Palladium catalyzed cyclization reactions of acetylenic lactams

Journal of Organometallic Chemistry 624 (2001) 244–258

www.elsevier.nl/locate/jorganchem

Willem F.J. Karstens ^a,1, Marianne Stol ^a, Floris P.J.T. Rutjes ^a,2, Huub Kooijman ^b,

Anthony L. Spek ^b,3, Henk Hiemstra ^a,*

^aInstitute of Molecular Chemistry, Uni6ersity of Amsterdam, Nieuwe Achtergracht 129, 1018 WS Amsterdam, The Netherlands

^bBij6oet Center for Biomolecular Research, Crystal and Structural Chemistry, Utrecht Uni6ersity, Padualaan 8,

3584 CH Utrecht, The Netherlands

Received 18 October 2000; accepted 6 December 2000

Dedicated to Professor Jean F. Normant on the occasion of his 65th birthday

Abstract

Lactams and oxazolidinones containing a 3-butynyl side chain at the four- and the three-position, respectively, have been

prepared by reductive alkylation of cyclic imides or by S_N2%-substitution of bromopropadiene with highly functionalized

enantiopure organozinc reagents. Treatment of these compounds with aryl halides and one vinyl bromide using Pd(PPh₃)₄as a

catalyst gives rise to a coupling-cyclization reaction, yielding bicyclic enamides in which the aryl or vinyl moiety is incorporated.

Remarkably, these groups are transferred stereoselectively cis with respect to the nitrogen nucleophile onto the triple bond.

Structural proof for this unusual stereochemical outcome has been obtained by crystal structure analysis and NOE-difference

Keywords: Palladium; Cyclization reactions; Acetylenic lactams

1. Introduction

oratory to enamide 2, when treated with iodobenzene,

Pd(PPh₃)₄, K₂CO₃and tetrabutylammonium chloride in

acetonitrile [6]. The organic part of the halide (e.g. the

phenyl group of iodobenzene) was transferred

stereospeciﬁcally trans with respect to the nucleophile.

This stereochemical outcome is generally encountered

in these types of reactions and probably stems from a

reductive elimination of an intermediate vinylpalladium

complex (e.g. 3), which is formed after anti attack of

the nucleophile onto the palladium-activated triple

bond [4,5].

The construction of N-heterocycles is an important

goal in organic synthesis due to the abundance of these

compounds in natural and pharmaceutical products [1].

Well-established methods for the preparation of such

compounds are heteroannulation processes involving

unsaturated functionality and Pd-catalysis [2,3]. In our

group, we recently focused on processes involving

cross-coupling reactions and cyclizations in a single

synthetic operation by treating alkynes that are tethered

to a heteroatom nucleophile with vinyl or aryl halides

and a palladium catalyst [4,5]. For example, (R)-

propargylglycine derivative 1 was converted in our lab-

* Corresponding author. Fax: +31-20-525-5670.

E-mail address: henkh@org.chem.uva.nl (H. Hiemstra).

¹Present address: Department of Medicinal Chemistry, N.V.

Organon, Oss, The Netherlands.

²Present address: Department of Organic Chemistry, University of

Nijmegen, The Netherlands.

³Corresponding address pertaining to crystallographic studies to

this author.

PII: S0022-328X(00)00935-9

W.F.J. Karstens et al. / Journal of Organometallic Chemistry 624 (2001) 244–258

245

Scheme 1. Reagents and conditions: (a) MeMgBr (1 equiv), THF, 0°C to rt, 1 h; (b) RC+CCH₂CH₂MgBr (2 equiv), THF, 0°C to rt, 1 h; (c)

NaBH₃CN, THF/HOAc, pH 3, rt, 1 h; (d) TBAF, THF, 0°C, 30 min.

In conjunction with this work, we now present palla-

dium-catalyzed cyclizations of acetylenic lactams 4 in

which the alkyne is also separated from the nucleophile

by a three carbon tether (cf. 1). We were particularly

interested in compounds containing a cyclic lactam

nucleophile, because we observed recently that the na-

ture of the nucleophile determines strongly the regio-

chemical outcome in related allene cyclizations. For

example, we showed that linear allenic amino acid

derivatives (5) can be converted selectively to azetidines

(6) and tetrahydropyridines (7) when treated with

iodobenzene in the presence of a palladium catalyst [7],

whereas cyclic allenic lactams (8) underwent a highly

unusual and unprecedented reaction in which the nitro-

gen atom attacked the central carbon atom of the allene

to give bicyclic enamides (9) [8,9]⁴.

2. Preparation of the starting materials

In order to obtain the desired cyclization precursors,

we decided to use a one pot reductive alkylation of

cyclic imides [10]. The method involves addition of the

Grignard reagent of the desired side chain to one of the

imide carbonyls, followed by reduction of the resulting

hydroxylactam to the lactam. The advantages of this

pathway are that readily available starting materials

can be used and that the use of protective groups is

avoided.

Thus, deprotonation of succinimide with methylmag-

nesium bromide (one equivalent) led to the magnesium

salt 10. This intermediate was allowed to react with the

Grignard reagent derived from 4-bromo-1-trimethylsi-

lylbut-1-yne (two equivalents), leading to addition

product 11 (Scheme 1). At this point sodium

cyanoborohydride was added and the mixture was aci-

diﬁed to pH 3 with acetic acid, resulting in the solvoly-

sis of the bis-magnesium salt to the corresponding

hydroxylactam 12. In the acidic medium, this N,O-ace-

tal was converted easily into the N-acyliminium ion 13,

which was reduced by the hydride donor to give pyrro-

lidinone 14b in a yield of 62%. Deprotection of the

Me₃Si–acetylene with TBAF in THF, afforded the

terminal acetylene 14a (98%), whereas methyl substi-

tuted acetylene 14c was obtained in 58% yield using the

same procedure with the Grignard reagent derived from

1-bromo-3-pentyne.

Subjection of bicyclic imide 15 to this process led to

the introduction of the side chain in a cis fashion with

respect to the cyclohexyl moiety, thus affording

acetylenic lactam 17b in a yield of 63%. The stereo-

chemical outcome of this process can be explained by

the steric crowding at the top face of N-acyliminium

ion 16. The hydride donor approaches 16 from the

convex side of the sterically demanding cyclohexyl moi-

ety, resulting in the observed cis stereochemistry. As

before, desilylation using TBAF afforded the terminal

acetylene 17a in almost quantitative yield (Scheme 2).

⁴This difference between cyclic and acyclic nucleophiles was also

found in the case of palladium catalyzed 1,2-oxidations of allenes.

246

W.F.J. Karstens et al. / Journal of Organometallic Chemistry 624 (2001) 244–258

Scheme 2.

Scheme 3.

The trans substituted bicyclic lactams could be pre-

simply changing the order of steps, the stereochemical

outcome of the reaction can be changed (Scheme 3).

Acetylenes can also be prepared by an S_N2% reaction

of organocopper reagents with allenyl halides [12]. By

analogy, it was envizaged that reaction of bromoallene

[13] with the previously used organozinc reagents 21

[8b,14] and 22 [8,15], after transmetallation to copper,

would provide enantiopure acetylenic lactams and oxa-

zolidinones. Indeed, preparation of the organozinc

reagents from the corresponding iodides followed by

treatment with a catalytic amount of CuBr·SMe₂(0.05

equivalents) and bromoallene (1.1 equivalents) in DMF

pared following an elimination-addition protocol, start-

ing from the same imide as for the preparation of the

cis isomers. Reduction of the imide with NaBH₄and

immediate ethanolysis afforded the ethoxylactam 18

[11], which on treatment with 4-trimethylsilylbut-3-

ynylmagnesium bromide (2.5 equivalents) generated the

imine 19 by elimination of ethanol. This reactive inter-

mediate was attacked from the least hindered side by a

second equivalent of the Grignard reagent, introducing

the acetylenic side chain opposite to the cyclohexyl

moiety to give the trans acetylenic lactam 20b. Thus, by

Table 1

W.F.J. Karstens et al. / Journal of Organometallic Chemistry 624 (2001) 244–258

247

Table 2

afforded the acetylenic lactam 23 in a good yield of

52% (X=CH₂). On the other hand, using the oxazo-

lidinone derived organozinc reagent 24 (X=O) in THF

afforded the desired acetylene 36 in only 29% yield.

of cyclized product to coupling product decreased to 1:

1 (entry 2).

The use of DMF as a solvent was not advantageous

either (entries 3 and 4); the yield was lower, and the

formation of 26 appeared the major reaction pathway

(entry 3). In THF, the reaction was sluggish, the start-

ing material being completely consumed after 20 h,

while the yield of 20% was quite disappointing (entry

5). A detrimental effect on the yield was also observed

if the source of palladium was changed, along with the

palladium to phosphine ratio (entries 6 and 7).

