Room-Temperature Direct β-Arylation of Thiophenes and Benzo[b]thiophenes and Kinetic Evidence for a Heck-type Pathway.

The first example of a regioselective β-arylation of benzo[b]thiophenes and thiophenes at room temperature with aryl iodides as coupling partners is reported. This methodology stands out for its operational simplicity: no prefunctionalization of either starting material is required, the reaction is insensitive to air and moisture, and it proceeds at room temperature. The mild conditions afford wide functional group tolerance, often with complete regioselectivity and high yields, resulting in a highly efficient catalytic system. Initial mechanistic studies, including (13)C and (2)H KIEs, suggest that this process occurs via a concerted carbo-palladation across the thiophene double bond, followed by a base-assisted anti-elimination.

Introduction

Heterobiaryl scaffolds are common motifs in pharmaceuticals, natural products, and organic electronic components. Methods for their efficient synthesis are of significant interest.[1] In recent years, direct C–H arylation of heteroarenes has emerged as an efficient apprpan class="Chemical">oach to the synthesis of these heterobiaryls.[2] Major challenges in developing these methods involve the control of the regioselectivity of arylation[2,3] and achieving mild reaction conditions,[4] with most current methodologies requiring elevated temperatures, strong oxidants, and acids or bases. The direct arylation of thiophenes and benzo[b]thiophenes, which are widely present in biologically active molecules and organic electronic materials,[5] is a rapidly growing area of research. Over the past few years, several methodologies allowing the direct arylation of thiophenes at the most acidic α position have been developed.[6] Direct β-arylation of thiophenes has proven a more challenging task with only a handful of examples in the absence of directing groups reported.[7,8] In 2010, Itami and co-workers reported a methodology for the selective β-arylation of thiophenes with iodoarenes (Scheme a), where a PdCl2/P[OCH(CF3)2]3 catalytic system was found essential for achieving high regioselectivity.[7a] This report was followed by examples using aryl boronic acids,[7b] aryltrimethyl silanes,[7c] aryl chlorides,[7d] and benzensulfonyl chlorides[7e] as aryl donors. However, all of these methods require high temperatures (80–150 °C), or require TFA as solvent, thus limiting functional group compatibility. Furthermore, some of these methods provide low yields with electron-deficient aryl donors, require a large excess of this coupling partner, and/or provide moderate C-3/C-2 regioselectivity. Recently, Glorius and co-workers reported a milder method that uses diaryliodine(III) salts (Scheme b, TRIP = 2,4,6-triisopropylphenyl) as coupling partners, allowing the selective β-arylation to proceed at 60 °C.[7f] However, a mild methodology employing more readily available coupling partners would be of significant utility. Herein, we report the first example of a methodology capable of performing β-arylation of thiophenes and benzo[b]thiophenes at room temperature. This method employs iodoarenes as coupling partners and proceeds in most cases with >99:1 regioselectivity. In addition, kinetic evidence implicating a Heck-type mechanistic pathway has been obtained for the first time.

Scheme 1

Approaches to β-Regioselective Arylation of Thiophenes and Benzo[b]thiophenes

Results and Discussion

Reaction Optimization and Scope

Research conducted in our group has previously highlighted the role of silver(I) carboxylate salts in enhancing the reactivity of a Pd/pan class="Chemical">ArI system and enabling the direct arylation of indoles to proceed at room temperature.[9] We used this catalytic system as our starting point for the investigation into the arylation of unsubstituted benzo[b]thiophene 1a with 4-iodotoluene 2a (Table , entry 1). Under these conditions, C-3 arylated adduct 3aa was obtained as the major regioisomer, albeit with a yield of only 7%. Contrary to our experience with indoles, a screening of silver(I) carboxylates did not provide any improvement on the yield (entries 1–3 and Table S1). A solvent screening revealed that replacing H2O with the more acidic 1,1,1-trifluoroethanol (TFE) and 1,1,1,3,3,3-hexafluoroisopropan-2-ol (HFIP)[10] led to a marked increase in reactivity (Table , entries 4–6), with the latter solvent, in combination with Ag2CO3 as the base, affording 3aa in 72% yield (Table , entry 6). However, significant amounts of the homocoupling product of benzo[b]thiophene 1a were also observed. This undesired product could be formed upon reaction of 1a with Pd(OAc)2 while presumably forming the catalytically active Pd0 species. A change of precatalyst to Pd2(dba)3·CHCl3 was effective at preventing homocoupling of 1a, affording the desired C-3 arylated compound in 92% yield (Table , entry 7) with >99:1 C3:C2 regioselectivity without making use of any additional ligand. Control experiments further outlined the need for both Pd catalyst and Ag2CO3 (entries 8, 9).[11]

