The regiochemistry of carbenoid insertion into zirconacycles

TETRAHEDRON

Pergamon

Tetrahedron 56 (2000) 2113±2129

The Regiochemistry of Carbenoid Insertion into Zirconacycles

*

George J. Gordon, Tim Luker, Mark W. Tuckett and Richard J. Whitby

Department of Chemistry, University of Southampton, High®eld, Southampton, Hampshire SO17 1BJ, UK

Accepted 7 December 1999

AbstractÐThe regioselectivity of insertion of lithium chloroallylides (allyl carbenoids) into a wide variety of unsymmetrical zirconacycles

has been determined. In all but one case a single regioisomer was obtained. A combination of steric and electronic effects is needed to

explain the results and imply that the carbenoid is acting predominantly as an electrophilic species. The ®rst carbenoid insertion into a

2

h ±imine complexes with unsaturated species, for example

Introduction

5

alkynes to afford 2. Takahashi has developed a wide range

The wide variety of zirconacycles available from simple

organic precursors either by cocyclisation of 1,n-dienes,

of copper catalysed elaborations of zirconacycles including

1,1- and 1,2-additions to alkynes (e.g. to form 3), 1,1-

6

7

additions to acid chlorides, and addition to 1,2-, 1,3- or

-

enynes and -diynes using a zirconocene `Cp Zr' equivalent,

2

8

1,4-dihalides. All the above processes retain the symmetry

of the starting zirconacycle so questions of regiochemistry

of the addition do not occur.

or by trapping of zirconocene h -alkene, -alkyne, and

benzyne complexes with alkenes or alkynes, make them

attractive as intermediates in organic synthesis (Scheme

-

1

1). Methods for further elaboration of these zirconacycles

forming carbon±heteroatom bonds include oxygenation,

Processes in which the two carbon±zirconium bonds of the

zirconacycle are differentially elaborated are also known

including monohalogenation, mixed dihalogenation,

2

halogenation, and metathesis with a variety of elemento-

3

dihalides `ACl ' (Scheme 2). Carbon±carbon bond form-

9

10

2

4

ing methods include carbonylation to give 1 or, more

9a

9

addition of Ph

tion,

PCl and R

addition of aldehydes, ketones and nitriles

and copper catalysed addition of acid chlorides, enones,

SnCl, isocyanide inser-

2

3

5

c,9b,11

1a,12

recently tandem processes involving the insertion of iso-

cyanides and trapping of the resulting zirconocene

1

3

and allyl-, aryl- and alkynyl-halides. We have recently

1

2

shown that the insertion of metal carbenoids (R R CLiX)

into zirconacycles provides many new pathways for

elaboration. The insertion reaction of lithium chloroally-

3

lides 4 to afford s,h -zirconacycles 6 which react with

Scheme 1. Formation of zirconacycles.

Keywords: zirconium; zirconacycle; carbenoid; insertion reactions.

* Corresponding author. Tel.: 144(0)2380-592777; fax: 144(0)2380-

593781; e-mail: rjw1@soton.ac.uk

Scheme 2. Elaboration of zirconacycles.

PII: S0040-4020(99)01094-7

2

114

G. J. Gordon et al. / Tetrahedron 56 (2000) 2113±2129

Scheme 3. Carbenoid insertion into zirconacycles.

many electrophiles, for example aldehydes and ketones, to

afford highly elaborated organic products 7 and 8 (Scheme

1

) is particularly useful. We have also shown that a wide

4

3

variety of carbenoids allow ring expansion of zirconacyclo-

ꢀ2

pentanes and -pentenes to 6-member zirconacycles 9

and 10, which in many cases may be further elaborated.

1

5

A reasonable mechanism for the carbenoid insertion is

by initial donation of an electron pair to the 16-electron

zirconium centre to form an 18-electron zirconate

Most of the published examples of differential elaboration

of the two carbon±zirconium bonds of saturated zircon-

acycles use symmetric systems where regiocontrol is not

relevant. Takahashi and Negishi showed that magnesium/

zirconium exchange of monocyclic zirconacyclopentanes

was selective for the bond closest to a b-substituent

1

6

complex 5 followed by a 1,2-metallate rearrangement

a process originally noted by Negishi for insertion

(

1

7

into acyclic organozirconocene species). For use in total

synthesis it is important to be able to predict the regio-

chemistry of processes which differentially elaborate

the two carbon±zirconium bonds of unsymmetrical

zirconacycles.

(

Eq. (3)) or for the bond adjacent to an a-phenyl substituent

Eq. (4)). Copper catalysed allylation or benzoylation

18

(

followed a similar selectivity (Eqs. 5 and 6).

1

3c

The

mechanism of a catalytic cyclomagnesiation reported by

Mori implies that an intermediate zirconacycle undergoes

selective transmetallation as shown in Eq. (7).

Selective insertion into zirconacyclopentenes (including

zirconaindenes) 11 is known. Most relevant to the work

described below is the regioselective insertion of iso-

cyanides into the alkyl±zirconium bond to afford 12

19,20

5

c,9b,11

9b

(

Eq. (1)).

hydes, ketones and nitriles,

halogenolysis with CBr or CCl Br also occur into the

Protonolysis (®rst site), addition of alde-

ꢀ

3

4

1

a,12

9b

trimethyltin chloride, and

9

b

4

3

alkyl±zirconium bond. For protonation and oxygen inser-

tion this selectivity has been demonstrated for the case

1

4f

R H. Halogenolysis with I or Br generally gives initial

2

ꢀ

attack on the vinyl±zirconium bond to afford 13 on hydroly-

sis (Eq. (2)). When the vinyl bond carries a phenyl sub-

stituent the selectivity is reversed. Copper catalysed

functionalisation of zirconacyclopentenes generally occurs

9

b

9

b

7

b,13a,b

®

rst at the vinyl±zirconium bond to give 13.

In

ꢀ

5

6

summary, direct attack on the carbon±metal bond of zircon-

acyclopentenes occurs on the alkyl side. Where the

reagents may ®rst complex with, or add to, the double

bond (halogens, organocopper species), the selectivity is

usually reversed.

ꢀ

ꢀ1

ꢀ7

G. J. Gordon et al. / Tetrahedron 56 (2000) 2113±2129

2115

In this paper we report our studies on the regiochemistry of

insertion of lithium chloroallylides into zirconacycles.²¹

carbon (RH). Cyclisation of terminal alkynes with the

Negishi reagent [zirconocene(1-butene), generated in situ

2

from dibutylzirconocene] fails, but reaction of 1,6-

heptenyne with zirconocene(ethylene), followed by heat-

2

3

Results

ing gave the zirconacycle 16. Insertion of lithium

chloroallylide followed by benzaldehyde gave a 2.2:1

mixture of regioisomeric insertion products 17 and 18,

favouring insertion into the alkyl±zirconium bond (Table

1, entry 3).

We have already reported that the insertion of lithium

chloroallylide into mono- and bi-cyclic zirconacyclo-

pentenes 14 and 15 derived from disubstituted alkynes

(

R±H, Table 1, entries 1 and 2) is completely selective

14e

for the alkyl±zirconium bond. The selectivity might be

electronically or sterically derived, a question which could

be probed with a substrate unsubstituted on the vinyl±

In an effort to shift the regioselectivity of insertion entirely

towards the vinyl±zirconium bond we examined zircon-

acyclopentenes where the alkyl carbon attached to the

Table 1. Carbenoid insertions into unsaturated zirconacycles

a

Zirconacycles in entry 1 were formed from the alkyne and zirconocene(ethylene) (Ref. 9b), in entries 3, 5 and 7 by reaction with zirconocene(ethylene)

ZrCl /Mg (Ref. 24) and in entry 2 by reaction with zirconocene(1-butene) (Ref. 1).

; (iii) aq. NaHCO . Method B: (i) lithium chloromethallylide; (ii) AcOH. Method C: (i) lithium

aq. Method D. As A but 5 equiv. lithium chloroallylide, PhCHO and BF .Et O used.

followed by thermolysis (Ref. 23), in entries 4 and 6 by reaction with Cp

2

b

Method A: (i) lithium chloroallylide; (ii) aldehyde, BF

3

.OEt

2

3

chloromethallylide; (ii) NaHCO

3

2

c

Ref. 14e.

2

116

G. J. Gordon et al. / Tetrahedron 56 (2000) 2113±2129

metal carried extra substitution. Co-cyclisation of substrate

9 containing a trans-1,2-disubstituted alkene and a termi-

nal alkyne using zirconocene dichloride and magnesium

recently reported conditions which are compatible with

terminal alkynes ) gave zirconacycle 20. High yielding

insertion of lithium chloromethallylide required removal

of residual magnesium salts by ®ltration. Presumably

rapid transmetallation of the lithium chloromethallylide

was giving a unreactive magnesium species. Protonation

of the product of insertion of lithium chloromethallylide

into 20 with glacial acetic acid gave the product 21 derived

entirely from insertion into the vinyl±zirconium bond

2788C with methanol could we obtain high yields of the

carbenoid insertion product 27. The result con®rmed the

selectivity for the more hindered alkyl±zirconium bond

noted with 23. The carbenoid insertion product 27 was

obtained as a single isomer, despite the diastereoisomeric

mixture of zirconacycles.

1

(

2

4

(

Table 1, entry 4). Protonation with NaHCO aq. gave a

3

ꢀ9

mixture of double bond positional isomers. Insertion of

acetone unexpectedly gave the product 31 (Eq. (8)) from

addition to the internal carbon of the allyl-system,

rather than the previously exclusively observed terminal

1

4a,b

addition.

b-Hydride elimination has also occurred

from the presumed intermediate oxazirconacycle to give

the observed triene 31. Although a single isomer, the double

bond stereochemistries in 31 have not been proven. syn-b-

Hydride elimination would give the (Z)-ethylidene stereo-

chemistry, but calculations indicate that this would be very

unstable with respect to the (E)-ethylidene form shown and

isomerisation during isolation and puri®cation is likely.

Addition of aldehydes to 20 induced by BF ´Et O gave an

Successful insertion into vinyl±zirconium bonds in Table 1,

entries 3 and 4, prompted us to examine reactions with a

suitable zirconacyclopentadiene substrate. Co-cyclisation

of 28 using Cp ZrCl /Mg gave the zirconacyclopentadiene

29. We were delighted to ®nd that insertion of lithium

chloroallylide followed by benzaldehyde gave an

excellent yield of the interesting triene 30 (Table 1,

entry 7), although 5 equiv. of the carbenoid were needed

for optimum yield.

2

3

2

inseparable mixture of products.

Insertions into zirconacyclopentanes were next examined.

Zirconacycles 34 and 36 derived from trans-alkenes carry-

ing terminal methyl, or phenyl substituents inserted lithium

chloroallylides exclusively into the less hindered side

(

Table 2, entries 1 and 2). Insertion into saturated zircon-

2

5

acycles 38 (previously reported by Mori ) and 40 derived

from co-cyclisation of a terminal alkene and a cyclohexene

occurred exclusively into the more hindered side (Table 2,

entries 3 and 4), as was observed with enyne derived

systems 23 and 26. The stereochemistry of 40 follows

from the precedent of 38, and close similarities in the

NMR spectra of the products 41 and 27. Whether the

dramatic change in regioselectivity between entries 1 and

ꢀ8

2

, and 3 and 4 of Table 2 is due to the alkene geometry, or its

incorporation in a cyclohexene ring was examined with the

zirconacycle 42 derived from an acyclic cis-disubstituted

alkene. Insertion of lithium chloroallylide followed by

benzaldehyde occurred exclusively into the less hindered

side (Table 2, entry 5) but the product 43 was contaminated

with the dehydrozirconation product 45 (Eq. (10)). If the

reaction of the allyl complex with benzaldehyde was left

at room temperature for two days 45 became the almost

exclusive product (72%). By carrying out the reaction

with benzaldehyde for 2 h at room temperature 43 could

be isolated containing ,10% of 45. For full characterisation

the mixture was hydrogenated to give 46 as a single

compound (Eq. (10)). Similarly insertion of lithium chloro-

methallylide into 42 followed by hydrolysis with

We next examined the cyclohexene derived zirconacycle 23

(

4

formed by a different route by Barluenga ). Much to our

f

surprise, addition of lithium chloroallylide gave only the

product of insertion into the alkyl±zirconium bond, albeit

in poor yield (Table 1, entry 5). To rule out additional effects

of the nitrogen atom we also examined the all carbon

analogue 26, formed as a 9:2 mixture of diastereoisomers

by co-cyclisation of the enyne 25 using Cp ZrCl /Mg.