Being unable to suppress the formation of coupling

product 26, it was decided to use the Me₃Si-protected

acetylenes in the cyclization reaction. Indeed, using the

conditions of entry 1 in Table 1, the Me₃Si-substituted

acetylene 14b afforded bicyclic enamide 27 cleanly with

a yield of 64%, while the Sonogashira pathway was

blocked efﬁciently⁶(Table 2, entry 1).

Having established a satisfactory cyclization proto-

col, the Me₃Si-protected acetylenic lactam 14b was al-

lowed to react under the same conditions with several

aromatic and vinylic halides, as depicted in Table 2.

When the phenyl ring was substituted with an electron-

withdrawing nitro group, a smooth cyclization occurred

to give 74% of 28, whereas the use of the electron rich

para-iodoanisole had a detrimental effect. A complex

mixture of products was obtained and although the

3. Cyclization reactions

With the precursors in hand, several reaction condi-

tions to effect cyclization were compared in terms of

yield and reaction time. First, identical conditions were

applied as for the cyclizations of the isomeric allenic

lactams [8]. Treatment of 14a with Pd(PPh₃)₄, iodoben-

zene, tetrabutylammonium chloride (TBAC) and

K₂CO₃in acetonitrile, afforded bicyclic enamide 25 in

40% yield, along with 16% of the non-cyclized ‘Sono-

gashira type’ coupling product 26 (entry 1, Table 1).

Remarkably, the phenyl group was incorporated in a

cis fashion with respect to the nitrogen nucleophile,

which contrasts with the usually observed stereochemi-

cal outcome of these types of cyclization reactions.

Unfortunately, we were not able to improve the yield

of the cyclic product, by varying solvent, palladium

source or omitting the tetrabutylammonium chloride.

Without this chloride source being present in acetoni-

trile, the yield dropped dramatically⁵[16] and the ratio

⁵This beneﬁcial effect of the use of quaternary ammonium chlo-

rides was observed previously for the coupling/cyclization of

acetylenic carboxylic acids (see Ref. [4c]) and acetylenic tosyl carba-

mates (Refs. [5a,b])

⁶The TBAC should be dried before use in order to prevent

desilylation under the reaction conditions.

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W.F.J. Karstens et al. / Journal of Organometallic Chemistry 624 (2001) 244–258

Table 3

Cyclizations of several acetylenic lactams with iodobenzene

2-Bromopropene, an example of a vinyl halide, af-

forded the cyclic product 32 in a good yield of 69%.

Remarkably, the use of vinyl triﬂates did not lead to

the formation of the desired bicyclic compounds.

The results of the cyclization reactions of several

acetylenic lactams with iodobenzene are summarized in

Table 3. The methyl-substituted acetylene 14c effec-

tively cyclized to the (Z)-substituted enamide 33 (entry

1), although the reaction was sluggish and needed to be

stirred at reﬂux temperature for 18 h. Mixtures of

double bond isomers were obtained when bicyclic lac-

tams 17a and 17b were subjected to the cyclization

conditions (entries 2 and 3).

Fig. 1. NOE-enhancements of compounds 25, 37 and 39.

cyclization product 29 was detectable on NMR (B

10%) it was not isolated. Heteroaromatic halides could

be successfully applied in the cyclization reaction as

illustrated by the use of 2-bromothiophene (entry 4)

and 2-chloro-5-iodopyridine[17] (entry 5). Although the

yield was relatively low (34%) in the latter case, 50% of

14b could be recovered, correcting the yield to 68%.

Unprotected acetylene 17a afforded the tricyclic (Z)-

enamide 34 as a major product (37%), accompanied by

5% of the (E)-isomer 35. The non-cyclized coupling

W.F.J. Karstens et al. / Journal of Organometallic Chemistry 624 (2001) 244–258

249

the Me₃Si-protected analogue 20b a small amount of

desilylated product 39 was also formed.

The enantiopure alkyne 23 reacted in the same way

as the racemate (cf. entry 1, Table 1), giving the bicyclic

enamide 42 in 40% yield, with concomitant formation

of non cyclized coupling product 43 (entry 6). The

enantiopure oxazolidinone 24 gave rise to the forma-

tion of 44 in 60% yield, but the Sonogashira type

product was not formed in this reaction (entry 7).

Moreover, oxazolidinone 45 — prepared from 5-

methoxy-2-oxazolidone and 4-trimethylsilylbut-3-ynyl-

magnesium bromide — afforded bicyclic product 46,

illustrating that acetylenic oxazolidinones behave simi-

larly under these cyclization conditions (entry 8).

Fig. 2. Crystal structure of compound 41.

product 36 was obtained in a considerable yield of 29%.

Me₃Si-protection of the acetylene (17b) blocked the

Sonogashira reaction and a similar mixture of double

bond isomers 37 and 38 was obtained, but due to the

required long reaction time desilylation occurred to

some extent, leading to products 34 and 35.

If the cyclohexyl group and the acetylenic tether are

trans with respect to each other, the stereoselectivity is

restored: the phenyl group was introduced exclusively

cis with respect to the nitrogen at the double bond

when the trans substituted bicyclic lactams 20a and 20b

were subjected to the cyclization conditions to give 39

and 41, respectively. However, the unprotected alkyne

20a gave rise to the formation of a considerable amount

of the uncyclized byproduct 40, whereas in the case of

4. Structural proof

Proof for the highly unusual stereochemistry of the

enamide double bond for this type of reactions was

obtained by NOE-difference spectroscopy. A NOE-en-

hancement of the signals of the allylic protons (2.6 and

3.6%) was observed upon irradiation of the vinylic

proton of enamide 25 which clearly established the

(Z)-conﬁguration of the double bond. The signal of the

aromatic protons in the ortho-position showed a NOE-

enhancement of 10.1%. Similar proof was obtained in

the case of the tricyclic enamides 37 and 39. Irradiation

of the signal of the Me₃Si-protons of 37 caused a small

Scheme 4.

Scheme 5.

250

W.F.J. Karstens et al. / Journal of Organometallic Chemistry 624 (2001) 244–258

but reproducible NOE-enhancement (0.4%) of the sig-

nal of the allylic protons. A stronger effect was ob-

served in the case of 39 as illustrated in Fig. 1. The

double bond geometry of all other compounds was not

This leaves several possibilities for the order of steps.

However, it is most likely that p-complex 47 is formed

at the start of the catalytic cycle (Scheme 5). This

p-complex has two possible modes of reaction. One

might consider a carbopalladation reaction (A), which

results in the formation the cis adduct 50. With the

stereochemistry ﬁxed at the double bond, the nitrogen

nucleophile can coordinate to the palladium giving the

six-membered ring chelate 51, which after reductive

elimination affords the observed product 27. Although

a reductive elimination of vinylpalladium amide com-

plexes is not precedented in literature, the correspond-

ing process of arylpalladium amide complexes has

recently been described [19].

1

explicitly proven, but assigned via comparison of H-

and ¹³C-NMR data.

The most convincing evidence for the double bond

geometry, however, was obtained by an X-ray crystal

structure determination of the tricyclic product 41⁷. It

unambiguously proved the cis orientation of the phenyl

group with respect to the lactam nitrogen (Fig. 2).

5. Mechanistic considerations

Secondly, 47 might undergo an intramolecular ligand

exchange reaction to give chelate 52 (B). This interme-

diate has also two plausible modes of reaction; a carbo-

palladation (C) would afford the already discussed

six-membered palladacycle 51, but is also possible that

the nitrogen ligand migrates instead of the phenyl

group (D) [20]⁸. This would lead to the bisorganopalla-

dium intermediate 53. This process seems feasible as the

lactam carbonyl might assist this migration by stabiliz-

ing the proposed intermediate 53. Reductive elimina-

tion yields the observed product and the palladium(0)

catalyst.

Although it is difﬁcult to differentiate between path

A or B, path B seems the most likely route. This is

based on the results obtained with cyclization precur-

sors 17a and 17b, which are the only examples in which

a mixture of double bond isomers was obtained. After

the initial formation of p-complex 54 (Scheme 6), path

A should not be affected by steric crowding at the

lactam because the acetylenic side chain can rotate

away from the steric bulk to give 55. Therefore, if path

A would be the reaction pathway, 17a and 17b should

lead to the exclusive cis introduction of the phenyl

Because the isolated products have the opposite dou-

ble bond geometry of what is normally observed, the

mechanistic details have to be different than in the case

of acyclic nucleophiles. The mechanism for the ‘normal’

mode of cyclization as is most frequently found in

literature [4,5], predicts the wrong stereochemistry

(Scheme 4). Oxidative addition of palladium(0) in the

phenyl iodide bond affords a phenylpalladium(II) inter-

mediate which can coordinate to the triple bond to give

p-complex 47. The acetylene is now sufﬁciently acti-

vated by the metal to undergo nucleophilic attack by

the tethered nitrogen. The attack of the nucleophile

should occur trans leading to bisorganopalladium inter-

mediate 48. Reductive elimination of palladium(0) re-

generates the catalyst and affords product 49.

