Aldehydes seven-ring formation

SCHEME 25.42. Seven-ring formation from a tethered alkene aldehyde. 

A further application of ring-closing metathesis in seven-membered heterocyclic ring formation is in the synthesis of the trans-fused oxpane systems. This process involved tandem RCM/allylstannane-aldehyde cyclizations and interaction of the process provides access to trans-fused polyoxepanes <00S883>. 

Studies by Mori demonstrate that triethylsilane and dienals undergo reductive cyclization in the presence of bis(T] -cycloocta-l,5-diene)nickel(0) (2) and triphenylphosphine (1 2) to produce the silyl ether of cycloalkanols P l in this instance, y.b-misaturated products are obtained. However, if the reaction is carried out in the presence of cyclohexa-l,3-di-ene, an analogous reaction proceeds to give 8,e-unsaturated products. This effect is reported to be derived from selective diene hydrometalation followed by addition of the or-ganonickel intermediate to the tethered aldehyde. The reaction proceeds with five-, six-, and seven-membered ring formation and with heterocyclic substrates. Several synthetic applications of this cyclization methodology are reported (Scheme 8). Intermolecular processes with simple dienes and aldehydes to afford y.S-unsaturated silyl ethers are also possible. 

Similar conditions have promoted five-, six-, and seven-membered ring formations by intramolecular cyclization of arylboron compounds onto ketones (Scheme 31). " Biaryl methanols can be obtained from aryl aldehydes by Rh-catalysed addition of an aryl ring bearing an Al-direcfing group ortho to the activated Cyclization... 

The formation of a-acetoxyketones by oxidation of enamines with thallic acetate has been studied in detail (27) and found to be of preparative value (80 % yields) particularly in five- and six-membered-ring ketone derivatives. Enamines of linear or seven-membered-ring ketones were oxidized also, but at very much slower rates. Enamines of aldehydes with a-hydrogen substituents underwent self-eondensations during the oxidation reactions. Lead tetraacetate was less satisfactory as an oxidizing agent. 

The Mannich reaction consists on the condensation of a CH-activated compound with a primary or a secondary amine and a non-enolizable aldehyde or ketone to afford p-aminocarbonyl derivatives known as Mannich bases (Scheme 20). This sequence is of great use for the constmction of heterocyclic targets, as illustrated for example by the Robinson-Schopf synthesis of tropinone in 1937 or by the preparation of some azabicyclo[3.3.1]nonanones or pyranocoumarine derivatives (Fig. 1) [100]. In the following, representative recent examples of the formation of five- to seven-membered ring heterocycles will be presented. 

The formation of rings with more than seven atoms has unfavorable rates because the addition step is often too slow to allow it to compete successfully with other pathways open to the radical intermediate. In stannane based chemistry for example, premature hydrogen abstraction from the organotin hydride is difficult to avoid. However, Baylis-Hillman adducts 111 derived from enantiopure 1-alkenyl (or alkynyl)-4-azetidinone-2-carbaldehydes are used for the stereoselective and divergent preparation of highly functionalized bicycles 112 and 113 fused to medium-sized heterocycles (Scheme 38) [80, 81]. The Baylis-Hillman reaction using nonracemic protected a-amino aldehydes has been attempted with limited success due to partial racemization of the chiral aldehyde by DABCO after... 

Two syntheses of (+ )-lycoramine (153) have been reported from the same group. The first approach required the construction of rings A and B, then of the seven-membered ring C, followed by the formation of the dihydropyran ring. Thus, the starting material was aldehyde... 

Lalande and coworkers have studied the regiochemistry of cyclization of keto aldehyde (44 equation 107). In this system, aqueous KOH gives exclusively the cyclopentenyl methyl ketone (45), while piperidinium acetate leads to cyclopentenecarbaldehyde (46). Similar results were obtained by Wolinsky with the isopropenyl analog of (44). These examples also demonstrate the preference for formation of a five- over a seven-membered ring. 

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... 

The first step was the Pd-catalyzed formylation of the commercially available bromoindole derivative 193 using a procedure reported by Belter and co-workers (Scheme 4.2) 146). It was found to be necessary to protect to alcohol function with TMSCl in situ to avoid formation of a seven-membered lactone. The crude aldehyde 194 was directly converted with 195 to the W-t-butanesulfinyl imine 196 in 53% yield over two steps. Double protection of the alcohol and the aromatic amine function from 196 yielded the bis-tosylated Al-sulfinyl imine 197 in good yield. The Rh(I)-catalyzed addition of the newly developed MIDA boronate 198 (747) provided sulfonamide 199 in 78% yield and with high diastereoselectivity. Deprotonation of the sulfonamide function of 199 led to closure of the azepine ring system to furnish 200. Subsequent removal of the protection groups in 200 afforded the natural product (-)-176 in quantitative yield and with high optical purity. 

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