Stereoselectivity in reactions of atropisomeric lactams and imides

Tetrahedron 60 (2004) 4491–4511

Stereoselectivity in reactions of atropisomeric

lactams and imides

D. Jonathan Bennett,^aAlexander J. Blake,^cPaul A. Cooke,^cChristopher R. A. Godfrey,^b

c

Paula L. Pickering,^cNigel S. Simpkins,^cMatthew D. Walker and Claire Wilson

,

*

^aOrganon Laboratories Ltd, Newhouse, Lanarkshire ML1 5SH, UK

^bSyngenta Agrochemicals, Jealott’s Hill Research Station, Bracknell, Berkshire RG42 6ET, UK

^cSchool of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK

Received 5 December 2003; revised 16 January 2004; accepted 21 January 2004

Abstract—A range ofreactionsofcycliclactamsystemsisdescribedinwhich anatropisomeric C–Naxiscontrolsthe stereochemicaloutcomeof

ring substitution or addition. In the case of enantiopure menthol adducts, substitution via N-acyliminium intermediates occurred with essentially

complete control. However, the range of nucleophiles that participate in the reaction is very limited and at present the removal of the N-aryl

substituent is problematic. A six-membered enamide is of moderate conﬁgurational stability and the axis exerts synthetically useful levels of

control over enolate alkylations of the system. A novel Lewis acid mediated enamide arylation process was identiﬁed.

1. Introduction

asymmetric N-allylation of N–H amides such as 1, or by

selective crystallisation of tartrate anilides 2.^7–10

The seminal contribution by Curran and co-workers in 1994

showed that anilides having a bulky ortho-substituent

showed signiﬁcant promise in stereocontrolled reactions in

which an atropisomeric C–N axis controls the formation of

new stereogenic centre(s).¹Since that time a number of

groups, including our own, have further developed this

chemistry with various amide, lactam and imide sys-

tems.^2–6Although some of this work has focused on the

atroposelective reactions of racemic systems, access to non-

racemic derivatives of known absolute conﬁguration has

emerged as a key issue. Some non-racemic anilides have

been obtained, either by the chiral pool approach, by

Our ownstudieshaveturnedtothechemistryofcyclicsystems

bearingthe N-ortho-tert-butylphenyl motif, and wepreviously

described some aspects of the N-acyliminium chemistry of

menthol-derived lactams of general structure 3.¹¹In attempt-

ing to progress this work, we also became interested in the

atroposelective reactions of cyclic enamides represented by

structure 4, and have now explored the chemistry of the six-

membered variant in some detail, including enolate alky-

lations, alkene reactivity and modiﬁcation of the aromatic

portion. The purpose of this paper is to describe these new

results, in addition to providing full details of our earlier work.

2. Results and discussion

2.1. N-Acyliminium chemistry of a 5-membered lactam

Keywords: Lactams; Imides; Enolate; N-Acyliminium; Atropisomerism;

Allylation.

Our initial explorations were focussed on the development

of a chiral auxiliary approach for N-acyliminium chemistry

*

Corresponding author. Fax: þ44-115-9513564;

e-mail address: nigel.simpkins@nottingham.ac.uk

doi:10.1016/j.tet.2004.01.100

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D. J. Bennett et al. / Tetrahedron 60 (2004) 4491–4511

Scheme 1.

of lactams of general structure 5, having a leaving group

(LG) derived from a readily available chiral pool material,

Scheme 1.

Initial attempts at N-acyliminium chemistry using Lewis

acids such as TiCl₄or BF₃–OEt₂were not fruitful, and

useful results were found only when we turned to the use of

Me₃SiOTf. Under the inﬂuence of this catalyst, we were

able to carry out efﬁcient allylation or propargylation of 10

as shown in Scheme 3.

The idea was to generate a stereoisomerically pure lactam 5,

in which stereocentres in the auxiliary LG would ﬁx the

chiral C–N axis (and presumably the stereochemistry at C-

5), allowing us to generate a chiral N-acyliminium

intermediate 6, the C–N axis in which would be responsible

for the eventual stereochemical outcome, leading to 7.¹²

A temperature of about 240 8C was found to be important,

since low temperatures (278 8C) gave little or no reaction,

whereas reaction at 0 8C was shown to give products of

eroded ee. The products 12 and 13 were both found to be

less stable with respect to the C–N axis than the menthol-

containing precursors and they rapidly equilibrated to a

diastereomeric mixture. As mentioned above, the use of the

other available starting lactam 11 gave the enantiomeric

product to 12 under the allylating conditions.

Molecular modelling studies of the parent lactam (5 LG¼H)

showed a relatively low energy barrier for rotation around

the aryl C–N bond, which did not augur well for the

conﬁgurational stability of the intermediate 6.¹³Also, even

if this intermediate was conﬁgurationally stable there was

no guarantee that the C–N axis would exert a high level of

control in the subsequent nucleophilic attack. Nevertheless,

we considered this sequence potentially viable and we

rapidly focussed on the idea of using readily available

L-menthol as the leaving group.

For ease of product analysis we chose to hydrogenate both

the allyl and allenyl compounds to give the corresponding

saturated propyl lactam 14, Scheme 4.

Analysis of this compound by HPLC allowed separation of

all four possible stereoisomers (one enantiomeric pair for

each atropisomer), enabling us to determine that the

substitution products 12 and 13 had been formed in

essentially enantiomerically pure form ($99% ee). We

also needed to assign the conﬁgurations of the substitution

products, and we chose to correlate allenyl adduct 13

(generated from 10) with the known methoxymethyl lactam

15, which had been described by Taguchi and co-workers,

Scheme 5.^7e

Reduction of the readily available imide 8 with DIBAL gave

the hydroxy lactam 9 in excellent yield. Condensation of

this material with L-menthol under mildly acidic conditions

then resulted in the formation of the two solid diastereo-

meric adducts 10 and 11, Scheme 2.

Both of the isolated compounds were assigned as having the

ortho-tert-butyl substituent on the opposite face of the

lactam ring to the bulky menthyl substituent. The structure

of the minor isomer 10 was readily secured by X-ray

crystallography, as shown in Figure 1. The structure shown

for 11 is based upon the fact that both 10 and 11 were shown

to equilibrate with another isomer on brief warming in

CDCl₃, but not with each other. In addition, isomers 10 and

11 gave enantiocomplementary results in substitution

chemistry, vide infra. Both 10 and 11 proved to be

reasonably stable as single atropisomers if stored as solids

in the freezer.

We assigned the stereochemistry shown on the basis of

HPLC data, namely that the sequence shown gives the

lactam with the longer elution time on analysis with a

Chiralpak AD column, under conditions described by

Taguchi. We have been unable to determine reliable speciﬁc

rotation values for samples of this compound, and in fact the

anomalously low [a]_Dvalue that we reported initially

prompted a re-examination of the sign of the value for 15,

Scheme 2.

D. J. Bennett et al. / Tetrahedron 60 (2004) 4491–4511

4493

Figure 1. X-ray structure of lactam 10 (displacement elipsoids are drawn at the 50% probability level).

Scheme 3.

from acetophenone as nucleophiles did not give the desired

products.

In a ﬁnal phase of this work, we also examined analogous

transformations of lactams bearing an additional methoxy

substituent on the N-aryl group. Imide 17 was prepared from

the readily available aniline 16, and subsequent DIBAL

reduction and menthol condensation were carried out as

described previously, Scheme 6.

Scheme 4.

leading to a revision.¹⁴Fortunately none of the stereo-

chemical assignments are affected.

This outcome of the menthol condensation was subject to an

initial mis-assignment by us in the original communi-

cation.¹¹Thus, we initially assigned the more polar isomer

as 19, based on erroneous speciﬁc rotation measurements of

a subsequent product, vide infra. In retrospect, the analogy

between Schemes 2 and 6 is very clear. Both systems

produce mainly two isomers, each of which have a trans

disposition of the menthol and tert-butyl groups, and in each

case the less polar isomer is the minor one. That the less

Overall, this work had established that substitution of the

menthol adducts along the lines indicated in Scheme 1 was

indeed possible, and we propose that this is due to

stereochemical control exerted by the chiral C–N axis of

the intermediate N-acyliminium ion. Unfortunately, we

were unable to broaden the scope of the substitution process

in that attempted reactions using Me₃SiCN or the enol silane

Scheme 5.

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D. J. Bennett et al. / Tetrahedron 60 (2004) 4491–4511

Scheme 6.

polar one has structure 19 is very strongly suggested by the

1

very close matching of the upﬁeld region of the H NMR

Although we are now conﬁdent of the assignment in Scheme

7 it rests solely on analogy with the earlier series, since we

have been unable to convincingly correlate with lactam 22.

spectrum for 19 with that of 10, whilst the spectra for 11 and

20 also match well, but are very distinct to the other pair.

Speciﬁc rotation data (all measured in CHCl₃at the same

concentration) also strongly suggest that 19 ([a]_D¼2113) is

analogous to 10 ([a]_D¼2101), and that 20 ([a]_D¼218) is

analogous to 11 ([a]_D¼219).

A natural extension of this work would have involved

probing the homologous six-membered ring family of

compounds. This did not prove possible since attempted

formation of menthol adducts from hydroxylactam 23

always led to the enamide 24, the product of elimination,

Scheme 8.

The more polar isomer 20 was allylated under our typical

conditions to give product 21, which was then subjected to

reaction with excess of CAN, in an effort to remove the N-

aryl substituent, Scheme 7.

It seemed to us that the double bond present in enamide 24

might enable useful substitution of the ring by sequential

treatment with a powerful electrophile, followed by a

nucleophile. To this end, we reacted enamide 24 with

DMDO (osmylation conditions gave a similar result) and

then exposed the crude product to reaction with allylsi-

lane.¹⁶As shown, we obtained two products 25 and 26 in

good overall yield, the stereochemistries of which were both

determined by X-ray crystallography, Figures 2 and 3.

Reaction of 20 with allylsilane gave 21, the ee of which was

shown by HPLC to be ca. 98% ee, which again demonstrates

the high level of ﬁdelity possible in this type of N-

acyliminium ion reaction. Unfortunately, subsequent con-

version into the known lactam 22 proved highly proble-

matic, both in terms of chemical yields, which were mainly

in the 30% region, and also that we obtained inconsistent

measurements of the [a]_Dvalue of the product.¹⁵The

enantiomer of 22 shown in Scheme 7 is well established to

be the (2)-isomer, but the enantiomerically pure compound

has a low speciﬁc rotation of only [a]_D¼4 (c 0.65,

CH₂Cl₂).^15dOur product showed very low positive values of

[a]_D, leading us to believe that we had made the enantiomer

of 22, and leading to a mis-assignment of 20 and 21.

This allylation reaction is much more sluggish than those

described with the ﬁve-membered menthol derived systems

and the extended reaction time and relatively elevated

temperature do not appear suitable for asymmetric synthesis

using enantiomerically pure derivatives (racemisation by

C–N rotation or reversible ring-opening of the intermedi-

ates would be expected). Also, the level of selectivity in the

Scheme 7.

D. J. Bennett et al. / Tetrahedron 60 (2004) 4491–4511

4495

Scheme 8.

Figure 2. X-ray structure of lactam 25 (displacement elipsoids are drawn at

the 30% probability level).

Figure 3. X-ray structure of lactam 26 (displacement elipsoids are drawn at

the 50% probability level). Only one of two independent molecules is

shown.

initial oxidation appears modest, judging by the ratio of

C–5 epimers. Although in both product isomers the allyl

group is arranged anti to the ortho-tert-butyl group, the

relative ease of C–N rotation for most compounds with a

saturated C–6 position means that this could be a

thermodynamic effect (as in 15). We also noted that these

types of piperidinone, bearing stereodeﬁned C-5 hydroxyl

and C-6 allyl groups have recently been used as key

intermediates in the synthesis of antimalarial alkaloids of

the febrifugine group.¹⁷

enamide 24, we optimised the supply of this material by

means of the route shown in Scheme 9.

The synthesis of the imide 28 proved very straightforward

and, following reduction to 23, elimination was best done

via mesylation, rather than simple acid catalysed dehy-

dration. This simple sequence easily gave access to multi-

gram quantities of the desired enamide 24.

We had previously studied the levels of diastereocontol in

enolate reactions of certain types of acyclic anilides having

the ortho-tert-butyl motif.³Although we achieved some

potentially useful levels of control the product analysis was

hampered by the complicated conformational behaviour of

these systems, and the products also proved recalcitrant to

further transformation, especially hydrolysis. By contrast

Although we did not pursue this line of investigation the

ready availability of enamide 24 made it an interesting

system for further study.

2.2. Synthesis and enolate chemistry of enamide 24

In order to conduct an extended study of the chemistry of

Scheme 9.

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D. J. Bennett et al. / Tetrahedron 60 (2004) 4491–4511

by the bulky ortho-tert-butyl substituent, leading to a

predominance of the anti isomer 29 in the product, although

we have no proof of this except in the case of sulﬁde 29g,

which proved amenable to X-ray crystallographic study, as

shown in Figure 4.

We also tested the enolate reactions of enamide 24 with a

range of aliphatic and aromatic aldehydes, but found that the

aldol reactions are poorly controlled, giving rise to at least

three major stereoisomeric products in each case. Therefore,

we did not pursue this area further.

Table 1. Alkylation of enamide 24

Entry

Electrophile

Product (%)

Ratio 29:30^a

1

2

3

4

5

6

7

8

MeI

H₂CvCHCH₂Br

PhCH₂Br

HCuCCH₂Br

ⁿC₅H₁₁Br

EtI

29a 81

29b 66

29c 79

29d 62

29e 88

29f 61

29 g 81

29 h 66

6:1

12:1

13:1

12:1

7:1

10:1

12:1

15:1

2.3. Kinetic resolution, absolute conﬁguration and

rotational energy barrier of enamide 24

In our previous work in this area we had used a chiral

lithium amide base to achieve kinetic resolution of an

acyclic atropisomeric amide, albeit with modest levels of

selectivity,³and it was decided to conduct a related study

with enamide 24 in order to obtain a sample of non-racemic

compound. This would then enable us to establish a

rotational energy barrier for the C–N axis through studying

the rate of racemisation, and we might also be able to assign

the absolute stereochemistry for this compound.

PhSSPh

Me₃SiC;CCH₂Br

a

Estimated from ¹H NMR spectra of crude reaction mixture.

enamide 24 is conformationally much simpler, and the

presence of two potentially reactive functions in the ring

might enable more facile removal of the aniline when

desired.¹⁸

Partial alkylation of enamide 24 was, therefore, carried out,

by initial deprotonation with a deﬁciency of the chiral base

shown, followedbyreaction withbenzylbromide, Scheme 10.

We started our investigation of the enolate chemistry of

enamide 24 by carrying out a range of alkylations, under

typical conditions, using LDA as the base, Table 1.

In reactions that were allowed to proceed to 53–74%

conversion we were able to recover quantities of (2)-24

(44–24%), along with the alkylated product 29c. We

analysed recovered enamide 24 from both a 74% and a 53%

conversion reaction and found it to be of 74 and 62% ee, by

HPLC, respectively. As in the related kinetic resolution

reactions of acyclic amides the selectivity appears to be

quite low, but the supply of small quantities of moderately

enriched material was adequate for our purposes.

Enolate alkylation occurred cleanly at 278 8C to give the

products in very good yields, and with good to excellent

levels of selectivity. Atropisomer ratios were measured

immediately after the alkylation, since we observed partial

equilibration in samples stored at room temperature over a

period of a few weeks. Although this gave us a rough idea of

the conformational stability of these systems we did not

quantify the energy barrier to rotation around the C–N axis

for these products, and a more detailed study was reserved

for the parent system, vide infra.

We next warmed a solution of 24 of 62% ee in CHCl₃at

60 8C and monitored the ensuing racemisation by HPLC. A

In all cases we assumed that the alkylation was controlled

Figure 4. X-ray structure of enamide 29g (displacement elipsoids are drawn at the 50% probability level).

D. J. Bennett et al. / Tetrahedron 60 (2004) 4491–4511

4497

Scheme 10.

graph of the logarithm of the relative ee values of 24 as a

function of time for the thermal racemisation indicates a

very good linear relationship, Figure 5.¹⁹

alongside enamide 29a, which was a compound that we had

prepared before in racemic form. To complete the

correlation it remained for us to take enantiomerically

enriched (73% ee) 24 from the kinetic resolution (recovered

(M)-24 in the Scheme) and methylate it to give 29a. At this

point both samples of 29a showed substantial (þ)-rotations

but the sample from the enolate alkylation had a ca. 7:1

anti:syn ratio, whereas the sample from the reduction–

elimination had a lower ratio (ca. 2:1). Therefore, in order to

make a better comparison each sample of 29a was

equilibrated in reﬂuxing CDCl₃until each had the same,

almost 1:1 ratio of rotamers. At this point both samples

showed a speciﬁc rotation of [a]_D¼þ55256. That the

values should match is a consequence of partial racemisa-

tion in the sequence leading to imide 33, bringing it to a

level (72% ee) almost matching our enamide recovered

from the kinetic resolution.

The energy barrier to rotation around the C–N axis

(DG ^–¼þ26.95 kcal mol²¹) was calculated using the

slope of the graph (22k_rot¼22.6£10²³s²¹) and Eyring’s

equation, and the half-life for racemisation at 25 8C

estimated to be 2.03£10⁶s (ca 3 weeks). Therefore the

enamide system is signiﬁcantly less stable than most of the

documented, ‘Curran type’, amide and imide systems

incorporating this motif, but still rather more stable than

the lactams having a saturated carbon at C-6 in the ring (like

25 and 26).

