Tandem with alkynes

The key features of the catalytic cycle are trapping of the radical generated after cycliza-tion by an a,P-unsaturated carbonyl compound, reduction of the enol radical to give an enolate, and subsequent protonation of the titanocene alkoxide and enolate. The diaster-eoselectivity observed is essentially the same as that achieved in the simple cyclization reaction. An important point is that the tandem reactions can be carried out with alkynes as radical acceptors. The trapping of the formed vinyl radical with unsaturated carbonyl compounds occurs with very high stereoselectivity, as shown in Scheme 12.21. 

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>. 

Later, Arcadi showed that /J-keto-imines react with alkynes intramolecularly to give pyrroles. The intermolecular animation with aniliaes was later developed by Hayashi and Tanaka using a cationic Au(I) catalyst to form imines (equation 27). More recently, Arcadi etal. developed an intramolecular version for the cyclization of o-alkynylanilines to form indoles (equation 28) and Li reported a double intra- and intermolecular hydroamination to obtain A-vinylindoles. " O-Substituted hydroxylamines can also undergo this type of transformation to dihydroisoxazole derivatives. " " Tandem sequences that involve a first alkyne-hydroamination step with anilines have been recently developed " " and are similar to the previonsly discnssed additions with phenols that access isoflavone skeletons. 

Scheme 9 Titanocene-catalyzed tandem reactions with alkynes in EtOAc [65]...

A comprehensive treatment of the benzannulation of Fischer carbene complexes with alkynes is not possible in this review, and thus instead the material presented here will hopefully serve to give the reader an overview of its scope and limitations. The first report of this reaction was in 1975 by Dotz in which he describes the formation of the naphthol chromium tricarbonyl complex (236) from the reaction of the phenyl chromium complex (la) with diphenylacetylene. In the intervening years over 100 papers have been published describing various aspects of this reaction.The reaction of the generic cartene complex (233 Scheme 34) with alkynes will serve to focus the organization of the scope and limitations of the benzaimulation reaction. The issues to be considered are (i) the regioselectivity with unsymmetri-cal alkynes (ii) possible mechanisms (iii) applications in natural product syntheses (iv) the effect of substitution on the aryl or alkenyl substituent of the carbene carbon (v) functionality on the alkyne (vi) effects of the solvent and the concentration of the alkyne (vii) tandem applications with other reactions of carbene complexes (viii) reactions where aromatization is blocked (cyclohexadienone annulation) (ix) annulation of aryl versus alkenyl carbene complexes (x) the effect of the ligands L on the metal (xi) the effect of the ancilliary substituent RX and (xii) reactions with —C X functionality. 

Oxazole cycloadditions have been reported with alkyne dienophiles (tandem Diels-Alder addition and retro Diels-Alder loss of a nitrile leads on to furans), benzyne (the primary adduct can be isolated), and with typical alkene dienophiles and the adducts can be transformed into pyridines (8.14.1.4). 

Neat reactions of liquid substrates can be quite successful. For example, the addition of P(0)-H bonds to alkenes has been accomplished using microwave irradiation in the absence of added solvent or catalyst (Scheme 25.4b). Tandem hydrophosphinylation reactions with alkynes afforded unsymmetrical species such as phosphine oxide—phosphinates. 

Bis(propargyl) ethers were converted to dihydrobenzo[c]furans through either a palladium-catalyzed tandem reaction with arylboronic acids <04CEJ5338> or an iridium-catalyzed <04JA8382> [2+2+21 cycloaddition reaction with alkynes. 

The synthetic utility of oxazoles as azadienes was further advanced when Grigg and co-workers reported that the Diels-Alder reactions of oxazoles with alkynes provided furans via a tandem Diels-Alder retro-Diels-Alder sequence. Thus 5-ethoxy-4-substituted oxazoles 119 reacted with dimethyl acetylenedicar-boxylate in cold ether to yield 2-ethoxy-3,4-furandicarboxylic acid dimethyl ester 121 in >50% yield (Fig. 3.33). In this case, the intermediate cycloaddition adduct 120 extrudes a molecule of hydrogen cyanide or a nitrile derived from the C-4 substituent of the oxazole, via a retro-Diels-Alder reaction to provide a substituted... 

