New indium-mediated cyclisation reactions of tethered haloenynes in aqueous solvent systems

Tetrahedron 62 (2006) 3582–3599

New indium-mediated cyclisation reactions of tethered

haloenynes in aqueous solvent systems

b

Andres Goeta,^aMatthew M. Salter^b,and Hummad Shah

*

^aDepartment of Chemistry, University Science Laboratories, South Road, Durham DH1 3LE, UK

^bDepartment of Chemistry, King’s College London, Strand, London, WC2R 2LS, UK

Received 22 October 2005; revised 26 December 2005; accepted 26 January 2006

Dedicated with great respect to Professor Steven V. Ley on the occasion of his 60th birthday

Abstract—The intramolecular cyclisation of tethered allyl bromides onto terminal alkynes mediated by metallic indium proceeds smoothly

and cleanly in mixtures of THF and H₂O to give unsaturated carbocycles and heterocycles in good yield. Alternatively, the cyclisation may

be carried out in anhydrous THF with the aid of acid catalysis. The reaction is also mediated by a range of indium salts and proceeds with

substoichiometric quantities of indium in the presence of a co-reductant. Deuteration studies show that the reaction proceeds via a concerted

syn carboindination of the carbon–carbon triple bond to give an intermediate, which is protonated in situ.

1. Introduction

In view of the obvious importance of indium-mediated

reactions, it is therefore surprising that the reactions of

organoindium reagents with carbon–carbon and carbo-

heteroatom triple bonds have received comparatively little

attention. In early work, Araki et al. reported the addition

reactions of allylic indium sesquihalides with alkynols¹³and

allenols¹⁴to give (E)-2,5-hexadien-1-ols and (E)-2,6-

heptadien-1-ols, respectively. They showed that the addition

of the organoindium reagent occurs regioselectively in the

anti-Markovnikov mode, which it was proposed arose as a

result of coordination of the intermediate organometallic

species by the hydroxyl group, which directs addition to the

terminal carbon of the alkyne. Subsequently the carboindi-

nation of unactivated terminal alkynes,¹⁵which do not bear

an adjacent hydroxyl group, to give 1,4-dienes via

Markovnikov addition and the carboindination of nitriles

to give enamines¹⁶was reported. Thus, while the synthetic

scope and mechanistic aspects of the intermolecular

carboindination of alkynes and nitriles have received

attention, the corresponding intramolecular carboindination

of alkynes with allyl halides remains is much less well

understood.

In recent years there has been a great deal of interest in the

application of indium to organic synthesis.¹Indium-

mediated Barbier²and Reformatsky-type³reactivity of

organoindium reagents derived from allylic and propargylic

precursors with a wide range of C]O and C]NR derived

functional groups⁴are well-documented, and the synthetic

utility of these methods has been demonstrated in the

synthesis of a number of pharmaceutical and natural

products.⁵The addition reactions of allylic indium reagents

to carbonyl-derived electrophiles proceed with high

diasteroselectivity via predominantly g-addition of the

organometallic, although the ratio of a:g-addition has

been found to be dependent on solvent.⁶Additionally,

indium-mediated methodology has also been extended to

take in a wide range of transformations including Michael

additions,⁷indium hydride⁸and dissolving metal

reductions,⁹and Pd(0) catalysed cross-coupling reactions

of organoindium reagents.¹⁰Additionally, indium reagents

have been used to facilitate radical cyclisation¹¹and atom

transfer cyclisation reactions.¹²

In the intramolecular reaction manifold, a number of

potential reaction pathways may be considered. For

example, it may be reasoned that exposure of tethered

haloenynes 1 (XZO, NR, CR¹R²) to indium metal would

give the corresponding allylindium species 2a which could

exist in equilibrium with the endo isomer 2b. Furthermore,

Keywords: Indium; Cyclisation; Aqueous; Enyne; Carbocycle;

Heterocycle.

*

Corresponding author. Address: Graduate School of Pharmaceutical

Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033,

Japan. Tel.: C81 3 5841 4794; fax: C81 3 5684 0634;

e-mail: matthew.salter@kcl.ac.uk

doi:10.1016/j.tet.2006.01.094

A. Goeta et al. / Tetrahedron 62 (2006) 3582–3599

3583

Hal

In(0)

X

1

[In]

X

2a

2b

Pathway A

Protonolysis

Pathway B

H

m

n

m

X

n

X

3a

4a

4b

3b

Scheme 1. Possible pathways for the reaction between indium and haloallylalkynes.

such intermediates could be expected to react by (i) a

process of carboindation of the alkyne triple bond by either

a Markovnikov (pathway A) or anti-Markovnikov (pathway

B) route to give the corresponding exo 1,4-dienes 3a or endo

1,3-dienes 3b, respectively¹⁷or (ii) proteodebromination of

the organometallic (for example, on workup) to give either

the crotyl 4a or allylic species 4b. At the outset of our work,

it was not clear whether the cyclisation reaction was

possible or whether the pathway of proteodebromination

would predominate (Scheme 1).

is greatly enhanced by the addition of water to the reaction

solvent.

