Ethyl Trichloroacetate

(R = Et)

[515-84-4]  · C4H5Cl3O2  · Ethyl Trichloroacetate  · (MW 191.44) (R = Me)

[598-99-2]  · C3H3Cl3O2  · Methyl Trichloroacetate  · (MW 177.41) (R = i-Pr)

[3974-99-0]  · C5H7Cl3O2  · Isopropyl Trichloroacetate  · (MW 205.47) (R = t-Bu)

[1860-21-5]  · C6H9Cl3O2  · t-Butyl Trichloroacetate  · (MW 219.50)

(convenient precursor of dichlorocarbene;1a,2b generates enolates that react with a number of electrophiles;14b,19,22 effects addition reactions with alkenes30,35-37)

Alternate Name: trichloroacetic acid ethyl ester.

Physical Data: R = Et, bp 168 °C, d20 1.3836 g cm-3; R = Me, bp 154 °C, d20 1.4874 g cm-3; R = i-Pr, bp 175 °C, d20 1.3034 g cm-3; R = t-Bu, bp 55 °C/7 mmHg, d20 1.2363 g cm-3.

Solubility: insol H2O; miscible with alcohol, ether, benzene.

Form Supplied in: colorless liquid with odor resembling menthol; widely available. Purity 97-99%; typical impurity: CCl3CO2H <1%.

Analysis of Reagent Purity: 1H NMR (CDCl3) d 1.4 (t, 3H, CH3), 4.4 (q, 2H, CH2). 13C NMR (CDCl3) d 13.7 (q, CH3), 65.5 (t, CH2), 90.0 (s, CCl3), 161.5 (s, CO). IR (CCl4) 1769 cm-1 (C=O).

Handling, Storage, and Precautions: combustible liquid; harmful and irritant. Incompatible with strong oxidizing agents and strong bases. Avoid prolonged or repeated exposure and contact with eyes, skin, and clothing. Keep tightly closed and store in a cool dry place. Use in a fume hood.

Carbene Precursor.1a,2b

The reaction of trichloroacetic acid esters with alkali metal alkoxides (RONa or ROK) generates dichlorocarbene (eq 1), which affords gem-dichlorocyclopropane adducts by cycloaddition reaction with various kinds of double bonds.

The alkyl trichloroacetate can be methyl, ethyl, or t-butyl1b and the alkoxide can be MeONa, EtONa,1a n-BuONa,5b or t-BuOK;1b the most usual combination is CCl3CO2Et and MeONa.2b,7b The best results are obtained by the use of excess (1.1 to 5 equiv) of both CCl3CO2Et and MeONa components in a nonpolar solvent with cooling. Reaction with the double bonds1 of alkenes leads to gem-dichlorocyclopropane adducts in good yield (eq 2).1a

Such cyclopropanation is also realized with enol ethers2 (eq 3)2b and enol thioethers.3 The yields of adducts obtained with this carbene procedure are generally higher than those obtained by other methods: (CHCl3, t-BuOK),4 (CCl3CO2Na, pyrolysis),5 and (n-BuLi, CBrCl3).6

This carbene procedure has also been applied to the preparation of cyclic allylic and vinylic dichloro derivatives by ring enlargement from polycyclic alkenic compounds (eq 4).7 The initially formed dichloro adduct rearranges spontaneously7b-d or by solvolysis in the presence of silver salts7a to provide dichloro compounds by ring expansion. In the norbornene series, such one-carbon-atom expansion leads to derivatives (1)-(5)7b-d in better yields than other methods of generating dichlorocarbene: (CHCl3, t-BuOK),8 (CCl3CO2Na, pyrolysis),5 (CCl3HgPh, pyrolysis),9 and (CHCl3, NaOH).10

The mild reaction conditions further allow access, albeit in moderate yields, to gem-dichloro adducts that are difficult to obtain by other routes. Reactive substrates such as allenes,11 unstable divinyl ethers12 that undergo polymerization with other methods, or highly strained polycyclic compounds such as bicyclo[3.2.0]hept-1(5)-ene13 give dichloro adducts (16-40%) by treatment with this reagent system.

