Diisopropyl Squarate

 · C10H14O4  · (198.22)

(reagent used as a highly oxygenated four-carbon building block in a wide variety of annulation reactions)

Physical Data: mp 43-44°C.

Solubility: soluble in alcohol, diethyl ether, and most organic solvents.

Form Supplied in: white crystalline solid readily prepared from squaric acid.

Purification: the compound is usually pure enough for subsequent use as obtained from the syntheses outlined below.

Preparative Methods: diisopropyl squarate (87%) is readily prepared by azeotropic removal of water from a solution of squaric acid in 1:1 benzene-2-propanol.1,2 The same compound (81%), as well as examples of other dialkyl squarates that can not be prepared by the above route, are available from a general method involving refluxing a solution of squaric acid in the appropriate alcohol (solvent) in the presence of the corresponding orthoformate (eq 1).

Handling, Storage, and Precautions: the solid can be stored under normal laboratory conditions for an extended period of time without apparent decomposition. However, as a precaution, storage in the refrigerator is recommended. One should be careful when preparing and handling dialkyl squarates since many members are powerful skin irritants and sensitizers.3

Synthesis of Substituted Cyclobutenones and Cyclobutenediones

Diisopropyl squarate and related esters are valuable synthetic intermediates for the construction of a variety of 4-substituted 3-alkoxycyclobutenediones. Monoalkylated cyclobutenones were prepared directly in one pot by treating a dialkyl squarate with the appropriate lithium reagent followed by quenching the reaction mixture with HCl or trifluoroacetic anhydride (TFAA) (eq 2).2,4

A modification of the above procedure leads to a general synthesis of substituted cyclobutenedione monoketals.5 An illustrative example is the synthesis of 2-phenyl-3,4,4-trimethoxycyclobutenone (85%) upon treatment of dimethyl squarate with phenyllithium followed by quenching with methanol and TFAA. Subsequent treatment of this product with methyllithium followed by TFAA gave 2-phenyl-3-methyl-4,4-dimethoxycyclobutenone in 94% yield (eq 3). By changing the order of substituent introduction, the regioisomer was obtained in good yield. These reaction sequences provide access to a variety of isomeric cyclobutenedione monoacetals in a regiodefined fashion. A related method leading to monoacetalization has also appeared.6

3-Tributylstannyl-4-isopropoxycyclobutenedione is readily prepared in 65% yield from diisopropyl squarate upon treatment with 1,1,1-trimethyl-2,2,2-tri-n-butyldistannane in the presence of a catalytic amount of cyanide ion.7 Stille cross-coupling reactions with alkyl iodides then provide a complementary route to 3-alkyl-4-isopropoxycyclobutenediones. This work was extended to include the synthesis of 3-acylcyclobutenediones, a rare class of compounds in which the cyclobutenediones bear an electron-withdrawing group (eq 4).8 The starting material is 3-(piperidinyl)-4-tri-n-butylstannylcyclobutenedione, prepared from 3-tri-n-butylstannyl-4-isopropoxycyclobutenedione upon treatment with piperidine.

Numerous examples of 4-allylcyclobutenones are available from the corresponding 4-hydroxy or 4-alkoxy analogs upon treatment with allylsilanes in the presence of Lewis acids. The example outlined in eq 5 provides evidence for a carbocationic intermediate in such transformations. Specifically, both regioisomeric starting cyclobutenones give nearly quantitative yields of a single adduct.9 This and related examples lead to the general conclusion that allylation of unsymmetrically substituted 4-hydroxycyclobutenones takes place predominately at that site best able to stabilize cationic charge density. A number of heterocyclic, carbocyclic, and acyclic 4-allylcyclobutenones are available from readily available cyclobutenedione monoketals, a transformation that has recently been reviewed.10 The example provided in eq 6 is illustrative.

Synthesis of 4-Methylidenecyclobutenones

A variety of cyclobutenediones and cyclobutenones have been shown to react with dimethyl titanocene to provide the corresponding methylidene product.11 For example, 3-phenyl-4-isopropoxycyclobutenedione reacts at the ketonic carbonyl group to give 4-methylidene-3-phenyl-2-isopropoxycyclobutenone in 75% yield (eq 7). The reaction also takes place with dialkoxy squarates. For example, diisopropyl squarate gives 4-methylidene-2,3-diisopropoxycyclobutenone in 80% yield.

In a related study, dialkyl squarates were shown to undergo olefination under Wittig or Horner-Emmons reaction conditions.12 For example, eq 8 outlines Wittig olefination of diisopropyl squarate to give the alkylidene product in 88% yield in an E/Z ratio of 1:1. Horner-Emmons conditions using a phosphonate gave the same product (91%) but in an E/Z ratio of 1:19. It is noteworthy that simple acid hydrolysis of the product gives squarylacetic acid esters, potentially valuable active methylene compounds.