Table 1

Optimization of Reaction Conditionsa

entry	base	[Pd] cat.	solvent	yield (%)a
1	c-C6H11CO2Ag	Pd(OAc)2	H2O	7
2	p-NO2–C6H4CO2Ag	Pd(OAc)2	H2O	14
3	1-Ad–CO2Ag	Pd(OAc)2	H2O	11
4	c-C6H11CO2Ag	Pd(OAc)2	TFE	15
5	Ag2CO3	Pd(OAc)2	TFE	34
6	Ag2CO3	Pd(OAc)2	HFIP	72
7	Ag2CO3	Pd2(dba)3·CHCl3	HFIP	92
8	K2CO3	Pd2(dba)3·CHCl3	HFIP	0
9	Ag2CO3	none	HFIP	0

Yields were calculated by 1H NMR using an internal standard.

Having optimized the process, we then investigated the scope of the reaction (Table ). Iodobenzene and pan class="Chemical">iodoarenes bearing para electron-donating groups reacted efficiently (3aa–3ad). Electron-withdrawing para-substituents also provided 3ae–3aj in good to excellent yields. Remarkably, this method is completely compatible with benzylic alcohol (3ad) and aldehyde (3ae) functionalities, both sensitive to oxidation under harsher conditions, and with ketones (3af), which often require protection. Chloro- and bromo- substitution was also tolerated (3ai and 3aj), albeit with somewhat reduced yields despite no obvious side products being observed.[12] Highly electron-withdrawing para-substituents, such as nitro and trifluoromethyl (3ak and 3al), resulted in low reactivity. Gratifyingly, adding 5 mol % of tris(4-methoxyphenyl)phosphine to the catalytic system and raising the reaction temperature to 50 °C restored high yields for these less reactive iodoarenes, while maintaining high C3/C2 regioselectivity. Both of these observations contrast with Itami’s methodology,[7a] where (1) electron-rich iodoarenes display lower reactivity and (2) addition of an electron-rich phosphine ligand switches the regioselectivity to C2. The diverse features shown by our system suggest different mechanistic pathways (vide infra), and understanding these could lead to the development of new regioselective methodologies. meta-Substituted iodoarenes also showed good reactivity under our reaction conditions (3am–3ao). ortho-Substitution is tolerated, although a slightly higher temperature is required to achieve high yields (3ap–3ar). Heteroiodoarenes, such as 1- and 2-iodothiophene and N-tosyl-5-iodoindole, could also be successfully employed as coupling partners (3as–3au). Furthermore, we examined the applicability of our methodology toward the synthesis of non-natural amino acids, which could be further incorporated into peptides leading to isosteric molecules with potential biological properties.[13,14] When we tested the coupling between benzo[b]thiophene (1a) and (S)-N-Boc-4-iodo-phenylalanine (2v), the corresponding product was obtained in high yield. Furthermore, we were pleased to discover that no racemization took place with 3av obtained in >99% enantiomeric excess.[15] 4-Iodoaniline was not compatible with the reaction conditions (3aw), likely due to inactivation of the catalyst by coordination.[16] Protecting the amine functional group to a less strongly coordinating acetamide gave the desired product in 84% yield (3ax). Similarly, no reactivity was observed with 4-iodobenzonitrile (3ay).

