New methods for the preparations of 2-arylaziridines, α -imidostyrenes, and allylamines from olefins via diphenylvinylsulfonium triflates

Reactions of diphenylvinylsulfonium triflates with primary amines and imides afforded 2-arylaziridines and α -imidostyrenes, respectively. These products were also obtained from styrenes in one vessel without isolation of the intermediate sulfonium salts. In addition, 1,1-disubstituted and trisubstituted alkenes were converted into allylamines via isomerization of initially formed vinylsulfonium salts to allylsulfonium salts in the presence of primary or secondary amines.


Introduction
Vinylphosphonium and vinylsulfonium salts are known as good Michael acceptors that undergo addition reactions with various nucleophiles.The former salts have been widely used as precursors of phosphonium ylides in the syntheses of heterocyclic compounds 1 and allylamines observed.The result of this methyl transfer reaction prompted us to study on reactions of diphenylvinylsulfonium salts with nitrogen nucleophiles in order to investigate chemical behaviors of the salts.
We recently reported three unique reactions of diphenylvinylsulfonium triflates 1 in a preliminary form as shown in Scheme 1: new synthetic approaches to (i) 2-arylaziridines 2 5 and (ii) α-imidostyrenes 3 6 from styrene derivatives via 1, and (iii) allylamines 5 7 from alkenes via unusual conversion of 1 to allylsulfonium salts 4. In this article, we would like to describe these three reactions in detail.

Synthesis of 2-arylaziridines from styrenes
An aziridine ring is known as a unique skeleton that is found in many natural products having interesting biological activities. 9Aziridines are also used as useful building units in organic and 2-(4-chlorophenyl)aziridines 2 were successfully synthesized in high yields (Table 1).When 1.1 equiv. of benzylamine alone was used, complete consumption of 1a was not observed even after prolonged reaction time or heating of the reaction mixture.On the other hand, when 2.2 equiv. of benzylamine was used, the aziridination led to completion to give 2a in 98% yield (entry 1).Combined use of 1.2 equiv. of benzylamine and 3 equiv.of tert-butylamine was preferable for shortening the reaction time because of the following reasons: The excess amount of tert-butylamine (bp 46 o C) was removed easily in the work-up procedure, and 1-tert-butyl-2-(4-chlorophenyl)aziridine was not formed because tert-butylamine was much less reactive than benzylamine.In the case of aziridination with 1-phenylethylamine, a mixture of diastereomeric aziridines 2d was obtained without any significant diastereoselectivity (entry 4).The aziridination with tert-butylamine proceeded very slowly as expected; therefore, it was carried out without the solvent to give 2e in 96% yield (entry 5).N-Nonsubstituted aziridine 2f was synthesized by using gaseous ammonia (entry 6).Moreover, sodium salts of sulfonamides reacted with 1a to afford "activated aziridines" in high yields (entries 7 and 8).c Determined by 1 H NMR analysis using an internal standard.d An excess amount of NH 3 gas was used.
Next, a one-pot synthesis of aziridines from styrenes and benzylamine without isolating the intermediate sulfonium salts 1 was examined (Table 2).The results of entries 1 and 5 indicated that the one-pot procedure (Method A) was more effective than the stepwise one (Method B), and would be useful even when the salts 1 were not stable.In the case of 1,1-diphenylethylene, the aziridination reaction proceeded very slowly compared to the others, which was due to its steric hindrance (entry 6).Aziridination of cis-and trans-β-methylstyrene gave the two diastereomeric aziridines in almost the same yields and diastereomeric ratios (1:1) (entries 7 and 8), which suggested that the stereochemistry of formed aziridines was not influenced by the configuration of styrenes.

α-Imidation of styrenes
Aziridine formation was accomplished by using diphenylsulfonium salts 1 and NH 2 type of nucleophiles.Next, we examined the reactions of 1 with NH type of nucleophiles such as imide compounds, and we found that an imido group was introduced regioselectively to the α-position of the styrenes to give α-imidostyrenes 3, useful precursors of vinylamines.

Reaction mechanisms for aziridination and α-imidation of styrenes
Proposed mechanisms for (i) aziridination and (ii) α-imidation of styrene derivatives are shown in Scheme 2. It was considered that these two reactions proceeded via the similar reaction paths.Initially, DPSD was formed from diphenyl sulfoxide and Tf 2 O at low temperature and was allowed to react with styrenes.
The aziridination was considered to proceed via the upper path in Scheme 2: Michael-type addition of R On the other hand, α-imidation of styrenes was considered to proceed via the lower path in Scheme 2: Michael-type addition of phthalimide anion, for example, to sulfonium triflate 1' gave sulfonium ylide 8 that was converted immediately into 9 by 1,2-prototropic shift.Successive regeneration of a double bond along with elimination of diphenyl sulfide produced α- phthalimidostyrene 3.
The behaviors of diphenylvinylsulfonium salts shown in the steps of 6 to 7 and 8 to 9 are unique and quite different from those of vinylphosphonium salts that undergo the so-called Schweizer reaction 1,2 via phosphonium ylides.

