C(sp³)–H functionalization of N-protected dialkylpyrrole derivatives with azodicarboxylates

Abstract

A metal-free, catalytic route to the activation of C(sp³)–H bonds in N-protected dialkylpyrroles to diazodicarboxylates is reported using HB(C₆F₅)₂ as the optimized catalyst. These reactions tolerate aryl and alkyl substituents on the pyrrole N-atom as well as variation in the azodicarboxylates giving rise to 41 examples. These reactions were also performed on a gram scale and conversion to the corresponding amino-esters is demonstrated. A DFT computation study reveals that the Lewis acid adduct of azodicarboxylates generates a Lewis acidic N-atom capable of hydride abstraction from dimethylpyrrole, ultimately effecting C(sp³)–H functionalization.

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Pyrrole is a privileged aromatic heterocycle that is found in chlorophyll, heme, vitamin B₁₂, and bile acids. Naturally occurring and synthetic molecules incorporating pyrrole units have been shown to exhibit a broad range of biological and pharmacological activities.¹ For example, over 20 synthetic pyrrole derivatives are commercially marketed drugs as such species exhibit anti-psychotic, anti-anxiolytic, anti-cancer, anti-bacterial, anti-fungal, anti-malarial, anti-inflammatory, and anti-hyperlipidemic behavior (Fig. 1a).^1a,1b

Fig. 1 (a) Representative pyrrole-derived drugs. (b) Metal free C(sp²)–H functionalization of N-protected pyrroles. (c) This work – C(sp³)–H functionalization of N-protected pyrroles with azodicarboxylates.

Synthetic efforts to derivatize pyrroles have led to the development of a wide variety of transition metal catalyzed processes.² These protocols allow the incorporation of a wide range of functional groups, typically leading to substitution at N or at the C(sp²) atoms at the C-2 or C-3 positions. These methods have been reviewed.^2b–e Alternatively main group species are known to mediate the derivatization of N-protected pyrroles.³ For example, Lewis acid mediated Friedel–Crafts methods readily provide substitution again at sp² carbons, where the steric demands of the N-protecting group can be used to direct substitution to either the C-2 or C-3 positions.³

In 2010, we showed that N-alkylpyrroles participate in frustrated Lewis pair (FLP) alkyne-addition reactions, leading to C–C bond formation at the C(sp²) atoms at the C-3 position.⁴ Several years later, in a seminal finding, Fontaine and coworkers⁵ exploited intramolecular N/B FLPs to effect borylation of N-methylpyrrole, thiophene and furan derivatives, again at the C-2 or C-3 positions depending on the other substituents (Fig. 1b). Subsequently, Shi and coworkers used BBr₃ to direct C(sp²)–H borylation of indoles at the C-7 or C-4 positions and other (hetero)arenes.⁶ More recently, Tan et al. elegantly used chiral phosphoric acid catalysts to functionalize N-protected-pyrroles at the C-3 position, affording axially chiral arylpyrroles (Fig. 1b).⁷

In contemplating alternative strategies for the functionalization of pyrroles, we considered activation of the C(sp³)–H bonds of substituents at the C-2 position. While the majority of the activation strategies for unactivated C(sp³)–H bonds have been achieved using transition-metal catalysts,⁸ we noted that boranes have been used as catalysts to promote C–C and C–heteroatom bond formation.⁹ For example, Wang and coworkers achieved C(sp³)–H alkylation of tertiary amines with electron-deficient olefins using B(C₆F₅)₃ as the catalyst.¹⁰ In another recent breakthrough, Lin et al.¹¹ used frustrated radical pairs (FRPs) to functionalize the C(sp³)–H bonds of various organic substrates, affording aminoxylated products. Nonetheless, to our knowledge, C(sp³)–H bond activation of pyrrole derivatives is not known. Herein, we develop a protocol for the C(sp³)–H bond functionalization of the methyl groups of N-protected methylpyrroles with azodicarboxylates using Piers’ borane HB(C₆F₅)₂ as the catalyst (Fig. 1c).

Our investigation began with the reaction of N-phenylpyrrole 1a and commercially available dibenzyl azodicarboxylate 2a in toluene. In the presence of 10 mol% Al(C₆F₅)₃, this gave mixtures of C(sp²)–H and C(sp³)–H activation products, with poor regioselectivity at 60 °C (Table 1, entry 1). In the presence of B(C₆F₅)₃ and HB(C₆F₅)₂, the selectivity for the C(sp³)–H functionalization product 3a improved (Table 1, entries 2 and 3). Using HB(C₆F₅)₂ as the catalyst, product 3a was obtained in 47% yield at 60 °C. Altering the reactant ratio of 1a : 2a to 1.5 : 1 afforded product 3a in 61% yield with a 13% yield of the C(sp²)–H functionalization product 4a (Table 1, entries 3–6), while further variations of the solvent, temperature and catalyst loading did not increase the yield (Table 1, entries 7–12).