In the present case however, the nucleophile was

attached to the same side of the triple bond as the

phenyl group, implying that the nitrogen–carbon bond

formation takes place within the coordination sphere of

the palladium. In other words, there has to be an

intermediate in the reaction mechanism in which the

palladium is coordinated to the amide before the nitro-

gen–carbon bond is formed [18].

Scheme 6.

Scheme 7.

⁸Similar insertions of acetylenes into palladium-halide bonds in-

stead of palladium–nitrogen bonds have been reported.

⁷See Section 8.

W.F.J. Karstens et al. / Journal of Organometallic Chemistry 624 (2001) 244–258

251

group and the nitrogen nucleophile, which was not the

case. On the other hand, path B would lead to 56, with

the palladium in close proximity of the cyclohexyl

group. Due to the shape of this chelate the palladium

and the coordinated ligands are expected to experience

a considerable steric repulsion by the proximal bulk,

destabilizing this intermediate. This opens the way for a

competitive reaction pathway such as direct nucle-

ophilic attack of the amide onto the triple bond of 54

(cf 4748, Scheme 4), leading to the formation of

trans-enamides.

In case of the terminal acetylenes there is an addi-

tional possibility. In principle, the isolated byproduct

26 in the cyclization of 14a to 25 can be an intermediate

in the reaction mechanism, since it is known that

acetylenic amides can be cyclized under the inﬂuence of

base to give (Z)-enamides [21]. In order to investigate

this possibility, 26 was prepared separately according to

a modiﬁed Sonogashira procedure [22] from 14a and

subjected to our standard cyclization conditions

(Scheme 7). In this case 25 was not formed, but the

only isolated product was the tetrasubstituted enamide

57, indicating that 26 is not an intermediate in the

formation of 25.

Perkin–Elmer 298 spectrophotometer or a Bruker IFS

28 FT-spectrophotometer and wavelengths (w) are re-

ported in cm⁻¹. Proton nuclear magnetic resonance

(¹H-NMR) spectra were determined in CDCl₃using a

Bruker AC 200 (200 MHz), a Bruker ARX 400 (400

MHz) or a Varian Inova (500 MHz) spectrometer. The

latter machines were also used for ¹³C-NMR (APT)

spectra (100 MHz and 125 MHz, respectively) in

CDCl₃. Chemical shifts (l) are given in ppm downﬁeld

from tetramethylsilane. Mass spectra and accurate mass

measurements were carried out using a JEOL JMS-SX/

SX 102 A Tandem Mass Spectrometer, a Varian NIAT

711 or a VG Micromass ZAB-HFQQ instrument. Ele-

mental analyses were performed by Dornis u. Kolbe

Mikroanalytisches Laboratorium, Mu¨lheim an der

Ruhr, Germany. Optical rotations were measured with

a Perkin–Elmer 241 polarimeter in a 1-dm cell in the

indicated solvent. R_fvalues were obtained by using thin

layer chromatography (TLC) on silica gel-coated plastic

sheets (Merck silica gel 60 F₂₅₄) with the indicated

solvent (mixture). Flash column chromatography was

performed with Merck silica gel 60 (230–400 mesh).

Melting and boiling points are uncorrected. Dry THF

and Et₂O were distilled from sodium benzophenone

ketyl prior to use. Dry DMF, CH₂Cl₂, and MeCN were

Despite the fact that the exact details of the mecha-

nism remain unclear, the products can be explained by

the mechanism presented in Scheme 5, most likely via

path B.

,

distilled from CaH₂and stored over MS 4 A under a

dry nitrogen atmosphere. All commercially available

reagents were used as received, unless indicated

otherwise.

6. Conclusions

7.1. 5-(But-3-ynyl)pyrrolidin-2-one (14a)

The preparation of v-homopropargyl substituted lac-

tams was described by means of an efﬁcient one-pot

reductive alkylation procedure of unprotected imides.

In the case of bicyclic imides, this process occurred

stereoselectively to give exclusively the cis-addition

products. If the order of steps was reversed (i.e. reduc-

tion before alkylation) the trans isomers were obtained

selectively. Enantiopure acetylenic lactams and oxazo-

lidinones could be prepared using highly functionalized

organozinc reagents that were also used for the prepa-

ration of the isomeric allenes [8b]. The palladium cata-

lyzed cyclizations of these acetylenic lactams with a

variety of organic halides proceeded in generally good

yield. Due to coordination of the lactam nitrogen to the

palladium, the organic part of the halide and the nitro-

gen nucleophile were introduced cis with respect to each

other.

A solution of 14b (208 mg, 1.0 mmol) in THF (2 ml)

was cooled to 0°C and a 1.0 M solution (THF) of

TBAF was added (1.2 ml, 1.2 mmol). The reaction

mixture was stirred at 0°C for 30 min followed by

concentration in vacuo. The residue was dissolved in

EtOAc (25 ml) and washed with water (3×15 ml) and

brine (15 ml). Drying (Na₂SO₄), concentration and

ﬂash chromatography (5% MeOH in EtOAc) gave 14a

(134 mg, 0.98 mmol, 98%) as a white solid; R_f0.2

(EtOAc); m.p. 94–95°C (EtOAc/PE); IR (CHCl₃) 3431,

1

3016, 1687, 1421; H-NMR (400 MHz, CDCl₃) l 6.50

(br s, 1H), 3.83–3.76 (m, 1H), 2.38–2.34 (m, 5H), 2.00

(t, J=2.7 Hz, 1H), 1.80–1.67 (m, 3H); ¹³C-NMR (100

MHz, CDCl₃) l 178.5, 83.0, 69.2, 53.6, 34.9, 30.0, 26.9,

15.2; Anal. Calc. for C₈H₁₁NO: C, 70.04; H, 8.08; N,

10.21. Found: C, 69.45; H, 8.00; N, 10.08%.

7.2. 5-(4-(Trimethylsilyl)but-3-ynyl)pyrrolidin-2-one

(14b)

7. Experimental

A solution of succinimide (2.97 g, 30 mmol) in THF

(100 ml) was cooled to 0°C, and MeMgBr (10.0 ml, 3.0

M in THF, 30 mmol) was added dropwise. After the

mixture was stirred at room temperature (r.t.) for 1 h,

All reactions were carried out under an inert atmo-

sphere of dry nitrogen. Infrared (IR) spectra were ob-

tained from CHCl₃solutions or neat, using

a

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W.F.J. Karstens et al. / Journal of Organometallic Chemistry 624 (2001) 244–258

it was recooled to 0°C and a solution of the Grignard

reagent prepared from 1-bromo-4-trimethylsilyl-3-bu-

tyne (60 ml, 1 M in THF, 60 mmol) was slowly added.

The suspension was stirred at r.t. and after TLC

(EtOAc) indicated full conversion of starting material,

NaBH₃CN (1.89 g, 30 mmol) and a few drops of

methylorange were added. The mixture was acidiﬁed

with acetic acid until the indicator turned from yellow

to pink and stirred for another 45 min. Neutralization

(5% aq. NaOH) and removal of the solvents in vacuo,

gave a solid residue that was dissolved into a saturated

aqueous solution of NaHCO₃(200 ml) and extracted

with EtOAc (3×150 ml). Washing of the combined

extracts with water (150 ml) and brine (150 ml), fol-

lowed by drying (Na₂SO₄) and concentration in vacuo

gave the crude product, which after silicagel column

chromatography gave 14b (3.89 g, 18.9 mmol, 62%) as

a white solid; R_f0.4 (EtOAc/Acetone 1:1); m.p. 96–

97°C (EtOAc/PE); IR (CHCl₃) 3428, 2962, 2173, 1690;

¹H-NMR (400 MHz, CDCl₃) l 5.89 (br s, 1H), 3.82–

3.72 (m, 1H), 2.75–2.25 (m, 5H), 1.80–1.68 (m, 3H),

0.16 (s, 9H); ¹³C-NMR (100 MHz, CDCl₃) l 178.2,

105.6, 85.9, 53.9, 35.1, 30.0, 27.1, 16.8, 0.0; Anal. Calc.

for C₁₁H₁₉NOSi: C, 63.11; H, 9.15; N, 6.69. Found: C,

62.73; H, 8.99; N, 6.62%.

J=2.7 Hz, 1H), 1.72–1.67 (m, 3H), 1.60–1.52 (br m,

2H), 1.46–1.37 (m, 1H), 1.26–1.03 (m, 3H); ¹³C-NMR

(100 MHz, CDCl₃) l 178.7, 83.2, 69.3, 55.7, 42.7, 38.6,

28.0, 23.8, 22.8, 22.5, 22.4, 15.9; Anal. Calc. for

C₁₂H₁₇NO: C, 75.35; H, 8.96; N, 7.32. Found: C, 75.20;

H, 8.94; N, 7.21%.

