Visible-Light-Promoted Click [3+2] Cycloaddition of Aziridine with Alkyne: An Efficient Synthesis of Dihydropyrrolidine

Abstract

A photocatalytic [3+2] cycloaddition of aziridines with activated alkynes is reported under visible-light irradiation in the presence of ruthenium catalyst. This chemical transformation provides polysubstituted pyrrolidines in good yields based on the click chemistry philosophy. The reaction successfully represents a primary trial of cyclocarboamination through photocascade catalysis combining energy transfer and redox neutral reactions.

 

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Key words

aziridine - alkyne - dihydropyrrolidine - visible light - click chemistry - photoredox catalysis

Using cycloaddition processes, click chemistry creates carbon–hetero atom bonds in an environmentally friendly manner. It is a broad-based technique that is quick, modular, effective, dependable, and easy to execute that may be utilized for the synthesis of new compounds with required functionalities. In this context, photocatalytic cycloadditions generated by visible light have been effectively used to synthesize a variety of carbo- and heterocyclic compounds.

Many natural compounds and pharmaceuticals with a variety of biological and therapeutic activities contain unsaturated N-heterocycles, such as pyrrole and its derivatives, as common structural motifs (Figure [1]).[1] As a result, they have attracted a lot of interest in material science, medicinal chemistry, and chemical synthesis. Given the significance of this class of chemicals, the synthetic community has been working hard to create extremely effective synthetic methods to obtain these compounds.[2]

Figure 1 Bioactive unsaturated N-heterocycles

Organic chemists have been fascinated by the aziridine ring’s distinctive structure and reactivity for a long time. Expanding aziridine chemistry further, important polysubstituted pyrrolidines can be created via atom-efficient and convergent cycloaddition reaction of aziridines with alkynes via C–C bond and C–N bond cleavage by photoredox catalysis.[3] It can be an atom-efficient and convenient approach to the preparation of useful polysubstituted pyrrolidines.[3]

Several techniques have been reported in the past for the synthesis of 2,3-dihydropyrroles, including the ring-closing metathesis of enamides,[4] cyclization of sulfonamide anions and alkynyl iodonium triflates,[5] ring expansion of imino cyclopropanes and alkenyl aziridines,[6] hydroamination,[7] double N-alkenylation,[8] iodoamidation,[9] isomerization of 3,4-dihydropyrroles,[10] cycloadditions of nitroalkenes to isocyanoesters,[11] reactions of 1-cyano or 1-nitro cyclopropyl ketones with aniline[12] and Ag-catalyzed [3+2] cycloaddition of alkynes with aziridines.[13] From the standpoints of synthetic variety and green chemistry, it is crucial to discover effective novel synthetic methods for the synthesis of 2,3-dihydropyrroles despite these well-known techniques. The ring-opening reaction of aziridines by visible-light photocatalysis employing Na₂S₂O₈ as an oxidant was revealed by Xia et al. in 2014.[14] We made the assumption that it could be possible to carry out a [3+2]-cycloaddition reaction of aziridines with alkynes under the hitherto reported conditions based on the visible-light-photocatalytic oxidative quenching cycle mechanism of this reaction. To the best of our knowledge, no method has yet been reported for producing 2,3-dihydropyrroles by visible-light photocatalysis and [3+2] cycloaddition of alkynes with aziridines.

As part of our continuing research interests in visible-light photoredox catalysis,[15] we have developed a novel visible-light-induced [3+2]-cycloaddition reaction of aziridines 1 with alkynes 2 (Scheme [1]). The method provides an efficient route to various polysubstituted pyrroles 3 under very mild reaction conditions (visible-light irradiation, one-pot methodology, and ambient temperature).

Scheme 1 Visible-light-induced [3+2]-cycloaddition reaction of aziridines with alkynes

