The First Catalytic Direct C–H Arylation on C2 and C3 of Thiophene Ring Applied to Thieno-Pyridines, -Pyrimidines and -Pyrazines

Joana F. Campos 1,2 ID , Maria-João R. P. Queiroz 2 and Sabine Berteina-Raboin 1,* ID 1 Institut de Chimie Organique et Analytique (ICOA), Université d’Orléans UMR-CNRS 7311, BP 6759, rue de Chartres, 45067 Orléans CEDEX 2, France; joana-filomena.mimoso-silva-de-campos@univ-orleans.fr 2 Departmento/Centro de Química, Escola de Ciências, Universidade do Minho, Campus de Gualtar, 4710-057 Braga, Portugal; mjrpq@quimica.uminho.pt * Correspondence: sabine.berteina-raboin@univ-orleans.fr; Tel.: +33-238-494-856


Introduction
The direct functionalization of C-H bonds in catalytic coupling reactions is considered to be a significant step to achieve molecular diversity and great progress has already been made in this field.Furthermore, environmentally benign, operationally simple, and robust reactions, particularly those employing heterogeneous catalysts, are of significant interest to the chemical industry.The direct palladium-catalyzed C-H activation of heteroaromatic compounds has recently been extensively studied.The main challenge of this approach is the control of regioselectivity with heterocyclic substrates containing multiple C-H bonds that may have similar reactivities [1][2][3][4][5][6].Thienopyridines, thienopyrimidines, and thienopyrazines are sulfur-containing heterocyclic molecules that, when functionalized, are often incorporated into important molecular scaffolds used in materials science and in particular in biology and medicine [7].To the best of our knowledge, however, no studies have yet been reported on the C-H activation of the thiophene ring in thieno [3,2-b]pyridines, thieno [3,2-d]pyrimidines, and thieno [2,3-b]pyrazines.The present study explores this topic.
McNamara et al. [8] presented the synthesis of a series of thieno [3,4-b]pyrazine derivatives as fluorescent compounds through the direct palladium-catalyzed activation of the C-H bonds of thiophene using Pd(OAc) 2 with X-Phos or PtBu 3 as ligands.Moderate yields were achieved, with some variation depending on the reagents (Scheme 1).

