Benzhydrol Derivatives

Diphenylmethane Base Method. In this method, the central carbon atom is derived from formaldehyde, which condenses with two moles of an arylamine to give a substituted diphenylmethane derivative. The methane base is oxidized with lead dioxide or manganese dioxide to the benzhydrol derivative. The reactive hydrols condense fairly easily with arylamines, sulfonated arylamines, and sulfonated naphthalenes. The resulting leuco base is oxidized in the presence of acid (Fig. 4). 

Inclusion of a second nitrogen atom in the side chain seemingly increases the spasmolytic effect of the benzhydrol derivatives. Alkylation of the benzdryl chloride (9) with the sodium... 

Benzyhydrol Derivatives Cyprolidol (26), a highly modified benzhydrol derivative, is reported to exhibit antidepressant activity it is of note that this agent bears little structural relation to either the MAO inhibitors or tricyclic antidepressants. Addition of the carbene from... 

In a variation of this method, isolation of the benzhydrol derivative is not required. The methane base undergoes oxidative condensation in the presence of acid with the same or a different arylamine directly to the dye. New fuchsine [3248-91-7], Cl Basic Violet 2 (16), is prepared by condensation of two moles of o-toluidine with formaldehyde in nitrobenzene in the presence of iron salts to give the corresponding substituted diphenylmethane base. This base is also not isolated, but undergoes an oxidative condensation with another mole of <> t olu idme to produce the dye. 

Benzaldehyde, benzoin and benzhydrol derivatives are obtained in the reaction of FefCO), with LiPh, followed by hydrolysis. The scheme in Egs. (f) and (g) is assumed to explain the observed products, starting with the formation of the anionic lithiated benzoyl derivative, which upon hydrolysis gives benzaldehyde. 

The reaction of hexacarbonyls of group VIB gives the anionic [MCOR(CO)5] complexes. Their protonation with mineral acids in water gives acetaldehyde (R = Me) and benzaldehyde (R = Ph), respectively. The formation of benzoin and benzhydrol derivatives in the Fe(CO),-LiR reaction is suggested to occur via C—C coupling of the unstable hydroxycarbene with benzaldehyde, whereas benzhydrol originates from further attack of lithiated Fe(CO)5 [Eq. (0] by LiR, followed by hydrolysis. 

From SAR studies, introduction of an amino group at the ortho position of the B-ring was expected to maintain the quasi cis conformation to obtain more potent anti-tubulin agents and also increase water solubility by potential salt formation. A variety of 2-aminobenzophenone derivatives was then synthesized via Grignard reaction of (3,4,5-trimethoxyphenyl)magnesium bromide with several commercially available or synthesized substituted 2-nitrobenzaldehydes, followed by oxidation of the obtained benzhydrol derivatives with PDC to 2-nitrobenzophenones, which were in turn reduced to the corresponding aminobenzophenones with Fe/AcOH (Scheme 19). 

Using this exchange reaction, some functionalizations of aryl halides were examined. As an example of 1,2-addition to a carbonyl group, the arylzinc prepared from 4-iodobenzoate and diethylzinc in the presence of Bu-P4 base in THF was reacted with benzaldehyde to give the benzhydrol derivative in 78% yield. As for the 1,4-addition reaction, the arylzinc prepared similarly in THF was reacted with chalcone and the 1,4-adduct was obtained in 71% yield under copper-free reaction conditions. Allylation was also carried out in the absence of copper additive, and allylbenzoate was obtained in 98% yield. It has been reported that arylzinc compounds are inert to 1,4-addition and allylation reaction in the absence of additives and conventionally the employment of copper species has been widely used. However, in this case the Bu-P4 base is considered to promote the reactivity of arylzinc compounds toward electrophiles [59] (Scheme 5.38). 

Under electrochemical reduction conditions, 2-propenyl bromide reacts with benzaldehyde in the presence of a catalytic amount of CrCl2 and Pd(OAc)2 and provides a-isopropenylbenzyl alcohols in moderate yield (Scheme 48). Phenyl bromide and iodide show similar reactivity and provide benzhydrol derivatives in comparable yield. 