Synthesis of Bicyclo[3.2.0]heptenones

4-Allylcyclobutenones, available as described above or from direct allylation of cyclobutenediones upon treatment with allyllithium reagents, are valuable reagents for the synthesis of highly substituted bicyclo[3.2.0]heptenones. For example, thermolysis of dialkoxy squarate-derived 4-allyl-2-ethenyl-3-methyl-4-trimethylsiloxycyclobutenone (refluxing toluene) provides the corresponding bicycloheptenone in nearly quantitative yield (eq 9).13 This general and efficient transformation is envisaged to proceed via electrocyclic ring opening of the starting cyclobutenone to give a vinylketene intermediate that is disposed to undergo intramolecular 2+2 cycloaddition to the proximal allyl double bond.

Synthesis of Quinones and Related Compounds

A particularly important transformation of dialkyl squarates is their conversion to cyclobutenones bearing a site of unsaturation at position 4. Such compounds undergo ring expansion to the corresponding aromatic compounds, thus constituting a valuable annulation method. Numerous examples of this method were reviewed in 1995.14 Selected examples are provided in eq 10-13.15-19 It is noted that the p-unsaturation at position 4 can be found in aryl, alkenyl, or acyl groups. The annulation method is general and accommodates multiple substitution patterns. An important example illustrating these points is its use as a key step in the synthesis of porphyrin-quinones as outlined in eq 13.

The above reactions are envisaged to involve 4p electrocyclic ring opening of the cyclobutenone followed by 6p electrocyclic ring closure of the resulting dienylketene.

Interesting variations of the above reactions are outlined in eq 14 and 15. The former depicts a general transformation of a 4-allenylcyclobutenone to a quinone methide intermediate that is trapped in an intramolecular Diels-Alder cycloaddition.20 This appears to be a general reaction and represents one of the few known routes to these reactive intermediates under neutral (thermal) conditions. The latter provides an example of a general reaction of 4-alkynylcyclobutenones. These undergo electrocyclic ring opening to the corresponding dienynylketene followed by ring closure to a diradical intermediate which suffers H-atom transfer to give the quinone directly.14,21,22

A diversity of compounds is available by this annulation methodology. Other ring systems stemming from this method include angucyclines,23 benzophenanthridines,24 piperidinoquinones,25 benzofurans,26 pyranoquinones,27 naphthols,28 naphthalenes,29,30 indolizines,31 naphthoquinones,32 dihydroquinolines,33 2-pyridinones,34 xanthones,35,36 and highly oxygenated angularly fused polycyclic aromatic compounds.37

A particularly interesting example is outlined in eq 16.29 Here the diisopropyl squarate-derived alkynylcyclobutenone provides the ring-opened allene upon treatment with butyllithium. Subsequently, the allene undergoes electrocyclic ring closure (toluene, 110°C) to give the substituted naphthalene.

Cascade Rearrangements Leading to Polycyclic Compounds

A series of papers have appeared which outline a remarkable cascade rearrangement induced by the addition of 2 equiv of an alkenyl or alkynyl lithium reagent to squarate esters. These remarkable reactions result in the stereo- and regio-controlled conversion of achiral reagents to complex polycyclic products possessing several sterogenic centers.38 A relatively simple example is outlined in eq 17, which shows the conversion of diisopropyl squarate to an a,b-bis(alkoxyl)-g-hydroxycyclopentenone, a common structural array found in the products arising from most of the cascade rearrangements. The reader is referred to an excellent review of this topic for a detailed analysis of the mechanism as well as an overview of the synthetic scope of this remarkable reaction.38 Selected examples revealing the exceptional complexity of structural features available in simple laboratory operations are provided in eq 18 and 19.

Synthesis of Polyquinanes from Dialkyl Squarate-derived Bicyclo[3.2.0]heptenones

A method complementary to the above squarate cascade starts with dialkyl squarate-derived bicyclo[3.2.0]heptenones.39-42 Illustrative examples are outlined in eq 20-23. These reactions proceed via an initial oxy-Cope ring expansion upon treatment of the starting bicycloheptenone with an alkenyllithium reagent. The resulting bicyclo[6.2.0]undecenes are generally not isolated but subjected directly to work-up conditions that hydrolyze the trimethylsilyl enol ether and thus induce an intramolecular transannular ring closure to the corresponding polyquinanes.

