Boron Trifluoride-Acetic Anhydride1


[7637-07-2]  · BF3  · Boron Trifluoride-Acetic Anhydride  · (MW 67.81) (Ac2O)

[108-24-7]  · C4H6O3  · Boron Trifluoride-Acetic Anhydride  · (MW 102.09)

(a mild Lewis acid catalyst, mainly used for the acylation of enolizable ketones and aromatic compounds)

Physical Data: see Acetic Anhydride and Boron Trifluoride.

Solubility: BF3 gas: very sol H2O to form two hydrates; with a large excess of H2O it slowly reacts to form fluoroboric acid; sol most organic solvents and forms well-defined complexes with ethers, alcohols, amines, and phosphines.

Form Supplied in: prepared in situ.

Preparative Methods: BF3 gas: prepared by heating boron trioxide with calcium fluoride, ammonium fluoroborate, or potassium fluoroborate with conc sulfuric acid.2

Handling, Storage, and Precautions: all forms of BF3 are extremely corrosive to eyes and skin. All work must be carried out in an efficient fume hood.

Acylation Reactions of Ketones.

A major use of the reagent system has been concerned with the conversion of enolizable ketones into 1,3-diketones. The reactions are carried out by treating a mixture of the carboxylic anhydride and ketone with a Lewis acid catalyst system based on Boron Trifluoride.2 The main catalyst systems used involve: (i) saturation of the reaction mixture with gaseous boron trifluoride, (ii) the use of either the solid (1:1) or liquid (1:2) complexes formed between boron trifluoride and acetic acid (see Boron Trifluoride-Acetic Acid) to which sometimes is added a protic acid such as p-Toluenesulfonic Acid, and (iii) the use of Boron Trifluoride Etherate. Where different isomeric products are possible, the reactions carried out under different conditions sometimes lead to different products or product ratios. For example, in the reaction of 3-methylbutanone with acetic anhydride under different reaction conditions, the two possible products are formed in the proportions shown in eq 1.3 Reaction conditions that use boron trifluoride diethyl etherate as the catalyst are less strong than the others and it is then not unusual for reaction not to occur at an a-carbon that carries two alkyl substituents.

The rapid saturation of the reaction mixture with boron trifluoride leads to the formation of the product derived from the kinetic enol, whereas in the presence of a protic acid the product formed from the thermodynamic enol may be the exclusive product. It is assumed that in the first case the nucleophile is the boron complex of the enol, while in the latter case an enol ester is involved (eq 2). In both sequences the final product is the boron difluoride complex (3) and in a number of examples such a complex has been isolated.4 This explains why, in most of the reactions, 100 mol % of catalyst is required. The formation of the diketone (2) (eq 1) shows, however, that it is not a requirement that a complex of type (3) is formed. In many of the examples reported the boron difluoride complex was not observed because the hydrolytic sequences that were used gave the 1,3-diketone directly. Checked procedures have been published.5 They include the preparation of pentane-2,4-dione in which the isolation of the product was facilitated by formation of the copper(II) complex.5a Reactions of cyclohexanone with a variety of anhydrides6 include the reaction with 3-nitropropanoic anhydride6b and, in the case of homoveratric anhydride, reaction resulted in the formation of an octahydrophenanthrene derivative.6c Recent reports include the preparation of 1,3-diketones for use in an alkene synthesis involving the elimination of nitro and keto groups.7 The acylation of benzyl methyl ketone8 and pinacolone9 proceed in good yield as expected. In the latter case the diketone was required in a tripyrrin-a-carboxylic acid synthesis.10 The acetylation of aromatic ketones sometimes results, eventually, in the formation of heterocyclic derivatives. For example, the acetylation of acetophenone under forcing conditions can lead to the formation of 2,4-diphenyl-6-methylpyrylium fluoroborate,11 and 4-(2-hydroxyphenyl)butane-2,4-dione was converted into 3-acetyl-2-methylchromone.12

In accord with the suggested mechanisms, the expected enol acetate was isolated in low yield in an acetylation of butanone. On the other hand, it was not possible to form the enol acetate from acetophenone, and so it was concluded that a boron difluoride enol complex was involved.2 The treatment of cyclohexanone with acetic anhydride and 14 mol % of boron trifluoride gave 1-acetoxycyclohexene in 22% yield, which was converted into 2-acetylcyclohexanone in 76% yield (eq 3).2 Enol acetates have also been shown to afford boron difluoride complexes and acetyl fluoride on treatment with acetic anhydride and boron trifluoride.13 Similarly, in a reaction of boron trifluoride with the enol benzoate derived from dibenzoylmethane, benzoyl fluoride was isolated along with the boron difluoride complex (eq 4).13 Other enol acetates and enol benzoates have been converted into b-diketones by saturating the enol esters with boron trifluoride.14 Boron difluoride complexes have also been isolated in reactions of chroman-4-one and its thia analog.15

