Substituted benzophenone synthesis

Asymmetric synthesis in aldol-type reaction involving magnesium ester or lactone enolates has also been reported. Enolate of (—)-menthyl or (-l-)-bornyl acetate reacts with substituted benzophenones or a-naphtophenones to yield, upon hydrolysis of the resulting esters, optically active /3-hydroxyacids. Although these results are interpreted in terms of a steric factor. Prelog s rules are not applicable to these reactions (equation 88). 

Early workers [103] detected benzilic acid formed during the reduction of benzophenone in dimethylformamide in the presence of carbon dioxide. The carbon dioxide radical anion system is known to have E" = —2.2V (vs. SCE) [104] and will thus not be formed in preference to the ketone radical anion. Reaction occurs through trapping of aromatic carbonyl radical anions by carbon dioxide, and this has been developed into a convenient synthesis of aryllactic acids. The modern technological process uses constant current conditions. On a small scale, a divided cell with mercury cathode has been used to obtain benzilic acids from substituted benzophenones and carbon dioxide in 70-90% yields [105] and to convert 4-isopropylacetophenone to the corresponding phenyllactic acid in 85% yield [106]. On a technical scale, these reactions are best carried out in an undivided cell using a lead cathode and a sacrificial aluminum anode with dimethylformamide as solvent... 

The total synthesis of the potent protein kinase C inhibitor (-)-balanol was accomplished by J.W. Lampe and co-workers. They took advantage of the anionic homo-Fries rearrangement to prepare the sterically congested benzophenone subunit. To this end, 2-bromo-3-benzyloxy benzyl alcohol was first acylated with a 1,3,5-trisubstituted benzoyl chloride to obtain the ester precursor in 84% yield. Next, the ester was treated with n-BuLi at -78 °C to perform a metal-halogen exchange. The resulting aryllithium rapidly underwent the anionic homo-Fries rearrangement to afford the desired tetra ortho-substituted benzophenone in 51% yield. 

A novel synthetic route for the preparation of unsymmetrically substituted benzophenones was developed in the laboratory of C.-M. Andersson utilizing an iron-mediated aromatic substitution as one of the key steps. The power of this method was demonstrated by the formal synthesis of the benzophenone moiety of the protein kinase C inhibitor balanol. In the late stages of the synthesis, it became necessary to convert the aromatic methyl ketone functionality of the highly substituted benzophenone substrate to the corresponding carboxylic acid. Bromine was added to sodium hydroxide solution, and the resulting sodium hypobromite solution was slowly added to the substrate at low temperature. Upon acidification the desired carboxylic acid was obtained in fair yield. 

Solid phase synthesis of organic molecules is exemplified by the pioneering work of Bunin and Ellman on solid phase synthesis of a small benzodiazepine library (29). As shown in Fig. 1, a substituted benzophenone was tethered to a solid support via a substituent (Ri). The solid supported benzophenone was then elaborated through five synthetic steps to the target benzodiazepines with four points of diversity. Cleavage from the solid support re-... 

From B. Pandey s research group comes a straightforward photochemical method for the synthesis of spirocyclic compounds. An intramolecular hydrogen abstraction by an excited enone group is followed by radical combination. It is remarkable that no product arising from photoenolization and subsequent cyclization was observed. This is usually observed in ortho-alkyl substituted benzophenone and acetophenone derivatives. 

IMI has also developed a general route for the synthesis of homo- and hetero-disubstituted benzophenones such as 4,4 -difluorobenzophenone (DFBP), 4,3 -di-fluorobenzophenone, and 4,4 -diphenoxybenzophenone (DPOBP). These substituted benzophenones are important materials, with a variety of uses as specialty monomers (for polyether ketones and polyarylene ether ketones) and pharmaceutical intermediates. These benzophenones are prepared by utilizing Heck technology in conjunction with an oxidative cleavage reaction. 

Subsequent testing revealed three hydroxy-substituted benzophenones that exhibited moderate levels of inhibition against HIV-1 protease and that could be used as leads for the design and synthesis of more potent inhibitors. 

In an instructive application for the construction of hindered benzophenones, an initial metal-halogen exchange of a bromo-benzyloxy ester with BuLi sets the stage for anionic homo-Fries rearrangement of the intermediate aryllithium species (eq 39). The resulting tetra orf/zo-substituted benzophenone serves as an intermediate for the synthesis of the potent protein kinase C inhibitor (—)-balanol. 

The synthesis of the substituted benzophenone shown below provides an instructive example of what we are trying to do. In principle, it could be synthesized by several possible pathways. However, if one asked any group of organic chemists how to make this compound, the Friedel-Crafts pathway would be suggested as the first choice by almost everyone. This speaks to the conceptual redirection that needs to be made if pollution prevention is to be successful. Our alternative involves the use of a quinone such as benzoquinone, an aldehyde and visible light (6). If the benzoquinone needed for the reaction was generated by the method of Frost (7), the overall approach would tmly be environmentally benign. 

