as well as the condensation with triethyl orthoformate, gives... 

Fig. 2. Synthesis of uma2enil (18). The isonitrosoacetanihde is synthesized from 4-f1iioroani1ine. Cyclization using sulfuric acid is followed by oxidization using peracetic acid to the isatoic anhydride. Reaction of sarcosine in DMF and acetic acid leads to the benzodiazepine-2,5-dione. Deprotonation, phosphorylation, and subsequent reaction with diethyl malonate leads to the diester. After selective hydrolysis and decarboxylation the resulting monoester is nitrosated and catalyticaHy hydrogenated to the aminoester. Introduction of the final carbon atom is accompHshed by reaction of triethyl orthoformate to...

Orthoesters are trivially named as derivatives of ortho acids such as triethyl orthoformate [122-51 -0] HC(OC2H )2, or named systematically as ethers, 1,1,1-triethoxymethane. 

N-Alkylations, especially of oxo-di- and tetra-hydro derivatives, e.g. (28)->(29), have been carried out readily using a variety of reagents such as (usual) alkyl halide/alkali, alkyl sulfate/alkali, alkyl halide, tosylate or sulfate/NaH, trialkyloxonium fluoroborate and other Meerwein-type reagents, alcohols/DCCI, diazoalkanes, alkyl carbonates, oxalates or malon-ates, oxosulfonium ylides, DMF dimethyl acetal, and triethyl orthoformate/AcjO. Also used have been alkyl halide/lithium diisopropylamide and in one case benzyl chloride on the thallium derivative. In neutral conditions 8-alkylation is observed and preparation of some 8-nucleosides has also been reported (78JOC828, 77JOC997, 72JOC3975, 72JOC3980). 

A series of 4-methyleneisoxazolin-5-ones was produced by the reaction of hydroxylamine with iminoether (508) (77ACH(94)403) or with a /3-ketoester and triethyl orthoformate (Scheme 147) (65CI(L)36). 

The neopentanedlol and triethyl orthoformate were purchased from Aldrich Chemical Co., Inc. and used as received. Failure to distil the methyl vinyl ketone, also obtained from Aldrich Chemical Co., to a clear, colorless liquid before use resulted in difficulty in determining the endpoint of the reaction with HBr. Therefore, the methyl vinyl ketone was distilled prior to use at reduced pressure. 

Triethyl orthoformate (1,1,1-triethoxymethane) [122-51-0] M 148.2, m 30°, b 60°/30mm, 144-146°, d 0.891, n 1.392. Fractionate first at atm press, then in a vac. If impure, then wash with H2O, dry over anhyd K2CO3, filter and fractionate through a Widmer column. [Sah and MaJ Am Chem Soc 54 2964 1932 Ohme and Schmitz Justus Liebigs Ann Chem 716 207 1968.] IRRITANT and FLAMMABLE. 

Estrone methyl ether (100 g, 0.35 mole) is mixed with 100 ml of absolute ethanol, 100 ml of benzene and 200 ml of triethyl orthoformate. Concentrated sulfuric acid (1.55 ml) is added and the mixture is stirred at room temperature for 2 hr. The mixture is then made alkaline by the addition of excess tetra-methylguanidine (ca. 4 ml) and the organic solvents are removed. The residue is dissolved in heptane and the solution is filtered through Celite to prevent emulsions in the following extraction. The solution is then washed threetimes with 500 ml of 10 % sodium hydroxide solution in methanol to remove excess triethyl orthoformate, which would interfere with the Birch reduction solvent system. The heptane solution is dried over sodium sulfate and the solvent is removed. The residue is satisfactory for the Birch reduction step. Infrared analysis shows that the material contains 1.3-1.5% of estrone methyl ether. The pure ketal may be obtained by crystallization from anhydrous ethanol, mp 99-100°. Acidification of the methanolic sodium hydroxide washes affords 10-12 g of recovered estrone methyl ether. 

Androst-4-ene-3,17-dione (83) is converted into the enol ether (84) by reaction with triethyl orthoformate. Treatment of the enol ether (84) with DDQ in aqueous acetone gives the title dienone (85). This method is particularly suitable for A" -3-ketones substituted at the 6-position. 

The orthoformate is formed by the acid-catalyzed reaction of a catechol with triethyl orthoformate (82% yield) and is cleaved by acid-catalyzed hydrolysis (TsOH, MeOH, H2O, rt, 16 h, 80-88% yield.). ... 

In order to expand the utility of the reaction, modification of the route to anilidomethylene malonic ester equivalents was developed. Simple condensation of triethyl orthoformate with cyanoacetic ester, acetoacetic ester, or malonic ester in the... 

