Carbonyl functions, condensations

The only acid-resistant protective group for carbonyl functions is the dicyanomethy-lene group formed by Knoevenagel condensation with malononitrile. Friedel-Crafts acylation conditions, treatment with hot mineral acids, and chlorination with sulfuryl chloride do not affect this group. They have, however, to be cleaved by rather drastic treatment with concentrated alkaline solutions (J.B. Basttis, 1963 H. Fischer, 1932 R.B. Woodward, 1960, 1961). 

Condensation of the carbonyl function with an amine from a second 1,2-diaminoethane molecule coupled with a repeat of the initial reaction sequence will lead to the cyclic product. It is of interest that this is one case in which the synthesis will also proceed in the absence of a metal ion. Starting from a mono-protonated salt of 1,2-diaminoethane in acetone, the metal-free condensation may proceed via a reaction such as [2.7], Once again, a hydrogen-bonding network may act as a template for the reaction and also serve to stabilize the product once it is formed. A revised synthesis of the metal-free ligand (61) has been published (Hay,... 

Urea acts not only as an ammonia source but also forms decomposition products, such as biuret and higher condensation products. 14C labeling has indicated that the carbon atom of the urea molecule is not incorporated into the phthalocyanine structure. Employing a phthalic anhydride molecule bearing one radioac-tively labeled carbonyl function affords labeled copper phthalocyanine and phthalimide (as a side product), while the liberated carbon dioxide was found not to show any radioactivity. Labeled carbon dioxide, on the other hand, has been obtained in corresponding experiments using 14C labeled urea. 

In studies not yet published (66), the A/-acyl-oxazolidine-2-one 62 has been found to exhibit exceptionally high levels of (Z)-enolization stereoselection with either amide bases (LDA, THF, -78°C) or boryl triflates [(n-C4H9)2BOTf, CH2CI2, -78°C] in the presence of diiso-propylethylamine (DPEA). Upon aldol condensation, the enolates 63a and 63b afford the aldolates 64 (Scheme 11), which react readily with nucleophiles at the carbonyl function (Table 22). As discussed earlier, the large preference for (Z)-enolate formation in this system can be attributed to allylic strain considerations (37)... 

With the aid of a Knoevenagel condensation and a Staudinger reaction, 2-azidocyclopent-l-ene 1-carbaldehydes (195) can be converted into suitable products for a cyclopenta[b]pyridine synthesis [89JCS(P1)1369], as shown in Scheme 72. In order to bring the ester carbonyl function and the imino-phosphorane group into close proximity suitable for cyclization reactions, the 1,3-diene system 196 should possess the s-cis conformation. Furthermore, the exocyclic double bond should show a cis conformation. To achieve... 

Treatment of the /3-keto ester 220 with sodium ethoxide at elevated temperature triggered off an epoxide ring opening by / -elimination that was followed by the desired Knoevenagel condensation to afford the tricyclic product 206 (Scheme 34). The enone moiety in the intermediate 221 did not show a propensity for deprotonation and, therefore, the ketone carbonyl function of the enone moiety was available for a Knoevenagel condensation. The reduction of the p-keto ester (206) to the corresponding diol was the next objective. Treatment of the TES-protected -keto ester (TES-206) with DIBAH afforded the diastereomeric diols 222 and 223 in a moderate diastereoselec-tivity in favour of the undesired diastereomer 222. The diastereomers were separated and the undesired diastereomer 222 was epimerized to 223 by a sequence that consists of Mitsunobu inversion and benzoate ester reduction [98, 99]. 

C=N bond formation has also been achieved starting from two additional carbonyl functions properly installed in an Ugi component. Cyclization has been accomplished in this case through a Paal-Knorr reaction of the dicarbonyl compound generated by the Ugi condensation, leading to pyrazinones [107]. 

