Diynes/isocyanates, cycloaddition

The NHC-nickel catalytic system is also useful in the synthesis of pyridones 48. The [2h-2h-2] cycloaddition of diynes 44 and isocyanates 47 affords a wide range of pyridones 48 in excellent yields in presence of [Ni(COD)2]/SIPr catalytic system (Scheme 5.14) [18]. 

Scheme 5.14 [2+2+2] Cycloaddition of diynes and isocyanates in presence of [Ni(COD) ]/SIPr catalytic system...

Itoh and co-workers reported the ruthenium(n)-catalyzed [2 + 2 + 2]-cycloaddition of 1,6-diynes with isocyanates to afford the corresponding bicyclic pyridones 163 (Scheme 72).356 357 For previously reported ruthenium-catalyzed [2 + 2 + 2]-cycloaddition of 1,6-diynes see Refs 358 and 358a, and for theoretical calculations of the cyclocotrimer-ization of alkynes with isocyanates, isothiocyanates, and carbon disulfide see Refs 359 and 359a. 

Analogously, aromatic high molecular weight poly(pyridone)s have been obtained using terminal and internal aromatic diynes, e.g. 1,4-diethynylbenzene [98] and l,4-bis(phenylethynyl)benzene [99] respectively, for 1 1 cycloaddition copolymerisation with isocyanates. 

Nitrogen-based heterocycles can also be prepared through Ni/NHC-catalyzed cyclo addition reactions. For example, Ni/SIPr catalyzed the cycloaddition of diynes with isocyanates under the mildest conditions to date [26]. In particular, excellent yields of pyridones are obtained from diynes and isocyanates at room temperature using only 3 mol % catalyst. As shown in Eq. 8, a variety of diynes were subjected to these optimized conditions. Both aryl and alkyl isocyanates were readily converted to the respective 2-pyridone. Sterically hindered substrates appeared to have very little effect on the reaction, as excellent yields of product were obtained with bulky isocyanates and bulky diynes. 

The increased reactivity of isocyanates, relative to carbon dioxide, was reflected in the wider range of cycloaddition partners. For example, terminal diynes as well as nontethered alkynes (e.g., 3-hexyne) were also successfully converted to 2-pyridones rather than undergoing rapid telomerization to aromatic by-products. Importantly, the cycloaddition of an asymmetrical... 

The NHCs were found to react with isocyanates to afford isocyanurates (Eq. 9) [27,28]. Although SIPr was found to be an effective catalyst for iso-cyanurate formation (for a wide variety of isocyanates), no isocyanurate was observed in most Ni-catalyzed cycloaddition reactions of diynes and isocyanates (Eq. 10). Furthermore, isocyanurates were not formed reversibly during the course of the reaction since no pyridones were obtained when isocyanurates were used as the sole source of isocyanate. These data further highlight the efficacy of the Ni/NHC catalyst system. 

The ruthenium complex Cp RuCl(COD) catalyzed the [2+2+2] cycloaddition of 1,6-diynes with heterocumulenes such as isocyanates, isothiocyanates, or carbon disulfide [99,100]. Bicyclic pyridones [99] and bicyclic thiopyrans [100] were thus obtained (Eq. 76). 

Related co-cyclotrimerizations of two alkyne molecules with limited isocyanates have also been achieved using cobalt and nickel catalysts. With respect to intramolecular versions, two examples of the cobalt(I)-catalyzed cycloaddition of a,m-diynes with isocyanates have been reported to afford bicyclic pyri-dones only in low yields, although 2,3-dihydro-5(lff)-indolizinones were successfully obtained from isocyanatoalkynes and several silylalkynes with the same cobalt catalysis [19]. On the other hand, the ruthenium catalysis using Cp RuCl(cod) as a precatalyst effectively catalyzed the cycloaddition of 1,6-diynes 21 with 4 equiv. of isocyanates in refluxing 1,2-dichloroethane to afford bicyclic pyridones 25 in 58-93% yield (Eq. 12) [20]. In this case,both aryl and aliphatic isocyanates can be widely employed. 

