Synthesis bis-thienyl-substituted cyclobutenedione via the Liebeskind-Srogl and Stille cross-coupling reactions

Dithien-2-yl and bis(dithien-2-yl)-substituted cyclobutenediones were prepared via Pd(0)-catalyzed cross-coupling reactions, namely, the Liebeskind-Srogl cross-coupling and Suzuki reactions in 85% and 82% yields, respectively.


Introduction
Oligothiophenes are among the most prominent π-conjugated organic oligomers.0][11] Herein, we present our efforts toward the synthesis of a novel derivative posessing a D-A architecture.[14][15] Figure1.Possible transformation of the cyclobutenedione nucleus.
7] In this contribution, we disclose the application of that methodology to achieve the synthesis of the thien-2-yl-cyclobutenedione derivatives.

Results and Discussion
Our initial efforts to prepare 7 focused on our recently developed cross-coupling of 3,4-bis-(4methoxyphenylthio)cyclobutenedione 4 with organoboron reagents to yield symmetric disubstituted cyclobutenediones. 18However, when this protocol was applied to the target molecule under a number of different reaction conditions, we always obtained a mixture of 4 and the mono-and bis-substituted products 6 (15% yield) and 7 (68% yield) (Scheme 1

Scheme 3
In order to incorporate the remaining thiophene units to 7 via a transition metal-catalyzed reaction, bromination of 7 was attempted with Br2 in AcOH.However, even at 120 °C, no reaction was observed, presumably, due to the deactivating effect of the electron-withdrawing cyclobutenedione unit.On the other hand, treatment of 7 with three equivalents of NBS in AcOH gave the desired product 12 in excellent yield (Scheme 4).

Scheme 5
Despite the excellent results obtained using the Suzuki coupling to prepare 13, when the reaction was repeated at a larger scale, it became very sluggish with a significant amount of 12 remaining even after 3 days.We then turned our attention to the Stille coupling [21][22] and carried out an optimization study for the synthesis of 13 (Table 1).The beneficial effect that fluoride has in the Stille reaction 23 was observed in this system as well, for 13 was isolated in 80% yield after only 10 min.

AUTHOR(S)
During the isolation and characterization of 13 we made an interesting observation.Once in solution (hexanes/EtOAc) and exposed to air, [13 remained unchanged if the solution remained under N2] the originally orange solution of 13 gradually turned deep red.TLC of this solution showed that 13 slowly transformed into a different compound. 1H NMR of the new compound was not very informative since it displayed the same signals as 13, only slightly shifted.However, 13 C NMR of this material showed no carbonyl signal in the region typical of cyclobutenediones (190-200 ppm), it did, however, show a signal of a carbonyl group at 164.6 ppm, which is typical of anhydride carbonyl groups (C=O signal of maleic anhydride appears at 164.5 ppm).Based upon this information, it is believed that oxygen inserted between the carbonyl groups of 13 (Scheme 6).

Scheme 6
In addition to the spectral data described above, HRMS analysis gives a molecular peak that matches the structure proposed.This oxidation reaction is unprecedented.Tidwell and Zhao 24 showed that bisketene 16, generated either thermally or photochemically from its corresponding cyclobutenedione precursor, formed the substituted maleic anhydride on exposure to oxygen (Scheme 7).A similar process may be operating in the transformation depicted in eq 6.It is important to notice that this process takes place only after two more thiophene units have been incorporated to 7.This seems to indicate that extension of the conjugated system activates the cyclobutenedione ring toward oxygen insertion.

Conclusions
An efficient methodology to prepare a D-A system comprising two bis-thienyl groups attached to a cyclobutenedione has been developed.Both the Liebeskind-Srogl and Stille cross-coupling reactions were attempted to furnish the target molecule, the latter being the method that gave the best results.The addition of CsF to the key Stille reaction was crucial to the success of the synthesis of 13.When 13 was exposed to air, the corresponding anhydride 17 was smoothly formed by the insertion of oxygen between the carbonyl groups.This transformation is currently under study in our laboratory and the results will be reported in due course.
2 8 With dibromide 12 in hand, we proceeded to react it with 2-thienylboronic acid according to the Suzuki conditions reported by Buchwald 20 (Scheme 5).

Table 1 .
Optimization of the Stille Reaction for the Synthesis of 13 a isolated yields.