Silver-catalysed [3 + 2] annulation reaction of aryldiazonium salts with allenes enabled by boronate direction

Abstract

Allenes are a unique type of powerful synthon used for the construction of various carbocycles and heterocycles, but their annulation reactions with N–N triple bond electrophiles have not been disclosed. Here we report an efficient silver-catalysed boronate-directed [3 + 2] annulation reaction of aryl diazonium salts with allenylboronates. This transformation offers unprecedented access to a wide scope of N¹-aryl-1H-pyrazoles with high regioselectivities under mild conditions. Preliminary experimental and computational studies support a transmetalation/stepwise cycloaddition/pyrazolyl silver hydrolysis pathway involving propargyl silver species as the key intermediate in enabling reactivity and controlling regioselectivity.

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Introduction

Allenes are a powerful class of reactive synthons with a unique cumulative double bond structure.¹ Allenes, especially allenoates, have been widely explored to react with carbon–carbon double bonds, carbon–nitrogen double bonds, carbon–oxygen double bonds, and carbon–carbon triple bonds to synthesize cyclopentenes, dihydropyrroles, dihydrofurans, four-membered carbocycles, and others.² However, the reaction of allenes with nitrogen–nitrogen unsaturated bonds is still in its infancy.³ Notably, allenylboronates could exhibit umpolung nucleophilic reactivity compared with their electrophilic parent counterparts, and have thus emerged as a novel type of useful reagent over the past decade.⁴ For example, the propargylation and allenylation reactions of aldehydes, ketones, imines, and activated alkenes have been extensively studied with allenylboronates for the construction of various homopropargylic and allenylic alcohols, amines, and so on (Scheme 1a).⁵ In sharp contrast, the annulation reaction of allenylboronates remains largely underexploited. To the best of our knowledge, the only example of using allenylboronates as a C₃-synthon to generate carbocycles was reported by Jarvo under palladium catalysis conditions in a cascade 1,4-nucleophilic addition/carbopalladation sequence with conjugate acceptors (Scheme 1b).⁶ Therefore, the method of engaging allenylboronates as all-carbon formal 1,3-dipoles with dipolarophiles to synthesize heterocycles is still under-developed.

Scheme 1 Reaction development of allenylboronates.

N ¹-Aryl-1H-pyrazoles have found an increasing number of applications in pharmaceuticals, agrochemicals, and related biologically active molecules.⁷ Generally, the construction of N¹-aryl-1H-pyrazoles is achieved by Knorr-type condensation/cyclization transformations of various arylhydrazines with the corresponding 1,3-dicarbonyl compounds.⁸ However, these processes inherently deliver regioisomeric mixtures with respect to substituents incorporated at the 3- and 5-positions of the pyrazole ring. In addition, arylhydrazine substrates are often produced by troublesome reduction of aryldiazonium salts.⁹ Therefore, the development of new protocols for the regioselective synthesis of N-aryl pyrazoles directly from readily accessible and abundant aryldiazonium salts is still highly desirable.¹⁰ We have recently disclosed silver-mediated cycloaddition reactions of trifluorodiazoethane with nitroolefins or alkynes for the synthesis of 4- or 5-substituted 3-trifluoromethylpyrazoles.¹¹ In the present study, we envisioned that the combination of allenylboronates with a silver catalyst could be capable of generating all-carbon formal 1,3-dipoles, thus holding promise for the subsequent annulation with aryldiazonium salts.¹² The realization of this transformation would further expand the utility of both aryldiazonium salts and allenes in heterocycle synthesis.¹³ Herein, we documented that N¹-aryl-1H-pyrazoles were constructed by the direct exploitation of a variety of aryldiazonium salts in the silver-catalysed [3 + 2] annulation reaction of allenylboronates (Scheme 1c). In this context, the boronate moiety could function as a traceless activating and directing group to facilitate regioselective allene incorporation, as supported by combined experimental and computational mechanistic studies.