A palladium-catalyzed amidation of halo(hetero)aromatics substituted in the ortAo-position by a carbonyl function with a primary or secondary amine has been introduced as an alternative to the Friedlander condensation for the synthesis of naphthyridinones (and quinolinones) (Scheme 32) <2004OL2433>. 

Replacement of the urethane carbonyl function by an aromatic ring leads to a benzo-thiazole that is described as an immune function modulator. In an analogous approach to that used above, anilinothiol (63-1) is condensed with the thiocarbamoyl chloride (63-2) again in the presence of a base. This leads directly to frentizole (63-3) [66]. 

Fused pyrroles have been prepared by the condensation of an amino group with a suitably positioned carbonyl function. Thus, reduction of ethyl (3-nitro-2-thienyl)pyruvate (226) with tin(IV) chloride gave 5-ethoxycarbonyl thieno[3,2-6]pyrrole (47), by the spontaneous cyclization of the intermediate amino derivative (227 Scheme 76) (64JOC2160). The formation of indolo[3,2-6]indole (229), a dibenzannelated pyrrolopyrrole, by the cyclization of (228) with tin(IV) chloride (Scheme 77) is an example of a case where reduction of the imino function in the starting material is necessary before cyclization will occur (78AHC(22)183). 

Whereas the ideas of Kwart and Kirk are primarily founded on the theory of steric effects, or nan-bonded interactions, Zimmerman and co-workers1 1. 1M have recently made the suggestion that product ciimpoBitiou in Darzens condensations may be under sterooelectronic control. If this theory, amply supported by experiments in other systems, is correct, the concepts of Kwart and Kirk would need only -light adjustment to accommodate the overlap requirement of the carbonyl function in As>) and rac. 

Glycidaldehyde condenses with three molar equivalents of methanol in the presence of a trace of acid (Eq 571), giving 1,1,3-trim ethoxy 2-propanol.1847 Attack thus appears to be favored at the epoxide terminal carbon atom furthest from the carbonyl function (or from the acetal function if acetal formation is the primary step in this reaction). 

The free carbonyl function of this ligand may undergo further condensation reactions. With amines RNH2, products [PdLL l are obtained where both L and L may be N,N -bonded chelates (42 R = Me, Et, Pr, Bu)264,265 or L may be bonded through N(imine) and 0(oxime) (43 R = H).266 Similar linkage isomerism is seen for other oximato ligands of this type.267... 

As secondary amines proceed from hydrogenation of secondary imines, the behaviour of these compounds is of importance in the reaction mixture. Secondary imines can result from the condensation of primary amino group with primary imines comparables in reactivity with a carbonyl function. 

The Knoevenagel reaction is a base-catalyzed condensation between a dialdehyde and an arene possessing two sites with relatively acidic protons. In this polymerization, shown schematically in Scheme 34, deprotonation affords a difunctional nucleophile that subsequently attacks the carbonyl functionalities present in the other monomers. Elimination is the final step in the Knoevenagel sequence, and the use of monomers with highly acidic protons drives the reaction to completion. A number of research groups have employed this method to obtain PPV and its substituted analogs 29 [126,140-146]. 

The resistance to cleavage is an indication of the superelectrophilic character of dication 150c. Several aromatic compounds have likewise been shown to produce dicationic species upon the protonation of carboxyl and carbonyl functional groups. Other bis-carboxonium dications have been described involving protonation of carbonyl, amide, and other groups.50 These distonic superelectrophiles (152-153) have been shown to be useful in condensation reactions (eqs 52-53). 

Returning to the condensation presented above, this leads to an important disconnection. The imine-like linkage present in several heterocycles (generalised structure 1.16) can arise from cyclisation of 1.17, containing amino and carbonyl functionalities. 

Difluoroboron complexes are used to protect enolisable carbonyl functions against electrophilic bromination, thus allowing regiospecific radical bromination of other (e.g. benzylic) sites. This is demonstrated in the benzylic bromination of condensed tetralones948. 

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