Ring-closing of 1,7-and 1,8-enynes of propargylic O,O-acetals by ruthenium-catalysed intramolecular metathesis

FULL PAPER

DOI: 10.1002/ejoc.201000305

Ring-Closing of 1,7- and 1,8-Enynes of Propargylic O,O-Acetals by

Ruthenium-Catalysed Intramolecular Metathesis

Don Antoine Lanfranchi,^[a]Christophe Bour,^[a]Bastien Boff,^[a]and Gilles Hanquet*^[a]

Keywords: Metathesis / Cyclization / Ruthenium / Enynes / Acetals

Acyclic 1,7- and 1,8-enynes with the alkyne moiety directly

connected to the asymmetric carbon of an ethyl acetal have

been obtained in two steps from the corresponding alde-

hydes. Ring-closing metathesis of these enynes delivered the

corresponding six- and seven-membered cyclic 1,3-dienes in

moderate-to-excellent yields. A competitive ethylene inser-

tion into the alkyne moiety leading to trienes was observed

for some substrates depending on their structure and relative

configuration.

scribed so far,^[10]with allylic O,O-acetal-tethered enynes

giving compounds 2 and 3 (Figure 2) as cis/trans diastereo-

isomeric mixtures in moderate yields (36 and 50%, respec-

tively). Dihydropyran and dihydropyridine analogues 4 pre-

pared by O- or N-tethered ring-closing enyne metathesis

(RCEYM) have also been described in the literature (Fig-

ure 2).^[11]

Introduction

Enyne metathesis has emerged as an important method

for constructing conjugated dienes,^[1,2]which can be trans-

formed into more complex organic molecules.^[3]The first

enyne metathesis was reported by Katz and Sivavec,^[4]who

used a tungsten Fischer-type carbene complex. With the ad-

vent of Ru–alkylidene catalysts,^[5]applications of both in-

tramolecular ring-closing and intermolecular enyne cross-

metathesis have rapidly expanded.^[2b,2d,2g]

During the course of our synthetic studies on bioactive

terpenoids (i.e., salvinorin A,^[6]methyl barbascoate^[7]or

manoalide^[8]) we planned to use the O,O-acetal 1b as an

intermediate (Figure 1).^[9]

Figure 2. Cyclic compounds prepared by RCEYM of O- and N-

tethered enynes or O,O-acetal-tethered enynes.

Starting from these few examples, we anticipated that

compounds of type A could result from the ring-closing me-

tathesis of propargylic O,O-acetals B (Scheme 1). The re-

sulting compounds are highly functionalised and may be

useful as precursors for the synthesis of natural products as

Figure 1. Examples of the possible synthesis of natural products they possess two double bonds that can be used for further

using 1b as intermediate.

transformations (i.e., cycloadditions) and an alkoxy group

adjacent to the ring heteroatom that would give access to

Cyclic O,O-acetals are rather sensitive and would be well

suited to the construction of conjugated dienes by a ring-

closing metathesis process. Interestingly, examples of the

ring-closing metathesis of linear acetals are scarce in the

literature and only two such transformations have been de-

the corresponding highly reactive oxocarbenium cation and

hence derivatisation at this position.^[10,12]

[a] Laboratoire de Stéréochimie associé au CNRS, ECPM,

Université de Strasbourg,

25 rue Becquerel, 67087 Strasbourg, France

Fax: +33-3-68852742

E-mail: ghanquet@unistra.fr

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201000305.

Scheme 1. Allylic O,O-acetal-tethered ring-closing enyne metathe-

sis.

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Ring-Closing of 1,7- and 1,8-Enynes of Propargylic O,O-Acetals

In the work reported herein, we explored the viability of Table 1. Transacetalisation of secondary alcohols 6–9.

applying this approach to six- and seven-membered rings

by describing an efficient synthesis of several unsaturated

cyclic O,O-acetals starting from diastereoisomerically pure

syn or anti enyne precursors. We have also explored for the

first time the influence of the relative configuration of the

starting O,O-acetal-tethered enynes on the cyclisation rate

and product distribution. Finally, we will discuss herein the

possible reaction mechanisms in terms of “yne-then-ene” or

“ene-then-yne” pathways to explain the observed products.

Results and Discussion

The overall synthesis of 1,3-dienes A is outlined in

Scheme 2. The ring-closing metathesis precursors were syn-

thesised by transacetalisation of the corresponding alcohols

using commercial propiolaldehyde diethyl acetal^[13]in the

presence of substoichiometric (0.05 equiv.) amounts of

camphorsulfonic acid. The secondary alcohols 6–9 were

prepared by the addition of vinyl-, allyl-, methallyl- and

homoallylmagnesium bromide to the corresponding alde-

hydes (Scheme 2, Table 1).

Scheme 2. Synthesis of 1,3 dienes of type A.

After a few unsuccessful attempts using classic transace-

talisation conditions, we found that by mixing the parent

alcohols 7a,b,e, 8 and 9 with 2 equiv. of propiolaldehyde

diethyl acetal in the presence of CSA under vacuum

(150 mbar) we obtained the O,O-acetal-tethered enynes

5a,b,e, 11 and 12 in moderate-to-good isolated yields.^[9]

When we started this study in 2005, there were no reports

in the literature about this reaction. Later, Len and co-

workers^[10b]reported other conditions for the preparation

[a] Reaction time more than 1 week, concentration 0.2 molL^–1.

of some O,O-acetal-tethered enyne precursors of 3 that were

less effective with our substrates, delivering the required

products in generally lower isolated yields. The solvent-free 10 and 5c were isolated in very low yields. In all cases, the

conditions were not adapted to alcohols 6 and 7c as these products were obtained as syn/anti diastereoisomeric mix-

compounds rapidly decompose under acidic conditions. tures.

This suggested that when secondary alcohols give rise to a

With these precursors in hand, we initially explored the

more stabilised carbocation than the oxonium, the reaction reactivity of enyne 5a. Whereas in the presence of Grubbs

would not proceed as the benzylic carbocation undergoes first-generation catalyst G-1 (2 mol-%) in dichloromethane

side-reactions more rapidly (entries 1, 4 and 5).^[14]Very low no cyclised compound was observed, even when heated at

conversions of alcohols 6 and 7c were observed in DMF reflux, the same reaction under ethylene^[11]at room tem-

(0.2 molL^–1) under vacuum and the corresponding acetals perature led to the expected cyclic acetal 1a as a 1:3 cis/trans

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mixture after 12 hours in good isolated yield (Figure 3). We Table 2. Propargylic O,O-acetal ring-closing metathesis of com-

pounds 5.

could point out a striking difference between the behaviour

of enyne acetals such as 5a and its enyne ether analogue

13.^[11]Regarding the latter, the use of ethylene gas was

needed to improve the yield of 4a, whereas it was manda-

tory to obtain 1a (Figure 3). As previously observed in

other studies,^[15]the use of microwave irradiation reduced

the reaction time, but in our case it did not improve the

yield of isolated products. Moving to the more active

Grubbs G-II and Grubbs–Hoveyda GH-II second-genera-

tion catalysts (2 mol-%), the cyclic acetal 1a was obtained

after 20 and 10 min, respectively, under ethylene with mi-

crowave irradiation in 86% and 80% isolated yields. Finally,

we found that by heating 5a at reflux in dichloroethane in

the presence of 2 mol-% of the G-II catalyst under ethylene

for 2 hours, the conversion occurred quantitatively and the

cyclic acetal 1a was obtained in 82% isolated yield. Again,

microwave irradiation reduced the reaction time without

significant improvement of the isolated yield (86%). The

same reaction performed in dichloromethane at room tem-

perature led to a nearly similar isolated yield but required

a longer reaction time (overnight).

[a] Reactions using G-I (2 mol-%) were performed at room tem-

perature in dichloromethane (12 h), those using G-II (2 mol-%)

were performed in dichloroethane (2 h) at reflux, both under ethyl-

ene.

Figure 3. Ring-closing metathesis of enynes 5a and 13.

previously observed for compound 5a, the ring-closing en-

yne metathesis reactions of acetals 5b and 5e are stereospec-

ific leading to a 1:3 diastereomeric mixture.

As the diastereoisomeric ratio of the resulting cyclic

acetal 1a appeared to be the same as the ratio of the starting

material, the stereospecificity of the metathesis was exam-

ined after careful separation of each diastereoisomer of en-

yne acetal 5a and cyclic acetal 1a. When treated under eth-

ylene with 2 mol-% of the G-I or G-II catalyst, each dia-

stereoisomer of 5a gave quantitatively the corresponding

diastereoisomer of 1a (Table 2, entries 2 and 3). The stereo-

chemical assignment of each diastereoisomer will be devel-

oped in the last part of tidine allylic acetal 5d regardless of

the catalyst used (entry 6).

In sharp contrast to allyl enyne acetals 5a,b,e, G-I-cata-

lysed ring-closing metathesis reactions of the seven-mem-

bered ring precursors 11a,b,e as well as of the methallyl

acetals 12a,b performed in dichloromethane at room tem-

perature were unsuccessful.

We first focused on the seven-membered ring precursors

and selected the G-II catalyst (Table 3). Cycloheptenes

14a,b,e were obtained in good isolated yields along with

small amounts of the trienes 15a,b,e by RCEYM reaction,

which did not affect the acetal stereogenic centre (Table 3

entries 2, 4 and 6). Compared with the cyclisation of allyl

enyne acetals 5a,b,e, larger amounts of catalyst (5%) were

required to observe a total conversion in a reasonable time.

Reactions performed in dichloromethane at room tem-

perature required several days but by heating at reflux in

dichloroethane the reaction time decreased to a few hours.

In contrast to the enynes 5a,b,e, the cyclisation reactions

of the major or minor diastereoisomers of enynes 11a,b,e

occurred at different rates as the reactions of the minor dia-

stereoisomers led to the formation of trienes in larger

Starting from these initial experiments, we applied the amounts compared with the major diastereoisomers. In all

same conditions to other enyne acetals. Good conversions cases, trienes 15a,b,e were formed as an inseparable dia-

were observed for 5b and 5e (Table 2, entries 4 and 5). As stereoisomeric mixture (Table 3, entries 1, 3 and 5) or as

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Ring-Closing of 1,7- and 1,8-Enynes of Propargylic O,O-Acetals

Table 3. Ring-closing enyne metathesis of tethered acetals leading to the corresponding seven-membered rings.

[a] Catalyst (5%), ethylene, dichloromethane, 72 h, room temp. [b] Catalyst (5 mol-%), ethylene, dichloroethane, 24 h, reflux. [c] First

term of the ratio corresponds to the major syn diastereoisomer and the second term to the minor anti diastereoisomer of the mixture

obtained from the trans-ketalisation reaction (Table 1).

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Table 4. Ring-closing enyne metathesis of methallyl acetals 12.

[a] Determined by GC. [b] Dichloromethane, 36 h, room temperature or dichloroethane, overnight, ethylene, reflux, 5 mol-% catalyst

loading.

pure diastereoisomers when the reaction was performed on ene insertion product and only 30% of the required cyclised

isolated diastereoisomers of the parent enynes (Table 3, en- product 16a was obtained (Table 3, entry 2). The minor iso-

tries 2, 4 and 6).

mer delivered quantitatively triene 17a as only one dia-

In no case did the use of the GH-II catalyst instead of stereoisomer in excellent isolated yield (83%) independent

the G-II catalyst under ethylene improve the conversion in of the conditions used (entry 3). Once again, the amount of

favour of the cyclised products 14.

diene 16 formed was correlated to the diastereoisomeric ra-

The results obtained with methallyl acetals 12a,b are tio of the parent enyne acetals.

summarised in Table 4. As previously observed, the reaction

had to be performed under ethylene and a loading of 5 mol-

Determination of the Stereochemistries of Dienes 5, 14 and

16 and Propargylic O,O-Acetals 1, 11 and 12

% of the G-II catalyst was required for total conversion.

Such an observation has already been reported for enynes

with different structures of the 1,1-disubstituted alkene

fragment.^[16]A mixture of only one diastereoisomer of

16a,b and two diastereoisomers of triene 17a,b was ob-

Six-Membered-Ring Compounds

Each diastereoisomer of 1a was cleanly separated by

served depending on the catalyst and the conditions used flash chromatography. We chose C₆D₆as the deuteriated

(Table 4, entries 1 and 4). In contrast to allylic and homoal- solvent to fully benefit from its known aromatic solvent-

lylic enyne acetals 5a,b,e and 11a,b,e, ring-closing enyne me- induced shift (ASIS). Our previous experiences with simpler

tathesis was less efficient and led to the trienes 17 as the O,O-acetal dienes led us to expect a mixture of conformers

major products when the reaction was performed in dichlo- in the NMR spectra.^[17]However, this was not the case and

romethane at room temperature. In dichloroethane at re- each diastereoisomer existed as a single conformer on the

flux, the reaction time decreased as well as the yields of NMR timescale. A set of ¹H irradiation experiments al-

trienes 17 in favour of the cyclised products 16. In this case, lowed us to clearly assign each proton of each diene and to

the major starting isomer reacted mainly to afford the ethyl- determine their corresponding coupling constants. The key

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Ring-Closing of 1,7- and 1,8-Enynes of Propargylic O,O-Acetals

features are the benzylic protons (H²) and their relationship

All the ring-closing metathesis reactions performed on

with the allylic protons [H³and H⁴; see Figure 4]. In both the diastereoisomerically pure starting enyne acetals 1a,

cases, we noted the presence of a large coupling constant 11a,e and 12a demonstrated total stereochemical fidelity in

(J Ͼ 10 Hz) along with a small one (J ≈ 3.5 Hz), which the cyclisation reactions and no epimerisation of the acetal

demonstrates a 1,3-trans-diaxial relationship between H²stereogenic centre was observed, even after long storage of

and one of the methylene protons. Only conformers A and the starting material on the bench. Consequently, the rela-

B could account for this 1,3-trans-diaxial relationship (Fig- tive configuration of each enyne acetal 5a and 16a as well

ure 4). These experimental results ruled out, on the NMR as by extension 5b and 16b can be determined from the

timescale, conformers C and D, which have, for both dia- relative configurations of the cyclised products (Figure 5).

stereoisomers, the phenyl group in an axial position. In the

case of conformer C (trans-1a), a preliminary examination

based upon theoretical data had essentially precluded its

existence: this conformer simultaneously suffers from the

very unfavourable 1,3-diaxial interaction between phenyl

and the H₁atom and the allylic A_1,2strain between the

vinyl and ethoxy groups. Having a clear view of the confor-

mational data was unfortunately not enough to determine

the cis/trans stereochemistry. However, taking a closer look

at conformers A and B (as well as C and D), we can easily

see that only conformer B (i.e., the cis diastereoisomer of

1a) should provide a positive NOE between the acetal pro-

ton (H¹) and the benzylic proton (H²), whereas its trans

analogue should not. A 2D NOESY experiment confirmed

the presence of a positive NOE for only one diene, thus

establishing without ambiguity its cis stereochemistry (OEt

vs. Ph) as well as its conformation (i.e., conformer B vs. D).

