Acetyl Chloride1

[75-36-5]  · C2H3ClO  · Acetyl Chloride  · (MW 78.50)

(useful for electrophilic acetylation of arenes,2 alkenes,2a,3 alkynes,4 saturated alkanes,3a,5 organometallics, and enolates (on C or O);6 for cleavage of ethers;7 for esterification of sterically unhindered8 or acid-sensitive9 alcohols; for generation of solutions of anhydrous hydrogen chloride in methanol;10 as a dehydrating agent; as a solvent for organometallic reactions;11 for deoxygenation of sulfoxides;12 as a scavenger for chlorine13 and bromine;14 as a source of ketene; and for nucleophilic acetylation15)

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).

Analysis of Reagent Purity: a GC assay for potency has been described;18 to check qualitatively for the presence of HCl, a common impurity, add a few drops of a solution of crystal violet in chloroform;19 a green or yellow color indicates that HCl is present, while a purple color that persists for at least 10 min indicates that HCl is absent.1b

Preparative Methods: treatment of Acetic Acid or sodium acetate with the standard inorganic chlorodehydrating agents (PCl3,1b,23 SO2Cl2,1a,24 or SOCl21b,25) generates material that may contain phosphorus- or sulfur-containing impurities.1b,23a,26 Inorganic-free material can be prepared by treatment of HOAc with Cl2CHCOCl (D; 70%),27 PhCOCl (D; 88%),28 PhCCl3 (cat. H2SO4, 90 °C; 92.5%),29 or phosgene30 (optionally catalyzed by DMF,30e magnesium or other metal salts,30a,b,d or activated carbon30b,c), or by addition of hydrogen chloride to acetic anhydride (85-90 °C; practically quantitative).1a,31

Purification: HCl-free material can be prepared either by distillation from dimethylaniline11c,20 or by standard degassing procedures.20c,21

Handling, Storage, and Precautions: acetyl chloride should be handled only in a well-ventilated fume hood since it is volatile and toxic via inhalation.22 It should be stored in a sealed container under an inert atmosphere. Spills should be cleaned up by covering with aq sodium bicarbonate.1a

Friedel-Crafts Acetylation.

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.

For example, Friedel-Crafts acetylation of toluene (AcCl/AlCl3, ethylene dichloride, rt) affords p-methylacetophenone predominantly (p:m:o = 97.6:1.3:1.2; eq 1).32

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.

Halogen substituents can be used to control regioselectivity. For example, by introduction of bromine ortho to methyl, it is possible to realize meta acetylation of toluene (eq 2).35

Regioselectivity is quite sensitive to reaction conditions (e.g. solvent, order of addition of the reactants, concentration, and temperature). For example, acetylation of naphthalene can be directed to produce either a 99:1 mixture of C-1:C-2 acetyl derivatives (by addition of a solution of arene and AcCl in CS2 to a slurry of AlCl3 in CS2 at 0 °C) or a 7:93 mixture (by addition of the preformed AcCl/AlCl3 complex in dichloroethane to a dilute solution of the arene in dichloroethane at rt).36 Similarly, acetylation of 2-methoxynaphthalene can be directed to produce either a 98:2 mixture of C-1:C-6 acetyl derivatives (using the former conditions) or a 4:96 mixture (by addition of the arene to a solution of the preformed AcCl/AlCl3 complex in nitrobenzene).37 Also, acetylation of 1,2,3-mesitylene can be directed to produce either a 100:0 mixture of C-4:C-5 isomers or a 3:97 mixture.36c

Frequently, regioselectivity is compromised by side reactions catalyzed by the HCl byproduct. For example, acetylation of p-xylene by treatment with AlCl3 followed by Ac2O (CS2, D, 1 h) produces a 69:31 mixture of 2,5-dimethylacetophenone and 2,4-dimethylacetophenone, formation of the latter being indicative of competitive acid-catalyzed isomerization of p-xylene to m-xylene.38 Also, although acetylation of anthracene affords 9-acetylanthracene regioselectively, if the reaction mixture is allowed to stand for a prolonged time prior to work-up (rt, 20 h) isomerization to a mixture of C-1, C-2, and C-9 acetyl derivatives occurs.39

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.

