2.4.6- Trichlorobenzoyl chloride, Yamaguchi

Esterification using 2,4,6-trichlorobenzoyl chloride (Yamaguchi reagent). 

Use of 2,4,6-trichlorobenzoyl chloride, Et3N, and DMAP, known as the Yamaguchi method,128 is frequently used to effect macrolactonization. The reaction is believed to involve formation of the mixed anhydride with the aroyl chloride, which then forms an acyl pyridinium ion on reaction with DMAP.129... 

Yamaguchi Esterification-. 2,4,6-trichlorobenzoyl chloride, (Yamaguchii Reagent). NEt3, DMAP... 

The Yamaguchi Esterification allows the mild synthesis of highly functionalized esters. After formation of a mixed anhydride between the Yamaguchi Reagent (2,4,6-trichlorobenzoyl chloride) and the carboxylic acid, the volatiles are removed and the reaction of the anhydride with an alcohol in presence of a stoichiometric amount of DMAP generates the desired ester. 

A mild method for forming ter/-butyl esters is the Yamaguchi esterification, which involves reaction of a carboxyl group with 2A6-trichlorobenzoyl chloride and triethylamine in THE The resultant mixed anhydride intermediate reacts with rm-butyl alcohol in the presence of DMAP to give the ferf-butyl ester in good yield.96... 

A variety of synthetic methods have been introduced for macrolacto-nizations. The most popular method seems to be the Yamaguchi-Yonemitsu reaction using 2,4,6-trichlorobenzoyl chloride (TCBC) for acid activation by the formation of mixed anhydrides. 

The Yamaguchi esterification (activation of an acid with trichlorobenzoyl chloride) is typically used to make macrolides, indicating its reliability. Unfortunately, these examples are typically done on very small scale, so a different example is shown. 

The Yamaguchi esterification utilises 2,4,6-trichlorobenzoyl chloride, also known as the Yamaguchi reagent, to form esters from carboxylic acids and alcohols. 

Yamaguchi and co-workers then screened a number of acid chlorides for the formation of the mixed anhydride with two features in mind (1) the component should be a good leaving group, and (2) the carbonyl group of the component should be sterically hindered from nucleophilic attack.5,6 Eventually, 2,4,6-trichlorobenzoyl chloride was deemed to be the best in terms of rate of reaction and yield. 

In a similar fashion, Dhimitruka and SantaLucia argue that the use of 2,4,6-trichlorobenzoyl chloride is not always necessary and that other inexpensive acid chlorides can be employed.15 This is attractive especially when dealing with scale-up reactions. The authors also postulate the formation of a symmetric aliphatic anhydride to explain the regioselectivity of the Yamaguchi esterification. The mechanism assumes that aliphatic carboxylates are better nucleophiles than aromatic carboxylates and... 

Variations in the Yamaguchi protocol also involve differing the order of addition. For example, in the synthetic studies toward bafilomycin A, the Cl-Cll and C12-C17 fragments were coupled by first premixing the acid 15 with DMAP (2 eq.) in toluene at room temperature, then adding triethylamine (4 eq.) and 2,4,6-trichlorobenzoyl chloride (2 eq.) successively, then finally adding the alcohol 16 in toluene.16 An excellent yield was obtained. 

Yamaguchi s methynolide synthesis is based on the coupling of the C1-C7 (13) and Cg-Cii (14) segments, both of which are prepared from the resolved compounds, and the macrolactonization using the mixed anhydride prepared by use of 2,4,6-trichlorobenzoyl chloride and dimethylaminopyridine (Yamaguchi method). 

Yamaguchi investigated the utility of a mixed anhydride composed of the 2,4,6-trichlorobenzoate moiety, which was generated from 2,4,6-trichlorobenzoyl chloride with EtjN (triethyl amine) [26]. Thermodynamic activation of the bulky mixed anhydride in the presence of DMAP (4-dimethylaminopyridine) afforded the corresponding lactones in good yields. Yamaguchi then used this methodology to synthesize methynolide (18), as depicted in Scheme 5.4 [27], and over 340 examples of the application of this procedure showed the usefulness of the protocol [17]. 

Rao synthesized the unnatural (-b)-cephalosporolide D (ent-1) using the Yamaguchi lactonization method [58]. Cyclization of the seco-acid 41 activated by 2,4,6-trichlorobenzoyl chloride and a catalytic amount of DMAP formed eight-membered lactone 42 in 68% yield (Scheme 5.13). 

Yamaguchi et al. [45] developed most efficient method through mixed anydride under basic conditions using 2,4,6-trichlorobenzoyl chloride and Et3N (triethyl amine), and the resultant mixed anhydride affords the corresponding lactone in the presence of 4-dime thylaminopyridine (DMAP) (Scheme 6.4). 

Yonemitsu et al. [46] modified the Yamaguchi conditions in which the mixed anhydride is not isolated and DMAP is directly introduced at room temperature from the beginning. Shiina et al. [47] described the use of 2-methyl-6-nitrobenzoic anhydride (MNBA) as an alternative to 2,4,6-trichlorobenzoyl chloride. Pivaloyl chloride [48], trifluoroacetic anhydride [49], AC2O [50], and B0C2O [51] are also employed for the lactonization via mixed anhydride under basic conditions. Furthermore, Yamamoto et al. [52] described the use of Sc(OTf)3 as a Lewis acid. 

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