Palladium‐Catalyzed Directed C(sp³)–H Arylation of Saturated Heterocycles at C‐3 Using a Concise Optimization Approach

Abstract

Saturated heterocycles, such as THFs, pyrrolidines, piperidines and THPs, are essential components of many biologically active compounds. Examples of C–H functionalization on these important ring systems remain scarce, especially at unactivated positions. Here we report the development of conditions for the palladium‐catalyzed stereoselective C(sp³)–H arylation at unactivated 3‐positions of 5‐ and 6‐membered N‐ and O‐heterocycles with aminoquinoline directing groups. Subtle differences in substrate structures altered their reactivity significantly; and different conditions were required to achieve high yields in each case. Successful conditions were developed using a short empirical optimization approach to cover reaction space with a limited set of variables. Excellent cis‐selectivity was achieved in all cases, except for the THP substrate where minor trans‐products were formed through a different palladacyclic intermediate. Here, differences in reactivity and selectivity with other directing groups were examined.

Introduction

Saturated heterocycles, particularly 5‐ and 6‐membered rings containing N or O, are crucial components across a wide range of biologically active compounds, featuring prominently in natural products and pharmaceuticals.1,2 Extensive synthetic studies have continued across many decades to provide efficient access to substituted heterocyclic derivatives.3 For medicinal chemistry this has become increasingly relevant, with recent calls for increased saturation and more 3‐dimensional characteristics in drug‐like and lead‐like compounds.4,5 The concepts of lead‐oriented synthesis4a and “escape from flatland”4d have provided renewed vigor in the study of polar saturated heterocycles.6 Compounds with reduced aromaticity, low lipophilicity and an increased fraction of sp³ centers (Fsp³) have been proposed to afford drug candidates more likely to successfully proceed through all stages of development.4,5 Reliable synthetic methods that can divergently access saturated heterocyclic frameworks with control over the 3D arrangement of substituents are therefore highly valuable.

Transition metal catalyzed functionalization of unactivated C–H bonds promises to revolutionize the synthesis of complex molecules.7 For C–C bond formation at sp³ centers, issues of stereochemistry, the stability of metalated intermediates, and selectivity across often poorly differentiated C–H bonds must be resolved. Recently, selective arylation of C(sp³)–H bonds has been achieved using directing groups to locate transition metal species and stabilize intermediates.8–22 Amide‐linked directing groups have permitted arylation processes for a variety of substrates, while also making subsequent removal of the directing group possible.9 In a seminal report in 2005, Daugulis reported the use of 8‐aminoquinoline (AQ) amides for C–H arylation at sp³ centers with aryl iodides, employing catalytic Pd(OAc)₂ and stoichiometric AgOAc (Scheme 1, a).10 Later, Daugulis introduced the 2‐(methylthio)aniline group as an effective auxiliary for the arylation of primary C–H bonds, while avoiding bis‐arylation, which was a characteristic of the AQ group.10b At a similar time, Yu reported the palladium‐catalyzed β‐C–H arylation of carboxamides employing monodentate directing groups to facilitate functionalization with aryl iodide coupling partners. This weaker coordination mode used finely‐tuned, designed ligands.11 This approach has subsequently been extended to enantioselective variants using enantioenriched ligands.12

Scheme 1.

Directed C(sp³)–H arylation: acyclic, cyclic and heterocyclic substrates.

The last few years has seen the development of alternative strongly coordinating bidentate directing groups for use with palladium catalysts.13–16 These approaches have extended palladium‐catalyzed arylation to a variety of methyl and methylene centers.9–17 A number of cyclic systems have been investigated, including cyclopropanes18 and cyclobutanes.12,19 Furthermore, C–H arylation of amino acid derivatives using both acid20 and amine,21,22 linked directing groups have been developed.23 These reactions with bidentate directing groups are likely to operate through a Pd^II/Pd^IV catalytic cycle.10 A concerted metalation‐deprotonation is often proposed, invoking an acetate ligand on Pd to assist in breaking the C–H bond and forming a Pd^II metallacycle.24 This intermediate undergoes oxidative addition with an aryl iodide, giving a Pd^IV intermediate, followed by reductive elimination to form the new C–C bond.25 There remain limited examples of successful arylation using aryl bromides,13a,26 and of using alkyl halides for C–H alkylation.10b,27 Examples of the use of Ni28 and Fe29 catalysts in C(sp³)–H arylation have recently been developed.

