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Org. Synth. 1978, 58, 37
DOI: 10.15227/orgsyn.058.0037
CARBENE GENERATION BY α-ELIMINATION WITH LITHIUM 2,2,6,6-TETRAMETHYLPIPERIDIDE: 1-ETHOXY-2-p-TOLYLCYCLOPROPANE
[Benzene, 1-(2-ethoxycyclopropyl)-4-methyl]
Submitted by Charles M. Dougherty1 and Roy A. Olofson2.
Checked by Mark W. Johnson and Robert M. Coates.
1. Procedure
Caution! Benzene has been identified as a carcinogen; OSHA has issued emergency standards on its use. All procedures involving benzene should be carried out in a well-ventilated hood, and glove protection is required.
A 250-ml., three-necked, round-bottomed flask equipped with a 50-ml. pressure-equalizing dropping funnel capped by a rubber septum, an efficient reflux condenser connected to a nitrogen inlet, and a magnetic stirrer (Note 1) is charged with 7.02 g. (0.0500 mole) of α-chloro-p-xylene (Note 2) and 45.6 g. (0.633 mole) of ethyl vinyl ether (Note 3). A solution of 7.06 g. (0.0501 mole) of 2,2,6,6-tetramethylpiperidine (Note 4) in 15 ml. of dry diethyl ether is injected through the septum into the dropping funnel. Lithium 2,2,6,6-tetramethylpiperidide is generated in situ by injecting 46.5 ml. (0.0502 mole) of a 1.08 M solution of methyllithium in ether (Note 5) through the septum over a 5–10-minute period (Note 6) and (Note 7). After another 10 minutes, the contents are added dropwise to the vigorously stirred solution in the flask at a rate that maintains a gentle reflux. When the ca. 2-hour addition period is complete, the white slurry is stirred overnight at room temperature (Note 8). Water (10 ml.) is added dropwise to the stirred suspension, and the contents of the flask are poured into a separatory funnel containing 100 ml. of ether and 100 ml. of water. The aqueous layer is separated and extracted with two 100-ml. portions of ether. The combined ether solutions are washed successively with 10% aqueous citric acid (Note 9), 5% aqueous sodium hydrogen carbonate, and water, dried with anhydrous calcium chloride, filtered and evaporated with a rotary evaporator. The residual liquid is distilled at reduced pressure, affording 6.6–7.0 g. (75–80%) of 1-ethoxy-2-p-tolylcyclopropane, b.p. 116–118° (10 mm.), 95–96° (3.2 mm.) (Note 10).
2. Notes
1. The glassware is dried in an oven at approximately 125° and assembled while still warm. The nitrogen inlet, which consists of a T-tube assembly connected to an oil bubbler, is attached, and the apparatus is allowed to cool while being swept with a stream of dry nitrogen. The septum is placed on top of the dropping funnel, and the nitrogen flow adjusted to maintain a slight positive pressure of nitrogen within the apparatus during the reaction.
2. α-Chloro-p-xylene was obtained from Aldrich Chemical Company, Inc., and purified by distillation under reduced pressure.
3. Ethyl vinyl ether was supplied by Aldrich Chemical Company, Inc., and distilled from sodium. If simple alkenes are used in place of ethyl vinyl ether, the submitters find that the yields of cyclopropanes are improved by dilution of the olefin with one or two volumes of ethyl ether.
4. 2,2,6,6-Tetramethylpiperidine, furnished by Aldrich Chemical Company, Inc., Fluka A G, and ICN Life Sciences Group, is sometimes contaminated with traces of water, hydrazine, and/or 2,2,6,6-tetramethyl-4-piperidone. These impurities may be removed by drying with sodium hydroxide or potassium hydroxide pellets, filtering, and distilling at atmospheric pressure, b.p. 153–154°. The purified amine can be stored indefinitely under a nitrogen atmosphere.
