Alcohols dissolving metals, reductions

Reduction of Ketones and Enones. Although the method has been supplanted for synthetic purposes by hydride donors, the reduction of ketones to alcohols in ammonia or alcohols provides mechanistic insight into dissolving-metal reductions. The outcome of the reaction of ketones with metal reductants is determined by the fate of the initial ketyl radical formed by a single-electron transfer. The radical intermediate, depending on its structure and the reaction medium, may be protonated, disproportionate, or dimerize.209 In hydroxylic solvents such as liquid ammonia or in the presence of an alcohol, the protonation process dominates over dimerization. Net reduction can also occur by a disproportionation process. As is discussed in Section 5.6.3, dimerization can become the dominant process under conditions in which protonation does not occur rapidly. 

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. 

Electrochemical reduction of camphor-and norcamphoroxime at a Hg cathode proceeds with a high degree of stereoselectivity to give products of opposite stereochemistry to those formed in the dissolving metal (Na-alcohol) reduction of the oximes. The electrolyses are proposed to proceed by a kinetically controlled attack by the electrode on each oxime from the less hindered side (Fig. 62) [348]. In contrast, the corresponding N-phenyl imines yield products of the same stereochemistry as those isolated from a dissolving metal reduction. Cyclic voltammetry and polarographic data point to RH and intermediates in this case that are proto-nated from the least hindered side [349]. 

Fairly selective reduction of certain alkenes can be achieved using the sodium-hexamethylphosphoramide (HMPA)-tm-butyI alcohol system,193 despite the general trend, that nonconjugated alkenes are usually quite resistant to the dissolving metal reduction method (see Section 11.3.2). In the case of 9(10)-octalin, the transformation leads to a nearly equilibrium product distribution ... 

Dihalocydopropanes readily undergo reductive dehalogenation under a variety of conditions. Suitable choice of reagents and reaction conditions will allow the synthesis of monohalocyclopropanes or the parent cyclopropanes.19 " The ease of reduction follows the expected order I > Br > Cl > F. In general, complete reduction of dibromo and dichloro compounds is accomplished by alkali metal in alcohol,99-102 liquid ammonia103 or tetrahydrofuran (equations 28 and 29).104 The dihalocydopropanes can be reduced conveniently with LAH (equation 30).105 LAH reduction is particularly suited for difluoro compounds which are resistant to dissolving metal reductions.19 106 It is noteworthy that the sequence of dihalocar-bene addition to an alkene followed by the reduction of the dihalocyclopropyl compounds (equation 31) provides a convenient and powerful alternative to Simmons-Smith cyclopropanation, which is not always reliable. 

The cyclohexene 121, which was readily accessible from the Diels-Alder reaction of methyl hexa-3,5-dienoate and 3,4-methylenedioxy-(3-nitrostyrene (108), served as the starting point for another formal total synthesis of ( )-lycorine (1) (Scheme 11) (113). In the event dissolving metal reduction of 121 with zinc followed by reduction of the intermediate cyclic hydroxamic acid with lithium diethoxyaluminum hydride provided the secondary amine 122. Transformation of 122 to the tetracyclic lactam 123 was achieved by sequential treatment with ethyl chloroformate and Bischler-Napieralski cyclization of the resulting carbamate with phosphorus oxychloride. Since attempts to effect cleanly the direct allylic oxidation of 123 to provide an intermediate suitable for subsequent elaboration to ( )-lycorine (1) were unsuccessful, a stepwise protocol was devised. Namely, addition of phenylselenyl bromide to 123 in acetic acid followed by hydrolysis of the intermediate acetates gave a mixture of two hydroxy se-lenides. Oxidative elimination of phenylselenous acid from the minor product afforded the allylic alcohol 124, whereas the major hydroxy selenide was resistant to oxidation and elimination. When 124 was treated with a small amount of acetic anhydride and sulfuric acid in acetic acid, the main product was the rearranged acetate 67, which had been previously converted to ( )-lycorine (108). 

Na, or Li in liquid ammonia, for example) to reduce aromatic rings and alkynes. The dissolving metal reduction of enones by lithium metal in liquid ammonia is similar to these reactions—the C=C bond of the enone is reduced, with the C=0 bond remaining untouched. An alcohol is required as a proton source and, in total, two electrons and two protons are added in a stepwise manner giving net addition of a molecule of hydrogen to the double bond. 

The stereochemical course of these, and other similar reductions, led Barton to suggest that dissolving metal reductions of ketones and oximes to secondary alcohols and primary amines would lead to mixtures of products rich in the thermodynamically more stable product. However, in the early 1960s a number of reports appeared in which the reduction of ketones gave primarily the thermodynamically less stable epimeric alcohol. These observations have prompted a continuing series of investigations into the mechanism of these reductions. 

The vast majority of the dissolving metal reductions of carbonyl compounds which have been carried out synthetically have used either alcohols or liquid NH3 as the solvent. " However, a variety of other solvents have been employed, frequently in connection with studies of the mechanism of the reductions or in exploratory synthetic studies. 

