Catalytic asymmetric heterogeneous aziridination using CuHY/

bis(oxazoline): effect of reaction conditions on enantioselectivity

Sophia Taylora, John Gullicka, Natasha Galeaa, Paul McMorna, Donald Bethellb, Philip C. Bulman Pagec,Frederick E. Hancockd, Frank Kingd, David J. Willocka, and Graham J. Hutchingsa,�

aDepartment of Chemistry, Cardiff University, P.O. Box 912, Cardiff CF10 3TB, UKbLeverhulme Centre for Innovative Catalysis, Department of Chemistry, University of Liverpool, Liverpool L69 3BX, UK

cDepartment of Chemistry, Loughborough University, Loughborough, Leics. LE11 3TU, UKdSynetix, P.O. Box 1, Billingham, Teeside TS23 1LB, UK

The copper-catalyzed aziridination of styrene with copper-exchanged zeolite HY (CuHY) and copper(II) triflate

(trifluoromethanesulfonate) ðCuðOTfÞ2Þ as catalysts is described using N-(p-tolylsulfonyl)imino]phenyliodinane (PhI¼NTs) as

the nitrene donor. The effects on the ee and yield of the aziridine when the catalyst is modified by the presence of a chiral

bis(oxazoline) are investigated in detail. The heterogeneously catalyzed reaction under these conditions shows a slight, but

significant, enhancement in ee with increasing conversion at 25 �C. This is not observed in the more rapid homogeneously catalyzed

reaction under identical reaction conditions using PhINTs as the nitrene donor. The enhancement in ee is proposed to result from

the preferential reaction of the (S)-aziridine with the Cu2þ : bis(oxazoline) complex in the presence of PhI¼NTs, leading to an

enhancement of the (R)-aziridine in the remaining aziridine product.

KEY WORDS: asymmetric heterogeneous catalysis; aziridination of styrene; bis (oxazoline)/zeolite catalysts.

1. Introduction

The synthesis of pure enantiomers remains ofcontinued importance for pharmaceutical and agro-chemical applications. There is currently significantresearch interest in the design of catalyst methodologies[1–7], and a specific objective concerns the synthesis ofhighly selective heterogeneous catalysts [8]. This isparticularly important for some catalysts that involveexpensive chiral ligands or require high concentrationsof the active species in solution. In previous studies, wehave developed an approach involving the modificationof cations ion-exchanged into the intracrystalline poresof zeolites and mesoporous materials, and we havedemonstrated that this approach leads to the design ofeffective immobilized catalysts [9–17].

Recently, we have concentrated on the heterogeneousasymmetric aziridination of alkenes [11–17] using Cu2þ

ion-exchanged into zeolite H-Y modified by a chiralbis(oxazoline). (The IUPAC name for 1,3-oxazoline is4,5-dihydro-1,3-oxazole.) We have shown that higherenantioselectivities [16] can be obtained with theimmobilized catalyst when compared with the homo-geneous catalyst, e.g., copper triflate (trifluoromethanesulfonate) [4,18–21]. Recently, Glos and Reiser [22] andBurgeute et al. [23] have investigated alternativemethodologies using polymeric supports for the immo-bilization of copper bis(oxazoline) complexes. In addi-tion, Clarke and Shannon [24] have shown that copper–

bis(oxazoline) complexes can be immobilized on meso-

porous silicas. Both of these approaches have been

shown to give high ee for reactions such as the

cyclopropanation of alkenes. In our previous paper

[16], we showed that, with careful control of the reaction

parameters, using N-(p-tolylsulfonyl)-imino]phenyliodi-

nane (The IUPAC name for iodinane is �3-iodane.)(PhI¼NTs) as the nitrene donor and 2,2-bis[(4R)-4-

phenyl-1,3-oxazolin-2-yl] propane 1 as chiral ligand, we

could obtain aziridine with high yields and high ee. In

this paper, we present the results of a study into the

effect of the reaction components on enantioselectivity

and show how the ee can be enhanced.

2. Experimental

2.1. Methods

(a) 1H NMR spectra were obtained using a Bruker‘‘Avance’’ 400MHz DPX spectrometer, equippedwith Silicon Graphics workstation. The chemicalshifts of 1H NMR spectra are recorded indeuteriated chloroform ðCDCl3Þ and deuteri-ated dimethylsulfoxide ðd6-DMSOÞ. Spectra were

�To whom correspondence should be addressed.

E-mail: hutch@cardiff.ac.uk

Topics in Catalysis Vol. 25, Nos. 1–4, November 2003 (# 2003) 81

1022-5528/03/1100–0081/0 # 2003 Plenum Publishing Corporation

recorded on the d scale and signals quoted in theform: chemical shift measured in ppm (No. ofprotons, multiplicity, assignment).

(b) Flash column chromatography was performed onMerck Kieselgel 60 (230–400 mesh) and analyticalTLC on silica gel 60F-254 plates.

