Enamines 2 + 2 cycloadditions

With 3-aminothiophenes (e.g., 11), which are potential enamines, (2 - - 2)-cycloaddition at the C-2/C-3 bond of thiophene is considerably facilitated, occurring even below 0°C. The cycloadducts (e.g., 12) are converted thermally into 3-aminophthalic acid derivatives... 

The stereochemistry of sulfene-enamine cycloaddition has also been followed by Drozd et who studied the method of asymmetric induction in the preparation of compounds 66 and 67. 

Most asymmetric Diels-Alder reactions have the chiral auxiliary attached to the dienophile as an ester or an amide. There is no such obvious place to attach an auxiliary to a diene but the chiral analogue 161 of Danishefsky s diene has a C2 symmetric amine 164 attached as an enamine. Cycloaddition without a Lewis acid gives good selectivity in the formation of adduct21 162. Reduction and hydrolysis releases the enone 163 in reasonable ee. 

The ring enlargement of pyrroles providing 3-chloropyridines has already been described (see p 93). Oxazoles react as masked 2-azadienes with alkenes yielding pyridine derivatives of various types (see p 131). With enamines and ynamines, diazines and triazines undergo Diels-Alder reactions with inverse electron demand (see p 441). This leads to pyridines (e.g. 201) by the enamine cycloaddition of the 1,2,4-triazine, as shown below ... 

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. 

Again, it is noteworthy that 4-substituted 5-hydrdxythiazoles (24) react like 5-hydroxy-THISs with alkynes to give pyrroles and sometimes with alkenes to give exo-cycloadducts (Scheme 22). In the latter case other processes compete with the cycloaddition, becoming dominant when 24 is treated with azo-compounds, enamines, or heterocumulenes (31). 

Cycloadditions of diazaquinones with unsaturated compounds yield diazacyc-lobutanes, from which N-substituted 3-hydroxypyridazin-6(l/f)-ones are formed after addition of water, t-butanol or acetic acid (Scheme 56). The same types of compound are also obtained from enamines. 

In 1959 Carboni and Lindsay first reported the cycloaddition reaction between 1,2,4,5-tetrazines and alkynes or alkenes (59JA4342) and this reaction type has become a useful synthetic approach to pyridazines. In general, the reaction proceeds between 1,2,4,5-tetrazines with strongly electrophilic substituents at positions 3 and 6 (alkoxycarbonyl, carboxamido, trifluoromethyl, aryl, heteroaryl, etc.) and a variety of alkenes and alkynes, enol ethers, ketene acetals, enol esters, enamines (78HC(33)1073) or even with aldehydes and ketones (79JOC629). With alkenes 1,4-dihydropyridazines (172) are first formed, which in most cases are not isolated but are oxidized further to pyridazines (173). These are obtained directly from alkynes which are, however, less reactive in these cycloaddition reactions. In general, the overall reaction which is presented in Scheme 96 is strongly... 

Since 1,3-dipolar cycloadditions of diazomethane are HOMO (diazomethane)-LUMO (dipolarophile) controlled, enamines and ynamines with their high LUMO energies do not react (79JA3647). However, introduction of carbonyl functions into diazomethane makes the reaction feasible in these cases. Thus methyl diazoacetate and 1-diethylaminopropyne furnished the aminopyrazole (620) in high yield. 

Other isocyanates undergo [2 + 2] cycloaddition, but only with very electron rich alkenes. Thus phenyl isocyanate gives /3-lactams with ketene acetals and tetramethoxyethylene. With enamines, unstable /3-lactams are formed if the enamine has a /3-H atom, ring opened amides are produced 2 1 adducts are also found. Photochemical addition of cis- and traH5-stilbene to phenyl isocyanate has also been reported (72CC362). 

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%. 

The following compounds have been obtained from thiete 1,1-dioxide Substituted cycloheptatrienes, benzyl o-toluenethiosulfinate, pyrazoles, - naphthothiete 1,1-dioxides, and 3-subst1tuted thietane 1,1-dioxides.It is a dienophile in Diels-Alder reactions and undergoes cycloadditions with enamines, dienamines, and ynamines. Thiete 1,1-dioxide is a source of the novel intermediate, vinylsulfene (CH2=CHCH=SQ2). which undergoes cyclo-additions to strained olefinic double bonds, reacts with phenol to give allyl sulfonate derivatives or cyclizes unimolecularly to give an unsaturated sultene. - Platinum and iron complexes of thiete 1,1-dioxide have been reported. 