The stereochemical assignment for 24 shown in Scheme 10

was determined by correlation with commercially available

diacid 31, as indicated in Scheme 11.

At this point we had established the key aspects of the

stereochemistry of enamide 24, and decided to explore one

ﬁnal aspect of the reactivity of the system, namely reactions

of the CvC bond.

Thus, conversion of the diacid (R)-31 into the known

glutaric anhydride (þ)-32, was followed by conversion into

the isomeric mixture of imides 33, which were easily

separated.²⁰An X-ray crystallographic structure determi-

nation of the minor product identiﬁed it as syn-33 (or P,3R),

as shown in Figure 6. We were then able to take the major

product (which was clearly anti-33), which was at this stage

of 72% ee, and subject it to our reduction–elimination

sequence, to give a mixture of the new compound 34,

2.4. Exploring the CvC reactivity of enamide 24

Initial studies showed that the CvC bond present in 24 was

extremely reluctant to participate in a variety of C–C bond

forming reactions, including [4þ2] cycloaddition with

either electron rich or poor diene partners, [2þ2] type

reactions with ketenes, or Heck reactions under a range of

conditions. This was very disappointing since a number of

common alkaloid systems might otherwise have been

accessed via this approach.

However, during the course of an investigation into

cleavage of the tert-butyl group from the N-aryl group of

enamide 24, we were surprised to discover some unexpected

reactivity of the CvC bond. The AlCl₃catalysed trans-tert-

butylation of aromatics is well known, and has been used for

the synthesis of substituted ﬂuorenes.²¹Treatment of

enamide 24 with AlCl₃in benzene resulted in the

anticipated loss of the tert-butyl group, but gave a product

in which the enamide CvC was no longer present.

Spectroscopic analysis revealed the product to be lactam

35a, in which the enamide function has undergone a

Friedel–Crafts alkylation reaction. Analogous reactions

using toluene, bromobenzene or iodobenzene as reaction

partners also gave arylated lactams 35b–d in good yield,

the products 35b and 35c being mixtures of ortho/para

regioisomers, Scheme 12.

Figure 5. Plot of the logarithm of the relative ee value of 24 (ln ee^t/ee⁰) vs

time (t) for thermal racemisation of 24. ee⁰¼the ee value obtained for

recovered 24 from the kinetic resolution. ee^t¼the ee value of 24 obtained

after heating at 60 8C in CHCl₃for the time indicated.

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D. J. Bennett et al. / Tetrahedron 60 (2004) 4491–4511

Scheme 11.

This type of enamide arylation appears novel in inter-

molecular mode, although we are aware of intramolecular

varaints involving an activated, tethered aromatic ring, for

example, Scheme 13.²²

recovered enamide and phenol. Since anisole appeared

incompatible with AlCl₃under these reaction conditions, we

switched the Lewis acid to TiCl₄, and two novel lactam

products 38 and 39 were obtained in which arylation

occurred but the tert-butyl group remained intact, Scheme

14.

Attempts to employ anisole in this process led to none of the

product lactam of structure 35, and instead gave only

The NMR spectra for the major product 38 appeared broad

and ill-resolved, presumbly due to conformational compli-

cations arising due to the highly congested nature of the

system. Deﬁnitive proof of structure was obtained through

an X-ray crystallographic structure determination, Figure 7.

This result seemed to indicate that addition to the enamide

CvC is faster than the trans-tert-butylation, at least for

anisole, which might enable the chiral axis to control the

formation of the new stereogenic centre at C-6. In the

interest of probing this possibility the reaction of enamide

24 of 63% ee with AlCl₃in benzene was carried out and

resulted in the recovery of the product 35a of identical ee.

The analogous reaction with bromobenzene did result in

some erosion of ee, as the product 35c from a reaction with

enamide 24 of 73% ee had a lower ee value of 57%. This

probably reﬂects a slower rate of alkylation for bromoben-

zene compared with benzene, allowing partial racemisation

of 24 via C–N bond rotation, thus resulting in erosion of the

product ee.

Figure 6. X-ray structure of imide syn-33 (displacement elipsoids are

drawn at the 50% probability level). One of the disordered tert-butyl

components is omitted for clarity.

On the basis of the above results it appears that the Friedel–

Crafts alkylation reaction occurs prior to cleavage of the

D. J. Bennett et al. / Tetrahedron 60 (2004) 4491–4511

4499

Scheme 12.

Scheme 13.

Scheme 14.

tert-butyl group and that the change from an sp²carbon in

the CvC bond to an sp³carbon may be a requirement for

the second step, cleavage of the tert-butyl group.

systems in which an atropisomeric C–N axis can control the

stereochemical outcome of ring substitution or addition

reactions. In the case of enantiopure menthol adducts 10, 11

or 20, substitution via N-acyliminium intermediates

occurred with essentially complete control. However, the

range of nucleophiles that participate in the reaction is very

limited and at present the removal of the N-aryl substituent

is problematic.

3. Summary and conclusion

We have described a range of reactions of cyclic lactam

The six-membered enamide 24 is of moderate conﬁgura-

tional stability and the axis exerts synthetically useful levels

of control over the enolate alkylations of the system. A

novel Lewis acid mediated enamide arylation process was

also identiﬁed, which may have further applications in

synthesis.

4. Experimental

4.1. General details

General experimental details can be found in our recent

paper.²³

In the present work, some high resolution mass spectra were

also acquired on a PerSeptive Biosystems Mariner TOF

instrument (TOF), with a resolution of 5000 ppm, calibrated

using internal standards. In addition, where stated, puriﬁ-

cation was carried out using pre-packed Biotage 40 ﬂash

Figure 7. X-ray structure of lactam 38 (displacement elipsoids are drawn at

the 50% probability level).

˚

columns (KP-Sil, 60 A, 32–63 mM).

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D. J. Bennett et al. / Tetrahedron 60 (2004) 4491–4511

The precursor chiral diamine base to the lithiated base

shown in Scheme 10 was prepared from (R)-a-methylben-

zylamine, according to a literature procedure.²⁴Aniline 16

was prepared by methylation of the corresponding hydroxy

aniline, which was in turn prepared according to the

literature procedure.²⁵

C₁₄H₁₉NO₂. C, 72.06; H, 8.21; N, 5.80%. Found: C,

71.88; H, 8.26; N, 6.01%.

4.1.3. (P,5R)-1-(2-tert-Butylphenyl)-5-(2S-iso-propyl-5R-

methylcyclohexyl-1R-oxy)-pyrrolidin-2-one (2)-10 and

(M,5S)-1-(2-tert-butylphenyl)-5-(2S-iso-propyl-5R-

methylcyclohexyl-1R-oxy)-pyrrolidin-2-one (2)-11. (2)-

All ¹³C NMR spectra of compounds in which atropisomers

were observed are quoted for the major isomer only.

Menthol 8 (3.70 g, 23.7 mmol) and PPTS (0.56 g,

2.23 mmol) were added to a stirred solution of hydro-

xylactam 9 (5.25 g, 22.5 mmol) and anhydrous copper

sulphate (10.0 g, 62.7 mmol) in CH₂Cl₂(100 mL) and

stirred at room temperature overnight. The reaction mixture

was poured onto H₂O (100 mL) and extracted with CHCl₃

(3£100 mL), the combined organic extracts were then dried

(MgSO₄) and evaporated under reduced pressure. The

resultant solid was then puriﬁed by ﬂash column chroma-

tography (25–50% EtOAc7–petroleum ether) to give ﬁrstly

the minor diastereoisomer (2)-10 as white crystals (1.84 g,

4.95 mmol, 25%), [a]_D²³¼2101 (c 1.00, CHCl₃); mp 89–

90 8C; n_max(CHCl₃)/cm²¹2956, 2921, 2871, 1698, 1061;

d_H(400 MHz; CDCl₃) 0.43 (1H, ddd, J¼12.3, 12.3,

10.8 Hz, 6⁰-H_A), 0.69 (3H, d, J¼6.6 Hz, 2⁰⁰-Me_A), 0.73–

0.79 (4H, m with d at 0.78, J¼7.0 Hz, 5⁰-Meþ3⁰-H_A), 0.86–

0.93 (4H, m with d at 0.92, J¼7.0 Hz, 2⁰⁰-Me_Bþ4⁰-H_A), 1.17

(2H, m, 2⁰-₀Hþ5⁰-H), 1.34–1.38 (10H, ₀m with s at 1.36,

C(CH₃)₃þ6 -H_B), 1.58 (2H, m, 3⁰-H_Bþ4 -H_B), 2.24 (3H, m,

4-Hþ1⁰⁰-H), 2.44 (1H, ddd, J¼17.0, 9.3, 1.6 Hz, 3-H_A), 2.73

(1H, ddd, J¼17.0, 9.9, 8.8 Hz, 3-H_B), 3.03 (1H, dt, J¼10.8,

10.3, 4.0 Hz, 1⁰-H), 5.07 (1H, d, J¼4.8 Hz, 5-H), 7.19 (2H,

m, Ar-H), 7.27 (1H, m, Ar-H), 7.48 (1H, m, Ar-H); d_C

(67.5 MHz; CDCl₃) 15.8 (CH₃), 21.0 (CH₃), 21.9 (CH₃),

22.8 (CH₂), 25.0 (CH), 26.2 (CH₂), 28.3 (CH₂), 31.0 (CH),

31.6 (CH₃), 34.0 (CH₂), 35.3 (C), 40.0 (CH₂), 47.8 (CH),

76.4 (CH), 90.4 (CH), 126.3 (CH), 127.3 (CH), 128.2 (CH),

133.6 (CH), 134.9 (C), 147.6 (C), 176.7 (CvO); m/z (EI)

371 (M^þ, 2%), 216 (61), 176 (25) (Found M^þ, 371.2824.

C₂₄H₃₇NO₂requires M, 371.2826), followed by the major

diastereoisomer (2)-11 as ﬁne white needles (4.68 g,

12.6 mmol, 41%), [a]_D²³¼219 (c 1.05, CHCl₃); mp 63–

65 8C; n_max(CHCl₃)/cm²¹2955, 2925, 2870, 1698, 1065;

d_H(400 MHz; CDCl₃) 0.29 (3H, d, J¼6.9 Hz, 2⁰⁰-Me_A),

0.68 (3H, d, J¼7.0 Hz, 2⁰⁰-Me_B), 0.80 (2H, m, 3⁰-H_Aþ4⁰-

H_A), 0.90 (3H, d, J¼6.5 Hz, 5⁰-Me), 0.99 (1H, ddd, J¼12.6,

12.1, 10.6 Hz, 6⁰-H_A), 1.13 (1H, m, 5⁰-H), 1.29–1.35 (10H,

m with s at 1.35, C(CH₃)₃þ2⁰-H), 1.55 (2H, m, 3⁰-H_Bþ4⁰-

H_B), 1.75 (1H, m, 1⁰⁰-H), 1.92 (1H, m, 6⁰-H_B), 2.12 (1H, m,

4-H_A), 2.39 (2H, m, 4-H_Bþ3-H_A), 2.72 (1H, m, 3-H_B), 3.00

(1H, ddd, J¼10.6, 10.4, 4.3 Hz, 4⁰-H), 5.09 (1H, d,

J¼4.8 Hz, 5-H), 7.17 (2H, d, J¼3.7 Hz, Ar-H), 7.26 (1H,

m, Ar-H), 7.47 (1H, d, J¼7.8 Hz, Ar-H); d_C(67.5 MHz;

CDCl₃) 15.3 (CH₃), 21.0 (CH₃), 22.2 (CH₃), 22.3 (CH₂),

24.1 (CH), 28.2 (CH₂), 28.4 (CH₂), 31.4 (CH), 31.7 (CH₃),

34.0 (CH₂), 35.5 (C), 42.8 (CH₂), 48.6 (CH), 78.3 (CH),

92.7 (CH), 126.4 (CH), 127.7 (CH), 128.2 (CH), 133.9

(CH), 134.5 (C), 147.3 (C), 176.4 (CvO); m/z (EI) 371

(M^þ, 0.7%), 215 (68), 158 (74) (Found M^þ, 371.2828.

C₂₄H₃₇NO₂requires M, 371.2826)

4.1.1. 1-(2-tert-Butylphenyl)-pyrrolidine-2,5-dione 8.²⁶

To solution of 2-tert-butylaniline (1.00 g, 6.70 mmol) in

toluene (25 mL) was added succinic anhydride (0.81 g,

8.09 mmol) and the reaction mixture reﬂuxed overnight,

cooled, and ﬁltered to give crude succinamic acid. A

solution of this acid, sodium acetate (3.08 g, 37.5 mmol) in

acetic anhydride (25 mL) was stirred at 70–80 8C over-

night. The reaction mixture was poured onto H₂O (50 mL),

extracted with CHCl₃(3£50 mL), the combined organic

extracts were washed with 2 N sodium hydroxide

(3£50 mL), dried (MgSO₄) and evaporated under reduced

pressure. The resulting white solid was recrystallised from

EtOH to yield 8 as a crystalline white solid (1.43 g,

6.18 mmol, 92%), mp 139–141 8C, (lit.²⁶131–132 8C);

n_max(CHCl₃)/cm²¹2969, 1714, 1382; d_H(400 MHz;

CDCl₃) 1.30 (9H, s, C(CH₃)₃), 2.88 (4H, s, 3-H), 6.85

(1H, dd, J¼7.5, 1.6 Hz, Ar-H), 7.29 (1H, ddd, J¼7.5, 7.3,

1.5 Hz, Ar-H), 7.40 (1H, ddd, J¼8.1, 7.3, 1.6 Hz, Ar-H),

7.59 (1H, dd, J¼8.1, 1.5 Hz, Ar-H); d_C(67.5 MHz; CDCl₃)

28.6 (CH₂), 31.5 (CH₃), 34.4 (C), 127.3 (CH), 128.8 (CH),

129.7 (CH), 130.3 (C), 130.5 (CH), 147.8 (C), 177.3

(CvO); m/z (EI) 231 (M^þ, 40%), 216 (100), 174 (26)

(Found M^þ, 231.1254. C₁₄H₁₇NO₂requires M, 231.1259).

Anal. Calcd for C₁₄H₁₇NO₂. C, 72.69; H, 7.41; N, 6.06%.

Found: C, 72.56; H, 7.53; N, 6.11%

4.1.2. 1-(2-tert-Butylphenyl)-5-hydroxypyrrolidin-2-one

9. DIBAL (6.90 mL of a 1 M solution in CH₂Cl₂) was

added dropwise to a stirred solution of imide 8 (0.80 g,

3.46 mmol) in CH₂Cl₂(10 mL) at 278 8C. After 10 min

stirring at 278 8C, H₂O (10 mL), and 2 N NaOH (2 mL)

were cautiously added and the reaction mixture extracted

with CHCl₃(3£20 mL). The organic extracts were then

washed with brine (20 mL), dried (MgSO₄) and evaporated

under reduced pressure to yield a white solid. The crude

mixture was then puriﬁed by ﬂash column chromatography

(100% EtOAc) to yield the title compound 9 (15:1 ratio of

isomers) as white crystals (0.74 g, 0.32 mmol, 92%), mp

136–138 8C; n_max(CHCl₃)/cm²¹3590, 3367, 2949, 2868,

1714; d_H(400 MHz, CDCl₃) 1.29 (9H major, s, C(CH₃)₃),

1.37 (9H minor, C(CH₃)₃), 1.97 (1H majorþ1H minor, m, 4-

H_A), 2.25 (2H majorþ2H minor, m, 4-H_Bþ3-H_A), 2.58 (1H

majorþ1H minor, m, 3-H_B), 4.24 (1H majorþ1H minor, d,

J¼5.5 Hz, OH), 5.18 (1H majorþ1H minor, t, J¼5.3 Hz, 5-

H), 7.03 (1H majorþ1H minor, dd, J¼7.7, 1.6 Hz, Ar-H),

7.17 (1H majorþ1H minor, ddd, J¼7.7, 7.4, 1.4 Hz, Ar-H),

7.27 (1H majorþ1H minor, ddd, J¼8.0, 7.4, 1.6 Hz, Ar-H),

7.48 (1H majorþ1H minor, dd, J¼8.0, 1.6 Hz, Ar-H); d_C

(CDCl₃, 68 MHz) 27.8 (CH₂), 28.3 (CH₂), 31.6 (CH₃), 35.4

(C), 86.2 (CH), 126.6 (CH), 128.0 (CH), 128.4 (CH), 132.8

(CH), 134.5 (C), 147.9 (C), 176.8 (CvO); m/z (EI) 233

(M^þ, 52%), 216 (100), 174 (33) (Found M^þ, 233.1409.