2. Results and discussion

2.1. Initial approaches to the indium-mediated

cyclisation reaction

The ﬁrst substrate chosen for investigation was the parent

bromoenyne, (E)-1-bromobut-2-ene-4-ol propargyl ether

7a, which may be readily synthesized from propargyl

alcohol and trans-1,4-dibromobut-2-ene. In a typical

procedure 7a and indium powder (1 equiv) were suspended

in the appropriate solvent and stirred at room temperature or

reﬂux for 12–21 h, before being subjected to standard

aqueous acidic workup (Table 1).

We herein report¹⁸that a broad range of bromooct-6-en-1-

ynes 5 undergo smooth cyclisation at room temperature in

the presence of indium metal via pathway A to give exo-1,4

carbocyclic and heterocyclic dienes 6 cleanly (Scheme 2).

Whilst the cyclisation of enynes to ﬁve-membered

carbocycles and heterocycles under the inﬂuence of a

range of transition metals has been previously demon-

strated¹⁹these procedures often necessitate the use of

expensive catalysts and/or ligands, which are often moisture

and air sensitive or must be prepared in situ immediately

prior to use. In contrast, not only is the method discussed in

the current submission robust, operationally simple and

relatively inexpensive, in fact the efﬁciency of the reaction

Initial results using these conditions were not encouraging.

Neither stirring an equimolar mixture of 7a and indium

powder in dry THF (entry 1) or dry DMF (entry 2) under an

N₂atmosphere at room temperature led to the formation of

the desired cyclised product but only to recovery of

unchanged starting material. Heating the reaction to reﬂux

in dry THF in line with the protocol reported for the

corresponding intermolecular reaction¹⁵also failed to yield

any of the cyclised product 8a (entry 3). However, to our

delight when the reaction was carried out in a 1:1 mixture of

THF/H₂O overnight, followed by mild protolytic workup,

the desired 3-vinyl-4-methylenetetrahydrofuran 8a was

obtained in 62% yield (entry 4) as a single product. This

result represents the ﬁrst example of an intramolecular

carboindination of alkynes, and is testament to the profound

effect that the addition of water is known to have on

In (1eq), rt

Hal

X

THF:H₂O (1:1)

X

5

6

Hal=Br, I

X=C(CO₂R), C(CN)₂, NR, O

Scheme 2. Indium-mediated cyclisation of tethered terminal

haloallylalkynes.

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A. Goeta et al. / Tetrahedron 62 (2006) 3582–3599

Table 1. Initial approaches to the In-mediated cyclisation

In (1eq), rt

Solvent

Br

X

Additive

X

7 or 9

Solvent

8 or 10

Entry

Haloenyne

X

Additive

t/h

Product

Conversion/%^a

1

2

3

4

5

6

7

8

9

10

7a

9a

O

THF (dry)

DMF (dry)

THF (dry)^b

THF/H₂O^c

THF (dry)^b

THF/H₂O^c

THF (dry)

—

14

12

14

16

21

17

—

8a

0

O95 (62)

Trace

O95 (74)

O95 (80)

72 (35)

65 (–)^e

15 (–)

C(CO₂Me)₂

—

10a

10

TFA (0.1 equiv)

4.5

AcOH^d(0.2 equiv)

PhCO₂H (0.15 equiv)

10-CSA^f(0.15 equiv)

16

20

17

^aConversion estimated from ¹H NMR. Isolated yields given in parentheses.

^bReaction heated at reﬂux.

^c1:1 ratio.

^dGPR glacial acetic acid.

^eProduct not isolated.

f

Dried by azeotroping from toluene.

the rate,²⁰as well as the stereo-²¹and regioselectivity²²of

indium-mediated reactions.²³

We also screened a number of aqueous and non-aqueous

solvent systems for the cyclisation of 9a to the carbocycle

10a and the conversion of the reaction was established by

1

Encouraged by this result we decided to examine the

possibility of using a substrate bearing a geminal diester

group in the hope of utilising the Thorpe–Ingold effect²⁴to

promote the cyclisation. To this end we prepared dimethyl

2-((E)-4-bromobut-2-enyl)-2-(prop-2-ynyl)malonate 9a in

one step from commercially available dimethyl-2-

(propynyl)malonate. Unsurprisingly, heating this new

substrate with indium metal in dry THF at reﬂux gave

only a trace of the desired heterocycle (entry 5).

