Carbonyl compounds aminoalkylation

In this section alkylation, Michael additions, hydroxyalkylation (reaction with carbonyl compounds), aminoalkylation, acylation and some other reactions of a-sulphinyl carbanions will be discussed. 

Photoredox systems involving carbonyl compounds and amines are used in many applications. Carbonyl compounds employed include benzophenone and derivatives, a-diketones [e.g. benzil, cainphoroquinone (85),2W 291 9,10-phenanthrene quinone], and xanthone and coumarin derivatives. The amines are tertiary and must have a-hydrogens [e.g. N,A7-dimethylani 1 ine, Michler s ketone (86)]. The radicals formed are an a-aminoalkyl radical and a ketyl radical. 

The reaction between the photoexcited carbonyl compound and an amine occurs with substantially greater facility than that with most other hydrogen donors. The rate constants for triplet quenching by amines show little dependence on the amine a-C-H bond strength. However, the ability of the amine to release an electron is important.- - This is in keeping with a mechanism of radical generation which involves initial electron (or charge) transfer from the amine to the photoexcited carbonyl compound. Loss of a proton from the resultant complex (exciplex) results in an a-aminoalkyl radical which initiates polymerization. The... 

Kobayashi et al. found that lanthanide triflates were excellent catalysts for activation of C-N double bonds —activation by other Lewis acids required more than stoichiometric amounts of the acids. Examples were aza Diels-Alder reactions, the Man-nich-type reaction of A-(a-aminoalkyl)benzotriazoles with silyl enol ethers, the 1,3-dipolar cycloaddition of nitrones to alkenes, the 1,2-cycloaddition of diazoesters to imines, and the nucleophilic addition reactions to imines [24], These reactions are efficiently catalyzed by Yb(OTf)3. The arylimines reacted with Danishefsky s diene to give the dihydropyridones (Eq. 14) [25,26], The arylimines acted as the azadienes when reacted with cyclopentadiene, vinyl ethers or vinyl thioethers, providing the tet-rahydroquinolines (Eq. 15). Silyl enol ethers derived from esters, ketones, and thio-esters reacted with N-(a-aminoalkyl)benzotriazoles to give the /5-amino carbonyl compounds (Eq. 16) [27]. The diastereoselectivity was independent of the geometry of the silyl enol ethers, and favored the anti products. Nitrones, prepared in situ from aldehydes and N-substituted hydroxylamines, added to alkenes to afford isoxazoli-dines (Eq. 17) [28]. Addition of diazoesters to imines afforded CK-aziridines as the major products (Eq. 18) [29]. In all the reactions the imines could be generated in situ and the three-component coupling reactions proceeded smoothly in one pot. 

In 1960, Hellmann and Opitz l realized that the majority of the previously discussed named reactions and other related processes are all a-aminoalkylations of nucleophilic compounds of sufficiently weak acids, corresponding to MCRs of type I, or they have secondary reactions of type II that are followed by the formation of heterocycles [the Hell-mann-Opitz three-component reaction (HO-3CR),t Scheme 2]. In 1921, Passerinih 47] jjj. troduced his three-component reaction (P-3CR), which involves the reaction of a carboxylic acid 7, a carbonyl compound 1, and an isocyanide 10, to form (via rearrangement of the first-formed product 11) an a-carboxy-substituted alkanamide 12 (Scheme 2). This was the first example of a MCR of type II that involved an isocyanide. 

Aminoalkyl and Related Acids. - Further development of the classical three component approach to aminoalkylphosphonates (the Kabachnik-Fields reaction) has been reported. The reaction of aldehydes, hydroxylamines and dimethyltrimethylsilyl phosphite using lithium perchlorate/diethyl ether as a catalyst gives N-trimethylsilyloxy-a-aminophosphonate derivatives. The catalytic activities of various lanthanide triflates as well as indium trichloride have been examined for the Kabachnik-Fields type reactions of aldehydes, amines and the phosphorus nucleophiles HP(0)(0Et)2 and P(OEt)3 in ionic liquids. TaCb-Si02 has been utilized as an efficient Lewis acid catalyst for the coupling of carbonyl compounds, aromatic amines and diethyl phosphite to produce a-... 

