Ynamides cycloaddition

Tandem azidination- and hydroazidination-Hiiisgen [3 +2] cycloadditions of ynamides are regioselective and chemoselective, leading to the synthesis of chiral amide-substituted 1,2,3-triazoles <06OBC2679>. A series of diversely l-substituted-4-amino-l,2,3-triazoles 132 were synthesized by the copper-catalyzed [3+2] cycloaddition between azides 130 and ynamides 131 <06T3837>. 

DFT calculations on the intramolecular Diels-Alder reaction of penta-l,3-dienyl acrylates predict stereoselectivities that are in good agreement with the experimen- (g) tal results.85 Another DFT study at the B3LYP/6-31G(d) level of the intramolecular Diels-Alder cycloaddition of 5-vinylcyclohexa-1,3-dienes has been reported. Reaction rates are influenced by dienophile twisting and substituent effects.86 The intramolecular dehydro-Diels-Alder reactions of ynamides (79) provides a new synthesis of benzo[fc]-, tetrahydrobenzo[fc]-, naphtho[l,2-/j -, and dibenzo[a,c]carbazoles... 

Scheme 22)87 The intramolecular 4 + 2-cycloaddition of ynamides with conjugated enynes produces substituted indolines that can be oxidized to indoles with o-chloranil.88 The double Diels-Alder cycloaddition of the linear conjugated tetraene... 

Ruthenium catalysts were used as alternatives to the usual copper catalysts. Ynamides 102 reacted with various azides 103 in the ruthenium-catalyzed Huisgen [3+2] cycloaddition reaction to yield l-protected-5-amido 1,2,3-triazoles 104 <07T8094>. The formation of 1,5-... 

CEJ4035>. Diastereospecific synthesis of r-/3-lactams can be effected via cycloaddition reaction of bisimines and the ketene derived from 582 (R = CH2CO2H) (Staudinger reaction) <2000T8555>. Ruthenium-catalyzed [2-1-2] cycloaddition of norbornene and ynamide 582 (R = C=CPh) <2006T3823> was reported. 

The final paragraph in this section details carbazole syntheses that involve the formation of C-C bonds. Intramolecular Diels-Alder cycloaddition of ynamides provided a new route to [b -fused carbazoles <05OL2213>. An electrocyclization of 2,3-divinylindole intermediates produced functionalized carbazoles <05TL4045>. A domino alkynylation/palladium migration/C-H activation approach to 4-vinylcarbazoles was reported <050L701>. For example, treatment of A-arylaniline 134 with diphenylacetylene in the presence of palladium acetate, cesium pivalate (CsPv), and bis(diphenylphosphino)methane (dppm) gave carbazole 136 via post-palladium migration intermediate 135. 

It is now usual to promote these cycloadditions by catalysts for example, reaction with A -tosyl-ynamides, using ruthenium or copper catalysts, giving 1-substituted 5- and 4-amino triazoles, respectively the formation of the 1,4-substitution pattern with copper catalysis and 1,5-pattem with ruthenium catalysis seems to be general. The latter metal will also promote addition to internal alkynes. ... 

In an effort to expand the click chemistry concept, Ijsselstijn et al. [43] have reported the use of two N-protected ynamides (60) as dienophiles in the Cu(I)-catalyzed cycloaddition reaction with a variety of azides, including glycosyl azides (Scheme 12). The ynamides were successfully clicked under the standard conditions for these reactions [Cu(OAc)2/Na-ascorbate] giving rise to 1-substituted 4-amino 1,2,3-triazole-Iinked sugars (61). These results are noteworthy as they allow direct access to amino triazole rings, which are found in some bio active molecules. However, additional studies are required in order to evaluate the scope and appUcability to more complex ynamides. 

Ruthenium-catalyzed [2 + 2] cycloadditions involving bicyclic alkadienes (377) and alkynyl phosphonates (378) have been investigated by Tam and co-workers. The corresponding cyclobutene cycloadducts (379) were obtained in low to excellent yield (up to 96%) (Scheme 87). Alkynyl phosphonates showed a lower reactivity than other heteroatom-substituted alkynes such as alkynyl halides, ynamides, alkynyl sulfides, and alkynyl sulfones and required a higher reaction temperature and much longer reaction times. 

