p-METHOXYBENZALDEHYDE

1

p-Methoxybenzaldehyde

MeO

CHO

[123-11-5]

C

8

H

8

O

2

(MW 136.16)

InChI = 1/C8H8O2/c1-10-8-4-2-7(6-9)3-5-8/h2-6H,1H3
InChIKey = ZRSNZINYAWTAHE-UHFFFAOYAA

(protection of diols as the versatile p-methoxybenzylidene acetal;
protection of dithiols,

1

amines, hydroxy amines,

2

and diamines

3

)

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
Chloride

4

,

5

or Zinc Chloride

6

. They can also be prepared

from the diol and p-MeOC

6

H

4

CH

2

OMe by oxidation with 2,3-

Dichloro-5,6-dicyano-1,4-benzoquinone (CH

2

Cl

2

, rt, 30 min,

49–82% yield)

7

or by acid-catalyzed acetal exchange with p-

MeOC

6

H

4

CH(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 epox-

ide with p-methoxybenzaldehyde in the presence of Tin(IV) Chlo-
ride results in the formation of the acetal without prior conversion
to the diol (eq 1).

13

MeO

CHO

CHO

O

MeO

O

O

CHO

+

3A MS, SnCl

4

(1)

CH

2

Cl

2

, –78 °C

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 ox-

idatively with Cerium(IV) Ammonium Nitrate (MeCN, H

2

O)

14

and it is relatively stable to Na/NH

3

.

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 Hydride

10

,

16

,

17

has

proven to be quite selective and is controlled by both electronic
and steric factors. Oxidative cleavage with DDQ

7

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

–

19

Use of LiAlH

4

/AlCl

3

,

12

BH

3

·NMe

3

/AlCl

3

,

4

BH

3

·THF, heat,

20

or NaBH

3

CN/TMSCl/MeCN

11

results in cleav-

age at the less-hindered side of the acetal, whereas NaBH

3

CN/

HCl,

4

or NaBH

3

CN/TFA/DMF

11

result in formation of an MPM

ether at the less-hindered alcohol.

NaBH

3

CN

TFA, DMF

O

MeO

BnO

OH

OBn

OMPM

O

MeO

BnO

O

OBn

O

Mp

NaBH

3

CN

TMSCl
MeCN

O

MeO

BnO

OMPM

OBn

OH

(2)

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., J. Am. Chem. Soc. 1973, 95,
6490.

2.

Witkop, B.; Patrick, J. P.; Kissman, H. M., Chem. Ber. 1952, 85,
949.

3.

Weidenhagen, R.; Train, G.; Wegner, H.; Nordstrom, L., Chem. Ber.
1936, 75, 1936.

4.

Serfontain, W. J.; Lourens, G. J.; De Waal, H. L., J. Med. Chem. 1965,
8

, 889.

5.

Smith, M.; Rammler, D. H.; Goldberg, I. H.; Khorana, H. G., J. Am.
Chem. Soc. 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., Tetrahedron Lett. 1983, 24,
4037.

8.

Kloosterman, M.; Slaghek, T.; Hermans, J. P. G.; Van Boom, J. H., Recl.
Trav. Chim. Pays-Bas 1984

, 103, 335.

9.

Oikawa, Y.; Yoshioka, T.; Yonemitsu, O., Tetrahedron Lett. 1982, 23,
889.

10.

Sviridov, A. F.; Ermolenko, M. S.; Yaskunsky, D. V.; Borodkin, V. S.;
Kochetkov, N. K., Tetrahedron Lett. 1987, 28, 3835.

11.

Yadav, J. S.; Chander, M. C.; Joshi, B. V., Tetrahedron Lett. 1988, 29,
2737.

12.

(a) Jones, A. B.; Yamaguchi, M.; Patten, A.; Danishefsky, S. J.; Ragan, J.
A.; Smith, D. B.; Schreiber, S. L., J. Org. Chem. 1989, 54, 17. (b) Smith,
A. B., III; Hale, K. J.; Laakso, L. M.; Chen, K.; Riera, A., Tetrahedron
Lett. 1989

, 30, 6963.

13.

Sturmer, R., Liebigs Ann. Chem. 1991, 311.

14.

Johansson, R.; Samuelsson, B., J. Chem. Soc., Chem. Commun. 1984,
201.

15.

Tone, H.; Hikota, M.; Hamada, T.; Nishi, T.; Oikawa, Y.; Yonemitsu, O.,
Chem. Pharm. Bull. 1989

, 37, 1155.

16.

Evans, D. A.; Kalder, S. W.; Jones, T. K.; Clardy, J.; Stout, T. S., J. Am.
Chem. Soc. 1990

, 112, 7001.

17.

Aicher, T. O.; Buszck, K. R.; Fang, F. G.; Forsyth, C. J.;
Jung, S. H.; Kishi, Y.; Scola, P. M., Tetrahedron Lett. 1992, 33,
1549.

Avoid Skin Contact with All Reagents

2

p-METHOXYBENZALDEHYDE

18.

(a) Johansson, R.; Samuelsson, B., J. Chem. Soc., Perkin Trans. 1 1984,
2371. (b) Garegg, P. J.; Hultberg, H.; Wallin, S., Carbohydr. Res. 1982,
108

, 97.

19.

Joniak, D.; Kôsíková, B.; Kosáková, L., Collect. Czech. Chem. Commun.
1978, 43, 769.

20.

Tsuri, T.; Kamata, S., Tetrahedron Lett. 1985, 26, 5195.

21.

Smith, A. B.; III, Rano, T. A.; Chida, N.; Sulikowski, G. A., J. Org.
Chem. 1990

, 55, 1136.

22.

(a) Lucas, R. A.; Dickel, D. F.; Dziemian, R. L.; Ceglowski, M. J.; Hensle,
B. L.; MacPhillamy, H. B., J. Am. Chem. Soc. 1960, 82, 5688. (b) Mootoo,
D. R.; Fraser-Reid, B., Tetrahedron Lett. 1989, 30, 2579. (c) Bergmann,
M.; Zervas, L., Chem. Ber. 1931, 64, 975.

Peter G. M. Wuts

The Upjohn Company, Kalamazoo, MI, USA

A list of General Abbreviations appears on the front Endpapers