Enamines cyclic, cycloaddition

Adduct 100 is formed from the 1,4 cycloaddition of o-quinone (99) with the morpholine enamine of cyclohexanone (125). Treatment of styrene oxide with cyclic enamines at elevated temperatures (about 230°C) produces O.N-ketals possessing a furan nucleus (125a). 

Another interesting example is provided by the phenylethynylcarbene complex 173 and its reactions with five-, six-, and seven-membered cyclic enamines 174 to form bridgehead-substituted five-, six-, and seven-membered cycloalkane-annelated ethoxycyclopentadienes with high regioselectivity under mild reaction conditions (Scheme 38) [119,120]. In these transformations the phenylethynylcarbene complex 173 acts as a C3 building block in a formal [3+2] cycloaddition. Like in the Michael additions (reaction route F in Scheme 4), the cyclic electron-rich enamines 174 as nucleophiles attack the... 

The slightly lower lowest unoccupied molecular orbital (LUMO) energy of pyrido[3,4-r71pyridazine 5 compared to its isomer [2,3-r7] 6, calculated by the AMI method <1985JA3902>, explained the shorter time required for the pyrido[3,4-r7j-pyridazine to complete the [4+2] cycloaddition reaction with cyclic enamines of different ring sizes <1995M211, 2001ARK21>. 

A simple preparation of electron-poor 2-azadienes and the preliminary study of their ability to participate in [4 + 2] cycloadditions was done almost simultaneously by out group (87CC1195) (Scheme 49). The preparation of 2-azadienes 212 with two appended methoxycarbonyl groups was achieved, in a multigram scale and in nearly quantitative yield, by the insertion reaction of N- trimethylsilyl imines 210 into the carbon—carbon triple bond of dimethyl acetylenedicarboxylate to give 211 followed by protodesilylation with CsF/MeOH. Azadienes 212 underwent at room temperature inverse-electron demand [4 + 2] cycloaddition with cyclic enamines to give exclusively exo-cycloadducts 213 in 82-95% yield. Acid hydrolysis of them resulted in their aromatization to yield 2-pyrindine (n = 1] and isoquinoline (n = 2) derivatives 214. 

Since no cycloaddition reactions between 1,3-diazadienes and electron-rich dienophiles, e.g., enamines, were previously recorded in the literature, we studied the inverse-electron demand [4 + 2] cycloaddition of 357 with acyclic and cyclic enamines derived from pyrrolidine or morpholine (89TL4573 90TH1) (Scheme 80). Thus, pyrimidinones and -thiones 359... 

Enamines represent nucleophilic alkenes which undergo cycloaddition reactions readily with electrophilic alkenes. For example, acrylonitrile (5) reacts with cyclic enamines 10 to give bicyclic aminocyclobutanenitrilcs 11, albeit in poor yields.29... 

The 1,3-dipolar cycloaddition of azidoalkylphosphonates to enamines afforded A2-1,2,3-triazoles which are further converted to the 1,2,3-triazoles [95H(40)543] fused triazoles are similarly obtained when a cyclic enamine was employed. Fused 1,2,3-triazole (88), a xanthine oxidase inhibitor, was prepared by the reaction of an alkyl azide with cyanoacetamide with further elaboration of intermediate (87) by treatment with HMDS in xylene [95FES257]. The fused 4H-l,2,3-triazolo[l,5- ][l,4]benzodiazepin-6(5H)-one (90) was obtained from propargylamide (89) via an intermediate azide [95S647]. 

Cycloadditions. The same type of Fischer-type complexes undergo cycloaddition with enamines. Interestingly, acyclic and cyclic enamines afford products of different skeletons. 