These results were reinforced by ¹³C NMR data. For cis-

1a, the chemical shift of the benzylic carbon was 73.6 ppm,

whereas its trans analogue had, for the same carbon, a

chemical shift of 68.4 ppm (∆δ = –5.2 ppm relative to cis-

Figure 5. Relative configurations of the starting enynes 5a and 12a.

1a). This upfield shift of 5.2 ppm for trans-1a is consistent

with the γ-syn effect^[18,19]between the ethoxy group and the

benzylic carbon (Figure 4). The latter result is also in good

Seven-Membered-Ring Compounds

agreement with the previously deduced conformation of

trans-1a (i.e., conformer A).

In the case of seven-membered rings, the situation is

more complicated because the cycloheptene ring is believed

to exist in stable chair and boat conformers, the latter being

of higher energy.^[20]However, there has been much disagree-

ment not only about the relative stability of the chair and

boat forms, but also about the relative energies of the dif-

ferent transition states during the chair/chair interconver-

sion of cycloheptene, which is highly dependent on the sub-

stitution pattern of the seven-membered ring. Nevertheless,

despite a proposed equilibrium between the chair and boat

conformation in solution at room temperature, the most

probable conformation has been experimentally deduced to

be the chair.^[21]Furthermore, qualitative energy minimis-

ation (MM2) of cis- and trans-14a (Figure 6) showed the

chair conformation to be the favoured one for both dia-

stereoisomers.

Starting from the four possible chair-like conformers A–

D and by analogy with the six-membered rings 5 and 16,

we assigned the trans relative configuration to the major

Figure 4. Possible conformers of trans- and cis-1a.

1

The H and ¹³C NMR spectra of each stereoisomer of isomer of 14 and the cis relative configuration to the minor

the analogues 1b,e and 12a,b show the same general pattern one. In particular, the presence of a positive NOE for only

as observed with 1a. Thus, based upon the previous results one diene (the minor one) established without ambiguity its

with 1a, we used the aforementioned γ-syn effect in the ¹³

C

cis stereochemistry (OEt vs. Ph) as well as its conformation

NMR spectrum to attribute the cis/trans stereochemistry of (i.e., conformer A vs. C). This assignment was confirmed

each diastereoisomer of the analogues 1a,e and 12a,b.

by the γ-syn effect in the ¹³C NMR spectrum (–4 ppm) ob-

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Furthermore, the intramolecular step leading to the forma-

tion of cyclic intermediates d, e, k and j is controlled by

steric interactions between the substituents and stereoelec-

tronic factors such as anomeric effects.

In the case of precursors 5a,b,e, which are enynes with

a monosubstituted alkene and a terminal alkyne, RCEYM

leading to the six-membered ring proceeded smoothly using

first- and second-generation ruthenium–carbene complexes

under ethylene (Table 2). The products were formed as the

same diastereoisomeric mixture of trans/cis isomers as the

starting enynes, which indicates that the reaction does not

affect the acetal stereogenic centre and that both precursor

diastereoisomers cyclised at a comparable rate. This was

confirmed by the cyclisation of isolated diastereoisomers

(Table 2, entries 2 and 3). Many kinetic and NMR investi-

gations indicate that in the formation of six- and seven-

membered rings, the ene-then-yne pathway yields the

smaller exo ring isomer.^{[2g,20,25–27]}The ene-then-yne path-

way consists of the alkylidenation of the alkene part fol-

lowed by intramolecular alkyne insertion leading to inter-

mediate j. This pathway is in good agreement with our re-

sults and is supported by the observed ethylene effect on

the reaction rate using the conditions of Mori et al.^[3,11a]In

this intermediate, substituent interactions (i.e., diaxial inter-

actions) are less important than in bicyclic intermediate d,

which arises from alkyne insertion first, independent of the

relative configuration of the parent enynes.

Figure 6. Possible conformers of trans- and cis-14a.

served for the major trans diastereoisomer (δ = 70.8 ppm

vs. 66.8 ppm).

Finally, from these stereochemical assignments we were

able to deduce the cis relationship between the aromatic

substituent and the ethoxy group of the acetal of the start-

ing enynes 11a–e (Figure 7).

The second-generation ruthenium–carbene complex G-

II with 5 mol-% loading was required to form the seven-

membered dienes 14a,b,e and a higher temperature was

necessary to perform the reaction in a reasonable time

(Table 3). Both diastereoisomers of the parent enynes

11a,b,e gave the cyclised dienes 14a,b,e in comparable

overall rates with the simultaneous formation of small

amounts of trienes 15a,b,e, probably by cross-metathesis

between ethylene gas and the alkyne part of the starting

enyne. However, the cyclisation of each diastereoisomer

did not occur at the same rate because the minor dia-

stereoisomer (anti) led to a larger amount of triene than

Figure 7. Relative configuration of the starting enyne 11a.

Discussion

In ring-closing metathesis (RCM) reactions of enynes, the major one (syn).

the substituents on the multiple bonds are important.^[16,22]

Regarding the cyclisation of methallyl acetal precursors

Steric and electronic factors in the environment of the al- 12 (Table 4), only the major syn diastereoisomers of the

kene and alkyne moieties can modify the site of catalyst parent enynes gave the cyclised dienes 14 with the trans rela-

initiation^[22]as well as the rates of cyclisation through enyne tive configuration (Ar vs. OEt) in moderate yields with

metathesis. The presence of geometrically disposed hetero- 5 mol-% of the carbene complex G-II. The minor dia-

atom groups on the tethering alkyne unit may also interfere stereoisomer (anti isomer) led selectively to the correspond-

through competing bidentate coordination^[2b]and recently ing trienes 15 by ethylene insertion into the alkyne part of

an accelerating effect of an allylic hydroxy group on ring- the starting enyne.

closing enyne metathesis has been described.^[23]

The cross-metathesis process leading to triene formation

Two possible reaction pathways have been proposed so is competitive because the RCEYM reaction, which yields

far for ruthenium–carbene RCEYM depending on the ini- the exo ring isomers 14 or 16, is slower. This has recently

tial reaction of the ruthenium–carbene complex (=Ru) with been demonstrated by Hansen and Lee^[27]for the formation

the alkynylic or vinylic part of enyne a.^[24]In both se- of large ring, which occurs with a relatively low rate of

quences, two alternative routes can be envisaged (a-exo and macrocyclisation by enyne metathesis.

a-endo pathways, Scheme 3).^[25]

In addition to the steric and electronic effects of the sub-

In either case, the first intermolecular reaction of the en- stituents, stereoelectronic factors may play an important

yne substrate with the catalyst has a strong effect on the role in the stability of the bicyclic intermediates through the

rate of the second step, which proceeds intramolecularly. anomeric effect. To evaluate the influence of the ethoxy

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Ring-Closing of 1,7- and 1,8-Enynes of Propargylic O,O-Acetals

Scheme 3. Yne-then-ene and ene-then-yne pathways for the RCEYM reactions. Routes printed in grey represent triene formation by

cross-metathesis with ethylene and subsequent potential reactions.

group on the RCEYM reaction, we prepared the corre-

In contrast to the enynes 11a,b,e, Ru-catalysed RCM re-

sponding ethers 18a,b (Scheme 4) and 20a,b (Scheme 5) and actions of enynes 18a,b gave 19a,b in 86 and 75% yields,

submitted them to RCEYM conditions.

respectively, without any triene formation. We observed

that the reaction was also effective but required a longer

reaction time when the G-I catalyst (6 mol-%) was used in-

stead of G-II.

These results clearly indicate that removal of the ethoxy

group prevented triene formation and led to shorter reac-

tion times. In the case of enynes 11a,b,e, the rate of the

second intramolecular step leading to intermediates j or d

of the minor diastereoisomer decreases due to steric interac-

tions and the formation of intermediate n becomes compet-

itive.

Seven-Membered Rings

We prepared enynes 18a,b from the corresponding alde-

hydes^[11b]and conducted the RCEYM reactions in the pres-

ence of the G-II catalyst (5 mol-%) and under ethylene

(Scheme 4).

Six-Membered Rings (from Methallyl Precursors)

Enynes 20a,b were prepared and submitted to RCEYM

(Scheme 5). The reaction performed with the G-I catalyst

did not proceed. The reaction proceeded very slowly (more

than 3 days) in the presence of carbene complex G-II

Scheme 4. Homoallylic O-tethered enyne ring-closing metathesis.

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(5 mol-%) in dichloroethane at reflux to give 1,3-dienes minimised 1,3-diaxial strains between the substituents. The

21a,b along with the trienes 22a,b. Under these conditions, cis isomers are less stable and the reaction proceeds through

about 20% of both substrates 20a,b remained in the reac- intermediate n leading to triene formation.

tion mixture after 3 days (Scheme 5). Thus, triene formation

The lower reaction rate observed for 20a,b compared

occurred with both methallylic O-tethered and O,O-acetal with the corresponding acetals 12a,b is quite surprising but

enynes 20a,b and 12a,b, respectively.

can be explained by a higher reactivity of the alkyne part

towards the ruthenium catalyst in substrates 12a,b due to

the presence of a second oxygen atom at the α-position.

Furthermore, the stabilisation of intermediates d or j

through the anomeric effect can accelerate the cyclisation

process.

The diverse synthetic utility of exo six-membered rings

was further demonstrated by the conversion of pure trans-

1a into cycloadducts 24 and 26 by Diels–Alder reaction

with dienophiles 23 and 25 in toluene at reflux (Scheme 6).

Slight facial selectivity was observed leading to a diastereo-

isomeric mixture of cycloadducts resulting from preferential

bottom-face attack of dienophiles on the 1,3-diene.

Investigation of the possible diastereomeric control with

chiral dienophiles^[28]aimed at the synthesis of terpenoids

(i.e., salvinorin J)^[29]will be reported in due course.

Scheme 5. Methallylic O-tethered enyne ring-closing metathesis.

Geminal alkene substitution retards the competitive alk-

ylidenation in favour of the intermolecular alkyne insertion

by the yne-then-ene pathway. This pathway leads in the case

of enynes 12a,b to vinylcarbene intermediate b for which

cyclisation to bicyclic intermediate d is subject to several

diaxial interactions (Scheme 3): two possible 1,2-diaxial in-

teractions between vinyl and ethoxy and vinyl and methyl

(R) substituents, three 1,3-diaxial interactions between

ethoxy and methyl (R), ethoxy and aromatic (Ar) substitu-

ents and finally methyl (R) and aromatic (Ar) substituents.

Conclusions

We have demonstrated the efficient transformation of al-

Moreover, stereoelectronic factors may play an important lylic and homoallylic O,O-acetals 5 and 11 into the corre-

role in the stability of the bicyclic intermediates through the sponding six- and seven-membered cyclic 1,3-dienes 1 and

anomeric effect. On the other hand, initiation at the double 14 by enyne ring-closing metathesis using ruthenium–car-

bond of methallylic substrates cannot be ruled out. The rate bene catalysts. These dienes appeared to be suitable sub-

of the intramolecular cyclisation leading to intermediate d strates for Diels–Alder cycloaddition as shown by two ex-

may be low due to steric constraints giving back the starting amples.

enyne a, which can react through the yne-then-ene pathway.

Ru-catalysed ring-closing enyne metathesis reactions in-

For both intermediates d and j the trans isomers are fav- volving enynes 5 and 11 are compatible with the ene-then-

oured due to the conjugation of the anomeric effect with yne mechanism. The rate of cyclisation is governed by the

Scheme 6. Cycloaddition reactions of diene 1a with dienophiles 23 and 24.

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Ring-Closing of 1,7- and 1,8-Enynes of Propargylic O,O-Acetals

(CH), 126.0 (CH), 126.8 (CH), 117.5 (CH), 113.9 (CH), 109.5

(CH), 69.6 (CH), 55.9 (CH₃), 42.2 (CH₂), 16.2 (CH₃) ppm. HRMS

(ESI): calcd. for C₁₃H₁₈Na₁O₃[M + Na]⁺245.115; found 245.116.

substitution and stereoelectronic patterns of the parent en-

ynes. In the case of the homoallylic and methallylic sub-

strates 11 and 12, the formation of the corresponding tri-

enes 13 and 17 was observed in a ratio that is correlated to

the relative configuration of the parent enynes. These tri-

enes resulted from ethylene insertion into the alkyne part

of the enyne by the competitive yne-then-ene mechanism.