2

Protonation of 26 gave a separable mixture of the octa-

hydroindenes 32 and 33 (Eq. (9)). The relative stereo-

chemistry of 32 and 33 was based on NMR, in particular

small coupling constants to the ring junction allylic C±H

in the major isomer 32. Further elaboration of 26 was

problematic and only by performing the carbenoid insertion

at low temperature (21008C), and quenching the reaction at

NaHCO aq. gave a mixture of alkene regioisomers which

3

afforded the single compound 44 on hydrogenation. A

conclusion from the regioselective insertion into 42 is that

the unexpected regioselectivity of Table 2, entries 3 and 4

(and by implication, Table 1, entries 5 and 6) is due to the

G. J. Gordon et al. / Tetrahedron 56 (2000) 2113±2129

Table 2. Carbenoid insertions into a-substituted saturated zirconacycles

2117

a

Zirconacycles were formed by reaction with zirconocene(1-butene) (Ref. 1).

Method A: (i) lithium chloroallylide; (ii) benzaldehyde, BF

/PtO

b

3

´OEt

2

; (iii) NaHCO

3

aq. Method B: (i) lithium chloromethallylide; (ii) NaHCO

3

aq. Method C: as

B, then H

2

.

cyclohexyl ring, rather than alkene geometry.

product 50 contained 20% of the isomer resulting from

formation of the trans-fused zirconacycle (the exclusive

isomer in all-carbon systems lacking the ring-junction

methyl group). The formation of the cis-fused isomer as

the major stereoisomer of 49 was proven by carbonylation

to afford the cyclopentanones 56 and 57 (Eq. (11)). Cis and

trans assignments were based on the close agreement of ring

junction methyl proton NMR resonances (cis, 1.14; trans,

ꢀ

10

0.82) with that of the known 1-methyl-bicyclo[3.3.0]-3-

octanone (cis, 1.18; trans, 0.75).

2

7

Finally we examined saturated zirconacyclopentanes where

the difference between the two carbon±zirconium bonds is

in a substituent b to the metal (Table 3). With the mono-

cyclic zirconocycle 47 insertion occurred exclusively into

the side closest to the b-substituent to give an excellent

yield of 48 (Table 3, entry 1). The bicyclic zirconacyclo-

pentane 49 carrying a methyl substituent at the ring junction

ꢀ11

(

i.e. b-to the metal) gave the same resultÐcarbenoid

insertion occurs exclusively into the `more hindered' side

to afford 50 after addition of acetone (Table 3, entry 2). This

regiochemical result has been used in the total synthesis of

the dolabellane diterpene natural product acetoxyodonto-

Co-cyclisation of N-allyl-N-benzyl-N-(2-methylallyl)amine

with zirconocene gave the zirconacycle 51 exclusively as

the cis-fused isomer. The stereochemistry of 51 was proven

1

4d,26

schismenol.

Both the zirconacycle 49, and the ®nal

2

118

G. J. Gordon et al. / Tetrahedron 56 (2000) 2113±2129

Table 3. Carbenoid insertions into b-substituted saturated zirconacycles

a

Zirconacycles were formed by reaction with zirconocene(1-butene) (Ref. 1) except entry 1 which was formed by reaction with zirconocene(ethylene)

Ref. 18).

(

b

Method A: (i) lithium chloroallylide; (ii) benzaldehyde, BF

lithium chloroallylide; (ii) acetone, 568C, 24 h; (iii) NaHCO

3

´OEt

2 3 3

; (iii) NaHCO aq. Method B: (i) lithium chloromethallylide; (ii) NaHCO aq. Method C: (i)

3

aq.

c

Zirconacycle and product contain 20% of trans-fused isomer.

Plus 40% protonated zirconacycle.

d

by quenching with D O to give 58 in which the carbon-13

2

product in high yield. We may speculate that an `ate'

complex 60 may eliminate the OMe group to form a volatile

cyclopropane 61 (Eq. (12)) and an effect on the observed

regiochemistry cannot be ruled out.

NMR shift of the deuterated methyl group on a quaternary

centre (22.8) was shifted up®eld compared to the undeuter-

2

8

ated one (28.4) by steric compression (`g-gauche effect' ).

Insertion of lithium chloromethylallylide into 51 was

incomplete, the product 59 of protonation of 51 being

recovered, but was exclusively into the side nearest the

b-substituent. We also examined the zirconacycle 53 carry-

ꢀ12

ing a CH OMe substituent on the ring junction to investigate

2

possible electronic effects (inductively electron withdraw-

ing rather than donating like Me) (Table 3, entries 4 and 5).

Interestingly the zirconacycle 53 was formed exclusively

cis-fused, proven by protonolysis and correlation to the

Discussion

The above regioselectivity results obtained for the insertion

2

9

known ((1S, 2S)-1,2-dimethylcyclopentyl)methanol. For

3 insertion of lithium chloroallylide occurred into the

carbon±zirconium bond closest to the extra substituent

Table 3, entries 4) and gave 54 in low yield after insertion

5

(

of benzaldehyde. Insertion of lithium chloromethallylide

followed by protonation gave the product 55 with the

same regiocontrol and slightly better yield. The low yields

of 54 and 55 arose in the carbenoid insertion step. Protona-

tion of the intermediate zirconacycle 53 gave the expected

Figure 1. Lateral attack.

G. J. Gordon et al. / Tetrahedron 56 (2000) 2113±2129

2119

2

Figure 2. Side views of 20 and 26 (CH OMe substituents replaced by H).

of lithium chloroallylide or chloromethallylide into zircon-

acycles do not have a simple explanation. The selectivity is

probably kinetically derived since the insertions occur in

less than 5 min at 2858C. The insertion mechanism (via

an `ate' complex 5) suggested in Scheme 3 implies initial

nucleophilic attack of the carbenoid at the metal centre. The

empty zirconium centred orbital upon which such attack

should occur exists in the s-ligand plane, and lateral attack

is expected (Fig. 1). It has been demonstrated both experi-

mentally and theoretically that this direction of attack

occurs with carbon-monoxide. Steric hindrance of attack

then provides a reasonable explanation for the regio-

selectivity displayed in Table 1, entries 1±4 and 7, and

Table 2, entries 1, 2, 5 and 6. In the particular case of

insertion into 16 (Table 1, entry 3) the vinyl C±H adjacent

to the zirconium lies in the plane of the LUMO, whereas the

valence orbitals to generate an electron density isosurface

2

(0.01 eA ), coloured using Fukui's frontier electron

3

Ê

3

density, the susceptibility towards nucleophilic attack

showed no difference between the two sides of 32, but for

electrophilic attack, again we observed a marked bias

towards the cyclohexyl side (Fig. 3). The implication is

that the mechanism suggested in Scheme 3 with initial

attack by a nucleophilic species to form an `ate' complex

may not be correct. Rapid reversible formation of a zirco-

nate complex (like 5) with the 1,2-metallate rearrangement

being rate and product determining is possible but dif®cult

to investigate experimentally or theoretically. The

unexpected regiochemistry of insertion into 23, 26, 38,

and 40 is more consistent with initial attack by an electro-

philic species. A concerted insertion into the C±Zr bond

seems most likely since calculations show that the zir-

conium centre is strongly electrophilic (Eq. (13)). Both

calculations and experimental results demonstrate that

1-chloro-1-lithio species are powerful electrophiles through

3

0

Zr±CH hydrogens lie above and below the plane and

2

provide less steric hindrance to the lateral attack. The

dramatic reversal in selectivity observed in Table 1 between

entry 4 and entries 5 and 6 is more dif®cult to explain. The

3

4

`metal assisted ionisation' (Eq. (14)). The lowest energy

structure of some 1-halo-1-lithium species may be

represented as 63, with a substantial positive charge on

the carbenoid carbon. It is interesting that in a similar

system to 38 Mori observes the opposite regiochemistry

for transmetallation with alkylmagnesium species (Table 2,

entry 3, cf. Eq. (7), notwithstanding the stereochemical

cyclohexane ring in 23 and 26 holds the `CH ' nearest

2

the metal well away from the plane of the LUMO whereas

the methyl group in 20 is in the plane (Fig. 2) so a change in

selectivity towards insertion in the alkyl side might be

expected. However, the alkyl side is bulkier in 23/26 than

in 16 so a further factor is needed to explain the change in

selectivity from 1:0 to 2.2:1 between Table 1, entries 3 and 5/

1

9

difference).

6. The unexpected regioselectivity caused by the fused cy-

clohexyl ring is clearly seen in Table 2, entries 3 and 4

where insertion occurs into the more sterically hindered

side of 38 and 40. In search of an explanation we carried

out geometry optimisation and molecular orbital calcula-

tions on the model 62 using the ZINDO program (theoreti-

ꢀ

13

14

3

1

cal INDO/1 parameters ), as implemented in the CAChe

3

2

workstation. The most stable starting conformations of the

zirconacycle for the calculations were determined using

MM2 calculations keeping the ZrCp₂fragment (taken

5

from the crystal structure of trans-2,2-bis(h -cyclopenta-

3

2

dienyl)-2-zircona-perhydropentalene) rigid. We were

disappointed to ®nd that the LUMO of 62 showed no sig-

ni®cant differences in coef®cients either side of the metal

ZINDO calculations on the zirconacycles 20, 29 and 34

demonstrated the same bias in the HOMO and the suscepti-

bility towards electrophilic attack on the side of the methyl

substituent. Presumably the steric blocking effect of the

methyl group in these cases overrides the `electronic bias'.

The same dominance of steric effects applies to the zircon-

acycles 14 and 15. It is interesting that in the zirconacycle

16 the HOMO shows little bias towards either carbon±

zirconium bond and we get a mixture of regioisomeric

(

Fig. 3). In comparison the HOMO showed a much larger

coef®cient on the C±Zr bond into which insertion occurs

Fig. 3). The NHOMO showed the opposite relative sizes of

coef®cients for the two C±Zr bonds, but was calculated to

(

2

1

be 140 kJ mol lower in energy than the HOMO and

should therefore have less in¯uence. Using the sum of all

2

120

G. J. Gordon et al. / Tetrahedron 56 (2000) 2113±2129

Figure 3. ZINDO calculations on 62.

insertion products. The result for insertion into zirconacycle

2 (Table 2, entries 5 and 6) seems anomalous since ZINDO

resembles the structure of the cyclohexyl-fused system 40)

(Fig. 4) overriding the electronic bias.

4

calculations show a strong preference for insertion into the

carbon±zirconium bond adjacent to the ethyl substituent,

and the ethyl group is orientated away from the direction

of lateral attack. Molecular mechanics calculations on 42

indicate that the conformation A in which the terminal

Zirconacycles where the symmetry breaking substituent is

b- to the zirconium (Table 3) insert allyl carbenoids with

excellent regiocontrol. Calculations show a slight bias of the

HOMO towards the observed sites of insertion (Fig. 5). The

LUMO again shows no signi®cant differences between the

two sides. The regioselectivity is the same as that observed

2

1

methyl group blocks attack on the metal is 6.9 kJ mol

lower in energy than conformation B (which more closely

2

Figure 4. Conformations of a model 64 for 42 (CH OMe replaced by H).

G. J. Gordon et al. / Tetrahedron 56 (2000) 2113±2129

2121

Figure 5. HOMOs for 65 and 66, models for 49 and 47, respectively. Cp rings hidden.

in related systems for transmetallations with organo-

magnesium and organocopper species (Table 3, entry 1,

of directly attached protons (0,1,2,3, respectively), this

being determined by DEPT experiments. Electron impact

(70 eV) (EI), Chemical Ionisation (using ammonia as the

reagent gas) (CI), and electrospray (ES) mass spectra,

including accurate masses, were recorded on a VG

Analytical 70±250-SE double focusing mass spectrometer.

Atmospheric pressure chemical ionisation (APCI) mass

spectra were recorded on a VG Platform spectrometer in

acetonitrile. M/z signals are reported as values in atomic

mass units followed by the peak intensity relative to the

base peak. Infrared spectra were recorded on a Perkin±

Elmer 1600 FT-IR spectrometer as ®lms between sodium

chloride plates unless otherwise stated. Peaks are described

as s (strong), m (medium), w (weak), and/or br (broad).

