Synthesis of cyclic and macrocyclic ethers using metathesis reactions of alkenes and alkynes

FULL PAPER

DOI: 10.1002/ejoc.200700291

Synthesis of Cyclic and Macrocyclic Ethers Using Metathesis Reactions of

Alkenes and Alkynes

Elisabetta Groaz,^[a]Donatella Banti,^[a,b]and Michael North*^[a,c]

Keywords: Oxygen heterocycles / Medium-ring compounds / Macrocycles / Metathesis / Ruthenium

The metathesis transformations of cyclohexanes and cyclo-

hexenes bearing allylic and/or propargylic ether substituents

has been investigated. A range of products containing fused

6,8-bicyclic ring systems resulting from alkene and/or enyne

metatheses were obtained using first and second generation,

well defined alkylidene ruthenium catalysts. However, the

unstrained cyclohexene unit did not participate in any of

these metathesis processes, even though doing so would

have led to a thermodynamically more stable product. This

contrasts with previous results on similar compounds and on

the corresponding amino-substituted cyclohexenes. The syn-

thesis of dienes and dihydrofurans by metathesis processes

involving the side chains of suitable cyclohexene ethers is

also reported. When the unstrained cyclohexene unit was re-

placed by a norbornene group, the strained alkene did par-

ticipate in a cascade of alkene and enyne metatheses. This

chemistry was extended to alkyne metatheses of cyclohex-

ene and norbornene esters, leading to 6,12-fused cycloal-

kynes which would subsequently undergo further enyne

and/or alkene metatheses. This culminated in the develop-

ment of the first one-pot metathesis process in which alkyne,

enyne and alkene metathesis reactions initiated by two dif-

ferent catalysts all occur sequentially to form a 5,12-fused

bicyclic diene product.

Germany, 2007)

Introduction

Ring-closing metathesis (RCM) of alkenes is now well

established as a highly versatile method for the synthesis

of cyclic compounds, especially those containing normal or

large rings. Progress in this area received a major boost

through the development of well-defined ruthenium based

metathesis initiators^[1]such as compounds 1^[2]and 2.^[3]

Compounds 1 and 2 not only induce metathesis processes

at synthetically useful rates, they do so at ambient or near

ambient temperature, tolerate many functional groups and

do not require strictly anhydrous or anaerobic conditions.

The related process of ring-closing enyne metathesis leading

to cyclic dienes is also induced by well-defined ruthenium

based catalysts such as 1 and 2, and leads to synthetically

useful cyclic dienes. Enyne metathesis has not been as

widely exploited as alkene metathesis, but is of growing syn-

thetic importance.^[4]

In a series of publications,^[5]we have reported the use of

catalysts 1 and 2 to initiate a cascade of alkene and enyne

metathesis reactions of readily available norbornene deriva-

tives. This chemistry provided a facile approach to the prep-

aration of polycyclic oxygenated heterocycles in a one-pot

process where in the metathesis transformations could be

combined with Diels–Alder reactions. The driving force for

the metathesis cascade in these reactions was initially as-

sumed to be the release of ring-strain during the ring-open-

ing metathesis (ROM) of the norbornene ring. However,

the results obtained indicated that the norbornene unit first

underwent ring-opening metathesis and cross metathesis to

give an unstrained cyclopentane derivative which sub-

sequently underwent the metathesis cascade leading to the

final products as shown in Scheme 1. Hence it appeared

that a strained starting material was not needed for this

metathesis chemistry, and indeed we have reported that suit-

ably functionalised 1,2-diaminocyclohexenes do undergo a

metathesis cascade in which the cyclohexene unit partici-

pates.^[6]To further investigate this area, we initiated a pro-

ject to investigate alkene, enyne and alkyne metatheses of

suitably substituted cyclohexane and cyclohexene deriva-

[a] Department of Chemistry, King’s College,

Strand, London, WC2R 2LS, UK

[b] School of Pharmacy and Chemistry, Kingston University,

Penrhyn Road, Kingston-upon-Thames, Surrey, KT1 2EE, UK

[c] School of Natural Sciences, Bedson Building, Newcastle Uni-

versity,

Newcastle upon Tyne, NE1 7RU, UK

Fax: +44-870-131-3783

E-mail michael.north@ncl.ac.uk

Supporting information for this article is available on the

WWW under http://ww w .eurjoc.org or from the author.

Eur. J. Org. Chem. 2007, 3727–3745

3727

E. Groaz, D. Banti, M. North

FULL PAPER

tives.^[7,8]In this manuscript we give full details of this work, benzene led initially to the formation of a mixture of com-

present additional results on the metathesis of norbornene pounds 6 and 10, but that prolonged reaction (6 h) resulted

derivatives for comparison, and show that alkyne,^[9]enyne in the formation of only compound 10.

and alkene metatheses can all be combined into a one-pot

process with a suitable substrate.

Scheme 2. Synthesis and metathesis of cyclohexene derivatives 5

and 6.

Scheme 1. Ring-closing metathesis of norbornene derivatives.

However, when the compounds 5 or 6 were treated with

catalysts 1 or 2 in dichloromethane, the only monomeric

products obtained were 6,8-fused bicycles 7 and 8. In both

cases, the dimers 12–13 were also isolated, and in the case

of the trans-substrate 6, small amounts of macrocyclic di-

Results and Discussion

The first substrates investigated in this project were the mer 14 were obtained. Compound 14 was obtained as a

cis- and trans-cyclohexene derivatives 5 and 6, which were single C₂-symmetrical stereoisomer, but the relative config-

prepared from the known diols 3^[10]and 4^[11]as shown in uration of the stereocentres and the stereochemistry of the

Scheme 2. The metathesis of these compounds could pro- alkene units could not be determined. For reactions involv-

ceed in two ways: a simple RCM leading to 6,8-fused bicy- ing the cis-substrate 5, use of 5 mol-% of catalyst 1 at 25 °C

clic bis-ethers 7 and 8, or a RCM-ROM-RCM cascade in- under nitrogen gave a 49% yield of compound 7 (Table 1).

volving the cyclohexene unit and leading to bis-dihydropy- Increasing the reaction temperature to 35 °C only slightly

rans 9 and 10 (Scheme 2). It was anticipated that bis-dihy- increased the yield, whilst an attempt to raise the tempera-

dropyrans 9 and 10 would be the thermodynamically most ture further by changing the solvent to toluene was detri-

stable metathesis products, and literature precedent for the mental. Changing the atmosphere to ethene resulted only

formation of compound 10 in a metathesis reaction existed in the quantitative recovery of unreacted starting material.

in the work of Mioskowski et al.^[12]These authors showed However, increasing the amount of catalyst 1 to 10 mol-%

that treatment of compound 11 with catalyst 1 at 60 °C in did slightly increase the yield of compound 7, though the

Table 1. Metathesis of 5 to 7 and 12.

Catalyst

Solvent

Temp. [°C]

Atmosphere

Time [h]

7 (% yield)

12 (% yield)

1, 5 mol-%

1, 10 mol-%

2, 5 mol-%

CH₂Cl₂

toluene

CH₂Cl₂

25

35

55

25

N₂

ethene

N₂

20

48

20

49

0

51

38

54

71

5

0

6

13

9

7

N₂

Table 2. Metathesis of 6 to 8, 13 and 14.

Catalyst

Solvent

Temp. [°C]

Atmosphere

Time [h]

8 (% yield)

13 (% yield)

14 (% yield)

1, 5 mol-%

1, 10 mol-%

2, 5 mol-%

CH₂Cl₂

25

35

25

N₂

ethene

N₂

20

48

20

82

0

92

86

97

9

0

6

9

0

5

0

2

5

0

3728

www.eurjoc.org

Eur. J. Org. Chem. 2007, 3727–3745

Cascade Metathesis Reactions of Alkenes and Alkynes

FULL PAPER

highest yield was obtained by the use of 5 mol-% of the products 17 and 18 in 83–86% yield. Consistent with the

second generation catalyst 2. Under these conditions, com- results of Grubbs’ et al.,^[13]the cis-isomer 15 was less reac-

pound 7 could be isolated in 71% yield along with 7% of tive towards RCM than trans-isomer 16 as the former re-

dimer 12. The trans-fused substrate 6 was generally more quired 10 mol-% of catalyst 1 to consume all the starting

reactive and only 5 mol-% of catalyst 1 was required to material, whilst the metathesis of compound 16 proceeded

form compound 8 in 82% yield (Table 2). This yield could under identical conditions with only 5 mol-% of catalyst 1.

be increased to 92% by carrying out the reaction at 35 °C, Final proof of the structure of compound 8 was obtained

though again the highest yield (97%) was obtained using by hydrogenating each of compounds 8 and 18 to give com-

catalyst 2, and in this case no dimeric products were iso- pound 19 (Scheme 3). Compound 19 was analysed by GC-

1

lated. The H and ¹³C NMR spectroscopic data for com- MS, and the product obtained from compounds 8 and 18

pound 8 were totally different to those given by Mioskowski had identical retention times and mass spectra.

et al. for compound 10,^[12]thus confirming that the prod-

ucts were different species.

Scheme 3. Synthesis of compounds 17–19.

On the basis of the above results, it was apparent that at

temperatures below 60 °C, metathesis cascades involving a

cyclohexene unit could not compete with RCM of terminal

alkenes even when the latter process generates the thermo-

A partial explanation for the difference between our re-

dynamically less stable product. Because enyne metatheses

sults and those of Mioskowski et al. may be the different

generally proceed less readily than alkene metatheses,^[4]the

reaction temperatures employed. All of the metathesis reac-

ability of a cyclohexene unit to intervene in a ring-closing

tions conducted by Mioskowski et al. were carried out at

enyne metathesis (RCEM) process was investigated.^[14]For

60 °C in benzene, whilst we chose to work in dichlorometh-

this study, allyl propargyl bis-ethers 22 and 23 were pre-

ane at 25–35 °C. It may be that the 6,8-bicyclic compounds

pared from the diols 3 and 4, respectively, as shown in

7 and 8 are the kinetic products of metathesis reactions

starting from compounds 5, 6 and 11 whilst the bis-dihy-

dropyrans 9, 10 are the thermodynamic products. However,

this cannot be the whole explanation because it does not

explain why metathesis of compound 5 at 55 °C in toluene

(Table 1) gave product 7 and not compound 9; nor does it

explain why Mioskowski et al. were able to isolate cyclohex-

ene 6 rather than compound 8 from their reactions. The

course of the metathesis reactions on these substrates may

also be very sensitive to other factors such as solvent and

concentration. Attempts to explore the further metathesis

of compounds 7 and 8 by re-exposing them to catalyst 1 or

2 under a range of reaction conditions resulted only in the

re-isolation of compounds 7 and 8.

To confirm the structures of compounds 7 and 8, the

metathesis of the corresponding cyclohexane derivatives 15

and 16 was undertaken (Scheme 3). Compounds 15 and 16

can only undergo RCM to give 6,8-fused bicyclic ethers 17

and 18 respectively, and the metathesis of these compounds

has previously been reported by Grubbs et al.^[13]using

RuCl₂(PCy₃)₂=CH–CH=CPh₂as the metathesis initiator.

When compounds 15 and 16 were treated with first genera-

tion Grubbs’ catalyst 1 at room temperature in dichloro-

methane, they were both converted into 6,8-fused bicyclic 23.

Scheme 4. Synthesis and enyne metathesis of compounds 22 and

Eur. J. Org. Chem. 2007, 3727–3745

www.eurjoc.org

3729

E. Groaz, D. Banti, M. North

FULL PAPER

Scheme 4. Thus, mono-allylation of the diols 3 and 4 gave of compounds 5 and 6, where use of the second generation

a moderate yield of the alcohols 20 and 21 which could be catalyst gave a higher yield of product than was obtained

propargylated to give the desired bis-ethers 22 and 23.

by use of the first generation catalyst 1. Both dienes 24 and

Tables 3 and 4 detail the results obtained when the bis- 25 readily underwent a Diels–Alder reaction with maleic

ethers 22 and 23 were treated with first- or second-genera- anhydride to give the tetracyclic anhydrides 26 and 27,

tion Grubbs’ catalyst. In every case, the only isolated prod- respectively. In the case of the cis-diene 24, the anhydride

uct was the 6,8-fused diene 24 or 25 resulting from a single was formed as a single diastereomer, whilst the anhydride

RCEM event, and no evidence for involvement of the cyclo- derived from the trans-diene 25 was formed as a 3:1 ratio of

hexene unit in the metathesis process was ever observed.^[15]diastereomers. Neither anhydride was crystalline, and their

However, the results do confirm that RCEM is a less NMR spectra (including 2D correlations and NOESY) did

favourable process than RCM since under identical reaction not allow the stereochemistry of the anhydrides to be de-

conditions, dienes 24 and 25 were obtained in significantly fined.

lower yields than compounds 7 and 8. Thus, whereas treat-

For comparison, the metathesis of the norbornene deriv-

ment of compound 5 with 5 mol-% of catalyst 1 at 25 °C ative 31 was also investigated. Compound 31 was prepared

gave a 49% yield of the cis-6,8-fused bicycle 7, treatment of from the known^[18]diol 28 as shown in Scheme 5. Treatment

compound 22 with the same catalyst under identical condi- of diol 28 with allyl bromide gave a mixture of the alcohol

tions gave only a 26% yield of the cis-6,8-fused bicycle 24. 29 and the bis-allyl ether 30.^[19]Compound 29 could then

A similar trend was apparent for the trans-fused products 8 be readily converted into allylpropargyl ether 31 by treat-

and 25 which were formed in 82 and 47% yield, respectively. ment with propargyl bromide. Treatment of compound 31

The optimal conditions for the formation of the dienes 24 with either catalyst 1 or 2 in the presence of ethene gave the

and 25 involved the use of 10 mol-% of catalyst 1 at 35 °C tricyclic diene 32, with optimal results being obtained by

in dichloromethane, and the trans-diene 25 was formed in the use of catalyst 1 at 25 °C in dichloromethane (Table 5).

higher yield than cis-diene 24, again consistent with the re- Thus, in contrast to substrates 22 and 23, the strained al-

sults obtained for the RCM of substrates 5 and 6 (Table 1 kene within compound 31 readily participates in

a

and Table 2).

RCMϪROMϪRCEM cascade.

Table 3. Metathesis of 22 to 24.

Catalyst

Solvent

Temp.

Atm. Time [h] % Yield

[°C]

1 (5 mol-%)

1 (10 mol-%)

2 (5 mol-%)

CH₂Cl₂

25

35

25

N₂

ethene

N₂

20

24

20

26

46

58

12

15

Table 4. Metathesis of 23 to 25.

Catalyst

Solvent

Temp.

Atm. Time [h] % Yield

[°C]

1 (5 mol-%)

1 (10 mol-%)

1 (5 mol-%)

1 (10 mol-%)

2 (5 mol-%)

CH₂Cl₂

toluene

CH₂Cl₂

25

35

25

60

25

N₂

ethene

N₂

1.5

3

(38)^[a]

(43)^[a]

47

72

78

11

25

32

20

24

20

24

Scheme 5. Synthesis and enyne metathesis of compound 31.

Table 5. Metathesis of 31 to 32.

Catalyst

Solvent Temp. [°C]

Atm.

Time [h] % Yield

N₂

1 (5 mol-%)

2 (5 mol-%)

CH₂Cl₂

toluene

25

35

25

60

ethene

N₂

6

100

82

0

[a] Brackets indicate conversion from NMR rather than isolated

yield.

20

24

ethene

54

Enyne metatheses are often accelerated by conducting

the reactions under ethene^[16](to prepare a more reactive

methylidene ruthenium complex^[17]in situ), but in the case

It was apparent from the results presented in Table 3 and

of substrates 22 and 23, this was detrimental to the product Table 4, that ring-opening of a cyclohexene unit could not

yield. This is consistent with previous observations on the compete with RCEM to form the eight-membered ring in

synthesis of eight-membered dienes by RCEM catalysed by compounds 22 and 23. Therefore, a different class of sub-

complex 1.^[15]Interestingly, use of the second generation strates was investigated: the bis-propargyl ethers 35–38.

metathesis catalyst 2 also resulted in decreased yields of Compounds 35–38 were readily prepared by propargylation

compounds 24 and 25, in marked contrast to the metathesis of diols 3,4,33,34, respectively, as shown in Scheme 6. Me-

3730

www.eurjoc.org

Eur. J. Org. Chem. 2007, 3727–3745

Cascade Metathesis Reactions of Alkenes and Alkynes

FULL PAPER

Table 6. Metathesis of 35 to 39, 40 and 41.

Catalyst

Solvent

Temp. [°C]

Atmosphere

Time [h]

39 (%)

40 (%)

41 (%)

1 (5 mol-%)

2 (5 mol-%)

2 (10 mol-%)

CH₂Cl₂

toluene

25

35

60

N₂

48

24

48

24

48

0

11

31

17

0

7

15

16

0

6

13

14

ethene

Table 7. Metathesis of 36 to 42, 43 and 44.

Catalyst

Solvent

Temp. [°C]

Atmosphere

Time [h]

42 (%)

43 (%)

44 (%)

1 (5 mol-%)

1 (10 mol-%)

2 (5 mol-%)

2 (10 mol-%)

2 (5 mol-%)

2 (10 mol-%)

2(10 mol-%)^[a]

CH₂Cl₂

toluene

25

35

25

60

80

60

N₂

48

24

19

24

16

20

24

0

7

18

3

14

13

0

5

14

3

11

10

ethene

0

11

28

7

20

27

[a] Added as two 5 mol-% portions.

tathesis reactions on substrates 35 and 36 were carried out

The formation of the compounds 39–50 can be ac-

with catalysts 1 and 2 under various reaction conditions counted for by an initial reaction between catalyst 2 and

(Table 6 and Table 7). Both substrates were inert to catalyst ethene to generate the corresponding methylidene complex,

1 under all reaction conditions investigated, and underwent followed by an enyne metathesis between this species and

metathesis reactions initiated by catalyst 2 only at elevated one of the terminal alkyne units of compounds 35–38. The

temperatures in the presence of ethene.^[20]In both cases, the resulting vinylidene can then either undergo cross metathe-

optimal reaction reactions involved the use of 10 mol-% of sis with another molecule of ethene to form dienes 39, 42,

catalyst 2 at 60 °C in toluene for 20–24 h, and under these 45 or 48 (and the process can be repeated at the other al-

conditions a mixture of three metathesis products (39–41 kyne to give the bis-dienes 40, 43, 46 or 49), or can undergo

and 42–44, respectively) was obtained from both substrates RCEM to form an eight-membered ring and produce tri-

(Scheme 6). The cyclohexane derivatives 37 and 38 reacted enes 41, 44, 47 or 50 after a subsequent cross metathesis

analogously under the optimised reaction conditions (cata- with ethene. Interestingly, whilst the diene and bis-diene

lyst 2 10 mol-%, 60 °C in toluene for 24 h) to give mixtures containing products can be accounted for by a mechanism

of compounds 45–47 and 48–50, respectively.

in which the initial metathesis occurs to attach the large

ruthenium unit at the terminus of the alkyne, formation of

the eight-membered ring trienes requires the opposite regi-

ochemistry for the initial metathesis reaction, thus placing

the large ruthenium unit at the internal end of the alkyne.

To further investigate the enyne metathesis potential of

the substrates 35 and 36, a series of reactions was carried

out in which the ethene atmosphere was replaced by a five-

fold excess of 1-hexene. Under these conditions, both cata-

lysts 1 and 2 reacted with the substrates 35 and 36 (Table 8

and Table 9) and did so to produce a mixture of dienes (51,

52) and bis-dienes (53, 54) as shown in Scheme 7. The

Table 8. Metathesis of 35 to 51 and 53.

Catalyst

Sol-

vent

Temp. [°C] Time [h]

51 (%)

53 (%)

1 (5 mol-%)

1 (10 mol-%)

2 (5 mol-%)

CH₂Cl₂

tolu-

25

35

25

60

24

27

53

60

18

16

27

40

10

ene

Scheme 6. Synthesis and enyne metathesis of compounds 35–38.

