By-products in Birch reductions

Origin of by-products in Birch reductions / 18 Acidity of proton donor. Effect of iron in Birch reductions / 19 Requirements of Birch reduction procedures / 22 Experimental conditions for Birch reductions / 25... 

More interesting cases arise when the products of Birch reduction (Chapter 24) are treated with ozone. Here it is the electron-rich enol ether bond that is cleaved, showing that ozone is an electrophilic partner in 1,3-dipolar cycloadditions. If the ozonide is reduced, a hydroxy ester is formed whose trisubstituted bond s Zgeometry was fixed by the ring it was part of (see Chapter 31). 

The product from Birch reduction of estradiol 3-methyl ether, nandrolone, 1-5, comprises one of the simplest androgens in the gonane series. This compound suffers extremely fast metabolic inactivation by attack at C17 most androgens consequently incorporate an additional substituent at that position. 

In the Birch amp process, nitro compounds are reduced to amines in the presence of iron and an acid. This is the oldest commercial process for prepariog amines, but in more recent years it has been laigely replaced by catalytic hydrogenation. Nevertheless, the Biichamp reduction is still used in the dyestuff industry for the production of small volume amines and for the manufacture of iron oxide pigments aniline is produced as a by-product. The Biichamp reduction is generally mn as a batch process however, it can also be run as a continuous (48) or semicontinuous process (49). 

The best-known if -diene complexes are those of iron. They can be prepared by treatment of dienes with either Fe(CO)5 or Fe2(CO)9 (Scheme 10.1). The complexation reaction can be promoted in various ways, including ultrasonically. If non-conjugated dienes are used, one alkene may migrate to give the if -complex. This is particularly useful for the synthesis of some cyclic complexes, as non-conjugated dienes are products of Birch reduction. 

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... 

Metal-ammonia solutions reduce conjugated enones to saturated ketones and reductively cleave a-acetoxy ketones i.e. ketol acetates) to the unsubstituted ketones. In both cases the actual reduction product is the enolate salt of a saturated ketone this salt resists further reduction. If an alcohol is present in the reaction mixture, the enolate salt protonates and the resulting ketone is reduced further to a saturated alcohol. Linearly or cross-conjugated dienones are reduced to enones in the absence of a proton donor other than ammonia. The Birch reduction of unsaturated ketones to saturated alcohols was first reported by Wilds and Nelson using lithium as the reducing agent. This metal has been used almost exclusively by subsequent workers for the reduction of both unsaturated and saturated ketones. Calcium has been preferred for the reductive cleavage of ketol acetates. 

The reduction of aromatic compounds 1 by alkali metals in liquid ammonia in the presence of an alcohol is called the Birch reduction, and yields selectively the 1,4-hydrogenated product " 2. 

Reduction of aromatic compounds to dihydro derivatives by dissolved metals in liquid ammonia (Birch reduction) is one of the fundamental reactions in organic chemistry308. When benzene derivatives are subjected to this reduction, cyclohexa-1,4-dienes are formed. The 1,4-dienes obtained from the reduction isomerize to more useful 1,3-dienes under protic conditions. A number of syntheses of natural products have been devised where the Birch reduction of a benzenoid compound to a cyclohex-1,3-diene and converting this intermediate in Diels-Alder fasion to polycyclic products is involved (equation 186)308f h. 

The second approach (224-226) employs O-methylhexadehydroyohimbine (420), prepared from spiroindeno-2-(l -tetrahydro-0-carboline)-l-onederivative 416 by photolysis and subsequent reduction, as the key intermediate. The side product (418) of the photolysis was also utilized for the preparation of 420 via subsequent phosphoryl chloride treatment and sodium borohydride reduction. Birch reduction of 420 resulted in enol ether 421, which could be transformed to 15,16-didehydroyohimbinone (410), prepared previously by Szantay et al. (74, 221) as a universal precursor of the synthesis of yohimbine-type alkaloids. 

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. 

In case of benzene, the potassium salt of its anion-radical can be separated as a precipitate after benzene reduction by potassium in the presence of low concentrations of 18-crown-6-ether. For benzene, the heavy-form content is greatest in the solution, not in the precipitate. It is in the solution where most of the nonreduced neutral molecules remain. Since the neutral molecules are inert toward protons, the anion-radicals combine with the protons to give dihydro derivatives (products of the Birch reaction). Therefore, it is possible to conduct the separation chemically. The easiest way is to protonate a mixture after the electron transfer, than to separate the aromatic compounds from the respective dihydroaromatics (cyclohexadiene, dihydronaphthalene, etc.) (Chang and Coombe 1971, Stevenson and Alegria 1976 Stevenson et al. 1986a, 1986c, 1988). 

It was realized that the mechanism of Birch reduction involves protonation of the anion-radical formed by the addition of one electron to the reacting aromatic compound. This is followed by rapid addition of a second electron and protonation of the forming carbanion to yield nonconjugated alicyclic products. Protonation of the anion-radical by added alcohol is the rate-limiting stage. Recent calculations show that the ortho and meta positions in anisole are most enhanced in density by electron introduction. The para position is not appreciably affected (Zimmerman and Alabugin 2001 Scheme 7.9). 

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