AcCl is not well suited for industrial scale Friedel-Crafts acetylations because it is not commercially available in bulk (only by the drum) and therefore must be prepared on site.1 The combination of Acetic Anhydride and anhydrous Hydrogen Fluoride, both of which are available by the tank car, is claimed to be more practical.43 On laboratory scale, AcCl/AlCl3 is more attractive than Ac2O/HF or Ac2O/AlCl3. Whereas one equivalent of AlCl3 is sufficient to activate AcCl, 1.5-2 equiv AlCl3 (relative to arene) are required to activate Ac2O.36a,37b,38,44 Thus, with Ac2O, greater amounts of solvent are required and temperature control during the quench is more difficult. Also, slightly lower isolated yields have been reported with Ac2O than with AcCl in two cases.36a,45 However, it should be noted that the two reagents generally afford similar ratios of regioisomers.36a,38,46

Acetylation of Alkenes.

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.

The acetylated products derived from higher alkenes are susceptible to protonation or solvolysis which produces carbenium ions that undergo Wagner-Meerwein hydride migrations.49 For example, on subjection of cyclohexene to standard Friedel-Crafts acetylation conditions (AcCl/AlCl3, CS2 -18 °C), products formed include not only 2-chlorocyclohexyl methyl ketone (in 40% yield)50 but also 4-chlorocyclohexyl methyl ketone.2a,51 If benzene is added to the crude acetylation mixture and the temperature is then increased to 40-45 °C for 3 h, 4-phenylcyclohexyl methyl ketone is formed in 45% yield (eq 3).49a,b

Wagner-Meerwein rearrangement also occurs during acetylation of methylcyclohexene, even though the rearrangement is anti-Markovnikov (b-tertiary -> g-secondary; eq 4).52 Acetylation of cis-decalin53 (see Acetylation of Saturated Alkanes section below) also produces a b-tertiary carbenium ion that undergoes anti-Markovnikov rearrangement. The rearrangement is terminated by intramolecular O-alkylation of the acetyl group by the g-carbenium ion to form a cyclic enol ether in two cases.49c,53

Higher alkenes themselves are also susceptible to protonation. The resulting carbenium ions decompose by assorted pathways including capture of chloride (with SnCl4 as the catalyst),51,54 addition to another alkene to form dimer or polymer,5b,55 proton loss (resulting in exo/endo isomerization), or skeletal rearrangement.56

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.

The following Lewis acids are also claimed to be superior to AlCl3: Zn(Cu)/CH2I2 (AcCl, CH2Cl2, D), by which cyclohexene is converted into acetylcyclohexene in 68% yield (after treatment with KOH/MeOH);58 ZnCl2 (AcCl, Et2O/CH2Cl2, -75 °C -> -20 °C), by which 2-methyl-2-butene is converted into a 15:85 mixture of 3,4-dimethyl-4-penten-2-one and 4-chloro-3,4-dimethyl-2-pentanone in quantitative combined yield;59 and SnCl4, by which cyclohexene (AcCl, CS2, -5 °C -> rt) is converted into acetylcyclohexene in 50% yield (after dehydrochlorination with PhNEt2 at 180 °C),60 methylcyclohexene (CS2, rt) is converted into 1-acetyl-2-methylcyclohexene in 48% yield (after dehydrochlorination),52 and camphene is converted into an acetylated derivative in ~65% yield.49c

Conducting the acetylation in the presence of a nonnucleophilic base or polar solvent is reported to be advantageous. For example, methylenecyclohexane can be converted into 1-cyclohexenylacetone in 73% yield by treatment with AcSbCl6 in the presence of Cy2NEt (CH2Cl2, -50 °C -> -25 °C, 1 h)61 and cyclohexene can be converted into 3-acetylcyclohexene in 80% yield by treatment with AcBF4 in MeNO2 at -25 °C.62

Employment of Ac2O instead of AcCl is also advantageous in some cases. For example, methylcyclohexene can be converted into 3-acetyl-2-methylcyclohexene in 90% yield by treatment with ZnCl2 (neat Ac2O, rt, 12 h).63

Finally, alkenes can be diacetylated to afford pyrylium salts by treatment with excess AcCl/AlCl3,55b,56,64 albeit in low yield (eq 5).64a

Acetylation of Alkynes.

