An amine-promoted aziridination of chalcones

Article abstract of DOI:10.1002/anie.200602586

(Chemical Equation Presented) Without protection: α-Keto aziridines have been formed in a novel amine-promoted direct aziridination of chalcones using an aminimide generated in situ from a tertiary amine and O-mesitylenesulfonylhydroxylamine (MSH) in the

Full text of DOI:10.1002/anie.200602586

Angewandte
Chemie
Small Ring Systems
DOI: 10.1002/anie.200602586
An Amine-Promoted Aziridination of
Chalcones**
Yu-Mei Shen, Mei-Xin Zhao, Jiaxi Xu, and Yian Shi*
Aziridines are versatile building blocks that can undergo
various synthetically useful transformations and are also an
important part of many biologically active molecules.[1] Great
efforts and progress have been made in the development of
various aziridination methods.[1–15] As part of our general
interest in the area of small-ring synthesis from olefins,we
have been investigating new methods to prepare aziridines,
particularly those without protecting groups on the nitrogen
atom,such as the aziridination of electron-deficient olefins
with aminimide 1 (Scheme 1).
[*] Y.-M. Shen, M.-X. Zhao, J. Xu, Prof. Dr. Y. Shi
Department of Chemistry
Colorado State University
Fort Collins, CO 80523 (USA)
Fax: (+1)970-491-1801
E-mail: yian@lamar.colostate.edu
[**] We are grateful to the generous financial support from the Monfort
Foundation (Colorado State University).
Supporting information for this article (aziridination procedures,
characterization including an X-ray crystallographic analysis, and
the determination of the ee values) is available on the WWW under
http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2006, 45, 8005 –8008
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8005

Communications
Table 1: Stoichiometric[a] and catalytic[b] aziridination of chalcones.
Entry
Substrate
Equiv.
of amine
Yield
[%][c]
1a
1b
1c
1d
1.0
0.1
0.1
0.2
85
52[d]
65
80
Scheme 1. Aziridination of electron-deficient olefins with aminimide 1.
EWG=electron-withdrawing group.
2a
2b
1.0
0.2
80
60
In 1980,Ikeda et al. reported that the aminimide
2
3a
3b
1.0
0.2
82
59
(prepared from 1,1-dimethylhydrazine and propylene oxide)
can directly iminate chalcones to form aziridines.[16] Since
4a
4b
1.0
0.2
49
65
5a
5b
1.0
0.2
56
21
then,little has been reported on this reaction. Initial studies
by our research group have shown that this aziridination
could be extended to other aminimides. For example,the
aminimide derived from hydrazinium nitrate 3 (prepared
from 1,4-diazabicyclo[2.2.2]octane (DABCO) and hydroxyl-
amine-O-sulfonic acid in the presence of barium oxide and
barium nitrate)[17] can effectively aziridinate chalcones.[18] To
further develop this aziridination reaction,we wanted to
investigate whether this system could be developed into a
catalytic and eventually an asymmetric process to form
nonracemic a-keto aziridines,and herein report our prelimi-
nary results.
6a
6b
1.0
0.2
64
39
7a
7b
1.0
0.2
78
67
8a
8b
1.0
0.2
54
42
[a] All reactions were carried out with substrate (0.5 mmol), NMM
(0.5 mmol), MSH (1.0 mmol), and KOH (1.5 mmol) in CH3CN (1.5 mL)
at room temperature for 4 h (for entry 5a, 3 h; for entry 8a, 5 h). [b] All
reactions were carried out with substrate (0.5 mmol), NMM (0.05–
0.10 mmol), MSH (1.0 mmol), and CsOH·H2O (3.0 mmol) in CH3CN/
CH2Cl2 (2:1, 2.5 mL) at 08C to room temperature for 7 h unless
otherwise noted. [c] Yield of isolated product. [d] KOH was used as the
base and CH3CN was used as the solvent.
