[541-41-3] · C3H5ClO2 · Ethyl Chloroformate · (MW 108.52)
(for ethoxycarbonylation of a wide variety of nucleophiles including anions of carboxylic acids4 and esters,5 nitriles,7 dithianes,9 ketones, enamines,10 imines,11 sulfones,12 cuprates,13 stannanes,14 Grignards,15 alanes,18 furans,17 alkynes;19 acylation of alcohols,20,22 carbonyls,23,25 amines, and aziridines;27 cleavage of tertiary amines;32 formation of mixed anhydrides38)
Physical Data: mp -81 °C; bp 95 °C; d 1.135 g cm-3.
Solubility: miscible with benzene, chloroform, diethyl ether, ethanol; insol water.
Form Supplied in: colorless liquid; widely available.
Purification: the liquid is washed with water then distilled at atmospheric pressure using an efficient fractionating column and CaCl2 guard tube.2
Handling, Storage, and Precautions: slowly hydrolyzed by water to CO2 and HCl; store at cool temperatures: pressure may develop within bottle; thermal decomposition to CO2 and EtCl occurs; highly flammable (fp 2 °C); toxic by inhalation and skin absorption; lachrymatory, irritant; use in a fume hood.
Ethyl chloroformate3 reacts with a wide range of nucleophiles. Enolates derived by deprotonation of aliphatic and aromatic carboxylic acids bearing at least one a-hydrogen with two equivalents of Lithium Diisopropylamide at low temperature in THF are ethoxycarbonylated to give the monoesters of malonic acids (eq 1).4 The yields are highest for alkyl carboxylic acids at -78 °C.5 Although higher yielding than with Diethyl Carbonate, treatment of the a-lithiated esters with Carbon Dioxide frequently gives better yields of the malonates.4,6 Mixed malonates, especially those derived from bulky alkyl esters, can be similarly prepared (eq 2).5
a-Lithionitriles are ethoxycarbonylated in good yield.7 Acetals8 and 1,3-dithianes9 are effectively ethoxycarbonylated (eq 3) if ethyl chloroformate is used as a cosolvent to prevent side reactions. Ethoxycarbonylation of ketones is achieved when enamines are treated with ethyl chloroformate, in some cases giving comparable yields to those obtained using metal enolates.10
Enantioselective ethoxycarbonylation has recently been attempted11 via deprotonation of N-benzylidenebenzylamine with two equivalents of a chiral lithium amide base and quenching with ethyl chloroformate; levels of asymmetric induction were low but higher than those obtained using other chloroformates (eq 4).
a,b-Unsaturated sulfones are a-ethoxycarbonylated (eq 5) on deprotonation with n-Butyllithium in THF at -78 °C and quenching with this reagent.12
Vinyl cuprates under Pd0 catalysis give a,b-alkenic esters (eq 6).13 Aryl, vinyl, and heterocyclic stannanes14 react smoothly under Pd0 catalysis at 100 °C to give ethyl esters (eq 7) in good yields if the catalyst and chloroformate are added to the reaction mixture slowly. A wide variety of functionality on tin is tolerated but allylstannanes are generally low yielding. Use of isobutyl chloroformate improves the yields in these acylcarbonylations.
Ethyl esters are produced from Grignard reagents15 if the organometallics are not present in excess. This is also the basis of the 5-ethoxycarbonylation of 2,4-dimethylpyrrole.16 2-Lithiofurans are ethoxycarbonylated in good yield (eq 8).17
Trans-a,b-unsaturated esters can be prepared by ethoxycarbonylation of vinylalanes derived from terminal alkynes bearing primary, secondary, or tertiary alkyl substituents without the necessity of forming an intermediate ate complex (eq 9).18 Cis-a,b-unsaturated esters result from ethoxycarbonylation of lithiated alkynes (eq 10)19 followed by reduction over Lindlar catalyst.
O-Ethoxycarbonylation is observed in some instances. Aliphatic alcohols, phenols,20 and cyanohydrins21 react in the presence of tertiary amines to give carbonates. Equatorial oriented steroid hydroxyls are selectively acylated in the presence of axial hydroxyl groups.22 Enol carbonates (eq 11)23 are readily derived from ketones by formation of the lithium enolate using Lithium 2,2,6,6-Tetramethylpiperidide in THF/HMPA at -78 °C followed by an ethyl chloroformate quench at room temperature. The use of HMPA prevents competitive C-acylation. LiTMP is necessary to avoid side reactions common with other amine-derived bases such as LDA. Sodium and potassium enolates are not useful, generally giving competitive C-acylation. This procedure avoids the use of classical methodology relying on the use of HgII salts.