Results and discussion

Reaction optimization

Our study commenced by employing allenylboronic acid pinacol ester 1a and aryl diazonium salt 2a as the model substrates. In the presence of 20 mol% of silver oxide and 1 equivalent of potassium hydrogen carbonate, the annulation process could occur smoothly in THF at 40 °C in only 20 minutes, giving the corresponding N-aryl pyrazole 3a in 86% yield (Table 1, entry 1). Other silver salts could also catalyse this transformation, albeit with variable reaction efficiencies (entries 2–6). Notably, gold, copper, palladium, and zinc all proved to be invalid catalysts for promoting the formation of the desired pyrazole products (entries 7–10). Further screening of the base, solvent, amount of silver catalyst, and reaction temperature led to no obvious enhancement of the reaction outcome (entries 11–20). Allenylboronate 1a could also be added in one portion at the expense of a compromised reaction yield (entry 21). Moreover, a one-pot protocol using 4-bromoaniline directly to undergo the diazotization/[3 + 2] annulation process was also attempted, but the desired pyrazole product 3a was not obtained.

Table 1 Optimized reaction conditions and variations^a

Entry	Variation from the standard conditions	Yield of 3a ^b
a General reaction procedure: to a mixture of phenyl diazonium salt 2a (81 mg, 0.3 mmol), a catalyst (0.04 mmol) and a base (0.2 mmol) in 1 mL of a solvent was added allenylboronate 1a (33 mg, 0.2 mmol) in 1 mL of a solvent slowly in 3 minutes, and the mixture reacted at 40 °C for 20 minutes unless otherwise noted. b Yield of the isolated pyrazole 3a. Safety note: handling of aryl diazonium salts should be carried out in a well-ventilated fume cupboard. “nd” means “not detected”.
1	None	86
2	Ag2CO3 instead of Ag2O	56
3	AgOAc instead of Ag2O	64
4	AgF instead of Ag2O	41
5	AgPF6 instead of Ag2O	14
6	AgBF4 instead of Ag2O	58
7	PPh3AuOTf instead of Ag2O	Trace
8	Cu(OTf)2 instead of Ag2O	nd
9	PdCl2(MeCN)2 instead of Ag2O	Trace
10	Zn(OAc)2 instead of Ag2O	nd
11	K2CO3 instead of KHCO3	55
12	KOAc instead of KHCO3	68
13	NaHCO3 instead of KHCO3	63
14	DIPEA instead of KHCO3	Trace
15	DBU instead of KHCO3	Trace
16	1,4-Dioxane instead of THF	27
17	DMF instead of THF	58
18	10 mol% of Ag2O was employed	69
19	50 mol% of Ag2O was employed	78
20	25 °C instead of 40 °C	43
21	1a was added in one portion	50

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Substrate scope

The substrate scope of this silver-catalysed annulation reaction is quite general in terms of aryldiazonium salts 2 (Scheme 2). A broad range of substitution groups, such as alkyl, alkoxyl, and halogens, located at different positions on the phenyl ring, were all well accommodated and afforded pyrazoles 3c–3m in moderate to good yields. The presence of electron-withdrawing substituents in aryl diazonium salts was found to be beneficial for this reaction, as exemplified by trifluoromethyl (–CF₃), pentafluorosulfanyl (–SF₅), nitro (–NO₂), cyano (–CN), and ester (–CO₂Me) substituents (products 3n–3t with up to 95% isolated yield). Among them, the scalability of this method was validated via the 10 mmol scale reactions of compounds 3j and 3r (see the ESI†). The presence of a labile boronate moiety in the aryl diazonium salt proved to be no problem, and the B(pin)-containing pyrazole 3v was obtained, which leaves a good reactive site for further derivatizations. Furthermore, this reaction could also be extended to aryl diazonium salts possessing naphthyl and heteroaryl groups (products 3w and 3x). More importantly, aryl diazonium salts derived from several biologically relevant molecules are also well compatible in this annulation reaction, offering the corresponding pyrazole-decorated phenylalanine (3y), aminoglutethimide (3z), pomalidomide (3a′), and the lapatinib fragment (3b′).

Scheme 2 Substrate scope of aryldiazonium salts in the annulation reaction with allenylboronate 1a.

