Hydroxyalkylation with Epoxides

Many of the organometallic compounds in this book are stable (i.e. are not ammonolysed) in liquid ammonia. They can be prepared simply by adding the substrate to an equivalent amount (or slight excess) of an in situ prepared alkali 

Under the usual conditions (THF or liquid ammonia as solvent), mono-substituted epoxides are attacked on the methylene carbon atom. The stereochemistry of the ring opening of vidnally di-substituted epoxides (e.g., epoxycyclohexane) is in accordance with an SN2-mechanism. 

For the introduction of a hydroxymethyl group our procedure with dry polymeric formaldehyde (paraform) in many cases works satisfactorily [2], We have noticed that, irrespective of the nature of the organometallic species (mostly Li as counterion), the reaction in Et20 or THF does not start below 15 °C. This might be explained by assuming that at room temperature a sufficiently high rate of dissociation into the monomer is attained. Liquid ammonia is generally unsuitable as a solvent for the hydroxymethylation with paraformaldehyde. 

Brandsma L (1988) Preparative Acetylenic Chemistry, Revised Edition, Elsevier 

Schaap A, Brandsma L, Arens JF (1965) Reel Trav C him Pays-Bas 84 1200 

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Solutions of aryllithium obtained by bromine-lithium exchange with butyllithium contain butyl bromide. In THF the aryllithium compounds are smoothly alkylated by this alkyl halide at temperatures above —10 °C. However, if Et20 is used as a solvent, this butylation is much slower. This observation permits successful hydroxyalkylation with epoxides (assisted by coordination between lithium and oxygen) and paraformaldehyde at temperatures between —10 and +35 °C. 

Based upon our observations we can make a gross subdivision into the groups A, B, and C for alkylations with alkyl halides and hydroxyalkylations with epoxides in THF-hexane (1 1) mixtures. 

Alkylation with R-X Hydroxyalkylation with epoxides Hydroxyalkylation with RCHO, R2CO Acylation with RCOX 1,4-Addtion to Enones, etc. 

Ethyleneimine reacts with epoxides to form hydroxyaLkylated products, eg, A/-(P-hydroxyethyla2iridine) [1072-52-2]. The epoxide component is frequentiy used in substoichiometric amount in order to prevent multiple aLkoxylation (180—190). Ethyleneimine and episulftdes react to give complex product mixtures, since the l-(2-mercaptoethyl)a2iridine produced initially can easily react further with both reactants (191,192). 

It also reacts with epoxides forming 2-hydroxyalkyl thiols, eg, 2-mercaptoethanol [60-24-2] and bis(2-hydroxyalkyl) sulfides such as bis (2-hydroxyethyl) sulfide [111-48-8], both products are made commercially ... 

All lene Oxides and Aziridines. Alkyleneamines react readily with epoxides, such as ethylene oxide [75-21-8] (EO) or propylene oxide [75-56-9] (PO), to form mixtures of hydroxyalkyl derivatives. Product distribution is controlled by the amine to epoxide mole ratio. If EDA, which has four reactive amine hydrogens, reacts at an EDA to EO mole ratio which is greater than 1 4, a mixture of mono-, di-, tri,-, and tetrahydroxyethyl derivatives of EDA are formed. A 10 1 EDA EO feed mole ratio gives predominandy 2-hydroxyethylethylenediamine [111-41-1], the remainder is a mixture of bis-(2-hydroxyethyl)ethylenediamines (7). If the reactive NH to epoxide feed mole ratio is less than one and, additionally, a strong basic catalyst is used, then oxyalkyl derivatives, like those shown for EDA and excess PO result (8,9). 

The morpholinone analogs 108 have been prepared from the reaction of sodium glyphosate with epoxides. Upon acidifrcation and heating, the resulting Al-hydroxyalkyl intermediates 107 produced the morpholinone monosodium salts 108 (66). 

SchOllkopf et al. reacted lithiated isocyanides with epoxides to obtain 3-hydroxyalkyl isocyanides. The reaction was also performed with cyclohexene oxide, and the hydroxyisocyanate formed was cyclized to oxazines with copper(I) oxide, resulting in a diastereomeric mixture of 174 and 175 (76LA2105 86AG755). Irradiation of aliphatic dieneamides yielded a variety of dihydrooxazines of type 167 (88T1959). 

Etherification with epoxides, such as ethylene oxide or propylene oxide, in aqueous medium in the presence of a basic catalyst yields O-hydroxyalkyl derivatives (11, 12) (Figure 5.6). The degree of substitution varies with the amount of epoxide ranging from 0.1 to 2. As the chain length of the epoxide increases, the water solubility decreases however, small amounts of 2-propanol increase the solubility. 

Several 2-thienylaodiuin8 have likewiae been treated, with epoxides to obtain the corresponding 2-( hydroxyalkyl]thiophenes (Eq. 801. Among the epoxides examined in ibis connexion are ethylene oxido. propylene oxide Biyrene oxide, l,2-epo -3-butene. and epddoro-hydrin ... 

The reactions between a-metalloalkyl sulfoxides and electrophiles have been extensively studied. Although alkylations of the sodium or potassium salts of dialkyl sulfoxides are not always very efficient since a,a -dialkylated sulfoxides are often produced (or stilbene in the case of methyl-sulfinyl carbanion and benzyl bromide ), those employing the lithioalkyl aryl sulfoxides work more efficiently with alkyl or allyl halides " and with epoxides. " " Typical examples of these alkylations, allylations and hydroxyalkylations (from epoxides) are illustrated in Scheme 86. 

