A Simple and Efficient Procedure for the Synthesis of Ketone Di-sec-alkyl ­Acetals

Abstract

Ketone di-sec-alkyl acetals are obtained in good to excellent yields by treatment of ketones with tri-sec-alkyl orthoformate and the corresponding alcohol in the presence of a catalytic amount of cerium(III) trifluoromethanesulfonate.

acetals - cerium(III) trifluoromethanesulfonate - ketones - Lewis acids - tri-sec-alkyl orthoformates

References and Notes

1a Kocienski PJ. Protecting Groups   3rd ed.:  Thieme; New York: 2004.  Chap. 2.

1b Wuts PGM. Greene TW. Greene’s Protective Groups in Organic Synthesis   4th ed.:  Wiley; New York: 2007.  Chap. 4.

2a Mukaiyama T. Murakami M. Synthesis  1987,  1043 

2b Alexakis A. Mangeney P. Tetrahedron: Asymmetry  1990,  1:  477 

3a Meskens FAJ. Synthesis  1981,  501 

3b Sandler SR. Karo W. Organic Functional Group Preparations   2nd ed., Vol. III:  Academic; New York: 1989.  Chap. 1.

3c Macpherson DT. Harshad KR. In Comprehensive Organic Functional Group Transformations   Vol. 4:  Kirby GW. Pergamon; Oxford: 1995.  p.159 

4 Howard WL. Lorette NB. J. Org. Chem.  1960,  25:  525 

5 Roelofsen DP. van Bekkum H. Synthesis  1972,  419 

6 α-Hydroxy ketone di-sec-alkyl acetals were obtained by addition of secondary alcohols to sec-alkyl epoxy ethers: Stevens CL. McLean RL. Weinheimer AJ. J. Am. Chem. Soc.  1958,  80:  2276 

For the use of Ce(OTf)₃ in other types of reactions, see:

7a Dalpozzo R. De Nino A. Maiuolo L. Procopio A. Tagarelli A. Sindona G. Bartoli G. J. Org. Chem.  2002,  67:  9093 

7b Keh CCK. Namboodiri VV. Varma RS. Li C.-J. Tetrahedron Lett.  2002,  43:  4993 

7c Dalpozzo R. De Nino A. Maiuolo L. Procopio A. Nardi M. Bartoli G. Romeo R. Tetrahedron Lett.  2003,  44:  5621 

7d Bartoli G. Dalpozzo R. De Nino A. Maiuolo L. Nardi M. Procopio A. Tagarelli A. Eur. J. Org. Chem.  2004,  2176 

7e Bartoli G. Dalpozzo R. De Nino A. Maiuolo L. Nardi M. Procopio A. Tagarelli A. Green Chem.  2004,  6:  191 

7f Bartoli G. De Nino A. Dalpozzo R. Maiuolo L. Nardi M. Procopio A. Tagarelli A. Lett. Org. Chem.  2005,  2:  51 

8 MacKenzie et al. reported the reaction of acetone, tri-sec-butyl orthformate, S-BuOH, and PTSA did not occur and the orthoester was recovered unchanged: MacKenzie CA. Stocker JH. J. Org. Chem.  1955,  20:  1695 

9

When this reaction was attempted in the absence of i-PrOH or triisopropyl orthformate, diisopropyl acetalization did not proceed at all.

10

None (85%), CH₂Cl₂ (80%), Et₂O (83%), THF (81%), MeCN (76%).