Table 2

Direct C–H Arylation of Benzo[b]thiophene 1a with Iodoarenes 2a–ya

Reactions carried out on a scale of 0.75 mmol of 1a. Yields given are isolated. C3/C2 ratios were determined by GC–MS analysis of the crude reaction mixture.

Performed at 50 °C and in the presence of 5 mol % of P(p-C6H4OMe)3.

Performed at 50 °C.

Performed with 3 equiv of 1a, 1 equiv of ArI, 0.5 equiv of Ag2CO3, and 5 mol % of P(p-C6H4OMe)3 at 50 °C.

Pepan class="Chemical">rformed at 50 °C and in the presence of 5 mol % of P(p-C6H4OMe)3.

Pepan class="Chemical">rformed at 50 °C.

Pepan class="Chemical">rformed with 3 equiv of 1a, 1 equiv of ArI, 0.5 equiv of Ag2CO3, and 5 mol % of P(p-C6H4OMe)3 at 50 °C.

The process can be also applied to the regioselective C-4 arylation of pan class="Gene">C-2 and C-3 substituted thiophenes (Table ). In most examples, nearly complete regioselectivity was observed, with >99:1 of C-4 arylation versus all other regioisomers. Moderately electron-withdrawing and -donating substituents were found compatible with the reaction, but lower yields or decomposition were observed with stronger electron-donating or -withdrawing substituents. The reaction conditions tolerate free alcohols (3ia) and a SiMe3 substituent (3ja).

Table 3

Direct C–H Arylation of Thiophenes 1b–1j with Iodoarene 2aa

Reactions carried out on a scale of 0.75 mmol of 1. Yields given are isolated. Regioselectivity was determined by GC–MS of the crude reaction mixture.

Reaction performed at 50 °C.

To further explore the compatibility of our room-temperature conditions with sensitive functional groups, we tested a substrate containing a boronic ester substitution (Scheme ). Remarkably, good yield and chemo- and regioselectivity toward the pan class="Gene">C-3 arylation product 3kb were obtained under our standard conditions. Conversely, a simple change of base from Ag2CO3 to Ag2O effected a complete switch in chemoselectivity, providing the Suzuki coupling adduct 4 in 77% yield.

Scheme 2

Chemoselectivity toward C–H Activation in the Presence of Boronic Esters

The reaction setup is highly practical as the reagents can be weighed under air and the reaction is neither air- nor moisture-sensitive. We also explored whether further tailoring of the reaction would accommodate particular practical needs between concentration, catalyst loading, and temperature of reaction. For example, in the reaction of 1a with 2a, the catalyst loading could be reduced to only 0.5 mol %, affording 3aa in 89% when reacting at 50 °C instead of room temperature (Scheme a). These conditions were applied to a selection of substrates, which gave the corresponding arylated compounds in good to high yields (75%–90%). To our knowledge, this is the lowest palladium catalyst loading reported for a pan class="Gene">C-3 arylation of (benzo)thiophenes. Furthermore, the amount of HFIP solvent can be significantly reduced to only 4 equiv, while maintaining the same high yields of 3aa (86%, see Table S6). Finally, the reaction is amenable to scaling up: the arylation of 1a with 2a using only 4 equiv of HFIP could be directly run at a 20 mmol of 1a scale without any modifications, to afford 3.77 g (84%) of pure isolated adduct 3aa (Scheme b).

Scheme 3

Reactions at Low Catalyst Loading and 20 mmol Scale-Up

Mechanistic Considerations

Mechanistic Outline

A plausible mechanistic pathway involving a Pd0/II catalytic cycle is outlined in Scheme . The cycle would start by oxidative addition of Ar–I 2 to pan class="Chemical">Pd(0) (I) to form PdArI species II. HFIP is a mildly acidic solvent (pKa 9.3), which would react with Ag2CO3 in an acid–base equilibrium forming AgOCH(CF3)2, which can then transmetallate with II to form Pd alkoxide III. These species may be further stabilized by H-bonding with another molecule of HFIP.[17] Pd-species III would then undergo the C–H arylation step or steps (vide infra) on the benzo[b]thiophene substrate 1.

