A Publicationof Reliable Methods
for the Preparationof Organic Compounds

Working with Hazardous Chemicals
The procedures in Organic Syntheses are intended for use only by persons with proper
training in experimental organic chemistry. All hazardous materials should be handledusing the standard procedures for work with chemicals described in references such as"Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C.,
2011;
thefulltext
canbeaccessed
freeofchargeathttp://www.nap.edu/catalog.php?record_id=12654).
All chemical waste should be
disposed of in accordance with local regulations. For general guidelines for themanagement of chemical waste, see Chapter 8 of Prudent Practices.
In some articles in Organic Syntheses, chemical-specific hazards are highlighted in red“Caution Notes” within a procedure. It is important to recognize that the absence of acaution note does not imply that no significant hazards are associated with the chemicals
involved in that procedure. Prior to performing a reaction, a thorough risk assessment
should be carried out that includes a review of the potential hazards associated with eachchemical and experimental operation on the scale that is planned for the procedure.
Guidelines for carrying out a risk assessment and for analyzing the hazards associatedwith chemicals can be found in Chapter 4 of Prudent Practices.
The procedures described in Organic Syntheses are provided as published and areconducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board ofDirectors do not warrant or guarantee the safety of individuals using these procedures andhereby disclaim any liability for any injuries or damages claimed to have resulted from orrelated in any way to the procedures herein.

These paragraphs were added in September 2014. The statements above do not supersede any specifichazard caution notes and safety instructions included in the procedure.

DOI:10.15227/orgsyn.069.0055

Organic Syntheses, Coll. Vol. 8, p.241 (1993); Vol. 69, p.55 (1990).

ASYMMETRIC SYNTHESIS OF 4,4DIALKYLCYCLOHEXENONES FROM CHIRAL BICYCLICLACTAMS: (R)-4-ETHYL-4-ALLYL-2-CYCLOHEXEN-1-ONE

Submitted by Albert I. Meyers and Daniel Berney1.
Checked by P. B. Madan, A. Schwartz, and David L. Coffen.

