Heterocyclic alcohols

Ugi I, Horl W, Hanusch-Kompa C, Schmid T, Herdtweck E (1998) MCR 6 chiral 2, 6-piperazinediones via Ugi reactions with alpha-amino acids, carbonyl compounds, isocyanides and alcohols. Heterocycles 47(2) 965-975... 

Ester linkages to hydroxymethyl-PS (5a) have also been cleaved by transesterification [167] in the presence of trimethylsilyl chloride (TMSCl) or by reduction [168] to give alcohols. Heterocycles have been synthesized using support 5a with a cyclization step in toluene serving to cleave the product from the resin, leaving acyclic impurities bound to the support [169]. Esters derived from hydroxyethyl-PS 5h do not afford benzylic cations when treated with acid and are thus not cleaved as easily. Nonetheless, resin 5b has been applied to syntheses in which the final cleavage of the ester anchor is effected by an intermolecular reaction with an amine in the presence of... 

Soai K, Hori H, Niwa S (1989) Enantioselective addition of dialkylzincs to pyridinecar-baldehyde in the presence of chiral aminoalcohols asymmetric synthesis of pyridylalkyl alcohols. Heterocycles 29 2065-2067... 

Potassium hydroxide/alcohol Heterocyclics from a-amino-), y-ethylenenitriles Benzimidazoles and benzoxazoles... 

Carboie lic acids have also been utilised as electrophiles for N-alkylation. Beller reported the reaction of primary or secondary amines with carboxylic acids in the presence of a platinum catalyst and phenylsilane to directly provide the products of reductive amination. The proposed mechanism involves initial amide formation followed by reduction to the amine. A diverse range of functional groups are tolerated, including olefins, alcohols, heterocycles, and esters (Scheme 12.15). 

Maki, Y., Makino, X, Hirota, K., and Sako, M., Distinct solvent-dependence in the photoreactions of purine nucleosides with pyrimido[5,4-g]pteridinetetraone N-oxide. Possible generation of hydroxyl radical from the excited N-oxide in alcohols. Heterocycles, 35, 325,1993. 

A white solid, m.p. 178 C. Primarily of interest as a brominaling agent which will replace activated hydrogen atoms in benzylic or allylic positions, and also those on a carbon atom a to a carbonyl group. Activating influences can produce nuclear substitution in a benzene ring and certain heterocyclic compounds also used in the oxidation of secondary alcohols to ketones. 

Typical nucleophiles known to react with coordinated alkenes are water, alcohols, carboxylic acids, ammonia, amines, enamines, and active methylene compounds 11.12]. The intramolecular version is particularly useful for syntheses of various heterocyclic compounds[l 3,14]. CO and aromatics also react with alkenes. The oxidation reactions of alkenes can be classified further based on these attacking species. Under certain conditions, especially in the presence of bases, the rr-alkene complex 4 is converted into the 7r-allylic complex 5. Various stoichiometric reactions of alkenes via 7r-allylic complex 5 are treated in Section 4. 

Thiazoles with Heterocyouc Substituents. Thiazoles with heterocyclic substituents in the 2- or 4-position have been synthesized (Table II-9). Thus thioacetamide (or its a-substituted derivatives) react with bromomethyl heteroarylketones under reflux in alcohol to give the corresponding 2-methyl-4-heteroarylthiazoles heteroaryl groups in the 4-position were 2 -thienyl (213, 692) a-pyrrolyl and 3-method derivatives... 

It melts at 39°C and may be purified by vacuum sublimation. The Hquid boils at 233°C to give a monomeric vapor in which the Ti—Br distance is 231 pm. Titanium tetrabromide is soluble in dry chloroform, carbon tetrachloride, ether, and alcohol. Like titanium tetrachloride, TiBr forms a range of adducts with molecules such as ammonia, amines, nitrogen heterocycles, esters, and ethers. 

Vinyl chloride reacts with sulfides, thiols, alcohols, and oximes in basic media. Reaction with hydrated sodium sulfide [1313-82-2] in a mixture of dimethyl sulfoxide [67-68-5] (DMSO) and potassium hydroxide [1310-58-3], KOH, yields divinyl sulfide [627-51-0] and sulfur-containing heterocycles (27). Various vinyl sulfides can be obtained by reacting vinyl chloride with thiols in the presence of base (28). Vinyl ethers are produced in similar fashion, from the reaction of vinyl chloride with alcohols in the presence of a strong base (29,30). A variety of pyrroles and indoles have also been prepared by reacting vinyl chloride with different ketoximes or oximes in a mixture of DMSO and KOH (31). 