Under Friedel-Crafts conditions (AcCl/AlCl3, CCl4, 0-5 °C), acetylene undergoes acetylation to afford b-chlorovinyl methyl ketone in 62% yield4 and under similar conditions (AcSbF6, MeNO2, -25 °C) 5-decyne undergoes acetylation to afford 6-acetyl-5-decanone in 73% yield.65

Acetylation of Saturated Alkanes.

Saturated alkanes, on treatment with a slight excess of AcCl/AlCl3 at elevated temperature, undergo dehydrogenation (by hydride abstraction followed by deprotonation) to alkenes, which undergo acetylation to afford vinyl methyl ketones. The hydride-abstracting species is believed to be either the acetyl cation66 or HAlCl4,67 with most evidence favoring the former. Perhaps because the alkenes are generated slowly and consumed rapidly, and therefore are never present in high enough concentration to dimerize, yields are typically higher than those of acetylation of the corresponding alkenes.53b,68 A similar hypothesis has been offered to explain the phenomenon that the yield from acetylation of tertiary alkyl chlorides is typically higher than the yield from acetylation of the corresponding alkenes.55b,64a For example, methylcyclopentane on treatment with AcCl/AlCl3 (CH2Cl2, D) undergoes acetylation to afford 1-acetyl-2-methylcyclopentene in an impressive 60% yield (eq 6).53b,66a

If the reaction is carried out with excess alkane, a second hydride transfer occurs, resulting in reduction of the enone to the corresponding saturated alkyl methyl ketone.69,70 For example, stirring AcCl/AlCl3 in excess cyclohexane (30-35 °C, 2.5 h) affords 2-methyl-1-acetylcyclopentane in 50% yield (unpurified; based on AcCl)55a,69,71 and stirring AcCl/AlBr3 in excess cyclopentane (20 °C, 1 h) affords cyclopentyl methyl ketone in 60% yield (based on AcCl; eq 7).55c

If the reaction is carried out with a substoichiometric amount of alkane, the product is either a 2:1 adduct (if cyclic)53b,66a or pyrylium salt (if acyclic).66b,68b

Unbranched alkanes also undergo acetylation, but at higher temperature, so yields are generally lower. For example, acetylation of cyclohexane by AcCl/AlCl3 requires refluxing in CHCl3 and affords 1-acetyl-2-methylcyclopentene in only 36% yield.55c,72

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 with Organometallic Reagents.

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.

b-Diketones can be synthesized by treatment of metal enolates with AcCl. O-Acetylation is often a significant side reaction, but the amount can be minimized by choosing a counterion that is bonded covalently to the enolate6 such as copper132 or zinc,133 and by using AcCl rather than Ac2O.6a Proton transfer from the product b-diketone to the starting enolate is another common side reaction.134 Alternative procedures for effecting C-acetylation that avoid or minimize these side reactions include Lewis acid-catalyzed acetylation of the trimethylsilyl enol ether derivative (AcCl/cat. ZnCl2, CH2Cl2 or CH2Cl2/Et2O, rt)135 and addition of ketene to the morpholine enamine (AcCl/Et3N, CHCl3, rt).136

Analogously, esters can be C-acetylated by conversion into the corresponding silyl ketene acetal followed by treatment with AcCl. Depending on the coupling conditions (neat AcCl137 or AcCl/Et3N138), either the cis-b-siloxycrotonate ester or the corresponding b,g-isomer is produced (eqs 8 and 9). The third possible isomer (trans-b-siloxycrotonate) is accessible either by silylation of the acetoacetic ester (TMSCl, Et3N, THF, D)139 or by HgBr2/Et3SiBr-catalyzed equilibration of the cis isomer.137

The silyl ketene acetal strategy can also be used to effect g-acetylation of a,b-unsaturated esters (AcCl/cat. ZnBr2, CH2Cl2, rt)140 and b-ketoesters (AcCl, Et2O, -78 °C).141

Enol Acetylation.