In a cycloaddition reminiscent of the Moody indole synthesis (Chapter 54), Ko5evar and Kranjc effected the high-pressure Diels-Alder cycloaddition of 2/7-pyran-2-ones with (Z)-l-methoxy-l-en-3-yne to afford indoles after acid-cycUzation (Scheme 10, equation 1) [39]. In some cases the 2,2-dimethoxyethyl intermediates were formed, but these were transformed to indoles under the same acidic conditions. An intramolecular [4+2] cycloaddition between ynamides and conjugated enynes to indolines and indoles was featured by Danheiser and Dunetz (equation 2)... 

Tokunaga and Wakatsuki reported a one-pot indole synthesis from anilines and propargyl alcohols using Rn3(CO)j2 [5], and Nicholas and colleagues reported a Ru-catalyzed indole synthesis via the reductive annulation of nitros-oarenes with alkynes (equation 3) [6, 7]. Saa and coworkers described the Ru-catalyzed cycloisomerization of o-alkynylanihnes (equation 4) [8, 9]. Nissen and Detert reported a total synthesis of lavendamycin that featnred a Ru-catalyzed [2-f2-f2] cycloaddition of an o-alkynyl-ynamide, a method that was superior to rhodium catalysis both in terms of efficiency and regiochemistiy [10]. 

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]. 

DeKorver, K. A., Hsung, R. R, Song, W. Z., Wang, X. N., Walton, M. C. (2012). An intramolecular 2-1-2 cycloaddition of ketenimines yia palladium-catalyzed rearrangements of N-allyl-ynamides. Organic Letters, 14, 3214-3217. 

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. 

Substituted indolines (Scheme 4.23) [30] and carbazoles (Scheme 4.24) [31] were synthesized by RhCl(PPh3)3-catalyzed [2 - - 2 - - 2] cycloaddition of 1,6-diynes, containing the ynamide moiety, with terminal alkynes. 

Clausine C (107) was synthesized in six steps with an overall yield of 40%, starting from commercially available iodoaniline 104. Notably, the yne-ynamide formation was realized though direct N-ethynylation of the corresponding tosylamide generated from 104 using the readily available alkynyliodonium salt 105. Thereafter, the rhodium-catalyzed crossed alkyne cyclotrimerization of 106 with methyl propri-olate furnished the corresponding crossed cycloaddition products in the ratio 4 1... 

Originally, the pyridine construction reaction was based on cobalt catalysis and restricted to the use of acetonitrile or alkyl nitriles as one of the cycloaddition partners. However, recent advancements in this area have led to the development of certain ruthenium or rhodium catalysts, allowing the use of methylcyanoformate as an electron-deficient nitrile component in crossed [2 - - 2 - - 2]-cycloaddition reactions [39]. From the point of view of applications, the use of methylcyanoformate in transition-metal-catalyzed pyridine formation reaction is quite beneficial because the ester moiety might serve as a functional group for further manipulations. It might also serve as a protective group of the cyanide moiety, because cyanide itself cannot be used in this reaction. These considerations led to the design of a quite flexible approach to substituted 3-(130)- and y-carbolines (131) based on transition-metal-catalyzed [2 -f 2 -I- 2] cycloaddition reactions between functionalized yne-ynamides (129) and methylcyanoformate (Scheme 7.28) [40]. 

Notably, use of the diyne 139 having a terminal ynamide and an internal alkyne moiety led in a related ruthenium-catalyzed [2 + 2 + 2] cycloaddition with... 

For the simultaneous construction of biaryl- and anilide-based axial chiralities, Tracey et al. investigated the RhCl(PPh3)3-catalyzed diastereoselective [2-I-2-I-2] cycloaddition of terminal 1,6-diynes 100 with ynamides 101, bearing chiral auxiliaries. Although the desired axially chiral anilides 102 were obtained in good to high yields, the diastereoselectivities observed were low to moderate (Scheme 9.35) [31]. 

An experimental and theoretical investigation of electronic effects in ruthenium catalyzed cycloadditions with internal diarylalkynes has shown that 5-electron-donating group substituted triazoles should be favored [155]. This effect was further observed in the synthesis of 5-amino-triazoles from ynamides (Scheme 65) [156]. 

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