5. Methyllithium in ethyl ether from Ventron Corporation was used. Directions for the preparation of ethereal methyllithium from methyl bromide are also available [see Org. Synth., Coll. Vol. 6, 901 (1988).] The checkers standardized the solution immediately before use by diluting a 2.5-ml. aliquot with 10 ml. of benzene and titrating with a 1 M solution of 2-butanol in xylene according to the procedure of Watson and Eastham3 [see Org. Synth., Coll. Vol. 6, 121 (1988)], with 1,10-phenanthroline as indicator. The submitters report that the yield of arylcyclopropane is lower if a commercially available solution of n-butyllithium in hydrocarbon solvents is used.
6. The methane generated is vented by passage through the oil bubbler.
7. Since the reaction between methyllithium and 2,2,6,6-tetramethylpiperidine is relatively slow at lower temperatures, lithium 2,2,6,6-tetramethylpiperidide is best prepared at room temperature. The reagent may, however, be used over a wide range of temperatures.
8. Approximately the same yields are obtained if the product is isolated after 2–3 hours.
9. The use of aqueous citric acid avoids the formation of insoluble gelatinous precipitates, which result when hydrochloric acid is employed. Sulfuric acid is a suitable alternative to citric acid but must be used in substantial excess to prevent precipitation 2,2,6,6-Tetramethylpiperidine may be recovered from the citric acid extract by making the aqueous solution basic and extracting with ether.
10. The product, a mixture of cis- and trans-isomers in the ratio of about 2:1, has the following spectral properties: IR (liquid film) cm−1 (strong): 1510, 1440, 1370, 1340, 1120, 1080; 1H NMR (CCl4), δ (multiplicity, number of protons, assignment): 0.63–1.3 (m, 5H, cyclopropyl CH2 and OCH2CH3), 1.4–2.0 (m, 1H, cyclopropyl CH), 2.23 (s, 1H, trans-aromatic CH3), 2.28 (s, ca. 2H, cis-aromatic CH3), 2.8–3.7 (m, 3H, CHOCH2CH3), 6.7–7.2 (m, 4H, C6H4). The following specific absorptions in the 1H NMR spectrum may be used to estimate the ratio of the two isomers, δ (multiplicity, coupling constant J in Hz., number of protons, assignment); cis-isomer: 0.92 (t, J = 7, 3H, OCH2CH3), 7.02 (center of AA'BB' m, 4H, C6H4); trans-isomer: 1.14 (t, J = 7, 3H, OCH2CH3), 6.88 (center of AA'BB' m, 4H, C6H4).
3. Discussion
This procedure describes the generation of the strong, nonnucleophilic amide base, lithium 2,2,6,6-tetramethylpiperidide, which is used in the regioselective abstraction of a proton from a very weak carbon acid containing other sites reactive toward nucleophilic attack.4,5 In contrast, most other strong bases undergo preferential alkylation with benzyl halides. 1-Ethoxy-2-p-tolylcyclopropane is one of over a dozen aryl cyclopropanes, cyclopropenes, and cyclopropanone ketals that have been prepared by this method5 (Table I). An analog, 1-methoxy-2-phenylcyclopropane, has been obtained in 8% yield from the reaction of methyllithium with dichloromethyl methyl ether in styrene.6 The alkene is present in large excess, as is commonly the case for reactions involving short-lived carbene intermediates. In the present procedure ethyl vinyl ether serves as both solvent and reactant. For best results with alkenes lacking alkoxy substituents, approximately two volumes of ether or tetrahydrofuran should be used as diluent. Alkoxy,7,8 acyloxy,9 alkenyl,5,10,11 trialkylsilyl,10 and trialkylstannyl10 carbenes have been generated and trapped in situ with alkenes and alkynes by this method, affording a variety of substituted cyclopropanes.
TABLE I
PREPARATION OF CYCLOPROPANES FROM ALKYL HALIDES, ALKENES, AND LITHIUM 2,2,6,6-TETRAMETHYLPIPERIDIDE

