Alcohols entries

The chemistry of indium metal is the subject of current investigation, especially since the reactions induced by it can be performed in aqueous solution.15 The selective reductions of ethyl 4-nitrobenzoate (entry 1), 2-nitrobenzyl alcohol (entry 2), l-bromo-4-nitrobenzene (entry 3), 4-nitrocinnamyl alcohol (entry 4), 4-nitrobenzonitrile (entry 5), 4-nitrobenzamide (entry 6), 4-nitroanisole (entry 7), and 2-nitrofluorenone (entry 8) with indium metal in the presence of ammonium chloride using aqueous ethanol were performed and the corresponding amines were produced in good yield. These results indicate a useful selectivity in the reduction procedure. For example, ester, nitrile, bromo, amide, benzylic ketone, benzylic alcohol, aromatic ether, and unsaturated bonds remained unaffected during this transformation. Many of the previous methods produce a mixture of compounds. Other metals like zinc, tin, and iron usually require acid-catalysts for the activation process, with resultant problems of waste disposal. 

An extension of this method can be used to prepare allylic alcohols. Instead of being protonated, the (3-oxido ylide is allowed to react with formaldehyde. The (J-oxido ylide and formaldehyde react to give, on warming, an allylic alcohol. Entry 12 is an example of this reaction. The reaction is valuable for the stereoselective synthesis of Z-allylic alcohols from aldehydes.245... 

Scheme 5.9 illustrates some of the conditions that have been developed for the reductive deoxygenation of alcohols. Entries 1 to 4 illustrate the most commonly used methods for generation of thiono esters and their reduction by tri-M-butylstannane. These include formation of thiono carbonates (Entry 1), xanthates (Entry 2), and thiono imidazolides (Entries 3 and 4). Entry 5 is an example of use of dimethyl phosphite as the hydrogen donor. Entry 6 uses r .s-(trimethylsilyl)silane as the hydrogen atom donor. 

Scheme 9.1 shows several examples of one-carbon homologations involving boron to carbon migration. Entry 1 illustrates the synthesis of a symmetrical tertiary alcohol. Entry 2 involves interception of the intermediate after the first migration by reduction. Acid then induces a second migration. This sequence affords secondary alcohols. 

Several aspects are particularly noteworthy. Good chemoselectivity is noted in the compatibility with epoxides, esters, olefins, and alcohols. Entries 44 and 45 demonstrate the chemoselectivity between an unsaturated and saturated ketone. 

Ketones are obtained in good yields from secondary benzylic alcohols (entry 3), whereas the oxidation is less satisfactory with aliphatic alcohols (entries 4 and 5). This is a... 

In toluene with 4 equiv methanol and a catalytic amount of the alkaloid. b ee values are determined by conversion of the monoesters to the (R)-l-(l-naphthalenyl)ethylamides (entries 1-14) and analysis by HPLC, by salt formation with (R)-l-phenylethylamine (entries 15-20) or by H-NMR spectroscopy in the presence of Eu(hfc)3. Absolute configurations are determined by chemical correlation or by X-ray analysis of the Mosher ester of the lactone alcohol (entry 21). With 20 equiv of methanol. d With 4 equiv of methanol. With 10 equiv of methanol. f With 3 equiv of methanol. 

Boronic acids can be reversibly esterified with resin-bound diols (Figure 3.15). The resulting boronic esters are stable under the standard conditions of amide bond formation, but can be cleaved by treatment with water under acidic or neutral conditions to yield boronic acids. Treatment of the resin-bound boronic esters with alcohols yields the corresponding boronic esters [197]. Resin-bound boronic esters are suitable intermediates for the Suzuki reaction [198], Treatment with H202 leads to the formation of alcohols (Entry 8, Table 3.36), while treatment of resin-bound aryl boronates with silver ammonium nitrate leads to the conversion of the C-B bond into a C-H bond (Entry 14, Table 3.46). 

Only a few examples have been reported of the etherification of alcohols with resin-bound diarylmethyl alcohols (Entry 5, Table 3.30 Entry 5, Table 3.31 [564]). Diarylmethyl ethers do not seem to offer advantages over the more readily accessible trityl ethers, which are widely used as linkers for both phenols and aliphatic alcohols. Attachment of alcohols to trityl linkers is usually effected by treating trityl chloride resin or 2-chlorotrityl chloride resin with the alcohol in the presence of a base (phenols pyridine/THF, 50 °C [565] or DIPEA/DCM [566] aliphatic alcohols pyridine, 20-70 °C, 3 h-5 d [567-572] or collidine, Bu4NI, DCM, 20 °C, 65 h [81]). Aliphatic or aromatic alcohols can be attached as ethers to the same type of light-sensitive linker as used for carboxylic acids (Section 3.1.3). 