(c) Microanalyses were performed by the CardiffUniversity, Department of Chemistry microanalysisservice.

(d) Atomic adsorption spectroscopy was performedusing a Perkin-Elmer 373 atomic absorption spec-trometer using an air-acetylene flame.

(e) HPLC analysis was recorded using a DynamaxSD200 pump equipped with a Dynamax Al-3autosampler, Dynamax injector and an UV absor-bance detector. An Apex ODS 5� column was usedfor analytical work. The eluent system was acetoni-trile-water (85 : 15). Baseline separation wasachieved for all reagents and products. For chiralHPLC analysis, a 25-cm Chiralcel OJ column wasused. The eluent system was hexane-propan-2-ol(82 : 18). Baseline separation was achieved for bothenantiomers. Absolute configuration was confirmedby optical polarimetry and comparison with theliterature [12].

2.2. Materials

Styrene and the bis-oxazolines were obtained fromAldrich. Ultrastabilized NHþ

4 Y zeolite (Union Carbide,LZY84, 5.0 g) was calcined (550 �C) for 5 h, then stirredin 0.5mol solution of copper(II) acetate solution(100mL) for 24 h at room temperature. The mixturewas then filtered and washed with distilled water. Thiswas repeated a further two times. The CuHY zeolite wasthen dried at 100 �C for 24 h, then recalcined (550 �C) for5 h. Cu content 3.2% by weight.

2.3. Preparation of [N-(p-tosylsulfonyl)imino]phenyl-iodinane (PhI¼NTs)

Iodobenzene diacetate (3.22 g; 1.0mmol) was addedto a stirred mixture of potassium hydroxide (1.4 g;0.025mmol) and p-toluenesulfonamide (1.71 g;1.0mmol) in HPLC grade methanol (40mL), keepingthe temperature below 10 �C during the addition. Theresulting clear yellow solution was stirred for 3 h atroom temperature and then poured into distilled water(250mL). Over a period of 12 h, a yellow precipitateformed and this was then filtered, washed with distilledwater and dried at room temperature in a vacuumdesiccator (2.56 g, 68.8%). �H (d6-DMSO, 400 MHz)7–7.8 (multiplet, 9H), 2.32 (singlet, 3H). Analysis:Calculated C 41.82, H 3.18, N 3.75; Found C 41.79, H3.29, N 3.74%.

2.4. Homogeneous aziridination reactions catalysed byCuðOTf Þ2

Styrene (0.101 g, 1.0mmol), nitrene donor (1.5mmol), copper(II) triflate (0.15mmol) were stirred inacetonitrile (2:5 cm3) at 25 �C. If a chiral bis(oxazoline)(0.07mmol, Aldrich, 98%) was added, this was addedtogether with the copper(II) triflate in dry acetonitrileprior to the addition of the styrene and nitrene donor.Reaction time varied according to the different nitreneprecursor. The reaction was stirred in air at 25 �C untilcomplete dissolution of the nitrene donor. The reactionmixture was then filtered through a plug of silica withethyl acetate (50 cm3) as eluent. Flash chromatographygave the aziridine as a white solid. Experiments werecarried out in triplicate and reproducible results arereported.

2.5. Heterogeneous aziridine reaction catalyzed byCuHY

Styrene (0.101 g, 1.0mmol), nitrene donor(1.5mmol), CuHY (0.3 g) were stirred together in dryacetonitrile (2:5 cm3) at 25 �C. If a chiral bis(oxazoline)(0.07mmol, Aldrich, 98%) was added, this was stirredwith the CuHY in the acetonitrile prior to the additionof the styrene and nitrene donor. Reaction times varieddepending on the nitrene donor. The reaction mixturewas stirred in air at 25 �C until complete dissolution ofthe nitrene donor. The reaction mixture was then filteredthrough a plug of silica with ethyl acetate (50 cm3) aseluent. Flash chromatography gave the aziridine as awhite solid. Experiments were carried out in triplicateand reproducible results are reported.

3. Results and discussion

3.1. Effect of reaction time on ee

In our previous studies [16] and in the previousstudies of Evans et al. [19–21], the ee is reportedfollowing the completion of the reaction, which issignified by the total disappearance of the nitrenedonor, which is only sparingly soluble in the reactionmixture. The homogeneously catalyzed reaction is rapidat 25 �C and total conversion is achieved in ca. 1 h[16–20]. The heterogeneously catalyzed reaction is muchslower under comparable conditions, taking ca. 3 h toreach completion [16], although we have shown that theheterogeneously catalyzed process can give higherenantioselection than the homogeneous counterpart[16]. The effect of reaction time on ee was investigatedfor both the heterogeneously and homogeneouslycatalyzed aziridination of styrene (acetonitrile as sol-vent, 25 �C, PhI¼NTs : styrene ¼ 1:5 :1mol ratio) bycarrying out the reaction for specified times, stoppingthe reaction and isolating the aziridine to determine the

