Reductive alkylations benzoic acids

The reduction of benzoic acids affords the dienolate (77) which may be alkylated in situ by a variety of electrophiles to afford 1-substituted derivatives. Clearly, the addition of alcohol must be avoided or limited to small quantities. It may also be necessary to remove the ammonia before adding the electrophile. The vast majority of applications have been based on reactions with alkyl halides to form (78), but additions of (77) to formaldehyde, epoxides and a,p-unsaturated esters to form the range of adducts (79) to (81) have also been reported (Scheme 14). 

Simple Birch reduction of benzoic acid 131 gives initially an intermediate that can be represented as dianion 132. Proton transfer from C02H to the less stable of the two anions gives the enolate 133 that you will recognise as a (doubly) extended enolate with one a- and two y-positions. Alkylation occurs at the a-position to give 134. This is a useful way to construct a quaternary centre on a six-membered ring the two remaining alkenes can be further developed in many ways.36... 

Birch reductions of alkyl benzoates are not normally feasible due to the preference for Bouveault-Blanc-type reduction of the ester group. However, it has now been found that if one to two equivalents of water are added to the ammonia before addition of the metal, then good yields of cyclohexadiene-esters [e.g. (191) from ethyl benzoate] can be realised. It is known that Birch reductions of benzoic acids can be used to generate dianonic species (192). These have been found to undergo conjugate additions to methyl acrylate and... 

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). ... 

The aerobic reduction of aryl and alkyl carboxylates to the corresponding aldehydes. The reaction involves formation of an acyl-AMP intermediate by reaction of the carboxylic acid with ATP NADPH then reduces this to the aldehyde (Li and Rosazza 1998 He et al. 2004). The oxidoreductase from Nocardia sp. is able to accept a range of substituted benzoic acids, naphthoic acids, and a few heterocyclic carboxylic acids (Li and Rosazza 1997). 

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. 

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... 

The original racemic patents described the use of resolution to give a chiral oxirane, such as 25, as an intermediate or the use of a chiral auxiliary (20) to produce the salmeterol enantiomers. Alkylation of chiral amine 20 with 2-benzyloxy-5-(2-bromo-acetyl)-benzoic acid methyl ester, followed by diastereoselective reduction of the ketone with lithium borohydride furnished intermediate 21 after chromatographic separation of the diasteromers. Removal of the benzyl group and the chiral auxiliary was... 

Enantioselective Birch reduction-alkylation The chiral benzoic acid derivative 1, prepared by condensation of o-hydroxybenzoic acid with L-prolinol followed by cyclization (Mitsunobu reaction), undergoes Birch reduction (K, NH3, THF, t-butyl alcohol) followed by alkylation with C2H5I to give essentially only 2. Acid hydrolysis returns the chiral auxiliary and provides the 2-alkylated cyclo-hexenone 3. 

Radical cyclization to perhydroindanes. A new route to this ring system from benzoic acids involves reductive alkylation to provide an unsaturated acid such as 1 followed by iodolactonization to 2. The radical obtained on reduction of 2 with Bu,SnH cyclizes mainly to a cii-fused perhydroindane (3) and a pcrhydronaphthalene (4). In this... 

Amphetamines can be metabolised by (1) oxidative deamination followed by oxidation or reduction of the ketone and conjugation of the resulting acid and alcohol products (2) 7V-oxidation (3) hydroxylation of the aromatic ring and of the alkyl side-chain at the p-position and (4) 7V-dealkylation. Amphetamine is converted by oxidative deamination to phenylacetone which is further oxidised to benzoic acid this latter product is excreted as its glycine conjugate, hippuric acid. 

Formation of Chiral Quaternary Carbon. Birch reduction-alkylation of benzoic acids and esters establishes quaternary carbon centers. Neighboring stereocenters will influence the stereochemical outcome of the tandem reaction sequence. The following example illustrates how a chiral auxiliary (derived from prolinol) controls the stereoselection in the Birch reduction-alkylation step. ... 

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