C₁₄H₁₉NO₂requires M, 233.1416). Anal. Calcd for

4.1.4. (P,5S)-5-Allyl-1-(2-tert-butylphenyl)-pyrrolidin-2-

one (2)-12. To a stirred solution of pyrrolidin-2-one (2)-10

(1.00 g, 2.69 mmol) and allyl trimethylsilane (4.20 mL,

26.8 mmol) in CH₂Cl₂(10 mL) at 240 8C, was added

dropwise trimethylsilyltriﬂuoromethanesulphonate (1.50 mL,

D. J. Bennett et al. / Tetrahedron 60 (2004) 4491–4511

4501

8.29 mmol). The reaction mixture was stirred at 240 8C for

8 h before H₂O (10 mL) was cautiously added. The reaction

mixture was extracted with CHCl₃(3£20 mL), the com-

bined organic extracts were dried (MgSO₄) and evaporated

under reduced pressure. The resulting yellow oil was

puriﬁed by ﬂash column chromatography (50% EtOAc–

petroleum ether) to yield the title compound (2)-12 (6:1

ratio of isomers) as a pale yellow oil (612 mg, 2.40 mmol,

88%), [a]²_D³¼235 (c 1.00, CHCl₃); n_max(CHCl₃)/cm²¹

2874, 1682; d_H(400 MHz; CDCl₃) 1.39 (9H major, s,

C(CH₃)₃), 1.41 (9H minor, C(CH₃)₃), 1.99 (1H majorþ1H

minor, m, 4-H_A), 2.15 (1H majorþ1H minor, m, 4-H_B), 2.44

(4H majorþ4H minor, m, 3-Hþ1⁰-H), 3.93 (1H majorþ1H

minor, m, 5-H), 5.07 (2H minor, m, 3⁰-H), 5.10 (2H major,

m, 3⁰-H), 5.67 (1H majorþ1H minor, m, 2⁰-H), 6.97 (1H

major, dd, J¼7.7, 1.6 Hz, Ar-H), 6.98 (1H minor, dd, J¼7.7,

1.6 Hz, Ar-H), 7.27 (2H majorþ2H minor, m, Ar-H), 7.56

(1H majorþ1H minor, m, Ar-H); d_C(67.5 MHz; CDCl₃)

23.7 (CH₂), 29.7 (CH₂), 31.7 (CH₃), 35.7 (C), 37.8 (CH₂),

61.5 (CH), 118.5 (CH₂), 126.7 (CH), 128.4 (CH), 128.9

(CH), 132.8 (CH), 133.2 (CH), 134.6 (C), 148.2 (C), 175.5

(CvO); m/z (EI) 257 (M^þ, 0.2%), 216 (100) (Found M^þ,

257.1785. C₁₇H₂₃NO requires M, 257.1780).

0.84 (3H minor, 3⁰-H), 0.86 (3H major, t, J¼7.2 Hz, 3⁰-H),

1.19 (2H majorþ2H minor, m, 2⁰-H), 1.30–1.41 (10H

majorþ10H minor, m with major s at 1.38 and minor s at

1.41, C(CH₃)₃þ1⁰-H_A), 1.49–1.56 (1H majorþ1H minor,

m, 1⁰-H_B), 1.99 (1H majorþ1H minor, m, 4-H_A), 2.44 (3H

majorþ3H minor, m, 4-H_Bþ3H), 3.89 (1H majorþ1H

minor, m, 5-H), 6.92 (1H major, dd, J¼7.7, 1.5 Hz, Ar-H),

6.96 (1H minor, dd, J¼7.7, 1.5 Hz, Ar-H), 7.24 (2H

majorþ2H minor, m, Ar-H), 7.55 (1H majorþ1H minor,

m, Ar-H); d_C(67.5 MHz; CDCl₃) 13.7 (CH₃), 18.4 (CH₂),

24.7 (CH₂), 30.0 (CH₂), 31.5 (CH₃), 35.4 (CH₂), 35.5 (C),

61.9 (CH), 126.4 (CH), 128.1 (CH), 128.6 (CH), 132.8

(CH), 134.6 (C), 148.0 (C), 175.3 (CvO); m/z (EI) 259

(M^þ, 2%), 216 (58) 202 (100) (Found M^þ, 259.1934.

C₁₇H₂₅NO requires M, 259.1936).

Similar reactions starting with allene 13 gave the same

results.

All four isomers of 14 were separated by HPLC using a

Chiralcel OD column [25 cm£0.46 cm i.d.; 2% i-PrOH in

hexane; ﬂow rate, 1.0 mL/min]. Samples of 14 originating

with 10 gave two atropisomers eluting at 21.2 and 29.0 min,

whereas samples originating with 11 gave two atropisomers

eluting at 22.8 and 24.8 min. Each sample proved to be

essentially enantiomerically pure ($99% ee).

4.1.5. (P,5S)-1-(2-tert-Butylphenyl)-5-propa-1,2-dienyl-

pyrrolidin-2-one (2)-13. To a stirred solution of pyrroli-

din-2-one

(2)-10

(300 mg,

0.81 mmol)

and

propargyltrimethylsilane (1.20 mL, 8.05 mmol) in CH₂Cl₂

(5 mL) at 240 8C was added dropwise trimethylsilyltri-

ﬂuoromethanesulphonate (0.43 mL, 2.38 mmol). The reac-

tion mixture was stirred at 240 8C for 8 h before H₂O

(5 mL) was cautiously added. The reaction mixture was

extracted with CHCl₃(3£10 mL), the combined organic

extracts were then dried (MgSO₄) and evaporated under

reduced pressure. The resulting yellow oil was puriﬁed by

ﬂash column chromatography (50% EtOAc–petroleum

ether) to yield the title compound (2)-13 (3:1 ratio of

isomers) as a colourless oil (152 mg, 0.60 mmol, 74%),

[a]²_D³¼261 (c 1.10, CHCl₃); n_max(CHCl₃)/cm²¹2968,

1954, 1682; d_H(400 MHz, CDCl₃) 1.28 (9H major, s,

C(CH₃)₃), 1.29 (9H minor, C(CH₃)₃), 2.08 (1H majorþ1H

minor, m, 4-H_A), 2.48 (3H majorþ3H minor, m, 4-H_Bþ3-

H), 4.36 (1H majorþ1H minor, m, 5-H), 4.68 (2H

majorþ2H minor, m, 3⁰-H), 5.01 (1H minor, 1⁰-H), 5.10

(1H major, dt, J¼7.5, 6.6 Hz, m, 1⁰-H), 6.90 (1H majorþ1H

minor, m, Ar-H), 7.19 (2H majorþ2H minor, m, Ar-H), 7.47

(1H majorþ1H minor, m, Ar-H); d_C(67.5 MHz, CDCl₃)

25.9 (CH₂), 30.1 (CH₂), 32.0 (CH₃), 35.9 (C), 62.2 (CH),

77.4 (CH₂), 90.6 (CH), 126.9 (CH), 128.6 (CH), 128.8 (CH),

133.3 (CH), 135.2 (C), 148.6 (C), 175.7 (CvO), 208.6

(CvCvC); m/z (EI) 255 (M^þ, 1%), 216 (100), 198 (66)

(Found M^þ, 255.1627. C₁₇H₂₁NO requires M, 255.1623).

4.1.7. (P,5S)-1-(2-tert-Butylphenyl)-5-methoxymethyl-

pyrrolidin-2-one 15.^7e,14Ozonolysis. Ozone was bubbled

through a solution of pyrrolidin-2-one (2)-13 (150 mg,

0.59 mmol) in CH₂Cl₂(5 mL) and MeOH (5 mL) at

278 8C, for 30 min, before sodium borohydride (75.0 mg,

1.98 mmol) was added and the reaction mixture stirred at

room temperature overnight. The reaction mixture was then

poured onto H₂O (10 mL) and extracted with CHCl₃

(3£10 mL), the combined organic extracts were then

washed with brine (10 mL), dried (MgSO₄) and evaporated

under reduced pressure to yield a yellow oil. The crude oil

was then puriﬁed by ﬂash column chromatography (100%

EtOAc) to yield an intermediate hydroxymethyl compound

as a white solid (94.0 mg, 0.38 mmol, 65%), [a]²_D³¼223 (c

1.00, CHCl₃); mp 132–133 8C; n_max(CHCl₃)/cm²¹3652,

3400, 2958, 2878, 1682; d_H(400 MHz; CDCl₃) 1.35 (9H, s,

C(CH₃)₃), 2.25 (3H, m, 4-Hþ3-H_A), 2.64 (1H, dt, J¼16.5,

9.3 Hz, 3-H_B), 3.43 (1H, dd, J¼11.3, 1.8 Hz, 1⁰-H_A), 3.55

(1H, dd, J¼11.3, 3.4 Hz, 1⁰-H_B), 3.74 (2H, m, 5-HþOH),

7.07 (1H, dd, J¼7.7, 1.4 Hz, Ar-H), 7.18 (1H, ddd, J¼7.7,

7.3, 1.5 Hz, Ar-H), 7.27 (1H, ddd, J¼8.0, 7.3, 1.4 Hz, Ar-

H), 7.50 (1H, dd, J¼8.0, 1.5 Hz, Ar-H); d_C(67.5 MHz;

CDCl₃) 22.0 (CH₂), 30.6 (CH₂), 31.8 (CH₃), 35.7 (C), 62.0

(CH₂), 63.7 (CH), 127.0 (CH), 128.4 (CH), 128.6 (CH),

132.4 (CH), 134.8 (C), 148.1 (C), 177.3 (CvO); m/z (FAB)

248 (MH^þ, 8%), 154 (100), 136 (66) (Found MH^þ,

248.1651. C₁₅H₂₂NO₂requires M, 248.1651).

4.1.6. (5R)-1-(2-tert-Butylphenyl)-5-propylpyrrolidin-2-

one (2)-14. A solution of pyrrolidin-2-one (2)-12

(610 mg, 2.37 mmol) and 10% palladium on carbon

(50.0 mg, 0.05 mmol) in MeCN (25 mL) was shaken

under an atmosphere of hydrogen overnight. The reaction

mixture was then ﬁltered through celite and evaporated

under reduced pressure to yield the title compound (2)-14

(3:1 ratio of isomers) as a colourless oil (610 mg,

2.35 mmol, 99%), [a]²_D³¼222 (c 1.00, CHCl₃); n_max

(CHCl₃)/cm²¹2934, 2875, 1682; d_H(400 MHz; CDCl₃)

Methylation. To a solution of the primary alcohol product

(90.0 mg, 0.36 mmol) and KOH (82.0 mg, 1.46 mmol) in

DMSO (2.5 mL) was added MeI (0.50 mL, 8.03 mmol) and

the reaction mixture stirred at room temperature overnight.

The reaction mixture was then poured onto H₂O (10 mL)

and extracted with CHCl₃(3£10 mL), the combined organic

extracts were then washed with brine (10 mL), dried

(MgSO₄) and evaporated under reduced pressure to yield

4502

D. J. Bennett et al. / Tetrahedron 60 (2004) 4491–4511

a yellow oil. The crude oil was then puriﬁed by column

chromatography (60% EtOAc–petroleum ether) to yield the

lactam 15 as a white solid (72 mg, 0.28 mmol, 76%), mp

94–95 8C (lit.^7e,1493–94.5 8C); n_max(CHCl₃)/cm²¹2958,

2881, 1682, 1121; d_H(400 MHz; CDCl₃) 1.38 (9H, s,

C(CH₃)₃), 2.16 (1H, m, 4-H_A), 2.37 (2H, m, 4-H_Bþ3-H_A),

2.66 (1H, m, 3-H_B), 3.31 (1H, dd, J¼9.9, 2.3 Hz, 1⁰-H_A),

3.36 (3H, s, 1⁰-OMe), 3.44 (1H, dd, J¼9.9, 3.5 Hz, 1⁰-H_B),

3.89 (1H, m, 5-H), 7.00 (1H, dd, J¼7.7, 1.6 Hz, Ar-H), 7.27

(2H, m, Ar-H), 7.53 (1H, dd, J¼8.0, 1.5 Hz, Ar-H); d_C

(67.5 MHz; CDCl₃) 22.7 (CH₂), 30.5 (CH₂), 31.8 (CH₃),

35.7 (C), 58.9 (CH₂), 62.0 (CH), 72.5 (CH₃), 127.0 (CH),

128.4 (CH), 128.7 (CH), 132.3 (CH), 135.1 (C), 148.4

(C), 176.9 (C); m/z (EI) 261 (M^þ, 2%), 216 (100), 204

(24) (Found M^þ, 261.1722. C₁₆H₂₃NO₂requires M,

261.1729).

J¼2.5 Hz, Ar-H); d_C(67.5 MHz, CDCl₃) 28.8 (CH₂), 31.5

(CH₃), 35.7 (C), 55.7 (CH₃), 111.7 (CH), 115.3 (CH), 123.3

(C), 132.0 (CH), 149.6 (C), 160.2 (C), 177.9 (CvO); m/z

(EI) 261 (M^þ, 100%), 246 (88) (Found M^þ, 261.1373.

C₁₅H₁₉NO₃requires M, 261.1365).

4.1.10. 1-(2-tert-Butyl-4-methoxyphenyl)-5-hydroxypyr-

rolidin-2-one 18. DIBAL (56.0 mL of a 1 M solution in

CH₂Cl₂) was added dropwise to a stirred solution of imide

17 (7.30 g, 27.9 mmol) in CH₂Cl₂(50 mL) at 278 8C. After

10 min stirring at 278 8C, H₂O (50 mL), and 2 N NaOH

(10 mL) were cautiously added and the reaction mixture

extracted with CHCl₃(3£50 mL). The organic extracts were

washed with brine (50 mL), dried (MgSO₄) and evaporated

under reduced pressure to yield a white solid. The crude

solid was then puriﬁed by ﬂash column chromatography

(100% EtOAc) to yield the title compound 18 (17:1 ratio of

isomers) as a white solid (6.32 g, 24.0 mmol, 86%), mp

136–138 8C; n_max(CHCl₃)/cm²¹3597, 2960, 2837, 1694,

1052; d_H(400 MHz, CDCl₃) 1.32 (9H major, s, C(CH₃)₃),

1.41 (9H minor, C(CH₃)₃), 2.09 (1H majorþ1H minor, m, 4-

H_A), 2.37 (2H majorþ2H minor, m, 4-H_Bþ3-H_A), 2.66 (1H

majorþ1H minor, m, 3-H_B), 3.53 (1H majorþ1H minor, d,

J¼4.6 Hz, OH), 3.81 (3H majorþ3H minor, s, OMe), 5.29

(1H majorþ1H minor, t, J¼5.0 Hz, 5-H), 6.77 (1H

majorþ1H minor, dd, J¼5.8, 2.9 Hz, Ar-H), 7.04 (2H

majorþ2H minor, m, Ar-H); d_C(67.5 MHz, CDCl₃) 27.5

(CH₂), 28.4 (CH₂), 31.5 (CH₃), 35.6 (C), 55.3 (CH₃), 86.3

(CH), 110.8 (CH), 115.1 (CH), 127.3 (CH), 133.6 (CH),

149.7 (C), 159.2 (C), 176.9 (CvO); m/z (EI) 263 (M^þ,

18%), 245 (50), 170 (36), 70 (100) (Found M^þ, 263.1509.

C₁₅H₂₁NO₃requires M, 263.1521).

The enantiomers of 15 were separated by HPLC using a

Chiralpak AD column [25 cm£0.46 cm i.d.; 10% i-PrOH in

hexane; ﬂow rate, 1.0 mL/min; t_R¼7.3 min and 8.2 min].

Samples of 15 originating with 10 gave mainly the

enantiomer with the longer retention time, allowing us to

assign the stereochemistry as (P,5S).^7e

4.1.8. 2-tert-Butyl-4-aminoanisole 16. To a stirred solution

of 1-amino-2-tert-butylphenol (16.5 g, 100 mmol) in

DMSO (250 mL) was added potassium tert-butoxide

(12.2 g, 100 mmol) and the reaction mixture stirred for

2 h. Dimethyl sulphate (10.0 mL, 106 mmol) was added in

one portion, the reaction mixture stirred for 5 min, poured

onto H₂O (500 mL) and extracted with EtOAc (3£250 mL).

The organic extracts were then washed with H₂O

(3£250 mL), dried (MgSO₄) and evaporated under reduced

pressure. The resultant black oil was then puriﬁed by

distillation (165 8C/10 mmHg) followed by ﬂash column

chromatography (40% Et₂O–hexanes) to yield the title

compound as a yellow oil (14.2 g, 80.1 mmol, 80%), n_max

(CHCl₃)/cm²¹3471, 3390, 2954, 2911, 2834, 1622, 1054;

d_H(400 MHz, CDCl₃) 1.41 (9H, s, C(CH₃)₃), 3.54 (2H, br.s,

NH₂), 3.74 (3H, s, OCH₃), 6.59 (2H, m, Ar-H) 6.86 (1H, d,

J¼2.5 Hz, Ar-H); d_C(67.5 MHz, CDCl₃) 29.8 (CH₃), 34.7

(C), 55.8 (CH₃), 111.3 (CH), 114.0 (CH), 119.0 (CH), 136.1

(C), 138.6 (C), 152.9 (C); m/z (EI) 179 (M^þ, 62%), 164

(100) (Found M^þ, 179.1307. C₁₁H₁₇NO requires M,

179.1310).

4.1.11. (P,5R)-1-(2-tert-Butylphenyl)-5-(2S-iso-propyl-

5R-methylcyclohexyl-1R-oxy)-pyrrolidin-2-one (2)-19

and (M,5S)-1-(2-tert-butylphenyl)-5-(2S-iso-propyl-5R-

methylcyclohexyl-1R-oxy)-pyrrolidin-2-one

(2)-20.