Gratifyingly however, exposure of 9a to indium metal in

THF/H₂O (1:1) at room temperature afforded the corre-

sponding carbocyclic exo-1,4 diene 10a with O95%

conversion and in 74% isolated yield (entry 6). Interest-

ingly, it was found that the cyclisation could be effected in

dry THF by the addition of a catalytic amount of an

anhydrous organic acid to the reaction mixture (entries

7–10). Although most common laboratory acids promoted

the reaction to some degree, the efﬁciency of the cyclisation

was related to the strength of the acid added, best results

being obtained with TFA (80% yield, 4.5 h). The exact

function of the acid in the reaction is still unclear although it

is possible that, at the very least, the acid acts to remove any

oxide on the surface of the indium thus rendering it more

reactive.

inspection of the H NMR spectra of the crude reaction

mixture. These studies showed that the cyclisation reaction

proceeds to some extent in most common laboratory

solvents (THFODMFOH₂OzMeOH[Et₂OzEtOAc,)

but that in all cases the conversion was improved by

conducting the reaction in a 1:1 mixture of the organic

solvent and H₂O. The best conversions and yields of the

carbocycle were obtained in THF/H₂O (1:1), although it

was possible to reduce the amount of THF to approxi-

mately 9% (THF/H₂O 1:10) without serious detrimental

effect on the conversion of 9a to 10a. The reaction was also

found to proceed in pure H₂O although the conversion

dropped to 75–80%, which may in part be due to the

insolubility of the substrate in a completely aqueous

environment.

2.2. Synthesis of other haloallyl alkyne cyclisation

precursors

The initial results described above prompted us to probe

further the scope of the indium-mediated cyclisation of

terminal haloenynes. To this end, we prepared three

groups of substrates in which the allylic halide and

alkyne were linked by an oxygen, nitrogen or carbon

atom. The heteroatom-tethered substrates 7a–d (Table 2,

XZO) and 11a–e (Table 2, XZNR) were prepared as

shown below from common starting materials in

moderate yields by allylation of the sodium salt of

propargyl alcohols 12a–d or N-protected propargyl

amines 13a–e with (E)- or (Z)-1,4-dibromo-2-butene in

moderate yields (Table 2). In some cases, the reaction

was promoted using a Pd(0) catalyst in accordance with

literature protocols.²⁵

The cyclisation reactions in THF/H₂O were extremely

clean. Inspection of the H NMR spectrum of the crude

1

reaction mixture shows only peaks corresponding to the

desired cyclic compound along with those of small amounts

of residual starting material. The success or failure of the

reactions in THF/H₂O can be conveniently assessed by

observing the state of the crude reaction mixture prior to

work-up. Appearance of a thick white precipitate of In(OH)₃

is normally indicative that the transformation has proceeded

smoothly. Typically the reaction mixture also contains a

metallic residue, which is approximately 25–30% of the

weight of the indium added to the reaction.

The carbon-tethered cyclisation substrates 9a–h were

synthesised in a similar manner, either from commercially

available active methylene compounds 14a–e (Table 3) or,

A. Goeta et al. / Tetrahedron 62 (2006) 3582–3599

Table 2. Synthesis of heteroatom-centered cyclisation precursors

3585

R

i. NaH, THF, 0˚C

Br

XH

12 or 13

12/13^a

X

R

Br

ii.

Br

Pd(0) cat.65˚C

7 or 11

Entry

X

R

Product/(% yield)

1

2

3

4

5

6

7

8

9

10

12a

12b

12c

12d (E)

12d (Z)

13a

13b

13c

O

H

7a (34)

7b (30)

7c (38)

7d (E) (37)

7d (Z) (33)^b

11a (34)^c

11b (35)^c

11c (46)

11d (63)

11e (37)

Ph

ⁿPr

ⁿPen

H

O

NTs

NBoc

NCbz

NBn

ⁿPen

H

13e

13g

^a(E)-geometry unless otherwise stated.

^bO97% (Z).

Reaction carried out in the presence of 5 mol% Pd (dba)₃C5 equiv (wrt Pd) PPh₃prepared by stirring in degassed reaction solvent for 1 h at rt then added via

cannular to the reaction mixture.

c

2

in the case of mixed ester/amide substrates 14f–h, from the

corresponding amide, which was in turn prepared in good

yield by treatment of commercially available ethyl malonyl

chloride with the appropriate amine in CH₂Cl₂–H₂O.

gem Dinitrile substrate 9i which was synthesised from

propargyl malononitrile 16 which itself was prepared by

dehydration of diamide 17, prepared from commercial

dimethylpropargyl malonate 15a (Scheme 3).²⁶

Table 3. Synthesis of carbon-centred terminal haloallylalkynes

i. NaH, THF, 0˚C

X

i. NaH, THF, 0˚C

Y

CO₂R

Y

ii. (E )- or (Z )–

ii.

Br

Y

CO₂R

15a-h

Br

14a-h

9a-h

Entry

14^a

R

Y

15/(%)

9/%^a

1

2

3

4

5

6

7

14a

14b

14c

14d

14e

14f

Me

Et

CO₂Me

CO₂Et

CO₂Me

^tBu

15a^b

9a (E) (53)

9a (Z) (47)^c

9b (18)^d

9c (17)^d

15a^b

15b (–)

15c (–)

15d (–)

15e (–)

15f (32)

^tBu

Me

Et

9d (27)^d

9e (49)^d

9f (37)

SO₂Ph

CONMe₂

O

8

9

14g

14h

Et

15g (52)

15h (48)

9g (38)

9h (32)

C N

O

C N

O

^a(E)-isomer unless otherwise stated.

^bPurchased from commercial sources.

^c(Z)/(E) ratio 94:6.