In contrast to isocyanates, isothiocyanates have hardly been examined as cycloaddition components, because the strong coordination of organosulfur compounds frequently deactivates a catalytic species [21]. Some organoruthe-nium complexes, however, recently proved to be efficient catalysts for the formation of carbon-sulfur bonds [21]. The catalytic cycloaddition of diynes with isothiocyanates was also successfully achieved using Cp RuCl(cod) as a precatalyst [22]. Importantly, the cycloaddition took place at the C=S double bonds of the isothiocyanates to afford thiopyranimines 26 (Eq. 13). This reaction requires 10 mol % of the precatalyst as well as the diynes possessing a quarternary carbon center at the 4-position. When excess amounts of carbon disulfide were also employed in place of the isothiocyanates, a bicyclic dithiopyrone 26 [X is C(C02Me)2, Z is S] was obtained in 50% yield. 

The use of Diels-Alder-type cycloaddition reactions is the most intensively investigated cycloaddition approach to the design of ladder polymers in a concerted process. Another methodology was published by Tsuda and coworkers [52, 53, 54]. They developed a nickel (0)-catalyzed [2 + 2 -l- 2] cycloaddition copolymerization of cyclic diynes 38 with heterocumulenes (like carbon dioxide or isocyanates 39). The soluble ladder-type products - poly(2-pyrone)s and poly(2-pyridone)s 40 - possess molecular weights M of up to 60000, corresponding to a Dp > 200. Unfortunately, the products formed were contaminated by nickel salts originating from the catalyst used Ni(COD)2. 

Scheme 2-47. Asymmetric[2+2+2] cycloaddition of diynes with isocyanates. Typical procedur ...

The related cycloaddition of diynes with carbon dioxide has also been developed as an efficient entry to pyrones (Scheme 3-29). As observed with isocyanate couplings, initial reports described the use of phosphine complexes of Ni(0), " but more recent work with A-heterocyclic carbene ligands demonstrated considerably milder conditions and broader scope. " Additionally, the cycloaddition of diynes with nitriles efficiently proceeds to generate pyridine derivatives under similar conditions. ... 

One direction for the development in this area is looking for more active and stable complex. In 2011, Hapke and coworkers prepared CpCo(H2C = CHSiMc3)2 complex and was found active in [2 + 2 + 2] cycloaddition reactions [26], The other direction is the exploration of applications. In 2005, Maryanoflf and coworkers applied [2 + 2 + 2] cycloaddition reaction in the preparation of macrocycles [27]. In the presence of CpCo(CO)2, pyridine containing macrocycles were prepared from long-chain a,cr-diyne and nitriles, cyanamides, or isocyanates (Scheme 3.11). The regioselectivity of these reactions was affected by the length and type of linker unit between the alkyne groups, as well as by certain stereoelectronic factors. 

The Rh(I)/dppf complex-catalysed 2-i-2-i-2-cycloaddition of oximes and diynes formed substituted pyridines in moderate to good yields (88%), under mild conditions. A one-pot procedure has been developed using aldehydes.The Ni-catalysed 2 -I-2 -I-2-cycloaddition of isocyanates (117) with 1,3-dienes (118) in MeCN produced 6-substituted dihydropyrimidine 2,4-diones (119). A key intermediate in this reaction is a five-membered azanickelacyclic species (Scheme 35). " The enantioselective cationic Rh(I)-catalysed 2-i-2-i-2-cycloaddition of diynes and isocyanates formed axially chiral pyridones with high ees (82%). The unique source of chirality is provided by a system containing [Rh(cod)Cl]2, l,4-bis(diphenylphosphino)butane, and the silver phosphate salt Ag(5)-TRIP. " " The Rh-catalysed 2-I-2-I-2-cycloaddition of diynes to sulfonimines in DCE, at r.t. to 80 °C, yielded 1,2-dihydropyridines in good yields (54-86%) and enantioselectivity (61-96%... 

