Phenolic Mannich bases

The synthesis of a large number of y-pyrones and y-pyranols from enamines has been brought about through the use of a wide variety of bifunctional molecules. These molecules include phenolic aldehydes (126,127), phenolic Mannich bases (128), ketal esters (129), and diketene (120-132). All of these molecules have an electrophilic carbonyl group and a nucleophilic oxygen center in relative 1,4 positions. This is illustrated by the reaction between salicylaldehyde (101) and the morpholine enamine of cyclohexanone to give pyranol 102 in a quantitative yield (127). 

The group of nitrogen-containing additives comprises phenolic mannich bases, phosphoric acid [1776], and oxalkylated alkylphenols with nitrogen-containing additives [996]. 

V. N. Umutbaev, M. G. Kamaletdinov, B. A. Andreson, R. G. Abdrakhmanov, A. U. Sharipov, and I. V. Utyaganov. Lubricant additive for water-based drilling muds—contains a mixture of phenolic mannich bases, additional phosphoric acid and water. Patent SU 1799895-A, 1993. 

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... 

Aminochromans also arise from the reaction of phenolic Mannich bases with enamines (70JHC1311). The route is attractive for a number of reasons the starting materials are readily available its scope is considerable since the enamines may be aldehyde or ketone based and the Mannich bases may be aromatic or heteroaromatic and the products themselves are precursors of hydroxychromans and 4//-chromenes. Mechanistically, the synthesis proceeds through a quinone methide followed by addition to the enamine and cyclization, which may be a concerted process (Scheme 71). 

The formation of the chromanochromans (286) during the reaction of the phenolic Mannich bases and 2-chloroprop-2-enonitrile probably arises through the decomposition of the base to a quinone methide and dimethylamine (80JOC3726). The initial product, a substituted 4//-chromene (285), undergoes a further [4+2]-cycloaddition to give the final product (Scheme 77). 

In an attempt to use phenolic Mannich bases in a synthesis of 3-chromanones, a mixture of 1 -[(dimethylamino)methyl]-2-naphthol and a-chloroacrylonitrile was heated under reflux in anhydrous dioxane. The product, however, which was formed in 55% yield, was shown to be the naphthonaphthopyranopyran 1. 

Chromenes (342) were prepared, via 0-quinone methides, from 0-phenolic Mannich bases and enamines202, but have also been obtained by reaction of functionalized enamines like 340, with an electron-withdrawing substituent in the -position, and substituted 0-hydroxybenzyl alcohols 341 in boiling acetic acid203 (equation 74). 

An anomalous behavior may be observed in 254 (Fig. 95), as the cleavage of the reagent molecule occurs in the course of the replacement reaction prtxiucing, simultaneously, C-alkylation of one fragment by the phenolic Mannich base and hydroxy group... 

Fig. 95. Reaction of phenolic Mannich bases with p-ketosulfones.

Fig. 120. Addition of organometals to thiolic or phenolic Mannich bases.

Interesting cyclic derivatives are obtained from phenolic Mannich bases having the amino acid moiety thus, the seven-membered hcterocyclc 323 is formed from the 323 ct-amino acidic residue and the phenolic hydroxy group by reaction with thionyl chloride. ... 

Mostly P-aminokctones, along with phenolic Mannich bases, arc usually employed in the synthesis of homo- and heterocyclic derivatives. As far as P-aminokctoncs are concerned, in particular, homocyclic compounds (Fig. 129) are prepared by the Diels-Aldcr reaction of the Mannich base, acting actually as dienophilc, with a conjugated dicnc. Interestingly, styryl ketobascs give styryl cycloalkenyl ketones (333, R = Ar—CH=CH—) by the same type of reaction, without any involvement of the styryl group. 

The majority of O-heterocycIic derivatives obtained from phenolic Mannich bases, however, are six-membered rings. In particular, 4-H-chromene (354 in Fig. 138) and... 

Fig. 138. Synthesis of. six-membered O-heterocycles from phenolic Mannich bases.

Finally, phenolic Mannich bases may provide heterodiene formation at the ortho-mcthylencquinone moiety originated by deamination (Fig. 139 sec also Fig. 134) this... 

Pochini, A., Ihiglia, G., and Ungaro, R.,, Se-lective synthesis of phenolic Mannich bases under solid-liquid phases transfer conditions,... 

Rumynskaya, I. G.. Study of intramolecular hydrogen bonding in phenolic Mannich bases. Deposited doc., 1981, VINITI 4213 81, 2.34 Chem. Ahsir.. 98,. 34145, 1983. 

