Tertiary alcohols alkylation with

Alkylation of these as their sodium salts with the ubiquitous N-C2-chloroethyl)dimethylamine affords the desired antihistamines. There are thus obtained, respectively, mephenhydramine (23a) chlorphenoxamine (23b), and mebrophenhydramine (23c)Alkylation of the tertiary alcohol, 22b, with the pyrrolidine derivative, 24, affords meclastine (25). In much the same vein, reaction of 2-acetylpyridine with phenyImagnesium bromide gives the tertiary alcohol, 27. Alkylation in the usual way leads to the potent antihistamine, doxylamine (28). " ... 

The reaction gives good yields with primary, secondary, and tertiary alcohols, and with alkyl and aryllithium reagents.Allylic alcohols also couple with certain... 

Similarly, like secondary and tertiary alcohols, amines with the alkyl groups branched ona-carbon atoms (i.e. containingthe grouping R R2CH—... 

Aube and co-workers have found that enolizable ketones react with benzyl azide in triflic acid to yield /V-(phenylamino)-methylated products [Eq. (5.354)]. The transformation is an aza-Mannich reaction interpreted with the involvement of the Mannich reagent A -phenyl iminium ion 295 formed in situ in a Schmidt rearrangement. Cyclic tertiary alcohols react with alkyl azides in triflic acid to yield N-alkylamines (296, 297)983 [Eq. (5.355)]. The Schmidt rearrangement was used to transform Merrifield resin into amino-polystyrene resin by reacting the azido derivative in excess triflic acid (CH2CI2, 0°C).984... 

Poor yields of alkyl chlorides from primary and secondary alcohols. Primary and secondary alcohols react with HC1 much more slowly than tertiary alcohols, even with zinc chloride added. Under these conditions, side reactions may prevent good yields of the alkyl halides. 

Another method for the conversion of alkyl hahdes to carboxylic esters is treatment of a halide with nickel carbonyl Ni(CO)4 in the presence of an alcohol and its conjugate base. When R is primary, RX may only be a vinylic or an aryl halide retention of configuration is observed at a vinylic R. Consequently, a carbocation intermediate is not involved here. When R is tertiary, R may be primary alkyl as well as vinylic or aryl. This is thus one of the few methods for preparing esters of tertiary alcohols. Alkyl iodides give the best results, then bromides. In the presence of an amine, an amide can be isolated directly, at least in some instances. 

Because of the low reactivity of the tertiary alcohol, alkylation of the 014-hydroxyl with alkyl halides such as propyl or isoamyl halides was unsuccessful [Schmidhammer H, unpublished observations]. Therefore, allylic halides were employed to introduce 14-O-alkenyl substituents using similar conditions as described above [ 43—461. Catalytic hydrogenation afforded the corresponding 14-O-alkyl derivatives [43 -5]. Thus, 14-hydroxy-5-methylcodeinone (20) was treated with 3,3-dimethylallyl bromide in DMF in the presence of NaH to give compound 21, which underwent catalytic hydrogenation to yield 14-O-isoamyl-substituted morphinan 24 (Scheme 5) [43]. Similarly 14-phenylpropoxymorphinans 25 and 26 were prepared from 14-hydroxycodeinone (3) and 21, respectively, via intermediates 22 and 23, which were obtained by alkenylation using cinnamyl bromide (Scheme 5) [44, 45],... 

Alkyl halides. Secondary and tertiary alcohols react with the reagent to form aUcyl fluorides. If an alkali halide (NaF, NaCl, NH4Br, Kl) is added to the reaction, alkyl halides, even primary, are formed corresponding to the added salt. The displacement proceeds with inversion. 

Primary, secondary, and tertiary alcohols react with 4-methoxybenzyl-2-pyri-dylthiocarbonate [197.1, Scheme 4.197] in the presence of silver(I) triflate at room temperature within 2 h to give the corresponding p-methoxybenzyl ethers in 72-90% yield. No N-alkylation is observed with amides, carbamates and pyrimidine-type nitrogens and no ester migrations, p-eliminations, or epimerisa-tions besmirch the method. Reagent 197.1 is a yellow crystalline solid at 0 that can be stored for several months without noticeable decomposition. It is prepared in 80% yield by the reaction of p-methoxybenzyl alcohol with di-(2-pyridyl)thiocarbonate. 

A short synthesis of calamenene (208) has been achieved by cyclodehydration of the tertiary alcohol (207) with phosphorus pentoxide. The mechanism of this reaction probably involves a carbonium ion re-organization followed by an intramolecular Friedel-Crafts alkylation. In an independent study Wender and... 

