Organic Syntheses Procedure

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Org. Synth. 1990, 69, 114

DOI: 10.15227/orgsyn.069.0114

DIRECT NUCLEOPHILIC ACYLATION BY THE LOW-TEMPERATURE, IN SITU GENERATION OF ACYLLITHIUM REAGENTS; α-HYDROXY KETONES FROM KETONES: 3-HYDROXY-2,2,3-TRIMETHYLOCTAN-4-ONE FROM PINACOLONE

[4-Octanone, 3-hydroxy-2,2,3-trimethyl-]

Submitted by Richard Hui and Dietmar Seyferth¹.

Checked by Hiroshi Koyano and Ryoji Noyori.

1. Procedure

A 2-L, three-necked flask was equipped with an overhead mechanical stirrer, a Claisen adapter that contained a low-temperature thermometer, and a no-air stopper that held a gas dispersion tube for the introduction of carbon monoxide (Note 1). The flask was charged with 400 mL each of tetrahydrofuran (THF) and diethyl ether, 100 mL of pentane, and pinacolone (7.92 g, 79.1 mmol) (Note 2). The reaction solution was cooled to −110°C (Note 3) and (Note 4) under an argon atmosphere and carbon monoxide (Note 5) was bubbled in for 30 min. Then a solution of butyllithium (2.53 N solution in pentane, 31.0 mL, 78.43 mmol) (Note 6) was added at 0.6–1.0 mL/min by means of a syringe pump (Note 7). The reaction mixture was orange after the addition had been completed. The reaction mixture was stirred at −110°C for 2 hr while the carbon monoxide stream was continued. The liquid nitrogen Dewar was removed, and the reaction mixture was allowed to warm to room temperature over the course of 1.5 hr, during which time the color changed to yellow. The reaction mixture subsequently was quenched by the addition of 300 mL of saturated ammonium chloride solution, which resulted in a light-yellow organic layer and a clear, colorless aqueous phase. The aqueous layer was separated and washed twice with 100 mL of pentane. The organic layers were combined, dried over anhydrous magnesium sulfate, and filtered. The solvents were removed by fractional distillation (9-in. Vigreux column). The residue was distilled through a 7-cm jacketed column to give 9.7–10.8 g (67–73%) of 3-hydroxy-2,2,3-trimethyloctan-4-one, 97% pure by GLC, bp 120–122°C (30 mm), and n_D20 1.442 (Note 8).

2. Notes

1. All glassware was dried for 15 hr in an oven at ca. 110°C and assembled while still warm.

2. Tetrahydrofuran (THF) and ether were distilled from sodium benzophenone ketyl. Pentane was distilled from lithium aluminum hydride and stored in bottles under a positive pressure of nitrogen. Pinacolone was distilled from potassium carbonate prior to use, bp 106°C (760 mm).

3. Total-immersion-type low-temperature pentane thermometers (Kessler) were used to measure the temperature in the partial immersion mode. The readings are usually 7–8°C higher compared to the actual temperature under our reaction conditions. The temperatures reported here are all corrected by subtracting 7°C from the thermometer readings. The checkers used a Delta MC-20R digital thermometer (Sato Keiryoki Co., Japan). Temperature control is very important to obtain a satisfactory yield.

4. The temperature was controlled by moving a liquid-nitrogen-filled Dewar flask up and down with a lab jack.

5. Carbon monoxide, purchased from Matheson Gas Products or Nihon Sanso Co., was used without further purification.

6. Butyllithium in pentane was purchased from Alfa Products, Morton/Thiokol, Inc. and was titrated by the method of Gilman and Cartledge.² The checkers used a 1.56 N hexane solution purchased from Mitsuwa Chemical Co. after titration by the Kofron–Baclawski procedure.³

7. Orion Research Inc., Model 341 was used. Alternatively, if a syringe pump is not available, the organolithium solution may be added manually by syringe, very slowly and at a reasonably constant rate.

8. GLC conditions were as follows: 2-m × 5-mm glass column packed with 20% silicone SE-30 on Chromosorb W AW; gas flow: 0.8 kg/cm²; temperature program 100–275°C at 6°C per minute; retention times: n-C₉H₂₀, 4.9 min; 3-hydroxy-2,2,3-trimethyloctan-4-one, 12.5 min. Spectral properties of the product are as follows: IR(thin film, NaCl) cm⁻¹: 3350–3580 (br, s, ν_OH), 2985 (s), 2872 (m), 1695 (s, ν_C=O), 1480 (m), 1465 (s), 1462 (s), 1395 (s), 1220 (m), 1170 (m), 1125 (s), 1040 (s), 990 (m), 910 (m); ¹H NMR (270 MHz, CDCl₃) δ: 0.92 (t, 3 H, J = 7.3, CH₂-CH₃), 0.97 (s, 9 H, C(CH₃)₃), 1.33 (tq, 2 H, J = 7.3, 7.3, CH₂=CH₃), 1.34 (s, 3 H, CH₃), 1.60 (tt, 2 H, J = 7.6, 7.6, CH₂CH₂C(O)), 2.52 (dt, 1 H, J = 15.2, 7.6, a proton of CH₂C(O)), 2.60 (dt, 1 H, J = 15.2, 7.6, a proton of CH₂C(O)), 3.64 (s, 1 H, OH).