Subsequently, the scope of allenylboronates 1 was probed with aryl diazonium salt 2a under the optimal reaction conditions (Scheme 3).¹⁴ α,α-Disubstituted allenylboronates participated in the annulation reaction smoothly and gave the 3-alkyl-N¹-aryl-pyrazoles 3ba and 3ca in practical yields with exclusive regioselectivity. More significantly, a series of 3,5-disubstituted-N¹-aryl-pyrazoles 3da–3ja were readily obtained from the corresponding trisubstituted allenylboronates and diazonium salt 2a under the standard conditions. Among them, the substituents at the γ position of allenylboronates (R²) could be changed from alkyl groups to aromatic moieties possessing different functionalities (alkyl, trifluoromethyl, and chlorine). It is worth noting that a single regioisomer was characterized in reactions performed with these substrates, whatever the nature of the substituents of the allenylboronate. The structure of compound 3ha was ascertained by X-ray crystallographic analysis.

Scheme 3 Substrate scope of allenylboronates in the annulation reaction with the aryldiazonium salt.

Synthetic utility

Furthermore, direct electrophilic chlorination of the obtained pyrazoles 3a and 3ba was readily attainable by using trichloroisocyanuric acid (TCICA) as the chlorinating reagent, thus giving 4-Cl-N¹-aryl-pyrazoles 4a and 4b in 95% yields (Scheme 4a). We also performed bromination and iodination of the obtained pyrazoles with N-bromo-succinimide (NBS) and N-iodo-succinimide (NIS) and obtained the corresponding 4-Br-N¹-aryl-pyrazoles 4c–4e and 4-I-N¹-aryl-pyrazoles 4f and 4g in good to high yields (Scheme 4a). Electrophilic fluorination of pyrazole 3b was realized by using Selectfluor in nitromethane to give 4-F-N¹-phenyl-pyrazole 5a in a moderate yield (Scheme 4b).¹⁵ In a similar vein, the introduction of a formyl group and a nitro group at the 4-position of the pyrazole ring was readily possible with urotropin and nitric acid, respectively (products 5b and 5c in Scheme 4b). Alternatively, treating pyrazole 3b with butyl lithium and 1-bromo-3-methylbut-2-ene allowed the formation of the alkylation product 5d in 68% yield with exclusive 5-position regioselectivity. Further derivatization on the aryl ring of the annulation products was also viable, as shown by the C–H alkylation of 3a and 3j with a diazo reagent under rhodium catalysis conditions, leading to the formation of malonate derivatives 6a and 6b in good yields with excellent regioselectivity (Scheme 4c).¹⁶ Importantly, pyrazole 3c′ was obtained in 84% yield under the standard reaction conditions (Scheme 4d). Zinc-promoted reduction of the nitro group in 3c′ gave the corresponding aryl primary amine 7, which could serve as a key intermediate for the synthesis of the phosphodiesterase 10A (PDE10A) inhibitor.¹⁷ This newly developed transformation was also smoothly applied in the synthesis of the gout drug Niraxostat intermediate 8 in a good overall yield from the readily available diazonium salt and allenylboronate 1a through a sequence of annulation and bromination with excellent regioselectivity in each step (Scheme 4e).¹⁸

Scheme 4 Synthetic transformation and applications.

Mechanistic studies

To shed some light on the reaction mechanism, a series of control experiments were performed (Scheme 5). First, the use of simple allene 9a or its propargyl counterpart 9b under otherwise model reaction conditions with phenyl diazonium salt 2a did not furnish the desired pyrazole, implying the crucial role of the boronate moiety (Scheme 5a). Notably, propargyl boronates 10a and 10b proved to be suitable partners in the annulation reaction with 2a under the standard conditions and resulted in the formation of 3-substituted N¹-aryl-pyrazoles 3ka and 3la with identical regioselectivity (Scheme 5b, compound 3la has been confirmed by X-ray analysis). These results support the generation of a common intermediate from either allenylic or propargylic starting materials that are involved in the mechanistic pathway. Furthermore, we conducted the model reaction in a solvent mixture consisting of deuterated water and tetrahydrofuran (Scheme 5c). In this scenario, the deuterium atom was exclusively incorporated at the 4-position of the pyrazole ring (D-3a), which is clearly indicative of a protonation event occurring on an organosilver intermediate at this 4-position.

