Reductive decarboxylation

If the reaction just described is conducted in the presence of a suitable hydrogen atom donor such as tri-n-butyltin hydride or tert-butyl hydrosulfide, reductive decarboxylation occurs via a radical chain mechanism to give an alkane (see 125—>128, Scheme 24). Carboxylic acids can thus be decarboxylated through the intermediacy of their corresponding thiohydroxamate esters in two easily executed steps. In this reducjtive process, one carbon atom, the carbonyl carbon, is smoothly excised... 

Scheme 24. Barton s thiohydroxamate ester chemistry reductive decarboxylation.

We see from these examples that many of the carbon nucleophiles we encountered in Chapter 10 are also nucleophiles toward aldehydes and ketones (cf. Reactions 10-104-10-108 and 10-110). As we saw in Chapter 10, the initial products in many of these cases can be converted by relatively simple procedures (hydrolysis, reduction, decarboxylation, etc.) to various other products. In the reaction with terminal acetylenes, sodium acetylides are the most common reagents (when they are used, the reaction is often called the Nef reaction), but lithium, magnesium, and other metallic acetylides have also been used. A particularly convenient reagent is lithium acetylide-ethylenediamine complex, a stable, free-flowing powder that is commercially available. Alternatively, the substrate may be treated with the alkyne itself in the presence of a base, so that the acetylide is generated in situ. This procedure is called the Favorskii reaction, not to be confused with the Favorskii rearrangement (18-7). ... 

In most other cases, however, the diene system simply becomes too unreactive to participate in radical chain reactions. Thus, the reductive decarboxylation of ester 7 by Barton-POC ester methodology20 or as the selenoester21 gives the reduced product 8, cleanly without any trace of product in which the diene system has participated in the reaction (equation 4)20-21. 

Compound 136 (Scheme 35) is classically used as a reagent for Barton s reductive decarboxylation, in the presence of triethylamine and/-BuSH <1995JOC6237, 1996JOC6189, 2003T6797>. 

Pathway A employed a reductive cyclization [21] to form 3-carboxy-4-alkyl-pyrrolidin-2-one (17), which could then be converted to pregabalin under acidic conditions pathway B employed a hydro lysis/reduction/decarboxylation analogous to the one used in the first-generahon route via intermediate 18 [7], and pathway C involving a heat-mediated decarboxylation to intermediate 19 followed by a hydrolysis/reduchon sequence to yield pregabalin. In pathway A, the hydro-genahon of 13 was performed in predominantly aqueous medium at neutral pH, with catalyhc amounts of Raney nickel, and afforded 17 in >95% isolated yield. The reduction could be performed at relatively high substrate loads (0.5-1.OM),... 

In the first, Fe(CO)5 is converted into the carbonyl hydride anion by reductive decarboxylation following initial OH" attack on a carbonyl carbon (55). The carbonyl group is thus oxidized to carbonate in basic medium. The second reaction, (3) (56), is one of E. O. Fischer s celebrated carbene forming reactions (57). Phenyl lithium reacts with Cr(CO)6 leading to an anionic acyl complex. A subsequent alkylation step using Me30+ yields the methoxy-phenylcarbene complex Cr(CO)5(CPh(OMe)). 

It is well known, for example, that CO in the presence of water is an effective reducing agent for more oxidized metal ions (27, 61). The mechanism for this reduction has long been established, and the case of rhodium, as studied by James and co-workers (62), is typical. These investigators find that coordination of CO to rhodium in the +3 oxidation state is followed by nucleophilic attack of water and reductive decarboxylation to give Rh(I), C02, and protons as shown in (6). 

Reductive decarboxylation of (20) yields C02, H+, and a Co(I) species at a measurable rate (94). In the presence of CO, the starting cobalt complex is regenerated, and a catalytic system for the oxidation of CO by ferricyanide is established. It is significant that in this system the metal-carbonyl bond is formed when the cobalt is in a reduced state. It is the subsequent oxidation of the cobalt by electron transfer that activated the carbonyl to attack by water or hydroxide. That this activation results in a weaker metal-carbonyl bond is evident since the Co(III)-carbonyl may be hydrolyzed in acidic solution with loss of the carbon monoxide ligand (94). 

