Birch reductions

Birch reduction of aromatic compounds involves reaction with an electron-rich solution of alkali metal lithium or sodium in liquid ammonia (sometimes called metal ammonia reduction). Usually a proton donor such as tert-butanol or ethanol is used to avoid the formation of excess amount of LiNH2 or NaNH2. The major product is normally a 1,4-diene. This reaction is related to the reduction of alkynes to frans-alkenes ° (section 6.2.2). 

When substituents are present, they may influence the regioselectivity of the Birch reduction. The product is determined by the site of the first protonation, since the second protonation is nearly always opposite (para to) the first. Electron-donating substituents such as ethers and alkyl groups favour protonation at an unoccupied site meta to the substituent whereas electron-attracting substituents such as carboxyl favour para protonation. This can be explained by the stability of the intermediates 6.29 and 6.30 formed in both cases. 

Reduction of aryl ethers is a particularly useful application of the Birch reduction. Thus, methoxybenzenes are reduced to 1,4-dienes, as expected, but one of the double bonds is enol ether and is readily hydrolyzed, followed by rearrangement to give the corresponding a,P-unsaturated-ketone h Li, NH, 

The Birch reduction is the 1,4-reduction of aromatics to their corresponding cyclohexadie-nes by alkali metals (Li, K, Na) dissolved in liquid ammonia in the presence of an alcohol. 

Benzene ring bearing an electron-donating substituent  

Benzene ring with an electron-withdrawing substituent  

Arthur Birch (1915—1995), an Australian, developed the Birch reduction at Oxford University dnring WWIl in Robert Robinson s laboratory. The Birch reduction was instrumental to the discovery of the birth control pill and many other drugs. 

The Birch reduction comprises a means for adding two hydrogen atoms to an aromatic ring by means of a metal, most often lithium, and an alcohol in liquid ammonia as solvent. A co-solvent, often tetrahydrofuran (THF), is often added due to the very poor solubility of steroids in ammonia. The use of the more expensive sodium was at one time precluded because traces of iron in that metal catalyzed the conversion of the metal to the strong base sodium amide. Very pure sodium, free of iron impurities, is now used for commercial-scale reductions. 

Steroid Chemistry at a Glance Daniel Lednicer 2011 John Wiley Sons, Ltd 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 21, Springer-Verlag Berlin Heidelberg 2009 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 25, Springer International Publishing Switzerland 2014 

In the first example (I) T.J. Donohoe et al. utilized the Birch reduction to reduce then alkylate electron-deficient 2- and 

3-substituted pyrroles. This reductive alkylation method proved to be very efficient for the synthesis of substituted 3- and 2-pyrrolines, respectively. An alcohol as a proton source was not necessary for the reduction to occur. In the second example (II) the same researchers performed a stereoselective Birch reduction on a substituted furan during the enantioselective total synthesis of (+)-nemorensic acid.  

In the laboratory of A.G. Schultz during the asymmetric total synthesis of two vincane type alkaloids, (+)-apovincamine and (+)-vincamine, it was necessary to construct a crucial c/s-fused pentacyclic diene intermediate. The synthesis began by the Birch reduction-alkylation of a chiral benzamide to give 6-ethyl-1-methoxy-4-methyl-1,4-cyclohexadiene in a 100 1 diastereomeric purity. This cyclohexadiene was first converted to an enantiopure butyrolactone which after several steps was converted to (+)-apovincamine. 

The total synthesis of galbulimima alkaloid GB 13 was accomplished by L.N. Mander and co-workers. The Birch reduction of a complex intermediate was necessary in order to prepare a cyclic a,p-unsaturated ketone. The treatment of the substrate with lithium metal in liquid ammonia first resulted in a quantitative reductive decyanation of the C6a cyano group. The addition of excess ethanol to the reaction mixture reduced the aromatic ring to the corresponding enol ether that was hydrolyzed in a subsequent step to afford the unsaturated ketone. 

There are a wide variety of synthetic applications of this chemistry, making it one of the most powerful reactions in organic chemistry (sec. 10.5.B.vi). An example is the Birch reduction of the methoxybenzene portion of 514, which gave 515.Subsequent treatment with methanolic HCl converted the vinyl ether moiety in 515 to the ketone unit (via the enol) found in 516. Note that Birch reduction formed a trans ring juncture in 515 from the conjugated C=C unit in 514. Initial hydrolysis of 515 led to a nonconjugated ketone, but under the acidic conditions the conjugated systems found in 516 was formed. However, it is 

It is possible to form partially reduced bicyclic and tricyclic aromatic derivatives by this method. One of the more interesting synthetic features of the Birch reduction is the ability to alkylate the carbanionic intermediate generated by the electron-transfer reaction. Birch reduction of 517, for example, gave a mixture of 518 and 519 in 96% yield upon addition of 2-(2-bromo-5-methoxyphenyl)-l-iodoethane to the initially produced anion. 