7.5. (3R*,3aR*,7aS*)-3-(4-(Trimethylsilyl)but-3-

ynyl)octahydroisoindol-1-one (17b)

Using the same procedure as for the preparation of

13b, hexahydro-isoindole-1,3-dione (21) (2.08 g, 13.7

mmol) was deprotonated with MeMgBr and subse-

quently reacted with the Grignard reagent derived from

1-bromopent-3-yne (20 ml, 1 M in THF, 20 mmol).

Reduction with NaBH₃CN (860 mg, 13.7 mmol) at pH

3 (AcOH) and work up gave after chromatography 17b

(2.26 g, 8.6 mmol, 63%) as a white solid; R_f0.3

(EtOAc/PE 1:1); m.p. 128–129°C (PE); IR (CHCl₃)

3431, 3004, 2937, 2860, 2172, 1692; ¹H-NMR (400

MHz, CDCl₃) l 6.57 (br s, 1H), 3.61 (br q, J=6.2 Hz,

1H), 2.48 (br t, J=5.8 Hz, 1H), 2.34–2.23 (m, 3H),

2.15 (br d, J=13.8 Hz, 1H), 1.70–1.65 (m, 3H), 1.60–

1.52 (br m, 2H), 1.44–1.35 (m, 1H), 1.20–1.01 (m, 3H),

0.12 (s, 9H); ¹³C-NMR (100 MHz, CDCl₃) l 178.4,

105.8, 85.7, 56.0, 42.7, 38.7, 28.0, 23.8, 22.8, 22.5, 22.4,

17.4, –0.1; Anal. Calc. for C₁₅H₂₅NOSi: C, 68.38; H,

9.56; N, 5.32. Found: C, 68.27; H, 9.43; N, 5.21%.

7.3. 5-(Pent-3-ynyl)pyrrolidin-2-one (14c)

Using the same procedure as for the preparation of

14b, succinimide (991 mg, 10 mmol) was deprotonated

with EtMgBr (10 ml, 1.0 M in THF, 10 mmol) and

subsequently reacted with the Grignard reagent derived

from 1-bromopent-3-yne (20 ml, 1 M in THF, 20

mmol). Reduction with NaBH₃CN (628 mg, 10 mmol)

at pH 3 (AcOH) and workup gave after chromatogra-

phy 14c (874 mg, 5.78 mmol, 58%) as a colorless solid;

R_f0.4 (EtOAc/acetone=1/1); m.p. 84–85°C; IR (neat)

7.6. (3S*,3aR*,7aS*)-3-(But-3-ynyl)octahydroisoindol-

1-one (20a)

The Me₄Si-protected acetylene 20b (920 mg, 3.5

mmol) was treated with TBAF, following the same

procedure as described for the preparation of 14a, to

give after work up and chromatography 20a (659 mg,

3.4 mmol, 98%) as a white solid; R_f0.2 (EtOAc/PE 3:1);

m.p. 120–121°C (EtOAc/PE); IR (CHCl₃) 3433, 3006,

1

3230, 2920, 1684; H-NMR (400 MHz, CDCl₃) l 7.46

1

(br s, 1H), 3.68–3.63 (m, 1H), 2.22–2.06 (m, 5H), 1.63

(t, J=2.5 Hz, 3H), 1.61–1.48 (m, 3H); ¹³C-NMR (100

MHz, CDCl₃) l 178.7, 77.5, 76.2, 53.7, 35.4, 30.0, 26.8,

15.4, 3.17; HRMS (EI) Calc. for C₉H₁₃NO₂151.0997.

Found 151.0989.

2936, 2858, 1691; H-NMR (400 MHz, CDCl₃) l 7.26

(br s, 1H), 3.30–3.26 (m, 1H), 2.51 (q, J=6.2 Hz, 1H),

2.37–2.26 (m, 2H), 2.10–2.04 (m, 1H), 1.97 (t, J=2.6

Hz, 1H) 1.89–1.82 (m, 1H), 1.76–1.16 (m, 9H); ¹³C-

NMR (100 MHz, CDCl₃) l 179.1, 83.0, 69.3, 57.0, 39.7,

39.4, 32.2, 27.4, 23.3, 23.3, 23.0, 15.8; Anal. Calc. for

C₁₂H₁₇NO: C, 75.35; H, 8.96; N, 7.32. Found: C, 74.91;

H, 8.94; N, 7.09%.

7.4. (3R*,3aR*,7aS*)-3-(But-3-ynyl)octahydroiso-

indol-1-one (17a)

Using the same procedure as for the preparation of

14a, 17b (659 mg, 2.5 mmol) was deprotected with

TBAF, to give after chromatography (EtOAc/PE 4:1)

the terminal acetylene 17a (467 mg, 2.44 mmol, 97%) as

a white solid; R_f0.2 (EtOAc/PE 2:1); m.p. 163–165°C

7.7. (3S*,3aR*,7aS*)-3-(4-(Trimethylsilyl)but-3-ynyl)-

octahydroisoindol-1-one (20b)

To a solution of 3-ethoxy-octahydro-isoindol-1-one

(18) (1.83 g, 10 mmol) in THF (100 ml) was added a 1

M solution of the Grignard reagent derived from 1-

bromo-4-trimethylsilylbut-3-yne in THF (25 ml, 25

mmol) and the reaction mixture was reﬂuxed for 5 h,

after which time all starting material was consumed

1

(EtOAc/PE); IR (CHCl₃) 3307, 2937, 2861, 1695; H-

NMR (400 MHz, CDCl₃) l 6.36 (br s, 1H), 3.66 (td,

J=6.8, 4.9 Hz, 1H), 2.48 (br t, J=5.9 Hz, 1H),

2.37–2.20 (m, 3H), 2.16 (br d, J=13.3 Hz, 1H), 2.00 (t,

W.F.J. Karstens et al. / Journal of Organometallic Chemistry 624 (2001) 244–258

253

(TLC). A saturated aqueous solution of NH₄Cl (100

ml) was added, and the aqueous layer was extracted

with EtOAc (2×50 ml). The combined organic layers

were washed with brine (2×75 ml), dried (Na₂SO₄) and

concentrated in vacuo. Puriﬁcation by chromatography

afforded 20b (1.55 g, 5.9 mmol, 59%) as a white solid;

R_f0.3 (EtOAc/PE 3:1); m.p. 81–83°C (PE); IR (CHCl₃)

3433, 3006, 2936, 2172, 1691; ¹H-NMR (400 MHz,

CDCl₃) l 5.78 (br s, 1H), 3.33–3.29 (m, 1H), 2.49 (q,

J=6.2 Hz, 1H), 2.32 (t, J=6.9 Hz, 2H), 2.17–2.11 (m,

1H), 1.94–1.87 (m, 1H), 1.78–1.26 (m, 9H), 0.16 (s,

9H); ¹³C-NMR (100 MHz, CDCl₃) l 178.8, 105.6, 85.9,

57.1, 39.7, 39.3, 32.2, 27.4, 23.4, 23.3, 23.1, 17.2, –0.1;

Anal. Calc. for C₁₅H₂₅NOSi: C, 68.38; H, 9.56; N, 5.32.

Found: C, 68.17; H, 9.60; N, 5.29%.

69.9, 69.8, 51.8, 33.5, 14.9; HRMS (EI) Calc. for

C₇H₉NO₂: 139.0633. Found 139.0635.

7.10. (5Z)-5-Benzylidenehexahydropyrrolidin-2-one (25)

To a mixture of K₂CO₃(553 mg, 4.0 mmol), Bu₄NCl

(416 mg, 1.5 mmol) was added benzene (5 ml) and the

solvent was removed in vacuo. After this evaporation

was repeated twice, Pd(PPh₃)₄(115 mg, 0.1 mmol) was

added and the ﬂask was purged with argon. MeCN was

added (20 ml) followed by PhI (816 mg, 4.0 mmol) and

14a (140 mg, 1.02 mmol) in MeCN (1 ml), the resulting

yellow mixture was reﬂuxed for 2–3 h (TLC showed

complete conversion). The mixture was cooled, diluted

with water (50 ml) and extracted with ether (3×50 ml).