Alkylation by simple alkylating agents seems not to have been investigated, but hydroxyalkylation by epoxides, cyanoethylation, addition of methyl vinyl ketone as well as of vinyl sulfones, e.g., with formation of 121, have been reported. 

Hydroxyalkylation of Lithiated Bis(methylthio)methane with Epoxides... 

Indoles react with epoxides and aziridines in the presence of Lewis acids (see section 17.5 for reaction of indolyl anions with such reactants) with opening of the three-membered ring and consequent 3-(2-hydroxyalkylation) and 3-(2-amino-alkylation) of the heterocycle. Both ytterbium triflate and phenylboronic acid are good catalysts for reaction with epoxides under high pressure " silica gel is also an effective catalyst, but slow at normal pressure and temperature." Lewis acid-mediated reaction with aziridines can be catalysed by zinc triflate or boron trifluoride.More reactive alkylating electrophiles react at lower temperatures, at room temperature with dimethylallyl bromide for example. ... 

Hydroxyalkyl CS Reacting CS with epoxide Marked surface activity and foam-enhancing properties of CS Antimicrobial, temperature sensitive injectable carrier for cells... 

A third method for preparing alkylcobalt tetracarbonyls is the reaction of cobalt hydrocarbonyl with epoxides. The products are 2-hydroxyalkyl-cobalt tetracarbonyl derivatives (9). Ethylene oxide produces 2-hydroxy-ethylcobalt tetracarbonyl. 

HydroxyethyUiydrazine (11) is a plant growth regulator. It is also used to make a coccidiostat, furazoHdone, and has been proposed, as has (14), as a stabilizer in the polymerization of acrylonitrile (72,73). With excess epoxide, polysubstitution occurs and polyol chains can form to give poly(hydroxyaLkyl) hydrazines which have been patented for the preparation of cellular polyurethanes (74) and as corrosion inhibitors for hydrauHc fluids (qv) (75). DialkyUiydrazines, R2NNH2, and alkylene oxides form the very reactive amineimines (15) which react further with esters to yield aminimides (16) ... 

Primary cycloaUphatic amines react with phosgene to form isocyanates. Reaction of isocyanates with primary and secondary amines forms ureas. Dehydration of ureas or dehydrosulfuri2ation of thioureas results in carhodiimides. The nucleophilicity that deterrnines rapid amine reactivity with acid chlorides and isocyanates also promotes epoxide ring opening to form hydroxyalkyl- and dihydroxyalkylaniines. Michael addition to acrylonitrile yields stable cyanoethylcycloalkylarnines. 

Other modifications of the polyamines include limited addition of alkylene oxide to yield the corresponding hydroxyalkyl derivatives (225) and cyanoethylation of DETA or TETA, usuaHy by reaction with acrylonitrile [107-13-1/, to give derivatives providing longer pot Hfe and better wetting of glass (226). Also included are ketimines, made by the reaction of EDA with acetone for example. These derivatives can also be hydrogenated, as in the case of the equimolar adducts of DETA and methyl isobutyl ketone [108-10-1] or methyl isoamyl ketone [110-12-3] (221 or used as is to provide moisture cure performance. Mannich bases prepared from a phenol, formaldehyde and a polyamine are also used, such as the hardener prepared from cresol, DETA, and formaldehyde (228). Other modifications of polyamines for use as epoxy hardeners include reaction with aldehydes (229), epoxidized fatty nitriles (230), aromatic monoisocyanates (231), or propylene sulfide [1072-43-1] (232). 

Epoxides give p-hydroxyalkyl carboxylates when treated with a carboxylic acid or a carboxylate ion and a suitable catalyst. Tetrahydrofiiran was opened to give O-benzoyl-4-iodo-l-butanol by treatment with benzoyl chloride and SmK. ... 

Reaction of the carbanion of chloromethyl phenyl sulphoxide 409 with carbonyl compounds yields the corresponding 0-hydroxy adducts 410 in 68-79% yield. Each of these compounds appears to be a single isomer (equation 242). Treatment of adducts 410 with dilute potassium hydroxide in methanol at room temperature gives the epoxy sulphoxides 411 (equation 243). The ease of this intramolecular displacement of chloride ion contrasts with a great difficulty in displacing chloride ion from chloromethyl phenyl sulphoxide by external nucleophiles . When chloromethyl methyl sulphoxide 412 is reacted with unsymmetrical ketones in the presence of potassium tcrt-butoxide in tert-butanol oxiranes are directly formed as a mixture of diastereoisomers (equation 244). a-Sulphinyl epoxides 413 rearrange to a-sulphinyl aldehydes 414 or ketones, which can be transformed by elimination of sulphenic acid into a, 8-unsaturated aldehydes or ketones (equation 245). The lithium salts (410a) of a-chloro-/ -hydroxyalkyl... 

A general method for the preparation of 2-hydroxyalkyl-l,4,7-triazacyclodecane macrocycles 202, 203, 204 with a single pendant arm < 1999J(P 1)1211 > through reaction of epoxides has been achieved from the ortho amide derivative l,4,7-triazatricyclo[5.2.1.04 10]decane 40 (Scheme 30) <1999J(P1)1211>. 

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