Organic Syntheses Procedure

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Org. Synth. 1999, 76, 239

DOI: 10.15227/orgsyn.076.0239

REGIOSELECTIVE MONOALKYLATION OF KETONES VIA THEIR MANGANESE ENOLATES: 2-BENZYL-6-METHYLCYCLOHEXANONE FROM 2-METHYLCYCLOHEXANONE

[ Cyclohexanone, 2-methyl-6-(phenylmethyl)- ]

Submitted by Gérard Cahiez¹ , François Chau, and Bernard Blanchot.

Checked by Jari Yli-Kauhaluoma and Rick L. Danheiser.

1. Procedure

A 500-mL, three-necked, round-bottomed flask is equipped with a mechanical stirrer, 100-mL pressure-equalizing dropping funnel, and a Claisen head fitted with a low-temperature thermometer and a nitrogen inlet (Note 1). The flask is charged with 80 mL of tetrahydrofuran (THF) (Note 2) and 5.55 g (55 mmol) of diisopropylamine (Note 3). The resulting solution is cooled to −15°C, and 34.4 mL (55 mmol) of a 1.6 M solution of butyllithium in hexane (Note 4) is added dropwise over a 10-min period. The reaction mixture is stirred at −15°C for 30 min and then cooled to −78°C in a dry ice-acetone bath. A solution of 5.6 g (50 mmol) of 2-methylcyclohexanone (Note 5) in 20 mL of THF is added over 5 min, and the reaction mixture is stirred for 2 hr at −78°C. A solution of 55 mmol of MnCl₂·2LiCl (dilithium tetrachloromanganate) in 80 mL of THF (Note 6) is added dropwise over a 15-min period, and after 30 min the resulting clear brown solution is allowed to warm to room temperature.

To this solution of the manganese enolate are added successively (each over 5 min) 80 mL of 1-methyl-2-pyrrolidinone (NMP) (Note 7) and 12.2 g (71.3 mmol) of benzyl bromide (Note 8). The resulting mixture is stirred for 2 hr and hydrolyzed by the dropwise addition of 100 mL of a 1 M aqueous hydrochloric acid solution (HCl) over 15 min. Petroleum ether (35-60°C, 100 mL) is added, and the aqueous layer is separated and extracted three times with 50-mL portions of diethyl ether . The combined organic layers are washed with 100 mL of an aqueous saturated sodium carbonate solution, dried over anhydrous magnesium sulfate , filtered, and concentrated under reduced pressure with a rotary evaporator to afford 13.7-22.3 g of a brown oil (Note 9). Short path distillation under reduced pressure affords 8.8-8.9 g (87-88%) of 2-benzyl-6-methylcyclohexanone as a pale yellow oil, bp 95-100°C (0.3 mm) (Note 10).

2. Notes

1. The apparatus is flame-dried under a stream of dry nitrogen or argon. A slight positive pressure of nitrogen or argon is maintained with an oil bubbler throughout the reaction.

2. THF was freshly distilled from sodium benzophenone ketyl under a nitrogen atmosphere.

3. Diisopropylamine (99%, Aldrich Chemical Company, Inc.) was distilled from calcium hydride prior to use.

4. Butyllithium (1.6 M solution in hexane) was purchased from Acros Organics and titrated immediately before use according to the procedure of Watson and Eastham.²

5. 2-Methylcyclohexanone (99%) was purchased from Aldrich Chemical Company, Inc. , and distilled prior to use.

6. A solution of 55 mmol of the ate complex MnCl₂·2LiCl is prepared by stirring a suspension of 6.93 g of anhydrous manganese chloride (MnCl₂) (Note 11) and 4.65 g of anhydrous lithium chloride (LiCl) (Note 12) in 80 mL of THF at room temperature until an amber solution is obtained. It should be noted that the rate of dissolution (formation of the ate-complex Li₂MnCl₄ ) is very dependent on both the grain size of the two salts (MnCl₂ and LiCl) and their purity. When unpulverized Aldrich Chemical Company, Inc., or Acros Organics material is used it is necessary to stir for 4 to 24 hr to obtain complete dissolution; on the other hand, with finely pulverized anhydrous MnCl₂ obtained by drying analytical grade manganese chloride tetrahydrate (e.g., manganese chloride tetrahydrate purum p.a. Fluka, Inc.), it is possible to obtain complete dissolution after only 5 to 10 min. The formation of the ate-complex in this case is exothermic.