(2)-Menthol (3.70 g, 23.7 mmol) and PPTS (0.56 g,

2.23 mmol) were added to a stirred solution of pyrrolidin-

2-one 18 (5.25 g, 22.5 mmol) and anhydrous copper

sulphate (10.0 g, 62.7 mmol) in CH₂Cl₂(100 mL) and

stirred at room temperature overnight. The reaction mixture

was poured onto H₂O (100 mL) and extracted with CHCl₃

(3£100 mL), the combined organic extracts were then dried

(MgSO₄) and evaporated under reduced pressure. The

resultant solid was then puriﬁed by ﬂash column chroma-

tography (25–50% EtOAc–petroleum ether) to give ﬁrstly

the minor diastereoisomer (2)-19 as a yellow oil (1.44 g,

3.59 mmol, 22%), [a]²_D³¼2113 (c 1.00, CHCl₃); n_max

(CHCl₃)/cm²¹2956, 2926, 2870, 1697, 1052; d_H

(400 MHz; CDCl₃) 0.49 (1H, ddd, J¼12.3, 12.3, 10.5 Hz,

6⁰-H_A), 0.73 (3H, d, J¼6.6 Hz, 2⁰⁰-Me_A), 0.78 (4H, m with d

at 0.78, J¼7.0 Hz, 5⁰-Meþ3⁰-H_A), 0.92 (4H, m with d at

0.92, J¼7.1 Hz, 2⁰⁰-Me_Bþ4⁰-H_A), 1.22 (2H, m, 2⁰-Hþ5⁰H),

1.34 (9H, s, C(CH₃)₃), 1.45 (1H, m, 6⁰-H_B), 1.60 (2H, m, 3⁰-

H_Bþ4⁰-H_B), 2.10 (1H, m, 1⁰⁰-H), 2.21 (2H, m, 4-H), 2.43

(1H, dd, J¼17.0, 9.3 Hz, 3-H_A), 2.68 (1H, ddd, J¼17.0, 9.8,

9.4 Hz, 3-H_B), 3.05 (1H, dt, J¼10.5, 4.0 Hz, 1⁰-H), 3.79

(3H, s, OMe), 5.05 (1H, d, J¼4.5 Hz, 5-H), 6.74 (1H, dd,

J¼8.6, 2.9 Hz, Ar-H), 7.01 (1H, d, J¼2.9 Hz, Ar-H), 7.12

(1H, d, J¼8.6 Hz, Ar-H); d_C(67.5 MHz; CDCl₃) 15.8

(CH₃), 21.1 (CH₃), 22.0 (CH₃), 22.9 (CH₂), 25.1 (CH), 26.1

(CH₂), 28.3 (CH₂), 30.4 (CH), 31.4 (CH₃), 33.9 (CH₂), 35.4

4.1.9. 1-(2-tert-Butyl-4-methoxyphenyl)-pyrrolidine-2,5-

dione 17. Succinic anhydride (4.70 g, 47.0 mmol) was

added to a solution of 3-tertbutyl-4-aminoanisole 16

(7.00 g, 39.1 mmol) in toluene (50 mL) and heated to reﬂux

overnight, cooled, and ﬁltered to give a beige solid. This

crude succinamic acid was added to solution of sodium

acetate (1.60 g, 19.5 mmol) and acetic anhydride (50 mL)

and was heated to 70 8C for 6 h. The reaction mixture was

then poured onto H₂O, extracted with CHCl₃, washed with

2 N sodium hydroxide, dried over magnesium sulphate and

evaporated under reduced pressure to yield a brown solid.

The crude solid was puriﬁed by ﬂash column chromatog-

raphy (40% EtOAc–petroleum ether) to yield the title

compound 17 as a white solid (7.81 g, 29.9 mmol, 77%), mp

130–131 8C; n_max(CHCl₃)/cm²¹3475, 2908, 2253, 1732;

d_H(400 MHz, CDCl₃) 1.27 (9H, s, C(CH₃)₃), 2.82 (4H, s, 3-

H), 3.79 (3H, s, OMe), 6.79 (2H, m, Ar-H), 7.09 (1H, d,

D. J. Bennett et al. / Tetrahedron 60 (2004) 4491–4511

4503

(C), 40.1 (CH₂), 48.0 (CH), 55.1 (CH₃), 76.1 (CH), 90.4

(CH), 110.4 (CH), 114.2 (CH), 127.8 (CH), 134.5 (CH),

149.1 (C), 158.9 (C), 177.1 (CvO); m/z (EI) 401 (M^þ, 9%),

259 (16), 245 (100) (Found M^þ, 401.2942. C₂₅H₃₉NO₃

requires M, 401.2930), followed by the major diastereo-

isomer (2)-20 as a white solid (3.67 g, 9.14 mmol, 56%),

[a]²_D³¼218 (c 1.00, CHCl₃); mp 85–88 8C; n_max(CHCl₃)/

cm²¹2955, 2925, 2870, 1698, 1065, 1051; d_H(400 MHz;

CDCl₃) 0.34 (3H, d, J¼6.9 Hz, 2⁰⁰-Me_A), 0.71 (3H, d,

J¼7.0 Hz, 2⁰⁰-Me_B), 0.81 (2H, m, 3⁰-H_Aþ4⁰-H_A), 0.91 (3H,

d, J¼6.5 Hz, 5⁰-Me), 0.99 (1H, ddd, J¼12.0, 11.8, 10.4 Hz,

6⁰-H_A), 1.14 (1H, m, 5⁰-H), 1.32–1.33 (10H, m with s at

1.33, C(CH₃)₃þ2⁰-H), 1.53 (2H, m, 3⁰-H_Bþ4⁰-H_B), 1.80

(1H, m, 1⁰⁰-H), 1.92 (1H, m, 6⁰-H_B), 2.12 (1H, m, 4-H_A),

2.37 (2H, m, 4-H_Bþ3-H_A), 2.70 (1H, m, 3-H_B), 3.02 (1H,

ddd, J¼10.5, 10.4, 4.1 Hz, 1⁰-H), 3.79 (3H, s, OMe), 5.05

(1H, d, J¼4.4 Hz, 5-H), 6.71 (1H, dd, J¼8.6, 1.5 Hz, Ar-H),

7.00 (1H, d, J¼1.5 Hz, Ar-H), 7.11 (1H, d, J¼8.6 Hz,

Ar-H); d_C(67.5 MHz; CDCl₃) 15.5 (CH₃), 21.2 (CH₃),

22.3 (CH₃), 22.5 (CH₂), 24.4 (CH), 28.3 (CH₂), 28.5 (CH₂),

31.6 (CH), 31.7 (CH₃), 34.2 (CH₂), 35.5 (C), 43.0 (CH₂),

48.9 (CH), 55.3 (CH₃), 78.4 (CH), 92.9 (CH), 110.6 (CH),

114.6 (CH), 128.4 (CH), 135.0 (CH), 149.1 (C), 158.7

(C), 177.6 (CvO); m/z (EI) 401 (M^þ, 0.8%), 246 (19), 245

(100) (Found M^þ, 401.2915. C₂₅H₃₉NO₃requires M,

401.2930).

peaks as by far the major, allowing estimation of the ee as

ca. 98%.

4.1.13. (R)-5-Allylpyrrolidin-2-one 22. To a solution of

pyrrolidin-2-one (þ)-21 (175 mg, 0.61 mmol) in MeCN

(12.5 mL), at 0 8C was added a solution of ceric ammonium

nitrate (3.30 g, 6.02 mmol) in water (12.5 mL). The reaction

mixture was then stirred at 0 8C for 5 h, before pouring onto

H₂O (100 mL) and extracting with CHCl₃(5£100 mL). The

combined organic extracts were dried (MgSO₄) and

evaporated under reduced pressure to yield a yellow oil.

The crude oil was then puriﬁed by ﬂash column chroma-

tography (100% EtOAc) to yield 22 as a yellow oil (21 mg,

0.17 mmol, 28%), n_max(CHCl₃)/cm²¹3432, 2927, 1693; d_H

(400 MHz, CDCl₃) 1.78 (2H, m, 4-H), 2.22 (4H, m, 3-Hþ1⁰-

H), 3.71 (1H, app. quin, J¼6.4 Hz, 5-H), 5.14 (2H, m, 3⁰-H),

5.75 (1H, m, 2⁰-H), 5.93 (1H, br. s, NH); d_C(126 MHz,

CDCl₃) 26.6 (CH₂), 29.9 (CH₂), 40.9 (CH₂), 53.3 (CH),

118.4 (CH₂), 133.5 (CH), 177.7 (CvO); m/z (EI) 125 (M^þ,

0.2%), 84 (100) (Found M^þ, 125.0834. C₇H₁₁NO requires

M, 125.0841).

4.1.14. 1-(2-tert-Butyl-phenyl)-piperidin-2,6-dione 28.

Amide bond formation. To a solution of 2-tert-butylaniline

27 (77.6 mL, 48.6 mmol) in toluene (50 mL) was added

glutaric anhydride (6.55 g, 57.4 mmol) and the reaction

mixture was heated at reﬂux for 1 h, cooled, and ﬁltered to

give the crude butyric acid. The solid was washed with

petroleum ether, to give the butyric acid (2:1 ratio of

rotamers) as a white solid (12.5 g, 48.4 mmol, 98%), mp

120–123 8C (recrystallised from petroleum ether/EtOAc);

4.1.12. (M,5R)-5-Allyl-1-(2-tert-butyl-4-methoxyphenyl)-

pyrrolidin-2-one (1)-21. To a stirred solution of pyrroli-

din-2-one (2)-20 (200 mg, 0.50 mmol) and allyltrimethyl-

silane (1.10 mL, 6.92 mmol) in CH₂Cl₂(5 mL) at 240 8C,

was added dropwise trimethylsilyltriﬂuoromethanesulpho-

nate (0.35 mL, 1.94 mmol). The reaction mixture was

stirred at 240 8C for 8 h before H₂O (5 mL) was cautiously

added. The reaction mixture was extracted with CHCl₃

(3£10 mL), the combined organic extracts were then dried

(MgSO₄) and evaporated under reduced pressure. The

resulting yellow oil was puriﬁed by ﬂash column chroma-

tography (60% EtOAc–petroleum ether) to yield the title

compound (þ)-21 (6:1 ratio of isomers) as a colourless oil

(177 mg, 0.62 mmol, 90%), [a]²_D³¼11 (c 1.00, CHCl₃); n_max

(CHCl₃)/cm²¹2959, 2838, 1682, 1051; d_H(400 MHz,

CDCl₃) 1.28 (9H major, s, C(CH₃)₃), 1.31 (9H minor,

C(CH₃)₃), 1.88 (1H majorþ1H minor, m, 4-H_A), 2.05 (1H

majorþ1H minor, m, 4-H_B), 2.36 (4H majorþ4H minor, m,

3-Hþ1⁰-H), 3.69 (3H minor, s, OMe), 3.70 (3H major, s,

OMe), 3.82 (1H majorþ1H minor, m, 5-H), 4.95 (2H minor,

m, 3⁰-H), 5.03 (2H major, m, 3⁰-H), 5.60 (1H majorþ1H

minor, m, 2⁰-H), 6.68 (1H majorþ1H minor, dd, J¼8.6,

2.9 Hz, Ar-H), 6.81 (1H majorþ1H minor, m, Ar-H), 6.99

(1H majorþ1H minor, d, J¼2.8 Hz, Ar-H); d_C(67.5 MHz,

CDCl₃) 23.5 (CH₂), 29.3 (CH₂), 31.4 (CH₃), 35.6 (C),

37.7 (CH₂), 55.0 (CH₃), 61.4 (CH), 110.7 (CH), 115.2

(CH), 118.4 (CH), 127.2 (C), 133.3 (CH₂), 133.6 (CH),

158.9 (C), 149.5 (C), 175.9 (CvO); m/z (EI) 287 (M^þ, 8%),

246 (100) (Found M^þ, 287.1882. C₁₈H₂₅NO₂requires M,

287.1885).

n

_max(CHCl₃)/cm²¹3516, 2969, 1710, 1578; d_H(400 MHz,

CDCl₃) 1.40 (9H majorþ9H minor, s, C(CH₃)₃), 1.95 (2H

minor, 4-H), 2.12 (2H major, apparent quin, J¼7.1 Hz, 4-

H), 2.17 (2H minor, 5-H/3-H), 2.38 (2H minor, 3-H/5-H),

2.51 (4H major, apparent q, J¼6.9 Hz, 5-Hþ3-H), 7.07 (1H

minor, Ar-H), 7.15–7.30 (2H majorþ2H minor, m, Ar-H),

7.30 (1H major, d, J¼7.0 Hz, Ar-H), 7.46 (1H minor, Ar-H);

7.51 (1H major, d, J¼7.5 Hz, Ar-H); d_C(100 MHz, CDCl₃)

20.6 (CH₂), 30.8 (CH₃), 33.1 (CH₂), 34.7 (C), 36.3 (CH₂),

126.7 (CH), 126.9 (CH), 127.2 (CH), 128.4 (CH), 134.9 (C),

143.0 (C), 170.9 (CvO), 178.2 (CvO); m/z (FAB) 264

(MH^þ, 60%), 246 (10) 154 (100) (Found MH^þ, 264.1603.

C₁₅H₂₂NO₃requires M, 264.1600). Anal. Calcd for

C₁₅H₂₁NO₃. C, 68.44; H, 7.98; N, 5.32%. Found: C,

68.22; H, 7.95; N, 5.41%.

Imide formation. To a solution of the butyric ₀acid (26.9 g,

0.10 mol) in CHCl₃(500 mL) was added 1,1 -carbonyldi-

imidazole (17.8 g, 0.11 mol) and the reaction mixture

heated at 70 8C overnight, and cooled. The reaction mixture

was washed with H₂O (2£600 mL), and the aqueous

re-extracted with CHCl₃(2£200 mL). The combined

organics were then washed with 2 N HCl (300 mL), then

with water until washings were neutral, washed with brine

(200 mL), dried (MgSO₄), and evaporated under reduced

pressure to yield the title compound as a white solid (23.9 g,

0.10 mol, 98%), mp 116–118 8C (recrystallised from

petroleum ether/EtOAc); n_max(CHCl₃)/cm²¹2966, 2908,

1734, 1682; d_H(400 MHz, CDCl₃) 1.31 (9H, s, C(CH₃)₃),

2.10 (2H, apparent quin, J¼6.6 Hz, 4-H), 2.81 (4H, apparent

t, J¼6.6 Hz, 3-H), 6.83 (1H, dd, J¼7.7 Hz, 1.5, Ar-H), 7.28

(1H, ddd, J¼7.7, 7.4, 1.5 Hz, Ar-H); 7.38 (1H, ddd, J¼8.0,

All four isomers of 21 were separated by HPLC using a

Chiralcel OD column [25 cm£0.46 cm i.d.; 2% i-PrOH in

hexane; ﬂow rate, 1.0 mL/min]. Two atropisomers eluted at

32.9 and 48.2 min, and a further pair at 38.7 and 44.9 min.

Samples of 21 originating with 20 gave the ﬁrst pair of

4504

D. J. Bennett et al. / Tetrahedron 60 (2004) 4491–4511

7.4, 1.5 Hz, Ar-H), 7.58 (1H, dd, J¼8.0, 1.5 Hz, Ar-H); d_C

(100 MHz, CDCl₃) 17.1 (CH₂), 31.7 (CH₃), 33.5 (CH₂),

35.9 (C), 127.3 (CH), 129.1 (CH), 131.0 (2£CH), 133.3 (C),

146.8 (C), 173.3 (CvO); m/z (EI) 245 (M^þ, 0.8%), 188

(100) (Found M^þ, 245.1410. C₁₅H₁₉NO₂requires M,

245.1416). Anal. Calcd for C₁₅H₁₉NO₂. C, 73.47; H, 7.76;

N, 5.71%. Found: C, 73.33; H, 7.78; N, 5.70%.

127.6 (CH), 128.6 (CH), 128.7 (CH), 130.9 (CH), 132.9

(CH), 139.5 (C), 147.6 (C), 170.3 (CvO); m/z (TOF) 252

(MþNa)^þ(Found MþNa^þ, 252.1364. C₁₅H₁₉NOþNa

requires M, 252.1364). Anal. Calcd for C₁₅H₁₉NO. C,

78.60; H, 8.30; N, 6.11%. Found: C, 78.28; H, 8.36; N,

6.16%.