The combined ether extracts were washed with water

(50 ml) and brine (50 ml), dried (Na₂SO₄) and concen-

trated. Flash chromatography (EtOAc/PE 1:2) afforded

25 (88 mg, 0.41 mmol, 40%) as a white solid, along with

26 (35 mg, 0.16 mmol, 16%) as a light yellow solid. 25:

R_f0.7 (EtOAc); m.p. 130–131°C; IR (CHCl₃) 3006,

7.8. (5R)-5-(But-3-ynyl)pyrrolidin-2-one (23)

A solution of the organozinc reagent derived from

(S)-5-iodomethylpyrrolidin-2-one (1.13 g, 5 mmol) in

DMF (5 ml) [8,14], was added to CuBrDMS (5 mol%)

in THF (15 ml) at −78°C. The mixture was brieﬂy

stirred at 0°C (10 min), cooled to −78°C after which

bromoallene [13] (1.1 equivalents) was added by sy-

ringe. The mixture was stirred at −30°C for 4 h and

then allowed to reach ambient temperature overnight.

After the addition of saturated aqueous NH₄Cl (100

ml), the aqueous layer was extracted with EtOAc (3×

50 ml). The combined organic layers were dried

(Na₂SO₄), concentrated and puriﬁed by ﬂash column

chromatography (2.5% MeOH in EtOAc) to give 23

(357 mg, 2.6 mmol, 52%) as a white solid; m.p. 50–

51°C; [h]_D= +33.6 (c 1.1, CHCl₃); All other data

identical to those of 14a.

1

1704, 1655; H-NMR (400 MHz, CDCl₃) l 7.27–7.21

(m, 4H), 7.14–7.03 (m, 1H), 5.94 (br s, 1H), 4.29 (dq,

J=9.5, 6.8 Hz, 1H), 2.91 (ddt, J=16.5, 9.7, 2.1 Hz,

1H), 2.82–2.73 (m, 2H), 2.49 (ddd, J=16.9, 9.6, 3.1

Hz, 1H), 2.45–2.36 (m, 1H), 2.17–2.09 (m, 1H), 1.90–

1.80 (m, 1H), 1.48 (dq, J=12.2, 9.8 Hz, 1H); ¹³C-NMR

(100 MHz, CDCl₃) l 171.8, 137.0, 133.7, 128.1, 127.4,

125.9, 111.8, 63.7, 34.2, 33.4, 30.1, 25.9; Anal. Calc. for

C₁₄H₁₅NO: C, 78.84; H, 7.09; N, 6.57. Found: C, 78.45;

H, 7.10; N, 6.44%.

7.11. 5-(4-Phenylbut-3-ynyl)pyrrolidin-2-one (26)

7.9. (4R)-4-(3-Butynyl)-1,3-oxazolidin-2-one (24)

Obtained as a by-product in the cyclization of 14a,

but also prepared separately: A solution of 5-but-3-

ynylpyrrolidin-2-one (14a) (446 mg, 3.37 mmol) in

pyrrolidine (3 ml) was degassed by bubbling trough

with N₂for 15 min. Iodobenzene (453 ml, 4.04 mmol)

was added, followed by Pd(PPh₃)₄(97 mg, 0.08 mmol)

and the resulting solution was stirred at r.t. for 1.5 h.

The solvent was removed in vacuo and the residue

taken up in EtOAc (75 ml). Washing with dilute HCl

(30 ml, 0.5 M) and brine (2×30 ml) followed by drying

(Na₂SO₄) and chromatography gave 26 (702 mg, 3.29

mmol, 98%) as a white solid. R_f0.4 (EtOAc/Acetone

A solution of the organozinc reagent derived from

(4S)-4-(iodomethyl)-1,3-oxazolidin-2-one (750 mg, 3.3

mmol) in THF (5 ml) [15] was added to a mixture of

CuBrDMS (5 mol%) and bromoallene [13] (1.1 equiva-

lents) in THF (15 ml) at −30°C. The reaction mixture

was stirred at −30°C for 4 h and then allowed to reach

ambient temperature overnight. After the addition of

saturated aqueous NH₄Cl (100 ml), the aqueous layer

was extracted with EtOAc (3×50 ml). The combined

organic layers were dried (Na₂SO₄), concentrated and

puriﬁed by ﬂash column chromatography (EtOAc/PE

3:1) to give 36 (135 mg, 0.97 mmol, 29%) as a light

yellow oil, contaminated with a small amount (B5%)

of the isomeric terminal allene. 24: R_f0.25 (EtOAc/PE

3:1); [h]_D+34.1 (c 1.2, CHCl₃); IR (CHCl₃) 1753,

1

1:1); IR (neat) 3431, 3015, 1691; H-NMR (400 MHz,

CDCl₃) l 7.52–7.08 (m, 5H), 6.8 (br s, 1H), 3.83–3.77

(m, 1H), 2.50 (t, J=6.8 Hz, 2H), 2.41–2.24 (m, 3H),

1.83–1.71 (m, 3H); ¹³C-NMR (100 MHz, CDCl₃)

l 178.1, 131.4, 128.2, 127.2, 123.3, 88.3, 81.5, 53.7,

35.3, 29.9, 27.1, 16.3; Anal. Calc. for C₁₄H₁₅NO: C,

78.84; H, 7.09; N, 6.57. Found: C, 78.49; H, 7.12; N,

6.59%.

1

1690; H-NMR (400 MHz, CDCl₃) l 6.72 (br s, 1H),

4.51 (t, J=7.8 Hz, 1H), 4.14–4.00 (m, 2H), 2.30 (td,

J=6.9, 2.6 Hz, 2H), 2.00 (t, J=2.6 Hz, 1H), 1.85–1.73

(m, 2H); ¹³C-NMR (100 MHz, CDCl₃) l 159.9, 82.2,

254

W.F.J. Karstens et al. / Journal of Organometallic Chemistry 624 (2001) 244–258

7.12. (5E)-5-(Phenyl(trimethylsilyl)methylene)-

hexahydropyrrolizin-3-one (27)

Hz, 1H), 6.68 (dd, J=3.5, 1.0 Hz, 1H), 4.11 (dq,

J=9.7, 6.9 Hz, 1H), 2.88 (ddd, J=16.8, 10.0, 2.2 Hz,

1H), 2.72 (ddd, J=16.8, 9.9, 8.2 Hz, 1H), 2.57 (dt,

J=16.6, 10.3 Hz, 1H), 2.34–2.24 (m, 2H), 2.14 (m,

J=12.2, 8.2, 6.3, 2.2 Hz, 1H), 1.70 (m, J=12.9, 11.1,

9.6, 7.2 Hz, 1H), 1.46 (dq, J=12.2, 9.9 Hz, 1H), 0.16

(s, 9H). ¹³C-NMR (100 MHz, CDCl₃) l 170.5, 144.8,

144.1, 126.3, 124.6, 122.2, 116.2, 62.3, 34.8, 33.0, 30.5,

26.1, 0.2.

Following the same procedure as for the preparation

of 25, 14b (312 mg, 1.50 mmol) in MeCN (0.05 M) was

treated with PhI (4 equiv) in the presence of TBAC (1.5

equivalents), K₂CO₃and Pd(PPh₃)₄(0.1 equivalents).

After reﬂux for 3 h, work up and chromatography gave

27 (283 mg, 1.0 mmol, 64%) as an off white solid; R_f0.3

(EtOAc/PE 1:1), m.p. 92–93°C (PE); IR (CHCl₃) 3005,

1670, 1609; ¹H-NMR (400 MHz, CDCl₃) l 7.21 (t,

J=7.6 Hz, 2H), 7.08 (br t, 7.4 Hz, 1H), 6.98 (br d,

J=7.5 Hz, 2H), 4.06 (dq, J=9.6, 6.8 Hz, 1H), 2.88

(ddd, J=16.5, 10.0, 2.4 Hz, 1H), 2.72 (ddd, J=16.5,

9.7, 8.2 Hz, 1H), 2.46 (dt, J=17.0, 10.3 Hz, 1H),

2.27–2.19 (m, 2H), 2.18–2.11 (m, 1H), 1.73–1.63 (m,

1H), 1.47 (dq, J=12.2, 9.9 Hz, 1H), 0.09 (s, 9H);

¹³C-NMR (100 MHz, CDCl₃) l 170.3, 144.0, 141.2,

128.4, 127.1, 125.0, 124.6, 62.1, 34.4, 32.4, 30.6, 25.8,

0.2; Anal. Calc. for C₁₇H₂₃NOSi: C, 71.53; H, 8.12; N,

4.91. Found: C, 71.45; H, 8.20; N, 4.84%.

7.15. (5E)-5-[(6-Chloro-3-pyridiny)trimethylsilyl-

methylene)hexahydropyrrolizin-3-one (31)

Following the same procedure as for the preparation

of 25, 14b (65 mg, 0.31 mmol) in MeCN (0.05 M) was

treated with 2-chloro-5-iodo-pyridine (four equivalents)

in the presence of TBAC (1.5 equivalents), K₂CO₃and

Pd(PPh₃)₄(0.1 equivalents). After work up and chro-

matography 31 (34 mg, 0.11 mmol, 34%) was obtained

as a light yellow solid. Unreacted 14b (32 mg, 50%)

could be recovered by continued elution (EtOAc). 31;

R_f0.3 (EtOAc/PE 1: 1); m.p. 101–106°C (Et₂O/PE);

¹H-NMR (400 MHz, CDCl₃) l 7.89 (d, J=2.3 Hz,

1H), 7.36 (dd, J=2.3, 8.4 Hz, 1H), 7.18 (d, J=8.4,

1H), 4.13–4.03 (m, 1H), 2.88 (ddd, J=2.3, 10.0, 16.8

Hz, 1H), 2.71 (ddd, J=8.2, 9.8, 16.8 Hz, 1H), 2.50 (dt,

J=17.2, 10.3 Hz, 1H), 2.30–2.23 (m, 2H), 2.16 (m,

J=2.3, 6.1, 8.4, 12.2 Hz, 1H), 1.78–1.69 (m, 1H),

1.54–1.41 (dq, J=12.2, 9.9 Hz, 1H), 0.10 (s, 9H).

