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Org. Synth. 1970, 50, 13
DOI: 10.15227/orgsyn.050.0013
cis-4-tert-BUTYLCYCLOHEXANOL
[Cyclohexanol, 4-(1,1-dimethylethyl)-, cis-]
Submitted by E. L. Eliel1, T. W. Doyle, R. O. Hutchins2, and E. C. Gilbert.
Checked by Mitchell Winnik and Ronald Breslow.
1. Procedure
To a solution of 4.0 g. (0.012 mole) of iridium tetrachloride (Note 1) in 4.5 ml. of concentrated hydrochloric acid is added 180 ml. of water followed by 52 g. (50 ml., 0.42 mole) of trimethyl phosphite (Note 2). This solution then is added to a solution of 30.8 g. (0.200 mole) of 4-tert-butylcyclohexanone (Note 3) in 635 ml. of 2-propanol contained in a 2-l. flask equipped with a reflux condenser. The solution is heated at reflux for 48 hours (Note 4), at which time the 2-propanol is removed with a rotary evaporator. The remaining solution is diluted with 250 ml. of water and extracted with four 150-ml. portions of diethyl ether. The combined ether extracts are washed with two 100-ml. portions of water, which are combined with the aqueous residue (Note 5), dried over magnesium sulfate or potassium carbonate, and concentrated on a rotary evaporator, yielding 29–31 g. (93–99%) of cis-4-tert-butylcyclohexanol as a white solid. Analysis of the crude product by GC shows it contains 95.8–96.2% cis-alcohol and 4.2–3.8% of the trans isomer with essentially no ketone remaining (Note 6). Recrystallization from 40% aqueous ethanol affords greater than 99% pure cis-alcohol, m.p. 82–83.5° after sublimation (Note 7).
2. Notes
1. Iridium tetrachloride was originally obtained from Platinum Chemicals, Inc., Box 565, Asbury Park, New Jersey 07712, or from Alfa Products, Thiokol/Ventron Division, P.O. Box 299, 152 Andover St., Danvers, Massachusetts 01923. More recently, the procedure has been repeated successfully with material obtained from Pfaltz and Bauer, Inc., a subsidiary of Aceto Chemical Co., Inc., 375 Fairfield Ave., Stamford, Connecticut 06902.
2. The order of mixing the catalyst components is required for good results, and the sequence described should be followed. Particular care should be taken not to add the trimethyl phosphite before the water, as the reaction between it and concentrated hydrochloric acid is extremely violent.
3. 4-tert-Butylcyclohexanone was obtained from Dow Chemical Company or Aldrich Chemical Co. Inc.
4. The reaction solution is often dark-colored at the beginning but lightens as reflux continues. The reflux time may be varied with the amount of ketone to be reduced. The completeness of the reaction may be followed by removing small aliquots, working up these samples as described in the text, and analyzing the product mixture by GC (see (Note 6)).
5. The iridium catalyst used in this preparation may be regenerated by reducing the volume of the aqueous residue to about 200 ml. at diminished pressure. This solution is then used instead of the iridium tetrachloride and water called for in the procedure.
6. The product was analyzed by GC using a 9-ft. 20% Carbowax 20M on 45/60 Chromosorb W column at 150°. The order of increasing retention times is: ketone, cis-alcohol, trans-alcohol.
7. Recrystallization is best accomplished by dissolving the crude product in hot ethanol (approx. 35 ml. per 10 g.) followed by adding water (approx. 25 ml. per 10g.) and allowing the solution to cool slowly to 0°. The fluffy white needles are filtered using a sintered-glass funnel and dried over P2O5 at atmospheric pressure. Recooling the filtrate affords a second crop of product, for an overall yield of 75–87%.
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 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; the full text can be accessed free of charge at http://www.nap.edu/catalog.php?record_id=12654). 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.

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 a caution 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 each chemical and experimental operation on the scale that is planned for the procedure. Guidelines for carrying out a risk assessment and for analyzing the hazards associated with chemicals can be found in Chapter 4 of Prudent Practices.

The procedures described in Organic Syntheses are provided as published and are 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.

