Reactions with Aliphatic Alcohols

1 Palladium-Catalyzed Reactions The coupling of tertiary alcohols with electron-deficient aryl bromides has been reported using Pd(0)/DPPF in the presence of fcrt-butoxide [109]. Palladium-BUjP L87 is also effective and the coupling of aryl halides (electron-deficient and -rich) can be achieved [110]. Parrish and Buchwald reported the synthesis of aryl fcrt-butyl ethers using biphenyl-based phosphine ligands L15, L17, and L97 [111]. 

TRANSITION METAL-MEDIATED CARBON-HETEROATOM CROSS-COUPLING 

SCHEME 20.39 Cross-coupling of aryl halides with aliphatic alcohols, 

SCHEME 20.40 Ligand effect in Pd-catalyzed C—O coupling of 2-bromotoluene with BuOH. 

SCHEME 20.41 Coupling of primary and secondary alcohols with aryl bromides/chlorides. 

---

Alcohols also may serve as carbonyl precursors. The reaction with aliphatic alcohols is thought to go through a carbonyl intermediate, but since no hydrogen is actually consumed, the reaction appears to be an amination, as it... 

The reactions of thionyl chloride with organic compounds having hydroxyl groups are important. Alkyl chlorides, alkyl sulfites, or alkyl chlorosulfites form from its reaction with aliphatic alcohols, depending on reaction conditions, stoichiometry, and the alcohol structure ... 

Some carbamates can be cleanly N-alkylated on insoluble supports, either by treatment with strong bases and alkylating agents, or by reaction with aliphatic alcohols under Mitsunobu conditions (Table 14.9). Alkylation under Mitsunobu conditions... 

Alcohols. Extremely violent reaction with aliphatic alcohols.2 Benzylamine. Mixture reacts violently.2... 

Multiply Alkylated Cyclopentanes, MACs Multiply alkylated cyclopentanes are a relatively new class of fluids prepared from dicyclopentadiene by reaction with aliphatic alcohols. Typical examples of commercial MAC fluids are shown in Table 12.5. The properties of this class of fluid are tailored by varying the nature of the alcohol in the synthesis. Vast ranges have been achieved. These fluids readily absorb additives. Pennzane SHF-X2000 has been under intensive investigation and is now widely used in spacecraft mechanisms. 

Toxicology LDLo (oral, rat) 1 g/kg, (IV, rat) 200 mg/kg poison by IV route mod. toxic by ing. corrosive questionable carcinogen experimental tumorigen TSCA listed Precaution Oxidizer stored as dust it heats spontaneously explosive reactions with aliphatic alcohols, benzylamine, or hydrazine hydrate... 

TABLE 1 Kinetic parameters of the ozone reaction with aliphatic alcohols at 25°C. 

Alam MS, Rao BSM, Janata E (2001) A pulse radiolysis study of H atom reactions with aliphatic alcohols evaluation of kinetics by direct optical absorption measurement. Phys Chem Chem Phys 3 2622-2624... 

But the reaction with aliphatic a-halocarbonyl compounds is usually complex, and a variety of compounds can be formed depending on the reactants and the reaction conditions. With chloroacetone in neutral medium (alcohol) the acyclic intermediate (144) analogous to those obtained with thiourea and thioamides was isolated (Scheme 70). 

The reactions of aliphatic alcohols with p-toluenesulfmic acid are accelerated by microwave irradiation under solvent-free conditions in the presence of silica gel, to afford a high-yielding synthesis of p-toluenesulfmate esters [74] (Eq. 21). 

Another system for transfer vinylation has utilized [Ir(COD)Gl]2 as the catalyst, and was applicable to the preparation of vinyl ethers from the reactions of aliphatic alcohols with vinyl acetate (COD = 1,4-cyclooctadiene Scheme 4).117 This protocol has been used for the preparation of chromenes by a vinylation-ring-closing metathesis sequence (Equation (19)).118... 

Pd-catalyzed intramolecular etherification reactions of aliphatic alcohols have also been practiced in tandem with other bond-forming processes, such as a Pd-catalyzed allyltin addition to an aldehyde (Equation (32)).160 Similarly, a tandem C-N and G-O bond formation sequence occurs (Equation (33)) during the reactions of /3-amino alcohols with biscarbonates in the presence of the N,O-acetal-derived ligand 43.161-163... 

