Alkyne-gold hydroamination

Similarly, Vasudevan and Verzal have found that terminal alkynes can be hydrated under neutral, metal-free conditions using water as solvent (Scheme 4.15) [41], While this reaction typically requires a catalyst such as gold(III) bromide, employing microwave-superheated distilled water allowed this chemistry to proceed without any catalyst. Extension of this methodology led to a one-pot conversion of alkynes to imines (hydroamination). 

The cationic gold complex with CAAC ligand 29 can also catalyze the unprecedented hydroamination reaction of alkynes and allenes using ammonia [59, 60]. It was also demonstrated that it can catalyze the simple hydroamination reaction. It... 

The excellent ability of late transition metal complexes to activate alkynes to nucleophilic attack has made them effective catalysts in hydroamination reactions. The gold(l)-catalyzed cyclizations of trichloroacetimidates 438, derived from homopropargyl alcohols, furnished 2-(trichloromethyl)-5,6-dihydro-4f/-l,3-oxazines 439 under exceptionally mild conditions (Equation 48). This method was successfully applied to compounds possessing aliphatic and aromatic groups R. With R = Ph, cyclization resulted in formation of 439 with complete (Z)-stereoselectivity <2006OL3537>. 

Hydroamination of Alkynes The discovery of palladium-catalyzed intramolecular addition of amines to acetylene coupled with the spectacular contribution of Hutchings opened the door for the synthesis of several nitrogen heterocycles. The first study in this field was performed by Utimoto et al., who researched gold catalyzed intramolecular 6-exo-dig hydroamination. Tautomerization of the initial enamines allowed them to obtain imines, which were thermodynamically more stable [111] (Scheme 8.20). 

Imines react with alkynes to give pyrroles (equation 29). " A related transformation of azides has been reported by the group of Toste to afford pyrroles by an acetylenic Schmidt reaction (equation 30). " In an intermolecular-related addition, gold triazolates are obtained. The intramolecnlar hydroamination of trichloroacetimidates derived from propar-gyl and homopropargyl alcohols also proceeds with cationic An(I) as catalysts. ... 

Gold-catalyzed organic reactions, particularly, olefin epoxydation and hydroamination or hydroalkoxylation of alkynes to give N- or O-het-... 

Synthesis of enantiomerically enriched secondary amines (168) with excellent ee values, through the tandem, intermolecular hydroamination with primary amines (166) /transfer hydrogenation of alkynes (167), using a the gold(I) complex-chiral phosphoric acid (127) protocol, has been developed by Che and Liu (Scheme 44). A wide variety of aryl, alkenyl, and aliphatic alkynes as well as anilines with different electronic properties were tolerated. 

The synthesis of benzo[f ][l,4]diazepines 66 by a tandem hydroamination-cychzation sequence was carried out using a gold(I)-N-hetereocyclic car-bene catalyst (14JOM438). The authors utilized readily available N-alkyl o-phenylenediamines 63 and arylacetylenes 64 as starting materials. They proposed that the reaction proceeds by amination of a gold-activated alkyne with subsequent cyclization of intermediate 65. 

A computational study unravelled two key factors that account for the efficiency of the gold(I)-catalysed hydroamination of alkynes with ammonia, using MeC=CMe as the model system (i) the excess nucleophile, NH3, which assists the proton transfer, and (ii) an unexpected [Au] migration, which allows a feasible enamine-imine tautomerization. ... 

Utimoto has also shown that simple gold(III) salts catalyze the intramolecular hydroamination of alkynes with arylamines [4]. For example, treatment of 2-(3,3-dimethyl-l.butynyl)aniline with a catalytic amount of sodium tetrachloroaurate in refluxing TH F for 30 min led to isolation of 2-f-butylindole in 90% yield (Eq. (11.3)). Marinelli has modified and expanded the scope of Utimoto s procedure through employment of ethanol, ethanol/water [5], or ionic liquids 6] solvents. As an example of this modified protocol, treatment of 2-alkynylaniline 2 with a catalytic amount of NaAuCU dihydrate in ethanol at room temperature for 6h led to isolation of 2-(4-chlorophenyl)indole 3 in 92% yield (Eq. (11.4)). A similar hydroamination protocol employing AUCI3 as a catalyst has been recently reported by Majumdar [7]. 

Arcadi has reported the gold(111)-catalyzed hydroamination of alkynes with en-aminones [8]. For example, treatment of 4 with a catalytic amount of NaAuCh dihydrate in ethanol at 60°C for 2h led to cychzation and subsequent isolation of... 

Carbamates are also effective nucleophiles for the gold(I)intramolecular hydroamination of alkynes [12]. For example, treatment of O-propargylic carbamate 10 with a catalytic 1 1 mixture of (PPh3)AuCl and AgOTf in dichloromethane at room temperature led to isolation of 2,5-dihydroisoxazole 11 in 88% yield (Eq. (11.8)). The transformation was effective for alkyl-, alkenyl- and aryl-substituted internal alkynes and terminal alkynes and for N-Boc, Cbz, and Ts derivatives. A similar... 