Phosphazene and its derivatives have been used as bases to catalyze the synthesis of highly substituted benzofurans. Krause and co-workers used phosphazenes in a key step of their total synthesis of amurensin H, an antiinflammatory compound. Treatment of a highly substituted benzophenone precursor with P4- Bu in benzene gave amuresin H after deprotection of the methyl esters with boron tribromide. 

Inamoto and Doi used C-H activation/cyclization of (V-tosylenamines to prepare 3-arylindoles (equation 3) [35]. The substrates were prepared from symmetrically substituted benzophenones. Chiba s team employed 0-acyloximes to effect a synthesis of indole-3-carboxam-ides (equation 4) [36]. The groups of Queiroz [37] and Thasana [38] employed C-H activation/C-C bond formation to prepare complex indoles (equations 5 and 6). 

Several methods exist for the synthesis of substituted 3-phenyl 1,2-benzisoxazoles or hetero-benzisoxazoles varying from heating of substituted benzophenone azides (Example 1), triethyl phosphite reduction of ortho-nitro benzophenone or heterophenone compounds (Example 2), even to nucleophilic substitution of nitro compounds with aryl acetonitriles (Example 3). °... 

The remarkable enantioselectivity and activity achieved by the Ru(bis-phosphine)(diamine) catalysts has been demonstrated in the synthesis of many pharmaceuticals. The reduction of orf/zo-substituted benzophenones published by Noyori shows the power of this methodology. Hydrogenation of o-methylbenzophenone 35 afforded (5)-o-methylbenzhydrol 37 in high enan-tioselectivily and complete conversion which can be converted to orphena-drine, an anticholinergic and antihistaminic agent (Scheme 14.13). 

Pyran-2-one, 4-hydroxy-6-phenacyl-benzophenones from, 3, 686 Pyran-2-one, 4-hydroxy-6-phenyl-synthesis, 3, 795 Pyran-2-one, 4-methoxy-6-substituted... 

The methoxy group of methoxythiophenes shows a reactivity which, in many respects, differs appreciably from the reactivity of the corresponding anisoles. Thus, in an attempted Hoesch synthesis with 5-methoxy-2-thenylcyanide (167) and phloroglucinol, the methoxy group reacted instead and 5-(2, 4, 6 -trihydroxyphenyl)-2-thenyl cyanide (168) was obtained. 2-Thenyl cyanide reacts normally in the Hoesch synthesis, Likewise, upon acid hydrolysis of the reaction product of 5-methoxy-2-thienyllithium with benzophenone, (169) was obtained instead of the expected substituted methoxythiophene. No defined products could be isolated from the attempted Claisen rear-... 

The Ullman reaction has long been known as a method for the synthesis of aromatic ethers by the reaction of a phenol with an aromatic halide in the presence of a copper compound as a catalyst. It is a variation on the nucleophilic substitution reaction since a phenolic salt reacts with the halide. Nonactivated aromatic halides can be used in the synthesis of poly(arylene edier)s, dius providing a way of obtaining structures not available by the conventional nucleophilic route. The ease of halogen displacement was found to be the reverse of that observed for activated nucleophilic substitution reaction, that is, I > Br > Cl F. The polymerizations are conducted in benzophenone with a cuprous chloride-pyridine complex as a catalyst. Bromine compounds are the favored reactants.53,124 127 Poly(arylene ether)s have been prepared by Ullman coupling of bisphenols and... 

A third modality is based on the use of orthogonal protection during SPPS synthesis to achieve selective removal of a specific side-chain protecting group, followed by selective modification with an activated benzophenone moiety. At the conclusion of the side-chain modification, which is carried out on the resin-bound peptide, stepwise elongation of the peptide chain is resumed.11571 Table 5 provides a current summary of reported biologically active peptides substituted with a benzophenone moiety and includes some synthetic details about their preparation. 

The Paterno-Biichi reaction has been employed in the synthesis, often in high yield, of a large variety of substituted oxetanes. In addition to simple aliphatic and aromatic alkenes, cycloaddition of ketones to, for example, fumaronitrile,284 l,3-diacetylimidazolin-2-one288 [Eq. (73)], and allenes286 has been reported. Allenes yield both 1,5- and l,6-dioxaspiro[3.3]heptanes as well as the 2-alkylidene-oxetane this is illustrated for benzophenone and tetramethylallene in Eq. (74). Cycloaddition of ketones to ketenimines to form 2- and... 

A new synthesis of sterically hindered o-substituted tetraphenylethenes via McMurry olefination of the corresponding 2,2 -disubstituted benzophenones exploits electronic effects that dominate over steric considerations.187... 

An important issue is the right choice of substrate 1 which functions as an anion precursor. Successful organocatalytic conversions have been reported with indanones and benzophenone imines of glycine derivatives. The latter compounds are, in particular, useful for the synthesis of optically active a-amino acids. Excellent enantioselectivity has been reported for these conversions. In the following text the main achievements in this field of asymmetric organocatalytic nucleophilic substitutions are summarized [1, 2], The related addition of the anions 2 to Michael-acceptors is covered by chapter 4. 

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