Dimethyl Michael addition

Another impo2rtant P—C-hond-forming reaction is the base-cataly2ed Michael addition to activated double bonds. For example, dimethyl phosphite can be added to dimethyl maleate to yield tetramethylphosphonosucciaate [2788-26-3] (TMPS), an iatermediate ia the synthesis of 2-phosphonobutane-l,2,4-tricarboxyhc acid [37971-36-1] (PBTC) with 98% yield (20). 

Imidazole, 2-ethyl-1 -(o-nitrophenyl)-cyclization, S, 431 Imidazole, 4-ethyl-2-phenyl-oxidation, S, 405 Imidazole, ethynyl-Michael addition, S, 437 Imidazole, 4-ethynyl-2-phenyl-synthesis, S, 494 Imidazole, 1-formyl-reactions, S, 452 Imidazole, 2-formyl-mass spectra, S, 360 Imidazole, 4-formyl-synthesis, S, 475-476 Imidazole, 2-formyl-1,5-dimethyl-mass spectra, S, 360 3-oxide... 

Pyridine and dimethyl acetylenedicarboxylate in methanol yield - a mixture of (33) and (34). It is tempting to assume that a zwitterion (30) is first formed and that this then adds a proton followed by a methoxide ion (Michael addition) under the influence of both the positive charge on the ring and the assisting ester group. The resulting structure (31) could then add another molecule of the ester and cyclize, as indicated, to (32). Subsequent aromatization accompanied by loss of one, or the other, substituent at position 3 would lead to the two products, (33) and (34), actually isolated. 

Pyrazole and its 3,5-dimethyl and 3,4,5-trimethyl derivatives combined with two moles of dimethyl acetylenedicarboxylate giving products of similar ultraviolet absorption spectra to the parent pyrazoles. These products [e.g., (69)] do not possess the strong broad absorption at ca. 3.20 /u, characteristic of the bonded N—H group which is present in the parent pyrazoles and are formed by two successive Michael addition reactions. In the case of 3,5-dimethylpyra-zole, the initial fumarate (68) has been isolated and possessed a more conjugated type of absorption spectrum to those of the dipyrazolyl-... 

More serious limitations and precautions apply to compounds in which not all three R, R, and R" groups are aromatic. Autocondensation of benzylideneacetone (111) yields an unstable chloroferrate which may be 113 or 115, according to whether a Michael addition to 112 or a crotonic condensation to 114 is first involved. Since compound 113 could readily be prepared from 2,6-dimethyl-4-phenylpyrylium and benzaldehyde, the structure of the reaction product should be easily soluble. Another equivocal product is formed from two moles of benzylideneacetone, but a definite structure (116) results from chalcone and benzylideneacetone. ... 

Reaction of tryptamine with simple ketones has not been widely explored. Acetone in the presence of benzoyl chloride has been reported to yield 2-benzoyl-1,1 -dimethyl-1,2,3,4-tetrahydro-j8-carbo-line. That the keto group is much less reactive than the aldehyde group is indicated by the fact that j8-keto aldehydes, in the form of their acetals or sodium salts, react with tryptamine at the aldehyde function to yield the conjugated enamine 24, which undergoes ring closure via an intramolecular Michael addition. The potentialities of this interesting modification of the Pictet-Spengler reaction have not yet been fuUy explored. 

The benzoquinone adduct is a 2 1 molecular complex of 2,3-dimethylquinoxaline and quinol, and is readily prepared by crystallizing quinol from toluene in the presence of excess of 2,3-dimethyl-quinoxaline. 2,3-Dimethylquinoxaline and A -phenylmaleimide undergo Michael addition to form the quinoxalinylmethyl-A -phenylsuccinimide... 

An interesting feature is the sometimes observed pressure dependence of the reaction. The Michael addition of dimethyl methylmalonate 12 to the bicyclic ketone 13 does not occur under atmospheric pressure, but can be achieved at 15 Kbar in 77% yield ... 

Aldol condensation of the methoxymethyl ether of m-methoxybenzaldehyde (83) with cyclohexanone affords the conjugated ketone 84. Michael addition of dimethyl amine leads to the ami noketone Reduction of the ketone... 

Michael addition of the enolate of (42 )-4-rm-butyl-3-methyl-2-oxetanone to dimethyl (Z)-butenedioate yields a single diastereomer. This provides a method to control two new vicinal stereogenic centers one quaternary and one tertiary. The topicity of the addition is u with respect to the 3,3 -bond and l with respect to the 3, 4 -bondI09. 