1. ProcedureA.
Hexahydro-3-(hydroxymethyl)-8a-methyl-2-phenyl[2S,3S,8aR]-5-oxo-5H-oxazolo[3,2-a]pyridine (Bicyclic lactam). To a warm solution of (1S,2S)-(+)-2-amino-1-phenyl-1,3-propanediol (32.4g, 194 mmol) (Note 1) in toluene (800 mL), 5-oxohexanoic acid (25 g, 912 mmol) (Note 2) is addedwith stirring. The stirred mixture is heated to reflux under argon with azeotropic removal of water for 18
hr. The reaction mixture is cooled, washed with 0.5 N hydrochloric acid (100 mL) and with saturated
sodium bicarbonate solution (50 mL), dried over magnesium sulfate, and evaporated to dryness. The
residue is crystallized from methylene chloride/hexane in the cold. The crystals are collected byfiltration and washed with cold ether to give 35.9–37.2 g (71–74% yield) of the bicyclic lactam in two
crops (Note 3).
B. Hexahydro-6-ethyl-3-(hydroxymethyl)-6-allyl-2-phenyl[2S,3S,6S,8aR]-5-oxo-5H-oxazolo[3,2-a]pyridine. In an oven-dried, 500-mL, round-bottomed flask, containing a magnetic stirring bar, is placed14.4 g (55.2 mmol) of dry bicyclic lactam prepared as described in Part A. The flask is flushed withargon and filled with 150 mL of anhydrous tetrahydrofuran (Note 4) and then sealed with a rubber
septum. The air in the flask is further replaced by argon (Note 5). After dissolution of the bicycliclactam, the flask is cooled in dry ice–acetone and the solution is stirred while preparing lithium
diisopropylamide (LDA).
To an oven-dried, 200-mL, conical flask (Note 6) with air replaced by argon, containing 50 mL ofdry tetrahydrofuran (THF) and sealed with a rubber septum, 13.9 g (19.3 mL, 137.4 mmol) ofdiisopropylamine (Note 7) is added with a syringe. The flask is placed in an ice–water bath. After 15min, 84 mL (134.4 mmol) of 1.6 M butyllithium in hexane (Note 8) is slowly added with a syringe andwith gentle swirling of the flask. The solution is kept for 5 min at this temperature.
The lithium diisopropylamide solution prepared as described above is transferred dropwise, via acannula, into the bicyclic lactam solution. The dry ice–acetone bath is replaced by an ice–water bath,where the reaction mixture is kept for 40 min to complete formation of the lithium enolate. The reaction
mixture is cooled again (30 min) with a dry ice–acetone bath. Freshly distilled ethyl iodide (25.8 g, 13.4mL, 165.4 mmol) (Note 9) is added slowly, via syringe, to the mixture and stirring is continued for 55
min in a dry ice–acetone bath. The cooling bath is replaced by an ice–water bath, and the mixture isstirred for exactly 40 min (Note 10) and is poured immediately into a separatory funnel containing 400mL of 1.0 N hydrochloric acid. The resulting emulsion is extracted once with 400 mL of ether and theorganic layer is washed with 200 mL of a 1 : 1 mixture of brine and a saturated solution of sodium
bicarbonate. The ether extract is dried over magnesium sulfate and evaporated to dryness in a 500-mL
round-bottomed flask. The residue is dissolved in 60 mL of dry toluene and evaporated again using awater bath (60°C for 45 min) to remove all traces of water and toluene. The product (17.2 g, > 100%) isused in the next step without further purification.
The 500-mL flask containing the crude dry product (17.2 g) is filled with argon and dry
tetrahydrofuran (150 mL), a magnetic stirring bar is added, the flask is sealed with a rubber septum, andargon is introduced once again. The flask is gently swirled until the viscous oil is totally dissolved andthen the flask is immersed in a dry ice–acetone bath.
Another portion of LDA is prepared as described above except that this time 12.6 g of
diisopropylamine (17.6 mL, 124.6 mmol) in THF (50 mL) and 78.0 mL (124.8 mmol) of 1.6 M
butyllithium/hexane are used. The LDA solution is added, through a cannula, to the ethylated bicyclic
lactam solution and the mixture is allowed to warm to 0°C; it is kept at this temperature for 3.0 hr (Note11). The solution is cooled to −75° to −80°C in a dry ice–acetone bath. A solution of 9.4 g of freshly
distilled allyl bromide (6.8 mL, 77.6 mmol) (Note 12) in dry THF (50 mL) is prepared in a 100-mL,oven-dried conical flask flushed with argon and sealed with a rubber septum. This solution is cooled ina dry ice–acetone bath and slowly added to the reaction mixture through a cannula (Note 13). After
addition of the allyl bromide, the mixture is kept in a dry ice–acetone bath for 2.5 hr; then the bath isreplaced by acetone at −50°C, which is allowed to warm to −30°C within a period of 45 min (Note 14).
The reaction is terminated by pouring it into 1 N hydrochloric acid (as above), extracting with ether,washing with sodium bicarbonate–brine, drying over magnesium sulfate, and evaporating the solvents.
The viscous or solid residue is dissolved in methylene chloride (10 mL), and petroleum ether (30–60°C)(140 mL) is added. The product is allowed to crystallize at room temperature for 1 hr, then at −15°C
overnight, to give 13.5 g (74%, mp 90–92°C) of a 9 : 1 mixture of diastereoisomers.
This mixture is recrystallized three times with the same mixture of solvents and the product iscollected after 1 hr at 0°C to give 8.7 g (47.9%, mp 101–103°C) of a 25 : 1 mixture of diastereoisomers(values based on the 8a-methyl signal integration on NMR spectra) (Note 15).
C. (R)-4-Ethyl-4-allyl-2-cyclohexen-1-one. In an oven-dried, 500-mL, round-bottomed flask,
containing dry toluene (300 mL) and a magnetic stirring bar, is placed the dialkylated lactam (7.8 g,23.7 mmol). The solution is cooled in a dry ice–acetone bath and a 1 M solution of Red-Al in toluene(55 mL, 55.0 mmol) is slowly added (Note 16). The flask is flushed with argon and sealed with a rubber
septum which is connected by a hypodermic needle to a rubber balloon filled with argon. The reaction
mixture is allowed to warm to room temperature and stirred for 3 days. The septum is removed, thereaction mixture is cooled to 0°C, and methanol (10 mL) is cautiously added with stirring to destroy
excess Red-Al. The solution is poured over 1 M aqueous potassium hydroxide (500 mL) in a 2-L
separatory funnel and thoroughly shaken with ether (200 mL) until both layers become almost clear.
The aqueous layer is extracted twice more with ether (2 × 100 mL), and, after the ethereal layers arecombined, the ethereal solution is dried over magnesium sulfate and evaporated to dryness in a 500-mLflask.
The residue is dissolved in ethanol (250 mL), a 1 M aqueous solution of tetrabutylammoniumdihydrogen phosphate (80 mL) (Note 17) is added, and the mixture is stirred under reflux for 24 hr.
After the solution is cooled, it is partly evaporated on a rotary evaporator with a bath temperature notexceeding 40°C (Note 18) to remove most of the ethanol. Water is added (500 mL) and the solution is
extracted twice with chloroform (200 mL). The chloroform extracts are washed with a 1 : 1 mixture ofbrine and 1 N hydrochloric acid and then with brine and saturated sodium bicarbonate solutions. Bothaqueous phases are extracted twice with chloroform and the extracts are combined, dried overmagnesium sulfate, and evaporated to dryness to give 5.8 g of crude 4,4-disubstituted cyclohexenone.
The product is distilled rapidly in a Kugelrohr apparatus at 3.5 mm and 115°C to give 3.0 g (77%) of
highly pure cyclohexenone (Note 19).

