DOI: 10.1002/chem.201101630

An Efficient, Overall [4+1] Cycloadditon of 1,3-Dienes and NitrenePrecursors

Qiong Wu,[b] Jian Hu,[a] Xinfeng Ren,[a] and Jianrong (Steve) Zhou*[a]

Introduction

Substituted pyrrolidines are frequently present in many nat-ural products and therapeutic agents. Due to their importantbiological activities, a wide variety of methods have beendeveloped to prepare these compounds, often with definedstereochemistry.[1] We are particularly interested in intermo-lecular cycloadditions for the construction of azacycles dueto material convergence and catalytic control of the stereo-chemical outcome. Typical examples are [3+2] cycloaddi-tions of olefins/alkynes with azomethine ylides[2]/aziridines[3]

and [3+2] cycloadditions of imines with allenes,[4] trimethy-lenemethanes,[5] or cyclopropanes.[6] However, these reac-tions usually require activation of the reactants (alkenes, al-kynes, allenes, and cyclopropanes) with electron-withdraw-ing groups.

We envision intermolecular [4+1] cycloaddition of conju-gated dienes and nitrene equivalents as an alternative gener-al approach to access pyrrolidines (Scheme 1). Besides theattributes of convergence and catalytic control of the stereo-chemistry, the [4+1] cycloaddition produces 3-pyrrolines, the

olefin groups of which can be readily transformed into otherfunctionalities. For example, olefine dihydroxylation canlead to stereoselective synthesis of 3,4-dihydroxypyrroli-dines,[7] which are core structures in many bioactive com-pounds.[8]

Formal intramolecular [4+1] cycloadditions have been ex-tensively studied by Hudlicky[9] and Pearson[10] via thermoly-sis of 1,3-dienyl azides, which proceeds via triazoline inter-mediates.[11] However, these reactions are often accompa-nied by side reactions and low yields of the [4+1] cycload-ducts. Furthermore, 2- and 3-pyrroline isomers are pro-duced, dependent on the substitution of the dienes.Intermolecular cycloadditions of stabilized nitrenes with1,3-dienes usually lead to aziridines[12] and a generally usefulmethod to directly produce [4+1] cycloadducts was lack-ing.[13] Thus, a separate step is needed to convert preformedvinylazirdines[14] into pyrrolines.[15] Herein, we report an effi-cient, intermolecular overall [4+1] cycloaddition of1,3-dienes and nitrene precursors.

Results and Discussion

For the model reaction (Table1), we selected an ester-con-taining 1,3-butadiene and a common nitrene precursor,(N-p-tosylimino)phenyliodinane (PhI=Ts).[16] After exten-sive research, we found that copper(II) 1,1,1,5,5,5-hexa-

Abstract: Intermolecular cycloaddi-tions of conjugated dienes and nitreneprecursors usually produce aziridines.A generally useful method was lackingto directly provide the [4+1] cycload-ducts, 3-pyrrolines. We have realizedthis transformation by using anuniquely active catalyst, copper(II)1,1,1,5,5,5-hexafluoroacetylacetonate([Cu ACHTUNGTRENNUNG(hfacac)2]). The method is applica-

ble to a wide array of dienes with goodyields. When 1,4-disubsituted dienesare used as substrates, good-to-excel-lent cis or trans selectivity can be ob-tained. Interestingly, the cis or trans

preference depends on the nature ofthe substituents, rather than diene ge-ometry. Mechanistic studies reveal thatthe [4+ 1] cycloaddition proceedsthrough diene aziridination and subse-quent ring expansion. Among commoncopper catalysts, only [Cu ACHTUNGTRENNUNG(hfacac)2] canefficiently catalyze both steps, whichexplains the unique efficiency of thecatalyst.

Keywords: aziridination · copper ·cycloaddition · nitrenes · ring ex-pansion

[a] Dr. J. Hu, Dr. X. Ren, Prof. Dr. J. ZhouDivision of Chemistry and Biological ChemistrySchool of Physical and Mathematical SciencesNanyang Technological University637371 (Singapore)Fax: (+65) 67911961E-mail : jrzhou@ntu.edu.sg

[b] Q. WuDepartment of Medicinal Natural ProductsWest China School of PharmacySichuan UniversityChengdu, 610041 (P. R. China)

Supporting information for this article is available on the WWWunder http://dx.doi.org/10.1002/chem.201101630.

