Heterocyclics, hydroformylation

Most ring syntheses of this type are of modern origin. The cobalt or rhodium carbonyl catalyzed hydrocarboxylation of unsaturated alcohols, amines or amides provides access to tetrahydrofuranones, pyrrolidones or succinimides, although appreciable amounts of the corresponding six-membered heterocycle may also be formed (Scheme 55a) (73JOM(47)28l). Hydrocarboxylation of 4-pentyn-2-ol with nickel carbonyl yields 3-methylenetetrahy-drofuranone (Scheme 55b). Carbonylation of Schiff bases yields 2-arylphthalimidines (Scheme 55c). The hydroformylation of o-nitrostyrene, subsequent reduction of the nitro group and cyclization leads to the formation of skatole (Scheme 55d) (81CC82). 

As demonstrated by Hoffmann and coworkers, hydroformylation can also be combined with an allylboration and a second hydroformylation, which allows the formation of carbocycles and also heterocycles [213]. A good regioselectivity in favor of the linear aldehyde was obtained by use of the biphephos ligand [214]. Reaction of the allylboronate 6/2-76 having an B-configuration with CO/H2 in the presence of catalytic amounts of Rh(CO)2(acac) and biphephos led to the lactol 6/2-80 via 6/2-77-79 (Scheme 6/2.17). In a separate operation, 6/2-80 was oxidized to give the lactone 6/2-81 using tetrabutyl ammonium perruthenate/N-methylmorpholine N-oxide. 

In a similar way as described for the hydroformylation, the rhodium-catalyzed silaformylation can also be used in a domino process. The elementary step is the formation of an alkenyl-rhodium species by insertion of an alkyne into a Rh-Si bond (silylrhodation), which provides the trigger for a carbocyclization, followed by an insertion of CO. Thus, when Matsuda and coworkers [216] treated a solution of the 1,6-enyne 6/2-87 in benzene with the dimethylphenylsilane under CO pressure (36 kg cm"2) in the presence of catalytic amounts of Rh4(CO)12, the cyclopentane derivative 6/2-88 was obtained in 85 % yield. The procedure is not restricted to the formation of carbocycles rather, heterocycles can also be synthesized using 1,6-enynes as 6/2-89 and 6/2-90 with a heteroatom in the tether (Scheme 6/2.19). Interestingly, 6/2-91 did not lead to the domino product neither could 1,7-enynes be used as substrates, while the Thorpe-Ingold effect (geminal substitution) seems important in achieving good yields. 

The phosphine-phosphite BINAPHOS ligand was first used in the Rh-catalyzed asymmetric hydroformylation of heterocyclic olefins such as 2,5-dihydrofuran, 3-pyrroline derivatives, and 4,7-dihydro-1,3-dioxepin derivatives. It provided the optically active aldehydes as single products with enantioselectivity between 64-76% ee. In the hydroformylation of 2,5-di-... 

Imines and enamines under hydroformylation conditions can also be reduced to give saturated amines. With or without additional reduction, these conversions can be used in synthesis of various types of heterocycles. 

They constitute the first rhodium phosphine modified catalysts for such a selective linear hydroformylation of internal alkenes. The extraordinary high activity of 32 even places it among the most active diphosphines known. Since large steric differences in the catalyst complexes of these two ligands are not anticipated, the higher activity of 32 compared to 31 might be ascribed to very subtle bite angle effects or electronic characteristics of the phosphorus heterocycles. 

Variation of the heterocyclic self assembly platform has an enormous impact on the resulting catalyst properties. New hydroformylation catalysts operating with excellent activity and outstanding regioselectivities were identified, which can now be applied even in protic solvents such as methanol. This is an important extension for the application range of the selfassembled catalysts based on hydrogen-bonding. 

Ruthenium-catalyzed hydroformylation of 1,4-dienes in the presence of amines produced eight-membered heterocycles in modest yields, and an example is presented in Scheme 67 <1999T4721>. 

Hydrogenolysis of metal carbonyls, such as Mnj(CO)jg [250 atm (25 MPa), 200°C] or COjCCOg [250 atm (25 MPa), 110°C], leads to metal-metal bond cleavage, forming HMn(CO)j or HCo(CO) The conversion of CoJiCO to HCo(CO) is the rate-determining step in Co-catalyzed hydroformylations at high P and T. Tertiary amines, nitrogen heterocycles, tertiary phosphorus bases or halide ions enhance the rate of HCo(CO) formation e.g., pyridine can increase the rate of HCo(CO).j formation 300-fold at 40°C. 

