Carbonyl derivatives amine addition

The first multicomponent reaction was the Strecker reaction reported in 1850 by Adolf Strecker [241aj. It is a three-component coupling between carbonyl derivatives, amines, and cyanide source, such as hydrogen cyanide, to provide a-aminonitriles which constitute potent starting materials to achieve important a-amino acids by simple hydrolysis. The mechanism of the Strecker reaction involves the initial formation of an imine from condensation of the amine component to the carbonyl component, after which addition of the cyanide component to this imine intermediate follows. Although the first enantioselective, metal-catalyzed Strecker... 

Just as ammonia undergoes a Michael addition with a,P-unsaturated carbonyl derivatives, amines also add to conjugated acids such as acrylic acid to give -amino... 

Reductive cleavage of phenylhydrazones of carbonyl compounds provides a route to amines. The reduction is carried out conveniently in ethanol containing ammonia over palladium-on-carbon. Ammonia is used to minimize formation of secondary amines, derived by addition of the initially formed amine to the starting material (160). Alternatively, a two-phase system of benzene, cyclohexane, toluene, or dioxane and aqueous hydrochloric acid can be used. 

It is assumed that the overall process is initiated by a Michael addition of the 1,3-dicarbonyl compound onto the ci,(5-uri saturated carbonyl derivative. There follows the formation of either an aminal and an iminium intermediate which is followed by the formation of two N.O-acetals. 

Nucleophilic catalysis is a process of particular significance in reactions of carboxylic acid derivatives. As an example we may cite hydrolysis catalyzed by a tertiary amine (Scheme 20). The catalysis is effective because initial attack of the amine will be faster than attack by the less nucleophilic water the amine addition yields the intermediate 27 which, because of the positive charge, has an extremely reactive carbonyl group and is attacked by water much faster than the original compound. The fact that a given base is acting by nucleophilic catalysis... 

The Strecker reaction is defined as the addition of HCN to the condensation product of a carbonyl and amine component to give a-amino nitriles. Lipton and coworkers reported the first highly effective catalytic asymmetric Strecker reaction, using synthetic peptide 43, a modification of Inoue s catalyst (38), which was determined to be inactive for the Strecker reactions of aldimines (see Scheme 6.5) [62], Catalyst 43 provided chiral a-amino nitrile products for a number of N-benzhydryl imines (42) derived from substituted aromatic (71-97% yield 64->99% ee) and aliphatic (80-81% yield <10-17% ee) aldehydes, presumably through a similar mode of activation to that for hydrocyanations of aldehydes (Table 6.14). Electron-deficient aromatic imines were not suitable substrates for this catalyst, giving products in low optical purities (<10-32% ee). The a-amino nitrile product of benzaldehyde was converted to the corresponding a-amino acid in high yield (92%) and ee (>99%) via a one-step acid hydrolysis. 

Amides The absorption for the carbonyl group of an amide appears in the region of 1690-1630 cm-1, lower wavenumbers than most other carbonyl bands. In addition, other relatively strong bands often appear at slightly lower wavenumbers. Amides derived from ammonia or primary amines have bands in the hydrogen region due to their NH bonds. 

The Michael addition of secondary amines to a,)S-unsaturated carbonyl compounds under MWI essentially required the presence of water to drive the amine addition to completion and the presence of at least 10 mole equivalents of the amine. Besides increasing the polarity and possibly some micellar effect, water facilitates protonation of the resulted enolate from amine addition. In a typical procedure, benzalacetophenone was mixed with morpholine (469) and water in a teflon flask and subjected to MWI for 2 min to yield 93% of the 1,4-adduct 471 (Scheme 92). The method was also extended to other morpholine derivatives 472 and 473 in 30% and 100% yields, respectively (00SC643). 

The conjugate addition reactions of a-aminoalkylcuprates (derived from r-butoxy-carbonyl protected amines) with Q, /3-/3,y-allenyl esters occurs with preferred approach from the side opposite the substituent on the 4-position and results in trans alignment of the respective groups about the unconjugated double bond on the 1,4-adduct (Scheme 11). ... 

