Palladium-catalyzed coupling reactions for the preparation of concatenated azoles

The coupling reactions mediated by sp 2 -sp 2 transition metals, mostly Pd, allowed the chemoselective preparation of some synthetic compounds and intermediate structures of great complexity. This work describes the methodology used to obtain several derivatives with bisoxazole and thiazole-oxazole units. The required organozinc reagents were prepared from n - BuLi and ZnCl 2 , and the bimetallic derivative of ethyl oxazole-4-carboxylate was obtained by a second transmetalation with CuI


Introduction
In recent decades, some marine natural products have been found to be an important source of new bioactive compounds and drug leads.The chemical structures of marine products with heterocycles, such as 2,4´-bisoxazole, trisoxazole and 2,4´-thiazole-oxazole, substituted in different positions of the ring are common in different families of natural products (Figure 1).© ARKAT-USA, Inc These heterocyclic fragments are abundant in many secondary metabolites isolated from marine organisms and, in many cases, they exhibit unusual and unexpected biological activities.However, at the same time these compounds possess complex structure, which makes their synthesis rather difficult.
Many examples of these compounds are characterized by a bisoxazole motive in their structure. 1Some of these include: hennoxazole A (antiherpes), isolated from the sponge polyfibrospongia; telomestatine, a chemotherapeutic agent that inhibits telomerase and shows a correlation between its activity and tumor growth; leucamide A, isolated from the Australian sponge Leucetta microraphis with cytotoxic activity; ulupualide A, which has an unusual range of biological activities, such as cytotoxic and antifungal properties, and participates in cell proliferation in leukemia; and finally, merchercharmycin and some of its reported analogs, which have shown cytotoxic activity against cancer cells.2][3][4] Transition metal-catalyzed cross-coupling reactions have emerged as a powerful synthetic tool that allows a wide range of cross-coupling partners to be combined efficiently. 5This method has been used for C-C bond formation in many synthetic procedures.Negishi 6 reactions allowed a vast number of cross-couplings, as highlighted by the Pd-catalyzed cross-coupling reactions.

Results and Discussion
This work reports the use of ZnCl 2 for the formation of derivatives containing bisoxazole and oxazole-thiazole.The initial studies performed were based on the methodology reported by Hodges et al. 7 These authors described that metalation of the oxazole with n-butyllithium leading to the formation of 2% of oxazole substituted at the 2 position and 20% of the product at the 4 position of the ring.Based on this study, different tests were carried out to obtain the activated oxazole at the 4 position.The preparation of 4-(tributylstannyl)oxazole, 4-bromooxazole and oxazole-4-boronic acid were unsuccessful. 21n the other hand, it was tested a direct oxidative cross-coupling reaction catalized by Pd(0) between 2,4-dibromothiazole and oxazole.Several coupling reactions were tried without detection of 2-(4-bromothiazol-2-yl)oxazole.The formation of small amounts of the 2,2'bisoxazole was detected using Pd(OAc) 2 and PPh 3 but we did not have any signs of achieving a coupling reaction with 2,4-dibromothiazole (see experimental procedure).

Negishi cross-couplings
Although the oxazole can be metalated in the 2 position with alkyl lithium giving the corresponding 2-lithium oxazole as Hodges described 7 , the balance with the intermediate reaction causes instability in the ring.A work published by Reeder et al. 9 explains that the balance may promote ring closure by the addition of an excess of zinc chloride obtaining a covalent character of the carbonzinc bond.
Zinc-derivative 1 was obtained by reaction of oxazole with n-BuLi, followed by in situ addition of solid ZnCl 2 in anhydrous THF at -78 ºC for 30 min.The cross-coupling reaction between 1 and 2,4-dibromothiazole in the presence of Pd (0) under reflux gave chemoselectively 3 in 40 % yield.The reactivity of oxazole derivative 1 was also tested for cross-coupling with triflate 4. 22 The reaction using Pd (0) as catalyst in THF at reflux temperature afforded 5 in a 51% yield (Scheme 1).The bromothiazole 3 was used for new coupling reactions with arylboronic acid or with zinc derivative 1. Cross-coupling between 3 and 4-methoxyphenylboronic acid using K 2 CO 3 and Pd (0) gave 6 in 45% yield.The same reaction conditions were used for the reaction coupling between 3 and 1, obtaining 7 in a 72 % yield (Scheme 2).The metalation of ethyl oxazole-4-carboxylate 8 was also tested for cross-coupling reactions because the possibility of the posterior transformation of the ester into a new azole ring is well known. 1 The metalation of 8 was performed with LDA instead of n-BuLi to avoid side reactions with the ester group.However, the same reaction conditions with ZnCl 2 to afford 9 and posterior addition of 4-iodoanisole gave only starting material (Scheme 3).
Harn et al. 23 described the acylation of oxazole with acid chlorides using a metaloxazole.A double transmetalation of 2-lithiooxazole was produced by treatment first with ZnCl 2 and finally with CuI.These reaction conditions were used to prepare the organometallic 10 by double transmetalation and the cross-coupling reaction was assayed with 4-iodoanisole catalyzed by Pd (0).Compound 11 substituted at the 2 position of the oxazole ring was obtained.The crosscoupling of the organometallic 10 and triflate 4 under the same conditions as before provided 12 in 52% yield (Scheme 3).
The stabilization of the oxazole ring with ZnCl 2 and CuI allowed the coupling with 4iodoanisole and with oxazole triflate obtaining the bisoxazole having a 2-4 link between the two heterocycles as it is present in several natural compounds.

Conclusions
The organometallic derivatives of B, Zn, Sn of the oxazole are difficult to obtain due to the great instability of the ring.

Figure 2 .
Figure 2. Compounds with oxazole and thiazole rings in their structure.