Enolate Precursor.

gem-Dichloroenolates are generated from CCl3CO2Et by C-Cl bond cleavage. The lithium enolate14 prepared by reaction of Me2NLi (generated from Lithium metal solution in HMPA/THF) with CCl3CO2Et at -78 °C, reacts with electrophiles (H2O, allyl halides, a-chloroalkyl ethers, aldehydes) to give moderate yields of a,a-dichloroacetate derivatives (E-CCl2CO2Et, 35-50%) by two-carbon homologation. Reformatsky-type reactions15 proceeding via magnesium gem-dichloroenolates lead to reduced b-hydroxy esters from aldehydes and ketones (eq 5), albeit with little preparative value.

Better yields (42-79%) of nonreduced compounds can be obtained14b,16 by preparing Mg enolates by halogen-metal exchange from i-PrMgCl and CCl3CO2Et in THF, at low temperature. Subsequent reaction of these enolates with various electrophiles (H2O, aldehydes, ketones, carboxylic anhydrides, alkyl halides, and a-halo ethers) affords nonreduced adducts (eq 6).

Reactions of D-glyceraldehyde17a and Boc-L-leucinal17b with the Mg enolates of methyl and isopropyl trichloroacetates (generated either by exchange with i-PrMgCl or by treatment of a phosphonium enolate (see below, eq 11) with MgCl2) in THF at low temperature provide the corresponding a,a-dichloro-b-hydroxy alkyl esters (70% and 50%). The ratios of diastereoisomers are 70:30 for (3R,4R):(3R,4S) and (3R,4S):(3S,4S) respectively. By the same route, steroidal ketones lead to rearranged b-chloro-a-keto esters.18

The zinc dichloroacetate enolate (also called Reformatsky reagent) is prepared prior to use by reaction of CCl3CO2Et with Zinc metal in THF and it reacts with the same substrates as the Grignard reagent with comparable yields (22-81%) (eq 7).19

In the presence of a Lewis acid such as Diethylaluminum Chloride,20 the Zn enolate reacts with carbonyl compounds to give a-chloro-a,b-unsaturated esters by Knoevenagel-type reaction (51-91%, Z > E). A dimetalated species such as ClZnC(Cl)=C(OZnX)OEt is the assumed intermediate in this reaction, which constitutes an alternative to the Emmons-Wadsworth-Horner reaction.21 This procedure has found use in the steroid field for the efficient preparation of a-chloro-a,b-unsaturated esters from ketones, with a two-carbon-chain extension (eq 8).20b

A phosphonium gem-dichloroenolate,22,23 generated in situ by reaction of TDAP (trisdimethylaminophosphine) with CCl3CO2Et at low temperature, reacts with carbonyl compounds to give rise, depending on the stoichiometry and the nature of both solvent and substrate, either to a-chloroglycidic esters (eq 9)22a,b or to a-chloro-a,b-unsaturated esters (eq 10).22c

Depending upon both substrate reactivity and reaction conditions, mixtures22b of a-chloroglycidic and a-chloro-a,b-unsaturated esters could be formed, arising from path 1 or path 2 (eq 11). Glycidic esters derived from ketones very often undergo isomerization to b-chloro-a-ketoesters.18,22a,b

Methyl and isopropyl trichloroacetates have also been used22b,c for such transformations. Because of the different reactivity of the phosphine, the Ph3P-CCl3CO2Me reagent system converts aromatic aldehydes into methyl a-chlorovinyl esters in good yields (60-74%, E > Z). Unlike (Me2N)3P (path 2, eq 11), this reaction proceeds via the stabilized ylide, Ph3P=CClCO2Me.24

In a special case,25 with (Me2N)2P(OMe) as the PIII compound, the alkyl moiety of the phosphite part reacts with the initially formed enolate to provide a product with one-carbon extension instead of the expected phosphate from a Perkow reaction (eq 12).26

The ethyl dichloroacetate anion, cathodically generated27 from CCl3CO2Et, adds to cyclic ketones.27a Rearrangement of the initially formed dichloro alkoxide affords a-chloro-b-keto esters with one-carbon ring expansion or the corresponding dehydrochlorinated ester (7-43%). Cycloaddition of such species with double bonds27b gives ethyl a-chlorocyclopropanecarboxylate (25-55%), expressing carbenoid properties.