S. Taylor et al./Catalytic asymmetric heterogeneous aziridination82

yield and the ee. The data are shown in figure 1. As

expected, the homogeneously catalyzed reaction was

rapid, reaching completion in ca. 1 h (figure 1(a)) and

there was no change in the observed ee with increasing

styrene conversion (figure 1(c)) within experimental

error. In contrast, the CuHY heterogeneously catalyzed

reaction under the same conditions was slower (figure

1(b)) and showed a small, but experimentally significant

increase in ee with increasing yield of aziridine and

styrene conversion (figure 1(c)). The results confirm that,

under these reaction conditions, CuHY modified by

bis(oxazoline) 1 gives higher enantioselection than the

homogeneous counterpart. However, the increase in ee

with conversion for the heterogeneous catalyst could

indicate that the active site for asymmetric aziridination

is being modified during the reaction or that theaziridine is being interconverted between enantiomers.Similar observations for the enhancement in ee withconversion have been observed for the asymmetrichydrogenation of ethyl pyruvate catalyzed by Ptmodified by cinchona alkaloids [25,26] but, as yet, theorigin of the effect for that catalyst system has not beensatisfactorily resolved. The significant differencebetween the heterogeneous Cu2þ-zeolite and the homo-geneous Cu2þ catalysts is that the micropores in thezeolite can introduce severe diffusion limitations for thereactants and products. In addition, it can be expectedthat the active site within the zeolite is more constrainedthan for the homogeneous catalyst in solution, a factorthat we have noted before as playing a role in theenhanced enantioselection observed [16]. In view of this,there are many interactions in the CuHY catalyst thatcould play a role in the evolution of the active site andthese include the interaction of the bis(oxazoline),PhI¼NTs, as well as the reaction by-product formedfrom PhI¼NTs, i.e., PhI and tosyl sulfonamide(TsNH2), as well as the aziridine product. In addition,the CuHY catalyst can contain traces of water as thematerial is difficult to dry rigorously prior to reactionand, consequently, the interaction with water could alsobe important. These effects are investigated in thefollowing sections.

3.2. Effect of water on enantioselection

Water is known to have an effect on the yield of theaziridine in both the homogeneously and hetero-geneously catalyzed reactions [27], as significant quan-tities of additional water, added to the reaction mixture,lead to the formation of benzaldehyde [16]. However, inthe experiments described in this paper, only relativelysmall amounts of water are likely to be present. In viewof this, a series of additional experiments were carriedout for both the CuðOTfÞ2 and CuHY catalysts in thepresence of the bis(oxazoline). First, following thecompletion of the two catalyzed reactions (i.e. ca. 1 hfor CuðOTfÞ2: 1 and ca. 3 h for CuHY: 1), the reactionmixtures were stirred at 25 �C for additional periods(0.5–24 h) prior to isolation of the aziridine. Noracemization or loss of aziridine was observed for eitherthe homogeneous or the heterogeneous system. Sec-ondly, following completion of the catalyzed reaction, asmall quantity of water (20�l) was added to bothreaction mixtures and the mixtures were stirred for anadditional 0.5 h. A small decrease in ee was observed ofca. 3–4% in both cases. This indicates that theinvolvement of small quantities of water is likely tohave a slight deleterious effect on ee during the reaction,and hence, cannot account for the increase in ee withconversion observed in the heterogeneously catalyzedreaction (figure 1).

0

20

40

60

80

100

0 1 2 3time (h)

yiel

d (

%)

70

72

74

76

78

80ee

(%

)

a

0

20

40

60

80

100

0 2.5 5 7.5 10time (h)

yiel

d (

%)

70

72

74

76

78

80

ee (

%)

b

70

72

74

76

78

80

50 60 70 80 90 100

Conversion (%)

ee (%

)

c

Figure 1. Effect of reaction time on yield and ee of aziridine [styrene

(1mmol) reacted with CuHY (0.3 g) or CuðOTfÞ2 (0.015 g), PhI ¼ NTs

(1.5mmol) with bis(oxazoline) 1 in CH3CN at 25 �C]. (a) CuðOTfÞ2, (b)

CuHY. Key: * aziridine yield; & aziridine ee, and (c) ee as a function

of styrene conversion. Key: * CuHY; & CuðOTfÞ2.