1-(Pyridin-2-yl)but-3-en-1-ol (7d): Compound 7d was prepared fol-

lowing the general experimental procedure G1 starting from pyr-

idine-2-carbaldehyde. Bulb-to-bulb distillation (112 °C under

20 mbar) gave 1-(pyridin-2-yl)but-3-en-1-ol as a yellow oil (90%).

¹H NMR (300 MHz, CDCl₃): δ = 8.56 (d, J = 4.9 Hz, 1 H), 7.71

(td, J = 7.7, 1.8 Hz, 1 H), 7.31 (d, J = 7.7 Hz, 1 H), 7.22 (dd, J =

7.7, 4.9 Hz, 1 H), 5.84 (ddt, J = 16.9, 10.5, 7 Hz, 1 H), 5.13 (app.

d, J = 7.0 Hz), 5.09 (app. t, 1 H), 4.83 (dd, J = 7.2, 4.8 Hz, 1 H),

3.66 (br. s, OH), 2.70–2.60 (m, 1 H), 2.50 (ddt, J = 14.2, 7.4, 1.4 Hz,

1 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 161.4 (C), 148.0 (CH),

136.8 (CH), 134.1 (CH), 122.4 (CH), 120.5 (CH), 118.0 (CH₂), 72.2

(CH), 42.9 (CH₂) ppm. HRMS (ESI): calcd. for C₉H₁₁Na₁O₁[M

+ Na]⁺172.073; found 172.072.

Experimental Section

General: Reagents and solvents were purchased and used without

further purification (reagent grade quality). THF was distilled from

sodium benzophenone ketyl. Dichloromethane was distilled from

CaH₂. Column chromatography: silica gel 60 (230–400 mesh,

0.040–0.063 mm). Demetalled silica gel was prepared according to

the published procedure.^[11a]Thin-layer chromatography (TLC) was

performed on glass sheets coated with silica gel 60 F₂₅₄(unless

otherwise stated) and visualisation by UV light. IR spectra were

recorded with a Universal ATR instrument. ¹H and ¹³C NMR

spectra were recorded at 200, 300 or 400 MHz. Chemical shifts are

reported as δ values (ppm) with the solvent (CDCl₃) resonance as

reference (δ = 7.26 ppm). Chemical shift data are reported as fol-

lows: s = singlet, d = doublet, t = triplet, q = quartet, m = mul-

tiplet, app. = apparent, mc = multiplet centre, coupling constants

J [Hz], signal integration. The following known compounds were

isolated as pure samples and their characterisation data matched

those of the reported compounds: 6,^[11a]4a,^[30]7a–7e,^[30,31]8a–

8e,^[32,33]9a–b^[34]and 13.^[11a]The G-I, G-II and GH-II catalysts were

purchased from Aldrich.

1-(3,4-Dichlorophenyl)but-3-en-1-ol (7e): Compound (7e) was pre-

pared following the general experimental procedure G1 starting

from 3,4-dichlorobenzaldehyde. Bulb-to-bulb distillation (125 °C

under 20 mbar) gave 1-(3,4-dichlorophenyl)but-3-en-1-ol as a yel-

low oil (93%). ¹H NMR (300 MHz, CDCl₃): δ = 7.48 (d, J =

2.1 Hz, 1 H), 7.42 (d, J = 8.3 Hz, 1 H), 7.19 (dd, J = 8.3, 2.1 Hz,

1 H), 5.78 (dddd, J = 18.1, 9.4, 7.7, 6.5 Hz, 1 H), 5.21 (app. s, 1

H), 5.17 (m, 1 H), 4.72 (dd, J = 7.8, 4.8 Hz, 1 H), 2.57–2.38 (m, 2

H), 1.97 (br. s, OH) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 144.1

(C), 133.6 (CH), 132.6 (C), 131.4 (C), 130.4 (CH), 127.9 (CH),

125.2 (CH), 119.4 (CH₂), 72.0 (CH), 43.9 (CH₂) ppm.

1-(3,4-Dichlorophenyl)pent-4-en-1-ol (8e): Compound 8e was pre-

pared following the general experimental procedure G2 starting

from 3,4-dichlorobenzaldehyde. Bulb-to-bulb distillation (95 °C un-

der 5 mbar) gave 1-(3,4-dichlorophenyl)pent-4-en-1-ol as a yellow

Synthesis of Homoallylic, Methallylic and Allylic Alcohols

1

oil (80%). H NMR (300 MHz, CDCl₃): δ = 7.45 (d, J = 2.1 Hz,

General Procedure for Methallylic and Allylic Addition (G1):

Methallyl- or allylmagnesium bromide (1.2 equiv., 1  and 0.5  in

diethyl ether purchased by Aldrich) was added to a stirred solution

of 0.1  aldehyde (1 equiv.) in diethyl ether over a 30 min period

(5–20 mmol scale). The mixture was stirred for 2 h and poured into

an aqueous NH₄Cl solution. The layers were separated and the

aqueous phase was extracted with diethyl ether. The combined or-

ganic phases were dried (MgSO₄) and concentrated in vacuo. The

residual oil was bulb-to-bulb distilled to give the corresponding

alcohols as colourless liquids.

1 H), 7.41 (d, J = 8.3 Hz, 1 H), 7.17 (dd, J = 8.3, 2.1 Hz, 1 H),

5.82 (ddt, J = 17.1, 10.2, 6.6 Hz, 1 H), 5.05 (ddd, J = 17.1, 3.2,

1.6 Hz, 1 H), 5.01 (ddd, J = 10.2, 3.2, 1.6 Hz, 1 H), 4.67 (dd, J =

7.4, 5.1 Hz, 1 H), 4.65 (br. s, OH), 2.15–2.01 (m, 2 H), 1.90–1.69

(m, 2 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 145.0 (C), 137.72

(CH), 132.5 (C), 131.2 (C), 130.4 (CH), 128.7 (C), 127.93 (CH),

125.2 (CH), 115.3 (CH₂), 72.7 (CH), 38.1 (CH₂), 29.8 (CH₂) ppm.

HRMS (ESI+): calcd. for C₁₁H₁₃Cl₂O [M + H]⁺231.00; found

231.03.

1-(Furan-3-yl)-3-methylbut-3-en-1-ol (9b): Compound 9b was pre-

pared following the general experimental procedure G1 starting

from 3-furaldehyde. Bulb-to-bulb distillation (100 °C under

10 mbar) gave 1-(furan-3-yl)-3-methylbut-3-en-1-ol as a yellow oil

General Procedure for Homoallylic Addition (G2): The Grignard

reagent solution was prepared from magnesium turnings

(1.2 equiv.) and 4-bromo-1-butene (1.15 equiv.) in anhydrous di-

ethyl ether at 0 °C under nitrogen and stirred for 1 h (5–20 mmol

scale). Aldehyde (1 equiv., 0.5  in diethyl ether) was added drop-

wise to the cold (0 °C) stirred solution. The reaction mixture was

stirred at room temperature for 1 h and hydrolysed with a saturated

ammonium chloride solution. The aqueous phase was extracted

with diethyl ether and the combined organic layers were dried and

the solvents evaporated to dryness. Distillation afforded the corre-

sponding homoallylic alcohols as yellow or colourless oils.

1

(79%). H NMR (300 MHz, CDCl₃): δ = 7.39–7.35 (m, 2 H), 6.4

(app. s, 1 H), 4.89 (app. s, 1 H), 4.82 (app. s, 1 H), 4.78 (td, J =

6.9, 1.6 Hz, 1 H), 2.45–2.40 (m, 2 H), 2.30 (br. s, OH), 1.77 (s, 3

H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 143.0 (CH), 141.9 (C),

138.8 (CH), 128.5 (CH), 113.8 (CH₂), 108.4 (CH), 64.2 (CH), 46.5

(CH₂), 22.2 (CH₃) ppm. HRMS (ESI+): calcd. for C₉H₁₂O₂[M +

H]⁺152.191; found 152.190.

Synthesis of Enyne O,O-Acetals

1-(2,5-Dimethoxy-4-methylphenyl)but-3-en-1-ol (7c): Compound 7c

was prepared following the general experimental procedure G1

starting from 2,5-dimethoxy-4-methylbenzaldehyde. Bulb-to-bulb

distillation (107 °C under 20 Torr) gave 1-(2,5-dimethoxy-4-meth-

ylphenyl)but-3-en-1-ol as a white solid (81%). ¹H NMR (300 MHz,

CDCl₃): δ = 6.87 (s, 1 H), 6.70 (1 H), 5.87 (dddd, J = 17.1, 10.2,

7.4, 6.6 Hz, 1 H), 5.19–5.10 (m, 2 H), 4.94 (dd, J = 7.9, 4.9 Hz, 1

H), 3.81 (s, 6 H), 2.65–2.42 (m, 2 H), 2.22 (s, 3 H) ppm. ¹³C NMR

(75 MHz, CDCl₃): δ = 151.8 (CH), 150.0 (CH), 135.3 (CH), 129.7

General Procedure for Transacetalisation: Homoallylic, methallylic

or allylic alcohol (1 equiv.), 3,3-diethoxypropyne (2.1 equiv.) and

camphorsulfonic acid (0.05 equiv.) were mixed at room temperature

(5–10 mmol scale). The reaction mixture was stirred at 175 mbar

(with an evaporator) for 15 h at 40 °C. The reaction was monitored

by TLC. The crude product was diluted with Et₂O, washed with a

saturated solution of NaHCO₃and then with brine, dried with

NaSO₄and evaporated to dryness. The two diastereoisomers were

Eur. J. Org. Chem. 2010, 5232–5247

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5241

D. A. Lanfranchi, C. Bour, B. Boff, G. Hanquet

FULL PAPER

separated by flash chromatography on silica gel (toluene/cyclohex-

ane, 10:90) to afford the anti (like) and syn (unlike) products as

colourless oils.

1,2-Dichloro-4-[1-(1-ethoxyprop-2-ynyloxy)but-3-enyl]benzene (5e):

¹H NMR (300 MHz, CDCl₃): δ = 7.44–7.39 (m, 2 H), 7.19–7.16

(m, 2 H), 5.83–5.61 (m, 1 H), 5.27 (d, J = 1.8 Hz, 0.6 H, one dia-

stereoisomer), 5.21–5.14 (m, 0.6 H, one diastereoisomer), 5.10 (d,

J = 1.8 Hz, 0.3 H, other diastereoisomer), 5.09–5.05 (m, 1 H), 5.10–

5.03 (m, 2 H), 4.72 (app. t, J = 6.6 Hz, 1 H), 3.77 (dq, J = 9.1,

7.1 Hz, 0.6 H, one diastereoisomer), 3.66 (q, J = 7.2 Hz, 1.3 H,

other diastereoisomer), 3.61 (dq, J = 9.1, 7.2 Hz, 0.6 H, one dia-

stereoisomer), 2.65–2.52 (m, 2 H), 2.57 (d, J = 1.8 Hz, 0.6 H, one

diastereoisomer), 2.55 (d, J = 1.8 Hz, 0.3 H, other diastereoiso-

mer), 1.25 (t, J = 7.1 Hz, 2 H, one diastereoisomer), 1.16 (t, J

= 7.1 Hz, 1 H, other diastereoisomer) ppm. ¹³C NMR (75 MHz,

CDCl₃): δ = 142.4 (C), 137.2 (CH), 132.0 (C), 131.7 (C), 130.6

(CH), 129.2 (CH), 116.5 (CH₂), 94.6 (CH), 78.6 (CH), 76.3 (CH),

73.4 (C), 59.9 (CH₂), 42.5 (CH₂), 15.1 (CH₃) ppm.

Compounds 10 and 5c were prepared in DMF (0.2 ) under

vacuum.

Compound 5a: Compound 5a was prepared following the general

procedure (starting from 7a). Chromatography on silica gel

(toluene/cyclohexane, 10:90) gave a 3:1 anti/syn mixture of 5a in

78% yield as a colourless oil.

R_f(mixture of diastereoisomers) = 0.4 (cyclohexane/Et₂O, 40:1, UV

and vaniline).

1-(1-Ethoxyprop-2-ynyloxy)but-3-enylbenzene [anti-5a (like)]: ¹H

NMR (200 MHz, CDCl₃): δ = 7.35–7.22 (m, 5 H), 5.72 (ddt, J =

17.1, 10.2, 7.0 Hz, 1 H), 5.04 (d, J = 1.8 Hz, 1 H), 5.05–5.02 (m, 1

H), 4.98–4.94 (m, 1 H), 4.67 (dd, J = 7.8, 6.0 Hz, 1 H), 3.52 (q, J

= 7.1 Hz, 1 H), 2.59 (ddd, J = 14.1, 7.9, 6.9 Hz, 1 H), 2.46 (d, J =

1.8 Hz, 1 H), 2.39 (ddd, J = 14.1, 7.9, 6.9 Hz, 1 H), 1.10 (t, J =

7.1 Hz, 3 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 140.4 (C),

128.4 (2 CH), 127.8 (CH), 127.0 (2 CH), 124.4 (CH), 117.0 (CH₂),

94.6 (CH), 78.6 (CH), 76.1 (CH), 73.5 (C), 59.9 (CH₂), 42.5 (CH₂),

15.1 (CH₃) ppm. HRMS (ESI+): calcd. for C₁₅H₁₉O₂[M + H]⁺

231.139; found 231.138.

