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One-pot and microwave-assisted synthesis of N-sulfonylaziridines Hao Xu a , Hua Tian a , Liangyu Zheng b,, Qingwen Liu a , Li Wang a , Suoqin Zhang a,a College of Chemistry, Jilin University, Changchun 130012, PR China b Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, Jilin University, Changchun 130012, PR China article info Article history: Received 23 December 2010 Revised 18 March 2011 Accepted 25 March 2011 Available online 1 April 2011 Keywords: N-sulfonylaziridines Microwave synthesis One-pot reaction Chiral amino alcohol abstract A novel and efficient microwave-assisted one-step reaction was developed to synthesize chiral N-sulf- onylaziridines by the reaction of different chiral amino alcohols and sulfonic chlorides. The newly devel- oped microwave synthetic method has the advantage of reducing the reaction time from 24 to 0.5 h with improved yields (84–93%) and minimizing by-products. Ó 2011 Elsevier Ltd. All rights reserved. Aziridines as building blocks 1 and chemical reagents 2 are important functional compounds in organic synthesis. The applica- tion of enantiomerically enriched aziridines as asymmetric syn- thetic intermediates continues to enjoy widespread exposure in asymmetric organic synthesis. In analogy to epoxides, enantiome- rically enriched aziridines react with different nucleophiles, via ring opening reactions, allowing the introduction of a chiral ethylamino group in a wide range of substrates. 3,4 In particular, chiral N-sulfonylaziridines, as reagents for chemical fixation of CO 2 , 5 as ligands 6,7 and as precursors of many synthetic targets, 4f,g are much more important. Due to the importance of chiral N-sulfonylaziridines, consider- able efforts have been devoted to their synthesis. N-sulfonylaziri- dines have been prepared from b-hydroxy-a-animoe-sters by intramolecular cyclization, 6,7 from N,O-disulfonyl derivatives 8 and N-trityl-O-tosyl derivatives by ring closure, 4e,9 and from al- kenes via nitrene insertion. 10 In 1992 Craig and Berry 11 employed a three-step process to synthesize aziridines from commercially available chiral amino acids. In 2003 Leighton and Krauss 12 dem- onstrated that aziridines could be prepared by a more effective, one-step sequence from either L-valinol or L-tert-leucinol. In 2004 Zhang 13 prepared N-sulfonylaziridines via the aziridination of tras-b-methylstyrene using iron as a catalyst. Even though many syntheses of N-sulfonylaziridines have been reported, the exploration of new methods has been very active in recent years. In 2007, Marzorati and Vitta 14 refined this process so that such N-sulfonylaziridines with withdrawing groups could be obtained in good yields by phase-transfer catalysts at the first time. In 2009 Groeper 15 demonstrated that other sulfonyl groups, such as camphorslfonyl chloride, could be used in the synthesis of N-sulfonylaziridines. However, in these methods synthesis of N-sulfonyl aziridines needed more steps, longer time (12–48 h), much lower tempera- ture ( 78 to 50 °C), or special reagents such as Aliquat 336 or camphorslfonyl chloride. Up to date aziridines have not been pre- pared effectively via one-pot reaction from amino alcohols and sul- fonic chlorides, probably due to the fact that other by-products are competitive with the main products in the cyclization reaction. Herein, based on the study of the main by-product, we report a novel and efficient microwave-assisted one-pot reaction that was developed to synthesize chiral N-sulfonylaziridines from different chiral amino alcohols and sulfonic chlorides. When microwave (MW) irradiation was used in the reactions, the ring-closure reac- tion time was shortened and the main by-products were minimized. Chiral amino alcohols (2a2d) were obtained in excellent yields by the reaction of commercially available chiral amino acids (1a1d) with an excess of LiAlH 4 in THF. Chiral amino alcohol (2e) was obtained by the esterification of commercially available L-ser- ine (1e) with sulfoxide chloride (SOCl 2 ) in methanol. Under microwave irradiation and different solvents conditions, compound 2a can also be converted into N-tosylaziridines 3a with high yields at higher temperature (40 °C), however, it is not possible to isolate 3a when the reaction is carried out without microwave irradiation, but instead only other by-products. Via complete characterizations by spectral methods, the main by- product was confirmed as a six-member ring compound (4a) (Scheme 1). To minimize 4a, we submitted chiral amino alcohol 0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2011.03.106 Corresponding authors. Tel.: +86 431 85155252; fax: +86 431 85168420 (L.Z.); tel.: +86 431 85168468; fax: +86 431 85168420 (S.Z.). E-mail addresses: [email protected] (L. Zheng), [email protected] (S. Zhang). Tetrahedron Letters 52 (2011) 2873–2875 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet

