Intermolecular nucleophilic acyl

Intermolecular nucleophilic acyl substitution is a fundamental carbon—carbon bondforming reaction. In spite of its high synthetic potential, however, its intramolecular version, that is, intramolecular nucleophilic acyl substitution (INAS) is rather rare because of the intrinsic difficulties involved in carrying it out. One difficulty associated with the INAS reaction is that a reactive nucleophilic species must be generated in the presence of carbonyl functionality, and at the same time this nucleophile is expected to react only with... 

Carbonates of y-vinyl alcohols such as 87 undergo the intermolecular nucleophilic acyl substitution reaction to afford the corresponding alkyltitanium complex 88 having a lactone moiety (Scheme 12.59). The titanium-carbon bond in the... 

Mermerian AH, Fu GC (2003) Catalytic enantioselective synthesis of quaternary stereocenters via intermolecular C-acylation of silyl ketene acetals dual activation of the electrophile and the nucleophile. J Am Chem Soc 125 4050-4051... 

Some mechanistic aspects of the above cascade reaction deserve comment. Thus, after the intermolecular addition of the nucleophilic acyl radical to the alkene, the electrophilic radical adduct A, instead of undergoing reduction, reacts intramolecularly at the indole 3-position (formally a 5-endo cyclization) to give a new stabilized captodative radical B, which is oxidized to the fully aromatic system. (For a discussion of this oxidative step, see Section 1.5.)... 

An interesting intermolecular version of this reaction has likewise been put forward for the preparation of seven-, eight-, and nine-mem-bered carbocycle, as illustrated with a sole example in Scheme 3 [7]. In contrast to the above, these reactions begin with a carbonyl addition reaction of chloroiodoalkanes to cyclic or acyclic keto esters leading to the formation of an intermediate lactone. An intramolecular nucleophilic acyl substitution then terminates the sequence. The example in Scheme 3 represents a simple method for the construction of the 5 8 5 tricyclic ring system. 

Fig. 2.19 Effective methods to generate all-carbon substituted quaternary stereocenters (a) Diels-Alder assembly of a complicated building block for the synthesis of (-tj-aspidospermidine (b) intermolecular C-acylation using a planar nucleophilic ferrocene type catalyst.

Intermolecular ketyl alkene coupling reactions have been incorporated into a cascade that ultimately affords medium sized rings [58]. Specifically, chloroalkyl ketones react with acrylates, whereupon chloroalkyl lactones are formed in situ. Photolysis of these intermediates in the presence of excess Sml2 initiates an intramolecular nucleophilic acyl substitution reaction between the halide and the lactone, creating the medium-sized ring (Eq. 50). 

The mechanism of the intramolecular Claisen cyclization, sho-wn in Figure 17.13, is the same as that of the intermolecular Claisen condensation. One of the two ester groups is converted into an enolate ion, which then carries out a nucleophilic acyl substitution on the second ester group at the other end of the molecule. A cyclic 8-keto ester product results. 

Acyl derivatives of azoles containing two different environments of nitrogen atoms can rearrange. For example, 1-acyl-1,2,3-triazoles are readily isomerized to the 2H-isomers in the presence of triethylamine or other bases the reaction is intermolecular and probably involves nucleophilic attack by N-2 of one triazole on the carbonyl group attached to another (74AHC(16)33). 

Fig. 7.2. a) The most common mechanism of base-catalyzed ester hydrolysis, namely specific base catalysis (HCT catalysis) with tetrahedral intermediate and acyl cleavage. Not shown here are an W mechanism with alkyl cleavage observed with some tertiary alkyl esters, and an 5n2 mechanism with alkyl cleavage sometimes observed with primary alkyl esters, particularly methyl esters, b) Schematic mechanism of general base catalysis in ester hydrolysis. Intermolecular catalysis (bl) and intramolecular catalysis (b2). c) The base-catalyzed hydrolysis of esters is but a particular case of nucleophilic attack. Intermolecular (cl) and intramolecular (c2). d) Spontaneous (uncatalyzed) hydrolysis. This becomes possible when the R moiety is... 

Intermolecular addition reaction is important. Generally, alkyl radicals derived from O-acyl esters (2) are nucleophilic, so treatment with electron-deficient olefins such as... 

Electron-rich arenes are suitable nucleophiles for this reaction as well. Thus, the addition of arenes to imines has been described in both intra- (equation 121) and intermolecular (equation 122) fashion catalyzed by AuCb/AgOTf The yields were increased in the intramolecular version by acylation of the amide intermediate to give acylamides. In... 

O-Acyltyrosine derivatives bear the disadvantage of being active esters capable of acylating amino groups or other nucleophiles in a particularly efficient manner by intermolecular O—> N transfer (Scheme 9). Due to the reactivity of these phenyl esters, acyl groups such as acetyl or benzoyl, which are commonly used in carbohydrate chemistry, cannot be recommended for the protection of the tyrosine hydroxy group.f l... 

Cinchona alkaloids such as 121 possess a nucleophilic quinuclidine structure and can act as versatile Lewis bases to react with ketenes generated in situ from acyl halides in the presence of an add scavenger. By acting as nucleophiles, the resulting ketene enolates can react intermolecularly [53] or intramolecularly [54] with electrophilic C=0 or C=N bonds to deliver formal [2 + 2]-cycloadducts, such as chiral P-lactones or [1-lactams, via aldol (or Mannich)-i intramolecular cydization sequence reactions (Scheme 8.46). The nucleophilic ammonium enolate can also read with energetic... 

A number of recent reviews exist about intermolecular and intramolecular reactions of the iV-acyl-iminium intermediate. Moreover, detailed accounts of the application in alkaloid synthesis have recently appeared. This chapter deals with reactions of species (1) with nucleophilic alkenes (and alkynes). Other synthetically useful nucleophiles like aromatic rings, active methylene compounds and organome-tallics will not be discussed here. In (1) R, and R are hydrogen or carbon substituents, and R may also be a hetero substituent, such as alkylamino or alkoxy. This chapter differs from previous reviews, as the material is ordered here on the basis of the structural features of the A -acyliminium intermediate. Major emphasis is placed on recent developments and stereochemical details. 

---