Treatment of phenol with 1,2-diols and excess of cyclopentene (Sequiv.) in the presence of a well-defined cationic ruthenium hydride complex [(C6H6)(PCy3)(CO)RuH]+BF4- (1 mol%) in toluene at 100 C for 8-12h led to the formation of benzofuran derivatives (Eq. (7.18)) [24]. The catalytic C-H couphng method exhibited a broad substrate scope, tolerated carbonyl and amine functional groups, obviated the use of any expensive and often toxic metal oxidants, and liberated water as the only by-product. Furthermore, excellent regioselective addition of the linear 1,2-diols were observed, which yielded the -substituted benzofuran products exclusively. Such dehydrative C—H alkenylation and annulation reactions could be applied for a number of functionalized phenol and alcohol substrates of biological importance. 

Monodithiocarbamates can be prepared from phenylene diamines in the presence of a second, more basic amine. For example, addition of carbon disulfide and NEta to 1,2-diaminobenzene affords the yellow triethylammonium dithiocarbamate salt in high yield (115). The latter can then be reacted with various a-halogenated carbonyl derivatives resulting in cyclization and dehydration to give the new amines. These in turn react with carbon disulfide and... 

Notably, proline was unique for this transformation, as all the other chiral secondary amines tested failed to promote the reaction. Another well-estabhshed organo-catalyst (4), invented by MacMillan [27], and unable to form secondary interactions with electrophiles like proUne, was used in the addition of aldehydes to indolyl and other carbocations derived from alcohols. The formation of stable carbenium ions from alcohols and their compatibility with water, generated by the organocatalytic cycle (formation of enamines from the corresponding carbonyl derivatives), was estabUshed by Cozzi in a SnI nucleophilic substitution of alcohols in the presence of water [28]. The enamine formed in situ by the MacMUlan catalyst approaches the carbocation from the less hindered side and the hindrance of the incipient carboca-tion controls the stereoselectivity of the reaction (Scheme 26.2) [29]. 

Unusual cyclocarbonylation of allylic acetates proceeds in the presence of acetic anhydride and an amine to afford acetates of phenol derivatives. The cinnamyl acetate derivative 408 undergoes carbonylation and Friedel-Crafts-type cyclization to form the a-naphthyl acetate 410 under severe condi-tions[263,264]. The reaction proceeds at 140-170 under 50-70 atm of CO in the presence of acetic anhydride and Et N. Addition of acetic anhydride is essential for the cyclization. The key step seems to be the Friedel-Crafts-type cyclization of an acylpalladium complex as shown by 409. When MeOH is added instead of acetic anhydride, /3,7-unsaturated esters such as 388 are... 

In addition to alcohols, some other nucleophiles such as amines and carbon nucleophiles can be used to trap the acylpalladium intermediates. The o-viny-lidene-/j-lactam 30 is prepared by the carbonylation of the 4-benzylamino-2-alkynyl methyl carbonate derivative 29[16]. The reaction proceeds using TMPP, a cyclic phosphite, as a ligand. When the amino group is protected as the p-toluenesulfonamide, the reaction proceeds in the presence of potassium carbonate, and the f>-alkynyl-/J-lactam 31 is obtained by the isomerization of the allenyl (vinylidene) group to the less strained alkyne. 

The reaction of amines with the 4-phenylazo derivative (228) results in their rearrangement into triazolines. Depending on the basicity of the amines and the size of the alkoxy group, three different triazolines (229. 230, and 231) are obtained (Scheme 117) (454. 459, 472). In all cases, the first step involves nucleophilic addition of the amine to the carbonyl group followed by ring opening and further ring closure. 

The first stage of the mechanism is exactly the same as for nucleophilic addition to the carbonyl group of an aldehyde or ketone Many of the same nucleophiles that add to aldehydes and ketones—water (Section 17 6) alcohols (Section 17 8) amines (Sections 17 10-17 11)—add to the carbonyl groups of carboxylic acid derivatives... 

---