Methylation with trimethyl orthoformate

Two efficient syntheses of strained cyclophanes indicate the synthetic potential of allyl or benzyl sulfide intermediates, in which the combined nucleophilicity and redox activity of the sulfur atom can be used. The dibenzylic sulfides from xylylene dihalides and -dithiols can be methylated with dimethoxycarbenium tetrafiuoroborate (H. Meerwein, 1960 R.F. Borch, 1968, 1969 from trimethyl orthoformate and BFj, 3 4). The sulfonium salts are deprotonated and rearrange to methyl sulfides (Stevens rearrangement). Repeated methylation and Hofmann elimination yields double bonds (R.H. Mitchell, 1974). 

In addition to aldehydes and a-diketones, a-ketoesters can also be used in the domino process, as shown by Tietze and coworkers [396]. Reaction of methyl pyruvate 2-791 with dimethylbarbituric acid (2-747) and the enol ether 2-792 in the presence of trimethyl orthoformate (TMOF) and a catalytic amount of EDDA gave the cycloadduct 2-793 in 84% yield (Scheme 2.176). 

Methyl cc-D-glucofuranosidurono-6,3-lactone (26) may be obtained exclusively by reaction of 4 with trimethyl orthoformate in the presence of boron trifluoride etherate.28 Its 2,5-dimethyl ether (27) is formed by methyl iodide-silver oxide methylation29,30 (Purdie-Ir-... 

Flumequine was prepared when 6-fluoro-2-methyl-1,2,3,4-tertrahydro-quinoline was first reacted with alkylidene malonates and trimethyl orthoformate in THF in the presence of p-toluenesulfonic acid, and then the products, alkylidene (6-fluoro-2-methyl-1,2,3,4-tetrahydroquinolin-1 -yl) methylenemalonates, were cyclized in xylene on the action of polyphos-phoric acid or ethyl polyphosphate at 110-115°C for 1 hr (89EUP310849). 

Organophosphorus compounds. Phosphorus-carbon bond formation takes place by the reaction of various phosphorus compounds containing a P—H bond with halides or triflates. Alkylaryl- or alkenylalkylphosphinates are prepared from alkylphosphinate[638]. The optically active isopropyl alkenyl-methylphosphinate 778 is prepared from isopropyl methylphosphinate with retention[639]. The monoaryl and symmetrical and asymmetric diary lphosphi-nates 780. 781, and 782 are prepared by the reaction of the unstable methyl phosphinate 779 with different amounts of aryl iodides. Trimethyl orthoformate is added to stabilize the methyl phosphinate[640]. 

Aflask was charged with methyl pyruvate (8.25 mol), trimethyl orthoformate (10 mol), methanol (1060 g), and para-toluenesulfonic acid monohydrate (0.041 mol) and then stirred at 58°C for 10 hours. It was then treated with 28% methanol solution of sodium methoxide (8 g) and concentrated. After distillation the product was isolated as a colorless transparent liquid in 98% purity having a boiling point (bp) of 80°C 40mmHg. 

Hydroxyhomophthalates. Complete details are available for construction of benzene rings by condensation of 1, as the dianion equivalent of methyl acctoacetate, with various 1,3-dicarbonyl equivalents.1 The reaction has been extended to condensation of 1 with a 1,3,5-tricarbonyl unit to form 3-hydroxyhomophthalates. Thus when 1 (2 equivalents) is treated with trimethyl orthoformate (1 equivalent) in the presence of TiCl4, dimethyl 3-hydroxy-homophlhalate (2) is formed in 68% yield. The reaction is believed to involve formation of the 1,3,5-lricarbonylequivuleni a, which then condenses with I to form 2. 

Methyla-arylacetates. These esters have been obtained by oxidative rearrangement of alkyl aryl ketones with thallium(III) nitrate in acidic methanol or trimethyl orthoformate (4,496 5, 656 7, 362). A new method, which avoids the toxic TTN, is based on the Woodward version of the Prevost reaction. Thus, treatment of the ketone with iodine (or bromine) and silver nitrate (2 equiv.) in refluxing methanol containing trimethyl orthoformate results in methyl a-arylacetates in 90% yield from simple substrates. Yields are lowered by electron-withdrawing substituents on the aromatic group and by a-branching in the alkyl group.2... 

