Introduction

Pyrrolidine is one of prevalent core structures found in biologically active natural products and medicinal molecules1,2,3. Development of synthetic methods to access pyrrolidine skeletons with broad scope and high functional group compatibility is of great importance not only to accelerate drug discovery research but also to explore chemical spaces of nitrogen-containing compounds. [3 + 2] cycloaddition reactions of azomethine ylides with alkenes and alkynes have been widely investigated, affording pyrrolidine derivatives with a wide range of substitution patterns and excellent stereoselectivity (Fig. 1a)4,5. Intramolecular cyclization approaches utilizing such as amination of unsaturated carbon-carbon bonds6,7,8,9 and insertion of nitrene species into sp3C–H bonds10,11,12 have also been recognized as powerful methods for efficient construction of pyrrolidine rings (Fig. 1b). However, preparation of the appropriate starting materials is necessary in most case of these reactions, thus limiting their versatility.

Fig. 1: Synthetic approaches to pyrrolidines and ring contraction reactions of pyridines.
figure 1

a [3 + 2]-Cycloaddition of azomethine ylides with alkenes and alkynes as a representative synthetic approach to pyrrolidine derivatives. b Examples for intramolecular cyclization reactions to access pyrrolidine skeletons via hydroamination and sp3C–H amination. c An early example of a photo-promoted direct ring contraction of pyridine to pyrrole upon UV light irradiation. d A ring contraction of pyridinium salts to cyclopentene derivatives under UV irradiation. e Synthesis of N-acylindoles via photo-promoted skeletal rearrangement of quinoline N-oxides to benzoxazepines followed by acidolysis. f This work: A photo-promoted ring contraction of pyridines to pyrrolidine derivatives bearing a 2-azabicyclo[3.1.0]hex-3-ene skeleton.

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Meanwhile, a ring contraction of cyclic compounds to smaller cycles that are valuable but difficult to synthetically access is a useful strategy in synthetic organic chemistry. This is regarded as skeletal editing, which has rapidly emerged as a powerful concept to expand molecular diversity13,14. Considering the synthesis of pyrrolidine derivatives via ring contractions, it is highly desirable to use pyridines as starting materials, which are abundant, cheap, and readily available bulk chemicals in chemical industry. However, such ring contraction reactions have scarcely been achieved to date. There are several examples of pyrrole synthesis from N-alkylpyridinium salts or pyridines via sequential ring-cleavage and ring-closure under oxidative conditions15,16,17,18,19. Photoreactions are promising to realize skeletal editing although direct excitation of pyridine itself requires ultraviolet irradiation20,21,22,23, which often causes side reactions and is not suitable for practical synthetic reactions. As an early example of a photo-promoted ring contraction of pyridines, in 1969, Kellogg reported that irradiation of 254 nm light to pyridine diester afforded dihydropyridine along with a small amount of pyrrole (Fig. 1c)24. In 1972, Kaplan and Wilzbach reported a photoreaction of an N-methylpyridinium salt in water to yield an aziridine derivative, 6-azabicyclo[3.1.0]hex-3-ene-2-ol, via 4π electrocyclization followed by hydration25. This reaction was further extended by Mariano into practical synthesis of aminocyclopentene derivatives by combining it with a subsequent nucleophilic ring-opening reaction of the aziridine moiety (Fig. 1d)26,27. The photolysis of pyridine N-oxides was reported to give 2-acylpyrroles in low yields28. Recently, optimizing this reaction, Levin realized skeletal editing of quinoline N-oxides to N-acylindoles via net one carbon deletion, in which quinoline N-oxides were photochemically converted to benzoxazepines upon 390 nm irradiation followed by ring-opening and closure under acidic conditions (Fig. 1e)29. These precedents evidenced high feasibility of the ring contraction strategy using pyridines as starting materials leading to 5-membered ring scaffolds, although most cases necessitate the preparation of N-alkylpyridinium salts or N-oxides as pre-activation steps. Several related studies on skeletal editing, not limited to ring contraction, of pyridine derivatives such as pyridinium ylides have also been reported30,31,32,33,34. The development of a ring contraction reaction of pyridines to give pyrrolidine skeletons without pre-activation remains a desirable but challenging task.

Herein we report a photo-promoted ring contraction of pyridines with silylborane to afford pyrrolidine derivatives bearing a 2-azabicyclo[3.1.0]hex-3-ene skeleton (Fig. 1f). Derivatization of the products to variously substituted and functionalized pyrrolidine derivatives and other nitrogen-containing compounds is demonstrated, disclosing their high synthetic utility as building blocks in organic synthesis.