1. Dehmlow, E. V.; Schell, H. G., Chem. Ber. 1980, 13, 1.
2. Leibeskind, L. S.; Fengl, R. W.; Wirtz, K. R.; Shawe, T. T., J. Org. Chem. 1988, 53, 2482.
3. Liu, H.; Tomoka, C. S.; Moore, H. W., Syn. Commun. 1997, 27, 2177.
4. Reed, M. W. Pollart, D.; Perri, S. T.; Foland, L.; Moore, H. W., J. Org. Chem. 1988, 53, 2477.
5. Gayo, L.; Moore, H. W., J. Org. Chem. 1992, 57, 6896.
6. Liebeskind, L. S.; Wirtz, K. R., J. Org. Chem. 1990, 55, 5350.
7. Liebeskind, L. S.; Fengl, R. W., J. Org. Chem. 1990, 55, 5359.
8. Leibeskind, L. S.; Yu, M. S.; Fengl, R. W., J. Org. Chem. 1993, 58, 3543.
9. Tiedemann, R.; Turnbull, P.; Moore, H. W., J. Org. Chem. 1999, 64, 4030.
10. Ohno, M.; Yamamoto, Y.; Eguchi, S., Synlett 1998, 1167.
11. Petasis, N. A.; Hu, Y. H.; Fu, D. K., Tetrahedron Lett. 1995, 34, 6001.
12. Hayashi, K.; Shinada, T.; Sakaguchi, K., Tetrahedron Lett. 1997, 38, 7091.
13. Santora, V. J.; Moore, H. W., J. Am. Chem. Soc. 1995, 117, 8486.
14. Moore, H. W.; Yerxa, B. R., Adv. Strain Org.Chem. 1995, 4, 81.
15. Onofrey, T. J.; Gomez, D.; Winters, M. P.; Moore, H. W., J. Org. Chem. 1997, 62, 5658.
16. Winters, M. P.; Stranberg, M.; Moore, H. W., J. Org. Chem. 1994, 59, 7572.
17. Mingo, P.; Zhang, S.; Liebeskind, L. S., J. Org. Chem. 1999, 64, 2145.
18. Shi, X.; Liebeskind, L. S., J. Org. Chem. 2000, 65, 1665.
19. Shi, X.; Amin, R.; Liebeskind, L. S., J. Org. Chem. 2000, 65, 1650.
20. Taing, M.; Moore, H. W., J. Org. Chem. 1996, 61, 329.
21. Folland, L. D.; Karlsson, J. O.; Perri, S. T.; Schwabe, R.; Xu, S. L.; Patil, S. Moore, H. W., J. Am. Chem. Soc. 1989, 111, 975.
22. Foland, L. D.; Owen, H. W.; Moore, H. W., J. Am. Chem. Soc. 1989, 111, 989.
23. Tiedemann, R.; Heileman, M. J.; Schaumann, E.; Moore, H. W., J. Org. Chem. 1999, 64, 2170.
24. Hergueta, A. R.; Moore, H. W., J. Org. Chem. 1999, 64, 5979.
25. Xiong, Y.; Moore, H. W., J. Org. Chem. 1996, 61, 9196.
26. Turnbull, P.; Heileman, M. J.; Moore, H. W., J. Org. Chem. 1996, 61, 2584.
27. Xiong, Y.; Xia, H.; Moore, H. W., J. Org. Chem. 1995, 60, 6460.
28. Turnbull, P.; Moore, H. W., J. Org. Chem. 1995, 60, 644.
29. Turnbull, P.; Moore, H. W., J. Org. Chem. 1995, 60, 3274.
30. Sun, L.; Liebeskind, S., J. Org. Chem. 1995, 60, 8194.
31. Yerxa, B.; Moore, H. W. Tetrahedron Lett. 1992, 33, 7811.
32. Lee, K.; Moore, H. W., Tetrahedron Lett. 1993, 34, 235
33. Zhang, D.; Llorente, I.; Liebeskind, L. S., J. Org. Chem. 1997, 62, 4330.
34. Zhang, S.; Liebeskind, L. S., J. Org. Chem. 1999, 64, 4042.
35. Sun, L.; Liebeskind, L. S., J. Am. Chem. Soc. 1996, 118, 12473.
36. Sun, L.; Liebeskind, L. S., Tetrahedron Lett. 1997, 38, 3663.
37. Koo, S.; Liebeskind, L. S., J. Am. Chem. Soc. 1995, 117, 3389.
38. For an excellent review of this topic see: Paquette, L. A., Eur. J. Org. Chem., 1998, 1709.
39. Santora, Vincent J.; Moore H. W., J. Org. Chem. 1995, 117, 886.
40. MacDougall, J. M.; Verma, S. K.; Santora, V. J.; Turnbull, P.; Hernandez, C.; Moore, H. W., J, Org. Chem. 1998, 63, 6905.
41. Erguden, J.; Moore, H. W., Org. Lett. 1999, 1, 375.
42. Verma, S. K.; Nguyen, Q. H.; McDougall, J. M.; Fleischer, E. B.; Moore, H. W., J. Org. Chem. 2000, 65, 3379.

Harold W. Moore & Antonio R. Hergueta

University of California, Irvine, CA, USA

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