Synthesis of allylamines from alkenes
Allylic amines are valuable target products in medicinal chemistry 18 and are versatile synthetic intermediates. 19Although many methods are available for the preparation of allylic alcohols by allylic oxidation of alkenes, reactions such as stoichiometric allylic aminations using imido derivatives of sulfur 21 or selenium 22 and catalytic aminations using the palladium, 23 molybdenum, 24 or iron 25 catalyst.
In the attempted aziridination of α-methylstyrene with benzylamine according to our procedure mentioned above, expected 1-benzyl-2-methyl-2-phenylaziridine was not formed, but N-benzyl-2-phenyl-2-propenylamine (5a) was obtained instead in 80% yield.This result might be attributed to the steric hindrance that prevented the initial Michael-type addition of benzylamine.The above reaction was then considered to be useful for introducing amino functions into alkenes to produce the corresponding allylamines.
The results of Table 5 indicated that α-methylstyrene was converted successfully into α-(aminomethyl)styrenes without forming aziridines by treatment with DPSD, followed by various primary or secondary amines.The reactions with monoalkylamines proceeded smoothly at room temperature (entries 1−4), whereas higher temperature (100 o C) was required in the case with aniline (entry 5).In a similar fashion, the reactions with secondary amines provided the corresponding tertiary allylic amines in good yields (entries 6 and 7).The above reaction was explained as follows (Scheme 3).Initially, an alkene was treated with DPSD to form the corresponding diphenylvinylsulfonium triflate 1, which was supported by 1 H NMR analysis.Then, triflate 1 reacted with a primary or secondary amine to give the corresponding allylamine 5 and diphenyl sulfide via isomerization 26 of vinylsulfonium salt 1 to allylsulfonium salt 4 and the subsequent nucleophilic substitution of 4 with the amine.Next, the scope and limitation of the present reaction were studied by using benzylamine as a model amine (Table 6).1,1-Disubstituted alkenes gave the allylamines in moderate to good yields (entries 1−8).2,3-Diphenyl-1-propene and 2-phenyl-1-butene afforded a mixture of E, Z stereoisomers of 5i and 5j, respectively (entries 3 and 4).In the case of 3-methyl-2-phenyl-1butene, consumption of the corresponding sulfonium salt 1 was incomplete even after prolonged reaction time or heating, presumably because the steric hindrance at C-3 inhibited smooth double bond migration of 1 (entry 5).2-Methyl-1-pentene gave the expected two regioisomers with no significant regioselectivity (entry 7).Furthermore, trisubstituted alkenes gave the corresponding allylamines (entries 9 and 10).In these cases, the yields were rather low, which was presumably due to substantial steric repulsion between the corresponding allylsulfonium salt 4 and benzylamine.In the cases of aliphatic monosubstituted and 1,2-disubstituted alkenes, the desired allylamines were not obtained.It seemed that the intermediate vinylsulfonium salts 1 were not formed from these alkenes presumably because secondary carbocations generated from alkenes and DPSD were not stable enough to form the adducts.phenylaziridine was obtained as a by-product.f E/Z ratio was 1:1.g Ph 2 SO (1.5 equiv.)and Tf 2 O (1.5 equiv.)were used.h 2:1 mixture of the stereoisomers.

Experimental Section
General Procedures.Melting points were determined with a micro melting point apparatus (Yanaco MP-J3) and were not corrected.Infrared (IR) spectra were recorded on a Shimadzu IR-440 infrared spectrophotometer.

13
C NMR spectra were recorded on a JEOL JNM-EX270 (68 MHz) spectrometer with complete proton decoupling.Chemical shifts (δ C ) are reported in ppm relative to TMS using the solvent resonance (CDCl 3 : δ C 77.0 ppm) as the internal standard.High resolution mass spectra (HRMS) were recorded on a JEOL LCmate, a JEOL MS700, or an Applied Biosystems Mariner Ver.4.0 mass spectrometer.Analytical thin-layer chromatography (TLC) was performed on Merck precoated TLC plates (silica gel 60 F 254 , 0.25 mm).Preparative TLC was carried out on silica gel Wakogel B-5F.All solvents were distilled from appropriate drying agents, and commercially available reagents were used without purification.Unless otherwise noted, reactions were carried out in oven-dried glassware with magnetic stirring under an atmosphere of argon.