Compound 11a: Compound 11a was prepared following the general

procedure (starting from 8a). Chromatography on silica gel (tolu-

ene/cyclohexane, 10:90) gave a 3:1 anti/syn mixture of 11a in 72%

yield as a colourless oil.

1-[1-(1-Ethoxyprop-2-ynyloxy)pent-4-enyl]benzene [anti-11a (like)]:

¹H NMR (300 MHz, CDCl₃): δ = 7.27–7.18 (m, 5 H), 5.75 (ddt, J

= 17.2, 10.4, 6.4 Hz, 1 H), 5.02 (d, J = 1.7 Hz, 1 H), 4.95 (ddd, J

= 17.2, 3.2, 1.5 Hz, 1 H), 4.90 (dd, J = 10.1, 3.2 Hz, 1 H), 4.64 (dd,

J = 7.6, 5.7 Hz, 1 H), 3.62 (qd, J = 7.1, 4.0 Hz, 2 H), 2.45 (d, J =

1.7 Hz, 1 H), 2.16–1.89 (m, 3 H), 1.73–1.66 (m, 1 H), 1.1 (t, J =

7.1 Hz, 3 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 141.2 (C),

137.9 (C), 128.4 (2 CH), 127.7 (CH), 126.9 (2 CH), 114.8 (CH₂),

88.8 (CH), 79.2 (C), 77.3 (CH), 73.4 (CH), 59.6 (CH₂), 37.0 (CH₂),

29.9 (CH₂), 14.9 (CH₃) ppm. HRMS (ESI): calcd. for

C₁₆H₂₀Na₁O₂[M + Na]⁺267.136; found 267.136.

1-(1-Ethoxyprop-2-ynyloxy)but-3-enylbenzene [syn-5a (unlike)]: ¹H

NMR (200 MHz, CDCl₃): δ = 7.35–7.22 (m, 5 H), 5.76 (ddt, J =

17.1, 10.2; 7.0 Hz, 1 H), 5.24 (d, J = 1.8 Hz, 1 H), 5.10–5.00 (m, 2

H), 4.69 (t, J = 6.7 Hz, 1 H), 3.74 (dq, J = 9.3, 7.3 Hz, 1 H), 3.40

(dq, J = 9.3, 7.1 Hz, 1 H), 2.72–2.66 (m, 1 H), 2.54–2.44 (m, 1 H),

2.51 (d, J = 1.8 Hz, 1 H), 1.05 (t, J = 7.1 Hz, 3 H) ppm. ¹³C NMR

(75 MHz, CDCl₃): δ = 142.1 (C), 128.4 (2 CH), 127.8 (CH), 127.0

(2 CH), 124.1 (CH), 117.2 (CH₂), 96.1 (CH), 78.4 (CH), 77.9 (CH),

74.2 (C), 61.7 (CH₂), 42.4 (CH₂), 15.1 (CH₃) ppm. HRMS (ESI+):

calcd. for C₁₅H₁₈NaO₂[M + Na]⁺253.120; found 253.116.

1-[1-(1-Ethoxyprop-2-ynyloxy)pent-4-enyl]benzene [syn-11a (un-

1

like)]: H NMR (300 MHz, CDCl₃): δ = 7.27–7.18 (m, 5 H), 5.75

(ddt, J = 17.2, 10.4, 6.4 Hz, 1 H maj + 0.5 H min), 5.12 (d, J =

1.7 Hz, 1 H maj), 5.02 (d, J = 1.7 Hz, 0.5 H min), 4.95 (ddd, J =

17.2, 3.2, 1.5 Hz, 1 H maj + 0.5 H min), 4.90 (dd, J = 10.1, 3.2 Hz,

1 H maj + 0.5 H min), 4.64 (dd, J = 7.6, 5.7 Hz, 0.5 H min), 4.54

(dd, J = 7.2, 5.7 Hz, 1 H maj), 3.69–3.56 (m, 2ϫ0.5 H min + 1 H

maj), 3.3 (dq, J = 9.3, 7.1 Hz, 1 H maj), 2.45 (d, J = 1.7 Hz, 0.5 H

min), 2.44 (d, J = 1.7 Hz, 1 H maj), 2.16–1.89 (m, 3ϫ0.5 H min,

3 H maj), 1.73–1.66 (m, 0.5 H min + 1 H maj), 1.1 (t, J = 7.1 Hz,

1.5 H min), 0.95 (t, J = 7.1 Hz, 3 H maj) ppm. ¹³C NMR (75 MHz,

CDCl₃): δ = 142.1 (C maj), 141.2 (C min), 137.9 (C maj + C min),

128.4 (2 CH min), 128.3 (2 CH maj), 127.7 (CH min), 127.6 (CH

maj), 126.9 (2CH min), 126.7 (2 CH maj), 114.9 (CH₂maj), 114.8

(CH₂min), 90.9 (CH maj), 88.8. (CH min), 79.3 (C min), 79.2 (C

min), 78.8 (CH maj), 77.3 (CH min), 73.7 (CH maj), 73.4 (CH

min), 61.3 (CH₂maj), 59.6 (CH₂min), 37.0 (CH₂min), 36.8 (CH₂

maj), 29.9 (CH₂min), 29.7 (CH₂maj), 14.9 (CH₃min), 14.6 (CH₃

maj) ppm.

Compound 5b: Compound 5b was prepared following the general

procedure (starting from 7b). Chromatography on silica gel

(toluene/cyclohexane, 10:90) gave a 3:1 anti/syn mixture of 5b in

66% yield as a colourless oil. R_f(mixture of diastereoisomers) =

0.7 (cyclohexane/Et₂O, 3:1, UV and p-anisaldehyde).

3-[1-(1-Ethoxyprop-2-ynyloxy)but-3-enyl]-furan [anti-5b (like)]: ¹H

NMR (200 MHz, CDCl₃): δ = 7.39 (m, 1 H), 7.25 (m, 1 H), 6.42

(m, 1 H), 5.77 (m, 1 H), 5.10 (d, J = 1.2 Hz, 1 H), 5.00 (m, 2 H),

4.75 (dd, J = 8.0, 6.0 Hz, 1 H), 3.79 (q, J = 6 Hz, 1 H), 2.70–2.35

(m, 2 H), 2.53 (d, J = 1.2 Hz, 1 H), 1.17 (t, J = 6.0 Hz, 3 H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ = 143.7 (CH), 140.7 (CH), 129.7

(CH), 125.2 (C), 117.0 (CH₂), 91.0 (CH), 88.3 (CH), 78.1 (CH),

70.5 (C), 59.9 (CH₂), 40.8 (CH₂), 15.2 (CH₃) ppm. HRMS (ESI⁺):

calcd. for C₁₃H₁₇O₃[M + H]⁺221.1174; found 221.1178.

3-[1-(1-Ethoxyprop-2-ynyloxy)-but-3-enyl]furan [syn-5b (unlike)]: ¹H

NMR (200 MHz, CDCl₃): δ = 7.39 (m, 1 H), 7.25 (m, 1 H), 6.40

(m, 1 H), 5.77 (m, 1 H), 5.15 (d, J = 1.0 Hz, 1 H), 5.00 (m, 2 H),

4.59 (dd, J = 8.0, 6.0 Hz, 1 H), 3.79 (q, J = 6 Hz, 1 H), 2.70–2.35

(m, 2 H), 2.50 (d, J = 1.0 Hz, 1 H), 1.04 (t, J = 6.0 Hz, 3 H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ = 143.7 (CH), 140.7 (CH), 129.7

(CH), 125.2 (C), 117.0 (CH₂), 91.5 (CH), 89.5 (CH), 78.6 (CH),

70.5 (C), 59.9 (CH₂), 40.7 (CH₂), 15.1 (CH₃) ppm.

Compound 11b: Compound 11b was prepared following the general

procedure (starting from 8b). Chromatography on silica gel

(toluene/cyclohexane, 10:90) gave a 3:2 anti/syn mixture of 11b in

53% yield as a colourless oil.

1

3-[1-(1-Ethoxyprop-2-ynyloxy)pent-4-enyl]furan [anti-11b (like)]: H

NMR (300 MHz, CDCl₃): δ = 7.39–7.37 (m, 2 H), 6.38 (d, J =

5.3 Hz, 1 H), 5.76 (ddt, J = 20.2, 10.2, 6.1 Hz, 1 H), 5.17 (d, J =

1.8 Hz, 1 H), 5.02 (d, J = 1.7 Hz, 1 H), 4.97–4.91 (m, 1 H), 4.66

(t, J = 6.7 Hz, 1 H), 3.74–3.60 (m, 2 H), 2.50 (d, J = 1.8 Hz, 1 H),

2.16–1.81 (m, 3 H), 1.75–1.68 (m, 1 H), 1.19 (t, J = 7.1 Hz, 3

H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 143.6 (CH), 140.7 (CH),

137.9 (CH), 125.3 (C), 114.9 (CH₂), 108.6 (CH), 88.4 (CH), 79.2

(C), 73.4 (CH), 69.2 (CH), 59.4 (CH₂), 35.5 (CH₂), 29.8 (CH₂),

Compound 5e: Compound 5e was prepared following the general

procedure (starting from 7e). Chromatography on silica gel

(toluene/cyclohexane, 30:70) gave a 3:1 anti/syn mixture of 5e in

65% yield as a colourless oil. R_f(mixture of diastereoisomers) =

0.6 (cyclohexane/Et₂O, 30:1, UV and vaniline).

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Eur. J. Org. Chem. 2010, 5232–5247

Ring-Closing of 1,7- and 1,8-Enynes of Propargylic O,O-Acetals

15.0 (CH₃) ppm. HRMS (ESI): calcd. for C₁₄H₁₉Na₁O₃[M +

Na]⁺257.115; found 257.122.

H), 2.63 (dd, J = 13.9, 7.9 Hz, 1 H), 2.53 (d, J = 1.8 Hz, 1 H), 2.38

(dd, J = 13.9, 5.9 Hz, 1 H), 1.75 (s, 3 H), 1.17 (t, J = 7.1 Hz, 3

H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 141.8 (C), 141.2 (C),

128.4 (2 CH), 127.8 (CH), 127.1 (2 CH), 113.3 (CH₂), 88.9 (CH),

79.2 (C), 77.2 (CH), 76.8 (CH), 73.4 (C), 59.7 (CH₂), 46.2 (CH₂),

22.8 (CH₃), 14.9 (CH₃) ppm. HRMS (ESI): calcd. for C₁₆H₂₀O₂Na

[M + Na]⁺267.136; found 267.131.

3-[1-(1-Ethoxyprop-2-ynyloxy)pent-4-enyl]furan [syn-11b (unlike)]:

¹H NMR (300 MHz, CDCl₃): δ = 7.39–7.36 (m, 2 H), 7.19–7.07

(m, 1 H), 6.42 (s, 1 H), 5.58 (ddt, J = 17.2, 10.2, 6.4 Hz, 1 H), 5.28

(d, J = 1.8 Hz, 0.3 H, one diastereoisomer), 5.17 (dd, J = 7.3,

1.8 Hz, 0.65 H, one diastereoisomer), 5.06 (br. s, 0.65 H, other

diastereoisomer), 5.00 (dd, J = 10.6, 1.8 Hz, 1.3 H, other dia-

stereoisomer), 4.69 (t, J = 6.7 Hz, 0.65 H, one diastereoisomer),

4.66 (t, J = 6.7 Hz, 0.35 H, other diastereoisomer), 3.80–3.58 (m,

1-[1-(1-Ethoxyprop-2-ynyloxy)-3-methylbut-3-enyl]benzene [syn-12a

(unlike)]: ¹H NMR (300 MHz, CDCl₃): δ = 7.36–7.18 (m, 5 H),

5.21 (d, J = 1.8 Hz, 1 H), 4.79–4.70 (m, 3 H), 3.72 (dq, J = 9.3,

1.5 H), 3.46 (dq, J = 9.3, 7.1 Hz, 0.35 H, other diastereoisomer), 7.1 Hz, 1 H), 3.37 (dq, J = 9.3, 7.1 Hz, 1 H), 2.65 (dd, J = 14.0,

2.55 (d, J = 1.8 Hz, 0.65 H, one diastereoisomer), 2.53 (d, J =

1.8 Hz, 0.35 H, other diastereoisomer), 2.13–1.95 (m, 4 H), 1.85–

1.75 (m, 2 H), 1.26 (t, J = 7.1 Hz, 1.95 H, one diastereoisomer),

1.14 (t, J = 7.1 Hz, 1.05 H, other diastereoisomer) ppm. ¹³C NMR

(75 MHz, CDCl₃): δ = 143.6 (CH, anti), 143.3 (C, syn), 140.7 (CH,

7.9 Hz, 1 H), 2.50 (d, J = 1.8 Hz, 1 H), 2.38 (dd, J = 14.2, 6.0 Hz,

1 H), 1.74 (s, 3 H), 1.03 (t, J = 7.1 Hz, 3 H) ppm. ¹³C NMR

(75 MHz, CDCl₃): δ = 142.0 (C), 141.7 (C), 128.2 (2 CH), 127.5

(CH), 126.7 (2 CH), 113.3 (CH₂), 90.8 (CH), 79.0 (C), 77.9 (CH),

76.8 (CH), 73.9 (C), 61.1 (CH₂), 46.2 (CH₂), 22.8 (CH₃), 14.6

anti), 139.9 (CH, syn), 137.9 (CH, syn and anti), 125.3 (C, anti), (CH₃) ppm.