4.1.17. (5S,6S)-6-Allyl-1-(2-tert-butyl-phenyl)-5-

hydroxy-piperidin-2-one 25 and (5R,6S)-6-allyl-1-(2-

tert-butyl-phenyl)-5-hydroxy-piperidin-2-one 26. To a

solution of 24 (1.20 g, 5.22 mmol) in dry acetone (30 mL)

at 0 8C, was added DMDO (100 mL of an approx. 0.10 M

solution). The reaction mixed was stirred at 0 8C for 1 h then

concentrated and redissolved in CH₂Cl₂(30 mL). To this

solution, was added allyl trimethylsilane (4.14 mL,

26.1 mmol) and TiCl₄(2.86 mL, 26.1 mmol) slowly. The

reaction mixture was stirred at room temperature for 3 days,

then diluted with CH₂Cl₂(60 mL), washed with H₂O

(50 mL), a saturated solution of NaHCO₃(50 mL), and

brine (50 mL), dried (MgSO₄), and evaporated under

reduced pressure. The resulting crude mixture was puriﬁed

by ﬂash column chromatography (20% EtOAc–petroleum

ether), to give: ﬁrstly the minor isomer 26 (R_f0.4, 70:30

petroleum ether–EtOAc) as a white solid (170 mg,

0.60 mmol, 11%), d_H(500 MHz, CDCl₃) 1.44 (9H, s,

C(CH₃)₃), 1.94–2.05 (1H, m, 4-H_A), 2.09 (1H, m, 1⁰-H_A),

2.18 (1H, dddd, J¼15.5, 9.9, 6.2, 4.0 Hz, 4-H_B), 2.51 (1H,

ddd, J¼17.6, 5.9, 4.0 Hz, 3-H_A), 2.65 (1H, dddd, J¼16.1,

5.6, 3.8, 1.7 Hz, 1⁰-H_B), 2.74 (1H, ddd, J¼17.6, 11.0,

6.2 Hz, 3-H_B), 3.78 (1H, ddd, J¼9.9, 3.3, 3.2 Hz, 5-H), 4.23

(1H, m, 6-H), 5.09₀(2H, m, 3⁰-H), 5.62 (1H, dddd, J¼18.9,

10.5, 6.8, 5.6 Hz, 2 -H), 6.91 (1H, dd, J¼7.7, 1.7 Hz, Ar-H),

7.20 (1H, ddd, J¼7.7, 7.3, 1.5 Hz, Ar-H), 7.29 (1H, ddd,

J¼8.2, 7.3, 1.7 Hz, Ar-H), 7.58 (1H, dd, J¼8.2, 1.5 Hz, Ar-

H); d_C(125 MHz, CDCl₃) 25.3 (CH₂), 28.2 (CH₂), 31.9

(CH₃), 36.1 (C), 37.8 (CH₂), 65.4 (CH), 66.9 (CH), 118.4

(CH₂), 126.3 (CH), 128.1 (CH), 129.8 (CH), 134.1 (2£CH),

138.2 (C), 147.0 (C), 171.2 (CvO); m/z (FAB) 288 (MH^þ,

35%), 230 (12) (Found MH^þ, 288.1962. C₁₈H₂₅NO₂

requires M, 288.1964); followed by the major isomer 25

(R_f0.3, 70:30 petroleum ether–EtOAc) as a white solid

(950 mg, 3.03 mmol, 63%), mp 140–142 8C (recrystallised

from petroleum ether); n_max(CHCl₃)/cm²¹3622, 2960,

1643, 1597; d_H(400 MHz, CDCl₃) 1.38 (9H, s, C(CH₃)₃),

1.93–2.00 (1H, m, 1⁰-H_A), 2.05–2.11 (2H, m, 4-H), 2.31

(1H, ddd, J¼14.2, 10.5, 8.5 Hz, 1⁰-H_B), 2.50 (1H, ddd,

J¼17.7, 7.6, 5.7 Hz, 3-H_A), 2.71 (1H, dt, J¼17.7, 8.0 Hz, 3-

H_B), 3.76 (1H, ddd, J¼10.7, 4.0, 2.9 Hz, 5-H), 4.48 (1H, m,

6-H), 5.07 (2H, m, 3⁰-H), 5.65 (1H, dddd, J¼18.9, 10.5, 6.3,

5.7 Hz, 2⁰-H), 7.01 (1H, dd, J¼7.8, 1.6 Hz, Ar-H), 7.19 (1H,

ddd, J¼7.8, 7.2, 1.7 Hz, Ar-H), 7.27 (1H, ddd, J¼8.0, 7.2,

1.6 Hz, Ar-H), 7.53 (1H, dd, J¼8.0, 1.7 Hz, Ar-H); d_C

(125 MHz, CDCl₃) 27.0 (CH₂), 28.4 (CH₂), 31.8 (CH₃),

34.6 (CH₂), 35.9 (C), 63.4 (CH), 64.2 (CH), 118.0 (CH₂),

126.4 (CH), 127.9 (CH), 129.0 (CH), 133.2 (CH), 134.5

(CH), 137.2 (C), 147.0 (C), 171.6 (CvO); m/z (FAB) 288

(MH^þ, 100%), 230 (24) (Found MH^þ, 288.1980.

C₁₈H₂₅NO₂requires M, 288.1964). Anal. Calcd for

C₁₈H₂₅NO₂. C, 75.26; H, 8.71; N, 4.88%. Found: C,

75.53; H, 8.81; N, 4.94%.

4.1.15. 1-(2-tert-Butyl-phenyl)-6-hydroxy-piperidin-2-

one 23. DIBAL (166 mL of a 1 M solution in CH₂Cl₂)

was added dropwise to a stirred solution of imide 28 (22.5 g,

91.7 mmol) in CH₂Cl₂(300 mL) at 278 8C. After 15 min

stirring at 278 8C, H₂O (160 mL), followed by 2 N NaOH

(50 mL) were cautiously added and the reaction mixture

poured into a saturated solution of Rochelles salt (1.20 L).

The mixture was then extracted with CH₂Cl₂(4£350 mL).

The combined extracts were then washed with brine

(350 mL), dried (MgSO₄), and evaporated under reduced

pressure to yield a yellow oil. The crude mixture was then

puriﬁed by ﬂash column chromatography (50% EtOAc–

petroleum ether) to give a yellow oil, which was triturated

with petroleum ether/EtOAc to yield the title compound 23

(3:1 ratio of isomers) as a white solid (14.5 g, 58.8 mmol,

64%), mp 104–106 8C; n_max(CHCl₃)/cm²¹3667, 3592,

3405, 3124, 2961, 1722, 1698, 1650, 1573; d_H(400 MHz,

CDCl₃) 1.31 (9H major, s, C(CH₃)₃), 1.38 (9H minor,

C(CH₃)₃), 1.77 (1H majorþ1H minor, m, 4-H_A), 1.96–2.04

(2H majorþ2H minor, m, 4-H_Bþ5-H_A), 2.22–2.39 (2H

majorþ2H minor, m, 5-H_Bþ3-H_A), 2.50–2.55 (1H

majorþ1H minor, m, 3-H_B), 3.69 (1H majorþ1H minor,

br.s, OH), 4.96 (1H major, m, 6-H), 5.26 (1H minor, 6-H),

6.96 (1H minor, Ar-H), 7.10 (1H major, dd, J¼7.6, 1.6 Hz,

Ar-H), 7.18 (1H majorþ1H minor, ddd, J¼7.6, 7.3, 1.6 Hz,

Ar-H); 7.27 (1H majorþ1H minor, ddd, J¼8.0, 7.3, 1.6 Hz,

Ar-H), 7.51 (1H major, dd, J¼8.0, 1.6 Hz, Ar-H) 7.56 (1H

minor, Ar-H); d_C(100 MHz, CDCl₃) 16.0 (CH₂), 29.4

(CH₂), 31.7 (CH₃), 33.1 (CH₂), 35.7 (C), 82.3 (CH), 126.8

(CH), 128.2 (CH), 128.9 (CH), 132.6 (CH), 139.0 (C),

146.6(C), 172.3 (CvO); m/z (TOF) 270 (MþNa)^þ(Found

MþNa^þ, 270.1476. C₁₅H₂₁NO₂þNa requires M,

270.1470). Anal. Calcd for C₁₅H₂₁NO₂. C, 72.87; H, 8.50;

N, 5.67%. Found: C, 72.67; H, 8.53; N, 5.65%.

4.1.16. 1-(2-tert-Butyl-phenyl)-3,4-dihydro-1H-pyridin-

2-one 24. To a solution of piperidine-2-one 23 (14.0 g,

56.8 mmol) in CH₂Cl₂(500 mL) at 0 8C, was added Et₃N

(24.0 mL, 172 mmol), then MsCl (6.66 mL, 86.1 mmol).

The reaction mixture was stirred at room temperature for

2 h, then washed with H₂O (500 mL), a saturated solution of

NaHCO₃(500 mL), and brine (500 mL), dried (MgSO₄),

and evaporated under reduced pressure. The resulting

orange oil was puriﬁed by ﬂash column chromatography

(20% EtOAc–petroleum ether), to give the title compound

as a white solid (10.6 g, 46.4 mmol, 81%), mp 91–93 8C

(recrystallised from petroleum ether); n_max(CHCl₃)/cm²¹

2960, 2775, 2577, 2465, 2263, 2144, 1723, 1698, 1672,

1573; d_H(400 MHz, CDCl₃) 1.38 (9H, s, C(CH₃)₃), 2.44–

2.49 (2H, m, 4-H), 2.66–2.70 (2H, m, 3-H), 5.24 (1H, dt,

J¼7.7, 4.4 Hz, 5-H), 6.07 (1H, dt, J¼7.7, 1.6 Hz, 6-H), 7.01

(1H, dd, J¼7.6, 1.7 Hz, Ar-H), 7.26 (1H, ddd, J¼7.6, 7.3,

1.6 Hz, Ar-H), 7.32 (1H, ddd, J¼8.0, 7.3, 1.7 Hz, Ar-H),

7.54 (1H, dd, J¼8.0, 1.6 Hz, Ar-H); d_C(100 MHz, CDCl₃)

20.5 (CH₂), 31.7 (CH₃), 32.2 (CH₂), 35.7 (C), 105.0 (CH),

4.1.18. 3-Alkyl-1-(2-tert-butyl-phenyl)-3,4-dihydro-1H-

pyridin-2-one 29a–f. General procedure for alkylation of

D. J. Bennett et al. / Tetrahedron 60 (2004) 4491–4511

4505

24. To a stirred solution of diisopropylamine (0.14 mL,

n

1.00 mmol) in THF (5 mL) at 278 8C was added BuLi

4.1.21. (3S)-3-Benzyl-1-(2-tert-butyl-phenyl)-3,4-dihydro-

1H-pyridin-2-one 29c. From 24 (200 mg, 0.87 mmol), the

resulting yellow oil was puriﬁed by ﬂash column chroma-

tography (10% EtOAc–petroleum ether) to yield the title

compound (13:1 ratio of isomers) as a yellow oil (218 mg,

0.68 mmol, 79%), n_max(CHCl₃)/cm²¹2959, 2358, 1668; d_H

(400 MHz, CDCl₃) 1.40 (9H majorþ9H minor, s, C(CH₃)₃),

2.19 (1H majorþ1H minor, dddd, J¼17.1, 8.7, 4.3, 1.6 Hz,

4-H_A), 2.36 (1H majorþ1H minor, dddd, J¼17.1, 6.6, 4.6,

1.6 Hz, 4-H_B), 2.78–2.88 (2H majorþ2H minor, m,

3-Hþ1⁰-H_A), 3.37 (1H major, dd, J¼12.6, 3.2 Hz, 1⁰-H_B),

3.46 (1H minor, d, J¼10.2 Hz, 1⁰H_B), 5.16 (1H major, dt,

J¼7.5, 4.5 Hz, 5-H), 5.21 (1H minor, 5-H), 6.09 (1H

majorþ1H minor, dt, J¼7.5, 1.6 Hz, 6-H), 7.00 (1H

majorþ1H minor, dd, J¼7.6, 1.6 Hz, Ar-H), 7.01 (1H

minor, dd, J¼7.4, 1.5 Hz, Ar-H), 7.24–7.30 (4H majorþ4H

minor, m, Ar-H); 7.31–7.37 (3H majorþ3H minor, m,

Ar-H), 7.56 (1H majorþ1H minor, dd, J¼8.0, 1.6 Hz,

Ar-H); d_C(100 MHz, CDCl₃) 24.6 (CH₂), 31.8 (CH₃),

35.6 (CH₂), 35.8 (C), 43.0 (CH), 103.8 (CH), 126.4 (CH),

127.5 (CH), 128.5 (CH), 128.6 (CH), 128.8 (CH), 129.4

(CH), 131.1 (CH), 132.6 (CH), 139.4 (C), 139.5 (C), 147.5

(C), 172.1 (CvO); m/z (FAB) 320 (MH^þ, 100%), 262

(77) (Found MH^þ, 320.2039. C₂₂H₂₆NO requires M,

320.2014).

(0.68 mL of a 1.60 M solution in hexanes), and the mixture

then warmed to room temperature for 15 min before cooling

to 278 8C. To the resulting solution of LDA, a solution of

pyridin-2-one 24 (200 mg, 0.87 mmol) in THF (5 mL) was

added. After 1.5 h the electrophile (8.70 mmol) was added

and the reaction mixture stirred at 278 8C for 1 h. Saturated

NH₄Cl solution (5 mL) was then added and the reaction

mixture was allowed to warm to room temperature. The

mixture was extracted with EtOAc (4£30 mL), the com-

bined organic extracts were washed with brine (30 mL),

dried (MgSO₄) and evaporated under reduced pressure. The

resulting crude product was puriﬁed by ﬂash column

chromatography.

4.1.19. (3R)-1-(2-tert-Butyl-phenyl)-3-methyl-3,4-dihydro-

1H-pyridin-2-one 29a. From 24 (200 mg, 0.87 mmol), the

resulting yellow oil was puriﬁed by ﬂash column chroma-

tography (20% EtOAc–petroleum ether) to yield the title

compound (6:1 ratio of isomers) as an oily solid (171 mg,

0.70 mmol, 81%), n_max(CHCl₃)/cm²¹2966, 2359, 1711,

1667; d_H(400 MHz, CDCl₃) 1.30 (3H major, d, J¼6.9 Hz,

3-Me), 1.33 (3H minor, 3-Me), 1.36 (9H major, s, C(CH₃)₃),

1.37 (9H minor, C(CH₃)₃), 2.24 (1H majorþ1H minor,

dddd, J¼16.9, 10.8, 4.0, 1.8 Hz, 4-H_A), 2.51 (1H majorþ1H

minor, dddd, J¼16.9, 14.1, 3.7, 1.2 Hz, 4-H_B), 2.72 (1H

majorþ1H minor, ddq, J¼14.1, 10.8, 6.9 Hz, 3-H), 5.17

(1H, ddd, J¼7.7, 4.0, 3.7 Hz, 5-H), 5.25 (1H minor, 5-H),

6.04 (1H, ddd, J¼7.7, 1.8, 1.2 Hz, 6-H), 6.07 (1H minor,

6-H), 6.98 (1H majorþ1H minor, dd, J¼7.6, 1.6 Hz, Ar-H),

7.24 (1H majorþ1H minor, ddd, J¼7.6, 7.3, 1.6 Hz, Ar-H),

7.31 (1H majorþ1H minor, ddd, J¼8.0, 7.3, 1.6 Hz, Ar-H),

7.52 (1H majorþ1H minor, dd, J¼8.0, 1.6 Hz, Ar-H); d_C

(100 MHz, CDCl₃) 15.7 (CH₃), 28.6 (CH₂), 31.7 (CH₃),

35.7 (C), 36.2 (CH), 104.0 (CH), 127.4 (CH), 128.5 (CH),

128.7 (CH), 131.1 (CH), 132.6 (CH), 139.6 (C), 147.4 (C),

173.1 (CvO); m/z (FAB) 244 (MH^þ, 100%), 186 (92)

(Found MH^þ, 244.1716. C₁₆H₂₂NO requires M, 244.1701).

4.1.22. (3S)-1-(2-tert-Butyl-phenyl)-3-prop-2-ynyl-3,4-

dihydro-1H-pyridin-2-one 29d. From 29 (200 mg.

0.87 mmol), the resulting yellow oil was puriﬁed by ﬂash

column chromatography (10% EtOAc–petroleum ether) to

yield the title compound (12:1 ratio of isomers) as a solid

(144 mg, 0.22 mmol, 62%), mp 105–108 8C (recrystallised

from petroleum ether); n_max(CHCl₃)/cm²¹3307, 2963,

2337, 1673, 1607; d_H(400 MHz, CDCl₃) 1.35 (9H major, s,

C(CH₃)₃), 1.37 (9H minor, s, C(CH₃)₃), 2.01 (1H minor,

apparent t, J¼2.7 Hz, 3⁰-H), 2.03 (1H major, apparent t,

J¼2.7 Hz, 3⁰-H), 2.42–2.51 (2H majorþ2H minor, m,

1⁰-H_Aþ4-H_A), 2.71–2.84 (2H majorþ2H minor, m,

4-H_Bþ3-H), 2.91 (1H majorþ1H minor, ddd, J¼17.0, 3.9,

2.7 Hz, 1⁰-H_B), 5.24 (1H major, dt, J¼6.6, 3.3 Hz, 5-H),

5.32 (1H minor, 5-H), 6.05 (1H majorþ1H minor, dt, J¼6.6,

1.8, 6-H), 6.99 (1H majorþ1H minor, dd, J¼7.7, 1.5 Hz,

Ar-H), 7.24 (1H majorþ1H minor, ddd, J¼7.7, 7.3, 1.6 Hz,

Ar-H); 7.32 (1H majorþ1H minor, ddd, J¼8.1, 7.3, 1.5 Hz,

Ar-H), 7.53 (1H majorþ1H minor, dd, J¼8.1, 1.6 Hz, Ar-

H); d_C(100 MHz, CDCl₃) 19.4 (CH₂), 25.6 (CH₂), 31.7

(CH₃), 35.7 (C), 40.4 (CH), 70.0 (CH), 82.0 (C), 104.2

(CH), 127.5 (CH), 128.7 (CH), 128.8 (CH), 131.1 (CH),

132.5 (CH), 139.1 (C), 147.2 (C), 170.4 (CvO); m/z (FAB)

268 (MH^þ, 64%), 210 (48) (Found MH^þ, 268.1718.

C₁₈H₂₂NO requires M, 268.1701).

