ETHYL TRICHLOROACETATE 1

Ethyl Trichloroacetate

CCl3CO2R

(R = Et)[515-84-4] C4H5Cl3O2 (MW 191.44)InChI = 1/C4H5Cl3O2/c1-2-9-3(8)4(5,6)7/h2H2,1H3InChIKey = SJMLNDPIJZBEKY-UHFFFAOYAX(R = Me)[598-99-2] C3H3Cl3O2 (MW 177.41)InChI = 1/C3H3Cl3O2/c1-8-2(7)3(4,5)6/h1H3InChIKey = VHFUHRXYRYWELT-UHFFFAOYAW(R = i-Pr)[3974-99-0] C5H7Cl3O2 (MW 205.47)InChI = 1/C5H7Cl3O2/c1-3(2)10-4(9)5(6,7)8/h3H,1-2H3InChIKey = JYXIYFNAIFVCAN-UHFFFAOYAC(R = t-Bu)[1860-21-5] C6H9Cl3O2 (MW 219.50)InChI = 1/C6H9Cl3O2/c1-5(2,3)11-4(10)6(7,8)9/h1-3H3InChIKey = YROVKSCEXQTHTJ-UHFFFAOYAS

(convenient precursor of dichlorocarbene;1a,2b generates enolatesthat 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 1.3034g 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) δ 1.4 (t, 3H, CH3),4.4 (q, 2H, CH2). 13C NMR (CDCl3) δ 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; harm-

ful and irritant. Incompatible with strong oxidizing agentsand strong bases. Avoid prolonged or repeated exposure andcontact with eyes, skin, and clothing. Keep tightly closed andstore in a cool dry place. Use in a fume hood.

Carbene Precursor.1a,2b The reaction of trichloroacetic acidesters with alkali metal alkoxides (RONa or ROK) generatesdichlorocarbene (eq 1), which affords gem-dichlorocyclopropaneadducts by cycloaddition reaction with various kinds of doublebonds.

(1)Cl3CCO2R + R′OM R′OCO2R + MCl + Cl2C

The alkyl trichloroacetate can be methyl, ethyl, or t-butyl1b andthe alkoxide can be MeONa, EtONa,1a n-BuONa,5b or t-BuOK;1b

the most usual combination is CCl3CO2Et and MeONa.2b,7b Thebest results are obtained by the use of excess (1.1 to 5 equiv) ofboth CCl3CO2Et and MeONa components in a nonpolar solventwith cooling. Reaction with the double bonds1 of alkenes leads togem-dichlorocyclopropane adducts in good yield (eq 2).1a

Cl Cl

(2)MeONa, CCl3CO2Et

pentane, –40 to –6 °C then rt86%

Such cyclopropanation is also realized with enol ethers2

(eq 3)2b and enol thioethers.3 The yields of adducts obtained withthis carbene procedure are generally higher than those obtained byother methods: (CHCl3, t-BuOK),4 (CCl3CO2Na, pyrolysis),5 and(n-BuLi, CBrCl3).6

O OCl

Cl(3)

MeONa, CCl3CO2Et

pentane, 0 °C then rt68–75%

This carbene procedure has also been applied to the prepa-ration of cyclic allylic and vinylic dichloro derivatives by ringenlargement from polycyclic alkenic compounds (eq 4).7 Theinitially formed dichloro adduct rearranges spontaneously7b–d orby solvolysis in the presence of silver salts7a to provide dichlorocompounds by ring expansion. In the norbornene series, such one-carbon-atom expansion leads to derivatives (1)–(5)7b–d in betteryields 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 inmoderate yields, to gem-dichloro adducts that are difficult toobtain by other routes. Reactive substrates such as allenes,11

unstable divinyl ethers12 that undergo polymerization with othermethods, or highly strained polycyclic compounds such asbicyclo[3.2.0]hept-1(5)-ene13 give dichloro adducts (16–40%) bytreatment with this reagent system.

