An Efficient and Versatile Procedure for the Synthesis of Acetals from ­Aldehydes and Ketones Catalyzed by Lithium Tetrafluoroborate

Abstract

Acetals are obtained in good to excellent yields by treatment of aldehydes and ketones with trialkyl orthoformate and the corresponding alcohol in the presence of a catalytic amount of ­lithium tetrafluoroborate. Due to the mild reaction conditions, this method is compatible with acid-sensitive substrates.

Key words

acetals - carbonyl compounds - Lewis acids - lithium tetrafluoroborate - protecting groups

References

• 1a Loewenthal HJE. In Protective Groups in Organic Chemistry   McOmie JFW. Plenum; London: 1973.  Chap. 9.
• 1b Kocienski PJ. In Protecting Groups   Thieme; Stuttgart: 1994.  Chap. 5.
• 1c Greene TW. Wuts PGM. In Protective Groups in Organic Synthesis   3rd ed.:  Wiley; New York: 1999.  Chap. 4.
• 2a Schmitz E. Eichhorn I. In The Chemistry of the Ether Linkage   Patai S. Wiley; New York: 1967.  Chap. 7.
• 2b Mukaiyama T. Murakami M. Synthesis  1987,  1043 
• 2c Alexakis A. Mangeney P. Tetrahedron: Asymmetry  1990,  1:  477 
• 3a Meskens FAJ. Synthesis  1981,  501 
• 3b Leonard NM. Oswald MC. Freiberg DA. Nattier BA. Smith RC. Mohan RS. J. Org. Chem.  2002,  67:  5202 ; and references cited therein
• 3c Gopinath R. Haque SJ. Patel BK. J. Org. Chem.  2002,  67:  5842 
• 3d Basu MK. Samajdar S. Becker FF. Banik BK. Synlett  2002,  319 
• For recent leading references, see:
• 4a Kazemi F. Kiasat AR. Ebrahimi S. Synth. Commun.  2003,  33:  999 
• 4b Yadav JS. Reddy BVS. Vishnumurthy P. Tetrahedron Lett.  2003,  44:  5691 
• 5 Sumida N. Nishioka K. Sato T. Synlett  2001,  1921 
• 7 Gandini A. Adv. Polym. Sci.  1977,  25:  47 
• 8 Dimethyl acetalization of citronellal using electrogenerated acid afforded 6-methoxy-3,7-dimethyl-7-octenal dimethyl acetal (18%) as a by-product: Gora J. Smigielski K. Kula J. Synthesis  1986,  586 
• 9 Thurkauf A. Jacobson AE. Rice KC. Synthesis  1988,  233 
• 11a Tirado-Rives J. Gandour RD. Org. Prep. Proced. Int.  1985,  17:  62 
• 11b Ma S. Venanzi LM. Synlett  1993,  751 ; and references cited therein
• For the success acetalization of carbonyl compounds in the presence of THP ethers, see:
• 12a Hwu JR. Leu L.-C. Robl JA. Anderson DA. Wetzel JM. J. Org. Chem.  1987,  52:  188 
• 12b Karimi B. Ebrahimian GR. Seradj H. Org. Lett.  1999,  1:  1737 
• 12c Karimi B. Golshani B. Synthesis  2002,  784 
• 13 Patwardhan SA. Dev S. Synthesis  1974,  348 
• 14a Firouzabadi H. Iranpoor N. Karimi B. Synth. Commun.  1999,  29:  2255 ; and references cited therein
• 14b Firouzabadi H. Iranpoor N. Karimi B. Synlett  1999,  321 
• 14c Karimi B. Seradj H. Ebrahimian G.-R. Synlett  1999,  1456 

6

Other lithium salts and alkali metal tetrafluoroborates are less effective than LiBF₄ in our reaction system. The reaction of benzaldehyde under the identical conditions is as follows: LiCl (19%), LiBr (15%), LiClO₄ (36%), LiOTf (35%), NaBF₄ (8%), KBF₄ (3%).

10

Both methanol and trimethyl orthformate were necessary in order to obtain the products in satisfactory yields. On the reaction of benzophenone (3 mmol) using LiBF₄ (0.3 mmol): HC(OMe)₃ (3.9 mmol) alone (90 °C, 19 h, 15%); MeOH (1.5 cm³) alone (reflux, 19 h, 2%).

15

The spectroscopic data of new compounds are shown as follows.
4-(Methoxymethoxy)benzaldehyde Dimethyl Acetal: ¹H NMR (CDCl₃): δ = 3.32 (s, 6 H), 3.48 (s, 3 H), 5.18 (s, 2 H), 5.35 (s, 1 H), 7.03 (d, J = 8.85 Hz, 2 H), 7.36 (d, J = 8.85 Hz, 2 H). ¹³C NMR (CDCl₃): δ = 52.6, 56.0, 94.4, 103.0, 115.9, 127.9, 131.6, 157.3.
4-(2-Methoxyethoxy)benzaldehyde Dimethyl Acetal: ¹H NMR (CDCl₃): δ = 3.32 (s, 6 H), 3.37 (s, 3 H), 3.53-3.57 (m, 2 H), 3.80-3.84 (m, 2 H), 5.27 (s, 2 H), 5.34 (s, 1 H), 7.05 (d, J = 8.70 Hz, 2 H), 7.36 (d, J = 8.70 Hz, 2 H). ¹³C NMR (CDCl₃): δ = 52.6, 59.0, 67.6, 71.6, 93.4, 103.0, 115.9, 127.9, 131.6, 157.3.
4-(Perhydro-2 H -pyran-2-yloxymethyl)benzaldehyde Dimethyl Acetal: ¹H NMR (CDCl₃): δ = 1.49-1.92 (m, 6 H), 3.33 (s, 6 H), 3.52-3.56 (m, 1 H), 3.89-3.95 (m, 1 H), 4.51 (d, J = 12.2 Hz, 1 H), 4.70 (t, J = 3.35 Hz, 1 H), 4.79 (d, J = 12.2 Hz, 1 H), 5.39 (s, 1 H), 7.37 (d, J = 7.95 Hz, 2 H), 7.43 (d, J = 7.95 Hz, 2 H). ¹³C NMR (CDCl₃): δ = 19.4, 25.5, 30.6, 52.7, 62.1, 68.5, 97.8, 103.1, 126.7, 127.6, 137.3, 138.6.
4-(5,5-Dimethyl-1,3-dioxan-2-yl)benzaldehyde Dimethyl Acetal: ¹H NMR (CDCl₃): δ = 0.80 (s, 3 H), 1.30 (s, 3 H), 3.29 (s, 6 H), 3.65 (d, J = 10.9 Hz, 2 H), 3.77 (d, J = 10.9 Hz, 2 H), 5.40 (s, 1 H), 5.41 (s, 1 H), 7.46 (d, J = 8.25 Hz, 2 H), 7.51 (d, J = 8.25 Hz, 2 H). ¹³C NMR (CDCl₃): δ = 21.9, 23.0, 30.2, 52.4, 77.7, 101.5, 102.6, 126.0, 126.7, 138.6.