Amides double carbonylation

The o-keto ester 513 is formed from a bulky secondary alcohol using tricy-clohexylphosphine or triarylphosphine, but the selectivity is low[367-369]. Alkenyl bromides are less reactive than aryl halides for double carbonyla-tion[367], a-Keto amides are obtained from aryl and alkenyl bromides, but a-keto esters are not obtained by their carbonylation in alcohol[370]. A mechanism for the double carbonylation was proposed[371,372],... 

Particularly alkyl halides which have a perfluoroalkyl group at the /3-position undergo smooth carbonylation. Probably the coordination of fluorine to form a five-membered chelate ring accelerates the reaction. Double carbonylation to give the a-keto amide 915 is possible in Et NH with the fluorine-bearing alkyl iodide 914[769,770]. The ester 917 is obtained by the carbonylation of the /3-perfluoroalkyl iodide 916 in ethanol. 

Ruy et al. have performed a similar reaction under microreactor conditions in a multiphase solvent system containing an ionic liquid as the catalyst carrier and reaction promoter [35]. Their system consisted of two T-shaped micromixers (i.d. 1,000 and 400 pm) and a capillary stainless steel tube as an RTU (1,000 pm i.d. and 18 m length, giving a 14.1 ml volume), equipped with pumps and control valves. Under the optimized conditions, Pd-catalysed carbonylation of aromatic iodides in the presence of a secondary amine provided only the double carbonylated product, ot-ketoamide, while the amide obtained by the single carbonylation was observed in high quantities only when the reaction was performed in batch (Scheme 13). 

A number of double carbonylations have been reported. In these reactions, two molecules of CO are incorporated in the product, leading to a-keto acids or their derivatives.1625 When the catalyst is a palladium complex, best results are obtained in the formation of a-keto amides.1626... 

Similarly, cyclizative tandem double-carbonylation reactions of 4-pentenyl iodide under irradiation conditions, is boosted by the addition of a catalytic amount of palladium complexes [72]. When performed in the presence of diethylamine, the carbonylation provided a triply carbonylated a,<5-diketo amide as the major product along with the doubly carbonylated y-keto amide (Scheme 6.48). Experimental evidence supports the interplay of two reactive species, radicals and organopalladium... 

By careful selection of reactions conditions, double carbonylation occurs, which is competitive with monocarbonylation. Utilizing alkylphosphines or DPPB, and secondary amines, the oc-keto amide 460 is obtained with high chemoselectivity [225,226],... 

Characteristic IR spectra of amides. The carbonyl group of butyramide (a) and the C=C double bond of 1-methylcyclopentene (b) absorb in the same region, but three clues distinguish the alkene from the amide (1) The amide C=0 absorption is much stronger and broader than the C=C (2) there are N—H absorptions (near 3300 cm-1) in the amide and (3) there is an unsaturated =C—H absorption in the alkene. 

A de novo isatin synthesis based upon a palladium catalysed double carbonylation of 0/7/20-haloacetanilides in the presence of Et2NH to yield the corresponding glyoxylic acid amide was reported by Yamamoto and co-workers63. Hydrolysis of this amide yielded the respective isatin (Scheme 20). 

Even after SO years of continuous development carbonylation chemistry has still not achieved its full potential and new reactions are still being discovered, a good recent example being double carbonylation leading to a-keto carboxylic acids, a-keto esters and a-keto amides. ... 

The realization that doubly carbonylated products can be formed in carbonylation reactions has only emerged in the last ten years, but specific syntheses of many a-keto acids, amides, esters and related products are being developed rapidly. Although many such syntheses depend on the use of CO pressures well above ambient, variation of other parameters such as catalyst, solvent and base can lead to efficient double carbonylation even at relatively low pressures. Selective, cobalt-catalyzed formation of phenylpy-mvic acid (97% selectively at 85% yield) from benzyl chloride was thus achieved at 50 bar pressure of CO in propan-2-ol, but more recent work has shown that similar selectivity and an even higher yield can be obtained at less than 2 bar when 1,2-dimethoxyethane is used as solvent (equation 62). °°... 

Upon confronting the asymmetric carbon-nitrogen hydrogenation problem, we noted that, like a-enamides, A-acylhydrazones 32 possess an amide-like carbonyl oxygen that is similarly situated three atoms from the double bond to be reduced, and which could allow for chelation of the substrate to the catalytic Rh center. 

The influence of the amount of amine can be elucidated by mechanistic considerations of the double carbonylation. An allyl halide readily forms an allypalladium halide by oxidative addition to Pd(0) species and the amine can attack the allyl ligand to generate allylamine. However, the nucleophilic attack is a reversible process and CO insertion into the allylpalladium species can take place in the presence of a small amount of amine to allow the formation of the acylpalladium species. Attack of the amine on the coordinated CO giving the carbamoylpalladium species followed by reductive elimination by coupling with another alkenoyl ligand produces the a-keto amide [132],... 

As further application of the double carbonylation a one-pot synthesis of a-amino amides has been achieved by using primary amines [133]... 