S. Taylor et al./Catalytic asymmetric heterogeneous aziridination 83

3.3. Effect of preforming the Cu2+-bis(oxazoline)complex

The major factor that determines enantioselection isthe formation of the Cu2þ-bis(oxazoline) complex. Inour previous studies, we have standardized the pretreat-ment by stirring the Cu catalyst (i.e., CuðOTfÞ2 orCuHY) in CH3CN together with the bis(oxazoline) for15min. It is possible that formation of the complex inthe Cu2þ ion-exchanged zeolite catalyst might takelonger due to the diffusion limitations expected for thetransport of the bis(oxazoline) into the pores. Hence,two further pretreatment methods were investigated inwhich the complex was formed over 3 h and 24 h. Thepretreatment time of 3 h was specifically selected since,for the CuHY catalyst, this represents the total reactiontime under the conditions used in the previous experi-ment and, during this time, the ee steadily increases(figure 1). The results shown in table 1 show that thesepretreatment methods lead to both lower ee and loweryields of the aziridine, which may be due to somedegradation of the ligand. Hence, we do not considerthat the enhancement in ee observed with increasingconversion for the heterogeneous CuHY-bis(oxazoline)catalyst is due to the formation of the Cu2þ-bis(oxazo-line) complex during the initial stages of the reactions.

3.4. Effect of reaction by-products on enantioselectivity

During the aziridination reaction, PhI and TsNH2

are formed as breakdown products of the PhI¼NTsnitrene donor. We have previously reported the effect ofthese by-products on the yield of aziridine [16] byinvestigating the effect of the addition of PhI andTsNH2 to the reaction mixture at the start of thereaction. The effect of addition of 10% PhI and 10%TsNH2 (based on styrene) to the reaction mixture at thestart of the reaction was investigated and the results areshown in table 2. Interestingly, the addition of these by-products had different effects on the homogeneous andheterogeneous catalyzed reactions. For the homo-geneous reaction, the addition of PhI reduces the

reaction time from 1h to 30min but also reduces thefinal yield. Thus, under these conditions, PhI seems toenhance unfavorable side reactions. With TsNH2, thereaction time is extended to 2–5 h suggesting TsNH2 isinhibiting the reaction. The reduced yield may be due tothe extended reaction time giving rise to by-products.When both PhI and TsNH2 are added together, thereaction time becomes 2 h with virtually the same yieldas TsNH2 alone. For the heterogeneous reaction, verydifferent results are observed. When PhI is added to thereaction, the reaction time is reduced compared to theunmodified reaction (2.5 rather than 2 h), similar to thatobserved for the homogeneous reaction. In contrast tothe homogeneous reaction, the yield increases slightly.Thus, the PhI has the same effect on the reaction time ofboth homogeneous and heterogeneous reactions but noton the yields. Presumably, the zeolite is playing a role inpreventing side reactions. When TsNH2 is added,although the reaction time increases, the yield alsoincreases significantly. The ee for the heterogeneouslycatalyzed reaction is adversely affected by the additionof 10% PhI and 10% TsNH2. However, in the case of thehomogeneously catalyzed reaction, the addition of 10%TsNH2 increased the ee from 73 to 83%, although theyield of aziridine was decreased and the reaction timewas significantly increased. This indicates that it ispossible for the reaction by-products to influence theenantioselectivity during the formation of the aziridine.

3.5. Reaction of aziridine with PhI=NTs

It is possible that the changes in enantioselectionobserved with conversion in the heterogeneously cata-lyzed reaction could be due to reaction of aziridine withthe catalyst after it is formed. This type of sequentialreaction is well known to affect yields and selectivity inheterogeneously catalyzed reactions. To investigate this,a sample of the aziridine [(R)-N-(p-tosylsulfonyl)-2-phenylaziridine, ee 76%] was isolated and reacted inCH3CN at 25 �C with either CuHY or CuðOTfÞ2 ascatalyst for 24 h. The effect of addition of the nitrenedonor (PhI¼NTs) on the bis(oxazoline) 1 was alsoinvestigated. The results are shown in table 3. It isapparent that, for both the homogeneously catalyzedand the heterogeneously catalyzed reactions, the azir-idine is unstable and the concentration is decreased.Stirring the aziridine in CH3CN at 25 �C with (i) theCu2þ catalyst, (ii) the Cu2þ-bis(oxazoline) complex or(iii) the Cu2þ catalyst with PhI¼NTs leads to racemiza-tion. The racemization observed is found to be similarfor both the homogeneous and heterogeneous catalysts.However, when the aziridine is stirred with the Cu2þ–bis(oxazoline) complex together with PhI¼NTs, anincrease in ee is observed for both the heterogeneousand homogeneous catalysts. Again, the effect on ee issimilar for both catalysts, although the loss of aziridine

Table 1

Effect of prestirring of CuHY and bis(oxazoline) prior to reactiona

CuHY þ 1 pretreatment Yield (%) ee (%)

Stirred 15min 78 (91) 6 (73)

Stirred 3 h 71 (88) 58 (60)

Refluxed 24 h 60 (74) 35 (35)

a2,2-bis[4(R)-4-phenyl-1,3-oxazolin-2-yl]propane (0.07mmol) stirred

with CuHY in CH3CN (2.5mL). Following pretreatment, styrene

(1mmol) and PhI¼NTs (1.5mmol) were added and the reaction

mixture stirred at 25 8C for 3 h. Data in parenthesis are for the

homogeneous catalyst Cu(OTf)2 (0.015mmol) under identical

conditions.