Li has reported that cationic gold(III) complexes also catalyze the intermolecular hydroamination of terminal alkynes with aniline derivatives [17]. For example, reaction of a neat 1 1.5 mixture of phenylacetylene and aniline catalyzed by AUCI3 at room temperature followed by reduction with sodium borohydride led to isolation... 

Che has reported the tandem hydroamination/hydroarylation of aromatic amines wirh terminal alkynes to form dihydroquinolines in which 1 equiv of aniline combines with 2 equiv of alkyne [23]. For example, reaction of 3-methoxyanilme with pheny-lacetylene (5 equiv) and a catalytic 1 1 mixture of the gold(I) N-heterocydic carbene complex (IPr)AuCl (IPr= l,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidine) and AgOTf at 150 °C under microwave irradiation led to isolation of dihydroquinoline 21 in 82 % yield (Eq. (11.15)). Alternatively, reaction of o-acetylaniline with pheny-lacetylene catalyzed by a mixture of (IPr)AuCl and AgOTf at 150 °C led to isolation of the quinoline derivative 22 in 93% yield via incorporation of a single equivalent of alkyne (Eq. (11.16)). Arcadi has reported the gold(IlI)-catalyzed hydroamination/ hydroarylation of 2-alkynylanilines with a,p-enones to form C3-alkyl indoles [24]. As an example of this transformation, treatment of 2-(phenylethynyl)aniline with 4-phenyl-3-buten-2-one and a catalytic amount of sodium tetrachloroaurate dihydrate in ethanol at 30°C formed 1,2,3-trisubstituted indole 23 in 88% yield (Eq. (11.17)). 

Cyclic(alkyl)(amino)carbene (CAAC) ligands are unique donor Hgands with an easily tailored steric environment and have yielded a variety of robust gold complexes with unusual catalytic activity with alkyne substrates [179-181]. Here a CAAC-gold complex (23) could mediate the hydroamination of 3-hexyne in a sealed tube at 160° C to give imine product as observed by H NMR spectroscopy (Scheme 15.23) [179]. 

Indeed, Cu can be used in combination with tungstophosphoric acid to realize solvent-free acid-catalyzed hydroarylation and hydroamination of alkynes to give the Markovnikov products with a variety of arylamines [211]. Furthermore, gold catalysts have been used extensively with acid additives for a variety of amine and protected amine substrates [120,212]. More recently, Bertrand [189] was able to illustrate the useful apphcation of his [(CAACjAulBlCgFj) complex for intermolecular alkyne hydroamination with both primary and secondary amines (Table 15.14). 

Table 15.15 Intermolecular alkyne hydroamination catalyzed by gold-phosphine complexes.

Gin returned with an equally impressive synthesis of (-)-crambidine utilizing a variant of the aza-annulation employing thioimidate 59 with vinyl carbodiimide 60 (10JA1802). A rare gold-catalyzed intramolecular alkyne hydroamination of 61 cyclized the third ring of the core affording 62. With the core tricyclic scaffold constructed, four additional steps were required for the completion of the synthesis in a relatively straightforward manner. 

In addition to these findings, the most remarkable example of the improvement of the stability of a gold catalyst was reported by Bertrand and coworkers. In their studies of intermolecular hydroamination reactions of allenes and alkynes, which were either conducted with ammonia or hydrazine, they showed that their gold catalysts based on abnormal NHC ligands have amazing thermal stability [38]. Due to the fact that the amines used are capable of coordinating to the open side of the catalytic species and therefore can block the catalyst, these reactions require high reaction temperatures. Therefore, the reactions are carried out at temperatures of 160-200 °C (see Scheme 9.19) [38]. 

In the hydroamination of unsaturated carbon-carbon bonds, gold catalysts play an important role. Intermolecular hydroamination of alkenes [177], 1,3-dienes [204], terminal and internal alkynes [205], and allenes [206] are known to proceed smoothly in the presence of PhsP AufI) or AuCls catalyst. In addition, amino olefins also efficiently undergo intramolecular hydroamination using similar gold catalysts. He and coworkers have developed the catalytic cycloaddition of tosylated amino olefins [207], A representative example is shown in Scheme 18.35. When N-tosylated y-amino olefin (97) is exposed to a mixture of PhsP AuCl and AgOTf (5 mol% each) in toluene at 85 °C, pyrrolidine (98) is obtained in 96% yield. The gold(I)-catalyzed intramolecular hydroamination is applicable to N-alkenyl carbamates [208], N-alkenyl carboxamides [209], and N-alkenyl ureas [210], The use of microwave irradiation results in completing the hydroamination in a much shorter time than that required under thermal reaction conditions [211], The... 

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