Both disubstituted alkynes (Chapter 3.3, this volume) and isolated terminal double bonds may be reduced by alkali metals in NH3, but isolated double bonds are usually stable to these conditions. However, 16,17-secopregnanes (10 equation 8) afford mixtures of cyclization products (11) and (12) in 61% to 80% yield with Na naphthalenide-THF, Na-NHs-THF, Na-THF or Li-NHs-THF. With Na-NHa-THF-r-butyl alcohol, a 91% yield of a 72 28 mixture of (11) (12) (R = Me) is obtained. This type of radical cyclization of alkenes and alkynes under dissolving metal reduction conditions to form cyclopentanols in the absence of added proton donors is a general reaction, and in other cases it competes with reduction of the carbonyl group. Under the conditions of these reactions which involve brief reaction times, neither competitive reduction of a terminal double bond nor an alkyne was observed. However, al-lenic aldehydes and ketones (13) with Li-NHs-r-butyl alcohol afford no reduction products in which the diene system survives. ... 

It was originally believed that the dissolving metal reduction of cyclic ketones would invariably afford the more stable of a pair of epimeric ketones as the major product. Although it has since been established beyond reasonable doubt that these reactions are kinetically controlled and that the less stable epimeric alcohol frequently predominates, the belief persists that these reductions are under thermodynamic control. ... 

Dissolving metal reductions remain the method of choice, and are frequently the only viable method, for the reduction of sterically hindered cyclohexanones to equatorial alcohols. In the early 1950s it was found that reduction of 11-keto steroids using either Na-propan-l-oP or Li-NHs-dioxane-ethanol gave good yields of the equatorial I la-alcohol. 11-Keto steroids, such as androstan-11-one (29 equation 12) have two axial methyl groups in a 1,3-relationship to the carbonyl group and afford exclusively the axial 11 P-ol (30) on reduction with metal hydrides. 

Although they have apparently not been studied in detail, dissolving metal reductions of 1 -keto steroids appear similar to those of the 12-keto steroids. In one report, cholestan-l-one (49 equation 17) on reduction with Na in either ethanol or I-pentanol gave the axial alcohol, cholestan-la-ol (50), as the major reduction product in unspecified yield. The equatorial ip-ol was detected by TLC, but could not be isolated. 

The reductions of 1- and 12-keto steroids and their 1-decalone derivatives graphically illustrate the fact that dissolving metal reductions of ketones do not necessarily afford the more stable of a pair of epimeric alcohols. As a corollary, while the reduction of cyclic ketones is a synthetically useful procedure for the stereoselective preparation of secondary alcohols, it cannot be assumed that the thermodynamically stable alcohol will be the product which is obtained stereoselectively. 

The dissolving metal reductions of bicyclo[2.2. l]heptanones have been studied extensively, and it has been established that both metal-alcohol and metal-NH -proton donor systems provide the cndr>-alcohol regardless of its stability relative to the exo isomer. " - In the case of camphor (1) which has been studied in the most detail, the ratio of endo-alcohol (bomeol 2) to CAo-alcohoI (isobomeol 3) is very close to 90 10 for all metal-NH3 conditions employed. The variables include temperature (-33 and -78 °C), cosolvent (ether and THF), metal (Li, Na, K, Rb) and proton donor (NH4CI and ethanol). - The same results are obtained with both (+)- and (+)-camphor. These results are, coincidentally, almost identical to the equilibrium ratio for alcohols (2) and (3). ... 

The reductions of two steroidal ketones, androstan-l7-one (63) and androst-5-en-16-one (64) under various conditions have been studied in some detail. In the case of 17-ketone (63) the -ol (65) is the stable epimer and for the 16-ol (66), the a-isomer is more stable. Dissolving metal reductions of both ketones in the presence of proton donors gave the more stable alcohol as the major product however, reduction of 17-keto steroid (63) is considerably more stereoselective as noted in Table 2. Although pina-cols are not usually obtained in dissolving metal reductions carried out in the presence of proton donors, ketone (63) gave from 6 to 34% of dimeric products under these conditions (Li, 6% Na, 34% K, 13%). 5... 

The mechanism of dissolving metal reductions depends on the nature of the solvent and the nature of the substrate. The proposed mechanism for the reduction of dialkylacetylenes by sodium in HMPA in the presence of a proton donor is illustrated in equation (18). The addition of an electron to the triple bond of (45) is proposed to produce the rran -sodiovinyl radical (46), or the corresponding radical anion (47), which undergoes protonation by the added alcohol to produce the radical (48). Further reduction of (48) by sodium produces the rrans-sodiovinyl compound (49), which on protonation produces the trans-a -kene (50). In the absence of a proton donor, the reduction of (45) with sodium in HMPA results in the formation of a mixture of cis- and trans-2- and 3-hexenes. Control studies showed that the isomerization products 2- and 3-hexene are not formed by rearrangement of the cis- or frans-3-hexenes. It was concluded that the starting alkyne (45) acts as a reversible proton donor reacting with an intermediate anion or radical anion to produce the delocalized anion (51) which is then protonated to produce the al-lene (52). Reduction of the allene (52), or further rearrangement to the alkyne (53) followed by reduction, then leads to the formation of the mixture of the cis- and trans-2- and 3-hexenes (equation 19). ... 

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