Elemental analyses were performed by the University

College London Microanalysis Service. Melting points

were measured on a Gallenkamp type apparatus and are

uncorrected. Organometallic reactions were performed

under argon using standard Schlenk techniques. Tetrahydro-

furan was freshly distilled from sodium/benzophenone.

Petrol refers to the fraction of petroleum ether that has a

boiling range 40±608C and was distilled before use.

1

8,13c

cf. Eq. (3) and entries 2/3, cf. Eq. (5)).

tions indicate that the oxygen substitution in zirconacycle

3 has little effect on the HOMOÐthere is a slight bias

ZINDO calcula-

5

towards the observed site of insertion.

Conclusion

In summary we have uncovered a complex pattern of regio-

selectivity in the insertion of carbenoids into zirconacycles. It

is pleasing that in all but one case examined so far insertion

is completely regioselective. Steric hindrance of attack on

one side of the zirconacycle provides a reasonable explana-

tion in only some cases. Theoretical calculations provide

an explanation of the regiocontrol in other cases only if

the dominant Frontier Molecular Orbital interaction is

between the LUMO of the carbenoid and HOMO of the

zirconacycle. These regioselectivity results suggest that

addition of lithium chloroallylides to zirconacycles should

be considered as a concerted insertion of an electrophilic

carbenoid into a carbon±zirconium bond, rather than

nucleophilic attack on the metal to form a zirconate species

followed by a 1,2-metallate rearrangement.

Synthesis of cyclisation precursors

General procedure for synthesis of malonate derived

precursors. Sodium (0.74 g, 30 mmol) was added portion-

wise to ethanol (25 mL). Once dissolution was complete a

solution of diethyl allylmalonate (4.00 g, 20 mmol) or

dimethyl propargylmalonate (3.40 g, 20 mmol) in ethanol

Experimental

General techniques

(

10 mL) was added slowly. After 10 min a solution of the

Molecular modelling (MM2) and semi-empirical (ZINDO)

calculations were carried out using CAChe Worksystem

Software version 4.0 (Oxford Molecular) running on a

PowerMac 7600 computer. Molecular orbital surfaces are

appropriate allyl or propargyl bromide (25 mmol) in ethanol

(10 mL) was added dropwise. The mixture was stirred at

room temperature overnight, then poured onto water

(250 mL) and extracted with diethyl ether (3£100 mL).

The combined extracts were washed with water

2

3

Ê

shown at the 0.06 eA contour. Electron density surfaces

2

are shown at the 0.01 eA contour and coloured using

3

Ê

(3£200 mL) and brine (200 mL), dried (MgSO ) and the

4

3

Frontier Density.

solvent removed in vacuo to afford the dialkylated malo-

nate. In some cases puri®cation was unnecessary, in others

puri®cation was by column chromatography on silica eluted

with 5% diethyl ether in petrol.

1 13

H and C NMR spectra were recorded on a Bruker AC300

spectrometer (300 MHz proton, 75 MHz carbon) in CDCl₃

unless otherwise stated. The chemical shifts in proton

spectra are reported as values in ppm relative to internal

tetramethylsilane standard, or residual solvent. The follow-

ing abbreviations are used to denote multiplicity and shape

of signal and may be compounded: ssinglet, ddoublet,

ttriplet, qquartet, mmultiplet, brbroad. Carbon-13

spectra were proton decoupled and referenced to solvent

and signals reported as s, d, t, q, depending on the number

To a suspension of lithium aluminium hydride (2.28 g,

60 mmol) in diethyl ether (100 mL) at 08C was added drop-

wise a solution of the substituted malonate ester formed

above, in diethyl ether (50 mL). The reaction was left to

stir overnight at room temperature. The reaction was

quenched by dropwise addition of a solution of ethyl acetate

(10 mL) in diethyl ether (40 mL) followed by water

2

122

G. J. Gordon et al. / Tetrahedron 56 (2000) 2113±2129

2

914 (m), 745 (m), 694 (m) cm . LRMS (EI): 260 (M ,

1

(

10 mL). The mixture was poured onto 2 M HCl solution

500 mL) and the organic layer separated. The aqueous

1

78%), 228 (M 2MeOH, 20), 196 (M 22MeOH, 17), 155

1

(34), 104 (22), 91 (62), 45 (100). HRMS (EI): Found: M ,

layer was extracted with diethyl ether (2£250 mL). The

combined organic extracts were dried (MgSO ) and the

4

260.1797. C H O requires: 260.1776. Anal. Found: C,

2

17 24

solvent removed in vacuo to give a diol as a clear, thick oil.

77.9; H, 9.65. C H O requires: C, 78.4; H, 9.29%.

17 24 2

Sodium hydride (1.60 g of a 60% suspension in oil,

40 mmol) was placed in a ¯ask under nitrogen, washed

with hexane (20 mL), and then suspended in anhydrous

THF (20 mL). A solution of the diol formed above in

THF (50 mL) was added dropwise over 30 min, followed

by a solution of methyl iodide (40 mmol, 2.49 mL) in THF

3-(1,1-Bis(methoxymethyl)-3-butenyl)-1-cyclohexene.

Final Kugelrohr distillation (110±1208C at 0.7 mmHg) gave

1

a clear, colourless oil (67%). H NMR: d 5.876 (1H, ddt,

J16.9, 10.0, 7.5 Hz), 5.65±5.72 (2H, m), 5.006 (1H, d,

J16.9 Hz), 4.994 (1H, d, J10.0 Hz), 3.319 (2H, s),

3.296 (3H, s), 3.282 (3H, s), 3.269 (2H, s), 2.36 (1H, m),

2.135 (2H, d, J7.5 Hz), 1.92±1.98 (2H, m), 1.68±1.80

(

20 mL). After 2 h the reaction was quenched by addition of

1

3

methanol (10 mL) then poured onto water (300 mL) and

extracted with diethyl ether (3£100 mL). The combined

extracts were washed with water (3£100 mL) and brine

(2H, m), 1.39±1.55 (2H, m) ppm. C NMR: d 135.80 (d),

128.52 (d), 128.33 (d), 116.83 (t), 75.42 (t), 75.28 (t), 59.27

(q), 59.24 (q), 43.55 (s), 38.87 (d), 36.64 (t), 25.46 (t), 24.17

(t), 23.16 (t) ppm. IR: 1637 (m), 1480 (m), 1447 (s), 1197

(s), 1163 (m), 1107 (s), 998 (m), 970 (m), 911 (s), 721

(

100 mL), dried (MgSO ) and the solvent removed in

4

vacuo to give a yellow oil. Puri®cation was by column

chromatography on silica eluted with 5% diethyl ether in

petrol, followed by Kugelrohr distillation. Using the above

method the following materials were prepared.

2

1

(m) cm . LRMS (APCI): 225.0 (M1H , 100%), 192.9

(M2MeOH1H , 80). Anal. Found: C, 74.65; H, 10.86.

1

C H O requires: C, 74.95; H, 10.78%.

2

1

4

24

(

E)-4,4-Bis(methoxymethyl)-6-octen-1-yne (19). The title

(Z)-4,4-Bis(methoxymethyl)-1,6-nonadiene. (Z)-1-Bromo-

3

5

compound was prepared as above, using `predominantly

trans' commercial crotyl bromide. Final Kugelrohr distilla-

tion (100±1108C at 1.0 mmHg) gave a clear, colourless oil

pent-2-ene was prepared by the method of Corey and used

crude in the reaction sequences described above to afford

the title diene (80%) as a clear, colourless oil after Kugel-

1

(

74% of a 1:5.9 Z/E ratio by GC). Data is given for the trans

rohr distillation (110±1258C at 1 mmHg). H NMR: d 5.782

1

isomer: H NMR: d 5.29±5.60 (2H, m), 3.284 (6H, s), 3.16±

.22 (4H, m), 2.133 (2H, d, J2.8 Hz), 2.043 (2H, d,

J7.4 Hz), 1.934 (1H, t, J2.8 Hz), 1.137 (3H, dd,

(1H, ddt, J18.1, 9.2, 7.5 Hz), 5.446 (1H, dtt, J11.0, 6.8,

1.2 Hz), 5.326 (1H, dtt, J11.0, 7.2, 1.2 Hz), 4.98±5.06

(2H, m), 3.275 (6H, s,), 3.134 (4H, s), 2.00±2.08 (6H, m),

3

1

3

13

J7.4, 0.9 Hz) ppm. C NMR: d 128.67 (d), 125.98 (d),

1.49 (s), 74.58 (2t), 70.13 (d), 59.30 (2q), 41.90 (s), 34.80

t), 22.00 (t), 18.18 (q) ppm. IR: 1606 (w), 1477 (m), 1457

0.931 (3H, t, J7.5 Hz) ppm. C NMR: d 134.61 (d),

8

134.23 (d), 123.97 (d), 117.53 (t), 75.13 (2t), 59.17 (2q),

42.14 (s), 36.75 (t), 29.57 (t), 20.57 (t), 14.36 (q) ppm. IR:

1638 (m), 1477 (s), 1458 (s), 1197 (s), 1178 (s), 1118 (s),

(

2

1

m), 1437 (m), 1196 (s), 1109 (s), 970 (s), 632 (s) cm .

1

21

LRMS (APCI): 197.2 (41%, M1H ), 183.1 (64), 152.9

(32). Anal. Found: C, 72.93; H, 10.42. C H O requires

2

C, 73.43; H, 10.27%.

995 (m), 973 (m), 914 (s), 734 (m) cm . LRMS (APCI):

213.2 (M1H , 100%). Anal. Found: C 73.14; H, 11.32.

1

2

20

C H O requires: C, 73.54; H, 11.39%.

1

3

24

2

3-(1,1-Bis(methoxymethyl)-3-butynyl)-1-cyclohexene (25).

Preparation of other cyclisation precursors

Obtained as a pale yellow oil after chromatography (52%).

Final puri®cation by Kugelrohr distillation was not possible

due to unexpected thermal instability. H NMR: d 5.65±

N-Benzyl-N-(2-cyclohexen-1-yl)-N-(2-propynyl)amine (22).

A solution of benzylamine (10 g, 93 mmol), propargyl bro-

mide (2.9 g, 24 mmol) and potassium carbonate (38 g,

279 mmol) in acetonitrile (50 mL) was stirred at room

temperature for 36 h. The reaction solution was then poured

into distilled water (150 mL) and the organic products

extracted with diethyl ether (200 mL). The organic portion

was washed with water (3£100 mL) and brine (2£100 mL)

1

5

2

.80 (2H, m), 3.381 (2H, s), 3.374 (2H, s), 3.309 (6H, s),

.45 (1H, m), 2.311 (2H, d, J2.8 Hz), 1.957 (1H, t,

1

.58 (2H, m) ppm. C NMR: d 128.77 (d), 128.06 (d),

J2.8 Hz), 1.90±2.00 (2H, m), 1.72±1.83 (2H, m), 1.45±

3

1

82.20 (s), 74.71 (t), 74.55 (t), 70.15 (d), 59.42 (2q), 43.47

(

ppm. IR: 2115 (w), 1448 (m), 1197 (m), 1110 (s), 637

s), 39.10 (d), 25.38 (t), 24.41 (t), 23.07 (t), 21.26 (t)

and dried over MgSO . Removal of solvent and distilla-

4

2

m) cm . LRMS (APCI): 223.0 (M1H , 27%), 190.9

1

36

(

tion (708C, 1 mmHg) gave N-(prop-2-ynyl)-benzylamine

1

M2MeOH1H , 87). HRMS (EI). Found M , 222.1614.

(1.57 g, 45%). To a suspension of potassium carbonate

(4.4 g, 32 mmol) in acetonitrile (40 mL) was added

N-(prop-2-ynyl)-benzylamine (1.5 g, 10.3 mmol) and

3-bromocyclohexene (1.58 mL, 13.7 mmol) and the solu-

tion was stirred at room temperature for 48 h. The reaction

solution was then poured into water (150 mL) and the

organic products extracted with diethyl ether (150 mL).

The organic portion was washed with water (3£100 mL),

C H O requires: 222.1620.

1

4

22

2

(

E)-4,4-Bis(methoxymethyl)-1-phenyl-1,6-heptadiene.

Final Kugelrohr distillation (150±1608C, 0.5 mmHg) gave a

1

clear, colourless oil (83%). H NMR: d 7.17±7.38 (5H, m),

6

5

.418 (1H, d, J15.8 Hz), 6.227 (1H, dt, J15.8, 7.6 Hz),

.85 (1H, m), 5.04±5.13 (2H, m), 3.336 (6H, s), 3.221 (4H,

s), 2.223 (2H, d, J7.3 Hz), 2.120 (2H, d, J7.6 Hz) ppm.

brine (2£100 mL) and dried over anhydrous MgSO .