Product

Yield (%)

Product

Yield (%)


667

219

667

648

748

399

467

628

359

20 (24)9


Lithium 2,2,6,6-tetramethylpiperidide has also been used to advantage in a number of other types of reactions. This base reacts with aryl halides5,10,12,13 (and, less cleanly, with aryl sulfonates14), giving benzynes, which have been trapped with thiolates,5 acetylides,5,14 enolates,10,13,14 and conjugated dienes.10,12,14 Replacement of halogen by hydrogen, a major reaction observed between other dialkylamide bases and aryl halides, does not occur with lithium 2,2,6,6-tetramethylpiperidide.5 While alkyl benzoates undergo selective deprotonation at the ortho-position upon treatment with this amide base,15 methyl thiobenzoate and N,N-dimethylbenzamide are metallated at the methyl group, forming dipole-stabilized carbanions.16 The organolithium intermediates produced condense with the remaining ester or amide, affording various aryl ketones. Lithiation of dibromomethane17 and at the α-position of isocyanides18 with lithium 2,2,6,6-tetramethylpiperidide produces an organolithium intermediate reactive toward carbonyl compounds. In the synthesis of enol carbonates from ketone enolates and chloroformates, this base is the only one to accomplish the reaction in high yield.19 Lithium 2,2,6,6-tetramethylpiperidide has been shown to be the base of choice for irreversible ketone enolate formation20 and has been used to discriminate sterically between two potential enolate sites to yield alkylation products with extremely high regioselectivity.21 The enolate anions of esters5,22 and dianions of β-keto esters23 and propiolic acid24 have been formed by reaction with lithium 2,2,6,6-tetramethylpiperidide. It is a superior base for metallation of selenides,25 selenoacetals, and selenoketals.26 Other reactions in which this hindered base has proved effective include the conversion of an epoxide to an enolate anion,27 the generation of certain α-lithioörganoboranes,28 the preparation of the highly strained tetracyclo(4.2.0.02,4.03,5)oct-7-ene from the appropriate tosylhydrazone,29 and the insertion of magnesium into bacteriopheophytin α.30 In many of these reactions, other bases, including less hindered amide bases such as lithium diisopropylamide, gave either lower yields or different products entirely.