Our studies started with the investigation of a one-pot
process which involved the in situ generation of a hydrazi-
nium salt,deprotonation of the hydrazinium to form an
aminimide,and subsequent aziridination (Scheme 2). It has
higher yield was obtained by replacing KOH with CsOH·H2O
(Table 1,entry 1c). This catalytic process was further illus-
trated by the aziridination of a number of substrates (Table 1,
entries 2b–8b). In some cases,the yields achieved were similar
to those obtained with a stoichiometric amount of tertiary
amine. However,in other cases (Table 1,entries 5b and 6b),
the yields dropped significantly.
While a detailed understanding of the reaction mecha-
nism awaits further study,a plausible catalytic cycle is shown
in Scheme 3.[21] The tertiary amine NMM reacts with MSH to
form the hydrazinium salt 6,which then reacts with
CsOH·H2O to give the aminimide 7. The aminimide 7 then
undergoes conjugate addition to the chalcone 4 followed by
cyclization to form the aziridine 5 and regenerate the tertiary
amine. No aziridination was observed in the absence of NMM
or CsOH·H2O,thereby indicating that a tertiary amine and
base are required for the reaction,which is consistent with the
proposed mechanism.
Scheme 2. Aziridination of chalcones 4 with aminimide formed in situ.
been shown that O-mesitylenesulfonylhydroxylamine (MSH)
can readily aminate various tertiary amines to give the
corresponding hydrazinium salts in high yield.[19,20] The
aziridination was then examined by treating MSH and tertiary
amines with base and chalcone 4. Treating MSH (2.0 equiv)
with DABCO (1.0 equiv),KOH (3.0 equiv),and
4 (Ar=
Ar’ = Ph,1.0 equiv) in CH 3CN at room temperature and
stirring the reaction mixture for four hours gave the aziridine
product 5 in 73% yield. A higher yield (85%) was obtained
on using N-methylmorpholine (NMM; Table 1,entry 1a). As
shown in Table 1 (entries 2a–8a),other chalcones can be
efficiently aziridinated in a short time with good yield.
Encouraged by the feasibility of this one-pot reaction,we
next pursued the possibility of making the process catalytic.
When NMM was reduced to 0.1 equivalents,the aziridine 5
was obtained in 52% yield (Table 1,entry 1b). A slightly
The feasibility of the aziridination using a catalytic
amount of the tertiary amine and MSH in the presence of
8006 www.angewandte.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 8005 –8008

Angewandte
Chemie
to 98% upon recrystallization (Table 2,entry 7). These results
illustrate that a catalytic asymmetric aziridination process
occurs.
In summary,we have found that the aminimide generated
in situ from tertiary amine and MSH in the presence of a base
is an effective NH-transfer reagent for the aziridination of
chalcones. The amine promoter in this aziridination process
can be used in a catalytic amount,and a reasonable level of
enantioselectivity can be obtained when the chiral tertiary
amine,Trögerꢀs base,is used. More effective tertiary amine
catalysts and also an expansion of the substrate scope are
currently being pursued.
Experimental Section
Representative procedure asymmetric aziridination (Table 2,
entry 7): MSH (22.0 mg,0.10 mmol) and CsOH·H 2O (25.0 mg,
0.15 mmol) were added to a solution of (+)-Trögerꢀs base (15.0 mg,
0.06 mmol) and 4’-chlorochalcone (24.0 mg,0.10 mmol) in CH 3CN/
Scheme 3. A proposed catalytic cycle for the aziridination.
CH2Cl2 (1.5 mL,2:1,v/v) at
À208C. After stirring the reaction
mixture for 1 h,further MSH (11.0 mg,0.05 mmol) and CsOH·H 2O
(12.5 mg,0.075 mmol) were added. After another 1 h,additional
MSH (11.0 mg,0.05 mmol) and CsOH·H 2O (12.5 mg,0.075 mmol)
were added. The reaction was stirred for a further 22h at À208C (total
reaction time of 24 h),then diluted with EtOAc (10 mL),filtered,and
the filter cake washed with EtOAc (2 ” 5 mL). The filtrate was
subsequently concentrated and purified by flash chromatography (the
silica gel was buffered with 1% Et3N in hexanes,hexanes/EtOAc =
10:1) to give the aziridine as a pale yellow solid (17.0 mg,66% yield,
67% ee).