A further improvement to the experimental method was achieved by the rapid addition of the ketone-anhydride mixture to a solid boron trifluoride-acetic acid complex. In this way the acetylation of cyclohexanone was improved to afford an 86% yield of 2-acetylcyclohexanone.16 The inverse addition method also gave an excellent yield of 2-butanoylcyclopentanone (eq 5).16 The method has been used for the acylation of a wide range of cyclic ketones, including five- to eight-membered ring ketones,17 including the example shown in eq 6.17a The acetylation of 3-methylcyclopentane-1,2,4-trione has also been reported.18 The functionalization of 5,8-dimethoxy-1-tetralone (eq 7) was used as part of a daunomycinone aglycon synthesis.19

1,3-Diketones are important intermediates in the synthesis of substituted pyrroles and, as a result, improvements to the original procedures have been reported. Another recent improvement was established in the preparation of precursors required for octaalkylporphyrin synthesis. The classical work-up procedure involving steam distillation was replaced by the hydrolysis of the boron fluoride complex with methanolic sodium hydroxide solution.20 For example, boron trifluoride gas was bubbled through a mixture of pentan-2-one and propanoic anhydride and the complex was isolated in 89% yield; hydrolysis then gave the diketone in 80% yield (eq 8). The advantage of the acetylation procedure for the preparation of 3-methylpentane-2,4-dione from butanone, as compared with the alkylation of acetylacetone, has been noted as one of the steps in a study of the pentapyrrolic sapphyrins. The methylation of pentane-2,4-dione was found to lead to an impure product, whereas there were no detectable impurities in the acetylation of butanone.21 A reaction of benzenesulfonylacetone with acetic anhydride and the boron trifluoride acetic acid 1:1 complex led to acetylation at the terminal methyl group in 85% yield.22 The electron-withdrawing effect of the benzenesulfonyl group apparently does not favor enolization towards the methylene group. The self-condensation of anhydrides has been reported under mild conditions,23 while under more forcing conditions diketones are formed.24 Enolizable aldehydes are not C-acylated by an anhydride in the presence of a boron trifluoride reagent, but good yields of the O,O-diacylated products are obtained.25

Reactions of steroidal ketone acetals, for example the ethylene acetals derived from cholestanone and androstan-17b-ol, give the related 2-acetyl enol ethers in good yield.26 In rigid systems, such as those found in steroids, the direction of the kinetically favored enolization of a ketone depends on the stereochemistry of the ring junction. With 3-keto steroids the 2,3-enol is formed more rapidly with a trans-5,6-ring junction, whereas the formation of the 3,4-enol is favored when the ring junction is cis. This effect is exemplified in eqs 9 and 10.27 Cholestenone is converted into a dienol acetate by acetic anhydride in the presence of boron trifluoride diethyl etherate; further reaction leads to the formation of a mixture of diastereomeric diketones.27,28

Acetylation of Nitriles and Amides.

The reaction between boron trifluoride and phenylacetonitrile in the presence of aqueous acetic acid had been shown to afford phenylacetamide in high yield.29 This result led to an investigation of the reaction of phenylacetamide and phenylacetonitrile with acetic anhydride in the presence of the boron trifluoride-diacetic acid complex. Both reactions gave the same product after an aqueous workup as shown in eqs 11 and 12.30 The suggested mechanism involves hydrolysis of phenylacetonitrile to phenylacetamide followed by C- and N-acylation. However, in view of the fact that p-tolunitrile and p-nitrobenzonitrile both afford the related benzamides on quenching the reaction mixtures with aqueous alkali, but not in the absence of an aqueous workup, it is suggested that the mechanisms probably involve an acylnitrilium species as shown in eq 13.

Friedel-Crafts Acylation Reactions.

