Alcohols 1,1-disubstituted

As expected, the formation of a carbonyl group is not possible with tert-allylic alcohols. Although the aromatic ring bears electron-donating groups, the 2,2-disubstituted chromene 119 was formed smoothly with the tert-allylic alcohol 118[100]. 

The formation of disubstituted alkynes by coupling of terminal alkynes, followed by intramolecular attack of an alcohol or amine, is used for the preparation of benzofurans and indoles. The benzo[il)]furan 356 can be prepared easily by the reaction of o-iodophenol with a terminal alkyne[262]. The 2-substituted indole 358 is prepared by the coupling of 2-ethynylaniline (357) with aryl and alkenyl halides or triflates, followed by Pd(ll)-catalyzed cycliza-tion[263]. 

Pyrrole derivatives are prepared by the coupling and annulation of o-iodoa-nilines with internal alkynes[291]. The 4-amino-5-iodopyrimidine 428 reacts with the TMS-substituted propargyl alcohol 429 to form the heterocondensed pyrrole 430, and the TMS is removed[292]. Similarly, the tryptophane 434 is obtained by the reaction of o-iodoaniline (431) with the internal alkyne 432 and deprotection of the coupled product 433(293]. As an alternative method, the 2,3-disubstituted indole 436 is obtained directly by the coupling of the o-alky-nyltrifluoroacetanilide 435 with aryl and alkenyl halides or triflates(294]. 

Table 11.1 lists some of the reaction conditions which have given prepara-tively useful yields of 3-alkylation. Entries 1-3 are typical alkylations using a magnesium salt and an alkyl halide. Even 2,3-disubstituted indoles are alkylated at C3 under these conditions (Entry 7). Entry 5 represents a more recently developed method in which an allylic alcohol and indole react in the... 

Alkyl-2-arylthiazoles and 4,5-disubstituted-2-(p-aminophenyl thiazoles were simflarly prepared from arylamides and a-halomethyl-ketones in alcoholic (239, 392, 641, 792) or acetonic solution (638, 651). 

In the reverse reaction, thioheteroaryl amides reacted under reflux in alcohol with haloketones or aldehydes to give the corresponding 2-heteroarylthiazole derivatives (238, 271, 482, 550, 751, 765, 776, 781). 2,2 -Bithiazoles (4,4 -disubstituted) have been obtained in 80 to 90% yield by cyclocondensation of 1 mole rubeanic acid with 2 moles of a-bromoketones in polyphosphoric acid at 95 to 135 C (780). Some multiheteroaryl substituted thiazoles have been also reported (704). 

Amyl alcohol describes any saturated aliphatic alcohol containing five carbon atoms. This class consists of three pentanols, four substituted butanols, and a disubstituted propanol, ie, eight stmctural isomers four primary, three secondary, and one tertiary alcohol. In addition, 2-pentanol,... 

Pyridine undergoes 2- and 4-alkylation with Grignard reagents, depending on whether free metal is present (19). Free metal gives mixtures or exclusive 4-alkylation. Substituent-directed metaHation (eq. 5) has become an important approach to the synthesis of disubstituted pyridines (12). For example, 2- uoro-pyridine [372-48-5] reacts with butyUithium and acetaldehyde to give a 93% yield of alcohol [79527-61-1]. 

The 5,6-amide function has been found to be unusually reactive in the 2,4-disubstituted pteridin-6-one series, forming the corresponding 6-alkoxy derivatives, e.g. (141), with alcoholic HCl directly (62CB755, 70CB735). 

Irradiation of 3,5-disubstituted isoxazoles in alcoholic solvents gave reaction products such as acetals incorporating the reaction solvent. The use of triethylamine in acetonitrile media produced ketene-aminals by reductive ring cleavage. The reductive ring cleavage product was also obtained by irradiation of the isoxazole in alcohol in the presence of copper(II) salts (Scheme 3) (76JCS(P1)783). 

Disubstituted and trisubstituted 3-isonitrosopyrroles rearrange to 3-acylisoxazoles under the influence of hot, dilute mineral acids. For example, isonitrosotriphenylpyrrole (436), when treated with boiling alcoholic mineral acid, is converted into 3-benzoyl-4,5-diphenyl-isoxazole (437) (62HC(17)1, p. 34). 