Table 1 Optimized reaction conditions for C–H functionalization

Entry^a	Cat.	1a : 2a	Solvent	T (°C)	Yield (%) 3a^b	Yield (%) 4a^b
a Unless otherwise noted, all reactions were performed using 10 mol% catalyst, 1a and 2a in solvent (2.0 mL) under argon for 12 h. b Isolated yield after chromatography. c 5 mol% catalyst.
1	Al(C6F5)3	1.0 : 1.5	Toluene	60	21	22
2	B(C6F5)3	1.0 : 1.5	Toluene	60	43	6
3	HB(C6F5)2	1.0 : 1.5	Toluene	60	47	6
4	HB(C6F5)2	1.0 : 1.0	Toluene	60	47	12
5	HB(C6F5)2	1.5 : 1.0	Toluene	60	61	13
6	HB(C6F5)2	2.0 : 1.0	Toluene	60	55	13
7	HB(C6F5)2	1.5 : 1.0	Benzene	60	57	14
8	HB(C6F5)2	1.5 : 1.0	p-Xylene	60	52	10
9	HB(C6F5)2	1.5 : 1.0	PhF	60	39	19
10	HB(C6F5)2	1.5 : 1.0	Toluene	45	47	11
11	HB(C6F5)2	1.5 : 1.0	Toluene	80	52	12
12^c	HB(C6F5)2	1.5 : 1.0	Toluene	60	23	26

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Using the optimized reaction conditions, the substrate scope for C(sp³)–H functionalization of N-protected dialkylpyrroles with azodicarboxylates was examined. Firstly, the reactions of a series of N-arylpyrroles with 2a in toluene were investigated. In the presence of 10 mol% HB(C₆F₅)₂, para-substituted N-arylpyrroles with electron-donating or electron-withdrawing substituents on the phenyl ring (Fig. 2, R = C₆H₅1a, 4-FC₆H₄1b, 4-ClC₆H₄1c, 4-BrC₆H₄1d, 4-IC₆H₄1e, 4-CF₃C₆H₄1f, 4-MeOC₆H₄1g, 4-MeC₆H₄1h) reacted smoothly with 2a to provide the corresponding products 3a–3h in 49–68% yields. Similarly, meta-substituted N-arylpyrroles bearing differing functional groups (Fig. 2, R = 3-FC₆H₄1i, 3-MeOC₆H₄1j, 3-MeC₆H₄1k) were tolerated, affording 3i–3k in 48–65% yields. ortho-Substituted N-arylpyrroles (Fig. 2, R = 2-FC₆H₄1l, 2-ClC₆H₄1m, 2-BrC₆H₄1n, 2-IC₆H₄1o, 2-CF₃C₆H₄1p, 2-MeC₆H₄1q, 2-iPrC₆H₄1r, 2-tBuC₆H₄1s) were also suitable substrates, affording the C(sp³)–H functionalization products 3l–3s in 30–64% yields. The identity of 3s was confirmed by X-ray crystallography (see the SI).¹²

Fig. 2 Scope of N-protected dialkylpyrroles. Reaction conditions: a solution of 1 (0.3 mmol), dibenzyl azodicarboxylate 2a (0.2 mmol) and HB(C₆F₅)₂ (10 mol%) in toluene (2.0 mL) was stirred at 60 °C for 1–2 h in argon.

In addition, N-arylpyrroles with 2 or 3 substituents on the phenyl ring (Fig. 2, R = 2-I,3-ClC₆H₃1t, 2-I,4-ClC₆H₃1u, 2-I,5-ClC₆H₃1v, 2-I,5-FC₆H₃1w, 2-I,5-BrC₆H₃1x, 2,5-(CF₃)₂C₆H₃1y, 3,5-(CF₃)₂C₆H₃1z, 3,5-Cl₂C₆H₃1aa, 3,5-Br₂C₆H₃1ab, 3,4,5-Cl₃C₆H₂1ac) were also successfully converted to the C(sp³)–H functionalized products 3t–3ac in 56–82% yields. The reactions of N-benzylpyrroles (Fig. 2, R = CH₂Ph 1ad, CH₂C₆H₄Me 1ae, CH₂C₆H₄Cl 1af) provided products 3ad–3af in 51–60% yields. The nature of 3ad was also confirmed by X-ray analysis (see the SI).¹² Moreover, alkylpyrroles (Fig. 2, R = Me 1ag, C₃H₅1ah, C₆H₁₁1ai) also reacted with 2a, giving the products 3ag–3ai, albeit in somewhat reduced yields of 27–35%. Furthermore, changing the pyrrole substituents to Et groups, as in 1aj, afforded 3aj in 50% yield, while the reaction of the dissymmetric pyrrole 2-Me-5-Ph-N-(C₆H₂Cl₃)-pyrrole 1ak with 2a gave the C(sp²)–H amination product 4ak in 55% yield (see the SI).