R′R

R′R

Cl

Cl

R′R

ClCl

R′R

R′R

MeONa, CCl3CO2Et

solvent, 0 °C then rt(4)

=

R′R

=

exo

=exo

endo

pet. ether

hexane

hexane

hexane

(2) 50%7c

(3) 96%7d

(4) 97%, 7e 50%10

(5) 91%, 7e 65%10

(1) 74–88%,7b 4–45%5,8,9pet. ether

Enolate Precursor. gem-Dichloroenolates are generatedfrom CCl3CO2Et by C–Cl bond cleavage. The lithium enolate14

prepared by reaction of Me2NLi (generated from Lithium metalsolution in HMPA/THF) with CCl3CO2Et at −78 ◦C, reacts withelectrophiles (H2O, allyl halides, α-chloroalkyl ethers, aldehy-des) to give moderate yields of α,α-dichloroacetate derivatives(E–CCl2CO2Et, 35–50%) by two-carbon homologation. Refor-matsky-type reactions15 proceeding via magnesium gem-dichloroenolates lead to reduced β-hydroxy esters from aldehydesand ketones (eq 5), albeit with little preparative value.

Avoid Skin Contact with All Reagents

2 ETHYL TRICHLOROACETATE

CCl3CO2Et, Mg, HgCl2 cat

RCO2Et

OHR′RCOR′ (5)

R = Me, R′ = Ph, 21.5%R = H, R′ = Ph, 25%

arom. solv. or Et2O or mixture, reflux

Better yields (42–79%) of nonreduced compounds can beobtained14b,16 by preparing Mg enolates by halogen–metal ex-change from i-PrMgCl and CCl3CO2Et in THF, at low temp-erature. Subsequent reaction of these enolates with variouselectrophiles (H2O, aldehydes, ketones, carboxylic anhydrides,alkyl halides, and α-halo ethers) affords nonreduced adducts(eq 6).

PrCO2Et

OH

Cl Cl

CCl3CO2Et, i-PrMgCl(6)PrCHO

[Cl2C=C(OEt)OMgCl]

THF, –78 °C, –20 °C then rt79%

Reactions of D-glyceraldehyde17a and Boc-L-leucinal17b withthe Mg enolates of methyl and isopropyl trichloroacetates (gener-ated either by exchange with i-PrMgCl or by treatment of a phos-phonium enolate (see below, eq 11) with MgCl2) in THF at lowtemperature provide the corresponding α,α-dichloro-β-hydroxyalkyl esters (70% and 50%). The ratios of diastereoisomers are70:30 for (3R,4R):(3R,4S) and (3R,4S):(3S,4S) respectively. Bythe same route, steroidal ketones lead to rearranged β-chloro-α-keto esters.18

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

CO2Et

O

Cl Cl

CCl3CO2Et, Zn(7)(MeCO)2O

[Cl2C=C(OEt)OZnCl]

THF, –15 °C65%

In the presence of a Lewis acid such as DiethylaluminumChloride,20 the Zn enolate reacts with carbonyl compounds togive α-chloro-α,β-unsaturated esters by Knoevenagel-type reac-tion (51–91%, Z > E). A dimetalated species such as ClZnC(Cl)=C(OZnX)OEt is the assumed intermediate in this reaction, whichconstitutes an alternative to the Emmons–Wadsworth–Hornerreaction.21 This procedure has found use in the steroid field forthe efficient preparation of α-chloro-α,β-unsaturated esters fromketones, with a two-carbon-chain extension (eq 8).20b

CCl3CO2Et, Zn, Et2AlCl(8)

O

OMe

ClCO2Et

THF, –10 °C then rt87%

A phosphonium gem-dichloroenolate,22,23 generated in situby reaction of TDAP (trisdimethylaminophosphine) withCCl3CO2Et at low temperature, reacts with carbonyl compoundsto give rise, depending on the stoichiometry and the nature of bothsolvent and substrate, either to α-chloroglycidic esters (eq 9)22a,b

or to α-chloro-α,β-unsaturated esters (eq 10).22c

O

RCl

CO2Et

(Me2N)3PTHF, –20 to 0 °C

RCHO + CCl3CO2Et (9)