^dYield from 14 over 2 steps.

i. NaH, THF, 0˚C

ii. (E )-

X

Br

X

NC

CN

Pd₂(dba)₃(1mol%)/Ph₃P

X=CO₂Me 15a

NH_3(aq)

9i (33%)

X=CONH₂16 (87%)

X=CN 17 (88%)

TFAA

DCM

Scheme 3. Synthesis of 2-(4-bromobut-2-enyl)-2-(prop-2-ynyl)malononitrile 9i.

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A. Goeta et al. / Tetrahedron 62 (2006) 3582–3599

2.3. Investigation of the scope of the indium-mediated

cyclisation reaction

The cyclisation reaction of the carbon-centred substrates

was also investigated using the precursors described above

(Table 5). Gratifyingly it was found that in nearly all

cases the substrates 9a–9i also underwent smooth indium-

mediated cyclisation in aqueous THF to give the

corresponding cyclopentyl dienes 10a–10i in moderate

to good yield. The only exception was the geminal di-tert-

butyl enyne 9d which did not give the expected

carbocycle on treatment with indium. In this case, a

complex reaction mixture was obtained from which two

compounds, tentatively assigned as the lactones 19 and

20, were isolated in low yield.²⁸In all other cases the

cyclisation of the substrates proceeded very cleanly

without the need for any additives to give the

corresponding hetero- or carbocycle as essentially the

only organic product.²⁹As with the oxygen and nitrogen-

tethered series, the cyclisation reaction proceeded equally

efﬁciently starting with either 9a(E)- (entry 1) or 9a(Z)-

(entry 2), or a mixture of both isomers of 9a (entry 3).

Having synthesised the desired substrates, our attention

turned to establishing the scope of the intramolecular

carboindination reaction. To this end the heteroatom-

tethered haloallylalkynes 7a–d and 13a–e were stirred

with indium powder (1 equiv) in THF/H₂O (1:1) at room

temperature for 15–18 h before being submitted to mild

acidic work up and puriﬁcation. As shown in Table 4, the

oxygen-tethered substrates 7a–d underwent smooth cycli-

sation to give the corresponding exo-diene tetra-

hydrofurans 8a–d in moderate to acceptable yield and

with a small preference for the syn diastereomer²⁷in the

case of substrates bearing a substituent in the a-position

(entries 2–5). The (E)/(Z) geometry of the allylic fragment

exerts little inﬂuence on the stereochemical course of the

reaction, as both the (E)- and (Z)-allyl bromide of 7d

undergo smooth cyclisation to give exo diene tetra-

hydrofuran 8d (entries 4 and 5). It is noteworthy that

although the diastereoselectivity of this reaction was

modest, the degree of selectivity and the sense of

selectivity (i.e., syn rather than anti) was the same

regardless of the geometry of the allylic group in the

starting material.

O

CO₂R

O

19 (R=^tBu)

20 (R=H)

Nitrogen-tethered substrates 13a–e bearing common

protecting groups the such as 4-toluenesulfonyl (13a–b,

XZNTs, entries 6 and 7), tert-butoxycarbonyl (13c, XZ

NBoc, entry 8) and benzyloxycarbonyl (13d, XZNCbz,

entry 9) also underwent smooth, clean cyclisation to

afford the corresponding pyrrolidines in relatively good

yield. One exception was the N-benzyl derivative (13e,

XZNBn, entry 10), which decomposed under the

reaction conditions, possibly by intramolecular S_N2⁰

attack of the nucleophilic nitrogen at the allylic position

assisted by Lewis acidic nature of the allylindium

intermediate.

In contrast to the heterocyclic series, the stereoselectivity

of the cyclisation of substrates that gave diastereomeric

products was poor (entries 5, 7–11) and it was generally

not possible to separate the individual diastereomers or

assign their syn or anti character with certainty by

NOESY spectroscopy. However, unambiguous conﬁr-

mation of the structure of the carbocyclic products was

obtained by single-crystal X-ray analysis of 9h (Fig. 1)³⁰

which was one of of the few cyclic products obtained as

a microcrystalline solid, the remainder being isolated as

clear, viscous oils.

Table 4. Cyclisation of heteroatom-tethered haloenynes

H

In powder (1 eq)

THF:H₂O (1:1), rt

Br

R

X

R

X

7 or 11

8 or 18

Entry

Haloenyne^a

X

R

t/h

Product/(%)^b

syn/anti^c

1

2

3

4

5

6

7

8

9

10

7a

7b

7c

7d (E)

7d (Z)^e

13a

13b

13c

O

H

16

17

16

17

16

15

17

8a (62)

8b (50)

8c (56)

8d (52)

8d (45)

18a (62)

18b (83)^c

18c (69)

18d (66)

18e (0)^g

—

Ph

ⁿPr

ⁿPen

H

2:1^d

3.5:1^d

3:1^d

3.6:1

—

O

NTs

NBoc

NCbz

NBn

ⁿPen

H

dr 14:1^f

—

13d

13e

—

^a(E)-isomer unless otherwise stated.

^bIsolated yields after chromatography.

^cIsomers assigned by analogy to 8d.