7. The submitters purchased 1-methyl-2-pyrrolidinone (NMP, 99%) from Aldrich Chemical Company, Inc. and distilled it prior to use. The checkers used 99.5% NMP (Aldrich Chemical Company, Inc.) without further purification.

8. Benzyl bromide (99%) was purchased by the submitters from Aldrich Chemical Company, Inc. , and distilled prior to use ( caution: lachrymator!).The checkers purified benzyl bromide by filtration through activated neutral alumina (EM Science, ca. 2 g of alumina/12 g of benzyl bromide).

9. The weight of crude product varies depending on how much of the NMP is removed during the work up. The residual NMP is easily separated from 2-benzyl-6-methylcyclohexanone during the subsequent purification by distillation. Alternatively, residual NMP can be removed during the workup by extracting the combined organic phases with four 50-mL portions of 1 M HCl prior to the aqueous Na₂CO₃ wash.

10. The checkers determined this material to consist of a mixture of 2-benzyl-6-methylcyclohexanone (94-97%) and 2-benzyl-2-methylcyclohexanone (3-6%). In 10 runs, the submitters found the yield to range from 85 to 90% and the regioselectivity (ratio of 2-benzyl-6-methylcyclohexanone to 2-benzyl-2-methylcyclohexanone) to range from 93:7 to 97:3. The regioisomeric ratio was determined by ¹H NMR according to House³ and by GC (capillary column SGE CYDEX B 25 m × 0.22 mm i.d., 0.25 μm film thickness, 165°C), retention time of 2-benzyl-6-methylcyclohexanone: 14.53 min, retention time of 2-benzyl-2-methylcyclohexanone: 14.99 min. The spectral properties of the product were as follows: ¹H NMR (C₆D₆, 500 MHz) δ: 0.92-1.16 (m, 3 H), 1.03 (d, 3 H, J = 6.4), 1.30-1.34 (m, 1 H), 1.59-1.63 (m, 1 H), 1.72-1.77 (m, 1 H), 1.83-1.90 (1 H, app. sept, J = 6.2), 2.17-2.21 (m, 1 H), 2.42 (dd, 1 H, J = 8.3, 13.7), 3.37 (dd, 1 H, J = 5.1, 13.9), 7.07-7.19 (m, 5 H) ; ¹³C NMR (CDCl₃, 125 MHz) δ: 14.5, 25.4, 34.6, 35.4, 37.3, 45.6, 52.5, 125.7, 128.1 (2C), 129.0 (2C), 140.6, 213.5 ; IR (thin film) cm⁻¹: 3082(m), 3058(m), 3023(m), 1710(s), 1604(m), 1495(m), 1451(m), 1375(m), 920(w), 745(m), 705(m) . Anal. Calcd for C₁₄H₁₈O: C, 83.12; H, 8.97. Found: C, 83.04; H,8.90.

11. Manganese(II) chloride tetrahydrate, purum p.a. (Fluka, Inc.) was finely ground using a mortar and pestle and then dried by heating at 180-200°C at 0.01-0.1 mm in a vacuum oven for 10 hr prior to use. The checkers dried 13.8 g of manganese(II) chloride tetrahydrate by heating in a 100-mL flask with magnetic stirring at 205°C/0.1 mm for 15 hr. The submitters found that it was sometimes necessary to grind the dried material again under a dry atmosphere before use. The anhydrous salt is very hygroscopic and must be protected against moisture (a well-closed bottle is adequate); it can, however, be handled very quickly in air without special precautions.

12. Anhydrous lithium chloride (99%), purchased from Aldrich Chemical Company, Inc. , was finely pulverized with a mortar and pestle and then dried by heating at 200°C under reduced pressure (0.1-0.01 mm) for 8 hr before use. The salt is hygroscopic and must be handled very quickly.

Handling and Disposal of Hazardous Chemicals

The procedures in this article are intended for use only by persons with prior training in experimental organic chemistry. All hazardous materials should be handled using 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 www.nap.edu). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.

These procedures must be conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein.

3. Discussion

The procedure described here illustrates a general and very convenient method⁴ ⁵ ⁶ ⁷ ⁸ to carry out the regioselective monoalkylation of ketones via their Mn-enolates. A comparison with the classical procedure previously reported by House in Organic Syntheses to prepare the 2-benzyl-6-methylcyclohexanone via the corresponding Li-enolates³ clearly shows that the Mn-enolate gives a higher yield of desired product since the regioselectivity is better and the formation of polyalkylated products is not observed.

Reaction Conditions	Yield (%)	Regioselectivity A/B	Polyalkylated Product (%)


Li-Enolate^a	42–45	76/24	18–19
Mn-Enolate	85	95/5	< 1

^aThe reaction described by House³ was performed in dimethoxyethane . The same results have been obtained by using THF.