Support-bound primary or secondary aliphatic alcohols can be acylated under conditions similar to those used in solution, provided that these conditions are compatible with the chosen linker. For instance, acids can be activated with a carbodiimide either as symmetric anhydrides or as O-acylisoureas, which quickly react with alcohols in the presence of a catalyst, such as DMAP or another base, to yield esters (Table 13.12). Further acid derivatives suitable for esterification reactions on solid phase include acyl halides and imidazolides. HOBt esters react only slowly with alcohols, but enable the selective acylation of primary alcohols in the presence of secondary alcohols (Entry 5, Table 13.12). 

Allyloxy)iodoarenes react with Sml2 to yield radical anions, which undergo thermal fragmentation. The resulting aryl radicals can cyclize to dihydrobenzofurans (Entries 8-10, Table 15.9). The radical obtained after cyclization can be reduced and treated with a proton source such as water or an alcohol to yield alkanes, or with carbonyl compounds to yield alcohols (Entry 10, Table 15.9). 

Cyclizations of chloral hemiacetal derivatives of cyclic allyl alcohols were regio- and stereo-selective (Table 6, entry 1), but a mixture of regioisomers was obtained from analogous derivatives of acyclic allyl alcohols with a nonterminal double bond.93 Hemiacetal derivatives of allyl alcohols with a terminal vinyl group have been cyclized with mercury(II) acetate to give acetal derivatives of threo 1,2-diols with moderate selectivities (equation 54 and Table 15, entries 1 and 2).147 Moderate to excellent stereoselectivity has been observed in the iodocyclizations of carbonate derivatives of allyl alcohols (entries 3-5).94a The currently available results do not provide a rationale for the variation in observed stereoselectivity. 

To recycle a valuable amine acylation catalyst, Janda and co-workers10 attached a proline-based catalyst to a polymeric support for the enan-tioselective kinetic resolution of alcohols (entry 6). The resin-bound catalyst behaves similarly to the soluble catalyst, providing good yields of secondary alcohols and their corresponding esters with good to excellent enantioselectivities for various substrates. 

Three main features are apparent from the results reported (i) the incomplete conversion of benzylic alcohols (entry 4) (ii) the lack of activity toward primary alcohols (entries 2 and 5) and (iii) the high activity toward unactivated secondary alcohols [58]. 

Table 2 shows that in addition to THF (1), ethers and an acetal such as diethyl ether (7), oxetane (9), 2-methyltetrahydrofuran (12) and 1,3-dioxolane (11) undergo a-C-H hydroxyalkylation to provide adducts in good yields. Dibutyl ether (8) (64% yield dr 71 29) and oxepane (10) (63% yield dr 88 12) have also been found to afford a-hydroxyalkylated ethers under the same conditions in moderate yields [20], It is interesting to note that the reaction selectively provides threo alcohols (entries 1-5). Occasionally, ethyl adducts and/or 4-methoxybenzylalcohol are produced, but the amounts of the byproducts are usually negligible. 

The scope of the Pd(II)-catalyzed enantioselective oxidation system has been the most extensively explored. The conditions are able to selectively oxidize a wide variety of benzylic alcohols with high selectivity (Table 1, entries 1-3,7) [4, 6-8]. Electron-withdrawing groups on the aromatic ring lead to lower oxidation rates and selectivity. Other types of aromatics can also be resolved successfully (entry 9), although N-containing heterocycles have little reactivity. Allylic and cyclopropyl alcohols are also well tolerated in the resolution (entries 5, 6), occasionally with extraordinary levels of selectivity (entry 4) [19]. As already mentioned, Sigman has shown that use of t-BuOH as solvent can also lead to useful enantioselective oxidation for some saturated alkyl alcohols (entries 10-12). 

The influence of the alcohol on the reaction was evaluated (Scheme 26). The results of a competition experiment between the alcohols are shown in Table 7. Both alcohols were treated with mono-alkoxysilane le using 10 % Pd/C as the catalyst. The silyl ketals of both alcohols were isolated as a mixture and the area under the methine protons, from the (+)-ethyl lactate moiety of both silyl ketals, was compared by NMR analysis. The difference in reactivity of primary, versus secondary, versus tertiary alcohol was small. The differences in reactivity range from 1.5 1 for 1° vs 2°, to 3 1 for 1° vs 3°. The reactivity of a benzyl alcohol is slower than the aliphatic alcohol as shown in entries 4 to 6. Entries 4 and 5 show an increase in the ratio of 1° 2° alcohol and a decrease in ratio for the 2° 3° for the secondary benzyl alcohol. Entries 6 and 7 confirm that benzyl alcohols are less reactive than aliphatic alcohols. The inductive electron withdrawing effect of the aryl group in the benzyl alcohol renders it less nucleophillic and this may affect the rate of reaction with the silane. Although the difference in reactivity is small, this trend may be informative. The influence of the alcohol s nucleophilicity on the reaction mechanism will be addressed in a later section. 

The reaction has been extensively used for the synthesis of a-amino acids (entries 3-5),559 //-/ -amino alcohols (entry 6),560 aminophenol (entry 7),561 optically active A-substituted glycines (entries 7 and 8),562 a-hydrazinocarboxylic acids (entry 9),563 A-sulfinyl and A-alkoxy-a-amino acids (entries 10 and ll),564 and propargyl amines (entry 12).565... 