R = i-Pr, 68%R = t-Bu, 85%

(or CH2Cl2)22c

(10)Cl

CO2Me

CCl3CO2Me

Et2 (Me2N)3P + EtCHO

THF, –20 °C40%

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

O–

OP(NMe2)3

ClP(NMe2)3

CClCO2EtRR′CO

(Me2N)3P + CCl3CO2EtRCOR′+

RR′CCCl2CO2Et

(11)

+

path 1 + Cl– ClP(NMe2)3+

RR'CCCl2CO2Et+

path 2P(NMe2)3 + Cl– ClP(NMe2)3

+RR′C=CClCO2Et

– OP(NMe2)3

(Me2N)3PCl –CCl2CO2Et

Cl–

Methyl and isopropyl trichloroacetates have also been used22b,c

for such transformations. Because of the different reactivity ofthe phosphine, the Ph3P–CCl3CO2Me reagent system convertsaromatic aldehydes into methylα-chlorovinyl esters in good yields(60–74%, E > Z). Unlike (Me2N)3P (path 2, eq 11), this reactionproceeds 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 initiallyformed enolate to provide a product with one-carbon extension in-stead of the expected phosphate from a Perkow reaction (eq 12).26

[(Me2N)2P(Cl)OMe –CCl2CO2Et]+

(Me2N)2P(Cl)O + MeCCl2CO2Et (12)

89%

CCl3CO2Et(Me2N)POMe

The ethyl dichloroacetate anion, cathodically generated27

from CCl3CO2Et, adds to cyclic ketones.27a Rearrangement ofthe initially formed dichloro alkoxide affords α-chloro-β-ketoesters with one-carbon ring expansion or the corresponding dehy-drochlorinated ester (7–43%). Cycloaddition of such species withdouble bonds27b gives ethyl α-chlorocyclopropanecarboxylate(25–55%), expressing carbenoid properties.

Addition Reactions. Double bonds undergo radical addi-tion 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).

RCl CO2Et

Cl ClRR

Cl CO2Et

Cl ClR

CCl3CO2Et

(13)+

1:1 adduct 2:1 adduct

catalyst

On prolonged heating in the presence of (PhCO)2O,CCl3CO2Et adds to 1-alkenes to give ethyl 2-alkyl-2,2,4-

A list of General Abbreviations appears on the front Endpapers

ETHYL TRICHLOROACETATE 3

trichloroacetates with two-carbon chain elongation from the start-ing alkene. Thus ethyl 2,2,4-trichlorononanoate is obtained from1-heptene after 20 h under reflux in ∼50% yield (purified) asa mixture with the 2:1 adduct.28 This method affords mainlytelomers of high molecular weight with vinyl monomers and onlya low yield of the 1:1 adduct with other reactive alkenes such asstyrene.36

The parent ester CBr3CO2Et adds readily in a 1,4-manner to1,3-butadiene. This reaction is induced by UV irradiation andprovides the 1:1 adduct quantitatively29 (compare with eq 15).The use of copper salts as catalysts directs the reaction mainlytowards the formation of the 1:1 adduct, but the yields of productsstill remain moderate (30–65%) (eq 14).30

(14)

CCl3CO2EtCuI (3 mol%) Cl

CCl2CO2EtMeCN, 120 °C

63%

Telomerization, especially for 2:1 adduct formation fromCCl3CO2Me and acrylic monomers with copper complex cataly-sis, has been studied.31 The 1,4-addition reaction with 1,3-buta-diene works well by redox catalysis with copper salts32 (eq 15).32b

The catalytic systems used make it possible to completely suppresspolymer and telomer formation and to obtain the 1:1 adduct withgood 1,4-selectivity, depending on the type of ligand on the coppercomplexes.

