Alcohols nucleophilic catalyst

Acylation of alcohols is often performed in the presence of an organic base such as pyridine. The base serves two purposes. It neutralizes the protons generated in the reaction and prevents the development of high acid concentrations. Pyridine also becomes directly involved in the reaction as a nucleophilic catalyst (see Section 8.5). 

Sulfonic esters are most frequently prepared by treatment of the corresponding halides with alcohols in the presence of a base. The method is much used for the conversion of alcohols to tosylates, brosylates, and similar sulfonic esters. Both R and R may be alkyl or aryl. The base is often pyridine, which functions as a nucleophilic catalyst, as in the similar alcoholysis of carboxylic acyl halides (10-21). Primary alcohols react the most rapidly, and it is often possible to sulfonate selectively a primary OH group in a molecule that also contains secondary or tertiary OH groups. The reaction with sulfonamides has been much less frequently used and is limited to N,N-disubstituted sulfonamides that is, R" may not be hydrogen. However, within these limits it is a useful reaction. The nucleophile in this case is actually R 0 . However, R" may be hydrogen (as well as alkyl) if the nucleophile is a phenol, so that the product is RS020Ar. Acidic catalysts are used in this case. Sulfonic acids have been converted directly to sulfonates by treatment with triethyl or trimethyl orthoformate HC(OR)3, without catalyst or solvent and with a trialkyl phosphite P(OR)3. ... 

An interesting variant involves the use of an allylic alcohol as the alkene component. In this process, re-oxidation of the catalyst is unnecessary since the cyclization occurs with /Uoxygen elimination of the incipient cr-Pd species to effect an SN2 type of ring closure. Both five- and six-membered oxacycles have been prepared in this fashion using enol, hemiacetal, and aliphatic alcohol nucleophiles.439,440 With a chiral allylic alcohol substrate, the initial 7r-complexation may be directed by the hydroxyl group,441 as demonstrated by the diastereoselective cyclization used in the synthesis of (—)-laulimalide (Equation (120)).442 Note that the oxypalladation takes place with syn-selectivity, in analogy with the cyclization of phenol nucleophiles (1vide supra). 

Although the initial report included amine nucleophiles, the scope was limited to activated amines such as indole (which actually undergoes C-alkylation at the 3-position), phthalimide, and 7/-methylaniline. Furthermore, enantioselectivities were inferior to those observed with alcohols as nucleophiles. Lautens and Fagnou subsequently discovered a profound halide effect in these reactions. The exchange of the chloride for an iodide on the rhodium catalyst resulted in an increased enantioselectivity that is now comparable to levels achieved with alcoholic nucleophiles ... 

Berkessel and co-workers have demonstrated the utility of the bifunctional cyclohexane-diamine catalysts in the dynamic kinetic resolution of azalactones (Schemes 60 and 61) [111, 112]. The authors proposed that the urea/thiourea moiety of the catalyst coordinates and activates the electrophilic azlactone. The allyl alcohol nucleophilicity is increased due to the Brpnsted base interaction with the tertiary amine of the catalyst. 

The first class of amine-based nucleophilic catalysts to give acceptable levels of selectivity in the KR of aryl alkyl. yec-alcohols was a series of planar chiral pyrrole derivatives 13 and 14, initially disclosed by Fu in 1996 [25, 26]. Fu and co-workers had set out to develop a class of robust and tuneable catalysts that could be used for the acylative KR of various classes of. yec-alcohols. Planar-chiral azaferrocenes 13 and 14 seemed to meet their criteria. These catalysts feature of a reasonably nucleophilic nitrogen and constitute 18-electron metal complexes which are highly stable [54-58]. Moreover, by modifying the substitution pattern on the heteroaromatic ring, the steric demand and hence potentially the selectivity of these catalysts could be modulated. 

Preparation of esters Acid chlorides react with alcohols to give esters through a nucleophilic acyl substitution. Because acid chloride is reactive towards weak nucleophile, e.g. alcohol, no catalyst is required for this substitution reaction. The reaction is carried out in base, most commonly in pyridine or triethylamine (EtaN). 

