O-alkylation procedure

O-ALKYLATION PROCEDURE. The extract was O-alkylated according to a method described earlier by Liotta al.(14) using tetrabutylanunonium hydroxide and the appropriate alkyl iodide. The extract (1.00 g) was stirred in freshly distilled tetrahydrofuran (THF) (30 mL) under nitrogen for 30 min. A solution of aqueous tetrabutylanunonium hydroxide (1.53 M, 2.3 ml 3.5 mmol base) was then added and this solution was stirred under nitrogen for 30 min. Alkyl iodide (7.2 mmol) was added and the mixture was stirred under nitrogen at room temperature for 2 days. THF and the alkyl iodide were removed by rotovaporization under reduced pressure. The residue was washed with a hot methanol/water mixture (50/50 vol.) until the filtrate was free of iodide (no precipitate with silver nitrate) and tetrabutylanunonium cation (no precipitate with sodium tetraphenylborate). The all lated extract was then dried under vacuum at 105 "C for 24 hours. 

N-Hydroxy-4-(p-chlorophenyl)thiazole-2(3H)-thione (1) is a valuable starting material for the synthesis of N-alkoxy derivatives 2 by a number of well-elaborated O-alkylation procedures (Figure 1)/ ... 

A typical example of an O-alkylation procedure is the synthesis of (-)-(5 )-2-amino-l-methoxy-3-phenylpropane [(5)-8] from (Vl-phenylalaninol2. 

Scheme 15. Anomeric O-alkylation procedure with secondary electrophiles. P = protecting group HMPT = hexamethylphosphoric triamide.

Manufacture of alkylsulfones, important intermediates for metal-complex dyes and for reactive dyes, also depends on O-alkylation. An arylsulphinic acid in an aqueous alkaline medium is treated with an alkylating agent, eg, alkyl haUde or sulfate, by a procedure similar to that used for phenols. In the special case of P-hydroxyethylsulfones (precursors to vinylsulfone reactive dyes) the alkylating agent is ethylene oxide or ethylene chlorohydrin. 

Another procedure relies on a domino Michael-O-alkylation reaction sequence to yield a variety of dihydrofurans. Combination of cyclohexanedione (30) with vinyl bromide 50 in the presence of l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) provides dihydrofuran 51 in 83% yield. Numerous 1,3-dicarbonyls and vinyl bromides are amenable to this methodology, and thus a wide range of products like 51 are available via this strategy. 

Amides are very weak nucleophiles, far too weak to attack alkyl halides, so they must first be converted to their conjugate bases. By this method, unsubstituted amides can be converted to N-substituted, or N-substituted to N,N-disubstituted, amides. Esters of sulfuric or sulfonic acids can also be substrates. Tertiary substrates give elimination. O-Alkylation is at times a side reaction. Both amides and sulfonamides have been alkylated under phase-transfer conditions. Lactams can be alkylated using similar procedures. Ethyl pyroglutamate (5-carboethoxy 2-pyrrolidinone) and related lactams were converted to N-alkyl derivatives via treatment with NaH (short contact time) followed by addition of the halide. 2-Pyrrolidinone derivatives can be alkylated using a similar procedure. Lactams can be reductively alkylated using aldehydes under catalytic hydrogenation... 

Decarboxylation of 16 using the previously described NMP, lithium chloride method provided the dione 32. Selective reduction of the least hindered carbonyl was readily effected using sodium borohydride providing 33. Hydroxymethylenation followed by O-alkylation of the butenolide unit by standard procedures provided the A-B-D-ring analog 34a,b (racemic mixture of epimers). 

Methods for the preparation of tris(0-ethyl dithiocarbonato) complexes of chromium(III), indium(III), and cobalt(III) are presented and serve to illustrate procedures applicable to the preparation of O-alkyl dithiocarbonato, alkyl trithiocarbonato, iV,A7-dialkyldithiocarbamato, and 0,0 -dialkyl dithiophosphato complexes of several metals. 

Besides N-alkylation reactions, there are also reports in the literature concerning microwave-promoted O-alkylations. A mild method for the O-alkylation of phenols with alkyl bromides and chlorides has been developed by Wagner and coworkers (Scheme 6.117 a) [235], The protocol is applicable to substrates that are sensitive to strong bases or to hydrolysis, or are difficult to extract from an aqueous phase. The procedure uses methanol as a solvent and a stoichiometric amount of potassium carbonate as a weak base. Optimum yields were obtained by heating the phenol with 1.2 equivalents of the alkyl bromide (or 3 equivalents of the less reactive chloride) at 100-140 °C for 15-30 min. 

In conventional methods, PTC has provided interesting procedures for O-alkylation, and coupling PTC conditions with microwave activation has proved to be quite fruitful for such reactions. 

In general, nitronates undergo O-alkylation. However, some procedures have been developed that overcome the preference for O-alkylation in favour of C-alkylation. For example, the double deprotonated nitronates introduced by Seebach74 can be C-alkylated and this strategy was used for the synthesis of nitro furanosyl and pyranosyl compounds.75... 

As the integrity of chiral alcohols are retained in the phase-transfer catalysed O-alkylation, the procedure is valuable for the synthesis of chiral ethers under mild conditions as, for example, in the preparation of alkoxyallenes via the initial formation of chiral propargyl ethers [8]. It has been proposed that a combination of 18-crown-6 and tetra-n-butylammonium iodide provide the best conditions for the O-benzylation of diethyl tartrate with 99% retention of optical purity [9]. 