¹³C-NMR (100 MHz, CDCl₃) l 170.7, 148.1, 147.4,

143.7, 139.5, 139.0, 122.7, 119.6, 62.2, 34.3, 32.4, 30.5,

25.7, −0.1; HRMS (EI) Calc. for C₁₆H₂₁ClN₂OSi

320.1111. Found 320.1112.

7.13. (5E)-5-((4-Nitrophenyl)(trimethylsilyl)-

methylene)hexahydropyrrolizin-3-one (28)

Following the same procedure as for the preparation

of 25, 14b (209 mg, 1.0 mmol) in MeCN (0.05 M) was

treated with 1-iodo-4-nitro-benzene (4 equiv) in the

presence of TBAC (1.5 equivalents), K₂CO₃and

Pd(PPh₃)₄(0.1 equivalents). After reﬂux for 3 h, work

up and chromatography gave 28 (244 mg, 0.74 mmol,

74%) as a light yellow solid; R_f0.4 (EtOAc/PE 1:2);

m.p. 139–141°C (EtOAc/PE); IR (neat) 2953, 2242,

1

1712, 1589, 1506; H-NMR (400 MHz, CDCl₃) l 8.07

(d, J=8.8 Hz, 2H), 7.12 (d, J=8.8 Hz, 2H), 4.13 (dq,

J=9.9, 6.8 Hz, 1H), 2.91 (ddd, J=16.8, 9.8, 2.0 Hz,

1H), 2.76 (ddd, J=16.8, 10.3, 8.1 Hz, 1H), 2.49 (dt,

J=17.1, 10.3 Hz, 1H), 2.32–2.16 (m, 3H), 1.77–1.66

(m, 1H), 1.55–1.41 (dq, J=12.2, 10.1 Hz, 1H), 0.11 (s,

9H); ¹³C-NMR (100 MHz, CDCl₃) l 170.7, 152.4,

145.2, 142.6, 129.0, 122.7, 122.5, 62.5, 34.6, 32.9, 30.7,

25.7, 0.2; HRMS (EI) Calc. for C₁₇H₂₂N₂O₃Si 330.1400.

Found 330.1410.

7.16. (5E)-5-(3-Methyl-1-(trimethylsilyl)but-2-

enylidene)hexahydropyrrolizin-3-one (32)

Following the same procedure as for the preparation

of 25, 14b (105 mg, 0.5 mmol) in MeCN (0.05 M) was

treated with 1-bromo-2-methyl-propene (four equiva-

lents) in the presence of TBAC (1.5 equivalents),

K₂CO₃and Pd(PPh₃)₄(0.1 equivalents). After work-up

and chromatography 32 (78 mg, 0.34 mmol, 69%) was

obtained as a colorless oil; R_f0.3 (EtOAc/PE 1:2); IR

7.14. (5E)-5-(2-Thienyl(trimethylsilyl)methylene)-

hexahydropyrrolizin-3-one (30)

1

(neat) 2965, 1713, 1608; H-NMR (400 MHz, CDCl₃) l

5.74 (br s, 1H), 4.00 (dq, J=9.5, 7.0 Hz, 1H), 2.77 (ddt,

J=16.4, 10.3, 2.4 Hz, 1H), 2.66 (ddd, J=16.4, 10.9,

9.7 Hz, 1H), 2.59–2.50 (m, 1H), 2.37 (ddd, J=16.4,

9.4, 2.2 Hz, 1H), 2.29–2.21 (m, 1H), 2.05 (m, J=12.2,

8.6, 6.1, 2.4 Hz, 1H), 1.73–1.63 (m, 1H), 1.65 (d,

J=1.1 Hz, 3H), 1.47–1.36 (dq, J=12.2, 9.8 Hz, 1H),

1.31 (d, J=0.9 Hz, 3H), 0.06 (s, 9H); ¹³C-NMR (100

MHz, CDCl₃) l 169.7, 139.2, 127.1, 126.4, 120.6, 61.5,

35.1, 31.5, 30.3, 26.4, 24.8, 18.5, –0.6; HRMS (EI)

Calc. for C₁₅H₂₅NOSi 263.1705. Found 263.1699.

Following the same procedure as for the preparation

of 25, 14b (209 mg, 1.0 mmol) in MeCN (0.05 M) was

treated with 2-bromothiophene (four equivalents) in the

presence of TBAC (1.5 equivalents), K₂CO₃and

Pd(PPh₃)₄(0.1 equivalents). After reﬂux for 2 h, work

up and chromatography gave 30 (226 mg, 0.78 mmol,

78%) as a white solid R_f0.3 (EtOAc/PE 1: 2); m.p.

1

101–102°C (EtOAc/PE); H-NMR (400 MHz, CDCl₃)

l 7.05 (dd, J=5.1, 1.0 Hz, 1H), 6.91 (dd, J=5.1, 3.5

W.F.J. Karstens et al. / Journal of Organometallic Chemistry 624 (2001) 244–258

255

7.17. (5Z)-5-(1-Phenylethylidene)hexahydropyrrolizin-

3-one (33)

J=10.9, 5.4 Hz, 1H), 3.11 (dd, J=16.0, 7.8 Hz, 1H),

3.03–2.93 (m, 2H), 2.37–2.30 (m, 1H), 2.25 (br d,

J=15.9 Hz, 1H), 1.84–1.71 (m, 3H), 1.63–1.54 (br m,

2H), 1.48–1.40 (m, 1H), 1.26–1.07 (m, 3H); ¹³C-NMR

(100 MHz, CDCl₃) l 171.7, 137.8, 136.8, 128.1, 127.7,

125.3, 108.4, 64.1, 48.3, 37.0, 33.1, 23.8, 23.5, 22.9, 22.6,

20.1.

Following the same procedure as for the preparation

of 25, 14c (151 mg, 1.0 mmol) in MeCN (0.05 M) was

treated with PhI (four equiv) in the presence of TBAC

(1.5 equivalents), K₂CO₃and Pd(PPh₃)₄(0.1 equiva-

lents). After work-up and chromatography 33 (151 mg,

0.66 mmol, 66%) was obtained as a light yellow oil; R_f

7.20. (3R*,3aR*,7aS*)-3-(4-(Phenyl)but-3-ynyl)-

octahydro-isoindol-1-one (36)

1

0.3 (EtOAc/PE 1:1); IR (CHCl₃) 3002, 1706; H-NMR

(400 MHz, CDCl₃) l 7.31–7.25 (m, 4H), 7.16–7.12 (m,

1H), 4.17 (dq, J=9.7, 6.8 Hz, 1H), 2.82 (br dd, J=

16.6, 10.3 Hz, 1H), 2.72–2.64 (m, 1H), 2.61–2.51 (m,

1H), 2.36–2.28 (m, 2H), 2.21–2.14 (m, 1H), 2.05 (s,

3H), 1.79–1.69 (m, 1H), 1.47 (dq, J=12.2, 10.0 Hz,

1H); ¹³C-NMR (100 MHz, CDCl₃) l 170.7, 143.4,

130.2, 127.6, 126.9, 125.8, 119.6, 62.7, 34.0, 30.9, 30.6,

25.7, 20.1; HRMS (EI) Calc. for C₁₅H₁₇NO 227.1310.

Found 227.1321.

Formed as a by-product in the cyclization of 17a to

34. Chromatography (EtOAc) afforded 36 as a light

yellow solid; R_f0.3 (EtOAc/PE 3:1); IR (CHCl₃) 3415,

1696; ¹H-NMR (400 MHz, CDCl₃) l 7.40–7.38 (m,

2H), 7.30–7.27 (m, 3H), 6.45 (br s, 1H), 3.76–3.72 (m,

1H), 2.59–2.44 (m, 3H), 2.38 (m, 1H), 2.19 (br d,

J=13.1 Hz, 1H), 1.78 (q, J=7.0 Hz, 2H), 1.68 (br d,

J=11 Hz, 1H), 1.59 (br t, J=12 Hz, 2H), 1.50–1.39

(m, 1H), 1.27–1.08 (m, 3H); ¹³C-NMR (100 MHz,

CDCl₃) l 178.5, 131.4, 128.2, 127.8, 123.2, 88.5, 81.5,

55.9, 42.8, 38.7, 28.2, 23.8, 22.9, 22.6, 22.5, 17.0;

HRMS (EI) Calc. for C₁₈H₂₁NO 267.1623. Found

267.1606.