The reactivity of isocyanates in [2+2] cycloaddition reactions is as follows alkyl < aryl < nitroaryl << arenesulfonyl < halosulfonyl. Also, the reactivity of the substrate is determined by the substituents. For example, vinyl ethers and enamines are more reactive than olefins. Often the formation of the [2+2] cycloadducts involves polar linear intermediates, which can be intercepted by the isocyanate or the substrate to form six-membered ring [2+2+2] cycloadducts (see Section 3.3.1.4). Also, diynes react with isocyanates to give six-membered ring [2+2+2] cycloadducts. In the latter reactions catalysts play an important role. From Q, ty-diynes macrocyclic adducts are obtained. 

Macrocycles are also obtained in the cobalt mediated [2+2+2] cycloaddition reaction of a, y-diynes with isocyanates. For example, 2-oxopyridinophanes 210 and 211 are... 

Louie and co-workers later used their methodology for the cycloaddition of diynes with isocyanates. In this case, SIPr was superior to IPr while isocyanates were found more reactive than carbon dioxide. Also of interest, it appeared that a 1 1 Ni/SIPr ratio was equally efficient to a 1 2 ratio. Except for some particular cases, the preparation of a large variety of highly substituted 2-pyridones were then efficiently obtained in the presence of 3 mol% catalyst under very mild conditions (Equation (10.20)). 

A Ni/SIPr (1 2) combination catalyzed the cycloaddition of diynes and nitriles into pyridines. Aryl, heteroaryl as well as alkyl nitriles were reactive under ambient conditions (Equation (10.23)). In contrast with aryl isocyanates vide supra), the reaction was not dependent on the electronic demand on the aryl nitrile since both electron-rich and electron-poor substrates gave similar results. Finally, and similarly to isocyanates reactions, the larger substituent was introduced in the 3-position of the pyridine ring. 

Isocyanates have been incorporated successfully in the cycloaddition reaction with diynes [21]. The reaction utilizes the combination of Ni(0) precursor and imidazoly-dene ligand (SIPr). This catalyst affected the cycloaddition of a variety of 1,6-and 1,7-diynes with alkyl and aryl isocyanates (Scheme 2.24). Malonate diyne and diynes bearing a nitrogen backbone reacted with phenyl isocyanate to afford pyridines (82 and 83) in high yields. Importantly, challenging terminal diynes... 

In contrast to isocyanates, isothiocyanates reacted with 1,6-diynes at their C=S double bonds [57,68], As summarized in Table 3.15, Al-aryl, Al-alkyl, and Al-acyl isothiocyanates (1.2 equiv) underwent cycloaddition with a malonate-derived 1,6-diyne using 10 mol % of 6 in refluxing DCE to afford thiopyran imines 85 in 50 to 88% yields (entries 1 to 4). Increased amounts of isothiocyanates were detrimental, presumably due to the strong coordination of the soft thiocarbonyl moiety impairing access of the diyne substrate. Diyne substrates with quaternary carbon centers in their tethers were also required for successful cycloaddition with isothiocyanates. Moderate regioselectivity of 86/87 = 9 1 was observed for the cycloaddition of a malonate-derived unsymmetrical diyne with A/-phenyl isothiocyanate (Scheme 3.18). Upon treatment of a malonate-derived diyne with 10 mol % of 6 in a mixed solvent of carbon disulfide and DCE at 90 °C, cycloaddition with CS2 at the C=S double bond occurred to deliver 2//-thiopyran-2-thione 88 in a moderate yield (Scheme 3.18). 

In the pyridone synthesis, the neutral rhodium(I)/monophosphine complexes are effective for the regioselective intermolecular [2- -2-f-2] cycloaddition of terminal alkynes with isocyanates, although a high reaction temperature is necessary. The cationic rhodium(I)/biartyl bisphosphine complexes are widely applicable catalysts for both intermolecular and intramolecular [2- -2-1-2] cycloaddition of alkynes with isocyanates under mild conditions. Interestingly, not the cationic rhodium(I)/biaryl bisphosphine complex but the neutral rhodium(I)/biaryl bisphosphine complex is effective for the [2-f 2-1-2] cycloaddition of 1,6-diynes with isothiocyanates. 

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