CsOH·H2O prompted us to investigate whether a chiral
tertiary amine could induce any enantioselectivity for the
aziridination. Treating chalcone 4 with 30 mol% (+)-Trögerꢀs
base,MSH,and CsOH·H 2O afforded the aziridine in 81%
[22]
yield and 55% ee (Scheme 4; Table 2,entry 3).
A slightly
higher enantioselectivity was obtained with 4’-chlorochalcone
(Table 2,entries 5 and 6),and the ee value could be improved
Received: June 29,2006
Revised: September 23,2006
Published online: November 6,2006
Keywords: asymmetric catalysis · aziridines · chalcones ·
.
nitrogen heterocycles · small ring systems
[1] For leading reviews on the synthesis and application of
aziridines,see: a) D. Tanner, Angew. Chem. 1994, 106,625;
Angew. Chem. Int. Ed. Engl. 1994, 33,599; b) J. Du Bois,C. S.
Tomooka,J. Hong,E. M. Carreira, Acc. Chem. Res. 1997, 30,
364; c) A.-H. Li,L.-X. Dai,V. K. Aggarwal, Chem. Rev. 1997, 97,
2341; d) H. M. I. Osborn,J. Sweeney, Tetrahedron: Asymmetry
1997, 8,1693; e) T. Ibuka, Chem. Soc. Rev. 1998, 27,145; f) E. N.
Jacobsen in Comprehensive Asymmetric Catalysis (Eds.: E. N.
Scheme 4. Asymmetric aziridination of 4 using Tröger’s base.
Table 2: Asymmetric aziridination of chalcones.[a]
Entry Substrate
Equiv. of
(+)-Tröger’s base [%][b]
Yield ee [%][c]
Jacobsen,A. Pfaltz,H. Yamamoto),Springer,Berlin,
1999,
1
2
3
1.0
0.6
0.3
90
85
81
55[d]
55
55
chap. 17; g) R. S. Atkinson, Tetrahedron 1999, 55,1519; h) W.
McCoull,F. A. Davis, Synthesis 2000,1347; i) J. B. Sweeney,
Chem. Soc. Rev. 2002, 31,247; j) M. D. Redlich,M. F. Mayer,
M. M. Hossain, Aldrichimica Acta 2003, 36,3; k) P. Müller,C.
Fruit, Chem. Rev. 2003, 103,2905; l) X. E. Hu, Tetrahedron 2004,
60,2701; m) Y. Tang,S. Ye,X.-L. Sun, Synlett 2005,2720; n) T.
Katsuki, Chem. Lett. 2005, 34,1304; o) I. D. G. Watson,L. Yu,
A. K. Yudin, Acc. Chem. Res. 2006, 39,194.
4
5
6
7
1.0
0.6
93
62
50
66
62
62
0.3
62
0.6[e]
67 (98[f])
[a] All reactions were carried out at 08C with substrate (0.1 mmol), (+)-
Tröger’s base (0.03–0.1 mmol), MSH (0.2 mmol), and CsOH·H2O
(0.3 mmol) in CH3CN/CH2Cl2 (2:1, 1.5 mL) for7 h (entires 1–3) or5 h
(entries 4–6). [b] Yield of isolated product. [c] The enantioselectivity was
determined by HPLC on a chiral stationary phase (chiracel OD). [d] The
absolute configuration was determined by comparing the rotation of a
known compound and is 2R,3S (see Ref. [9c]). [e] At À208C for24 h.
[f] After recrystallization.