Eur. J. Org. Chem. 2007, 3727–3745

www.eurjoc.org

3731

E. Groaz, D. Banti, M. North

FULL PAPER

dienes 51 and 52 were formed as a 1:1 ratio of E- and Z-

The effect of setting up an intramolecular enyne cascade

isomers, whilst bis-dienes 53 and 54 were each formed as a was investigated through the reaction of diols 3 and 4 with

1:1 ratio of EE- and ZZ-isomers.

bromide 55^[24]to give compounds 56 and 57, respectively,

as shown in Scheme 8. Compounds 56 and 57 underwent

enyne metathesis reactions to give bis-dienes 58 and 59,

respectively, only when treated with first-generation

Grubb’s catalyst 1, and only in the absence of ethene

(Table 10 and Table 11). In the case of the cis-substrate 56,

a high yield of compound 58 was obtained by use of

10 mol-% of the catalyst 1 at 25 °C, whilst for the corre-

sponding trans-substrate 57, a temperature of 35 °C was

necessary to obtain complete conversion to product 59.

Compounds 58 and 59 decomposed over a period of a few

hours at room temperature, presumably as a result of

double-bond migrations. As a result, it was not possible to

carry out Diels–Alder reactions on the isolated dienes.

Table 9. Metathesis of 36 to 52 and 54.

Catalyst

Solvent

Temp.

Time [h] 52 (%) 54 (%)

[°C]

1 (5 mol-%)

1 (10 mol-%)

2 (5 mol-%)

CH₂Cl₂

toluene

25

35

25

60

24

19

32

50

22

12

16

26

14

Scheme 7. Cross metathesis between compounds 35, 36 and 1-hex-

ene.

Comparison of the results obtained for the metathesis of

compounds 35–36 in the presence of ethene and 1-hexene

reveals some interesting differences. Most notably, catalyst

1 was more active than catalyst 2 for reactions carried out

with 1-hexene, whilst catalyst 1 was totally inactive in the

presence of ethene. It is known that catalyst 1 reacts with

ethene to form the analogous methylidene complex which

subsequently decomposes relatively rapidly compared to

other alkylidenes ruthenium compounds.^[21]Given that the

metathesis reactions involving substrates 35–36 are rela-

tively slow, it is likely that the rate of decomposition of the

methylidene complex is greater than the rate of initiation of

metathesis, thus accounting for the lack of reactivity ob-

served using catalyst 1 with substrates 35–36. In contrast,

the methylidene complex derived from catalyst 2 is known

to be much more stable (its half life is 8.5 times longer^[22]),

so that it is able to initiate the metathesis of substrates 35–

36 faster than it decomposes. However, in the presence of

1-hexene the methylidene complex will be in equilibrium

with the pentylidene complex which will have a similar sta-

bility to complex 1 and which serves to protect the more

reactive methylidene complex when it is not involved in pro-

ductive metatheses.^[23]The other interesting contrast be-

tween the use of ethene and 1-hexene is the total lack of

any cyclic triene formation in the latter case which may be

due to steric hindrance caused by the butyl groups since the

formation of compounds 51–54 indicates that the regio-

chemistry of the enyne metathesis is such that the ruthe-

nium unit is located at the internal end of the alkyne.

Scheme 8. Synthesis and metathesis of substrates 56 and 57.

Table 10. Metathesis of 56 to 58.

Catalyst

Solvent Temp. [°C]

Atm.

Time [h] % Yield

1 (5 mol-%)

1 (10 mol-%) CH₂Cl₂

2 (5 mol-%)

CH₂Cl₂

25

60

N₂

ethene

N₂

15

24

7

0

93

0

CH₂Cl₂

toluene

0

Table 11. Metathesis of 57 to 59.

Catalyst

Solvent Temp. [°C]

Atm.

Time [h] % Yield

1 (5 mol-%)

1 (10 mol-%) CH₂Cl₂

2 (5 mol-%)

CH₂Cl₂

25

35

25

35

25

60

N₂

ethene

N₂

22

24

22

21

24

48

24

28

0

32

68

100

0

CH₂Cl₂

toluene

N₂

0

3732

www.eurjoc.org

Eur. J. Org. Chem. 2007, 3727–3745

Cascade Metathesis Reactions of Alkenes and Alkynes

FULL PAPER

However, the bis-anhydride 60 could be accessed as a 1:1:1 strate 63 bearing two internal alkynes under identical condi-

ratio of diastereomers in 75% yield from the trans-substrate tions gave the expected cyclic alkyne 64 in 63% yield, along

57 by carrying out the enyne metathesis and Diels–Alder with 3% of the dimeric bis-alkyne 65. Compound 64 could

reactions sequentially without purifying the intermediate not be induced to undergo alkene or enyne metatheses in

bis-dihydrofuran 59.

the presence of catalyst 1, but in the presence of catalyst 2

Compounds such as 35–38 which contain two alkyne and ethene, it did undergo enyne cross-metathesis to give

units could in principle also undergo alkyne metathesis re- diene 66 in quantitative yield.^[20b]No products arising from

actions; so we decided to investigate if reaction conditions metatheses involving the cyclohexene unit could be de-

could be found, under which a suitable substrate could un- tected. Compound 66 could also be prepared directly from

dergo sequential alkyne and enyne or alkene metatheses. bis-alkyne 63 by sequential addition of the alkyne and en-

Alkylideneruthenium compounds such as catalysts 1 and 2 yne metathesis catalysts to a solution of compound 63 in

do not initiate alkyne metatheses, and of the various cata- chlorobenzene. This one-pot process gave a higher chemical

lytic systems available for alkyne metathesis,^[9]the (hexacar- yield of diene 66 (72%) and demonstrated that catalyst 2

bonyl)molybdenum/2-fluorophenol system developed by was stable to the (hexacarbonyl)molybdenum, 2-fluorophe-

Grela^[25]appeared to be experimentally convenient. Ring- nol and their decomposition products formed during the

closing alkyne metathesis (RCAM) usually requires that the initial alkyne metathesis.

cycloalkyne being formed contains at least 12 carbon

To extend this combination of alkyne and enyne metathe-

atoms,^[25–27]so compounds 35–38 would not be expected to ses to substrates containing an alkene unit which would

undergo RCAM. Hence, substrates 62 and 63 were pre- participate in metathesis reactions, the norbornene diesters

pared because RCAM would provide a 12-membered ring 70–73 were prepared. The starting material for the synthesis

and they contain an additional alkene unit which might be

involved in subsequent enyne metathesis reactions. Com-

pounds 62 and 63 were readily available by esterification of

diacid 61^[28]as shown in Scheme 9.

Scheme 9. Synthesis and alkyne metathesis of substrates 62 and 63.

Treatment of compound 62 with (hexacarbonyl)molyb-

denum/2-fluorophenol in refluxing chlorobenzene gave only

intractable polymeric materials, in line with previous re-

ports of the failure of terminal alkynes to undergo alkyne

metathesis reactions.^[25,29]In contrast, treatment of sub- Scheme 10. Synthesis and metathesis reactions of substrates 70–73.

Eur. J. Org. Chem. 2007, 3727–3745

www.eurjoc.org

3733

E. Groaz, D. Banti, M. North

FULL PAPER

of these diesters was endo-norborn-5-ene-2,3-dicarboxylic and propargylic ether substituents did undergo a cascade of

anhydride (67) which underwent ring-opening with water to enyne and alkene metatheses involving the norbornene unit,

give the diacid 68.^[30]DCC-induced diesterification of the leading to the formation of a 6,5,6-tricyclic diene. This is

diacid 68 gave the symmetrical diesters 71–73 (Scheme 10). consistent with previous work on the metathesis of norbor-

For the synthesis of unsymmetrical diester 70, anhydride 67 nene derivatives.^[5]

was first ring-opened with but-2-yn-1-ol to give acid 69,

then esterified to give the desired diester 70.

Alkyne metathesis of cyclohexene and norbornene esters

was also investigated using (hexacarbonyl)molybdenum/2-

Diesters 70–71 failed to undergo alkyne metathesis when fluorophenol as the metathesis initiator. 6,12-Fused bicyclic

treated with (hexacarbonyl)molybdenum/2-fluorophenol alkynes could be formed in good yield, and the products

under the conditions used for diester 63. RCAM in these were substrates for further alkene or enyne metatheses initi-

cases would have given 10- to 11-membered ring-containing ated by catalysts 1 and 2. Although the conditions required

alkynes for which there is only very limited precedent in for alkyne metatheses are very different to those employed

alkyne metathesis chemistry.^[27]However, no dimeric prod- for alkene or enyne metatheses, it has been shown that the

ucts (analogous to 65) were detected either. The terminal two processes can also be carried out sequentially in a one-

diyne 72 did react under these conditions, but produced an pot process using molybdenum hexacarbonyl/2-fluorophe-

insoluble polymeric material.^[25,29]Compound 73, however, nol followed by either catalyst 1 or 2. The culmination of

was an excellent substrate for RCAM induced by the Grela this work was the illustration that all three types of metath-

catalyst system,^[25]giving cyclic alkyne 74 in 87% yield esis: alkyne, enyne and alkene could be carried out sequen-

(Scheme 10). Treatment of compound 74 with first-genera- tially on a substrate in a one-pot process. This opens up

tion Grubbs metathesis catalyst 1 in the presence of ethene new potential for sequential and cascade metathesis pro-

resulted only in the ROM of the strained norbornene ring, cesses involving multiple catalysts and reaction types as well

giving the bis-alkene 75. In contrast, use of the second-gen- as non-metathesis transformations.

eration catalyst 2 resulted in both ROM of the norbornene

unit and enyne cross metathesis, leading to diene 76.^[20b]

The synthesis of compounds 75 and 76 could also be

carried out directly from bis-yne 73 in a one-pot process by

sequential addition of the two metathesis catalysts. In the

case of the synthesis of the compound 76, this involves all

three classes of metathesis reactions (alkyne, enyne and al-

kene) occurring sequentially in a one-pot process. Such a

400 mesh) supplied by Merck. Analytical thin layer chromatog-

combination of metathesis transformations has not pre-

Experimental Section

Dichloromethane was dried by distillation over calcium hydride.

Toluene was dried by distillation from metallic sodium prior to use.

All reactions were carried out under an inert atmosphere. Chroma-

tographic separations were performed using silica gel 60 (230–

raphy (TLC) was carried out on Merck polyester backed sheets

viously been reported.

coated with silica gel 60 F254, using short wavelength (254 nm)

ultraviolet light, or basic potassium permanganate (KMnO₄) stains

to visualise components.

Melting points were determined with a Gallenkamp melting point

apparatus and are uncorrected. Infrared spectra were recorded with

a Perkin–Elmer Paragon 1000 Fourier transform IR spectrometer

using sodium chloride plates. Characteristic absorptions are re-

ported in wavenumbers (cm^–1) with the following abbreviations:

strong (s), medium (m) or weak (w).

Conclusions

Treatment of allyl or propargyl ethers of cyclohexenes

with ruthenium-based metathesis initiators at temperatures

of up to 60 °C results in metathesis occurring exclusively at

alkene or alkyne units within the side-chains to give 6,8-

fused bicyclic bis-ethers as a result of a kinetically con-

trolled reaction rather than the thermodynamically more

stable bis-dihydropyran derivatives that could have been

formed by participation of the cyclohexene unit in the me-

tathesis cascade. This contrasts with previous work on the

metathesis of cyclohexene ethers at elevated tempera-

tures,^[12]and with previous work on diamino cyclohexene

derivatives.^[6]These metathesis sequences were also ex-

tended to cross-metatheses leading to bis-dienes, and to in-

tramolecular enyne metatheses leading to dihydrofurans.

These results illustrate some significant differences in reac-

tivity between the first- and second-generation Grubbs’ cat-

alysts 1 and 2, and show that for enyne metatheses, the first-

generation catalyst 1 sometimes gives better results than the

second-generation catalyst 2, a result which can be ex-

plained on the basis of the stability of the various alkylidene

ruthenium compounds formed during the metathesis cas-

¹H and ¹³C NMR spectra were recorded with Bruker Avance digital

NMR spectrometers operating at 360, 400 or 500 MHz for protons

and 90, 100 or 125 MHz for carbon atoms. All spectra were re-

corded at room temperature in CDCl₃(unless otherwise stated) and

referenced to tetramethylsilane. Chemical shifts are expressed in

parts per million. Coupling constants are given in Hertz. The multi-

plicity of signals is reported as singlet (s), doublet (d), triplet (t),

quartet (q), multiplet (m), broad (br) or a combination of any of

these. Determination of structures was achieved with the aid of

DEPT spectra and two-dimensional NMR techniques including

COSY, long-range COSY, NOESY, one-bond heteronuclear corre-

lation and multiple bond heteronuclear correlation as appropriate.

Low- and high-resolution mass spectra were recorded at the

EPSRC national service at the University of Wales, Swansea, or

with a Bruker Apex III FTMS or Jeol AX505W spectrometer

within the chemistry department at King’s College London. The

sample was ionized by electron ionisation (EI), chemical ionisation

(CI) or electrospray ionisation (ESI). The major fragment ions are

cades. In contrast, a norbornene derivative bearing allylic reported and only the molecular ions are assigned. GCMS was

3734 Eur. J. Org. Chem. 2007, 3727–3745

www.eurjoc.org

Cascade Metathesis Reactions of Alkenes and Alkynes

FULL PAPER

performed with the Jeol AX505W spectrometer using a 0.25-µm

BP1 column (25 mϫ0.25 mm) with helium as the carrier gas at

12 psi. The temperature was held at 60 °C for 2 min, then increased

at 8 °C/min to 280 °C.

2.19–2.15 (m, 2 H, CH₂) ppm. ¹³C NMR: δ = 135.5 (=CH), 129.6

(=CH), 124.2 (2 =CH), 116.4 (=CH₂), 77.1 (2 OCH), 71.1 (OCH₂),

70.3 (OCH₂), 30.7 (2 CH₂) ppm. MS (CI): m/z (%) = 378 (100) [M

+ NH₄⁺]; found (ESI) 378.2642 (M + NH₄⁺), C₂₂H₃₆NO₄requires

378.2639.

All metathesis products were purified by flash chromatography so

that the concentration of residual ruthenium species and/or phos-

phane was below the detection limits of ¹H and ¹³C NMR spec-

troscopy.

Metathesis of 5 to 7 and 12. Method B: To a stirring solution of

compound 5 (0.1 g, 0.5 mmol) in dry CH₂Cl₂(46 mL) was added

a solution of catalyst 2 (0.023 g, 0.026 mmol, 5 mol-%) in dry

CH₂Cl₂(5 mL). The reaction mixture was stirred for 20 h at room

temperature under N₂, then the solvent was evaporated in vacuo,

and the residue subjected to flash chromatography (hexane/EtOAc,

90:10) to give compound 7 (0.06 g, 71%) and compound 12

(0.013 g, 7%) as colourless oils.

cis-1,2-Bis(allyloxy)cyclohex-4-ene (5): To a stirring solution of cis-

1,2-dihydroxycyclohex-4-ene^[10](3, 0.50 g, 4.4 mmol) in DMF

(25 mL) at 0 °C was slowly added NaH (60% in mineral oil, 0.53 g,

13.2 mmol). After stirring for 1 h at 0 °C, allyl bromide (2.65 g,

21.9 mmol) was added and the reaction mixture was warmed to

room temperature and stirred overnight. After hydrolysis with

water (10 mL), the mixture was extracted with Et₂O (4ϫ10 mL).

The combined organic phases were dried (MgSO₄), filtered, evapo-

rated in vacuo and the residue purified by flash chromatography

(hexane/EtOAc, 90:10) to give compound 5 as a colourless oil

Metathesis of 6 to 8, 13 and 14: To a stirring solution of compound

6 (0.1 g, 0.51 mmol) in dry CH₂Cl₂(46 mL) was added a solution

of catalyst 1 (0.021 g, 0.03 mmol, 5 mol-%) in dry CH₂Cl₂(5 mL).

The reaction mixture was stirred for 20 h at 35 °C under N₂, then

the solvent was evaporated in vacuo and the residue subjected to

(0.68 g, 80%). IR (neat): ν

= 3078 (w), 3028 (m), 2908 (s), 2983 flash chromatography (hexane/EtOAc, 90:10) to give compound 8

˜

max

(m), 2907 (s), 1646 (m) cm^–1. ¹H NMR: δ = 6.01–5.90 (m, 1 H, (0.08 g, 92%), compound 13 (0.013 g, 6%) and compound 14

CH=CH₂), 5.60 (t, J = 1.5 Hz, 1 H, CH=CH), 5.30 (dq, J = 17.2,

1.7 Hz, 1 H, =CH₂), 5.17 (ddd, J = 10.4, 3.1, 1.4 Hz, 1 H, =CH₂),

(0.005 g, 2%) as transparent oils. Data for 8: IR (neat): ν_max= 3027

˜

(m), 2904 (s), 2845 (m), 1656 (w) cm^–1. ¹H NMR: δ = 5.71–5.63

4.20–4.09 (m, 2 H, CH₂O), 3.78–3.75 (m, 1 H, OCH), 2.42–2.36 (m, 1 H, OCH₂CH=), 5.48–5.41 (m, 1 H, CHCH₂CH=), 4.41–4.26

(m, 1 H, CH₂), 2.26 (ddd, J = 16.4, 4.5, 1.8 Hz, 1 H, CH₂) ppm. (m, 2 H, OCH₂), 3.42–3.34 (m, 1 H, OCH), 2.45–2.37 (m, 1 H,

¹³C NMR: δ = 135.9 (=CH), 124.6 (=CH), 116.9 (=CH₂), 75.0 CH₂CH=), 2.06–1.98 (m, 1 H, CH₂CH=) ppm. ¹³C NMR: δ =

(OCH), 70.5 (CH₂O), 29.7 (CH₂) ppm. MS (EI): m/z (%) = 194 (5) 129.8 (=CH), 124.8 (=CH), 82.1 (OCH), 69.4 (OCH₂), 33.2 (CH₂)

[M⁺], 153 (2), 167 (11), 137 (100); found (ESI) 217.1196 [M + Na⁺],

C₁₂H₁₈O₂Na requires 217.1199.

ppm. MS (CI): m/z (%) = 184 (100) [M + NH₄⁺], 167 (4) [MH⁺];

found (ESI) 184.1332 (M + NH₄⁺), C₁₀H₁₈NO₂requires 184.1332.

Data for 13: IR (neat): ν

= 3015 (w), 2931 (s), 2959 (m), 1653

˜

max

trans-1,2-Bis(allyloxy)cyclohex-4-ene (6):^[12]To a stirring solution

of trans-1,2-dihydroxycyclohex-4-ene^[11](4, 1.0 g, 8.8 mmol) in

DMF (60 mL) at 0 °C was slowly added NaH (60% in mineral oil,

1.05 g, 26.3 mmol). After stirring for 1 h at 0 °C, allyl bromide

(5.3 g, 43.8 mmol) was added and the reaction mixture was warmed

to room temperature and stirred overnight. After hydrolysis with

water (20 mL) the mixture was extracted with Et₂O (4ϫ20 mL).

The combined organic phases were dried (MgSO₄), filtered, evapo-

rated in vacuo and the residue purified by flash chromatography

(hexane/EtOAc, 90:10) to give compound 6 (1.4 g, 81%) as a

colourless oil with identical spectroscopic properties to those pre-

(w) cm^–1. H NMR: δ = 5.92–5.81 (m, 1 H, CH=CH₂), 5.76 (t, J

= 2.9 Hz, 1 H, OCH₂CH=CH), 5.47 (s, 2 H, CHCH₂CH=CH),

5.22 (dd, J = 17.2, 1.7 Hz, 1 H, =CH₂), 5.09 (dd, J = 10.3, 1.5 Hz,

1 H, =CH₂), 4.11–4.05 (m, 4 H, 2 OCH₂CH=), 3.51 (t, J = 3.7 Hz,

2 H, 2 OCH), 2.41–2.37 (m, 2 H, CH₂), 2.03–1.98 (m, 2 H, CH₂)

ppm. ¹³C NMR: δ = 135.5 (=CH), 129.6 (=CH), 124.2 (2 CH=),

116.4 (=CH₂), 77.2 (2 OCH), 71.1 (OCH₂), 70.2 (OCH₂), 30.7 (2

CH₂) ppm. MS (CI): m/z (%) = 378 (6) [M + NH₄⁺], 108 (100);

found (ESI) 378.2641 (M + NH₄⁺), C₂₂H₃₆NO₄requires 378.2639.