4

1

3

C NMR (62.9 MHz): d 137.87 (s), 134.40 (d), 132.67 (d),

28.47 (2d), 126.91 (d), 126.43 (d), 126.00 (2d), 117.60 (t),

5.22 (2t), 59.16 (2q), 42.45 (s), 36.89 (t), 35.86 (t) ppm. IR:

639 (w), 1599 (w), 1449 (m), 1198 (m), 1109 (s), 968 (m),

Removal of solvent and Kugelrohr distillation (1408C at

0.1 mmHg) gave the title compound as a colourless oil

1

7

1

(2.242 g, 95%). H NMR: d 7.45±7.30 (5H, m), 5.95±

5.84 (2H, m), 3.94 (1H, d, J13.6 Hz), 3.75 (1H, d,

G. J. Gordon et al. / Tetrahedron 56 (2000) 2113±2129

2123

2

1192 (s), 1109 (s), 992 (m), 908 (s) cm . LRMS (APCI):

1

J13.6 Hz), 3.58 (1H, m), 3.41 (1H, d, J2.4 Hz), 3.40

1H, d, J2.4 Hz), 2.26 (1H, t, J2.4 Hz), 2.15±1.55 (6H,

1

141.0 (M1H , 100%). Anal. Found: C, 76.79; H, 11.78.

(

1

3

m) ppm. C NMR: d 139.80 (s), 130.51 (d), 130.16 (d),

28.83 (d, 2C), 128.29 (d, 2C), 126.95 (d), 81.45 (s), 72.44

C H O requires: C, 77.09; H, 11.50%.

9 16

1

(

d), 57.56 (d), 53.13 (t), 39.29 (t), 25.36 (t), 24.90 (t), 31.34

t) ppm. IR: 3296 (s), 2356 (w), 1648 (w), 1601 (w), 1492

m), 1451 (s), 1144 (s), 1122 (s), 740 (s), 698 (s) cm .

Formation and elaboration of zirconacycles

2

1

Method A. Co-cyclisation using Cp ZrCl /2 EtMgCl. To

2

1

LRMS (ES): 226 (M1H , 100%), 150 (20). HRMS (EI):

Found: M , 225.1502. C H N requires: 225.1517.

a stirred solution of zirconocene dichloride (0.292 g,

1 mmol) in THF (5 mL) under argon at 2808C was added

ethylmagnesium bromide (0.64 mL of a 3.2 M solution in

diethyl ether, 2 mmol) and the reaction stirred at this

temperature for 40 min before the enyne or diyne

1

6

19

N-Benzyl-N-(2-butynyl)-N-(2-propynyl)amine (28). To a

suspension of potassium carbonate (4.4 g, 32 mmol) in

acetonitrile (40 mL) was added N-(prop-2-ynyl)-benzyl-

amine (1.5 g, 10.3 mmol, prepared as described above)

and 2-butynyl p-toluenesulphonate (Lancaster, 3.3 g,

(

1 mmol) in THF (2 mL) was added dropwise. The

reaction mixture was allowed to warm to room temperature

over 1 h, then heated at 608C for 5 h to afford the required

zirconacycle as a solution in THF.

1

3.7 mmol). The solution was stirred at room temperature

for 48 h. The reaction solution was then poured into distilled

water (150 mL) and the organic products extracted with

diethyl ether (150 mL). The combined organic phases

were washed with water (3£100 mL), brine (2£100 mL)

Method B. Co-cyclisation using Cp ZrCl /Mg. To a

2

suspension of magnesium powder (0.039 g, 1.5 mmol) in

THF (1 mL) was added 1,2-dibromoethane (0.30 mL of a

0.5 M solution in THF, 0.15 mmol). The mixture was stirred

at room temperature for 30 min then the solvent removed in

vacuo. A solution of the enyne (1 mmol) in THF (4 mL) was

added and the reaction mixture cooled to 08C under argon. A

solution of zirconocene dichloride (0.322 g, 1.1 mmol) in

THF (6 mL) was added dropwise over 30 min. Over 3 h

the reaction changed colour through yellow to a deep

brown. The reaction solution was ®ltered through a sinter

under argon to remove excess magnesium powder, giving

the zirconacycle as a solution in THF.

and dried over anhydrous MgSO . Removal of solvent and

4

Kugelrohr distillation (1208C at 0.1 mmHg) gave the title

compound as a colourless oil (1.368 g, 67%). H NMR: d

1

7

3

.42±7.25 (5H, m), 3.71 (2H, s), 3.45 (2H, d, J2.4 Hz),

.39 (2H, q, J2.2 Hz), 2.30 (1H, t, J2.4 Hz), 1.87 (3H, t,

1

3

J2.4 Hz) ppm. C NMR: d 138.04 (s), 129.26 (d, 2C),

1

7

3

1

28.38 (d, 2C), 127.35 (d), 80.80 (s), 78.96 (s), 74.26 (s),

3.25 (d), 57.18 (t), 42.44 (t), 41.67 (t), 3.61 (q) ppm. IR:

288 (s), 2231 (w), 1602 (m), 1494 (s), 1453 (s), 1359 (s),

2

1

327 (s), 1128 (s), 1074 (s), 971 (s), 741 (s), 699 (s) cm .

1

LRMS (ES): 198 (M1H , 100%), 150 (10%). HRMS (EI):

Found: M , 197.1189. C H N requires: 197.1204.

1

4

15

Method C. Co-cyclisation using in situ generated zir-

conocene(1-butene). To a solution of zirconocene di-

chloride (0.293 g, 1 mmol) in THF (5 mL) under argon at

2788C was added n-BuLi (0.80 mL of a 2.5 M solution in

hexanes, 2 mmol) followed by a solution of the appropriate

diene (1 mmol) in THF (1 mL). The reaction mixture was

allowed to warm to room temperature overnight to give the

zirconacycle as a solution in THF.

2

-(Methoxymethyl)-1,6-heptadiene. 2-Hydroxymethyl-1,6-

3

7

heptadiene ^w^a^s^p^r^e^p^a^r^e^d^b^y^Lⁱ^A^l^H4 reduction of the

sodium salt of diethyl 4-pentenylmalonate and contained

2

0% of the over reduced compound 2-hydroxymethyl-6-

heptene. To a solution of 2-hydroxymethyl-1,6-heptadiene

3.2 mmol, 0.504 g of ca. 80% pure compound) in dry

CH Cl (10 mL) at 2508C was added triethylamine

(

2

(

6 mmol, 0.83 mL) and methanesulphonyl chloride

5 mmol, 0.40 mL). The reaction was warmed to 2208C

Method D. Insertion of lithium chloroallylide or lithium

chloromethyallylide into a zirconacycle with protic

work-up. The zirconacycle solution was cooled to 2788C

and allyl chloride or methallyl chloride (1.5 mmol) was

added followed by the dropwise addition of a solution of

lithium diisopropylamide [1.5 mmol, prepared from n-BuLi

(0.60 mL of a 2.5 M solution in hexanes, 1.5 mmol) and

diisopropylamine (0.152 g, 1.5 mmol) in THF (2 mL) at

08C for 30 min]. The reaction was warmed to room tempera-

ture over 2 h before quenching by addition of methanol

(2 mL) and saturated sodium bicarbonate solution (5 mL).

After stirring for 30 min the reaction mixture was poured

onto water (50 mL) and extracted with diethyl ether

(3£25 mL). The combined extracts were washed with

over 4 h, then poured onto water (100 mL) and extracted

with CH Cl (100 mL). The organic extract was dried

(

crude methanesulphonate as a yellow oil, which was

dissolved in methanol (5 mL) and added to a solution of

sodium (16.7 mmol, 0.40 g) in methanol (20 mL). The reac-

tion was stirred at room temperature overnight then poured

onto water (200 mL), and extracted with diethyl ether

2

MgSO ) and the solvent removed in vacuo to give the

4

(

3£100 mL). The combined extracts were washed with

water (3£100 mL) and brine (100 mL), dried (MgSO )

4

and the solvent removed in vacuo to give the crude title

product as a yellow oil. Puri®cation by column chromato-

graphy (silica, 5% diethyl ether in petrol), followed by

Kugelrohr distillation (100±1058C at 10 mmHg) gave the

water (3£50 mL) and brine (50 mL), dried (MgSO ), and

4

the solvent removed in vacuo to afford the crude product.

1

title compound (0.356 g, 80%) as a colourless oil. H NMR:

d 5.809 (1H, ddt, J17.1, 10.3, 6.6 Hz), 5.004 (1H, d,

Method E. Sequential insertion of lithium chloroallylide

or lithium chloromethyallylide and benzaldehyde into a

zirconacycle. The zirconacycle solution was cooled to

2788C and allyl chloride or methallyl chloride (1.5 mmol)

was added followed by the dropwise addition of a solu-

tion of lithium 2,2,6,6-tetramethylpiperidide [1.5 mmol,

J17.1 Hz), 4.999 (1H, s), 4.954 (1H, d, J10.3 Hz),

4

(

1

(

.905 (1H, s), 3.847 (2H, s), 3.308 (3H, s), 2.03±2.10

1

3

4H, m), 1.550 (2H, pentet, J7.6 Hz) ppm. C NMR: d

45.96 (s), 138.73 (d), 114.75 (t), 111.62 (t), 75.68 (t), 57.94

q), 33.58 (t), 32.58 (t), 26.95 (t) ppm. IR: 1641 (s), 1451 (s),

2

124

G. J. Gordon et al. / Tetrahedron 56 (2000) 2113±2129

prepared from n-BuLi (0.60 mL of a 2.5 M solution in

hexanes, 1.5 mmol) and 2,2,6,6-tetramethylpiperidine

zirconacycle 30 was prepared from (E)-4,4-bis(methoxy-

methyl)-6-octen-1-yne 19 via method B and lithium chloro-

methallylide inserted as in method D. The solvent was then

removed in vacuo and replaced with benzene (5 mL). The

reaction mixture was ®ltered through an in-line sinter under

argon and the residue extracted with more benzene (3 mL).

The resulting solution was concentrated in vacuo to 1 mL

and dry acetone (1 mL) added. The resulting mixture was

heated at 508C overnight. After cooling to room temperature

methanol (2 mL) and saturated sodium bicarbonate solution

(2 mL) were added. The mixture was stirred for 1 h, then

poured onto water (50 mL) and extracted with diethyl ether

(3£50 mL). The combined extracts were washed with water

(

0.212 g, 1.5 mmol) in THF (2 mL) at 08C for 30 min].

The reaction was warmed to 2308C over 2 h, then cooled

to 2788C and benzaldehyde (0.20 mL, 2 mmol,) and

BF ´OEt (0.29 mL, 2 mmol) were added. After 15 min

3

2

at 2788C the reaction was allowed to warm to room

temperature over 5 h. Methanol (2 mL) and saturated

sodium bicarbonate solution (2 mL) were added and the

mixture stirred for 1 h, then poured onto water (50 mL)

and extracted with diethyl ether (3£50 mL). The combined

extracts were washed with water (3£100 mL), brine

(

50 mL), dried (MgSO ) and the solvent removed in vacuo

4

to afford the crude product.