Results

Reaction development

Considering the photochemical reactivity of pyridine derivatives, we expected that a Lewis acid–base adduct derived from pyridine and a certain boron reagent could be photochemically activated upon irradiation with practical wavelengths, possibly undergoing ring contractions as seen in the cases of pyridinium salts. After examining various boron reagents and reaction conditions, it was found that photoirradiation of a benzene-d6 solution of pyridine and silylborane (2-(dimethylphenylsilyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, PhMe2SiBpin) using a 365 nm LED at 25 °C in a J Young NMR tube afforded a pyrrolidine derivative, N-boryl-6-silyl-2-azabicyclo[3.1.0]hex-3-ene 2a, in excellent yield (Fig. 2a). 2a was unstable in air and not isolable. The structure of 2a was fully characterized by NMR analyses (Fig. 2b) and also confirmed by XRD analyses after derivatizing to solid compounds (vide infra). Three hydrogen atoms on the cyclopropane ring appear at δ = 3.91 (He), 2.10 (Hc), and –0.59 (Hd), which is significantly shifted upfield due to the shielding effect of both a cyclopropane ring and a silyl group. The diastereomer locating the silyl group trans to the nitrogen atom on the cyclopropane ring was formed selectively. The reaction using bis(pinacolato)diboron (B2pin2) or 1,1,2,2-tetramethyl-1,2-diphenyldisilane ((PhMe2Si)2) instead of PhMe2SiBpin did not proceed at all (Entries 1 and 2, Fig. 2c). Importantly, visible light irradiation using 430 nm LEDs also promoted the reaction to give 2a in 85% yield although the reaction time was extended to 11 h for sufficient conversion (Entry 3). Moreover, reducing the amount of silylborane to 1.0 equiv. did not cause any problems, yielding 2a in 91% yield after 5 h (Entry 4).

Fig. 2: The photo-promoted ring contraction of pyridine with silylborane to form a pyrrolidine derivative, N-boryl-6-silyl-2-azabicyclo[3.1.0]hex-3-ene 2a.
figure 2

a The optimized ring contraction reaction of pyridine with silylborane to give the pyrrolidine derivative 2a in 90% yield. b The 1H NMR spectrum of 2a with connectivities observed by the H-H COSY measurement. c Selected data obtained in the screening of reaction conditions.

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With the optimal reaction conditions in hand, derivatization of 2a to an air-stable and isolable compound by protecting the nitrogen atom was examined. Screening of various N-protecting groups and reaction conditions disclosed that addition of 1.0 equiv. each of benzoyl chloride and pyridine to the solution of 2a obtained after the photoreaction afforded N-benzoyl enamide 3a as a single diastereomer in 83% (based on pyridine), which was successfully purified and isolated by basic alumina column chromatography in air (Fig. 3). This one-pot procedure enabled facile preparation of N-benzoyl-2-azabicyclo[3.1.0]hex-3-ene derivatives 3 from various pyridines as starting materials. The reaction of 4-substituted pyridines with R2 = Me, Bn, n-Pr, and Ph proceeded smoothly to give 3b-e, having the alkyl or aryl substituents at the 5-position of the 2-azabicyclo[3.1.0]hex-3-ene skeleton. The relative stereochemistry of the major isomer is trans/trans (defined as the relationship of R2/Si to the nitrogen atom on the cyclopropane ring), although the stereoselectivity is affected by the size of R2. Interestingly, the selectivity was completely reversed when employing 4-tert-butylpyridine as a substrate, giving a trans/cis isomer of 3f selectively due to the large steric repulsion between the tBu and the Si groups. tert-Butyldimethylsilyl ether and acetate as protected alcohols were tolerant to the reaction conditions, affording the corresponding products 3g-i bearing the functionalized alkyl chains in good yields. Importantly, pyridines bearing various carbonyl groups, such as ethyl ester and Weinreb’s amide, were successfully used to give the corresponding pyrrolidine derivatives 3j-l in moderate to good yields. Various protecting groups were employable under the reaction conditions as demonstrated in the facile formation of enamide 3m, 3n, 3o, which bear a cyclic acetal moiety as masked aldehyde or a tert-butyl carbamate (Boc) moiety as protected amine. The reaction of 4-trifluoromethylpyridine proceeded to generate a CF3-containing product 2p in 54% yield, enabling easy access to fluorinated pyrrolidine building blocks. Importantly, pyridines containing alkyl chloride, alkene, and internal/terminal alkyne underwent the ring contraction reaction to afford 3q-t without any problems. This reaction realizes facile synthesis of pyrrolidine derivatives 3 equipped with an enamide moiety and a functionalized alkyl chain, which would work as promising building blocks for polycyclic alkaloid synthesis via further C–C bond formation. Furthermore, this protocol was successfully applied to 3,5-dimethylpyridine to give N-benzoyl-4,6-dimethyl-6-silyl-2-azabicyclo[3.1.0]hex-3-ene 3u stereoselectively in good yield, thus demonstrating generality with substituents at 3,5-positions. 3-Methyl and 3-ethylpyridines afforded two regioisomers that possess the substituent at the enamine moiety or the cyclopropane carbon adjacent to the silyl group (3v:3v’ = 37%:42%, 3w:3w’ = 36%:24%). 3,4-Dimethylpyridine were also employable to give 3x and 3x’ stereoselectively (3x:3x’ = 26%:39%). 2-Substituted pyridines such as 2-picoline and 2-fluropyridine and other aromatic heterocycles such as pyrimidine did not react at all, probably due to the difficulty of forming pyridine-silylborane adducts. Synthetic utilization of a particular N-Boc-2-azabicyclo[3.1.0]hex-3-ene derivative, which is prepared by monocyclopropanation of N-Boc pyrrole with diazoacetate, has been extensively studied by Reiser and other research groups. However, the preparation method suffers from low yield and limited substrate scope due to selectivity issues in the cyclopropanation step35,36,37,38,39,40,41. This reaction demonstrates wide substrate generality and excellent functional group compatibility, thus establishing a practical method to access pyrrolidine derivatives bearing a 2-azabicyclo[3.1.0]hex-3-ene skeleton from easily available pyridines.