124.9 (C, syn), 115.0 (CH₂, syn), 114.9 (CH₂, anti), 108.8 (CH, syn),

Compound 12b: This compound was prepared following the general

108.6 (CH, anti), 90.6 (CH, syn), 88.4(CH, anti), 79.2 (C, syn and

anti), 73.7 (CH, syn), 73.4 (CH, anti), 70.7 (CH, syn), 69.2 (CH,

anti), 61.2 (CH₂, syn), 59.4 (CH₂, anti), 35.5 (CH₂, anti), 35.3 (CH₂,

syn), 29.8 (CH₂, anti), 29.5 (CH₂, syn), 15.0 (CH₃, anti), 14.7 (CH₃,

syn) ppm. HRMS (ESI): calcd. for C₁₄H₁₈Na₁O₃[M + Na]⁺

257.115; found 257.119.

procedure, starting from 3-methyl-1-phenylbut-3-en-1-ol (9b).

Chromatography on silica gel (toluene/cyclohexane, 10:90) gave a

3:2 anti/syn mixture of 12b in 42% yield as a colourless oil. R_f

(mixture of diastereoisomers) = 0.5 (cyclohexane/Et₂O, 4:1, UV

and p-anisaldehyde).

3-[1-(1-Ethoxyprop-2-ynyloxy)-3-methylbut-3-enyl]furan (12b): ¹H

NMR (300 MHz, CDCl₃): δ = 7.40–7.36 (m, 2 H), 6.43 (app. s, 1

H), 5.25 (d, J = 1.7 Hz, 0.4 H, one diastereoisomer), 5.20 (d, J =

1.8 Hz, 0.6 H, other diastereoisomer), 4.81–4.78 (m, 1 H), 4.76–

4.73 (m, 1 H), 3.78–3.63 (m, 1.6 H), 3.49 (dq, J = 9.3, 7.0, 0.4 Hz,

one diastereoisomer), 2.68–2.58 (m, 1 H), 2.55 (d, J = 1.7 Hz, 0.4

Compound 11e: This compound was prepared following the general

procedure (starting from 8e). Chromatography on silica gel (tolu-

ene/cyclohexane, 10:90) gave a 2:1 anti/syn mixture of 11e in 66%

yield as a colourless oil.

1,2-Dichloro-4-[1-(1-ethoxyprop-2-ynyloxy)pent-4-enyl]benzene [anti-

1

11e (like)]: H NMR (300 MHz, CDCl₃): δ = 7.44 (d, J = 2.1 Hz, H, one diastereoisomer), 2.53 (d, J = 1.8 Hz, 0.6 H, other dia-

1 H), 7.43 (d, J = 8.3 Hz, 1 H), 7.18 (dd, J = 8.3, 2.1 Hz, 1 H),

stereoisomer), 2.44–2.35 (m, 1 H), 1.76 (s, 0.4 H, one diastereoiso-

5.80 (ddt, J = 17.1, 10.2, 6.5 Hz, 1 H), 5.09 (d, J = 1.8 Hz, 1 H), mer), 1.75 (d, 0.6 H, other diastereoisomer), 2.44–2.35 (m, 1 H),

5.06–4.97 (m, 2 H), 4.69 (dd, J = 7.6, 5.7 Hz, 1 H), 3.66 (m, 2 H),

1.21 (t, J = 7.1 Hz, 0.6 H, one diastereoisomer), 1.15 (t, J = 7.1 Hz,

2.57 (d, J = 1.8 Hz, 1 H), 2.18–2.06 (m, 2 H), 2.02–1.91 (m, 1 H), 0.6 H, other diastereoisomer) ppm. ¹³C NMR (75 MHz, CDCl₃): δ

1.78–1.68 (m, 1 H), 1.16 (t, J = 7.1 Hz, 1 H) ppm. ¹³C NMR = 143.5, 143.1, 141.5, 140.6, 139.9, 125.9, 124.9, 113.4, 113.2, 108.9,

(75 MHz, CDCl₃): δ = 142.0 (C), 137.6 (CH), 132.6 (C), 131.7 (C), 108.7, 90.6, 88.5, 79.1, 79.0, 73.8, 73.5, 69.8, 68.7, 61.1, 59.5, 44.8,

130.5 (CH), 130.5 (CH), 129.0 (CH), 115.2 (CH₂), 86.3 (CH), 78.8

(C), 76.0 (CH), 73.9 (CH), 60.1 (CH₂), 37.0 (CH₂), 29.8 (CH₂),

14.9 (CH₃) ppm. HRMS (ESI): calcd. for C₁₆H₁₉Na₁Cl₂O₂[M +

Na]⁺335.058; found 335.058.

44.7, 22.7, 14.9, 14.8 ppm. HRMS (ESI): calcd. for C₁₄H₁₉O₃Na

[M + Na]⁺257.115; found 257.114.

Enyne Metathesis

General Procedure for Enyne Ring-Closing Metathesis of Prop-

argylic O,O-Acetals 5, 11 and 12: The enyne (0.15–0.2 mmol) and

the Grubbs II or Grubbs I catalyst (2–5 mol-%) were dissolved in

dichloroethane (0.1 m). Ethylene was bubbled through the mix-

ture for 10 min whilst stirring at reflux. After the time indicated in

Tables 2, 3 and 4 (GC monitoring), the reaction mixture was fil-

tered through a charcoal pad, concentrated and then directly puri-

fied through a short column of silica (toluene/cyclohexane) to give

the corresponding dienes. Alternatively, toluene could be used as

solvent at 70 °C to give a similar conversion rate.

1,2-Dichloro-4-[1-(1-ethoxyprop-2-ynyloxy)pent-4-enyl]benzene [syn-

11e (unlike)]: ¹H NMR (300 MHz, CDCl₃): δ = 7.45 (d, J = 2.1 Hz,

1 H), 7.42 (d, J = 8.3 Hz, 1 H), 7.19 (dd, J = 8.3, 2.1 Hz, 1 H),

5.80 (ddt, J = 17.1, 10.2, 6.5 Hz, 1 H), 5.22 (d, J = 1.8 Hz, 1 H),

5.06–4.97 (m, 2 H), 4.62 (dd, J = 7.1, 5.8 Hz, 1 H), 3.74 (dq, J =

9.3, 7.1 Hz, 1 H), 3.41 (dq, J = 9.3, 7.1 Hz, 1 H), 2.52 (d, J =

1.8 Hz, 1 H), 2.18–2.05 (m, 2 H), 2.02–1.90 (m, 1 H), 1.78–1.69 (m,

1 H), 1.07 (t, J = 7.1 Hz, 1 H) ppm. ¹³C NMR (75 MHz, CDCl₃):

δ = 142.8 (C), 137.6 (CH), 132.4 (C), 131.4 (C), 130.3 (CH), 128.6

(CH), 126.0 (CH), 115.3 (CH₂), 91.1 (CH), 78.7 (C), 76.0 (CH),

74.3 (CH), 61.4 (CH₂), 36.9 (CH₂), 29.5 (CH₂), 14.7 (CH₃) ppm.

6-Ethoxy-2-phenyl-5-vinyl-3,6-dihydro-2H-pyran

(trans-1a):

(Table 2) ¹H NMR (300 MHz, C₆D₆): δ = 7.35–7.31 (m, 2 H), 7.19–

7.06 (m, 3 H), 6.19 (dd, J = 17.7, 11.1 Hz, 1 H), 5.58 (dd, J = 5.6,

2.4 Hz, 1 H), 5.33 (s, 1 H), 5.26 (d, J = 17.8 Hz, 1 H), 5.04 (dd, J

= 11.0, 3.6 Hz, 1 H), 4.99 (d, J = 11 Hz, 1 H), 3.75 (dq, J = 9.7,

7.1 Hz, 1 H), 3.37 (dq, J = 9.7, 7.1 Hz, 1 H), 2.17 (ddd, J = 18.2,

11.1, 2.1, 1.6 Hz, 1 H), 1.97 (ddd, J = 18.5, 5.7, 4.0 Hz, 1 H), 1.03

(t, J = 7.1 Hz, 3 H) ppm. ¹³C NMR (75 MHz, C₆D₆): δ = 143.3

Compound 12a: Compound 12a was prepared following the general

procedure [starting from 3-methyl-1-phenylbut-3-en-1-ol (9a)].

Chromatography on silica gel (toluene/cyclohexane, 10:90) gave a

3:1 anti/syn mixture of 12a in 51% yield as a colourless oil. R_f

(mixture of diastereoisomers) = 0.6 (cyclohexane/Et₂O, 4:1, UV

and vaniline).

1-[1-(1-Ethoxyprop-2-ynyloxy)-3-methylbut-3-enyl]benzene [anti-12a (C), 136.3 (CH), 135.1 (C), 128.9 (CH), 127.5 (C), 127.9 (CH),

1

(like)]: H NMR (300 MHz, CDCl₃): δ = 7.35–7.28 (m, 5 H), 5.10

(d, J = 1.8 Hz, 1 H), 4.86 (dd, J = 7.9, 6.1 Hz, 1 H), 4.78 (br. q, J

126.6 (2 CH), 113.2 (CH₂), 96.4 (CH), 68.8 (CH), 63.8 (CH), 34.1

(CH₂), 15.9 (CH₃) ppm. HRMS (ESI): calcd. for C₁₅H₁₉O₂Na [M

= 1.8 Hz, 1 H), 4.72 (br. q, J = 1.8 Hz, 1 H) 3.68 (q, J = 7.0 Hz, 2 + Na]⁺253.120; found 253.121.

Eur. J. Org. Chem. 2010, 5232–5247

www.eurjoc.org

5243

D. A. Lanfranchi, C. Bour, B. Boff, G. Hanquet

FULL PAPER

6-Ethoxy-2-phenyl-5-vinyl-3,6-dihydro-2H-pyran (cis-1a): (Table 2) 1.94 (m, 1 H), 1.89–1.81 (m, 1 H), 1.02 (t, J = 7.1 Hz, 1 H) ppm.

¹H NMR (300 MHz, C₆D₆): δ = 7.38–7.35 (m, 2 H), 7.22–7.08 (m,

3 H), 6.22 (dd, J = 17.7, 11.2 Hz, 1 H), 5.68 (dd, J = 6.3, 2.5 Hz,

¹³C NMR (75 MHz, C₆D₆): δ = 144.4 (C), 139.7 (C), 138.8 (CH),

131.31 (CH), 126.95 (CH), 126.08 (CH), 114.6 (CH₂), 99.5 (CH),

1 H), 5.54 (app. t, J = 8.8 Hz, 1 H), 5.06 (d, J = 11.2 Hz, 1 H), 72.6 (CH), 63.8 (CH₂), 36.9 (CH₂), 24.9 (CH₂), 14.9 (CH₃) ppm.

4.40 (dd, J = 10.3, 3.3 Hz, 1 H), 3.82 (dq, J = 9.4, 7.1 Hz, 1 H),

3.60 (dq, J = 9.4, 7.1 Hz, 1 H), 2.29–2.17 (m, 1 H), 1.90 (ddd, J =

17.8, 6.3, 3.3 Hz, 1 H), 1.16 (t, J = 7.2 Hz, 3 H) ppm. ¹³C NMR

(75 MHz, C₆D₆): δ = 143.0 (C), 137.0 (C), 135.6 (CH), 129.5 (CH),

128.8 (2 CH), 128.6 (CH), 127.9 (CH), 126.5 (2 CH), 114.5 (CH₂),

98.8 (CH), 73.59 (CH), 62.3 (CH₂), 33.9 (CH₂), 15.9 (CH₃) ppm.

HRMS (ESI): calcd. for C₁₅H₁₉O₂Na [M + Na]⁺253.120; found

253.120.

HRMS (ESI): calcd. for C₁₆H₂₂O₂[M + H]⁺245.154; found

245.156.

7-Ethoxy-2-phenyl-6-vinyl-2,3,4,7-tetrahydrooxepine

(cis-14a):

(Table 3) ¹H NMR (400 MHz, C₆D₆): δ = 7.35 (d, J = 7.5 Hz, 2

H), 7.21 (t, J = 7.5 Hz, 2 H), 7.11 (d, J = 7.6 Hz, 1 H), 6.44 (dd,

J = 18.0, 10.8 Hz, 1 H), 5.81 (t, J = 7.0 Hz, 1 H), 5.37 (d, J =

17.5 Hz, 1 H), 5.32 (s, 1 H), 5.01 (d, J = 11.6 Hz, 1 H), 4.45 (dd,

J = 8.6, 5.4 Hz, 1 H), 3.85 (dq, J = 9.4, 7.0 Hz, 1 H), 3.38 (dq, J

6-Ethoxy-2-(furan-3-yl)-5-vinyl-3,6-dihydro-2H-pyran

(trans-1b): = 9.4, 7.0 Hz, 1 H), 2.63–2.52 (m, 1 H), 2.09–2.00 (m, 1 H), 1.88–

1

(Table 2) H NMR (300 MHz, CDCl₃): δ = 7.45 (m, 1 H), 7.42 (t, 1.73 (m, 2 H), 1.12 (t, J = 7.1 Hz, 1 H) ppm. ¹³C NMR (75 MHz,

J = 1.7 Hz, 1 H), 6.45 (dd, J = 1.8, 0.9 Hz, 1 H), 6.28 (dd, J =

17.8, 10.9 Hz, 1 H), 5.98 (dd, J = 5.5, 2.7 Hz, 1 H), 5.29 (s, 1 H),

C₆D₆): δ = 144.4 (C), 139.9 (C), 138.7 (CH), 131.3 (CH), 126.95

(CH), 126.08 (CH), 115.0 (CH₂), 101.6 (CH), 78.5 (CH), 61.4

5.23 (d, J = 18.0 Hz, 1 H), 5.08 (d, J = 11.0 Hz, 1 H), 5.03 (dd, J (CH₂), 37.5 (CH₂), 24.9 (CH₂), 15.5 (CH₃) ppm.