The other regioisomer, the 2-benzyl-2-methylcyclohexanone, can also be selectively obtained in good yield from the more substituted Mn-enolate.⁷ In fact, these results prove that the deprotonation equilibrium that is responsible for the formation of side-products from Li-enolates does not exist under the reaction conditions in the case of Mn-enolates.

As a rule, this procedure also compares favorably with the other methods previously reported to achieve regioselective monoalkylation of ketones.⁹ It gives similar or higher yields and selectivities, and it is clearly easier to carry out since no toxic, expensive or hazardous material such as Et₃Al (Al-enoates), KH then Et₃B (B-enolates), Bu₃SnCl (Sn-enolates) or Et₂Zn (Zn-enolates) is required. Moreover, a large excess of alkylating reagents (Al- and Sn-enolates) is not required.

As shown, Mn-enolates are easily and quantitatively obtained from Li-enolates by transmetalation.⁵^,⁷^,⁸ They can also be prepared by deprotonation of ketones with Mn-amides.⁴^,⁶

Note that only Mn-amides prepared from aromatic amines, ArRNH or Ar₂NH, give quantitative yields of enolization products. A procedure using only a catalytic amount of aromatic amine has also been described.¹⁰

The deprotonation reactions occur regio- and stereoselectively to give the less- substituted Z enolates that can be readily silylated or acylated to afford mainly the less-substituted Z silyl enol ethers or Z enol esters in high yields.⁴^,¹¹

The regioselective monoalkylation of ketones described above has wide applicability. The monoalkylated products are regioselectively obtained in high yields by reacting Mn-enolates prepared in THF from a wide range of ketones with various reactive organic halides in the presence of a polar cosolvent such as DMSO , NMP, sulfolane , DMF , MeCN ⁴^,⁵^,⁶^,⁷ (Tables I and II) as well as DMPU.⁸ With less reactive alkylating reagents (e.g., BuBr) the reaction rate is slower, and the reaction generally leads to lower yields (Table I). Note that alkyl sulfonates do not undergo reaction. (Table I).

TABLE I
MONOALKYLATION OF Mn-ENOLATES OBTAINED BY DEPROTONATION OF KETONES WITH Mn-AMIDES
Ketone	Solvent (Alkylation Step)^a	Reaction Conditions	Alkylating Agent^b	Yield^c (%)


BuCOBu	THF/DMSO	20°C, 2 hr	MeI	93
PrCOPr	THF	20°C, 3 hr	PhCH₂Br	43
PrCOPr	THF/NMP	20°C, 2 hr	PhCH₂Br	86
PrCOPr	THF/DMSO	20°C, 2 hr	PhCH₂Br	91
PrCOPr	THF/NMP	20°C, 2 hr	CH₂=CHCH₂Br	81
PrCOPr	THF/DMSO	20°C, 2 hr	PhCH=CHCH₂Br	86
PrCOPr	THF/DMSO	20°C, 2 hr		87
PrCOPr	THF/NMP	−30°C, 2 hr	BrCH₂COOEt	88
PrCOPr	THF/DMSO	50°C, 2 hr	BuI	67
PrCOPr	THF/DMSO	50°C, 24 hr	BuBr	48
PrCOPr	THF/DMSO	50°C, 24 hr	BuOSO₂Ph	0

^aDeprotonation step: PhMeNMnZ (Z = Cl, Ph), 0°C, 1 hr. ^b1.25 equiv. ^cYield of isolated product. ^dOnly the S_N2 product is obtained. The geometry of the allylic double bond is retained (Z > 99%).

TABLE II
REGIOSELECTIVE MONOALKYLATION OF Mn-ENOLATES OBTAINED BY DEPROTONATION OF UNSYMMETRICAL KETONES WITH Mn-AMIDES
Ketone	Alkylating Agent^a	Monoalkylated Ketone(%)^b	Regioselectivity^c


iso-PrCOHex	CH₂=CHCH₂Br	80	> 99:1
iso-PrCOHex	PhCH₂Br	85	> 97:3
PhCH₂(Et)CHCOPr	CH₂=CHCH₂Br	89	>99:1
2-Me cyclohexanone	PhCH₂Br	90	93:7

^aAlkylation step: THF-NMP or THF-DMSO, 20°C, 1 hr. ^bYield of isolated product. ^cRatio of αα'/αα-disubstituted ketones.