Enol acetylation of ketones can be effected by formation of a metal enolate in which the metal is relatively dissociated6 (such as potassium142 or magnesium143) followed by quenching with AcCl. Alternatively, enol acetates can be synthesized directly from the ketones. For example, 3-keto-D4,6-steroids can be converted into D2,4,6-trienol acetates by treatment with AcCl/PhNMe2 or into D3,5,7-trienol acetates by treatment with AcCl/Ac2O.144

Acetyl Bromide (AcBr) is apparently superior to AcCl as a catalyst for enol acetylation, based on a report that 17b-benzoyloxyestra-4,9(10)-dien-3-one is converted into estradiol 3-acetate-17-benzoate in higher yield at much lower temperature using AcBr rather than AcCl (87.5% yield with 1:2 AcBr:Ac2O, CH2Cl2, rt, 1 h (eq 10) vs. 81.0% yield with 1:2 AcCl:Ac2O, D, 4.5 h).145

b-Keto esters can be converted into either trans or cis enol acetates. The trans isomer is accessible by treatment with AcCl/Et3N (HMPA, rt)146 or AcCl/DBU (MeCN, 5 °C ->  rt; eq 11),147 while the cis isomer is accessible by treatment with isopropenyl acetate/HOTs.146 Each isomer couples with dialkylcuprates with retention of configuration to afford stereoisomerically enriched a,b-unsaturated esters.146,148

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).

AcCl also adds to ketones,150e,151,152 but the adducts are much less thermodynamically stable, so significant amounts of the starting materials are present at equilibrium.151,152a,b The equilibrium can be biased in favor of the adduct by employing high concentration, low temperature, a nonpolar solvent, excess AcCl, or AcBr or AcI instead of AcCl.151,153 For example, the acetone/AcCl adduct can be obtained in good yield (85%) by treatment of acetone with excess (2 equiv) AcCl (cat. ZnCl2, CCl4, -15 °C).152c

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.

Cleavage of Ethers.

THF can be opened by treatment with AcCl in combination with either Sodium Iodide (MeCN, rt, 21 h; 91% yield of 4-iodobutyl acetate)157 or a Lewis acid such as ZnCl2 (D, 1.5 h; 76% yield of 4-chlorobutyl acetate),158 SnCl4,159 CoCl2 (rt, MeCN; 90%),160 ClPdCH2Ph(PPh3)2/Bu3SnCl (63 °C, 48 h; 95%),161 Mo(CO)6 (hexane, D; 78%),162 KPtCl3(H2CCH2), and [ClRh(H2CCH2)2]2 (rt; 75% and 83%, respectively).163 Acyclic dialkyl ethers can also be cleaved efficiently and in many cases regioselectively.159

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).

Finally, t-alkyl esters can be cleaved to anhydrides and t-alkyl chlorides by treatment with AcCl (MeNO2, 70 °C).168

Esterification.

Although AcCl is intrinsically more reactive than Ac2O, in combination with various acylation catalysts the reverse reactivity order is exhibited. For example, Ac2O 4-Dimethylaminopyridine (DMAP) acetylates ethynylcyclohexanol three times faster than AcCl/DMAP (CDCl3, 27 °C).169 Also, isopropanol does not react with AcCl/Bu3P (CD3CN, -8 °C; <5% conversion after 30 min), but after addition of sodium acetate reacts rapidly to form isopropyl acetate (complete in <10 min).170 As a general rule, therefore, Ac2O is preferable for acetylation of hindered alcohols while AcCl is preferable for selective monoacetylation of polyols.171

Examples of selective acetylations involving AcCl include: acetylation of primary alcohols in the presence of secondary alcohols by AcCl/2,4,6-collidine or i-PrNEt2 (CH2Cl2, -78 °C);8,172 acetylation of primary alcohols in the presence of secondary alcohols,173 and secondary alcohols in the presence of tertiary alcohols,174 by AcCl/pyridine (CH2Cl2, -78 °C); monoacetylation of a 2,4-dihydroxyglucopyranose by AcCl/pyridine/-15 °C (Ac2O/pyridine/0 °C is less selective);175 and acetylation of steroidal 5a-hydroxyls (not 5b) by AcCl/PhNMe2 (CHCl3, D).176