References and Notes
  1. Department of Chemistry, Herbert H. Lehman College, City University of New York, Bronx, New York 10468.
  2. Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802.
  3. S. C. Watson and J. F. Eastham, J. Organomet. Chem., 9, 165 (1967).
  4. R. A. Olofson and C. M. Dougherty, J. Am. Chem. Soc., 95, 581 (1973).
  5. R. A. Olofson and C. M. Dougherty, J. Am. Chem. Soc., 95, 582 (1973).
  6. W. K. Kirmse and H. Schütte, Chem. Ber., 101, 1674 (1968).
  7. R. A. Olofson, K. D. Lotts, and G. N. Barber, Tetrahedron Lett., 3779 (1976).
  8. G. N. Barber and R. A. Olofson, Tetrahedron Lett., 3783 (1976).
  9. R. A. Olofson, K. D. Lotts, and G. N. Barber, Tetrahedron Lett., 3381 (1976).
  10. R. A. Olofson, D. H. Hoskin, and K. D. Lotts, Tetrahedron Lett., 1677 (1978).
  11. R. A. Moss and R. C. Munjal, Synthesis, 11, 425 (1979).
  12. K. L. Shepard, Tetrahedron Lett., 3371 (1975).
  13. I. Fleming and T. Mah, J. Chem. Soc. Perkin Trans. I, 964 (1975).
  14. I. Fleming and T. Mah, J. Chem. Soc. Perkin Trans. I, 1577 (1976).
  15. C. J. Upton and P. Beak, J. Org. Chem., 40, 1094 (1975).
  16. P. Beak and R. Farney, J. Am. Chem. Soc., 95, 4771 (1973); P. Beak, B. G. McKinnie, and D. B. Reitz, Tetrahedron Lett., 1839 (1977).
  17. H. Taguchi, H. Yamamoto, and H. Nozaki, Tetrahedron Lett., 2617 (1976).
  18. U. Schöllkopf, F. Gerhart, I. Hoppe, R. Harms, K. Hantke, K.-H. Scheunemann, E. Eilers, and E. Blume, Justus Liebigs Ann. Chem., 183 (1976).
  19. R. A. Olofson, J. Cuomo, and B. A. Bauman, J. Org. Chem., 43, 2073 (1978).
  20. X. Creary, J. Org. Chem., 45, 2419 (1980); X. Creary and A. J. Rollin, J. Org. Chem., 44, 1798 (1979).
  21. J. D. White and Y. Fukuyama, J. Am. Chem. Soc., 101, 226 (1979).
  22. S. R. Wilson and R. S. Meyers, J. Org. Chem., 40, 3309 (1975).
  23. S. N. Huckin and L. Weiler, J. Am. Chem. Soc., 96, 1082 (1974).
  24. H. H. Meyer, Justus Liebigs Ann. Chem., 337 (1978); B. S. Pitzele, J. S. Baran, and D. H. Steinman, J. Org. Chem., 40, 269 (1975).
  25. H. Reich, Acc. Chem. Res., 12, 22 (1979).
  26. D. van Ende, A. Cravador, and A. Krief, J. Organomet. Chem., 177, 1 (1979).
  27. L. S. Trzupek, T. L. Newirth, E. G. Kelley, N. E. Sbarbati, and G. M. Whitesides, J. Am. Chem. Soc., 95, 8118 (1973).
  28. M. W. Rathke and R. Kow, J. Am. Chem. Soc., 94, 6854 (1972); R. Kow and M. W. Rathke, J. Am. Chem. Soc., 95, 2715 (1973); D. S. Matteson and R. J. Moody, J. Am. Chem. Soc., 99, 3196 (1977).
  29. G. E. Gream, L. R. Smith, and J. Meinwald, J. Org. Chem., 39, 3461 (1974).
  30. M. R. Wasielewski, Tetrahedron Lett., 1373 (1977).

Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)

Lithium 2,2,6,6-tetramethylpiperidide

calcium chloride (10043-52-4)

sulfuric acid (7664-93-9)

hydrochloric acid (7647-01-0)

Benzene (71-43-2)

ether,
ethyl ether,
diethyl ether (60-29-7)

hydrogen (1333-74-0)

sodium hydroxide (1310-73-2)

citric acid (77-92-9)

sodium hydrogen carbonate (144-55-8)

magnesium (7439-95-4)

nitrogen (7727-37-9)

methane (7782-42-5)

potassium hydroxide (1310-58-3)

sodium (13966-32-0)

methyl bromide (74-83-9)

xylene (106-42-3)

hydrazine (302-01-2)

dibromomethane (74-95-3)

styrene (100-42-5)

n-butyllithium (109-72-8)

Tetrahydrofuran (109-99-9)

Methyllithium (917-54-4)

ethyl vinyl ether (109-92-2)

Dichloromethyl methyl ether (4885-02-3)

2-Butanol (78-92-2)

lithium diisopropylamide (4111-54-0)

1,10-phenanthroline (66-71-7)

Benzene, 1-(2-ethoxycyclopropyl)-4-methyl,
1-Ethoxy-2-p-tolylcyclopropane

2,2,6,6-tetramethylpiperidine (768-66-1)

2,2,6,6-tetramethyl-4-piperidone (826-36-8)

1-methoxy-2-phenylcyclopropane

methyl thiobenzoate

propiolic acid (471-25-0)

tetracyclo(4.2.0.02,4.03,5)oct-7-ene

α-chloro-p-xylene (104-82-5)

N,N-dimethylbenzamide (611-74-5)