Fig. 3: Substrate scope of the photo-promoted ring contraction of pyridines.
figure 3

Wide generality of pyridine substrates and excellent compatibility with various functional groups are demonstrated, enabling facile access to pyrrolidine derivatives bearing a 2-azabicyclo[3.1.0]hex-3-ene skeleton from easily available pyridines. TBS tert-butyldimethylsilyl, Ac acetyl, Boc tert-butoxycarbonyl, TMS trimethylsilyl.

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Transformation to functionalized pyrrolidine derivatives and other nitrogen-containing compounds

The ring contraction product 3 furnishes an enamine, a cyclopropane, and a silyl moieties as reactive functional groups usable for further C–C bond formation and functionalization36,37,38,39,40,41,42. To demonstrate its synthetic utility as a synthon for various functionalized pyrrolidines, reactivity of 2a and 3a was investigated. The photo-promoted ring contraction reaction was scalable with the same setup for photoirradiation, enabling preparation of ca. 3 g of 3a from 10 mmol of pyridine at one time (Fig. 4a). Treatment of N-borylenamine 2a with phenyl thioglycolate afforded tricyclic lactam 4a having an N,S-acetal moiety in 75% yield, which is expected to work as a precursor to an iminium ion by acidic activation for further C–C bond formation (Fig. 4b). Hydrogenation of 3a with Pd/C gave a saturated pyrrolidine derivative 5a in 72% yield (Fig. 4c) along with 2-(silylmethyl)pyrrolidine 6a via regioselective reductive C–C bond cleavage of the cyclopropane ring (Fig. 4d)43. The silyl group of 5a was converted to a hydroxy group by the Tamao-Fleming oxidation (HF/KF/H2O2)44, providing cyclopropanol-fused pyrrolidine 7a in 41% yield (Fig. 4e). The reaction of 5a with 2 equiv. of TBAF afforded a desilylation product 8a in 47% yield (Fig. 4f). The enamide moiety of 3a underwent an inverse electron demand Diels-Alder reaction with a 2-pyrone derivative 9 to give 10a in good yield45, realizing rapid construction of the complex tetracyclic pyrrolidine skeleton from pyridine in three steps (Fig. 4g). Furthermore, it was also revealed that acidic methanolysis of 3a afforded a cyclopropylamine derivative 11a equipped with a silyl group and an acetal moiety stereoselectively (Fig. 4h). This is a highly useful and practical method to rapidly access to the functionalized cyclopropane derivatives starting from readily available pyridines. The structures of 4a, 10a, and 11a were clarified by XRD analyses. These results demonstrate high versatility of the 6-silyl-2-azabicyclo[3.1.0]hex-3-ene skeleton as a building block for the synthesis of various pyrrolidines and nitrogen-containing compounds.