1

Data for 14: IR (neat): ν

= 3026 (w), 2921 (s), 2850 (m), 1655

˜

max

(m), 1632 (m) cm^–1. ¹H NMR: δ = 5.84–5.82 (m, 1 H, OCH₂CH=),

5.50–5.48 (m, 1 H, CHCH₂CH=), 4.18–4.15 (m, 1 H, OCH₂), 4.02–

3.95 (m, 1 H, OCH₂), 3.55–3.53 (m, 1 H, OCH), 2.44–2.39 (m, 1

H, CH₂), 2.04–1.98 (m, 1 H, CH₂) ppm. ¹³C NMR: δ = 128.4

(=CH), 128.2 (=CH), 123.2 (=CH), 108.6 (=CH), 75.5 (OCH), 75.3

(OCH), 68.8 (OCH₂), 68.6 (OCH₂), 29.3 (CH₂), 29.2 (CH₂) ppm.

MS (CI): m/z (%) = 350 (100) [M + NH₄⁺], 167 (10); found (ESI)

355.1869 [M + Na⁺], C₂₀H₂₈O₄Na requires 355.1879.

viously reported.^[12]Found (ESI) 217.1197 [M

C₁₂H₁₈O₂Na requires 217.1199.

+

Na⁺],

Metathesis of 5 to 7 and 12. Method A: To a stirring solution of

compound 5 (0.1 g, 0.5 mmol) in dry CH₂Cl₂(46 mL) was added a

solution of catalyst 1 (0.04 g, 0.05 mmol, 10 mol-%) in dry CH₂Cl₂

(5 mL). The reaction mixture was stirred for 20 h at room tempera-

ture under N₂, then the solvent was evaporated in vacuo and the

residue purified by flash chromatography (hexane/EtOAc, 90:10) to

give compound 7 (0.05 g, 54%) and compound 12 (0.02 g, 9%) as

Metathesis of 6 to 8: To a stirring solution of compound 6 (0.1 g,

0.51 mmol) in dry CH₂Cl₂(46 mL) was added a solution of catalyst

2 (0.02 g, 0.026 mmol, 5 mol-%) in dry CH₂Cl₂(5 mL). The reac-

tion mixture was stirred for 20 h at room temperature under N₂,

then the solvent was evaporated in vacuo and the residue subjected

to flash chromatography (hexane/EtOAc, 90:10) to give compound

8 (0.083 g, 97%) as a colourless oil.

transparent oils. Data for 7: IR (neat): ν

= 3025 (m), 2898 (s),

˜

max

2828 (m), 1718 (w), 1656 (m) cm^–1. H NMR: δ = 6.07–5.99 (m, 2

H, OCH₂CH=), 5.84 (t, J = 1.6 Hz, 2 H, CHCH₂CH=), 5.14 (d, J

= 2.4 Hz, 1 H, CH), 5.10 (d, J = 2.4 Hz, 1 H, CH), 4.28–4.23 (m,

4 H, 2 OCH₂), 2.56–2.54 (m, 4 H, 2 CH₂) ppm. ¹³C NMR: δ =

129.5 (=CH), 124.4 (=CH), 73.1 (OCH), 66.0 (OCH₂), 30.2 (CH₂)

1

ppm. MS (CI): m/z (%) = 184 (100) [M + NH₄⁺], 167 (8) [MH⁺]; cis-1,2-Bis(allyloxy)cyclohexane (15):^[13]To a stirring solution of

found (ESI) 189.0884 [M + Na⁺], C₁₀H₁₄O₂Na requires 189.0886.

= 3017 (w), 2932 (s), 2959 (m), 1657

cis-cyclohexane-1,2-diol^[31](33, 1.0 g, 8.6 mmol) in DMF (15 mL)

at 0 °C was slowly added NaH (60% in mineral oil, 1.0 g,

25.9 mmol). After stirring for 1 h at 0 °C, allyl bromide (5.2 g,

43.1 mmol) was added and the reaction mixture was warmed to

room temperature and stirred overnight. After hydrolysis with

water (15 mL), the mixture was extracted with Et₂O (4ϫ15 mL).

Data for 12: IR (neat): ν

˜

max

(w) cm^–1. ¹H NMR: δ = 5.87 (ddd, J = 17.2, 10.5, 5.6 Hz, 1 H,

CH=CH₂), 5.76 (t, J = 2.9 Hz, 1 H, OCH₂CH=CH), 5.50 (s, 2 H,

CHCH₂CH=CH), 5.21 (dq, J = 17.2, 1.7 Hz, 1 H, CH=CH₂), 5.09

(ddd, J = 10.4, 3.1, 1.4 Hz, 1 H, CH=CH₂), 4.10–4.01 (m, 4 H, 2

OCH₂), 3.67 (t, J = 5.8 Hz, 2 H, 2 OCH), 2.32–2.26 (m, 2 H, CH₂), The combined organic phases were dried (MgSO₄), filtered, evapo-

Eur. J. Org. Chem. 2007, 3727–3745

www.eurjoc.org

3735

E. Groaz, D. Banti, M. North

FULL PAPER

rated in vacuo and the residue purified by flash chromatography

(hexane/EtOAc, 90:10) to give compound 15 (1.3 g, 75%) as a

colourless oil with identical spectroscopic properties to those pre-

viously reported.^[13]MS (CI): m/z (%) = 197 (17) [MH⁺], 155 (5),

139 (100).

combined organic phases were dried (MgSO₄), filtered, evaporated

in vacuo and the residue purified by flash chromatography (hexane/

EtOAc, 70:30) to give compound 20 (0.65 g, 48%) as a colourless

oil. Compound 5 (0.23 g, 15%) was also obtained. IR (neat): ν

˜

max

= 3441 (br), 3028 (m), 2907 (s), 1646 (m) cm^–1. ¹H NMR: δ = 5.95

(ddt, J = 17.2, 10.4, 5.6 Hz, 1 H, CH=CH₂), 5.60 (d, J = 1.5 Hz,

2 H, CH=CH), 5.31 (dq, J = 17.2, 1.5 Hz, 1 H, =CH₂), 5.20 (dq,

J = 10.2, 1.2 Hz, 1 H, =CH₂), 4.15–4.04 (m, 3 H, OCH₂, CHOH),

3.65 (td, J = 6.5, 2.2 Hz, 1 H, CHOCH₂), 2.33–2.27 (m, 4 H, 2

CH₂), 2.19–2.17 (br. s, 1 H, OH) ppm. ¹³C NMR: δ = 135.4 (CH=),

124.2 (CH=), 124.1 (CH=), 117.4 (=CH₂), 76.2 (OCH), 69.9

(OCH₂), 67.1 (OCH), 32.0 (CH₂), 27.7 (CH₂) ppm. MS (CI): m/z

(%) = 172 (100) [M + NH₄⁺], 155 (6) [MH⁺]; found (ESI) 172.1333

(M + NH₄⁺), C₉H₁₈NO₂requires 172.1332.

trans-1,2-Bis(allyloxy)cyclohexane (16):^[13,32]To a stirring solution

of trans-1,2-dihydroxycyclohexane^[33](34, 0.50 g, 4.3 mmol) in

DMF (15 mL) at 0 °C was slowly added NaH (60% in mineral oil,

0.52 g, 12.9 mmol). After stirring for 1 h at 0 °C, allyl bromide

(2.6 g, 21.5 mmol) was added and the reaction mixture was warmed

to room temperature and stirred overnight. After hydrolysis with

water (10 mL), the mixture was extracted with Et₂O (4ϫ10 mL).

The combined organic phases were dried (MgSO₄), filtered, evapo-

rated in vacuo and the residue purified by flash chromatography

(hexane/EtOAc, 90:10) to give compound 16 (0.68 g, 80%) as a

colourless oil with identical spectroscopic properties to those pre-

trans-2-Allyloxy-1-hydroxycyclohex-4-ene (21): To a stirring solu-

tion of trans-1,2-dihydroxycyclohex-4-ene^[11](4, 3.2 g, 27.7 mmol)

in DMF (50 mL) at 0 °C was slowly added NaH (60 % in mineral

oil, 1.1 g, 27.7 mmol). After stirring for 1 h at 0 °C, allyl bromide

(3.4 g, 27.7 mmol) was added and the reaction mixture was warmed

to room temperature and stirred overnight. After hydrolysis with

water (30 mL) the mixture was extracted with Et₂O (4ϫ30 mL).

The combined organic phases were dried (MgSO₄), filtered, evapo-

rated in vacuo and the residue purified by flash chromatography

(hexane/EtOAc, 70:30) to give compound 21 (2.5 g, 58%) as a

colourless oil. Compound 6 (1.5 g, 27%) was also obtained. IR

viously reported.^[13,32]IR (neat): ν

= 3078 (w), 2929 (s), 2859

˜

max

(s), 1647 (m) cm^–1.

Metathesis of 15 to 17:^[13]To a stirring solution of compound 15

(0.10 g, 0.51 mmol) in dry CH₂Cl₂(46 mL) was added a solution

of catalyst 1 (0.04 g, 0.05 mmol, 10 mol-%) in dry CH₂Cl₂(5 mL).

The reaction mixture was stirred for 20 h at 35 °C under N₂, then

the solvent was evaporated in vacuo and the residue purified by

flash chromatography (hexane/EtOAc, 90:10) to give product 17

(0.07 g, 86%) as a transparent oil with identical spectroscopic prop-

erties to those previously reported.^[13]MS (CI): m/z (%) = 186 (100)

[M + NH₄⁺], 169 (32) [MH⁺].

(neat): ν

= 3440 (br), 3030 (m), 2904 (s), 1646 (m) cm^–1. ¹H

˜

max

NMR: δ = 6.02–5.91 (m, 1 H, CH=CH₂), 5.61–5.52 (m, 2 H,

CH=CH), 5.31 (dq, J = 17.1, 1.6 Hz, 1 H, =CH₂), 5.21 (dq, J =

10.1, 1.3 Hz, 1 H, =CH₂), 4.22–4.17 (m, 1 H, OCH₂), 4.06–4.00

(m, 1 H, OCH₂), 3.84–3.77 (m, 1 H, CHOH), 3.48–3.42 (m, 1 H,

OCH), 2.85 (br. s, 1 H, OH), 2.60–2.49 (m, 2 H, CH₂), 2.15–1.96

(m, 2 H, CH₂) ppm. ¹³C NMR: δ = 135.3 (CH=), 125.0 (CH=),

124.4 (CH=), 117.6 (=CH₂), 79.6 (OCH), 70.6 (OCH), 70.5

(OCH₂), 33.0 (CH₂), 30.8 (CH₂) ppm. MS (CI): m/z (%) = 172

(100) [M + NH₄⁺]; found (ESI) 172.1332 (M + NH₄⁺), C₉H₁₈NO₂

requires 172.1332.

Metathesis of 16 to 18:^[13]To a stirring solution of compound 16

(0.1 g, 0.5 mmol) in dry CH₂Cl₂(46 mL) was added a solution of

catalyst 1 (0.02 g, 0.03 mmol, 5 mol-%) in dry CH₂Cl₂(5 mL). The

reaction mixture was stirred for 20 h at room temperature under

N₂, then the solvent was evaporated in vacuo and the residue puri-

fied by flash chromatography (hexane/EtOAc, 90:10) to give prod-

uct 18 (0.071 g, 83%) as a transparent oil with identical spectro-

scopic properties to those previously reported.^[13]MS (CI): m/z (%)

= 186 (100) [M + NH₄⁺], 169 (17) [MH⁺].

cis-2-Allyloxy-1-(prop-2-ynyloxy)cyclohex-4-ene (22): To a stirring

solution of compound 20 (0.36 g, 2.3 mmol) in DMF (15 mL) at

0 °C was slowly added NaH (60% in mineral oil, 0.28 g, 7.0 mmol).

After stirring for 1 h at 0 °C, propargyl bromide (80% solution in

toluene, 0.7 g, 0.5 mL, 4.7 mmol) was added and the reaction mix-

ture was warmed to room temperature and stirred overnight. After

hydrolysis with water (10 mL), the mixture was extracted with Et₂O

(4ϫ10 mL). The combined organic phases were dried (MgSO₄),

filtered, evaporated in vacuo and the residue purified by flash

chromatography (hexane/EtOAc, 80:20) to give compound 22

Synthesis of Compound 19. Method A Hydrogenation of Compound

8: Compound 8 (0.05 g, 0.30 mmol) was dissolved in EtOAc

(10 mL) and hydrogenated at 1 atmosphere pressure overnight

using 10% Pd on activated carbon (0.005 g) as catalyst. The sus-

pension was then filtered through a pad of Celite and the filtrate

was evaporated in vacuo to give compound 19 (0.05 g, 98%) as

a colourless oil which was analysed by GC-MS without further

purification. GCMS: retention time 13.453 min. MS (EI): m/z (%)

= 170 (35) [M⁺], 71 (100).

(0.34 g, 75%) as a colourless oil. IR (neat): ν

= 3296 (s), 3029

˜

Synthesis of Compound 19. Method B Hydrogenation of Compound

18: Compound 18 (0.05 g, 0.30 mmol) was dissolved in EtOAc

(10 mL) and hydrogenated at 1 atmosphere pressure overnight

using 10% Pd on activated carbon (0.005 g) as catalyst. The sus-

pension was then filtered through a pad of Celite and the filtrate

was evaporated in vacuo to give compound 19 (0.05 g, 99%) as

a colourless oil which was analysed by GC-MS without further

purification. GCMS: retention time 13.461 min. MS (EI): m/z (%)

= 170 (35) [M⁺], 71 (100).

max

(m), 2908 (s), 2857 (m), 2113 (w), 1652 (w) cm^–1. ¹H NMR: δ =

5.96 (ddt, J = 17.2, 10.5, 5.6 Hz, 1 H, CH=CH₂), 5.64–5.57 (m, 2

H, CH=CH), 5.31 (dq, J = 17.2, 1.7 Hz, 1 H, =CH₂), 5.18 (dq, J

= 10.4, 1.4 Hz, 1 H, =CH₂), 4.41–4.30 (m, 2 H, OCH₂), 4.20–4.09

(m, 2 H, OCH₂), 4.05 (td, J = 5.3, 1.6 Hz, 1 H, CHOCH₂Cϵ),

3.78–3.74 (m, 1 H, CHOCH₂CH=), 2.42 (t, J = 2.5 Hz, 1 H, ϵCH),

2.40–2.27 (m, 4 H, 2 CH₂) ppm. ¹³C NMR: δ = 136.4 (=CH), 125.4

(=CH), 124.9 (=CH), 117.7 (=CH₂), 81.4 (ϵC), 75.8 (OCH), 75.0

(ϵCH), 74.7 (OCH), 71.0 (OCH₂), 57.5 (OCH₂), 30.3 (CH₂), 29.9

(CH₂) ppm. MS (CI): m/z (%) = 210 (100) [M + NH₄⁺], 193 (11)

[MH⁺], 154 (7); found (ESI) 215.1044 [M + Na⁺], C₁₂H₁₆O₂Na

requires 215.1043.

cis-2-Allyloxy-1-hydroxycyclohex-4-ene (20): To a stirring solution

of cis-1,2-dihydroxycyclohex-4-ene^[10](3, 1.0 g, 8.8 mmol) in DMF

(20 mL) at 0 °C was slowly added NaH (60% in mineral oil, 0.35 g,

8.8 mmol). After stirring for 1 h at 0 °C, allyl bromide (1.1 g,

8.8 mmol) was added, the reaction mixture was warmed to room

temperature and stirred overnight. After hydrolysis with water

(15 mL) the mixture was extracted with Et₂O (4ϫ15 mL). The

trans-2-Allyloxy-1-(prop-2-ynyloxy)cyclohex-4-ene (23): To a stir-

ring solution of compound 21 (0.9 g, 5.8 mmol) in DMF (30 mL)

at 0 °C was slowly added NaH (60% in mineral oil, 0.7 g,

3736

www.eurjoc.org

Eur. J. Org. Chem. 2007, 3727–3745

Cascade Metathesis Reactions of Alkenes and Alkynes

FULL PAPER

17.5 mmol). After stirring for 1 h at 0 °C, propargyl bromide (80%

solution in toluene, 1.7 g, 1.3 mL, 11.7 mmol) was added and the

reaction mixture was warmed to room temperature and stirred

overnight. After hydrolysis with water (10 mL), the mixture was

extracted with Et₂O (4ϫ10 mL). The combined organic phases

were dried (MgSO₄), filtered, evaporated in vacuo and the residue

purified by flash chromatography (hexane/EtOAc, 70:30) to give

leic anhydride (0.009 g, 0.09 mmol). The mixture was stirred for 8 h

at room temperature, then the solvent was evaporated under re-

duced pressure and the residue dissolved in CH₂Cl₂and filtered

twice through a pad of Celite, leaving product 26 (0.008 g, 88%) as

a colourless oil. IR (neat): ν

= 3027 (w), 2918 (m), 2859 (w),

˜

max

1

1848 (m), 1778 (s) cm^–1. H NMR: δ = 5.82 (t, J = 5.0 Hz, 1 H,

=CH), 5.55–5.48 (m, 2 H, CH=CH), 4.39 (d, J = 15.0 Hz, 1 H,

OCH₂C=), 4.14 (dd, J = 14.9, 1.3 Hz, 1 H, OCH₂C=), 4.08–4.02

compound 23 (0.9 g, 80%) as a colourless oil. IR (neat): ν

=

˜

max

3293 (s), 3031 (m), 2908 (s), 2855 (m), 2117 (w), 1657 (m) cm^–1. ¹H (m, 1 H, OCH₂CH), 3.87 (t, J = 6.2 Hz, 1 H, CHOCH₂C=), 3.76–

NMR: δ = 6.01–5.91 (m, 1 H, CH=CH₂), 5.57 (t, J = 1.2 Hz, 2 H, 3.71 (m, 2 H, CHOCH₂), 3.33–3.27 (m, 2 H, O =CCHCHC=O),

CH=CH), 5.31 (dq, J = 17.2, 1.7 Hz, 1 H, =CH₂), 5.18 (dq, J = 3.24–3.19 (m, 1 H, OCH₂CH), 2.51–2.39 (m, 3 H, 2 =CHCH₂),

10.4, 1.3 Hz, 1 H, =CH₂), 4.43–4.32 (m, 2 H, OCH₂Cϵ), 4.16 (dt, 2.31–2.14 (m, 3 H, CH₂CH=CHCH₂) ppm. ¹³C NMR: δ = 173.6

J

=

5.7, 1.5 Hz,

2

H, OCH₂CH=), 3.79–3.73 (m,

1

H,

(C=O), 171.7 (C=O), 141.1 (=C), 124.1 (=CH), 123.7 (=CH), 122.2

(=CH), 74.9 (OCH), 74.7 (OCH), 69.5 (OCH₂), 65.3 (OCH₂), 43.6

(CHC=O), 39.5 (CHC=O), 37.4 (CH), 30.3 (CH₂), 28.0 (CH₂), 23.1

(CH₂) ppm. MS (CI): m/z (%) = 308 (100) [M + NH₄⁺]; found

CHOCH₂Cϵ), 3.66–3.60 (m, 1 H, CHOCH₂CH=), 2.55–2.47 (m,

2 H, CH₂), 2.43 (t, J = 2.3 Hz, 1 H, ϵCH), 2.17–2.07 (m, 2 H,

CH₂) ppm. ¹³C NMR: δ = 135.3 (=CH), 124.2 (=CH), 124.1

(=CH), 116.5 (=CH₂), 80.5 (ϵC), 77.3 (OCH), 76.8 (OCH), 73.7 (ESI) 313.1048 [M + Na⁺], C₁₆H₁₈O₅Na requires 313.1046.

(ϵCH), 70.9 (OCH₂), 57.7 (OCH₂), 30.8 (CH₂), 30.7 (CH₂) ppm.

Diels–Alder Adduct 27: To

a solution of diene 25 (0.01 g,

MS (CI): m/z (%) = 210 (22) [M + NH₄⁺], 193 (100) [MH⁺], 151 (3),

135 (23); found (ESI) 210.1484 (M + NH₄⁺), C₁₂H₂₀NO₂requires

210.1489.

0.05 mmol) in EtOAc (2 mL) at room temperature was added ma-

leic anhydride (0.025 g, 0.26 mmol). The mixture was stirred over-

night at room temperature, then the solvent was evaporated under

reduced pressure and the residue dissolved in CH₂Cl₂and filtered

twice through a pad of Celite, leaving product 27 (0.011 g, 73%) as

Metathesis of 22 to Diene 24: To a stirring solution of compound

22 (0.05 g, 0.26 mmol) in dry CH₂Cl₂(22 mL) was added a solution

of catalyst 1 (0.02 g, 0.03 mmol, 10 mol-%) in dry CH₂Cl₂(4 mL).

