By the Mannich reaction

The preparation of extranuclear aminopyrazines by the Mannich reaction has been described in Section IV.2C(6) (657, 715, 716). 

---

Methyl vinyl ketone can be produced by the reactions of acetone and formaldehyde to form 4-hydroxy-2-butanone, followed by dehydration to the product (267,268). Methyl vinyl ketone can also be produced by the Mannich reaction of acetone, formaldehyde, and diethylamine (269). Preparation via the oxidation of saturated alcohols or ketones such as 2-butanol and methyl ethyl ketone is also known (270), and older patents report the synthesis of methyl vinyl ketone by the hydration of vinylacetylene (271,272). 

TABLE XX. Aminomethylethynylpyrazoles Prepared by the Mannich Reaction [72IZV2524 93MIP1],... 

NaOH/10% NaCl solution. After 24 hours, the capacity had fallen to 0.44 meq/g (82% loss) and after twelve days no capacity remained. The conversion of PAM grafts to useful anion exchangers clearly requires a much more inert linkage than that introduced by the Mannich reaction. 

As indicated in Section 3.05.2.2, the heteroarylmethylamines, generated by the Mannich reaction, are versatile precursors for the synthesis of a range of more sophisticated functionalized alkyl derivatives. 

Other methods for the preparation of gem-diaminoalkyl residues have been reported. Some of them are directly applicable to synthesis of PMRI-peptides and some are only remotely related. Katritzky et al.1901 synthesized racemic, monoprotected diaminoalkyl derivatives by the Mannich reaction (Scheme 5). The diastereomeric mixtures of A-peptidyl gem-diaminoalkyl compounds were resolved to afford the diastereomerically pure retro-inverso surrogates. 

Direct (IV-substituted)-aminomethylation at the 5-position of pyrimidines with at least two electron-releasing groups can be done by the Mannich reaction a methyl or an amino substituent may also (or preferentially) undergo the reaction, especially if the... 

Methylthymol blue and methylxylenol blue, prepared by the Mannich reaction from thymol-sulfonphthalein and p- xylenol blue respectively, have been intensively studied and resemble xylenol orange in many respects. If only one chelating group is introduced into cresol red, semi-xylenol orange results which is a common contaminant in XO and proves to be a more sensitive reagent for zirconium. 

Alkylation of acetylacetone chelates is generally unsuccessful, but carbon—methylene bonds can be formed by chloromethylation,279 reaction with ethyl diazoacetate,287 reaction with thioacetals288 (equations 64, 65 and 66) and by the Mannich reaction (Scheme 73).279 The Mannich base can be quatemized with methyl iodide and converted by cyanide ion into a cyanomethyl-substituted chelate. 

The first preparation of 5-methylfurfurylamines by the Mannich reaction was by Holdren and Hixon.2 The present modification has been published previously 3 without the steam-distillation step, which facilitates separation of the product. 

Instead of following the procedure described in Scheme 35, 1,4-benzothiazepine 206 can also be formed by the Mannich reaction of 2-benzoylmethylthio-4,5-dimethoxybenzoylamine hydrochloride 209 with benzaldehyde in the presence of NaOH in methanol. A good yield is observed for the diastereoisomers 92a and 92b in a ratio of 6 5 (Scheme 36) <1995TL753>. 

The quaternary salts produced by the Mannich reaction undergo a number of conversions useful in synthesis. For example, although stable at room temperature they eliminate an amine hydrochloride on heating to yield an a,/J unsaturated ketone (e.g. the conversion of dimethylaminopropiophenone to phenyl vinyl ketone, Expt 6.147). 

The Polonovski reaction on catharanthine Nb-oxide (170) leads to fission of the 5,6-bond and re-cyclization with formation of (171) 106 in the presence of other nucleophiles (e.g. vindoline), this reaction forms the basis of the synthesis of the vinblastine group of alkaloids (q.v.). The formation of (171) is reversible in acid solution, and under appropriate conditions the methylene group (C-5) is lost as formaldehyde re-cyclization by the Mannich reaction then gives 5-norcatharan-thine (173) (Scheme 23).106"... 

Fortunately, we know from the last chapter how to make a,j3-unsaturated carbonyl compounds so the disconnection of the enone 3 poses no problems. Both starting materials are ketones one 4 must provide the specific enolate and the other 16 the enone 3 by the Mannich reaction. 

The unsymmetrical diketones 47 were needed for photochemical experiments. The better 1,5-diCO disconnection 47a is at the branchpoint. The enone 49 can be made by the Mannich reaction (chapter 20). 

Gramine - 3-(dimethylaminomethyl)indole (14) - is a readily obtainable derivative of indole and is produced with a quantitative yield by the Mannich reaction. In [19] it was phosphorylated with diethyl chlorophosphite. 3-(Dimethylaminomethyl)-l-(triethoxyphosphito)indole (15) was obtained also by the method in [20] using diethyl penten-3-on-2-yl phosphite. Compound 15 readily adds sulfur with the formation of the corresponding gramine 1-thiophosphate 16 and reacts with chloral according to the scheme of the Perkow reaction, forming phosphate 17 ... 

A closely related synthesis of symmetrically substituted bispidinones 19a-w is provided by the Mannich reaction with acetone derivatives 319, paraformaldehyde, and the acetate salts of various amines. Such a reaction is formally a C2N + C2N + 2C synthesis but is reported here because of its relationship to the above bispidinone synthesis. In this case the intermediate piperidinone cannot be isolated but once formed, it reacted with the primary amine and formaldehyde to give the eight-membered ring <1995T2055, 19970M1167>. Similarly, the diamine 320 reacted with dibenzyl ketone and formaldehyde to give the macrocycle 321 in 48% yield <1995T4819>. 

Good regioselectivity is shown by the Mannich reaction on acetonyl theobromine, which exclusively gives the product 459, deriving from attack of the aminc/formaldehyde reagent on the methyl group of the acetonyl moiety.- ... 

Certain /3>dialkylaminoethyl aryl ketones, readily prepared by the Mannich reaction (method 444), are converted to /3-aroyIpropionitriles in good yields by the action of hot aqueous potassium cyanide. /S-Benzoylpropionitrile is made in this way in 67% yield. The reaction has been successfully applied to the formation of /3-2-furoylpropionitrile (57%) and / -2-thienoylpropionitrile (67%). 

---