7.18. (3Z,5aS*,9aR*,9bR*)-3-Benzylidenedecahydro-

pyrrolo[2,1-a]isoindol-5-one (34)

Following the same procedure as for the preparation

of 25, 17a (96 mg, 0.5 mmol) in MeCN (0.05 M) was

treated with PhI (four equivalents) in the presence of

TBAC (1.5 equivalents), K₂CO₃and Pd(PPh₃)₄(0.1

equivalents). After work-up and chromatography

(EtOAc/PE 1:2) a mixture of 34 and 35 (34/35=1:0.13,

56 mg, 0.21 mmol, 42%) as a yellow solid. Continued

elution with EtOAc afforded the non-cyclized coupling

product 36 (39 mg, 29%, 0.15 mmol). Fractional crys-

tallization from dichloromethane/hexane afforded an

analytically pure sample of 34 as off white crystals; R_f

0.3 (EtOAc/PE 1:2); m.p. 130–131°C (CH₂Cl₂/hexane);

7.21. (3E,5aS*,9aR*,9bR*)-3-(Phenyl(trimethylsilyl)-

methylene)decahydropyrrolo[2,1-a]isoindol-5-one (37)

Following the same procedure as for the preparation

of 25, 17b (395 mg, 1.5 mmol) in MeCN (0.05 M) was

treated with PhI (four equivalents) in the presence of

TBAC (1.5 equivalents), K₂CO₃and Pd(PPh₃)₄(0.1

equivalents). Work-up and chromatography (EtOAc/

PE 1:5) gave 37 (209 mg, 0.61 mmol, 41%) as a light

yellow oil and a fraction containing a mixture of 34, 35

and 38 (0.75:0.42:1, 117 mg, 0.39 mmol, 26%). 37; IR

(CHCl₃) 2930, 1716, 1607; ¹H-NMR (400 MHz, CDCl₃)

l 7.21 (br t, J=7.3 Hz, 2H), 7.07 (br t, J=7.4 Hz,

1H), 6.99 (br d, J=7.8 Hz, 2H), 4.11 (ddd, J=5.3, 6.8,

8.4 Hz, 1H), 2.78–2.64 (m, 2H), 2.59 (app t, 1H),

2.29–2.22 (m, 1H), 1.96–1.79 (m, 2H), 1.67–1.59 (br

m, 2H), 1.44–1.41 (br m, 1H), 1.26–0.87 (m, 5H), 0.10

(s, 9H); ¹³C-NMR (100 MHz, CDCl₃) l 170.2, 143.8,

141.1, 128.5, 127.2, 124.6, 123.8, 62.8, 45.9, 38.4, 32.1,

23.9, 23.2, 22.6, 22.3, 20.1, 0.3.

1

IR (CHCl₃) 1704; H-NMR (400 MHz, CDCl₃) l 7.23

(br t, J=7.3 Hz, 2H), 7.16 (br d, J=7.1 Hz, 2H), 7.11

(br t, J=7.2 Hz, 1H), 5.88 (br s, 1H), 4.41–4.36 (ddd,

J=8.2, 6.4, 5.4Hz, 1H), 2.92 (br t, J=5.7 Hz, 1H),

2.85–2.67 (m, 2H), 2.44–2.37 (m, 1H), 2.14 (br d,

J=12 Hz, 1H), 1.93–1.83 (m, 2H), 1.68 (br d, J=10

Hz, 2H), 1.52–0.93 (m, 5H); ¹³C-NMR (100 MHz,

CDCl₃) l 171.6, 137.1, 133.6, 128.1, 127.3, 125.7, 110.3,

64.7, 46.1, 39.1, 33.5, 23.9, 23.2, 22.7, 22.2, 19.8; Anal.

Calc. for C₁₈H₂₁NO: C, 80.86; H, 7.92; N, 5.24. Found:

C, 80.32; H, 7.87; N, 5.14%.

7.22. (3Z,5aS*,9aR*,9bS*)-3-Benzylidenedecahydro-

pyrrolo[2,1-a]isoindol-5-one (39)

7.19. (3E,5aS*,9aR*,9bR*)-3-Benzylidenedecahydro-

pyrrolo[2,1-a]isoindol-5-one (35)

Following the same procedure as for the preparation

of 25, 20a (191 mg, 1.0 mmol) in MeCN (0.05 M) was

treated with PhI (four equivalents) in the presence of

TBAC (1.5 equivalents), K₂CO₃and Pd(PPh₃)₄(0.1

equivalents). The mixture was reﬂuxed for 3 h, after

which time work up and chromatography (EtOAc/PE

1:2) afforded 39 (161 mg, 0.60 mmol, 60%) as a light

Formed as a by-product in the cyclization of 17a to

48. Crystallization from EtOAc/hexane afforded an an-

alytically pure sample of 35 as off white crystals; R_f0.3

(EtOAc/PE 1:2); m.p. 168–171°C (EtOAc/hexane); IR

(CHCl₃) 1706; H-NMR (400 MHz, CDCl₃) l 7.31–

7.26 (m, 5H), 7.13 (br t, J=6.7 Hz, 1H), 4.20 (dt,

1

256

W.F.J. Karstens et al. / Journal of Organometallic Chemistry 624 (2001) 244–258

yellow oil. Continued elution afforded impure 40 (ca.

25%); 39: R_f0.3 (EtOAc/PE 1:2; IR (CHCl₃) 2937,

1704, 1657; H-NMR (400 MHz, CDCl₃) l 7.25–7.17

reﬁned mosaicity 0.370(1)°, no absorption correction).

The structure was solved by direct methods (^SHELXS

-

97) [24] and reﬁned on F²using SHELXL-97-2 [25].

Hydrogen atoms were located on a difference Fourier

map and their coordinates were included as parameters

in the reﬁnement. All non-hydrogen atoms were reﬁned

with anisotropic displacement parameters; hydrogen

atoms were reﬁned with a ﬁxed isotropic displacement

parameter related to the value of the equivalent

isotropic displacement parameter of their carrier atoms

by a factor of 1.5 for the methyl hydrogen atoms and

1.2 for the other hydrogen atoms. Reﬁnement of 304

parameters converged at wR₂=0.1044, w=1/[|²(F²)+

(0.0495P)²+0.69P], where P=(max(F_o², 0)+2F²_c)/3,

1

(m, 4H), 7.11 (br t, J=7.1 Hz, 1H), 5.90 (br s, 1H),

4.18 (dt, J=6.6, 8.3 Hz, 1H), 2.92 (dddd, J=16.4, 3.6,

10.0, 1.8 Hz, 1H), 2.78 (m, 1H), 2.49 (dt, J=11.1, 6.6

Hz, 1H), 2.28–2.22 (m, 1H), 2.13 (m, J=12.1, 6.7, 8.2,

3.6 Hz, 1H), 2.06–1.99 (m, 1H), 1.76–143 (m, 7H),

1.28–1.19 (m, 1H); ¹³C-NMR (100 MHz, CDCl₃) l

174.4, 137.1, 134.1, 128.1, 127.3, 125.7, 111.0, 64.8,

46.7, 40.8, 33.8, 27.8, 25.2, 24.8, 23.4, 21.6; HRMS (EI)

Calc. for C₁₈H₂₁NO 267.1623. Found: 267.1627.

7.23. (3E,5aS*,9aR*,9bS*)-3-(Phenyl(trimethylsilyl)-

methylene)decahydropyrrolo[2,1-a]isoindol-5-one (41)

R₁=0.0372 (for 3817 I\2|(I)), S=1.086 and −

−3

,

0.28BDzB0.24 e A

.

