Ruthenium(II)-catalyzed switchable C3-alkylation versus alkenylation with acrylates of 2-pyridylbenzofurans via C–H bond activation

Abstract

We documented an interesting observation of ruthenium(II)-catalyzed benzofuran C–H activation and subsequent functionalization with acrylates that reveals that a simple base can switch the process from alkylation to alkenylation.

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The transition metal-catalyzed carbon–carbon and carbon–heteroatom bond formation via the activation of sp² and sp³ C–H bonds is recognized as a powerful alternative to classical cross-coupling reactions involving a preformed organometallic partner.¹ Since the discovery of Ru(0)-catalyzed chelation-assisted C–H bond functionalization and subsequent alkylation via insertion of olefin into the (C–Ru–H) Ru–H bond and reductive elimination by Murai and co-workers in 1993,² this reaction has been extensively investigated by employing various transition metal complexes.³ However, olefins with conjugation, such as α,β-unsaturated acceptors, were found not to perform this alkylation.⁴ Interestingly, a few reports on the utilization of conjugated olefins such as acrylates in these directed C–H alkylation reactions have appeared only recently with ruthenium(II)-complexes,⁵ favoured by strongly chelating directing groups,^5b whereas there have been several examples since 2011 of alkenylation with acrylates employing the Ru(II)/Cu(II) catalytic system.⁶ Thus, it is a challenging task to design efficient catalytic systems for tuning the alkylation over alkenylation and vice versa.

Benzofuran is one of the commonly encountered structural units in natural products and pharmaceutically important compounds.⁷ The functionalization of benzofurans via C–H activation is attractive because this enables an efficient approach to various analogues from simple precursors.⁸ 2-(2-Pyridyl)benzofuran derivatives have recently been identified as promising scaffolds in the PET imaging of β-amyloid (Aβ) plaques and thus for the diagnosis of and the discovery of effective therapeutic agents for Alzheimer's disease.⁹ However, as the reports on either the synthesis or the functionalization of 2-(2-pyridyl)benzofurans are few, the C–H activation and selective functionalization of 2-(2-pyridyl)benzofurans will provide simple tactics and promote further advances in this class of compounds.¹⁰

Recently, we have showed that an acyl-directing group in 2-aroylbenzofuran could allow the insertion of an acrylate into the C3–H bond of furan, but more importantly, the nature of the catalyst could selectively lead to the branched insertion product (Ru(PPh₃)₃Cl₂) or to the linear insertion product {[Ru(p-cymene)Cl₂]₂}.^5a Of course, alkylation took place due to the preference of the RCO directing group. Thus, it was of interest to understand how different directing groups could selectively orchestrate the insertion leading to alkylation or favour β-elimination and thus alkenylation.¹¹ We now wish to report our initial findings and to show for the first time how acrylates can, via ruthenium(II) C–H bond activation, simply lead to alkylation or alkenylation of heterocyclic C–H bonds [Fig. 1(a) and (b), respectively]. We reasoned that due to the pyridine directing group being a strong electron donor, the Ru–C bond in the intermediate ruthenacycle is expected to be more polarized and thus favour the coordination and insertion of the olefin based upon the electronic preferences, i.e. the electrophilic β-carbon of the acrylate binding to nucleophilic carbon providing the linear alkylation product. This was indeed observed, but in addition, the conditions for selective alkylation or alkenylation were discovered.

Fig. 1 Proposal for the selective alkylation or alkenylation with acrylates.

Our investigations in this regard started with the reaction of 2-pyridylbenzofuran and methyl acrylate in the presence of Ru(PPh₃)₃Cl₂, AgOAc and in the presence of K₂CO₃ in toluene at 140 °C for 24 h. Surprisingly, the formation of the alkenylated product 4aa with complete linear selectivity has been observed. Linear selectivity was anticipated; however, the observed complete cross-dehydrogenative coupling without any alkylation product was surprising, since no oxidant was employed, such as the Cu(II) salt.^5a However, considering the fact that the base was employed in excess and that in Heck-like couplings it is known that the base facilitates the final reductive elimination step, the same reaction was attempted in the absence of base.¹² Interestingly, when the reaction was conducted under identical conditions except for the absence of base, the linear alkylation product 3aa was obtained exclusively. This important observation revealed that with this Ru(II) complex, the alkylation reactions proceed through the ruthenacycle formation followed by the commonly proposed coordinative insertion mechanism and that the involvement of a Ru–H intermediate is not necessary.

Next, the compatibility of other bases has been studied. As summarized in Table 1, with many other bases employed the reactions are incomplete and the starting 1a was recovered in substantial amounts. When Cu(OAc)₂ was used as an additive in place of AgOAc, the reaction in the presence of base provided 4aa in comparable yields. However, when there was no base, unlike with AgOAc, where the alkylation reaction was exclusive, with Cu(OAc)₂ the products resulting from both the alkylation and the alkenylation were obtained in a 3 : 4 ratio. Next, [Ru(p-cymene)Cl₂]₂ was examined as a catalyst for these transformations. The reactions were conducted under similar conditions and the results are comparable. In the presence of base, 4aa was obtained in 69% yield, whereas in the absence of base over the [Ru(p-cymene)Cl₂]₂ catalyst, the linear alkylation product 3aa was obtained exclusively. This is quite important, as it reveals that with both the ruthenium complexes, the course of the reactions seems to be similar.