(3£100 mL) and brine (50 mL), dried (MgSO ) and the

4

solvent removed in vacuo. Puri®cation by column chroma-

tography (silica, 10±20% diethyl ether in petrol) gave the

title compound (0.148 g, 51%) as a colourless oil. H NMR:

(

3

E)-5-(2-Methylenecyclopentyl)-1-phenyl-3-penten-1-ol

17) and (3E,5Z)-5-(2-methylcyclopentylidene)-1-phenyl-

-penten-1-ol (18). Co-cyclisation of hept-1-en-6-yne

1

4

c

d 5.913 (1H, dt, J10.7, 2.5 Hz), 5.860 (1H, qt, J6.0,

2.6 Hz), 4.86 (2H, m), 3.317 (3H, s), 3.312 (3H, s), 3.225

(1H, d, J11.2 Hz), 3.228 (1H, d, J10.1 Hz), 3.202 (1H, d,

J11.2 Hz), 3.198 (1H, d, J10.1 Hz), 2.912 (1H, d,

J10.7 Hz), 2.328 (1H, dd, J16.0, 2.3 Hz), 2.22±2.27

(2H, m), 2.229 (1H, dd, J16.0, 2.3 Hz), 1.795 (3H, dd,

J1.4, 0.9 Hz), 1.660 (3H, dt, J7.0, 1.5 Hz), 1.195 (3H,

using method A and elaboration of the zirconacycle using

method E (allyl chloride) followed by column chromato-

graphy (silica, 8% diethyl ether in petrol) gave the title

compounds as a clear yellow oil in a combined yield of

7

9% (0.191 g). Ratio of products 17:18, determined from

1

H NMR of the crude product to be 2.2:1. H NMR: d 7.40±

1

3

7

.15 (5H, m), 6.32 (1H(18), m), 5.90 (1H(18), dd, J11.0,

s), 1.185 (3H, s) ppm. OH not seen. C NMR: d 146.18 (s),

141.32 (s), 139.98 (s), 116.98 (d), 114.31 (d), 113.74 (t),

76.03 (t), 75.84 (t), 72.95 (s), 59.42 (q), 59.39 (q), 57.58 (d),

45.05 (s), 36.34 (t), 25.95 (t), 28.44 (q), 28.08 (q), 23.13 (q),

14.85 (q) ppm. IR: 3456 (s, br), 1637 (m), 1449 (s), 1374 (s),

1.7 Hz), 5.65±5.40 (2H(17)11H(18), m), 4.91(1H(17), br.

s), 4.80 (1H(17), br. s), 4.75±4.65 (1H(17)11H(18), m),

.85 (1H(17), m), 1.65±1.15 (11H(17)110H(18), m), 1.02

2

1

3

(

3H(18), d, J7.0 Hz) ppm. C NMR: d 156.33 (s), 152.06

2

1

(

s), 144.12 (s, 2C), 133.67 (d), 131.66 (d), 128.50 (d, 4C),

1198 (s), 1112 (s), 954 (m), 910 (m), 734 (s) cm . LRMS

(APCI): 331.3 (M1Na , 9%), 309.3 (M1H , 16), 291,

1

127.55 (d, 2C), 126.88 (d), 125.98 (d, 4C), 120.11 (d, 2C,

18), 104.69 (t, 17), 73.81 (d, 18), 73.56 (d, 17), 43.78 (d, 17),

43.16 (t), 43.04 (t), 37.67 (t), 35.40 (d, 18), 35.01 (t), 33.70

1

(M2H O1H , 100), 259.2 (M2H O2MeOH1H , 41%).

1

2

1

HRMS (EI). Found: M , 308.2345. C H O requires:

308.2345.

1

9

32

3

(

t), 33.51 (t), 32.40 (t), 24.29 (t), 23.98 (t), 21.26 (q, 18)

ppm. IR: 3362 (br. s), 1649 (m), 1602 (w), 1492 (m), 1451

2

s), 1047 (m), 969 (s), 699 (s) cm . LRMS (EI): 242 (M ,

1

(

rac-(3E)-4-(3aS,4S,7aS)-1-Benzyl-3-methyleneoctahydro-

1H-indol-4-yl)-1-phenyl-3-buten-1-ol (24). N-Benzyl-N-

(2-cyclohexen-1-yl)-N-(2-propynyl)amine (22) was co-

cyclised using method A, and the zirconacycle elaborated

using method E except that 5 equiv. of allyl chloride/LiTMP

and PhCHO/BF ´Et O were used. The crude product was

1

%), 225 (M 2OH, 25), 143 (25), 136 (100), 121 (15), 107

4

1

(

requires: 242.1671.

66), 79 (42). HRMS (EI): Found: M , 242.1677. C H O

17 22

(

4Z)-3-Ethyl-1,1-bis(methoxymethyl)-4-(3-methyl-2-

3

2

butenylidene)cyclopentane (21). (E)-4,4-Bis(methoxy-

methyl)-6-octen-1-yne 19 was co-cyclised using method

B, and the zirconacycle elaborated using method D (methallyl

chloride), except that protonolysis was carried out with

glacial acetic acid (2 mL) for 24 h. The crude product was

puri®ed by column chromatography (silica, 5±10% diethyl

puri®ed by column chromatography (grade III basic

Al O , 50% diethyl ether in petrol) to afford the title

2

3

1

compound as an orange oil (0.108 g, 28%). H NMR: d

7.45±7.10 (10H, m), 6.06 (1H, dt, J15.5, 7.6 Hz), 5.32

(1H, m), 4.95 (1H, br. d, J7.8 Hz), 4.80 (1H, br. d,

J7.8 Hz), 4.55 (1H, m), 3.74 (1H, dd, J13.2, 4.1 Hz),

3.35±3.25 (2H, m), 3.17 (1H, dd, J13.2, 5.9 Hz), 2.96

(1H, ddt, J14.5, 6.2, 2.3 Hz), 2.76±2.61 (2H, m), 2.45±

ether in petrol) to give the title diene 21 as a colourless oil

(

1

0.167 g, 66%). H NMR: d 6.072 (1H, d, J11.5 Hz),

1

3

5

3

.892 (1H, d, J11.5 Hz), 3.353 (3H, s,), 3.307 (3H, s),

.25±3.37 (4H, m), 3.131 (1H, d, J10.9 Hz), 3.094 (1H,

2.20 (3H, m), 1.75±1.05 (6H, m) ppm. C NMR: d 149.79

(s), 145.19 (s), 140.06 (s), 138.54 (d), 137.99 (d), 128.84 (d,

2C), 128.57 (d, 2C), 128.46 (d, 2C), 127.29 (d), 127.14 (d),

126.20 (d, 2C), 105.56 (t), 73.72 (d), 62.84 (d), 58.68 (t),

57.19 (t), 48.02 (d), 43.14 (t), 41.50 (d), 28.49 (t), 23.99 (t),

19.83 (t) ppm. IR: 3392 (s, br), 1666 (m), 1602 (s), 1494

d, J10.9 Hz), 2.66 (1H, m), 2.298 (1H, d, J15.5 Hz),

2

1

.149 (1H, d, J15.5 Hz), 1.791 (3H, s), 1.733 (3H, s),

1

3

C

.22±1.37 (2H, m), 0.889 (3H, t, J8.1 Hz) ppm.

NMR: d 146.27 (s), 132.21 (s), 121.92 (d), 118.57 (d),

2

1

7

4

7.70 (t), 74.93 (t), 59.48 (q), 59.42 (q), 46.59 (s), 41.06 (t),

0.67 (d), 37.53 (t), 29.66 (t), 26.43 (q), 18.16 (q), 11.96 (q)

(m), 1453 (s), 1377 (m), 1046 (m), 970 (m), 699 (s) cm .

LRMS (ES): 374 (M1H , 100%). HRMS (EI): Found: M ,

1

ppm. IR: 1622 (w), 1476 (m), 1458 (m), 1377 (m), 1198 (m),

1

(

373.2390. C H ON requires: 373.2406.

2

6

31

2

1

112 (s), 734 (s) cm . LRMS (APCI): 252.3 (M , 9%), 221.2

1

M2MeOH1H , 100), 189.1 (M22MeOH1 H , 18).

1

rac-(3aR,4S,7aS)-1,1-Bis(methoxymethyl)-3-methylene-

-(2-methyl-2-propenyl)octahydro-1H-indene (27). 3-(1,1-

4

3((Z)-((2E)-2-Ethylidene-4,4-bis(methoxymethyl)cyclo-

pentylidene)methyl)-2,4-dimethyl-4-penten-2-ol (31). The

Bis(methoxymethyl)-3-butynyl)-1-cyclohexene 25 was co-

cyclised using method B and the zirconacycle 26 elaborated

G. J. Gordon et al. / Tetrahedron 56 (2000) 2113±2129

2125

by method D (methallyl chloride) except that carbenoid

addition was carried out at 21008C, and the reaction

quenched below 2608C. Column chromatography (silica,

butynyl)-N-(2-propynyl)amine 28 was co-cyclised using

method A, and the zirconacycle elaborated using method

E except that 5 equiv. of allyl chloride/LiTMP and

PhCHO/BF ´Et O were used. The crude product was puri-

5% diethyl ether in petrol) followed by Kugelrohr distilla-

tion (155±1608C at 1 mmHg) gave the title compound

3

2

®ed by column chromatography (grade III basic Al O , 50%

2

3

1

(

0.206 g, 74%) as a pale yellow oil. H NMR: d 4.960

1H, d, J2.6 Hz), 4.889 (1H, d, J2.6 Hz), 4.748 (1H,

diethyl ether in petrol) to afford the title compound as an

orange oil (0.265 g, 76%). H NMR: d 7.40±7.05 (10H, m),

1

(

s), 4.696 (1H, s), 3.360 (3H, s), 3.315 (3H, s), 3.24±3.42

6.78 (1H, dd, J14.8, 11.8 Hz), 5.91±5.80 (2H, m), 5.61

(1H, dt, J15.2, 7.5 Hz), 4.45 (1H, dd, J7.3, 5.5 Hz), 3.48

(2H, s), 3.26 (2H, s), 3.20 (2H, s), 2.46 (2H, m,), 1.41 (3H, d,

(

4H, m), 2.72±2.76 (1H, m), 2.22±2.36 (3H, m), 2.038 (1H,

dd, J17.0, 1.3 Hz), 1.74±1.82 (3H, m), 1.733 (3H, s),

1

3

13

1

(

5

(

.04±1.56 (5H, m) ppm. C NMR: d 149.63 (s), 144.81

s), 111.27 (t), 107.41 (t), 75.19 (t), 73.86 (t), 59.35 (q),

9.17 (q), 46.84 (d), 46.14 (s), 45.13 (d), 43.25 (t), 39.16

t), 37.54 (d), 26.62 (t), 26.47 (t), 23.78 (t), 22.52 (q) ppm.

IR: 1650 (m), 1497 (m), 1447 (s), 1198 (s), 1112 (s), 910 (s),

J7.2 Hz) ppm. OH not observed. C NMR: d 143.92 (s),

138.51 (s), 137.55 (s), 136.26 (s), 130.69 (d), 130.15 (d),

128.90 (d, 2C), 128.40 (d, 2C), 128.31 (d, 2C), 127.52 (d),

127.17 (d), 125.86 (d, 2C), 121.26 (d), 120.97 (d), 73.66 (d),

61.78 (t), 60.71 (t), 58.07 (t), 42.98 (t), 15.53 (q) ppm. IR:

3392 (m, br.), 1667 (m), 1602 (m), 1493 (m), 1451 (s), 1320

2

1

8

2

88 (s), 734 (s) cm . LRMS (APCI): 279.2 (M1H , 9%),

1

47.2, (M2MeOH1H , 100), 215.1 (M22MeOH1H ,

1

21

1

(m), 752 (s), 699 (s) cm . LRMS (ES): 346 (M1H ,

100%). HRMS (EI): Found: M , 345.2088. C H ON

requires: 345.2093.

1

36). Anal. Found: C, 77.39; H, 10.96. C H O requires:

C, 77.65; H, 10.86%.

1

8

30

2

24 27

rac-(3aR,7aS)-1,1-Bis(methoxymethyl)-3-methyleneocta-

hydro-1H-indene (32) and rac-(3aS,7aS)-1,1-bis(methoxy-

methyl)-3-methyleneoctahydro-1H-indene (33). The

zirconacycle 26 was prepared from 3-(1,1-bis(methoxy-

methyl)-3-butynyl)-1-cyclohexene 25 via method B and

quenched at room temperature by addition of methanol

rac-(2R,3R)-2-Ethyl-8,8-dimethyl-3-(3-methyl-2-butenyl)-

7,9-dioxa-spiro[4.5]decane (35). 5-Allyl-5-((E)-2-butenyl)-

2, 2-dimethyl-1, 3-dioxane was co-cyclised according to the

method C, and the zirconacycle elaborated using method D

(methallyl chloride). Column chromatography (silica, 5%

ether in petrol) followed by Kugelrohr distillation (1428C,

0.1 mmHg) gave the title compound as a colourless oil

(2 mL) and saturated sodium bicarbonate solution (5 mL).