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Page 1: One-pot and microwave-assisted synthesis of N-sulfonylaziridines

Tetrahedron Letters 52 (2011) 2873–2875

Contents lists available at ScienceDirect

Tetrahedron Letters

journal homepage: www.elsevier .com/ locate/ tet le t

One-pot and microwave-assisted synthesis of N-sulfonylaziridines

Hao Xu a, Hua Tian a, Liangyu Zheng b,⇑, Qingwen Liu a, Li Wang a, Suoqin Zhang a,⇑a College of Chemistry, Jilin University, Changchun 130012, PR Chinab Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, Jilin University, Changchun 130012, PR China

a r t i c l e i n f o

Article history:Received 23 December 2010Revised 18 March 2011Accepted 25 March 2011Available online 1 April 2011

Keywords:N-sulfonylaziridinesMicrowave synthesisOne-pot reactionChiral amino alcohol

0040-4039/$ - see front matter � 2011 Elsevier Ltd. Adoi:10.1016/j.tetlet.2011.03.106

⇑ Corresponding authors. Tel.: +86 431 85155252; ftel.: +86 431 85168468; fax: +86 431 85168420 (S.Z.

E-mail addresses: [email protected] (L. Zheng), su

a b s t r a c t

A novel and efficient microwave-assisted one-step reaction was developed to synthesize chiral N-sulf-onylaziridines by the reaction of different chiral amino alcohols and sulfonic chlorides. The newly devel-oped microwave synthetic method has the advantage of reducing the reaction time from 24 to 0.5 h withimproved yields (84–93%) and minimizing by-products.

� 2011 Elsevier Ltd. All rights reserved.

Aziridines as building blocks1 and chemical reagents2 areimportant functional compounds in organic synthesis. The applica-tion of enantiomerically enriched aziridines as asymmetric syn-thetic intermediates continues to enjoy widespread exposure inasymmetric organic synthesis. In analogy to epoxides, enantiome-rically enriched aziridines react with different nucleophiles, viaring opening reactions, allowing the introduction of a chiralethylamino group in a wide range of substrates.3,4 In particular,chiral N-sulfonylaziridines, as reagents for chemical fixation ofCO2,5 as ligands6,7 and as precursors of many synthetic targets,4f,g

are much more important.Due to the importance of chiral N-sulfonylaziridines, consider-

able efforts have been devoted to their synthesis. N-sulfonylaziri-dines have been prepared from b-hydroxy-a-animoe-sters byintramolecular cyclization,6,7 from N,O-disulfonyl derivatives8

and N-trityl-O-tosyl derivatives by ring closure,4e,9 and from al-kenes via nitrene insertion.10 In 1992 Craig and Berry11 employeda three-step process to synthesize aziridines from commerciallyavailable chiral amino acids. In 2003 Leighton and Krauss12 dem-onstrated that aziridines could be prepared by a more effective,one-step sequence from either L-valinol or L-tert-leucinol. In 2004Zhang13 prepared N-sulfonylaziridines via the aziridination oftras-b-methylstyrene using iron as a catalyst.

Even though many syntheses of N-sulfonylaziridines have beenreported, the exploration of new methods has been very active inrecent years. In 2007, Marzorati and Vitta14 refined this processso that such N-sulfonylaziridines with withdrawing groups could

ll rights reserved.

ax: +86 431 85168420 (L.Z.);).