= 11.0, 4.0 Hz, 1 H), 3.95 (dq, J = 9.8, 7.1 Hz, 1 H), 3.69 (dq, J =

1-[1-(1-Ethoxy-2-methylenebut-3-enyloxy)pent-4-enyl]benzene (15a):

9.8, 7.1 Hz, 1 H), 2.48 (dd, J = 18.5, 10.7 Hz, 1 H), 2.35 (ddd, J =

18.5, 5.6, 4.1 Hz, 1 H), 1.29 (t, J = 7.0 Hz, 3 H) ppm. ¹³C NMR

(75 MHz, CDCl₃): δ = 143.3 (CH), 139.3 (CH), 135.2 (CH), 135.1

(C), 128.2 (CH), 126.4 (C), 113.0 (CH₂), 108.9 (CH), 95.3 (CH),

63.5 (CH), 61.4 (CH₂), 31.6 (CH₂), 15.4 (CH₃) ppm. HRMS (ESI):

calcd. for C₁₃H₁₆O₃Na [M + Na]⁺243.100; found 243.100.

(Table 3) ¹H NMR (300 MHz, CDCl₃): δ = 7.42–7.25 (m, 5 H),

6.73 (dd, J = 18.1, 11.4 Hz, 1 H), 6.41 (d, J = 8.6 Hz, 1 H), 5.31–

4.65 (m, 6 H), 4.60 (t, J = 6.9 Hz, 1 H), 3.90 (qd, J = 7.1, 5.8 Hz,

2 H), 2.49–2.21 (m, 2 H), 2.05–1.83 (m, 2 H), 1.32–1.23 (m, 3

H) ppm. ¹³C NMR (75 MHz, C₆D₆): δ = 145.6 (CH), 145.05 (CH),

143.9 (C), 142.5 (C), 129.3 (CH), 129.3 (CH), 128.4 (CH), 128.3

(CH), 127.3 (CH), 127.0 (CH), 126.0 (CH), 125.5 (CH), 12.0 (CH₂),

111.8 (CH₂), 111.4 (CH₂), 80.7 (CH), 80.5 (CH), 78.2 (CH), 78

(CH), 68.6 (CH₂), 36.32 (CH₂), 35.2 (CH₂), 34.0 (CH₂), 32.8 (CH₂),

31.8 (CH₂), 15.4 (CH₃), 15.3 (CH₃) ppm.

6-Ethoxy-2-(furan-3-yl)-5-vinyl-3,6-dihydro-2H-pyran

(cis-1b):

1

(Table 2) H NMR (300 MHz, CDCl₃): δ = 7.45 (m, 1 H), 7.39 (t,

J = 1.8 Hz, 1 H), 6.46 (dd, J = 1.8, 0.9 Hz, 1 H), 6.25 (dd, J =

17.8, 11.2 Hz, 1 H), 6.08 (dd, J = 5.3, 2.8 Hz, 1 H), 5.52 (t, J =

2.5 Hz, 1 H), 5.38 (d, J = 18.0 Hz, 1 H), 5.08 (d, J = 11.4 Hz, 1

H), 4.71 (dd, J = 9.4, 4.0 Hz, 1 H), 3.83 (dq, J = 9.8, 7.1 Hz, 1 H),

3.65 (dq, J = 9.8, 7.1 Hz, 1 H), 2.57–2.47 (m, 1 H), 2.40–2.30 (m,

1 H), 1.22 (t, J = 7.0 Hz, 3 H) ppm. ¹³C NMR (75 MHz, CDCl₃):

δ = 143.0 (CH), 139.3 (CH), 136.0 (CH), 134.6 (C), 128.4 (CH),

126.5 (C), 114.1 (CH₂), 109.1 (CH), 97.5 (CH), 66.6 (CH), 62.4

(CH₂), 31.6 (CH₂), 15.2 (CH₃) ppm.

7-Ethoxy-2-(furan-3-yl)-6-vinyl-2,3,4,7-tetrahydrooxepine

(trans-

1

14b): (Table 3) H NMR (400 MHz, C₆D₆): δ = 7.35 (s, 1 H), 7.13

(t, J = 1.6 Hz, 1 H), 6.25 (dd, J = 17.7, 11.1 Hz, 1 H), 6.24 (s, 1

H), 5.67 (t, J = 5.7 Hz, 1 H), 5.53 (s, 1 H), 5.16 (d, J = 17.7 Hz, 1

H), 5.11 (t, J = 14.3 Hz, 1 H), 4.94 (d, J = 11.0 Hz, 1 H), 3.69 (dq,

J = 9.6, 7.1 Hz, 1 H), 3.31 (dq, J = 9.7, 7.1 Hz, 1 H), 2.33–2.21

(m, 1 H), 2.08–1.96 (m, 2 H), 1.82–1.74 (m, 1 H), 1.05 (t, J =

7.1 Hz, 1 H) ppm. ¹³C NMR (75 MHz, C₆D₆): δ = 143.5 (CH),

140.3 (C), 139.6 (CH), 139.3 (CH), 134.1 (CH), 129.2 (C), 121.7

(CH), 111.8 (CH₂), 109.7 (CH), 99.8 (CH), 67.2 (CH), 64.5 (CH₂),

36.0 (CH₂), 25.3 (CH₂), 15.6 (CH₃) ppm. HRMS (ESI): calcd. for

C₁₄H₁₈Na₁O₃[M + H]⁺257.115; found 257.120.

2-(3,4-Dichlorophenyl)-6-ethoxy-5-vinyl-3,6-dihydro-2H-pyran (1e):

(Table 2) ¹H NMR (300 MHz, CDCl₃): δ = 7.70–7.48 (m, 1.5 H,

mixture of diastereoisomers), 7.47–7.39 (m, 1.5 H, mixture of dia-

stereoisomers), 7.25–7.20 (m, 2 H, mixture of diastereoisomers),

6.30 (dd, J = 17.7, 11.1 Hz, 1 H, maj), 6.25 (dd, J = 17.8, 11.1 Hz,

0.3 H, min), 6.09 (dd, J = 5.6, 3.2 Hz, 0.3 H, min), 5.99 (dd, J =

5.1, 2.9 Hz, 1 H, maj), 5.44 (s, 0.3 H, min), 5.33 (s, 1 H, maj), 5.26

(d, J = 17.7 Hz, 1 H, maj), 5.11 (d, J = 11.61 Hz, 1 H, mixture of

diastereoisomers), 5.01 (dd, J = 10.0, 5.2 Hz, 1 H, maj), 4.23 (dd,

J = 5.9, 3.8 Hz, 0.3 H, min), 3.90 (dq, J = 9.1, 7.1 Hz, 1 H, maj),

3.87 (dq, J = 9.1, 7.1 Hz, 0.3 H, min), 3.67 (dq, J = 9.1, 7.1 Hz, 1

H, maj), 2.43–2.33 (m, 2 H, mixture of diastereoisomers), 1.27 (t,

J = 7.1 Hz, 3 H, maj), 1.25 (t, J = 7.1 Hz, 1 H, min) ppm. ¹³C

NMR (75 MHz, CDCl₃): δ = 142.3 (C), 142.1 (C), 136.1 (CH),

135.2 (CH), 135.04 (CH), 132.5 (C), 131.4 (C), 130.4 (CH), 128.8

(C), 128.1 (C), 128.0 (CH), 127.8 (CH), 125.3 (CH), 125.2 (CH),

113.3 (CH₂), 98.1 (CH), 95.5 (CH), 77.2 (C), 68.1 (C), 67.0 (CH),

63.6 (CH), 62.5 (C), 32.8 (CH₂), 32.7 (CH₂), 15.3 (CH₃), 15.2

(CH₃) ppm. HRMS (ESI): calcd. for C₁₅H₁₆Cl₂NaO₂Na [M +

Na]⁺321.04; found 321,00.

7-Ethoxy-2-(furan-3-yl)-6-vinyl-2,3,4,7-tetrahydrooxepine (cis-14b):

1

(Table 3) H NMR (400 MHz, C₆D₆): δ = 7.25 (s, 1 H), 7.11 (t, J

= 1.6 Hz, 1 H), 6.41 (dd, J = 17.8, 11.0 Hz, 1 H), 6.23 (s, 1 H),

5.78 (t, J = 6.3 Hz, 1 H), 5.34 (d, J = 17.8 Hz, 1 H), 5.30 (s, 1 H),

4.99 (d, J = 11.0 Hz, 1 H), 4.37 (dd, J = 8.8, 5.1 Hz, 1 H), 3.80

(dq, J = 9.3, 7.1 Hz, 1 H), 3.36 (dq, J = 9.0, 7.2 Hz, 1 H), 2.51–

2.41 (m, 1 H), 1.91–1.79 (m, 2 H), 1.66–1.55 (m, 1 H), 1.09 (t, J =

7.1 Hz, 1 H) ppm. ¹³C NMR (75 MHz, C₆D₆): δ = 143.5 (CH),

140.9 (C), 139.3 (CH), 137.7 (CH), 131.8 (CH), 128.7 (CH), 127.7

(C), 112.8 (CH₂), 109.8 (CH), 102.8 (CH), 71.1 (CH), 64.0 (CH₂),

34.0 (CH₂), 24.7 (CH₂), 15.7 (CH₃) ppm. HRMS (ESI): calcd. for

C₁₄H₁₈Na₁O₃[M + H]⁺257.115; found 257.118.

Signals of trace amounts of compound 15b were observed in the

NMR spectra of 14b.

7-Ethoxy-2-phenyl-6-vinyl-2,3,4,7-tetrahydrooxepine

(trans-14a):

2-(3,4-Dichlorophenyl)-7-ethoxy-6-vinyl-2,3,4,7-tetrahydrooxepine

(trans-14e): (Table 3) H NMR (400 MHz, CDCl₃): δ = 7.50 (d, J

= 2.0 Hz, 1 H), 7.39 (d, J = 8.3 Hz, 1 H), 7.19 (dd, J = 8.3, 2.0 Hz,

1

(Table 3) ¹H NMR (400 MHz, C₆D₆): δ = 7.42 (d, J = 8.0 Hz, 2

H), 7.22 (t, J = 7.7 Hz, 2 H), 7.11 (d, J = 7.4 Hz, 1 H), 6.28 (dd,

J = 17.7, 11.2 Hz, 1 H), 5.69 (t, J = 5.6 Hz, 1 H), 5.62 (s, 1 H), 1 H), 6.25 (dd, J = 17.7, 11.2 Hz, 1 H), 5.91 (t, J = 5.7 Hz, 1 H),

5.20 (d, J = 17.7 Hz, 1 H), 5.19 (dd, J = 7.5, 3.1 Hz, 1 H), 4.96 (d,

J = 11.3 Hz, 1 H), 3.64 (dq, J = 9.6, 7.1 Hz, 1 H), 3.28 (dq, J =

9.6, 7.1 Hz, 1 H), 2.35–2.26 (m, 1 H), 2.16–2.08 (m, 1 H), 2.03–

5.52 (s, 1 H), 5.11 (d, J = 17.8 Hz, 1 H), 5.07 (dd, J = 7.2, 3.9 Hz,

1 H), 4.99 (d, J = 11.2 Hz, 1 H), 3.72 (dq, J = 9.8, 7.1 Hz, 1 H),

3.55 (dq, J = 9.6, 7.1 Hz, 1 H), 2.51–2.38 (m, 1 H), 2.33–2.19 (m,

5244

www.eurjoc.org

Eur. J. Org. Chem. 2010, 5232–5247

Ring-Closing of 1,7- and 1,8-Enynes of Propargylic O,O-Acetals

4 H), 1.93–1.83 (m, 1 H), 1.22 (t, J = 7.1 Hz, 1 H) ppm. ¹³C NMR 11.3 Hz, 1 H), 5.01 (app. s, 1 H), 4.90 (t, J = 7.0 Hz, 1 H), 4.76

(75 MHz, C₆D₆): δ = 144.1 (C), 138.8 (C), 138.1 (CH), 133.7 (CH),

(app. d, J = 11.9 Hz, 2 H), 3.45 (dq, J = 9.2, 7.0 Hz, 1 H), 3.34

133.8 (C), 130.8 (C), 128.0 (CH), 125.3 (CH), 111.7 (CH₂), 99.2 (dq, J = 9.2, 7.0 Hz, 1 H), 2.62 (dd, J = 14.2, 7.0 Hz, 1 H), 2.40

(CH), 71.6 (CH), 64.2 (CH₂), 36.3 (CH₂), 29.7 (CH₂), 24.8 (CH₂), (dd, J = 14.2, 7.0 Hz, 1 H), 1.76 (s, 3 H), 1.17 (t, J = 7.0 Hz, 1

15.06 (CH₃) ppm. HRMS (ESI): calcd. for C₁₆H₁₉Cl₂NaO₂[M + H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 143.2 (CH), 142.9 (C),

Na]⁺335.058; found 335.063.

140.4 (C), 135.0 (CH), 125.6 (C), 117.1 (CH₂), 115.3 (CH₂), 113.1

(CH₂), 108.96 (CH), 97.28 (CH), 68.4 (CH), 59.1 (CH₂), 45.06

(CH₃), 29.6 (CH₃) ppm.