Addition Reactions.

Double bonds undergo radical addition reactions with CCl3CO2Et (and other trichloroacetate esters) in the presence of various catalysts such as organic peroxides, UV irradiation, a redox system of copper salts, metal carbonyls, ruthenium salts-phosphine complexes, and palladium salts (eq 13).

On prolonged heating in the presence of (PhCO)2O, CCl3CO2Et adds to 1-alkenes to give ethyl 2-alkyl-2,2,4-trichloroacetates with two-carbon chain elongation from the starting alkene. Thus ethyl 2,2,4-trichlorononanoate is obtained from 1-heptene after 20 h under reflux in ~50% yield (purified) as a mixture with the 2:1 adduct.28 This method affords mainly telomers of high molecular weight with vinyl monomers and only a low yield of the 1:1 adduct with other reactive alkenes such as styrene.36

The parent ester CBr3CO2Et adds readily in a 1,4-manner to 1,3-butadiene. This reaction is induced by UV irradiation and provides the 1:1 adduct quantitatively29 (compare with eq 15). The use of copper salts as catalysts directs the reaction mainly towards the formation of the 1:1 adduct, but the yields of products still remain moderate (30-65%) (eq 14).30

Telomerization, especially for 2:1 adduct formation from CCl3CO2Me and acrylic monomers with copper complex catalysis, has been studied.31 The 1,4-addition reaction with 1,3-butadiene works well by redox catalysis with copper salts32 (eq 15).32b The catalytic systems used make it possible to completely suppress polymer and telomer formation and to obtain the 1:1 adduct with good 1,4-selectivity, depending on the type of ligand on the copper complexes.

Microwave irradiation effects a 20-fold increase in rate in the reaction of CCl3CO2Et with styrene catalyzed by a CuCl/i-PrNH2 complex (>90%, 15-40 min).33 Under those conditions, but without microwave activation, the 1:1 adduct is formed exclusively with deactivated chloroethylenes (eq 16) and even with easily polymerizable alkenes such as styrenes.34

Reaction of CCl3CO2Me with 1-alkenes catalyzed by dinuclear metal carbonyls35 (Co2(CO)8, [CpMo(CO)3]2, and [CpFe(CO)2]2) provides different results, depending on the catalyst nature. The Co catalyst gives methyl 4-alkyl-2,2,4-trichlorobutyrate (eq 17), while 4-alkyl-2,2-dichloro-g-butyrolactone is the main product with the Mo (eq 18) and Fe catalysts. With benzene as the solvent the dichloro lactone (R = H, RŽ = Me) is obtained almost exclusively.

In the presence of Dichlorotris(triphenylphosphine)ruthenium(II) the reaction of CCl3CO2Et (or CO2Me) with 1-alkenes leads to the formation of ethyl 2,2,4-trichloroalkanoates (eq 19)36 in good yields, even with easily polymerizable alkenes such as styrene, acrylonitrile, methyl vinyl ketone, and methyl methacrylate.

With CCl3CO2Me, 1-decene, and Pd(OAc)2-Ph3P as catalyst in the presence of base (AcONa or K2CO3) the addition reaction proceeds under milder conditions to afford the 1:1 adduct in good yield (eq 20). Unlike the reactions with previous catalysts, this reaction proceeds even at room temperature.37

1. (a) Parham, W. E.; Schweizer, E. E. JOC 1959, 24, 1733. (b) Parham, W. E.; Loew, F. C. JOC 1958, 23, 1705. (c) Brun, P.; Casanova, J.; Hatem, J.; Waegell, B. BSF(2) 1977, 521. (d) Taylor, K. G.; Chaney, J. JACS 1976, 98, 4158.
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