4.1.20. (3R)-3-Allyl-1-(2-tert-butyl-phenyl)-3,4-dihydro-

1H-pyridin-2-one 29b. From 24 (200 mg, 0.87 mmol),

the resulting yellow oil was puriﬁed by ﬂash column

chromatography (10% EtOAc–petroleum ether) to yield the

title compound (12:1 ratio of isomers) as a yellow oil

(155 mg, 0.58 mmol, 66%), n_max(CHCl₃)/cm²¹2963,

1710, 1668; d_H(400 MHz, CDCl₃) 1.37 (9H majorþ9H

minor, s, C(CH₃)₃), 2.29–2.35 (2H majorþ2H minor, m,

4-H), 2.52 (1H majorþ1H minor, dddd, J¼16.7, 6.0, 3.9,

1.2 Hz, 1⁰-H_A), 2.62–2.72 (2H majorþ2H minor, m,

1⁰-H_Bþ3-H), 5.08–5.19 (3H majorþ2H minor, m,

3⁰-Hþ5-H), 5.25 (1H minor, 5-H), 5.81–5.88 (1H majorþ1

H minor, m, 2⁰-H), 6.04 (1H majorþ1H minor, dt, J¼7.8,

1.5 Hz, 6-H), 6.96 (1H majorþ1H minor, dd, J¼7.6, 1.7 Hz,

Ar-H), 7.25 (1H majorþ1H minor, ddd, J¼7.6, 7.3, 1.6 Hz,

Ar-H); 7.31 (1H majorþ1H minor, ddd, J¼8.0, 7.3, 1.7 Hz,

Ar-H), 7.53 (1H majorþ1H minor, dd, J¼8.0, 1.6 Hz,

Ar-H); d_C(100 MHz, CDCl₃) 25.2 (CH₂), 31.7 (CH₃), 34.2

(CH₂), 35.7 (C), 40.8(CH), 103.9 (CH), 117.2 (CH₂), 127.5

(CH), 128.5 (CH), 128.7 (CH), 131.1 (CH), 132.5 (CH),

136.0 (CH), 139.5 (C), 147.5 (C), 172.0 (CvO); m/z (FAB)

270 (MH^þ, 100%), 212 (80) (Found MH^þ, 270.1851.

C₁₈H₂₄NO requires M, 270.1858).

4.1.23. (3R)-1-(2-tert-Butyl-phenyl)-3-pentyl-3,4-dihydro-

1H-pyridin-2-one 29e. From 29 (200 mg, 0.87 mmol), the

resulting yellow oil was puriﬁed by ﬂash column chroma-

tography (4% EtOAc–petroleum ether) to yield the title

compound (7:1 ratio of isomers) as an oil (229 mg,

0.77 mmol, 88%), n_max(CHCl₃)/cm²¹2929, 2860, 1667,

1572; d_H(400 MHz, CDCl₃) 0.91 (3H majorþ3H minor, t,

J¼7.0 Hz, 5⁰-₀H) 1.27–1.55 (16H majorþ16H minor, m,

C(CH₃)₃þ1 -H_Aþ2⁰-H þ3⁰Hþ4⁰-H), 1.90–1.93 (1H

majorþ1H minor, m, 1⁰-H_B), 2.25 (1H majorþ1H minor,

dddd, J¼19.1, 10.6, 4.4, 1.5 Hz, 4-H_A), 2.52–2.58 (2H

4506

D. J. Bennett et al. / Tetrahedron 60 (2004) 4491–4511

majorþ2H minor, m, 3-Hþ4-H_B), 5.16 (1H major, dt,

J¼7.7, 4.4 Hz, 5-H), 5.23 (1H minor, 5-H), 6.03 (1H

majorþ1H minor, dt, J¼7.7, 1.5 Hz, 6-H), 6.95 (1H

majorþ1H minor, dd, J¼7.6, 1.7 Hz, Ar-H), 7.28 (1H

majorþ1H minor, ddd, J¼7.6, 7.3, 1.6 Hz, Ar-H), 7.34

(1H majorþ1H minor, ddd, J¼8.0, 7.3, 1.7 Hz, Ar-H), 7.52

(1H majorþ1H minor, dd, J¼8.0, 1.6 Hz, Ar-H); d_C

(100 MHz, CDCl₃) 14.1 (CH₃), 22.6 (CH₂), 25.7 (CH₂),

26.9 (CH₂), 29.7 (CH₂), 31.7 (CH₃), 31.9 (CH₂), 35.7 (C),

41.2 (CH), 103.8 (CH), 127.5 (CH), 128.4 (CH), 128.7

(CH), 131.1 (CH), 132.4 (CH), 139.7 (C), 147.6 (C), 172.8

(CvO); m/z (FAB) 300 (MH^þ, 54%), 242 (64) (Found

MH^þ, 300.2339. C₂₀H₃₀NO requires M, 300.2327).

J¼5.6, 3.4 Hz, 3-H), 5.23 (1H, ddd, J¼7.6, 6.3, 2.8 Hz,

5-H), 6.14 (1H, dd, J¼7.6, 2.9 Hz, 6-H), 7.06 (1H, dd,

J¼7.6, 1.2 Hz, Ar-H), 7.25–7.34 (5H, m, Ar-H), 7.52 (1H,

dd, J¼7.8, 1.2 Hz, Ar-H), 7.61 (2H, d, J¼7.6 Hz, Ar-H); d_C

(125 MHz, CDCl₃) 27.4 (CH₂), 31.8 (CH₃), 35.8 (C), 48.7

(CH), 102.2 (CH), 127.8 (2£CH), 128.6 (CH), 128.8 (CH),

129.0 (2£CH), 130.3 (CH), 132.8 (2£CH), 133.3 (CH),

136.7 (C), 139.4 (C), 147.8 (C), 168.0 (CvO); m/z (EI)

(Found M^þ, 337.1490. C₂₁H₂₃NOS requires M, 337.1500);

followed by the syn-adduct of 29g (R_f0.75, 30:70 petroleum

ether–EtOAc) as an oil (30.0 mg, 0.09 mmol, 15%), n_max

(CHCl₃)/cm²¹2962, 2873, 1672, 1587, 1485, 1440, 1398,

1358, 1303, 1146; d_H(500 MHz, CDCl₃) 1.35 (9H, s,

C(CH₃)₃), 2.63 (1H, ddd, J¼17.8, 5.3, 5.2 Hz, 4-H_A), 2.97

(1H, ddd, J¼17.8, 6.2, 3.4, 2.2 Hz, 4-H_B), 4.10 (1H, dd,

J¼6.3, 6.2 Hz, 3-H), 5.21 (1H, ddd, J¼7.6, 5.2, 3.4 Hz,

5-H), 6.10 (1H, dd, J¼7.6, 2.2 Hz, 6-H), 7.01 (1H, dd,

J¼7.6, 1.2 Hz, Ar-H), 7.21–7.33 (5H, m, Ar-H), 7.51 (1H,

dd, J¼7.9, 1.2 Hz, Ar-H), 7.57 (2H, dd, J¼7.6, 1.3 Hz, Ar-

H); d_C(125 MHz, CDCl₃) 28.1 (CH₂), 31.6 (CH₃), 35.7 (C),

48.4 (CH), 103.4 (CH), 127.3 (CH), 127.5 (CH), 128.5

(CH), 128.8 (CH), 129.0 (2£CH), 131.3 (CH), 131.8

(2£CH), 133.0 (CH), 134.2 (C), 139.4 (C), 147.7 (C),

167.6 (CvO); m/z (EI) (Found M^þ, 337.1486. C₂₁H₂₃NOS

requires M, 337.1500).

4.1.24. (3R)-1-(2-tert-Butyl-phenyl)-3-ethyl-3,4-dihydro-

1H-pyridin-2-one 29f. From 24 (200 mg, 0.87 mmol), the

resulting yellow oil was puriﬁed by ﬂash column chroma-

tography (10% EtOAc–petroleum ether) to yield the title

compound (10:1 ratio of isomers) as an oil (153 mg,

0.60 mmol, 61%), n_max(CHCl₃)/cm²¹2966, 2877, 1687; d_H

(400 MHz, CDCl₃) 1.03 (3H majorþ3H minor, t, J¼7.5 Hz,

2⁰-H) 1.37 (9H majorþ9H minor, s, C(CH₃)₃), 1.55–1.64

(1H majorþ1H minor, m, 1⁰-H_A), 1.98 (1H majorþ1H

minor, dqd, J¼13.4, 7.5, 5.6 Hz, 1⁰-H_B), 2.28 (1H majorþ1

H minor, dddd, J¼16.6, 8.2, 4.4, 1.3 Hz, 4-H_A), 2.45–2.58

(2H majorþ2H minor, m, 4-H_Bþ3-H), 5.17 (1H major, dt,

J¼7.8, 4.4 Hz, 5-H), 5.23 (1H minor, 5-H), 6.03 (1H

majorþ1H minor, dt, J¼7.8, 1.3 Hz, 6-H), 6.95 (1H

majorþ1H minor, dd, J¼7.6, 1.8 Hz, Ar-H), 7.22–7.51

(2H majorþ2H minor, m, Ar-H), 7.52 (1H majorþ1H

minor, dd, J¼8.0, 1.6 Hz, Ar-H), d_C(100 MHz, CDCl₃)

11.7 (CH₃), 22.9 (CH₂), 25.3 (CH₂), 31.7 (CH₃), 35.7 (C),

42.7 (CH), 103.8 (CH), 127.6 (CH), 128.4 (CH), 128.7

(CH), 131.1 (CH), 132.4 (CH), 139.7 (C), 147.5 (C), 172.6

(CvO); m/z (TOF) 280 (MþNa)^þ(Found MþNa^þ,

280.1682. C₁₇H₂₃NOþNa requires M, 280.1677).

4.1.26. 1-(2-tert-Butyl-phenyl)-3-(3-trimethylsilanyl-

prop-2-ynyl)-3,4-dihydro-1H-pyridin-2-one 29h. To a

stirred solution of diisopropylamine (0.03 mL, 0.22 mmol)

n

in THF (2 mL) at 278 8C was added BuLi (0.14 mL of a

1.60 M solution in hexanes), followed by warming to room

temperature for 15 min, then recooled to 278 8C. To the

resulting LDA, a solution of pyridin-2-one 24 (50.0 mg,

0.22 mmol) in THF (2 mL) was added. After 1 h TMS-

propargyl bromide (0.31 mL, 2.20 mmol) was added and the

reaction mixture stirred at 278 8C for 1 h, saturated NH₄Cl

solution (5 mL) was then added and the reaction mixture

was allowed to warm to room temperature. The reaction

mixture was extracted with EtOAc (2£20 mL), the com-

bined organic extracts were washed with brine (20 mL),

dried (MgSO₄) and evaporated under reduced pressure. The

resulting crude product was puriﬁed by biotage chromatog-

raphy (5% EtOAC–petroleum ether) to yield the title

compound (15:1 ratio of isomers) as a yellow oil (50.0 mg,

0.15 mmol, 68%), n_max(CHCl₃)/cm²¹2961, 2908, 1673,

1488, 1440, 1399, 1364, 1286, 1151; d_H(500 MHz, CDCl₃)

0.18 (9H majorþ9H minor, s, Si(CH₃)₃), 1.35 (9Hþ9H

minor, s, C(CH₃)₃), 2.38–2.51 (2H majorþ2H minor, m

with dd at 2.47, J¼17.1, 10.2 Hz, 7-H and 4-H_A), 2.72–

2.82 (2H majorþ2H minor, m, 4-H_Band 3-H), 2.96 (1H

majorþ1H minor, dd, J¼17.1, 3.7 Hz, 7-H_B), 5.24 (1H

major, ddd, J¼7.7, 5.0, 3.5 Hz, 5-H), 5.27 (1H minor,

5-H), 6.05 (1H majorþ1H minor, dd, J¼7.7, 1.9 Hz,

6-H), 6.98 (1H majorþ1H minor, dd, J¼7.7, 1.4 Hz,

Ar-H), 7.24 (1H majorþ1H minor, ddd, J¼7.7, 7.5,

1.2 Hz, Ar-H), 7.31 (1H majorþ1H minor, ddd, J¼8.2,

7.5, 1.4 Hz, Ar-H), 7.52 (1H majorþ1H minor, dd,

J¼8.2, 1.2 Hz, Ar-H); d_C(125 MHz, CDCl₃) 0.18 (CH₃),

20.9 (CH₂), 25.6 (CH₂), 31.7 (CH₃), 35.7 (C), 40.5 (CH),

86.4 (C), 104.3 (CH), 104.7 (C), 127.4 (CH), 128.6 (CH),

128.7 (CH), 131.1 (CH), 132.5 (CH), 139.2 (C), 147.2

(C), 170.5 (CvO); m/z (EI) (Found M^þ, 339.2026.

C₂₁H₂₉NOSi requires M, 339.2018).

4.1.25. (3R)-1-(2-tert-Butyl-phenyl)-3-phenylsulfanyl-

3,4-dihydro-1H-pyridin-2-one anti-29g, (3S)-1-(2-tert-

butyl-phenyl)-3-phenylsulfanyl-3,4-dihydro-1H-pyri-

din-2-one syn-29g. To a stirred solution of diisopropyla-

mine (0.12 mL, 0.87 mmol) in THF (5 mL) at 278 8C was

n

added BuLi (0.56 mL of a 1.60 M solution in hexanes),

followed by warming to room temperature for 15 min, then

recooling to 278 8C. To the resulting LDA solution was

added a solution of enamide 24 (200 mg, 0.87 mmol) in

THF (5 mL). After 1 h at 278 8C, phenyl disulﬁde (1.90 g,

8.70 mmol) in a solution of THF (4 mL) was added and the

reaction mixture stirred at 278 8C for 1 h. A solution of

saturated NH₄Cl solution (5 mL) was then added and the

reaction mixture was allowed to warm to room temperature.

The reaction mixture was extracted with EtOAc (2£40 mL),

the combined organic extracts were washed with brine

(40 mL), dried (MgSO₄) and evaporated under reduced

pressure. The resulting crude product was puriﬁed by

biotage chromatography (2–20% EtOAc–petroleum ether)

to give ﬁrstly the anti-adduct of 29g (R_f0.8, 70:30

petroleum ether–EtOAc) (10:1 ratio of anti:bis products)

as a white solid (200 mg, 0.59 mmol, 68%), mp 85–90 8C;

n_max(CHCl₃/cm²¹2962, 1672, 1488, 1467, 1440, 1396,

1356, 1299, 1145; d_H(500 MHz, CDCl₃) 1.37 (9H, s,

C(CH₃)₃), 2.69 (1H, ddd, J¼17.4, 6.3, 3.4 Hz, 4-H_A), 2.96

(1H, dddd, J¼17.4, 5.6, 2.9, 2.8 Hz, 4-H_B), 3.99 (1H, dd,

D. J. Bennett et al. / Tetrahedron 60 (2004) 4491–4511

4507

4.1.27. Kinetic resolution of 1-(2-tert-butyl-phenyl)-3,4-

dihydro-1H-pyridin-2-one 24. To a stirred solution of

chiral diamine²⁴(273 mg, 0.65 mmol) in THF (5 mL) at

278 8C was added ⁿBuLi (0.42 mL of a 1.60 M solution in

hexanes), followed by warming to room temperature for

15 min, then recooled to 278 8C. To the resulting chiral

base, a solution of pyridin-2-one 24 (200 mg, 0.87 mmol) in

THF (5 mL) was added. After 1 h benzyl bromide (1.03 mL,

8.70 mmol) was added and the reaction mixture stirred at

278 8C for 1 h, saturated NH₄Cl solution (5 mL) was then

added and the reaction mixture was allowed to warm to

room temperature. The reaction mixture was extracted with

EtOAc (2£40 mL), the combined organic extracts were

washed with brine (20 mL), dried (MgSO₄) and evaporated

under reduced pressure. The crude NMR indicated the

reaction had proceeded to 74% conversion. The ee of the

remaining starting material (73%) was determined by HPLC

analysis using a Chirapak AD-H column [25 cm £0.46 cm

i.d.; 3% i-PrOH in hexane; ﬂow rate, 0.4 mL/min; (2)-24;

t_R¼25.7 min, (þ)-24; t_R¼29.0 min].

