Decarboxylation synthetic utility

By 1984, the palladium-catalyzed aUyhc alkylation reaction had been extensively studied as a method for carbon-carbon bond formation, whereas the synthetic utility of other metal catalysts was largely unexplored [1, 2]. Hence, prior to this period rhodium s abihty to catalyze this transformation was cited in only a single reference, which described it as being poor by comparison with the analogous palladium-catalyzed version [6]. Nonetheless, Yamamoto and Tsuji independently described the first rhodium-catalyzed decarboxylation of allylic phenyl carbonates and the intramolecular decarboxylative aUylation of aUyl y9-keto carboxylates respectively [7, 8]. These findings undoubtedly laid the groundwork for Tsuji s seminal work on the regiospecific rho-... 

The construction of a quaternary a-stereocenters was demonstrated in the 117-catalyzed Mannich addition [72] of methylcyclo-pentanone-2-carboxylate to N-Boc-protected aromatic aldimines and furnished the adducts 1-3 in 70-97% yield, with good ee values (85-87%) and diastereoselectivities (Scheme 6.115). The authors exemplified the synthetic utility of the protocol by a simple racemization-free decarboxylation of the Mannich adduct of N-Boc benzaldimine and dimethyl malonate to obtain the respective N-Boc-protected p-amino ester (68% yield/89%... 

In contrast to the extensive investigation of fluorovinylzinc reagents and their synthetic utility, only limited literature exists on fluorinated arylzinc reagents. Bis(pentafluorophenyl) zinc can be prepared by the reaction of zinc chloride with either pentafluorophenyllithium or pentafluorophenylmagnesium bromide (equation 70)64,65. An alternative route is via decarboxylation of zinc bis(pentafluorobenzoate) (equation 71)65. 

The synthesis of 2,2-dimethylsuccinic acid (Expt 5.135) provides a further variant of the synthetic utility of the Knoevenagel-Michael reaction sequence. Ketones (e.g. acetone) do not readily undergo Knoevenagel reactions with malonic esters, but will condense readily in the presence of secondary amines with the more reactive ethyl cyanoacetate to give an a, /f-unsaturated cyanoester (e.g. 15). When treated with ethanolic potassium cyanide the cyanoester (15) undergoes addition of cyanide ion in the Michael manner to give a dicyanoester (16) which on hydrolysis and decarboxylation affords 2,2-dimethylsuccinic acid. 

The stabilisation of an enolate (intermediate or product) is also important in the decarboxylation reaction of /3-ketoacids. The decarboxylation of such compounds is facile, and is the key to the synthetic utility of ethyl acetoacetate and diethyl malonate. The mechanism of decarboxylation involves the formation of an enol (Fig. 5-21), and so is expected to be subject to metal ion control. 

The utilization of perfluorodiacyl peroxides for this purpose has been more widely developed. The rate of decomposition of perfluorodiacyl peroxides in the presence of electron-rich benzene derivatives is enhanced by a significant factor via a process of electron-transfer [66, 280], As can be seen by the contrasting examples below [281], highly reactive arenes are capable of trapping the per-fluoroalkyl carboxyl radical before it decarboxylates to RF, a result which can diminish the synthetic utility of this process. 

Ketonic decarboxylation, in which two molecules of acid are thermally converted to a symmetrical ketone plus carbon dioxide and water, has been reviewed.316 Radical, f >-keto acid, and concerted mechanisms are considered, with the reviewer favouring the last, albeit not conclusively. It is suggested that development of bifunctional catalysts may be the best way to improve the energetics of the process, and hence its synthetic utility and green credentials. 

Finally, as examples of similar types of reactions, photolytic treatment of O-acyl ester (D) of benzophenone oxime, A-acyloxy-phthalimide (E), and O-acyl ester (F) of A-hydroxy-2-pyridone with a mercury lamp generates the corresponding alkyl radicals via decarboxylation. However, these reactions can be used only for the alkylation of aromatics (solvents such as benzene) and reduction [86-89], so their synthetic utility is extremely limited. 

The synthetic utility of alkylation of enolates is utilized in the syntheses of malonic ester (3.3) and acetoacetic ester (3.2). For example, carbanion generated from malonic ester undergoes an Sn2 reaction with alkyl halide to yield alkyl-substituted malonic ester. The monosubstituted malonic ester still has an active hydrogen atom. The second alkyl group (same or different) can be introduced in a similar manner. Acid-catalyzed hydrolysis or base-catalyzed hydrolysis of mono- or disubstituted derivative of malonic ester followed by acidification gives the corresponding mono- or disubstituted malonic acid, which on decarboxylation yields the corresponding monocarboxylic acid (Scheme 3.3). 

To our knowledge, only one report exists in which the formation of carboxylic acid by radical carboxylation with carbon dioxide has been documented. Curran and co-workers observed the formation of 9-anthracenecarboxylic acid in 10% yield, together with 71% yield of anthracene, when the radical reduction of 9-io-doanthracene with the ethylene-spaced fluorous tin hydride was run using supercritical CO2 (90°C, 280 atm) as the reaction media (Scheme 4-41) [69], As demonstrated in this example, the CO2 trapping reaction by radicals is not an efficient process and therefore is of limited synthetic utility. The rate constant for the addition is yet to be determined, but kinetic studies to date indicate that generally the decarboxylation of acyloxyl radicals is a rapid process [70]. 