^dsyn/anti ratios provisionally assigned by ¹H NOESY spectral analysis of mixture of diastereomers.

^e95:5 (Z)/(E) ratio of isomers.

f

syn/anti isomers could not be identiﬁed.

^gDecomposition/polymerisation only observed.

A. Goeta et al. / Tetrahedron 62 (2006) 3582–3599

3587

Table 5. Cyclisation of carbon-tethered haloenynes

H

In powder (1 eq)

Br

THF:H₂O (1:1), rt

R¹R²

9a-h

10a-h

Entry

Haloenyne^a

R¹

R²

t/h

Product/(%)^b

dr^c

1

2

3

4

5

6

7

8

9a

9a (Z)^d

CO₂Me

CO₂Et

CO₂Me

CO^t₂Bu

SO₂Ph

CO₂Me

CO₂Et

17

16

17

18

16

17

16

18

10a (74)

10a (75)

10a (74)

10b (71)

10c (56)

10d (0)

—

1:1

—

4.5:1

1.3:1

9a (E)/(Z)^e

9b

9c

9d

9e

9f

CO^t₂Bu

CO₂Me

CO₂Et

10e (44)

10f (84)

CONMe₂

O

9

9g

CO₂Et

17

10g (77)

1:1

C N

O

10

11

9h

9i

CO₂Et

CN

17

10h (63)

10i (49)

1.3:1

—

C N

O

CN

^a(E)-isomers (O99%) unless otherwise stated.

^bIsolated yields after chromatography.

^csyn and anti diastereomers could not been conclusively distinguished by NOESY NMR.

^d94:6 (Z)/(E) mixture of alkene isomers.

^e67:33 (E)/(Z) mixture of alkene isomers.

2.4. Effect of the allylic precursor on the cyclisation

reaction

chloro analogue 22 was almost completely inert to the

reaction conditions³¹(entry 2) even in the presence of NaBr

(entry 3), although NaI (entry 4) or KI (entry 5) were more

effective in promoting the reaction. The corresponding allyl

mesylate 23 (3:2 cis/trans mixture) was similarly inert

(entry 6) but could also be made to undergo smooth

cyclisation in aqueous THF by the addition of KI (entry 7).

We also investigated the inﬂuence of the nature of the allylic

precursor on the course of the reaction. Although the (E)-

allyl bromides were used as the precursors of choice due to

their ready availability we found that the (E)-iodo analogue

21, which could be prepared in 79% yield from dimethyl 2-

((E)-4-bromobut-2-enyl)-2-(prop-2-ynyl)malonate 9a by

treating it with NaI (5 equiv) in acetone, also underwent

efﬁcient indium-mediated cyclisation under standard con-

ditions to give carbocycle 10a in O95% conversion and

73% isolated yield (Table 6, entry 1). By contrast, the (E)-

2.5. Inﬂuence of the nature of the indium reagent on the

cyclisation reaction

Having demonstrated the viability of the indium mediated

cyclisation of terminal haloallylalkynes we wished to

investigate the scope of the reaction with respect to the indium

reagent. Accordingly a number of indium reagents were

screenedfor their efﬁciencyinpromotingthecyclisation of9a.

In a typical procedure the indium was added as In(0) powder

(1 equiv, 99.99 atom% In) (Table 7, entry 1), a procedure

which afforded the carbocyclic product in 75%. We found

that the amount of indium could be reduced to 0.67 equiv

without compromising yield (entry 2) but that the use of

smaller amounts (entries 3 and 4) led to a reduction in the

efﬁciency of reaction, giving lower conversions in direct

proportion to the amount of indium added. A combination of

sub-stoichiometric indium metal and excess manganese

failed to turn the reaction over (entry 5).³²

It was found that presenting the indium as wire (entry 6),

2–5 mm shot (entry 7) or 0.5 mm foil (entry 8) had a

marginally detrimental effect on yield presumably due to the

greatly reduced surface area of these forms relative to

Figure 1. X-ray structural analysis of carbocycle 9h.

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A. Goeta et al. / Tetrahedron 62 (2006) 3582–3599

Table 6. Scope of the allylic precursor

In powder

X

THF:H₂O (1:1), rt

MeO₂C

CO₂Me

MeO₂C

10a

CO₂Me

Additive

21-23

Entry

Haloenyne

X

Additive

Conversion 10a/(%)^a

1

2

3

4

5

6

7

21

22

23

I

Cl

OMs

—

O95 (75)

17 (–)^b

12 (–)^b

80 (–)^b

50 (14)

0^c

NaBr (2 equiv)

NaI (5 equiv)

KI (5 equiv)

—

KI (5 equiv)

97 (71)

^aIsolated yield in parentheses.

^bProduct not isolated.

^cApprox. 8% of the corresponding allyl alcohols arising from hydrolysis of the starting mesylate was observed.