Trans-1-(1,3-butadienyl) carbamates24 and carbonates25 are useful dienes in Diels-Alder chemistry. The carbonates are produced when Crotonaldehyde (and its congeners) are deprotonated and treated at -78 °C with ethyl chloroformate (eq 12). Use of higher temperatures results in loss of some of the (Z) geometry. Similar treatment of crotonaldehyde imines affords the carbamates.
O-Ethylation occurs when the sodium enolates of a-formyl g- and d-lactones are refluxed in THF with ethyl chloroformate.26
N-Ethoxycarbonylation forms the basis of a variety of reactions of nitrogenous compounds. Aziridines form N-ethoxycarbonylaziridines which are converted, on heating, to allylic amines (eq 13).27
Tertiary amines may be cleaved by ethyl chloroformate in certain circumstances. N-Demethylation has been noted. For example, tropine acetate (eq 14) is readily converted to nortropine hydrochloride28 on refluxing with ethyl chloroformate and subsequent acid-mediated hydrolysis of the intermediate urethane.
Reductive C-N bond cleavage has been demonstrated in more complex systems using ethyl chloroformate as a solvent.29 Chlorination of corticosteroid cyclic ethers has been observed.30 Tertiary aliphatic and alicyclic amines can be dealkylated.31 Phenyl chloroformate, however, is usually regarded as the reagent of choice. In summary, deamination, demethylation, debenzylation, and deallylation of tertiary amines can all occur on treatment with ethyl chloroformate but the regioselectivities of these reactions are difficult to predict.32
Imides (e.g. phthalimide) are ethoxycarbonylated if the potassium salt is treated with ethyl chloroformate at 5-10 °C. At elevated temperatures (60-110 °C) the lithium salts are N-ethylated in high yield. N-Alkylation also occurs with other imide systems such as barbiturates, hydantoins, and succinimides.33 Thiols give the corresponding monothiocarbonates.34 Thioamides form ethyl imidates35 and cyclic iminoethers36 are obtained from thiolactams on mild warming with ethyl chloroformate. Sulfinic and sulfonic acids yield their ethyl esters.37
The preparation of mixed anhydrides from ethyl chloroformate and carboxylic acids enables coupling of peptides and amino acids.38 This coupling procedure has largely been superseded by more effective methods relying on the use of superior reagents; see 1,3-Dicyclohexylcarbodiimide (DCC) and 1-Hydroxybenzotriazole (HOBT).
Ethyl chloroformate enables the one-step cyclization of peptides (eq 15),39 yields generally being superior to those obtained if Bis(2,4-dinitrophenyl) Carbonate is used. However, Isobutyl Chloroformate/N-methylmorpholine is now the reagent of choice for many solution-phase anhydride couplings.40
N-Protected amino acids and peptides are rapidly converted to the corresponding amino alcohols in high yields with complete retention of optical purity via reduction of the mixed anhydride by cold Sodium Borohydride in THF with dropwise addition of methanol (eq 16).41 The disulfide bridges of cystine, the methyl and benzyl esters of o-carboxyl-protected glutamic and aspartic acids of peptides, and N-Cbz and N-Boc protection are compatible with the methodology. The anhydrides derived from ethyl chloroformate are superior to isobutyl and benzyl carbonates both in terms of yield and retention of optical purity.
Carboxylic acid triethylamine salts yield mixed anhydrides which, when treated with ethoxymagnesiomalonic esters give the benzoylated malonate.42 Alternatively, treatment of the mixed anhydrides with sodium tetracarbonylferrate(II) produces the aldehyde derived from the parent aliphatic or aromatic carboxylic acid in good yield.43
Formation of mixed anhydrides also provides the basis for the synthesis of acyl azides (eq 17)44 and hence amines via the Curtius rearrangement. The azide ion is usually delivered to the most electrophilic carbonyl,45 but steric considerations may be important. The method is applicable even to strained cyclopropyl- and cyclobutylcarboxylic acids.46 Diisopropylethylamine (Hünig's base) has been mooted as a superior base for the formation of mixed anhydrides.47
(Z)-Ethylenic mixed anhydrides are easily prepared without isomerization and react with vinyl cuprates (and other organometallics) under Pd0 catalysis with >99% stereochemical control to give unsymmetrical divinyl ketones (eq 18).13 Alternative routes via (Z)-ethylenic acyl chlorides produce (E/Z) mixtures.
b-Cyanoesters (eq 19)48 are produced from b-amido acids providing that the acid and amide functionality are sufficiently close to enable formation of a cyclic intermediate.
Aromatics undergo Friedel-Crafts alkylation in the presence of Aluminum Chloride, probably due to the formation of EtCl in situ.49
Ethyl chloroformate has been used to moderate reactivity in polymerizations. For example, PVC with good thermal stability is prepared in the presence of this reagent.50
Andrew N. Payne
University of Cambridge, UK