3. Discussion

In situ generated acyllithium reagents not only can acylate ketones, but also can acylate aldehydes,¹¹ esters,¹² lactones,¹⁵ isocyanates and isothiocyanates,¹⁷ carbodiimides,¹⁸ carbon disulfide and carbonyl sulfide,¹⁶ organic disulfides,¹⁴ and trialkylchlorosilanes.¹⁰ For reviews, see ⁴ and ¹³ This direct, nucleophilic acylation procedure, when applicable, makes unnecessary the usually applied method of "masked acyl anion equivalents" for nucleophilic acylation.⁵ ⁶ ⁷ ⁸ The present procedure finds only very limited applicability in the case of aryllithium/CO systems,⁹ but seems to be generally applicable to alkyllithium systems.

TABLE I
LOW-TEMPERATURE, IN SIRU, DIRECT NUCLEOPHILIC ACYLATION WITH THE RLi/CO REAGENT
Electrophile	Quench Reagent	Reference


(CH₃)₃SiCl	H₂O	¹⁰
	H₂O	¹¹^,¹²
	H₂O	¹²
	H₂O	¹³
	H₂O	¹⁴
	H₂O	¹¹
	(CH₃)₃SiCl	¹⁵
R'SSR'	H₂O	¹⁴
	CH₃I	¹⁴
S₈	CH₃I	¹⁴
COS	CH₃I	¹⁶
CS₂	CH₃I	¹⁶
R'NCO	H₂O	¹⁷
R'NCS	H₂O	¹⁷
R'NCS	CH₃I	¹⁷
R'N=C=NR'	H₂O	¹⁸
Fe(CO)₅		¹⁹

References and Notes

Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139.
Gilman, H.; Cartledge, F. K. J. Organometal. Chem. 1964, 2, 447;
Kofron, W. G.; Baclawski, L. M. J. Org. Chem. 1976, 41, 1879.
Seyferth, D.; Weinstein, R. M.; Wang, W. L.; Hui, R. C.; Archer, C. M. Isr. J. Chem. 1984, 24, 167.
See the leading reviews of masked acyl anion equivalents for examples and references: (a) Hase, T. A.; Koskimies, J. K. Aldrichim. Acta 1981, 14, 73; 1982, 15, 35;
Lever, O. W., Jr. Tetrahedron 1976, 32, 1943;
Albright, J. D. Tetrahedron 1983, 39, 3207;
Gröbel, B.-T.; Seebach, D. Synthesis 1977, 357.
Seyferth, D.; Wang, W.-L.; Hui, R. C. Tetrahedron Lett. 1984, 25, 1651.
Seyferth, D.; Weinstein, R. M. J. Am. Chem. Soc. 1982, 104, 5534.
Seyferth, D.; Weinstein, R. M.; Wang, W.-L.; Hui, R. C. Tetrahedron Lett. 1983, 24, 4907.
Seyferth, D.; Weinstein, R. M.; Wang, W.-L. J. Org. Chem. 1983, 48, 1144.
Seyferth, D.; Hui, R. C.; Weinstein, R. M.; W.-L. Nova Acta Leopold. 1985, 59, 335; Chem. Abstr. 1988, 108, 6056t.
Seyferth, D.; Hui, R. C. Organometallics 1984, 3, 327.
Weinstein, R. M.; Wang, W.-L.; Seyferth, D. J. Org. Chem. 1983, 48, 3367.
Seyferth, D.; Hui, R. C. Tetrahedron Lett. 1984, 25, 2623.
Seyferth, D.; Hui, R. C. Tetrahedron Lett. 1984, 25, 5251.
Seyferth, D.; Hui, R. C. J. Org. Chem. 1985, 50, 1985.
Dötz, K. H.; Wenicker, U.; Müller, G.; Alt, H. G.; Seyferth, D. Organometallics 1986, 5, 2570.

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

benzophenone ketyl

(CH₃)₃SiCl

CH₃I

S₈

COS

CS₂

Fe(CO)₅

potassium carbonate (584-08-7)

ether,
diethyl ether (60-29-7)

ammonium chloride (12125-02-9)

carbon monoxide (630-08-0)

nitrogen (7727-37-9)

Pinacolone (75-97-8)

sodium (13966-32-0)

carbon disulfide (75-15-0)

Pentane (109-66-0)

magnesium sulfate (7487-88-9)

butyllithium (109-72-8)

Tetrahydrofuran (109-99-9)

lithium aluminum hydride (16853-85-3)

hexane (110-54-3)

argon (7440-37-1)

3-Hydroxy-2,2,3-trimethyloctan-4-one,
4-Octanone, 3-hydroxy-2,2,3-trimethyl- (85083-71-2)

carbonyl sulfide

Notes

References/EndNotes

Article Compounds

Authors