Quickly FeCl₃-catalyzed highly chemo- and stereo-selective [3 + 2] dipolar cycloaddition of aziridines with isothiocyanates

Abstract

A FeCl₃-catalyzed [3 + 2] cycloaddition reaction of aziridine with isothiocyanate was developed. The cycloaddition reaction was completed in two minutes with high chemoselectivity, stereoselectivity. 15 (tosylthiazolidin-2-ylidene)anilines were obtained with moderate to excellent yields.

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[3 + 2] cycloaddition reactions of nitrones, azides, and related 1,3-dipolar species have emerged as powerful tools for the construction of cyclic compounds with great utility in organic synthesis, chemical biology, and materials science.¹ Huisgen has conducted pioneering studies for [3 + 2] dipolar cycloaddition reactions, provided detailed explanations for the mechanism, and also predicted the structures of several unknown 1,3-dipoles at the same time.² After that, a variety of dipoles and unsaturated compounds were applied in [3 + 2] cycloadditions.² Recently, [3 + 2] dipolar cycloadditions of aziridines as 1,3-dipolar species with unsaturated bonds such as C≡C,^3a,5 C=C,^3e C=O,^3f C=N,^3j C≡N^3k and N=C=Se^3l have been applied to the synthesis of many nitrogen-containing biologically active molecules and functional materials.³ However, highly chemoselective and stereoselective [3 + 2] cycloaddition reaction of aziridines with a molecule bearing two unsaturated bonds via C–N cleavage of aziridines remains a challenge.^4,7

Wender and Ding's works,^3a and our recent research results⁵ suggested that Lewis acid-catalyzed aziridine ring-opening is highly efficient to generate a zwitterionic intermediate. Encouraged by our previous work, the stable dipolar ion generated from the ring-opening of aziridine, with some reagents containing two unsaturated bonds, should be also translated to a new structural cycloaddition product.

Herein, we report a novel [3 + 2] dipolar cycloaddition reaction of aziridine with isothiocyanate catalyzed by FeCl₃ (Table 1). Notably, C=S bond selectively participates in cycloaddition rather than C=N bond of the isothiocyanate, and X-ray analysis demonstrated the structure of cycloaddition products (Z)-N-phenyl-5-(p-tolyl)-3-tosylthiazolidin-2-imine (3ba) was a stereospecific five-membered ring, the tosyl group and aniline group were in the trans position of the five-member ring (Fig. 1). A series of multifunctional (tosylthiazolidin-2-ylidene)anilines were obtained via one step [3 + 2] dipolar cycloaddition.

Table 1 Optimization of the reaction conditions^a,b

Entry	Catalyst	Solvent	T/°C	t/min	Yield/%
a Reaction conditions: aziridine 1a (136 mg, 0.5 mmol), isothiocyanatobenzene 2a (1 mmol), catalyst (0.05 mmol), solvent (1.0 mL).b Yield of isolated product.c 0.1 g 4 Å molecular sieve.
1	FeCl3	CH3NO2	rt	2	60
2	FeCl2·4H2O	CH3NO2	rt	2	Trace
3	Fe(OTf)3	CH3NO2	rt	1	41
4	Fe(NO3)3·9H2O	CH3NO2	rt	30	Trace
5	Fe2(SO4)3·5H2O	CH3NO2	rt	30	Trace
6	Fe(acac)3	CH3NO2	rt	30	0
7	Zn(OTf)2	CH3NO2	rt	60	45
8	Cu(OTf)2	CH3NO2	rt	120	38
9	Zr(OTf)4	CH3NO2	rt	30	25
10	CuI	CH3NO2	rt	30	Trace
11	FeCl3	CH2Cl2	rt	120	43
12	FeCl3	(CH2)2Cl2	rt	2	52
13	FeCl3	CH3NO2	0	2	68
14	FeCl3	CH3NO2	−20	2	73
15	FeCl3	CH3NO2	−20	2	80^c
16	FeCl3 + Ph3P	CH3NO2	−20	30	0
17	Binol phosphonic acid	CH3NO2	rt	30	0

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Fig. 1 X-ray structure of 3ba.

In our initial studies, 2-phenyl-1-tosylaziridine (1a) and isothiocyanatobenzene (2a) were chosen the model substrates in the catalysis of FeCl₃ in CH₃NO₂ as the solvent at room temperature for two minutes, affording (Z)-N-(5-phenyl-3-tosylthiazolidin-2-ylidene)aniline (3aa) in 60% yield. When different Lewis acids including iron, copper, zinc, and zirconium salts were examined, FeCl₃ gave the highest yield for this cycloaddition reaction (Table 1, entries 1–9). Next, dichloromethane, dichloroethane, nitromethane⁵ were chosen as solvent in the iron–catalyst reaction, and nitromethane was found to be the best solvent for the reaction. To our delight, lowering temperature to −20 °C increased the reaction yield up to 73% (Table 1, entries 14).⁶ In addition, adding 4 Å molecular sieve can inhibit hydrolysis of aziridine, the yield increased to 80% (Table 1, entries 15). FeCl₃ co-ordinated with Ph₃P did not catalyzed the reaction at all (Table 1, entries 16). Furthermore, Brønsted acid binol phosphonic acid was also not effective under the same reaction conditions (Table 1, entry 17).‡

