Ynamides coupling

Certain ynamides are obtained from 1-alkynes and amine derivatives (e.g., 3-acylindoles, imidazolidinones, oxazolidinones, and sulfonamides) by coupling under oxygen, using the CuCl2-pyridine catalyst. 

A-Sulfonylamidines can be prepared by three-component coupling [31] of alkynes (R = alkyl, aryl or silyl), sulfonyl azide and amine, which is known as click chemistry. [32] The use of alkyl azides in place of sulfonyl azide without a copper catalyst results in the formation of 1,2,3-triazoles (Scheme 3.18). This reaction shows substrate tolerance to each component. Reaction with an optically active amino ester is performed without racemiza-tion. A-Boc-ynamide (R = NPhBoc) can act as the alkyne component in the synthesis of N-Boc-aminoamidines [33]. 

Kim, J.Y., Kim, S.H. and Chang, S. (2008) Highly efficient synthesis of (a-amino amidines from ynamides hy the Cu-catalysed three-component coupling reactions. Tetrahedron Letters, 49, 1745-1749. 

An indium-mediated radical cyclization sequence has been used to synthesize stereoselectively 3-alkylideneoxindoles [65, 66]. The generation of predominantly the i -isomer, such as seen with 96 below, is attributed to the strong coordination of the indium to the carbonyl of the oxindole intermediate, and the transformation of various iodo-ynamides to the cyclized oxindoles occurred in good yield. Selective approaches to the E- and disubstituted 3-alkylideneoxindoles involving a tandem palladium-catalyzed cross coupling reaction were also highlighted in this report. 

Evano and colleagues disclosed a modular indole synthesis via the intramolecular carbocupration of N-aryl-ynamides (124 125) (130L3122).A series of indole derivatives was prepared by Jiao via the palladium-catalyzed aerobic oxidative intramolecular hydroamination and C-H functionalization of N-alkynylanilines (13T4408). Suh reported a microwave-assisted synthesis of 3-functionalized indoles via an intramolecular arene-alkene coupling of o-iodoanilino enamines (13T7211). 

N. Saito, T. Katayama, Y. Sato, Org. Lett. 2008, 10, 3829-3832. Nickel-catalyzed highly regioselective multicomponent coupling of ynamides, aldehydes and silane a new access to functionalized enamides. 

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]. 

Ynamide preparation via oxidative coupling of amides and alkynes represents an efihcient alternative to known multi-step methods, such as alkyne halogenation or the synthesis of alkynyliodonium salts followed by C-N formation. The only shortcoming of this system is that 5 equiv of the amide are necessary to achieve satisfactory yields. 

Other important molecules that are useful intermediates in the synthesis of natural products are chiral diols. anli-l,2-Diols of type 30 were obtained in good yields (75-85%) and moderate to good diastereoselectivity (76-96% de) by a nickel-catalyzed three-component addition of a-silyloxy aldehydes 27, alkynyl silanes 28a, and reduction with triisopropyl silane (29a) (Scheme 11.11) [31]. The diastereoselectivity of this process could be explained by the Felkin model. Alternatively, a chiral alkynyl derivative can control the outcome of the reaction. Thus, the coupling of optically active, oxazolidinone-derived ynamides, aldehydes, and silane as reducing agent led to the formation of y-siloxyenamide derivatives with diastereoselectivities up to 99% [32]. 

Saito, N., Katayama, T., Sato, Y. (2010). Asymmetric synthesis of y-siloxyenamides via chiral auxiliary-mediated diastereoselective coupling of ynamides, aldehydes, and silane by nickel catalyst. Heterocycles, 82, 1181-1187. 

A metal-free coupling of terminal acetylenes with a functionalized iodine(III) reagent generated high yields of the ynamides [163], An aerobic copper coupling reaction between terminal alkynes and secondary amides has also been successful [165]... 

Tricyclic fused 3-aminopyridines 93 could also be assembled via intramolecular CpCo(C2H4)2-catalyzed [2- -2-1-2] cycloaddition between ynamides, nitriles, and alkynes (Scheme 1.26) [47]. Of particular interest, one of the cycloadducts could be used in a rare type of silylated pyridine Hiyama cross-coupling to give 95 in 77 % yield. 

Kaspar and Ackermann also reported that the process could be performed as a three-component system, featuring in situ generation of the key o-alkynylhaloarenes via the incorporation of a tandem Sonogashira reaction [35]. Related chemistries have been reported for the synthesis of 2-aminoindoles from ynamide-based substrates [36], A-aminoindoles from hydrazine-based nucleophiles [37], and N-unsubstituted indoles via the use of ammonia as the coupling partner [38,39],... 

In a complementary manner, the regioselective coupling of ynamides and ethylene has been reported to be mediated by a low valent ruthenium catalyst (Cp RuCl(cod)). The formation of a ruthenacyclopentene 209 where the ruthenium... 

R = H, Ar, Aik, TMS,CH2CH2OTBS Scheme 83 Coupling of ynamides with ethylene... 

A dehydrohalogenative coupling of alkynyl bromides with amides affords ynamides (Scheme 4-267). As substrates mostly cyclic carbamates or sulfonamides are applied. The reaction is performed employing catalytic amounts of iron(III) chloride in the presence of AA -dimethylethylenediamine as ligand. ... 

Interestingly, a related copper catalyst system was recently utilized by Evano and co-workers for the synthesis of N,N-acetals when coupling 1,1-dibromoalkenes with certain amides [107]. Unexpectedly, this particular transformation did not proceed through two consecutive copper-catalyzed C-N bond formations and experiments conducted on ynamides under the same experimental conditions supported the plausible role of the latter species as active intermediates in the amidation process (Scheme 28). The mechanism pathway proposed by the authors consists of a first C-N cross-coupling of the alkene with the amide, followed by dehydrobromination of the coupling product and subsequent hydroamidation of the... 

Through a sequential metal-catalyzed C-N bond formation, 2-amidoindoles 40 were conveniently constructed from o-haloaryl acetylenic bromides 38, carbamate 39 and primary amines (Scheme 13) [41]. It is believed that Cu-catalyzed intermo-lecular amidation occurred first, and the resultant o-haloaryl substituted ynamides were coupled with primary amines, affording indoles 40 after intramolecular nucleophilic attack. 

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

Witulski has reported the first hydroboration of 1-alkynylamides. Thus, the hydroboration of ynamide 112 with catechol borane in THF proceeded chemo- and regioselectively yielding only the monohydroboration product, alkenyl boronic ester 113 [90]. However, the isolation of the boronic ester 113 was complicated due to its instability and difficulties of storage and purification. Therefore, it was directly subjected to Suzuki-Miyaura cross-coupling yielding (E)-y3-arylenamide and 3-(2 -amidovinyl)indoles such as 114 (Scheme 3.58). 

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