Oxidative rearrangement of aryl methyl ketonesThese ketones have been converted into methyl a-methoxyarylacetates on reaction with T1(N03)2 in trimethyl orthoformate (7, 362). This oxidative rearrangement can also be effected with C6H5I(OAc)2 (2 equiv.) in trimethyl orthoformate in equally good yield. 

A mixture of DIB (70.8 g, 22 mmol), the acetophenone (10 mmol) and sulphuric acid (0.25 ml) in trimethyl orthoformate (30 ml) was stirred overnight at room temperature. Concentration was followed by treatment of the residue with saturated aqueous sodium bicarbonate, extraction with dichloromethane (3 x 50 ml), drying and concentration. The residue was purified by column chromatography on silica gel (benzene-petroleum ether, 4 1) to yield methyl a-methoxyarylacetates in 80-84% yield. 

Sulphuric acid (2 mmol) was added dropwise to a stirred solution of DIB (0.386 g, 1.2 mmol) and the propiophenone (1 mmol) in trimethyl orthoformate (3 ml), at room temperature. The mixture was stirred for 5-60 min at 0 or 60°C, quenched with water (10 ml) and extracted with ether (2 x 10 ml). The extract was washed with water (20 ml), dried and concentrated the residue was purified by column chromatography (silica gel) or by distillation to give the pure methyl a-methylaryl acetates in 81-88% yield. 

To a stirred solution of chalcone (5 mmol) in trimethyl orthoformate (20 ml) was added Dowex 50 x 4 cation exchange resin (3 g). After stirring at room temperature for 20 h, the mixture was filtered into a solution of HTI (2.37 g, 6 mmol) in trimethyl orthoformate (10 ml) and kept for 12 h. It was then quenched with 10% aqueous sodium bicarbonate (25 ml) and extracted with dichloromethane. The combined organic layers were washed with water, dried and concentrated the residue was purified by column chromatography on silica gel (benzene), to afford methyl 2,3-diaryl-3-methoxypropanoates in 80-94% yield. This method was better than that reported with thallium (III) nitrate not only because this toxic reagent is avoided but also because yields were considerably higher. 

The product from Step 1 (5.0 g), 5.0 ml of trimethyl orthoformate and 30 ml methyl alcohol were stirred in the presence of IR 120H ion-exchange resin (0.5 g, pre-washed with methyl alcohol) at ambient temperature 3 hours. Thereafter, the mixture was filtered, extracted with EtOAc, washed with saturated NaHC03 solution and brine, dried, concentrated, and 2.8 g of product isolated. H-NMR and MS data supplied. 

Alkyl bromides. Alcohols are converted into bromides by reaction with bromotrimethylsilane (1.5-4 equiv.) in CHCI3 at 25-50° (equation I). The reaction occurs with inversion. Tertiary and benzylic alcohols react more rapidly than primary or secondary alcohols. Bromides are not formed under the same conditions from Irimethylsilyl ethers of alcohols. However, trimethyl orthoformate is converted into methyl formate, HC(OCH3)3 —s HCOOCH3. Unlike iodotrimethylsUane, the bromosilane does not dealkylate esters, ethers, or carbamates. 

Cycloalkenones. Attempted preparation of the methyl enol ether of 1 with trimethyl orthoformate and perchloric acid results in formation of 2 in 41% yield. 

A keteneacetal, the Brassard diene, has also been bound to polystyrene-based resin (308). This has been achieved by the reaction of diketene with alcohol functions on polystyrene resin. The ketone function of the resulting acet-oacetate could readily be enolized by TMOF (trimethyl orthoformate) and a catalytic amount of H, giving the methyl enolate. The remaining ester function was then deprotonated with LDA and subsequently silylated with TBDMSCl. The resulting diene (311) was used in many hetero-Diels-Alder reactions (HDA) with aldehydes and ketones as dienophiles, giving a library... 

Application of the Vilsmeier reaction (review [1676]) to an o-methyl-amine may result in the formation of a fused pyrrole-3-carboxaldehyde ring. The same functional groups are annulated by reaction with trimethyl orthoformate to give a 2,3-unsubstituted pyrrole ring. 

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