Table 7. Use of different indium sources for the cyclisation reaction

Indium reagent

+

9a

Br

THF:H₂O (1:1), rt

CO₂Me

Additive

MeO₂C

CO₂Me

MeO₂C

10a

CO₂Me

9a

24

Entry

In source

Mol% In

Additive

t/h

Yield 10a/%

Ratio 10a:9a:24^a

1

2

3

4

5

6

7

8

In(0) powder

In(0) wire^c

In(0) shot^e

In(0) foil^f

None

100

67

50

10

—

17

16

18

15

17

18

17

18

17

16

17^j

17

18

16

17

18

16

75

73

95:5:0

75:25:0

51:49:0

10:90:0

!5:95:0

64:36 (21)^d:0

94:6:0

b

—

b

—

b

10

Mn (5 equiv)

—

100

—

100

10

100

50

71

63

0

53

34

0

80:20:0

9

Ga (1 equiv)

—

0:100 (90)^g:0

69:21(18)ⁱ:0

66:34 (15)ⁱ:0

0:100 (95)^g:0

0:100 (80)^g:0

0:100:0

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

InBr^h

InI^h

InBr₃

InCl₃

0

In(OH)₃

InBr₃

—

Zn (5 equiv)

Zn (2 equiv)

Zn (1 equiv)

Mn (5 equiv)

Mg (5 equiv)

Ga (3 equiv)

Al (3 equiv)

Fe (3 equiv)

Zn (5 equiv)

72

44

17

87:0:13

13:77:0

24:0:76 (79)^k

50:0:50

0:100:0

b

—

0

62

0:100:0

0:10 0:0^l

0:100:0

InBr₃

InCl₃

64:0:36

^aEstimated from ¹H NMR.

^bNot isolated.

^c99.99% In cut into approx. 1 mm lengths.

^dIsolated yield in parentheses.

^e2–5 mm shot (99.99C% In).

f

99.99% In cut into 1–2 mm squares.

^gRecovered starting material yield in parentheses.

^h99.99% InX beads crushed to powder.

i

Starting material recovered as 2:1 mixture of iodo- and bromo isomers (16% total recovery).

Dry THF only used as solvent.

j

^kIsolated yield in parentheses.

l

Some hydrolytic decomposition observed.

A. Goeta et al. / Tetrahedron 62 (2006) 3582–3599

3589

indium powder. In addition, the comparative softness of

indium metal also meant that adding it in any form other

than a ﬁne powder (which is light enough to be suspended in

the solvent) often resulted in it being ﬂattened into a

‘mirror’ on the inside of the ﬂask. The same problem was

experienced with gallium metal, which did not promote the

reaction at all (entry 9).

the In(III) source in the presence of zinc dust (5 equiv)

did facilitate the cyclisation reaction, however, whilst

conversion of the starting allylbromoalkyne was in line

with other methods much higher quantities of the

proteodebrominated by-product 24 was generated.

The failure of more highly oxidised salts alone to facilitate

the cyclisation is unsurprising in view of the likely

sesquihalide nature of the organoindium intermediate

which may be assumed to develop in this type of reaction.³⁴

The generation of such an intermediate from the allyl halide

would require formal oxidative addition of the indium

reagent to the substrate, which would be possible for both

In(0) and In(I) but would not be possible for In(III) species.

In addition to elemental indium, the reaction was found

to proceed in the presence of indium salts. Use of InBr

(entry 10) and InI (entry 11) in aqueous THF promoted the

cyclisation but under these conditions the reaction was more

capricious than with In(0) and proceeded with lower

conversions and in poorer chemical yield. Additionally in

the case of InI the product mixture also contained 2-((E)-4-

iodobut-2-enyl)-2-(prop-2-ynyl)malonate 19 as well as the

carbocyclic product and unreacted allyl bromide starting

material. It should be noted that when using indium(I) salts,

it was essential to crush the reagent to a powder before

addition due to the poor solubility of In(I) in the reaction

medium.

2.6. Deuteration studies aimed at elucidating the

mechanism of the cyclisation reaction

Whilst the synthetic scope of the indium-mediated

cyclisation had been established, a number of the

mechanistic aspects of the reaction remained unexplored.

For example, it was still not known whether the addition of

the allyl bromide fragment to the alkyne proceeded by

regioselective syn or anti carboindination of the carbon–

carbon triple bond or by another, non-regioselective,

pathway. Furthermore, it was also unclear whether the

protonation of the organindium intermediate generated on

cyclisation of the precursor takes place during the reaction,

or occurs on acidic work-up. In order to investigate

the protonation process a deuteration study of the

indium-mediated cyclisation reaction of (E)-9a was carried

out (Table 8).