After 30 min the reaction mixture was poured onto water

1

(0.231 g, 87%). H NMR: d 5.101 (1H, t septet, J7.2,

(

50 mL) and extracted with diethyl ether (3£25 mL). The

1.5 Hz), 3.545 (4H, m), 2.221 (1H, ddd, J14.3, 7.2,

4.4 Hz), 1.908 (1H, dd, J13.2, 7.1 Hz), 1.838 (1H, dd,

J13.4, 7.2 Hz), 1.754 (1H, J14.9, 7.9 Hz), 1.693±1.600

(2H, m), 1.672 (3H, s), 1.580 (3H, s), 1.398 (2H, m), 1.398

combined extracts were washed with water (3£50 mL),

brine (50 mL), dried (MgSO ), and the solvent removed in

4

vacuo to give a yellow oil which was puri®ed by column

chromatography (silica, CH Cl ) to afford 32 (0.156 g, 70%)

1

3

(6H, s), 0.982 (2H, m), 0.875 (3H, t, J7.4 Hz) ppm.

C

2

1

and 33 (35 mg, 16%). Data for 32: H NMR: d 4.901 (1H,

tdd, J3.1, 2.0, 0.9 Hz), 4.768 (1H, qd, J2.6, 1.1 Hz),

NMR: d 131.81 (s), 123.28 (d), 97.71 (s), 70.42 (t), 70.39

(t), 46.03 (d), 45.01 (d), 40.08 (t), 39.82 (t), 39.66 (s), 32.14

(t), 26.89 (t), 25.97 (q), 24.23 (q), 23.76 (q), 17.91 (q), 12.70

(q) ppm. IR: 1651 (w), 1452 (m), 1385 (s), 1199 (s), 1078

3.331 (3H, s), 3.308 (3H, s), 3.21±3.37 (4H, m), 2.733

(

2

1H, br s), 2.323 (1H, ddt, J17.6, 2.3, 1.2 Hz), 2.081

2

1

1H, dq, J17.6, 2.3 Hz), 1.925 (1H, ddt, J16.9, 5.0,

(m), 1032 (m), 832 (m) cm . LRMS (CI, NH ): 284

3

1

4

1

(M1NH , 2%), 267 (M1H , 100), 251 (34), 209 (57),

.6 Hz), 1.837 (1H, dt, J11.5, 6.5 Hz), 1.46±1.66 (3H,

1

191 (59). HRMS (EI): Found: M , 266.2223. C H O

requires: 266.2246.

m), 1.33±1.41 (1H, m), 1.242 (1H, tq, J3.3, 12.7 Hz),

1

7

30

2

1

.111 (1H, ddq, J2.1, 3.2, 12.2 Hz), 0.940 (1H, dq,

1

3

J3.2, 12.2 Hz) ppm. C NMR: d 151.58 (s), 104.94 (t),

7

4

4.93 (t), 73.95 (t), 59.37 (q), 59.23 (q), 47.39 (s), 42.69 (d),

1.87 (d), 37.08 (t), 25.75 (t), 25.12 (t), 24.14 (t), 21.21 (t)

rac-(3E)-(1R,2R)-(2-Benzyl-4,4-bis(methoxymethyl)cyclo-

pentyl)-1-phenyl-3-penten-1-ol (37). (E)-4,4-Bis(methoxy-

methyl)-1-phenyl-1,6-heptadiene was co-cyclised using

method C, and the zirconacycle elaborated using method

E (allyl chloride). Column chromatography (silica, 10±

25% diethyl ether in petrol) gave the title compound

ppm. IR: 1656 (m), 1478 (m), 1448 (s), 1197 (s), 1110 (s),

9

2

1

64 (s), 913 (m), 873 (s) cm . LRMS (APCI): 225.1

1

(

M1H , 6%), 193.0 (M2MeOH1H , 100) Data for 33:

H NMR: d 4.724 (1H, dtd, J2.4, 2.1, 1.4 Hz), 4.665

1H, qd, J2.6, 1.4 Hz), 3.327 (3H, s), 3.315 (3H, s),

1

(

3

2

(0.177 g, 45%) as a colourless oil. H NMR: d 7.11±7.34

.22±3.40 (4H, m), 2.427 (1H, ddt, J17.3, 1.1, 2.6 Hz),

.155 (1H, dddd, J17.3, 2.6, 1.8, 0.6 Hz), 1.94±2.05 (2H,

(10H, m), 5.558 (1H, dt, J14.8, 6.6 Hz), 5.398 (1H, dt,

J14.8, 6.6 Hz), 4.69 (1H, m), 3.316 (3H, s), 3.250 (3H,

s), 3.162 (1H, d, J13.8 Hz), 3.144 (1H, d, J13.8 Hz),

3.112 (1H, d, J13.8 Hz), 3.095 (1H, d, J13.8 Hz),

2.894 (1H, dd, J17.7, 3.9 Hz), 2.39±2.35 (2H, m), 2.306

(2H, dd, J9.3, 13.2 Hz), 2.048 (1H, d, J3.0 Hz), 1.855

(1H, m), 1.75±1.67 (2H, m), 1.52±1.62 (2H, m), 1.04±1.15

m), 1.73±1.85 (3H, m), 1.09±1.26 (4H, m), 1.04 (1H, m)

ppm. C NMR: d 154.24 (s), 102.29 (t), 78.11 (t), 74.64 (t),

1

3

5

2

1

9.34 (q), 59.21 (t), 51.89 (d), 47.61 (d), 46.42 (s), 38.57 (t),

9.65 (t), 27.82 (t), 26.97 (t), 26.10 (t) ppm. IR: 3068 (m),

978 (s), 2921 (s), 2850 (s), 1657 (s), 1476 (m), 1446 (s),

392 (w), 1257 (w), 1196 (s), 1110 (s), 963 (m), 872

1

3

(2H, m) ppm. C NMR (62.9 MHz): d 144.09 (s),

141.61(s), 133.33 (d), 128.66 (2d), 128.35 (2d), 128.17

(2d), 127.39 (s), 126.53 (s), 125.83 (2d), 125.66 (d), 77.85

(t), 77.77 (t), 73.50 (s), 59.18 (2q), 46.22 (d), 45.11 (s),

2

1

(

m) cm . LRMS (APCI): 225.1 (M1H , 3%), 193.0

M2MeOH1H , 100). Anal. (on mixture). Found: C,

1

7

5.23; H, 10.96. C H O requires: C, 74.95; H, 10.78%.

14 24 2

44.76 (d), 42.76 (t), 40.31 (t), 39.14 (t), 38.70 (t), 36.71(t)

ppm. IR: 3436 (s, br), 1603 (w), 1494 (m), 1453(s), 1266

rac-(3E,5E)-5-((4Z)-1-Benzyl-4-ethylidenepyrrolidinyli-

dene)-1-phenyl-3-penten-1-ol (30). N-Benzyl-N-(2-

2

1

(m), 1199 (m), 1108 (s), 967 (s), 739 (s), 701 (s) cm .

2

126

G. J. Gordon et al. / Tetrahedron 56 (2000) 2113±2129

1

LRMS (CI, NH ): 426 (M1NH , 50%), 408 (M , 37),

13

1.60 (8H, m), 0.892 (3H, t, J7.1 Hz) ppm. C NMR: d

3

4

1

91 (M2H O1H , 40), 359 (M2H O2MeOH1H ,

3

1

144.19 (s), 133.81 (d), 128.47 (2s), 127.49 (d), 126.38 (d),

125.96 (2d), 77.98 (2t), 73.61 (d), 59.38 (2q), 45.25 (s),

45.18 (d), 44.43 (d), 42.95 (t), 39.32 (t), 39.04 (t), 36.89

(t), 36.46 (t), 21.52 (t), 14.64 (q) ppm. IR: 3415 (s, br),

2

1

00), 327 (M2H O22MeOH1H , 91). HRMS (EI):

2

1

Found: (M1H) , 409.2739. C H O

3

requires

2

7

37

4

09.2743.

1453 (s), 1197 (m), 1108 (s), 1045 (m), 1026 (m), 965

(m), 700 (s) cm LRMS (APCI): 343.4 (M2H O1H ,

2

1

rac-(3S,3aS,4S,7aS)-1-Benzyl-3-methyl-4-(2-methyl-1-

propenyl)-octahydro-1H-indole (39). N-Allyl-N-benzyl-

2

1

59%), 311.3 (M2H O2MeOH1H , 100), 279.3

2

1

9

1

(M2H O22MeOH1H , 92). HRMS (EI): Found: M2

N-(2-cyclohexen-1-yl)amine

method C and the zirconacycle elaborated using method D

methallyl chloride). Column chromatography (silica, 50%

diethyl ether in petrol) gave the title compound (0.187 g,

was co-cyclised using

2

1

PhCHOH1H , 254.2241. C H O requires: 254.2245.

1

6

30

2

(

rac-(3S,4S)-3-(3-Methylbutyl)-1,1-bis(methoxymethyl)-

4-propylcyclopentane (44). (Z)-4,4-Bis(methoxymethyl)-

1,6-nonadiene was co-cyclised using method C, and the

zirconacycle elaborated using method D (methallyl chlo-

ride) to afford a crude product (0.227 g, 85%) as a mixture

of double bond isomers. The alkene mixture was dissolved

in CH Cl (5 mL) and hydrogenated at 1000 psi in the

1

6

(

6%) as a yellow oil. H NMR: d 7.22±7.40 (5H, m), 5.116

1H, d, J9.5 Hz), 3.709 (1H, d, J13.2 Hz), 3.626 (1H, d,

J13.2 Hz), 2.96 (1H, m), 2.917 (1H, t, J9.2 Hz), 2.57

(

1

1H, m), 2.285 (1H, dd, J5.2, 9.2 Hz), 2.16 (1H, m),

.88±2.04 (2H, m), 1.54±1.79 (2H, m), 1.709 (3H, s),

.645 (3H, s), 1.15±1.42 (3H, m), 1.025 (3H, d,

2

1

3

J6.6 Hz) ppm. C NMR: d 139.97 (s), 130.04 (s),

28.93 (d), 128.75 (2d), 128.26 (2d), 126.79 (d), 63.06

d), 60.16 (t), 56.53 (t), 49.54 (d), 36.24 (d), 31.03 (d),

7.97 (t), 25.89 (q), 22.28 (q), 22.24 (t), 22.12 (t), 18.06

q) ppm. IR: 1494 (m), 1452 (s), 1375 (m), 1264 (m), 909

presence of PtO (10 mg) for 16 h. The reaction mixture

2

1

(

2

was ®ltered through celite, solvent removed and the residue

Kugelrohr distilled (150±1558C, at 1.0 mmHg) to give the

1

title compound (0.227 g, 84%) as a colourless oil. H NMR:

(

d 3.330 (6H, s), 3.14±3.20 (4H, m), 1.757 (1H, d,

J12.8 Hz), 1.735 (1H, d, J12.8 Hz), 0.90±1.68 (13H,

m), 0.872 (3H, t, J8.0 Hz), 0.863 (3H, d, J6.6 Hz),

2

1

s), 735 (s), 699 (s) cm . LRMS (ES): 284.3 (M1H ,

1

00%). HRMS (EI): Found: M , 283.2299. C H N

1

requires: 283.2300.

20 29

1

3

0.840 (3H, d, J6.6 Hz) ppm. C NMR: d 78.04 (2t),

5

9.38 (2q), 45.55 (d), 45.31 (s), 45.15 (d), 39.62 (t), 39.50

rac-(E)-4-[(3R,3aR,4S,7aS)-1,1-Bis(methoxymethyl)-3-

methyloctahydro-1H-inden-4-yl)-1-phenyl-3-buten-1-ol

(t), 27.77 (t), 26.64 (t), 31.96 (t), 28.48 (d), 23.13 (q), 22.53

(q), 21.62 (t), 14.67 (q) ppm. IR (thin ®lm) 1458 (s), 1384

(m), 1260 (m), 1198 (s), 1111 (s), 965 (m), 735 (m) cm .

2

1

(

41). 3-(1,1-Bis(methoxymethyl)-3-butenyl)-1-cyclohexene

1

was co-cyclised using method C and the zirconacycle

elaborated using method E (allyl chloride). Column

chromatography (silica, 10±25% diethyl ether in petrol)

gave the title compound (0.294 g, 79%) as a pale yellow

HRMS (EI). Found: M , 270.2570. C H O requires:

1

7

34

2

270.2559. Anal. Found: C, 75.13; H, 12.78. C H O

2

1

7

34

requires: C, 75.50; H, 12.67%.

