Organic Syntheses, CV 6, 571
Submitted by Charles M. Dougherty
1 and Roy A. Olofson
2.
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.
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.
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 (CCl
4), δ (multiplicity, number of protons, assignment): 0.63–1.3 (m, 5H, cyclopropyl C
H2 and OCH
2C
H3), 1.4–2.0 (m, 1H, cyclopropyl C
H), 2.23 (s, 1H,
trans-aromatic C
H3), 2.28 (s,
ca. 2H,
cis-aromatic C
H3), 2.8–3.7 (m, 3H, C
HOC
H2CH
3), 6.7–7.2 (m, 4H, C
6H4). 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, OCH
2C
H3), 7.02 (center of
AA'BB' m, 4H, C
6H4);
trans-isomer: 1.14 (t,
J = 7, 3H, OCH
2C
H3), 6.88 (center of
AA'BB' m, 4H, C
6H4).
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 method
5 (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 trialkylstannyl
10 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 halides
5,10,12,13 (and, less cleanly, with aryl sulfonates
14), 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 isocyanides
18 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 formation
20 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 esters
5,22 and dianions of β-keto esters
23 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.
Appendix
Compounds Referenced (Chemical Abstracts 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)
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