[2] For leading references on the bromine- and iodine-catalyzed
aziridination of olefins,see: a) J. U. Jeong,B. Tao,I. Sagasser,H.
Henniges,K. B. Sharpless, J. Am. Chem. Soc. 1998, 120,6844;
b) T. Ando,D. Kano,S. Minakata,I. Ryu,M. Komatsu,
Tetrahedron 1998, 54,13485.
[3] For leading references on the asymmetric aza-Darzens-type
aziridination,see: a) F. A. Davis,P. Zhou,G. V. Reddy, J. Org.
Chem. 1994, 59,3243; b) A. B. McLaren,J. B. Sweeney, Org.
Angew. Chem. Int. Ed. 2006, 45, 8005 –8008
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 8007

Communications
Lett. 1999, 1,1339; c) S. Hanessian,L.-D. Cantin, Tetrahedron
43,4329; e) A. Mekonnen,R. Carlson, Tetrahedron 2006, 62,
852.
Lett. 2000, 41,787; d) T. Satoh,Y. Fukuda, Tetrahedron 2003, 59,
9803; e) F. Ferreira,M. Audouin,F. Chemla, Chem. Eur. J. 2005,
11,5269.
[9] For leading references using RONH2,see: a) I. Coldham,A. J.
Collis,R. J. Mould,R. E. Rathmell, Tetrahedron Lett. 1995, 36,
3557; b) G. Cardillo,S. Casolari,L. Gentilucci,C. Tomasini,
Angew. Chem. 1996, 108,1939; Angew. Chem. Int. Ed. Engl.
1996, 35,1848; c) X. L. Jin,H. Sugihara,K. Daikai,H. Tateishi,
Y. Z. Jin,H. Furuno,J. Inanaga, Tetrahedron 2002, 58,8321;
d) N. Yamagiwa,S. Matsunaga,M. Shibasaki, J. Am. Chem. Soc.
2003, 125,16178.
[4] For leading references on the aziridination of imines with ylides,
see: a) A.-H. Li,L.-X. Dai,X.-L. Hou, Chem. Commun. 1996,
491; b) V. K. Aggarwal,A. Thompson,R. V. H. Jones,M. C. H.
Standen, J. Org. Chem. 1996, 61,8368; c) A.-H. Li,Y.-G. Zhou,
L.-X. Dai,X.-L. Hou,L.-J. Xia,L. Lin, Angew. Chem. 1997, 109,
1375; Angew. Chem. Int. Ed. Engl. 1997, 36,1317; d) V. K.
Aggarwal,E. Alonso,G. Fang,M. Ferrara,G. Hynd,M.
Porcelloni, Angew. Chem. 2001, 113,1482; Angew. Chem. Int.
Ed. 2001, 40,1433.
[5] For leading references on the aziridination of imines with diazo
compounds,see: a) R. Bartnik,G. Mloston, Synthesis 1983,924;
b) K. B. Hansen,N. S. Finney,E. N. Jacobsen, Angew. Chem.
1995, 107,750; Angew. Chem. Int. Ed. Engl. 1995, 34,676; c) J. C.
Antilla,W. D. Wulff, J. Am. Chem. Soc. 1999, 121,5099; d) K.
Juhl,R. G. Hazell,K. A. Jørgensen, J. Chem. Soc. Perkin Trans. 1
1999,2293; e) V. K. Aggarwal,M. Ferrara, Org. Lett. 2000, 2,
4107.
[6] For leading references on the metal-catalyzed aziridination of
olefins,see: for racemic systems: a) H. Kwart,A. A. Khan, J.
Am. Chem. Soc. 1967, 89,1951; b) J. T. Groves,T. Takahashi, J.
Am. Chem. Soc. 1983, 105,2073; c) D. Mansuy,J.-P. Mahy,A.
Dureault,G. Bedi,P. Battioni, J. Chem. Soc. Chem. Commun.