S. Taylor et al./Catalytic asymmetric heterogeneous aziridination84

is much higher in the heterogeneous catalyst. The results

indicate that the (S)-aziridine is being preferentially

consumed leading to an enhancement in the amount of

the (R)-aziridine remaining in the reaction mixture.It is possible that the results provide an indication as

to the origin of the enhancement in ee that is observed

with conversion in the CuHY heterogeneously catalyzed

reaction (figure 1). It is possible that some of the (S)-

aziridine initially formed is preferentially reacted leading

to the observed enhancement in ee, especially consider-

ing that the experiments were carried out with an excess

of nitrene donor. This is observed with the hetero-

geneously catalyzed reaction since this proceeds more

slowly (ca. 3 h for completion) than the homogeneously

catalyzed reaction (ca. 1 h for completion). Hence, the

homogeneous reaction may be completed too rapidly for

the effect to be observed and following this reaction,

since all the PhI¼NTs initially added would have

reacted, no further enhancement in ee would have

been expected when the reaction mixture was stirred for

a further 24 h.

There is no evidence for hydrolysis products beingobserved (e.g., tosylated amino alcohols) in either theHPLC analysis or in the NMR spectra of the reactionproducts. This tentatively rules out a kinetic resolutionprocess based on hydrolysis. To determine if thehydrolysis product, if formed, had been retained withinthe pores of the heterogeneous catalyst, soxhlet extrac-tion was carried out. NMR spectroscopy of theextracted material revealed it to be exclusively theaziridine. The absence of hydrolysis products suggeststhat the R and S enantiomer of the aziridine can beinterconverted.

The experiments were repeated using racemic azir-idine in place of the enantiomerically enriched aziridine.The results are shown in table 4 for the reaction of theracemic aziridine in CH3CN stirred with the CuHYbis(oxazoline) complex and PhI¼NTs. A smallenhancement in ee is observed at 25 �C, which isconsistent with the previous data set. However, at lowertemperatures, a much more marked enhancement in eeis observed.

The data in table 3 clearly show that the presence ofthe nitrene donor in conjunction with Cu2þ and thebis(oxazoline) is required for an enhancement in ee to beobserved. The most plausible explanation of this effect isthat the Cu�þ/bis(oxazoline)/nitrene donor complexplays a key role in determining the degree of enantio-selection rather than just the Cu2þ–bis(oxazoline)complex. The observed interconversion could occur viathe intermediate shown in scheme 1 as, once the three-

membered ring is broken, rotation about the C–C bondallows inversion of the stereogenic center, which may becatalyzed by Cu2þ acting as a Lewis acid. There is aprecedent for transition metals forming complexes withN-tosylaziridines, a recent example is reported by Linet al. [28]. When the aziridine interacts with the Cu�þ/bis(oxazoline)/nitrene donor complex, the increasedsteric bulk of the system may favor the conversion ofS-aziridine to R-aziridine. It may also be possible for the

Table 2

Effect of addition of reaction by-products on yield and enantioselec-

tivity of the aziridination reactiona

Additive Reaction timeb Yield (%) ee (%)

None 3 (1) 78 (91) 76 (73)

10% PhI 2.5 (0.33) 83 (66) 63 (72)

10% TsNH2 4 (2.5) 98 (82) 46 (83)

10% TsNH2 24 (2.0) 37 (85) 53 (75)

þ 10% PhI

aCuHY (0.3 g) prestirred with 2,2-bis[4(R)-4-phenyl-1,3-oxazoline-2-

yl]propane (0.07mmol) for 15min at 25 8C in CH3CN (2.5mL).

Following pretreatment, styrene (1mmol) and PhI¼NTs (1.5mol)

were added and the reaction mixture stirred at 25 8C. Data in paren-

thesis are for the homogeneous catalyst Cu(OTf)2 (0.015mmol)

under identical conditions.bReaction time followed by dissolution of PhI¼NTs.

Table 3

Reaction of chiral aziridine with reaction components

Additivea Aziridineb (� mol) eec (%)

Cu 878 (791) 58 (55)

Cu þ 1 893 (896) 64 (70)

Cu þ PhI¼NTs 914 (700) 65 (61)

Cu þ 1 þ PhI¼NTs 827 (914) 81 (82)

a(R)-N-(p-tosylsulfonyl)-2-phenylaziridine (1mmol) reacted in CH3CN

(2.5mL) at 25 8C for 24 h with Cu catalyst : CuHY (0.3 g) or Cu(OTf)2(0.015mmol), 2,2-bis[4(R)-4-phenyl-1,3-oxazolin-2-yl]propane (0.07

mmol), PhI¼NTs (1.5mmol). Data in parenthesis are for the homo-

geneous reaction catalyzed by Cu(OTf)2.b1000 � mol at start of reaction.c76% at start of reaction.