2. Notes
1. The amino diol was purchased from Aldrich Chemical Company, Inc. and was recrystallized beforeuse from methanol/ethyl acetate (the material used had mp 111–113°C).
2. 5-Oxohexanoic acid was purchased from Aldrich Chemical Company, Inc. and was used without
further purification.
3. The bicyclic lactam thus prepared has the following physical properties: mp 98–99°C; [α]D21 + 13.54°(EtOH, c 1.55); IR (KBr) cm−1: 3360, 2950, 1625, 1500, 1395; 1H NMR (270 MHz, CDCl3) δ: 3.75 (dd,C10H, J = 11.3, 8.5), 3.90 (dd, C10H, J = 11.3, 1.9), 4.07 (dt, C3H, J = 8.5, 1.9), 4.79 (d, C2H, J = 8.6),
4.89 (br s, 1 H, OH), 7.38 (s, 5 H, phenyl) and unresolved signals.
4. THF was distilled from a blue solution of benzophenone ketyl obtained by refluxing THF in thepresence of a sodium dispersion in paraffin and benzophenone.
5. All reactions were done under argon atmosphere. The argon was introduced through hypodermic
needles at a pressure below 50 mm across the rubber septum. An exhaust line was also provided toremove air or excess pressure.
6. A conical flask was used in order to allow efficient transfer of the LDA solution.
7. Commercial diisopropylamine wa distilled over calcium hydride and stored over potassium hydroxideor Linde 4A molecular sieves.
8. 1.6 M Butyllithium in hexane was purchased from Aldrich Chemical Company, Inc.
9. Ethyl iodide was distilled over anhydrous potassium carbonate and stored in the refrigerator overcopper turnings.
10. If the reaction mixture is kept for longer than 40 min in the ice-water bath, undesirable amounts ofthe diethylated product are produced.
11. This is the minimum time to allow complete enolate formation.
12. Allyl bromide was distilled over anhydrous potassium carbonate and stored in the refrigerator overLinde 4A molecular sieves.
13. The allyl bromide solution was allowed to cool efficiently by dripping it against the cold walls of theflask. It is important that allyl bromide reach the reaction mixture at the lowest possible temperature inorder to obtain an optimal stereo-selective alkylation. The cannula was protected against heat exchangewith air by coating it with a fine rubber tubing.
14. Dry ice was removed, leaving only acetone in the Dewar vessel. The temperature was then adjusted
to −50°C by adding warm (room temperature) acetone; the temperature was allowed to rise slowly to−30°C by adding small portions of acetone.
15. The physical properties for the dialkylated bicyclic lactam are as follows: [α]D21 +38.89° (EtOH, c1.77); IR (KBr) cm−1: 3250, 2490, 1600, 1450, 1370, 1330, 1070, 890, 750; 1H NMR (270 MHz, CDCl3)
δ: 0.91 (t, 3 H, C12H, J = 7.3), 1.57 (s, 3 H, C9H); 2.42 (ddd, 2 H, C13H, J = 63.6, 13.4, 7.4), 3.65 (br, 1H, OH), 3.75 (dd, C10H, J = 11.3, 8.8), 3.90 (dd, C10H, J = 11.2, 2.5), 4.13 (dt, C3H, J = 8.8, 2.5), 4.78
(d, C2H, J = 8.5), 5.11–5.16 (m, 2 H, C15H), 5.73–5.88 (m, C14H), 7.37 (s, 5 H, phenyl) and unresolved
signals. Anal. calcd. for C20H27NO3: C, 72.91: H, 8.26; N, 4.25. Found: C, 72.77; H, 8.25; N, 4.24.
16. 1 M Red-Al is prepared, by diluting to 100 mL with toluene, 29.5 mL of commercially available 3.4
M Red-Al solution in toluene (Aldrich Chemical Company, Inc.; the checkers used Vitride brandsupplied by Hexcel Corp.). Before use, this solution should be warmed to room temperature since it
tends to separate into two layers at low temperatures. The first milliliter of Red-Al produces a vigorous
evolution of gas; therefore, the flask should be kept open until the Red-Al addition is complete. Thenthe reaction vessel is sealed as described.
17. 1 M Tetrabutylammonium dihydrogen phosphate aqueous solution was purchased from Aldrich
Chemical Company, Inc.