Fig. 4: Large-scale synthesis and transformation of 2 and 3 to various pyrrolidine derivatives and other nitrogen-containing compounds.
figure 4

a A large scale reaction using 10 mmol pyridine. b The formation of tricyclic lactam 4a having an N,S-acetal moiety by the reaction of 2a with phenyl thioglycolate. c Hydrogenation of the enamide moiety of 3a to give a saturated derivative 5a. d Reductive ring-opening of the cyclopropane moiety to give 2-(silylmethyl)pyrrolidine 6a. e The Tamao-Fleming oxidation of the silyl group of 5a to afford cyclopropanol 7a. f Desilylation of 5a with TBAF to afford 8a. g The Diels-Alder reaction of 3a with a 2-pyrone derivative 9 to afford a tetracyclic compound 10a. h. Acidic alcoholysis to afford a functionalized cyclopropane 11a.

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Mechanistic study

We carried out several UV-Vis measurements and NMR experiments to gain insights into the reaction mechanism. Firstly, in the UV-Vis absorption spectra, neither pyridine or silylborane showed any absorptions above 350 nm, while a mixture of both reagents displayed an absorption at 350 nm (Fig. 5a). These observations indicate that the pyridine-silylborane adduct generated in situ is photochemically excited upon 365 nm LED irradiation to undergo the reaction as initially expected. Secondly, time course analysis of the reaction by 1H NMR disclosed that small amounts of N-boryl-2-silyl-1,2-dihydropyridine 12a and N-boryl-4-silyl-1,4-dihydropyridine 13a were generated along with 2a in the beginning of the reaction using 430 nm LEDs although the reaction upon 365 nm irradiation did not show any detectable intermediates (Fig. 5b). The 2-silyl isomer 12a disappeared after a long period of irradiation while the 4-sily isomer 13a remained and accumulated (up to 3%, 11 h), which was finally consumed after additional irradiation at 365 nm for 2 h. These data are highly indicative of the intermediacy of dihydropyridines 12a and 13a in the reaction. Thirdly, we found that the product 2a underwent skeletal rearrangement by heating at 140 °C for 2 h to give 1,2-dihydropyridine 12a quantitatively (Fig. 5c). Then, the formed 12a was confirmed to be fully converted to 2a upon photoirradiation at 365 nm for 1 h, thus proving the photoreactivity of 12a leading to 2a. No formation of the 4-silyl isomer 13a was observed during the thermolysis of 2a. Furthermore, it was revealed that the product 2u derived from 3,5-dimethylpyridine also exhibited the same interconvertible reactivity with heat and light, affording 3,5-dimethyl-2-silyl-1,2-dihydropyridine 12 u as a single product bearing a silyl group at the 2-position and Me-substituents at the 3- and 5-positions. These experimental data clarify that the photoreaction of pyridines with silylborane initially generates 2-silyl-1,2-dihydropyridines 12 as a major intermediate via the pyridine-silylborane adduct, which is then converted to the products 2 under the influence of photoenergy through the migration of the silyl group from the 2-position to the 3-position. Regarding the photochemical skeletal rearrangement reaction of 1,2-diydropyridine derivatives, in 1971, Biellmann reported a photoreaction of a particular Hantzsch ester derivative to form a 2-azabicyclo[3.1.0]hex-3-ene derivative in low yield46, which was proposed to proceed via electrocyclization to generate a 1-azatriene intermediate (Fig. 5d)47,48,49. This is a very specific example and has not been developed as a synthetic reaction to date. Moreover, the mechanism via the 1-azatriene intermediate is not consistent with our system, as shown in Fig. 5c (R = Me), which demonstrates that the silyl group is migrating between the carbon atoms at the 2- and 3-positions of the dihydropyridine ring.

Fig. 5: Investigations on the reaction mechanism.
figure 5

a UV-Vis spectra of benzene solutions of pyridine (a blue line), silylborane (a yellow line), and a mixture of pyridine and silylborane (a red line). b Time course analysis of the ring contraction reaction of pyridine with silylborane. c Interconversion between the products 2 and 1,2-dihydropyridines 12. d An example of thermolysis and photolysis of a particular Hantzsch ester derivative reported by Biellmann. e DFT calculations (ωB97XD/def2-TZVPP/SMD(benzene)). Grel refer to Gibbs’ free energies relative to that of pyridine and PhMe2SiBpin in kcal/mol.

