Aminolysis of N -tosylaziridines: an approach to asymmetric synthesis of symmetric and unsymmetric chiral sulfonamide ligands

The ring-opening of N -tosylaziridines with aliphatic amines can be efficiently catalyzed by lithium perchlorate to provide derivatives of the trans -1,2-diamine in high yields. The reaction was used in desymmetrization of several cyclic N -tosylaziridines using chiral amines. Using this strategy, an efficient synthesis was developed of chiral vicinal C 2 symmetric bis-(sulfonamides), unsymmetrical bis(sulfonamides) and other symmetric and unsymmetric ligands based on trans - 1,2-cyclohexanediamine.


Introduction
2][3] C 2 -Symmetric bis(sulfonamide) ligands of the type 1 (Figure 1) are electronically different and bind well to early transition metals 4 and main-group elements. 5This type of ligand has been used in the asymmetric Diels-Alder reaction, 5,6 the alkylation of aldehydes, 7 the cyclopropanation of allylic alcohols 8 and the amination of N-acyloxazolidones. 9he chemistry of these ligands has been very well studied in the field of asymmetric synthesis.However, not much work has been done using unsymmetrical bis(sulfonamide) ligands of type 2. 10,11 This is mainly due to their non-availability and difficulty in the mono-sulfonylation of the 1,2-diamine such as 3. Palladium-catalyzed monoarylation of 1,2-diamine 3 has been developed, but the yields were not high. 12Walsh and coworkers have developed a very good procedure for the synthesis of unsymmetrical bis(sulfonamides) via an amino-sulfonamide 4 from the commercially available corresponding diamine.13a,b In this paper we describe full details of our work towards a general approach to this kind of chiral ligand, based on the aminolysis of aziridines.13c

