Amides, cross-coupling

Synthesis of Ynamides Amidative Cross-Coupling of Terminal Alkynes... 

Ynamides can be easily synthesized by metal-catalyzed amidative cross-coupling of alkynes (Scheme 4.50). Other alternatives employ lithiated amides with al-kynyliodonium salts [196], or metal-catalyzed coupling of amides with alkynyl bromides [196], potassium alkynyltrifluoroborates [197], 1,1-dihalo-1-alkenes [198], or propylic acids [199]. 

Scheme 4.50 Copper-catalyzed amidative cross-coupling of alkynes...

The first synthesis of A-phosphoryl ynamides (80) featuring C- and P-chirality via the copper(I)-catalysed amidative cross-couplings between... 

The ester 870 is prepared by the cross-coupling of the chloroformate 869 with an organotin reagent. Some chloroformates are easily decomposed by a Pd catalyst, and hence the reaction should be carried out by slow addition of the chloroformates. Similarly, the amide 872 is prepared by the reaction of the carbamoyl chloride 871 [742]. The coupling of alkylcopper with ethyl chloroformate catalyzed by Pd affords esters[743]. 

In recent years, cross-coupling methodology has emerged as a viable tool for enamide synthesis, and, indeed, there are a number of published protocols which employ palladium- or copper-catalyzed stereospecific amidations of vinyl halides [17]. For example, Buchwald and coworkers had recently shown that a copper-catalyzed cross-coupling of vinyl bromides or iodides proceeded with retention of stereochemistry (Scheme 9.16), though the only example using a tetrasubstituted vinyl halide, 23, lacked the need for any stereochemical control in the halide portion [18]. Based on this it seemed feasible that the desired enamide 22 could potentially be assembled via a comparable coupling between amide 24 and a stere-odefined vinyl halide such as 25. 

Amides of phosphorous acid (e.g., P(NMe2)3 and the bicyclic compound (L16)) are useful ligands for cross-coupling of arylboronic acids with aryl bromides and chlorides (system Pd(OAc)2/2L, Cs2C03, toluene, 80 °C), the bicyclic amide being markedly more effective than simple acyclic ones.421 Amides of phosphinous acids are also excellent bidentate ligands with PN coordination mode ((L6), Section 9.6.3.4.2). 

During the cross-couplings to form C—N, C—O, C—S, and C—P bonds, the arylpalladium halide complexes are converted to arylpalladium amide, alkoxide, thiolate, and phosphide complexes. Examples of each type of complex have now been isolated, and the reductive elimination of the organic products has been studied. Although the reductive elimination to form carbon-hydrogen and carbon-carbon bonds is common, reductive elimination to form carbon-heteroatom bonds has been studied only recently. This reductive elimination chemistry has been reviewed.23... 

In the chemistry described in Scheme 6.151, Coats and a group of researchers from Johnson and Johnson utilized successive reductive aminations and Suzuki cross-coupling reactions to prepare a 192-member library of tropanylidene benz-amides [295], This series of tropanylidene opioid agonists proved to be extremely tolerant with regard to structural variation while maintaining excellent opioid activity. 

Abell utilized a Suzuki cross-coupling reaction on resin 153. Subsequent acid treatment effected cyclization to indole 154, which was readily cleaved with amines and alcohols to form potential libraries of amides and esters, respectively [162],... 

Other tin reagents have found use in Pd-catalyzed cross-couplings with halopyridines as well. The Stille coupling of 3-iodopyridine with ethoxy(tributylstannyl)acetylene gave rise to 3-ethoxyethynylpyridine (100), which was then hydrolyzed to the corresponding ethyl 3-pyridylacetate (101) [88], Carbamoylstannane 102 was prepared by sequential treatment of lithiated piperidine with carbon monoxide and trimethyltin chloride. Stille coupling of carbamoylstannane 102 and 3-bromopyridine provided a unique entry to amide 103 [89],... 

Snieckus et al. enlisted a combination of directed orrAo-lithiation and Suzuki coupling to assemble some unsymmetrical heterobiaryls [22], Carboxamidophenylboronic acid 30 was derived from sequential metalation of amide 29 and treatment with B(OMe)3 followed by acidic workup. Hetero cross-coupling of 30 with 2-bromothiazole occurred smoothly to furnish phenylthiazole 31. Similarly, a hetero cross-coupling between 2-bromothiazole and 3-formyl-4-methoxyphenylboronic acid produced a heterobiaryl as an intermediate of an orally bioavailable NKi receptor antagonist [23]. 

Formation of the P—N bond has been observed when the cross-coupling of dialkylphosphites (59) with amines (60) proceeds by an iodo cation [I]+-promoted electrooxidation, affording N-substituted dialkylphosphor-amidates (61) (Scheme 22) [76]. Lack of alkali iodide in the electrolysis media results in the formation of only a trace of (61), indicating that the iodide plays an important role in the P—N bond-forming reaction. In contrast, usage of sodium bromide or sodium chloride brings about inferior results since the current drops to zero before the crosscoupling reaction is completed. 

Scheme 22 Cross coupling of dialkylphosphites with amines to dialkylphosphor-amidates.

Cross coupling between an aryl halide and an activated alkyl halide, catalysed by the nickel system, is achieved by controlling the rate of addition of the alkyl halide to the reaction mixture. When the aryl halide is present in excess, it reacts preferentially with the Ni(o) intermediate whereas the Ni(l) intermediate reacts more rapidly with an activated alkyl halide. Thus continuous slow addition of the alkyl halide to the electrochemical cell already charged with the aryl halide ensures that the alkyl-aryl coupled compound becomes the major product. Activated alkyl halides include benzyl chloride, a-chloroketones, a-chloroesters and amides, a-chloro-nitriles and vinyl chlorides [202, 203, 204], Asymmetric induction during the coupling step occurs with over 90 % distereomeric excess from reactions with amides such as 62, derived from enantiomerically pure (-)-ephedrine, even when 62 is a mixture of diastereoisomcrs prepared from a racemic a-chloroacid. Metiha-nolysis of the amide product affords the chiral ester 63 and chiral ephedrine is recoverable [205]. 

Making use of an earlier finding that Sn compounds containing Sn—CH2R bonds were suitable for Stille cross-coupling reactions,one-pot C—H activation and cross-coupling products were isolated in modest yields (21 % from MeOBu and 5 % from n-CsH 12 based on Sn amide) as shown in Equation (9.13) (R CH2OBU or n-CsHn). ... 

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