Cycloaddition of Alkyne and Nitrile

Success of the cycloaddition of alkynes and nitriles was originally attributed solely to the highly sigma-donating nature of NHCs, which make the metal center 

TABLE 2.2 Comparison of Ni/Xantphos Catalyst with Other Known Catalysts 

Entry xmol% [M] catalyst Nitrile a (equiv) Temp. Conv. (%) 1 Yield (%) la 

Interestingly, the Ni/Xantphos catalyst system was found to be superior not only to the other known state-of-the-art catalyst systems but also to a Ni/NHC system reported previously (see entry 6 vs. 1 to 5, Table 2.2). The [Co] catalyst developed by Kase et al. affected the cycloaddition of diyne 61 with benzonitrile to afford 62 [13]. These conditions required the use of 20 equiv of nitriles, and even after 24 h full conversion of diyne was not achieved (entry 1). Performing the reaction under Tanaka et al. s conditions led to comparable yields however, a higher temperature was necessary for excellent conversions and yields (entries 2 and 3) [14]. Additionally, the [Ru] catalyst was completely ineffective in the cycloaddition reactions [15]. Hence, Ni/Xantphos is a highly effective catalyst for the aforementioned transformation. Although other state-of-the-art catalysts were less effective or ineffective for this specific transformation, we believe that all these catalysts complement each other in their respective, overall reactivity profiles. 

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The homogeneous catalytic [2+2+2]-cycloaddition of alkynes and nitriles was first discovered by Yamazaki and Wakatsuki [3] using the phosphine-stabilized cobalt(III) complex (Stmcture 5). At the same time, Bdnnemann and co-workers [5] observed the co-cyclization (eq. (2)) at cobalt catalysts prepared in situ, as well as using phosphine-free organocobalt(I) diolefm complexes. 

Gutnov et al. gave the first report on the Co(I)-catalyzed asymmetric [2+2+2] cycloaddition of alkynes and nitriles leading to enantiomerically... 

Niobium catalyzes an intermolecular [2 + 2 + 2] cycloaddition of alkynes and nitriles, which forms 2,3,6-trisubstituted pyridines (Scheme 20) (13JOC7771). The catalytic mixture involves low-valent niobium from NbCls, Zn, and an alkoxysilane. In addition to the desired 2,3,6-pyridines, a small amount of substituted arene was isolated in each reaction. Benzoni-triles with a variety of substituents underwent cycloaddition smoothly. Moreover, benzylnitriles also reacted smoothly however, the reaction was sluggish wnth aliphatic nitriles. 

Obora and Satoh showed that low-valent niobium can be applied as catalyst in the cycloaddition of alkynes and nitriles as well [58], By the combination of NbCls, Zn, and an alkoxysilane, pyridine derivatives were produced in good yields from the intermolecular cycloaddition of alkynes and nitriles via a niobacyclopentadiene intermediate (Scheme 3.25). Zn acts as a reducing agent here, the active low-valent Nb species might also be stabilized by the alkoxysilane, and generated chloro (methoxy)diphenylsilane. 

Figure 9.2 (a, b) The generation of group 9 catalyst complexes and an overview of the [2+2+2] cycloaddition of alkynes and nitriles [If], (Reproduced from Ref. [1f with permission from The Royal Society of... 

In 2004, Gutnov et al. [13b] reported a Co(I)-catalyzed asymmetric [2+2+2] cycloaddition of alkynes and nitriles, which gave enantiomerically enriched atropoisomeric 2-arylpyridines (Scheme 9.8). The reaction was carried out with chiral Co(I) complexes with visible-light irradiation. Unfortunately, the yields were only moderate and a highest enantioslectivity of 71% ee was obtained. The best overall catalyst in terms of the yield/enantioselectivity balance is that shown in Scheme 9.8. 

Due to the utmost importance of pyridines in catalysis and medicinal chemistry, efficient routes to these heterocycles are highly desirable. The transition-metal-mediated [2 -I- 2 -I- 2] cycloaddition of alkynes and nitriles serves as an important approach to access free as well as fused pyridine motifs in an efficient manner (Scheme 2.13). 

Gutnov, A., Heller, B., Fischer, C. et al. (2004) Cobalt(I)-catalyzed asymmetric [2-1-24-2] cycloaddition of alkynes and nitriles synthesis of enantiomerically enriched atropoisomers of 2-arylpyridines. Angewandte Chemie International Edition, 43(29), 3795-3797. 

The cycloaddition of alkynes and alkenes to nitrile oxides has been used in the synthesis of functionalised azepine systems <96JHC259>, <96T5739>. The concomitantly formed isoxazole (dihydroisoxazole) ring is cleaved by reduction in the usual way. Other routes to 1-benzazepines include intramolecular amidoalkylation <96SC2241> and intramolecular palladium-catalysed aryl amination and aryl amidation <96T7525>. Spiro-substituted 2-benzazepines have been prepared by phenolic oxidation (Scheme 5) <96JOC5857> and the same method has been applied to the synthesis of dibenzazepines <96CC1481>. 