2-(3,4-Dichlorophenyl)-7-ethoxy-6-vinyl-2,3,4,7-tetrahydrooxepine

1

(cis-14e): (Table 3) H NMR (400 MHz, CDCl₃): δ = 7.50 (d, J =

2.0 Hz, 1 H), 7.39 (d, J = 8.3 Hz, 1 H), 7.19 (dd, J = 8.3, 2.0 Hz,

1 H), 6.31 (dd, J = 17.7, 11.2 Hz, 1 H), 5.64 (s, 1 H), 5.48 (t, J =

5.7 Hz, 1 H), 5.34 (d, J = 17.8 Hz, 1 H), 4.99 (d, J = 11.2 Hz, 1

H), 4.47 (dd, J = 7.2, 3.9 Hz, 1 H), 3.80 (dq, J = 9.7, 7.1 Hz, 1 H),

3.36 (dq, J = 9.7, 7.1 Hz, 1 H), 2.51–2.38 (m, 1 H), 2.33–2.19 (m,

4 H), 1.93–1.83 (m, 1 H), 1.10 (t, J = 7.1 Hz, 1 H) ppm.

3-[1-(1-Ethoxy-2-methylenebut-3-enyloxy)-3-methylbut-3-enyl]furan

[anti/syn-17b (1:1)]: (Table 4) ¹H NMR (300 MHz, CDCl₃): δ =

7.40–7.35 (m, 2 H), 6.45 (app. s, 0.5 H, one diastereoisomer), 6.38

(app. s, 0.5 H, other diastereoisomer), 6.29 (dd, J = 18.8, 10.9 Hz,

0.5 H, one diastereoisomer), 6.28 (dd, J = 17.8, 11.3 Hz, 0.5 H,

other diastereoisomer), 5.54 (d, J = 17.8 Hz, 0.5 H, one dia-

stereoisomer), 5.45 (d, J = 17.8 Hz, 0.5 H, other diastereoisomer),

5.40 (app. s, 0.5 H, one diastereoisomer), 5.33 (d, J = 12.2 Hz, 0.5

H, other diastereoisomer), 5.26 (s, 0.5 H, one diastereoisomer), 5.13

(d, J = 11.0 Hz, 0.5 H, one diastereoisomer), 5.07 (d, J = 11.3 Hz,

0.5 H, other diastereoisomer), 5.01 (app. s, 0.5 H, one diastereoiso-

mer), 5.00 (app. s, 0.5 H, other diastereoisomer), 4.90 (t, J = 7.0 Hz,

0.5 H, one diastereoisomer), 4.76–4.68 (m, 2 H), 4.55 (t, J = 7.0 Hz,

0.5 H, other diastereoisomer), 3.54 (dq, J = 9.4, 7.0 Hz, 0.5 H, one

diastereoisomer), 3.45 (dq, J = 9.2, 7.0 Hz, 0.5 H, other dia-

stereoisomer), 3.34 (dq, J = 9.2, 7.0 Hz, 0.5 H, one diastereoiso-

mer), 3.32 (dq, J = 9.2, 7.0 Hz, 0.5 H, other diastereoisomer), 2.62

(dd, J = 14.2, 7.0 Hz, 1 H), 2.40 (dd, J = 14.2, 7.0 Hz, 1 H), 1.76

(s, 1.5 H, one diastereoisomer), 1.70 (s, 1.5 H, other diastereoiso-

mer), 1.17 (t, J = 7.0 Hz, 1.5 H, one diastereoisomer), 1.17 (t, J =

7.0 Hz, 1.5 H, other diastereoisomer) ppm.

1,2-Dichloro-4-[1-[1-ethoxy-2-methylenebut-3-enyloxy)pent-4-enyl]-

1

benzene (15e): (Table 3) H NMR (300 MHz, CDCl₃): δ = 7.41 (d,

J = 2.0 Hz, 1 H), 7.39 (d, J = 8.3 Hz, 1 H), 7.16 (ddd, J = 13.6,

8.3, 2.0 Hz, 1 H), 6.28 (dd, J = 17.8, 11.2 Hz, 1 H), 5.82 (mc, 1 H),

5.47–5.41 (m, 2 H), 5.29 (s, 1 H), 5.11–4.97 (m, 4 H), 4.71 (t, J =

6.9 Hz, 1 H), 3.45 (dq, J = 9.4, 7.1 Hz, 1 H), 3.33 (dq, J = 9.4,

7.1 Hz, 1 H), 2.14–2.07 (m, 2 H), 2.05–1.73 (m, 2 H), 1.32–1.14 (m,

3 H) ppm.

6-Ethoxy-4-methyl-2-phenyl-5-vinyl-3,6-dihydro-2H-pyran (trans-

1

16a): (Table 4) H NMR (300 MHz, CDCl₃): δ = 7.43–7.30 (m, 5

H), 6.72 (dd, J = 17.7, 11.4 Hz, 1 H), 5.33 (s, 1 H), 5.26 (d, J =

17.7 Hz, 1 H), 5.18–5.08 (m, 2 H), 3.92 (dq, J = 9.7, 7.1 Hz, 1 H),

3.65 (dq, J = 9.7, 7.1 Hz, 1 H), 2.45 (dd, J = 18.2, 11.5 Hz, 1 H),

2.23 (dd, J = 18.2, 4.2 Hz, 1 H), 1.87 (s, 3 H), 1.27 (t, J = 7.1 Hz,

1 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 142.0 (C), 134.5 (C),

131.0 (CH), 128.4 (2 CH), 127.9 (C), 127.5 (CH), 126.0 (2 CH),

113.0 (CH₂), 96.0 (CH), 68.0 (CH), 63.2 (CH₂), 39.1 (CH₂), 18.6

(CH₃), 15.4 (CH₃) ppm. HRMS (ESI): calcd. for C₁₆H₂₀NaO₂[M

+ Na]⁺267.136; found 267.136.

Synthesis of Enynes 18 and 20

General Procedure for Alkylation (G3): Enynes 18 and 20 were pre-

pared by Snapper and co-workers’ modified procedure.^[11b]The

1-[(1-Ethoxy-2-methylenebut-3-enyloxy)-3-methylbut-3-enyl]benzene alcohol (1 equiv.) was added neat through a syringe to a flask

1

(trans-17a): (Table 4) H NMR (300 MHz, CDCl₃): δ = 7.34–7.28

(m, 5 H), 6.32 (dd, J = 17.6, 11.1 Hz, 1 H), 5.54 (dd, J = 17.8,

1.6 Hz, 1 H), 5.33 (m, 2 H), 5.12 (d, J = 11.4 Hz, 1 H), 4.94 (s, 1

H), 4.71 (br. s, 1 H), 4.63 (br. s, 1 H), 4.51 (t, J = 6.9 Hz, 1 H),

3.49 (dq, J = 9.5, 7.0 Hz, 1 H), 3.19 (dq, J = 9.5, 7.0 Hz, 1 H),

2.64 (dd, J = 13.9, 7.6 Hz, 1 H), 2.38 (dd, J = 13.9, 6.3 Hz, 1 H),

1.66 (s, 3 H), 0.99 (t, J = 7.1 Hz, 1 H) ppm. ¹³C NMR (75 MHz,

charged with NaH (1.5 equiv.) in THF (0.5 ) at 0 °C with vigorous

stirring (5 mmol scale). The mixture was warmed to room temp.

and stirred for 1 h before cooling to 0 °C. 15-Crown-5 (1 equiv.)

was added slowly and the reaction mixture was stirred for 0.5 h at

room temp. After cooling again to 5 °C, neat propargyl bromide

(3 equiv.) was added and the reaction mixture was stirred for 2 h to

completion. The reaction was quenched with ice–water and diethyl

CDCl₃): δ = 142.4 (C), 141.9 (C), 134.4 (C), 128.2 (CH), 128.1 (2 ether. The aqueous layer was extracted with diethyl ether and the

CH), 127.5 (CH), 127.0 (2 CH), 116.9 (CH₂), 115.8 (CH₂), 113.4 combined organics washed with sat. Na₂S₂O₃, water and brine,

(CH₂), 100.4 (CH), 77.2 (CH), 61.4 (CH₂), 46.3 (CH₂), 22.9 (CH₃), dried with MgSO₄, filtered and concentrated in vacuo. Purification

14.9 (CH₂) ppm. MS (ESI): calcd. for C₁₈H₂₄NaO₂[M + Na]⁺

295.37; found 267.38.

of the residue by short-column silica gel chromatography afforded

the enynes as oils.

6-Ethoxy-2-(furan-3-yl)-4-methyl-5-vinyl-3,6-dihydro-2H-pyran

(trans-16b): (Table 4) H NMR (300 MHz, CDCl₃): δ = 7.46 (m, J

1-(Prop-2-ynyloxy)pent-4-enylbenzene (18a): Compound 18a was

prepared following the general experimental procedure G3 starting

from 8a. Purification by flash chromatography gave 1-(prop-2-

1

= 1.4 Hz, 1 H), 7.42 (d, J = 1.9 Hz, 1 H), 6.70 (dd, J = 17.7,

11.3 Hz, 1 H), 6.45 (d, J = 1.9 Hz, 1 H), 5.26 (s, 1 H), 5.17 (d, J =

17.6 Hz, 1 H), 5.11–5.04 (m, 2 H), 3.93 (dq, J = 9.8, 7.1 Hz, 1 H),

3.66 (dq, J = 9.8, 7.1 Hz, 1 H), 2.50–2.45 (m, 1 H), 2.24–2.15 (m,

1 H), 1.87 (s, 3 H), 1.30 (t, J = 7.1 Hz, 1 H) ppm. ¹³C NMR

(75 MHz, CDCl₃): δ = 143.0 (C), 139.3 (C), 134.1 (C), 132.5 (CH),

131.0 (CH), 113.0 (CH₂), 108.9 (CH), 96.0 (CH), 68.2 (CH), 63.2

(CH₂), 43.4 (CH₂), 18.6 (CH₃), 15.4 (CH₃) ppm. MS (ESI): calcd.

for C₁₄H₁₈NaO₃[M + Na]⁺257.11; found 257.22.

1

ynyloxy)pent-4-enylbenzene (18a) as a yellow oil (89%). H NMR

(300 MHz, CDCl₃): δ = 7.23–7.18 (m, 5 H), 5.83 (ddt, J = 17.1,

10.3, 6.6 Hz, 1 H), 5.03 (ddd, J = 17.1, 3.3, 1.7 Hz, 1 H), 4.98 (ddd,

J = 10.4, 3.3, 1.7 Hz, 1 H), 4.85 (d, J = 16 Hz, 1 H), 4.49 (d, J =

7.7, 5.7 Hz, 1 H, 1 H), 4.11 (dd, J = 15.5, 2.4 Hz, 1 H), 3.85 (dd,

J = 15.5, 2.4 Hz, 1 H), 2.41 (t, J = 2.4 Hz, 1 H), 2.21–2.05 (m, 2

H), 2.02–1.90 (m, 1 H), 1.75 (ddt, J = 13.4, 9.2, 6.0 Hz, 1 H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ = 141.1 (C), 138.1 (CH), 128.5 (2

3-[1-(1-Ethoxy-2-methylenebut-3-enyloxy)-3-methylbut-3-enyl]furan CH), 128.1 (C), 127.8 (CH), 126.9 (2 CH), 114.8 (CH₂), 80.2 (CH),

(anti-17b): (Table 4) ¹H NMR (300 MHz, CDCl₃): δ = 7.37 (app. s, 80.0 (C), 73.9 (CH), 55.6 (CH₂), 36.9 (CH₂), 29.9 (CH₂) ppm.

2 H), 6.38 (app. s, 1 H), 6.28 (dd, J = 17.8, 11.3 Hz, 1 H), 5.45 (d,

J = 17.8 Hz, 1 H), 5.40 (app. s, 1 H), 5.26 (s, 1 H), 5.07 (d, J = 239.104.

HRMS (ESI): calcd. for C₁₄H₁₆K₁O [M + K]⁺239.083; found

Eur. J. Org. Chem. 2010, 5232–5247

www.eurjoc.org

5245

D. A. Lanfranchi, C. Bour, B. Boff, G. Hanquet

FULL PAPER

3-[1-(Prop-2-ynyloxy)pent-4-enyl]furan (18b): Compound 18b was

prepared following the general experimental procedure G3 starting

from 8b. Purification by flash chromatography (toluene/cyclohex-

1

cyclohexane) to give 19b in 75%. H NMR (300 MHz, C₆D₆): δ =

7.08 (dd, J = 2.3, 1.2 Hz, 1 H), 6.95 (t, J = 1.7 Hz, 1 H), 6.08 (s, 1

H), 6.06 (dd, J = 18.0, 11.2 Hz, 1 H), 5.49 (t, J = 5.8 Hz, 1 H),

ane, 50:50) gave 1-(prop-2-ynyloxy)pent-4-enylbenzene (18b) as a 4.68 (d, J = 10.9 Hz, 1 H), 4.63 (d, J = 4.3 Hz, 1 H), 4.37 (dd, J =

1

yellow oil (84%). H NMR (300 MHz, CDCl₃): δ = 7.41–7.38 (m,

7.7, 5.2 Hz, 1 H), 4.33 (d, J = 14.9 Hz, 1 H), 3.97 (dq, J = 15.5,

2 H), 6.37 (app. s, 1 H), 5.82 (ddt, J = 17.1, 10.3, 6.6 Hz, 1 H), 5.2 1.5 Hz, 1 H), 2.03–1.83 (m, 2 H), 1.65–1.47 (m, 2 H) ppm. ¹³C

(ddd, J = 17.0, 3.2, 1.6 Hz, 1 H), 4.97 (ddd, J = 10.3, 3.2, 1.6 Hz,

1 H), 4.50 (t, J = 6.7 Hz, 1 H), 4.12 (dd, J = 15.6, 2.4 Hz, 1 H),

3.91 (dd, J = 15.6, 2.4 Hz, 1 H), 2.39 (t, J = 2.4 Hz, 1 H), 2.18–

2.06 (m, 2 H), 2.02–1.90 (m, 1 H), 1.79–1.68 (m, 1 H) ppm. ¹³C

NMR (75 MHz, CDCl₃): δ = 143.6 (CH), 149.7 (CH), 137.9 (CH),

124.9 (C), 114.9 (CH₂), 108.5 (CH), 80.05 (CH), 74.0 (C), 71.8

(CH), 55.13 (CH₂), 35.3 (CH₂), 29.8 (CH₂) ppm. HRMS (ESI):

calcd. for C₁₂H₁₄Na₁O₂[M + Na]⁺229.084; found 229.083.

