2- substituted-1 -alkanols

Scheme 3.100 General strategy for the synthesis of feebly chiral 2-substituted 1-alkanols of >99% ee by ZACA-lipase-catalyzed acetylation-Pd- or Cu-catalyzed coupling sequential process [318].

Negishi reported the zirconium-catalyzed enantioselective carboalumination of alkenes, which consisted of a hydroalumination/alkylalumination tandem process.133-135 This permits the asymmetric syntheses of methyl-substituted alkanols and other derivatives, typically with >90% ee, which represents an increase in ee value by 15% from the previously obtained 70-80%.136-138 The hydroalumination/zirconium-catalyzed enantioselective carboalumination of alkenes was carried out using (—)-bis(neomenthylindenyl)zirconium dichloride as the catalyst (Table 15).133... 

The results indicate that 3-butenols and longer cj-alkenols can be alkylaluminated with a variety of alkyldiiso-butylalanes 128 to produce, after hydrolysis, the corresponding methyl-substituted alkanols 130 in good yields and with 90-93% ee. 

Although the application of carboalumination to the synthesis of natural products is still in its infancy, a few preliminary results shown in Scheme 1.50 [167,168,171,172] suggest that it promises to become a major asymmetric synthetic reaction, provided that (i) the singularly important case of methylalumination can be made to proceed with S90% ee, and (ii) satisfactory and convenient methods for enantiomeric and diastereo-meric separation/purification can be developed. In this context, significant increases in ee in the synthesis of methyl-substituted alkanols from around 75 % to 90—93 % achieved through some strategic modifications are noteworthy (Scheme 1.50) [168]. Shortly before the discovery of the Zr-catalyzed enantioselective carboalumination, a fundamentally discrete Zr-catalyzed asymmetric reaction of allylically heterosubstituted alkenes proceeding via cyclic carbozirconation was reported, as discussed later in this section. 

Ammonium Nitrate Slurry Sensitized with Nitro substituted Alkanols... 

Three-membered cyclic compounds can generally be prepared from difunctional compounds by 1,3-elimination. In the formation of oxiranes from 2-substituted alkanols, the alkoxide produced in the basic medium participates in an internal nucleophilic attack, which promotes the departure of the substituent on the adjacent carbon atom leading to ring-closure. A stereochemical condition for the reaction is that the reacting groups should be in an antiperiplanar conformation relative to each other (Eq. 51). 

If the substrate contains a nucleophile in addition to a vinylcyclopropane moiety, the halonium ion formed during the addition of bromine or iodine to the double bond, can be trapped which results in the formation of cyclization products. Examples of compounds that react in this way are 1-phosphoryl-substituted 2-vinylcyclopropanes, 2-vinylcyclopropyl-sub-stituted alkanoic acids, and 2-vinylcyclopropyl-substituted alkanols, which afford oxaphosphabicycloalkanes, bi- and polycyclic lactones and polycyclic ethers, respectively. However, 2-vinylcyclopropyl-substituted alkylamines behave differently, Very good yields have been obtained in some cases, e.g. formation of 4 from 3. ... 

The a values obtained in this manner have an uncertainty of 0.08 and are listed in Table 3.9 adopted from [3]. Water has a large value of a = 1.17, but certain phenols and halogen-substituted alkanols and carboxylic acids are considerably more acidic hexafluoro-i-propanol has a = 1.96, dichloroacetic add has a = 2.24, and trifluoro-methanesulfonic acid has AN = 131.7, much higher than the value for water, 54.8, but these are rarely used as solvents for electrolytes and therefore are not dealt with further here. 

Table 1.2. 2-Alkyl-substituted 1-, Substrate alkanols via Zr-catalyzed alkylalumi nation-oxidation ...

This hydroxycyclopropanation of a terminal double bond also works perfectly well in an intramolecular situation, e. g. with terminally alkenyl-substituted esters, to yield substituted l-hydroxybicyclo[n.l.O]alkanols [85a,85b,100], aminobicyclo[n.l.O]alkanols [85c], and heterocyclic analogues [99a,99b,100], in which five- and six-membered rings are formed (Table 11.7). 

Microwave spectroscopy is probably the ultimate tool to study small alcohol clusters in vacuum isolation. With the help of isotope substitution and auxiliary quantum chemical calculations, it provides structural insights and quantitative bond parameters for alcohol clusters [117, 143], The methyl rotors that are omnipresent in organic alcohols complicate the analysis, so that not many alcohol clusters have been studied with this technique and its higher-frequency variants. The studied systems include methanol dimer [143], ethanol dimer [91], butan-2-ol dimer [117], and mixed dimers such as propylene oxide with ethanol [144]. The study of alcohol monomers with intramolecular hydrogen-bond-like interactions [102, 110, 129, 145 147] must be mentioned in this context. In a broader sense, this also applies to isolated ra-alkanols, where a weak Cy H O hydrogen bond stabilizes certain conformations [69,102]. Microwave techniques can also be used to unravel the information contained in the IR spectrum of clusters with high sensitivity [148], Furthermore, high-resolution UV spectroscopy can provide accurate structural information in suitable systems [149, 150] and thus complement microwave spectroscopy. 