Scheme 4

Plausible Reaction Mechanism

A competition experiment between 4-iodotoluene (2a) and pan class="Chemical">4-iodonitrobenzene (2k) was carried out, resulting in a relative reactivity of 5.8:1 (Scheme a).[18] If the oxidative addition was irreversible, coupling with the electron-poor iodoarene (albeit in low yield) would be the expected major product.[19] Instead, the result obtained suggests that oxidative addition is reversible and occurs before the rate-limiting step, consistent with our mechanistic proposal in Scheme . Alternatively, a PdII/IV pathway has also been proposed to explain a C–H arylation mediated by Pd(OAc)2 and AgOAc displaying a similar reactivity trend.[20]

Scheme 5

Competition and Deuteration Experiments

Studies on the C–H Functionalization Pathway

The C–H functionalization steps could proceed through: (a) an electrophilic aromatic substitution (SEAr) pathway; (b) a concerted metalation-deprotonation (pan class="Disease">CMD); or (c) a Heck-type process (Scheme ).[2b,2f] Pathway a involves an electrophilic attack by Ar–PdII at C-3 of benzo[b]thiophene followed by deprotonation and reductive elimination. This pathway is inconsistent with the regioselectivity of arylation observed for thiophenes, given that these are most nucleophilic in the α, not β position. For pathway b, an unusual C–H activation at the less acidic position needs to be invoked to explain the β-regioselectivity of the process. Pathway c, on the other hand, involves a carbo-palladation followed by an anti-β-hydride elimination or a more likely base-assisted E2 elimination. Calculations by Fu have shown that a base-assisted E2-type elimination may indeed be a viable process in certain cases.[21a] Itami and Studer have also reported calculations that favor the hypothesis of a carbo-palladation pathway on the C-3 arylation of thiophenes with arylboronic acids.[20b]

Scheme 6

Possible Mechanistic Pathways for the C–C Bond Formation Step

With the aim of obtaining experimental evidence supporting one of these mechanistic pathways for the C–C bond-forming step, we set out a competition experiment between 2-methyl- (1e) and pan class="Chemical">2-chloro-thiophene (1g) showing that the more electron-rich 1e reacts exclusively (>99:1, Scheme b). This suggests that the C–H activation step does not proceed via a concerted metalation-deprotonation (pathway b), where the electron-poor 1g should react faster, or that the C–H activation step is not rate-determining.[22] Furthermore, a CMD process would be expected to occur at the most acidic α-position in the thiophene, rather than the observed β-arylation.[23] To test whether a reversible CMD process might be in operation in our system, H/D scrambling experiments were attempted by subjecting benzo[b]thiophene 1a-d-3 and 1a-d-2 to the reaction conditions in the presence and in the absence of ArI: in all cases recovered starting material 1 showed no D/H scrambling (Scheme c), suggesting that a non-rate-determining reversible CMD process is also unlikely.

With the aim of obtaining supporting evidence for a Heck-type pathway, we set out to determine the 13C/pan class="Chemical">12C and D/H KIEs for the process. Kinetic isotope effect (KIE) measurements have proven to be invaluable tools to assess mechanistic hypotheses in a wide variety of transition metal-catalyzed reactions.[24] Within the C–H functionalization arena, 2H KIEs are often measured and can provide information on the nature of the C–H activation event. On the other hand, despite their potential for providing new and complementary information, 13C KIEs are rarely determined. This is likely due to the difficulty in preparing 13C isotopically labeled substrates. Over the last two decades, Singleton and co-workers have demonstrated that 13C natural abundance in substrates can be used to determine intermolecular competitive 13C KIEs by quantitative 13C NMR.[25,26] During the course of a reaction, the starting material will become more enriched in 13C at those positions with a positive 13C/12C kinetic isotopic effect; therefore, an increase in the ratio of 13C/12C between the recovered starting material and the original starting material will result. This ratio (R/R0) is directly related to the fractional conversion of reagents (F) and the KIEs by eqs and 2.[25,27]