While our proposed mechanism was interesting, it left some unanswered questions. What was the nature of the catalyst complex and more importantly, why was this not behaving like a classic acid catalysis Boe [11, 12] had postulated protonation of the alkoxy species followed by SN2 attack by the alcohol nucleophile. This is consistent with the negative value that he found for p. This does not agree though with the idea of a catalyst complex, nor does it agree with the findings reported here of a positive value of p. 

Torgov introduced an important variation of the Michael addition allylic alcohols are used as vinylogous a3-synthons and 1,3-dioxo compounds as d2-reagents (S.N. Ananchenko, 1962, 1963 H. Smith, 1964 C. Rufer, 1967). Mild reaction conditions have been successful in the addition of 1,3-dioxo compounds to vinyl ketones. Potassium fluoride can act as weakly basic, non-nucleophilic catalyst in such Michael additions under essentially non-acidic and non-basic conditions (Y. Kitahara, 1964). 

Miller et al. have shown that short peptides containing alkylated histidine residues can be used as catalysts for the kinetic resolutions of secondary and some tertiary alcohols. These catalysts are also postulated to effect catalysis by a nucleophilic mechanism. The backbone amides and ancillary functionality are proposed to govern selectivity through catalyst-substrate contacts (e.g., hy-... 

Sometimes, over-oxidation of benzylic alcohol to benzoic acid is observed with IBX.88a This over-oxidation does not happen in all benzylic alcohols and can be avoided by running the oxidation under anhydrous conditions. In fact, IBX is quite resistant to produce over-oxidation to acids even in the presence of a great excess of water. The water-soluble IBX analogue 46 is able to transform a number of benzylic alcohols into the corresponding benzaldehydes with no over-oxidation to acid, using water as solvent.92 When the oxidation of alcohol to acid is purposefully looked after, it can be performed with IBX in DMSO with the addition of certain nucleophilic catalysts, such as 2-hydroxypyridine (HYP) or TV-hydro-xysuccinimide (NHS).110... 

The slow step in the process is then the attack by a second nucleophile at an R—X edge to give a hexacoordinate intermediate or transition state. The second nucleophile is the alcohol in the case of alcoholysis or the nucleophilic catalyst in the case of racemization (equations 12 and 13). 

Most work on this subject is based on the use of alcohols as reagents in the presence of enantiomerically pure nucleophilic catalysts [1, 2]. This section is subdivided into four parts on the basis of classes of anhydride substrate and types of reaction performed (Scheme 13.1) - desymmetrization of prochiral cyclic anhydrides (Section 13.1.1) kinetic resolution of chiral, racemic anhydrides (Section 13.1.2) parallel kinetic resolution of chiral, racemic anhydrides (Section 13.1.3) and dynamic kinetic resolution of racemic anhydrides (Section 13.1.4). 

Kinetic resolution of chiral, racemic anhydrides In this process the racemic mixture of a chiral anhydride is exposed to the alcohol nucleophile in the presence of a chiral catalyst such as A (Scheme 13.2, middle). Under these conditions, one substrate enantiomer is converted to a mono-ester whereas the other remains unchanged. Application of catalyst B (usually the enantiomer or a pseudo-enantiomer of A) results in transformation/non-transformation of the enantiomeric starting anhydride ). As usual for kinetic resolution, substrate conversion/product yield(s) are intrinsically limited to a maximum of 50%. For normal anhydrides (X = CR2), both carbonyl groups can engage in ester formation, and the product formulas in Scheme 13.1 are drawn arbitrarily. This section also covers the catalytic asymmetric alcoholysis of a-hydroxy acid O-carboxy anhydrides (X = O) and of a-amino acid N-carboxy anhydrides (X = NR). In these reactions the electrophilicity of the carbonyl groups flanking X is reduced and regioselective attack of the alcohol nucleophile on the other carbonyl function results. 

