Hydroxy halides, alkylation

Other classes of molecules which have been benzylated using this reagent include hydroxy ketones, hydroxy halides and esters such as tartrates, hydroxy propionates or butanoaies, long alkyl chain hydroxy esters, and hydroxy lactones. Under basic conditions problems such as enolization, aldol reactions, elimination and epoxide formation can cause problems and when 2-substituted esters, such as ethyl (5)-lactate, are required as homochiral starting materials, then protection using this method circumvents the considerable risk of racemization that accompanies the use of bases (eq 6). 

Alkylation of aldol type educts, e.g., /3-hydroxy esters, using LDA and alkyl halides leads stereoselectively to erythro substitution. The erythro threo ratio of the products is of the order of 95 5. Allylic and benzylic bromides can also be used. The allyl groups can later be ozonolysed to gjve aldehydes, and many interesting oligofunctional products with two adjacent chiral centres become available from chiral aldol type educts (G. Prater, 1984 D. Seebach, 1984 see also M. Nakatsuka, 1990, p. 5586). 

A special problem arises in the preparation of secondary amines. These compounds are highly nucleophilic, and alkylation of an amine with alkyl halides cannot be expected to stop at any specifle stage. Secondary amides, however, can be monoalkylated and lydrolyzed or be reduced to secondary amines (p. 11 If.). In the elegant synthesis of phenyl- phrine an intermediate -hydroxy isocyanate (from a hydrazide and nitrous acid) cyclizes to pve an oxazolidinone which is monomethylated. Treatment with strong acid cleaves the cyclic irethan. 

When large groups, such as phenyl, bromo, ethoxycarbonyl or nitro are attached at position 3, the principal products are l-alkylcinnolin-4(l/f)-ones. Cyanoethylation and acetylation of cinnolin-4(l/f)-one takes place exclusively at N-1. Phthalazin-l(2/f)-ones give 2-substituted derivatives on alkylation and acylation. Alkylation of 4-hydroxyphthala2in-l(2/f)-one with an equimolar amount of primary halide in the presence of a base leads to 2-alkyl-4-hydroxyphthalazin-l(2/f)-one and further alkylation results in the formation of 4-alkoxy-2-alkylphthalazinone. Methylation of 4-hydroxy-2-methyl-phthalazinone with dimethyl sulfate in aqueous alkali gives a mixture of 4-methoxy-2-methylphthalazin-l(2/f)-one and 2,3-dimethylphthalazine-l,4(2//,3//)-dione, whereas methylation of 4-methoxyphthalazin-l(2/f)-one under similar conditions affords only 4-methoxy-2-methylphthalazinone. 

Pyrazoles, isoxazoles and isothiazoles with a hydroxyl group in the 3-position (491 Z = NR, O, S) could isomerize to 3-azolinones (492). However, these compounds behave as true hydroxy derivatives and show phenolic properties. They give an intense violet color with iron(III) chloride and form a salt (493) with sodium hydroxide which can be O-alkylated by alkyl halides (to give 494 R = alkyl) and acylated by acid chlorides (to give 494 R = acyl). 

Weiss ° treated 16-dehydro- (6), 17a-acetoxy- (8), 17a-hydroxy- (9) and 17a-bromopregnan-20-one (11) with a solution of lithium, barium, calcium or sodium in liquid ammonia and reacted the intermediate enolate anion (7) with the appropriate alkyl halide. 

Reductive amination of dihydropyran (which may be regarded as the dehydration product of the cyclic acetal of 5-hydroxy-pentanal) in the presence of isopropylamine and a trace of acid affords the aminoalcohol, 96. Treatment of this compound with thionyl chloride affords the haloamine, 97. Alkylation of the quinoline, 92, with this halide yields pentaquine (98). ... 

The procedure involves C-alkylation of an a-sulfonyl carbanion derived from 245 with alkyl halides or carbonyl compounds, followed by cleavage of the cyclopropanols 247 produced by deprotection of the hydroxy group of 246 to give (E)-substituted aldehydes141. 

In the alkyl chain hydroxy groups or side chains may be present. The reaction is somewhat different when acyl halides are used. Hydroxymethanediphosphonic acid is prepared by reacting phosgene with an alkali metal, dialkyl phosphite. The reaction is rapid and exothermic. The temperature is controlled between 10 and 20°C. After hydrolysis with HC1, hydroxymethanediphosphonic acid is recovered [91,92]. 

A stmple and general synthesis of 2,2,4,5-tetrasubstituted furan-3(2//)-ones from 4-hydroxyalk-2-ynones and alkyl halides via tandem CO, addition-elimination protocol is described <96S 1431>. Palladiuni-mediated intramolecular cyclization of substituted pentynoic adds offers a new route to y-arylidenebutyrolactones <96TL1429>. The first total synthesis of (-)-goniofupyrone 39 was reported. Constmction of the dioxabicyclo[4.3.0]nonenone skeleton was achieved by tosylation of an allylic hydroxy group, followed by exposure to TBAF-HF <96TL5389>. 