The reaction mixture was stirred for 20 h at 35 °C under N₂, then

the solvent was evaporated in vacuo and the residue subjected to

flash chromatography (CH₂Cl₂) to give compound 24 (0.03 g, 58%)

a 3:1 mixture of diastereomers. IR (neat): ν

= 3032 (w), 2919

˜

max

(m), 2859 (w), 1852 (m), 1777 (s) cm^–1. H NMR: δ = (major dia-

stereomer) 5.74 (t, J = 4.5 Hz, 1 H, C=CH), 5.44–5.41 (m, 2 H,

CH=CH), 4.45 (d, J = 14.1 Hz, 1 H, OCH₂C=), 4.24–4.21 (m, 2

H, OCH₂CH), 4.12 (d, J = 14.9 Hz, 1 H, OCH₂C=), 3.66–3.40 (m,

2 H, OCHCHO), 3.36–3.23 (m, 2 H, O=CCHCHC=O), 2.92 (m,

1 H, OCH₂CH), 2.58–2.49 (m, 1 H, C=CHCH₂), 2.42–2.29 (m, 2

H, =CHCH₂), 2.21–2.17 (m, 1 H, =CHCH₂), 2.12–1.90 (m, 2 H,

=CHCH₂) ppm. (minor diastereomer): δ = 5.68 (ddd, J 5.1, 3.2,

1.5 Hz, 1 H, C=CH), 5.44–5.41 (m, 2 H, CH=CH), 4.24–4.21 (m,

2 H, OCH₂CH), 3.77 (dd, J 11.1, 5.5 Hz, 1 H, OCH₂C=), 3.66–

1

as a transparent oil. IR (neat): ν_max= 3292 (w), 3028 (m), 2900 (s),

˜

2844 (m), 1656 (w), 1605 (w) cm^–1. ¹H NMR: δ = 6.25 (dd, J =

17.8, 11.1 Hz, 1 H, CH=CH₂), 5.75 (t, J = 6.2 Hz, 1 H, CH=C),

5.60–5.52 (m, 2 H, CH=CH), 5.10 (d, J = 17.8 Hz, 1 H, =CH₂),

5.02 (dd, J = 14.5, 6.1 Hz, 1 H, OCH₂CH=), 4.99 (d, J = 11.1 Hz,

1 H, =CH₂), 4.91 (dd, J = 15.3, 1.6 Hz, 1 H, OCH₂C=), 4.24 (d, J

= 15.3 Hz, 1 H, OCH₂C=), 4.05–4.01 (m, 1 H, OCH₂CH=), 3.99

3.40 (m,

1 H, OCH₂C=), 3.36–3.23 (m, 5 H, OCHCHO,

(t,

J = 3.3 Hz, 1 H, CHOCH₂C=), 3.88–3.84 (m, 1 H,

CHOCH₂CH=), 2.35–2.20 (m, 4 H, 2 CH₂) ppm. ¹³C NMR: δ =

139.4 (=C), 138.2 (=CH), 128.3 (=CH), 124.0 (=CH), 123.8 (=CH),

112.6 (=CH₂), 75.0 (OCH), 70.6 (OCH), 65.6 (OCH₂), 64.2

(OCH₂), 30.0 (CH₂), 29.3 (CH₂) ppm. MS (CI): m/z (%) = 210

(100) [M + NH₄⁺], 193 (52) [MH⁺]; found (ESI) 193.1224 [MH⁺],

C₁₂H₁₇O₂requires 193.1223.

CHCHCH), 2.58–2.49 (m, 1 H, C=CHCH₂), 2.42–2.29 (m, 3 H, 3

= CHCH₂), 2.12–1.90 (m, 2 H, 2 =CHCH₂) ppm. ¹³C NMR (major

diastereomer): δ = 173.5 (C=O), 171.8 (C=O), 140.7 (=C), 124.9

(=CH), 124.6 (=CH), 123.2 (=CH), 83.2 (OCH), 81.1 (OCH), 74.3

(OCH₂), 73.7 (OCH₂), 42.9 (CHC=O), 41.8 (CHC=O), 38.4 (CH),

33.4 (CH₂), 32.8 (CH₂), 23.7 (CH₂) ppm. (minor diastereomer) δ =

173.5 (C=O), 171.8 (C=O), 139.3 (=C), 124.5 (=CH), 124.4 (=CH),

119.6 (=CH), 82.7 (OCH), 80.9 (OCH), 72.6 (OCH₂), 68.3 (OCH₂),

42.9 (CHC=O), 39.7 (CHC=O), 38.1 (CH), 33.1 (CH₂), 31.8 (CH₂),

21.5 (CH₂) ppm. MS (CI): m/z (%) = 308 (100) [M + NH₄⁺], 226

(34), 212 (38); found (ESI) 313.1049 [M + Na⁺], C₁₆H₁₈O₅Na re-

quires 313.1046.

Metathesis of 23 to Diene 25: To a stirring solution compound 23

(0.05 g, 0.26 mmol) in dry CH₂Cl₂(22 mL) was added a solution

of catalyst 1 (0.02 g, 0.03 mmol, 10 mol-%) in dry CH₂Cl₂(4 mL).

The reaction mixture was stirred for 20 h at 35 °C under N₂, then

the solvent was evaporated in vacuo and the residue subjected to

flash chromatography (CH₂Cl₂) to give compound 25 (0.04 g, 78%)

as a transparent oil. Unreacted starting material (0.008 g, 16%)

endo,endo-3-Allyloxy-2-hydroxy-5-norbornene (29): To a stirring

solution of diol 28^[18](1.0 g, 7.9 mmol) in DMF (15 mL) at 0 °C

was slowly added NaH (60% in mineral oil, 0.32 g, 7.9 mmol). Af-

ter stirring for 1 h at 0 °C, allyl bromide (0.96 g, 7.9 mmol) was

added and the reaction mixture was warmed to room temperature

and stirred overnight. After hydrolysis with water (15 mL) the mix-

ture was extracted with Et₂O (4ϫ15 mL). The combined organic

phases were dried (MgSO₄), filtered, evaporated in vacuo and the

residue purified by flash chromatography (hexane/Et₂O, 70:30) to

give compound 29 as a colourless oil (0.73 g, 55%). Bis-ether 30^[19]

(0.47 g, 29%) and unreacted diol 28 (0.16 g, 16%) were also iso-

was also recovered. IR (neat): ν_max= 3029 (m), 2904 (s), 2847 (m),

˜

1653 (w), 1606 (m) cm^–1. ¹H NMR: δ = 6.23 (dd, J = 17.8, 11.1 Hz,

1 H, CH=CH₂), 5.74 (t, J = 5.6 Hz, 1 H, CH=C), 5.48–5.41 (m, 2

H, CH=CH), 5.07 (d, J = 17.8 Hz, 1 H, =CH₂), 4.94 (d, J =

11.1 Hz, 1 H, =CH₂), 4.67 (d, J = 15.6 Hz, 1 H, OCH₂CH=), 4.51–

4.35 (m, 3 H, OCH₂), 3.48–3.37 (m, 2 H, 2 OCH), 2.46–2.38 (m, 2

H, CH₂), 2.08–1.96 (m, 2 H, CH₂) ppm. ¹³C NMR: δ = 140.3

(=CH), 140.0 (=C), 131.7 (=CH), 126.0 (=CH), 125.9 (=CH), 113.5

(=CH₂), 83.9 (OCH), 81.9 (OCH), 70.3 (OCH₂), 69.2 (OCH₂), 34.3

(CH₂), 34.2 (CH₂) ppm. MS (CI): m/z (%) = 210 (100) [M + NH₄⁺],

193 (80) [MH⁺]; found (ESI) 193.1225 [MH⁺], C₁₂H₁₇O₂requires

193.1223.

lated. IR (neat): ν_max= 3361 (br), 3074 (m), 2974 (s), 2870 (s), 1724

˜

(m), 1646 (s) cm^–1. ¹H NMR: δ = 6.23–6.18 (m, 2 H, CH=CH),

5.92 (ddt, J = 17.2, 10.5, 5.6 Hz, 1 H, CH=CH₂), 5.29 (dq, J =

17.2, 1.6 Hz, 1 H, =CH₂), 5.20 (dq, J = 10.4, 1.3 Hz, 1 H, =CH₂),

4.21 (dt, J = 7.8, 3.9 Hz, 1 H, CHOH), 4.12–4.01 (m, 2 H, OCH₂),

Diels–Alder Adduct 26: To a solution of diene 24 (0.006 g,

0.03 mmol) in EtOAc (2 mL) at room temperature was added ma-

Eur. J. Org. Chem. 2007, 3727–3745

www.eurjoc.org

3737

E. Groaz, D. Banti, M. North

FULL PAPER

3.95 (dd, J = 7.5, 3.7 Hz, 1 H, CHOCH₂), 3.05–3.02 (m, 2 H,

CHCH=CHCH), 2.48 (d, J = 8.0 Hz, 1 H, OH), 1.48 (dt, J = 9.6,

2.2 Hz, 1 H, CHCH₂CH), 1.16 (d, J = 9.6 Hz, 1 H, CHCH₂CH)

compound 35 (1.3 g, 89%) as a colourless oil. IR (neat): ν

=

˜

max

3290 (s), 3029 (w), 2910 (m), 2114 (w), 1653 (w) cm^–1. ¹H NMR: δ

= 5.53 (t, J = 1.5 Hz, 1 H, =CH), 4.31–4.20 (m, 2 H, OCH₂), 3.97–

ppm. ¹³C NMR: δ = 135.2 (=CH), 135.0 (=CH), 134.9 (=CH), 3.93 (m, 1 H, OCH), 2.35 (t, J = 2.4 Hz, 1 H, ϵCH), 2.31–2.20

117.5 (=CH₂), 78.5 (OCH), 71.5 (OCH₂), 71.3 (OCH), 48.3 (CH), (m, 2 H, CHCH₂) ppm. ¹³C NMR: δ = 124.4 (=CH), 80.6 (ϵC),

46.2 (CH), 41.9 (CH₂) ppm. MS (CI): m/z (%) = 184 (46) [M + 74.6 (ϵCH), 74.2 (OCH), 56.6 (OCH₂), 29.2 (CH₂) ppm. MS (CI):

NH₄⁺], 167 (45) [MH⁺], 150 (20), 90 (100); found (ESI) 167.1067 m/z (%) = 208 (100) [M + NH₄⁺], 179 (2), 151 (1), 135 (8); found

[MH⁺], C₁₀H₁₅O₂requires 167.1067.

(ESI) 213.0887 [M + Na⁺], C₁₂H₁₄O₂Na requires 213.0886.

endo,endo-3-Allyloxy-2-(prop-2-ynyloxy)-5-norbornene (31): To a

stirring solution of compound 29 (0.32 g, 1.9 mmol) in DMF

(12 mL) at 0 °C was slowly added NaH (60% in mineral oil, 0.23 g,

5.8 mmol). After stirring for 1 h at 0 °C, propargyl bromide (80%

in toluene, 0.57 g, 0.43 mL, 3.85 mmol) was added and the reaction

mixture was warmed to room temperature. The reaction was stirred

overnight, hydrolysed with water (10 mL) and extracted with Et₂O

(4ϫ10 mL). The combined organic phases were dried (MgSO₄),

filtered and evaporated in vacuo. The residue was purified by flash

chromatography (hexane/EtOAc, 70:30) to give compound 31

trans-1,2-Bis(prop-2-ynyloxy)cyclohex-4-ene (36): To a stirring solu-

tion of trans-1,2-dihydroxycyclohex-4-ene^[11](4, 1.0 g, 8.8 mmol) in

DMF (60 mL) at 0 °C was slowly added NaH (60% in mineral oil,

1.1 g, 26.3 mmol). After stirring for 1 h at 0 °C, propargyl bromide

(80% solution in toluene, 6.5 g, 4.9 mL, 43.8 mmol) was added and

the reaction mixture was warmed to room temperature and stirred

overnight. After hydrolysis with water (20 mL), the mixture was

extracted with Et₂O (4ϫ20 mL). The combined organic phases

were dried (MgSO₄), filtered, evaporated in vacuo and the residue

purified by flash chromatography (hexane/EtOAc, 90:10) to give

(0.32 g, 81%) as a colourless oil. IR (neat): ν

= 3294 (m), 3246

compound 36 (1.6 g, 96%) as a colourless oil. IR (neat): ν

=

˜

max

(m), 3073 (w), 2975 (s), 2934 (m), 2870 (m), 2112 (w), 1737 cm^–1. 3292 (s), 3030 (m), 2906 (s), 2854 (m), 2115 (w), 1656 (w) cm^–1. ¹H

1

(s). H NMR: δ = 6.28 (br. s, 2 H, CH=CH), 5.96 (ddt, J = 17.1,

10.3, 5.9 Hz, 1 H, CH=CH₂), 5.28 (dq, J = 17.3, 1.5 Hz, 1 H,

NMR: δ = 5.58–5.51 (m, 1 H, =CH), 4.33 (d, J = 2.4 Hz, 2 H,

OCH₂), 3.81–3.73 (m, 1 H, OCH), 2.50 (ddd, J = 17.5, 5.0, 3.1 Hz,

=CH₂), 5.19 (dq, J = 10.3, 1.2 Hz, 1 H, =CH₂), 4.30–4.25 1 H, CH₂), 2.43 (t, J = 2.4 Hz, 1 H, ϵCH), 2.12 (ddd, J = 15.6,

(m, 3 H, CHOCH₂Cϵ), 4.09–4.04 (m, 3 H, CHOCH₂CH=), 3.13– 4.9, 2.6 Hz, 1 H, CH₂) ppm. ¹³C NMR: δ = 123.3 (=CH), 79.6

3.12 (m,

1

H, CH₂CHCHOCH₂Cϵ), 3.09–3.08 (m,

1

H,

(ϵC), 76.2 (ϵCH), 73.2 (OCH), 56.7 (OCH₂), 29.8 (CH₂) ppm.

MS (CI): m/z (%) = 191 (4) [MH⁺], 154 (51), 136 (69), 122 (39),

95 (48), 79 (100); found (ESI) 191.1069 [MH⁺], C₁₂H₁₅O₂requires

191.1067.

CH₂CHCHOCH₂CH=), 2.43 (t, J = 2.4 Hz, 1 H, ϵCH), 1.49 (dt,

J = 9.6, 2.3 Hz, 1 H, CHCH₂CH), 1.19 (d, J = 9.6 Hz, 1 H,

CHCH₂CH) ppm. ¹³C NMR: δ = 135.6 (=CH), 134.8 (2 =CH),

117.6 (=CH₂), 81.2 (ϵC), 79.1 (ϵCH), 78.4 (OCH), 74.6 (OCH),

71.7 (OCH₂), 57.5 (OCH₂), 46.3 (2 CH), 42.2 (CH₂) ppm. MS (CI):

m/z (%) = 222 (100) [M + NH₄⁺], 205 (17) [MH⁺]; found (CI)

222.1491 (M + NH₄⁺), C₁₃H₂₀NO₂requires 222.1489.

cis-1,2-Bis(prop-2-ynyloxy)cyclohexane (37): To a stirring solution

of cis-1,2-dihydroxycyclohexane^[13](33, 1.0 g, 8.6 mmol) in DMF

(15 mL) at 0 °C was slowly added NaH (60% in mineral oil, 1.0 g,

25.9 mmol). After stirring for 1 h at 0 °C, propargyl bromide (80%

solution in toluene, 6.4 g, 4.8 mL, 43.1 mmol) was added and the

reaction mixture was warmed up to room temperature and stirred

overnight. After hydrolysis with water (15 mL) the mixture was ex-

tracted with Et₂O (4ϫ15 mL). The combined organic phases were

dried (MgSO₄), filtered, evaporated in vacuo and the residue puri-

fied by flash chromatography (hexane/EtOAc, 90:10) to afford

Metathesis of 31 to Tricyclic Diene 32: Norbornene derivative 31

(0.10 g, 0.49 mmol) was dissolved in dry CH₂Cl₂(45 mL) and eth-

ene was passed through the stirred solution for 10 min. A solution

of catalyst 1 (0.02 g, 0.024 mmol, 5 mol-%) in dry CH₂Cl₂(4 mL)

was added and the reaction mixture was stirred at 35 °C for 20 h

under ethene. The solvent was evaporated in vacuo and the residue

purified by flash chromatography (hexane/EtOAc, 80:20) to afford

compound 37 as a colourless oil (1.25 g, 76%). IR (neat): ν

=

˜

max

1

tricyclic diene 32 (0.10 g, 100%) as a colourless oil. IR (neat): ν

3288 (s), 2939 (s), 2861 (m), 2117 (m), 1715 (w) cm^–1. H NMR: δ

= 4.26–4.16 (m, 2 H, OCH₂), 3.73 (dd, J = 6.1, 2.5 Hz, 1 H, OCH),

2.33 (t, J = 2.5 Hz, 1 H, ϵCH), 1.84–1.76 (m, 1 H, CH₂CH), 1.58–

˜

max

= 3345 (s), 2931 (s), 2874 (s), 1736 (s), 1646 (s) cm^–1. H NMR: δ

1

= 6.19 (dd, J = 17.8, 11.1 Hz, 1 H, CH=CH₂), 5.81–5.73 (m, 3 H,

CH=CH, C=CH), 4.94–4.89 (m, 2 H, =CH₂), 4.51 (d, J = 15.1 Hz, 1.42 (m, 2 H, CH₂CH₂CH), 1.30–1.21 (m, 1 H, CH₂CH) ppm. ¹³C

1 H, OCH₂CH=), 4.26–4.13 (m, 3 H, OCH₂CH=, OCH₂C=), 4.09– NMR: δ = 80.4 (ϵC), 75.7 (ϵCH), 73.9 (OCH), 55.6 (OCH₂), 27.2

4.01 (m, 2 H, OCHCHO), 2.29–2.27 (m, 1 H, CHCH=CH), 2.20– (CH₂), 21.9 (CH₂) ppm. MS (EI): m/z (%) = 191 (M–H⁺, 2), 153

2.17 (m, 1 H, CH-CH=C), 1.95 (dt, J = 12.3, 6.3 Hz, 1 H, (21), 137 (20), 97 (35); found (ESI) 215.1046 [M

CHCH₂CH), 1.56–1.44 (m, 1 H, CHCH₂CH) ppm. ¹³C NMR: δ = C₁₂H₁₆O₂Na requires 215.1042.

136.3 (=CH), 135.7 (=C), 127.3 (=CH), 126.7 (=CH), 126.4 (=CH),

+ Na],

trans-1,2-Bis(prop-2-ynyloxy)cyclohexane (38): To a stirring solu-

tion of trans-1,2-dihydroxycyclohexane^[13,32](34, 1.0 g, 8.6 mmol)

in DMF (15 mL) at 0 °C was slowly added NaH (60% in mineral

oil, 1.0 g, 25.9 mmol). After stirring for 1 h at 0 °C, propargyl bro-

mide (80% solution in toluene, 6.4 g, 4.8 mL, 43.1 mmol) was

added and the reaction mixture was warmed to room temperature

and then stirred overnight. After hydrolysis with water (20 mL), the

mixture was extracted with Et₂O (4ϫ20 mL). The combined or-

ganic phases were dried (MgSO₄), filtered, evaporated in vacuo and

the residue purified by flash chromatography (hexane/EtOAc,

90:10) to give compound 38 (1.2 g, 73%) as a colourless oil. IR

111.8 (=CH₂), 77.5 (OCH), 77.0 (OCH), 65.4 (CH₂O), 65.0

(CH₂O), 40.0 (CH), 39.5 (CH), 36.3 (CH₂) ppm. MS (CI): m/z (%)

= 222 (100) [M + NH₄⁺], 205 (72) [MH⁺]; found (ESI) 205.1226

[MH⁺], C₁₃H₁₇O₂requires 205.1223.

cis-1,2-Bis(prop-2-ynyloxy)cyclohex-4-ene (35): To a stirring solu-

tion of cis-1,2-dihydroxycyclohex-4-ene^[10](3, 0.9 g, 7.8 mmol) in

DMF (20 mL) at 0 °C was slowly added NaH (60% in mineral oil,

0.94 g, 23.5 mmol). After stirring for 1 h at 0 °C, propargyl bromide

(80% solution in toluene, 3.5 g, 2.6 mL, 23.5 mmol) was added and

the reaction mixture was warmed to room temperature and stirred

overnight. After hydrolysis with water (15 mL), the mixture was

extracted with Et₂O (4ϫ15 mL). The combined organic phases

were dried (MgSO₄), filtered, evaporated in vacuo and the residue

purified by flash chromatography (hexane/EtOAc, 90:10) to afford

(neat): ν_max= 3290 (s), 2934 (s), 2861 (m), 2116 (w), 1716 (w) cm^–1.

