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Physical Data: bp 51.8 °C;1a mp -112.9 °C;1a d 1.1051 g cm-3;1a refractive index 1.38976.1b IR (neat) n 1806.7 cm-1;16 1H NMR (CDCl3) d 2.66 ppm; 13C NMR (CDCl3) d 33.69 ppm (q) and 170.26 ppm (s); the bond angles (determined by electron diffraction17) are 127.5° (O-C-C), 120.3° (O-C-Cl), and 112.2° (Cl-C-C).
Arenes undergo acetylation to afford aryl methyl ketones on treatment with acetyl chloride (AcCl) together with a Lewis acid, usually Aluminum Chloride3. This reaction, known as the Friedel-Crafts acetylation, is valuable as a preparative method because a single positional isomer is produced from arenes that possess multiple unsubstituted electron-rich positions in many instances.
Acetylation of chlorobenzene under the same conditions affords p-chloroacetophenone with even higher selectivity (p:m = 99.5:0.5).33 Acetylation of bromobenzene33 and fluorobenzene33 afford the para isomers exclusively. The para:meta34 and para:ortho32,34 selectivities exhibited by AcCl/AlCl3 are greater than those exhibited by most other Friedel-Crafts electrophiles.
These side reactions can be minimized by proper choice of reaction conditions. Isomerization of the arene can be suppressed by adding the arene to the preformed AcCl/AlCl3 complex. This order of mixing is known as the Perrier modification of the Friedel-Crafts reaction.40 Acetylation of p-xylene using this order of mixing affords 2,5-dimethylacetophenone exclusively.38 Isomerization of the product aryl methyl ketone can be suppressed by crystallizing the product out of the reaction mixture as it is formed. For example, on acetylation of anthracene in benzene at 5-10 °C, 9-acetylanthracene crystallizes out of the reaction mixture (as its 1/1 AlCl3 complex) in pure form.39 Higher yields of purer products can also be obtained by substituting Zirconium(IV) Chloride41 or Tin(IV) Chloride42 for AlCl3.
Alkenes, on treatment with AcCl/AlCl3 under standard Friedel-Crafts conditions, are transformed into mixtures of b-chloroalkyl methyl ketones, allyl methyl ketones, and vinyl methyl ketones, but the reaction is not generally preparatively useful because both the products and the starting alkenes are unstable under the hyperacidic reaction conditions. Preparatively useful yields have been reported only with electron poor alkenes such as ethylene (dichloroethane, 5-10 °C; >80% yield of 4-chloro-2-butanone)47 and Allyl Chloride (CCl4, rt; 78% yield of 5-chloro-4-methoxy-2-pentanone after methanolysis),48 which are relatively immune to the effects of acid.
Higher alkenes can be acetylated in synthetically useful yield by treatment with AcCl together with various mild Lewis acids. One that deserves prominent mention is Ethylaluminum Dichloride (CH2Cl2, rt), which is useful for acetylation of all classes of alkenes (monosubstituted, 1,2-disubstituted, and trisubstituted).57 For example, cyclohexene is converted into an 82/18 mixture of 3-acetylcyclohexene and 2-chlorocyclohexyl methyl ketone in 89% combined yield.
Despite the modest to low yields, acetylation of alkanes provides a practical method for accessing simple methyl ketones because all the input raw materials are cheap.
Coupling of organometallic reagents with AcCl is a valuable method for preparation of methyl ketones. Generally a catalyst (either a Lewis acid or transition metal salt) is required.
Due to the large number and varied characteristics of the organometallics, comprehensive coverage of the subject would require discussion of each organometallic reagent individually, which is far beyond the scope of this article. Information pertaining to catalyst and condition selection should therefore be accessed from the original literature; some seminal references are given in Table 1.
C-Acetylation of Enolates and Enolate Equivalents.
Attempted enol acetylation of b-keto esters by quenching the sodium enolate146,147 or magnesium chelate149 with AcCl afforded C-acetylated products.
Adducts with Aldehydes and Ketones.
AcCl combines with aldehydes150 (cat. ZnCl2 or AlCl3150f) to afford a-chloroalkyl acetates. The reaction is reversible,151 but at equilibrium the ratio of adduct to aldehyde is usually quite high, and the reaction is otherwise clean (92% yield for acetaldehyde,150e 97% yield for benzaldehyde; eq 12150f).
Reduction of the aldehyde/AcBr adducts151,154 with Zinc or Samarium(II) Iodide to a-acetoxyalkylzinc154,155 and -samarium156 compounds, respectively, completes an umpolung of the reactivity of the aldehyde.
Many of these methods are applicable to deprotection of ether-type protecting groups. For example, benzyl and allyl ethers can be deprotected by treatment with AcCl/cat. CoCl2160 or AcCl/cat. ClPdCH2Ph(PPh3)2/cat. Bu3SnCl.161 Dimethyl acetals can be cleaved selectively to aldehydes in the presence of ethylene acetals (AcCl/cat. ZnCl2, Me2S/THF, 0 °C),164 or to a-chloro ethers (AcCl/cat. SOCl2, 55 °C).165 Tetrahydropyranyl (THP) ethers166 and t-butyl ethers167 can be deprotected by stirring in 1:10 AcCl:HOAc (40-50 °C).
Although acetylations with AcCl/pyridine produce an acidic byproduct (pyridine hydrochloride), it is possible to acetylate highly acid-sensitive alcohols such as 2-(tributylstannylmethyl)allyl alcohol (eq 13)9b and 2-(trimethylsilylmethyl)allyl alcohol9a with AcCl/pyridine in >90% yield without competing protiodestannylation or protiodesilylation by selecting a solvent (CH2Cl2, 0 °C) in which the pyridine hydrochloride is insoluble.
Alternatively, acid-sensitive alcohols may be acetylated by deprotonation with n-Butyllithium (THF, -78 °C)183 or Ethylmagnesium Bromide (Et2O, rt)184 followed by quenching with AcCl.
Generation of Solutions of Anhydrous Hydrogen Chloride in Methanol.
Esterification of alcohols by AcCl proceeds in the absence of HCl scavengers. For example, on addition of AcCl to methanol at rt, a solution of hydrogen chloride and methyl acetate in methanol forms rapidly.10 This reaction provides a more practical method for access to solutions of HCl in methanol than the apparently simpler method of bubbling anhydrous HCl into methanol because of the difficulty of controlling the amount of anhydrous HCl delivered. Solutions of anhydrous HCl in acetic acid can presumably be prepared analogously by addition of AcCl and an equimolar amount of H2O to HOAc.
Primary,186 secondary,187 and tertiary alcohols178a,188 also react with AcCl, but the product is the alkyl chloride rather than the ester in most cases. Thus as a preparative esterification method this reaction has limited generality.
In Situ Generation of High-Valent Metal Chlorides.
The key step in a method for a-acetoxylation of aldehydes involves rearrangement of an AcCl-nitrone adduct (eq 14).201 Analogous methods for a-benzoylation and a-pivaloylation are higher yielding.
A high-yielding method for deoxygenation of sulfoxides to sulfides involves treatment with 1.1 equiv Tin(II) Chloride in the presence of a catalytic amount (0.4 equiv) of AcCl (MeCN/DMF, 0 °C -> rt).12 The mildness of this method is demonstrated by its usability for deoxygenation of a cephalosporin sulfoxide (eq 16).
Acetic Anhydride; Acetyl Bromide; Acetyl Fluoride.
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