The application of 3-aminopropyl phosphine (3) [41,46] as a building block for incorporation into -COOH functionalized frameworks provides an excellent example of the utility of preformed primary phosphine frameworks (Scheme 8) [46]. The reactions involved Michael addition of ferf-butyl acrylate to malonic acid dimethyl ester to produce the intermediate adduct, 2-methoxycarbonyl-pentanedioc acid 5-ferf-butyl ester 1-methyl ester, which upon treatment with trifluro-acetic acid (TFA) produced the corresponding diester acid,2-methoxy-carbonyl-pentanedioic acid 1-methyl ester, in near quantitative yield. It is remarkable to note that the reaction of NH2(CH2)3PH2 (3) with the diester acid is highly selective as the -COOH group remained unattacked whereas the reaction occurred smoothly and selectively at the -COOMe groups to pro-... 

Karachine (505) (253), the first natural protoberberine incorporating an acetone unit, was synthesized from berberine (15) (254). Heating of 15 with siloxydiene 503 in dimethyl sulfoxide afforded karachine (505) in 66% yield through Mannich condensation, intramolecular Michael addition, and then further Mannich condensation via 504 (Scheme 106). 

The pyrrolo-fused system 135 could also be converted with dimethyl acetylenedicarboxylate into the bicyclic 136. The reaction involves a Michael addition and ring opening initiated by traces of water during the work-up (Equation 18) <2003ARK62>. 

A series of 2-(thiazol-5-yl)acetamides and acetates 35a/b has been prepared in one pot from the reactions of benzotriazolylthione derivatives 32 with A,A-dimethyl-4-A ,A -bis(trimethylsilyl)aminobut-2-yne amide 31a and ethyl 4-A,A-bis(trimethylsilyl)aminobut-2-ynoate 31b, respectively <06TL8661>. Presumably, the initial adducts 33a/b undergo intramolecular thia-Michael addition to give 34a/b, which isomerize to thiazoles 35a/b. 

Reactions of a,(3-unsaturated acylzirconocene chlorides with stable carbon nucleophiles (sodium salts of dimethyl malonate and malononitrile) at 0°C in THF afford the Michael addition products in good yields (Scheme 5.38). Direct treatment of the reaction mixture with allyl bromide in the presence of a catalytic amount of Cul -2LiCl (10 mol%) in THF at 0 °C gives the allylic ketone in a one-pot reaction. This sequential transformation implies the electronic nature of a,P-unsaturated acylzirconocene chloride to be of type E as shown in Scheme 5.37. 

The utilization of the Robinson annellation method for the synthesis of cory-nanthe-type alkaloids has been thoroughly investigated by Kametani and coworkers (149-152). The tetracyclic ring system was efficiently formed via the Michael addition of dimethyl 3-methoxyallylidenemalonate (247) to the enamine derived from 3,4-dihydro-1 -methyl-(3-carboline (150). Alkylation of 248, followed by hydrolysis and decarboxylation, resulted in a mixture of stereosiomeric enamides 250 and 251. Hydrogenation of 250 afforded two lactams in a ratio of 2 1 in favor of the pseudo stereoisomer 253 over the normal isomer 252. On the other hand, catalytic reduction of 251 gave 254 as the sole product in nearly quantitative yield. Deprotection of 254, followed by lithium aluminum hydride reduction, yielded ( )-corynantheidol (255) with alio relative configuration of stereo centers at C-3, C-15 and C-20. Similar transformations of 252 and 253 lead to ( )-dihydrocorynantheol and ( )-hirsutinol (238), respectively, from which the latter is identical with ( )-3-epidihydrocorynantheol (149-151.). 

The Michael addition of ylide 132 with dimethyl acetylenedicarboxylate (DMAD) has been investigated < 1998T3913>. Depending on the solvent, different adducts are isolated. Using acetonitrile, 3-methylthiazolo[3,2-f][l,2,3]triazole 105... 

Intermediates such as 224 resulting from the nudeophilic addition of C,H-acidic compounds to allenyl ketones such as 222 do not only yield simple addition products such as 225 by proton transfer (Scheme 7.34) [259]. If the C,H-acidic compound contains at least one carbonyl group, a ring dosure is also possible to give pyran derivatives such as 226. The reaction of a similar allenyl ketone with dimethyl mal-onate, methyl acetoacetate or methyl cyanoacetate leads to a-pyrones by an analogous route however, the yields are low (20-32%) [260], The formation of oxaphos-pholenes 229 from ketones 227 and trivalent phosphorus compounds 228 can similarly be explained by nucleophilic attack at the central carbon atom of the allene followed by a second attack of the oxygen atom of the ketone at the phosphorus atom [261, 262], Treatment of the allenic ester 230 with copper(I) chloride and tributyltin hydride in N-methylpyrrolidone (NMP) affords the cephalosporin derivative 232 [263], The authors postulated a Michael addition of copper(I) hydride to the electron-... 

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