1984,1161; d) D. A. Evans,M. M. Faul,M. T. Bilodeau, J. Org.
Chem. 1991, 56,6744; e) D. A. Evans,M. M. Faul,M. T.
Bilodeau, J. Am. Chem. Soc. 1994, 116,2742; f) J. Du Bois,J.
Hong,E. M. Carreira,M. W. Day, J. Am. Chem. Soc. 1996, 118,
915; g) S.-M. Au,J.-S. Huang,W.-Y. Yu,W.-H. Fung,C.-M. Che,
J. Am. Chem. Soc. 1999, 121,9120; h) P. Brandt,M. J. Södergren,
P. G. Andersson,P.-O. Norrby, J. Am. Chem. Soc. 2000, 122,
8013; i) P. Dauban,L. Sani›re,A. Tarrade,R. H. Dodd, J. Am.
Chem. Soc. 2001, 123,7707; j) A. Padwa,T. Stengel, Org. Lett.
2002, 4,2137; k) K. Guthikonda,J. Du Bois, J. Am. Chem. Soc.
2002, 124,13672; l) Y. Cui,C. He, J. Am. Chem. Soc. 2003, 125,
16202; m) W.-L. Man,W. W. Y. Lam,S.-M. Yiu,T.-C. Lau,S.-M.
Peng, J. Am. Chem. Soc. 2004, 126,15336; n) A. J. Catino,J. M.
Nichols,R. E. Forslund,M. P. Doyle, Org. Lett. 2005, 7,2787;
o) H. Lebel,K. Huard,S. Lectard, J. Am. Chem. Soc. 2005, 127,
14198. for asymmetric systems: p) D. A. Evans,K. A. Woerpel,
M. M. Hinman,M. M. Faul, J. Am. Chem. Soc. 1991, 113,726;
q) R. E. Lowenthal,S. Masamune, Tetrahedron Lett. 1991, 32,
7373; r) Z. Li,K. R. Conser,E. N. Jacobsen, J. Am. Chem. Soc.
1993, 115,5326; s) D. A. Evans,M. M. Faul,M. T. Bilodeau,
B. A. Anderson,D. M. Barnes, J. Am. Chem. Soc. 1993, 115,
5328; t) Z. Li,R. W. Quan,E. N. Jacobsen, J. Am. Chem. Soc.
1995, 117,5889; u) S. Minakata,T. Ando,M. Nishimura,I. Ryu,
M. Komatsu, Angew. Chem. 1998, 110,3596; Angew. Chem. Int.
Ed. 1998, 37,3392; v) C. J. Sanders,K. M. Gillespie,D. Bell,P.
Scott, J. Am. Chem. Soc. 2000, 122,7132; w) H. Kawabata,K.
Omura,T. Katsuki, Tetrahedron Lett. 2006, 47,1571.
[10] For leading references using NsONHCO2R,see: a) S. Fioravanti,
L. Pellacani,S. Stabile,P. A. Tardella,R. Ballini,
Tetrahedron
1998, 54,6269; b) S. Fioravanti,A. Morreale,L. Pellacani,P. A.
Tardella, J. Org. Chem. 2002, 67,4972; c) D. Colantoni,S.
Fioravanti,L. Pellacani,P. A. Tardella, Org. Lett. 2004, 6,197.
[11] For leading references on asymmetric aziridination using
1
2
=
R R S NH,see: a) T. Yoshimura,T. Akasaka,N. Furukawa,S.
Oae, Heterocycles 1977, 7,287; b) N. Furukawa,T. Yoshimura,
M. Ohtsu,T. Akasaka,S. Oae, Tetrahedron 1980, 36,73.
[12] For leading references using diaziridine,see: a) K. Hori,H.
Sugihara,Y. N. Ito,T. Katsuki, Tetrahedron Lett. 1999, 40,5207;
b) H. Ishihara,Y. N. Ito,T. Katsuki, Chem. Lett. 2001,984; c) H.