isomer anti-33 (R_f0.9, 1:1 petroleum ether–EtOAc) as an

oil which slowly solidiﬁed (1.20 g, 4.60 mmol, 43%), mp

48–52 8C; [a]_D²⁵¼þ20.6 (c 1.0, CHCl₃); n_max(CHCl₃)/

cm²¹2962, 1732, 1682, 1488, 1460, 1355, 1311, 1284;

d_H(500 MHz, CDCl₃) 1.29 (9H, s, C(CH₃)₃), 1.39 (3H, d,

J¼6.9 Hz, 3-Me), 1.89 (1H, dddd, J¼13.7, 11.8, 11.4,

4.6 Hz, 4-H_A), 2.17 (1H, dddd, J¼13.7, 5.2, 5.0, 4.7 Hz,

4-H_B), 2.72 (1H, m, 3-H), 2.76 (1H, ddd, J¼17.2, 11.9,

5.2 Hz, 5-H_A), 2.95 (1H, ddd, J¼17.2, 4.7, 4.6 Hz, 5-H_B),

6.78 (1H, dd, J¼7.7, 1.3 Hz, Ar-H), 7.25 (1H, ddd, J¼7.7,

7.5 Hz, 1.4, Ar-H), 7.35 (1H, ddd, J¼7.9, 7.5, 1.3 Hz,

Ar-H), 7.57 (1H, dd, J¼7.9, 1.4 Hz, Ar-H); d_C(125 MHz,

CDCl₃) 16.0 (CH₃), 25.5 (CH₂), 31.7 (CH₃), 33.0 (CH₂),

35.9 (C), 37.9 (CH), 127.2 (CH), 128.9 (CH), 129.1 (CH),

131.0 (CH), 133.5 (C), 146.7 (C), 173.5 (CvO), 176.1

(CvO); m/z (EI) (Found M^þ, 259.1568. C₁₆H₂₁NO₂

requires M, 259.1572). The ee of anti-33 (72% ee) was

determined by HPLC analysis using a Chirapak AD-H

column [25 cm£0.46 cm i.d.; 3% i-PrOH in hexane; ﬂow

rate, 0.4 mL/min; (2)-anti-33; t_R¼34.2 min, (þ)-anti-33;

t_R¼38.7 min]; followed by the most polar diastereoisomer

syn-33 (R_f0.8, 1:1 petroleum ether–EtOAc) as a white

solid (0.75 g, 3.00 mmol, 27%), mp 172–177 8C;

[a]²_D⁵¼þ19.0 (c 0.93, CHCl₃); n_max(CHCl₃)/cm²¹2970,

1732, 1682, 1602, 1460, 1356, 1310, 1171; d_H(500 MHz,

CDCl₃) 1.29 (9H, s, C(CH₃)₃), 1.40 (3H, d, J¼7.0 Hz, 3-

Me), 1.92 (1H, dddd, J¼14.2, 12.3, 12.2, 4.7 Hz, 4-H_A),

2.14 (1H, dddd, J¼14.2, 5.3, 4.5, 4.4 Hz, 4-H_B), 2.74 (1H,

m, 3-H), 2.78 (1H, ddd, J¼17.8, 12.3, 5.3 Hz, 5-H_A), 2.96

(1H, ddd, J¼17.8, 4.7, 4.4 Hz, 5-H_B), 6.80 (1H, dd,

J¼7.6, 1.2 Hz, Ar-H), 7.27 (1H, ddd, J¼7.6, 7.3, 1.2 Hz,

Ar-H), 7.35 (1H, ddd, J¼7.8, 7.3, 1.2 Hz, Ar-H), 7.56

(1H, dd, J¼7.8, 1.2 Hz, Ar-H); d_C(125 MHz, CDCl₃)

16.5 (CH₃), 24.8 (CH₂), 31.8 (CH₃), 32.9 (CH₂), 35.9 (C),

38.0 (CH), 127.3 (CH), 128.8 (CH), 128.9 (CH), 131.1

(CH), 134.0 (C), 146.7 (C), 173.2 (CvO), 175.8 (CvO);

m/z (EI) (Found M^þ, 259.1563. C₁₆H₂₁NO₂requires M,

259.1572). The ee of syn-33 (78% ee) was determined

by HPLC analysis using a Chirapak AD-H column

[25 cm£0.46 cm i.d.; 3% i-PrOH in hexane; ﬂow rate,

0.4 mL/min; (þ)-syn-33; t_R¼42.4 min, (2)-syn-33;

t_R¼47.3 min].

The reaction was also carried using 0.25 equiv. of chiral

base [chiral amine (92.0 mg, 0.22 mmol) and ⁿBuLi

(0.14 mL of a 1.60 M solution in hexanes)] to give enamide

24 of 15% ee; and 0.5 equiv. of chiral base [chiral amine

(184 mg, 0.44 mmol) and ⁿBuLi (0.27 mL of a 1.60 M

solution in hexanes)] to give enamide 24 of 62% ee.

4.1.28. (3R)-(1)-Methylglutaric anhydride 32. A solution

of (R)-(2)-2-methylglutaric acid 31 (2.00 g, 14.0 mmol) in

Ac₂O (50 mL) was reﬂuxed for 24 h. Removal of excess

Ac₂O by azeotropic codistillation with dry toluene

(27£40 mL) yielded a brown solid 32 (1.75 g, 13.7 mmol,

98%), which was used without further puriﬁcation, mp 48–

50 8C (lit.²⁰35–36 8C); [a]_D²³¼þ38.9 (c 1.50, CHCl₃) (lit.²⁰

[a]_D¼þ44.4 (neat); n_max(CHCl₃)/cm²¹2978, 2941, 2883,

1814, 1770, 1460, 1384, 1352, 1326; d_H(400 MHz, CDCl₃)

1.38 (3H, d, J¼6.9 Hz, 3-Me), 1.78 (1H, dddd, J¼13.8,

12.1, 12.0, 5.1 Hz, 4-H_A), 2.07 (1H, dddd, J¼12.0, 8.0, 5.3,

3.5 Hz, 4-H_B), 2.66 (1H, dqd, J¼13.8, 6.9, 5.3 Hz, 3-H),

2.73 (1H, ddd, J, 18.2, 12.1, 5.9 Hz, 5-H_A), 2.93 (1H, ddd,

J¼18.2, 5.1, 3.5 Hz, 5-H_B); d_C(125 MHz, CDCl₃) 15.8

(CH₃), 24.4 (CH₂), 30.2 (CH₂), 35.8 (CH), 166.9 (CvO),

169.7 (CvO); m/z (EI) (Found M^þ, 128.0479. C₆H₈O₃

requires M, 128.0474).

The above procedure was also carried out using racemic

2-methylglutaric anhydride and yielded the racemic

diastereoisomers anti-33 (1.30 g, 5.00 mmol, 40%) and

syn-33 (0.42 g, 1.62 mmol, 14%).

The above procedure was also carried out using racemic 2-

methylglutaric acid and yielded the racemic anhydride

(1.80 g, 14.0 mmol, 100%).

4.1.30. (M,3R)-1-(2-tert-Butyl-phenyl)-3-methyl-3,4-

dihydro-1H-pyridin-2-one 29a and (P)-1-(2-tert-butyl-

4.1.29. (M,3R)-1-(2-tert-Butyl-phenyl)-3-methyl-piper-

idine-2,6-dione anti-33 and (P,3R)-1-(2-tert-butyl-phe-

nyl)-3-methyl-piperidine-2,6-dione syn-33. A solution of

2-tert-butylaniline 27 (1.69 mL, 10.8 mmol) and (R)-(þ)-2-

methylglutaric anhydride 32 (1.67 g, 13.0 mmol) in

toluene (50 mL) was reﬂuxed for 15 h, evaporated and

subsequently heated at 80 8C with NaOAc (5.32 g,

64.8 mmol) in Ac₂O (50 mL) for 15 h then poured into

H₂O (150 mL), extracted with CHCl₃(4£60 mL), washed

with 2 N NaOH (60 mL), brine (60 mL), dried (MgSO₄)

and concentrated to yield the crude product, which was

puriﬁed by biotage chromatography (10–60% EtOAc–

petroleum ether) to give ﬁrstly the least polar diastereo-

phenyl)-5-methyl-3,4-dihydro-1H-pyridin-2-one

34.

DIBAL (3.47 mL of a 1 M solution in CH₂Cl₂) was added

dropwise to a stirred solution of imide anti-33 (500 mg,

1.93 mmol) in CH₂Cl₂(10 mL) at 278 8C. After 45 min

stirring at 278 8C, H₂O (4 mL), followed by 2 N NaOH

(2 mL) were added and the reaction mixture poured into a

saturated solution of Rochelles salt (25 mL). The mixture

was then extracted with CH₂Cl₂(2£15 mL). The combined

extracts were then washed with brine (20 mL), dried

(MgSO₄), and evaporated under reduced pressure to give

an oil which was dissolved in CH₂Cl₂(15 mL). To this

solution, at 0 8C, was added Et₃N (0.81 mL, 5.79 mmol),

then MsCl (0.22 mL, 2.90 mmol). The reaction mixture was

4508

D. J. Bennett et al. / Tetrahedron 60 (2004) 4491–4511

stirred at room temperature for 1 h, then washed with H₂O

(25 mL), a saturated solution of NaHCO₃(25 mL), and

brine (25 mL), dried (MgSO₄), and evaporated under

reduced pressure. The resulting oil was puriﬁed by biotage

chromatography (5–30% EtOAc–petroleum ether), to give

ﬁrstly 29a (2:1 ratio of isomers) (R_f0.75, 1:1 petroleum

ether–EtOAc) as an oily solid (110 mg, 0.45 mmol, 23%),

[a]²_D⁷¼þ46.6 (c 0.86, CHCl₃). All remaining data was in

agreement with that previously reported for 29a; followed

by 34 (R_f0.5, 1:1 petroleum ether–EtOAc) as an oily solid

(110 mg, 0.45 mmol, 23%): [a]²_D⁷¼þ10.3 (c 0.86, CHCl₃);

n_max(CHCl₃)/cm²¹2967, 2936, 1666, 1488, 1393, 1364,

1285; d_H(500 MHz, CDCl₃) 1.37 (9H, s, C(CH₃)₃), 1.77

(3H, s, 5-Me), 2.39 (2H, m, 4-H), 2.67 (2H, m, 3-H), 5.83

(1H, d, J¼1.2 Hz, 6-H), 7.00 (1H, dd, J¼7.5, 1.4 Hz, Ar-H),

7.25 (1H, ddd, J¼7.7, 7.5, 1.5 Hz, Ar-H), 7.31 (1H, ddd,

J¼8.0, 7.7, 1.4 Hz, Ar-H), 7.52 (1H, dd, J¼8.0, 1.5 Hz,

Ar-H); d_C(125 MHz, CDCl₃) 19.5 (CH₃), 26.1 (CH₂), 31.7

(CH₃), 31.9 (CH₂), 35.7 (C), 114.6 (C), 127.5 (CH), 127.6

(CH), 128.5 (CH), 128.7 (CH), 131.0 (CH), 139.7 (C), 147.5

(C), 169.6 (CvO); m/z (EI) (Found M^þ, 243.1624.

C₁₆H₂₁NO requires M, 243.1623).

0.20 mmol, 90%), mp 125–127 8C; n_max(CHCl₃)/cm²¹

2953, 1639, 1596, 1494, 1456, 1404, 1344, 1301; d_H

(400 MHz, CDCl₃) 1.83 (1H, m, 4-H_A), 1.93 (1H, m, 4-H_B),

2.03 (1H, m, 5-H_A), 2.36 (1H, dddd, J¼13.5, 10.4, 5.3,

3.6 Hz, 5-H_B), 2.68 (1H, ddd, J¼18.1, 8.3, 6.7 Hz, 3-H_A),

2.76 (1H, dt, J¼18.1, 6.1 Hz, 3-H_B), 5.03 (1H, t, J¼5.1 Hz,

6-H), 7.12–7.16 (3H, m, Ar-H), 7.22–7.26 (5H, m, Ar-H),

7.27–7.34 (2H, m, Ar-H); d_C(125 MHz, CDCl₃) 17.5

(CH₂), 32.2 (CH₂), 32.5 (CH₂), 65.0 (CH), 126.6

(CH), 126.9 (2£CH), 127.2 (2£CH), 127.4 (CH), 128.4

(2£CH), 128.7 (2£CH), 141.3 (C), 142.3 (C), 170.7 (CvO);

m/z (EI) (Found M^þ, 251.1308. C₁₇H₁₇NO requires M,

251.1310).

The above reaction was also carried out using enantioen-

riched (63% ee) enamide 24 (50.0 mg, 0.22 mmol) to yield

the product 35a described above (40.0 mg, 0.16 mmol,

72%, showing no erosion of ee (63% ee). The ee was

determined by HPLC analysis using a Chirapak AD-H

column [25 cm£0.46 cm i.d.; 5% i-PrOH in hexane; ﬂow

rate, 1.0 mL/min; (þ)-35a; t_R¼35.9 min, (2)-35a;

t_R¼30.9 min]; [a]²_D⁵¼þ66.2 (c 0.52, CHCl₃).

4.1.31. (M,3R)-1-(2-tert-Butyl-phenyl)-3-methyl-3,4-

dihydro-1H-pyridin-2-one 29a. To a stirred solution of

diisopropylamine (0.07 mL, 0.53 mmol) in THF (3 mL) at

278 8C was added ⁿBuLi (0.33 mL of a 1.60 M solution in

hexanes), followed by warming to room temperature for

15 min, then recooled to 278 8C. To the resulting LDA, a

solution of M-pyridin-2-one 24 (73% ee) (100 mg,

0.44 mmol) in THF (3 mL) was added. After 1 h MeI

(0.27 mL, 4.40 mmol) was added and the reaction mixture

stirred at 278 8C for 1 h, saturated NH₄Cl solution (3 mL)

was then added and the reaction mixture was allowed to

warm to room temperature. The reaction mixture was

extracted with EtOAc (2£20 mL), the combined organic

extracts were washed with brine (20 mL), dried (MgSO₄)

and evaporated under reduced pressure. The resulting crude

product was puriﬁed by biotage chromatography (10%

EtOAc–petroleum ether) to yield the title compound (7:1

ratio of isomers) as an oily solid (75 mg, 0.03 mmol, 70%),

[a]²_D⁷¼þ22.6 (c 0.69, CHCl₃). All remaining data was in

agreement with that previously reported for 29a.

4.1.33. 1-Phenyl-6-tolyl-piperidin-2-one 35b. A solution

of enamide 24 (50.0 mg, 0.22 mmol) and AlCl₃(294 mg,

2.20 mmol) in toluene (20 mL) was heated at 50 8C for 12 h.

After cooling, the reaction mixture was poured into H₂O

(20 mL) and extracted with CHCl₃(3£20 mL). Combined

extracts were washed with brine (20 mL), dried (MgSO₄),

and evaporated under reduced pressure to give the crude

product, which was puriﬁed by ﬂash column chromatog-

raphy (CH₂Cl₂, then 10–60% EtOAc–petroleum ether) to

give the title compound (4:1 ratio of isomers) as pale brown

solid (50.0 mg, 0.19 mmol, 86%), mp 112–115 8C; n_max

(CHCl₃)/cm²¹2953, 1638, 1596, 1494, 1455, 1402, 1335,

1306; d_H(500 MHz, CDCl₃) 1.75–1.82 (1H majorþ1H

minor, m, 4-H_A), 1.87–2.00 (2H majorþ2H minor, m,

5-H_Aþ4-H_B), 2.20 (3H minor, Ar-Me), 2.26–2.34 (4H

major, m with s at 2.29, 5-H_BþAr-Me and 1H minor, 5-

H_B), 2.64 (1H majorþ1H minor, ddd, J¼18.1, 8.6, 6.8 Hz,

3-H_A), 2.73 (1H majorþ1H minor, dt, J¼18.1, 6.0 Hz,

3-H_B), 4.98 (1H major, t, J¼5.1 Hz, 6-H), 5.25 (1H minor,

6-H), 7.02–7.08 (3H minor, m, Ar-H), 7.09–7.15 (7H

major, m, Ar-H and 2H minor, m, Ar-H), 7.20–7.26 (2H

major, m, Ar-H and 3H minor, m, Ar-H), 7.39 (1H minor, d,

J¼7.5 Hz, Ar-H); d_C(125 MHz, CDCl₃) 17.6 (CH₂), 21.1

(CH₃), 32.3 (CH₂), 32.6 (CH₂), 64.8 (CH), 126.5 (CH),

126.7 (2£CH), 127.2 (2£CH), 128.7 (2£CH), 129.0

(2£CH), 137.0 (C), 138.3 (C), 142.4 (C), 170.8 (CvO);

m/z (EI) (Found M^þ, 265.1469. C₁₈H₁₉NO requires M,

265.1467).

For a direct comparison of the samples of (M,3R)-1-(2-tert-

butyl-phenyl)-3-methyl-3,4-dihydro-1H-pyridin-2-one 29a,

synthesised from the chiral diacid precursor (R)-(2)-31 and

from the enantioenriched enamide M-24, both samples were

thermally equilibrated to a ratio of 1.1:1 (from 2:1 and 7:1,

respectively) and the resulting optical rotations measured

as: [a]²_D⁶¼þ54.8 (c 0.54, CHCl₃) and [a]²_D⁷¼þ55.4 (c 0.24,

CHCl₃), respectively.

4.1.34. 6-(4-Bromo-phenyl)-1-phenyl-piperidin-2-one

35c. A solution of enamide 24 (50.0 mg, 0.22 mmol) and

AlCl₃(294 mg, 2.20 mmol) in bromobenzene (15 mL) was

heated at 50 8C for 12 h. After cooling, the reaction mixture

was poured into H₂O (15 mL) and extracted with CHCl₃

(3£20 mL). Combined extracts were washed with brine

(20 mL), dried (MgSO₄), and evaporated under reduced

pressure to give the crude product, which was puriﬁed by

ﬂash column chromatography (CH₂Cl₂, then 10–70%

EtOAc–petroleum ether) to give ﬁrstly the major isomer

(R_f0.3, 70:30 petroleum ether–EtOAc) as a pale brown

4.1.32. 1,6-Diphenyl-piperidin-2-one 35a. A solution of

enamide 24 (50.0 mg, 0.22 mmol) and AlCl₃(294 mg,

2.20 mmol) in benzene (20 mL) was heated at 50 8C for

12 h. After cooling, the reaction mixture was poured into

H₂O (20 mL) and extracted with CHCl₃(3£20 mL).