Results and Discussion
Pursuing our previous work [11] on various annelated sulfur-containing heterocycles, where we investigated the functionalization of the C3 position of the thiophene ring in several thieno-pyridines, -pyrimidines, and -pyrazines (Figure 1) using C3-bromoderivatives and various boronic acids in optimized Suzuki conditions, we worked on a Pd-catalyzed direct arylation to generate diversity.
Herein we report our investigation of the development of efficient Pd-catalyzed direct arylation on position C-3 of the thiophene ring from the thieno-pyridines, -pyrimidines, and -pyrazines presented in Figure 1.In a first attempt, the thienoderivatives 1 and 4 were reacted using the conditions already described by our team for the Pd-catalyzed direct arylation of pyrazolo[1,5-a]pyrimidine [12].
Unfortunately, these conditions did not yield the expected products (Table 1).The thienoderivatives 1 and 4 in presence of 1.5 equivalent of 1-iodo-4-methoxybenzene, Pd(OAc) 2 (10% mol), P(tBu) 3 (20% mol), and cesium carbonate (2 equiv.) in toluene after 48 h at 110 • C led only to recovery of the starting material and no trace of the expected product was detected.The use of P(Cy) 3 HBF 4 as ligand did not lead to any improvement even when the reaction time was increased up to 70 h (Scheme 4).Applying the conditions reported by Hull and Sanford [13] on thienoderivatives 3 and 5 was likewise unsuccessful.This methodology involves the direct oxidative coupling of two arene C-H substrates with a very large excess of one of them.The use of Pd(OAc) 2 in presence of Ag 2 CO 3 as base and benzoquinone Bzq as oxidant in DMSO at 130 • C with 100 equivalents of 1,2-dichlorobenzene did not yield the expected compound after 16 h, and once again only the starting material was recovered.After 24 h of reaction time 20% of the expected compound was obtained from 2-(pyridin-2-yl)thieno[3,2-b]pyridine 3 and 10% from 6-(pyridin-2-yl)thieno[2,3-b]pyrazine 5.When 100 equivalents of 1,2-dimethoxybenzene, nitrobenzene, methoxybenzene, or 1,3-dimethoxy-2-nitrobenzene were used in the same conditions, only the starting material was recovered and no product was detected.Although the product was obtained with a very low yield in two cases, given the large quantity of one of the reagents that had to be used in this method, we made no further attempts to optimize the conditions in terms of time or other factors (Scheme 5).The work by Wei et al. [14] and Yang et al. [15] reported procedures for Pd-catalyzed direct arylation with aryl boronic acids which were applied to our thienoderivatives 2 and 3 using phenyl boronic acid but yet again, the reaction was unsuccessful (Scheme 6).
One of the other possible options was to use aryl bromides [16,17].The 2-phenylthieno[3,2b]pyridine 2 was chosen for these experiments and was reacted with various amounts of Pd(OAc) 2 , K 2 CO 3 , or KOAc as base, with or without ligands in different solvents.The results are summarized in Table 1.In entries 1 to 4 copper was added as co-catalyst without any improvement, while in entries 5 to 8 P(t-Bu) 2 MeHBF 4 was used as ligand with which the best yield was obtained (Table 1, Entry 7, yield 26%).
Despite several attempts, however, we did not manage to exceed a 26% yield.Using a different strategy, with 4-chlorothieno[3,2-d]pyrimidine 6 as starting material in the conditions reported by Hull and Sanford [13], also proved unsuccessful (Scheme 7).
To avoid a possible interaction of the chlorine atom in the Pd-catalyzed direct arylation (Scheme 7), it was substituted by various amines, generating a new series of potentially biologically active molecules.This new strategy is shown in Scheme 8.After adding one chain by SnAr, the scope of the reactivity and regioselectivity of Pd-catalyzed direct arylation in positions 2 or 3 of the thiophene moiety was evaluated.Several strategies to conduct an SnAr reaction of 4-chlorothieno[3,2-d]pyrimidine using amino derivatives are reported in the literature [18][19][20][21][22].With a view to developing procedures with the lowest possible environmental impact, we tested the use of PEG 400 as solvent.This compound, like the other heterocyclic scaffolds, underwent the SnAr reaction using amines and produced good yields in only 5 min [23], but our goal was to diversify our core structure by C-H activation which tried using Polyethylene glycol 400 as solvent without success in a one-pot process.We therefore decided, in the present work, to use toluene with various amines to generate precursors of C-H catalyzed cross-coupling.In these conditions all the expected substituted 4-amino-thieno[3,2-d]pyrimidine compounds were successfully synthesized in good yields of 60% to 96%.The lowest yield was obtained for the deactivated aniline substituted in the ortho position by the electro-withdrawing trifluoromethyl group (Table 2).Optimization of the Pd-catalyzed direct arylation and its regioselectivity in position C-2 was achieved starting from 4-(thieno[3,2-d]pyrimidin-4-yl)morpholine 7 using bromobenzene and by varying the amount of Pd(OAc) 2 with or without ligand, and the type and amount of K 2 CO 3 or KOAc as base.Various solvents and temperatures were also tested, as summarized in Table 3.The desired compound was obtained in moderate to good yields in presence of Pd(OAc) 2 with K 2 CO 3 in toluene (Table 3, Entries 1 and 3) and the presence of ligand increased the regioselectivity (Table 3, Entries 3-4).When the reaction was performed in water no results were obtained and only the starting material was recovered (Table 3, entry 6).The temperature had a pronounced effect on regioselectivity: when 4-(thieno[3,2-d]pyrimidin-4-yl)morpholine was stirred using Pd(OAc) 2 , TTBP • HBF 4 as ligand, K 2 CO 3 in toluene at 100 • C, complete regioselectivity was obtained.
This process proved to be a good alternative to the most commonly used synthetic routes [24-29] (Figure 2).
Based on our results (Table 3, Entry 7) the scope and limitations of the one pot SnAr-Pd-catalyzed direct arylation on 4-chlorothieno[3,2-d]pyrimidine 6 were assessed using several bromo-benzenes (Table 4).Several 2-aryl-thieno[3,2-d]pyrimidine compounds amino-substituted in position 4 were synthesized in moderate to excellent yields, demonstrating the generalizability of this method.From these results, we started to develop the Pd-catalyzed direct C-H activation on position C-3 of the thiophene moiety.This was studied from compound 14 using bromobenzene (2 equiv.),different amounts of Pd(OAc) 2 and K 2 CO 3 with or without ligand, in toluene at different temperatures (Table 5).The desired product was obtained in moderate yields (Table 5, Entries 1-3).A temperature between 130-140 • C induced activation in the C-3 position, but when the reaction was performed at 100 • C, direct C-H activation did not take place (Table 5, Entry 4).The scope and limitations of the one-pot reaction were then explored.We started with morpholine; then bromobenzene was used for the Pd-catalyzed C-H activation on the C-2 position, and for the last step, the Pd-catalyzed C-H activation on the C-3 position, bromobenzene and bromobenzonitrile were tested.The conditions of entry 2 (Table 5) were chosen even though they required a ligand because the reaction can be carried out with a smaller amount of base and at a lower temperature, which may be important for some sensitive reagents.These conditions appeared to be a good compromise.The results obtained for the one-pot three-step activation are summarized in Table 6.
For these two examples of one-pot three-step SnAr, C-H activation in C-2 then C-H activation in C-3 positions, we were able to obtain the expected compounds with reasonable yields.This method is also a valid alternative to standard synthetic strategies.To validate our Pd-catalyzed C-H arylation conditions on a large panel of heterocycles possessing a thiophene moiety we chose two compounds used at the beginning of this work, and investigated the scope and limitations first on the 2-phenylthieno[3,2-b]pyridine core structure (Table 7) and then on the 6-phenyl thieno[2,3-b]pyrazine, a heterocycle known to have a particularly low reactivity (Table 8) [11].

Conclusions
In summary, we have disclosed a convenient one-pot synthesis of thieno-pyridine, -pyrimidine, and -pyrazine scaffolds.The conditions reported make this methodology an interesting alternative to conventional routes, as it avoids the bromination, iodination, or chlorination processes generally used to synthesize various annelated sulfur-containing heterocycles.

Figure 1 .
Figure 1.Thienopyridines and thienopyrazines used in first attempts of Pd-catalyzed direct arylation.

Scheme 6 .Scheme 8 .
Scheme 6. Results of conditions reported by Wei et al. and Yang et al. on thienoderivatives.

Figure 2 .
Figure 2. Literature and previous work.

Table 6 .a
One pot three-step selective SnAr, Pd-catalyzed C-H activation on the C-2 then on the C-3 positions of the thiophene moiety.Isolated yield after column chromatography.

Table 2 .
SnAr substitution of chlorine on the six-membered ring by various amines.
a Isolated yield after column chromatography.
a Isolated yield after column chromatography.
a Isolated yield after column chromatography.
a Isolated yield after column chromatography.