Table 1 Optimization of Reaction Conditions^a

Entry	Photocatalyst (mol%)	Oxidant	Solvent	Yield (%)b
1	Ru(bpy)3Cl2·6H2O	PhN2BF4	i-PrOH	72
2	–	PhN2BF4	i-PrOH	14
3c	Ru(bpy)3Cl2·6H2O	PhN2BF4	i-PrOH	traces
4d	Ru(bpy)3Cl2·6H2O	PhN2BF4	i-PrOH	72
5e	Ru(bpy)3Cl2·6H2O	PhN2BF4	i-PrOH	80
6e	Ru(bpy)3Cl2·6H2O	–	i-PrOH	0
7e	eosin Y	PhN2BF4	i-PrOH	41
8e	Ru(bpy)3(BF4)2	PhN2BF4	i-PrOH	83
9e,f	Ru(bpy)3(BF4)2	see footnote	i-PrOH	0
10e	Ru(bpy)3(BF4)2	(NH4)2S2O8	i-PrOH	61
11e,g	Ru(bpy)3(BF4)2	PhN2BF4	i-PrOH	10, 16, 33, and 72
12e,h	Ru(bpy)3(BF4)2	PhN2BF4	DCM	40
13e,h	Ru(bpy)3(BF4)2	PhN2BF4	THF	30
14e,h	Ru(bpy)3(BF4)2	PhN2BF4	DMSO	22
15e	Ru(bpy)3(BF4)2	PhN2BF4	DMSO	0
16i	Ru(bpy)3(BF4)2	PhN2BF4	i-PrOH	88
17i	–	PhN2BF4	i-PrOH	traces

^a Reaction conditions: 1a (1 mmol), 2a (2 mmol), oxidant (1.5 equiv), PC (2 mol%), blue LED irradiation at r.t. for 4 h under air.

^b Determined by GC.

^c No light.

^d Reaction time 7 h.

^e Under N₂.

^f I₂, DDQ, NBS, Na₂S₂O₈, K₂S₂O₈, or PhI(OAc)₂.

^g PhN₂BF₄ was used at 5 mol%, 10 mol%, 20 mol% and 50 mol%, respectively.

^h Hantzsch ester (1 equiv).

ⁱ λ = 427 nm.

We first began our investigation through the formal [3+2]-cycloaddition reaction between N-tosylaziridine (1a) and phenylacetylene (2a) as model substrates with 1.5 equiv of PhN₂BF₄ under irradiation from a blue LED (3 W, λ = 475.5 nm) in the presence of 2 mol% Ru(bpy)₃Cl₂·6H₂O as a photoredox catalyst in i-PrOH at room temperature (Table [1]). To our satisfaction, we obtained the desired product 3a in 72% yield in 4 h (Table [1], entry 1). Subsequently, control experiments were conducted which established that both the photocatalyst and light were essential for the reaction because in the absence of either of the two, the product was formed in traces (Table [1], entries 2 and 3). The yield of the product did not increase on extending the reaction time to even 7 h (Table [1], entry 4). The yield increased to 80% when the reaction was carried out under nitrogen atmosphere (Table [1], entry 5). The desired product could not be obtained without PhN₂BF₄, which suggested that an oxidant was essential for the reaction (Table [1], entry 6). Other tested catalysts also promoted the reaction (entries 7 and 8) and the best yield was obtained with Ru(bpy)₃(BF₄)₂ as a photocatalyst (entry 8 vs entries 5 and 7).

The reaction failed when I₂, DDQ, NBS, Na₂S₂O₈, K₂S₂O₈, or PhI(OAc)₂ were used as the substituted oxidant (entry 9). On using (NH₄)₂S₂O₈ as the oxidant, the product was obtained in 61% yield (entry 10).[16] When the concentration of PhN₂BF₄ was changed to 5 mol%, 10 mol%, 20 mol%, and 50 mol%, the product was obtained in 10%, 16%, 33%, and 72% yield, respectively (entry 11). A small amount of biphenyl was also detected in the reaction mixture. Among the various solvents tested, best yield was obtained in i-PrOH (Table [1], entry 8 vs entries 12–15). When the reaction was performed using lower wavelength light (λ = 427 nm), the yield of the reaction increased (entry 16). However, in the absence of photocatalyst, the product was formed in traces even with lower wavelength light (entry 17).

Table 2 Substrate Scope of Aziridines for the Cycloaddition Reaction^a

Entry	Aziridines R1, R2, R3, R4	Product	Isolated yield (%)b,c
1	H, H, Ph, Ts	3a	88 (97:3)d
2	H, H, 4-FC6H4, Ts	3b	91 (92:8)
3	H, H, 4-ClC6H4, Ts	3c	86 (94:6)
4	H, H, 2-ClC6H4, Ts	3d	88 (96:4)
5	H, H, 4-MeC6H4, Ts	3e	74 (93:7)
6	H, H, 4-BrC6H4, Ts	3f	66 (95:5)
7	H, H, C8H17, Ts	3g	35 (97:3)
8	N-tosylcyclohexanoaziridine	3h	55
9	Ph, Me, H, Ts	3i	53 (66:44)
10	H, H, H, Ns	3j	88
11	Me, H, Ph, Ts	3k	65 (92:8)

^a Reaction conditions: 1 (1 mmol), 2a (2 mmol), PhN₂BF₄ (1.5 equiv), Ru(bpy)₃(BF₄)₂ (2 mol%), blue LED (λ = 427 nm) irradiation at r.t. under N₂ for 3–4 h in 3 mL i-PrOH.