11

Typical Procedure (Table 1, Entry 1)
To a mixture of cyclopentanone (84 mg, 1.0 mmol), Ce(OTf)₃ (Alfa Aesar, 5.9 mg, 0.01 mmol), i-PrOH (1 mL), and toluene (1 mL) triisopropyl orthoformate (247 mg, 1.3 mmol)was added at 0 ˚C. After the mixture was kept stirring at the same temperature for 6 h, it was quenched by adding Et₃N (101 mg, 1.0 mmol). The resulting mixture was passed through a short plug of neutral Al₂O₃ (activity III), which was then washed with Et₂O (30 mL), and the solvent was removed under reduced pressure. The ^¹H NMR (500 MHz) analysis of the crude product showed the absence of
1-cyclopentenyl isopropyl ether. The residue was chroma-tographed on neutral Al₂O₃ (activity III, hexane) to afford cyclopentanone diisopropyl acetal (168 mg, 90%). ^¹H NMR (500 MHz, CDCl₃): δ = 1.17 (d, J = 6.1 Hz, 12 H), 1.65-1.70 (m, 4 H), 1.75-1.81 (m, 4 H), 4.01-4.09 (m, 2 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 21.7, 24.4, 35.6, 63.8, 111.6. 2-Octanone Diisopropyl Acetal
^¹H NMR (500 MHz, CDCl₃): δ = 0.88 (t, J = 7.1 Hz, 3 H), 1.14 (d, J = 6.4 Hz, 12 H), 1.24-1.37 (m, 8 H), 1.27 (s, 3 H), 1.54-1.59 (m, 2 H), 3.99-4.08 (m 2 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 14.1, 22.6, 23.7, 24.5, 24.6, 24.8, 29.7, 31.9, 39.8, 62.1, 102.6.
1-Cyclohexyl-1-ethanone Diisopropyl Acetal
^¹H NMR (500 MHz, C₆D₆): δ = 0.92-2.10 (m, 11 H), 1.10 (d, J = 6.0 Hz, 6 H), 1.13 (d, J = 6.0 Hz, 6 H), 1.15 (s, 3 H), 3.97-4.05 (m, 2 H). ^¹³C NMR (125 MHz, C₆D₆): δ = 19.7, 24.6, 25.0, 27.1, 27.2, 29.0, 45.9, 62.0, 104.5.
Acetophenone Diisopropyl Acetal
^¹H NMR (500 MHz, C₆D₆): δ = 0.98 (d, J = 6.5 Hz, 6 H), 1.12 (d, J = 6.0 Hz, 6 H), 1.61 (s, 3 H), 3.96-4.04 (m, 2 H), 7.08-7.76 (m, 5 H). ^¹³C NMR (125 MHz, C₆D₆): δ = 24.2, 24.9, 28.3, 63.7, 101.3, 127.3, 127.6, 145.0.
Cyclohexanone Di- sec -butyl Acetal
^¹H NMR (500 MHz, C₆D₆): δ = 0.87 (t, J = 7.7 Hz, 3 H), 0.88 (t, J = 7.7 Hz, 3 H), 1.14 (d, J = 6.4 Hz, 3 H), 1.16 (d, J = 6.1 Hz, 3 H), 1.26-1.35 (m, 2 H), 1.43-1.74 (m, 12 H), 3.82-3.93 (m, 2 H). ^¹³C NMR (125 MHz, C₆D₆): δ = 9.5, 9.6, 21.3, 21.5, 23.8, 26.1, 31.3, 36.1, 36.2, 36.5, 66.8, 67.0, 101.3.
Cyclohexanone Dicyclohexyl Acetal ^¹H NMR (500 MHz, C₆D₆): δ = 1.10-1.87 (m, 30 H), 3.82-3.89 (m, 2 H). ^¹³C NMR (125 MHz, C₆D₆): δ = 23.8, 24.8, 26.2, 35.2, 36.7, 67.9, 101.5.

12

Other Brønsted and Lewis acids are less effective than Ce(OTf)₃ in our reaction system. The reaction of 2-octanone under identical conditions are as follows: TfOH (23%), BF₃˙OEt₂ (0%), AlCl₃ (15%), Mg(OTf)₂ (0%), TMSOTf (58%), Sc(OTf)₃ (62%), Cu(OTf)₂ (63%), Zn(OTf)₂ (35%), La(OTf)₃ (36%), Gd(OTf)₃ (63%), Bi(OTf)₃˙4H₂O (51%).

13

Reaction of benzophenone (r.t., 24 h) followed by the standard workup gave benzophenone diisopropyl acetal (5%) and the starting ketone (90%).

14

Di-sec-butyl acetalization of cyclohexanone by the Roelofsen method [5] afforded cyclohexanone di-sec-butyl acetal (80%) and sec-butyl 1-cyclohexenyl ether (15%).