Heterocyclic ketones preparation

The ketoxime derivatives, required as starting materials, can be prepared from the appropriate aromatic, aliphatic or heterocyclic ketone. Aldoximes (where R is H) do not undergo the rearrangement reaction, but rather an elimination of toluenesulfonic acid to yield a nitrile. With ketoxime tosylates a Beckmann rearrangement may be observed as a side-reaction. 

The first example describes the synthesis of a pyrimidine derivative. Starting from a, 3-unsaturated ketones (see Schemes 1, 8), a library of different heterocycles was prepared in research (Felder and Marzinzik 1998). In preparation for any large-scale synthesis, the availability of starting materials is always considered (Lee and Robinson 1995). For this work, we had to replace Rink amide resin B (Rink 1987), which was used by our colleagues in research for the synthesis of pyrimidine 1 due to its unavailability in large quantities (see Fig. 1). It was replaced with the Rink amide acetamido resin 4, which is well established in peptide amide synthesis (Bernatowicz et al. 1989) and easily accessible. 

A series of conformationally restricted analogues of nicotine and anabasine have been prepared as part of a program studying models of Parkinson s disease and pain (Scheme 8). Transformations of the heterocyclic ketone were key to the program, including cyclization to a third heterocyclic ring <1998BML2173>. 

Uses. Although cyanoacetic acid can be used in applications requiring strong oiganic acids, its principal use is in the preparation of malonic esters and other reagents used in the manufacture of pharmaceuticals, eg, barbital, caffeine, and B vitamins (see Alkaloids Hypnotics Vitamins). Cyanoacetic acid can be used for the preparation of heterocyclic ketones. 

Bicyclic keto esters can easily be prepared by a process called a,a -annulation.29 Thus, treatment of the enamine of cyclopentanone (64) with ethyl a-(bromomethyl)acrylate (98) affords, after work-up, the bicyclic keto ester (99) in 80% yield (equation IS).2911 The mechanism probably involves an initial Michael addition and elimination (or a simple Sn2 or Sn2 alkylation) followed by an intramolecular Michael addition of the less-substituted enamine on the acrylate unit. The use of the enamine of 4,4-bis(ethoxycarbonyl)cyclohexanone (100 equation 26) with (98) gives a 45% yield of the adaman-tanedione diester (101) (yield based on 100 70% when based on 98) via a,a -annulation followed by Dieckmann condensation.29 Enamines of heterocyclic ketones can also serve as the initial nucleophiles, e.g. (102) and (103) give (105) via (104), formed in situ, in 70% yield (Scheme 11 ).29>... 

Enamines 10 (RjR R2 = H,Me X = 0,S,NMe X1 = morpholino, pyrrolidino, piper-idino) were prepared by reaction of the appropriate heterocyclic ketones with the heterocyclic base144. 

Both exo- and endo-cyclic alicyclic and heterocyclic ketones have been reduced. Important examples are found in the preparations of cyclo-pentanol (95%), cycloheptanol (92%), /S-pyridylmethylcarbinol (85%), and l-alkyl-4-piperidinols (90%). A comparison of four reagents—sodium and alcohol, lithium aluminum hydride, hydrogen and Raney nickel, and hydrogen and copper-chromium oxide—has been made in the preparation of methyl cyclopropylcarbinol. The last method is superior for the preparation of this compound (SH)%). ... 

The action of hydrogen bromide or hydrogen chloride on diazo ketones represents a general preparative method (50-90%) for pure halomethyl alkyl, halomethyl aryl, or halomethyl heterocyclic ketones. N ... 

The over-all yields (R equals w-C,-Q, -C , and -C ) from the esters vary from 55% to 78%. Certain heterocyclic ketones, namely, 8-acetyl-quinoline and /3-acetylpyridine, have been prepared through a mixed ester condensation. (3) If acetoacetic ester is acylated in the form of its sodium enolate and carefully hydrolyzed, a new /3-keto ester is formed. Alkylation of this keto ester followed by hydrolysis gives ketones of the type RCOCH,R. ... 