Notably absent through these extensive works are studies on the catalytic C–H functionalization of saturated heterocycles at unactivated positions (Scheme 1, b).30–33 Yu has shown a single example of arylation17a and alkynylation34 of a 4‐amido‐tetrahydropyran derivative, with C–H functionalization occurring at the 3‐positions, beta to the directing groups. Chen demonstrated a single example of β‐C–H alkylation on a 2‐piperidinecarboxamide with ethyl iodoacetate, employing the AQ directing group.27a We recently published the stereospecific palladium‐catalyzed C–H arylation at the 3‐position of proline derivatives, starting from N‐Cbz‐protected proline with the AQ directing group.35,36 During the course of this work Babu reported the arylation of THF derivatives.37 This limited set of examples is surprising given the importance of saturated heterocycles in biologically active compounds, and the potential for C–H functionalization to provide efficient divergent and iterative synthesis of derivatives, which is essential in the optimization of compounds in drug discovery.

Here, we report the development of C–H arylation protocols for various heterocyclic derivatives using the aminoquinoline directing group (Figure 1). Different arylation conditions are developed for each of the THF, pyrrolidine, piperidine and THP substrates to achieve high yields. We present a comparison of substrate success in these transformations, and provide a condensed optimization approach using only a limited set of reaction conditions. A comparison of directing groups was undertaken on the THP substrate in terms of reactivity and stereoselectivity. Finally, our optimization approach was demonstrated on a carbocyclic and an acyclic aminoquinoline amide to demonstrate the flexibility and applicability of this process, providing comparisons with literature results (Figure 1).

Figure 1.

Substrate classes in this study optimized through a concise optimization protocol, posing questions of stereoselectivity or mono vs. bis‐arylation (DG = CONHQ, X = Boc, Cbz).

Results and Discussion

Scope of Study and Optimization Protocol

For our study we selected to use Daugulis' bidentate aminoquinoline directing group, which has been shown to be compatible with several substrate classes and varying conditions. Our preliminary investigations indicated that one set of conditions was unlikely to be applicable across the range of substrates of interest; indeed, in our previous study, there was a remarkable variation in reaction outcome even between N‐Boc‐ and N‐Cbz‐prolinecarboxamides.35 In many cases in the literature, extensive optimization is reported for C–H arylation of different AQ‐amide substrates, and there are no general conditions. However, it was striking that these final optimized conditions frequently fell within a limited set. We considered that a logical, programmed route to optimization of different substrates would be valuable in expanding access to new heterocyclic derivatives. Consequently, based on examination of the literature and our prior experience we selected a much‐reduced set of reaction variables that we considered would cover the relevant reaction space and offer the best chance of success. The resulting optimization process we designed is illustrated in Figure 2.

Figure 2.

Process and parameters used for optimization of the C–H arylation for each substrate. [a] Reactions were performed at 0.3 m concentration with respect to amide. [b] Using preferred solvent and Pd source from round 1; 1 equiv. Ag₂CO₃, 30 mol‐% PivOH. [c] Using preferred solvent, Pd source and base from rounds 1 and 2.

A number of parameters were maintained constant throughout the optimization process: catalyst loading (5 mol‐%), equivalents of base (2 equiv.), iodobenzene (3 equiv.), temperature (110 °C), time (18 h) and scale (0.20 mmol). For efficiency, we limited the optimization to three rounds and 4 new sets of conditions per round, along with selected repeat reactions as control experiments. Initial experiments (round 1) were to establish the viability of the reaction, the preferred Pd source and solvent.38 One significant decision was to run the reaction under solvent‐free conditions early on. Examples in the literature,10 as well as our own work,35 indicated this could be advantageous for challenging substrates, particularly when using AgOAc, but may then offer little scope for further optimization. Next, round 2 would examine halophilic bases, with K, Cs and Ag^I salts featuring prevalently in the literature. Acidic additives (PivOH) were used with Ag₂CO₃ or K₂CO₃, where they appeared most advantageous. For conditions that used a solvent, the concentration of the reaction would then be varied (round 3). Finally, we considered it prudent to allow some flexibility in reaction time or catalyst loading, to generate isolated yields. We anticipated that this study could provide valuable insight into the reactivity of differing substrates, as well as an opportunity for comparison of conditions and directing groups across related substrates.

