Squaric Acid1

[2892-51-5]  · C4H2O4  · Squaric Acid  · (MW 114.06)

(synthesis of cyclobutenediones, quinones, and hydroquinones1)

Alternate Name: 3,4-dihydroxy-3-cyclobutene-1,2-dione.

Physical Data: mp >300 °C.

Solubility: sol H2O.

Form Supplied in: white crystals.

Analysis of Reagent Purity: IR n 2326 (OH), 1818 (C=O), 1639 (C=C) cm-1.

Handling, Storage, and Precautions: the crystals should be handled with gloves.


Treatment of squaric acid (1) with Thionyl Chloride and a trace amount of N,N-Dimethylformamide affords dichlorocyclobutenedione (DCCB) (2) (eq 1).2

DCCB (2) reacts with nucleophiles by displacement of the chlorine atoms.1d For example, reaction of (2) with 2-nitroaniline in a solution of o-dichlorobenzene at 150 °C for 40 min affords diaminocyclobutenedione (3) (eq 2).3

DCCB reacts similarly with Sodium Azide at 0 °C to afford chlorocyanoketene,4 with cyanamides5 and carbodiimides6 to afford carboxyimidoyl chlorides, with thiols to afford dithiocyclobutenediones,7 with tertiary amines, phosphines, arsines, and thioethers to afford betaines,8 and with carbonylmetallates to afford metallocyclobutenediones.9

DCCB also reacts with carbon nucleophiles. For example, treatment with Aluminum Chloride in benzene affords diphenylcyclobutenedione (4) (eq 3).10 Furthermore, (2) reacts with Tetrakis(triphenylphosphine)palladium(0) and alkynylstannanes to give dialkynylcyclobutenediones in 11-70% yield.11


Treatment of squaric acid (1) with Sodium Hydroxide followed by Silver(I) Nitrate affords disilver salt (5) (eq 4); this reacts with Iodomethane to give dimethyl squarate (DMS) (6a).12 Similarly, treatment of (5) with t-butyl chloride affords di-t-butyl squarate (6b).13

Other esters can be prepared by refluxing a solution of squaric acid in the appropriate alcoholic solvent.12 A specific example is given in eq 5, showing the formation of diisopropyl squarate (DIPS) (7).14


Dialkoxysquarates can be converted to a wide variety of other cyclobutenediones. For example, treatment of (7) with Methyllithium yields methyl adduct (8) (eq 6). The crude material is then subjected to acidic hydrolysis to afford dione (9) in 89% overall yield.14 Alternatively, this transformation can be accomplished in a one-pot procedure with comparable yields by treatment of the intermediate lithium alkoxide with Trifluoroacetic Anhydride followed by an aqueous extraction.15

Disubstituted cyclobutenediones can be made by the following procedure. First, a 4-hydroxycyclobutenone such as (8) is silylated with 4-Dimethylaminopyridine and t-Butyldimethylchlorosilane (eq 7).14 Then, a second lithium reagent is added (e.g. n-Butyllithium) followed by acidic hydrolysis of the crude material to afford dione (10) in 79% yield.

The two carbonyl groups of cyclobutenediones can be differentiated by forming a monoacetal. One such method produces cyclobutenedione ethylene acetal.16 Another method is described in eq 8. Acetal (11) is made from DMS (6a) by the addition of Phenyllithium followed by treatment with TFAA and MeOH. A second lithium reagent (e.g. MeLi) is then added; addition of TFAA and aqueous extraction affords disubstituted acetal (12).17

In eq 9, DIPS is treated with n-Bu3SnSiMe3 and a catalytic amount of n-Bu4NCN to afford dione (13).18 Stannylcyclobutenediones are versatile intermediates for the synthesis of other cyclobutenediones, utilizing palladium-catalyzed coupling reactions.19

Quinones and Aromatic Compounds.

Lithium anions add to cyclobutenediones and cyclobutenedione monoacetals to afford 4-alkynyl-, 4-aryl-, and 4-alkenylcyclobutenones. When heated, these compounds rearrange to give quinones or related aromatic compounds.20 The reaction is general and is limited only by the availability of the starting cyclobutenedione. For example, eq 10 depicts the thermolysis of 4-alkynylcyclobutenone (14), which was made by the addition of the lithium salt of benzylacetylene to 3-butyl-4-methoxycyclobutenedione, to produce quinone (15).20a Upon heating, 4-arylcyclobutenone (16), which was made from acetal (12) by addition of PhLi followed by hydrolysis with HCl, rearranges to afford naphthoquinone (17) after oxidation in 70% yield from (12) (eq 11).17 Finally, 4-alkenylcyclobutenone (18) is thermolyzed to afford coenzyme Q0 (19) after oxidation (eq 12).20d

Besides the methods described above, another regioselective route to 2,3-disubstituted furano- and naphthoquinones has been developed,21 as illustrated in eq 13. Cyclobutenone (20) is made from 2-methyl-3-isopropoxy-4-methoxy-4-(2-methoxyphenyl)-3-cyclobutenone by reduction with Lithium Aluminum Hydride followed by treatment with TFAA and aqueous extraction in 54% yield. Thermolysis of (20) then produces naphthoquinone (21).