Method A The 0,5-dialkyl dithiocarbonate is prepared by procedure 4.1.14 from O-alkyl potassium dithiocarbonate (50 mmol). The mixture is cooled to 50 °C and, without isolation of the ester, KOH pellets (14 g, 0.25 mol) are added portionwise at <80 °C. The mixture is stirred at 80 °C until GLC analysis indicates the complete disappearance of the ester (ca. 30 min). Petroleum ether (b.p. 40-60 °C, 150 ml) is added and the organic phase is separated, dried (Na2S04), filtered through silica, and fractionally distilled to give the thioether. 

Alkylation of p-oxophosphonates, using a procedure analogous to 6.2.19.A, produces both C- and O-alkylated products [74] in ratios varying from ca. 2 1 to 5 1 depending on the alkylating agent and the structure of the p-oxophosphonate. 

C). The substrate is deprotonated [pK(PhCH2COOMe) 22.7] and trapped by an alkyliodide (—78°C). This procedure leads selectively to mono a-alkylation (81-99%) [103]. Selective monoalkylation of 8-diketones in 70 to 95% yield was obtained by a similar procedure, and only in a few cases (bulky secondary alkylhalides) were the O-alkylated substrate found as a side product. Tetraalky-lammonium counter cations were necessary in stabilizing the enolate Na+ counter cations did not give selective C-alkylation [104]. 

Schwesingefs phosphazene base 2-tert-butylamino-2-diethylamino-l,3-dimethyl-perhydro-l,3,2-diazaphosphorine (PS-BEMP has a pKb = 27.5 in MeCN) has been immobilized and shown to have immense utility in the N- and O-alkylation of many weakly acidic heterocycles. Kim et al. has made extensive use of this reagent in the multi-step synthesis of a small collection of guanines possessing potential antiviral activity [90]. The generic procedure involved the direct alkylation of the purine moiety (20) (Scheme 2.64), promoted by PS-BEMP, resulting in a mixture... 

Although the procedure for the O-methylation of the carbinol from acetylene and acetone (exp. 2.4) gives a fair yield, it is less suitable for the O-methyladon of alcohols that are not available in large amounts. In such cases there is need for a very clean high-yield method. The procedure for the O-methylation of ethynylcyclohexanol meets this condition. Ethynylcyclohexanol can be O-lithiated quantitatively by BuLi in a mixture of THF and hexane. Since O-alkylations of lithium alkoxides in solvents of moderate polarity proceed very sluggishly (even in the case of methyl iodide), a sufficient amount of the polar DMSO has to be added as a co-solvent. The methyladon with methyl iodide can then be accomplished under relatively mild conditions and there is no indication for decomposition of the lithium carbinolate into LiCsCH and cyclohexanone. 

Ta1 adducts with ethylene have been obtained as highly air sensitive solids by reduction of the corresponding Ta111 compounds under argon (equation 85),292 or by reductive elimination of H2 from [TaH2ClL4] (Scheme 9). A similar procedure, but under dinitrogen, gave Tav nitrenes (Section 34.2.3.6). The same Tam precursor (60) provided o alkyl derivatives (equation 86). Complex (63) catalyzes the selective dimerization of ethylene to 1-butene. 

Sliwa (70BSF646) was the first to prepare the parent compound (6) using an intramolecular O-alkylation of a pyridone (Scheme 4). Furo[2,3-6]pyridine was obtained as a colorless oil with b.p. 95 °C (22mmHg). Essentially the same procedure has been used for the preparation of 4-methylfuro[2,3-ft]pyridine (17 Scheme 5) (73MI31700) and 6-methyl-furo[2,3]pyridine (26) (72CHE1395). 

Methylation of alkaloids containing either phenolic hydroxy groups or secondary amine functions is the most common procedure for converting such alkaloids to known derivatives many examples are given in Section II,C. Diazomethane is the reagent of choice for O-methylation, and diazoethane for O-ethylation. It is possible to effect O-alkylation in the presence of secondary amine functions, as in the conversion of peinamine to its trideuteriomethyl ether (Section II,C,92) and of A-desmethylthalrugosidine to the O-ethyl ether (Section II,C,29). Another O-alkylation method, exemplified by the preparation of O-methyl, O-ethyl, and O-isopropyl ethers of berbamine (364), consisted of heating the alkaloid in... 

A similar approach was reported by Lygo and co-workers who applied comparable anthracenylmethyl-based ammonium salts of type 26 in combination with 50% aqueous potassium hydroxide as a basic system at room temperature [26, 27a], Under these conditions the required O-alkylation at the alkaloid catalyst s hydroxyl group occurs in situ. The enantioselective alkylation reactions proceeded with somewhat lower enantioselectivity (up to 91% ee) compared with the results obtained with the Corey catalyst 25. The overall yields of esters of type 27 (obtained after imine hydrolysis) were in the range 40 to 86% [26]. A selected example is shown in Scheme 3.7. Because the pseudo-enantiomeric catalyst pairs 25 and 26 led to opposite enantiomers with comparable enantioselectivity, this procedure enables convenient access to both enantiomers. Recently, the Lygo group reported an in situ-preparation of the alkaloid-based phase transfer catalyst [27b] as well as the application of a new, highly effective phase-transfer catalyst derived from a-methyl-naphthylamine, which was found by screening of a catalyst library [27c],... 

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