In addition to primary and secondary aliphatic alcohols (entries 2-7), benzylic alcohols were also efficiently oxidised (entries 9 and 10), complete conversion being observed within 30 minutes. In competition experiments, the catalyst showed a marked preference for primary alcohols (entries 8 and 11). This is analogous to the already reported homogeneous3 and heterogeneous13 TEMPO systems. A stereogenic centre at the a-position is not affected during oxidation as shown by the selective oxidation of (S)-2-methylbutan-l-ol to (S)-2-methylbutanal (entry 12).20... 

We next carried out selective esterification of two substrates in this reaction system. When a 1 1 mixture of lauric acid and acetic acid was esterified with dodecanol in the presence of DBSA under neat conditions at 40°C for 48 h, the laurate ester and the acetate ester were obtained in 63% and 35% yields, respectively (Table 13.7, entry 1). On the other hand, when the same reaction was conducted in water, the laurate ester was predominantly obtained in 81% yield, and the yield of the acetate was only 4% (entry 2). Similar selective esterification of lauric acid over acetic acid was also observed in the reaction of another alcohol (entry 4), Furthermore, even cyclohex-anecarboxylic acid, which is an a-disubstituted acid, was preferentially esterified in the presence of acetic acid (entries 5 and 6). These selectivities are attributed to the hydrophobic nature of lauric acid and cyclohexanecarboxylic acid as well as to the high hydrophilicity of acetic acid. These unique selectivities became possible by using water as a solvent. Selective esterification based on the difference in hydrophobicity was also attained in the reaction of two alcohols, one of which is hydrophobic and the other water-soluble. 

Table 1 shows that various functional groups are compatible with the reaction conditions used in this procedure alcohols (entries 15 and 16), ethers (entries 17 and 23), ketones (entries 20 and 21), kctals (entries 18 and 19), esters (entries 22 -25) and carbamates (entry 26). 

The sole exception of preferential endo attack is seen in the reaction of cuprates with oxanorbornenyl ketones [106]. The unusual and unprecedented endo delivery of the nucleophile is proposed to proceed via a prior complexation of the bridgehead oxygen with one equivalent of the cuprate on the less hindered side, followed by addition of another equivalent of cuprate from the more hindered endo face of the carbonyl group. Table 2 shows the reactions of 88 with various cuprates to give the exo alcohols (entries 1 -3). The remote olefin shows a positive effect in promoting endo nucleophilic attack, as shown by the reactions of 88 and 89 respectively (entry 1 vs. 4). 

Both enantiomers of the alcohol (entry 1) were oxidized with moderate enantiose-lectivities (E = 7) for the (S) enantiomer. For bicyclic alcohols, the position of the hydroxyl group with respect to the methyl group is essential. Only at a relative trans configuration of both substituents significant oxidation occurred. 

A mixture of cyclohexanecarboxaldehyde (0.120 mL, 1.0 mmol, 1 equiv.), tin powder (0.178 g, 1.5 mmol, 1.5 equiv.) and crotyl bromide (0.125 mL, 1.2 mmol, 1.2 equiv.) in dichloromethane (0.385 mL, 6 equiv.) and water (0.108 mL, 6 equiv.) was stirred in a 10-mL round-bottomed flask equipped with a glass septum at room temperature for 48 hours. 50-mL water was added and the reaction mixture extracted with 50 mL portions of ethyl acetate. The combined organic layer was washed with 50 mL brine and 50 mL water and dried over anhydrous magnesium sulfate. The mixture was then filtered and the solvent removed in vacuo. The crude product was purified by column chromatography to afford a 78% (131 mg) yield mixture of (95%) and (5%) homoallylic alcohols (Entry 13, Table 8.1) as a colorless oil. 

The ether layer was washed with 20 mL sodium bicarbonate, followed with 20 mL brine and dried over anhydrous magnesium sulfate. The mixture was filtered and the solvent removed in vacuo. The crude product was purified by column chromatography to afford a 66% (110 mg) yield mixture of (95%) and (5%) homoallylic alcohols (Entry 19, Table 8.1) as a colorless oil. 

Several examples of Pd/P(t-Bu)2Me-catalyzed Suzuki couplings of primary, P-hydrogen-containing alkyl tosylates are illustrated in Table 1 (entries 9-12). Functional groups such as acetals (entry 9), amides (entry 10), ketones (entry 11), and tertiary alcohols (entry 12) are tolerated. Furthermore, both alkyl-and aryl-9-BBN compounds are suitable coupling partners. These Suzuki reactions of alkyl tosylates proceed in comparable yield at room temperature, albeit much more slowly. 

Cul/N,N-dimethylglycine (L2) was found effective for the coupling reaction of aryl iodides with aliphatic alcohols (entry 4) [60], although excess alcohol was required to ensure complete consumption of the coupling partners. 

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