Toniolo reported the carbonylation of aromatic aldehydes containing electron-donating substituents with a Pd/PPh3 catalyst system in the presence of HC1 to give phenylacetic acid derivatives [64]. No activity was observed in the absence of PPI13 or HC1, and high yields could be achieved with alkanols as solvent (e.g., EtOH). It is believed that the mechanism involves HC1 addition to the aldehyde, with the resultant chlorohydrin being subject to oxidative addition to Pd, CO insertion, and alcoholysis. Upon Cl -o- OR substitution with the formed mandelic acid derivative, a second carbonylation takes place,... 

Several elegant syntheses of anthra-cyclinone aglycons are based on the ability to intercept the intermediate radical cation (76) formed from the oxidation of aromatic ethers (75) and (79) in situ with alkanols [9, 44, 45]. Inter- and intramolecular capture can occur. As illustrated in Scheme 19, the methodology leads to the facile construction of substituted quinone mono- and bisketals. 

This reaction has been successfully applied to cyclopentenone annelation onto cycloalkenes. By modifying Danheiser s protocol [15], alkynyl-substituted bi-cyclo[n.l.0]alkanol derivatives are prepared by the reaction of gem-lithio-bromocyclopropanes 27 with alkynylborons, as shown in Scheme 10. 

Alkalimetall-alkanolate reagieren in alkoholischer Losung zu 3-Alkoxy-l, 2,4-oxadiazo-len321. Mit Natriumethanolat in Ethanol erhalt man aus 3-Chlor-5-phenyl-l,2,4-oxadiazol 3-Ethoxy-5-phenyl-1,2,4-oxadiazol (Schmp. 48 )261. Beim Erhitzen von 3-Chlor-5-phenyl-l, 2,4-oxadiazol mit 1 N Natronlauge erfolgt eine Substitution dcs Chlor-Atoms unter Bildung von 3-Hydroxy-5-phenyl-1,2,4-oxadiazol (Schmp. 202°)261. 

Unsubstituted aliphatic carboxylic acids are only very slowly further oxidized to the lower homologous acid in the oxidation of primary alkanols less than 2% of this acid are found. However, with substituted carboxylic acids the cleavage can become the main reaction. Thus anodic oxidation of phenylacetic acid at the nickel hydroxide electrode leads to 87% benzoic acid . Cleavages of similar to a lesser extent are observed with amino acids (Chapter 3.1) or P-alkoxy substituted acids (Chapter 2.4). 

The reductive cleavage of the C—O bond in 2- and 4-substituted hydroxy-methylpyridines was mentioned in Part I. The optically active l-(4-pyridyl)-alkanols are reduced in good yield to the optically inactive alkylpyridine, whereas the 2-substituted derivatives were reduced in lower yield to the optically active alkylpyridine (and some tetrahydropyridine derivatives).384,385 The difference in behavior was explained by orientation of the adsorbed pro-tonated pyridine, allowing contact between the electrode and the 2-substituent, but not the 4-substituent. This model was used in later work however, not excluded was the possibility that the higher stability of the p-quinonoid dihydropyridine intermediate, compared to the o-quinonoid dihydropyridine, played a role in the relative ease of reduction of the 4- and 2-substi-tuted pyridines. 

Method of Wakita, Yoshlmoto, Miyamoto, and Watanabe The Wakita et al. method [46] has been derived with a set of 307 liquid compounds, including alkanes, alkenes, alkynes, halogenated alkanes, alkanols, oxoalkanes, alkanones, alkyl alkanoates, alkanethiols, alkanenitriles, nitroalkanes, and substituted benzenes, naphthalenes, and biphenyles. The model equation is... 

The estimation of the aqueous solubility at rmin and at other temperatures requires data on the enthalpy and the heat capacity of the solution. These properties are themselves temperature dependent and have been systematically studied for various sets of compounds such as hydrocarbons [58,59], 1-alkanols [60], alkoxyethanols, and 1,2-dialkoxyethanes [61], carboxylic acids, amines, and N-substituted amides [62], monoesters, ethylene glycol diesters, glycerol triesters [63], and crown ethers [64], Additive schemes for the estimation of aqueous solution heat capacities have been evaluated [65,66],... 

Various racemic secondary alcohols with different substituents, eg, a-hydroxyester (60), are resolved by PFL neady quantitatively (75). The effect of adjacent unsaturation on enzyme-catalyzed kinetic resolutions was thoroughly studied for a series of allylic (61), propargylic (62), and phenyl-substituted 2-alkanols (76,77). Excellent selectivity was observed for (E)-allylic alcohols whereas (Z)-isomers showed poor selectivity (76). 

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