A heterobimetallic BINOL-Ga/Li complex 53 has been developed for the enantioselective ARO of meso-cpoxides (BINOL = l,T-bi(2-naphthol)).278 Using />-methoxyphenol as the nucleophile, this etherification reaction was observed to take place with a high level of asymmetric induction. An improved catalyst 54 has also been reported that exhibits greater stability under the reaction conditions and delivers higher yields and ee s (Equation (78)).279 A simple catalyst derived from Sc(OTf)3 and the chiral bipyridine ligand 52 has been shown to be effective for the ARO of aryl-substituted /// -epoxides with aliphatic alcohols to give high ee s (Equation (79)).280... 

Many of the reactions of A-chloro- and A-bromo-imides are extremely violent or explosive. Those observed include A-chlorosuccinimide with aliphatic alcohols or benzylamine or hydrazine hydrate A-bromosuccimmidc with aniline, diallyl sulfide, or hydrazine hydrate or 3-nitro-A-bromophthalimide with tetrahydrofur-furyl alcohol l,3-dichloro-5,5-dimethyl-2,4-imidazolidindione with xylene (violent explosion). Individually indexed compounds are ... 

There are numerous reactions of interest that fit the description mentioned above. For example, the reaction of tert-butoxyl with aliphatic alcohols is essentially invisible or silent in nLFP. A practical example would be the reaciton of f-BuO" with 2-propanol, in which the reaction with benzhydrol (diphenyl methanol) could be used as a probe. The mechanism is shown in Scheme 18.3 for this example. 

Salicylic acid, upon reaction with amyl alcohol and sodium, reduces to a ring-opened aliphatic dicarboxylic acid, ie, pimelic acid (eq. 5). The reaction proceeds through the intermediate cyclohexanone-2-carboxylic acid. This novel reaction involves the fission of the aromatic ring to tfj-hexahydrosalicylic acid when salicylic acid is heated to 310°C in an autoclave with strong alkali. Pimelic acid is formed in 35—38% yield and is isolated as the diethyl ester. 

Mood, A. R. H., Haghighi, S., and Gholami, M. R. (2004), Fluorometric variable-temperature kinetic investigations of the transesterification reaction of procaine with aliphatic alcohols, / Pharm. Pharm. Sci.., 7(1), 88-91. 

Dihydroxybenzene derivatives readily form complexes of the type [Pd(02CeH3R)(PPh3)2].178,179 The increased acidity of aromatic alcohols compared with aliphatic alcohols combined with the chelate effect makes these compounds much more stable than alkoxide complexes. Their stability is such that they can be subjected to further reactions involving the side chain group R to generate compounds suitable for use as indicators for immunoassay.178... 

Strategies for preparing mixed, acyclic acetals on insoluble supports include the oxidative haloalkoxylation of support-bound enol ethers (Entry 6, Table 6.1) and the acid-catalyzed reaction of alcohols with resin-bound enol ethers [627]. Alternatively, resin-bound a-chloro ethers can be converted to mixed acetals by reaction with alcohols or phenols in the presence of strong bases (KO/Bu, HOfBu, DMF, 5 h) [550,628]. Polystyrene-bound a-(phenylseleno)ethers react with aliphatic alcohols under slightly acidic conditions (NIS, TfOH, DCM/dioxane (1 1), 0°C to 20 °C, 1 h) to yield mixed, acyclic acetals [628],... 

Sulfonamides of primary amines are readily deprotonated (pAia 9-11) and can thus be N-alkylated or N-arylated. Because of their high nucleophilicity and low basicity, deprotonated sulfonamides also react smoothly with less reactive electrophiles, such as n-alkyl bromides [136] (Table 8.9). Sulfonamides can also be N-alkylated with aliphatic alcohols under Mitsunobu conditions. Suitable solvents for the N-alkylation of sulfonamides on polystyrene by Mitsunobu reaction are DCM, toluene, and THF. 

The Mitsunobu reaction is usually only suitable for the alkylation of negatively charged nucleophiles rather than for the alkylation of amines, and only a few examples of such reactions (mainly intramolecular N-alkylations or N-benzylations) have been reported (Entry 15, Table 10.2). Halides, however, are very efficiently alkylated under Mitsunobu conditions, and it has been found that the treatment of resin-bound ammonium iodides with benzylic alcohols, a phosphine, and an azodicarboxylate leads to clean benzylation of the amine (Entry 9, Table 10.3). Unfortunately, alkylations with aliphatic alcohols do not proceed under these conditions. The latter can, however, also be used to alkylate resin-bound aliphatic amines when (cyanomethyl)-phosphonium iodides [R3P-CH2CN+][r] are used as coupling reagents [62]. These reagents convert aliphatic alcohols into alkyl iodides, which then alkylate the amine (Entry 10, Table 10.3). 

