Aminocarbonylation protocol

The optimized Mo(CO)6-based aminocarbonylation protocol was applied in the synthesis of a variety of benzamides. Both electron-rich and electron-poor aryl iodides proved to be efficient coupling partners. In the set of amines examined in this reaction, the previously investigated piperidine produced improved yields. Furthermore, aniline and benzylamine also reacted easily. The sterically hindered... 

The positive results achieved in developing aminocarbonylation protocols prompted the evaluation of other nucleophiles in similar microwave-promoted carbonylations. Surprisingly, few reports concerning the direct carbonylation of aryl or vinyl halides with hydrazides to the corresponding N,N -diacylhydrazines are found in the literature and an effort was made to modify the previously reported aminocarbonylation protocol [17] for the carbonylative synthesis of N, /-diacylhydrazines [19]. 

In a 2006 paper outlining the rapid microwave synthesis of novel cyclic sulfamide HIV-1 protease inhibitors, the aminocarbonylation protocol presented in ref. 17 was applied in the decoration of mono- and bis-aryl bromide containing cyclic sulfamide starting materials [33]. Aniline and benzylamine were used as nucleophiles for the production of two symmetric bis-functionalized and two unsymmetrical monosub-stituted compounds in good yields (59-80%) (Scheme 4.19). Unfortunately, of these anilide or benzylamide containing compounds only one displayed weak HIV-1 protease inhibition [33]. 

For stereoselective synthesis of a-aminocarbonyl compounds, a number of protocols have been reported using chiral enolates and A-(alkoxycarbonyl)-0-(arenesulfonyl) hydroxylamines. 

As mentioned earlier, the synthesis of primary amides is rather challenging due to technical difficulty in handling gaseous ammonia. Thus, the use of ammonia substitutes such as HMDS and formamide has been studied (see Schemes 21 and 22). With the use of microwave irradiation, however, it has been shown that it is possible to generate both CO and ammonia at the same time for the synthesis of primary amides from aryl bromides. This protocol is very useful for laboratory organic syntheses, especially combinatorial syntheses. As Scheme 29 illustrates, the Pd-catalyzed aminocarbonylation of aryl bromides 200 with formamide (33.5 equiv.) in the presence of KOBu (1.5 equiv.) and imidazole (1 equiv.) with microwave irradiation for 400 s (6.7 min) gave the corresponding benzamides... 

The present F C reaction proceeded through the in situ generation of aliphatic imines that were delivered via the protonation of the enecarbamates by the phos phoric acid catalyst (Figure 3.4). Phosphoric acid functioned as an efficient catalyst for the dual transformation that involved the in situ generation of imine and the enantioselective carbon carbon bond formation with indole. This protocol offers the distinct advantage of generating in situ unstable aliphatic imines from storable and thus easily handled enecarbamates, and hence is applicable to other organic transformations. In fact, Terada et al. applied the present method to an enantiose lective direct Mannich reaction [51]. The method provides an efficient pathway to p alkyl P aminocarbonyl derivatives in optically active forms. 

By using Pd(OAc)2 and commercially available di-l-adamantyl-n-butylphos-phine (cataCXium A) as the catalyst system, various aromatic and heteroaromatic esters, amides, and acids were prepared from the corresponding bromoarenes in Beller s group [140]. Compared to most known carbonylation protocols, excellent yields can be achieved at relatively low catalyst loadings (<0.5 mol% Pd) and carbon monoxide pressure (5 bar). Most recently, this catalyst system was applied to synthesize novel potentially bioactive 3-alkoxycarbonyl- and 3-aminocarbonyl-4-indolylmaleimides from 3-bromo-indolylmaleimide (Scheme 2.15) [141]. 

The Carbonylative Heck Reaction is not the same as those that were traditionally called Heck carbonylations . Heck carbonylations normally include alkoxycarbonylation, aminocarbonylation and hydroxycarbonylation, while a carbonylative Heck reaction is more related to a Heck reaction. In the late 1960s, Richard Heck developed several coupling reactions of arylmercury compounds in the presence of either stoichiometric or catalytic amounts of palladium salts [1-7]. Based on this work in 1972, he described a protocol for the coupling of iodo-benzene with styrene, which today is known as the Heck reaction [8]. In contrast to this, the catalytic insertion of olefins into acylpalladium complexes is called a Carbonylative Heck reaction . Here the acylpalladium complexes can either by CO insertion or by the oxidative addition of benzoyl precursors [9, 10]. 

Simultaneously to Orellana s results, Bhanage and cowoikm desaibed a green catalytic procedure for the aminocarbonylation of aryl iodides with amines. The reaction was carried out using water as solvent and a polymer-supported Pd-NHC catalyst (PS-Pd-NHC, XXIV Scheme 5.55), which could be easily recycled up to four consecutive runs without loss of activity or selectivity. This protocol allowed the aminocarbonylation of different aryl iodides with both aryl and alkyl primary/secondary amines using 100 psi of carbon monoxide. In aU studied examples, the corresponding amides 77 were obtained in good to excellent yields, except for aromatic secondary amines [75]. 

Thereafter, a full paper describing aminocarbonylations in water was published [29]. In addition to presenting the results achieved with aryl bromides, aminocarbo-nylation protocols for aryl iodides and aryl chlorides were also disclosed. More than 90 successful aminocarbonylations in water were presented (Scheme 4.14), including a medicinal chemistry application where this amidation procedure was used to synthesize a potent HIV-1 protease inhibitor from the aryl bromide (Scheme 4.15) [29]. 

The first Mo(CO)6-promoted, microwave-assisted protocols for aminocarbonylation of aryl bromides and iodides to primary benzamides were presented in 2006 [34]. Hydroxylamine hydrochloride was used as a solid ammonia equivalent as it was found that hydroxylamine was smoothly reduced in situ by Mo(CO)6, generating free ammonia that could undergo the carbonylation. The conditions found suitable for this reaction included an aryl halide, Mo(CO)6, NH2OH HCI, 1,2, DBU, and DIEA in dioxane followed by 20 min of microwave heating at 110 °C for Ar-I and 150 °C for Ar-Br. Eight primary benzamides were synthesized from aryl bromides in 70-81% yield and the same amides from aryl iodides in 76-84% yield (Scheme 4.20). The method was also used in the synthesis of weak HIV-1 protease inhibitors (Scheme 4.21) [34]. 

The syntiiesis of DPP-4 inhibitor, Saxagliptin 1 (Figure 4.21) required key intermediate (5S)-5-aminocarbonyl-4,5-dihydro-lH-pyrrole-l-carboxylic acid,l-(l,l-dimethyl ethyl)-ester 76 [22-24]. Direct chemical ammonolysis resulted in unacceptable levels of amide racemization and side-product formation. Milder, two-step hydrolysis-condensation protocols using coupling agents such as 4-(4,6-dimetiioxy-l,3,5-triazin-2-yl)-4-methyl-morpholinium chloride (DMT-MM) were compromised by reduced overall yields [103]. 

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