Butyrolactone formation

By analogy with ethyl 4-bromobutyrate thermolysis, the kinetics of the pyrolysis and the product formed from ethyl 4-chlorobutyrate were examined172. At the same time, the pyrolysis of the expected stable product 4-chlorobutyric acid product (equation 78), which results in butyrolactone formation, was also carried out. 

C. Manufactured from butyrolactone and ammonia. Easily hydrolysed to 4-amino-butanoic acid, its most important use is for the formation of N-vinylpyrrolidone by reaction with elhyne. 

As an application of maleate formation, the carbonylation of silylated 3-butyn-l-ol affords the 7-butyrolactone 539[482], Oxidative carbonylation is possible via mercuration of alkynes and subsequent Lransmetallation with Pd(II) under a CO atmosphere. For example, chloromercuration of propargyl alcohol and treatment with PdCF (1 equiv.) under 1 atm of CO in THF produced the /3-chlorobutenolide 540 in 96% yield[483]. Dimethyl phenylinale-ate is obtained by the reaction of phenylacetylene, CO, PdCU, and HgCl2 in MeOH[484,485]. 

Ring closure resulting from attack of a heteroatom on a carboxyl group or its equivalent is merely a case of intramolecular esterification or amide formation. The y-butyrolactones or pyrrolidones obtained from such reactions are usually regarded as the province of aliphatic chemistry, so only a few examples are offered by way of illustration in Scheme 15. 

The mechanism of this reaction has been studied by several groups [133,174-177]. The consensus is that interaction of ester with the phenolic resole leads to a quinone methide at relatively low temperature. The quinone methide then reacts rapidly leading to cure. Scheme 11 shows the mechanism that we believe is operative. This mechanism is also supported by the work of Lemon, Murray, and Conner. It is challenged by Pizzi et al. Murray has made the most complete study available in the literature [133]. Ester accelerators include cyclic esters (such as y-butyrolactone and propylene carbonate), aliphatic esters (especially methyl formate and triacetin), aromatic esters (phthalates) and phenolic-resin esters [178]. Carbamates give analogous results but may raise toxicity concerns not usually seen with esters. 

Five-membered unsubstituted lactone, y-butyrolactone (y-BL), is not polymerized by conventional chemical catalysts. However, oligomer formation from y-BL was observed by using PPL or Pseudomonas sp. lipase as catalyst. Enzymatic polymerization of six-membered lactones, 8-VL and l,4-dioxan-2-one, was reported. 8-VL was polymerized by various lipases of different origins. The molecular weight of the enzymatically obtained polymer was relatively low (less than 2000). 

Homoenolate Reactivity The ability to generate homoenolates from enals and its application to the preparation of y-butyrolactones 30, through reaction with an aldehyde or aryl trifluoromethyl ketone, was reported independently by Glorius [8], and Bode and Burstein [9] (Scheme 12.4). A sterically demanding NHC catalyst is required to promote reactivity at the d terminus and to prevent competitive benzoin dimerisation. Nair and co-workers have reported a similar spiro-y-lactone formation reaction using cyclic 1,2-diones, including cyclohexane-1,2-dione and substituted isatin derivatives [10]. 

The transformation proceeds with excellent stereoselectivity by kinetic formation of the 2,5-trans-disubstituted pyrrolidine 2-328 [182]. The tertiary amine can now initiate a nucleophilic backside displacement of the vicinal iodide in 2-328, leading to an aziridinium salt 2-329 [183]. This event ensures a net retention of the stereochemistry at C-13 in the following attack of the ester carbonyl in the butyrolactone ring closure to give 2-330. 

Five-membered unsubstituted lactone, y-butyrolactone, is not polymerized by conventional chemical catalysts. On the other hand, oligomer formation from y-butyrolactone was observed by using PPL or Pseudomonas sp. lipase as catalyst [23,69]. 

The transformation of A-oxides (150a,b) into butyrolactone derivatives (151a,b), accompanied by the formation of oximes (152) as by-products, is yet another example (331) (Scheme 3.122). 

A variety of functionalities, tether lengths, and alkene substitution patterns were tolerated (Equation (35)).52,53 Of particular significance is the synthesis of a-methylene-y-butyrolactone 55, as only Zhang had reported successfully using Alder-ene chemistry to gain access to this novel system (see Section 10.12.4.3). The reaction was sensitive to the length of the tether, since there was a marked decrease in yield for the formation of the six- and seven-membered carbocycles (53 and 54, respectively) compared to the five-membered case 52. 

Zhang68 has applied the cyclization of esters to the formation of a-methylene-y-butyrolactones, thus offering a novel and enantioselective entry to these substructures. The importance of this unsaturated lactone is evidenced by its ubiquitous presence in nearly a third of all naturally occurring secondary metabolites. The Alder-ene reaction has been applied to a formal total synthesis of (+)-pilocarpine, a leading therapeutic reagent for the treatment of narrow and wide glaucoma. Zhang intersected Btichi s synthetic intermediate (i )-181 (Scheme 47) in only two steps with a 99% ee and a 91% overall yield. In comparison, Biichi synthesized (i )-181 in five steps with a 92% ee and a 20% overall yield. 

The original preparation of y-crotonolactone by Lespieau involved a five-step sequence from epichlorohydrin and sodium cyanide. A recent detailed study of this procedure reported an overall yield of 25% for the lactone. Glattfeld used a shorter route from glycerol chlorohydrin and sodium cyanide hydrolysis and distillation of the intermediate dihydroxy acid yielded y-cro-tonolactone in 23% yield and -hydroxy-y-butyrolactone in 28% yield. The formation of y-crotonolactone in 15% yield has also been reported from pyrolysis of 2,5-diacetoxy-2,5-dihydrofuran at 480-500 . ... 

The formation of a-bromo-y-butyrolactone has been reported in 70% yield by uncatalyzed reaction of bromine at 160-170°, as well as by the catalyzed procedure used here. ... 

Lu, H., Wang, J., Zhao, Y., Xuan, X., and Zhuo, K. Excess molar volumes and viscosities for binary rtrixtrrres of y-butyrolactone with methyl formate, ethyl formate, methyl acetate, ethyl acetate, and acetonitrile at 298.15 K,J. Chem. Eng. Data, 46(3) 631-634, 2001. 

The buffer species were suggested to increase the rate of formation of butyrolactone by the cyclic concerted mechanism [5]. Hydrolysis of 7-hydroxybutyranilide is also catalysed by H2 PO4 and HCOJ but not by imidazole. A similar mechanism has been postulated in the hydrolysis of trifluoroacetanilide [6] (Eriksson and Holst, 1966). 

Homoenolates generated catalytically with NHCs can also be employed for C-C and C-N bond formation. Bode and Glorias have independently accomplished the diastereoselective synthesis of y-butyrolactones by annulation of enals and aldehydes [121, 122]. Bode and co-workers envisioned that increasing the steric bulk of the acyl anion equivalent would allow reactivity at the homoenolate position. While trying to suppress the competing benzoin and enal dimerization the authors comment on the steric importance of the catalyst. Thiazolium pre-catalyst 173 proved unsuccessful at inducing annulation. A-mesityl substituted imidazolium salt 200 was found to provide up to 87% yield and moderate diastereoselectivities (Scheme 34). 

Scheme 35 Proposed mechanism of NHC catalyzed formation of y-butyrolactone...

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