˜

¹H NMR: δ = 4.37–4.27 (m, 2 H, OCH₂), 3.45–3.39 (m, 1 H,

OCH), 2.42 (t, J = 2.3 Hz, 1 H, ϵCH), 2.06–2.03 (m, 1 H,

CH₂CH), 1.69–1.67 (m, 1 H, CH₂CH₂CH), 1.33–1.21 (m, 2 H,

3738

www.eurjoc.org

Eur. J. Org. Chem. 2007, 3727–3745

Cascade Metathesis Reactions of Alkenes and Alkynes

FULL PAPER

CH₂CH₂) ppm. ¹³C NMR: δ = 80.8 (OCH), 80.6 (ϵC), 73.7 (OCH), 69.5 (OCH₂), 57.8 (OCH₂), 30.7 (CH₂), 30.5 (CH₂) ppm.

(ϵCH), 57.2 (OCH₂), 30.1 (CH₂), 23.5 (CH₂) ppm. MS (CI): m/z

MS (CI): m/z (%) = 236 (88) [M + NH₄⁺], 219 (22) [MH⁺], 152

(%) = 210 (100) [M + NH₄⁺]; found (ESI) 215.1041 [M + Na⁺], (38), 126 (39), 112 (62); found (ESI) 219.1380 [MH⁺], C₁₄H₁₉O₂

C₁₂H₁₆O₂Na requires 215.1042.

requires 219.1380. Data for 43: IR (neat): ν

= 3029 (m), 2903

˜

max

(s), 1653 (w), 1596 (s) cm^–1. ¹H NMR: δ = 6.31 (dd, J = 17.8,

11.0 Hz, 1 H, CH=CH₂), 5.51–5.45 (m, 1 H, =CH), 5.24 (d, J =

17.5 Hz, 1 H, CH=CH₂), 5.23 (s, 1 H, C=CH₂), 5.09 (s, 1 H,

C=CH₂), 5.02 (d, J = 11.0 Hz, 1 H, CH=CH₂), 4.30–4.22 (m, 2 H,

OCH₂), 3.59–3.53 (m, 1 H, OCH), 2.44–2.40 (m, 1 H, CH₂), 2.05

(ddd, J = 15.6, 4.6, 2.6 Hz, 1 H, CH₂) ppm. ¹³C NMR: δ = 143.9

(=C), 134.4 (=CH), 125.0 (=CH), 117.7 (=CH₂), 115.0 (=CH₂),

78.0 (OCH), 70.5 (OCH₂), 31.3 (CH₂) ppm. MS (CI): m/z (%) =

264 (100) [M + NH₄⁺], 247 (37) [MH⁺], 180 (32), 135 (23); found

(ESI) 247.1692 [MH⁺], C₁₆H₂₃O₂requires 247.1693. Data for 44:

Metathesis of 35 to 39, 40 and 41: Compound 35 (0.1 g, 0.53 mmol)

was dissolved in dry toluene (48 mL) and ethene was passed

through the stirred solution for 20 min. A solution of catalyst 2

(0.05 g, 0.05 mmol, 10 mol-%) in dry toluene (5 mL) was then

added and the reaction mixture was stirred at 60 °C for 24 h under

ethene. The solvent was evaporated in vacuo and the residue sub-

jected to flash chromatography (CH₂Cl₂) to afford three products,

39 (0.04 g, 31%), 40 (0.02 g, 15%) and 41 (0.015 g, 13%) as colour-

less oils. Data for 39: IR (neat): ν_max= 3295 (s), 3029 (m), 2907 (s),

˜

2114 (w), 1721 (m), 1596 (m) cm^–1. ¹H NMR: δ = 6.31 (dd, J =

17.7, 11.0 Hz, 1 H, CH=CH₂), 5.55–5.49 (m, 2 H, CH=CH), 5.26

(d, J = 18.0 Hz, 1 H, CH=CH₂), 5.24 (s, 1 H, C=CH₂), 5.10 (s, 1

H, C=CH₂), 5.03 (d, J = 11.0 Hz, 1 H, CH=CH₂), 4.31–4.26 (m,

2 H, OCH₂Cϵ), 4.26–4.19 (m, 2 H, OCH₂C=), 3.98–3.96 (m, 1 H,

CHOCH₂Cϵ), 3.70–3.67 (m, 1 H, CHOCH₂C=), 2.34 (t, J =

2.4 Hz, 1 H, ϵCH), 2.32–2.19 (m, 4 H, 2 CH₂) ppm. ¹³C NMR: δ

= 142.6 (=C), 136.5 (=CH), 124.2 (=CH), 123.7 (=CH), 116.9

(=CH₂), 114.1 (=CH₂), 80.3 (ϵC), 77.0 (ϵCH), 74.8 (OCH), 73.8

(OCH), 68.4 (OCH₂), 56.4 (OCH₂), 29.3 (CH₂), 28.5 (CH₂) ppm.

MS (CI): m/z (%) = 236 (100) [M + NH₄⁺], 219 (17) [MH⁺]; found

(ESI) 219.1380 [MH⁺], C₁₄H₁₉O₂requires 219.1380. Data for 40:

IR (neat): ν

= 3029 (m), 2908 (s), 2847 (m), 1656 (w), 1604 (m)

˜

max

cm^–1. H NMR: δ = 6.74 (dd, J = 17.6, 11.4 Hz, 1 H, CH=CH₂),

5.44 (s, 1 H, =CH), 5.24 (d, J = 17.7 Hz, 1 H, =CH₂), 5.13 (d, J =

11.5 Hz, 1 H, =CH₂), 4.71–4.63 (m, 2 H, OCH₂), 3.49–3.47 (m, 1

H, OCH), 2.44–2.40 (m, 1 H, CH₂), 2.06–2.02 (m, 1 H, CH₂) ppm.

¹³C NMR: δ = 133.3 (CH=), 133.1 (=C), 123.3 (=CH), 114.2

(=CH₂), 79.5 (OCH), 67.8 (OCH₂), 31.6 (CH₂) ppm. MS (CI): m/z

(%) = 236 (100) [M + NH₄⁺], 219 (41) [MH⁺], 125 (62), 107 (74);

found (ESI) 236.1646 (M + NH₄⁺), C₁₄H₂₂NO₂requires 236.1645.

1

Metathesis of 37 to 45, 46 and 47: Diyne 37 (0.1 g, 0.5 mmol) was

dissolved in dry toluene (48 mL) and ethene was passed through

the stirred solution for 20 min. A solution of catalyst 2 (0.04 g,

0.05 mmol, 10 mol-%) in dry toluene (4 mL) was then added and

the reaction mixture was stirred at 60 °C for 24 h under ethene. The

solvent was evaporated in vacuo and the residue was purified by

flash chromatography (CH₂Cl₂) to afford three products, 45 (0.04 g,

36%), 46 (0.03 g, 22%) and 47 (0.02 g, 19%). Data for 45: IR

IR (neat): ν

= 3027 (m), 2919 (s), 2114 (w), 1652 (w), 1596 (m)

˜

max

cm^–1. H NMR: δ = 6.31 (dd, J = 17.8, 11.1 Hz, 1 H, CH=CH₂),

5.52 (t, J = 1.5 Hz, 1 H, =CH), 5.51 (s, 1 H, C=CH₂), 5.25 (d, J =

17.6 Hz, 1 H, CH=CH₂), 5.09 (s, 1 H, C=CH₂), 5.02 (d, J =

11.1 Hz, 1 H, CH=CH₂), 4.28–4.20 (m, 2 H, OCH₂), 3.72–3.70 (m,

1 H, OCH), 2.36–2.17 (m, 2 H, CH₂) ppm. ¹³C NMR: δ = 141.0

(=C), 134.7 (=CH), 122.3 (=CH), 114.9 (=CH₂), 112.2 (=CH₂),

73.0 (OCH), 66.7 (OCH₂), 27.3 (CH₂) ppm. MS (CI): m/z (%) =

264 (100) [M + NH₄⁺], 247 (7) [MH⁺], 194 (29), 163 (26), 135 (77);

found (ESI) 264.1959 (M + NH₄⁺), C₁₆H₂₆NO₂requires 264.1958.

1

(neat): ν

= 3302 (m), 2934 (s), 2858 (m), 2114 (w), 1596 (m)

˜

max

1

cm^–1. H NMR: δ = 6.31 (dd, J = 17.8, 11.1 Hz, 1 H, CH=CH₂),

5.27 (d, J = 17.3 Hz, 1 H, CH=CH₂), 5.25 (s, 1 H, C=CH₂), 5.09

(s, 1 H, C=CH₂), 5.02 (d, J = 10.9 Hz, 1 H, CH=CH₂), 4.22–4.21

(m, 2 H, OCH₂Cϵ), 4.19–4.18 (m, 2 H, OCH₂C=), 3.75–3.73 (m,

1 H, OCH), 3.47–3.45 (m, 1 H, OCH), 2.31 (t, J = 2.3 Hz, 1 H,

ϵCH), 1.82–1.73 (m, 2 H, CH₂CHO), 1.56–1.52 (m, 2 H,

CH₂CH₂CHO), 1.44–1.38 (m, 2 H, CH₂CH₂CHO), 1.28–1.18 (m,

2 H, CH₂CHO) ppm. ¹³C NMR: δ = 142.0 (=C), 135.7 (=CH),

115.8 (=CH₂), 113.2 (=CH₂), 79.7 (OCH), 76.2 (OCH), 74.8 (ϵC),

72.6 (ϵCH), 67.2 (OCH₂), 54.9 (OCH₂), 26.7 (CH₂), 26.4 (CH₂),

21.3 (CH₂), 20.7 (CH₂) ppm. MS (EI): m/z (%) = 220 (1) [M⁺], 153

(7), 137 (79), 67 (100); found (ESI) 243.1359 [M + Na⁺],

Data for 41: IR (neat): ν

= 3027 (m), 2918 (s), 2845 (m), 1652

˜

max

(w), 1606 (m) cm^–1. H NMR: δ = 6.81 (dd, J = 17.6, 11.4 Hz, 1

H, CH=CH₂), 5.56 (s, 1 H, =CH), 5.28 (d, J = 17.6 Hz, 1 H,

=CH₂), 5.15 (d, J = 11.3 Hz, 1 H, =CH₂), 5.14 (d, J = 14.7 Hz, 1

H, OCH₂), 4.29 (d, J = 14.9 Hz, 1 H, OCH₂), 3.91 (t, J = 4.7 Hz,

1 H, OCH), 2.34–2.22 (m, 2 H, CH₂) ppm. ¹³C NMR: δ = 132.7

(=C), 132.6 (=CH), 122.9 (=CH), 114.4 (=CH₂), 71.9 (OCH), 64.8

(OCH₂), 28.6 (CH₂) ppm. MS (CI): m/z (%) = 236 (100) [M +

NH₄⁺], 219 (13) [MH⁺]; found (ESI) 236.1645 (M + NH₄⁺),

C₁₄H₂₂NO₂requires 236.1645.

1

C H O Na requires 241.1356. Data for 46: IR (neat): ν_max= 3086

˜

14 20

2

Metathesis of 36 to 42, 43 and 44: Diyne 36 (0.10 g, 0.53 mmol)

was dissolved in dry toluene (48 mL) and ethene was passed

through the stirred solution for 20 min. A solution of catalyst 2

(0.05 g, 0.05 mmol, 10 mol-%) in dry toluene (5 mL) was then

added and the reaction mixture was stirred at 60 °C for 24 h under

ethene. The solvent was evaporated in vacuo and the residue puri-

(w), 2936 (s), 2859 (m), 1653 (w), 1596 (m) cm^–1. ¹H NMR: δ =

6.40 (dd, J = 17.8, 11.0 Hz, 1 H, CH=CH₂), 5.34 (s, 1 H, C=CH₂),

5.34 (d, J = 17.6 Hz, 1 H, CH=CH₂), 5.17 (s, 1 H, C=CH₂), 5.10

(d, J = 11.0 Hz, 1 H, CH=CH₂), 4.32–4.23 (m, 2 H, OCH₂), 3.58

(dd, J = 6.0, 2.4 Hz, 1 H, OCH), 1.91–1.89 (m, 1 H, CH₂CHO),

1.69–1.62 (m, 1 H, CH₂CH₂CHO), 1.57–1.48 (m, 1 H, CH₂CHO),

fied by flash chromatography (hexane/EtOAc, 90:10) to afford 1.35–1.29 (m, 1 H, CH₂CH₂CHO) ppm. ¹³C NMR: δ = 143.2 (=C),

three products, 42 (0.03 g, 28%), 43 (0.02 g, 18%) and 44 (0.02 g,

14%). Data for 42: IR (neat): ν = 3296 (m), 3029 (w), 2904 (s),

136.8 (=CH), 115.6 (=CH₂), 113.0 (=CH₂), 76.2 (OCH), 67.3

(OCH₂), 26.8 (CH₂), 21.1 (CH₂) ppm. MS (CI): m/z (%) = 266

(100) [M + NH₄⁺], 249 (34) [MH⁺], 182 (20), 165 (8); found (ESI)

˜

max

2115 (w), 1596 (m) cm^–1. ¹H NMR: δ = 6.32 (dd, J = 17.7, 11.0 Hz,

1 H, CH=CH₂), 5.48–5.45 (m, 2 H, CH=CH), 5.26 (d, J = 18.2 Hz, 249.1848 [MH⁺], C₁₆H₂₅O₂requires 249.1849. Data for 47: IR

1 H, CH=CH₂), 5.23 (s, 1 H, C=CH₂), 5.10 (s, 1 H, C=CH₂), 5.05

(neat): ν

= 3089 (w), 2936 (s), 2859 (m), 1605 (w) cm^–1. ¹H

˜

max

(d, J = 11.0 Hz, 1 H, CH=CH₂), 4.32–4.27 (m, 2 H, OCH₂Cϵ), NMR: δ = 6.77 (dd, J = 17.6, 11.4 Hz, 1 H, =CH), 5.25 (d, J =

4.24–4.23 (m, 2 H, OCH₂C=), 3.71–3.66 (m, 1 H, OCH), 3.59–3.54 17.6 Hz, 1 H, =CH₂), 5.17–5.11 (m, 2 H, =CH₂, OCH₂), 4.23 (d,

(m, 1 H, OCH), 2.46–2.41 (m, 2 H, 2 CH₂), 2.34 (t, J = 2.4 Hz, 1 J = 14.8 Hz, 1 H, OCH₂), 3.65 (d, J = 8.1 Hz, 1 H, OCH), 1.98–

H, ϵCH), 2.05 (dd, J = 15.4, 7.5 Hz, 2 H, 2 CH₂) ppm. ¹³C NMR:

δ = 143.0 (=C), 136.6 (=CH), 124.2 (=CH), 124.1 (=CH), 117.2

(=CH₂), 114.4 (=CH₂), 80.6 (ϵC), 77.4 (ϵCH), 76.8 (OCH), 73.8

1.73 (m, 1 H, CH₂CHO), 1.64–1.57 (m, 1 H, CH₂CH₂CHO), 1.50–

1.47 (m, 1 H, CH₂CHO), 1.31–1.19 (m, 1 H, CH₂CH₂CHO) ppm.

¹³C NMR: δ = 132.6 (=C and =CH), 114.2 (=CH₂), 76.2 (OCH),

Eur. J. Org. Chem. 2007, 3727–3745

www.eurjoc.org

3739

E. Groaz, D. Banti, M. North

FULL PAPER

65.3 (OCH₂), 27.9 (CH₂), 21.3 (CH₂) ppm. MS (CI): m/z (%) = 238

(100) [M + NH₄⁺], 221 (11) [MH⁺]; found (ESI) 243.1360 [M +

Na⁺], C₁₄H₂₀O₂Na requires 243.1361.

OCH_cis+trans), 2.32 (t, J = 2.3 Hz, 2 H, ϵCH_cis+trans), 2.31–2.18 (m,

8

H, CH₂CH=CHCH_2cis+trans), 2.02 (q, J = 6.1 Hz, 4 H,

=CHCH₂CH_2cis+trans), 1.35–1.24 (m, 8 H, MeCH₂CH_2cis+trans), 0.83

(t, J = 7.1 Hz, 6 H, CH_3cis+trans) ppm. ¹³C NMR: δ = 142.7 (C=),

134.0 and 129.6 (=CH), 131.6 and 126.9 (=CH), 124.5 (=CH),

123.8 (=CH), 114.8 and 114.6 (=CH₂), 80.5 (ϵC), 74.7 (OCH),

74.6 (ϵCH), 73.9 and 73.7 (OCH), 71.8 and 69.2 (OCH₂), 56.6

(OCH₂), 32.8 and 32.2 (CH₂), 31.4 (CH₂), 29.6 (CH₂), 28.7 and

28.6 (CH₂), 22.4 and 22.2 (CH₂), 14.0 and 13.4 (CH₃) ppm. MS

(CI): m/z (%) = 292 (100) [M + NH₄⁺], 135 (13); found (ESI)

297.1816 [M + Na⁺], C₁₈H₂₆O₂Na requires 297.1825. Data for 53:

Metathesis of 38 to 48, 49 and 50: Diyne 38 (0.1 g, 0.52 mmol) was

dissolved in dry toluene (48 mL) and ethene was passed through

the stirred solution for 20 min. A solution of catalyst 2 (0.04 g,

0.05 mmol, 10 mol-%) in dry toluene (4 mL) was then added and

the reaction mixture was stirred at 60 °C for 24 h under ethene. The

solvent was then evaporated in vacuo and the residue was purified

by flash chromatography (CH₂Cl₂then hexane/EtOAc, 90:10) to

afford three products, 48 (0.04 g, 36%), 49 (0.03 g, 24%) and 50

IR (neat): ν

= 3030 (w), 2958 (s), 2927 (s), 2854 (s), 1728 (m),

˜

max

(0.02 g, 20%). Data for 48: IR (neat): ν

= 3300 (m), 2934 (s),

˜

max

1680 (m), 1635 (w) cm^–1. H NMR: δ = 5.99 (d, J = 16.0 Hz, 1 H,

=C-CH=_trans), 5.78–5.70 (m, 2 H, =C-CH=CH_cis+trans), 5.51–5.43

(m, 3 H, =C-CH=_cis, CHCH₂CH=_cis+trans), 5.22 (br. s, 1 H,

=CH_2trans), 5.08 (br. s, 1 H, =CH_2cis), 4.96 (br. s, 2 H, =CH_2cis+trans),

4.25 (d, J = 13.0 Hz, 1 H, OCH_2trans), 4.18 (d, J = 13.0 Hz, 1 H,

OCH_2cis), 4.08 (d, J = 13.4 Hz, 1 H, OCH_2trans), 4.04 (d, J =

13.4 Hz, 1 H, OCH_2cis), 3.69 (t, J = 4.6 Hz, 2 H, CH_cis+trans), 2.34–

1

2860 (m), 2115 (w), 1596 (w) cm^–1. ¹H NMR: δ = 6.31 (dd, J =

17.8, 11.0 Hz, 1 H, =CH), 5.25 (d, J = 17.6 Hz, 1 H, CH=CH₂),

5.24 (s, 1 H, C=CH₂), 5.09 (s, 1 H, C=CH₂), 5.04 (d, J = 11.0 Hz,

1 H, CH=CH₂), 4.25 (t, J = 4.7 Hz, 2 H, OCH₂Cϵ), 4.21–4.17 (m,

2 H, OCH₂), 3.36–3.30 (m, 1 H, OCH), 3.25–3.19 (m, 1 H, OCH),

2.33 (t, J = 2.5 Hz, 1 H, ϵCH), 1.98–1.94 (m, 2 H, CH₂CHO),

1.61–1.59 (m, 2 H, CH₂CH₂CHO), 1.25–1.14 (m, 4 H, CH₂CH₂)

ppm. ¹³C NMR: δ = 143.2 (=C), 136.7 (=CH), 117.0 (=CH₂), 114.2

(=CH₂), 81.4 (ϵC), 80.7 (ϵCH), 76.3 (OCH), 73.5 (OCH), 69.3

(OCH₂), 57.6 (OCH₂), 30.4 (CH₂), 30.0 (CH₂), 23.6 (CH₂), 23.5

(CH₂) ppm. MS (CI): m/z (%) = 221 (2) [MH⁺], 153 (7), 137 (79),

67 (100); found (ESI) 243.1359 [M + Na⁺], C₁₄H₂₀O₂Na requires

2.28 (m,

2 H, CHCH_2cis+transCH=), 2.19–2.14 (m, 4 H,

CHCH_2cis+transCH=, =CHCH_2cis+transCH₂), 2.01 (q, J = 6.8 Hz, 2

H, =CHCH_2cis+transCH₂), 1.34–1.23 (m, 8 H, MeCH₂CH_2cis+trans),

0.82 (t, J = 7.0 Hz, 6 H, CH_3cis+trans) ppm. ¹³C NMR: δ = 142.9

and 142.6 (C=), 133.9 and 129.7 (=CH), 131.4 and 127.0 (=CH),

124.3 and 124.2 (=CH), 114.5 and 114.3 (=CH₂), 74.7 and 74.5

(OCH), 72.0 and 69.4 (OCH₂), 32.8 and 32.2 (CH₂), 31.4 and 29.4

(CH₂), 29.3 and 28.7 (CH₂), 22.4 and 22.3 (CH₂), 14.0 and 13.9

(CH₃) ppm. MS (CI): m/z (%) = 376 (100) [M + NH₄⁺], 359 (23)

[MH⁺], 247 (51); found (ESI) 381.2753 [M + Na⁺], C₂₄H₃₈O₂Na

requires 381.2764.