[email protected] (S. Zhang).

be obtained in good yields by phase-transfer catalysts at the firsttime. In 2009 Groeper15 demonstrated that other sulfonyl groups,such as camphorslfonyl chloride, could be used in the synthesisof N-sulfonylaziridines.

However, in these methods synthesis of N-sulfonyl aziridinesneeded more steps, longer time (12–48 h), much lower tempera-ture (�78 to �50 �C), or special reagents such as Aliquat 336 orcamphorslfonyl chloride. Up to date aziridines have not been pre-pared effectively via one-pot reaction from amino alcohols and sul-fonic chlorides, probably due to the fact that other by-products arecompetitive with the main products in the cyclization reaction.

Herein, based on the study of the main by-product, we report anovel and efficient microwave-assisted one-pot reaction that wasdeveloped to synthesize chiral N-sulfonylaziridines from differentchiral amino alcohols and sulfonic chlorides. When microwave(MW) irradiation was used in the reactions, the ring-closure reac-tion time was shortened and the main by-products wereminimized.

Chiral amino alcohols (2a–2d) were obtained in excellent yieldsby the reaction of commercially available chiral amino acids (1a–1d) with an excess of LiAlH4 in THF. Chiral amino alcohol (2e)was obtained by the esterification of commercially available L-ser-ine (1e) with sulfoxide chloride (SOCl2) in methanol.

Under microwave irradiation and different solvents conditions,compound 2a can also be converted into N-tosylaziridines 3a withhigh yields at higher temperature (40 �C), however, it is notpossible to isolate 3a when the reaction is carried out withoutmicrowave irradiation, but instead only other by-products. Viacomplete characterizations by spectral methods, the main by-product was confirmed as a six-member ring compound (4a)(Scheme 1). To minimize 4a, we submitted chiral amino alcohol

Page 2: One-pot and microwave-assisted synthesis of N-sulfonylaziridines

Table 2Preparation of N-tosylaziridinesa (3a–3e)

5d

MW

DCM/DMAPN

R3a-3e2a-2e

OHNH2

+ TsCl TsR

Entry Amino alcohol Base Time (h) Yieldb (%)

1 2a K2CO3 0.5 932 2b K2CO3 0.5 933 2c K2CO3 0.5 894 2d K2CO3 0.5 885c 2e K2CO3 1 90

2a: valinol; 2b: L-phenylalaninol; 2c: L-leucinol; 2d: L-alaninol; 2e: L-serine methylester.

a Conditions: the reaction were preformed at 40 �C, in DCM, under microwaveirradiation (400 W), 20% DMAP.

b Isolated yield.c Without DMAP.

3a 4a2a

OH

NH2+ TsCl N

Ts+

Ts

Ts

5d

Scheme 1. The reaction of tosyl chloride and valinol.

Table 3

2874 H. Xu et al. / Tetrahedron Letters 52 (2011) 2873–2875

(2a) to react with tosyl chloride, inorganic bases, and 4-dimethyl-aminopyridine (DMAP) in dichloromethane (DCM) under micro-wave irradiation. When the reaction was performed after 30 min,only one new spot was observed by TLC (ethyl acetate/petroleumether = 1:6, Rf = 0.45). Complete characterizations by spectralmethods confirmed the product as N-tosyl-2-benzlyaziridine(3a).16 The ring closure reaction was completed as expected undermicrowave irradiation.

The results of the synthesis of N-tosyl-2-benzlyaziridine 3afrom the Valinol (2a) in different reaction conditions are summa-rized in Table 1. When the reaction was performed at 40 �C withDMAP and K2CO3 in dichloromethane, product 3a was obtainedin good yields in 30 min. When the reaction was performed inother solvents (THF, MeCN, diethyl ether), the results were reason-able. Via altering different inorganic and organic bases, such asK2CO3, Na2CO3, Cs2CO3, NaOH, and TEA, the excellent results wereobtained, when K2CO3 and Cs2CO3 were applied in the reaction.Under microwave irradiation 4a was scarcely observed, probablydue to the fact that intramolecular cyclization was much morefavorable than intermolecular reaction under the microwave irra-diation condition. Compared to the previous reported methodswhich needed 16–48 h11,12 or special reagents14,15 for the synthesisof N-tosylaziridines from amino alcohols and sulfonic chlorides inreasonable yields, the present one-pot microwave assisted cycliza-tion reaction is much more efficient.