NMR (75 MHz, CDCl₃): δ = 143.1 (CH), 142.3 (C), 140.3 (C),

139.5 (CH), 138.8 (CH), 133.7 (2 CH), 128.8 (CH), 110.4 (CH₂),

109.6 (CH), 75.3 (CH), 64.6 (CH₂), 33.9 (CH₂), 25.03 (CH₂) ppm.

HRMS (ESI): calcd. for C₁₂H₁₄Na₁O₃[M + Na + O]⁺229.084;

found 239.091.

4-Methyl-2-phenyl-5-vinyl-3,6-dihydro-2H-pyran (21a): Compound

21a was prepared following the general experimental procedure for

the metathesis starting from 20a. After the time indicated in

Scheme 5 (monitored by GC), the reaction mixture was concen-

trated and then directly purified through a short column of silica

(toluene/cyclohexane = 50:50) to give 21a and 22a in 46 and 30%

yields, respectively. ¹H NMR (300 MHz, CDCl₃): δ = 7.40–7.23 (m,

5 H), 6.76 (dd, J = 17.7, 11.5 Hz, 1 H), 5.04 (d, J = 4.0 Hz, 1 H),

4.99 (d, J = 10.4 Hz, 1 H), 2.49–2.41 (m, 1 H), 2.24 (dt, J = 17.4,

2.6 Hz, 2 H), 1.86 (s, 3 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ =

142.3 (C), 131.2 (CH), 130.8 (C), 128.3 (2 CH), 127.5 (CH), 125.8

(2 CH), 111.0 (CH₂), 75.8 (CH), 66.4 (CH₂), 39.3 (CH₂), 18.4

(CH₃) ppm. HRMS (ESI): calcd. for C₁₄H₁₆Li₁O₁[M + Li]⁺

207.136; found 207.139.

1-[3-Methyl-1-(prop-2-ynyloxy)but-3-enyl]benzene (20a): Com-

pound 20a was prepared following the general experimental pro-

cedure G3 starting from 9a. Purification by flash chromatography

(toluene/cyclohexane, 50:50) gave 3-methyl-1-(prop-2-ynyloxy)but-

3-enylbenzene (20a) as a yellow oil (71%). ¹H NMR (300 MHz,

CDCl₃): δ = 7.28–7.18 (m, 5 H), 4.78 (d, J = 11.5 Hz, 1 H), 4.71

(dd, J = 8.4, 5.4 Hz, 1 H), 4.14 (dd, J = 15.8, 2.5 Hz, 1 H), 3.85

(dd, J = 15.8, 2.5 Hz, 1 H), 2.62 (dd, J = 14.4, 8.4 Hz, 1 H), 2.41

(t, J = 2.4 Hz, 1 H), 2.36 (dd, J = 14.4, 5.3 Hz, 1 H), 1.76 (s, 3

H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 142.6 (C), 140.4 (C),

128.4 (2 CH), 127.7 (CH), 126.9 (2 CH), 117.0 (CH₂), 80.3 (CH),

79.6 (C), 74.2 (CH), 55.7 (CH₂), 42.1 (CH₂), 22.4 (CH₃) ppm.

HRMS (ESI): calcd. for C₁₄H₁₆KO [M + K]⁺239.083; found

239.103.

1-[3-Methyl-1-(2-methylenebut-3-enyloxy)but-3-enyl]benzene (22a):

¹H NMR (300 MHz, CDCl₃): δ = 7.39–7.28 (m, 5 H), 6.36 (dd, J

= 17.8, 11.0 Hz, 1 H), 5.25 (d, J = 5.6 Hz, 1 H), 5.17 (d, J = 5.6 Hz,

1 H), 5.05 (d, J = 11.3 Hz, 1 H), 4.76 (d, J = 1.9 Hz, 1 H), 4.07 (d,

J = 1.9 Hz, 1 H), 4.46 (dd, J = 8.0, 5.6 Hz, 1 H), 4.10 (d, J =

12.6 Hz, 1 H), 3.91 (d, J = 13.2 Hz, 1 H), 2.60 (dt, J = 14.1, 8.0 Hz,

1 H), 2.34 (dd, J = 14.2, 5.5 Hz, 1 H), 1.73 (s, 3 H) ppm. ¹³C NMR

(75 MHz, CDCl₃): δ = 142.6 (C), 142.4 (C), 142.2 (C), 136.6 (CH),

128.32 (2 CH), 127.54 (2 CH), 111.1 (CH₂), 114.2 (CH₂), 112.8

(CH₂), 80.5 (CH), 68.0 (CH₂), 46.7 (CH₂), 22.9 (CH₃) ppm.

3-[3-Methyl-1-(prop-2-ynyloxy)but-3-enyl]furan (20b): Compound

20b was prepared following the general experimental procedure G3

starting from 9b. Purification by flash chromatography (toluene/

cyclohexane, 50:50) gave 3-[3-methyl-1-(prop-2-ynyloxy)but-3-

enyl]furan (20b) as a yellow oil (71%). ¹H NMR (300 MHz,

CDCl₃): δ = 7.43–7.40 (m, 2 H), 6.41 (app. s, 1 H), 4.78 (d, J =

11.6 Hz, 1 H), 4.72 (dd, J = 7.9, 6.1 Hz, 1 H), 4.15 (dd, J = 15.8,

2.4 Hz, 1 H), 3.93 (dd, J = 15.9, 2.4 Hz, 1 H), 2.63 (dd, J = 14.3,

7.9 Hz, 1 H), 2.41 (t, J = 2.4 Hz, 1 H), 2.38 (dd, J = 14.5, 6.4 Hz,

1 H), 1.76 (s, 3 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 143.5

(CH), 141.8 (C), 140.7 (CH), 124.7 (C), 112.9 (CH₂), 108.7 (CH),

79.8 (C), 74.1 (C), 70.6 (CH), 55.01 (CH₂), 44.5 (CH₂), 22.6

(CH₃) ppm. HRMS (ESI): calcd. for C₁₂H₁₄K₁O₂[M + K]⁺

229.063; found 229.170.

2-(Furan-3-yl)-4-methyl-5-vinyl-3,6-dihydro-2H-pyran (21b): Com-

pound 21b was prepared following the general experimental pro-

cedure for the metathesis starting from 20b. After the time indicated

in Scheme 5 (monitored by GC), the reaction mixture was concen-

trated and then directly purified through a short column of silica

(toluene/cyclohexane = 50:50) to give 21b and 22b in 32 and 45%

yields, respectively. ¹H NMR (300 MHz, CDCl₃): δ = 7.43 (m, 1

H), 7.41 (t, J = 1.7 Hz, 1 H), 6.76 (dd, J = 17.8, 11.3 Hz, 1 H),

6.45 (dd, J = 1.9, 0.9 Hz, 1 H), 6.45 (dd, J = 2.3, 1.3 Hz, 1 H), 5.02

(d, J = 6.7 Hz, 1 H), 4.97 (d, J = 13.6 Hz, 1 H), 4.56 (dd, J = 10.2,

3.7 Hz, 1 H), 4.38 (dq, J = 14.8, 2.1 Hz, 1 H), 2.57–2.42 (m, 1 H),

2.22 (dt, J = 17.2, 2.6 Hz, 2 H), 1.86 (s, 3 H) ppm. ¹³C NMR

(75 MHz, CDCl₃): δ = 143.2 (CH), 139.2 (CH), 131.2 (CH), 130.2

(C), 126.9 (C), 126.6 (C), 111.0 (CH₂), 108.6 (CH), 68.6 (CH), 65.8

(CH₂), 37.7 (CH₂), 18.4 (CH₃) ppm.

2-Phenyl-6-vinyl-2,3,4,7-tetrahydrooxepine (19a): Compound 19a

was prepared following the general experimental procedure for the

metathesis starting from 18a. After the time indicated in Scheme 4

(GC monitoring), the reaction mixture was concentrated and then

directly purified through a short column of silica (toluene/cyclohex-

1

ane) to give 19a in 86%. H NMR (300 MHz, CDCl₃): δ = 7.40–

7.23 (m, 5 H), 6.33 (dd, J = 17.9, 11.1 Hz, 1 H), 5.94 (t, J = 5.5 Hz,

1 H), 5.02 (d, J = 17.8 Hz, 1 H), 4.95 (d, J = 11.0 Hz, 1 H), 4.80

(dd, J = 7.8, 5.2 Hz, 1 H), 4.69 (d, J = 15.5 Hz, 1 H), 4.35 (d, J =

15.5, 1.8 Hz, 1 H), 2.60–2.47 (m, 1 H), 2.40–2.19 (m, 2 H), 2.02–

1.90 (m, 1 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 142.4 (C),

138.9 (C), 137.3 (CH), 133.7 (CH), 127.2 (2 CH), 126.2 (CH), 124.9

(CH), 109.5 (CH₂), 81.5 (CH), 64.7 (CH₂), 33.8 (CH₂), 24.0

(CH₂) ppm. HRMS (ESI): calcd. for C₁₄H₁₆K₁O₁[M + K]⁺

239.083; found 239.101.

1

3-[3-Methyl-1-(2-methylenebut-3-enyloxy)but-3-enyl]furan (22b): H

NMR (300 MHz, CDCl₃): δ = 7.41 (t, J = 1.8 Hz, 1 H), 7.37 (s, 2

H), 6.44 (d, J = 1.8 Hz, 1 H), 6.36 (dd, J = 17.79, 11.0 Hz, 1 H),

5.65 (d, J = 7.5 Hz, 1 H), 5.23 (d, J = 9.3 Hz, 1 H), 5.21 (s, 1 H),

5.07 (d, J = 11.0 Hz, 1 H), 4.75 (dt, J = 17.2, 1.9 Hz, 1 H), 4.47 (t,

J = 7.0 Hz, 1 H), 4.15 (d, J = 12.5 Hz, 1 H), 3.96 (d, J = 12.6 Hz,

1 H), 2.62 (dd, J = 14.0, 7.5 Hz, 1 H), 2.37 (dd, J = 14.0, 6.4 Hz,

1 H), 1.73 (s, 3 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 143.3

(CH), 142.6 (C), 142.1 (C), 140.2 (CH), 136.6 (CH), 125.9 (CH),

117.3 (CH₂), 114.4 (CH₂), 112.9 (CH₂), 108.8 (C), 72.0 (CH), 67.7

(CH₂), 44.9 (CH₂), 22.8 (CH₃) ppm.

2-(Furan-3-yl)-6-vinyl-2,3,4,7-tetrahydrooxepine (19b): Compound

19b was prepared following the general experimental procedure for

the metathesis starting from 18b. After the time indicated in

Scheme 4 (GC monitoring), the reaction mixture was concentrated

and then directly purified through a short column of silica (toluene/

5246

www.eurjoc.org

Eur. J. Org. Chem. 2010, 5232–5247

Ring-Closing of 1,7- and 1,8-Enynes of Propargylic O,O-Acetals

2003, 68, 3026–3042; b) C. Held, R. Fröhlich, P. Metz, Adv.

Synth. Catal. 2002, 344, 720–727.

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[14] Alcohols 5 and 6c readily decompose in the presence of CSA

without any solvent.

Supporting Information (see also footnote on the first page of this

article): Experimental procedure for the preparation of cycload-

ducts 24 and 26, full analytical data for compounds 5c, 5d, 6, 7a,

1

7b, 8a, 8b, 9a, 10, 24 and 26 and H and ¹³C NMR spectra for 6–

26.

[15] C. O. Kappe, Angew. Chem. Int. Ed. 2004, 43, 6250–6284.

[16] V. Sashuk, K. Grela, J. Mol. Catal. A 2006, 257, 59–66.

[17] The O,O-acetal 1,3-diene below exists as a 1:4 mixture of con-

formers (CDCl₃, C₆D₆, CD₂Cl₂, room temp.), unpublished re-

sults.

Acknowledgments

This research was financially supported by the Centre National de

la Recherche Scientifique (CNRS) (C. B.). The Collectivité Territo-

riale de Corse is kindly acknowledged for providing a research

grant to D. A. L.

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Received: March 4, 2010

Published Online: August 3, 2010

Eur. J. Org. Chem. 2010, 5232–5247

www.eurjoc.org

5247

Article Doi

Ring-closing of 1,7-and 1,8-enynes of propargylic O,O-acetals by ruthenium-catalysed intramolecular metathesis

DOI: 10.1002/ejoc.201000305

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