Enamines 3,3 -sigmatropic rearrangement

Another application of this strategy is the construction of cyclic systems bearing 1,4-dissonant relationships. For example, the synthesis of the hasubanan alkaloid ring system 35. reported in 1972 by Evans [24], involves the Diels-Alder cycloaddition of a dienyl sulphoxide 32 with an endocyclic enamine 33, followed by a [2,3]-sigmatropic rearrangement of the resulting cycloadduct 34 (Scheme 5.21). 

On thermolysis, appropriately substituted A-allyl-A-silyloxy enamines 19 undergo smooth [3,3]-sigmatropic rearrangements to the corresponding A-silyloxy imino ethers laP (equation 5). Two stereogenic centers are created but no reference to chiral induction is referred. High diastereoselectivity was observed and short reaction times favoured the syn A-silyloxy imino ether diastereomers. 

The reaction of 77 with alkynes has further been elaborated for the synthesis of substituted phthalonitriles 81. An alternative for the synthesis of these compounds is the cycloaddition reaction of 77 with enamines followed by a retro-Diels-Alder loss of N2 and elimination of the amine (Scheme 16). Generally, more forcing reaction conditions are required and lower yields are obtained in reactions with alkynes than in reactions with enamines, for example, 4-ethyl-5-methylphthalonitrile is obtained in 51% yield from 2-pentyne (xylene, 150°C, 18 days) and in 73% yield from 4-(l-ethylprop-l-en-l-yl)morpholine (CHCI3, 70°C, 7 days) <1998T1809>. The mechanism of the reaction with enamines has been studied in detail. This revealed a [1,5] sigmatropic rearrangement in the cyclohexa-2,4-dien-1-amine intermediates formed after the loss of N2 <1998T10851>. 

The reaction of aliphatic and aromatic ketone oximes 97 with a dialkyl carbonate 98 in the presence of K2CO3 at 180-190 °C yields 3-alkyl-4,5-disubstituted-2(3//)-oxazolones 104 in 22-48% yields. Mechanistically, it is proposed that N-alkylation of the initially formed oxime O-carbonate 99 yields 100, which affords the enamine 101 in the presence of base. A [3,3] sigmatropic rearrangement ensues to produce 102, which then cyclizes to 104. In cases where 97 contains two methylene groups in proximity to the C=N bond, one of which is benzylic, the above reaction sequence is regioselective for the benzylic methylene group (Fig. 5.25 Table 5.6, Fig. 5.26). ... 

Similar enamine cyclization processes occur in several other successful heterocycle syntheses, e.g. in the Fischer indole synthesis. In this case, however, a labile N—N bond of a l-aryl-2-vinylhydrazine is cleaved in a [3,3]-sigmatropic rearrangement, followed by cyclization and elimination of ammonia to yield the indole (B. Robinson, 1963, 1969 R. J. Sundberg, 1970). Regioselectivity is only observed if R2 contains no enolizable hydrogen, otherwise two structurally isomeric indoles are obtained. Other related cyclization reactions are found in the Pechmann synthesis of triazoles (T.L. Gilchrist, 1974) and in G. Bredereck s (1939) imidazole synthesis (M.R. Grimmett, 1970). 

The enamine is ideally set up for a [3,3]-sigmatropic rearrangement in which the a bond to be brokers the weakN-N a bond and one of the K bonds is in the benzene ring. 

A [1,3] sigmatropic rearrangement (equation 22) of the enamine 199, which yielded 2-pyrrolidino-3-(2-furyl)-2-methyl-2-propenal (200), was observed315 by heating to 80 °C... 

Several [l,3]-sigmatropic rearrangements of enamines are known. The enamine substrates are mainly V-functionalized enamines, and the rearrangements usually give the secondary enamines with a transferred functional group at /2-carbon. 

Among the examples of [l,3]-sigmatropic rearrangements is the photoinduced [1,33-acyl shift of A-acylenamines, which has been investigated extensively and reviewed in 197868 xhus, the irradiation of /V-acyl enamines, known as enamides, provides a facile synthesis of enaminones. 

Thermal [l,3]-sigmatropic rearrangements of enamines have also been reported75. Compound 78 obtained from the reaction of dihydroisoquinoline and phenyl isocyanate,... 

JV-Alkyl-JV-allyl enamines 128 (X = NR), like their carbon and oxygen counterparts 128 (X = CH2jO), can undergo [3,3]-sigmatropic rearrangement to form y,<5-unsaturated imines 129 (X = NR) (equation 27). This reaction has been defined as a 3-aza-Cope or the aliphatic amino-Claisen rearrangement8. 

Except for protic and Lewis acids, other electrophilic reagents can also promote the aliphatic 3-aza Cope rearrangement. In fact, the first example of a [3,3]-sigmatropic rearrangement of 7V-allylenammonium salt may date back to the early 1960s102. When enamine 152 reacted with crotyl bromide at 80 °C, it gave after hydrolysis 2,2,3-trimethyl-4-pentenal (153) rather than 2,2-dimethyl-4-hexenal (equation 32). 

Similar a,a -annulations were achieved from reaction of oc,/ -unsaturated acid chlorides with cyclic ketone enamines which afforded bicyclo[3.3.1]nonane-2,9-diones41,60 65 or bicyclo[4.3.1]decanones66. In this reaction, 7V-acylation of the enamine 109 occurs as the first step giving 110, followed by a [3,3] sigmatropic rearrangement to a ketene intermediate (111). Ketene 111 subsequently cyclized via 112 to a bicyclic immonium salt (113) which after hydrolysis gave the corresponding dione 11463. If there is an axially oriented electrophilic substituent at C-4 of the enamine (for example, R = COPh) the enolate anion 115 may cyclize to an adamantane derivative 116 (equation 20). 

Aza-Clatsen rearrangements. TiCL has been reported to catalyze enamine formation. It has now been found to catalyze also sigmatropic rearrangement (aza-Claisen rearrangement) of enamines. This rearrangement without a catalyst requires temperatures near 250°, but proceeds at 25-75° in the presence of TiCU. Simple ketones do not react under comparable conditions." ... 

The cascade of reactions in hot nitrobenzene starts with a [3,3]-sigmatropic rearrangement thr unusual in that it forms an allene but is otherwise straightforward. To get to the next intermeci the stable conjugated primary enamine, we must enolize and go back to the ketone again but r the double bond into conjugation. 

Clean conjugate addition of appropriate nucleophiles to allenic sulfoxides has been used to produce allylic sulfoxide systems. Homer has described the formation of functionalized allylic alcohols when adding nucleophiles like amines, alcohols or thiols to allenic sulfoxides in excess. If the addition is performed with equimolar amounts at lower temperature, so that the 2,3-sigmatropic rearrangement is avoided, the intermediate addition products (enamines or enol ethers) can be hydrolyzed to the synthetically valuable 3-keto sulfoxides (Scheme 20). ... 

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