In the case of enamines derived from aldehydes a cycloaddition to give a cyclobutane occurs (48-50). Thus the enamine (16) reacted with methyl acrylate in acetonitrile to give a 91 % yield of methyl 2-dimethylamino-3,3-dimethylcyclobutane carboxylate (56). Similarly, treatment of (16) with diethylmaleate at 170° gave a 70% yield of diethyl 4-dimethylamino-3,3-dimethyl-l,2-cyclobutanedicarboxylate (57), and 16 and acrylonitrile gave a 65% yield of 2-dimethylamino-3,3-dimethylcyclobutanecarbonitrile (58). 

Enamines having a hydrogen on the enamine carbon also undergo cycloaddition to give cyclobutane derivatives. The latter are less stable, so that the reaction must be carried out under milder conditions in order to obtain... 

A more conventional cycloaddition occurs with activated acetylenes, however, the intermediate cyclobutene adducts undergo rearrangement to give insertion of two carbon atoms into the enamine chain (55). Thus the enamine (16) reacted with methyl propiolate to give the dienamino ester (73), presumably via the cycloaddition product (65a). 

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). 

The types of cycloadditions discovered for enamines range through a regular sequence starting with divalent addition to form a cyclopropane ring, followed by 1,2 addition (i) of an alkene or an alkyne to form a cyclo-cyclobutane or a cyclobutene, then 1,3-dipolar addition with the enamine the dipolarophile 4), and finally a Diels-Alder type of reaction (5) with the enamine the dienophile. 

The reactions of electrophilic alkenes (alkenes attached to electron-withdrawing groups) with enamines produce one or more of the following products simple alkylation (2), 1,2 cycloaddition (3), and 1,4 cycloaddition (4). Competition with C alkylation by N alkylation is inconsequential and therefore will be largely ignored (5,7). A stepwise ionic mechanism leading to these products necessarily involves the formation of a zwitterion intermediate (1) as the first step, which is then followed either by one of the... 

The first reported cyclization involving an enamine was the 1,4 cycloaddition of methyl vinyl ketone with the enamine of cyclohexanone to give. 

The initial product formed when methyl vinyl ketone is mixed with an enamine [such as N,N-dimethylisobutenylamine (10)] is the dihydropyran (11) from a 1,4 cycloaddition (ll,20a,20b). The chemical reactions that the dihydropyran undergoes indicate that it is readily equilibrated with the cyclobutane isomer 12a and zwitterion 12 (11). Treatment of adduct 11 with phenyllithium gives cyclobutane 13, possibly via intermediate 12a (11). 

Heterocyclic enamines often undergo two-step 1,3 cycloaddition with methyl vinyl ketone. This involves electrophilic attacks by an olefinic carbon and by a carbonyl carbon (24,25). For example, 1,2-dimethyl-Zl -pyrroline (14), when treated with methyl vinyl ketone, produces 1,6-dimethyl-2,3,4,5-tetrahydroindole (15) (24). The requirement which must be met so that this type of cyclization reaction can take place is that the a position of the heterocyclic enamine be carbon substituted. This provides... 

The vinylogous 3,5-hexadien-2-one (16) adds in a 1,4 cycloaddition with zl -dehydroquinolizidine (17) to form compound 18 (26). A similar 1,4-cycloaddition reaction takes place between pyrylium salts and the pyrrolidine or morpholine enamines of cycloalkanones (26a). 

A substituted a,/3-unsaturated aldehyde, cinnamaldehyde, has been observed to undergo the same type of two-step 1,3-cycloaddition reaction with a cyclohexanone enamine as acrolein does, forming in this case a stereo-isomeric mixture of substituted bicycloaminoketones in excellent yield (29a,31a,31b). 

The reaction of methyl or ethyl acrylate with the enamine of an alicyclic ketone results in simple alkylation when the temperature is allowed to rise uncontrolled in the reaction mixture (7,34,35). If the reaction mixture is kept below 30°C, however, a mixture of the simple alkylated and cyclobutane (from 1,2 cycloaddition) products are obtained (34). Upon distillation of this mixture only starting material and simple alkylated product is obtained because of the instability of the cyclobutane adduct. 

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