Trimethylorthoformate

The synthesis which forms the basis of production at Hoffmaim-La Roche (Fig. 5) proceeds via the pyrimidinenitrile [698-29-3] (26) made from malononittile, trimethylorthoformate, ammonia, and acetonitrile (42,43). High pressure catalytic reduction of the nitrile furnishes diamine (16). The overall sequence is short, highly efficient, and generates almost no waste. However, malononittile is a relatively expensive and ha2ardous three-carbon source. 

Ketcha and Wilson reported the solid-phase version of the classic Nenitzescu indole synthesis in a process involving initial acetoacetylation of ArgoPore-NH2 resin with diketene to afford a polymer bound acetoacetamide <00TL6253>. Formation of the corresponding enaminone 102 via condensation with primary amines in the presence of trimethylorthoformate followed by addition of 1,4-benzoquinones 103 leads to formation of polymer bound 5-hydroxyindole-3-carboxamides 104 which could be cleaved from the resin using TFA yielding the indoles 105. 

When the pyrrolo[l,2-c]oxazole 269 was treated with trimethyl orthoformate in the presence of BF3 Et20, in dichloromethane at — 78 °C, a mixture of compounds was obtained from which the expected 5-dimethoxymethyl derivative, 270, was isolated in poor yield (12%) with another dimethoxylated compound 271 (23%). The formation of 271 could be explained by the addition of the formyl cation equivalent at C-7, followed by the protonation at C-6 of the resulting enamide 272 leading to the electrophilic iV-acyliminium ion 273 (Scheme 40). The regioselectivity of this electrophilic addition of trimethylorthoformate to the silyloxypyrrole 269 at C-7, in a non-vinylogous manner, is unusual <1999TL2525>. 

When trimethylorthoformate is utilized as the dehydration agent (Equation 8.), heavies due to Aldol condensation are eliminated. Methyl formate can be easily recovered from the reaction products, but synthetic routes to regenerate trimethylorthoformate are very involved and costly. An advancement to improve trimethylorthoformate synthesis would enhance the attractiveness of the homogeneous oxycarbonylation route to adipic acid. 

A reactor was charged with 2,2-dimethoxy-propane-l,3-diol (0.139 mol), trimethylorthoformate (0.278 mol), p-toluenesulfonic acid (100 mg), and 300 ml of methanol and then stirred for 12 hours. The mixture was then treated with Na2C03 (300 mg) and stirred for an additional 12 hours and then filtered and concentrated. The solid was recrystallized in diethyl ether and 17.5 g of product isolated. 

This type of resonance stabilized oxonium ion is the chain carrier proposed by Dreyfuss and Dreyfuss (25) in the transfer reaction with trimethylorthoformate (Section III D). 

Aromatic aldehydes (10 mmol) and trimethylorthoformate (20 mmol) was added to a mixture of sulfonamide (10 mmol), finely powdered calcium carbonate (9 g) and K-10 clay (2 g). The solid homogenized mixture was placed in a modified reaction tube which was connected to a removable cold finger and sample collector to trap the ensuing methanol and methyl formate. The reaction tube is inserted into Maxidigest MX 350 (Prolabo) microwave reactor equipped with a rotational mixing system. After irradiation for a specified period, the contents were cooled to room temperature and mixed thoroughly with ethyl acetate (2 x 20 mL). The solid inorganic material was filtered off and solvent was evaporated to afford tlie residue which was crystallized from the mixture of hexane and ethyl acetate. 

Trimethylorthoformate forms a stabilized dioxocarbenium ion which activates the lactone towards attack by methanol with Sn2 inversion at the methyl-substituted carbon. 

Deuterated ethyl benzene Benzoyl chloride Trimethylorthoformate... 

Rearrangement was avoided by ketalization at lower temperature with a mixture of ethylene glycol, trimethylorthoformate and/ -toluenesulfonic acid as a catalyst. 

Trimethylorthoformate 17 is a highly activated Cl building block and a formic acid equivalent which is commonly applied in organic condensation reactions. 17 can be produced on an industrial scale by two major routes. The first starts with chloroform and sodium methanolate, but produces 3 equiv. of sodium chloride as waste. The second route is based on the acidic methanolysis of cyanhydric acid, which also produces stoichiometric amounts of ammonium chloride. Despite the reduced salt waste, the use and handling of cyanhydric acid mean high safety costs. Therefore, anodic methoxylation of formaldehyde dimethylacetal (16) to... 

Fig. 5.5 Electrochemical synthesis of trimethylorthoformate (6). Reagents and conditions undivided cell, BDD anode, steel cathode, 24% MeOH, 70% FADMA, LiN(S02CF3)2/Na0Me, 20°C, 9Adm-2...

It has been demonstrated that N-hydroxytryptophan can be converted to /3-carbolines in two ways (Fig. 41). Pictet-Spengler reaction of 1 with acetals provided the N -hydroxytetrahydro-/8-carbolines (2) (287). A modified Bischler-Napieralski reaction of 1 with trimethylorthoformate gave N -0X0-3,4-dihydro-/3-carbolines (3), the nitrone function of which can undergo 1,3-dipolar cycloaddition with alkenes (288) and nitriles (289), providing isoxazolidine (4) and dehydro-1,2,4-oxadiazoline (5), annulated TBCs, respectively. Nitrone 3 also was obtained by oxidation of the N-hydroxy-j8-carboline 2 with 2,3-dichloro-5,6-dicyano-l, 4-benzoquinone (DDQ). N-Oxygenated TBCs showed no affinity for the benzodiazepine and tryptamine receptors (290). Unfortunately, no toxicity data were recorded for these substituted hydroxylamines. 

