Palladium aminocarbonylation

In this chapter we describe a novel, safe and efficient large-scale synthetic approach to tricycle thienobenzazepines. The key steps in the synthesis include a chemoselective hydrogenation of an aryl-nitro functionality in the presence of a 3-bromo thiophene and a subsequent palladium-catalyzed intramolecular aminocarbonylation telescoped sequentially after simple catalyst and solvent exchange. 

Scheme 6.46 Palladium-catalyzed aminocarbonylations using molybdenum hexacarbonyl as a solid source of carbon monoxide.

Scheme 6.48 Palladium-catalyzed aminocarbonylations using formamides as sources of carbon monoxide.

In a more recent report, Larhed and coworkers have presented microwave-mediated fluorous reaction conditions for palladium-catalyzed aminocarbonylations [100]. 

Aside from alkoxycarbonylations, hydroxycarbonylations in the presence of water to yield allenic carboxylic acids [15] (93, Y = OH) and aminocarbonylations in the presence of amines to give the analogous amides [139] (93, Y = NRR ) have also been carried out, respectively (Scheme 7.13). These products of structure 102 can also be obtained if using the propargylamines 101 with R1 = Ph or R3 Z H as starting materials (Scheme 7.15) [140]. Additionally, hydroxycarbonylations, also termed carboxyla-tions, are successful without palladium catalysis by reaction of propargyl halides and carbon monoxide in the presence of nickel(II) cyanide under phase-transfer conditions [141, 142]. 

Starting with bromoallenes 133, nucleophilic substitution supported by the use of cuprous cyanide lead to cyanoallenes of type 134 (Scheme 7.22) [126, 131, 181]. Pro-pargyl precursors and also cumulenes of type 133 can be utilized for palladium-catalyzed aminocarbonylation to give allenic amides 135 (cf. Section 7.2.6) [182]. 

Palladium-catalyzed aminocarbonylations, using solid Mo(GO)6 as the carbon monoxide source, have been performed under microwave-assisted conditions, with both 5-bromopyrimidine and 2-substituted-5-bromopyrimidines 273 <2007TL2339>. 

Aminocarbonylation provides an efficient method for the synthesis of carboxamides from readily available alkenyl halides. This reaction finds many applications in organic synthesis, especially for the introduction of amides with a variety of A -substituents. For example, steroidal alkenyl iodide 137 was transformed to the corresponding amide derivative 138 in 88% yield through aminocarbonylation (Equation (10)). In this reaction, the palladium catalyst was recovered by using an ionic liquid, l-butyl-3-methylimidazolium salt 139, as reaction media, and reused five times with only a minor loss of activity. ... 

Wan, Y.Q., Alterman, M., Larhed, M. and Hallberg, A., Dimethylformamide as a carbon monoxide source in fast palladium-catalysed aminocarbonylations of aryl bromides, /. Org. Chem., 2002, 67, 6232-6235. 

Similar stereochemical results have been reported in iodolactamizations of thioimidates (equation 105)217b 217c and the palladium(II)-catalyzed aminocarbonylation reaction (equation lOb).50 237 In some cases, the stereoselectivity in the aminocarbonylation reaction varied considerably with changes in the group on nitrogen or reaction conditions. 

As stated above, aliphatic amines are potent ligands for electrophilic transition metals and are efficient catalyst poisons in attempted alkene animation reactions. However, tosylation of the basic amino group greatly reduces its complexing ability, yet does not compromise its ability to nucleophilically attack complexed alkenes. Thus, a variety of alkenic tosamides efficiently cyclized under palladium(II) catalysis producing N-tosylenamines in excellent yield (equations 17 and 18).32 Again, this alkene amination proceeded through an unstable a-alkylpalladium(II) species, which could be intercepted by carbon monoxide, to result in an overall aminocarbonylation of alkenes. With ureas of 3-hydroxy-4-pentenyl-amines (Scheme 7), this palladium-catalyzed process was quite efficient but it was somewhat less so with... 

Palladium-catalyzed aminocarbonylation of alkynes followed by cyclization produced furans with different substitution pattern in good yields <07S4247>. 

Preparation of /I-Alkoxycarbonyl Cyclic Amines by Palladium(II)-Catalyzed Intramolecular Aminocarbonylation... 

Palladium(II)-Catalyzed Aminocarbonylation of Unsaturated Ureas, Carbamates, and Tosylamides General... 