241.1356. Data for 49: IR (neat): ν

= 3087 (w), 2932 (s), 2860

˜

max

(m), 1596 (m) cm^–1. H NMR: δ = 6.30 (dd, J = 17.8, 11.0 Hz, 1

H, =CH), 5.25 (s, 1 H, C=CH₂), 5.23 (d, J = 17.4 Hz, 1 H,

CH=CH₂), 5.08 (s, 1 H, C=CH₂), 5.01 (d, J = 11.0 Hz, 1 H,

CH=CH₂), 4.23 (s, 2 H, OCH₂), 3.27–3.21 (m, 1 H, OCH), 1.95

(dd, J = 10.4, 2.6 Hz, 1 H, CH₂CHO), 1.61–1.58 (m, 1 H,

CH₂CH₂CHO), 1.26–1.12 (m, 2 H, CH₂CH₂) ppm. ¹³C NMR: δ =

143.3 (=C), 136.8 (=CH), 116.8 (=CH₂), 114.1 (=CH₂), 81.2

(OCH), 69.5 (OCH₂), 30.1 (CH₂), 23.6 (CH₂) ppm. MS (CI): m/z

(%) = 266 (100) [M + NH₄⁺], 249 (34) [MH⁺], 182 (20), 165 (8);

found (ESI) 271.1671 [M + Na⁺], C₁₆H₂₄O₂Na requires 271.1668.

1

Metathesis of 36 to 52 and 54: To a stirring solution of compound

36 (0.05 g, 0.26 mmol) and 1-hexene (0.11 g, 1.3 mmol) in dry

CH₂Cl₂(22 mL) under N₂was added a solution of catalyst 1

(0.02 g, 0.026 mmol, 10 mol-%) in dry CH₂Cl₂(4 mL). The reaction

mixture was stirred for 24 h at room temperature under N₂, then

the solvent was evaporated in vacuo and the residue purified by

flash chromatography (CH₂Cl₂) to afford mono-cross metathesis

product 52 (0.05 g, 50%) and bis-cross metathesis product 54

(0.02 g, 26%) as transparent oils. Each compound was isolated as

Data for 50: IR (neat): ν

= 3089 (w), 2938 (s), 2863 (m), 1605

˜

max

(w) cm^–1. H NMR: δ = 6.76 (dd, J = 17.6, 11.3 Hz, 1 H, =CH),

5.25 (d, J = 17.7 Hz, 1 H, =CH₂), 5.13 (d, J = 11.5 Hz, 1 H, =CH₂),

4.69 (d, J = 14.8 Hz, 1 H, OCH₂), 4.54 (d, J = 14.8 Hz, 1 H,

OCH₂), 3.18–3.15 (m, 1 H, OCH), 1.93–1.90 (m, 1 H, CH₂CHO),

1.61–1.60 (m, 1 H, CH₂CH₂CHO), 1.19–1.10 (m, 2 H, CH₂CH₂)

ppm. ¹³C NMR: δ = 133.3 (=C and =CH), 114.2 (=CH₂), 81.4

(OCH), 65.6 (OCH₂), 31.6 (CH₂), 30.7 (CH₂), 28.7 (CH₂), 23.3

(CH₂) ppm. MS (CI): m/z (%) = 238 (100) [M + NH₄⁺], 221 (11)

[MH⁺]; found (ESI) 243.1357 [M + Na⁺], C₁₄H₂₀O₂Na requires

243.1356.

1

a 1:1 ratio of E- and Z-isomers. Data for 52: IR (neat): ν_max= 3284

˜

(m), 3030 (w), 2955 (s), 2929 (s), 2871 (m), 2117 (w), 1719 (m),

1698 (m) cm^–1. ¹H NMR: δ = 6.00 (d, J = 16.0 Hz, 1 H, =C-

CH_trans=), 5.78–5.72 (m, 2 H, =C-CH=CH_cis+trans), 5.52–5.48 (m,

5 H, =C-CH_cis=, CH₂CH =CHCH_2cis+trans), 5.21 (br. s, 1 H,

=CH_2trans), 5.07 (br. s, 1 H, =CH_2cis), 4.97 (br. s, 2 H, =CH_2cis+trans),

4.32–4.23 (m, 4 H, OCH_2cis+transCϵ), 4.20 (s, 2 H, OCH_2transC=),

4.06 (s, 2 H, OCH_2cisC=), 3.70–3.66 (m, 2 H, OCH_cis+trans),

Metathesis of 35 to 51 and 53: To a stirring solution of compound

35 (0.05 g, 0.26 mmol) and 1-hexene (0.11 g, 1.3 mmol) in dry

CH₂Cl₂(22 mL) under N₂was added a solution of catalyst 1

3.58–3.52 (m,

2

H, OCH_cis+trans), 2.44–2.41 (m,

4

H,

=CHCH_2cis+transCHO), 2.34–2.33 (m, 2 H, ϵCH_cis+trans), 2.17 (q, J

(0.02 g, 0.026 mmol, 10 mol-%) in dry CH₂Cl₂(4 mL). The reaction = 6.9 Hz, 2 H, CH=CHCH_2trans), 2.03 (q, J = 6.9 Hz, 6 H,

mixture was stirred for 24 h at room temperature under N₂, then

the solvent was evaporated in vacuo and the residue purified by

flash chromatography (CH₂Cl₂) to afford mono-cross metathesis

product 51 (0.04 g, 60%) and bis-cross metathesis product 53

(0.04 g, 40%) as transparent oils. Each compound was isolated as

CH=CHCH_2cis

, =CHCH_2cis+transCHO), 1.33–1.23 (m, 8 H,

MeCH₂CH_2cis+trans), 0.83 (t, J = 7.2 Hz, 6 H, CH_3cis+trans) ppm. ¹³

C

NMR: δ = 143.3 and 142.9 (=C), 134.5 and 130.0 (=CH), 132.0

and 127.4 (=CH), 124.6 (CH=CH), 115.2 and 115.1 (=CH₂), 81.0

(ϵC), 77.6 (OCH), 77.5 (OCH), 74.1 (ϵCH), 73.4 and 70.6

(OCH₂), 58.2 (OCH₂), 33.2 and 29.1 (CH₂), 32.6 and 31.8 (CH₂),

31.1 (CH₂), 30.9 and 30.8 (CH₂), 22.8 and 22.7 (CH₂), 14.4 and

14.3 (CH₃) ppm. MS (EI): m/z (%) = 274 (3) [M⁺], 217 (5), 151

a 1:1 ratio of E- and Z-isomers. Data for 51: IR (neat): ν_max= 3282

˜

(m), 3028 (w), 2953 (s), 2930 (s), 2872 (m), 2117 (w), 1720 (m),

1696 (m) cm^–1. ¹H NMR: δ = 5.99 (d, J = 16.0 Hz, 1 H, =C-

CH=_trans), 5.76 (dt, J = 15.9, 6.9 Hz, 2 H, =C-CH=CH_cis+trans), (11), 135 (16), 124 (24), 95 (37), 79 (100); found (ESI) 297.1834 [M

5.52–5.47 (m, 5 H, CH=CH_cis+trans, =C-CH=_cis), 5.07 (br. s, 2 H,

=CH_2cis+trans), 4.97 (br. s, 2 H, =CH_2cis+trans), 4.27 (t, J = 2.2 Hz,

4 H, OCH₂Cϵ_cis+trans), 4.20 (s, 2 H, OCH₂C=_trans), 4.19 (s, 2 H,

+ Na⁺], C₁₈H₂₆O₂Na requires 297.1825. Data for 54: IR (neat):

= 3029 (w), 2958 (s), 2926 (s), 2857 (s), 1732 (m), 1682 (m),

ν

˜

max

1645 (w) cm^–1. ¹H NMR: δ = 5.99 (d, J = 15.9 Hz, 1 H, =C-

OCH₂C=_cis), 3.97–3.96 (m, 2 H, OCH_cis+trans), 3.68–3.64 (m, 2 H, CH=_trans), 5.76–5.71 (m, 2 H, =C-CH=CH_cis+trans), 5.50–5.45 (m,

3740

www.eurjoc.org

Eur. J. Org. Chem. 2007, 3727–3745

Cascade Metathesis Reactions of Alkenes and Alkynes

FULL PAPER

3 H, =C-CH=_cis, CHCH₂CH=_cis+trans), 5.22 (br. s, 1 H, =CH_2trans), CH₂Cl₂(3 mL). The reaction mixture was stirred for 24 h at room

5.08 (br. s, 1 H, =CH_2cis), 4.96 (br. s, 2 H, =CH_2cis+trans), 4.26–4.19 temperature under N₂, then the solvent was evaporated in vacuo

(m, H, OCH_2cis+trans), 4.08–4.05 (m, H, OCH_2cis+trans), and the residue subjected to flash chromatography (hexane/EtOAc,

3.54 (br. s, 2 H, OCH_cis+trans), 2.40 (d, J = 17.0 Hz, 2 H, 70:30) to give bis-diene 58 (0.046 g, 93%) as a transparent oil. IR

=CHCH_2cis+transCH), 2.18–2.15 (m, 2 H, =CHCH_2cis+transCH₂), (neat): ν = 3429 (br), 3027 (w), 2847 (s), 1641 (m), 1603 (w)

2

˜

max

2.03–2.01 (m, 4 H, =CHCH_2cis+transCH₂, =CHCH_2cis+transCH), cm^–1. ¹H NMR: δ = 5.93 (br. s, 1 H, CH=C), 5.52 (br. s, 1 H,

1.30–1.24 (m, 8 H, MeCH₂CH_2cis+trans), 0.83 (t, J = 7.1 Hz, 6 H,

CH=CH), 5.25 (br. s, 1 H, =CH₂), 4.84 (br. s, 1 H, =CH₂), 4.72–

4.68 (m, 4 H, CH₂OCH₂), 4.24 (s, 2 H, OCH₂C=), 3.72 (t, J =

CH_3cis+trans) ppm. ¹³C NMR: δ = 143.1 and 142.7 (=C), 133.9 and

129.7 (=CH), 131.4 and 127.0 (=CH), 124.2 (=CH), 114.6 and 5.6 Hz, 1 H, OCH), 2.34 (dd, J = 15.1, 5.1 Hz, 1 H, CH₂), 2.19

114.4 (=CH₂), 76.8 (OCH), 73.2 and 70.3 (OCH₂), 32.7 and 28.7 (dd, J = 13.9, 1.7 Hz, 1 H, CH₂) ppm. ¹³C NMR: δ = 137.9 (=C),

(CH₂), 32.2 and 31.4 (CH₂), 30.5 and 30.4 (CH₂), 22.4 and 22.3 137.4 (=C), 124.6 (=CH), 122.8 (=CH), 115.0 (=CH₂), 77.2

(CH₂), 14.0 and 13.9 (CH₃) ppm. MS (CI): m/z (%) = 376 (100) [M

+ NH₄⁺], 359 (34) [MH⁺], 247 (39); found (ESI) 359.2944 [MH⁺],

C₂₄H₃₉O₂requires 359.2945.

(OCH₂), 75.6 (OCH₂), 75.3 (OCH), 70.5 (OCH₂), 29.5 (CH₂) ppm.

MS (CI): m/z (%) = 348 (100) [M + NH₄⁺], 331 (26) [MH⁺], 315

(15), 262 (9); found (ESI) 353.1721 [M + Na⁺], C₂₀H₂₆O₄Na re-

quires 353.1723.

cis-1,2-Bis[4-(allyloxy)but-2-ynyloxy]cyclohex-4-ene (56): To a stir-

ring solution of cis-1,2-dihydroxycyclohex-4-ene^[10](3, 0.35 g,

3.1 mmol) in DMF (25 mL) at 0 °C was slowly added NaH (60%

in mineral oil, 0.37 g, 9.2 mmol). After stirring for 1 h at 0 °C, bro-

mide 55^[24](1.45 g, 7.7 mmol) was added and the reaction mixture

warmed to room temperature. The reaction was stirred overnight,

hydrolysed with water (10 mL) and extracted with Et₂O

(4ϫ10 mL). The combined organic phases were dried (MgSO₄),

filtered, evaporated in vacuo and the residue purified by flash

chromatography (hexane/EtOAc, 70:30) to give compound 56

Metathesis of 57 to 59: To a stirring solution of compound 57

(0.05 g, 0.15 mmol) in dry CH₂Cl₂(12 mL) was added a solution

of catalyst 1 (0.012 g, 0.015 mmol, 10 mol-%) in dry CH₂Cl₂

(3 mL). The reaction mixture was stirred for 24 h at 35 °C under

N₂, then the solvent was evaporated in vacuo and the residue puri-

fied by flash chromatography (hexane/EtOAc, 80:20) to give bis-

diene 59 (0.05 g, 100%) as a transparent oil. IR (neat): ν_max= 3028

˜

1

(w), 2845 (s), 1645 (m), 1602 (w) cm^–1. H NMR: δ = 5.91 (t, J =

1.8 Hz, 1 H, CH=), 5.49 (br. s, 1 H, CH=CH), 5.24 (br. s, 1 H,

(0.74 g, 73%) as a colourless oil. IR (neat): ν

= 3079 (w), 3029

=CH₂), 4.84 (br. s, 1 H, =CH₂), 4.72–4.66 (m, 4 H, CH₂OCH₂),

˜

max

(m), 2908 (s), 2854 (s), 2239 (w), 1670 (m), 1648 (m) cm^–1. ¹H 4.27 (s, 2 H, OCH₂C=), 3.58–3.53 (m, 1 H, OCH), 2.46–2.40 (m,

NMR: δ = 5.84 (ddt, J = 17.1, 10.4, 5.8 Hz, 1 H, CH=CH₂), 5.52

(br. s, 1 H, CH=CH), 5.24 (ddd, J = 17.2, 3.1, 1.5 Hz, 1 H, =CH₂),

5.16 (dd, J = 10.3, 1.4 Hz, 1 H, =CH₂), 4.30 (dd, J = 3.3, 1.6 Hz,

1 H, CH₂), 2.05 (ddd, J = 15.5, 4.8, 2.7 Hz, 1 H, CH₂) ppm. ¹³C

NMR: δ = 138.0 (=C), 137.5 (=C), 124.6 (=CH), 122.9 (=CH),

115.1 (=CH₂), 77.8 (OCH), 77.1 (OCH₂), 75.6 (OCH₂), 71.6

2 H, CHOCH₂), 4.13 (t, J = 1.7 Hz, 2 H, CH₂OCH₂CH=), 3.99 (OCH₂), 31.1 (CH₂) ppm. MS (CI): m/z (%) = 348 (100) [M +

(dt, J = 5.7, 1.3 Hz, 2 H, OCH₂CH=), 3.93 (t, J = 5.8 Hz, 1 H,

NH₄⁺], 331 (29) [MH⁺]; found (ESI) 353.1698 [M + Na⁺],

OCH), 2.32 (dd, J = 15.5, 5.8 Hz, 1 H, CH₂), 2.25–2.20 (m, 1 H, C₂₀H₂₆O₄Na requires 353.1723.

CH₂) ppm. ¹³C NMR: δ = 134.3 (CH=), 124.5 (CH=), 118.3

Diels–Alder Adduct 60: To a stirring solution of compound 57

(=CH₂), 83.2 (ϵC), 82.4 (ϵC), 74.1 (OCH), 71.1 (OCH₂), 57.9

(OCH₂), 56.9 (OCH₂), 29.2 (CH₂) ppm. MS (CI): m/z (%) = 348

(100) [M + NH₄⁺], 331 (4) [MH⁺]; found (ESI) 348.2169 (M +

NH₄⁺), C₂₀H₃₀NO₄requires 348.2169.

(0.05 g, 0.15 mmol) in dry CH₂Cl₂(12 mL) was added a solution

of catalyst 1 (0.012 g, 0.015 mmol, 10 mol-%) in dry CH₂Cl₂

(3 mL). The reaction mixture was stirred for 20 h at room tempera-

ture under N₂. The solvent was then evaporated in vacuo and the

residue was redissolved in EtOAc (6 mL). Maleic anhydride

(0.074 g, 0.76 mmol) was added and the mixture was stirred for a

further 20 h. The solvent was evaporated in vacuo and the residue

was purified by flash chromatography (CH₂Cl₂) to yield a 1:1:1

ratio of diastereomeric Diels–Alder adducts 60 (0.061 g, 75%) as a

trans-1,2-Bis[4-(allyloxy)but-2-ynyloxy]cyclohex-4-ene (57): To

a

stirring solution of trans-1,2.dihydroxycyclohex-4-ene^[11](4, 0.4 g,

3.5 mmol) in DMF (25 mL) at 0 °C was slowly added NaH (60%

in mineral oil, 0.42 g, 10.5 mmol). After stirring for 1 h at 0 °C,

bromide 55^[24](2.0 g, 10.5 mmol) was added. The reaction mixture

was warmed to room temperature, stirred overnight, hydrolysed

with water (10 mL) and extracted with Et₂O (4ϫ15 mL). The com-

bined organic phases were dried (MgSO₄), filtered, evaporated in

vacuo and the residue purified by flash chromatography (hexane/

EtOAc, 70:30) to give compound 57 (0.92 g, 79%) as a colourless

transparent oil. IR (neat): ν_max= 3030 (w), 2853 (s), 1847 (m), 1775

˜

1

(s) cm^–1. H NMR: δ = 5.46 (br. s, 1 H, =CH), 4.37–4.28 (m, 2 H,

CHOCH₂), 4.26–4.17 (m, 1 H, C=CCH₂O), 4.13–4.04 (m, 1 H,

C=CCH₂O), 4.00–3.93 (m, 2 H, CHCH₂O), 3.52–3.44 (m, 2 H,

COCHCHCO), 3.40 (br. s, 1 H, OCH), 2.76–2.65 (m, 2 H,

CH₂C=CCH), 2.37 (d, J = 17.6 Hz, 1 H, =CHCH₂), 2.17 (br. s, 1

oil. IR (neat): ν

= 3079 (w), 3029 (w), 2904 (s), 2852 (s), 2243

˜

max

(w), 1647 cm^–1(w). ¹H NMR: δ = 5.93 (ddt, J = 17.1, 11.5, 5.8 Hz, H, CH₂C=CCH), 1.98–1.95 (m, 1 H, =CHCH₂) ppm. ¹³C NMR:

1 H, CH=CH₂), 5.60–5.53 (m, 1 H, CH=CH), 5.33 (dq, J = 17.2,

δ = 173.8, 173.7 and 173.6 (C=O), 171.1 (C=O), 138.0, 137.7, and

1.6 Hz, 1 H, =CH₂), 5.23 (dq, J = 10.4, 1.3 Hz, 1 H, =CH₂), 4.44– 137.6 (=C), 137.4 (=C), 124.1, 124.0, and 123.9 (=CH), 77.8, 77.7,

4.34 (m, 2 H, CHOCH₂), 4.22 (t, J = 1.8 Hz, 2 H, CH₂OCH₂Cϵ), and 77.4 (OCH), 70.2, 70.1, and 70.0 (OCH₂), 68.9, 68.8, and 68.7

4.08 (dt, J = 5.5, 1.1 Hz, 2 H, OCH₂CH=), 3.80–3.73 (m, 1 H,

(OCH₂), 68.6, 68.5, and 68.4 (OCH₂), 41.5 (CH), 41.4 (CH), 41.3

OCH), 2.53 (d, J = 16.2 Hz, 1 H, CH₂), 2.12 (ddd, J = 15.6, 4.8, (CH), 30.2, 30.1, and 29.7 (CH₂), 26.9, 26.8, and 26.7 (CH₂) ppm.