The reaction of a,(3-unsaturated Fischer carbene complexes 42 with cyclic enamines 43 gives cyclopentannulation products 46 with complete regioselectivity by a formal [3-1-2] cycloaddition (Scheme 5.11) [20]. The formal [3-1-2] cycloaddition is assumed to occur in a stepwise manner via the 1,4-addition of cyclic enamines 43 to the alkynyl carbene complexes 42 (formation of iminium intermediate 44), the intramolecular cyclization to the formed iminium moiety from the carbene carbon (formation of intermediate 45), and the hydrolysis reaction. When (—)-8-phenylmenthyl derivatives of Fischer carbene complexes 42 are reacted with indoles 43, the corresponding indolinones 46 are obtained with >97% ee. 

The Brpnsted acid-mediated formal 3 + 3-cycloaddition reaction of /i-enaminones with cf, -unsaturated aldehydes formed tetrahydroquinolinones. The Yb(NTf2)3-catalysed 3 + 3-cycloaddition reaction of isatin ketonitrones (122) and cyclopropanes (123) yielded spiro[tetrahydro-l,2-oxazine]oxindoles (124) in moderate to good yields and good regioselectivities (Scheme 38). The Cu-catalysed 3 + 3-cycloaddition reaction of propargyl esters with cyclic enamines yielded chiral e r/o-adducts with bicyclo[ .3.1] frameworks. The catalyst was prepared by the combination of Cu(0Ac)2 H20 with a chiral tridentate ferrocenyl-PA(,(V-ligand. The cationic... 

Thermal and photochemical electrocyclic reactions are particularly useful in the synthesis of alkaloids (W. Oppolzer, 1973,1978 B K. Wiesner, 1968). A high degree of regio- and stereoselectivity can be reached, if cyclic olefin or enamine components are used in ene reactions or photochemical [2 + 2]cycloadditions. 

The present preparation illustrates a general and convenient irethod for ring contraction of cyclic ketones. The first step is the usual procedure for the preparation of enamines. The second step involves 1,3-dipolar cycloaddition of diphenyl phosphorazidate to an enamine followed by ring contraction with evolution of nitrogen. Ethyl acetate and tetrahydrofuran can be used as a solvent in place of toluene. Pyrrolidine enamines from various cyclic ketones smoothly undergo the reaction under similar reaction conditions. Diphenyl (cycloalkyl-1-pyrrolidinylmethylene)phosphoramidates with 5,6,7, and 15 members in the ring have been prepared in yields of 68-76%. 

There is some spectral evidence that acylation of enamines of cyclic ketones with acid chlorides having an a-hydrogen in the presence of triethylamine proceeds via the ketene and subsequent cycloaddition (84). The intermediate cyclobutanone is then opened to give the enamino ketone which is hydrolyzed to the 2-acyl cyclohexanone. In the case of enamines of larger cyclic ketones the alternate mode of the cyclobutanone opening predominates, with the formation of ring-expanded 1,3-diketones upon... 

Enamines of cyclic ketones do not form cycloaddition products, but give the mono- or dicarboxanilides (110,111). Thus the enamine (113) on reaction with 1 equivalent of phenyl isocyanate gave 160. Treatment of 113 with 2 equivalents, or 160 with 1 equivalent, of phenyl isocyanate gave the 2,6-disubstituted product (161). Mild acid hydrolysis of 160 and 161 produced the corresponding cyclohexanone(2-mono- and 2,5-di)carbox-anilides (110). 

It has been reported that perfluoroisobutylene and perfluorocyclobutene undergo 1,2 cycloaddition with l-(N-morpholino)isobutylene in ether at room temperature to give the corresponding perfluorocyclobutane derivatives ]20a). Enamines of cyclic ketones produce only simple alkylation products when treated with these perfluoroolefins. 

The reaction of cyanogen azide with enamines of cyclic ketones to yield a cyanoamidine with one less member in the carbocyclic ring represents a potentially valuable method of ring contraction under mild conditions (199a). The reaction probably proceeds first by 1,3 cycloaddition of the azide to the enamine followed by rearrangement and elimination of a molecule of nitrogen. 

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