More highly oxidised In(III) salts such as InBr₃(entry 12),

InCl₃(entry 13) or In(OH)₃(entry 14) did not promote

cyclisation; the unreacted starting bromide being the only

species present in the crude reaction mixture as determined

by ¹H NMR spectroscopy. Whilst InX₃salts alone were not

effective reagents for the transformation, the use of a co-

reductant such as zinc (entry 15) with InBr₃(1 equiv) to

generate a reduced indium species in situ afforded the

carbocyclic product smoothly and cleanly in essentially the

same yield as that obtained with In(0) powder. Signiﬁcantly,

it was found that under these conditions the reaction could

be made to turn over even in the presence of substoichio-

metric quantities of InBr₃(0.1 equiv)³³(entries 16–18)

although both the conversion and isolated yield of the

carbocycle was dramatically reduced. In all cases where

InBr₃was used to mediate the reaction, proteodebrominated

product 24 was also generated in varying amounts. A

number of co-reductants in addition to zinc were screened

(entries 20–23) but none were found to be effective in

promoting the reaction. Use of the cheaper InCl₃as

Firstly, 9a was allowed to react with indium in a mixture of

dry THF/H₂O (1:1) under a N₂atmosphere for 16 h

whereupon the reaction mixture was evaporated to dryness

in vacuo. The resulting milky-white solid was suspended in

diethyl ether and treated with 18% DCl in D₂O (99.99

atom% D), stirred at room temperature for 5 min and then

the mixture was partitioned between diethyl ether and water,

and the organic layer was washed with brine and then dried

(MgSO₄). The ¹H NMR spectrum of the residue obtained on

Table 8. Deuterium labling studies

R

X

Y

In powder (1 eq)

Br

solvent, rt,16-18h

MeO₂C

CO₂Me

MeO₂C

CO₂Me

9a or 9a-d₁

(Z ) / (E ) 10a-d₁

or 10a

Entry

R

Solvent^a

Work-up

Conversion (%)^b

X

Y

1

2

3

4

H

THF/H₂O

THF/D₂O

THF/H₂O

d₈-THF/H₂O

18% DCl/D₂O

15% HCl_(aq)

O95 (65)

O95 (50)

O97 (86)

O95 (73)

H

D^c

H

D^d

H

D^d

H

^a(1:1) mixture of solvents.

^bEstimated from ¹H NMR. Isolated yield in parentheses.

^c90% incorporation.

^d50% incorporation.

3590

A. Goeta et al. / Tetrahedron 62 (2006) 3582–3599

ﬁltration and removal of solvent showed that cyclisation had

occurred as expected but that no deuterium had been

incorporated into the product (Table 8, entry 1). The

procedure was repeated using dry THF/D₂O (1:1) as solvent

and the reaction was worked up according to the method

described above except that 15% HCl in H₂O was used to

quench the reaction. Signiﬁcantly, the cyclised product

generated under these conditions contained an atom of

deuterium at the terminal end of the 1,1-disubstituted

exocyclic alkene generated by carboindination of the alkyne

moiety (entry 2). The geometry of the newly-formed double

bond in (Z)-10a–d₁was established by NOESY spec-

troscopy. No incorporation into the (E) position was

observed. Interestingly, deuterated haloallylalkyne 9a–d₁

in which the acetylinic proton has been replaced with

deuterium (50%) also underwent smooth reaction with In(0)

in THF/H₂O to give the cyclised product (E)-10a–d₁with

essentially quantitative conversion and in 86% isolated

yield with no loss of deuterium (entry 3). No scrambling of

the deuterium into the (Z)-position was observed. Unsur-

prisingly, the use of d₈-THF/H₂O as the solvent followed by

HCl_(aq)work-up did not lead to the incorporation of

deuterium into the product (entry 4).

the possibility that the reaction proceeds via an acetylinic

indium species, an observation that is consistent with

the mechanism for the intermolecular addition of organoin-

dium reagents to aliphatic terminal alkynes.^16b

2.7. Cyclisation of non-terminal haloallyl alkynes in

THF/H₂O (1:1)

Whilst terminal haloenynes undergo indium-mediated

cyclisation under mild conditions in aqueous solvent

systems without the need for additives, attempts to extend

this methodology to the cyclisation of non-terminal

haloallyl alkynes were largely unsuccessful. Exposure of

non-terminal gem-diester haloallylalkyne 25 or 26 to indium

metal in THF/H₂O (1:1) at room temperature did not lead to

the generation of either of the desired carbocyclic products

30 or 31 but instead gave the corresponding proteode-

brominated materials (Table 9, entries 1 and 2) as the major

product of the reaction. Attempts to effect the cyclisation of

25 by generation of a more active indium species by in situ

reduction of InBr₃(1 equiv) with Zn (5 equiv) also met with

failure (entry 3). Addition of KI either in THF/H₂O (1:1) or

DMF/H₂O (1:1) did not improve matters. Indeed, it was

necessary to move to much more forcing conditions (DMF,

100 8C, entry 5) to effect the cyclisation of non-terminal

alkyne systems 25, 26 (entries 4 and 5).³⁵

These results indicate that the protonation (deuteration)

event in the cyclisation occurs as the reaction cycle is

turning over and not at the time of the protolytic

(deuterolytic) work-up. It follows therefore that an organic

and/or inorganic indium hydroxide (deuteroxide) species is

present in the mixture during the reaction cycle. Further-

more, the exclusive (Z)-geometry of the newly-formed

exocyclic alkene strongly suggests that the reaction

proceeds via a syn-selective concerted carboindination of

the alkyne, a postulate that is reinforced by the observation

that the d₁-alkyne substrate undergoes cyclisation to give

exclusively the (E)-deuterated carbocylic product. The fact

that this latter transformation proceeds without the integrity

of the alkynic deuterium atom being compromised rules out

2.8. Intramolecular carboindination of non-terminal

haloenynes

Although unactivated non-terminal alkynes proved inert

to cyclisation using the aqueous protocol, electron-poor

haloallyl alkyne 27 underwent smooth and clean cyclisa-

tion to give the corresponding carbocycle 32 in good yield

(Table 9, entry 6). It is reasonable to suggest that the

greatly altered electronic nature of 27 compared with that

of 25 or 26 in which the alkyne triple bond is essentially

unpolarised, shifts the mechanism of the reaction from an

Table 9. Cyclisation of non-terminal bromoenynes

R

+

In (1eq)