18. The product has a high vapor pressure and can easily be lost by evaporation. Thus, the yields willvary because of this property. The more caution exerted in the evaporation and distillation step, thehigher will be the yield of product.
19. If the distillation is performed slowly, a substantial amount of the product may polymerize, resulting
in lower yield. The physical data are as follows: [α]D21 −23.12° (EtOH, c, 1.67); IR (film) cm−1: 2960,1680, 1450, 1380, 1210; 1H NMR (270 MHz, CDCl3) δ: 0.95 (t, 3 H, C8H, J = 7.6), 1.49–1.57 (m, 2 H,C3H), 1.87 (t, 2H, C5H, J = 6.8), 2.23 (d, 2 H, C9H, J = 6.6), 2.45 (t, 2 H, C6H, J = 6.8), 5.07–5.14 (m,C11H), 5.65–5.82 (m, C10H), 5.94 (d, C2H, J = 10.3), 6.71 (d, C3H, J = 10.3). Anal. calcd. for C11H16O:C, 80.45; H, 9.82. Found: C, 79.67; H, 10.05. By GLC analysis, the product is 93–95% pure with 5–7%
of diethylcyclohexenone detectable by GLC–MS.

3. Discussion
Chiral bicyclic lactams such as those described here are useful in reaching a variety of chiralquaternary carbon derivatives. Thus, 1 can be doubly alkylated to the bicyclic lactam 2 in highdiastereoselectivity. Acidic hydrolysis leads to α,α-substituted γ-keto acids 3,2 whereas reduction andhydrolysis furnish the chiral keto aldehydes 4. Base-catalyzed aldolization affords chiral
cyclopentenones 5.3 In addition, several total syntheses of natural products have been accomplished,further demonstrating the synthetic usefulness of these bicyclic lactams 1. Thus, (−)-α-cuparenone (6),4(−)-grandisol (7),5 (+)-mesembrine (8),6 and (−)-silphiperfol-6-ene (9)7 have been prepared in highenantiomeric excess.