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

3. Discussion
4-tert-Butylcyclohexanol has been prepared from p-tert-butylphenol by reduction under a variety of conditions.3,4 Eliel and Ro5 obtained cis-rich 4-tert-butylcyclohexanol by the reduction of 4-tert-butylcyclohexanone with hydrogen on platinum oxide in glacial acetic acid containing some hydrogen chloride; Sommerville and Theimer have similarly reduced p-tert-butylphenol with 5% rhodium on carbon.6,7 They have also prepared cis-rich alcohol by fractional distillation of the cis-trans mixture over an equilibrating catalyst, such as aluminum isopropoxide in the presence of 4-tert-butylcyclohexanone.6 Eliel and Nasipuri8 have also obtained 4-tert-butylcyclohexanol containing 80–92% of the cis isomer by the reduction of 4-tert-butylcyclohexanone with isobornyloxyaluminum dichloride.
The present9 procedure employs a readily available starting material and produces essentially pure cis isomer in good yield. In view of the fact that the catalyst may be reused several times with little loss in stereoselectivity, the expense of the iridium tetrachloride is not a serious impediment.
The method is useful in the preparation of other axial alcohols. Henbest9 has reported the reductions of 3-tert-butylcyclohexanone, 3,3,5-trimethylcyclohexanone, and cholestanone to the axial alcohols by this procedure, although for the preparation of cholestan-3α-ol the procedure of Edward10 is preferred by the checkers. Recently11 2,4,4-trimethylcyclohexanone has been reduced to the pure axial alcohol by this method in 90% yield.
Since this preparation was submitted, a number of reductions of 4-tert-butylcyclohexanone to the cis alcohol, with 93–100% selectivity, using various bulky, complex metal hydrides have been described: lithium tri-sec-butylborohydride (L-Selectride),12,13 lithium trisiamylborohydride,13,14,15 lithium tri-trans-2-methylcyclopentylborohydride,14 lithium dimesitylborohydride,16 lithium 2,6-di-tert-butylphenoxyneopentoxyaluminumhydride;17 high (94–99%) selectivity is also attained by catalytic hydrogenation with various rhodium catalysts.18,19 Hydrogenation over rhodium-on-carbon18 (94% cis) followed by purification with liquid chromatography appears to be an attractive method, one which avoids the need for special reagents.
References and Notes
  1. Department of Chemistry, University of Notre Dame, Notre Dame, Indiana 46556. [Present address: Department of Chemistry, University of North Carolina, Chapel Hill, North Carolina 27514.]
  2. Present address: Department of Chemistry, Drexel University, Philadelphia, Pennsylvania 19104.
  3. G. Vavon and M. Barbier, Bull. Soc. Chim. Fr., [4] 49, 567 (1931).
  4. H. Pines and V. Ipatieff, J. Am. Chem. Soc., 61, 2728 (1939).
  5. E. L. Eliel and R. S. Ro, J. Am. Chem. Soc., 79, 5992 (1957).
  6. W. T. Sommerville and E. T. Theimer, U.S. Pat. 2,840,599 (1958) [Chem. Abstr., 52, 18265 (1958)].
  7. W. T. Sommerville and E. T. Theimer, U.S. Pat. 2,927,127 (1960) [Chem. Abstr., 54, 13027g (1960)].
  8. E. L. Eliel and D. Nasipuri, J. Org. Chem., 30, 3809 (1965).
  9. Y. M. Y. Haddad, H. B. Henbest, J. Husbands, and T. R. B. Mitchell, Proc. Chem. Soc., 361 (1964).
  10. J. T. Edward and J-M. Ferland, Can. J. Chem., 44, 1311 (1966).
  11. D. J. Pasto and F. M. Klein, J. Org. Chem., 33, 1468 (1968).
  12. H. C. Brown and S. Krishnamurthy, J. Am. Chem. Soc., 94, 7159 (1972).
  13. H. C. Brown, J. L. Hubbard, and B. Singaram, J. Org. Chem., 44, 5004 (1979).
  14. S. Krishnamurthy and H. C. Brown, J. Am. Chem. Soc., 98, 3383 (1976).
  15. H. C. Brown, S. Krishnamurthy, and J. L. Hubbard, J. Organomet. Chem., 166, 271 (1979).
  16. J. Hooz, S. Akiyama, F. J. Cedar, M. J. Bennett, and R. M. Tuggle, J. Am. Chem. Soc., 96, 274 (1974).
  17. H. Haubenstock, J. Org. Chem., 40, 926 (1975).
  18. S. Mitsui, H. Saito, Y. Yamashita, M. Kaminaga, and Y. Senda, Tetrahedron, 29, 1531 (1973).
  19. S. Nishimura, M. Ishige, and M. Shiota, Chem. Lett., 963 (1977).

