[123-11-5]  · C8H8O2  · p-Methoxybenzaldehyde  · (MW 136.16)

(protection of diols as the versatile p-methoxybenzylidene acetal; protection of dithiols,1 amines, hydroxy amines,2 and diamines3)

Alternate Name: p-anisaldehyde.

Physical Data: bp 248 °C; d 1.119 g cm-3.

Form Supplied in: clear liquid; widely available.

Protection of Diols.

p-Methoxybenzylidene acetals are easily prepared from diols by reaction of the aldehyde in the presence of an acid catalyst such as Hydrogen Chloride4,5 or Zinc Chloride.6 They can also be prepared from the diol and p-MeOC6H4CH2OMe by oxidation with 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (CH2Cl2, rt, 30 min, 49-82% yield)7 or by acid-catalyzed acetal exchange with p-MeOC6H4CH(OMe)2.8 The p-methoxybenzylidene acetal can be prepared by DDQ oxidation of a p-methoxybenzyl group that has a neighboring hydroxy function.9 This methodology has been used to advantage in a number of syntheses.10-12 Reaction of an epoxide with p-methoxybenzaldehyde in the presence of Tin(IV) Chloride results in the formation of the acetal without prior conversion to the diol (eq 1).13

The advantages of the p-methoxybenzylidene acetal are that acid-catalyzed hydrolysis (80% AcOH, 25 °C, 10 h, 100% yield) is 10 times faster than that of the benzylidene group;5 it is cleaved oxidatively with Cerium(IV) Ammonium Nitrate (MeCN, H2O)14 and it is relatively stable to Na/NH3.15

As with the benzylidene group, a variety of methods have been developed to effect cleavage of one of the two C-O bonds in this acetal. Cleavage with Diisobutylaluminum Hydride10,16,17 has proven to be quite selective and is controlled by both electronic and steric factors. Oxidative cleavage with DDQ7 results in the formation of a mixture of the two possible monobenzoates. In the carbohydrate field, selective cleavage to give either the more- or less-substituted derivative is possible with the proper choice of reagents (eq 2).4,14,18,19 Use of LiAlH4/AlCl3,12 BH3.NMe3/AlCl3,4 BH3.THF, heat,20 or NaBH3CN/TMSCl/MeCN11 results in cleavage at the less-hindered side of the acetal, whereas NaBH3CN/HCl,4 or NaBH3CN/TFA/DMF11 result in formation of an MPM ether at the less-hindered alcohol.

Protection of Amines.

p-Methoxybenzaldehyde has been used to protect an amine as the MPM derivative by reductive amination with Sodium Borohydride.21 It is also used to prepare imine derivatives of glucosamines which are used in glycoside couplings.22

1. Kishi, Y.; Fukuyama, T.; Nakatusuka, S. JACS 1973, 95, 6490.
2. Witkop, B.; Patrick, J. P.; Kissman, H. M. CB 1952, 85, 949.
3. Weidenhagen, R.; Train, G.; Wegner, H.; Nordstrom, L. CB 1936, 75, 1936.
4. Serfontain, W. J.; Lourens, G. J.; De Waal, H. L. JMC 1965, 8, 889.
5. Smith, M.; Rammler, D. H.; Goldberg, I. H.; Khorana, H. G. JACS 1962, 84, 430.
6. Hanessian, S.; Kloss, J.; Sugawara, T. In Trends in Synthetic Carbohydrate Chemistry; Horton, D.; Hawkins, L. D.; McGarvey, G. J., Eds.; ACS Symposium Series 386; American Chemical Society; Washington, 1989; p 64.
7. Oikawa, Y.; Nishi, T.; Yonemitsu, O. TL 1983, 24, 4037.
8. Kloosterman, M.; Slaghek, T.; Hermans, J. P. G.; Van Boom, J. H. RTC 1984, 103, 335.
9. Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. TL 1982, 23, 889.
10. Sviridov, A. F.; Ermolenko, M. S.; Yaskunsky, D. V.; Borodkin, V. S.; Kochetkov, N. K. TL 1987, 28, 3835.
11. Yadav, J. S.; Chander, M. C.; Joshi, B. V. TL 1988, 29, 2737.
12. (a) Jones, A. B.; Yamaguchi, M.; Patten, A.; Danishefsky, S. J.; Ragan, J. A.; Smith, D. B.; Schreiber, S. L. JOC 1989, 54, 17. (b) Smith, A. B., III; Hale, K. J.; Laakso, L. M.; Chen, K.; Riera, A. TL 1989, 30, 6963.
13. Sturmer, R. LA 1991, 311.
14. Johansson, R.; Samuelsson, B. CC 1984, 201.
15. Tone, H.; Hikota, M.; Hamada, T.; Nishi, T.; Oikawa, Y.; Yonemitsu, O. CPB 1989, 37, 1155.
16. Evans, D. A.; Kalder, S. W.; Jones, T. K.; Clardy, J.; Stout, T. S. JACS 1990, 112, 7001.
17. Aicher, T. O.; Buszck, K. R.; Fang, F. G.; Forsyth, C. J.; Jung, S. H.; Kishi, Y.; Scola, P. M. TL 1992, 33, 1549.
18. (a) Johansson, R.; Samuelsson, B. JCS(P1) 1984, 2371. (b) Garegg, P. J.; Hultberg, H.; Wallin, S. Carbohydr. Res. 1982, 108, 97.
19. Joniak, D.; Kôsíková, B.; Kosáková, L. CCC 1978, 43, 769.
20. Tsuri, T.; Kamata, S. TL 1985, 26, 5195.
21. Smith, A. B., III; Rano, T. A.; Chida, N.; Sulikowski, G. A. JOC 1990, 55, 1136.
22. (a) Lucas, R. A.; Dickel, D. F.; Dziemian, R. L.; Ceglowski, M. J.; Hensle, B. L.; MacPhillamy, H. B. JACS 1960, 82, 5688. (b) Mootoo, D. R.; Fraser-Reid, B. TL 1989, 30, 2579. (c) Bergmann, M.; Zervas, L. CB 1931, 64, 975.

Peter G. M. Wuts

Upjohn Co., Kalamazoo, MI, USA

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