Synthesis of substituted imid(thi)azolidines by [3+2] cycloaddition of aziridines with nitriles(isothiocyanates) via visible light photocatalysis

The [3+2] cycloaddition reaction of aziridines with nitriles (isothiocyanates) has been developed using visible light photocatalysis. Two types of five-membered heterocyclic compounds, imidazolidines and thiazolidines, were synthesized in mild conditions. An oxidative quenching cycle mechanism is probably involved


Introduction
Photoredox catalysis by means of visible light is considered an ideal route for green, economic and abundant chemical synthesis.2][3][4][5] Since it was proposed by Ciamician in 1912, this concept has been almost silent for half a century or more. 6It was not until 2008 that MacMillan firstly reported α-alkylation of aldehydes and ketones by photocatalysis, which attracted considerable attention from chemists. 7Subsequently, many research groups have made extensive and outstanding contributions in this field 1 and photocatalysis has evolved into an important means in organic synthesis.
1] Some derivatives are used for the synthesis of anti-inflammatory, antioxidant, anti-nociceptive and anticarcinogenic drugs.Additionally, imidazolines have been used as metal complex ligands 12 and auxiliary groups 13 in asymmetric synthesis.
Many methods have been developed for the synthesis of imidazolines and thiazolines.The traditional process for imidazolines is the cyclization of 1,2-diamines with carboxylic acids under rigorous conditions.Unfortunately, 1,2-diamines are not easy to synthesize and the substrate scopes are quite narrow. 146] In 2016, Xu developed the synthesis of imidazoline via visible light catalysis from alkenes, an N-Ts-1-aminopyridinium salt and a nitrile but the transformation was unsuccessful for non-conjugated alkenes. 17

