Birch reduction cyclohexenone

The Y appendage of 2-cyclohexenone 191 cannot be directly disconnected by an alkylation transform. (y-Extended enolates derived from 2-cyclohexenones undergo alkylation a- rather than y- to the carbonyl group). However, 191 can be converted to 192 by application of the retro-Michael transform. The synthesis of 192 from methoxybenzene by way of the Birch reduction product 193 is straightforward. Another synthesis of 191 (free acid) is outlined in... 

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. 

HEPTYL-2-CYCLOHEXENONE ALKYLATION OF THE ANION FROM BIRCH REDUCTION OF o-ANISIC ACID... 

Alkeuyl-3-methyl-2-eyclohexene-t-ones. The kinetic enolate of 3-methyl-3-cyclohexene-l-one is alkylated only by reactive halides such as allyl bromide. An alternate route to compounds of type 2 starts with the 2-diethy1aminoethyl ether of 2,5-dihydro-m-cresol (1), obtained by Birch reduction. (The corresponding methyl ether is not readily metalated.) n-Butyllithium-HMPT in THF can metalate 1. The resulting carbanion is alkylated by a variety of alkyl bromides to give, after acid hydrolysis, cyclohexenones 2 in yields of 80-90%. ... 

The Birch reduction of aromatic hydrocarbons and ethers to the 2,5-dihydro derivatives proceeds most satisfactorily when the substitution pattern allows the addition of hydrogen to two unsubstituted positions in a para relationship. If this requirement is satisfied, better yields are obtained from more highly substituted aromatic rings than from (say) anisole itself, which affords a substantial amount (20%) of 1-methoxycyclohexene (c/. Scheme 1). Extra substitution presumably hinders protonation at the terminus of the dienyl anion (which would lead to a conjugated diene and overreduction). The utilization of anisole moieties as precursors to cyclohexenones has been of very limited value with many 1,2,3-substitution patterns and more densely substituted derivatives. Compounds (23) to (26), for example, have only been reduced by employing massive excesses (200-600 equiv.) of lithium metal,2 while the aromatic ring in (28) is completely resistant to reduction. ... 

Formation of Cyclohexenones. Hydrolysis of the initial enol ether (vinyl ether) formed from Birch reduction of anisole or substituted anisoles under mild acidic conditions leads to P,y-unsaturated cyclohexenones. Under more drastic acidic conditions, these isomerize to the conjugated a, 3-cyclohexenones. Birch reduction of anisoles followed by hydrolytic workup is one of the best methods available for preparing substituted cyclohexenones. ... 

It should be noted that Birch reduction of 4-substituted anisoles followed by acidic workup (aq HCl, THF) produces mixtures of isomeric cyclohexenones containing an appreciable amount of the P,y-unsaturated product. ... 

Alkyl-6-hydroxy-2-cyclohexenones The heterocycle of the Birch reduction (Na,... 

Preparation of 6-alkyl-A -cyclohexenones. A procedure developed by Stork and White, as illustrated by the preparation of the 6-methyl derivative, involves Birch reduction of o-toluidine to a mixture of dihydrides converted on mild acid hydrolysis to what proved to be a mixture of the unsaturated ketones, (3) and (4), and some... 

Birch reduction of aromatic ethers is well known to afford alicyclic compounds such as cyclohexadienes and cyclohexenones, from which a number of natural products have been synthesized. Oxidation of phenols also affords alicyclic cyclohexadienones and masked quinones in addition to C—C and/or C—O coupled products. All of them are regarded as promising synthetic intermediates for a variety of bioactive compounds including natural products. However, in contrast to Birch reduction, systematic reviews on phenolic oxidation have not hitherto appeared from the viewpoint of synthetic organic chemistry, particularly natural products synthesis. In the case of phenolic oxidation, difficulties involving radical polymerization should be overcome. This chapter demonstrates that phenolic oxidation is satisfactorily used as a key step for the synthesis of bioactive compounds and their building blocks. 

New and continuing efforts towards the total synthesis of dendrobine (59 R = H) have been reported.In one sequence (Scheme 8), the butyric acid (85) was readily transformed into the ketal (86), which was submitted to a Birch reduction and hydrolysis to yield the cyclohexenone (87) as the single diastereomeric product. Acid treatment of (87) gave a stereoisomeric mixture of products (88) which were not separated but subjected to reaction with base to give compound (89). The same compound was obtained directly by treatment of (87) with strong base (Michael and aldol condensations combined). After some discouraging results, the tricyclic compound (89) was transformed into the desired keto-acid (90) via an abnormal ozonolysis reaction. Compound (90) possesses the correct stereochemistry at three asymmetric centres required for elaboration of dendrobine (59 R = H). 

Cyclohexenone ring from phenolethers Birch reduction... 

Substituent groups on the benzene ring influence the course of the reaction. Birch reduction of methoxybenzene (anisole) leads to the formation of 1-methoxy-1,4-cyclohexadiene, a compound that can be hydrolyzed by dilute acid to 2-cyclohexenone. This method provides a useful synthesis of 2-cyclohexenones ... 

A Birch reduction of 40, followed by acylation of the amino group in the resulting dihydro derivatives 41 with cyanoacetic acid and subsequent hydrolysis of the enol ether moiety gave cyclohexenones 42. Treatment of 42 with a substoichiometric amount of NaOEt caused the isomerization of the carbon—carbon double bond to give an a,P-enone and the closure of the piperidine B ring by an intramolecular Michael addition, leading to the ds-fused perhydroisoquinoUne derivatives 43 as mixtures of C-9 epi-mers. A stereoselective allylation from the most accessible face of 43... 

The ether (19) is smoothly formed by a Birch reduction metallation followed by addition of alkyl halide gives, after hydrolysis, cyclohexenones (Scheme 33). ... 

Methyl-3-cyclohexenone was prepared by Birch reduction of p-methylanisole followed by hydrolysis of the resulting enol ether, cf. A. J. Birch, J. Chem. Soc., 596 (1946). 

---