THF Substrate

Tetrahydrofuran AQ‐amide 1 was investigated first through this process (Table 1). Applying round 1 of the optimization process, the solvent‐free conditions gave the best result, with a 79 % yield of the desired 3‐phenyl‐THF 2a by ¹H NMR spectroscopy (Entry 4). No further improvement was obtained when examining bases (Entries 5–8).

Table 1.

Optimization of the C–H arylation of THF carboxamide 1.

Entry	Round	Varied conditions	Yield 2a [%][a]	RSM 1 [%][a]
1	1	AgOAc, Pd(OAc)2, toluene	46[b]	54[b]
2	1	AgOAc, Pd(TFA)2, toluene	13	87
3	1	AgOAc, Pd(OAc)2, tert‐amyl‐OH	57	43
4	1	AgOAc, Pd(OAc)2, no solvent	79[b]	21[b]
5[c]	2	Ag2CO3, Pd(OAc)2, no solvent	19	81
6[c], [d]	2	Ag2CO3, PivOH, Pd(OAc)2, no solvent	56	44
7[d]	2	K2CO3, PivOH, Pd(OAc)2, no solvent	6	94
8	2	CsOAc, Pd(OAc)2, no solvent	17	83

^[a]Yield of product 2a or recovered starting material 1 determined by ¹H NMR spectroscopy with respect to an internal standard (1,3,5‐trimethoxybenzene).

^[b]Average yield of 2 reactions.

^[c]1 equiv. Ag₂CO₃.

^[d]30 mol‐% PivOH.

Crucial to our hypothesis was that this result was likely to be a maximum yield for this substrate subject to the imposed constraints (i.e. the AQ directing group with these loadings of base and iodide). To demonstrate this, we progressed a full standard optimization at the same time.39 By this alternative route we also converged on the same solvent‐free conditions, and did not obtain an improved yield.

Encouraged, we ran a small scope with the successful conditions, using a representative range of electron rich, electron poor and heterocyclic aryl iodides (Scheme 2). This was performed using AgOAc as a base with no solvent, but the reaction time was increased to 24 h in an attempt to further conversion. High yields were obtained across the substrates types; the phenyl example 2a proceeded in 78 % yield, electron rich 4‐iodoanisole gave 83 % of the arylated compound 2b and the p‐chlorophenyl example 2c was isolated in a 78 % yield. Additionally, a chloropyridyl substituent could be installed in an excellent yield of 81 %. When using enantiopure (R)‐1, an 88 % ee of the phenylated product (–)‐2a was obtained, suggesting a small degree of racemization of the starting material occurred under these conditions. Notably, only the cis‐diastereoisomer of the product was observed in all cases.

Scheme 2.

Selected scope of aryl iodides compatible with the C–H arylation reaction of THF carboxamide 1.

During the course of this work Babu reported a related set of conditions for the arylation of THF carboxamide 1,37 obtaining a 73 % yield for 2a, a 62 % yield for 2c and 56 % yield for 2d.40 The optimization process we describe here afforded improved yields with lower catalyst and reagent loadings, based on the examination of reaction concentration as a variable (solvent‐free vs. 0.08 m).

The AQ directing group was then removed under two sets of conditions to provide either the cis or trans isomer selectively (Scheme 3).41

Scheme 3.

Selective removal of the 8‐aminoquinoline directing group to afford either the trans‐acid 3 or cis‐acid 4.

Hydrolysis and epimerization to the trans‐THF acid 3 was observed in 88 % yield, upon treating the THF carboxamide 1 with sodium hydroxide in ethanol at 70 °C for 24 h, with 8‐aminoquinoline recovered in 99 %. Alternatively, the cis‐acid 4 could be isolated in the same yield, when using conditions reported by Babu.37

N‐Boc Pyrrolidine Substrate

In our previous work on the arylation of N‐Cbz‐proline derivatives we observed significantly reduced reactivity for N‐Boc‐proline AQ‐amide 5.35 Applying the first round conditions to the N‐Cbz substrate gave quantitative conversion to the arylated product under the solvent‐free conditions, similar to the final conditions developed previously. With the N‐Boc‐pyrrolidine derivative 5 the best yield achieved through round 1 was also under solvent‐free conditions, giving a 21 % yield by ¹H NMR spectroscopy (Table 2, Entries 1–4), with the majority of the starting material returned unreacted in each case. As the solvent‐free conditions were only marginally better than the reaction using Pd(OAc)₂ in toluene, we chose to examine conditions using toluene as solvent to provide greater scope for optimization. On examining bases, the Ag₂CO₃ and pivalic acid additive combination was found to be best, providing a 40 % yield by NMR spectroscopy. Varying the concentration of the reaction with these sets of conditions did not improve the yield (Table 2).