Cun++

N

Ph

Ts

Cun+N

Ph

Ts

Cun+N

Ph

N

Ts

Ph

+Cun+

Scheme 1.

S. Taylor et al./Catalytic asymmetric heterogeneous aziridination 85

nitrene to interact with the aziridine as shown in scheme

2. The formation of the five-membered intermediate,

along with the presence of the bis(oxazoline) may give

improved control of the chiral center and, hence, the

observed increase in ee. This could be caused by

unfavorable interactions between the phenyl group of

the aziridine and the phenyl group of the bis(oxazoline).

To support our experimental work, we have also used

density functional theory (DFT) to consider the

mechanism of aziridination. For these calculations, the

Amsterdam density functional theory package, ADF

[29,30], was used with gradient corrections to the

exchange energy due to Becke [31] and the form for

the correlation energy suggested by Lee, Yang, and Parr

[32]. ADF uses a basis set of Slater-type functions, and

we employ a triple zeta basis set on all atoms with

polarization functions on main group elements. The

frozen core approximation was used for core electrons

of all atoms except H. Atomic cores being defined as the

1s shell of C, N, and O, up to 2p for S and Cu and up to4p for I. This is the ADF standard level IV basis set withthe smallest possible core for each element.

To gain accurate structures for the nitrene inter-mediate, we have used more extensive models than havepreviously appeared in the literature [33], including thetosyl group and a coordinated acetonitrile solventmolecule. This model gives a triplet ground state(19 kJ mol�1 below the corresponding singlet) with amono-dentate nitrene and a significant spin density onthe nitrogen atom, as shown in figure 2. This suggeststhat ring opening of an aziridine in the presence ofnitrene intermediate could take place via coordinationof the aziridine to the Cu center followed by ringopening and the formation of a five-membered metallo-cycle intermediate, as shown in scheme 2. Thisintermediate would be difficult to optimize using theDFT method owing to the large number of atomspresent, but we note that in the earlier work on Diels–Alder reactions employing the same catalyst, PM3 levelcalculations have been able to yield useful informationon selectivity [34]. In that case, the coordination ofoxygen atoms was based on the XRD structure for the½ðCuðoxazolineÞOH2Þ2�

2þ complex. It was also notedthat despite the strong preference of Cu2þ for squareplanar coordination, the ligand bulk forces the H2Ocomplex to be twisted. In a similar way, we base ourcalculations on the DFT structure for the intermediateusing the calculated nitrene structure as a basis forconstructing the proposed metallocycle complex. Sincethe PM3 method is not parameterized for transitionmetals, the Cu center was replaced by a dummy atomthat was used to constrain the positions of thecoordinating nitrogen atoms. The five-membered ringis constructed so that each nitrogen atom is 1.825 Afrom the dummy atom (the Cu–N distance from the

Table 4

Reaction of racemic aziridine with chirally modified CuHY in presence

of PhI¼NTsa

Temperature

(0 8C)Aziridine (� mol) ee (%)

0 h 24 h

R S R S

37 485 485 432 398 4

25 470 470 460 400 7

10 500 500 531 319 25

0 460 460 545 215 33

�10 485 485 476 214 38

aN-(p-tosylsulfonyl)-2-phenylaziridine reacted with 2,2-bis[4(R)-4-

phenyl-1,3-oxazolin-2-yl]propane (0.07mmol), PhI¼NTs (1.5mmol),

CuHY (0.3 g) in CH3CN (2.5mL) for 24 h.

-0.05

1.15

0.39

0.130.12

0.03 0.03

0.04

0.02

0.07

0.030.03

Figure 2. The DFT calculated structure for the Cu nitrene inter-

mediate in its triplet state. The figures indicate the spin density at each

atom center according to a Mulliken-type analysis.

N

NCu=NTs

O

O

Ph

Ph

n++

N

Ts

Ph

n+

N

NCu

O

O

Ph

Ph

N

N Ts

PhTs

n+

N

NCu

O

O

Ph

Ph

N

N

PhTs

Ts

n+

N

NCu=NTs

O

O

Ph

Ph

+N

Ts

Ph

Scheme 2.

S. Taylor et al./Catalytic asymmetric heterogeneous aziridination86

DFT calculations on the copper nitrene intermediate),and the nitrogen valence is satisfied by adding hydrogenatoms such that the N–H bonds are aligned with the N-dummy atom direction. The oxazoline nitrogen atomsare fixed at 2.060 and 2.077 A (again, values taken fromthe DFT results), and a torsional restraint is used toensure that the two oxazoline rings remain coplanar.Since the Cu center in this proposed structure is highlysterically congested, it is unlikely that the square planarpreference of the metal can be satisfied and so nogeometric restriction was imposed.