Efforts to identify by-products were undertaken. Even on doubling the reaction scale for all reactions, most by-products were not unambiguously identifiable although the C(sp²)–H amination products 4ah and 4ai were observed in 10 and 11% yields, respectively, while the double C(sp²)–H amination product 4ag′ was observed in 9% yield (see the SI).

The reaction also tolerated variations in the azodicarboxylates. Thus, the reaction of the commercially available (RO₂CN)₂ (Fig. 3, R = CH₂C₆H₄Cl 2b, Et 2c, iPr 2d) with 1ac proceeded smoothly to give products 3ak–3am in 43–83% yields. In contrast, the use of 2e (R = tBu) gave only a 19% yield of 3an (Fig. 3). We note that this diazo-species is known to react with boranes to liberate CO₂ and isobutylene.¹³ Notably, 4-phenyl-1,2,4-triazoline-3,5-dione 2f also reacted smoothly with 1ac, affording the desired product 3ao in 40% yield.

Fig. 3 Scope of azodicarboxylates. Reaction conditions: a solution of 1ac (0.3 mmol), dibenzyl azodicarboxylate 2 (0.2 mmol) and HB(C₆F₅)₂ (10 mol%) in toluene (2.0 mL) was stirred at 60 °C for 1–2 h in argon.

The scalability of this protocol to gram-scale reactions was demonstrated. Thus, using over 2 grams of 1ac with 2a in the presence of 10 mol% HB(C₆F₅)₂ afforded 2.35 g of 3ac in an overall yield of 82% (Fig. 4). In addition, 3ac was reacted with bromoacetate and Cs₂CO₃ using the method of Magnus et al.,¹⁴ affording C₄H₂Me(CH₂NH(CO₂CH₂Ph)N(C₆H₂Cl₃) 5 in 70% yield (Fig. 4). This carbamate ester was characterized by X-ray crystallography (see the SI).¹²

Fig. 4 Scale-up synthesis and synthetic transformation.

The mechanism of these reactions was established via a computational study using density functional theory (DFT) computations at the PW6B95-D3/def2-QZVP + COSMO-RS//TPSS-D3/def2-TZVP + COSMO level of theory.¹⁵ As B(C₆F₅)₃ and HB(C₆H₅)₂ showed similar reactivity, B(C₆F₅)₃ was used in the calculations to avoid the complexity associated with the dimerization equilibrium of Piers’ borane in solution. The initial interaction of B(C₆F₅)₃ with the carbonyl fragment of azodicarboxylate 2c enhances the Lewis acidity of the remote N-atom, allowing it to abstract hydride from methylpyrrole 1a over a free energy barrier of 22.5 kcal mol⁻¹ (TS1). This generates the transient ion pair 1a⁺ and 2cBH⁻ (Fig. 5), which reacts exothermically to form a new C–N bond. The release of borane is slightly endergonic, allowing the catalytic reaction to continue, consistent with both experimental conditions and the improved catalysis for (C₆F₅)₂BH, where the slightly reduced Lewis acidity presumably accelerates the Lewis acid release. Regarding the role of the N-Lewis acid, we note that such species have been pioneered by Gandelman,¹⁶ although we¹⁷ and others¹⁸ have described related diazo-derived Lewis acid systems.

Fig. 5 DFT computed mechanism (in kcal mol⁻¹, at 298 K and 1 M concentration) for C(sp³)–H functionalization of N-Ph-dimethylpyrrole to azodicarboxylates.

In conclusion, we have reported a metal-free, catalytic and scalable protocol for the functionalization of C(sp³)–H bonds in N-protected dimethylpyrroles with azodicarboxylates. The resulting diazo-pyrrole derivatives can be converted to the corresponding amino-esters. A mechanistic study showed that the Lewis acid adduct of the azodicarboxylate generates a Lewis acidic N-atom capable of hydride abstraction from the C(sp³) carbon on the pyrrole. We are continuing to study metal-free avenues for C–H functionalization and Lewis acid applications in organic synthesis.

The authors thank the Ningbo Natural Science Foundation (No. 2023J379) and the Ningbo Top Talent Project (No. 215-432094250) for financial support. Z.-W. Q. and S. G. are grateful to the Deutsche Forschungsgemeinschaft (project 490737079). We also acknowledge the Analysis Center of Institute of Drug Discovery Technology for collecting spectral data.

Conflicts of interest

There are no conflicts to declare.

Data availability

The data that support this study are available in the SI of this article.

Experimental and spectral data are available as SI See DOI: https://doi.org/10.1039/d5cc03254g

3s: CCDC 2434837; 3ad: CCDC 2434838 and 5: CCDC 2434839 contain the supplementary crystallographic data for this paper.^19–21

Notes and references

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Footnote

† J. Guo and M. Yan contributed equally to this work.

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