A vinylogous

The Michael reaction is of central importance here. This reaction is a vinylogous aldol addition, and most facts, which have been discussed in section 1.10, also apply here the reaction is catalyzed by acids and by bases, and it may be made regioselective by the choice of appropriate enol derivatives. Stereoselectivity is also observed in reactions with cyclic educts. An important difference to the aldol addition is, that the Michael addition is usually less prone to sterical hindrance. This is evidenced by the two examples given below, in which cyclic 1,3-diketones add to o, -unsaturated carbonyl compounds (K. Hiroi, 1975 H, Smith, 1964). 

Structural analogy of aliphatic amino ketones can be found in the heterocyclic series. A simple example of such compounds is /) -octahydro-7-quinolone (767) which, as a vinylog of an amide, can possess enonamine-enolimine tautomerism (168). 

The stereospecific generation of enamines by -elimination reactions (187) and a vinylogous elimination, which leads to a dienamine (188), have been reported. The loss of an a substituent from a tertiary amine is seen in the generation of enamines by elimination of hydrogen cyanide from benzylic a-aminonitriles (189,190). 

The condensation of a vinylogous formamide with an enamine has been applied to an aza azulene synthesis (351). The point of attachment of the aldehyde to the enamine in condensations with indolenin derived poly-enamines was found to favor the second double bond (352,353). 

The formation of 3-acylpyridinium compounds (59/) from primary amines and l-methoxybutene-3-one can be regarded as the enamine alkylation of a vinylogous amide followed by cyclization and loss of methanol and water. 

This is a vinylogous analogue of the cyanoethyl group that is removed by... 

An interesting synthesis of quinolizidines was achieved using a vinylogous variation of the Bischler-Napieralski reaction. Angelastro and coworkers reported that treatment of amide 26 with PPSE (polyphosphoric acid trimethylsilyl ester) followed by reductive... 

An intensely colored by-product of the photolysis reaction of methyl-2-azidobenzoate has been identified as the first known derivative of 3,3 -diazaheptafulvalene 70 (94LA1165). Its molecular mass was established by elemental analysis and mass spectroscopy as that of a formal nitrene dimer, whereas and NMR studies demonstrated the twofold symmetry as well as the existence of a cross-conjugated 14 7r-electron system in 70. Involving l-azido-2,3-dimethoxy-5,6-dimethoxycarbonylbenzene in thermal decomposition reactions, the azaheptafulvalene 71 could be isolated and characterized spectroscopically and by means of X-ray diffraction. Tliis unusual fulvalene can be regarded as a vinylogous derivative of azafulvalenes (96JHC1333) (Scheme 28). 

The carbonyl substrate 3 to be reacted with the organozinc compound 2 can be an aldehyde or ketone that may contain additional functional groups. With a vinylogous halo ester—i.e. a y-halocrotyl ester—the corresponding y-crotylzinc derivative is formed. 

Reduction of unsaturated carbonyl compounds to the saturated carbonyl is achieved readily and in high yield. Over palladium the reduction will come to a near halt except under vigorous conditions (73). If an aryl carbonyl compound, or a vinylogous aryl carbonyl, such as in cinnamaldehyde is employed, some reduction of the carbonyl may occur as well. Carbonyl reduction can be diminished or stopped completely by addition of small amounts of potassium acetate (i5) to palladium catalysts. Other effective inhibitors are ferrous salts, such asferroussulfate, at a level of about one atom of iron per atom of palladium. The ferrous salt can be simply added to the hydrogenation solution (94). Homogeneous catalysts are not very effective in hydrogenation of unsaturated aldehydes because of the tendencies of these catalysts to promote decarbonylation. 

Isoxazoles are stable toward many reagents yet undergo alkylation and hydrogenolysis readily. These features make isoxazoles, which may be considered masked diketones, a useful grouping in synthesis (22). Alkylation of 3,5-dimethyllsoxazole, followed by hydrogenolysis and hydrolysis, have been used to prepare a number of diketones (44) and tetraones (4i). Isoxazoles can be opened readily lo the amino ketone, a vinylogous amide (9). 

Reduction of 3,5-dimethylisoxazolo[5,4-h]pyridine over 5% Pd-on-C proceeded with loss of the aromatic system to give 3-(l-aminoethyliden)-5-methyl-2-oxopiperidine (94). The product is a vinylogous amide, a type of structure resistant to further hydrogenation (118). 

Although a number of reagents can be used to reduce an isoxazole ring, molybdenum hexacarbonyl31 was selected for use in this synthesis. The action of this reagent on 24 reduces the weak N-0 bond of the isoxazole ring and produces a //-amino-a,//-unsaturated aldehyde (i.e. a vinylogous formamide) (see Scheme 19). Intermediate 87 forms smoothly upon deprotection of the terminal acetylene carbon with basic methanol-THF. 

When the enolate of an ,) - or a /j,y-unsatunited amide is used, it can react in an a or in a y fashion with a,/i-unsaturated esters, however, in most cases only a-selectivity is observed. Using l-(l-oxo-2-butenyl)pyrrolidine and lithium diisopropylamide at — 78 °C in a THF/HM-I A mixture (1 1), high. syn-selective formation of 3-alkyl-5-oxo-5-(l-pyrrolidinyl)-4-vinylpen-tanoates is achieved78,381 382. Related syn- or anti-selective additions of a vinylogous urethane also are known79. 

Bicyclic 2-pyridones fused over the nitrogen is another important heterocyclic scaffold. In the quest towards the total synthesis of Camptothecin, Danishefsky and co-workers developed a method where a vinylogous urethane was reacted with 1,3-dicarboxymethoxyallene generated in situ from dimethyl 3-chloroglutaconate to a bicyclic 2-pyridone intermediate [31-34]. This method has later been successfully applied in the synthesis of other... 

The interesting aspect of this oxidation is that it is a vinylogous a-hydroxylation, and it offers the possibility that the following rearrangement could occur. 

Entries 10 to 12 illustrate the use of organocopper conjugate addition in the synthesis of relatively complex molecules. The installation of a f-butyl group adjacent to a quaternary carbon in Entry 10 requires somewhat forcing conditions, but proceeds Transition Metals in ooc yie - I 1 Entry 11, the addition is to a vinylogous ester, illustrating the ability... 

Hydroxyisoxazoles were prepared by reaction of a vinylogous imidazole carboxy-late with hydroxylamine hydrochloride and sodium methoxide [140]... 

The a-chloroketone is proposed as an intermediate in the NaOCl oxidation of a vinylogous amide Staskun B (1988) J Org Chem 53 5287... 

The reaction of a-halosulphonc with a base to give an olefin is known as Ramberg-Backlund reaction52. A vinylogous version of this rearrangement results in the formation of 1,3-dienes (equation 21)53. Another variation of this reaction is shown in equation 2254. These rearrangements proceed with moderate stereoselectivity. 

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