Since a carboxylic anhydride and boron trifluoride constitute a mild Friedel-Crafts acylating system, it is not surprising that nucleophilic aromatic substrates such as toluene, mesitylene, and anisole have been acetoacetylated,31a as has fluorene31b and h5-(acetylcyclopentadienyl)tricarbonylmanganese.31c The expected 1,3-diketones are formed when a sufficient excess of acetic anhydride is present in the reaction mixtures. The process is illustrated with anisole in eq 14.31a The acetylation of thiophene gives the so-called 2-triacetylthiophene,32 but the product is in fact identical with the boron difluoride complex formed in the acetylation of 2-acetylthiophene.33 Fries rearrangement reactions may be involved in some reactions of phenols; in the case of the acetylation of 4,8-dimethoxy-1-naphthol it was possible to isolate the initial O-acylated phenol in very high yield.34 Reactions involving a wide variety of electron-rich heterocyclic compounds have been reported but, not surprisingly, low yields are sometimes obtained when electron-withdrawing groups are present.35 Normally the yields are good,36 although it may be that destruction of labile heterocycles such as indole and pyrrole requires that great care is taken to avoid the presence of strong protic acids. Acetylation of 2-ethoxycarbonyl-5-hydroxybenzo[b]furan occurs in high yield at the 4-position.37 The acylation of 1-benzenesulfonylpyrrole is of great interest because reaction occurs predominantly at the 2-position using boron trifluoride etherate as the Lewis acid (eq 15), while the regioselectivity is reversed using Aluminum Chloride.38

The acylation of a number of heterocyclic arylacetic acid derivatives has been used to great advantage in benzannulation reactions that proceed by way of a-pyrone derivatives.39 The protocol is exemplified in eq 1639e and has also been used in a synthesis of the staurosporine aglycon.39f

Alkylation and Acetoxylation Reactions.

The Pomeranz-Fritsch isoquinoline synthesis, where an acetal is cyclized to afford an isoquinoline after the loss of an alcohol, can be carried out using the boron trifluoride-diacetic acid complex in the presence of trifluoroacetic anhydride.40 In many cases the conversion of quinones into acetoxyhydroquinone acetates is best achieved using boron trifluoride etherate together with acetic anhydride.41a Thus 1,4-naphthoquinone is converted into 1,2,4-triacetoxynaphthalene in 81% yield by this method,41b and although 2,5-dimethyl-1,4-benzoquinone reacts similarly, the related 2,6-dimethyl-1,4-benzoquinone apparently does not.41c

Cleavage and Rearrangement Reactions.

A large number of rearrangement reactions are initiated by boron trifluoride complexes in the presence of acetic anhydride, including the synthesis of functionalized and optically active pyrans from (+)-(R,R)-diethyl tartrate as indicated in eq 17.42 The reaction of 1,4,5,5-tetramethylcyclopentene with paraformaldehyde and acetic anhydride in the presence of boron trifluoride etherate has been used in an approach to necrodane-type monoterpenes.43 Other examples include the conversion of bicyclic into monocyclic44 and tricyclic into bicyclic systems,45 the acetolysis of glycosides resulting in the formation of the fully acetylated acyclic derivative,46 the unusual migration of nitrogen in the dienone-phenol rearrangement of an N-methoxy-b-lactam,47 and the cleavage of the tetrahydrofuran ring in compound (4) which gave the diacetate (5) (eq 18) with inversion of configuration at C-20.48 Among other interesting reactions are the synthesis of adamantanone derivatives (eq 19)49 and a one step synthesis of the twistane system (eq 20).50

Protection and Deprotection Reactions.

There are a number of cases where the acetylation of hydroxy and amino groups is difficult to achieve and where the use of acetic anhydride in the presence of boron trifluoride etherate has been successful. Two representative examples are carbazole51 and a hindered 17b-hydroxy steroid.52 The demethylation-acetylation of methyl ethers has been carried out using the same system but with the addition of Lithium Bromide,53 while a number of steroidal alcohols have been regenerated from their ethers in the absence of lithium bromide. Thus cholesterol methyl ether gave the corresponding acetate in 93% yield after 15 h at 0 °C, while the related 7b-methoxycholest-4-ene was more resistant to cleavage and gave the acetate after 50 h. The retention of configuration indicates homoallylic participation and, in accord with that suggestion, it was found that saturated steroidal methyl ethers gave mixtures of epimeric acetates and elimination products.54 Acetic anhydride in the presence of catalytic boron trifluoride etherate in THF at low temperature has been reported more recently to give good chemoselectivity in the acetylation of the polyhydroxy tumor inhibitor oridonin. Among the wide range of additional examples, alcohols were shown to be acetylated in the presence of phenols.55 The removal of the methoxymethyl group from indoles proved difficult. The involvement of the lone pair electrons in the aromatic system diminishes the hydrolytic lability of what would otherwise be an aminol ether; as a result, the reaction conditions that were found to be necessary restrict the substituent types that may be accommodated at other positions.56 The deblocking of the anomeric position, protected as the 2-trimethylsilylethyl ether, has been achieved in high yields in examples drawn from mono-, di-, and trisaccharides.57 The method is exemplified in eq 21. In the absence of acetic anhydride, the product with a free anomeric hydroxy group is obtained.

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Harry Heaney

Loughborough University of Technology, UK

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