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According to the experimental results, a plausible reaction mechanism involving 2-silyl-1,2-dihydropyridine as an intermediate was investigated by DFT calculations (ωB97XD/def2-TZVPP/SMD(benzene)) (Fig. 5e). Gibbs free energies and Cartesian coordinates of the optimized structures are provided in  Supplementary Dataset. The pyridine-silylborane adduct A is less stable than starting compounds and generated reversibly. The TD-DFT calculation supports that the adduct A exhibits an absorption maximum at 349 nm, which is almost identical to that observed in the UV-Vis spectrum (Fig. 5a). We propose that photoexcited states of A, either or both a singlet state 1A* and a triplet state 3A*, induce migration of the silyl group from the boron atom to the C2-position of the pyridine ring to form 2-silyl-1,2-dihydropyridine D (Fig. S10)50,51. As a photochemical reaction pathway from the 2-silyl-1,2-dihydropyridine intermediate D to the product, we found that a singlet excited state 1D* undergoes 1,2-silyl migration via a 1TS1* (∆E = 6.4 kcal/mol) to generate vinylazomethine ylide E bearing the silyl group at the 3-position. Finally, a thermally-promoted, disrotatory electrocyclic ring-closing reaction of E proceeds almost barrierlessly according to the Woodward-Hoffmann (W–H) rules, furnishing the 6-silyl-2-azabicyclo[3.1.0]hex-3-ene skeleton of F52. The ring-closing and -opening electrocyclic reactions are reversible at room temperature, thus suggesting that the ratio of diastereomers of F is thermodynamically controlled. Regarding the thermally-promoted reaction from F to D, the reverse 1,2-silyl migration from E to D is not plausible under thermal conditions due to the mismatched orbital symmetry. Instead of that, 1,4-silyl migration of the silyl group from the 3-position to the 6-position in E, which is regarded as a thermally-allowed 1,4-sigmatoropic rearrangement reaction, proceeds via TS2 to afford 2-silyl-1,2-dihydropyridine D. This is the rate-determining step of the thermally promoted reverse reaction requiring an activation energy of 32.8 kcal/mol from trans F, which can be overcome by heating at 140 °C. Moreover, the electrocyclic ring-opening reaction of F to generate a 1-azatriene intermediate G needs an activation energy of 44.9 kcal/mol via TS3 and is ruled out. Consequently, we have elucidated that the ring contraction proceeds via the N-boryl-2-silyl-1,2-dihydropyridine intermediate 12 that is photochemically generated from pyridines and silylboranes. The 2-silyl-1,2-dihydropyridine undergoes unprecedented photo-induced 1,2-silyl migration to form 3-silylazomethine ylide, which furnishes the pyrrolidine skeleton via a thermally-allowed disrotatory ring-closing reaction. The details of the theoretical calculations are descried in the supplementary information (Fig. S9–S14).

In conclusion, we have developed a photo-promoted ring contraction reaction of pyridines with silylborane to give pyrrolidine derivatives bearing a 2-azabicyclo[3.1.0]hex-3-ene skeleton. The reaction demonstrates broad substrate scope with high functional group compatibility, and the obtained products work as a powerful synthon for the synthesis of functionalized pyrrolidines and other nitrogen-containing compounds. The reaction proceeds via 2-silyl-1,2-dihydropyridine and vinylazomethine ylide as intermediates, which are connected by unprecedented photochemical or thermal silyl migration. This reaction provides a synthetic strategy to rapidly access pyrrolidine skeletons from readily available pyridines, leading to acceleration of drug development research and exploration of chemical spaces of nitrogen-containing compounds.

Methods

General procedure for one-pot synthesis of 3 via ring contraction followed by N-benzoylation

A solution of pyridine derivatives 1 (0.40 mmol) and PhMe2SiBpin (200 μL, 0.87 mmol) in benzene (2.0 mL) was placed in a sealed glass tube. The solution was photo-irradiated at 365 nm with stirring at 25 °C for 10 h. To the solution of the generated N-boryl-6-silyl-2-azabicyclo[3.1.0]hex-3-ene 2 were added pyridine (32.0 μL, 0.397 mmol) and benzoyl chloride (48.0 μL, 0.413 mmol) at room temperature for N-benzoylation. After stirring for 12 h, the mixture was filtered through a short pad of Celite®. The solvent was removed under reduced pressure to give a crude mixture, which was purified by alumina chromatography to give 3.