The palladium(II)-catalyzed oxidative aminocarbonylation of 0-(2-propenyl)-Ar-tosyl carbamates 12 was achieved under acidic buffer conditions, although the reaction was very sluggish, or, preferably in the presence of acetate ion and methyl orthoacetate, which suppresses palladium(II) chloride consuming side reactions114. Substitution at C-l led to the prevalent formation of the trans-4,5-disubstituted 1,3-oxazolidin-2-ones 13 (NMR). 

The disubstituted imidazole 400 was brominated to give 5-bromoimidazole 401, which underwent direct aminocarbonylation in the presence of palladium acetate and l,3-bis(diphenylphosphino)propane (1,3-DPPP) to give carboxamide 402, a selective HI antagonist as a potential treatment for allergy (Scheme 97) <2005JME2154>. 

Vinyl bromides are directly aminocarbonylated by nickel carbonyl and amines. Very similarly, Rh (CO)i6 and BU4NCI as cat yst convert allylphosphates to. -y-unsaturated amides via rr-allylrhodium complexes (equation 43). Although palladium(O) complexes are more reactive than rhodium(I) complexes, palladium(O) complexes undergo side reactions, like reductive elimination in the presence of carbon monoxide, and direct nucleophilic attack by amines. 

As an alternative to the use of sodium, hydrogenation in ethanolic ammonia over palladium is effective. Thus 4-amino-5-aminocarbonyl-3-benzyl-l-methyl-l,2,3-triazolium toluene-p-sulfonate gave 4-amino-l-methyltriazole-5-carboxamide (75°C, 4 atm, 3 hr, 82%) [68JCS(C)344 72JCS(P1)461]. 4-Amino-3-benzyltriazole-5-fV-butylcarboxamidine was similarly debenzylated (70 C, 3 hr, 85%) [74JCS(P1)2030]. 

Palladium-catalyzed carbonylation of heteroaryl halides provides a quick entry to heteroaryl carbonyl compounds such as heteroaryl aldehydes, carboxylic acids, ketones, esters, amides, a-keto esters, and a-keto amides. In addition, Pd-catalyzed alkoxycarbonylation and aminocarbonylation are compatible with many functional groups, and therefore have advantages over conventional methods for preparing esters and amides [78]. 

Gabriele et al. reported that the 2-oxazolidinones 462 were synthesized by the palladium-catalyzed oxidative carbonylation of the 2-amino- 1-alkanols 461 (Scheme 144).206 The aminocarbonyl palladium complex 463 is formed as an intermediate, and subsequent ring closure gives 462. 

Similarly. palladium(II)/copper(II)-catalyzed intramolecular aminocarbonylation of A-protected 3-hydroxy-4-pentenamines 6 exclusively leads to ri.s-fused hexahydro-2-oxo-2f/-furo[3,2- >]pyrroles 7 in high yield1 16. As an A-protecting group, urea is the most reactive and versatile A-nucleophile. Carbamates are less reactive, but still better than sulfonamides. The diastereose-lectivity of the cyclization is dependent on the. V-protccting group, the solvent (protic better than aprotic) and the electrophile. 

The group also reported DME in the presence of potassium tert-butoxide to be an efhcient source of carbon monoxide and dimethyl-amine in palladium-catalyzed aminocarbonylation (Heck carbonylation Scheme 25.2D). The addition of excess amines to the reaction mixture provided good yields of the corresponding aryl amides. The reaction proceeded smoothly with bromobenzene and more electron-rich aryl bromides, but not with electron-deficient aryl bromides. 

Microwave-mediated fluorous reaction conditions for palladium-catalyzed aminocarbonylations have been discussed in a more recent report [101]. A set of aryl halides was reacted with carbonyl hydrazides and molybdenum hexacarbonyl [Mo(CO)e] as source of carbon monoxide, with fluorous triphenylphosphine (F-TPP) as ligand and the perfluorocarbon liquid FC-84 as perfluorinated solvent (Scheme 16.67). 

In 2008, BeUer and coworkers reported catalytic and stoichiometric synthesis of novel 3-aminocarbonyl-,3-alkoxycarbonyl-, and 3-amino-4-indolyl-maleimides [162]. For instance, t-butyl ester 117 was prepared in 29% yield from 3-bromo-4-indolyl-maleimide 116 under the palladium-catalyzed carbOTiylation conditimis using f-butanol as the solvent and TMEDA as the base. 

Palladium-catalyzed aminocarbonylations of alkenyl phosphates have been investigated using Mo(CO)6 as a solid carbon monoxide source. The reactions afforded a wide variety of acrylamides (78) after 20 min of microwave irradiation in moderate to good yields (Scheme 16). ... 

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