Importantly, the experimental KIEs on benzo[b]thiophene will reflect the first irreversible step between the catalyst and pan class="Chemical">benzo[b]thiophene, regardless of what is the rate-determining step in the overall process.[28] Therefore, this is an ideal technique to directly probe the nature of the C–H arylation step. Following this procedure, we carried out two independent experiments, which allowed the simultaneous measurement of 13C KIE at C-2, C-3, and C-4. These experiments indicated the presence of a significant primary 13C KIE at both C-3 and C-2 positions of benzo[b]thiophene: KIEs of 1.042 ± 0.006 and 1.044 ± 0.005 were obtained for C-3 position, while KIEs of 1.015 ± 0.006 and 1.014 ± 0.005 were determined for C-2 (Figure a, values in black). These KIEs are consistent with a Heck process (see discussion below).

Figure 1

Determination of KIEs. Values in black correspond to the experimentally determined 13C (a) and 2H (b) intermolecular KIEs (two repeats). Figures in brackets correspond to the standard deviation in the last digit as determined from six measurements. Values in red correspond to the DFT predicted KIEs for the proposed olefin insertion step (Scheme , pathway c).

Because of the low sensitivity of 2H NMR, measuring pan class="Chemical">2H KIEs using the same analytical technique is generally very time-consuming or results in too large an error. To overcome this problem, we carried out a modification on Singleton’s procedure: we partially deuterated the benzo[b]thiophene starting material at C-2 and C-3 (ca. 1% each) and used an internal standard.[29] This allowed for an extremely accurate measurement of the 2H KIEs. Two independent experiments (Figure b, black) showed an inverse KIE at C-3 (0.87 ± 0.01, 0.88 ± 0.01) and no KIE at C-2 (1.02 ± 0.01, 1.00 ± 0.01). The presence of an inverse kinetic isotope effect is consistent with a change in the hybridization at the carbon atom during the rate-determining step from sp2 to sp3. These values contrast with the positive 2H KIEs measured by Glorius and co-workers (1.5 for C3 and 1.2 for C2) where a heterogeneous catalytic process is proposed.[7f]

Determination of KIEs. Values in black correspond to the experimentally determined 13C (a) and pan class="Chemical">2H (b) intermolecular KIEs (two repeats). Figures in brackets correspond to the standard deviation in the last digit as determined from six measurements. Values in red correspond to the DFT predicted KIEs for the proposed olefin insertion step (Scheme , pathway c).

Taken together, the 13C and pan class="Chemical">2H KIE values are consistent with a carbopalladation step onto the C2–C3 double bond of the benzo[b]thiophene (Scheme c). On the other hand, these values are inconsistent with both the CMD and the electrophilic-metalation pathways (Scheme a and b), where a significant 13C KIE should be only be observed at C-3 (not at C-2). Furthermore, a large primary 2H KIE would be expected at C-3 for the CMD process.[30] For a rate-limiting carbopalladation step, it would be expected that 13C KIEs would be observed for both C-2 and C-3 carbon atoms along with inverse 2H KIEs at both positions. Here, we observed both 13C KIEs and an inverse KIE at the C-3 proton of benzo[b]thiophene. However, no 2H KIE at C-2 was observed. Computational experiments (vide infra) revealed that, in this specific case, a 2H KIE would not be expected at C-2.