Different reagents such as HX and PX3 may be used to prepare alkyl halides from primary and secondary alcohols. However, because elimination reactions predominate when tertiary alcohols are treated with phosphorous trihalides, preparing tertiary alkyl halides from tertiary alcohols proceeds with good yields only if concentrated hydrogen halides, HX, are used. The reaction of 2-methyl-2-butanol with hydrochloric acid to produce 2-chloro-2-methylbutane (Eq. 14.17) illustrates this transformation. 

We ve already seen one general reaction of alcohols—their conversion to alkyl halides (Section 12.3). Tertiary alcohols react with HGl and HBr by an SnI mechanism through a carhocation intermediate. Primary and secondary alcohols react with SOCI2 and PBra by an Sn2 mechanism through backside attack on a chlorosulfite or dibromophosphite intermediate. 

Tertiary alcohols react with the reagent immediately, with the separation of alkyl chlorides, the formation of which is indicated first by incipient turbidity and after a while by the separation of a layer. Secondary alcohols react in this manner after 2 — 5 min after 10 min a distinct layer is formed. Primary alcohols do not react imder these conditions, and if they are lower than C, they are soluble in the reagent. Impurities can also be a cause of the formation of turbidity, but they do not produce a layer. Allyl alcohol behaves as a secondary alcohol, because its OH group is activated by the double bond of the neighboring carbon atom. 

Tertiary alcohols react with HCl alone. The rate of this reaction is such that the corresponding alkyl chloride is formed at room temperature within a few minutes. Primary and secondary alcohols do not react under similar conditions. The following test can be utilized for the diflferenciation of tertiary alcohols from secondary alcohols To 1 ml of alcohol in a test tube 6 ml of cone. HCl are added and allowed to stand. After 2 min one can see whether the separation of the alkyl halide has set in (turbidity) and whether a layer is formed. 

Like the reaction of alkyl halides with nucleophiles such as hydroxide ion, alcohols react with nucleophiles by two reaction mechanisms. The mechanism depends on the structure of the alkyl group. Primary alcohols react with nucleophiles by an Sj j2 mechanism. Tertiary alcohols react with nucleophiles by an Sj l mechanism. The mechanism for the reaction of nucleophiles with secondary alcohols is often, but not always, Sj l. In every class of alcohol, the leaving group is a water molecule, not hydroxide ion. An acid catalyst is required to form the conjugate acid of the alcohol, an alkyloxonium ion. 

The resulting esters differ sufficiently in odour and water solubility to be readily distinguished from the original alcohol. With tertiary alcohols the product is largely the alkyl chloride ... 

Acid-catalyzed alkylation of aromatics with alcohols themselves is widely used. Whereas tertiary (and secondary) alcohols react with rel-... 

The order of reactivity of the hydrogen halides parallels their acidity HI > HBr > HCl >> HF Hydrogen iodide is used infrequently however and the reaction of alco hols with hydrogen fluoride is not a useful method for the preparation of alkyl fluorides Among the various classes of alcohols tertiary alcohols are observed to be the most reactive and primary alcohols the least reactive... 

Tertiary alcohols are converted to alkyl chlorides m high yield within minutes on reaction with hydrogen chloride at room temperature and below... 

Because tertiary alcohols are so readily converted to chlorides with hydrogen chlo nde thionyl chlonde is used mainly to prepare pnmary and secondary alkyl chlondes Reactions with thionyl chlonde are normally carried out m the presence of potassium carbonate or the weak organic base pyndme... 

Additional evidence for carbocation intermediates in certain nucleophilic substitutions comes from observing rearrangements of the kind normally associated with such species For example hydrolysis of the secondary alkyl bromide 2 bromo 3 methylbutane yields the rearranged tertiary alcohol 2 methyl 2 butanol as the only substitution product... 

With secondary and tertiary alcohols Ihis slage is an 8 1 reaclion m which Ihe alkyl oxonium ion dissociates to a carbocalion and water... 

The few studies that have been carried out with optically active tertiary alcohols indicate that almost complete racemization accompanies the preparation of tertiary alkyl halides by this method... 

Unbranched primary alcohols and tertiary alcohols tend to react with hydrogen halides without rearrangement The alkyloxonmm ions from primary alcohols react rap idly with bromide ion for example m an Sn2 process Tertiary alcohols give tertiary alkyl halides because tertiary carbocations are stable and show little tendency to rearrange... 

The reactions of alcohols with hydrogen halides to give alkyl halides (Chapter 4) are nucleophilic substitution reactions of alkyloxonium ions m which water is the leaving group Primary alcohols react by an 8 2 like displacement of water from the alkyloxonium ion by halide Sec ondary and tertiary alcohols give alkyloxonium ions which form carbo cations m an S l like process Rearrangements are possible with secondary alcohols and substitution takes place with predominant but not complete inversion of configuration... 

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