Scheme 1. Intermolecular [4+1] cycloaddition of conjugated dienes andnitrene equivalents to access 3-pyrrolines.

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fluoroacetylacetonate ([Cu ACHTUNGTRENNUNG(hfacac)2]) can catalyze the for-mation of the desired [4+1] cycloadducts in good yield at100 8C. When 1.0 equivalent of the diene was used, the yielddropped to 63 %. The results of our studies of the catalystand solvent effects are summarized in Table 1. The two CF3

EWGs on the hfacac ligand proved to be essential for thehigh catalytic activity, in comparison with copper(II)1,1,1-trifluoroacetylacetonate ([Cu ACHTUNGTRENNUNG(tfacac)2]) and copper(II)acetylacetonate ([Cu ACHTUNGTRENNUNG(acac)2]) (Table 1, entries 2 and 3).Other copper catalysts, such as copper(II) triflate (Cu-ACHTUNGTRENNUNG(OTf)2), CuI, and CuOAc, are much less active (Table 1, en-tries 4 and 5). With regards to the choice of solvent, manyaromatic solvents work well, with the exception of toluenedue to benzylic CH amination (Table 1, entries 11–14).[17]

To access more active catalysts, we prepared 1,3-diketo-nate complexes [Cu(L1)2] and [Cu(L2)2] from CuACHTUNGTRENNUNG(OAc)2

and neutral ligands (see formula in Table 1 for structures).[18]

[Cu(L1)2], which bears n-C7F15 side chains, is more activethan [Cu ACHTUNGTRENNUNG(hfacac)2] and allows the catalyst loading to be re-duced to 2 mol % (PhCF3 is used as the solvent for solubilityreasons, Table 1, entry 8). [Cu(L2)2], which bears perfluori-nated acac ligands, is much less active, probably due toligand fragmentation (Table 1, entries 9 and 10).[19]

Because [CuACHTUNGTRENNUNG(hfacac)2] is highly active and commerciallyavailable, we chose to use this catalyst to study the dienescope (Scheme 2). A wide range of mono-, di-, and trisubsti-tuted conjugated dienes gave the target [4+1] cycloadducts.Common nitrene precursors PhI=NTs and PhI=NNs(Ns=p-nitrobenzenesulfonyl) both work well in the reaction.

Notably, presence of the alkyl groups in isoprene and 2,3-di-methyl-1,3-butadiene allows the reactions to proceed atroom temperature in high yields. The method is tolerant ofester groups at both the terminal and internal positions ofthe dienes. Also, cyclic diene, 1,3-cyclooctadiene, and a cy-clopropyl-substituted diene gave acceptable yields of the re-spective cycloadducts. In the latter case, no cyclopropyl ring-opened byproducts were detected.[20]

When 1,4-disubstituted dienes are used, formation of cisand trans isomers of the 3-pyrrolines is possible. In our reac-tions, good-to-excellent cis/trans selectivity can be obtained,depending on the nature of the substituents, rather than thediene geometry. If both substituents are alkyl groups, theformation of trans-pyrrolines is favored; if one or both sub-stituents are aryl groups, the cis isomers are the major prod-ucts. For example, trans,trans-1,4-diphenyl-1,3-butadiene fur-nishes the cis isomer almost exclusively (Scheme 2). A1,6-disubstituted triene also selectively provided cis-pyrro-lines. Interestingly, the triene also gave <10 % of the [6+1]cycloadduct. The configuration of the 2,5-disubstituted pyr-rolines was determined by X-ray crystallography.[18]

With regards to the mechanism, we have considered threepossible pathways: 1) a concerted [4+1] cycloaddition be-tween a copper–nitrene complex and a diene to directlyform the 3-pyrroline (Scheme 3 a); 2) a facile, irreversibleaziridination of the diene with the copper–nitrene com-plex,[21] followed by ring expansion (Scheme 3 b); 3) a fast,reversible aziridination, in coexistence with a slow, irreversi-

Table 1. Optimization of the reaction parameters for [4+1] cycloadditionof a 1,3-diene with PhI=NTs.