^b Yield of the pure isolated products 3; the proportion of isomers given in parentheses was determined by ¹H NMR spectroscopy.

^cAll compounds are known in the literature and gave ¹H NMR and ¹³C NMR data in accordance with it.

^d regioisomeric ratio determined by GC-MS.

Using the optimum conditions at hand, different arylaziridine and arylalkyne combinations were researched (Tables 2 and 3). The substituents on the aryl ring of the 2-aryl-N-tosylaziridine, such as F, Cl, and Me, generated the cycloaddition products in good yields with high regioselectivity (Table [2, 3b–e]). However, the bromo-substituted starting material gave a slightly lower yield (3f). Both 2-octyl-N-tosylaziridine and N-tosylcyclohexanoaziridine were appropriate for the reaction and gave 3g and 3h, respectively. 2-Methyl-2-phenylaziridine furnished tetrasubstituted cycloadduct 3i with lower yield and regioselectivity. Furthermore, N-nosylaziridine efficiently generated N-Ns-cycloadduct 3j, providing options for N-protection and deprotection.[17] An all-carbon quaternary stereocenter in 3k was successfully installed using 2-methyl-2-phenylaziridine.

Various arylalkynes were also compatible with the developed protocol and produced the target molecules in good to excellent yields (Table [3]). However, dialkylalkyne 2h produced the desired product 3q in very low yields on using 10 equiv of the alkyne (entry 7).

Table 3 Substrate Scope of Alkynes for the Cycloaddition Reaction^a

Entry	Alkyne, R, R′	Product	Isolated yield (%)b,c
1	2b, 4-MePh, H	3l	89 (92:8)
2	2c, 4-Ph-C6H4, H	3m	77 (98:2)
3	2d, 4-FPh, H	3n	69 (94:6)
4	2e, Ph, Ph	3o	65 (98:2)
5	2f, Ph, Et	3p	96 (96:4)
6	2g, Ph, (CH2)2OPiv	3q	79 (92:8)
7	2h,d C2H5, C2H5	3r	24 (95:5)

^a Reaction conditions: 1a (1 mmol), 2 (2 mmol), PhN₂BF₄ (1.5 equiv), Ru(bpy)₃(BF₄)₂ (2 mol%), blue LED (λ = 427 nm) irradiation at r.t. under N₂ for 3–4 h in 3 mL i-PrOH.

^b Yield of the pure isolated products 3; the proportion of isomers given in parentheses was determined by ¹H NMR spectroscopy.

^c All compounds are known in literature and gave ¹H NMR and ¹³C NMR data in accordance with it.

^d 10 equiv.

The regiochemistry of compounds 3a–f and 3l–n was assigned on the basis of a J coupling of 2.9–2.3 Hz between the benzylic and vinylic protons at the a and b positions (Figure [2]). Compounds 3g, 3k, and 3p were assigned by analogy.

Figure 2 Regiochemistry assignment

Based on literature precedents[14] [15a] [16] and our observations (Table [1], entries 2 and 3), a plausible reaction mechanism is proposed to illustrate the oxidative [3+2]-cycloaddition reaction (Scheme [2]). Initially under visible-light irradiation, the ground state of Ru²⁺ is changed to excited state (Ru*²⁺) which is oxidized by PhN₂BF₄ (4) to produce Ru³⁺. PhN₂BF₄ (4) itself is reduced to generate the phenyl radical 5 which undergoes homocoupling to give 6. Meanwhile, aziridine1 is oxidized to generate a nitrogen radical cation 7 by Ru³⁺, simultaneously reducing itself to the original oxidation level Ru²⁺. Intermediate 7 is attacked by alkyne 2, to give the ion intermediate 8 via electron exchange and intermediate 8 finally undergoes intramolecular cyclization and HAT with solvent leading to the formation of dihydropyrrolidine 3.

Scheme 2 Plausible mechanistic pathway for the visible-light photoredox catalysis enabled cycloaddition of aziridines with alkynes

In summary, we have developed a visible-light-triggered [3+2]-cycloaddition reaction of aziridines with alkynes under simple and mild reaction conditions with a wide range of substrates.[18] The reaction is scalable, uses low catalyst loadings, is highly regioselective, and provides a variety of polysubstituted dihydropyrroles in moderate to high yields. Visible light as a clean energy source makes this route a good substitute to the existing synthetic protocols.