Although Ac2O/DMAP177 and Ac2O/Bu3P170 are the preferred reagents for acetylation of most hindered alcohols, satisfactory results can be obtained with AcCl in combination with PhNMe2 (CHCl3, D),178 PhNEt2 (CHCl3, D),179 AgCN (benzene or HMPA, 80 °C),180 magnesium powder (Et2O, D; 45-55% yield of t-BuOAc),181 and Na2CO3 (cat. PhCH2NEt3Cl, CH2Cl2, D; 79% yield of t-BuOAc).182 Use of the combination of AcCl/DMAP is not recommended since unidentified byproducts may be generated.169

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.

Finally, by using a chiral tertiary amine as the base, it is possible to effect enantioselective acetylations. For example, racemic 1-phenethyl alcohol has been partially resolved by treatment with AcCl in combination with (S)-(-)-N,N-dimethyl-1-phenethylamine (CH2Cl2, -78 °C -> rt; ee of acetate 52%, ee of alcohol 59.5%).185

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.

AcCl also reacts with anhydrous p-toluenesulfonic acid (3-4 equiv AcCl, D) to afford acetyl p-toluenesulfonate in 97.5% yield along with anhydrous HCl.189 AcCl does not react with HOAc to generate HCl and Ac2O, at least in appreciable amounts.31

Dehydrating Agent.

AcCl reacts with H2O to afford HCl and HOAc rapidly and quantitatively31b and thereby qualifies as a strong dehydrating agent. Examples of reactions in which AcCl functions as a dehydrating agent include: cyclization of dicarboxylic acids to cyclic anhydrides (neat AcCl, D);190 cyclization of keto acids to enol lactones (neat AcCl, D);191 dehydration of nitro compounds into nitrile oxides (by treatment with NaOMe followed by AcCl);192 and conversion of allylic hydroperoxides into unsaturated ketones (AcCl/pyridine, CHCl3, rt).193 The dehydrating power of AcCl has been invoked as a possible explanation for its effectiveness for activation of zinc dust.194

In Situ Generation of High-Valent Metal Chlorides.

Many high-valent metal chlorides are useful as reagents in organic synthesis but are difficult to handle due to their moisture sensitivity. AcCl can be used to generate such reagents in situ from the corresponding metal oxides11 or acetates.195 Examples include: a-chlorination of ketones by treatment with AcCl/Manganese Dioxide (HOAc, rt);196 cis-1,2-dichlorination of alkenes by treatment with AcCl/(Bu4N)4Mo8O26 (CH2Cl2, rt);197 and dichlorination of alkenes by treatment with AcCl/MnO2/MnCl2 (DMF, rt).198 Attempts to dichlorinate alkenes by treatment with AcCl/MnO2 in THF, however, failed due to cleavage of THF to 4-chlorobutyl acetate.196,199 A milder reagent that can be used to activate MnO2 for dichlorination of alkenes in THF is Chlorotrimethylsilane.199

Solvent for Organometallic Reactions.

Because of its cheapness, volatility, and ability to form moisture-stable solutions of metal chlorides, AcCl is useful as a solvent for reactions involving hygroscopic metal salts.11 For example, AcCl has been used as a co-solvent for 1,2-chloroacetoxylation of alkenes by Chromyl Chloride (1:2 AcCl:CH2Cl2, -78 °C -> rt).200

Reaction with Heteroatom Oxides.

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.

b-Nitrostyrenes cyclize to indolinones on treatment with AcCl (FeCl3, CH2Cl2, 0 °C; eq 15).202

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).

Another method for deoxygenation of sulfoxides involves treatment with two equiv AcCl (CH2Cl2, rt);203 the oxidized byproduct is claimed to be gaseous chlorine.203

Chlorine and Bromine Scavenger.