The preparation of metal carbamoyl [M-C(0)NR2] and silaacyl [M-C(0)SiR3] derivatives by the migratory insertion of CO in the appropriate metal amide (M-NR2) or silyl (M-SiR3) complexes is also precedented. " Although CO reacts with metal-acyl bonds to give a-ketoacyl compounds, this and related reactions that appear to be double carbonylations but do not actually involve two consecutive CO migratory insertions have also been teported. ... 

Carbonylation in the presence of secondary amines provides either amides or a-keto amides by single and double carbonylations. Also, the corresponding a-keto esters are prepared. It was reported that ratios of single and double carbonylations depend mainly on the nature of the phosphine ligands. It was claimed that PMePh2 or DPPB is a suitable ligand for double carbonylation [16]. 

The scope of aminocarbonylations was extended by the works from various groups. For example, Skoda-Fbldes and Kollar studied the carbonylation reactions of ferrocene derivatives in the presence of Pd(OAc)2/PPh3 [126-128]. Ferrocene amides and novel ferrocene a-ketoamides were synthesized in good yields based on palladium-catalyzed aminocarbonylation or double carbonylation of iodofer-rocene at 40-50 bar of CO. The double-carbonylated products were favored at 40-60 °C and amides were produced almost exclusively at 100 °C, as the selectivity of the reaction with less sterically hindered secondary amines is highly dependent on the reaction temperature. Analogous aminocarbonylation reactions of l,l -diiodoferrocene led to I -iodo-ferrocenecarboxamides and I -iodo-ferro-ceneglyoxylic amide-type products. 

Additionally, primary amides and ketoamides were synthesized in good yields via a more traditional carbonylation-deprotection sequence in the presence of Pd(OAc)2/2PPh3 (Scheme 2.13) [134]. Initially, aryl iodides were reacted with ferf-butylamine under 1 bar of CO. When the reaction proceeded at 60 °C, ketoamides resulting from double carbonylation were mainly produced, whereas formation of the amides was favored at 100 °C. The desired primary amides were produced after heating the previous isolated products with one equivalent of tert-butyldimethylsilyl triflate (TBDMSOTf) in toluene at 100 °C. 

Keto-amides. - A detailed mechanistic study has been carried out on the useful palladium-catalysed double carbonylation of aryl... 

The use of secondary amides as nucleophiles has been also documented by Mori et al.f Synthesis of imides by this method is not always satisfactory, but phthalimides are prepared in high yield (Scheme 44). An interesting modification of this method consists of the double carbonylation of o-aryl diiodides and proceeds via an initial intermole-cular amidation, followed by the intramolecular one described by Mori (Scheme 45). ° The formation of seven-membered rings was demonstrated by the synthesis of diazepam and a number of anthramycin alkaloids, including Prothracarcin and Tomaymycin (Scheme 46). As mentioned above, for seven-membered rings direct amination is observed as a side reaction. Secondary ureas are also substrates for this reaction, yielding seven-membered cyclic ureas. ... 

Before discussing the double carbonylation processes it may be helpful to understand the mechanism of the single carbonylation of aryl halides into carboxylic acid derivatives (Heck processes). The first step in the catalytic process is oxidative addition of an aryl halide to Pd(0) species formed from a catalyst precursor to yield an arylpal-ladium halide intermediate (A) in Scheme 1. Insertion of carbon monoxide into the aryl-palladium bond in A gives an acylpalladium halide complex (B). Attack of a nucleophile such as alcohol, amine, and water assisted by a base on the acylpalladium complex yields carboxylic ester, amide, and carboxylic acid, although details of the mechanism have not been unequivocally established. The palladium(O) species regenerated in the process further undergoes oxidative addition to carry out the catalytic cycle (Scheme 1). 

Detailed mechanistic studies on the elementary processes putatively involved in the catalytic double carbonylation process established that the latter mechanism involving the reductive elimination of the bis-acyl ligands most reasonably accounts for the features of the double carbonylation. Scheme 2 presents the proposed mechanisms for generation of the a-keto amide and amide in the reaction of an aryl halide with CO in the presence of a secondary amine and a catalytic amount of a palladium complex (yide infra). Table 1 summarizes the representative results of the double carbonylation with various aryl halides. 

Primary amines also serve as reagents for the double carbonylation to give a-keto amides or their Shiff bases, which are produced by further attack of the primary amines on the a-keto amides generated in the reaction (Eq. 3). ° a-Amino amide can be produced by Pd-catalyzed hydrogenation from the corresponding Shiff base (Eq. 4). ° ... 

On the left hand of Scheme 2 is shown the catalytic cycle to produce a-keto amide (Cycle 1), whereas the right-hand catalytic cycle shows the route to amide (Cycle II). The process common to both processes is oxidative addition of aryl halide to give arylpalladium halide. Further CO coordination to the arylpalladium intermediate gives a CO-coordinated complex. If CO insertion into the aryl-palladium bond takes place, an acylpalladium complex is produced to drive the double carbonylation cycle. Further coordination of CO followed by attack of amine on the carbonyl ligand produces the aroyl(carbamoyl)palladium species as the bis-acyl-type intermediate. Reductive elimination of the a-keto amide by combination of the benzoyl ligand with the carbamoyl ligand regenerates the Pd(0) species that carries the catalytic cycle. 

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