Benzamides, reduction

Further substitution of benzoic acid leads to a drug with antiemetic activity. Alkylation of the sodium salt of p-hydroxy-benzaldehyde (8) with 2-dimethylaminoethyl chloride affords the so-called basic ether (9). Reductive amination of the aldehyde in the presence of ammonia gives diamine, 10. Acylation of that product with 3,4,5-trimethoxybenzoyl chloride affords trimetho-benzamide (11). ... 

Carnell et al. discovered that whole cells of Cunninghamella echinulata NRRL1384 were able to deracemize racemic N-(l-hydroxy-l-phenylethyl)benzamide (24) to produce the (R) enantiomer (Figure 5.17) [30]. The deracemization involves fast, highly (S)-selective oxidation, followed by slower, partially (R)-selective reduction of the ketone (25). Optimization by removing competing extracellular amidase/prote-ase activity resulted in 82% yield and 92% ee. 

Amides can also be deacylated by partial reduction. If the reduction proceeds only to the carbinolamine stage, hydrolysis can liberate the deprotected amine. Trichloroac-etamides are readily cleaved by sodium borohydride in alcohols by this mechanism.237 Benzamides, and probably other simple amides, can be removed by careful partial reduction with diisobutylaluminum hydride (see Section 5.3.1.1).238... 

This reduction in crystal symmetry is conveniently illustrated in the systems cinnamide, benzamide, or, in general, any amide RCONH2 packing in a ribbon motif comprising centrosymmetric hydrogen-bonded dimers interlinked by translation (Scheme 16). 

In contrast to the aforementioned monosubstitutions, much less is known about the effect of disubstitution. It appears that such benzamides are resistant to hydrolysis. The metabolic fate of nitromide (3,5-dinitrobenzamide, 4.63), a chicken-feed additive for the prevention of coccidosis, was investigated in rats. The metabolite 3-amino-5-nitrobenzoic acid (4.64), formed by ni-tro reduction and hydrolysis, was excreted in only trace amounts. Nitromide was metabolized mainly via nitro reduction [36], Similarly, no hydrolysis was... 

Whether the dianion of azohenzene is able to deprotonate MeCN (pK 31.3) has been discussed [62, 64, 68]. However, on a preparative scale generation of CH2CN takes place at the potential of the second reduction of azohenzene, and reactions initiated by cyanomethylation of benzamide [108], carbonyl compounds (or their Schiff bases) or Q , 8-unsaturated nitriles either present in situ [69, 109] or added subsequently [110-112] have been studied. A mixture of products is normally obtained. 

Synthetic applications of the asymmetric Birch reduction and reduction-alkylation are reported. Synthetically useful chiral Intermediates have been obtained from chiral 2-alkoxy-, 2-alkyl-, 2-aryl- and 2-trialkylsllyl-benzamides I and the pyrrolobenzodlazeplne-5,ll-diones II. The availability of a wide range of substituents on the precursor benzoic acid derivative, the uniformly high degree of dlastereoselection in the chiral enolate alkylation step, and the opportunity for further development of stereogenic centers by way of olefin addition reactions make this method unusually versatile for the asymmetric synthesis of natural products and related materials. 

Birch reduction of the chiral benzamide 5 generates the amide enolate 6 (Scheme 4). This enolate has been characterized by NMR spectroscopy and by an extensive examination of the effects of changes in alkali metal, solvent, reaction... 

It is important to perform both the Birch reduction of 5 and the alkylation of enolate 6 at —78 °C. Enolate 6 obtained directly from 5 at low temperatures is considered to be a kinetic enolate . A thermodynamic enolate obtained from 6 by equilibration techniques has been shown to give an opposite sense of stereoselection on alkylation. Although a comprehensive study of this modification has not been carried out, diastereoselectivities for formation of 8 were found to be greater than 99 1 for alkylations with Mel, EtI, and PhCH2Br. Thus, it should be possible to obtain both enantiomers of a target structure by utilization of a single chiral benzamide. SE... 

A structural requirement for the asymmetric Birch reduction-alkylation is that a substituent must be present at C(2) of the benzoyl moiety to desymmetrize the developing cyclohexa-1,4-diene ring (Scheme 4). However, for certain synthetic applications, it would be desirable to utilize benzoic acid itself. The chemistry of chiral benzamide 12 (X = SiMes) was investigated to provide access to non-racemic 4,4-disubstituted cyclohex-2-en-l-ones 33 (Scheme 8). 9 Alkylation of the enolate obtained from the Birch reduction of 12 (X = SiMes) gave cyclohexa-1,4-dienes 32a-d with diastereoselectivities greater than 100 1 These dienes were efficiently converted in three steps to the chiral cyclohexenones 33a-d. 