Morioka, M., Kato, M., Yoshida, H., Ogata, T. Anomalous Bamford-Stevens reaction of cis-N-alkyl-3-phenyl-2-aziridinyl phenyl ketones. Preparation of 1,6-dihydro-1,2,3-triazine derivatives. Heterocycles 1996, 43, 1759-1765. 

A series of titanium chelate complexes with biologically active monofunctional bidentate semicarbazones having 0,N donors have been prepared by reacting Cp2TiCl2 with the appropriate ligand in 1 1 and 1 2 stoichiometries. The ligands were prepared by condensing heterocyclic ketones and semicarbazide hydrochlorides in presence of NaOAc.1583... 

Mo(Tp)(NO)(L)(r]2-L/)] (L = Meim or NH3, and V = alkene, alkyne, ketone, polyaromatic hydrocarbon, or aromatic heterocycle) were prepared and their properties discussed.53... 

The five-membered heterocyclic ketone (39) has been prepared by the reaction of dimeric 5,5-dimethyl-l,3A, 2,4,5-dithiadiazastannole (40), obtained by the reaction of S4N4 with tris(trimethylstannyl)amine, with an excess of carbonyl difluoride at room temperature. The cyclic, ketone is the first representative of a new class of compounds that have become readily accessible by this method. 

Table 4.23 Preparation of fluorenone and related cyclic and heterocycles ketones via cycloacylation of the corresponding aryl carboxylic acids promoted by Nation...

An efficient method prepares a variety of polycondensed 1, 8-naphth)U idines from pyridines 378,379, and 380 and cyclic and heterocyclic ketones (Figure 18) (84ACP268,91AJC481,95H(41)1001,96H(43)53, 03EJM265,08T3446). 

Preparation of fluorenone and related cyclic and heterocyclic ketones 25 from the corresponding compounds 24 or the appropriate benzoic acid derivatives can be obtained under relatively mild conditions [98, 99]. The reaction is carried out by heating a mixture of the carboxylic acid derivatives 24 and the solid Nafion in 1,2-dichlorobenzene at about 180°C, affording products 25 in 82-95% yields (Scheme 3.15). 

The same transformation, although limited to aldehydes as the carbonyl partner, can be achieved using guanidine hydrochloride in water. a-Amino-cyclobutyl-, -cyclopentyl-, -cyclohexyl- and -4 (and -3)-heterocyclohexyl-phosphonates can be efficiently prepared from carbocyclic and heterocyclic ketones by nucleophilic... 

Mataka S, Hosoki A, Takahashi K, Tashiro M (1980) Sulfur nitride in organic chemistry. 9. The reaction of tetrasulfur tetranitride with benzyl ketones. Preparation of 3,4-disubstituted-1,2,5-thiadiazoles. J Heterocycl Chem 17 1681-1685... 

As an alternative to baker s yeast, the use of plant tissues (e.g., from apple, carrot, cucumber, onion, or potato) has been suggested [112,113]. It remains unclear, however, whether endophytic microorganisms are involved in these reductions [114]. Heterocyclic ketones [111, 115-117] as well as many a-hydroxy ketones [96,118-121] have been the subject of yeast-mediated reductions. For the latter compounds very high ee values have been obtained, albeit the yields were moderate. Monobenylated (S)-l,n-diols have been prepared using highly diluted yeast suspensions, and ee values up to 95% could be achieved [122]. Yeast-mediated reductions of acyclic ketones were key steps in the total synthesis of the pheromone sulcatol [123], brefeldin A [124], and endo-brevicomin [125]. 

As a class of compounds, nitriles have broad commercial utility that includes their use as solvents, feedstocks, pharmaceuticals, catalysts, and pesticides. The versatile reactivity of organonitnles arises both from the reactivity of the C=N bond, and from the abiHty of the cyano substituent to activate adjacent bonds, especially C—H bonds. Nitriles can be used to prepare amines, amides, amidines, carboxyHc acids and esters, aldehydes, ketones, large-ring cycHc ketones, imines, heterocycles, orthoesters, and other compounds. Some of the more common transformations involve hydrolysis or alcoholysis to produce amides, acids and esters, and hydrogenation to produce amines, which are intermediates for the production of polyurethanes and polyamides. An extensive review on hydrogenation of nitriles has been recendy pubHshed (10). 

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