Table 2.

Optimization of C–H arylation of N‐Boc‐pyrrolidinecarboxamide 5.

Entry	Round	Varied conditions	Yield 6a [%][a]	RSM 5 [%][a]
1	1	AgOAc, Pd(OAc)2, toluene (0.3 m)	18[b]	82[b]
2	1	AgOAc, Pd(TFA)2, toluene (0.3 m)	0	100
3	1	AgOAc, Pd(OAc)2, tert‐amyl‐OH (0.3 m)	10	90
4	1	AgOAc, Pd(OAc)2, no solvent	21	79
5[c]	2	Ag2CO3, Pd(OAc)2, toluene (0.3 m)	24	76
6[c], [d]	2	Ag2CO3, PivOH, Pd(OAc)2, toluene (0.3 m)	40[e]	60[e]
7[d]	2	K2CO3, PivOH, Pd(OAc)2, toluene (0.3 m)	3	97
8	2	CsOAc, Pd(OAc)2, toluene (0.3 m)	12	88
9[c], [d]	3	Ag2CO3, PivOH, Pd(OAc)2, toluene (0.2 m)	33	67
10[c], [d]	3	Ag2CO3, PivOH, Pd(OAc)2, toluene (0.5 m)	33	67
11[c], [d]	3	Ag2CO3, PivOH, Pd(OAc)2, toluene (1.0 m)	36	64
12[c], [d]	3	Ag2CO3, PivOH, Pd(OAc)2, no solvent	34	66

^[a]Yield of product 6a or recovered starting material 5 determined by ¹H NMR spectroscopy with respect to an internal standard (1,3,5‐trimethoxybenzene).

^[b]Average yield of 3 reactions.

^[c]1 equiv. Ag₂CO₃.

^[d]30 mol‐% PivOH.

^[e]Average yield of 2 reactions.

For this challenging substrate, additional variables were considered to improve the yield to an acceptable value. Increasing the reaction time to 72 h gave a similar conversion. Increasing the Pd(OAc)₂ loading to 10 mol‐% at this longer reaction time gave a conversion of 70 %. These conditions were then used to examine the reactivity of the representative scope of aryl iodides (Scheme 4). Pleasingly, all four aryl iodides were compatible in modest to good yields. The phenyl example 6a was isolated in 53 %, as a single enantiomer, yields ranged from 38 % for the pyridyl example 6d to 59 % for the p‐methoxyphenyl example 6b. In all cases, single cis‐diastereoisomers were observed.42

Scheme 4.

Selected scope of aryl iodides compatible with the C–H arylation reaction of N‐Boc‐pyrrolidinecarboxamide 5.

N‐Cbz‐Piperidine: A Highly Reactive Substrate

For N‐Cbz‐piperidinecarboxamide 7 all conditions attempted in the first round of optimization provided quantitative conversion to the 3‐phenyl‐piperidine 8a (Table 3, Entries 1–4). This is a remarkable increase in reactivity vs. the five‐membered ring derivatives. The conditions using Pd(OAc)₂ and toluene (Entry 1) were selected to examine reaction scope due to the increased ease of processing of the crude reaction compared to the reactions without solvent. This gave excellent yields with all examples, ranging from 90 % for the p‐chlorophenyl example 8c to 98 % for the p‐methoxyphenyl 8b and pyridyl 8d examples (Scheme 5). In all cases, only the cis‐configured isomer was observed.43,44

Table 2.

Optimization of C–H arylation of N‐Boc‐pyrrolidinecarboxamide 5.