1

oil. H NMR: d 7.27±7.36 (5H, m), 5.627 (1H, dd, J6.1,

rac-(E)-5-((1S,2R)-4,4-Bis(methoxymethyl)-2-((E)-1-

propenyl)cyclopentyl)-1-phenyl-3-penten-1-ol (45). (Z)-

4,4-Bis(methoxymethyl)-1,6-nonadiene was co-cyclised

using method C and the zirconacycle elaborated using

method E (allyl chloride) except that after addition of the

benzaldehyde the reaction was warmed to room temperature

and stirred for 48 h, then quenched and worked up as

normal. Column chromatography (10±25% diethyl ether

in petrol) gave the title compound (0.258 g, 72%) contami-

1

3

5.6 Hz), 5.334 (1H, dt, J15.6, 6.6 Hz), 4.68 (1H, m),

.357 (3H, s), 3.305 (3H, s), 3.20±3.36 (4H, m), 2.46 (1H,

m), 2.36 (1H, m), 2.198 (1H, d, J3.1 Hz), 2.03 (1H, m),

1

.91 (1H, m), 1.68±1.79 (3H, m), 1.46±1.54 (2H, m), 1.06±

1

3

.34 (5H, m), 0.948 (3H, d, J6.5 Hz) ppm. C NMR: d

44.22 (s), 140.43 (d), 128.42 (2d), 127.48 (d), 125.92 (2d),

22.70 (d), 75.83 (t), 74.16 (t), 73.80 (d), 59.34 (q), 59.15

(

q), 50.44 (d), 48.76 (s), 45.41 (d), 43.12 (t), 41.98 (d), 39.65

t), 30.03 (d), 26.52 (t), 25.64 (t), 23.86 (q), 23.84 (t) ppm.

1

nated with ,5% 43 as a colourless oil. H NMR: d 7.27±

IR: 3423 (s, broad), 1603 (w), 1493 (m), 1392 (m), 1376

7.37 (5H, m), 5.551 (1H, dt, J15.1, 7.0 Hz), 5.33±5.47

(2H, m), 5.236 (1H, ddq, J15.1, 7.9, 1.3 Hz), 4.67 (1H,

m), 3.346 (6H, s), 3.23±3.16 (4H, m), 2.35±2.51 (2H, m),

2.26 (1H, m), 2.181 (1H, br s), 2.015 (1H, dddd, J18.8,

16.0, 11.0, 7.7 Hz), 1.665 (3H, d, J6.2 Hz), 1.50±1.81

(4H, m), 1.216 (1H, dd, J13.1, 11.4 Hz), 1.038 (1H, dd,

2

m), 1197 (s), 1158 (s), 1107 (s), 734 (s), 700 (s) cm .

1

(

LRMS (APCI1, no cone): 372.5 (M , 2%), 354.5

1

(

M 2H O, 3), 323.3 (M2H O2MeOH1H , 100), 291.2

2 2

1

M2H O22MeOH1H , 41). HRMS (EI): Found: M2

PhCHOH1H , 266.2237. C H O requires: 266.2246.

2

1

7

30

1

3

J12.9, 11.2 Hz) ppm. C NMR: d 144.22 (s), 134.31 (d),

133.24 (d), 128.27 (2d), 127.28 (d), 126.40 (d), 125.90 (2d),

125.05 (d), 77.83 (t), 77.74 (t), 73.55 (d), 59.18 (2q), 48.59

(d), 45.31 (s), 45.13 (d), 42.77 (t), 39.82 (t), 38.51 (t), 36.37

(t), 18.04 (q) ppm. IR: 3417 (s, broad), 1452 (s), 1388 (m),

rac-(E)-5-[(1S,2S)-4,4-Bis(methoxymethyl)-2-propylcyclo-

pentyl)-1-phenyl-3-penten-1-ol (43). (Z)-4,4-Bis(methoxy-

methyl)-1,6-nonadiene was co-cyclised using method C and

the zirconacycle elaborated using method E (allyl chloride)

except that after addition of the benzaldehyde the reaction

was warmed to 08C over 2 h before quenching. Column

chromatography (10±25% diethyl ether in petrol) gave the

title compound (0.195 g, 54%) contaminated with ,10% 45

2

1

1197 (s), 1110 (s), 964 (s), 732 (s), 700 (s) cm . LRMS

(APCI): 341.4 (M2H O1H , 26%), 309.3 (M2H O2Me-

1

2

1

OH1H , 100), 277.3 (M2H O22MeOH1H , 69). HRMS

1

2

1

(EI): Found: M2PhCHOH1H , 252.2086. C H O

requires: 252.2089.

1

6

28

2

1

as a colourless oil. H NMR: d 7.27±7.38 (5H, m), 5.550

(

1H, dt, J13.6, 6.6 Hz), 5.390 (1H, dt, J13.6, 7.0 Hz),

4

2

.682 (1H, br s), 3.343 (6H, s), 3.14±3.23 (4H, m), 2.41±

.47 (2H, m), 2.24±2.29 (2H, m), 1.65±1.84 (3H, m), 0.95±

rac-(5-((1S,2R)-4,4-Bis(methoxymethyl)-2-propylcyclo-

pentyl)pentyl)benzene (46). (Z)-4,4-Bis(methoxymethyl)-

G. J. Gordon et al. / Tetrahedron 56 (2000) 2113±2129

2127

1

,6-nonadiene was co-cyclised using method C and the

up. The solvent was then removed in vacuo and benzene

(8 mL) added. After ®ltration, acetone (2.5 mL) was added

and the mixture heated at 858C for 12 h in a sealed Carius

tube. Removal of solvent and column chromatography

(silica, 30±50% ether in petrol) yielded (4Z)-2-methyl-6-

((2S,3R)-2,3,8,8-tetramethyl-7, 9-dioxaspiro[4.5]dec-2-yl)-

4-hexen-2-ol 50 as an inseparable mixture of two dia-

stereoisomers (ca. 4:1) (0.152 g, 49%). To isolate the

major diastereoisomer in purer form the mixture of alcohols

(0.113 g, 0.36 mmol) was acetylated [acetic anhydride

(1 mL), pyridine (5 mL), DMAP (0.050 g), 5 h, room

temperature]. Column chromatography (silica, 10% ether

in petrol) gave the title acetate as a yellow oil (0.093 g,

73%) with partial separation of the diastereoisomers (9:1)

zirconacycle elaborated using method E (allyl chloride) to

give a mixture of 43 and 45 (0.324 g). The crude product

was dissolved in CH Cl (5 mL), 5% palladium on carbon

2

(

10 mg) added, and the mixture stirred under hydrogen

1.5 bar) for 48 h before ®ltration through celite, removal

of solvent, and Kugelrohr distillation (210±2208C at

mmHg) gave the title compound 46 (0.308 g, 89%) as a

1

colourless oil. H NMR: d 7.01±7.22 (5H, m), 3.255 (6H, s),

.06±3.15 (4H, m,), 2.512 (2H, t, J7.7 Hz), 1.685 (1H, d,

J13.2 Hz), 1.664 (1H, d, J13.2 Hz), 1.40±1.60 (4H, m),

.10±1.36 (8H, m), 0.83±0.98 (4H, m), 0.769 (3H, t,

3

1

3

J7.3 Hz) ppm. C NMR: d 143.05 (s), 128.54 (2d),

1

4

3

28.36 (2d), 125.70 (d), 78.02 (2t), 59.39 (2q), 45.35 (s),

5.34 (d), 45.13 (d), 39.55 (t), 39.49 (t), 36.63 (t), 36.13 (t),

4.22 (t), 31.69 (t), 29.86 (t), 28.36 (t), 21.61 (t), 14.67 (q)

1

H NMR: d 5.533 (1H, dtd, J17.4, 6.3, 1.6 Hz), 5.476 (1H,

dtd, J17.4, 6.3, 1.6 Hz), 3.564 (4H, m), 2.470 (2H, d,

J6.0 Hz), 1.948 (3H, s), 1.944 (1H, dd, J13.2, 6.4 Hz),

1.863 (2H, d, J6.2 Hz), 1.719 (1H, ddq, J11.4, 6.8,

6.7 Hz), 1.607 (1H, d, J14.3 Hz), 1.406 (6H, s), 1.379

(3H, s), 1.371 (3H, s), 1.317 (1H, dd, J13.3, 11.4 Hz),

1.032 (1H, d, J14.2 Hz), 0.916 (3H, s), 0.883 (3H, d,

ppm. IR: 1454 (m), 1198 (m), 1111 (s), 1030 (w), 964 (m),

2

44 (m), 698 (m) cm . LRMS (APCI): 347.3 (M1H ,

1

7

5

1

7%), 315.4 (M2MeOH1H , 8), 283.2 (M22MeOH1

1

H , 100). Anal. Found: C, 79.51; H, 11.16. C H O

2

requires: C, 79.71; H, 11.05%.

3

38

2

1

3

J6.9 Hz). C NMR: d 170.52 (s), 129.49 (d), 126.04

(d), 97.58 (s), 82.31 (s), 71.22 (t), 70.30 (t), 44.34 (t),

44.05 (d), 43.67 (s), 41.02 (t), 39.41 (s), 38.51 (t), 32.08

(t), 26.25 (q), 26.07 (q), 26.05 (q), 25.58 (q), 22.59 (q),

22.38 (q), 13.68 (q). IR: 1732 (s), 1658 (w), 1454 (m),

1382 (s), 1368 (s), 1252 (s), 1202 (s), 1156 (m), 1128 (m),

(

E)-6-Ethyl-1-phenyl-3-dodecen-1-ol (48). To a solution

of zirconocene dichloride (0.585 g, 2 mmol) in THF

10 mL) under nitrogen at 2788C was added ethyl mag-

nesium chloride (2.0 mL of a 2.0 M solution in THF,

(

4

2

mmol) followed by a solution of 1-octene (0.246 g,

.2 mmol) in THF (1 mL). The reaction mixture was

2

1

1071 (m), 1032 (m), 1014 (m), 831 (m) cm . LRMS (CI,

1

allowed to warm to 08C over 2 h. At 2788C allyl chloride

0.30 mL, 3 mmol) was added followed by a solution of

NH ): 370 (M1NH , 14%), 353 (M1H , 19), 293 (98),

3 4

(

235 (100), 217 (73), 109 (32), 35 (58). HRMS (CI, NH ):

3

1

Found: (M1H) , 353.2682. C H O requires: 353.2692.

LiTMP (previously prepared by adding n-BuLi (1.9 mL of

a 1.6 M solution in hexanes, 3 mmol) to a solution of tetra-

methylpiperidine (0.423 g, 3 mmol) in THF (4 mL) at 08C

and stirring for 20 min). The reaction was warmed to room

temperature over 1 h, then cooled to 2788C and benzalde-

hyde (1.00 mL, 10 mmol) and BF ´Et O (1.45 mL,

2

1

37

4

rac-(1R,5S)- and rac-(1R,5R)-1-Methyl-bicyclo[3.3.0]oc-

0

tan-3-one-7-spiro-5 -(2 , 2 -dimethyl-1 , 3 -dioxane) 56

and 57. 5-Allyl-2,2-dimethyl-5-(2-methyl-2-propenyl)-1,

3-dioxane (1 mmol) was co-cyclised using method C to

afford zirconacycle 49 as a 4:1 isomeric mixture by NMR.