The reaction can be performed under a variety of conditions. Origin-aiiyi2o,i26,234 acetylene and potassium in liquid ammonia were used. Subsequently, this was simplified by the use of potassium r-amylate in r-amyl alcohol and later this system was found to react selectively at C-17 in the presence of an A-ring a,j5-unsaturated ketone. A closer investigation of these reaction conditions revealed the formation of a small amount (2-3 %) of the disubstituted acetylene this can be avoided by reacting the 17-keto steroid with acetylenedimagnesium bromide in ether-tetrahydrofuran (see chapter 10.)... 

As with i -substituted allyl alcohols, 2,i -substituted allyl alcohols are epoxidized in excellent enantioselectivity. Examples of AE reactions of this class of substrate are shown below. Epoxide 23 was utilized to prepare chiral allene oxides, which were ring opened with TBAF to provide chiral a-fluoroketones. Epoxide 24 was used to prepare 5,8-disubstituted indolizidines and epoxide 25 was utilized in the formal synthesis of macrosphelide A. Epoxide 26 represents an AE reaction on the very electron deficient 2-cyanoallylic alcohols and epoxide 27 was an intermediate in the total synthesis of (+)-varantmycin. 

Dichloro-s-triazine and its 6-alkyl analogs are as easily hydrolyzed by water as trichloro-s-triazine and, on suspension in aqueous ammonia (25°, 16 hr), the first is diaminated in good yield. 2,4-Bistrichloromethyl-6-methyl- and -6-phenyl-s-triazines (321) require a special procedure for mono-alkoxylation (0-20°, 16 hr, alcoholic triethylamine) disubstitution occurs at reflux temperature (8 hr). Aqueous triethylamine (100°, 3 hr) causes complete hydroxy-lation of 2,4,6-tris-trichloromethyl-s-triazine which can be mono-substituted with ammonia, methylamine, or phenoxide ion at 20°. 

In 2,4-disubstituted quinazolines, the 4-position reacts fastest with nucleophiles, generally even when the 4-substituent is a poorer leaving group. 2,4-Dichloroquinazoline undergoes mono-substitution at the 4-position with alcoholic alkoxides (25°, 2 hr, 80-98% yield), phenolic phenoxide (20°, 16 hr, 50% yield), aqueous hydroxide (30°, 3 hr), alcoholic methylmercaptide (20°, exothermically), alkylamines (20°, 10-60 min, 100%... 

Chiral N,N-disubstituted 2-(aminomethyl)pyrrolidines as catalysts for asymmetric acylation of alcohols 99YGK598. 

Disubstituted and trisubstituted isoxazoles are generally stable to alcoholic and aqueous alkali. Such stability of the ring is characteristic both of alkyl-substituted compounds and of the esters, nitriles, etc., of isoxazole carboxylic acids,for example (127 ->128). 

In 1991, El-Ali and Alper reported the cyclocarbonylation reaction of terminal propargyl alcohols with formation of 5,5-disubstituted 2(5//)-furanones using Pd(dba)2 and l,4-bis(diphenylphosphino)butane (dppb) (91JOC4099). However, this reaction was not applicable to internal alkynols. 

In fact, esters of amino alcohols and 2,2-disubstituted plii iiylacetic acids show useful antitussive activity the mecha-lM iii of action may include bronchiodilation. Double alkylation III the anion of phenylacetonitrile with 1,4-dibromobutane gives llit i cyclopentane-substituted derivative (33). Saponification... 

In the procedure given here, the reaction is applied to a cyclic alcohol to produce a bridged ether. The product is of interest in that it can be cleaved to produce disubstituted cyclooctanes of known geometry (cf. Chapter 6, Section V). 

Structurally isomeric disubstituted paraffins. The number of structurally isomeric alcohols is, apparently, the same... 

Methyl-2-hexcne has a disubstituted double bond, RCH=CHR, and would probably give a mixture of two alcohols with either hydration method since Markovnikov s rule does not apply to symmetrically substituted alkenes. 3-MethyI-3-hexene, however, has a trisubstituted double bond, and would give only the desired product on non-Markovnikov hydration using the hydroboration/oxidation method. 

Conversion of Acid Halides into Amides Aminolysis Acid chlorides react rapidly with ammonia and amines to give amides. As with the acid chloride plus alcohol method for preparing esters, this reaction of acid chlorides with amines is the most commonly used laboratory method for preparing amides. Both monosubstituted and disubstituted amines can be used, but not trisubstituted amines (R3N). 

Bromohydrin (Section 7.3) A 1,2-disubstituted bromo-alcohol obtained by addition of I lOBr to an alkene. 

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