Checked by Lawrence Snyder and Albert I. Meyers.
1. Procedure
B.
Methyl 2,2-dimethyl-3-(trimethylsiloxy)-1-cyclopropanecarboxylate (
2).
CAUTION: This step should be performed behind a safety shield. A
500-mL flask, equipped with a
magnetic stirring bar and a reflux condenser that contains at its head a pressure-equalizing dropping funnel connected to a
gas bubbler, is charged with
1.04 g (4.00 mmol) of copper(II) acetylacetonate [Cu(acac)
2] (Note
7) and
28.8 g (200 mmol) of silyl enol ether 1. The suspension is heated to 90–100°C (oil bath temperature) and a solution of
24.0 g (240 mmol) of methyl diazoacetate (Note
8) dissolved in
250 mL of dry ethyl acetate (Note
9) is added dropwise within 3–4 hr (Note
10). After a short induction period, vigorous
nitrogen evolution is observed and the suspension turns from blue to brownish-yellow. Addition of the diazo compound is regulated so that continuous liberation of
nitrogen is observed at the gas bubbler. After the resulting black-brown suspension is cooled to room temperature, the solvent is removed on a
rotary evaporator (bath temperature below 35°C). The residue is treated with
50 g of alumina (Note
11) and
100 mL of pentane; the slurry is filtered and placed on a
column that contains 200 g of alumina. Elution with
pentane is accelerated by applying a slight pressure of
nitrogen at the top of the column. Concentration of the colorless solution obtained (Note
12) provides crude
2 (
55 g) that is distilled (bp
86–88°C, 12 mm) to give
35.0 g (
81%, (Note
13)) of pure cyclopropane derivative
2 as a mixture of cis/trans isomers (Note
14).
2. Notes
2. The procedure described is a slight variation of the published method.
3 We found addition of ca. 10%
sodium iodide to be advantageous in terms of reaction times and yields.
Sodium iodide was dried at 120°C/0.2 mm for 6 hr.
5. The washing process was performed until the aqueous phase was acidic to pH paper. The checkers found that gas pressure build-up was common, so the
separatory funnel should be vented frequently during acidification.
6. The fraction boiling at
94–108°C was found to be

99% pure by GLC and contained a trace of
hexamethyldisiloxane. The impurity does not affect the outcome of the next step. The NMR spectrum was as follows:
1H NMR (270 MHz, CDCl
3) δ: 0.14 (s, 9 H), 1.52 (s, 3 H), 1.57 (s, 3 H), 5.98 (m, 1 H).
7.
Copper(II) acetylacetonate, as supplied by Dynamit Nobel or by other commercial sources, was used.
8.
Methyl diazoacetate was obtained according to a procedure for
ethyl diazoacetate (Searle, N.E.
Org. Synth., Coll. Vol. IV 1963, 42). Although the experiments were usually performed with distilled
methyl diazoacetate (bp
43°C at 25 mm, bath temperature below 60°C) without any problems, the cyclopropanation reaction described works equally well with undistilled diazo compound. If distilled diazo compound is desired, the submitters have stated that "a
spatula of K
2CO
3 is added to the crude diazo ester to trap traces of acid and then distill behind a safety shield". The checkers did not evaluate this aspect of the procedure.
Crude
methyl diazoacetate contains up to 20% of the solvent
dichloromethane, which has to be taken into account when calculating the stoichiometry. The checkers had no problems in preparing, handling, and using undistilled
methyl diazoacetate; however, it must be emphasized that this compound is a potential explosive and all operations should be performed behind an efficient safety shield.
10. If the solution of
methyl diazoacetate is dropped through the condenser the diazo compound is further diluted by the refluxing solvent. This simple technique diminishes formation of
dimethyl fumarate and
dimethyl maleate as side products. For small scale experiments a motor driven syringe pump may replace the dropping funnel with good success.
12.
Siloxycyclopropane 2 is eluted very quickly. Final fractions contain
dimethyl fumarate and maleate. If mixtures of
2 with these carbene dimers are obtained, the filtration through alumina has to be repeated.
13. Yields of
75–85% have been obtained in several experiments on this scale.
14. The cis/trans ratio is 25:75. The spectra are as follows: IR (CCl
4) cm
−1: 1728 (CO
2Me);
1H NMR (270 MHz, CDCl
3) δ: 0.12 (s, 9 H, SiCH
3), 1.04, 1.15, 1.19, 1.30 (4 s, 6 H, 2-CH
3 of cis-
2 and trans-
2), 1.35, 3.42 (2 d, J = 7, 0.25 H each, 1-H and 3-H of cis-
2), 1.43, 3.60 (2 d, J = 3, 0.75 H each, 1-H and 3-H of trans-
2), 3.63 (s, 3 H, CO
2CH
3). For
13C NMR data, mass spectrum, and combustion analysis see reference
4.