Results and Discussion
Although many methods have been reported for the synthesis of substituted imidazolidines and thiazolidines, it is important to find new synthetic methods from the viewpoint of synthetic diversity.In 2014, Xia group reported the ring opening reaction of aziridines by visible light photocatalysis with Na2S2O8 as an oxidant. 27ccording to the oxidative quenching cycle mechanism of visible light photocatalysis of this reaction, we speculated it might be possible to carry out a [3+2] cycloaddition reaction of aziridines and nitriles under these conditions.
In order to find optimal conditions, the reaction of aziridine 1a and acetonitrile 2a was performed with 1.2 eq of PhN2BF4 in the presence of 1 mol% Ru(bpy)3Cl2•6H2O under air (Table 1).The reaction mixture was illuminated with a 45W white household lamp at room temperature for four hours monitored by TLC.We were delighted to find that the desired product 3a could be isolated in 73% yield (entry 1).Extending the reaction time to five, six, and seven hours respectively, did not increase the yield.The reaction proceeded very slowly and the yields were very low in the absence of light or photocatalyst (entries 2-3).The yield was improved slightly when the reaction was carried out under a N2 atmosphere (entry 4).The desired product could not be obtained without PhN2BF4, which indicated that an oxidant was essential for the reaction (entry 5).All of the tested catalysts promoted the reaction (entries 6-11), but the best yield was obtained using Ru(bpy)3(BF4)2 as a photocatalyst (entry 8).Using I2, DDQ, NBS, Na2S2O8, K2S2O8, or PhI(OAc)2 as the substituted oxidant, the reaction failed (entry 12).A 64% yield of the product could be detected by GC analysis when (NH4)2S2O8 was used as the oxidant (entry 13).The desired product could not be obtained when Ir[dF(CF3)ppy]2(dtbbpy)PF6 (E1/2III * /II=+1.21V vs SCE in CH3CN) or Ru(bpz)3(PF6)2 (E1/2III/II=+1.86Vvs SCE in CH3CN) were tried in the absence of PhN2BF4 (entries 14-15).The yields were 7%, 15%, 30% and 70% respectively when PhN2BF4 was used at 5%, 10%, 20% and 50%.A small amount of biphenyl was detected by GC analysis.With the optimal reaction conditions in hand, the substrate scope of the 2-alkyl(aryl)-N-tosylaziridine was investigated (Table 2).The substituent of the aryl ring of the 2-aryl-N-tosylaziridine, such as F, Cl, Me generated the cycloaddition products in good yields (3b-e).However, the bromo substituted starting material gave slightly lower yield (3f). 2-Methyl-2-phenyl-N-tosylaziridine, 2-octyl-N-tosylaziridine, Ntosylcyclohexanoaziridine, were also suitable for the reaction (3g-i).Next, several alkyl nitriles were examined and the corresponding products were obtained in moderate yields (3j-n).Only one nitrile group participated in the reaction when 1,4-dicyanobenzene was used as the substrate (3m).To further demonstrate the generality of the [3+2] cycloaddition reaction, we employed isothiocyanates 4 as dipolarophiles to synthesize 2-iminothiazolidines. Based on the reaction of 1a and 2a, the reaction conditions of 1a and 4a were screened briefly.The reaction did not proceed without light or photocatalyst.A lower yield was obtained under blue LED illumination perhaps because the six-membered ring dimer was formed as the by-product. 28Diphenyl was also detected by GC analysis in the reaction mixture.Screening the solvent, oxidant, etc. showed the optimal conditions were similar to that for the synthesis of 3a (see above).
A series of aryl or alkyl isothiocyanates were surveyed under the optimal conditions (Table 3).The expected products 5 were obtained in moderate yields.No obvious electronic effect was observed.The yield was slightly lower when 2-(2-chlorophenyl)-N-tosylaziridine 5d was used as the substrate and the steric effect may be responsible for this result.2-Phenyl-1-(phenylsulfonyl)aziridine 5q was also a good candidate and afforded the corresponding product in 62% yield.According to the literature 16 and the above experimental results, a plausible reaction mechanism is proposed in Scheme 1. Firstly, under the visible light, the ground state of Ru 2+ is excited to provide Ru *2+ which is oxidized by PhN2BF4 6 to produce Ru 3+ .Thus, the diazonium salt is reduced to generate the phenyl radical 7 which produces 8 by homo-coupling.The aziridine 1 is oxidized to generate a nitrogen radical cation 9 by Ru 3+ which itself is reduced to the original oxidation level, Ru 2+ .Intermediate 9 is attacked by the dipolarophile, nitrile 2 or isothiocyanate 4, to give the ion intermediates 10 or 11 via electron exchange with 1 or intermediate 7, intramolecular cyclization then leading to the imidazoline 3 or thiazolidine 5. Scheme 1.A plausible reaction mechanism.

Conclusions
In summary, we have developed a [3+2] cycloaddition of aziridines with nitriles isothiocyanates by visible light photocatalysis under simple and mild reaction conditions.The reaction is applicable to aryl and alkyl nitriles or isothiocyanates and various substituted imidazolines and iminothiazolidines can be prepared with moderate yields.Visible light as a clean energy source makes this route a good substitute for the existing synthetic protocols.

Experimental Section
General.All of the commercial reagents were used without further purification unless otherwise specified and were purchased from Aladdin, Macklin, Energy or Bide Pharmatech.All of the chemical reactions and manipulations were implemented in oven-dried glassware under an atmosphere of N2 using standard Schlenk technique.The solvents were made absolutely anhydrous and freshly distilled prior to use.Reactions were monitored by thin-layer chromatography (TLC) on GF254 Silica plates, visualizing with UV-light (254 nm) or I2 stain. 1 H NMR and 13 C NMR spectra were recorded in ppm at 500 MHz and 125 MHz using CDCl3 as solvent and TMS as internal standard using a Bruker AVANCE III 500MHz Nuclear Magnetic Resonance Spectrometer.Lowresolution MS (Varian 1200 Mass Spectrum Analyzer) and HRMS (Bruker ApexIII Fourier Transform Ion Cyclotron Resonator) were obtained using ESI ionization.Elemental analyses were performed on a vario Micro cube.GC spectra were measured using an Agilent 7890B.Melting points were measured using a SGW® X-4.

Table 1 .
Optimization of the reaction conditions a