A number of unusual classes of quinones are available by the rearrangement of 4-alkynylcyclobutenones. For example, thermolysis of cyclobutenone (22) affords silylquinone (23) (eq 14).20a,22 Analogously, thermolysis of cyclobutenones in the presence of Tri-n-butyl(methoxy)stannane provides stannylquinones in good yields (eq 15).23

Cyclobutenone ring expansions have been employed as key steps in the synthesis of a variety of natural products and biologically active molecules such as isoarnebifuranone,24 nanaomycin D,24,25 mycophenolic acid,26 D6-tetrahydrocannabinol,27 danshenxinkun B,28 terreic acid,29 perezone and isoperezone,29,30 lonapalene,31 and khellin.32


Treatment of cyclobutenones with Palladium(II) Trifluoroacetate triggers a ring expansion to alkylidenecyclopentenediones.33 For example, eq 16 shows the rearrangement of cyclobutenone (24). The palladium intermediate can be efficiently trapped with N-Bromosuccinimide to afford vinyl bromide (25) in 77% yield.

1. (a) Moore, H. W.; Yerxa, B. Chemtracts: Org. Chem. 1992, 5, 273. (b) Moore, H. W.; Decker, O. H. W. CRV 1986, 86, 821. (c) Liebeskind, L. S. T 1989, 45, 3053. (d) Schmidt, A. H. S 1980, 961. (e) Cohen, S.; Lacher, J. R.; Park, J. D. JACS 1959, 81, 3480. (f) Park, J. D.; Cohen, S.; Lacher, J. R. JACS 1962, 84, 2919.
2. De Selms, R. C.; Fox, C. J.; Riordan, R. C. TL 1970, 781.
3. Ehrhardt, H.; Hünig, S.; Pütter, H. CB 1977, 110, 2506.
4. Fishbein, P. L.; Moore, H. W. JOC 1984, 49, 2190.
5. Ried, W.; Kümbel, B.; Tauer, M.-L. LA 1984, 564.
6. Gruenefeld, J.; Zinner, G. AP 1985, 318, 992, 1057, and 1062.
7. Eggerding, D.; West, R. JOC 1976, 41, 3904.
8. (a) Schmidt, A. H.; Botzet, D.; Straus, M. CZ 1986, 110, 273. (b) Schmidt, A. H.; Straus, M.; Botzet, D. S 1985, 1055. (c) Schmidt, A. H.; Schneider, M.; Aimene, A.; Straus, M.; Botzet, D. CZ 1985, 109, 333. (d) Schmidt, A. H.; Aimene, A.; Hoch, M. S 1984, 754.
9. Beck, W.; Schweiger, M. J.; Müller, G. CB 1987, 120, 889.
10. Green, B. R.; Neuse, E. W. S 1974, 46.
11. Rubin, Y.; Knobler, C. B.; Diederich, F. JACS 1990, 112, 1607.
12. Cohen, S.; Cohen, S. G. JACS 1966, 88, 1533.
13. (a) Pericás, M. A.; Serratosa, F. TL 1977, 50, 4437. (b) Dehmlow, E. V.; Schell, H. G. CB 1980, 113, 1.
14. Liebeskind, L. S.; Fengl, R. W.; Wirtz, K. R.; Shawe, T. T. JOC 1988, 53, 2482.
15. Reed, M. W.; Pollart, D. J.; Perri, S. T.; Foland, L. D.; Moore, H. W. JOC 1988, 53, 2477.
16. Liebeskind, L. S.; Wirtz, K. R. JOC 1990, 55, 5350.
17. Gayo, L. M.; Winters, M. P.; Moore, H. W. JOC 1992, 57, 6896.
18. Liebeskind, L. S.; Fengl, R. W. JOC 1990, 55, 5359.
19. Liebeskind, L. S.; Zhang, J. JOC 1991, 56, 6379.
20. For alkynes see: (a) Foland, L. D.; Karlsson, J. O.; Perri, S. T.; Schwabe, R.; Xu, S. L.; Patil, S.; Moore, H. W. JACS 1989, 111, 975. For aryls see: (b) Perri, S. T.; Foland, L. D.; Decker, O. H. W.; Moore, H. W. JOC 1986, 51, 3067 and (c) Liebeskind, L. S.; Iyer, S.; Jewell, C. F., Jr. JOC 1986, 51, 3065. For alkenes see: (d) Perri, S. T.; Moore, H. W. JACS 1990, 112, 1897.
21. Liebeskind, L. S.; Granberg, K. L.; Zhang, J. JOC 1992, 57, 4345.
22. Karlsson, J. O.; Nguyen, N. V.; Foland, L. D.; Moore, H. W. JACS 1985, 107, 3392.
23. Liebeskind, L. S.; Foster, B. S. JACS 1990, 112, 8612.
24. Foland, L. D.; Decker, O. H. W.; Moore, H. W. JACS 1989, 111, 989.
25. Decker, O. H. W.; Moore, H. W. JOC 1987, 52, 1174.
26. Danheiser, R. L.; Gee, S. K.; Perez, J. J. JACS 1986, 108, 806.
27. Kowalski, C. J.; Lal, G. S. JACS 1988, 110, 3693.
28. Danheiser, R. L.; Casebier, D. S.; Loebach, J. L. TL 1992, 33, 1149.
29. Perri, S. T.; Dyke, H. J.; Moore, H. W. JOC 1989, 54, 2032.
30. Enhsen, A.; Karabelas, K.; Heerding, J. M.; Moore, H. W. JOC 1990, 55, 1177.
31. Perri, S. T.; Moore, H. W. TL 1987, 28, 4507.
32. (a) Reed, M. W.; Moore, H. W. JOC 1987, 52, 3491. (b) Reed, M. W.; Moore, H. W. JOC 1988, 53, 4166.
33. Liebeskind, L. S.; Mitchell, D.; Foster, B. S. JACS 1987, 109, 7908.

Damian O. Arnaiz & Harold W. Moore

University of California at Irvine, CA, USA

Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.