Chloro-alcohol

Chlorohydrin (Section 7.3) A 1,2-disubstituted chloro-alcohol obtained by addition of HOC1 to an alkene. 

The p-bromo (or chloro) alcohol (50 ml) in PhH (330 ml) is refluxed with aqueous NaOH (29%, 17 ml) and TEBA-CI (3.3 g, 18 mmol) for 0.5-1 h. The cooled organic phase is separated, washed well with H20, dried (Na2S04), and evaporated to yield the oxirane, which can be purified by chromatography. 

The first example Is for the alkyl and aryl chloro alcohols. 

Figure 2. Alkyl Chloro Alcohols ( ) and Aryl Chloro Alcohols (A). Group a A6, 15, 18 group b A4, 14, 16 group c A12, 17 group d A10, 19.

The y-chloro alcohol 160 was lithiated, after deprotonation with a n-butyllithium in THF at —78°C, using lithium and a catalytic amount of naphthalene (1%) at the same temperature to give the corresponding intermediate 161, which was quenched with water, yielding 1-phenylpropanol (162) (Scheme 57). ... 

Pearson and Lin (52) developed an elegant approach to the synthesis of optically active ( )-swainsonine (247) from isopropylidene-D-erythrose (242) (Scheme 9.52). Wittig reaction of the acetonide 242 led to the (Z) alkene 252 in 86% yield. The chloro alcohol 252 was converted to the azide 253 in 76% yield, which subsequently underwent 1,3-dipolar cycloaddition, isomerization and hydroboration-oxidation to give the indolizidine 255 in 70% overall yield. Cleavage of the acetonide unit in 255 using 6 N HCl gave the target molecule 247 in 85% yield. 

Since 2000, atorvastatin (1) has been the world s top selling prescription drug, with sales in the 12 months to June 2008 of 13.8 billion [4]. The conversion of the chloro alcohol 2 to the key atorvastatin intermediate hydroxy nitrile 3 (Scheme 11.1) provides a good case history for the development of a continuous process, as it demonstrates... 

In the aliphatic series it has been reported49 60 that a number of long-chairi tertiary hypochlorites (illustrated by 3) undergo photodecomposi-tion to give the 5-chloro alcohols (4). It has been suggested that the reaction involves long chains, since the solutions are stable in the dark,... 

Prins reaction (cf 10, 186-187). Dimethylaluminum chloride is an effective catalyst for the ene addition of formaldehyde (as trioxane or paraformaldehyde) to mono- and 1,2-disubstituted alkenes.5 When 1.5-2.0 equiv. of the Lewis acid is used, homoallylic alcohols are obtained, usually in high yield. y-Chloro alcohols, formed by cis-addition of -Cl and -CH2OH to the double bond, are sometimes also observed when only 1 equiv. of the Lewis acid is present. The advantage of this reaction over the Prins reaction (using HC1) is that m-dioxanes are not formed as by-products, because formaldehyde no longer functions as a nucleophile when complexed to the Lewis acid. 

The difference between the most kinetically favoured cyclisations is easily seen in the type of base needed to cyclise chloro-alcohols to three- and five-membered cyclic ethers (epoxides and THFs). Chloroethanol 19 cyclises only as the oxyanion specific base is needed, i.e. a strong enough base to remove the OH proton completely. By contrast, 4-chlorobutanol cyclises by general base catalysis the proton is removed during the cyclisation 22 and weak bases will do.1, 2... 

You are already familiar with the simple formation of epoxides 26 by the action of peroxyacids such as mCPBA on alkenes 27. They can equally well be made by cyclisation of chloro-alcohols 25 as in the Comforth addition of a Grignard reagent to an a-chloroketone and cyclisation in base.3... 

The synthetic application of the a-chloro aldehydes has been demonstrated by the preparation of a variety of important chiral building blocks (Scheme 2.35) [26b]. The a-chloro aldehydes could be reduced to the corresponding optically active a-chloro alcohols in more than 90% yield, maintaining the enantiomeric excess by using NaBFU. It was also shown that optically active 2-aminobutanol - a key intermediate in the synthesis of the tuberculostatic, ethambutol - could be obtained in high yields by standard transformations from 2-chlorobutanol. Furthermore, the synthesis of an optically active terminal epoxide was demonstrated. The 2-chloro aldehydes could also be oxidized to a-chloro carboxylic acids in high yields without loss of optical purity, and further transformations were also presented. 

Various transformations of the optically active a-chloro ketones were also presented [28] optically active 2-chloro cyclohexanone was oxidized by a Baeyer-Villiger oxidation to the corresponding lactone in 81% yield without reduction in enantiomeric excess, and the ketone functionality was selectively reduced to the corresponding syn-a-chloro alcohol with a high diastereomeric ratio. 

C3) Is there a procedure available for preparing vicinal chloro-alcohols in one step ... 