Results and Discussion
It was envisaged that if N-tosylcyclohexyl aziridine were opened with a benzylamine in a diastereoselective manner, the product could be converted into an amino-sulfonamide after debenzylation.With this idea, several N-tosyl aziridines were synthesized using known procedures. 14Although ring-opening of such N-activated aziridines with aromatic amines has been studied extensively using Lewis acids, 15 little has been published on the opening with aliphatic amines. 16At the outset, 10 mol.% of several Lewis acids such as Cu(OTf) 2 (70%), Zn(OTf) 2 (81%), Sn(OTf) 2 (78%), YbCl 3 (70%), ErCl 3 (68%), and LiClO 4 (88%), were screened for opening of N-tosylcyclohexyl aziridine (1 mmol) with benzylamine (1.25 mmol) in MeCN at room temperature over more than 24 h.From this study, it appeared that LiClO 4 is more effective, as indicated by isolated yields.Long reaction times at room temperature prompted us to try the same reaction at reflux temperature using LiClO 4 as a catalyst.To our delight, the reaction was complete in 4 h and the ring-opened product was obtained in 94% yield (Table 1, entry 1).The trans-stereochemistry in the product was deduced from the coupling constants (J = 10.5 Hz and 3.9 Hz) of the signal at 2.29 ppm (-CH-NH-) in the 1 H-NMR spectrum.The ring opening reaction was also tried with other amines such as phenylethylamine, piperidine, morpholine, and N-ethoxycarbonyl piperazine.In all cases, high yields of product were obtained (Table 1, entries 2-5).The reaction was extended to a few other N-tosyl aziridines and the results are summarized in Table 1.Aziridines derived from cyclopentene and cyclohexa-1,4-diene gave the ring-opened products in good to excellent yields (Table 1, entries 6-9).An acyclic terminal aziridine gave products resulting from terminal attack only (Table 1, entries 10 and 11).
Once the methodology for cleavage of N-tosylaziridines with aliphatic amines, 18 especially benzylamine, was established it was extended to chiral amines.Initially, (R)-αmethylbenzylamine (1.25 mmol) was used for desymmetrization of N-tosylcyclohexyl aziridine (1 mmol) in the presence of LiClO 4 (0.1 mmol) in MeCN.The reaction was complete in 6 h at reflux temperature and the product was obtained in 94% yield as a separable mixture of diastereomers in a 1:1 ratio (Table 2, entry 1).The reaction was scaled up to 25 g scale without any problem.The (S,S,R)-9 diastereomer is more polar (R f 0.28) than (R,R,R)-9 (R f 0.42).The absolute stereochemistry was established by X-ray analysis (vide infra).The ring opening reaction proceeded well with (R)-3,3-dimethyl-2-butylamine also, and a separable mixture of diastereomers (1:1 ratio) was obtained in 82% yield (Table 2, entry 2).In all cases the diastereomeric ratio was determined by 1 H-NMR spectroscopy.The above reaction was extended to the tosylaziridine derived from cyclopentene also.Although good-to excellent yields of the ring-opened products were obtained, the diastereomers could not be separated by column chromatography.Another chiral amine, (R)-1-(3-methoxy phenyl)ethylamine, was also tried, but was no help (Table 2, entry 4).The mono tosylaziridine of cyclohexa-1,4-diene gave a similar result to that of cyclohexene, where diastereomers could be separated (Table 2, entry 6 90 (4 h) a The ratio of N-tosylaziridine, aliphatic amine, and LiClO 4 was 1.0:1.25:0.1.b Isolated yield after column chromatography over silica gel, using hexane and ethyl acetate as eluents.
In order to prove the absolute stereochemistry of the product 9, one of its diastereomers (the less polar) was methylated with MeI to prepare 15a whose crystal structure (Figure 2) proved it to be (R,R,R)-9.In order to show the versatility, several alkylated amines were synthesized (Scheme 1).Surprisingly, alkylation of (R,R,R)-9 with 2-methoxybenzyl bromide under identical conditions did not give the desired product.Instead, the reaction took place on the nitrogen to which the tosyl group was attached, thus giving 16 in 72% yield (Scheme 1).The structure was confirmed by an X-ray crystal structure determination (Figure 2).This result is strange, especially given the fact that the same reaction with benzyl bromide provided 15f where alkylation took place on the other nitrogen.The reason for this anomaly could be due to steric interaction between the methyl group on the chiral center and ortho-methoxy group on the benzyl bromide.83 (8 h) a The ratio of N-tosylaziridine, chiral amine, and LiClO 4 was 1.0:1.25:0.1 and the products were obtained in 1:1 diastereomeric ratio.b The diastereomeric ratio was determined by 1 H-NMR spectroscopy in all cases.c The diastereomers separated on TLC only for entries 1, 2, and 6.After successful chromatographic separation of the enantiopure ring-opened product 9, we planned to synthesize several chiral ligands.Thus, the (S,S,R)-9 diastereomer was subjected to debenzylation (Pd/C and HCOONH 4 ) to provide the amino-sulfonamide (S,S)-4 in 91% yield.This is an important precursor for several chiral ligands.For example, (S,S)-4 was tosylated to provide the C 2 symmetric bis(sulfonamide) ligand (S,S)-1.Its treatment with various sulfonyl chlorides provided a series of enantiopure unsymmetrical vicinal bis(sulfonamide) ligands (S,S)-2a-h in good to excellent yields.The amino-sulfonamide (S,S)-4 compound was also converted into an important chiral ligand 17 10a in quantitative yield.13a Pyridine-based bis(amide) is also well known ligand to bind well to transition metal complexes. 20These ligands are also important as far as enantioselective transformations are concerned.The aminosulfonamide (S,S)-4 furnished the C 2 -symmetric pyridyl bis(amide) bis(sulfonamide) ligand (S,S)-18 when treated with 0.5 equivalent of 2,6-pyridinedicarbonyl dichloride in dichloromethane in the presence of triethylamine.Similarly, (S,S)-19 was prepared using 3-picolinic acid (Scheme 3).13b We have synthesized L-Prolinamide based on trans-1,2diaminocyclohexane (S,S,S)-21 and (R,R,S)-21 by the coupling of aminosulfonamide (S,S)-4 with N-Boc-L-Proline followed by deprotection of the Boc group using HCOOH.These chiral ligands would be useful in asymmetric organocatalytic aldol reactions.In conclusion, we have developed an efficient method for the desymmetrization of N-tosyl aziridines in the presence of LiClO 4 . 22We have used the method to synthesize a variety of symmetrical and unsymmetrical chiral ligands based on trans-1,2-diaminocyclohexane.To the best of our knowledge, this is the first straightforward method for the synthesis of chiral unsymmetrical bis(sulfonamide) ligands based on trans-1,2-diaminocyclohexane.

Experimental Section
General Procedures.1H-NMR spectra were recorded on a 400 MHz spectrometer.Chemical shifts are expressed in ppm downfield from TMS as internal standard, and coupling constants are reported in Hz.Routine monitoring of reaction was performed by TLC, using precoated silica gel TLC plates obtained from E-Merck.All the column chromatographic separations were done by using silica gel (Acme's, 60-120 mesh).The petroleum used was of boiling range 60-80 °C.Reactions that needed anhydrous conditions were run under an atmosphere of nitrogen or argon using flame-dried glassware.The organic extracts were dried over anhydrous sodium sulfate.Evaporation of solvents was performed under reduced pressure.Dichloromethane and acetonitrile were distilled over CaH 2 , and THF over sodium and benzophenone.

Table 1 .
). Reaction of N-tosyl aziridines with aliphatic amines catalyzed by LiClO 4 in MeCN at reflux temperature a

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(1 mmol)and salicylaldehyde(1 mmol)in MeOH (10 mL) was treated with Na 2 SO 4 (500 mg) and the reaction mixture was left at RT overnight.After completion of the reaction (checked by running TLC), the solid residue was filtered off and the filtrate concentrated.The crude material was purified by column chromatography over silica gel 454 (M + +1); Anal.Calcd.for C 19 H 23 N 3 O 6 S 2 : C, 50.32;H, 5.11; N, 9.27.