Condensation with ketones

Aminofurazans underwent condensation with ketones to form either aminals [86MI2], Schiff bases (74JA7812, 91JHC1677), or fused furazans (86JHC1519), depending on the nature of reagents and reaction conditions (Scheme 120). 

Mixed Claisen-like reactions can also be carried out between an ester and a ketone, resulting in the synthesis of a jS-diketone. The reaction works best when the ester component has no a hydrogens and thus can t act as the nucleophilic donor. For example, ethyl formate gives high yields in mixed Claisen condensations with ketones. 

This is an example of a general reaction by which haloesters are condensed with ketones by means of sodium,2 sodium ethox-ide,3 4 or sodium amide.5 6 1... 

Arylhydrazonoacetamides 155 undergo acid-catalyzed condensation with ketones to give the corresponding 4,5-dihydro-1,2,4-triazoles 156a-m in good yields (Equation 48 and Table 30) <2002T5317>. 

Aerobic Co(II) catalysed hydroperoxysiiyiation of allylic alcohols provides silyl peroxides that can be condensed with ketones to produce 1,2,4-trioxanes or 1,2,4-trioxepanes by a simple one-pot procedure (Scheme 35A). A recent improvement in the use of Co(acac)2 is the use of Co(thd)2 (thd = bis (2,2,6,6-tetramethyl-3,5-heptanedionato)). This more reactive catalyst allows cyclic allylic alcohols to be oxygenated and the resulting peroxysilyl alcohol can be transformed to spiro trioxanes, some of which have potent in vitro antimalarial activity (Scheme 35B). For example, compound 87 expresses activity around 20 nM (artemisinin = 10 nM). 

DAMN condenses with ketones to give l,7-dihydro-6H-l,4-diazepines. For example, acetone gives 141 (74JOC2341). Acetylacetone and DAMN form 5,7-dimethyl-6//-l,4-diazepine (142) (74JOC2341). An unusual bridged diazepine results from condensation of DAMN with 4,6-dimethylbicyclo[3.3.1]nona-3,6-diene-2,8-dione (Scheme 51) (82S325). 

The transformation of o-aminocarbonylthiophenes of type (291) into thieno[3,2-f>]-pyridines can be effected in several ways. 3-Amino-2-benzoylthiophenes (291) are condensed with ketones (equation 25 cf. equation 20) in the presence of perchloric acid. 

These in situ oxidations, followed by condensation with a phosphorous reagent, are normally not possible on ketones, because of their lack of reactivity with stabilized phosphoranes and phosphonate anions. Nevertheless, one-pot condensation with ketones can occur in very favourable... 

A further application of zinc is seen in a reaction first carried out by Refonuatsky in 1887, in which halogen substituted esters are condensed with ketones or with ketonic esters. An example is afforded by the production of /3-liydroxy-isovaleric ester from acetone and iodo-acetic ester a zinc addition compound is probably formed, and on the addition of dilnte acids is decomposed. This reaction is therefore represented in the following manuer ... 

A range of imines and enamines, formed from tir/Zw-haloaminopyridines and ketones, may be converted to a variety of substituted 4-, 5-, 6-, and 7-azaindoles by microwave-assisted intramolecular Heck reaction <2005S2571>. As an example, 4-amino-3-iodopyridine is converted to azaindole 85 in 46% yield by condensation with ketone 86 followed by Heck reaction of the resulting enamine (Equation 59). 

Condensation with Carbonyl Groups The hydrogen atom at the 4-position is sufficiently activated for 5-hydroxypyrazoles (pyrazolin-5-ones) to undergo condensation with ketones in acid media to yield 4-alkylidenepyrazolin-5-ones (61) in alkali, dipyrazolinonylmethane (62) derivatives are formed.644,645... 

The reduction of alkyl tellurium trihalides is a convenient method for the preparation of the corresponding dialkyl ditellurium when the trihalides can be obtained by reactions other than the halogenolysis of the dialkyl ditellurium. Addition of tellurium tetrachloride to olefins and condensation with ketones produces alkyl tellurium trichlorides. Sodium sulfide nonahydrate4 and sodium or potassium disulfite5 8 were used as reducing agents. 

Diethyl oxalate also gives well-controlled condensations with ketones and we shall take the syn-j thesis of a new drug as an example. One way to try and prevent heart disease is to reduce the amount of bad lipoproteins in the blood, The drug Acifran does this, and a key step in its synthesis is the base-catalysed reaction between diethyl oxalate and a methyl ketone. 

The other two unenolizable esters we mentioned on p. 728 undergo cross-condensations with ketones. Unlike formaldehyde, formate esters are well behaved—no special method is necessary to correspond with the Mannich reaction in aldol chemistry, Here is what happens with cyclohexanone. 

Although enamines readily undergo intramolecular condensation with ketones (Section VI.D) the only intermolecular reaction we are aware of is that with diethyl ketomalonate156. Whereas cyclic ketone enamines gave the aldol product, with enamines of acyclic ketones only the morpholine enamine of pentan-3-one gave the aldol product (73). The more reactive pyrrolidine enamine cyclysed onto the ester group to give the... 

The reaction of aliphatic, alicyclic, and aromatic aldehydes and ketones with cyanoacetic ester, NCCHjCOjCjH, is general. The products are 0L,/3-olefinic cyanoacetates. The aldehydes are condensed with the ester in the presence of amines or with sodium cyanoacetate in the presence of sodium hydroxide, Similarly, cyanoacetic ester is condensed with ketones by catalysts such as acetamide or the acetates... 

CgH, CH CHCOCjHj (85%). Many substituted chalcones have been prepared with substituents on one or both of the phenyl groups. Furfural, 5-methylfurfural, and 2 thiophenealdehyde condense with ketones in good yields. Examples are furfuralacetone (66%), furfural-acetophenone (S)0%), and furfuralacetofuran (89%) from acetone, acetophenone, and acetylfuran, respectively. 

Ethyl cyanoacetate condenses with ketones and ammonia in absolute ethanol at 0-5° to give 44-73% yields of cyclic dicyanoimides. Endocyclic ketones may be used, giving imides in which the two radicals are p>art of an alicyclic ring. The imides are hydrolyzed and decarboxylated in almost theoretical yields to yS,/S-disubstituted glutaric acids. A similar reaction takes place between aldehydes or ketones and cyanoacetamide, NCCHjCONHj, in the presence of piperidine or potassium hydroxide. When aldehydes are used, the condensation products are dicyanoamides, RCH[CH(CN)CONHj]j, rather than cyclic imides. 

The isolation of the initial aldol products from the condensation of the enolates of carbene complexes and carbonyl compounds is possible if the carbonyl compound is pretreated with a Lewis acid. As indicated in equation (9), the scope of the aldol reaction can also be extended to ketones and enolizable aldehydes by this procedure. The condensations with ketones were most successful when boron trifluoride etherate was employed, and for aldehydes, the Lewis acid of choice is titanium tetrachloride. The carbonyl compound is pretreated with a stoichiometric amount of the Lewis acid and to this is added a solution of the anion generated from the caibene complex. An excess of the carbonyl-Lewis acid complex (2-10 equiv.) is employed however, above 2 equiv. only small improvements in the overall yield are realized. 

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