Isothioureas can be prepared on insoluble supports by S-alkylation or S-arylation of thioureas (Entry 7, Table 14.6). Further methods for the preparation of isothioureas on insoluble supports include the N-alkylation of polystyrene-bound, A/,/V -di(alkoxy-carbonyl)isothioureas with aliphatic alcohols by Mitsunobu reaction (Entry 7, Table 14.6) and the addition of thiols to resin-bound carbodiimides [7]. Resin-bound dithio-carbamates, which can easily be prepared from Merrifield resin, carbon disulfide, and amines [76], react with phosgene to yield chlorothioformamidines, which can be converted into isothioureas by treatment with amines (Entry 8, Table 14.6). The conversion of support-bound a-amino acids into thioureas can be accompanied by the release of thiohydantoins into solution (see Section 15.9). The rate of this cyclization depends, however, on the type of linker used and on the nucleophilicity of the intermediate thiourea. 

Support-bound quinazolin-2,4-diones can be N-alkylated, either with alkyl halides under basic conditions or with aliphatic alcohols by means of the Mitsunobu reaction (Entries 12-14, Table 15.29). The methyl group of a 2-methylquinazolin-4-one is sufficiently acidic to undergo aldol condensations with aldehydes [343]. Aminations of chloroquinazolines are discussed in Section 10.1.2. 

In case of dealing with aliphatic alcohols (such as glycerin), it exerts an unfavorable influence on the equilibrium of the reaction and 2) In case of aromatic nitrations, it represses the formation of nitryl or nitromium ion,... 

Aliphatic or aromatic alcohols can be alkylated by epoxides under either basic or acidic reaction conditions. Reaction of aliphatic alcoholates with epoxides can be complicated by base-induced rearrangement or oligomerization of the epoxide, because alcoholates are strongly basic and because the product of epoxide ring opening is again an alcoholate. These side reactions can be suppressed by using only catalytic amounts of base (Scheme 4.78). The examples sketched in Scheme 4.78 show that under basic reaction conditions nudeophilic attack occurs preferentially at the sterically most accessible carbon atom. 

Several catalysts have been found for the ring opening of epoxides. For instance, cyclohexene oxide gave an excellent yield of the trans-fi-amino alcohol when treated with either aromatic or aliphatic amines in the presence of a scandium triflate catalyst.21 Aromatic epoxides react in a regiospeciflc reaction at the benzylic carbon when treated with aromatic amines and scandium triflate but at the least substituted carbon of the epoxide ring when aliphatic amines react. Electronic effects are more important in the reactions of the aromatic epoxides whereas steric factors control the reaction with aliphatic epoxides. 

Vanadate reacts only very weakly with aliphatic amines such as ethylamine. As a consequence, reactions with aliphatic amines have not been extensively studied, but the information available suggests the reactions are analogous to those of alcohols. Additionally, there have been numerous studies of multidentate ligands where amino functionality is a critical component of vanadium ligation (Section 4.4). 

Wiberg determined the relative rates of addition of various alcohols and amines to silene 6, the results of which have been summarized above in Table 26. The fastest rates of addition were observed with aliphatic alcohols and amines, leading to the hypothesis that the first step of the reaction involves complexation of the neutral nucleophile at silicon, followed by proton transfer to the silenic carbon. Subsequent reports of the X-ray crystal... 

Absolute rate constants have been reported for the reaction of aliphatic alcohols with the transient disilenes 103, 104 and 35 in hydrocarbon solvents and are collected in Table 1768, l48. In all cases, linear dependences of fcdecay on alcohol concentration were observed, indicative of a mechanism that is first order in alcohol over the range of concentrations examined. Product studies carried out with 103 (equation 78) indicate that the reaction is highly regioselective, with the alkoxy group affixing itself to the less hindered... 

TABLE 17. Absolute rate constants for reaction of transient ddsilenes 103, 104 and 35 with aliphatic alcohols in methylcyclohexane or isooctane solution at 20-23 °C... 

---