Typical experimental procedure for the synthesis of aziridines (Table 1 and Table 2, Method B)
To a stirred solution of 1a or 1b (0.20 mmol) in DMSO (0.2 mL) was added a solution of a primary amine (0.24 mmol) in DMSO (0.3 mL) at room temperature.Then, a solution of tertbutylamine (0.60 mmol) in DMSO (0.3 mL) was added and the mixture was stirred at room temperature for 1 h.The reaction was quenched with a 0.1 M NaOH solution (10 mL), and the organic material was extracted with CHCl 3 (10 mL x 2).The organic layer was dried over anhydrous Na 2 SO 4 and filtrated.The filtrate was concentrated in vacuo, and the residue was purified by preparative TLC to give the corresponding aziridine 2. H NMR analysis using triphenylmethane (δ H 5.55) as an internal standard.

2-(4-Chlorophenyl)-1-phenylsulfonylaziridine (2g)
. 28 To a stirred suspension of NaH (55% dispersion in mineral oil, 15.7 mg, 0.36 mmol) in THF (1.0 mL) was added benzenesulfonamide (56.6 mg, 0.36 mmol) at room temperature.After 0.5 h, a solution of 1a (141.9 mg, 0.30 mmol) in THF (1.0 mL) was added, and the reaction mixture was stirred at room temperature for 12 h.The reaction was quenched with a 0.1 M NaOH solution (10 mL), and the organic material was extracted with EtOAc (10 mL x 2).The organic layer was dried over anhydrous Na 2 SO 4 and filtrated.The filtrate was concentrated in vacuo, and the residue was purified by preparative TLC to give 2g (85.

Typical experimental procedure for the synthesis of α-imidostyrenes (Table 3, Method A)
To a stirred suspension of NaH (55% dispersion in mineral oil, 0.22 mmol) in DMSO (0.4 mL) was added an imide compound (0.22 mmol) at 10 o C.After stirring the mixture for 0.5 h at room temperature, the salt 1a (0.20 mmol) was added, and the mixture was stirred at room temperature for the time indicated in Table 3.The reaction was quenched with cold water (10 mL), and the organic material was extracted with Et 2 O (10 mL x 2).The organic layer was dried over anhydrous Na 2 SO 4 and filtrated.The filtrate was concentrated in vacuo, and the residue was purified by preparative TLC to give the corresponding α-imidostyrene 3.An analytical sample was prepared by crystallizing 3 from MeOH.

2-[1-(4-Chlorophenyl)vinyl]isoindoline-1,3-dione (3c). Method B:
A mixture of 1a (23.6 mg, 0.05 mmol) and potassium phthalimide (10.2 mg, 0.055 mmol) in DMSO (0.25 mL) was stirred at room temperature for 12 h.The reaction was quenched with cold water (10 mL), and the organic material was extracted with Et 2 O (10 mL x 2).The organic layer was dried over anhydrous Na 2 SO 4 and filtrated.The filtrate was concentrated in vacuo, and the residue was purified by preparative TLC to give 3c (12.8  Cl 2 (0.3 mL) was then added dropwise at -78 °C.After 10 min, the mixture was warmed up to 0 °C, and the solvent was removed in vacuo.

a
Method A: After a solution of the sulfonium salt was evaporated at 0 o C, BnNH 2 was added to the residue and stirred.Method B: BnNH 2 was added to a solution of the sulfonium salt at -78 o C, and then the mixture was warmed up to rt. b Isolated yield.c BnNH 2 (5 equiv.) was used.d E/Z ratio was 4.4:1, confirmed by the NOE difference experiment.e 1-Benzyl-2-ethyl-2-

Table 2 .
One-pot synthesis of aziridines from styrenes and benzylamine b Product a Method A: one-pot procedure described in the text.Method B: Benzylamine (1.2 equiv.)andtert-butylamine(3 equiv.)wereadded to a solution of isolated sulfonium salt 1a (entry 1) or 1b (entry 5) in DMSO, and the mixture was stirred at rt for 1 h.Method C: A mixture of benzylamine (9 equiv.)andisolatedsulfonium salt 1c was stirred at rt for 1 day.bIsolatedyield (2 steps).cThereaction time for the second step was 12 h.d Combined yield of the chromatographically separable diastereomers (1:1).

Inc Typical experimental procedure for the synthesis of α-(aminomethyl)styrenes (Table 5 )
To a solution of diphenyl sulfoxide (121.4 mg, 0.60 mmol) in CH 2 Cl 2 (1 mL) was added triflic anhydride (0.098 mL, 0.60 mmol) at -78 °C, followed by dropwise addition of α-methylstyrene (59.1 mg, 0.50 mmol) in CH 2 Cl 2 (1 mL) at -78 °C.After 10 min, the reaction mixture was warmed up to 0 °C, and the solvent was removed in vacuo.A solution of an amine (2.50 mmol) in CH 2 Cl 2 (1 mL) was added to the residue and stirred at room temperature.The reaction was quenched with a 0.1 M NaOH solution (20 ml), and the organic material was extracted with CH 2 Cl 2 (20 mL x 2).The organic layer was dried over anhydrous Na 2 SO 4 and filtrated.The filtrate was concentrated in vacuo, and the residue was purified by preparative TLC to give the corresponding allylamine 5.