TABLE 27. Arrhenius parameters for pyrolysis of w-chloro alcohols at 440 °C... 

In the synthetic studies on cembranoid natural products by Marshall et al. [155], an alcohol-halide coupUng was used to construct the macrocycles. As shown in Scheme 87, the linear precursor 259 was cyclized to 260 in 71 /o yield by addition of 1 equiv of EtMgBr to a solution of the chloro alcohol 259 in HMPA-THF and stirring at reflux for 4 h. There are also other examples of this macrocyclization method [156]. 

Asymmetric induction occurs during the alkylation of ketones with the a-sulfinyl carbanion derived from optically active 1-chloroalkyl-p-tolyl sulfoxides (equation 18). The resulting chloro alcohol may be converted to an optically active epoxide under alk ine conditions and the sulfinyl group is removed with n-butyllithium. While the process benefits from high asymmetric induction in the alkylatitm reaction, it must be recognized that, when either R 91H and/or R R diasteretHnerk compounds are formed and require separation. 

A related reaction occurs on irradiation of a hypochlorite (Scheme 2). The alkoxyl radical can again abstract a hydrogen atom in a l,S-shift, and the final chloro alcohol can be cyclized to form a tetrahydro-furan. Some processes lead directly to the cyclic product For instance, an alcohol with an accessible 8-hydrogen can be directly converted to a tetrahydrofuran on refluxing with lead tetraacetate. In a related reaction, treatment of an alcohol with silver carbonate and bromine can lead to the cyclic ether by initial formation of a hypohalite. The cyclization occurs when the rearranged radical is converted to a cation, either by oxidation with Pb(OAc)4 or by silver-assisted loss of halide ion. Hypoiodites are also fiequent-ly used, generated in situ. ... 

The reaction of formaldehyde with alkenes is of industrial interest and has been extensively studied. Reaction of excess formaldehyde as formalin with an alkene and aqueous acid gives 1,3-dioxanes (2) in 40-90% yield. Reaction of 2-butenes with paraformaldehyde and hydrogen chloride at -65 C gives a mixture of diastereomeric y-chloro alcohols rich in the isomer formed by trans addition to the alkenyl double bond. For example frans-2-butene gives an 85 15 mixture of erythro- and fAreo-3-chloro-2-methyl-1-butanol (equation 2). Reaction of 1-alkenes under similar conditions gives 3-alkyl-4-chlorotet-rahydropyrans (5) in 50-80% yield (Scheme 2). Initial reaction occurs via addition of formaldehyde to the terminal carbon of the double bond, followed by loss of a proton to give the 3-alken-l-ol. Reaction of... 

Cyclopentanol ene type products have been obtained in stepwise reactions. Treatment of (223) with SnCU gives (222) in 42% yield. Cyclization with TiCU affords chloro alcohol (224) in 80-90% yield.85 Treatment of (225) with formic acid at 45 °C results in loss of methanol to give the unsaturated ketone, followed by transannular Prins reaction and loss of a proton to give, after hydrolysis of formate esters,... 

Michael addition of methyl vinyl ketone to 24, followed by base-catalyzed cyclization, afforded the j8-diketone 25. Reaction of 25 with phosphorus oxychloride in dimethylformamide gave the vinylogous acid chloride 26 which afforded the corresponding chloro alcohol on reduction with lithium aluminum tri-f-butoxyhydride. Hydrolysis and concomitant dehydration of this chloro alcohol then gave the desired unsaturated ketone (23). 

Conversion of crude chloro alcohol 47 to amino alcohol 48 was accomplished by dissolving 47 in a methanol/tcrt-butylamine mixture and heating to reflux (56 to 60°C) in the presence of 1 equiv of solid NaOH. The use of NaOH allows the rapid formation of intermediary epoxide 51, whose formation was confirmed by NMR and HPLC. Initially, with 1 1 MeOH/tert-butylamine, the displacement produced an 80 20 ratio of amino alcohols 48 52. Decreasing the amount of methanol led to reduced levels of the undesired regioisomer, with only 4% 52 being formed with a 1 5 ratio of MeOH/tcrt-butylamine. Further reduction in the amount of MeOH led to much slower reaction rates. After workup of the latter conditions, crystallization from heptane afforded an 89.8% isolated yield of amine 48 (from ketone 46) that was 99.9% pure with >99.9% ee as the (5)-enantiomer. 

The full paper (Vol. 8, p. 58) on the biogenetic-type synthesis of the linalyl oxides has been published and dihydro-ocimenoyl oxide (230) has been synthesized by the regiospecific reaction of 2-methylbutanal with the y-carbon atom of a,a-dimethylallyltrimethylsilane catalysed by TiCU, presumably via cyclization of the corresponding y-chloro-alcohol. ° Straightforward syntheses of perillene (231 X = H,H) and egomaketone (231 X = O) involve prenylation... 

---