2.6 Hz, 1 H, CH₂) ppm. ¹³C NMR: δ = 134.4 (=CH), 124.5 (=CH),

MS (CI): m/z (%) = 544 (100) [M + NH₄⁺], 338 (66); found (ESI)

118.3 (=CH₂), 83.4 (ϵC), 82.2 (ϵC), 77.3 (OCH), 71.0 (OCH₂), 549.1736 [M + Na⁺], C₂₈H₃₀O₁₀Na requires 549.1731.

58.1 (OCH₂), 57.9 (OCH₂), 31.0 (CH₂) ppm. MS (CI): m/z (%) =

cis-Dibut-3-ynyl Cyclohex-4-ene-1,2-dicarboxylate (62): To a sus-

348 (100) [M + NH₄⁺]; found (ESI) 348.2168 (M + NH₄⁺),

C₂₀H₃₀NO₄requires 348.2169.

pension of cis-cyclohex-4-ene-1,2-dicarboxylic acid^[28](61, 1.0 g,

5.9 mmol) in CH₂Cl₂(30 mL) were added N,NЈ-dicyclohexylcar-

Metathesis of Compound 56 to 58: To a stirring solution of com-

pound 56 (0.05 g, 0.15 mmol) in dry CH₂Cl₂(12 mL) was added a

solution of catalyst 1 (0.012 g, 0.015 mmol, 10 mol-%) in dry

bodiimide (3.0 g, 14.7 mmol), 3-butyn-1-ol (1.0 g, 1.11 mL,

14.7 mmol) and 4-(dimethylamino)pyridine (0.07 g, 0.59 mmol).

The reaction mixture was stirred overnight at room temperature,

Eur. J. Org. Chem. 2007, 3727–3745

www.eurjoc.org

3741

E. Groaz, D. Banti, M. North

FULL PAPER

filtered, washed with 1  HCl (2ϫ10 mL), 20% aqueous NaHCO₃

(2ϫ10 mL) and water (2ϫ10 mL). The organic layer was dried

(MgSO₄), filtered and evaporated in vacuo. The residue was puri-

fied by flash chromatography (hexane/EtOAc, 90:10) to give com-

Diene 66 from 6,12-Fused Bicycle 64: The 6,12-fused bicycle 64

(0.06 g, 0.22 mmol) was dissolved in dry toluene (20 mL) and eth-

ene was passed through the solution for 10 min. A solution of cata-

lyst 2 (0.009 g, 0.01 mmol, 5 mol-%) in dry toluene (2 mL) was

added and the reaction mixture was stirred at 60 °C for 20 h. The

pound 62 (0.9 g, 55%) as a colourless oil. IR (neat): ν

= 3291

˜

max

(s), 3029 (w), 2963 (m), 2920 (m), 2851 (w), 2121 (w) and 1735 (s) solvent was evaporated in vacuo and the residue was purified by

cm^–1. ¹H NMR: δ = 5.72 (t, J = 1.5 Hz, 1 H, =CH), 4.29–4.20 (m,

2 H, OCH₂), 3.14–3.10 (m, 1 H, CHCO), 2.62 (ddd, J = 17.8, 4.0,

1.9 Hz, 1 H, CH₂CH), 2.56 (dt, J = 6.8, 2.7 Hz, 2 H, CH₂Cϵ),

2.41 (ddd, J = 16.0, 4.5, 1.3 Hz, 1 H, CH₂CH), 2.04 (t, J = 2.7 Hz,

flash chromatography (CH₂Cl₂/EtOAc, 95:5) to give compound 66

(0.06 g, 100%) as a colourless oil. IR (CH Cl ): ν = 3028 (w),

˜

max

2

2957 (m), 1735 (s), 1638 cm^–1(m). ¹H NMR: δ = 5.58 (s, 1 H,

=CH), 5.03 (s, 2 H, =CH₂), 4.29–4.24 (m, 1 H, OCH₂), 4.20–4.13

1 H, ϵCH) ppm. ¹³C NMR: δ = 172.9 (C=O), 125.1 (=CH), 80.1 (m, 1 H, OCH₂), 2.97–2.93 (m, 1 H, CHC=O), 2.68 (ddd, J = 14.5,

(ϵC), 69.8 (ϵCH), 62.3 (OCH₂), 39.6 (CH), 25.7 (CH₂), 18.9

(CH₂) ppm. MS (CI): m/z (%) = 292 (100) [M + NH₄⁺], 275 (27)

[MH⁺], 222 (11); found (ESI) 297.1100 [M + Na⁺], C₁₆H₁₈O₄Na

requires 297.1097.

9.8, 4.6 Hz, 1 H, CH₂C=), 2.53 (dt, J = 14.6, 4.2 Hz, 1 H, CH₂C=),

2.41 (dd, J = 16.0, 4.8 Hz, 1 H, CH₂CH=), 2.21 (dd, J = 16.4,

4.8 Hz, 1 H, CH₂CH=) ppm. ¹³C NMR: δ = 173.1 (C=O), 144.3

(=C), 125.2 (=CH), 114.6 (=CH₂), 63.6 (OCH₂), 40.2 (CH), 33.7

(CH₂), 25.6 (CH₂) ppm. MS (CI): m/z (%) = 294 (100) [M + NH₄⁺],

277 (13) [MH⁺]; found (ESI) 294.1698 (M + NH₄⁺), C₁₆H₂₄O₄N

requires 294.1700.

cis-Dipent-3-ynyl Cyclohex-4-ene-1,2-dicarboxylate (63): To a sus-

pension of cis-cyclohex-4-ene-1,2-dicarboxylic acid^[28](61, 1.0 g,

5.9 mmol) in CH₂Cl₂were added N,NЈ-dicyclohexylcarbodiimide

(3.0 g, 14.7 mmol), 3-pentyn-1-ol (1.2 g, 14.7 mmol) and 4-(dimeth-

ylamino)pyridine (0.07 g, 0.6 mmol). The reaction mixture was

stirred overnight at room temperature, filtered, washed with 1 

HCl (2ϫ10 mL), 20% aqueous NaHCO₃(2ϫ10 mL) and water

(2ϫ10 mL). The organic layer was then dried (MgSO₄), filtered

and evaporated in vacuo. The residue was purified by flash

chromatography (hexane/EtOAc, 90:10) to give compound 63

Diene 66 from Diyne 63: A solution of cis-dipent-3-ynyl cyclohex-

4-ene-1,2-dicarboxylate (63, 0.10 g, 0.33 mmol), Mo(CO)₆(0.004 g,

0.016 mmol, 5 mol-%) and 2-fluorophenol (0.04 g, 0.33 mmol) in

chlorobenzene (5 mL) was refluxed for 20 h. The reaction mixture

was cooled to room temperature and ethene was passed through

the stirred solution for 10 min. A solution of catalyst 2 (0.014 g,

0.016 mmol, 5 mol-%) in chlorobenzene (2 mL) was then added

and the mixture was stirred at 60 °C for 20 h under ethene. The

solvent was evaporated in vacuo and the residue was subjected to

flash chromatography (CH₂Cl₂/EtOAc, 95:5) to give compound 66

(0.07 g, 72%) as a colourless oil. Data as reported above.

(1.0 g, 55%) as colourless oil. IR (neat): ν_max= 3029 (w), 2960 (m),

˜

2920 (m), 2854 (w), 2195 (w), 1739 (s) cm^–1. ¹H NMR: δ = 5.69 (t,

J = 1.4 Hz, 1 H, =CH), 4.22–4.11 (m, 2 H, OCH₂), 3.10–3.07 (m,

1 H, CHC=O), 2.59 (dd, J = 16.1, 4.8 Hz, 1 H, CH₂CH=), 2.49–

2.43 (m, 2 H, CH₂Cϵ), 2.37 (dd, J = 16.5, 5.0 Hz, 1 H, CH₂CH=),

1.79 (t, J = 2.6 Hz, 3 H, ϵCCH₃) ppm. ¹H NMR: δ = 172.9 (C=O),

125.1 (CH=), 77.2 (ϵC), 74.7 (ϵC), 63.0 (OCH₂), 39.7 (CH), 25.7

(CH₂), 19.1 (CH₂), 3.5 (CH₃) ppm. MS (EI): m/z (%) = 302 (4)

[M⁺], 218 (46), 188 (54), 79 (28), 67 (100); found (ESI) 303.1597

[MH⁺], C₁₈H₂₃O₄requires 303.1591.

3-[(But-2-ynyloxy)carbonyl]norborn-5-ene-endo,cis-2-carboxylic

Acid (69): Norborn-5-ene-2,3-endo,cis-dicarboxylic anhydride (67,

3.0 g, 18.3 mmol) was dissolved in CH₂Cl₂(60 mL) and but-2-yn-1-

ol (1.35 g, 19.2 mmol) was added, followed by 4-(dimethylamino)-

pyridine (0.223 g, 1.83 mmol). The reaction was stirred for 16 h,

then the solvent was evaporated in vacuo and the residue purified

by flash chromatography (CH₂Cl₂/EtOAc, 90:10) to provide com-

pound 69 (4.0 g, 93%) as a white solid. M.p. 127–130 °C. IR (neat):

Metathesis of cis-Dipent-3-ynyl Cyclohex-4-ene-1,2-dicarboxylate 63

to 64 and 65: A solution of cis-dipent-3-ynyl cyclohex-4-ene-1,2-

dicarboxylate (63, 0.3 g, 1.0 mmol), Mo(CO)₆(0.013 g, 0.05 mmol,

5 mol-%) and 2-fluorophenol (0.1 g, 1.00 mmol) in chlorobenzene

(20 mL) was refluxed for 6 h, then the solvent was evaporated in

vacuo and the residue subjected to flash chromatography (cyclo-

hexane/EtOAc, 80:20) to give compounds 64 (0.16 g, 63%) and 65

(0.01 g, 3%) as white solids. Starting material 63 (0.006 g, 2%) was

ν

= 3077 (w), 2978 (m), 2874 (w), 2242 (w), 1743 (s) and 1710

˜

max

(s) cm^–1. ¹H NMR: δ = 12.0 (br. s, 1 H, OH), 6.35 (dd, J = 5.6,

2.9 Hz, 1 H, =CH), 6.24 (dd, J = 5.6, 2.9 Hz, 1 H, =CH), 4.69 (dq,

J = 15.2, 2.3 Hz, 1 H, OCH₂), 4.49 (dq, J = 15.3, 2.4 Hz, 1 H,

OCH₂), 3.39–3.30 (m, 2 H, COCHCHCO), 3.22 (br. s, 2 H,

CHCH₂CH), 1.87 (t, J = 2.4 Hz, 3 H, ϵCCH₃), 1.52 (dt, J = 8.7,

1.7 Hz, 1 H, CHCH₂), 1.36 (d, J = 8.7 Hz, 1 H, CHCH₂) ppm. ¹³

C

also recovered. Data for 64: M.p. 69–72 °C. IR (CH Cl ): ν =

˜

max

2

NMR ([D₆]DMSO): δ = 173.4 (C=O), 171.9 (C=O), 135.5 (=CH),

134.7 (=CH), 83.2 (ϵC), 74.4 (ϵC), 52.3 (OCH₂), 48.4 (CH₂), 48.2

(CH), 47.2 (CH), 46.4 (CH), 45.9 (CH), 3.4 (CH₃) ppm. MS (CI):

m/z (%) = 252 (100) [M + NH₄⁺], 235 (37) [MH⁺], 182 (41); found

(ESI) 257.0781 [M + Na⁺], C₁₃H₁₄O₄Na requires 257.0784.

1

3028 (m), 2915 (s), 2848 (m), 1740 (s), 1657 cm^–1(m). H NMR: δ

= 5.63 (t, J = 1.5 Hz, 1 H, =CH), 4.33 (ddd, J = 10.5, 8.2, 4.3 Hz,

1 H, OCH₂), 4.07 (dt, J = 10.3, 5.0 Hz, 1 H, OCH₂), 3.10–3.06 (m,

1 H, CHC=O), 2.56 (dd, J = 16.3, 4.5 Hz, 1 H, CH₂CH=), 2.49–

2.32 (m, 3 H, CH₂CH=, CH₂Cϵ) ppm. ¹³C NMR: δ = 173.2

(C=O), 124.9 (CH=), 78.9 (ϵC), 61.4 (OCH₂), 39.4 (CH), 25.8 But-2-ynyl Pent-3-ynyl endo,cis-Norborn-5-ene-2,3-dicarboxylate

(CH₂), 19.6 (CH₂) ppm. MS (EI): m/z (%) = 248 (17) [M⁺], 220 (70): To a suspension of compound 69 (2.0 g, 5.6 mmol) in CH₂Cl₂

(41), 106 (90), 79 (100); found (ESI) 271.0941 [M + Na⁺], (40 mL) were added N,NЈ-dicyclohexylcarbodiimide (1.9 g,

C₁₄H₁₆O₄Na requires 271.0941. Data for 65: M.p. 122–125 °C. IR

9.4 mmol), pent-3-yn-1-ol (0.8 g, 9.4 mmol) and 4-(dimethyl-

amino)pyridine (0.1 g, 0.9 mmol). The reaction was stirred over-

night at room temperature, filtered, washed with 1  HCl

(CH Cl ): ν_max= 3030 (w), 2961 (m), 2919 (m), 2851 (w), 1734 cm^–1

˜

2

1

2

(s). H NMR: δ = 5.61 (s, 1 H, =CH), 4.19–4.11 (m, 1 H, OCH₂),

4.09–4.02 (m, 1 H, OCH₂), 3.03 (t, J = 4.9 Hz, 1 H, CHC=O), 2.45 (2ϫ20 mL), 20% aqueous NaHCO₃(2ϫ20 mL) and water

(t, J = 6.6 Hz, 3 H, CH₂CH=, CH₂Cϵ), 2.27 (dd, J = 16.7, 4.8 Hz, (2ϫ20 mL). The organic layer was then dried (MgSO₄), filtered

1 H, CH₂CH=) ppm. ¹³C NMR: δ = 172.8 (C=O), 125.1 (=CH), and evaporated in vacuo. The residue was purified by flash

77.6 (ϵC), 63.0 (OCH₂), 39.9 (CH), 25.7 (CH₂), 19.1 (CH₂) ppm.

chromatography (hexane/EtOAc, 80:20) to provide compound 70

(1.97 g, 77%) as a colourless oil. IR (neat): ν = 2977 (s), 2920

MS (EI): m/z (%) = 496 (79) [M⁺], 354 (8), 326 (10), 249 (30),

˜

max

79 (100); found (ESI) 519.1978 [M + Na⁺], C₂₈H₃₂O₈Na requires (m), 2872 (w), 2242 (w) and 1742 (s) cm^–1. ¹H NMR: δ = 6.31–6.26

271.1989.

(m, 2 H, CH=CH), 4.66 (dq, J = 15.3, 2.4 Hz, 1 H, OCH₂Cϵ),

3742

www.eurjoc.org

Eur. J. Org. Chem. 2007, 3727–3745

Cascade Metathesis Reactions of Alkenes and Alkynes

FULL PAPER

4.53 (dq, J = 15.3, 2.4 Hz, 1 H, OCH₂Cϵ), 4.13–4.04 (m, 2 H,

diester 73 (0.84 g, 49%) as a colourless oil. IR (neat): ν

= 2963

max

˜

OCH₂CH₂), 3.34–3.33 (m, 2 H, COCHCHCO), 3.20 (t, J = 1.5 Hz, (s), 2919 (m), 2871 (w), 1742 (s), 1716 (m) cm^–1. ¹H NMR: δ = 6.21

2 H, CHCH₂CH), 2.46–2.41 (m, 2 H, CH₂CH₂Cϵ), 1.87 (t, J = (t, J = 1.7 Hz, 2 H, CH=CH), 4.07–3.93 (m, 4 H, 2 OCH₂), 3.24

2.4 Hz, 3 H, ϵCCH₃), 1.80 (t, J = 2.5 Hz, 3 H, ϵCCH₃), 1.49

(dt, J = 8.6, 1.8 Hz, 1 H, CHCH₂CH), 1.34 (d, J = 8.6 Hz, 1 H,

(t, J = 1.5 Hz, 2 H, 2 CHCO), 3.11 (s, 2 H, 2 CHCHCO), 2.37–

2.33 (m, 4 H, 2 CH₂Cϵ), 1.71 (t, J = 2.5 Hz, 6 H, 2 CH₃), 1.42–

CHCH₂CH) ppm. ¹³C NMR: δ = 172.5 (C=O), 172.2 (C=O), 135.3 1.39 (m, 1 H, CHCH₂), 1.26 (d, J = 8.6 Hz, 1 H, CHCH₂) ppm.

(2 =CH), 83.4 (ϵC), 77.5 (ϵC), 75.3 (ϵC), 73.7 (ϵC), 63.2 ¹³C NMR: δ = 172.1 (C=O), 134.9 (=CH), 77.1 (ϵC), 74.9 (ϵC),

(OCH₂), 53.2 (OCH₂), 49.7 (CH), 49.0 (CH₂), 48.6 (CH), 48.4

62.8 (OCH₂), 48.6 (CH₂), 48.0 (CH), 46.4 (CH), 19.1 (CH₂), 3.5

(CH), 46.8 (CH), 19.5 (CH₂), 4.1 (CH₃), 3.9 (CH₃) ppm. MS (CI): (CH₃) ppm. MS (EI): m/z (%) = 314 [M⁺, 4], 249 (40), 203 (19),

m/z (%) = 318 (100) [M + NH₄⁺], 301 (45) [MH⁺], 234 (12); found

165 (24), 157 (10), 67 (100); found (ESI) 337.1404 [M + Na⁺],

C₁₉H₂₂O₄Na requires 303.1410.

(ESI) 323.1252 [M + Na⁺], C₁₈H₂₀O₄Na requires 323.1254.

Cyclic Alkyne 74: A solution of compound 73 (0.3 g, 1.0 mmol),

Mo(CO)₆(0.013 g, 0.05 mmol, 5 mol-%) and 2-fluorophenol (0.1 g,

1.0 mmol) in chlorobenzene (20 mL) was refluxed for 6 h, then the

solvent was evaporated in vacuo and the residue was subjected to

flash chromatography (cyclohexane/EtOAc, 80:20) to give product

Dibut-2-ynyl endo,cis-Norborn-5-ene-2,3-dicarboxylate (71): To a

suspension of endo,cis-norborn-5-ene-2,3-dicarboxylic acid^[30](68,

1.0 g, 5.5 mmol) in CH₂Cl₂(30 mL) were added N,NЈ-dicyclohex-

ylcarbodiimide (2.8 g, 13.7 mmol), 2-butyn-1-ol (1.0 g, 1.03 mL,

13.7 mmol) and 4-(dimethylamino)pyridine (0.07 g, 0.549 mmol).

The reaction mixture was stirred overnight at room temperature,

then filtered, washed with 1  HCl (2ϫ10 mL), 20% aqueous

NaHCO₃(2ϫ10 mL) and water (2ϫ10 mL). The organic layer

was dried (MgSO₄), filtered, evaporated in vacuo and the residue

purified by flash chromatography (hexane/EtOAc, 90:10) to provide

diester 71 (0.89 g, 56%) as a white solid. M.p. 67–70 °C. IR (neat):

74 (0.23 g, 87%) as a white solid. M.p. 134–136 °C. IR (neat): ν

˜

max

= 3075 (w), 2970 (m), 2909 (w), 1744 (s) cm^–1. H NMR: δ = 6.21

(t, J = 1.7 Hz, 2 H, =CH), 4.45–4.38 (m, 2 H, OCH₂), 3.74 (ddd,

J = 10.4, 4.6, 1.8 Hz, 2 H, OCH₂), 3.31 (t, J = 1.4 Hz, 2 H, CHCO),

3.08 (t, J = 1.5 Hz, 2 H, CHCHCO), 2.51–2.42 (m, 2 H, CH₂Cϵ),

2.22 (d, J = 15.1 Hz, 2 H, CH₂Cϵ), 1.45 (dt, J = 8.6, 1.8 Hz, 1 H,

CHCH₂), 1.29 (d, J = 8.6 Hz, 1 H, CHCH₂) ppm. ¹³C NMR: δ =

172.3 (C=O), 134.7 (=CH), 78.9 (ϵC), 61.6 (OCH₂), 48.7 (CH),

48.1 (CH₂), 46.0 (CH), 19.7 (CH₂) ppm. MS (EI): m/z (%) = 260

[M⁺, 14], 193 (15), 182 (32), 164 (12), 66 (100); found (ESI)

283.0938 [M + Na⁺], C₁₅H₁₆O₄Na requires 283.0940.

