Alkynyl imines

Recently, a method for synthesizing substituted pyridines incorporating 3-azadienynes as substrates in ruthenium-catalyzed cycloisomerizations was described <06JA4592>. This route is a two-step process that first converts readily available JV-vinyl or JV-arylamides (e.g., 26) to the corresponding C-silyl alkynyl imines (e.g., 27) and subsequent ruthenium-catalyzed protodesilylation and cycloisomerization results in the formation of the corresponding substituted pyridines (e.g., 28). 

This system was described in one report and has been synthesized by a copper-assisted cycloisomerization of alkynyl imines. The authors proposed the following mechanism at first, 372 could undergo a base-induced propargyl-allenyl isomerization to form 373 next, coordination of copper to the terminal double bond of the allene (intermediate 374) would make it subjected to intramolecular nucleophilic attack to produce a zwitterion 375. The latter would isomerize into the more stable zwitterionic intermediate 376, which would be transformed to the thiazole 377 (Scheme 55) <2001JA2074>. 

Akiyama et al. extended this reaction to alkynylimines for the preparation of quinoline derivatives [28]. Treatment of N-aryl(alkynyl)imines 99 with 20 mol% W (CO)5(thf) in THF at reflux followed by oxidative work-up using NMO gave 2-arylquinolines 100 in reasonable yield through electrocydization of the vinylidene intermediate (Scheme 5.31). 

Scheme 5.31 Electrocyclization of N-aryl(alkynyl)imines leading to quinoline derivatives.

Movassaghi et al. [21[ reported the synthesis of substituted pyridine derivatives via ruthenium-catalyzed cycloisomerization of 3-azadienynes. To avoid the isolation of the chemically active alkynyl imines, trimethysilyl alkynyl amines served as initial substrates, as shown in Scheme 6.19. The formation of ruthenium vinylidene intermediates is accompanied by a 1,2-silyl migration according to controlled... 

The copper mediated cycloisomerisation of alkynyl imines provides a facile access to pyrroles and fused aromatic pyrroloheterocycles.50 In a recent example, shown in 8.39., the pyrrolopyrimidine bearing an acetylene moiety in the appropriate position cyclized smoothly to give the desired tricyclic compound in 89% yield.51... 

The proposed mechanism involves the initial rearrangement of alkynyl imine 137 into allenyl imine 138. Subsequent coordination of copper(I) to the terminal bond of the allene triggers intramolecular attack of the aromatic ring, a process that finally leads to quinolines 139 via several intermediates. 

TABLE 10.3. Asymmetric Mannich Reactions of Enol Ethers with Alkynyl Imines... 

It has been diseovered that the one-pot reaction of alkynylzirconocenes with alkynyl imines (480), dimethylzinc and a zinc carbenoid, leads to unprecedented C,C-dicyclopropylmethylamines (481) as single isomers. This reaction proceeds via the rare bicyclo[1.1.0]butane intermediates (482). This novel methodology tolerates a number of common protecting groups used in synthesis (Scheme 111). ... 

Kel in et al. reported that the copper-assisted cycloisomerization of the alkynyl imines 320 gave the pyrroles 321 in high yields (Scheme 101).169 Mechanistic studies revealed that this reaction proceeded via the propargyl-allenyl isomerization of 320 to the... 

Gevorgyan describes a novel copper-assisted cycloisomerization of alkynyl imines 31 to 2,5-disubslituted pyrroles 32 as well as fused systems containing a pyrrole ring <01JA2074>. It was found that utilization of easily deprotectable N-substituents such as trityl or 3-(ethylbutyryl) (EB) groups allows for facile access to IV-unsubstituled pyrroles. 

New synthesis of pyridones using conjugate addition reactions of active methine compounds to alkynyl imines and ketones 06Y251. 

To a THE solution of 0.4 mmol sodium methoxide was added 0.5 mmol dimethyl methyl-malonate in 2 mL THE at room temperature, followed by 2 mL THE solution containing 0.2 mmol alkynyl imine. The mixture was refluxed for 7 h and then cooled to room temperature. Brine (10 mL) was added to quench the reaction, and the mixture was extracted with CH2CI2 (3 X 15 mL). The combined organic layers were dried over Na2S04 and concentrated. The residue was purified by preparative TLC to give 47% 2-pyridone and 42% decarboxylated 2-pyridone, respectively. 