Following the same procedure as for the preparation

of 25, 20b (138 mg, 0.5 mmol) in MeCN (0.05 M) was

treated with PhI (four equivalents) in the presence of

TBAC (1.5 equivalents), K₂CO₃and Pd(PPh₃)₄(0.1

equivalents). The mixture was reﬂuxed for 5 h, after

which time work up and chromatography (EtOAc/PE

1:2) afforded 41 (114 mg, 0.34 mmol, 68%) as a white

solid. Continued elution afforded the desilylated

product 39 (15 mg, 0.06 mmol, 11%); 41: R_f0.3

(EtOAc/PE 1:2); m.p. 114–115°C (Hexane); IR

(CHCl₃) 2939, 1697; ¹H-NMR (400 MHz, CDCl₃) l

7.20 (br t, J=7.6 Hz, 2H), 7.06 (br t, J=7.4 Hz, 1H),

6.97 (br d, J=7.5 Hz, 2H), 3.98 (td, J=8.7, 6.6 Hz,

1H), 2.89 (ddd, J=16.4, 10.3, 2.8 Hz, 1H), 2.75 (dt,

J=16.6, 8.8 Hz, 1H), 2.26–2.08 (m, 3H), 1.65–1.56 (m,

4H), 1.54–1.35 (m, 3H), 1.26–1.04 (m, 2H), 0.11 (2,

9H); ¹³C-NMR (100 MHz, CDCl₃) l 172.4, 144.0,

141.6, 128.9, 127.1, 124.6, 123.8, 62.8, 47.4, 40.8), 32.8,

28.7, 24.9, 24.3, 23.3, 21.5, 0.3; Anal. Calc. for

C₂₁H₂₉NOSi: C, 74.28; H, 8.61; N, 4.13. Found: C,

74.33; H, 8.64; N, 4.08%.

7.25. (5Z,R)-5-Benzylidenehexahydropyrrolidin-2-one

(42)

Following the same procedure as for the preparation

of 25, 23 (95 mg, 0.69 mmol) in MeCN (0.05 M) was

treated with PhI (four equivalents) in the presence of

TBAC (1.5 equivalents), K₂CO₃and Pd(PPh₃)₄(0.1

equivalents). After work-up and chromatography 42

(59 mg, 0.28 mmol, 40%) was obtained as a white solid;

m.p. 96–97°C (EtOAc/PE); [h]_D+256 (c 0.84, CHCl₃);

All other data identical to those for 25 (=rac-57).

7.26. (5Z,R)-5-(Benzylidene)tetrahydropyrrolo[1,2-c]-

oxazol-3-one (44)

Following the same procedure as for the preparation

of 25, 24 (100 mg, 0.72 mmol, contaminated with 5% of

the analogous allene) in MeCN (0.05 M) was treated

with PhI (four equivalents) in the presence of TBAC

(1.5 equivalents), K₂CO₃and Pd(PPh₃)₄(0.1 equiva-

lents). After work-up and chromatography 44 (90 mg,

0.42 mmol, 60%) was obtained as a white solid; m.p.

153–155°C (EtOAc/PE); [h]_D+143 (c 1.0, CHCl₃); R_f

0.4 (EtOAc/PE 1:1); IR (CHCl₃) 3014, 1765, 1384;

¹H-NMR (400 MHz, CDCl₃) l 7.47 (d, J=7.4 Hz,

2H), 7.30–7.28 (m, 2H), 7.18–7.14 (m, 1H), 6.05 (s,

1H), 4.60 (td, J=8.4, 1.1 Hz), 4.26–4.19 (m, 2H), 2.90

(dd, J=16.9, 9.5 Hz, 1H), 2.78–2.68 (m, 1H), 2.18–

2.11 (m, 1H), 1.74–1.63 (m, 1H); ¹³C-NMR (100 MHz,

CDCl₃) l 135.8, 128.1, 127.9, 126.5, 114.9, 60.8, 31.0,

28.9; Anal. Calc. for C₁₃H₁₃NO₂: C, 72.54; H, 6.09; N,

6.51. Found: C, 72.21; H, 6.10; N, 6.23%.

7.24. Crystal structure determination (see Section 8)

Recrystallization of 41 from hot hexane gave crystals

suitable for X-ray analysis: C₂₁H₂₉NOSi, M_r=339.55.

A colorless, block-shaped crystal (0.1×0.2×0.3 mm³)

was glued on a Lindemann-glass capillary and trans-

ferred into the cold nitrogen stream on a Nonius

Kappa CCD area detector system on rotating anode.

The measured crystal was monoclinic, space group

P2₁/c (no. 14) with a=13.4482(12), b=8.9962(12), c=

3

,

19.647(2) A, i=126.60(6)°, V=1908.3(15) A , Z=4,

D_x=1.182 g cm⁻³, F(000)=736, v(Mo–K_a)=0.13

mm⁻¹. A total of 33485 reﬂections were measured,

4499 of which were independent, R_int=0.0417 (1.5B

qB28.5°, T=150 K, Mo–K_aradiation, graphite

7.27. 4-(4-Trimethylsilylbut-3-ynyl)-1,3-oxazolidin-

2-one (45)

,

monochromator, u 0.71073 A, scan with distance

crystal to detector 29 mm, ꢀ scan with distance crystal

Using the same procedure as for the preparation of

14b, 4-methoxy-oxazolidin-2-one [26] (1.17 g, 10 mmol)

in THF (10 ml) was treated with the Grignard reagent

to detector 50 mm, data reduction by DENZO [23],

W.F.J. Karstens et al. / Journal of Organometallic Chemistry 624 (2001) 244–258

257

derived from 1-bromo-4-trimethylsilyl-3-butyne (30 ml,

1 M in THF, 30 mmol). After work-up and column

chromatography 45 (858 mg, 4.1 mmol, 41%) was

obtained as a white solid; R_f0.3 (EtOAc/PE 1:2); m.p.

92–93°C; IR (CHCl₃) 1760; ¹H-NMR (400 MHz,

CDCl₃) l 6.54 (br s, 1H), 4.51 (t, J=8.4 Hz, 1H), 4.08

(dd, J=8.6, 6.1Hz, 1H), 4.02–3.96 (m, 1H), 2.32 (td,

J=6.9, 1.7 Hz, 2H), 1.85–1.70 (m, 2H), 0.13 (s, 9H);

¹³C-NMR (100 MHz, CDCl₃) l 159.7, 105.3, 83.4, 70.1,

52.0, 33.2, 16.1; HRMS (EI) Calc. for C₁₀H₁₇NO₂Si

211.1029. Found 211.1020.

been deposited with the Cambridge Crystallographic

Data Centre, CCDC no. 150989 for compound 41.

Copies of this information may be obtained from The

Director, CCDC, 12 Union Road, Cambridge, CB2

1EZ, UK (fax: +44-1233-336033; e-mail: deposit@

ccdc.cam.ac.uk or www: http://www.ccdc.cam.ac.uk).

Acknowledgements

This research has been ﬁnancially supported by the

Council for Chemical Sciences of the Netherlands Or-

ganization for Scientiﬁc Research (CW-NWO).

7.28. (5Z)-5-(Phenyl(trimethylsilyl)methylene)-

tetrahydropyrrolo[1,2-c]oxazol-3-one (46)

References

Following the same procedure as for the preparation

of 25, 45 (211 mg, 1.0 mmol) in MeCN (0.05 M) was

treated with PhI (four equivalents) in the presence of

TBAC (1.5 equivalents), K₂CO₃and Pd(PPh₃)₄(0.1

equivalents). After work up and chromatography 46

(205 mg, 0.71 mmol, 71%) was obtained as a white

solid; m.p. 97–98°C (CH₂Cl₂/PE); R_f0.4 (EtOAc/PE

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1:2); IR (CHCl₃) 2954, 1769, 1623, 1247; H-NMR (400

MHz, CDCl₃) l 7.26-7.22 (m, 2H), 7.14–7.07 (m, 3H),

4.36 (dd, J=8.8, 7.7 Hz, 1H), 4.06 (dd, J=8.8, 2.8Hz,

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Following the same procedure as for the preparation

of 25, 26 (107 mg, 0.50 mmol) in MeCN (0.05 M) was

treated with PhI (four equivalents) in the presence of

TBAC (1.5 equivalents), K₂CO₃and Pd(PPh₃)₄(0.1

equivalents). After reﬂux for 18 h, work-up and chro-

matography (EtOAc) gave 57 (77 mg, 0.26 mmol, 53%)

as a light yellow solid; R_f0.3 (EtOAc/PE 1:2); ¹H-

NMR (400 MHz, CDCl₃) l 7.37–7.13 (m, 10H), 4.23

(quint, J=7.6 Hz, 1H), 3.00 (ddd, J=16.9, 10.7, 3.7

Hz, 1H), 2.62 (ddd, J=16.7, 11.1, 9.5 Hz, 1H), 2.48

(dt, J=16.9, 8.5 Hz, 1H), 2.41–2.32 (m, 2H), 2.16–

2.07 (m, 1H), 1.83–1.73 (m, 1H), 1.60–1.51 (m, 1H).

¹³C-NMR (100 MHz, CDCl₃) l 170.3, 142.5, 142.0,

132.1, 130.0, 128.7, 127.9, 127.6, 127.4, 126.7, 126.0,

62.1, 34.9, 31.4, 29.7, 27.4; HRMS (EI) Calc. for

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8. Supplementary material

Crystallographic data for the structural analysis have

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