Entry Modification ofreaction conditions[a]

GC yield[%]

1 [Cu ACHTUNGTRENNUNG(hfacac)2] 892 [Cu ACHTUNGTRENNUNG(tfacac)2] 203 [Cu ACHTUNGTRENNUNG(acac)2] 134 Cu ACHTUNGTRENNUNG(OTf)2 145 CuI, CuOAc, or Cu ACHTUNGTRENNUNG(MeCN)4PF6 <106 5 % [Cu(L1)2] in PhCl 687 5 % [Cu(L1)2] in PhCF3 838 2 % [Cu(L1)2] in PhCF3 839 5 % [Cu(L2)2] in PhCl 30

10 5 % [Cu(L2)2] in PhCF3 2711 chlorobenzene 8912 toluene 4813 benzene 8614 a,a,a-trifluorotoluene 76

[a] Initial conditions (entries 1 and 11): [CuACHTUNGTRENNUNG(hfacac)2] (5 mol %), PhI=NTs, PhCl, 100 8C, 24h. Scheme 2. Scope of the [4+1] cycloaddition of dienes (d.r.= diastereo-

meric ratio).

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ble [4+1] cycloaddition (Scheme 3 c). The following experi-ments indicate that pathway b is most likely:

1) Cycloaddition of 1,3-cyclooctadiene at 100 8C only gavevinylaziridines, but continued heating of the reactionmixtures at 150 8C provided 3-pyrrolines. This is in agree-ment with Njardarson�s earlier observation that [Cu-ACHTUNGTRENNUNG(hfacac)2]-catalyzed ring expansion of such vinylaziri-dines requires high-temperature conditions.[15a]

2) Cycloaddition of trans trans-2,4-hexadienes at 25 8C onlygives a 1.6:1 mixture of two vinylaziridine isomers in64 % yield, with the cis-aziridine as the major product.When the isolated vinylaziridine isomers are subjected tocopper catalysis at 100 8C, they cleanly isomerize to3-pyrrolines in high yield (Scheme 4).

3) When the isomerization of isolated vinylaziridines wasconducted in the presence of a second diene (10 equiv),no crossover vinylaziridines or crossover 3-pyrrolineswere detected in either case (Schemes 4 and 5). Thus, thelack of crossover rules out pathway c.

4) Cycloadditions of both trans, trans- and cis,trans-1,4-di-phenyl-1,3-butadiene were studied separately at a lower

temperature (36 8C) so that more mechanistic detailscould be revealed (Figure 1). From both dienes, severalvinylaziridine isomers are produced as intermediates,which isomerize to 3-pyrroline (p) at the same tempera-ture. Notably, trans,trans-vinylaziridine (tt) is bothformed and isomerized to p much faster than trans,cis-vi-nylaziridine (tc). In the cycloadditions of both tt and tc,p is produced with >90:1 d.r. in favor of the cis isomer,regardless of the diene geometry. In the reaction of thecis,trans-diene, no isomerization to the trans,trans-dienewas observed at 36 8C.

A close examination of the kinetics in Figure 1 suggeststhat, in both cases, tt is concurrently isomerized to both pand tc. This was confirmed by a separate study, in whichpure tt was subjected to [Cu ACHTUNGTRENNUNG(hfacac)2]-catalyzed ring expan-sion (Figure 2 a). In a second experiment (Figure 2 b), thecopper-catalyzed ring expansion of pure tc is shown to alsoproduce p in a cis/trans ratio of 19:1, but the conversion ismuch slower than that of tt.

Recently, Njardarson et al. reported that [CuACHTUNGTRENNUNG(hfacac)2]-catalyzed ring expansion of vinylaziridines to 3-pyrrolineswas stereospecific.[22] The active catalyst was proposed to bea cationic [CuACHTUNGTRENNUNG(hfacac)] species and ring expansion was con-sidered to proceed via a reactive conformation with all fourcarbon atoms of the vinylaziridine in an s-cisoid arrange-ment.[15a] To account for the stereoselectivity in the overall[4+1] cycloaddition of 1,4-disubstituted dienes, we have putforth a mechanistic proposal (Scheme 6). 1,4-Diaryl dienes

tt and tc, the more stable isomer, can slowly interconvertunder the catalytic conditions.[23] Direct ring expansion of ttforms the cis-pyrroline, whereas that of tc forms the trans-pyrroline. However, the latter process is impeded by stericrepulsion when an aryl group is present in the reactive con-formation of tc. Consequently, tc is slowly converted back tott and the cis-pyrroline is formed as the major product inthe overall [4+1] cycloaddition. In contrast, if both of theterminal substituents are primary alkyl groups,[24] such stericrepulsion in tc’ can be minimized by single-bond rotation.Thus, the more stable aziridine tc’, which may exist in higherconcentration than tt’, can produce the trans-pyrroline pref-erentially.