Scheme 5.7 illustrates these and other applications of the hydride donors. Entries 1 and 2 are examples of reduction of alkyl halides, whereas Entry 3 shows removal of an aromatic halogen. Entries 4 to 6 are sulfonate displacements, with the last example using a copper hydride reagent. Entry 7 is an epoxide ring opening. Entries 8 and 9 illustrate the difference in ease of reduction of alkynes with and without hydroxy participation. 

Carbon monoxide rapidly inserts into the carbon—zirconium bond of alkyl- and alkenyl-zirconocene chlorides at low temperature with retention of configuration at carbon to give acylzirconocene chlorides 17 (Scheme 3.5). Acylzirconocene chlorides have found utility in synthesis, as described elsewhere in this volume [17]. Lewis acid catalyzed additions to enones, aldehydes, and imines, yielding a-keto allylic alcohols, a-hydroxy ketones, and a-amino ketones, respectively [18], and palladium-catalyzed addition to alkyl/aryl halides and a,[5-ynones [19] are examples. The acyl complex 18 formed by the insertion of carbon monoxide into dialkyl, alkylaryl, or diaryl zirconocenes may rearrange to a r 2-ketone complex 19 either thermally (particularly when R1 = R2 = Ph) or on addition of a Lewis acid [5,20,21]. The rearrangement proceeds through the less stable... 

AK5-Hydroxy-6-methyl-2-pyridyl)aminomethylenemalonate (1492, R = H) was alkylated with alkyl halides in DMF in the presence of potassium carbonate at 90-110°C for 1 hr to give the 5-alkoxy derivatives (1492, R = Et, /Pr, CH2Ph, CH2OMe) [81JAP(K)131583]. 

Asymmetric introduction of azide to the a-position of a carbonyl has been achieved by several methods. These include amine to azide conversion by diazo transfer,2 chiral enolate azidation,3 and displacement of optically active trifluoromethanesulfonates,4 p-nitrobenzenesulfonates,5 or halides.6 Alkyl 2-azidopropionates have been prepared in optically active form by diazo transfer,2 p-nitrobenzenesulfonate displacement,5 and the Mitsunobu displacement using zinc azide.7 The method presented here is the simplest of the displacement methods since alcohol activation and displacement steps occur in the same operation. In cases where the a-hydroxy esters are available, this would be the simplest method to introduce azide. 

Nucleophilic Reactions.—Attack on Saturated Carbon. Selected examples of the Arbusov reaction include phosphorylation of the chloroacetophenones (1) to give phosphonates, which cyclized to (2) in the presence of acid chlorides,1 formation of the azodiphosphonate (3) from 2,2 -dichloro-2,2 -azopropane,2 3 and the reaction of 2-chloro-3,4-dihydro-3-oxo-2//-l,4-benzothiazine (4) with triethyl phosphite to give the 2-phosphonate (5), which is used as an olefin synthon.8 Bis(trimethylsilyl) trimethylsiloxymethylphosphonite (6) has been synthesized by silylation of hydroxy-methylphosphonous acid, and, as expected, undergoes a normal Arbusov reaction with alkyl halides to give the phosphonates (7).4 This series of reactions, followed by... 

An alternative route to sulphones utilizes the reaction of the appropriate activated halide with sodium dithionite or sodium hydroxymethanesulphinite [6], This procedure is limited to the preparation of symmetrical dialkyl sulphones and, although as a one-step reaction from the alkyl halide it is superior to the two-step oxidative route from the dialkyl sulphides, the overall yields tend to be moderately low (the best yield of 62% for dibenzyl sulphoxide using sodium dithionite is obtained after 20 hours at 120°C). The mechanism proposed for the reaction of sodium hydroxymethanesulphinite is shown in Scheme 4.20. The reaction is promoted by the addition of base and the best yield is obtained using Aliquat in the presence of potassium carbonate. It is noteworthy, however, that a comparable yield can be obtained in the absence of the catalyst. The reaction of phenacyl halides with sodium hydroxy-methane sulphinite leads to reductive dehalogenation [7]. 

A novel Michael-type addition of alkyl halides to a,/3-enones (239) has been realized using either aquocobalamin (232) or dibromo[l-hydroxy-8H-HDP]cobalt(111)... 

The reaction of acceptor-substituted carbene complexes with alcohols to yield ethers is a valuable alternative to other etherification reactions [1152,1209-1211], This reaction generally proceeds faster than cyclopropanation [1176], As in other transformations with electrophilic carbene complexes, the reaction conditions are mild and well-suited to base- or acid-sensitive substrates [1212], As an illustrative example, Experimental Procedure 4.2.4 describes the carbene-mediated etherification of a serine derivative. This type of substrate is very difficult to etherify under basic conditions (e.g. NaH, alkyl halide [1213]), because of an intramolecular hydrogen-bond between the nitrogen-bound hydrogen and the hydroxy group. Further, upon treatment with bases serine ethers readily eliminate alkoxide to give acrylates. With the aid of electrophilic carbene complexes, however, acceptable yields of 0-alkylated serine derivatives can be obtained. 

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