Ishihara,K. Hori,H. Sugihara,Y. N. Ito,T. Katsuki, Helv. Chim.
Acta 2002, 85,4272.
[13] For a recent leading reference on the aziridination by addition of
azides to olefins,see: J. M. Mahoney,C. R. Smith,J. N. Johnston,
J. Am. Chem. Soc. 2005, 127,1354.
[14] For aziridination of olefins with HN(OCH3)2/BF3 or trimethyl-
silyltriflate,see: a) V. F. Rudchenko,S. M. Ignatov,R. G. Kos-
tyanovsky, J. Chem. Soc. Chem. Commun. 1990,261; b) E.
Vedejs,H. Sano, Tetrahedron Lett. 1992, 33,3261.
[15] For aziridination of olefins with MSH,see: a) J. C. Bottaro, J.
Chem. Soc. Chem. Commun. 1980,560; b) P. Mꢁtra,J. Hamelin,
J. Chem. Soc. Chem. Commun. 1980,1038.
[16] I. Ikeda,Y. Machii,M. Okahara, Synthesis 1980,650.
[17] G. A. Olah,M. B. Sassaman,M. Zuanic,C. B. Rao,G. K. S.
Prakash, J. Org. Chem. 1992, 57,1585.
[18] a) J. Xu,P. Jiao, J. Chem. Soc. Perkin Trans. 1 2002,1491;
Erratum: b) J. Xu,P. Jiao, J. Chem. Soc. Perkin Trans. 1 2002,
2561.
[19] For leading references on amination of tertiary amines with
MSH,see: a) Y. Tamura,J. Minamikawa,Y. Kita,J. H. Kim,M.
Ikeda, Tetrahedron 1973, 29,1063; b) Y. Tamura,J. Minamikawa,
M. Ikeda, Synthesis 1977,1.
[20] For the preparation of MSH,see: a) C. R. Johnson,R. A.
Kirchhoff,H. G. Corkins, J. Org. Chem. 1974, 39,2458; b) Y.
Tamura,J. Minamikawa,K. Sumoto,S. Fujii,M. Ikeda,
J. Org.
Chem. 1973, 38,1239.
[21] For an amine-catalyzed asymmetric cyclopropanation,see: C. D.
Papageorgiou,M. A. Cubillo de Dios,S. V. Ley,M. J. Gaunt,
Angew. Chem. 2004, 116,4741; Angew. Chem. Int. Ed. 2004, 43,
4641.
[22] About 93% of the chiral Trögerꢀs base could be recovered after
the reaction,and the recovered chiral amine provided similar
reactivity and enantioselectivity for the aziridination.
[7] For recent leading references on nitrogen transfer to olefins
using N-acetoxyamino compounds,see: a) R. S. Atkinson,R. D.
Draycott,D. J. Hirst,M. J. Parratt,T. M. Raynham, Tetrahedron
Lett. 2002, 43,2083; b) T. Siu,A. K. Yudin, J. Am. Chem. Soc.
2002, 124,530; c) K.-S. Yang,K. Chen, Org. Lett. 2002, 4,1107;
d) J. Li,P. W. H. Chan,C.-M. Che, Org. Lett. 2005, 7,5801.
[8] For leading references on the addition of primary amines to 2-
halo-substituted a,b-unsaturated carbonyl compounds,see: a) O.
Ploux,M. Caruso,G. Chassaing,A. Marquet, J. Org. Chem. 1988,
53,3154; b) P. Garner,O. Dogan,S. Pillai,
Tetrahedron Lett.
1994, 35,1653; c) G. Cardillo,L. Gentilucci,C. Tomasini,M. P. V.
Castejon-Bordas, Tetrahedron: Asymmetry 1996, 7,755; d) M. T.
Barros,C. D. Maycock,M. R. Ventura, Tetrahedron Lett. 2002,
8008 www.angewandte.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 8005 –8008