Scheme 5 Control experiments for mechanistic studies.

Subsequently, the reaction mechanism was further explored via DFT calculations (Scheme 6).¹⁹ The computational results show that allenylboronate could undergo transmetalation smoothly with silver oxide via a six-membered cyclic transition state TS2 to give the propargyl silver intermediate Int3 with a barrier of 9.7 kcal mol⁻¹. The reaction of the propargyl silver species with aryl diazonium was predicted to be a stepwise process consisting of nucleophilic addition to produce η²-coordinated silver complex Int4 and intramolecular cyclization to form Int5, with an overall barrier of only 6.7 kcal mol⁻¹. The direct protonolysis of Int5viaTS5′ was found to be unfavorable. Base-promoted deprotonation was proved to be a more operative path, leading to a relatively stable pyrazolyl silver intermediate Int6, which is consistent with the experimental observation that 4-deuterated product D-3a was obtained (Scheme 5c). The final protonolysis of this organosilver species would generate the desired pyrazole product 3a. Based on the DFT-computed free energy profile, this reaction is an exergonic process (106.2 kcal mol⁻¹) and the protonolysis of pyrazolyl silver is found to be the rate-determining step (26.1 kcal mol⁻¹). Importantly, we have probed into the regioselectivity-determining step (TS3) for α-methyl-substituted allenylboronate 1b, which exclusively led to N¹-aryl-3-methyl pyrazole 3ba. As illustrated in Scheme 6b, TS3-1 is more favorable than TS3-1′ by 4.5 kcal mol⁻¹, owing to the increased steric hindrance in the latter case, which is in line with the excellent regioselectivity observed for 3ba. On the basis of these results and previous studies,²⁰ a plausible mechanism is outlined in Scheme 6c. Transmetalation of allenylboronate 1 with a silver catalyst provides a propargylic silver species Int-3. Subsequent [3 + 2] cycloaddition of Int-3 with aryl diazonium salt 2 proceeds in a step-wise manner to form cyclic intermediate Int-5, which could undergo deprotonation to generate a more stable pyrazole-4-silver complex Int-6. Finally, protonolysis releases the silver catalyst and provides the pyrazole product 3.

Scheme 6 Computational mechanistic studies and the proposed mechanism.

Conclusions

In summary, we have developed a new silver-catalysed annulation reaction of aryldiazonium salts with allenes by taking advantage of a boronate motif as a traceless activating and directing group. The mild reaction conditions, wide substrate scope, excellent regioselectivity, and decent scalability render this protocol highly useful for the synthesis of N¹-aryl-1H-pyrazoles. Further application of this method in the synthesis of related drug intermediates illustrated the potential utility. The reaction mechanism has been explored via experimental and computational approaches, revealing the critical role of the propargyl silver intermediate. This study discloses the practicality of allenylboronates as all-carbon formal 1,3-dipoles for heterocycle synthesis, and future applications are currently underway in our laboratory.

Author contributions

X. P. and P. Q. carried out the experimental and data analysis work. M.-M. Z. and X.-S. X. conducted the DFT studies. F.-G. Z. and J.-A. M. conceived and directed the project. F.-G. Z. and J.-A. M. wrote the manuscript with input from all authors.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was supported by the National Key Research and Development Program of China (2019YFA0905100) and the National Natural Science Foundation of China (no. 92156025, 21901181, 22122104, and 21961142015). We would like to thank Dr Guosheng Ding and Dr Xiaojuan Deng at the Analysis and Testing Center of Tianjin University for their assistance with NMR testing and analysis. This work is dedicated to the 60th anniversary of the Institute of Elemento-organic Chemistry at Nankai University.

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19. DFT calculations were performed at the B3LYP-D3(BJ)/6-311+G(2d,p)+SDD(Ag) level of theory. Detailed references on the computational methods and all the optimized structures are provided in the ESI.†.
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Footnotes

† Electronic supplementary information (ESI) available. CCDC 2090718 (3r), 2090719 (3ha), and 2090720 (3la). For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d2qo01585d

‡ Equal contribution.

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