The PM3 level of simulation allows us to consider thesteric affects of the complete phenyl-substituted oxazo-line ligand and the tosyl groups on the five-memberedring. There are four possible positions for the phenylgroup from the styrene on the proposed intermediate.Accordingly, four models were constructed and geom-etry optimized using the PM3 method with dummy tonitrogen distances fixed as described above.

The four structures resulting from these calculationsare shown in figure 3 and their relative energies reportedin table 5. The structures show that the five-memberedring can be accommodated without significant stericconflict with the oxazoline ligand. To generate anaziridine from this structure, we expect that the five-membered ring will collapse such that the N–C bond tothe phenyl-substituted carbon atom is the first to becleaved. This allows the radical generated on the carbonatom to be stabilized by the phenyl group, the newaziridine will then be formed by the closure of the three-

membered ring on the other nitrogen atom. Experi-

mental evidence for the presence of radical species has

been previously observed in the form of oxygenated

byproducts [35]. From this argument, the favored

product chirality from each ring system can be estimated

and is listed in table 5. The PM3 calculations show only

small energy differences between the four structures

indicating that there is little steric preference in the five-

membered ring intermediate. So that, while these

calculations show that the proposed exchange mechan-

ism is sterically feasible, they do not indicate the

selectivity to be expected. The change in selectivity

observed experimentally may be due to the initial

alignment of the aziridine with the nitrene complex

rather than the collapse of the intermediate. In addition,

these calculations are for the structures in isolation and

so no account has been taken of the influence of the

zeolite environment. Both these aspects are currently

under consideration.

4. Conclusions

In this paper, we have presented a study on the

relationship between ee and conversion during the

aziridination reaction. For the heterogeneously cata-

lyzed reaction, using Cu2þ ion-exchanged into zeolite

HY modified with bis(oxazoline) 1, an enhancement in

ee is observed with increasing conversion during the

total reaction time of ca. 3 h. In contrast, the homo-

geneously catalyzed reaction, using CuðOTfÞ2: bis(ox-

azoline) 1 with PhI=NTs as nitrene donor, did not

show this effect. This is considered to be due to the

homogeneous reaction being significantly more rapid.

The enhancement in ee is considered to be due to the

preferential reaction of the (S)-aziridine with the

reaction components leading to an enhancement in the

(R)-aziridine in the product and we have presented a

possible mechanistic pathway for this to occur via the

copper nitrene intermediate. These results indicate that

the Cu2þ-bis(oxazoline) catalyzed aziridination reaction

may be significantly influenced by additional reaction

components.

(a) (b)

(c) (d)

Figure 3. Structures from constrained PM3 optimizations. In each

structure, the oxazoline ligand has been given a single color, all other

atoms are colored according to element type. The structures differ in

the position of the styrene phenyl ring in the proposed five-membered

ring.

Table 5

Relative energies of calculated five-member ring structures

Reference from

figure 3

Favored

aziridine

Relative energy

(kJmol�1)

a R 6

b S 0

c R 1

d S 0

S. Taylor et al./Catalytic asymmetric heterogeneous aziridination 87

Acknowledgments

We thank Synetix and the EPSRC for funding.

References

[1] R. Noyori, Asymmetric Catalysis in Organic Synthesis (Wiley,

New York, 1994).

[2] T. Katsuki and K.B. Sharpless, J. Am. Chem. Soc. 102 (1980)

5974.

[3] W. Zhang, J.L. Loebach, S.R.W. Wilson and E.N. Jacobsen,

J. Am. Chem. Soc. 112 (1990) 2801.

[4] J.S. Johnson and D.A. Evans, Acc. Chem. Res. 33 (2000) 325.

[5] K. Soai, T. Shibata and I. Sato, Acc. Chem. Res. 33 (2000) 382.

[6] K. Mikami, M. Terada, T. Korenaga, Y. Matsumoto and S.

Matsukawa, Acc. Chem. Res. 33 (2000) 391.

[7] D.G. Blackmond, Acc. Chem. Res. 33 (2000) 402.

[8] G.J. Hutchings, Chem. Commun. (1999) 301.

[9] S. Feast, D. Bethell, P.C.B. Page, F. King, C.H. Rochester,

M.R.H. Siddiqui, D.J. Willock and G.J. Hutchings, J. Chem.

Soc., Chem. Commun. (1995) 2499.

[10] S. Feast, M.R.H. Siddiqui, R.P.K. Wells, D.J. Willock, F. King,

C.H. Rochester, D. Bethell, P.C.B. Page and G.J. Hutchings,

J. Catal. 167 (1997) 533.

[11] C. Langham, P. Piaggio, D. Bethell, D.F. Lee, P. McMorn, P.C.