The first asymmetric total synthesis of (+)-lycorine is outlined in Scheme 15. While our earlier applications of the Birch reduction-alkylation of chiral benzamide 5 were focused on target structures with a quaternary stereocenter derived from C(l) of the starting benzoic acid derivative, the synthesis of 64 demonstrates that the method also is applicable to the construction of chiral six-membered rings containing only tertiary and trigonal carbon atoms. s... 

Birch reduction-methylation of the 2,3-dialkyl substituted benzamide 85 (Scheme 19) provided the cyclohexa-1,4-diene 86 with diastereoselectivity comparable to that observed with the 2-alkylbenzamides illustrated in Scheme 4. Cyclohexadiene 86 was converted to iodolactone 87 and reduction of 87 with BusSnH occurred with exclusive equatorial delivery of hydrogen to give the axial methoxyethyl derivative 88. Lactone 88 was converted to the Caribbean fruit fly pheromone (+)-epia-nastrephin 90 (> 98% ee) in 9.5% overall yield from the chiral benzamide 85. °... 

Chiral benzamides I and the pyrrolobenzodiazepine-5,11-dio-nes n have proven to be effective substrates for asymmetric organic synthesis. Although the scale of reaction in our studies has rarely exceeded the 50 to 60 g range, there is no reason to believe that considerably larger-scale synthesis will be impractical. Applications of the method to more complex aromatic substrates and to the potentially important domain of polymer supported synthesis are currently under study. We also are developing complementary processes that do not depend on a removable chiral auxiliary but rather utilize stereogenic centers from the chiral pool as integral stereodirectors within the substrate for Birch reduction-alkylation. 

Product yields from reduction of substituted 2-haIogcno-N-methyl-benzamides at a mercury cathode in dimethylformamide. Ref. [165]. 

Procainamide Procainamide, 4-amino-N-[2-(diethylamino)ethyl]benzamide (18.1.3), is synthesized by reacting 4-nitrobenzoic acid chloride with N,N-diethylethylendiamine and subsequent reduction of the nitro gronp of the resnlting 4-nitro-N-[2-(diethylamino)ethyl]ben-zamide (18.1.2) into an amino group [8,9]. 

Base-catalyzed cyclization of A -benzoyl-a-chloroacetamide is a classical method used to prepare 2-phenyl-4(5//)-oxazolone. Extension of this methodology to the A -aroylcinnamides 35 afforded a series of 5-arylidene analogues 37 albeit in unstated yield (Scheme 6.12). " Thus, acylation of the sodium salt of a benzamide with a cinnamoyl chloride gave the imides 35 that were converted to 36 via a bromination-dehydrobromination sequence. Cyclization to 37 was affected with sodium hydride in 1,2-dimethoxyethane (DME). The authors noted that catalytic reduction of 37 afforded the 5-(arylidene)oxazolidine from which 37 could be regenerated in the presence of air. 

Birch reduction of enantiomcrieally pure benzamides followed by alkylation of the amide enolate was used with remarkable success to obtain chiral cyclohexadiene derivatives22. In this case the chiral auxiliary was located in the benzamide moiety. 

The reversed sense of diastereoselectivity is also observed in the direct Birch reduction alkylation of a number of ort/w-alkylated benzamides of 2-(methoxymethyl)pyrrolidine [i.e., l-(2-alkylbenzoyl)-2-(methoxymethyl)pyrrolidines, 8] which also give high diastereoselectivities of a-methylated products (see Table 6)33. Diastereomeric ratios (TR/TS) for the different R groups range from 5 95 for R = ethyl to 2 98 for R = 2-(tm-butyldimethylsilyloxy)ethyl33. 

Curious observation were made on attempted condensation of certain phenyl -substituted ethylene oxides with thiourea and related reagents, among them acetamide, benzamide, and thiobarbituric acid. Ktilbene oxide and ethyl epoxy tin nam a te, for example, underwent remarkably ready reduction on treatment with thiourea (Eq, 686), giving itilbene and ethyl cinnamate respectively, together with urea and free sulfur. 

The reduction of benzamide to benzylamine is the illustrative example (Expt... 

Birch reductive alkylation of benzamide (24) was optimized to give the corresponding cyclohexa-1,4-diene products in 66-78% isolated yield and with high diastereo- (g) selectivity.386... 

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