Synthesis of transient functionalized dienes by electrocyclic ring-opening of cyclobutene derivatives

Cyclobutenes bearing various functional groups were synthesized by derivatization of squaric acid, and their thermolytic ring-opening reactions were investigated. This sequence was found an effective approach to prepare a multi-functionalized diene, which could be used for subsequent Diels-Alder cycloaddition provided that its s-cis form was fixed


Introduction
Thermal electrocyclic ring-opening of cyclobutene derivatives, to produce 1,3-diene compounds, has been extensively studied since the 1960's, and the theoretical aspects of this fundamental reaction have been elucidated by means of the theory of conservation of orbital symmetry. 1ile numerous studies concerning the stereochemical course of this ring-opening reaction have enabled prediction of the structure of the asymmetric 1,3-diene product, researches aiming at utilizing the resulting dienes as tools for organic synthesis appear to be limited to a few examples.Particularly notable is the synthesis of differently benzoquinones and phenols, in which conjugated ketene intermediates generated by the thermolysis of ethynyl-or vinyl-substituted cyclobutenones yielded the ring-expanded aromatic products as a result of subsequent ring closure and tautomerization. 2 This methodology has also been applied for intermolecular trapping of the vinylketene intermediate by alkynes, 3 and this process has been applied for the synthesis of natural products such as cylindrocyclophane. 4On the other hand, the 1,3-diene compounds generated by the thermolysis of substituted cyclobutenes, except for the unstable vinylketenes mentioned above, have rarely been utilized for organic synthesis in spite of their importance as synthetic blocks for the construction of complex molecules.We report herein the syntheses of several substituted cyclobutenes by functionalization of commercially available squaric acid, their thermal ring-opening to prepare multi-functionalized dienes, and the investigation of their synthetic utility.

Results and Discussion
The symmetrically substituted 3,4-dimethylcyclobutene-1,2-dione (2), readily synthesized from squaric acid (1) in five steps, 5 was selected as a starting material for functionalization of the cyclobutene ring.Introduction of a vinyl group, which is a versatile functional group for further transformations via conjugate addition, was performed using higher-order vinylcuprate according to the reported procedure, 6 and the resulting enolate was trapped as a silyl ether.The adduct 3 was transformed with osmium tetroxide into the corresponding diol 4, which was protected as an isopropylidene ketal.The ketone 5 was treated with sodium borohydride, and the alcohol 6 thus obtained was subjected to methylation using methyl triflate and 2,6-di-tert-butyl-4-methylpyridine (DTBMP) to afford the methyl ether 7 (Scheme 1).Although the cyclobutene 7 was a mixture of diastereomers and the ratio and stereo-structures could not be determined from its spectral data, introduction of the multi-functionality on the cyclobutene ring was achieved successfully in this way, providing a precursor for a functionalized diene.Scheme 1. Preparation of the functionalized cyclobutene 7.
Thermal ring-opening of the cyclobutene 7 proceeded in refluxing toluene to give a ca.1:1 mixture of two geometrical isomers (dienes 8 and 8'), the structures of which were determined on the basis of the conrotatory ring-opening process 1 and NOE experiments (indicated in Scheme 2).Formation of these products indicates that preferential outward rotation of the methoxy group occurred, 7 and that the cyclobutene 7, having the trans relative configuration (of the methoxy group and the dioxolane unit) was converted into the diene 8, and the cisisomer produced 8'.
These functionalized dienes, which would be difficult to synthesize in other ways, are expected to be versatile synthetic blocks.In the course of our study on o-quinodimethane chemistry, i.e., the thermolytic cleavage of benzocyclobutene derivatives and subsequent Diels-Alder cycloaddition, 8 we were interested in the extension to monocyclic cyclobutenes.Moore's group have reported that cyclobutenes possessing a dithioacetal structure readily underwent ring-opening reaction, while the resulting dienes resisted Diels-Alder reaction except for a particular case. 9We supposed that replacement of the dithioacetal structure by the more electron-donating ethylene ketal would facilitate Diels-Alder reaction, to increase their utility as synthetic blocks.Thus, the cyclobutenes having an ethylene ketal structure were prepared by the modified procedure developed by Liebeskind et al. 10 Di-isopropyl squarate (9), easily prepared from squaric acid (1), 10 was treated with methyllithium to yield the alcohol 10, which was converted into the TMS ether 11.For the ketalization, Noyori's conditions 11 were adopted and the monoketal 12 was obtained selectively.

OMe
These transformations have already been reported. 10Subsequent addition of methyllithium followed by acid treatment afforded the cyclobutenone 14, which was subjected to DIBAL reduction and methylation to furnish the required cyclobutene derivative 16 (Scheme 3).With these results in hand, we tried to synthesize a fused-cyclobutene derivative 26 and to investigate its electrocyclic reaction.According to the procedure shown in Scheme 3, the cyclobutene 24 bearing vinyl and butenyl substituents was prepared, namely, by vinylation of the squarane 9, 12 ketalization, introduction of the butenyl group, and treatment with hydrochloric acid (Scheme 5).The cyclobutene 24 thus obtained was subjected to ring-closing metathesis using Grubbs' catalyst 12 to give the fused-cyclobutene derivative 25, which was transformed into the methyl ether 26.The result of the thermolysis of 26 is shown in Scheme 6.As expected, in the presence of TCNE thermolytic cleavage and subsequent Diels-Alder reaction proceeded to give the cycloadduct 28 in 60% yield.In this case, the inevitable fixation of the diene 27 to the s-cis form would serve as the factor facilitating Diels-Alder reaction.

Conclusions
In this study, we have reported the synthesis of functionalized cyclobutenes as precursors of multi-functionalized dienes.Several derivatizations of the commercially available squaric acid and the stereospecific electrocyclic ring-opening of the derivatives could be exemplified.The attempt to illustrate the utility of the resulting dienes in Diels-Alder cycloaddition revealed that, in the case of the fused-cyclobutene derivative, such applications were warranted.The construction of polycyclic systems for the synthesis of natural products using this methodology is now in progress.

Experimental Section
General Procedures.All non-aqueous reactions were carried out under an Ar atmosphere.
Reagents were purchased from commercial sources and used as received.Anhydrous solvents were obtained from commercial sources or dried by distillation over CaH 2 or P 2 O 5 .