Bulman Page, D.J. Willock, C. Sly, F.E. Hancock, F. King and

G.J. Hutchings, Chem. Commun. (1998) 1601.

[12] C. Langham, S. Taylor, D. Bethell, P. McMorn, P.C. Bulman

Page, D.J. Willock, C. Sly, F.E. Hancock and G.J. Hutchings, J.

Chem. Soc., Perkin 2, (1999) 1043.

[13] P. Piaggio, P. McMorn, C. Langham, D. Bethell, P.C. Bulman

Page, F.E.Hancock andG.J. Hutchings, New J. Chem. (1998) 1167.

[14] P. Piaggio, C. Langham, P. McMorn, D. Bethell, P.C. Bulman

Page, F.E. Hancock, C. Sly and G.J. Hutchings, J. Chem. Soc.,

Perkin Trans. 2, (2000) 143.

[15] P. Piaggio, P. McMorn, D.M. Murphy, D. Bethell, P.C. Bulman

Page, F.E. Hancock, C. Sly, O.J. Kerton and G.J. Hutchings,

J. Chem. Soc., Perkin Trans. 2, (2000) 2009.

[16] S. Taylor, J. Gullick, P. McMorn, D. Bethell, P.C. Bulman Page,

F.E. Hancock, F. King and G.J. Hutchings, J. Chem. Soc., Perkin

Trans. 2, (2001) 1714.

[17] S. Taylor, J. Gullick, P. McMorn, D. Bethell, P.C. Bulman Page,

F.E. Hancock, F. King and G.J. Hutchings, J. Chem. Soc., Perkin

Trans. 2, (2001) 1724.

[18] E.N. Jacobsen, in Comprehensive Asymmetric Catalysis, Vol. 2,

E.N. Jacobsen, A. Pfaltz and H. Yumamoto (eds.) (Springer-

Verlag, Berlin, 1999) p. 607.

[19] D.A. Evans, M.M. Faul and M.T.J. Bilodeau, J. Org. Chem. 56

(1991) 6744.

[20] D.A. Evans, M.M. Faul and M.T. Bilodeau, J. Am. Chem. Soc.

116 (1994) 2741.

[21] D.A. Evans, K.A. Woerpel, M.M. Hinman and M.M. Faul,

J. Am. Chem. Soc. 113 (1991) 726.

[22] M. Glos and O. Reiser, Org. Lett. 2 (2000) 2045.

[23] M.I. Burguete, J.M. Fraile, J.I. Garcıa, E. Garcıa-Verdugo, S.V.

Luis and J.A. Mayoral, Org. Lett. 2 (2000) 3905.

[24] R.J. Clarke and I.J. Shannon, Chem. Commun. (2001) 1936.

[25] T. Mallat, Z. Bodnar, B. Minder, K. Borszeky and A. Baiker,

J. Catal. 168 (1997) 183.

[26] J. Wang, Y. Sun, C. Lebland, R.N. Landua and D.G. Black-

mond, J. Catal. 161 (1996) 752.

[27] C. Langham, P. Piaggio, D. Bethell, D.F. Lee, P.C. Bulman Page,

D.J. Willock, C. Sly, F.E. Hancock, F. King and G.J. Hutchings,

in Catalysis of Organic Reactions, Vol. 3, F.E. Herkes (ed.)

(Marcel Dekker, 1998) p. 25.

[28] B.L. Lin, C.R. Clough and G.L. Hillhouse J. Am. Chem. Soc. 124

(2002) 2890.

[29] ADF2002.01 was obtained from SCM, Theoretical Chemistry,

Vrije Universiteit, Amsterdam, The Netherlands, http://

www.scm.com

[30] C. Fonseca Guerra, J.G. Snijders, G. te Velde and E.J. Baerends,

Theor. Chem. Acc. 99 (1998) 391; G. te Velde, F.M. Bickelhaupt,

S.J.A. van Gisbergen, C. Fonseca Guerra, E.J. Baerends, J.G.

Snijders and T. Ziegler, J. Comput. Chem. 22 (2001) 931.

[31] A.D. Becke, Phys. Rev. A, 38 (1988) 3098.

[32] C. Lee, W. Yang and R.G. Parr, Phys. Rev. B, 37 (1988)

785.

[33] P. Brandt, M.J. Sodergren, P. Gandersson and P.-O. Norrby,

J. Am. Chem. Soc. 112 (2000) 8013.

[34] D.A. Evans, S.J. Miller, T. Lectka and P. von Matt, J. Am. Chem.

Soc. 121 (1999) 7559.

[35] J. Gullick, S. Taylor, O. Kerton, P. McMorn, F. King, F.E.

Hancock, D. Bethell, P.C.B. Page and G.J. Hutchings, Catal.

Lett. 75 (2001) 151.

S. Taylor et al./Catalytic asymmetric heterogeneous aziridination88