In a series of papers, Wong and co-workers detailed the preparation and use of 3,4-bis(trimethylsilyl)furans. Thus, after heating an equimolar mixture of 4-phenyloxazole and bis(trimethylsilyl)acetylene with 5 mol % of triethylamine in a sealed tube at 250°C for 2 days, an 80% yield of the desired furan 130 was obtained (Fig. 3.38). If the same reaction is performed in the presence of a catalytic amount of formic or trifluoroacetic acid instead of triethylamine, the analogous 2,4-bis-trimethylsilylfuran is obtained in good yield. Furan 130 itself reacts with alkynes in a tandem Diels-Alder retro-Diels-Alder sequence to provide other fiirans, e.g., 3,4-furandicarboxylic acid dimethyl ester 131. Friedel-Crafts acylations can also be performed using 130. In addition, 130 reacted with boron... 

Enyne metathesis RCM can be performed in tandem with RCM using appropriately spaced diene-yne substrates. Many examples of this reaction featuring various degrees of complexity have been reported. Representative examples of tandem enyne metathesis-RCM are depicted in Scheme 30 and include (i) formation of the fused bicyclic compound 257 from dienyne 255 for securinine total synthesis/ (ii) synthesis of cyclic ethers (e.g., 261 and 262) from diene-alkynes (e.g, 258) and control of the product distribution through alkene substitution pattern,and (iii) double tandem RCM-enyne metatheses (conversion of 263 into 266) of appropriate polyene-polyyne systems. 

RXN21 Tandem Carbonylation-Arylation with Alkynes 120... 

The utility of the Paal-Knorr reaction allows it to stiU remain at the forefront of organic chemistry for the preparation of highly complex substrates and drug-like compounds. The Paal-Knorr reaction was used to synthesize iV-aryl pyrroles 25 with an azide group on the aryl ring. These substrates were subsequently employed in a tandem azide-alkyne 1,3-dipolar cycloaddition reaction to synthesize medicinally important molecules with a diazepine scaffold 27 (14OL560). 

In some cases, after insertion, no (3-hydrogen is available and the t -intermediate is stable. This situation arises with alkynes, which undergo insertion to yield vinyl organometallic species. The situation also arises with certain trisubstituted alkenes when insertion gives rise to a (3-blocked, neopentyl-like intermediate. With constrained hydrocarbons, such as norbornene, where Bredt s rule may operate, stable t -intermediates can also form (see Figure 1.19)." In these cases, the reaction will therefore stop unless a reagent is present to intercept the intermediate. This allows the chemist the chance to design tandem processes. 

Various cyclohexadienes can be obtained through the rhodium-catalyzed cyclotrimerization of 1,6-diynes with alkenes [12] or 1,6-enynes with alkynes [13], Valorization of these cyclohexadienes was reported with the development of original tandem [2-I-2-I-2] cycloaddition/[4-l-2] Diels-Alder cascades. For example, Tanaka and coworkers recently achieved the construction of bridged polycyclic lactam products, by performing a [2-1-2-1-2] cycloaddition/[4-l-2] Diels-Alder cascade between... 

Rapid method to prepare 3,4-disubstituted 2-trifluoromethylqumolines 94 by a palladium catalyzed tandem Sonogashira-alkyne carbocyclization of p-trifluoro-methyl p-enaminoketones 93 with arynes has been suggested (Scheme 38) [59]. 

The Huisgen azide-alkyne 1,3-dipolar cycloaddition (AAC) [75] and later developed Cu-catalyzed azide-alkyne cycloadditions (CuAAC) [76-80], which are the most commonly utilized methods for the synthesis of N-substituted 1,2,3-triazoles, will not covered here. Very recently, Bi and co-workers [81] developed an elegant silver-catalyzed tandem hydroazidation/alkyne-azide cycloaddition of diynes with TMSN3 providing an easy access to 1,5-fused 1,2,3-triazole frameworks [82, 83]. 

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