The authors used (5)-carvotanacetone (dihydrocarvone) as starting material (Scheme 34). To prepare the linearly conjugated sUylenol ether, they used the Kharash protocol and attained y-alkylation by Mukaiyama aldol reaction with trimethylorthoformate (195). The ketoacetal 295 was a-hydroxylated according to Rubottom by silylenol ether formation followed by epoxidation and silyl migration. Acid treatment transformed 296 to the epimeric cyclic acetals 297 and 298. endo-Aceta 297 was equilibrated thereby increasing the amount of exo-acetal 298. The necessary unsaturated side chain for the prospected radical cyclization was introduced by 1,4-addition of a (trimethylsilyl)butynylcopper compound. 

Mukaiyama aldol reactions of various silyl enol ethers or ketene silyl acetals with aldehydes or other electrophiles proceed smoothly in the presence of 2 mol % B(CgF5)3 [151a,c]. The following characteristic features should be noted (i) the products can be isolated as j8-trimethylsilyloxy ketones when crude adducts are worked-up without exposure to acid (ii) this reaction can be conducted in aqueous media, so that the reaction of the silyl enol ether derived from propiophenone with a commercial aqueous solution of formaldehyde does not present any problems (iii) the rate of an aldol reaction is markedly increased by use of an anhydrous solution of B(C6Fs)3 in toluene under an argon atmosphere and (iv) silyl enol ethers can be reacted with chloromethyl methyl ether or trimethylorthoformate hydroxymethyl, methoxy-methyl, or dimethoxymethyl Cl groups can be introduced at the position a to the carbonyl group. These aldol-type reactions do not proceed when triphenylborane is used (Eq. 92). 

Compound 5 (29 g 155 mmol, 1 eq) and trimethylorthoformate (685 mmol, 4.4 eq) were dissolved in dichloromethane (75 ml). Paratoluenesulfonic acid (300 mg, 1.7 mmol, 0.01 eq) was added, and the mixture was stirred at room temperature during 2 h. The reaction medium was diluted with dichloromethane (500 ml) and washed successively with NaHCOj sat (3x200 ml), and NaClsat... 

Bromooctyltrimethoxysilane. A 3 neck 1 liter flask equipped with magnetic stirrer, addition funnel and condensor was charged with 400ml of trimethylorthoformate and warmed to 30-35°. Over the course of three hours 327g of 8-bromooctyl-trichlorosilane was added. The mixture was distilled. The fraction boiling at 127-130°/2mm was identified as 8-bromooctyl-trimethoxysilane, 93% yield. 

Variations on this synthetic route remain the method of choice for accessing derivatives of 14-aminocodeinone. Improvements were made through process research at Reckitt Colman (now Reckitt Benckiser). In this modification, adduct (17) was treated with ethylene glycol and trimethylorthoformate followed by acetyl chloride to yield ethylene ketal (19) (Scheme 3). This was reduced using zinc in ammonium carbonate with subsequent hydrolysis to the codeinone (13). This remains the current method of choice. 

GC Look, MM Murphy, DA Campbell, MA Gallop. Trimethylorthoformate a mild and effective dehydrating reagent for solution and solid phase imine formation. Tetrahedron Lett 36 2937-2940, 1995. 

The most common ketals are dioxolane and dioxane these form more readily and have fewer problems with enol ether contamination. Sometimes, however, they can be difficult to hydrolyze, particularly when the molecule contains sensitive functional groups. The reaction is acid catalyzed, with some of the more common acids being para-toluenesulfonic, pyridinium para-toluenesulfonic, and eamphorsulfonie. The eluninated water can be removed either with an azeotroping solvent (such as toluene or benzene) or by the addition of a dehydrating agent such as trimethylorthoformate. 

General procedure for Ugi reaction with support-bound isonitrile [346] A 1.2 m solution of 2-chlorobenzylamine (0.133 mL, 1.1 mmol) and 2-phenylpropio-naldehyde (0.146 mb, 1.1 mmol) in trimethylorthoformate (TMOF) was allowed to react for 30 min. (]3-Isocyano-ethyl)-alkyl-carbonate resin (126 mg, 110 pmol, 0.87 mmol g ) was suspended in 1,2-dichloroethane (1.75 mL) in a 5-mL Bohdan fritted reaction tube and allowed to stand for 15 min. The 1.2 M solution ofimine in trimethylorthoformate was added to the resin, and... 

Universal Rink-isonitrile resin (450) has been applied to the synthesis of imi-dazo[l,2-a]pyridines (452) [356], a novel [357] MCR consisting of a condensation among 2-aminopyridines, aldehydes, and isonitriles. During the course of the reaction, the isonitrile component becomes an enamine. The reaction was performed in the presence of a catalytic amount of para-toluenesulfonic add in a desiccating mixture of CHCU/MeOH/trimethylorthoformate (TMOF) (Scheme 92). 

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