Birch aromatization reaction

Under pro tic conditions, aromatic hydrocarbons and compounds with activated double bonds usually undergo Birch-Kke reactions [172]. The reaction sequence has been elucidated by the classical work of Hoijtink [15-17, 173, 174], who used the HMO theory to rationalize both chemical and electrochemical steps. 

The Birch reduction is the organic reduction of aromatic rings by sodium in liquid ammonia invented by Arthur Birch. The reaction product is a 1,4-cyclohexadiene. The metal can also be lithium or potassium and the hydrogen atoms are supplied by an alcohol such as ethanol or tertbutanol. Sodium in liquid ammonia gives an intense blue color. 

Lanthanide metals are powerful reducing agents (E°Ln /Ln - 2.0 to - 2.3 V for most of lanthanides). However, only few applications can be found in synthetic organic chemistry. It was found (11) that solutions of ytterbium in liquid ammonia are able to give Birch-type reactions on aromatic systems (eq. [ l] ) ... 

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

A remarkable feature of the Birch reduction of estradiol 3-methyl ether derivatives, as well as of other metal-ammonia reductions, is the extreme rapidity of reaction. Sodium and -butyl alcohol, a metal-alcohol combination having a comparatively slow rate of reduction, effects the reduction of estradiol 3-methyl ether to the extent of 96% in 5 minutes at —33° lithium also effects complete reduction under the same conditions as is to be expected. Shorter reaction times were not studied. At —70°, reduction with sodium occurs to the extent of 56 % in 5 minutes, although reduction with lithium is virtually complete (96%) in the same time. (The slow rates of reduction of compounds of the 5-methoxytetralin type is exemplified by 5-methoxy-tetralin itself with sodium and f-butyl alcohol reduction occurs to the extent of only 50% in 6 hours vs. 99+% with lithium.) The iron catalyzed reaction of sodium with alcohols must be very fast since it competes so well with the rapid Birch reduction. One cannot compensate for the presence of iron in a Birch reduction mixture containing sodium by adding additional metal to extend the reaction time. The iron catalyzed sodium-alcohol reaction is sufficiently rapid that the aromatic steroid still remains largely unreduced. 

Many aromatic steroids submitted to the Birch reduction contain hydroxyl groups which are deprotonated to the corresponding alkoxides during the reduction, particularly if a tertiary alcohol is used as the proton donoi. The steroidal alkoxides and the one derived from the proton donor often precipitate and cause foaming of the reaction mixture, as was noted by Wilds and Nelson. These alkoxides can be kept in solution by adding an excess of the proton donor alcohol to the mixture the alcohol also assists in dissolving the starting hydroxylic steroid. A particularly useful reaction medium for hydroxylic steroids contains ammonia, tetrahydrofuran and -butyl alcohol in the volume ratio of 2 1 (Procedure 2, section V). This mixture... 

The elaboration of a method for the reduction of aromatic rings to the corresponding dihydrobenzenes under controlled conditions by A. J. Birch opened a convenient route to compounds related to the putative norprogesterone. This reaction, now known as the Birch reduction,is typified by the treatment of... 

Reaction No. 5 (Table 11) is part of a synthetically useful method for the alkylation of aromatic compounds. At first the aromatic carboxylic acid is reductively alkylated by way of a Birch reduction in the presence of alkyl halides, this is then followed by an eliminative decarboxylation. In reaction No. 9 decarboxylation occurs probably by oxidation at the nitrogen to the radical cation that undergoes decarboxylation (see... 

Direct Electron Transfer. We have already met some reactions in which the reduction is a direct gain of electrons or the oxidation a direct loss of them. An example is the Birch reduction (15-14), where sodium directly transfers an electron to an aromatic ring. An example from this chapter is found in the bimolecular reduction of ketones (19-55), where again it is a metal that supplies the electrons. This kind of mechanism is found largely in three types of reaction, (a) the oxidation or reduction of a free radical (oxidation to a positive or reduction to a negative ion), (b) the oxidation of a negative ion or the reduction of a positive ion to a comparatively stable free radical, and (c) electrolytic oxidations or reductions (an example is the Kolbe reaction, 14-36). An important example of (b) is oxidation of amines and phenolate ions ... 