Similar to IBX, the synthetic utility of DMP goes beyond the standard selective oxidation of primary and secondary alcohols. A simple and mild method of decarboxylative bromination of a,p-unsaturated carboxylic acids has been developed using DMP in combination with tetraethylammonium bromide (TEAB) at room temperature.22 It was observed that electron donating groups attached to the phenyl ring of the a,P-unsaturated carboxylic acids undergo fast decarboxylation/bromination in excellent yields (48 — 49). 

An important utility of the Krapcho reaction is not necessarily the decarboxylation step itself. Rather, the fact that the decarboxylation can be made to occur allows several reactions that require malonates or their derivatives to find general synthetic utility. For example, elegant work in the area of rhodium carbenoid chemistry relies on diazomalonates to generate the carbenoid. As utilized by Wee,20 diazomalonate 14 is treated with Rh20Ac4 to generate the carbenoid which inserts into the stereochemically defined tertiary C—H bond. The reaction proceeds exclusively with retention of configuration in forming the new quaternary carbon stereocenter. Decarboxylation of 15 under Krapcho s conditions provides lactone 16, a key intermediate in the synthesis of (-)-ebumamonine. 

When this reaction is carried out on the parent diethyl malonate, acetic acid results, and the process is of no practical synthetic utility. As with the synthesis of ketones starting from P-keto esters, this process is far more usefiil when combined with the alkylation reaction. One or two alkylations of malonic ester give substituted diesters that can be hydrolyzed and decarboxylated to give carboxylic acids (Fig. 19.62). Substituted acetic acids are potential sources of esters, acid halides, and any other compound that can be made from a carboxylic acid. 

C-H alkenylation and decarboxylation (Scheme 4.48) [53], as in the reaction of benzoic acids described above (Schemes 4.28 and 4.29). Since the palladium-catalyzed Fujiwara-Moritani type direct alkenylation of indoles usually takes place at the C3-position, it enables alkenylation at a position complementary to that of the Fujiwara-Moritani reaction, being of unique synthetic utility. On the other hand, the reaction of thiophene-2-carboxylic acid leads to the formation of a mixture of C2- and C3-alkenylated products. Decarboxylation may take place too early to complete directed C-H alkenylation at the C3-position. In contrast, the exclusive C3-alkenylation on a thiophene ring is possible under rhodium catalysis (Scheme 4.49) [34b]. 

Having seen how to prepare j8-dicarbonyl compounds, let us explore their synthetic utility. This section will show that the corresponding anions are readily alkylated and that 3-ketoesters are hydrolyzed to the corresponding acids, which can be decarboxylated to give ketones or new carboxylic acids. These transformations open up versatile synthetic routes to other functionalized molecules. 

Pyrrole Carboxylic Acids and Esters. The acids are considerably less stable than benzoic acid and often decarboxylate readily on heating. However, electron-withdrawing substituents tend to stabilize them toward decarboxylation. The pyrrole esters are important synthetically because they stabilize the ring and may also act as protecting groups. Thus, the esters can be utilized synthetically and then hydrolyzed to the acid, which can be decarboxylated by heating. Often P-esters are hydrolyzed more easily than the a-esters. 

Although the utility of transaminases has been widely examined, one such limitation is the fact that the equilibrium constant for the reaction is near unity. Therefore, a shift in this equilibrium is necessary for the reaction to be synthetically useful. A number of approaches to shift the equilibrium can be found in the literature.53 124135 Another method to shift the equilibrium is a modification of that previously described. Aspartate, when used as the amino donor, is converted into oxaloacetate (32) (Scheme 19.21). Because 32 is unstable, it decomposes to pyruvate (33) and thus favors product formation. However, because pyruvate is itself an a-keto acid, it must be removed, or it will serve as a substrate and be transaminated into alanine, which could potentially cause downstream processing problems. This is accomplished by including the alsS gene encoding for the enzyme acetolactate synthase (E.C. 4.1.3.18), which condenses two moles of pyruvate to form (S)-aceto-lactate (34). The (S)-acetolactate undergoes decarboxylation either spontaneously or by the enzyme acetolactate decarboxylase (E.C. 4.1.1.5) to the final by-product, UU-acetoin (35), which is meta-bolically inert. This process, for example, can be used for the production of both l- and d-2-aminobutyrate (36 and 37, respectively) (Scheme 19.21).8132 136 137... 

In Fig. (12) keto ester (94) was selected as starting material. It was converted to the formyl derivative (95) which yielded a,P-unsaturated aldehyde (96) by treatment with DDQ. Michael addition of the sodium enolate of tert-butyl- isovalerylacetate to aldehyde (96) afforded the adduct (97) as a mixture of C-ll diastereomers. By fractional crystallization one of the adducts could be separated but for the synthetic purpose the mixture was not separated. Treatment of the adduct (97) with p-toluenesulfonic acid in glacial acetic acid caused t-butyl ester cleavage, decarboxylation and cyclodehydration leading the formation of tricyclic enedione (98) in 80% yield. This approach was previously utilized by Meyer in the synthesis of nimbiol [29], Treatment of (98) with pyridinium bromide perbromide, followed by hydrogenolysis with palladium and carbon caused aromatization of (98) leading the formation of the phenolic ester (99). 

The failure of trifluoroacetate decarboxylation as a general synthetic procedure is perhaps not surprising since such reactions are usually of limited utility. Furthermore, trifluoroacetate groups are quite resistant... 

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