AcCl (cat. H2SO4, 40-70 °C) scavenges Cl2 efficiently (to afford chloroacetyl chloride in 87.1% yield).13 AcCl also scavenges Br2 efficiently at 35 °C.14

Source of Ketene.

AcCl reacts with Triethylamine at low temperature (-20 °C) to afford acetyltriethylammonium chloride.204 This salt functions as a source of ketene (or the functional equivalent). For example, it reacts with silyl ketene acetals (THF, rt) to afford silyl enol ethers of acetoacetic esters (eq 9),138 with a-alkoxycarbonylalkylidenetriphenylphosphoranes (CH2Cl2, rt) to afford allenic esters,205 with enamines (Et2O, 0 °C) to afford cyclobutanones,136a with certain acyl imines (Et2O, 0 °C) to form formal [4 + 2] ketene cycloadducts,206 and with certain nonenolizable imines (Et2O, rt) to afford formal [4 + 2] diketene cycloadducts in up to 55% yield.207 Also, on refluxing in Et2O in the absence of a trapping agent, diketene is formed in 50% yield.208

AcCl/AlCl3 decomposes to acetylacetone on heating (CHCl3, 54-61 °C, 6 h; 82.5% yield after aqueous work-up).209 The mechanism presumably involves ketene as an intermediate. However, an attempt to trap the ketene was unsuccessful.210

N-Acetylation.

Primary and secondary amines can be N-acetylated to form acetamides by treatment with AcCl under Schotten-Baumann conditions (aq NaOH),211 but hydrolysis of AcCl is a significant competing side reaction.212 Use of Ac2O (2.5 equiv; D, 10-15 min) is therefore recommended.211

Tertiary amines react with AcCl to afford acetylammonium salts. Ordinarily, these salts fragment to ketene on warming (see above). However, those that possess a labile alkyl group fragment by loss of the alkyl group (von Braun cleavage). For example, bis(dimethylamino)methane reacts with AcCl (Et2O, rt) to afford chloromethyldimethylamine,213 a useful Mannich reagent, and 1,3,5-trimethylhexahydro-s-triazine reacts with AcCl (CHCl3, D, 1 h) to afford chloromethylmethyl acetamide,214 a useful amidomethylation reagent.215 Also, aziridines react with AcCl (PhH, 0 °C) to afford chloroethylacetamides.216 Allylic amines react with in situ-generated AcI (AcCl/CuI, THF, rt) to afford acetamides.217

AcCl also activates pyridines toward nucleophilic addition. For example, phenylmagnesium chloride adds to pyridine in the presence of AcCl (cat. CuI, THF, -20 °C -> rt) to afford, after catalytic hydrogenation, N-acetyl-4-phenylpiperidine in 65% yield.218 Also, AcCl catalyzes the reaction between sodium iodide and 2-chloropyridine to afford 2-iodopyridine (MeCN, D, 24 h; 55%).219

N-Acetylation of enolizable imines to afford enamides can be accomplished by treatment with AcCl/PhNEt2. For example, treatment of crotonaldehyde cyclohexylimine with AcCl followed by PhNEt2 (toluene, rt) affords the enamide in 88% yield.220

Primary urethanes can be N-acetylated to afford imides by treatment with AcCl (100 °C, 1 h).221 Alternatively, urethanes can be converted into acetamides by treatment with AcBr (120-130 °C)221 or in situ-generated AcI222 (MeCN, 60 °C).223

Finally, a convenient method for preparation of N-Trimethylsilylacetamide (MSA), a useful trimethylsilyl transfer reagent, involves treatment of Hexamethyldisilazane with AcCl (hexane, D; 88%).224

S-Acetylation.

Both aliphatic and aromatic thiols can be S-acetylated by treatment with AcCl (cat. CoCl2, MeCN, rt).225

Nucleophilic Acetylation.

AcCl together with SmI2 (MeCN, rt) or SmCp2 delivers the acetyl anion synthon to ketones to afford the corresponding acyloins (eq 17).15

Related Reagents.

Acetic Anhydride; Acetyl Bromide; Acetyl Fluoride.


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