The zirconacycle solution was cooled to 2788C and

subjected to 3 evacuate-re®ll cycles with carbon monoxide

gas. After stirring under a CO atmosphere (1.5 atm) for 1 h

the reaction mixture was quenched at 2708C by the addition

of methanol (3 mL), and then warmed to room temperature

over 45 min. Water (25 mL) was added and the products

3

2

10 mmol) were added. After 15 min, the reaction was

warmed to room temperature over 2 h. Methanol (2 mL)

and saturated sodium bicarbonate solution (2 mL) were

added and the mixture stirred for 1 h, then poured onto

water (100 mL) and extracted with diethyl ether

(

3£50 mL). The combined extracts were washed with

water (3£100 mL) and brine (50 mL), dried (MgSO ) and

4

the solvent removed in vacuo. Puri®cation by column

chromatography (silica, 10% diethyl ether in iso-hexane)

gave the title alcohol (0.513 g, 89%) as a pale yellow oil.

extracted into ether (3£20 mL), dried (MgSO ) and solvent

4

removed. The residue was dissolved in dichloromethane

(2 mL) and added in one portion to pyridinium dichromate

(12.5 mmol) [made from CrO (12.5 mmol, 1.25 g) and

1

H NMR: d 7.24±7.36 (5H, m), 5.32±5.61 (2H, m), 4.67

1H, m), 2.35±2.54 (2H, m), 1.96±2.05 (2H, m), 1.16±1.39

14H, m), 0.885 (3H, t, J6.8 Hz), 0.842 (3H, t, J6.6 Hz)

3

(

pyridine (25 mmol, 1.98 g)] in CH Cl (30 mL). After stir-

2

ring for 15 min, the dichloromethane solution was decanted

from the black tarry deposit and the residue washed with

ether (60 mL). The solvent was removed from the combined

organic extracts in vacuo. The crude organic product was

dissolved in ether (40 mL), ®ltered through Celite, washed

with saturated aqueous NaHCO₃(20 mL) and brine

1

3

ppm. C NMR: d 139.25 (s), 130.52 (d), 128.65 (d), 123.45

(

2d), 122.49 (d), 120.99 (2d), 68.68 (d), 38.02 (t), 34.31 (d),

3

1

2.12 (t), 31.88 (t), 31.49 (t), 27.12 (t), 25.38 (t), 24.90 (t),

7.88 (t), 14.69 (q), 9.30 (q) ppm. IR: 3370 (m, broad), 1454

2

1

(

NH₃): 306 (M1NH , 8%), 288 (M , 100), 271

m), 1048 (m), 970 (m), 757 (m), 699 (s) cm . LRMS (CI,

1

4

1

(20 mL), dried (MgSO ) and solvent removed in vacuo to

4

1

M2H O1H , 37). HRMS (EI): Found: M2PhCHOH1

(

H , 182.2024. C H requires: 182.2035.

yield a yellow oil. Column chromatography (silica, 20%

ether in petrol) afforded a 9:2 mixture of the ketones 56

and 57 as a pale yellow oil (0.185 g, 62%). Further chroma-

tography and recrystallisation (ether, 20 to 2408C followed

by cold pentane wash) yielded the major (cis) diastereo-

isomer 56 in pure form (mp 75±778C from ether, white

needles), and the minor (trans) diastereoisomer 57 in 90%

pure form (mp 68±708C from ether, off white needles).

2

1

3

26

rac-(4Z)-2-Methyl-6-((2S,3R)-2,3,8,8-tetramethyl-7, 9-di-

oxaspiro[4.5]dec-2-yl)-4-hexen-2-yl acetate. 2,2-Dimethyl-

5-(2-methyl-prop-2-en-1-yl)-5-allyl-1,3-dioxane was co-

cyclised using method C and the zirconacycle elaborated

using method D (allyl chloride) but without protic work-

2

128

G. J. Gordon et al. / Tetrahedron 56 (2000) 2113±2129

1

Major (cis) isomer 56. H NMR (360 MHz): d 3.640 (1H, d,

J11.5 Hz), 3.614 (1H, d, J6.9 Hz), 3.592 (1H, d,

J6.8 Hz), 3.569 (1H, d, J11.7 Hz), 2.448 (1H, ddd,

J19.1, 7.9, 1.3 Hz), 2.321 (1H, dtd, J10.5, 7.8, 2.2 Hz),

144.18 (s), 132.69 (d), 128.48 (2d), 127.52 (d), 127.48 (d),

126.00 (2d), 79.40 (t), 73.50 (d), 59.41 (q), 47.67 (s), 43.04

(t), 40.53 (d), 35.01 (t), 33.59 (t), 33.26 (t), 22.06 (t), 15.36

(q) ppm. IR: 3414 (s broad), 1603 (w), 1493 (m), 1454 (s),

2

1

2

(

.213±2.079 (3H, m), 2.111 (1H, dd, 19.3, 1.3 Hz), 1.678

1195 (m), 1107 (s), 972 (s), 700 (s) cm . LRMS (APCI):

1

1H, d, J14.5 Hz), 1.602 (1H, d, J14.5 Hz), 1.377 (3H,

271.2 (M2H O1H , 32%), 239.1 (M2H O2MeOH1H ,

2 2

1

100). HRMS (EI): Found: (M2H O) , 270.1981. C H O

requires: 270.1984.

s), 1.370 (3H, s), 1.301 (1H, dd, J13.8, 9.8 Hz), 1.142 (3H,

2

19 26

1

s). C NMR: d 219.44 (s), 97.85 (s), 70.88 (t), 69.60 (t),

3

5

4

1

2.24 (t), 46.71 (s), 46.62 (t), 46.30 (d), 43.19 (t), 42.64 (s),

0.36 (t), 28.05 (q), 24.76 (q), 23.08 (q). IR (CCl ): 1742 (s),

rac-(1S,2R)-1-(Methoxymethyl)-2-methyl-1-(3-methyl-2-

butenyl) cyclopentane (55). 2-Methoxymethyl-1,6-hepta-

diene (0.196 g, 1 mmol) was co-cyclised using method C,

and the zirconacycle elaborated using method D (methallyl

chloride) to afford, after chromatography (silica, 5±10%

diethyl ether in petrol) and Kugelrohr distillation (100±

1058C at 0.8 mmHg) the title compound (0.070 g, 36%).

4

2

453 (m), 1406 (m), 1383 (m), 1253 (m), 1201 (m) cm .

1

Anal. Found: C, 70.30; H, 9.44. C H O requires: C,

3

1

4

22

1

7

(

0.56; H, 9.30%. Minor (trans) isomer 57. H NMR

360 MHz): d 3.838 (1H, dd, J11.3, 0.7 Hz), 3.773 (1H,

dd, J11.3, 1.5 Hz), 3.650 (1H, dt, J11.3, 0.8 Hz), 3.574

1H, dd, 11.3, 1.5 Hz), 2.223 (1H, dd, J17.0, 6.8 Hz),

(

2

1

.202 (1H, d, J16.5 Hz), 2.120±1.900 (4H, m), 1.623

H NMR: d 5.141 (1H, t septet, J7.4, 1.0 Hz), 3.294

(

1H, d, J13.0 Hz), 1.438 (3H, s), 1.422 (3H, s), 1.427

(3H, s), 3.161 (1H, d, J8.8 Hz), 3.075 (1H, d, J

8.8 Hz), 2.025 (1H, dd, J14.3, 7.4 Hz), 1.76±1.95 (3H,

m), 1.716 (3H, d, J1.0 Hz), 1.617 (3H, d, J1.0 Hz),

(

1H, m), 1.223 (1H, dq, J13.0, 0.8 Hz), 0.824 (3H, s).

1

3

C NMR: d 220.09 (s), 97.72 (s), 70.57 (t), 69.87 (t),

1

3

5

(

1

3.47 (t), 48.41 (d), 46.91 (s), 44.66 (s), 43.05 (t), 38.53

t), 32.25 (t), 25.56 (q), 22.07 (q), 19.84 (q). IR (CCl₄):

747 (s), 1451 (w), 1382 (m), 1202 (s), 1095 (s), 832

1.22±1.58 (5H, m), 0.924 (3H, d, J6.8 Hz) ppm.

C

NMR: d 132.76 (s), 121.72 (d), 78.76 (t), 59.29 (q), 48.04

(s), 40.49 (d), 33.81 (t), 33.07 (t), 29.51 (t), 26.29 (q), 22.31

(t), 17.91 (q), 15.34 (q) ppm. IR: 1451 (s), 1375 (s), 1259

(m), 1198 (m), 1110 (s), 964 (m) cm . LRMS (APCI):

197.1 (M1H , 100%), 165.2 (M2MeOH1H , 10). Anal.

2

1

4

(

m) cm . LRMS (CI): 256 (M1NH , 44%), 239

1

M1H , 100), 223 (25), 181 (11), 163 (14). HRMS (CI,

21

(

NH ): Found: (M1NH ) , 256.1902. C H O N requires:

1

3

4

14 26

3

256.1913.

Found: C, 79.48; H, 12.38. C H O requires: C, 79.53; H,

1

3

24

1

2.32%.

rac-(3R,4S)-1-Benzyl-3,4-dimethyl-3-(3-methyl-2-butenyl)-

pyrrolidine (52). N-Allyl-N-benzyl-N-(2-methylallyl)-

1

9

amine (0.201 g, 1 mmol) was co-cyclised using method

C, and the zirconacycle elaborated using method D (methallyl

chloride). Column chromatography (silica, 10±50% diethyl

ether in petrol) gave the title compound containing an equi-

molar amount of 1-benzyl-3,3,4-trimethyl-pyrrolidine

Acknowledgements

We would like to thank Zeneca Pharmaceuticals and the

EPSRC for ®nancial support through the CASE scheme

(M. W. T.) and Quota studentships (T. L. and G. J. G.),

and Dr Will J. Watkins and Dr Ed Grif®n for their help

and interest. R. J. W. thanks P®zer Central Research, Zeneca,

and Glaxo Wellcome for generous uncommitted support.

(

0.185 g). Spectral data is given for the title compound

1

only: H NMR: d 7.26±7.38 (5H, m), 5.165 (1H, t,

J6.7 Hz), 3.710 (1H, d, J13.2 Hz), 3.616 (1H, d,

J13.2 Hz), 2.937 (1H, dd, J14.2, 7.4 Hz), 2.480 (2H,

broad s), 2.304 (1H, dd, J14.2, 7.4 Hz), 2.102 (1H, dd,

J14.2, 7.4 Hz), 2.00 (1H, m), 1.877 (1H, dd, J14.3,

References

7

(

.4 Hz), 1.737 (3H, s), 1.658 (3H, s), 1.024 (3H, s), 0.937

1

3

3H, d, J7.0 Hz) ppm. C NMR: d 139.71 (s), 133.12 (s),

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1

6

2

1

2

28.78 (2d), 128.27 (2d), 126.89 (d), 121.68 (d), 65.43 (t),

1.43 (t), 61.00 (t), 43.49 (d), 43.28 (s), 33.51 (t), 26.25 (q),

5.50 (q), 18.15 (q), 13.22 (q) ppm. IR: 1494 (s), 1453 (s),

2

1

375 (s), 1124 (m), 1072 (m), 1028 (m) cm . LRMS (ES):

58 (M1H , 100%). HRMS (EI): Found: M , 257.2123.

C H N requires: 257.2144.

27

1

8

rac-(E)-5-[(1S,2R)-1-(Methoxymethyl)-2-methylcyclo-

pentyl]-1-phenyl-3-penten-1-ol (54). 2-Methoxymethyl-

1

,6-heptadiene (0.196 g, 1 mmol) was co-cyclised using

3. Fagan, P. J.; Nugent, W. A.; Calabrese, J. C. J. Am. Chem. Soc.

1994, 116, 1880. Spence, R. E. V.; Hsu, D. P.; Buchwald, S. L.;

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Seki, T.; Saburi, M.; Uchida, Y. J. Org. Chem. 1989, 54, 3521. (b)

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method C, and the zirconacycle elaborated using method

E (allyl chloride) to afford, after chromatography (silica,

10±25% diethyl ether in petrol) the title compound

1

(

0.078 g, 27%) as a pale yellow oil. H NMR: d 7.24±

.37 (5H, m,), 5.602 (1H, dt, J15.1, 7.4 Hz), 5.406 (1H,

dt, J15.1, 7.4 Hz), 4.609 (1H, dd, J5.2, 7.6 Hz), 3.298

3H, s), 3.152 (1H, d, J8.8 Hz), 3.101 (1H, d, J8.8 Hz),

.38±2.56 (3H, m), 2.098 (1H, dd, J7.4, 13.8 Hz,), 1.887

1H, dd, J7.4, 13.8 Hz), 1.77±1.85 (2H, m), 1.20±1.64

7

(

2

(

1

3

5H, m), 0.906 (3H, d, J6.6 Hz) ppm. C NMR: d

G. J. Gordon et al. / Tetrahedron 56 (2000) 2113±2129

2129

J. Am. Chem. Soc. 1989, 111, 3336. (d) Takahashi, T.; Kotora, M.;

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4

183. (e) Takahashi, T.; Huo, S. Q.; Hara, R.; Noguchi, Y.; Naka-

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. Takahashi, T.; Xi, Z. F.; Yamazaki, A.; Liu, Y. H.; Nakajima,

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1

999, 38, 949. Kotora, M.; Xi, C. J.; Takahashi, T. Tetrahedron

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7

. (a) Takahashi, T.; Xi, Z. F.; Kotora, M.; Xi, C. J.; Nakajima, K.

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Article Doi

The regiochemistry of carbenoid insertion into zirconacycles

DOI: 10.1016/S0040-4020(99)01094-7

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