Further work by the Ye group has shown that NHCs derived from pre-catalyst 215 can also promote the asymmetric dimerisation of alkylarylketenes 193 to generate alkylidene P-lactones 216 in good diastereo- and enantio-selectivity [83], The asymmetric [4+2] addition of enones and alkylarylketenes to generate 8-lactones 218 in high ee has also been accomplished [84], as has the asymmetric esterification of alkylarylketenes to give esters 217 using benzhydrol, which is assumed to proceed via a Lewis-base mediated mechanism (Scheme 12.46) [85]. 

From these data, it can be estimated that chlorphenoxamine (11.24, R = 4-C1, R = Me) should hydrolyze ca. 17 times faster than diphenhydramine. This decreased stability appears sufficient to drive formation of detectable amounts of the benzhydrol metabolite (11.25, R = 4-C1, R = Me) in the stomach of patients dosed with chlorphenoxamine. Indeed, ether bond cleavage to form this and derived metabolites was a major pathway in humans [49], Whether the reaction was entirely nonenzymatic or resulted in part from oxidative O-dealkylation (Chapt. 7 in [50]) remains unknown. 

F. Bellamy, D. Horton, J. Millet, F. Picart, S. Samreth, and J. B. Chazan, Glycosylated derivatives of benzophenone, benzhydrol and benzhydril as potential venous antithrombotic agents,./. Med. Chem., 36 (1993) 898-903. 

The morpholine derivatives phenmetrazine (173 R = H) and phendimetrazine (173 R = Me) have stimulant properties like those of amphetamine. They have been used as anorectics, but they are liable to abuse. Another CNS stimulant used as an anorectic is mazindol (174), which bears some resemblance to certain benzhydrols with antidepressant activity. 

Annulation of a benzene derivative to the naphthalene framework normally requires a number of steps. A recent one-pot procedure involves heating the benzhydrols 1 in toluene with a five-fold excess of maleic anhydride for several hours, and gives the 1-arylnaphthalene derivatives 2 in moderate yield. 

Displacement of a chloride, conveniently derived from the benzhydrol, has often been utilized. However, running the reaction with sodium iodide in acetonitrile improved yields of the displacement reaction, presumably via a Finklestein reaction (Scheme 2). 

OPD and o-dibenzoylbenzene (68CC1202). Benzodiazocine 166 (R = Me, Ar = P-CIC6H4), upon treatment with acetic anhydride, yields, in addition to isoindole 167 (vide supra), the benzhydrol 191 (70CJC1670). Mild alkaline hydrolysis of pyridazinobenzodiazocine 74 yielded 5-(o-aminophenyl-carbamoyl)pyridazine-4-carboxylic acid (74JCS(P 1)1022). The diazocine 192 or its saturated derivative, when condensed with diacetylene in dry benzene or without a solvent, gave heterochain polyamine 193 (70MI1). 

Carboxylic acid derivatives such as esters and amides undergo nucleophilic acyl substitution reactions with the ketone dianion derived fiom benzophenone, providing modest yields of the corresponding carbonyl products (equations 102 and 103). Benzhydrol is a significant by-product in these reactions. 

Treatment of benzophenone with 153 in THF gave good yields of benzhydrol and imines 156 and 157 but no trace of cyclic products derived from 155 (formed via oxidation of 153 to give 154). The anion 153 does not cyclize under the reaction conditions. Cyclic products would be expected if 153 had been oxidized to radical 154 since 154 cyclizes 111). This and other experiments led to the conclusion that the reduction of benzophenone by dialkyl amides containing P-hydrogen atoms occurs via hydride and not via electron transfer. 

Pavia, M. R., Lobbestael, S. J., Nugiel, D., Mayhugh, D. R., Gregor, V. E., Taylor, C. P., Schwarz, R. D., Brahce, L., Vartanian, M. G. Structure-activity studies on benzhydrol-containing nipecotic acid and guvacine derivatives as potent, orally-active inhibitors of GABA uptake. J. Med. Chem. 1992, 55, 4238-4248. 

---