The successful cyclization of Valinol (2a) encouraged us to ex-plore more chiral amino alcohols (2b–2e). The results are summa-rized in Table 2. As expected, N-tosylaziridines (3b–3e) wereobtained in 30 mins in good yields (88–93%). Methyl (2S)-1-[(4-methylphenyl)sulfonyl]aziridine-2-carboxylate (3e), includingan electron withdrawing group, was more difficult to be synthesizedthan other analogues with an electron donating group using the re-ported methods.14 Though different phase-transfer catalysts wereapplied in the reaction, (2S)-1-[(4-methylphenyl)sulfonyl]aziri-

Table 1Preparation of N-tosylaziridinea (3a)

NH2

OH+

3a 4a2a

+ TsCl NTs N

N

Ts

TsMW

DCM/DMAP

5d

Entry Solvent Base Time (h) Yield (%) 3ab Yield (%) 4ab

1 Diethyl ether K2CO3 0.5 91 Trace2 THF K2CO3 0.5 87 103 MeCN K2CO3 0.5 89 Trace4 DCM K2CO3 0.5 93 —5c DCM K2CO3 96 69 266 DCM Na2CO3 2 48 —7 DCM Cs2CO3 0.5 92 —8 DCM NaOH 0.5 85 —9 DCM TEA 1 80 Trace

a Conditions: the reaction were preformed at 40 �C, in DCM, under microwaveirradiation (400 W), 20% DMAP.

b Isolated yield.c Without microwave irradiation.

dine-2-carboxylate (3e) was only obtained in a reasonable yield(54%) in previous reports. When 3e was synthesized according tothe new one-pot method under the same condition as 3a, numer-ous by-products occurred. The possible reason is that DMAP couldactivate the acyl groups, which resulted in the side-reactionsoccurring. However, the synthesis of (2S)-1-[(4-methylphenyl)sul-fonyl]aziridine-2-carboxylate (3e) was also explored in a higheryield (90%) in 60 min under microwave irradiation without DMAP.

Enantiomerically pure N-tosylaziridines from chiral amino alco-hols should be obtained if racemization does not occur in the con-version. Thus, the specific rotation of all the products (3a–3e) wasdetermined. Compared to the reported specific rotation, theN-tosylaziridines of >98% ee were obtained. The results confirmedthat racemization was avoided under microwave irradiation.

For demonstrating that the method is extensive, other sulfonicchlorides have been used to react with chiral amino alcohols toperform the intramolecular cyclization. The results are summa-rized in Table 3. With more active sulfonic chlorides (5a–5b), azir-idines were obtained in high yields. When chiral amino alcoholswere converted into aziridines via the reactions with inactive sul-

Preparation of N-sulfonylaziridines via the reaction of sulfonic chlorides and aminoalcoholsa

5a-5c 3f-3i

SClOO

R1+ OH MW

DCM/DMAPN SO

OR1

RNH2

R

Entry Sulfonic chloride Amino alcohol Time (h) Yieldc,e (%)

1 5a 2b 0.5 84 (3f)2 5b 2b 0.5 89 (3g)3d 5b 2e 1 65 (3h)4 5c 2b 1 88 (3i)5b 5a 2b 96 75 (3f)6b 5b 2b 96 48 (3g)7b,d 5b 2e 96 —8b 5c 2b 96 39 (3i)

a: R 1 = methyl, b: R1 = phenyl, c: R1 = 4-methoxyphenyl.a Conditions: the reactions were preformed at 40 �C, in DCM, under microwave

irradiation (400 w), 20% DMAP.b Without microwave irradiation.c Isolated yield.d Without DMAP.e HPLC was used for determination. For analysis of 3f–3i: Chiralcel OD-H,

n-hexane/isopropyl alcohol = 95:5. The racemizations of products were notobserved under microwave irradiation, and 3f–3i of >99% ee were obtained.