The bond between carbon and rhodium is extremely stable, thus allowing mono- or biphasic hydroformylations without any excess of ligands. Due to this stability, for the first time ever an anchoring to a polymer support seems possible without leaching. These N-heterocyclic carbenes appear to be excellent ligands to stabilize catalytically active metals even under harsh temperature conditions, e. g. Heck C-C-coupling reactions at 130 °C [152 b]. 

Dupont and van Leeuwen studied hydroformylation reactions in [bmim]PF6 [63] and observed the formation of catalytically active rhodium species in operando (Fig. 13). The same class of reaction has been studied again by Dupont, this time in the IL [bmim]Tf2N [64]. Here, they reported H/D exchange in the 2-position of the imidazolium ring of the IL, especially in the presence of a base - a finding that has been reported earlier already ([3,9], and references therein). The involvement of A-heterocyclic carbene species was discussed but not proven. 

Transition metal complexes with heterocycles as ligands in hydroformylation including hydroformylation of heterocycles 02CCR(228)61, 03CCR(241)295. 

Some heterocyclic systems such as tetrahydrofuxan, tetrahydropyran, thiophene, and pyrrolidine are foimd in a wide range of biologically active compounds. Hydroformylation of these heterocyclic olefins provides a potential synthetic route for the synthesis of these targets (Scheme 11) [93,94]. Asymmetric hydroformylation of a-methylene-y-butyrolactone using the cationic Rh(I)-(l )-BINAP complex as a catalyst is also reported to give an aldehydic lactone containing a quaternary chiral center in up to 37% ee [95]. 

Importantly, a similar result was obtained with heterocyclic alkenes such as 2,5-dihydrofuran and N-Boc-pyrroline which were converted to the corresponding 3-aldehyde. It must be noted that the P[0(2,4-di-/BuC6H3)]3 rhodium-based catalyst, which is one of the most active catalyst for this type of transformation, also furnished the 2-aldehyde derivative resulting from the hydroformylation of the 2,3-dihydroheterocyclopentenes (Scheme 34). 

In this review, the use of N-heterocyclic carbene complexes derived from imidazoHum salts as a part of the different strategies involving ionic liquids has not been considered. Nevertheless, it can be important to take into account this reactivity, especially when 1,3-dialkylimidazolium ILs are involved. For more details about this aspect and applications in hydroformylation, one can refer to Herrmanrfs recent review [55] and the later publication of Poyatos et al. in 2003 [56]. 

Reductive amination of aldehydes prepared from hydrofonnylation is a useful route to amines. Botteghi, et al. reported the synthesis of racemic Tolterodine by sequential hydroformylation-reductive amination [18]. Hydroaminomethylation (tandem hydroformylation/reductive amination) has recently been used to prepare a wide variety of pharmaceutical compounds [19]. Representative examples are shown in Fig. 5. Hydroaminomethylation of 1,1-diarylethenes leads to l-(3, 3-diaiylpropyl)amines, such as fenpiprane [20, 21]. Heterocyclic aUyUc amines undergo hydroaminomethylation to form pharmaceutically active diamines, such as etymemazine [22]. Ibutilide and fexofenadine have been prepared by hydroamino-methylatiOTi of 1-aiylallyl alcohols in the presence of the requisite amines [23,24]. Although none of these reactirais has been developed into a commercial process, the widespread utility of the hydroaminomethylation reaction makes it likely that it will be used commercially... 

There are numerous reports of hydrofonnylation reactions where an amine substituent in the substrate condenses with the aldehyde product to form a heterocyclic ring (Fig. 6). Intramolecular hydroaminomethylation reactions are often referred to as cyclohydrocarbonylation reactimis. A Cbz-protected homoallylic amine underwent cyclohydrocarbonylatiOTi with Rh-biphephos to form the natural product, ( )-coniine (Fig. 6, 13) [25]. Alper recently reported the formation the seven-membered ring of 2-benzazepines (Fig. 6, 14) by hydroformylation of 2-isopropenylbenzaldehydes in the presence of anilines [26]. Intramolecular hydroaminomethylation of 2-isopropenylanilines produces 1,2,3,4-tetrahydroquinolines (Fig. 6, 15) [27]. In some instances, the enamine derived from intramolecular condensation of the resulting aldehyde is desired. For example, the synthesis of a key intermediate (Fig. 6,16) in the synthesis of a series of ACE inhibitors was... 

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