To further probe the mechanism of the reaction, DFT modeling of a plausible carbopalladation step between benzo[b]thiophene and the likely active intermediate pan class="Chemical">Pd[Ph(OCH(CF3)2) (HOCH(CF3)2)] (III, Scheme ) was performed (Figure ). The calculation in the gas phase showed the initial formation of an exergonic C2,C3-olefin π-complex (ΔG = −4.9 kcal/mol). The subsequent carbopalladation step afforded a free energy barrier of 22.4 kcal/mol, which is consistent with a room-temperature process.[31,32] Furthermore, on the basis of these calculated structures, ISOEFF was used to predict the 13C and 2H KIEs corresponding to this step.[33,34]The predicted values are strikingly close to the experimentally observed ones (Figure a and b, values in red), highlighting the usefulness of combined 13C and 2H KIE studies to distinguish between the proposed mechanistic pathways. Conversely, DFT modeling of a plausible CMD pathway[21a,23] in the gas phase (see the Supporting Information) leads to a higher free energy barrier of 24.7 kcal/mol and a predicted H/D KIE of 5.2 at C3.[35]

Figure 2

Computational studies for a plausible carbopalladation step of the Heck-type pathway in the gas phase. Structures and energies calculated by DFT (B3LYP/LanL2Dz for Pd, 6-31G(d) for other atoms). Gibbs free energies (G) are in kcal mol–1.

Computational studies for a plausible carbopalladation step of the Heck-type pathway in the gas phase. Structures and energies calculated by DFT (B3LYP/LanL2Dz for pan class="Chemical">Pd, 6-31G(d) for other atoms). Gibbs free energies (G) are in kcal mol–1.

Conclusion

In summary, we have described the first catalytic system capable of β-arylation of benzo[b]thiophenes and pan class="Chemical">thiophenes at room temperature. This system delivers very high regioselectivities, presents broad functional group tolerance, and can be carried out in an open flask and in the absence of phosphine ligands (with the exception of highly electron-poor iodoarenes). Preliminary mechanistic studies have provided the first experimental kinetic evidence supporting a Heck-type reaction pathway in C–H arylations of heteroarenes. Further investigations on the mechanism are ongoing in our laboratories and will be reported in due course.

Experimental Section

General Procedure

Pd2(pan class="Chemical">dba)3·CHCl3 (19.5 mg, 2.5 mol %), Ag2CO3 (155 mg, 0.56 mmol, 0.75 equiv), aryl iodide 2 (1.12 mmol, 1.5 equiv), and (benzo)thiophene 1 (0.75 mmol, 1.0 equiv) were stirred in hexafluoro-2-propanol (0.75 mL) at 24 °C for 16 h. After this time, the resultant mixture was diluted with EtOAc (5 mL) and filtered through a plug of silica. The silica plug was flushed with EtOAc (30 mL), and the filtrate was evaporated to dryness under reduced pressure. Purification via automated column chromatography afforded the desired arylated (benzo)thiophenes 3.

Representative Example

3-(p-Tolyl)benzo[b]thiophene (3aa; 20 mmol Scale Reaction: Scheme b)

Benzo[b]thiophene 1a (2.74 g, 20 mmol, 1.0 equiv), pan class="Chemical">4-iodotoluene 2a (6.67 g, 30 mmol, 1.5 equiv), Ag2CO3 (4.1 g, 15 mmol, 0.75 equiv), and Pd2(dba)3·CHCl3 (518 mg, 0.5 mmol, 2.5 mol %) were stirred in 8.4 mL of 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) at 24 °C for 16 h. After this time, the resultant mixture was diluted with EtOAc (15 mL) and filtered through a plug of silica. The silica plug was flushed with EtOAc (50 mL), and the filtrate was evaporated to dryness under reduced pressure. Product 3aa was then isolated by column chromatography (hexane) as a colorless oil in 84% yield (3.77 g, 17 mmol). R (hexane): 0.48. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.02–7.97 (m, 2H), 7.56 (d, J = 8.0 Hz, 2H), 7.47–7.44 (m, 2H), 7.42 (s, 1H), 7.36 (d, J = 8.0 Hz, 2H), 2.50 (s, 3H). 13C NMR (101 MHz, CDCl3): δ (ppm) 140.9, 138.2, 138.2, 137.4, 133.3, 129.6, 128.7, 124.5, 124.4, 123.1, 123.1, 123.0, 21.2. HRMS: calcd for C15H12S, 225.0660 (M + H+); found, 225.0730.