Select one compound from (37) - (40) for synthesis by each of the methods of this chapter Robinson annelation, Diels-Alder reaction, total reduction of aromatics, and Birch reduction. 

Dissolving-Metal Reduction of Aromatic Compounds and Alkynes. Dissolving-metal systems constitute the most general method for partial reduction of aromatic rings. The reaction is called the Birch reduction,214 and the usual reducing medium is lithium or sodium in liquid ammonia. An alcohol is usually added to serve as a proton source. The reaction occurs by two successive electron transfer/proto-nation steps. 

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. 

A solution of lithium, sodium, potassium or calcium in liquid ammonia can reduce a wide variety of unsaturated groups. Thus when aromatic rings are reduced by such metals in liquid ammonia, non-conjugated cyclohexadienes are produced. The reaction is called Birch reduction. 

At the outset of our studies of the reactivity of I and II, it was necessary to investigate claims that tertiary henzamides were inappropriate substrates for the Birch reduction. It had been reported that reduction of A,A-dimethylbenzamide with sodium in NH3 in the presence of tert-butyl alcohol gave benzaldehyde and a benzaldehyde-ammonia adduct. We formd that the competition between reduction of the amide group and the aromatic ring was strongly dependent on reaction variables, such as the alkali metal (type and quantity), the availability of a proton source more acidic than NH3, and reaction temperature. Reduction with potassium in NH3-THF solution at —78 °C in the presence of 1 equiv. of tert-butyl alcohol gave the cyclohexa-1,4-diene 2 in 92% isolated yield (Scheme 3). At the other extreme, reduction with lithium in NH3-THF at —33 °C in the absence of tert-butyl alcohol gave benzaldehyde and benzyl alcohol as major reaction products. ... 

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. 

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). 

Early examples of electron transfer processes are shown in equations (2), (12), and (13). Birch in 1944 followed up the findings of Wooster, and demonstrated that Na metal and ethanol in ammonia reduce benzene, anisole, and other aromatics to 1,4-cyclohexadienes. Birch speculated about the mechanism of this reaction, but did not explicitly describe a radical pathway involving 55 (equation 87) until later, as described in his autobiography. Electron transfer from arenes was found by Weiss in 1941, who obtained crystalline salts of Ci4H]o from oxidation of anthracene. ... 

A clever application of this reaction has recently been carried out to achieve a high yield synthesis of arene oxides and other dihydroaromatic, as well as aromatic, compounds. Fused-ring /3-lactones, such as 1-substituted 5-bromo-7-oxabicyclo[4.2.0]oct-2-en-8-ones (32) can be readily prepared by bromolactonization of 1,4-dihydrobenzoic acids (obtainable by Birch reduction of benzoic acids) (75JOC2843). After suitable transformation of substituents, mild heating of the lactone results in decarboxylation and formation of aromatic derivatives which would often be difficult to make otherwise. An example is the synthesis of the arene oxide (33) shown (78JA352, 78JA353). 

Direct electron transfer We have already met some reactions in which the reduction is a direct gain of electrons or the oxidation a direct loss of them. An example is the Birch reduction (5-10), where sodium directly transfers an electron to an aromatic ring. An example from this chapter is found in the bimolecular reduction of ketones (9-62), where again it is... 

Alkali metals in liquid ammonia represent the most important class of the so-called dissolving-metal reductions of aromatics. First described in 1937, it is a highly efficient and convenient process to convert aromatic hydrocarbons to partially reduced derivatives.201 The recognition and extensive development of this electron-transfer reduction came from A. J. Birch,202,203 and the reaction bears his name. 

---