Entry	Round	Varied conditions	Yield 6a [%][a]	RSM 5 [%][a]
1	1	AgOAc, Pd(OAc)2, toluene (0.3 m)	18[b]	82[b]
2	1	AgOAc, Pd(TFA)2, toluene (0.3 m)	0	100
3	1	AgOAc, Pd(OAc)2, tert‐amyl‐OH (0.3 m)	10	90
4	1	AgOAc, Pd(OAc)2, no solvent	21	79
5[c]	2	Ag2CO3, Pd(OAc)2, toluene (0.3 m)	24	76
6[c], [d]	2	Ag2CO3, PivOH, Pd(OAc)2, toluene (0.3 m)	40[e]	60[e]
7[d]	2	K2CO3, PivOH, Pd(OAc)2, toluene (0.3 m)	3	97
8	2	CsOAc, Pd(OAc)2, toluene (0.3 m)	12	88
9[c], [d]	3	Ag2CO3, PivOH, Pd(OAc)2, toluene (0.2 m)	33	67
10[c], [d]	3	Ag2CO3, PivOH, Pd(OAc)2, toluene (0.5 m)	33	67
11[c], [d]	3	Ag2CO3, PivOH, Pd(OAc)2, toluene (1.0 m)	36	64
12[c], [d]	3	Ag2CO3, PivOH, Pd(OAc)2, no solvent	34	66

^[a]Yield of product 6a or recovered starting material 5 determined by ¹H NMR spectroscopy with respect to an internal standard (1,3,5‐trimethoxybenzene).

^[b]Average yield of 3 reactions.

^[c]1 equiv. Ag₂CO₃.

^[d]30 mol‐% PivOH.

^[e]Average yield of 2 reactions.

Scheme 5.

Selected scope of aryl iodides compatible with the C–H arylation reaction of N‐Cbz‐piperidinecarboxamide 7.

Given the much increased reactivity of this substrate, the first round of optimization was repeated using bromobenzene (Table 3, Entries 5–8). Aryl bromides are generally considerably less expensive than aryl iodides, but have been mostly ineffective in this mode of C–H arylation. On this substrate, the yields were lower than those reactions employing the aryl iodide, but by using AgOAc as a base in neat conditions, the desired 3‐phenylpiperidine 8a was formed in 99 % conversion, which corresponded to a 95 % isolated yield, comparable to using the aryl iodide. However, despite the increased reactivity of this substrate, attempts to use 2‐iodotoluene as a coupling partner were unsuccessful, demonstrating the difficulties of using ortho‐substituted aryl iodides in directed C–H arylation processes.45

N‐Boc Piperidine Substrate

Given the reduced propensity of N‐Boc‐pyrrolidine amide 5 to undergo C–H arylation compared to the N‐Cbz derivative, we were interested to compare this trend in the piperidine series. Indeed, on subjecting the N‐Boc‐piperidine derivative 9 to round 1 of the optimization, reduced yields were obtained compared with N‐Cbz‐piperidine substrate 7 (Table 4). Only 14 % of 3‐phenyl‐N‐Boc‐piperidine 10a was obtained with Pd(TFA)₂ (Entry 2), but 90 % was obtained with Pd(OAc)₂ under solvent‐free conditions (Entry 4). For the N‐Cbz derivative these reaction conditions both gave quantitative conversion to the desired arylated compound, indicating that the Boc group again caused a reduction in reactivity. With the solvent‐free conditions significantly better than the others investigated, we took these forward to the base screen. The silver carbonate and pivalic acid additive combination gave the best yield of arylated compound 10a (Entry 6, 96 % by ¹H NMR spectroscopy). This combination of Ag₂CO₃ and pivalic acid has not been previously reported under solvent‐free conditions.

Table 4.

Optimization of the C–H arylation of N‐Boc‐piperidinecarboxamide 9.

Entry	Round	Varied conditions	Yield 10a [%][a]	RSM 9 [%][a]
1	1	AgOAc, Pd(OAc)2, toluene	47[b]	50[b]
2	1	AgOAc, Pd(TFA)2, toluene	14	85
3	1	AgOAc, Pd(OAc)2, tert‐amyl‐OH	53	47
4	1	AgOAc, Pd(OAc)2, no solvent	90[b]	10[b]
5[c]	2	Ag2CO3, Pd(OAc)2, no solvent	88	12
6[c], [d]	2	Ag2CO3, PivOH, Pd(OAc)2, no solvent	96	4
7[d]	2	K2CO3, PivOH, Pd(OAc)2, no solvent	29	71
8	2	CsOAc, Pd(OAc)2, no solvent	48	52

^{[d], [a]}Yield of product 10a or recovered starting material 9 determined by ¹H NMR spectroscopy with respect to an internal standard (1,3,5‐trimethoxybenzene).

^[b]Average yield of 2 reactions.

^[c]1 equiv. Ag₂CO₃.