Attempted dehydrocyclization of the 6-acylhydrazinopyrimidine 65 by heating with polyphosphoric acid led, instead, to pyrimidine ring rupture, yielding the l,l-diamino-2-nitro-2-(3-phenyl-l,2,4-triazol-5-yl)ethene 66. Cyclocondensation of the latter with triethyl orthoformate gave the fully aromatic triazolopyrimidine 67 (94JHC1171) (Scheme 23). 

The carbocyanine dyes 26 containing benzotellurazole fragments were obtained by treatment of the salt 19 with triethyl orthoformate (89KGS989). 

A preparation of the parent system 4 has been claimed starting from the precursor 133. Thus, when treated with triethyl orthoformate under acidic conditions (H2SO4), 133 underwent transformatirai into 4 in 80% yield. This experiment did not lead to the formation of the isomeric system 167. This outcome was rationalized in terms of the initial formation of an indoleninium ion, followed by rearrangement... 

Reactions of 3-hydrazino-l,2,4-triazine 1-oxide 31 or 3-hydrazinopyrido [2,3-c]-l,2,4-triazine 1-oxide 32 with diethoxymethyl acetate or triethyl orthoformate proceed as cyclization reactions at the N(4) atom and the amino group to form the corresponding pyrazolo[3,4-c]-l,2,4-triazine 6-oxides 33 and 34 (74MI, 80JOC5421, 80MI). 

Anilinofervenulin 4-oxides 151 were synthesized by the reaction of 6-hydra-zino-l,3-dimethyluracil with triethyl orthoformate, followed by the treatment of the hydrazide 152 with aniline and further cylization of 153 in the presence of potassium nitrate in acetic acid (82JHC1309). 

Reaetion of l-amino-2-eyanoquinolinium perehlorate 769 with triethyl orthoformate gave the formamidine derivative 770 whieh upon treatment with primary amines afforded the triazoloquinolinium perehlorate 771 (90H289) (Seheme 134). 

Nitromethane reacts v/ith triethyl orthoformate in the presence of secondary amines to give isfEq 5 9) ... 

In a 250-ml. round-bottomed flask equipped with a gas-inlet tube and reflux condenser 20 g. (0.094 mole) of N.N -diphenyl-ethylenediamine (1,2-dianilinoethane) (Note 1) and 100 ml. of purified triethyl orthoformate (Note 2) are heated by an oil bath under nitrogen (Note 3) for 5 hours. The oil bath is maintained between 190° and 200°, and water is allowed to stand in the condenser. The water in the condenser begins to boil slowly, and the alcohol which is produced is allowed to escape (Note 4). The reaction product which crystallizes during the reaction is filtered after cooling and washed with ether. There is obtained 19-20 g. (91 95%) of product, m.p. 285° (dec.) (Note 5). 

Diphenylcyclopropenone, 47, 62 Dii henyldiacetylene, 45, 39 Diphenyl disulfide, oxidation to methyl benzenesulfinate, 46, 62 1,1-Diphenylethylene, reaction with N,or diphenylmtrone, 46,129 N,N -Diphi iiyli tiiyleni diamine, condensation with triethyl orthoformate, 47, 14... 

In general, the O-alkylation of benzoxepinones is accomplished via the anion. Alternatively, an acid-catalyzed process employing ortho esters may be used. For the acid-catalyzed formal O-alkylation of l-chloro-8-methoxydibenz[ft,/]oxepin-10(ll//)-ones with triethyl orthoformate rather drastic conditions are required (hot concentrated sulfuric acid) to give the 10-ethoxy derivative 12 in excellent yield.109... 

Benzoxadiazepines 1 are formed by the action of triethyl orthoformate on the (Z)-oximes of 2-aminoarenecarbaldehydes.313... 

Method B A suspension of the hydrazide 1 (1.52 g, 10 mmol) in EtOH (lOmL) was treated with triethyl orthoformate or orthoacetate (lOmmol) and the mixture was refluxed for 17 h. Evaporation, followed by chromatography (silica gel, CH2C1,) gave the product. 

Cyclization of 8-hydrazinO 3-phenyl-l-azaazulenes 69 with triethyl orthoformate gave 4,5-triazabenz[c(f]azulene derivative 70 which was easily hydrolyzed on silica gel and gave (2-chloro-8-imino-3-phenyl-l-aza-l,8-dihydoazulen-l-yl) formaldehyde oxime (87H767) (Scheme 17). 

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