The chemistry of enediynes, enyne allenes and related compounds  

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. 

Alkali metals in liquid ammonia can transfer an electron to the solvent, leading to so-called solvated electrons. These can add to the aromatic substrate 1 to give a reduced species, the radical anion 3  

Evidence for the radical anion 3 came from esr spectroscopic experiments, thus supporting this mechanism. The radical anion is protonated by the alcohol to give 

The negative charge of the cyclohexadienyl anion 5 is delocalized over several carbon centers, as is illustrated by the following resonance structures  

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Tran orm-based or long-range strategies The retrosynthetic analysis is directed toward the application of powerful synthesis transforms. Functional groups are introduced into the target compound in order to establish the retion of a certain goal transform (e.g., the transform for the Diels-Alder reaction, Robinson annulation, Birch reduction, halolactonization, etc.). 

Birch Reductions reduction of aromatic rings Organic Reactions 1976, 23, 1. Tetrahedron 1986, 42, 6354. Cornprehensice Organic Synthesis 1991, voJ. 8, 107. 

Another way to make cyclohexenes is by the partial reduction of benzene rings ( Birch reduction, described in Norman, p.553-557) such as ... 

Analysis The strategy for any modem syntheses of these compounds would be based on the Diels-Alder reaction or the Birch reduction ... 

Synthesis Since we can make both compounds from the same intermediate 395A, we ll use the Birch reduction route ... 

The use of reducing metals nowadays is mainly restricted to acyloin and pinacol coupling reactions (see p. 53f.) and Birch reductions of arenes (A.A. Akhrcm, 1972 see p. 103f.) and activated C—C multiple bonds (see p. 103f.). 

The less hindered f/ans-olefins may be obtained by reduction with lithium or sodium metal in liquid ammonia or amine solvents (Birch reduction). This reagent, however, attacks most polar functional groups (except for carboxylic acids R.E.A. Dear, 1963 J. Fried, 1968), and their protection is necessary (see section 2.6). 

In polycyclic systems the Birch reduction of C—C double bonds is also highly stereoselective, e.g. in the synthesis of the thermodynamically favored trans-fused steroidal skeletons (see p. 104 and p. 278). 

The Birch reductions of C C double bonds with alkali metals in liquid ammonia or amines obey other rules than do the catalytic hydrogenations (D. Caine, 1976). In these reactions regio- and stereoselectivities are mainly determined by the stabilities of the intermediate carbanions. If one reduces, for example, the a, -unsaturated decalone below with lithium, a dianion is formed, whereof three different conformations (A), (B), and (C) are conceivable. Conformation (A) is the most stable, because repulsion disfavors the cis-decalin system (B) and in (C) the conjugation of the dianion is interrupted. Thus, protonation yields the trans-decalone system (G. Stork, 1964B). 

Selective reduction of a benzene ring (W. Grimme, 1970) or a C C double bond (J.E. Cole, 1962) in the presence of protected carbonyl groups (acetals or enol ethers) has been achieved by Birch reduction. Selective reduction of the C—C double bond of an a,ft-unsaturated ketone in the presence of a benzene ring is also possible in aprotic solution, because the benzene ring is redueed only very slowly in the absence of a proton donor (D. Caine, 1976). 

Akhrem, A. A. Reshetova, I. G. Titov, Yu. A. 1972, Birch Reduction of Aromatic Compound, Plenum New York... 

Metal-ammonia-alcohol reductions of aromatic rings are known as Birch reductions, after the Australian chemist Arthur J Birch who demonstrated their usefulness begin nmg m the 1940s... 

The mechanism by which the Birch reduction of benzene takes place (Figure 118) IS analogous to the mechanism for the metal-ammonia reduction of alkynes It involves a sequence of four steps m which steps 1 and 3 are single electron transfers from the metal and steps 2 and 4 are proton transfers from the alcohol... 

The Birch reduction not only provides a method to prepare dienes from arenes which cannot be accomplished by catalytic hydrogenation but also gives a nonconju gated diene system rather than the more stable conjugated one... 

A single organic product was isolated after Birch reduction of... 

Section 1111 An example of a reaction m which the ring itself reacts is the Birch reduction The ring of an arene is reduced to a nonconjugated diene by treatment with a Group I metal (usually sodium) m liquid ammonia m the presence of an alcohol... 

Birch reduction (Section 11 11) Reduction of an aromatic nng to a 1 4 cyclohexadiene on treatment with a group I metal (Li Na K) and an alcohol in liquid ammonia Boat conformation (Section 3 7) An unstable conformation of cyclohexane depicted as... 

Birch leaf extract Birch reduction Birch-type reactions Bird feathers Bird repellents Bireactive dyes Birkeland-Eyde process Birnessite [1244-32-5] b-Bisabolene [495-61-4]... 

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