Cl CO2Et

Cl Cl

CCl3CO2EtCuCl, Et2NH (0.5–1 mol%)

CO2Et

Cl Cl

95:5

+Cl

(15)

MeCN, 100 °C80%

Microwave irradiation effects a 20-fold increase in rate in thereaction of CCl3CO2Et with styrene catalyzed by a CuCl/i-PrNH2

complex (>90%, 15–40 min).33 Under those conditions, but with-out microwave activation, the 1:1 adduct is formed exclusivelywith deactivated chloroethylenes (eq 16) and even with easilypolymerizable alkenes such as styrenes.34

Cl

R R CO2Et

Cl Cl Cl Cl

CCl3CO2EtCuCl, Et2NH (5 mol%)

(16)

R = H, 38%; Cl, 45%

CH2ClCH2Cl, 80 °C

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

Bu CO2Me

Cl ClClCCl3CO2Et

Co2(CO)8 (2 mol%)(17)BuCH=CH2 neat, 150 °C

74%

R′

R

O CCl2

RR′

O

ClMeO2C

RR′

Cl

Cl

CCl3CO2Et[CpMo(CO)3]2 (1–2 mol%)

+ (18)

42–99% 1–20%R = H, Me; R′ = C1 to C6 alkyl

neat or solvent (5 sorts)

In the presence of Dichlorotris(triphenylphosphine)ruthe-nium(II) the reaction of CCl3CO2Et (or CO2Me) with1-alkenes leads to the formation of ethyl 2,2,4-trichloroalkanoates(eq 19)36 in good yields, even with easily polymerizable alkenessuch as styrene, acrylonitrile, methyl vinyl ketone, and methylmethacrylate.

(19)R′

R

R = H, Me; R′ = hexyl, phenyl, CN, Ac, CO2Me

CO2Et

ClCl

Cl

RR′

CCl3CO2EtRuIICl2(Ph3P)3 (0.4 mol%)

neat or PhH, 120 °C62–83%

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

Octyl CO2Me

Cl ClClOctylCH=CH2

CCl3CO2Me, AcONaPd(OAc)2(Ph3P)3 (1 mol%)

(20)PhH or PhMe, 80–100 °C

62–64%

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

2. (a) Schweizer, E. E.; Parham, W. E., J. Am. Chem. Soc. 1960, 82, 4085.(b) Parham, W. E.; Schweizer, E. E.; Mierzwa, S. A., Jr., Org. Synth.1961, 41, 76. (c) Parham, W. E.; Huestis, L. D., J. Am. Chem. Soc. 1962,84, 813. (d) Greco, C. V.; Grosso, V. G., J. Org. Chem. 1973, 38, 146.(e) Müller, P.; Pautex, N., Helv. Chim. Acta 1991, 74, 55.

3. Parham, W. E.; Koncos, R., J. Am. Chem. Soc. 1961, 83, 4034.

4. (a) Doering, W. von E.; Hoffmann, A. K., J. Am. Chem. Soc. 1954, 76,6162. (b) Winberg, H. E., J. Org. Chem. 1959, 24, 264.

5. Wagner, W. M.; Kloosterziel, H.; van der Ven, S., Recl. Trav. Chim.Pays-Bas 1961, 80, 740.

6. Miller, W. T.; Kim, C. S. Y., J. Am. Chem. Soc. 1959, 81, 5008.

7. (a) Parham, W. E.; Sperley, R. J., J. Org. Chem. 1967, 32, 924. (b) Jefford,C. W.; Gunsher, J.; Hill, D. T.; Brun, P.; Le Gras, J.; Waegell, B., Org.Synth. 1971, 51, 60. (c) Takaishi, N.; Inamoto, Y.; Aigami, K., J. Org.Chem. 1975, 40, 276. (d) Johnson, R. P.; Exarchou, A.; Jefford, C. W., J.Org. Chem. 1977, 42, 3758. (e) Popescu, A.; Pârvulescu, L.; Stànescu,L.; Gheorghiu, M. D., Rev. Roum. Chem. 1986, 31, 1025.