After the optimization of the reaction conditions, we examined the generality of the transformation. Firstly, we focused on the reactivity of different aromatic substituent aziridines 1 (Table 2). A variety of aromatic substituted aziridines with electron-donating or electron-withdrawing groups were employed as the reaction substrates, which afforded the corresponding products 3 in moderate to excellent yields in two minutes. Electron-donating substituents favored the reaction for electron-donating substituents high-efficiency stabilizing benzyl cation, so the corresponding (tosylthiazolidin-2-ylidene)anilines were obtained in excellent yields (Table 2, 3ba, 3ca, 3fa and 3ga). On the other hand, electron-withdrawing substituted aziridines were used, the cyclization reaction still worked well, but with a slightly low yield (Table 2, 3ea, 3ha, 3ia). When 1,1-disubstituted aziridine was used in the selective cycloaddition, the reaction still worked very well, no obvious steric effect was found, 2-methyl-2-phenyl-1-tosylaziridine could get 85% yield (Table 2, 3da). Another (Z)-3-phenyl-1-tosylaziridin-2-yl methanol also afforded 63% yield and kept the trans-structure (Table 2, 3ja). In another part of isothiocyanate, we predicted different isothiocyanate to give similar cycloaddition products. Aromatic 1-isothiocyanatonaphthalene and nonaromatic isothiocyanatocyclohexane were chosen the substrates, but aliphatic substituted isothiocyanate afforded lower yield (Table 2, 3ab and 3ac). Carbon disulfide could participate in the selective [3 + 2] cycloaddition, however, only giving a moderate yield (Table 2, 3ad).

Table 2 Scope of the reaction of aromatic aziridines with isothiocyanates^a,b

a Reaction conditions: aziridines 1 (0.5 mmol), isothiocyanate 2 (1 mmol), FeCl₃ (8 mg, 0.05 mmol), CH₃NO₂ (1.0 mL), 0.1 g 4 Å molecular sieve, −20 °C, 2 min, N₂.b Yield of isolated product.c syn : anti = 2 : 12 was determined by ¹H NMR spectroscopy.d 5 min.

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The results led us to address the question, could FeCl₃ catalyze cycloaddition between aliphatic–aziridine and isothiocyanate? With the questions, we synthesized an aliphatic aziridine 7-tosyl-7-azabicyclo[4.1.0]heptane (1k), greatly, we obtained the corresponding cycloaddition products 3ka, only with slightly lower yield and longer reaction time (Table 3). Exciting, carbon disulfide and 7-tosyl-7-azabicyclo[4.1.0]heptane converted to 3-tosylhexahydrobenzo[d]thiazole-2(3H)-thione with 47% yield (Table 3, 3kb). Furthermore, we also got similar cycloaddition product 3kc from 1k and isothiocyanatocyclohexane (Table 3, 3kc).

Table 3 The scope of the reaction of aliphatic aziridines with isothiocyanates^a,b

a Reaction conditions: aziridines 1k (125 mg, 0.2 mmol), isothiocyanate 2 (0.4 mmol), FeCl₃ (3.3 mg, 0.02 mmol), CH₃NO₂ (1.0 mL), 0.1 g 4 Å molecular sieve, −20 °C, 5 min, N₂.b Yield of isolated product.

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In the reaction process, the ring-opening of aziridine is the most important stage. The ring-opening of aziridine is high-efficiency in the catalyst of Lewis acid to generate a stable dipolar ion, because tosyl group could stable nitrogenanion and phenyl could stable carbocation. We examined the reaction activity of aziridine without the tosyl group [Scheme 1, eqn (1)], as expected, no desired product were detected when unactivated aziridines 1l or 1m were employed in the reaction with isothiocyanatobenzene.

Scheme 1 The proving reaction for the mechanism.

In consideration of the low yields of some substrates and some reports, we designed the reaction aziridine 1a with FeCl₃ [Scheme 1, eqn (2)], as expected, N-(2-chloro-2-phenylethyl)-4-methylbenzenesulfonamide 4a was isolated in 16% yield.⁶ Under the above control experimental results and reports, we proposed a plausible mechanism in Scheme 2. Aziridine 1a was catalyzed ring opening by FeCl₃ to form a zwitterionic intermediate A, which is stabilized by tosyl group and phenyl group (Scheme 2). The carbon of isothiocyanatobenzene was attacked by the nitrogen anion of the 1,3-dipolar ion, and then FeCl₃ combined with sulphur to generate intermediate B. Last, sulphur attacked intramolecular carbocation to generate FeCl₃ to catalyze the next reaction circulation.

Scheme 2 A plausible mechanism for the selective [3 + 2] cycloaddition of aziridine and isothiocyanatobenzene.

Conclusions

In conclusion, we have developed a new chemo- and stereo-selective [3 + 2] dipolar cycloaddition of aziridine with isothiocyanate catalysed by cheap Lewis acid FeCl₃. A series of new heterocyclic (tosylthiazolidin-2-ylidene)anilines were synthesized from readily available aziridines and isothiocyanates under mild conditions in two minutes. Simple FeCl₃ as catalyst renders the protocol be suitable for large-scale synthesis.

Acknowledgements

We are grateful to the University of Science and Technology of China and the great support from the School of Chemistry and Chemical Engineering, University of Jinan.

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available: General Information, further optimizing for the reaction conditions, synthesis of substrates, characterization data for the products and crystallographic data. CCDC 110418. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra04923k

‡ Representative procedure for selective [3 + 2] dipolar cycloaddition of aziridine with isothiocyanate: FeCl₃ (8 mg, 0.05 mmol) and aziridine 1a (137.0 mg, 0.5 mmol), 1 mL CH₃NO₂, 0.1 g 4 Å molecular sieve were loaded into a 10 mL oven-dried flask and the system put under vacuum and charged with N₂ three times. The system was cooled to −20 °C and isothiocyanatobenzene 2a (127.0 mg, 1.0 mmol) was added. The resulting mixture was maintained at −20 °C for another 2 min, then the reaction was quenched with 0.5 mL H₂O and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using PE : EtOAc : Et₃N (20 : 1 : 0.03, v/v/v) as eluent to give (tosylthiazolidin-2-ylidene)aniline 3aa as a white solid (163.0 mg, 80%).

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