High enantiomeric excess in organocatalytic desymmetrization of meso-diols using chiral phosphines as nucleophilic catalysts was achieved for the first time by Vedejs et al. (Scheme 13.21) [36a], In this approach selectivity factors up to 5.5 were achieved when the C2-symmetric phospholane 42a was employed (application of chiral phosphines in the kinetic resolution of racemic secondary alcohols is discussed in Section 12.1). A later study compared the performance of the phos-pholanes 42b-d with that of the phosphabicyclooctanes 43a-c in the desymmetrization of meso-hydrobenzoin (Scheme 13.21) [36b], Improved enantioselectivity was observed for phospholanes 42b-d (86% for 42c) but reactions were usually slow. Currently the bicyclic compound 43a seems to be the best compromise between catalyst accessibility, reactivity, and enantioselectivity - the monobenzoate of hydrobenzoin has been obtained with a yield of 97% and up to 94% ee [36b]. 

This process relies on rapid base-induced racemization of the azlactone and rate-limiting ring opening by the alcohol nucleophile. In this process the DMAP derivative 79a acts as both Bronsted-basic and as nucleophilic catalyst. With 2-propanol as reagent enantiomeric excesses up to 78% were achieved for the product amino acid esters [87]. 

As most of the chiral nucleophilic catalysts that have been described to date were initially developed or tested for Type I acylative KR of sec-alcohols, these are the first class of reactions considered here. 

The first class of amine-based nucleophilic catalysts to give acceptable levels of selectivity in the KR of aryl alkyl sec-alcohols were a series of planar chiral pyrrole... 

This procedure offers a convenient method for the esterification of carboxylic acids with alcohols2 and thiols2 under mild conditions. Its success depends on the high efficiency of 4-dialkylaminopyridines as nucleophilic catalysts 1n group transfer reactions. The esterification proceeds without the need of a preformed, activated carboxylic acid derivative, at room temperature, under nonacidic, mildly basic conditions. In addition to dichloromethane other aprotic solvents of comparable polarity such as diethyl ether, tetrahydrofuran, and acetonitrile can be used. The reaction can be applied to a wide variety of acids and alcohols, including polyols,2 6 a-hydroxycarboxylic acid esters,7 and even very acid labile... 

Pyridine is. in fact, more nucleophilic than the alcohol, and it attacks the acyl chloride rapidly, forming a highly electrophilic (because of the positive charge) intermediate. It is then this intermediate that subsequently reacts with the alcohol to give the ester. Because pyridine is acting as a nucleophile to speed up the reaction, yet is unchanged by the reaction, it is called a nucleophilic catalyst. 

The answer is to protect the hydroxyl group, and the group chosen here was a silyl ether. Such ethers are made by reacting the alcohol with a trialkylsilyl chloride (here f-butyl dimethyl silyl chloride, or TBDMSCl) in the presence of a weak base, usually imidazole, which also acts as a nucleophilic catalyst (Chapter 12). 

Pyridine is a reasonable nucleophile for carbonyl groups and is often used as a nucleophilic catalyst in acylation reactions. Esters are often made in pyridine solution from alcohols and acid chlorides (die full mechanism is onp. 281 of Chapter 12). 

Two other groups have described useful nucleophilic catalysts for the kinetic resolution of secondary alcohols. Fu and coworkers have pre-... 

Chromatography) (equation 82). These complexes are used as enantioselective nucleophilic catalysts for reactions such as the rearrangements of O-acylated azlactones, oxindoles, and benzofuranones, and the kinetic resolution of secondary alcohols via acylation. X-ray crystal structures have been obtained for iV-acylated derivatives of (366), allowing for characterization of a likely intermediate along the catalytic pathway. 

The general mechanism of dimerization by nucleophilic catalysts has been described above. As Arnold et al. (9) remark, the availability of a pair of unshared electrons on the catalyst is not in itself. sufficient, however. Obviously, structural or other factors must be involved. For example, dimethylphenylphosphine and dimethylaniline are about equal in base strength (in 50% alcohol), but the phosphine is an extremely active catalyst and the amine is completely inactive. 

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