^[d]30 mol‐% PivOH.

These conditions were then used to examine the reaction scope with the same selection of aryl iodides. Good to excellent yields were achieved, ranging from 52 % for the pyridyl example 10d to 89 % for the p‐chlorophenyl example 10c (Scheme 6).

Scheme 6.

Selected scope of aryl iodides compatible with the C–H arylation reaction of N‐Boc‐piperidinecarboxamide 9. [a] 36 h reaction time.

Using 4‐iodoanisole in a one gram scale reaction gave an identical yield after 36 h. With this more challenging N‐Boc‐piperidine substrate, a wider selection of aryl iodides was employed to demonstrate functional group tolerance under these relatively forcing conditions. The reaction was successful with 3‐iodobenzonitrile as well as para‐ester and methyl ketone substituents to give piperidines 10e–10g respectively. In addition, 2‐iodothiophene afforded piperidine 10h in good yield. Again, in all cases, only a single diastereoisomer was observed.43

From 3‐(4‐methoxyphenyl)piperidine derivative 10b the Boc group could be removed with TFA to give the free amine 11 (Scheme 7). Alternatively, heating in concentrated aqueous HCl gave full deprotection, removing the Boc group, the aminoquinoline directing group, and also converted the anisole to the phenol. Subsequent Boc protection of the resulting amino acid afforded pipecolinic acid derivative 12 which constituted an interesting scaffold for further elaboration in multiple directions.

Scheme 7.

Deprotection of 10b to form amine 11 or 3‐arylpipecolinic acid derivative 12.

THP Substrate: cis/trans Selectivity

When tetrahydropyran AQ‐carboxamide 13 was subjected to round 1 of optimization, a mixture of 3‐phenyl‐THP products was observed (14a‐cis and 14a‐trans, Table 5). Unlike in the previous cases, the trans‐configured arylated product was now observed as a minor component under all conditions.46 The solvent‐free conditions showed the most reactivity, but provided low cis‐trans selectivity (Entry 4). The best balance of yield and diastereomeric ratio (dr) was observed using tert‐amyl‐OH and Pd(OAc)₂ (Entry 3), therefore these conditions were progressed to the next round. On varying the bases, both Ag₂CO₃ (Entry 5) and Ag₂CO₃/PivOH (Entry 6) gave similar results, with 66 % cis‐14a and approximately 11 % trans‐14a under both conditions. The set of conditions without PivOH were taken forward to the concentration screen for reasons of experimental simplicity. In this case, the concentration of the reaction was found to have little effect on yield and dr (Entries 9–12).

Table 5.

Optimization of the C–H arylation of THP carboxamide 13.

Entry	Round	Varied conditions	cis [%][a]	trans [%][a]
1	1	AgOAc, Pd(OAc)2, toluene (0.3 m)	38[b]	13[b]
2	1	AgOAc, Pd(TFA)2, toluene (0.3 m)	22	3
3	1	AgOAc, Pd(OAc)2, tert‐amyl‐OH (0.3 m)	47[b]	11[b]
4	1	AgOAc, Pd(OAc)2, no solvent	49	23
5[c]	2	Ag2CO3, Pd(OAc)2, tert‐amyl‐OH (0.3 m)	66	13
6[c], [d]	2	Ag2CO3, PivOH, Pd(OAc)2, tert‐amyl‐OH (0.3 m)	66	11
7[d]	2	K2CO3, PivOH, Pd(OAc)2, tert‐amyl‐OH (0.3 m)	24	10
8	2	CsOAc, Pd(OAc)2, tert‐amyl‐OH (0.3 m)	32	6
9[c], [d]	3	Ag2CO3, PivOH, Pd(OAc)2, tert‐amyl‐OH (0.2 m)	65	13
10[c], [d]	3	Ag2CO3, PivOH, Pd(OAc)2, tert‐amyl‐OH (0.5 m)	62	17
11[c], [d]	3	Ag2CO3, PivOH, Pd(OAc)2, tert‐amyl‐OH (1.0 m)	62	11
12[c], [d]	3	Ag2CO3, PivOH, Pd(OAc)2, no solvent	61	16

^[a]Yield determined by ¹H NMR spectroscopy with respect to an internal standard (1,3,5‐trimethoxybenzene). In all cases, the remainder of the mass balance corresponded to unreacted starting material 13.

^[b]Average yield of 2 reactions.