Josephsohn, N. S., Carswell, E. L., Snapper, M. L. and Hoveyda, A. H. 2005. Practical and highly enantioselective synthesis of 3-alkynyl-P-amino esters through Ag-catalyzed asymmetric Mannich reactions of silyUcetene acetals and alkynyl imines. Org. Lett. 7 2711-2713. 

The same group reported a novel approach toward the not so easily available 1,2,3-trisubstituted pyrroles (Scheme 8.79) [118, 124]. Accordingly, alkynyl imines 213, possessing a sulfanyl group at the propargylic C4-position, underwent the Cu(I)-... 

A similar concept was applied to the two-component synthesis of indoles 164 via cydoisomerization of alkynyl imines 162 (Scheme 9.61) [220]. N-(Alkoxymethyl) indoles 164 were readily prepared through the Cu(I)-catalyzed cyclization-hydroxyla-tion reaction of the imine precursors 162 in the presence of a variety of external O-nucleophiles 163, such as alcohols and phenols, with good functional group compatibility. The authors believe that this domino reaction begins with the Cu( I)-activation of alkyne 162 toward 5-ewdo-digcyclization to form a cydic metal-containing azomethine... 

The Au(III)-catalyzed double hydroamination cascade reaction of ortho-alkynyla-nilines 167 with terminal alkynes 168 affording N-vinylindoles 169 was reported by li (Scheme 9.63) [221]. In the case of alkyl-substituted acetylenes, this protocol provided mixtures of isomeric N-vinylindoles with both terminal and internal double bonds. This transformation is believed to occur via the Au(III)-catalyzed cydoisomerization of transient key alkynyl imines, similar to 162 utilized by Yamamoto, which were generated via the initial Au(111)-catalyzed hydroamination of the corresponding anilines 167 with alkynes 168. 

Recently, Iwasawa established a set of transition metal-catalyzed protocols for an efficient construction of N l-C2-fused polycydic indole skeletons via a cycloisomerization-cycloaddition domino reaction of alkynyl imines 172 [222-224]. It was shown that the latter substrates, upon activation with transition metal catalysts, such as W(0), Pt(II), and Au(III), generate reactive azomethine ylide intermediates 174 similar to 166 (Scheme 9.64). Interception of such yUdes with a variety of suitably substituted alkenes 17S via a [3 - - 2]-cydoaddition affords fused indole products 177 through a transient formation of the corresponding metallocarbenoids 176. Transformation of terminal alkynyl imines proceeds with a 1,2-H shift in the 176, whereas... 

Addressing the allenylpyridine instability problem, Gevorgyan developed the Cu(I)-catalyzed cycloisomerization of conjugated alkynyl imines 317, perfect allene 318 surrogates, as an alternative route for the construction of indolizine and other pyrrole-fused cores 319 (Scheme 9.110) [291-293]. This protocol proved to be very general and efficient for the synthesis of a variety of diversely functionalized C3-substituted heterocycles 319. On the other hand, this approach was not applicable... 

Movassaghi and Hill developed a ruthenium-catalyzed cycloisomerization of 3-azadienynes to the corresponding pyridines [11]. The alkynyl imines were produced from a variety of iV-vinyl and iV-aryl amides by amide activation and nucleophilic addition of copper(I) (trimethylsilyl) acetylide sequence reaction. Then by Ru-catalyzed protodesilylation and cycloisomerization, the desired pyridine derivatives were formed selectively in good to excellent yields (Scheme 2.7). For the reaction mechanism, C-silyl metal vinylidene was found to be the key intermediate. 

A Mannich-type reaction of j0-keto ester with C-alkynyl imines generated in situ delivers asymmetric synthesis of propargylamines with two adjacent stereocentres organocatalytically. " ... 

Successful cycloisomerization of acyclic alkynyl imines to pyrroles caused an attempt to the cycloisomerization of the cyclic alkynyl imines thus 2-alkynyl pyridine with CFs-group gave a product of cyclization, indolizine 53 [38]. 

Kel in AV, Sromek AW, Gevorgyan V (2001) A novel Cu-assisted cycloisomerization of alkynyl imines efficient synthesis of pyrroles and pyrrole-containing heterocycles. J Am Chem Soc 9 2074-2075... 

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