Nucleophiles alcohols

FIGURE 22.5 The diazonium ion generated by treatment of a primary alkylamine with nitrous acid loses nitrogen to give a carbocation. The isolated products are derived from the carbocation and include, in this example, alkenes (by loss of a proton) and an alcohol (nucleophilic capture by water). 

As shown in Scheme 199, the 5-aminopyrimidine stmcture may be also incorporated into a more complex bicyclic system. Thus, diazotization of 3-amino-4-oxo-4//-pyrimido[ 1,23 lpyndazincs 1198 followed by treatment with 50% aqueous tetrafluoroboric acid results in precipitation of salts 1199. When heated with alcohols, nucleophilic attack on the carbonyl group opens the pyrimidine ring. The obtained species 1200 assume conformation 1201 that is more suitable for bond formation between the opposite charged nitrogen atoms. Alkyl l-(pyridazin-3-yl)-l//-l,2,3-triazole-4-carboxylates 1202 are obtained in 31-66% yield <2002ARK(viii)143>. 

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). 

The carbon-metal cr-bond emanating from the addition of an alcohol nucleophile to a 7t-alkene complex may undergo a protonolytic cleavage to effect overall hydroalkoxylation of the alkene. While this process is difficult to achieve due to the propensity of the cr-metal species to undergo f3-H elimination, some encouraging progress in this area has recently been forthcoming. 

Although aliphatic alcohols are typically poor acceptors in the Mitsunobu-type glycosylation, Szarek and coworkers have highlighted one advance to this end [95]. For the triphenylphosphine and diethylazodicarboxylate promoted glycosylation of a monosaccharide acceptor, the addition of mercuric bromide is necessary to promote the reaction. For example, the (1,6)-disaccharide 44 was obtained in 80% yield using this modified Mitsunobu protocol. Unlike previous examples with phenol or N-acceptors, preactivation of the hemiacetal donor was performed for 10 min at room temperature prior to addition of the aliphatic alcohol nucleophile. 

The cyclic sulfites were first found to react with lithium phenoxides as nucleophiles in DMF in a one-pot procedure commencing from the unprotected diol [357]. Subsequent work opened up this class of donor to alcohol nucleophiles in conjunction with the use of a Lewis add, such as Yb(OTf)3 or Ho(OTf)3, to activate the donor in refluxing toluene (Scheme 4.57) [314,358,359]. The very high degree of P-selec-tivity observed in these reactions is consistent with an SN2-like displacement of the sulfite oxygen. 

The contrast between the lack of enantioselectivity in Scheme 39 and the moderate to excellent diastereoselectivity seen with alcohol nucleophiles in Schemes 19 and 33 can be attributed to the difference in leaving groups (diphenyl phosphate vs diethyl phosphate) and to the differences in the radical cations themselves, all of which impinge on the rate of equilibration of the contact alkene radical cation/anion pair. 

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. 

Carbonyl Compound Homoallyl alcohol Nucleophile Products... 

Substituents can play a part in the reaction of 1,2,4-trioxolanes with oxygen nucleophiles, for example 3-acyl or 3-aldehydic substituents can lead to fragmentation pathways via attack at the carbonyl (Section 4.16.6.2). Also, it is possible to displace suitable leaving groups in the 3-position with alcohol nucleophiles (Sections 4.16.6.3 and 4.16.9.4). 

In the presence of alcohols, nucleophilic cleavage of acylpalladium intermediate becomes the major pathway to give esters (Scheme 12). 

Mechanism. The first step is the typical acid-catalysed addition to the carbonyl group. Then the alcohol nucleophile attacks the carbonyl carbon, and forms a tetrahedral intermediate. Intramolecular proton transfer from nitrogen and oxygen yields a hemiacetal tetrahedral intermediate. The hydroxyl group is protonated, followed by its leaving as water to form hemi-acetal, which reacts further to produce the more stable acetal. 

The reaction of 14 may remind one of the well-established reaction mechanism for chymotrypsin (Fig. 5) (20). By comparing the acyl-trans-fer reaction of complex 14 with that of chymotrypsin 17, we find that the alcoholic nucleophiles in 14 and 17 are activated by Zn11—OH- and imidazole (in a triad), respectively. Several common features should be pointed out (i) Both reactions proceed via two-step reaction (i.e., double displacement), (ii) The basicity of Zn11—OH (pKa = 7.7) is somewhat similar to that of imidazole (plfa = ca. 7). (iii) The initial acyl-transfer reactions to alcoholic OH groups are rate determining, (iv) In NA hydrolysis with chymotrypsin, the pH dependence of both the acylation (17 — 18) and the deacylation (19 — 17) steps point to the involvement of a general base or nucleophile with a kinetically revealed piFCa value of ca. 7. A major difference here is that while the... 

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. 

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. 

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]. 

In the closed conformation the carbonyl group is orientated towards the naphthalene system, and consequently its Si-face is blocked such that only the Re-face is available to react with an incoming alcohol nucleophile. The relative orientation of the nucleophile was also suggested to be ordered by 7t-7r-staclcing interactions because sec-alcohol nucleophiles incorporating an electron-rich aryl amide gave the highest selectivities. 

Scheidt et al. [62] reported the formation of saturated esters utilizing benzimi-dazolium salts when protonating the intermediate 67 (see Scheme 9.19) and trapping the resulting activated carbonyl unit with an alcohol nucleophile (Scheme 9.21). These authors were able to show that the electrophile (phenol) and the nucleophile (primary or secondary alcohols) can be decoupled, enabling a broad substrate scope, though they had to employ an excess of phenol (2 eq.) and the nucleophile (5 eq.), accompanied by rather harsh conditions (100 °C). 

Yamamoto described a cascade cyclization reaction to prepare allene-substituted isochromenes 39 (Scheme 5.18).68 Diynones 38, when submitted to the action of AgSbI V, (5mol%), formed a benzopyrylium intermediate Z (identified by NMR spectroscopy), which could undergo a 1,4-Michael-type addition with alcohol nucleophiles to produce allenylisochromenes 39 (Scheme 5.18). 

Because phenols are stronger acids than alcohols, nucleophilic phenoxide ions can be prepared by reacting the phenol with bases such as hydroxide ion or carbonate ion. 

Like hydrates, hemiacetals are not favored at equilibrium and, in general, cannot be isolated. The equilibrium is shifted in their favor by the inductive effects of electron-withdrawing groups, similar to the case of hydrates. In addition, the equilibrium is shifted in their favor if the alcohol nucleophile and carbonyl electrophile are part of the same molecule as in the following example ... 

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