If this iron carbonyl hydride is formed by a -elimination from the intermediate (CO)4Fe(COOH)-, a carbonyl must be lost in a prior step since this hydroxycarbonyl is coordinatively saturated. An alternative mechanism would be reductive decarboxylation followed by protonation of the very basic Fe(CO) intermediate. 

This section has dealt with the oxidation of CO to C02, especially as it enters into the water-gas shift reaction (26a). A reasonable view of the homogeneous catalysis of this reaction, whether in basic or acidic media, is emerging in which CO formation proceeds from nucleophilic attack of water or OH" on an activated carbonyl followed by either reductive decarboxylation or hetero-atom -elimination yielding, respectively, a reduced metal or a metal hydride species. 

The original conception of reductive decarboxylation was in terms of tin hydride chemistry, simply because of previous experience. The earlier observations,7 in the case of dihydro-phenanthrene esters, led us to think of incorporating the C=N double bond to be formed (Scheme 2) by fragmentation, into an aromatic system. This was to provide an additional driving... 

Reductive decarboxylation has been found to be very useful for the conversion of R-C02H - R-H by several research... 

During their studies on the stereochemistry of intramolecular 1,3-diyl trapping reaction as depicted in Scheme 13, Little and collaborators utilized the reductive decarboxylation in preparing the required compound 31.24 The usefulness of Barton decarboxylation was also realized by Braekman and colleagues during their studies on ichthyotoxic sesterterpenoids in providing the needed methyl ketone 32 from the carboxylic acid 33.25 Helmchen has developed an easy route to a stable... 

It has been referred to as a "reductive decarboxylation" in both plants (28) and insects (2). However, Kolattukudy and co-workers have presented evidence that in plant (29,30) and vertebrate tissues (31) the reaction js a decarbonylation and that the carboxyl carbon is reduced to the aldehyde before being removed in the form of carbon monoxide. Clearly more work is needed to determine the nature of this reaction in insects. 

Reductive decarboxylation. The reaction of y-carbamoyloxy-a.p-unsaturated esters with a lithium dialkyl cuprate (10 equiv.) in cther-HMPT results in loss of CO, and formation of a p,y-unsaturated ester. Zinc-acetic acid has been used for this reaction," but yields are lower. 

Reductive decarboxylation of aryl and vinyl acids, not readily achieved by any of the methods described here, is best brought about by the classical copper/quinoline procedure. ... 

Reductive decarboxylation has been achieved by heating the acid with LTA in chlorofoim as solvent and hydrogen donor. Only a moderate number of examples are known. The more facile oxidation of secondary and tertiary radicals by LTA effectively limits the method to primary carboxylic acids. It should be noted that stoichiometric quantities of trichloromethyl radicals are generated in the course of this reaction. 

The photolysis of 0-acyI benzophenone oximes in isopropyl alcohol in the presence of r-butyl thiol leads to overall reductive decarboxylation. Yields for simple aliphatic and amino acids are reported to be good. It is especially noteworthy that reductive decarboxylation of 2- and 4-quinolinecarboxylic acids (although not of the 3-isomer, nor 1- or 2-naphthalenecarboxyIic acids) was achieved in moderate yield by this method (equation 9). 

The free radical chain reaction of 0-acyl thiohydroxamates with a tertiary thiol (r-butyl, triethylmethyl or more recently t-dodecyl) is by far the most wide-ranging reductive decarboxylation method describe to date7 A wide variety of functional groups, including aldehydes, ketones, esters, amides, isolated and conjugated double bonds, are tolerated. Representative examples are given in equations (10) and (11). ... 

Overall reductive decarboxylation of a carboxylic acid may be achieved by the reaction of the derived acyl chloride with triisopropyisilane (equation 12). Relatively high temperatures are required to bring about efficient decarbonylation of die intermediate acyl radical. A related mediod involves the reaction of acyl phenyl selenides with tri-it-butyltin hydride. Here again relatively high temperatures are required for primary and secondary, although not for tertiary, acids (equation 13). 

---