^[c]1 equiv. Ag₂CO₃.

^[d]30 mol‐% PivOH.

This substrate provided an interesting opportunity to compare reactivity and selectivity with different directing groups. Therefore, Shi's PIP‐amine directing group and the 2‐(methylthio)aniline auxiliary were examined and taken through the optimization procedure. However, these gave reduced reactivity and reduced selectivity vs. the aminoquinoline auxiliary (Figure 3; see the Supporting Information for full details). For the PIP‐amine tetrahydropyran carboxamide, round 1 of optimization gave the desired arylation with just 14 % cis and 4 % trans products 15a as the best conditions [tert‐amyl‐OH, Pd(OAc)₂]. These conditions were carried forward to the second round of optimization, where the Ag₂CO₃/PivOH additive combination was found to be the best base/additive mixture, giving 48 % cis and 11 % trans‐configured arylated THP 15a. The concentration of the reaction was found to have little effect on yield or dr. These optimised conditions gave a 34 % isolated yield of 15a as the cis‐isomer. Interestingly, the optimized conditions were very similar for 14a and 15a. The 2‐(methylthio)aniline directing group was also examined, but less than 5 % yield of the corresponding product 16a was observed in all cases. This unbiased comparison, indicated the AQ amide 13 to be most successful in this case, and therefore this derivative was used to exemplify the C–H arylation on the THP ring (Scheme 8).

Figure 3.

Comparison of optimal yields and product ratios of different directing groups on THP carboxamides, following the standard optimization procedure, yields and diastereomeric ratio (dr) quoted as observed in the crude reaction mixture against an internal standard after 18 h reaction time.

Scheme 8.

Selected scope of aryl iodides compatible with the C–H arylation reaction of THP carboxamide 11, yield and dr of products on isolation after a 24 h reaction time.

Under the conditions optimized for THP AQ‐amide 13 the reaction scope was investigated, with an increased reaction time of 24 h. Good to excellent yields were achieved in all cases. Diastereomeric ratios of between 83:17 and 80:20 were obtained on isolation of phenyl derivatives 14a–14c, with the pyridyl example 14d giving a 72:28 dr.

Stereochemical Outcomes

To provide insight into the origin of the diastereomeric mixture formed from THP 13, the purified product 14a (as an 81:19 cis/trans mixture of diastereoisomers by ¹H NMR) was resubjected to the reaction conditions for 18 h. Identical dr (81:19 cis/trans) was observed on workup. In addition, the reaction of THP 13 with PhI, under the optimized conditions, was stopped after a series of time points, and at each time point the same dr was observed.47 These results indicate that epimerization of the product does not occur under the reaction conditions. We propose that this is a result of both cis and trans‐palladacycles being formed, leading to the two diastereoisomers. These would correspond to three feasible intermediates leading to the syn and anti‐substituted products (Scheme 9).

Scheme 9.

Viable conformations of the palladacyclic intermediate formed from THP carboxamide 13.

This is consistent with the outcome observed by Yu on C(sp³)–H arylation of a 4‐amido tetrahydropyran, which afforded a 6:1 cis/trans mixture, albeit with a different substitution pattern on the heterocycle (Scheme 1, b). Also, Daugulis reported the di‐arylation of a cyclohexane AQ‐carboxamide, which afforded a 69 % all‐cis to 13 % cis‐trans mixture of isomers, using 4‐iodoanisole and AgOAc as base under solvent‐free conditions.10b

By contrast, for the THF and pyrrolidine substrates, the trans‐5,5‐palladacycle would likely be significantly higher in energy, hence the observation that only cis diastereoisomers are formed in these cases. Interestingly, both N‐carbamate piperidine examples (7 and 9) gave only the cis‐diastereoisomers, which is likely due to the strong preference for the ring to adopt conformations with the directing group in an axial position, to minimize A(1,3) strain with the N‐carbamate group.48

Cyclopentane and Propionamide Substrates: Selectivity in Mono/Di‐Arylation

To further study the applicability of this optimization process, we examined two non‐heterocyclic substrates to provide a comparison with previously reported conditions, particularly with substrates that can undergo multiple arylation reactions to probe for selectivity.