Scheme 3. Possible pathways for the catalytic [4+1] cycloaddition.

Scheme 6. Proposed model for the stereoselectivity.

Scheme 4. Isomerization of the isolated dimethyl-substituted aziridine.

Scheme 5. Isomerization of the isolated diphenyl-substituted aziridine.

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The overall copper-catalyzed [4+1] cycloaddition occursin two steps. We performed the experiment described belowto compare the activity of [Cu ACHTUNGTRENNUNG(hfacac)2] in each step, in rela-tion to other copper catalysts. [CuACHTUNGTRENNUNG(hfacac)2]-catalyzed cyclo-addition of trans,trans-1,4-diphenyl-1,3-butadiene at 25 8Cfor 24 h afforded vinylaziridine (tc) in 36 % yield and 3-pyr-

roline (p) in 46 % yield(Table 2, entry 1). Subsequentheating at 100 8C cleanly gener-ated p in high yield. In con-trast, other copper catalystsproduced both tc and p inmuch lower yields. Because pis formed after the initial aziri-dination, the results indicatethat [Cu ACHTUNGTRENNUNG(hfacac)2] is a muchmore active catalyst in boththe aziridination and ring-ex-pansion steps.

To confirm the superior ac-tivity of [CuACHTUNGTRENNUNG(hfacac)2] in thering expansion,[15a] isolated vi-nylaziridines tt and tc weresubjected to isomerization con-ditions (Table 3). After heatingat 100 8C for 24 h, [Cu-ACHTUNGTRENNUNG(hfacac)2] gave p in 94 % yieldwith a high d.r. (21:1), whereasother copper catalysts providedvery complex mixtures, whichcontained <10 % yield of p.

Figure 1. Kinetic studies of the overall [4+1] cycloaddition of 1,4-diphenyl-1,3-butadiene isomers.

Figure 2. [CuACHTUNGTRENNUNG(hfacac)2]-catalyzed ring expansion of tt and tc.

Table 2. Comparison of the activity of copper catalysts in the overall[4+1] cycloaddition.

Entry Catalyst 25 8C, 24 h 100 8C, 24 htc [%] p [%] tc [%] p [%]

1 [Cu ACHTUNGTRENNUNG(hfacac)2] 36 46 0 722 [Cu ACHTUNGTRENNUNG(tfacac)2] 34 3 0 103 [Cu ACHTUNGTRENNUNG(acac)2] 25 3 0 34 Cu ACHTUNGTRENNUNG(OTf)2 0 2 0 45 CuI 4 (tc)

12 (tt)0 0 1

Table 3. Comparison of the activity of copper catalysts for vinylaziridineisomerization.

Entry Catalyst p [%]

1 [CuACHTUNGTRENNUNG(hfacac)2] 942 [CuACHTUNGTRENNUNG(tfacac)2] 73 [CuACHTUNGTRENNUNG(acac)2] 24 CuACHTUNGTRENNUNG(OTf)2 85 CuI 1

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J. Zhou et al.

Conclusion

In summary, we have developed an efficient, intermolecularoverall [4+1] cycloaddition of conjugated dienes andcommon nitrene precursors. This method is applicable to arange of conjugated dienes to provide 3-pyrrolines. When1,4-disubstituted dienes are used as substrates, good-to-ex-cellent cis/trans selectivity can be obtained. The cis or transpreference depends on the nature of the substituents ratherthan the geometry of the diene. Mechanistic studies revealthat the reaction proceeds through diene aziridination andsubsequent ring expansion. Among several copper catalysts,only [Cu ACHTUNGTRENNUNG(hfacac)2] displays high activity in both steps. De-velopment of an asymmetric variant and application to syn-thesis of bioactive pyrrolidines is underway.

Experimental Section

In an argon-filled glove box, a dry 25 mL Schlenk tube was charged with[Cu ACHTUNGTRENNUNG(hfacac)2] (12 mg, 0.025 mmol), (E)-ethyl 4,6-hepta-dienoate (116 mg,0.75 mmol), and dry chlorobenzene (2.5 mL). 1-Dodecane (10 mL, GC in-ternal standard), TsN=IPh (187 mg, 0.50 mmol), and dry chlorobenzene(5.0 mL) were added to this green solution to wash all of the solids intothe tube. The Schlenk tube was capped tightly. After stirring at 25 8C for1 h, the mixture was heated with vigorous stirring in a 100 8C oil bath for24 h until no more product was formed (monitored by GC). The reactionmixture was cooled to 25 8C and subjected to flash chromatography(Et3N-treated silica gel; hexane to 5:1 hexane/EtOAc as eluent) to givethe cycloadduct as colorless oil (139 mg, 86 %).