Mannich reaction The condensation of CH activated compound with a primary or secondary amine and a non-enolizable carbonyl compound to afford aminoalkylated derivatives. 274... 

Accordingly, the Ugi reaction is closely related to the Mannich reaction and may be classified as an a-aminoalkylation. However, at the same time, a special type of Ugi reaction, the formation of a-acylami-nocarboxamides (42g) by 4CC of carboxylic acids and primary amines with carbonyl compounds and isocyanides, resembles the Passerini reaction (see Section 4.6.2). 

The formation of dialkyl (a-aminoalkyl)phosphonothioates (33) through the Kabachnik-Medved -Fields interaction of dialkyl hydrogenphosphonothioates and carbonyl compounds in the presence of anmionia was established in the early days of the study of that reaction, as was the formation of dialkyl [a-(arylamino)arylmethyl]phos-phonothioates (34) by the addition of (RO)2P(S)H to anils (Scheme... 

Of the other stationary phases, the amino phases have been used extensively to separate sugars and peptides the nitrile phase has found application in the separation of porphyrins. An important consideration in the use of polar bonded-phase materials is an awareness of the reactivity of the terminal functional group, for example, aminoalkyl bonded phase should not be used for the chromatography of carbonyl compounds due to possible condensation reactions and formation of Schiff s bases. 

Aminoalkylation of carbonyl compounds. The ylide 2 formed on treatment of 1 with n-butyllithium in THF, reacts with ketones to form aminoethylidene compounds (equation II). 

Compounds capable of forming an enol react with imines from formaldehyde and a primary or secondary amine to yield /3-aminoalkyl carbonyl compounds called Mannich bases. The following reaction of acetone, formaldehyde, and diethylamine is an example ... 

Mannich reaction (Section 19.8) The reaction of an enol with an iminium cation (formed from the reaction of a primary or secondary amine with formaldehyde) to yield a j8-aminoalkyl carbonyl compound. 

The classic direct Mannich reaction discovered in 1912 [192a] is an aminoalkylation of carbonylic compounds involving ammonia (or a primary or secondary amine derivative), a non-enolizable aldehyde (usually formaldehyde) or a ketone, and an enolizable carbonyl compound, leading to P-aminocarbonyl derivatives [192b-e]. The indirect version of the Mannich reaction is the corresponding two-component reaction of a preformed iminium salt [193] and an enolizable carbonyl compound. 

Oximes of some carbonyl compounds can undergo further cyclization reactions (46). jS-Diketones give, for example, heterocyclic compounds. The oxime of propargylaldehyde cannot be isolated because a ring formation takes place and an oxazine is formed. The reaction of hydroxylamine with aromatic a-aminoalkyl ketones is similar to osazone formation (47). Chloral reacts with two molecules of hydroxylamine (48). Carboxylic acids or lactonic oxygen can also react with hydroxylamine (49). 

The transamidation-like reactions of the 2-(aminoalkyl)-l,2-thiazetidin-3-one 1,1-dioxides 172 in the presence of (piperidinomethyl)-polystyrene give the ring-enlarged eight-membered products 13 in 42-87% yields (Equation 35 <1999HCA354>). To prove the exclusive attack of the amine at the carbonyl rather than at the sulfonyl group, compound 13 (R = Me) and its stmcture with an asymmetrically situated methyl substituent was then established by X-ray crystallography (see Section 14.08.3.1.5). 

General experimental details are as follows.697b It is usual first to mix the carbonyl component with the amine, which is presented as, e.g., hydrochloride or acetate. An appropriate hydrogen ion concentration must be maintained. For the preparation of aminoalkyl compounds that are liable to hydrolysis it is recommended that the water produced be removed by a drying agent or by azeotropic distillation. Dioxan is a suitable solvent, but it is often recommended that acetic acid be added to it. Ketones react better in alcohol with paraformaldehyde. Copper chloride or iron chloride is said to be a useful addition in reactions of acetylenes. Reactions of amines, phenols, and furans, even under mild conditions, may be accompanied by multiple condensation or resinification. 4-Hydroxybenzylamine is reported706 to be obtained in 92% yield when ammonia is led into a mixture of phenol and formaldehyde. 

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