Mn-enolates can also be hydroxyalkylated (Table III). They react easily with a vast array of aldehydes (even enolizable or α,β-unsaturated aldehydes), to give synaldol products in good yields.¹² The stereoselectivity obtained from Mn- and Li-enolates are very similar.

TABLE III
REACTION OF Mn-ENOLATES WITH ALDEHYDES
Ketone	Aldehyde	Yield (%)^a	Syn/Anti


EtCOEt	PrCHO	83	66/33
EtCOEt	Et₂CHCHO	86	77/23
EtCOEt	MeCH=CHCHO	86	64/36
EtCOEt	Furfural	79	71/29
EtCOEt	PhCHO	94	71/29
PrCOPr	PhCHO	88	88/12
tert-BuCOPr	PhCHO	81	99/1
PrCOPr	PrCHO	86	85/15
BuCOBu	PrCHO	83	51/49
PhCOPr	PrCHO	87	72/28

^aYield of isolated product.

α-Halogeno ketones lead to β-keto epoxides.¹²

Finally, Mn-enolates are useful synthetic reagents for Michael additions.

References and Notes

Ecole Supérieure de Chimie Organique et Minerale (E.S.C.O.M.) Département de Chimie, 13 Boulevard de I'Hautil, F-95092 Cergy Pontoise, France.
Watson, S. C.; Eastham, J. F. J. Organomet. Chem. 1967, 9, 165-168. See also Ref. ³.
Gall, M.; House, H. O. Org. Synth., Coll. Vol. VI 1988, 121-130.
Cahiez, G.; Figadère, B.; Tozzolino, P.; Cléry, P. Fr. Pat. Appl. 1988, 88/15,806; Eur. Pat. Appl. 1990, EP 373, 993; Chem. Abstr. 1991, 114, 61550y;
Cahiez, G.; Cléry, P.; Laffitte, J. A. Fr. Pat. Appl. 1991, 91/11,814; PCT Int. Appl. 1993, WO 93 06,071; Chem. Abstr. 1993, 119, 116519f;
Cahiez, G.; Figadère, B.; Cléry, P. Tetrahedron Lett. 1994, 35, 3065-3068;
Cahiez, G.; Chau, K.; Cléry, P. Tetrahedron Lett. 1994, 35, 3069-3072;
Reetz, M. T.; Haning, H. Tetrahedron Lett. 1993, 34, 7395-7398.
Sn and Al-enolates: Tardella, P. A. Tetrahedron Lett. 1969, 1117-1120; B-enolates: Negishi, E.-i.; Chatterjee, S. Tetrahedron Lett. 1983, 24, 1341-1344; Zn-enolates: Morita, Y.; Suzuki, M.; Noyori, R. J. Org. Chem. 1989, 54, 1785-1787.
Cahiez, G.; Kanaan, M.; Cléry, P. Synlett 1995, 191-192.
Cahiez, G.; Figadère, B.; Cléry, P. Tetrahedron Lett. 1994, 35, 6295-6298.
Cahiez, G.; Cléry, P.; Laffitte, J. A. Fr. Demande FR 2/671,085, Fr. Pat. Appl. 1990, 90/16,413; Chem. Abstr. 1993, 118, 69340b.

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

2-Benzyl-6-methylcyclohexanone:
Cyclohexanone, 2-benzyl-6-methyl- (8);
Cyclohexanone, 2-methyl-6-(phenylmethyl)- (9); (24785-76-0)

2-Methylcyclohexanone:
Cyclohexanone, 2-methyl- (8,9); (583-60-8)

Diisopropylamine (8);
2-Propanamine, N-(1-methylethyl)- (9); (108-18-9)

Butyllithium:
Lithium, butyl- (8,9); (109-72-8)

Dilithium tetrachloromanganate (MnCl₂·2 LiCl; Cl₄Mn·2 Li):
Manganate (2-), tetrachloro-, dilithium, (I-4)- (9); (57384-24-4)

1-Methyl-2-pyrrolidinone:
2-Pyrrolidinone, 1-methyl- (8,9); (872-50-4)

Benzyl bromide:
Toluene, α-bromo- (8);
Benzene, (bromomethyl)- (9); (100-39-0)

Manganese(II) chloride:
Manganese chloride (8,9); (7773-01-5)

Lithium chloride (8,9); (7447-41-8)

2-Benzyl-2-methylcyclohexanone:
Cyclohexanone, 2-benzyl-2-methyl- (8);
Cyclohexanone, 2-methyl-2-(phenylmethyl)- (9); (1206-21-9)

Notes

References/EndNotes

Article Compounds

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