 

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Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We sincerely thank SAIF, Punjab University, Chandigarh for providing spectroscopic facilities.

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• 18 General Procedure for the Synthesis of 2,3-Dihydropyrroles 3 To a stirred solution of aziridine (1 mmol) and alkyne (2 mmol) in isopropyl alcohol (3 mL) was added PhN₂BF₄ (1.5 equiv) and Ru(bpy)₃(BF₄)₂ photocatalyst (2 mol%) at room temperature under visible-light irradiation (blue LED, 3 W, λ = 427 nm). The reaction typically turned yellow or orange/brownish as the reaction progressed. Upon complete consumption of aziridine (TLC control), the reaction was added onto a short SiO₂ flash column (flushed with Et₃N (5%) doped eluent) or an Al₂O₃ (neutral) flash column and eluted with 6.25% ethyl acetate in petroleum ether. Product-containing fractions were concentrated under reduced pressure to leave the corresponding dihydropyrroles 3. Characterization Data of Representative Compounds 3 3,5-Diphenyl-1-tosyl-2,3-dihydro-1H-pyrrole (3a) ¹H NMR (400 MHz, CDCl₃): δ = 7.70–7.65 (m, 2 H), 7.60–7.50 (m, 2 H), 7.49–7.44 (m, 3 H), 7.26–7.21 (m, 2 H), 7.19–7.14 (m, 3 H), 6.79–6.74 (m, 2 H), 5.32 (d, J = 2.4 Hz, 1 H), 4.40 (dd, J = 11.9, 8.7 Hz, 1 H), 3.83 (dd, J = 11.9, 9.4 Hz, 1 H), 3.61 (ddd, J = 10.0, 8.0, 2.3 Hz, 1 H), 2.45 (s, 3 H).¹³C NMR (100 MHz, CDCl₃): δ = 144.9, 142.9, 141.4, 133.4, 132.6, 129.6, 128.9, 128.5, 128.01, 128.0, 127.6, 127.1, 125.9, 120.0, 59.6, 46.9, 21.9. HRMS (ESI): m/z calcd for [C₂₃H₂₁NO₂S + Na⁺]: 398.1191; found: 398.1196. 3-(4-Bromophenyl)-5-phenyl-1-tosyl-2,3-dihydro-1H-pyrrole (3f) ¹H NMR (400 MHz, CDCl₃): δ = 7.69–7.66 (m, 2 H), 7.42–7.30 (m, 5 H), 7.29–7.21 (m, 2 H), 7.29–7.20 (m, 2 H), 6.76–6.65 (m, 2 H), 5.39 (d, J = 2.8 Hz, 1 H), 4.28 (dd, J = 12.6, 9.9 Hz, 1 H), 3.82 (dd, J = 12.6, 7.3 Hz, 1 H), 3.69 (ddd, J = 9.9, 7.2, 2.7 Hz, 1 H), 2.32 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 146.4, 144.0, 142.6, 133.9, 132.6, 131.9, 129.2, 130.1, 129.0, 128.6, 128.0, 127.3, 120.9, 118.1, 59.9, 45.2, 21.6. HRMS (ESI): m/z calcd for [C₂₃H₂₀NO₂SBr + Na⁺]: 476.0296; found: 476.0290. 3-Methyl-3,5-diphenyl-1-tosyl-2,3-dihydro-1H-pyrrole (3k) ¹H NMR (400 MHz, CDCl₃): δ = 7.63–7.56 (m, 2 H), 7.42–7.35 (m, 3 H), 7.33–7.28 (m, 2 H), 7.16–7.08 (m, 3 H), 7.04 (dd, J = 8.0, 0.5 Hz, 2 H), 6.98–6.92 (m, 2 H), 5.40 (s, 1 H), 4.16 (d, J = 12.3 Hz, 1 H), 4.05 (d, J = 12.2 Hz, 1 H), 2.34 (s, 3 H), 2.24 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 147.6, 143.7, 143.5, 133.2, 132.7, 129.2, 128.8, 128.4, 128.3, 127.8, 127.7, 125.9, 125.5, 123.7, 65.6, 48.2, 29.0, 21.5. HRMS (ESI): m/z calcd for [C₂₄H₂₃NO₂S + Na⁺]: 412.1347; found: 412.1345.

Publication History

Received: 20 February 2023

Accepted after revision: 24 May 2023

Accepted Manuscript online:
24 May 2023

Article published online:
26 June 2023