Trimethylorthoformate synthesis

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. 

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. 

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...

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). 

The methodology was then applied to acid-catalyzed reactions, namely the synthesis of acetals [38] from a premixed solution of aldehyde or ketone and trimethylorthoformate. The reaction products were subsequently collected and concentrated in vacuo before analysis of the crude product by NMR spectroscopy. As Table 14.4 illustrates, using this approach, excellent product purities and yields were again obtained. 

Isoquinoline derivatives are an important family of natural products. They have diverse biological activities and are used, for example, as bronchodi-lators, skeletal muscle relaxants, and antiseptics. The solid-phase synthesis of a 43,000-compound tetrahydroisoquinoline 2 combinatorial library has been reported by Griffith et al. [32]. The library was synthesized by a three-step procedure. An imine was formed by reacting a substituted benzaldehyde with a methylbenzhydrylamine (MB HA) resin-bound amino acid. Imine formation was driven to completion using trimethylorthoformate as a dehydrating reagent. Treatment of the imine with homophthalic anhydride provided the desired tetrahydroisoquinoline (Fig. 3a). 

Ruhland et al. [38] reported the combinatorial synthesis of structurally diverse )3-lactams 6, Following removal of the Fmoc protecting group from resin-bound amino acids, a 10- to 15-fold excess of alkyl, aromatic, or a,j3-unsaturated aldehydes in a 1 1 mixture of trimethylorthoformate in dichlo-romethane (DCM) was added to yield resin-bound imines. The [2+2] cycloaddition occurred by addition of acid chlorides to a DCM suspension of... 

Murphy et al. [39] reported the synthesis of pyrrolidine 7 combinatorial libraries. Starting from polystyrene resin-bound amino acids, the a-amino ester was condensed with aromatic and heteroaromatic aldehydes in neat trimethylorthoformate to afford the resin-bound aryl imine. Pyrrolidine and pyrroline derivatives were obtained through cycloaddition of the 1,3-dipoles azomethine ylides to olefin and acetylene dipolarophiles. A library of 500 compounds was reported. The screening of this library for in vivo inhibition of angiotensin-converting enzyme (ACE) led to the identification of l-(3 -mercapto-2 -(S)-methyl-1 -oxopropyl)-5-phenyl-2,4-pyrrolidinedicarboxy-lic acid 4-methyl ester as a potent ACE inhibitor that incorporates the mer-captoisobutyryl side chain (Fig. 3e). 

E. C. Taylor, A. McKillop, and coworkers. Thallium in organic synthesis 49. Oxidative rearrangement of chalcone dimethylketals to methyl-2,3-diaryl-3-methoxypropanoates with thallium(m) trinitrate in trimethylorthoformate. J. Org. Chem., 1977, 42, 4167 50. A convenient synthesis of thallium(i) cyanide, a useful reagent in organic synthesis (for conversion of aroyl chlorides to aromatic a-ketonitriles). J. Org. Chem., 1978, 43, 2280 51. Oxidation of enolizable ketones to a-nitratoketones by thallium(in) nitrate in acetonitrile. 

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