1

ν

= 3075 (w), 2978 (m), 2942 (w), 2873 (w), 2241 (w) and 1745

˜

max

(s) cm^–1. ¹H NMR: δ = 6.21 (t, J = 1.8 Hz, 2 H, CH=CH), 4.59

(dq, J = 15.2, 2.3 Hz, 2 H, 2 OCH₂), 4.43 (dq, J = 15.3, 2.4 Hz, 2

H, 2 OCH₂), 3.27 (t, J = 1.5 Hz, 2 H, 2 CHCO), 3.13 (t, J = 1.6 Hz,

2 H, 2 CHCHCO), 1.79 (t, J = 2.5 Hz, 6 H, 2 CH₃), 1.42 (dt, J =

8.6, 1.8 Hz, 1 H, CHCH₂), 1.25 (d, J = 8.6 Hz, 1 H, CHCH₂) ppm.

¹³C NMR: δ = 172.1 (C=O), 135.3 (=CH), 83.5 (ϵC), 73.6 (ϵC),

53.3 (OCH₂), 49.0 (CH₂), 48.5 (CH), 46.7 (CH), 4.1 (CH₃) ppm.

MS (CI): m/z (%) = 304 (100) [M + NH₄⁺], 287 (31) [MH⁺]; found

(ESI) 309.1111 [M + Na⁺], C₁₇H₁₈O₄Na requires 309.1097.

Diene 75 from 74: Compound 74 (0.05 g, 0.19 mmol) was dissolved

in dry toluene (16 mL) and ethene was passed through the stirred

solution for 10 min. A solution of catalyst 1 (0.008 g, 0.01 mmol,

5 mol-%) in dry toluene (3 mL) was added and the reaction mixture

was stirred at room temperature for 20 h under ethene. The solvent

was evaporated in vacuo and the residue subjected to flash

chromatography (CH₂Cl₂/EtOAc, 98:2) to give compound 75

(0.04 g, 76%) as a white solid. Unreacted starting material 74

Dibut-3-ynyl endo,cis-Norborn-5-ene-2,3-dicarboxylate (72): To a

suspension of endo,cis-norborn-5-ene-2,3-dicarboxylic acid^[30](68,

1.0 g, 5.5 mmol) in CH₂Cl₂(30 mL) were added N,NЈ-dicyclohex-

ylcarbodiimide (2.8 g, 13.7 mmol), but-3-yn-1-ol (1.0 g, 13.7 mmol)

and 4-(dimethylamino)pyridine (0.07 g, 0.55 mmol). The reaction

mixture was stirred overnight at room temperature, filtered, washed

with 1  HCl (2ϫ10 mL), 20% aqueous NaHCO₃(2ϫ10 mL) and

water (2ϫ10 mL). The organic layer was dried (MgSO₄), filtered,

evaporated in vacuo and the residue purified by flash chromatog-

raphy (hexane/EtOAc, 90:10) to provide diester 72 (0.80 g, 51%) as

(0.011 g, 22%) was also recovered. M.p. 68–71 °C. IR (CH₂Cl₂):

1

ν

= 3074 (w), 2957 (m), 2911 (w), 1738 (s), 1639 cm^–1(m). H

˜

max

NMR: δ = 5.99 (ddd, J = 17.1, 10.1, 8.4 Hz, 2 H, =CH), 4.99 (ddd,

J = 17.1, 1.8, 1.0 Hz, 2 H, =CH₂), 4.94 (ddd, J = 10.2, 1.8, 0.6 Hz,

2 H, =CH₂), 4.41 (dt, J = 10.3, 3.7 Hz, 2 H, OCH₂), 3.88 (dt, J =

10.4, 4.5 Hz, 2 H, OCH₂), 3.31–3.27 (m, 2 H, CHCO), 2.91–2.83

(m, 2 H, CHCH₂), 2.48–2.40 (m, 2 H, CH₂Cϵ), 2.31 (dt, J = 15.2,

2.9 Hz, 2 H, CH₂Cϵ), 1.97 (dt, J = 13.1, 7.3 Hz, 1 H, CHCH₂),

1.76 (dt, J = 13.0, 10.9 Hz, 1 H, CHCH₂) ppm. ¹³C NMR: δ =

171.4 (C=O), 139.0 (=CH), 114.6 (=CH₂), 79.2 (ϵC), 61.4 (OCH₂),

51.1 (CH), 45.0 (CH), 37.7 (CH₂), 19.5 (CH₂) ppm. MS (CI): m/z

(%) = 306 (100) [M + NH₄⁺], 289 (65) [MH⁺]; found (ESI) 289.1436

[MH⁺], C₁₇H₂₁O₄requires 289.1434.

a colourless oil. IR (neat): ν

= 3291 (s), 2972 (s), 2121 (w) and

˜

max

1743 (s) cm^–1. H NMR: δ = 6.29 (d, J = 1.6 Hz, 2 H, CH=CH),

4.20–4.07 (m, 4 H, 2 OCH₂), 3.33 (br. s, 2 H, 2 CHCO), 3.20 (br.

s, 2 H, 2 CHCHCO), 2.53–2.48 (m, 4 H, 2 CH₂Cϵ), 2.01 (t, J =

2.7 Hz, 2 H, 2 ϵCH), 1.50 (dt, J = 8.6, 1.7 Hz, 1 H, CHCH₂), 1.35

(d, J = 8.6 Hz, 1 H, CHCH₂) ppm. ¹³C NMR: δ = 172.1 (C=O),

134.9 (=CH), 80.3 (ϵC), 69.7 (ϵCH), 62.1 (OCH₂), 48.6 (CH₂),

47.9 (CH), 46.4 (CH), 18.9 (CH₂) ppm. MS (CI): m/z (%) = 304

(100) [M + NH₄⁺], 287 (52) [MH⁺], 234 (24); found (ESI) 287.1279

[MH⁺], C₁₇H₁₉O₄requires 287.1278.

1

Diene 75 from 73: A solution of compound 73 (0.1 g, 0.32 mmol),

Mo(CO)₆(0.004 g, 0.016 mmol, 5 mol-%) and 2-fluorophenol

(0.036 g, 0.32 mmol) in chlorobenzene (5 mL) was refluxed for

20 h. The reaction mixture was cooled to room temperature and

ethene was passed through the stirred solution for 10 min. A solu-

tion of catalyst 1 (0.013 g, 0.016 mmol, 5 mol-%) in chlorobenzene

(2 mL) was then added and the mixture was stirred at room tem-

perature for 20 h under ethene. The solvent was then evaporated in

vacuo and the residue was purified by flash chromatography

(CH₂Cl₂/EtOAc, 98:2) to give compound 75 (0.061 g, 67%) as a

white solid. Data as reported above.

Dipent-3-ynyl endo,cis-Norborn-5-ene-2,3-dicarboxylate (73): To a

suspension of endo,cis-norborn-5-ene-2,3-dicarboxylic acid^[30](68,

1.0 g, 5.5 mmol) in CH₂Cl₂(30 mL) were added N-NЈ-dicyclohex-

ylcarbodiimide (2.8 g, 13.7 mmol), 3-pentyn-1-ol (1.15 g,

13.7 mmol) and 4-(dimethylamino)pyridine (0.07 g, 0.55 mmol).

The reaction mixture was stirred overnight at room temperature,

then filtered, washed with 1  HCl (2ϫ10 mL), 20% aqueous

NaHCO₃(2ϫ10 mL) and water (2ϫ10 mL). The organic layer

was dried (MgSO₄), filtered, evaporated in vacuo and the residue

purified by flash chromatography (hexane/EtOAc, 90:10) to provide

Diene 76 from 74: Compound 74 (0.05 g, 0.19 mmol) was dissolved

in dry toluene (16 mL) and ethene was passed through the stirred

solution for 10 min. A solution of catalyst 2 (0.008 g, 0.01 mmol,

Eur. J. Org. Chem. 2007, 3727–3745

www.eurjoc.org

3743

E. Groaz, D. Banti, M. North

FULL PAPER

[6]

[7]

E. Groaz, D. Banti, M. North, Tetrahedron Lett. 2007, 48,

1927–1930.

For a preliminary account of some of the work reported in this

manuscript see: E. Groaz, D. Banti, M. North, Adv. Synth.

Catal. 2007, 349, 142–146.

For a previous report of cyclohexene ring opening during cross

metathesis see: S. Randl, S. J. Connon, S. Blechert, Chem. Com-

mun. 2001, 1796–1797.

For reviews of alkyne metathesis see:a) W. Zhang, J. S. Moore,

Adv. Synth. Catal. 2007, 349, 93–120; b) A. Fürstner, P. W.

Davies, Chem. Commun. 2002, 2307–2320; c) U. H. F. Bunz,

Acc. Chem. Res. 2001, 34, 998–1010.

T. J. Donohoe, L. Mitchell, M. J. Waring, M. Helliwell, A. Bell,

N. J. Newcombe, Org. Biomol. Chem. 2003, 1, 2173–2186.

S. Michaud, J. Viala, Tetrahedron 1999, 55, 3019–3024.

C. Baylon, M.-P. Heck, C. Mioskowski, J. Org. Chem. 1999,

64, 3354–3360. The ¹H and ¹³C NMR spectra of compound 10

are given in the supplementary information to this paper.

S. J. Miller, S.-H. Kim, Z.-R. Chen, R. H. Grubbs, J. Am.

Chem. Soc. 1995, 117, 2108–2109.

5 mol-%) in dry toluene (3 mL) was added and the reaction mixture

was stirred at 60 °C for 20 h under ethene. The solvent was evapo-

rated in vacuo and the residue purified by flash chromatography

(CH₂Cl₂/EtOAc, 95:5) to give compound 76 (0.06 g, 100%) as a

white solid. M.p. 55–57 °C. IR (CH Cl ): ν = 3076 (w), 2954

˜

max

2

1

[8]

[9]

(m), 1749 (s), 1638 (w), 1595 cm^–1(w). H NMR: δ = 5.89 (ddd, J

= 17.1, 10.1, 8.5 Hz, 1 H, =CH), 5.07 (s, 1 H, C=CH₂), 5.03 (s, 1

H, C=CH₂), 4.97 (ddd, J = 17.1, 1.7, 0.9 Hz, 1 H, CH=CH₂), 4.91

(dd, J = 10.1, 1.4 Hz, 1 H, CH=CH₂), 4.31–4.25 (m, 1 H, OCH₂),

3.99 (ddd, J = 10.8, 4.3, 3.4 Hz, 1 H, OCH₂), 3.15–3.10 (m, 1 H,

CHCO), 2.85–2.74 (m, 1 H, CHCHCO), 2.65 (ddd, J = 14.8, 11.8,

4.4 Hz, 1 H, CH₂C=), 2.49 (dt, J = 14.5, 3.1 Hz, 1 H, CH₂C=),

1.95–1.86 (m, 1 H, CHCH₂) ppm. ¹³C NMR: δ = 173.2 (C=O),

145.4 (=C), 140.4 (=CH), 116.6 (=CH₂), 116.5 (=CH₂), 65.0

(OCH₂), 53.0 (CH), 47.0 (CH), 39.0 (CH₂), 35.2 (CH₂) ppm. MS

(CI): m/z (%) = 334 (100) [M + NH₄⁺], 317 (83) [MH⁺]; found

(ESI) 317.1747 [MH⁺], C₁₉H₂₅O₄requires 317.1747.

[10]

[11]

[12]

[13]

[14]

Diene 76 from 73: A solution of cis-dipent-3-ynyl-5-norbornene-

endo-2,3-dicarboxylate (73, 0.1 g, 0.3 mmol), Mo(CO)₆(0.004 g,

0.016 mmol, 5 mol-%) and 2-fluorophenol (0.036 g, 0.32 mmol) in

chlorobenzene (5 mL) was refluxed for 20 h. The reaction mixture

was cooled to room temperature and ethene was passed through

the stirred solution for 10 min. A solution of catalyst 2 (0.013 g,

0.016 mmol, 5 mol-%) in chlorobenzene (2 mL) was then added

and the mixture was stirred at 60 °C for 20 h under ethene. The

solvent was evaporated in vacuo and the residue purified by flash

chromatography (CH₂Cl₂/EtOAc, 95:5) to give compound 76

(0.07 g, 69%) as a white solid. Data as reported above.

For previous reports of enyne metathesis involving ring-open-

ing of a cyclohexene unit see: a) T. Kitamura, M. Mori, Org.

Lett. 2001, 3, 1161–1163; b) T. Kitamura, Y. Kuzuba, Y. Sato,

H. Wakamatsu, R. Fujita, M. Mori, Tetrahedron 2004, 60,

7375–7389. See also ref.^[6]

.

[15]

[16]

For a related use of catalyst 1 to form eight-membered rings

by enyne metathesis see: a) M. Mori, T. Kitamura, N. Sakakib-

ara, Y. Sato, Org. Lett. 2000, 2, 543–545; b) M. Mori, T. Kita-

mura, Y. Sato, Synthesis 2001, 654–664.

a) M. Mori, N. Sakakibara, A. Kinoshita, J. Org. Chem. 1998,

63, 6082–6083; b) A. J. Giessert, N. J. Brazis, S. T. Diver, Org.

Lett. 2003, 5, 3819–3822.

A. Kinoshita, N. Sakakibara, M. Mori, Tetrahedron 1999, 55,

8155–8167.

a) A. Newman, J. Am. Chem. Soc. 1955, 77, 3789; b) G. A.

Russell, K. D. Schmitt, J. Mattox, J. Am. Chem. Soc. 1975, 97,

1882.

Supporting Information (see footnote on the first page of this arti-

[17]

[18]

cle): Copies of the ¹³C NMR spectra of all new compounds and

1

the H NMR spectrum of compound 8.

[19]

[20]

G. S. Weatherhead, J. G. Ford, E. J. Alexanian, R. R. Schrock,

A. H. Hoveyda, J. Am. Chem. Soc. 2000, 122, 1828–1829.

For previous reports on the higher activity of catalyst 2 than

catalyst 1 in enyne metathesis see: a) R. Stragies, U. Voigtmann,

S. Blechert, Tetrahedron Lett. 2000, 41, 5465–5468; b) K. Tono-

gaki, M. Mori, Tetrahedron Lett. 2002, 43, 2235–2238.

M. S. Sanford, J. A. Love, R. H. Grubbs, J. Am. Chem. Soc.

2001, 123, 6543–6554.

S. H. Hong, M. W. Day, R. H. Grubbs, J. Am. Chem. Soc.

2004, 126, 7414–7415.

Decomposition of ruthenium alkylidenes is known to be a sec-

ond order process in contrast to the first order decomposition

of methylidene complexes: M. Ulman, R. H. Grubbs, J. Org.

Chem. 1999, 64, 7202–7207.

a) A. G. M. Barrett, S. P. D. Baugh, D. C. Braddock, K. Flack,

V. C. Gibson, M. R. Giles, E. L. Marshall, P. A. Procopiou,

A. J. P. White, D. J. Williams, J. Org. Chem. 1998, 63, 7893; b)

L. J. van-Boxtel, S. Koerbe, M. Noltemeyer, A. de Meijere, Eur.

J. Org. Chem. 2001, 2283.

a) K. Grela, J. Ignatowska, Org. Lett. 2002, 4, 3747–3749; b)

V. Sashuk, J. Ignatowska, K. Grela, J. Org. Chem. 2004, 69,

7748–7751.

A. Fürstner, G. Seidel, Angew. Chem. Int. Ed. 1998, 37, 1734–

1736.

For examples of the formation of eleven-membered rings in

low yields see: a) A. Fürstner, C. Mathes, C. W. Lehmann,

Chem. Eur. J. 2001, 7, 5299–5317; b) G. Brizius, U. H. F. Bunz,

Org. Lett. 2002, 4, 2829–2831.

Acknowledgments

The authors thank the EPSRC national mass spectrometry service

at the University of Wales, Swansea for recording mass spectra.

[21]

[22]

[23]

[1] For recent reviews of the development and applications of ru-

thenium based metathesis initiators see: a) R. H. Grubbs, Adv.

Synth. Catal. 2007, 349, 34–40; b) R. H. Grubbs, Angew. Chem.

Int. Ed. 2006, 45, 3760–3765; c) T. J. Donohoe, A. J. Orr, An-

gew. Chem. Int. Ed. 2006, 45, 2664–2670; d) D. J. Wallace, An-

gew. Chem. Int. Ed. 2005, 44, 1912–1915; e) R. H. Grubbs, Tet-

rahedron 2004, 60, 7117–7140; f) M. D. McReynolds, J. M.

Dougherty, P. R. Hanson, Chem. Rev. 2004, 104, 2239–2258; g)

D. S. Blechert, S. J. Connon, Angew. Chem. Int. Ed. 2003, 42,

1900–1923.

[24]

[25]

[2] P. Schwab, R. H. Grubbs, J. W. Ziller, J. Am. Chem. Soc. 1996,

118, 100–110.

[3] M. Scholl, S. Ding, C. W. Lee, R. H. Grubbs, Org. Lett. 1999,

1, 953–956.

[4] For recent reviews of enyne metathesis see:a) M. Mori, Adv.

Synth. Catal. 2007, 349, 121–135; b) S. V. Maifeld, D. Lee,

Chem. Eur. J. 2005, 11, 6118–6126; c) S. T. Diver, A. J. Giessert,

Chem. Rev. 2004, 104, 1317–1382; d) C. S. Poulsen, R. Madsen,

Synthesis 2003, 1–18.

[5] a) D. Banti, E. Groaz, M. North, Tetrahedron 2004, 60, 8043–

8052; b) D. Banti, M. North, Tetrahedron Lett. 2003, 44, 8157–

8160; c) D. Banti, M. North, Adv. Synth. Catal. 2002, 344, 694–

704; d) D. Banti, M. North, Tetrahedron Lett. 2002, 43, 1561–

1564.

[26]

[27]

[28]

a) P. Mohr, N. Waespesarcevic, C. Tamm, K. Gawronska, J. K.

Gawronski, Helv. Chim. Acta 1983, 66, 2501–2511; b) M. Gay,

Á. M. Montaña, V. Moreno, M. Font-Bardia, X. Solans, J. Or-

ganomet. Chem. 2005, 690, 4856–4866.

3744

www.eurjoc.org

Eur. J. Org. Chem. 2007, 3727–3745

Cascade Metathesis Reactions of Alkenes and Alkynes

FULL PAPER

[29] a) A. Mortreux, F. Petit, M. Petit, T. Szymanska-Buzar, J. Mol.

Catal. A 1995, 96, 95–105; b) R. R. Schrock, in Handbook of

Metathesis, vol. 1, Catalyst Development (Ed.: R. H. Grubbs),

Wiley-VCH, Weinheim, Germany, 2003, pp. 173–189.

[30] D. N. Ford, W. Kitching, P. R. Wells, Aust. J. Chem. 1969, 22,

1157–1168.

[32] A. Dahlén, A. Sundgren, M. Lahmann, S. Oscarson, G. Hil-

mersson, Org. Lett. 2003, 5, 4085–4088.

[33] S. Göksu, H. Seçen, Y. Sütbeyaz, Synthesis 2002, 2373–2378.

Received: April 2, 2007

Published Online: June 12, 2007

[31] S. Y. Jonsson, K. Färnegårdh, J.-E. Bäckvall, J. Am. Chem. Soc.

2001, 123, 1365–1371.

Eur. J. Org. Chem. 2007, 3727–3745

www.eurjoc.org

3745

Article Doi

Synthesis of cyclic and macrocyclic ethers using metathesis reactions of alkenes and alkynes

DOI: 10.1002/ejoc.200700291

Source and publish data:

Authors:

Article abstract of DOI:10.1002/ejoc.200700291

Full text of DOI:10.1002/ejoc.200700291

Products guided by the article

R&D Labs maybe for 951697-31-7

Relevant to this article

Hot Product