The reaction can also be conducted without the use of a glove box. Inair, a dry 25 mL Schlenk tube that contained a magnetic stir bar wascharged with [CuACHTUNGTRENNUNG(hfacac)2] (12 mg, 0.025 mmol) and TsN=IPh (187 mg,0.50 mmol). After three cycles of evacuation and refilling with argon, thediene (116 mg, 0.75 mmol) and dry PhCl (7.5 mL) were added by syringe.After stirring at 25 8C for 1 h, the mixture was heated with vigorous stir-ring in a 100 8C oil bath for 24 h. The cycloadduct (131 mg, 81%) was iso-lated by flash chromatography as described above.

Acknowledgements

We thank Singapore National Research Foundation (NRF-RF2008–10)and Nanyang Technological University for financial support.

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[18] CCDC-815942 ([Cu(L2)2] bis(perfluoro-2,4-pentanedionato)copper(-II)), 815943 ([Cu(L1)2] bis[9,9-dihydroperfluoro-8,10-heptadecane-dionato)copper(II)), 815944 (trans-N-p-Nosyl-2,5-dimethyl-3-pyrro-

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FULL PAPERCycloaddition of 1,3-Dienes and Nitrene Precursors

line), 815945 (cis-N-p-Nosyl-2-ethoxycarbonyl-5-phenyl-3-pyrroline),815946 ((E)-cis-N-p-Nosyl-2-phenyl-5-styryl-3-pyrroline), 815947(trans-N-p-Tosyl-2,5-dibenzyl-3-methyl-3-pyrroline), 815948 (-N-p-Nosyl-2,5-diphenyl-3-pyrroline), and 815949 (cis-N-p-Tosyl-2-methyl-5-phenyl-3-pyrroline) contain the supplementary crystallo-graphic data for this paper. These data can be obtained free ofcharge from The Cambridge Crystallographic Data Centre viawww.ccdc.cam.ac.uk/data_request/cif.

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[20] 1-Methoxy- and 1-acetoxy-1,3-butadiene can undergo cycloaddition,but the [4+1] cycloadducts directly eliminate methanol and aceticacid to give N-p-tosylpyrrole in 35 and 20% yield, respectively.

[21] Evidence supporting copper(I) nitrene active species in aziridina-tion: a) Y. M. Badiei, A. Krishnaswamy, M. M. Melzer, T. H.Warren, J. Am. Chem. Soc. 2006, 128, 15056; b) T. R. Cundari, A.Dinescu, A. B. Kazi, Inorg. Chem. 2008, 47, 10067; c) Z. Li, R. W.Quan, E. N. Jacobsen, J. Am. Chem. Soc. 1995, 117, 5889; Copper(-

II) nitrene as active species: d) D. A. Evans, M. T. Bilodeau, M. M.Faul, J. Am. Chem. Soc. 1994, 116, 2742; e) P. Comba, C. Haaf, A.Lienke, A. Muruganantham, H. Wadepohl, Chem. Eur. J. 2009, 15,10880.

[22] M. Brichacek, M. N. Villalobos, A. Plichta, J. T. Njardarson, Org.Lett. 2011, 13, 1110.

[23] Pd-catalyzed isomerization of vinyl-substituted trans-N-tosylaziri-dines to more stable cis-aziridines: a) T. Ibuka, N. Mimura, H.Aoyama, M. Akaji, H. Ohno, Y. Miwa, T. Taga, K. Nakai, H. Tama-mura, N. Fujii, Y. Yamamoto, J. Org. Chem. 1997, 62, 999; b) N.Mimura, T. Ibuka, M. Akaji, Y. Miwa, T. Taga, K. Nakai, H. Tama-mura, N. Fujii, Y. Yamamoto, Chem. Commun. 1996, 351.

[24] Presence of a secondary alkyl group on the terminal position of adiene led to low yield of 3-pyrrolines. For example, 1-cyclohexyl-1,3-butadiene forms the N-Ts-3-pyrroline in 36% yield.

Received: May 27, 2011Published online: September 2, 2011

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J. Zhou et al.