Heterocyclic Alcohols. Thek reactions with chloroformates lead to carbonates. Thus furan- and tetrahydrofuran-derived alcohols give the corresponding carbonates in 75% yield (15). Inorganic bases and tertiary amines as acid acceptors increase the rate and yield in this reaction. 

This interesting conversion of a five- into a six-membered heterocyclic ring was proven by the isolation of the enzyme GTP-cyclohydrolase from E. coli (71MI21600) and a similar one from Lactobacillus platarum (B-71MI21601) which catalyzes the reaction (300)(303). Dephosphorylation leads to 7,8-dihydro-D-neopterin (304), which is then cleaved in the side-chain to 6-hydroxymethyl-7,8-dihydropterin (305), the direct precursor of 7,8-dihy-dropteroic acid and 7,8-dihydrofolic acid (224). The alcohol (305) requires ATP and Mg " for the condensation with p-aminobenzoic and p-aminobenzoylglutamic acid, indicating pyrophosphate formation to (306) prior to the substitution step. 

Most ring syntheses of this type are of modern origin. The cobalt or rhodium carbonyl catalyzed hydrocarboxylation of unsaturated alcohols, amines or amides provides access to tetrahydrofuranones, pyrrolidones or succinimides, although appreciable amounts of the corresponding six-membered heterocycle may also be formed (Scheme 55a) (73JOM(47)28l). Hydrocarboxylation of 4-pentyn-2-ol with nickel carbonyl yields 3-methylenetetrahy-drofuranone (Scheme 55b). Carbonylation of Schiff bases yields 2-arylphthalimidines (Scheme 55c). The hydroformylation of o-nitrostyrene, subsequent reduction of the nitro group and cyclization leads to the formation of skatole (Scheme 55d) (81CC82). 

The direct combination of selenium and acetylene provides the most convenient source of selenophene (76JHC1319). Lesser amounts of many other compounds are formed concurrently and include 2- and 3-alkylselenophenes, benzo[6]selenophene and isomeric selenoloselenophenes (76CS(10)159). The commercial availability of thiophene makes comparable reactions of little interest for the obtention of the parent heterocycle in the laboratory. However, the reaction of substituted acetylenes with morpholinyl disulfide is of some synthetic value. The process, which appears to entail the initial formation of thionitroxyl radicals, converts phenylacetylene into a 3 1 mixture of 2,4- and 2,5-diphenylthiophene, methyl propiolate into dimethyl thiophene-2,5-dicarboxylate, and ethyl phenylpropiolate into diethyl 3,4-diphenylthiophene-2,5-dicarboxylate (Scheme 83a) (77TL3413). Dimethyl thiophene-2,4-dicarboxylate is obtained from methyl propiolate by treatment with dimethyl sulfoxide and thionyl chloride (Scheme 83b) (66CB1558). The rhodium carbonyl catalyzed carbonylation of alkynes in alcohols provides 5-alkoxy-2(5//)-furanones (Scheme 83c) (81CL993). The inclusion of ethylene provides 5-ethyl-2(5//)-furanones instead (82NKK242). The nickel acetate catalyzed addition of r-butyl isocyanide to alkynes provides access to 2-aminopyrroles (Scheme 83d) (70S593). 

Other solvents can be divided into several classes. In hydrogen bond-breaking solvents (dipolar aprotics), the simple amino, hydroxy and mercapto heterocycles all dissolve. In the hydrophobic solvents, hydrogen bonding substituents greatly decrease the solubility. Ethanol and other alcohols take up a position intermediate between water and the hydro-phobic solvents (63PMH 1)177). 

The most versatile derivative from which the free base can be readily recovered is the picrate. This is very satisfactory for primary and secondary aliphatic amines and aromatic amines and is particularly so for heterocyclic bases. The amine, dissolv in water or alcohol, is treated with excess of a saturated solution of picric acid in water or alcohol, respectively, until separation of the picrate is complete. If separation does not occur, the solution is stirred vigorously and warmed for a few minutes, or diluted with a solvent in which the picrate is insoluble. Thus, a solution of the amine and picric acid in ethanol can be treated with petroleum ether to precipitate the picrate. Alternatively, the amine can be dissolved in alcohol and aqueous picric acid added. The picrate is filtered off, washed with water or ethanol and recrystallised from boiling water, ethanol, methanol, aqueous ethanol, methanol or chloroform. The solubility of picric acid in water and ethanol is 1.4 and 6.23 % respectively at 20°. 