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9. Logan, T. J., Org. Synth. 1966, 46, 98.

10. Pârvulescu, L.; Gheorghiu, M. D., Rev. Roum. Chem. 1977, 22, 1089.

11. (a) Billups, W. E.; Blakeney, A. J.; Rao, N. A.; Buynak, J. D., Tetrahedron1981, 37, 3215. (b) Dolbier, W. R., Jr.; Lomas, D.; Garza, T; Harmon,C.; Tarrant, P., Tetrahedron 1972, 28, 3185.

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14. (a) Castro, B.; Villieras, J., C. R. Hebd. Seances Acad. Sci., Ser. C 1967,264, 1609. (b) Villieras, J.; Castro, B., Bull. Soc. Chem. Fr. 1968, 246.

Avoid Skin Contact with All Reagents

4 ETHYL TRICHLOROACETATE

15. Miller, R. E.; Nord, F. F., J. Org. Chem. 1951, 16, 728.

16. Villieras, J.; Normant, H., C. R. Hebd. Seances Acad. Sci., Ser. C 1967,264, 593.

17. (a) Rague, B.; Chapleur, Y.; Castro, B., J. Chem. Soc., Perkin Trans. 11982, 2063. (b) Hayon, A. F.; Fehrentz, J. A.; Chapleur, Y.; Castro, B.,Bull. Soc. Chem. Fr. Part 2 1983, 207.

18. (a) Castro, B.; Amos, J., Bull. Soc. Chem. Fr. Part 2 1974, 2559.(b) Amos, J.; Castro, B., Bull. Soc. Chem. Fr. Part 2 1991, 550.

19. (a) Villieras, J.; Castro, B.; Ferracutti, N., C. R. Hebd. Seances Acad.Sci., Ser. C 1968, 267, 915. (b) Castro, B.; Villieras, J.; Ferracutti, N.,Bull. Soc. Chem. Fr. Part 2 1969, 3521.

20. (a) Takai, K.; Hotta, Y.; Oshima, K.; Nozaki, H., Bull. Chem. Soc. Jpn.1980, 53, 1698. (b) Daniewski, A. R.; Wojciechowska, W., J. Org. Chem.1982, 47, 2993.

21. Wadsworth, W. S., Jr.; Emmons, W. D., Org. Synth., Coll. Vol. 1973, 5,547.

22. (a) Villieras, J.; Lavielle, G.; Burgada, R.; Castro, B., C. R. Hebd. SeancesAcad. Sci., Ser. C 1969, 268, 1164. (b) Villieras, J.; Lavielle, G.; Combret,J. C., Bull. Soc. Chem. Fr. Part 2 1971, 898. (c) Lavielle, G.; Combret, J.C.; Villieras, J., C. R. Hebd. Seances Acad. Sci., Ser. C 1971, 272, 2175.

23. Vorbrüggen, H.; Bohn, B. D.; Krolikiewicz, K., Tetrahedron 1990, 46,3489.

24. Burton, D. J.; Greenwald, J. R., Tetrahedron Lett. 1967, 1535.

25. Hargis, J. H.; Alley, W. D., J. Am. Chem. Soc. 1974, 96, 5927.

26. Kharasch, M. S.; Bengelsdorf, I. S., J. Org. Chem. 1955, 20, 1356.

27. (a) Karrenbrock, F.; Schäfer, H. J., Tetrahedron Lett. 1978, 1521.(b) Baizer, M. M.; Chruma, J. L., J. Org. Chem. 1972, 37, 1951.

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33. Adámek, F.; Hájek, M., Tetrahedron Lett. 1992, 33, 2039.

34. Kotora, M.; Hájek, M., RKC 1991, 44, 415, (Chem. Abstr. 1991, 115,182 556j).

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Jean-Robert Dormoy & Bertrand CastroSANOFI Chimie, Gentilly, France

A list of General Abbreviations appears on the front Endpapers