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

cis-rich 4-tert-butylcyclohexanol

lithium trisiamylborohydride

rhodium-on-carbon

ethanol (64-17-5)

potassium carbonate (584-08-7)

hydrogen chloride,
hydrochloric acid (7647-01-0)

acetic acid (64-19-7)

ether,
diethyl ether (60-29-7)

hydrogen (1333-74-0)

platinum oxide

carbon (7782-42-5)

2-propanol (67-63-0)

aluminum isopropoxide

magnesium sulfate (7487-88-9)

Cholestanone (566-88-1)

trimethyl phosphite (121-45-9)

iridium tetrachloride (10025-97-5)

iridium (7439-88-5)

rhodium (7440-16-6)

isobornyloxyaluminum dichloride

3,3,5-trimethylcyclohexanone (873-94-9)

cholestan-3α-ol

2,4,4-trimethylcyclohexanone

lithium dimesitylborohydride

4-tert-Butylcyclohexanone (98-53-3)

4-tert-Butylcyclohexanol (98-52-2)

p-tert-butylphenol (98-54-4)

cis-4-tert-Butylcyclohexanol,
Cyclohexanol, 4-(1,1-dimethylethyl)-, cis- (937-05-3)

3-tert-butylcyclohexanone (936-99-2)

lithium tri-sec-butylborohydride

lithium tri-trans-2-methylcyclopentylborohydride

lithium 2,6-di-tert-butylphenoxyneopentoxyaluminumhydride

Copyright © 1921-2025, Organic Syntheses, Inc. All Rights Reserved

Notes

1. Iridium tetrachloride was originally obtained from Platinum Chemicals, Inc., Box 565, Asbury Park, New Jersey 07712, or from Alfa Products, Thiokol/Ventron Division, P.O. Box 299, 152 Andover St., Danvers, Massachusetts 01923. More recently, the procedure has been repeated successfully with material obtained from Pfaltz and Bauer, Inc., a subsidiary of Aceto Chemical Co., Inc., 375 Fairfield Ave., Stamford, Connecticut 06902.

2. The order of mixing the catalyst components is required for good results, and the sequence described should be followed. Particular care should be taken not to add the trimethyl phosphite before the water, as the reaction between it and concentrated hydrochloric acid is extremely violent.

3. 4-tert-Butylcyclohexanone was obtained from Dow Chemical Company or Aldrich Chemical Co. Inc.

4. The reaction solution is often dark-colored at the beginning but lightens as reflux continues. The reflux time may be varied with the amount of ketone to be reduced. The completeness of the reaction may be followed by removing small aliquots, working up these samples as described in the text, and analyzing the product mixture by GC (see (Note 6)).

5. The iridium catalyst used in this preparation may be regenerated by reducing the volume of the aqueous residue to about 200 ml. at diminished pressure. This solution is then used instead of the iridium tetrachloride and water called for in the procedure.

6. The product was analyzed by GC using a 9-ft. 20% Carbowax 20M on 45/60 Chromosorb W column at 150°. The order of increasing retention times is: ketone, cis-alcohol, trans-alcohol.

7. Recrystallization is best accomplished by dissolving the crude product in hot ethanol (approx. 35 ml. per 10 g.) followed by adding water (approx. 25 ml. per 10g.) and allowing the solution to cool slowly to 0°. The fluffy white needles are filtered using a sintered-glass funnel and dried over P2O5 at atmospheric pressure. Recooling the filtrate affords a second crop of product, for an overall yield of 75–87%.

References/EndNotes

Article Compounds

Authors

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