This synthesis came shortly after one by Prelog, Kohlberg, Cerkovnikov, Rezek and Piantanida (1937) based on a series of reactions which, with modifications and extensions. Prelog and his colleagues have applied to the syntheses of bridged heterocyclic nuclei, of which this is an example. 4-Hydroxymethyltetrahydropyran (VI R =. OH) is converted via the bromo-compound (VI R = Br) and the nitrile (VI R = CN) into tetrahydropyran-4-acetic acid of which the ethyl ester (VII) is reduced to 4-()3-hydroxyethyl)-tetrahydropyTan (VIII). This is converted by fuming hydrobromic acid into 3-(2-bromoethyl)-l 5-dibromopentane (IX) which with ammonia in methyl alcohol yields quinuclidine (V). 

A one-pot conversion of benzyl alcohols to benzyl fluorides by treatment of the alcohols with a combination of methanesulfonyl fluoride, cesium fluoride and 18-crown 6 ether in tetrahydrofuran has been repotted The reaction involves mesylation of the alcohols followed by cleavage of the resultant mesyl esters with a fluoride ion The reaction has been extended also to certain heterocycles bearing the N hydroxymethyl group [43] (equation 31)... 

In the case of the bases derived from quaternary heterocyclic ammonium salts, the carbinolamines (5) can react as cyclic aldehyde-ammonias with many reagents with which the amino-aldehyde (7) could react. However, reactions of the carbinolamines which are not characteristic of amino-aldehydes are also known. Carbinolamines can easily be reconverted into the quaternary salts by the action of dilute acids, and they form alkyl ethers very easily with alcohols. If these last reactions do not occur, then this is convincing evidence for the base possessing the amino-aldehyde structure. However, if these reactions do occur this does not provide unambiguous confirmation of the carbinolamine structure. They are also given by the bi-molecular ethers (8), and, in the case of a tautomeric equilibrium... 

A few studies on solvolyses by alcohols and by water are available. The hydrolyses studied include displacement of alkylamino groups from acridine antimalarials and of halogen from other systems. In all cases, these reactions appeared to be first-order in the heterocyclic substrate. By a detailed examination of the acid hydrolysis of 2-halogeno-5-nitropyridine, Reinheimer et al. have shown that the reaction rate varies as the fourth power of the activity of water, providing direct evidence that the only reactive nucleophile is neutral water, as expected. 

Heterocyclic compounds that have water bound covalently across a C=N bond behave as secondary alcohols. When subjected to very gentle oxidative conditions, they are converted into the corresponding 0x0 compounds. Potassium permanganate in 0. IN sodium hydroxide at room temperature has been used to oxidize 2- and 6-hydroxypteri-dine to 2,4- and 6,7-dihydroxypteridine, respectively. In contrast, 4-hydroxypteridine was not attacked by this reagent even at 100°. Hydrogen peroxide in acid solution was used to oxidize quinazoline quinazoline 3-oxide 1,3,5-, 1,3,7-, and 1,3,8-triazanaphthalene and pteridine (which hydrate across the 3,4-double bond in the... 

The activating effect of a trichloromethyl group is seen in the 2-dechlorination reactions of 2-chloro-4,6-bis(trichloromethyl)-s-tria-zine (175) with arylsulfonylhydrazides (24 hr) and heterocyclic amines (3 hr) at 20° and with unbasifled primary and secondary alcohols (65°, 30 min). The 4,6-diphenyl or 4,6-bis(4-chlorophenyl) analogs do not react in this manner. ... 

Reactions of aliphatic nitro alcohols with heterocycles 98UK39. 

Palladium(II)-catalyzed cyclization of N-alkylation of allyl alcohols by ure-tanes and its application to the synthesis of natural saturated heterocycles 98YGK34. 

Synthetic versatility of 2-oxazolone heterocycle for stereocontrolled construction of 2-amino alcohols 97YGK1018. 

JA742). However, the heterocyclization of 4-phenylethynylpyrazole-3- and 4-phenylethynylpyrazole-5-carboxylic acid in alcohol or acetonitrile solutions in the presence of AgNOs caused, once again, the closure of the six-membered lactones. 

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