Higashi, K., Kitamura. T Fukusaki. Y., and Imoto, E.. Reaction of phenolic Mannich bases with phenols. Kdgyo Kagaku Zdsshi, 61, 1035, 1958 Chem Abstr., 55, 2221ft l%l. 

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. 

Balasubramanian, K. K. and Selvaraj, S., Novel reaction of o-phenolic Mannich bases with a-chloroacrylonitrile, J. Org. Chem., 45, 3726, 1980. 

Epoxy resins, mostly employed in the coating industry, are characterized by the presence of a phenolic Mannich base, usually deriving from bisphenol A or alkyl phenols, - " linked to an epoxy oligomer, mixed with various crosslinking agents,- 20.1.207 dispersed into aqueous solution in the presence of organic acid. 

Voskresenskaya, O. M., Gotlib, Fi. M., Ver-ezhnikov, L. V., and Liakumovich, A. G Effect of benzoyl peroxide on curing of epoxy oligomers with phenolic Mannich bases, /zv. Vyssh. UchebtL Zaved. Khim. Khim. Tekhnol,. 32, 87. 1989 C/iem. Abstr.. 112. 180514, 1990. 

Bakirova, I. N., Zenitova, L. A., and Roz-ental, N. A., Study of the behaviour of polyfurcthane isocyanurates) produced by using phenolic Mannich bases at elevated temperatures, Svoistva Cretan. Elasiom. M, 62, 1984 Chem. Abstr, 102, 186419, 1985. 

Steric factors may influence the conformational equilibria of phenolic Mannich bases, as is demonstrated by the quantitative relationship observed between the molecular volume of alkyl substituents linked to the amino group and the thermodynamical parameters.- - ... 

Both the above mechanisms are proposed in the literature with Mannich bases of nitroalkanes the substitution is clearly favored by the steric hindrance of the amine moiety, thus suggesting path 1, - whereas NMR studies on the reaction of P-amino-ketones with hydroxy coumarins do not reveal the presence of vinyl ketone intermediates. lodomethylated phenolic Mannich bases arc also claimed to react according to path 2, although the formation as by-products of dimers and methylene-bis-derivatives accounts for the participation of methylenequinone intermediates in the process. "... 

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... 

Nevertheless, in many cases, hydrogcnolysis docs not occur readily however, the ammonium salt of the Mannich base appears more suitable for a successful reaction. Thus, several ortho-phenolic Mannich bases arc hydrogenated as hydrochlorides, in order to avoid the presence of the intramolecular hydrogen bond between OH and N, which is responsible for the weak reactivity of the free Mannich base. ITie ferroccnyl Mannich base 282, containing both tertiary and quaternary amino groups, gives 2-di-methylaminomethyl-l-(2-methylferroccn-l-yl) ferrocene (283) upon reaction of the more reactive quaternary ammonium moiety. ... 

By contrast, some phenolic Mannich bases (314, R = phenolic residue), heated in the presence of organomagnesium in toluene, afford amine elimination with formation of the R -substituted product (316). Analogous behavior is observed with organobor-anes. By this method, the otherwise unfeasible replacement of an amine by alkyl or aryl groups is thus made possible. 

Phenolic Mannich bases afford cyclic derivatives as the result of deamination, O-heterocycles being prepared to a larger extent than N-heterocycles, although an interesting example of homocycle synthc.sis (Fig. 135) from para-aminomethylated phenolic Mannich bases is worth mentioning. ... 

Fig. 135. Spiro derivalives from para-phenolic Mannich bases.

Fig. 136. Synthesis of bcnzxxjuinoiinc derivatives from phenolic Mannich bases (bold line.s represent the original skeleton of the Mannich base).

Fig. 139. Synthesis of benzopyrans and benzoxazincs from phenolic Mannich bases.

When the o-amino nitroso derivative 363 is subjected to reaction with various N-indolic or phenolic Mannich bases, closure of the imidazole ring by the methylene moiety occurs, thus making it possible to obtain the interesting purine derivatives 364. 

Balasubramanian, K. K. and Selvaraj, S., Studies in phenolic Mannich bases. Reaction with acetylenes. Tetrahedron Lett., 851, 1980. Von Straitdtmann, M., C ohen, M. P., and Shavcl. J., Reaction of phenolic Mannich bases with imines and oximes. Synthesis of fased ring systems containing 1,3-oxa7ine.s, J. Heterocyd. Chem.. 6, 429, 1969. 

Among the limited examples of polymers originated by path b (Fig. 153), the polymerization- of diallylamino Mannich bases leading to poly(pyrrolidine)s 397 (Fig. 155) is worth mentioning. The synthesis of ionene polymers of the type 398, used in water clarification, by reaaion between /ran.v-l,4-dichloro-2-butene and a phenolic Mannich base,- is also interesting. 

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