15. The reagent was generated in situ by sequential addition of 1.63 mL of
triethylamine trishydrofluoride (obtained from Riedel deHaen, Merck, or Aldrich Chemical Company, Inc.) and
2.80 mL of triethylamine to the solution of
2. The procedure reported in reference
15 provides a reagent with an approximate stoichiometry of NEt
3·2HF that can also be used for the purpose described.
5
17. This procedure can be performed without any problems on a larger scale (
2.6 g,
90% yield was obtained by checkers). However, aldehyde
3 is of limited stability and should be stored with exclusion of
oxygen at low temperature. It is advantageous to generate only the amount of
3 required for subsequent reactions and to use it immediately. The physical properties are as follows: IR (CCl
4) cm
−1: 1739, 1730 (CO
2Me, CO);
1H NMR (270 MHz, CDCl
3) δ: 1.13 (s, 6 H, 3-CH
3), 2.52 (s, 2 H, CH
2), 3.63 (s, 3 H, CO
2CH
3), 9.53 (s, 1 H, CHO). Anal. Calcd for C
7H
12O
3: C, 58.32; H, 8.39. Found: C, 58.59; H, 8.77.
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
This sequence illustrates a very general method for the synthesis of methyl γ-oxoalkanoates which are valuable intermediates in organic synthesis.
4,6 The scope of the cyclopropanation reaction is very broad; only functional groups interacting with the carbenoid generated from
methyl diazoacetate are not compatible. Use of Rh
2(OAc)
4 instead of Cu(acac)
2 as catalyst did not afford better yields.
4 The cyclopropanation reaction has been performed with similar efficiency on scales from 4 mmol up to 500 mmol.
Silyl enol ethers derived from aldehydes (see Table, entries 1–5) or ketones (entries 6–9) can be used. If unsymmetrical ketones are used as starting material, the regiochemistry established at the silyl enol ether stage is cleanly transferred to the siloxycyclopropanes and eventually to the methyl γ-oxoalkanoates (entries 7–9). For some chiral silyl enol ethers, high stereoselectivities can be attained in the [2+1]-cycloaddition. Because of the very mild conditions for the ring opening step, using the only weakly acidic fluoride reagent, the stereoselectivity is transmitted to the γ-oxoalkanoate without accompanying epimerization (entry 9).
5,7 This mild, ring-opening procedure that uses NEt
3·HF is essential for preparation of the β-formyl esters as described in the procedure and for entries 1–5 in the Table. For simple ketone-derived products ring cleavage can also be effected with 2 N
hydrochloric acid.
5
The methyl γ-oxoalkanoates shown are not available by alternative methods with similar efficiency and flexibility. Although the reaction of enamines with alkyl α-bromoacetates proceeds well in some cases, yields are only moderate in many examples.
8 A further drawback is that the methods for enamine generation lack the high degree of selectivity and mildness that is characteristic of the preparation of silyl enol ethers. Related alkylations of lithium enolates often afford low yields or polyalkylated products, and are in general very inefficient when aldehydes are utilized as the starting materials.
9
An alternative method to prepare β-formyl esters uses different building blocks to assemble the 1,4-dicarbonyl system and is complementary in many cases.
10 Base-catalyzed addition of
nitromethane to α,β-unsaturated esters, followed by a variation of the Nef reaction, provides γ-dialkoxy-substituted esters. The scope of this sequence has not yet been explored. Another approach involves cuprate additions to norephedrine-derived 2-alkenyloxazolidines; this process allows small-scale synthesis of several β-formyl esters in optically active form (ee up to 95%).
11
A major advantage of the sequence presented here is that the aldehyde group is protected at the siloxycyclopropane stage, which allows convenient storage of this stable intermediate. Of equal importance is the valuable carbanion chemistry that can be carried out α to the ester function. Efficient substitution can be achieved by deprotonation with LDA and subsequent reaction with electrophiles.
12,13,6 This process makes several α-substituted β-formyl esters available. Other ring opening variants of siloxycyclopropanes—mostly as one-pot-procedures—are contained in Scheme I. They underscore the high versatility of these intermediates for the synthesis of valuable compounds.
6 Chiral formyl esters (see Table, entries 2–5) are of special interest as starting materials for chelate-controlled synthesis of disubstituted γ-lactones.
14
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