Mannich base methiodide

An obvious way to avoid methylenebisphenol formation would be to generate the quinonemethide in the absence of any unreacted parent phenol. Therefore, a suitable intermediate was sought. The preparation of chloromethyl and hydroxymethyl intermediates was ruled out as being difficult to achieve in good yields by the methods then known. The use of Mannich base methiodides (4) was considered uneconomical. Our answer came in the form of an intermediate which had been prepared for another purpose. 

Gardner, P. D. and Rafsanjani, H. S.. Reaction of phenolic Mannich bases methiodides and oxides with various nucleophiles, J. Am. Chem. Soc., 81, 3.364. 1959. 

Triton B as catalyst, but a note indicates that the Mannich base methiodide (with an added equivalent of base) was equally satisfactory. 

An attempt has been made to synthesize the morphinane ring-system in this way, and l-(/3-diethylaminoethyl)-2-keto-1 2 3 4-tetrahydro-naphthalene was converted to [oxxvm] by condensation with the appropriate Mannich base methiodide, the product brominated with N-bromosuccinimide, and finally converted to the quaternary salt [cxxix]. Work on the corresponding N-dimethyl series was abandoned when it was found impossible to obtain the requisite substituted /3-tetralone in a state even approaching purity. The synthesis of [cxxx] has been accomplished by the same method, its production being accompanied by the production of [cxxxi] as a result of further ring-extension [43]. 

The same intermediate occurs in the Lehmann method463 for converting the methiodides of phenolic Mannich bases into 2,3-dihydrobenzo-furans, through reaction with dimethyloxosulfonium methylide. Thus, o-benzoquinone methide (207) leads to 2,3-dihydrobenzofuran according to Scheme 4. Similarly, 2-naphtholgives l,2-dihydronaphtho[2,l-6]furan through 208 and 209, formed and rearranged in situ.i6i The reaction has been applied to the synthesis of polycyclic benzofurans.483,485... 

The forward synthetic sequence would therefore involve the Michael reaction of 2-methylcyclopentane-l,3-dione with methyl vinyl ketone to give (20), followed by cyclisation to the hydroxyketone (19), and then dehydration to the target molecule (13a). The overall process of addition and cyclisation is known as the Robinson annelation reaction.3 In this preparative example (Expt 7.6) the methyl vinyl ketone is used directly under conditions which minimise its polymerisation 48 it should be noted, however, that many literature examples of the annelation reaction use Mannich bases or the corresponding methiodides as an in situ source of the a, /J-unsaturated carbonyl component (see Section 5.18.2, p. 801). 

In the presence of a Mannich base, hydroxymethyl derivatives 268 may behave, in turn, as alcoholic reagents, thus affording amino group replacement with formation of the symmetrical ether 269 (R = R —CH ). Indeed, alcohols and phenols allow the synthesis of ethers 269, starting from phenolic Mannich bases as well as from the methiodides of aminomethylfcrrocenes, by reaction with alkoxide or phenoxide. Good results have been obtained with a thioporphirine Mannich base and zinc acetate. Esters 270 (Fig. 102) can be synthesized from various Mannich bases such as those derived from tropolones or purines, which are converted into acetoxymethyl... 

Badman, G. T. and Rce,se, C. B., Reactions between methiodides of nucleoside Mannich bases and caibon nuclcophile.s, J. Chem. Soc. Chem. Commun., 1732. 1987. 

Steroid synthesis. In developing a method of cyclization which has been of immeasurable -walue in the total synthesis of steroids, Robinson at first experimented with the condensation of ketones with methyl vinyl ketone itself, but encountered difficulties associated with the tendency of the ketone to polymerize. He then turned to possible prectnsors and met with some success with methyl /3-chloroacetyl ketone, CHsCOCHzCH CI. Still better, however, was the methiodide (2) of the Mannich base (1), l-diethylamino-3-butanone. Treated with a strong base such as sodamide in... 

Annelation. The Robinson annelation of (—)-dihydrocarvone (1) to give the ketol (2) was originally carried out using the Mannich base 1 -diethylamino-3-pentanone methiodide and sodamide in ether-pyridine.3 Halsall1 improved the... 

A number of very successful preparative methods involve removal of an amino group and depend on treatment of a Mannich base or its hydrochloride or methiodide with a compound containing an acidic CH group. Relatively few examples can be given here, but others can be found in the excellent review by Hellmann and Opitz.697c... 

Although other mechanisms are conceivable, the most likely scheme involves direct nucleophilic displacement by phosphite on carbon to furnish a trialkoxy phosphonium halide intermediate as in the Michaehs-Arbuzov reaction. Recently, we have developed an improved method for the preparation of Mannich bases of steroids and carried ouf reactions with their methiodides and trialkyl phosphite to obtain the first steroidal phosphonates to be reported (132). 

Preparations of (3-oxoalkyl)phosphonic diesters through the Michaelis-Arbuzov reaction appear to have been limited to the use of trialkyl phosphites in combination with the methiodides, hydrochlorides " " or acetates derived from Mannich bases (reaction 29). 

The Robinson annulation is the reaction of alkali metal derivatives of cyclohexanones with a-,p>unsaturated methyl ketones to produce cycloketones and polycycloketones. The standard method for Robinson annulation is exemplified in the mechanism shown above. For the synthesis of the 1,5-diketone side chain, the enolate nucleophile reacts with a Michael acceptor this Michael acceptor is usually a substituted vinyl ketone or the parent methyl vinyl ketone (MVK), although the latter gives low yield due to its propensity to polymerize under the standard reaction conditions. To overcome the drawbacks for using MVK, Robinson, McQuillin and Du Feu introduced the Robinson-Mannich variation of the annulation reaction. This modification uses a quatemized Mannich base formed from the vinyl entity the Maimich base is made in situ and acts as a methyl vinyl ketone precursor after it is converted to its methiodides. The formed methiodides of the Mannich adduct 4-(trimethylamino-2-butanone) is condensed with sodioderivatives of ketones or with the parent ketone in the presence of sodium ethoxide. 

Oximes are useful in preparing isoxazolines and isoxazoles. Since some ring closures to produce these heterocycles may involve oxime anchi-merism, Scott and MacConaill " studied the reaction with a number of Mannich base oxime methiodides. They found that the oximate anion was a powerful nucleophile and that displacement of trimethylamine, as in (266), occurred stereospecifically. The oxime of structure (267) undergoes elimination rather than cyclization. 

The use of the methiodide of the corresponding Mannich base instead of the free ketone leads to a several-fold decrease in the yield of (316). 

Ivanov, B. E. and Khismatullina, U. A., Reaction of hydrochloric acid and Mannich methiodide phenol base with thiethyl phosphite, Izv. Akad. Nauk SSSR. Ser. Khim., 2150, 1968 Chem. Ahstr, 70, 20164, 1969. 

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