Addition of CH-acidic compounds

Nitromethane adds to JV-benzylideneaniline by formation of a carbon-carbon bond to the doubly bonded atom 238 

N-Phenyl-a-(nitromethyl)benzylamine JV-Benzylideneaniline (100 g, 0.55 mole) and nitro-methane (100 g, 1.64 moles) are heated together in anhydrous ethanol (50 ml) under reflux for 6 h. The solvent and excess of nitromethane are then removed in a vacuum by a current of air at room temperature. The residue is digested with 95% ethanol and collected. Washing it with cold alcohol several times leaves a 79% yield (106 g) of air-dry material, m.p. 85-87°. When recrystallized from 95 % ethanol this forms yellow prisms, m.p. 86-87.5°. 

Use of nitropropane as above, but for 2 h under reflux, affords iV-phenyl-oc-(l-nltropropyl)-benzylamine as yellow prisms, m.p. 128-130° (55% yield). 

TV-Phenyl- -nitro-a-phenylphenethylamines 239 When AT-benzylideneaniline (9.1 g), co-nitro-toluene (10.3 g), and diethylamine (0.5 ml) are kept for 10 days in a refrigerator, this product separates in 91% yield after two recrystallizations from light petroleum it has m.p. 124° (dec.). 

Dornow and Frese240 studied the addition of ethyl nitroacetate to Schiff s bases and, adding an equimolar amount of diethylamine, obtained reactions of the following type  

---

More interestingly, Michael additions of CH-acidic compounds 139 onto the vinyl ketone — generated from 132 by action of the catalyst Triton B (0.08 equiv. in methanol) — smoothly afford adducts 140 in good yields (Eq. 57)83). Under these conditions methoxide acts as the desilylating agent as well as the base to form the corresponding carbanions. 

Scheme 2. CAN-mediated radical additions of CH-acidic compounds 1 to arenes 6...

For Michael additions of CH acidic compounds (e.g. diethyl malonate with a,3-unsaturated ketones) the following recommendations are given "When possible, relatively weak basic catalysts such as piperidine... should be selected. If stronger bases are required, it is normally appropriate to use only 0.1 to 0.3 equivalent of the base." The analogy of these conditions to those specified by our rule A is obvious (concentration control). On the other hand, preformed carbanions (organometallies) are usually employed when the addend is more basic than the enolate produced by attack at the unsaturated carbonyl compound. Though the nature of the metal ion plays a crucial rule in many "carbanionic" addition reactions, a first understanding of the principles involved can be... 

The addition of CH-acidic compounds, hydrogen cyanide and amines to acylaminoacrylic acid compounds has occasionally been employed for the synthesis of more complex amino acids. 

Similar results are observed in the conjugative addition of CH-acidic methylene compounds with the metal derivatives of 2-nitro-5,10,15.20-tetraphenylporphyrin (6). The nickel porphyrin 6 (M = Ni) yields with an excess of dimethyl malonate the cyclopropane derivative 7 whereas the copper porphyrin 6 (M — Cu) forms with two equivalents of malononitrile the bisadduct 8.111... 

In addition to the cathodic hydrodimerization of activated olefins and the Kolbe reaction, the anodic dimerization of CH-acidic compounds is another possibility for the electrochemical C—C coupling. Monsanto 281 > has used the anodic dimerization of malonates in a laboratory synthesis of intermediates for useful sequestrants and detergency builders. 

Alkali metal derivatives of CH-acidic compounds are usually highly aggregated in solvents of low relative permittivity such as benzene (fir = 2.3). The accelerating influences of a variety of EPD solvents used as additives in the alkylation of diethyl sodio- -butylmalonate with 1-bromobutane in benzene according to Eq. (5-126) was discovered by Zaugg et al. [350] cf. Table 5-21. 

The reaction of CH acidic compounds with CS2 in the presence of excess base yields dianions of dithiocarboxylic acids. Starting from camphor, neutralization with HCl and addition of primary amines yields 3-oxonorbomanethiocarboxamides (11) with undefined stereochemistry (Scheme 3). ... 

In a sequential aUcylation/heterocycHzation protocol, electrolyticaUy generated anions of CH-acidic compounds (generaHzed R3C-H nitro compounds, malonates, P-ketoesters) induced heterocycHzation to quinoHnes 77 by Michael addition to the ynones (73) and subsequent cycloeHmination of H2O (76 77) [170]. Ynones of type 73 can be cycHzed... 

The overall process is the addition of a CH-acidic compound to the carbon-carbon double bond of an o ,/3-unsaturated carbonyl compound. The Michael reaction is of particular importance in organic synthesis for the construction of the carbon skeleton. The above CH-acidic compounds usually do not add to ordinary carbon-carbon double bonds. Another and even more versatile method for carbon-carbon bond formation that employs enolates as reactive species is the aldol reaction. 

Fewer procedures have been explored recently for the synthesis of simple six-membered heterocycles by microwave-assisted MCRs. Libraries of 3,5,6-trisubstituted 2-pyridones have been prepared by the rapid solution phase three-component condensation of CH-acidic carbonyl compounds 44, NJ -dimethylformamide dimethyl acetal 45 and methylene active nitriles 47 imder microwave irradiation [77]. In this one-pot, two-step process for the synthesis of simple pyridones, initial condensation between 44 and 45 under solvent-free conditions was facilitated in 5 -10 min at either ambient temperature or 100 ° C by microwave irradiation, depending upon the CH-acidic carbonyl compound 44 used, to give enamine intermediate 46 (Scheme 19). Addition of the nitrile 47 and catalytic piperidine, and irradiation at 100 °C for 5 min, gave a library of 2-pyridones 48 in reasonable overall yield and high individual purities. 

In addition to the carboxylates, other anions can be dimerized at the anode, presumably via radicals. Anionized or enolized 1,3-dicarbonyl compounds and heteroanalogs of CH acids couple in satisfactory yields (Table 10, numbers 1-3). 

In the reaction of OH-, NH-, SH- and CH-acidic compounds with phosphacumulene ylides the anion Nu of the initially formed phosphonium salt (c/. equation 101) is so nucleophilic, that addition of the anion to give a new alkylidenephosphorane is faster than cycloaddition of a second mole of starting ylide (equation 105). ° ... 

Oligomerizations, polymerizations and telomerizations are covered in other parts of this section, since C-C/C-C bond forming additions (dicarborations) are involved. Metal-mediated hydroalkylations of olefins with CH acidic compounds and hydroarylations with formal addition of aromatic C—H bonds to olefins are also known2, however, only a few examples of stereoselective applications have been reported (Section 1.5.8.2.6.). 

With strained alkenes or with addition intermediates which, for steric reasons, are not capable of dehydropalladation, dicarboration occurs with aryl or vinyl halides5. Unsymmetrical addition is possible if, in addition to the organohalide, a CH acidic compound and a base5, tetraphenylborate6 or an organotin compound7 is present. 

A very useful reaction in organic synthesis is the so-called Michael addition of an organic compound RH to an a,/ -unsaturated system C=C—X, in which X may represent an electron-withdrawing group such as C=0, COOR, C=N, N02, S(=0)R. The addition, in which R attaches to the / -carbon atom to give R—C—CH—X, occurs in a protic medium with sufficiently acidic compounds, e.g., nitroalkanes, alcohols, thiols, malonic esters and requires a basic catalyst. 

---