To produce a 1,2-azole, a 1,3-dicarbonyl compound needs to be condensed with a unit providing the two heteroatoms - a hydrazine or hydroxylamine. The dipolar cycloaddition of alkynes with nitrile oxides or nitrile imines provides a route to isoxazoles and pyrazoles. 

A fascinating approach to the synthesis of pyridine heterocycles has been discovered by using (arene)Fe(O) complexes to catalyze [2+2+2] cycloaddition reactions. The proposed method consists of a cross cyclization of alkynes and nitriles [45]. An example of such a reaction is depicted in Scheme 25. In the presence of (Ty -l,5-cyclooctadiene)(Ty -phosphinine)Fe(0) 85, butyronitrile 86 combines with two molecules of methyl propargyl ester 87 yielding a mixture of isomeric pyrroles 88 and 89. The reaction proceeds at ambient temperature, but relatively long reaction times are required to obtain good yields. The symmetric... 

A systematic study on the use of [CpCo(CO)(dmfu)] (dmfu = dimethyl fumarate) [12] as a precatalyst for the cocyclization of alkynes and nitriles was published in 2011 [13]. By this catalyst, the incorporation of electron-deficient nitriles into the pyridine core was realized. 3- or 4-Aminopyridines can be produced regioselectively by modifying the substitution pattern at the yne-ynamide. Based on DFT computations, the author suggested that 3-aminopyridines are formed by formal [4 + 2] cycloaddition between the nitrile and the intermediate cobaltacyclopenta-diene, whereas 4-aminopyridines arise from an insertion pathway. This catalytic system was applied in the synthesis of bicyclic 3- or 4-aminopyridines from yne-ynamides and nitriles (Scheme 3.1) [14]. 

The first report of rhodium-catalyzed [2 - - 2 - - 2] cycloaddition of alkynes with nitriles involves intermolecular reactions catalyzed by a cyclopentadienyl rhodium(I) ethylene complex, which was reported in 1987 (Scheme 4.52) [54a,b]. These reactions required excess nitriles and high temperature. 

In the pyridine synthesis, the cationic rhodium(I)/biaryl bisphosphine complexes are widely applicable catalysts for both intermolecular and intramolecular [2 + 2 + 2 cycloaddition of alkynes with nitriles under mild conditions. Wilkinson s complex [RhCl(PPh3)3] is effective for intramolecular [2-f 2-1-2] cycloaddition of diyneni-triles under microwave heating. 

Cycloaddition reactions also have important applications for acyclic chalcogen-nitrogen species. Extensive studies have been carried out on the cycloaddition chemistry of [NSa]" which, unlike [NOa]", undergoes quantitative, cycloaddition reactions with unsaturated molecules such as alkenes, alkynes and nitriles (Section 5.3.2). ° The frontier orbital interactions involved in the cycloaddition of [NSa]" and alkynes are illustrated in Fig. 4.13. The HOMO ( Tn) and LUMO ( r ) of the sulfur-nitrogen species are of the correct symmetry to interact with the LUMO (tt ) and HOMO (tt) of a typical alkyne, respectively. Although both... 

Salts of the linear [S=N=S]" cation (isoelectronic with CS2) are readily prepared. This cation undergoes quantitative, 1,3-dipolar cycloaddition reactions with unsaturated molecules such as alkenes, alkynes and nitriles, and also with NS" , to give a variety of ring compounds (Scheme 2.8). The... 

An intramolecular double nitrile oxide cycloaddition with alkyne and olefin moieties was exploited in the synthesis of novel unsymmetrical hybrid spiro (isoxazole-isoxazoline) ligands 14 which were effective in promoting a Pd-catalyzed tandem cyclization <07TA919>. 

Nitrile oxides undergo efficient [3-1-2] cycloadditions with alkynes and alkenes to generate isoxazoles and 4,5-dihydroisoxazoles, respectively. With unsymmetrical dipolarophiles there exists the possibility of regioisomeric mixtures of products however, it is generally found that steric effects control the regioselectivity and the more encumbered end of the dipolarophile becomes attached to the oxygen of the nitrile oxide. Thus, terminal alkynes and alkenes afford almost exclusively 3,5-disubstituted isoxazoles and dihydroisoxazoles, respectively (Scheme 91). 

Acetyl- and 3-benzoylisoxazoles 389 (and isoxazolines) have been prepared by one-pot reactions of alkynes (and alkenes) with ammonium cerium(iv) nitrate (CAN(lv)) or ammonium cerium(lll) nitrate tetrahydrate (CAN(m))-formic acid, in acetone or acetophenone. These processes probably involve 1,3-dipolar cycloaddition of nitrile oxides produced via nitration of the carbonyl compound by cerium salts. The existence of nitrile oxides as reaction intermediates was proved by the formation of the dimer furoxan 390 when the above reaction was carried out in absence of any dipolarophile (Scheme 95) <2004T1671>. An analogous improved procedure has been applied to alkynyl glycosides as dipolarophiles for the preparation of carbohydrate isoxazoles <2006SL1739>. 

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