Table 1 Optimization of reaction conditions for directed C–H functionalization^a,b

S. No	Catalyst	Base	Additive	3aa	4aa
a Reagents and conditions: benzofuran (1 eq.), methyl acrylate (3 eq.), catalyst (5 mol%), base (3 eq. unless otherwise mentioned), additive (30 mol%), 140 °C, toluene, 24 h. b Isolated yield after column chromatographic purification. c 25% of 1a was recovered. d 63% of 1a was recovered. e 61% of 1a was recovered. f 41% of 1a was recovered.
1	Ru(PPh3)3Cl2	K2CO3	AgOAc	No	77
2	Ru(PPh3)3Cl2	Absent	AgOAc	75	No
3	Ru(PPh3)3Cl2	Na2CO3	AgOAc	No	74^c
4	Ru(PPh3)3Cl2	Cs2CO3	AgOAc	No	66^d
5	Ru(PPh3)3Cl2	NaHCO3	AgOAc	No	63^e
6	Ru(PPh3)3Cl2	NaOAc	AgOAc	No	42^f
7	Ru(PPh3)3Cl2	K2CO3	Cu(OAc)2	No	67
8	[Ru(p-cymene)Cl2]2	K2CO3	AgOAc	No	69
9	[Ru(p-cymene)Cl2]2	Absent	AgOAc	66	No
10	Ru(PPh3)3Cl2	Absent	Cu(OAc)2	31	43

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Having discovered two complementary conditions for alkylation or alkenylation, we next explored the generality of these reactions by employing a wide range of olefins. Table 2 summarizes the results obtained with the alkylation and alkenylation reactions. Various acrylates such as ethyl- and tert-butyl- (2b and 2c) gave the corresponding alkylation or alkenylation products in moderate to good isolated yields. However, the reactions with N-isopropylacrylamide (2d) were found to be sluggish and the products were obtained in poor yields. With styrene (2e), the linear alkylated product was obtained exclusively even in the presence of K₂CO₃. As shown in Table 2, the presence of an electron-withdrawing substituent on the benzofuran ring has, at most, only a nominal influence on the selectivity. Interestingly, when a methyl group is present in place of chlorine, the yields were found to decrease slightly. These observations indicate that the C–H bond strength of the C3 carbon of benzofuran and the steric environment around the olefin have some influence on the yield of the reaction.

Table 2 Scope of the Ru(II)-catalyzed alkylation versus alkenylation of 2-(2-pyridyl)benzofurans with acrylates

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Deuterium labelling experiments have been carried out in order to understand the course of the deprotonation and also the possibility of hydrometalation or carbometalation followed by proto-demetalation. The reactions were conducted in the presence of D₂O and under conditions a) and b), excluding the olefin. Deuterium incorporation was observed at the C3 position of benzofuran. The C3-deuterated benzofuran 5 reacted with acrylate under the optimized conditions. As shown in Scheme 1, only a nominal incorporation of deuterium at the α-position of the alkylated product was observed.

Scheme 1 Deuterium labelling experiments.

Although the mechanism cannot be demonstrated yet, we extend the following proposal to explain these two reactions. The reaction of the Ru(PPh₃)₃Cl₂ complex with 2 eq. of AgOAc generates Ru(OAc)₂(PPh₃)₃.^13,14 The coordination of the pyridyl nitrogen and the subsequent acetate-mediated deprotonation lead to the intermediate ruthenacycle I and release AcOH. The easy dissociation of the AcO–Ru(II) bond from complex I, especially in the presence of AcOH, favours the coordination of the olefin to the cationic intermediate II. Due to the polar Ru–C bond present in complex II, the olefin insertion takes place with addition of the nucleophilic Ru–C carbon atom to the acrylate electrophilic β-carbon to give the linear insertion product precursor III. When there is no base present, this intermediate, upon proto-demetalation by the released AcOH, affords the linear alkylation product 3 and thus regenerates the ruthenium acetate complex. When the base is present, since β-elimination (commonly encountered in Heck coupling) is not possible (as it requires the M–C_α and C_β–H bonds to align in a syn-coplanar arrangement), we propose that the base abstracts the β-proton at the anti-position of the Ru atom to form the alkenylation product 4 (Scheme 2).¹⁵

Scheme 2 Proposed mechanism for the alkylation vs. alkenylation.

Conclusions

In conclusion, our current investigations reveal two important observations in the directed C–H activation and functionalization. First, the donating ability of the chelating group, inter alia, the electronic factors override the steric influence when the Ru–C bond is polar. Secondly, we show for the first time that the presence of base avoids alkylation and favours, in the absence of an oxidant (Cu^II), dehydrogenative cross coupling processes via C–H activation. We believe that these findings will provide fresh impetus for further efforts to understanding how the nature of the substrate, catalyst and base will be fine-tuned in order to achieve alkylation or alkenylation with the desired regioselectivity.

Acknowledgements

We thank the CSIR (India) for funding this project under the CSIR-NCL NICE program (CSC0109) and a research fellowship to YK.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Characterization data and spectra of all new compounds. See DOI: 10.1039/c4cy01268b

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