Combined extracts were washed with brine (20 mL), dried

(MgSO₄), and evaporated under reduced pressure to give the

crude product, which was puriﬁed by ﬂash column

chromatography (20–70% EtOAc–petroleum ether) to

give the title compound as a pale orange solid (50.0 mg,

D. J. Bennett et al. / Tetrahedron 60 (2004) 4491–4511

4509

solid (35.0 mg, 0.11 mmol, 48%), mp 117–120 8C; n_max

(CHCl₃)/cm²¹2954, 1642, 1596, 1494, 1465, 1406, 1340;

d_H(500 MHz, CDCl₃) 1.83–1.90 (2H, m, 4-H_Aand 4-H_B),

2.07–2.18 (1H, m, 5-H_A), 2.29–2.36 (1H, m, 5-H_B), 2.68

(1H, dt, J¼18.1, 7.9 Hz, 3-H_B), 2.77 (1H, dt, 18.1, 5.6, 3-

H_A), 5.48 (1H, t, J¼5.1 Hz, 6-H), 7.08–7.18 (4H, m, Ar-H),

7.24–7.28 (2H, m, Ar-H), 7.32 (1H, t, J¼7.5 Hz, Ar-H),

7.44 (1H, d, J¼7.6 Hz, Ar-H), 7.47 (1H, d, J¼8.2 Hz, Ar-

H); d_C(125 MHz, CDCl₃) 17.5 (CH₂), 29.6 (CH₂), 32.7

(CH₂), 63.9 (CH), 122.5 (C), 126.8 (CH), 127.0 (2£CH),

127.3 (CH), 128.9 (3£CH), 129.1 (CH), 133.4 (CH), 139.7

(C), 142.0 (C), 171.0 (CvO); m/z (EI) (Found M^þ,

329.0421 and 331.0346. C₁₇H₁₆⁷⁹BrNO requires M,

329.0415 and C₁₇H₁₆⁸¹BrNO requires M, 331.0395); and

secondly, a minor regioisomer (R_f0.3, 70:30 petroleum

ether–EtOAc) (8:1 mixture of atropisomers) as a brown oil

(15.0 mg, 0.05 mmol, 20%), n_max(CHCl₃)/cm²¹2954,

1643, 1595, 1491, 1455, 1396, 1333, 1298; d_H(500 MHz,

CDCl₃) 1.81–2.00 (3H majorþ3H minor, m, 4-H_Aand

4-H_Band 5-H_A), 2.31–2.37 (1H majorþ1H minor, m,

5-H_B), 2.66 (1H majorþ1H minor, ddd, J¼17.9, 8.1, 7.0 Hz,

3-H_A), 2.73 (1H majorþ1H minor, dt, J¼17.9, 6.3 Hz,

3-H_B), 4.99 (1H major, t, J¼5.2 Hz, 6-H), 5.02 (1H minor,

6-H), 7.10–7.18 (4H majorþ4H minor, m with d at 7.11,

J¼8.1 Hz, Ar-H), 7.23–7.32 (4H majorþ4H minor, m,

Ar-H), 7.43 (1H majorþ1H minor, d, J¼8.3 Hz, Ar-H); d_C

(125 MHz, CDCl₃) 17.6 (CH₂), 32.3 (CH₂), 32.6 (CH₂),

64.6 (CH), 121.4 (C), 126.9 (CH), 127.3 (2£CH), 128.7

(2£CH), 129.0 (2£CH), 131.7 (2£CH), 140.6 (C), 142.1

4.1.36. 1-(2-tert-Butyl-phenyl)-6-(2-methoxy-phenyl)-

piperidin-2-one 38 and 1-(2-tert-butyl-phenyl)-6-(4-

methoxy-phenyl)-piperidin-2-one 39. A solution of enam-

ide 24 (50.0 mg, 0.22 mmol) and TiCl₄(0.24 mL,

2.20 mmol) in anisole (15 mL) was heated at 50 8C for

12 h. After cooling, the reaction mixture was poured into

H₂O (20 mL) and extracted with CHCl₃(3£20 mL).

Combined extracts were washed with brine (20 mL), dried

(MgSO₄), treated with decolourising charcoal, and evapor-

ated under reduced pressure to give the crude product,

which was puriﬁed by ﬂash column chromatography (30–

90% EtOAc–petroleum ether) to give ﬁrstly the major

isomer 38 (R_f0.20, 1:1 petroleum ether–EtOAc) as a white

solid (50.0 mg, 0.15 mmol, 68%), mp 145–147 8C (recrys-

tallised from petroleum ether/CH₂Cl₂); n_max(CHCl₃)/cm²¹

2960, 1633, 1599, 1489, 1463, 1409, 1364, 1332, 1294,

1107, 1056; d_H(500 MHz, CDCl₃, 50 8C) 1.49 (9H, s,

C(CH₃)₃), 1.84 (1H, br m, 4-H_A), 1.96 (1H, br m, 5-H_A),

2.05 (1H, br m, 4-H_B), 2.40 (1H, dddd, J¼12.8, 12.4, 5.7,

3.9 Hz, 5-H_B), 2.59 (1H, ddd, J¼18.0, 10.2, 7.0 Hz, 3-H_A),

2.76 (1H, ddd, J¼18.0, 5.5, 3.5 Hz, 3-H_B), 3.70 (3H, br.s,

OMe), 5.29 (1H, br.s, 6-H), 6.76–6.89 (3H, m, Ar-H), 7.00

(1H, m, Ar-H), 7.11 (1H, dd, J¼7.6, 7.2 Hz, Ar-H), 7.25

(2H, m, Ar-H), 7.48 (1H, d, J¼8.0 Hz, Ar-H); d_C(125 MHz,

CDCl₃) 17.0 (CH₂), 28.2 (CH₂), 32.1 (CH₃), 32.7 (CH₂),

36.0 (C), 55.3 (CH₃), 58.6 (CH), 110.9 (CH), 119.7 (CH),

126.3 (CH), 127.6 (CH), 128.6 (CH), 128.9 (CH), 129.1

(CH), 131.5 (CHþC), 140.4 (C), 146.4 (C), 153.2 (C), 172.2

(CvO); m/z (FAB) (Found MH^þ, 338.2120 C₂₂H₂₈NO₂

requires M, 338.2120). Anal. Calcd for C₂₂H₂₇NO₂. C,

78.34; H, 8.01; N, 4.15%. Found: C, 78.00; H, 7.93; N,

4.07%; followed by the minor isomer 39 (R_f0.15, 1:1

petroleum ether–EtOAc) as an oil (15.0 mg, 0.04 mmol,

7%), n_max(CHCl₃)/cm²¹2958, 2838, 1729, 1633, 1612,

1510, 1487, 1463, 1406, 1364, 1295, 1167, 1136; d_H

(500 MHz, CDCl₃) 1.47 (9H, s, C(CH₃)₃), 1.82–1.88 (2H,

m, 5-H_Aand 4-H_A), 2.13–2.19 (1H, m, 4-H_B), 2.42–2.50

(1H, m, 5-H_B), 2.63 (1H, ddd, J¼17.9, 10.9, 6.9 Hz, 3-H_A),

2.81 (1H, br dd, J¼17.9, 5.0 Hz, 3-H_B), 3.80 (3H, s, OMe),

4.72 (1H, dd, J¼4.8, 3.4 Hz, 6-H), 6.63 (1H, d, J¼8.0 Hz,

Ar-H), 6.86–6.89 (3H, m, Ar-H), 7.12–7.15 (3H, m, Ar-H),

7.49 (1H, d, J¼8.1 Hz, Ar-H); d_C(125 MHz, CDCl₃) 16.8

(CH₂), 30.5 (CH₂), 32.1 (CH₃), 32.6 (CH₂), 35.9 (C), 55.3

(CH₃), 65.6 (CH), 113.7 (2£CH), 126.3 (CH), 127.7 (CH),

128.9 (2£CH), 129.1 (CH), 131.9 (CH), 133.3 (C), 140.0

(C), 146.2 (C), 159.1 (C), 171.5 (CvO); m/z (EI) (Found

M^þ, 337.2039 C₂₂H₂₇NO₂requires M, 337.2042).

(C), 170.7 (CvO); m/z (EI) (Found M^þ, 329.0410.

79

16

C₁₇H BrNO requires M, 329.0415).

The above reaction was also carried out using enantioen-

riched (73% ee) enamide 24 (50.0 mg, 0.22 mmol) to yield

the product 35c described above (20.0 mg, 0.06 mmol, 28%,

showing some erosion of ee (57% ee). The ee was

determined by HPLC analysis using a Chirapak AD-H

column [25 cm£0.46 cm i.d.; 5% i-PrOH in hexane; ﬂow

rate, 1.0 mL/min; (þ)-35c; t_R¼32.9 min, (2)-35c;

t_R¼29.5 min]; [a]²_D⁵¼þ21.1 (c 0.36, CHCl₃).

4.1.35. 6-(4-Iodo-phenyl)-1-phenyl-piperidin-2-one 35d.

A solution of enamide 24 (50.0 mg, 0.22 mmol) and AlCl₃

(294 mg, 2.20 mmol) in iodobenzene (15 mL) was heated at

50 8C for 12 h. After cooling, the reaction mixture was

poured into H₂O (15 mL) and extracted with CHCl₃

(3£20 mL). Combined extracts were washed with brine

(20 mL), dried (MgSO₄), and evaporated under reduced

pressure to give the crude product, which was puriﬁed by

ﬂash column chromatography (CH₂Cl₂, then 20–70%

EtOAc–petroleum ether) to give the title compound as a

pale brown solid (50.0 mg, 0.13 mmol, 60%), mp 115–

119 8C; n_max(CHCl₃)/cm²¹2954, 1640, 1596, 1494, 1456,

1405, 1344; d_H(500 MHz, CDCl₃) 1.83 (1H, m, 4-H_A), 1.93

(1H, m, 4-H_B), 2.09 (1H, m, 5-H_A), 2.35 (1H, dddd, J¼14.2,

9.9, 5.2, 3.7 Hz, 5-H_B), 2.67 (1H, ddd, J¼18.1, 8.3, 7.0 Hz,

3-H_A), 2.74 (1H, dt, J¼18.1, 6.0 Hz, 3-H_B), 5.01 (1H, t,

J¼5.1 Hz, 6-H), 7.12–7.14 (3H, m, Ar-H), 7.22–7.32 (6H,

m, Ar-H); d_C(125 MHz, CDCl₃) 17.6 (CH₂), 32.4 (CH₂),

32.7 (CH₂), 65.1 (CH), 126.8 (CH), 127.0 (2£CH), 127.3

(2£CH), 127.5 (C), 128.5 (2£CH), 128.9 (2£CH), 140.5

(C), 141.4 (C), 170.9 (CvO); m/z (EI) (Found M^þ,

377.0268. C₁₇H₁₆INO requires M, 377.0277).

4.2. X-ray crystallographic data

The structures of 10, 25, 26, 29g, 33 and 38 were determined

by single-crystal X-ray diffraction studies. Crystal data and

other details are given in Table 2. Data were collected on a

Bruker SMART CCD area detector diffractometer in all

cases except that of 10, for which a Stoe Stadi-4

diffractometer was used, using Mo K_aX-radiation (l¼

˚

0.71073 A). In all cases the diffractometers were equipped

with an Oxford Cryosystem open-ﬂow nitrogen cryostat and

data were collected at 150 K. The structures were solved by

direct methods (SHELXS-97) and reﬁned using full matrix

least squares reﬁnement against F², all non-H atoms were

reﬁned with anisotropic atomic displacement parameters

(adps) and H atoms placed in geometrically calculated

4510

D. J. Bennett et al. / Tetrahedron 60 (2004) 4491–4511

Table 2. Crystallographic data and structure reﬁnement details

Compound

Chemical formula

Mr

10

C₂₄H₃₇NO₂

371.55

25

C₁₈H₂₅NO₂

287.39

26

C₁₈H₂₅NO₂

287.39

29g

C₂₁H₂₃NOS

337.46

33

C₁₆H₂₁NO₂

259.34

38

C₂₂H₂₇NO₂

337.45

Crystal system

Space group

Monoclinic

P2₁

10.787 (3)

7.747 (3)

13.402 (5)

Orthorhombic

P2(1)2(1)2(1)

9.226 (2)

11.873 (3)

14.639 (4)

Triclinic

P-1

Monoclinic

P2₁/c

11.9803 (10)

11.8217 (10)

13.1329 (11

Orthorhombic

P2₁2₁2₁

8.510 (3)

9.914 (3)

16.963 (5)

Triclinic

P-1

˚

a (A)

10.1547 (8)

11.8289 (9)

14.3724(11)

83.764 (2)

77.925 (2)

81.422 (2)

1664.0 (2)

4

8.2002 (8)

9.8021(10)

11.9046(12)

103.989 (2)

92.632 (2)

100.153 (2)

910.0 (3)

2

˚

b (A)

˚

c (A)

a (8)

b (8)

g (8)

98.34 (3)

106.460 (2)

3

˚

V (A )

1108.1 (7)

2

150

1603.6 (12)

4

150

1783.8 (4)

4

150

1431.1 (8)

4

150

Z

T (K)

150

Crystal form, colour

Crystal size (mm)

No. of measured reﬂections 2429

Block, colourless Column, colourless Block, colourless Tablet, colourless Column, colourless Column, colourless

0.41£0.27£0.19

0.28£0.09£0.09

0.50£0.41£0.33

0.54£0.49£0.21

0.40£0.12£0.12

0.43£0.25£0.16

9977

1627, 1154

19321

7432, 5943

15736

4097, 3631

6762

1478, 843

7994

4091, 3420

Unique, obsd (I.2s(I))

reﬂections

R_int

2110, 1722

0.023

0.040

0.022

0.029

0.121

0.030

R[F ².2s(F ²)], wR(F ²), S 0.048, 0.104, 1.18 0.079, 0.212, 1.06 0.041, 0.118, 1.07 0.038, 0.108, 1.06 0.056, 0.146, 0.95 0.042, 0.124, 1.07

No. of parameters

˚

Dr_max, Dr_min(eA

245

0.18, 20.22

190

0.53, 20.53

381

0.31, 20.18

217

0.42, 20.19

177

0.16, 20.22

226

0.30, 20.18

23

)

6. Kishikawa, K.; Tsuru, I.; Kohmoto, S.; Yamamoto, M.;

Yamada, K. Chem. Lett. 1994, 1605.

positions and reﬁned as part of a riding model, unless

otherwise stated. The hydroxyl H-atom in 26 was located

from a difference Fourier map and reﬁned as a rigid rotor, as

were the methyl H-atoms in 33. There was also disorder

present in the t-butyl group of 33, which was modeled over 2

half occupied sites with isotropic adps.

7. (a) Hughes, A. D.; Simpkins, N. S. Synlett 1998, 967.

(b) Kitagawa, O.; Izawa, H.; Taguchi, T. Tetrahedron Lett.

1997, 38, 4447. (c) Kitagawa, O.; Izawa, H.; Sato, K.;

Dobashi, A.; Taguchi, T. J. Org. Chem. 1998, 63, 2634.

(d) Kitagawa, O.; Momose, S.; Fushimi, Y.; Taguchi, T.

Tetrahedron Lett. 1999, 40, 8827. (e) Fujita, M.; Kitagawa,

O.; Yamada, Y.; Izawa, H.; Hasegawa, H.; Taguchi, T.

J. Org. Chem. 2000, 65, 1108.

Crystallographic data (excluding structure factors) for the

structures in this paper have been deposited with the

Cambridge Crystallographic Data Centre as supplementary

publication numbers CCDC 221091–221096. Copies of the

data can be obtained free of charge, on application to

CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK [fax:

þ44(0)-1223-336033 or e-mail: deposit@ccdc.cam.ac.uk].

8. (a) Kitagawa, O.; Kohriyama, M.; Taguchi, T. J. Org. Chem.

2002, 67, 8682. (b) Terauchi, J.; Curran, D. P. Tetrahedron:

Asymmetry 2003, 14, 587.

9. Ates, A.; Curran, D. P. J. Am. Chem. Soc. 2001, 123, 5130.

10. Rios, R.; Jimeno, C.; Carroll, P. J.; Walsh, P. J. J. Am. Chem.

Soc. 2002, 124, 10272.

Acknowledgements

11. Godfrey, C. R. A.; Simpkins, N. S.; Walker, M. D. Synlett

2000, 388.

We thank the University of Nottingham, Syngenta Agro-

chemicals, and Organon Laboratories for studentship

support for P. L. P. and M. D. W.

12. Ukaji, Y.; Tsukamato, K.; Nasada, Y.; Shimizu, M.; Fujisawa,

T. Chem. Lett. 1993, 221.

13. MM2 force ﬁeld calculations using Macromodel gives values

for the energy barrier to racemisation as 85 kJ mol²¹for 5

(LG¼H) and 88 kJ mol²¹for 6. These ﬁgures translate to

non-viable conﬁgurational stability for synthesis at room

temperature (t_1/2of ca. 1000 s), but considerable stability at

lower temperature (t_1/2of ca. 6 months at 240 (C).

14. Fujita, M.; Kitagawa, O.; Yamada, Y.; Izawa, H.; Hasegawa,

H.; Taguchi, T. J. Org. Chem. 2000, 65, 5076.

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Article Doi

Stereoselectivity in reactions of atropisomeric lactams and imides

DOI: 10.1016/j.tet.2004.01.100

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