Cyclopentanecarboxamide 17 can undergo mono or di‐arylation, to provide trifunctionalized cyclopentanes. The best yields of mono β‐C–H arylation of cyclopentane carboxylic acid derivatives have been achieved by Daugulis (52 % yield)10b and Yu (71 % yield as a 7:1 mono/di mixture).17a,49 Shi demonstrated di‐arylation of cyclopentanecarboxamide 17, installing two phenyl groups in 51 % yield, as the all‐cis diastereoisomer, using diarylhyperiodonium salts as coupling partners.17b

Cyclopentanecarboxamide 17 was subjected to the round 1 of optimization. All reaction conditions gave over 90 % conversion to mixtures of mono and di‐arylated products,50 displaying considerably increased reactivity compared to the five‐membered heterocyclic derivatives. The highest mono‐selectivity was obtained using toluene with Pd(OAc)₂ as catalyst (64 % yield of mono‐arylated cyclopentane 18). These conditions were taken on to the base screen, where CsOAc gave an improvement to 71 % yield. The concentration of the reaction had little effect on the yield, but with a 1.0 m concentration the yield of mono‐arylated compound 18 increased to 72 % (corresponding to 63 % isolated yield), with a 24 % yield of di‐arylated 19 also observed (Scheme 10).

Scheme 10.

Isolated yields for the mono and di‐selective β‐C–H arylations of cyclopentanecarboxamide 17.

During the first optimization round, di‐arylation of cyclopentanecarboxamide 17 was achieved in 71 % yield under the solvent‐free conditions (25 % mono‐arylation). Varying the bases did not afford an improved yield. The di‐arylated product 19 was isolated in a 75 % yield under these conditions using AgOAc as base with a 24 h reaction time (Scheme 10). This short optimization process enabled selective mono‐arylation of the cyclopentane derivative in 63 % yield, or di‐arylation in 75 % yield, which provides similar or improved outcomes in comparison to the literature results.

A similar process was performed with propionamide 20 where sequential C–H arylations may occur on the same carbon atom, the second at a more acidic benzylic position. This short optimization process provided conditions for selective mono or bis‐arylation, using Pd(OAc)₂ and an excess of aryl iodide in both cases.50 Using Ag₂CO₃ in tert‐amyl‐OH gave mono‐selective arylation product 21 in 58 % yield (Scheme 11). On the other hand, using a K₂CO₃/PivOH combination and tert‐amyl‐OH as solvent provided quantitative conversion to bis‐arylated product 22 (91 % isolated yield), giving a similar set of conditions to those reported by Zeng. These results compare favorably with those previously reported for this substrate.51

Scheme 11.

Isolated yields for the mono and bis‐selective β‐C–H arylations of propionamide 20.

Conclusions

In conclusion, C–H functionalization can rapidly afford 2,3‐substituted heterocycles with stereocontrol. We have developed successful conditions for C–H arylation at the 3‐position of THF and pyrrolidine derivatives, and the first examples on piperidine and THP substrates, using AQ carboxamide directing groups at C‐2. High yields were achieved with each heterocyclic substrate across a representative collection of aryl iodides. Complete cis‐selectivity was achieved for the THFs, pyrrolidines, and piperidines. The THP substrate was also cis‐selective, but the trans‐configured product was also formed as a minor component. Removal of the aminoquinoline group was demonstrated on the THF substrate, to selectively access either trans or cis‐configured THF carboxylic acids.

The same concise optimization process was adopted across all substrates, using a limited number of variables designed to cover appropriate reaction space. This process afforded successful conditions for each heterocyclic substrate. We have also demonstrated that this short optimization procedure could afford conditions that were selective for either mono‐arylation or di‐arylation of cyclopentane and propionamide substrates. We consider this may provide a useful process for developing C–H arylation reactions.

This programmed approach allowed facile comparison of the reactivity of the different substrates. The six‐membered rings (piperidine and THP) were considerably more reactive than the corresponding five‐membered ring derivatives (pyrrolidine and THF). Interestingly, the N‐Boc‐protected N‐heterocycles were much less reactive than the analogous N‐Cbz derivatives for both 5‐ and 6‐membered rings. The reasons for the differences in substrate reactivity are not yet well‐explained by current models and require further investigation, which will be reported in due course.

Experimental Section

Supporting Information (see footnote on the first page of this article): All experimental details can be found in the supporting information. This includes experimental procedures, characterization data, copies of ¹H and ¹³C NMR spectra and further details of reaction optimization.

Supporting information

As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re‐organized for online delivery, but are not copy‐edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.

miscellaneous_information