To reach chiral cyclohexenones, we have found that the bicyclic lactam 10, derived from 5oxohexanoic acid and the commercially available amino diol, gave excellent results. A number ofexamples were obtained (Table I).8

TABLE ICHIRAL 4,4-DIALKYLCYCLOHEXENONES(11)aR1R210R3R1R2R311Yield(%)

Me Me PhCH2 H ME PhCH2[α]D−65.6°

53MePhCH2 MeH PhCH2 Me+64.8°

68MePhCH2 Allyl H PhCH2 Allyl+48.9°47

Et Me PhCH2Me Me PhCH2−39.7°

66

Me PhMeHPhMe+122.2°

47
aYields refer to reduction and hydrolysis of 10 to 11. All products are 99% opticallypure (see 8).

Furthermore, in place of reduction of 10 it was possible to add organolithium reagents such that theresulting alkyl carbinolamine, after hydrolysis, gave either 12 or 13 depending on hydrolysis
conditions.6 In summary, these bicyclic lactams have provided a route to a variety of chiral, nonracemic
cyclohexenones and cyclopentenones containing quaternary stereocenters.
This preparation is referenced from:zz

Org. Syn. Coll. Vol. 9, 457
Org. Syn. Coll. Vol. 9, 530

References and Notes
1.
2.
3.
4.
5.
6.
7.
8.

Department of Chemistry, Colorado State University, Fort Collins, CO 80523.
Meyers, A. I.; Harre, M.; Garland, R. J. Am. Chem. Soc. 1984, 106, 1146.
Meyers, A. I.; Wanner, K. T. Tetrahedron Lett. 1985, 26, 2047.
Meyers, A. I.; Lefker, B. A. J. Org. Chem. 1986, 51, 1541.
Meyers, A. I.; Fleming, S. A. J. Am. Chem. Soc. 1986, 108, 306.
Meyers, A. I.; Hanreich, R.; Wanner, K. T. J. Am. Chem. Soc. 1985, 107, 7776.
Meyers, A. I.; Lefker, B. A. Tetrahedron 1987, 43, 5663.
Meyers, A. I.; Lefker, B. A.; Wanner, K. T.; Aitken, R. A. J. Org. Chem. 1986, 51, 1936.

Appendix
Chemical Abstracts Nomenclature (Collective Index Number);(Registry Number)petroleum ether
benzophenone ketyl
brine
Red-AlHexahydro-3-(hydroxymethyl)-8a-methyl-2-phenyl[2S,3S,8aR]-5-oxo-5H-oxazolo[3,2-a]pyridine(Bicyclic lactam)
ethanol (64-17-5)

potassium carbonate (584-08-7)hydrochloric acid (7647-01-0)
ethyl acetate (141-78-6)
methanol (67-56-1)
ether (60-29-7)
chloroform (67-66-3)
sodium bicarbonate (144-55-8)
Allyl bromide (106-95-6)
allyl (1981-80-2)
copper turnings (7440-50-8)acetone (67-64-1)
potassium hydroxide (1310-58-3)
toluene (108-88-3)
Benzophenone (119-61-9)
sodium (13966-32-0)
methylene chloride (75-09-2)
magnesium sulfate (7487-88-9)
Ethyl iodide (75-03-6)
butyllithium (109-72-8)
Tetrahydrofuran,
THF (109-99-9)
hexane (110-54-3)
argon (7440-37-1)
calcium hydride (7789-78-8)
lithium diisopropylamide (4111-54-0)
diisopropylamine (108-18-9)

5-oxohexanoic acid (3128-06-1)
tetrabutylammonium dihydrogen phosphate (5574-97-0)(R)-4-Ethyl-4-allyl-2-cyclohexen-1-one (122444-62-6)(1S,2S)-(+)-2-amino-1-phenyl-1,3-propanediol
Hexahydro-6-ethyl-3-(hydroxymethyl)-6-allyl-2-phenyl[2S,3S,6S,8aR]-5-oxo-5H-oxazolo[3,2-a]pyridine
Copyright © 1921-2005, Organic Syntheses, Inc. All Rights Reserved