Page 3: One-pot and microwave-assisted synthesis of N-sulfonylaziridines

H. Xu et al. / Tetrahedron Letters 52 (2011) 2873–2875 2875

fonic chlorides (5c), which have not been reported in previous re-ports, aziridines were also obtained easily in 60 min. The resultssuggest that N-sulfonylaziridines with active or inactive sulfonylgroups were easily prepared under microwave irradiation.

In summary, the cyclization reaction of chiral amino alcoholsand sulfonic chlorides under microwave irradiation is an efficientone-pot procedure to prepare chiral N-sulfonylaziridines. It isapplicable to synthesize N-sulfonylaziridines by the reaction ofreadily available b-hydroxy-a-animo derivatives with electronwithdrawing groups or electron donating groups and active sul-fonic chlorides or inactive sulfonic chlorides. The conditions ofthe cyclization reactions were optimized in different solvents withinorganic or organic bases. The reactions by using microwave irra-diation gave the object products in a better yield (84–93%) inshorter time with higher purity.

Acknowledgments

The authors are grateful for the financial support from NationalNatural Science Foundation of China (No. 20802025) and Jilin Pro-vincial Science & Technology Sustentation Program (Nos.20090585 and 20100538).

References and notes

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20.16. General procedure for preparation of N-sulfonylaziridines: A solution of 2a

(0.103 g, 1 mmol) in anhydrous dichloromethane (20 mL) was cooled to 0 �C.K2CO3 (0.552 g, 4 mmol), DMAP (24.0 mg, 0.2 mmol) and tosyl chloride(0.416 g, 2.2 mmol) were added to the reaction mixture. The mixture wasstirred under microwave irradiation (400 W) at 40 �C. After 30 min, thereaction mixture was washed with saturated brine. Organic phase was driedover anhydrous Na2SO4 and concentrated in vacuum. The crude product waspurified by silica gel column to give 3a (0.209 g, 0.877 mmol, 87.7%) as a whitesolid. 1H NMR (CDCl3, 300 MHz) d (ppm) 7.83 (d, J = 8.2 Hz, 2H), 7.34(d, J = 8.2 Hz, 2H), 2.62 (d, J = 7.0 Hz, 1H), 2.55–2.48 (m, 1H), 2.45 (s, 3H),2.11 (d, J = 4.6 Hz, 1H), 1.47–1.36 (m, 1H), 0.90 (d, J = 6.8 Hz, 3H), 0.79(d, J = 6.8 Hz, 3H). MS (ESI) m/z: calcd for (M+H)+ 240, found 240.15. Anal. Calcdfor C12H17NO2S: C, 60.22; H, 7.16; N, 5.85; S, 13.40. Found: C, 60.29; H, 7.14; N,5.82; S, 13.39. The by-product 4a (trace) was obtained at the same time as awhite solid. 1H NMR (CDCl3, 300 MHz) d (ppm) 7.98 (d, J = 8.0 Hz, 4H), 7.35(d, J = 8.0 Hz, 4H), 4.46–4.41 (m, 2H), 4.27 (t, J = 8.7 Hz, 2H), 4.15 (dd, J = 9.0,3.0 Hz, 2H), 2.52–2.43 (m, 8H), 0.93 (d, J = 6.9 Hz, 6H), 0.76 (d, J = 6.9 Hz, 6H).MS (ESI) m/z: calcd for (M+H)+ 479, found 479.04. Anal. Calcd forC24H34N2O4S2: C, 60.22; H, 7.16; N, 5.85; S, 13.40. Found: C, 60.27; H, 7.15;N, 5.81; S, 13.42.