Conditions A or B

Br

X

25-29

30-34

Cyclic product

Alkene product

Entry

Enyne

X

R

In source

In(0)

InBr₃/Zn

In(0)

Conditions^a

Product

Cyclic/alkene^b

1

2

3

4

5

6

7

8

25

26

25

26

25

27

28

29

C(CO₂Me)₂

O

Me

Ph

Me

Ph

A

30

31

30

31

30

32

33

34

0:88(59)^c

0:100(66)

0:100(84)

91(85):9^d

89(65):11

95(65)^e:5

40(30):60

A

B

A

Me

CO₂Me

Ph

f

O

ⁿPr

—

^aConversion estimated from ¹H NMR. Isolated yields in parentheses.

b

2

Condition A: THF/H O (1:1), rt. Condition B: DMF (anhydrous), 100 8C.

^cRef. 36

^dStarting material also recovered.

^e92:8 (E)/(Z) mixture of diastereomers.

f

Decomposition of starting material observed.

A. Goeta et al. / Tetrahedron 62 (2006) 3582–3599

3591

alkyne carbometalation pathway to an intramolecular

Michael addition-type pathway. Intriguingly however,

the oxygen-centred haloallyl alkyne 28 did undergo

indium-mediated cyclisation in THF/H₂O (1:1) at room

temperature to a certain extent (entry 7) to give 33

although the major product was still the proteodebromi-

nated material. The contrast in reactivity of the 28 the

carbon-centred non-terminal haloenynes may be partially

due to the C–O bond in 28 being slightly shorter than the

analogous C–C bond in the carbon-centred substrates.

However, the failure of propyl-substituted oxygen-centred

substrate 29 to undergo cyclisation indicates that the

reaction is ﬁnely balanced and is governed by both steric

and electronic factors.

carboindination the ratio of allyl group to alkyne is

necessarily ﬁxed at 1:1. Thus if the organoindium species

generated during the cyclisation of tethered terminal

haloallyl alkynes in THF/H₂O is an indium sesquihalide,

the maximum possible yield for the reaction would be 66%

with the remaining 33% of the organic reagent being lost as

a ligand for the indium complex generated in the reaction.

The fact that the cyclisation in THF/H₂O proceeds without

loss of yield with only 0.67 equiv of indium with respect to

the substrate (Table 6, entry 2) would appear to support a

sesquihalide intermediate. However, this is offset by the

observation that the yield of the reaction can exceed 66%,

and that the reaction does not proceed in dry THF (which

would be expected to lead to the formation of an indium

sesquihalide) but only turns over in aqueous solvent systems

(which would promote a dimeric or monomeric allylic

indium species). Therefore, whilst it is still not possible to

identify the exact nature of the intermediate in THF/H₂O,

these data suggest that it is most likely composed of a

mixture of mono- and dimeric organoindium species which

are Lewis acidic enough to undergo addition to a terminal

alkyne but not sufﬁciently reactive to add to more sterically

congested non-terminal alkynes, in contrast to the indium

sesquihalide intermediate which would likely be present in

more polar DMF. Furthermore, the fact that the (E)/(Z)

geometry of the allylic precursor has no effect on the yield

or stereoselectivity of the reaction indicates that the

cyclisation to a ﬁve-membered ring proceeds from a

common intermediate.³⁸

2.9. Nature of the allyindium intermediate

The difference in the reactivity of non-terminal haloallyl

alkynes towards indium in aqueous THF and anhydrous

DMF is striking especially in view of the fact that it has been

established that the cyclisation does not proceed via a route

involving insertion into a C^C–H bond (vide supra). The

explanation of this observation lies in the likely nature of the

organoindium intermediate present in each reaction. It is

known that reactions of allyindium reagents in highly polar

solvents such as DMF or THF proceed via an indium

sesquihalide intermediate (R₃In₂X₃) 35 but that this

structure can be transformed into the corresponding

dialkylindium species by the addition of KBr or KI.

However under aqueous conditions, the monomeric allyl-

indium species 36 has been shown to be present in the

reaction mixture.³⁷

Something of the constraints placed upon on the cyclisation

of this intermediate can be understood by contrasting the

smooth cyclisation of the substrates described above with

indium in THF/H₂O to give ﬁve-membered carbo- and

heterocycles with the failure of 1-bromo-2-nonene-8-ynes

37–38 and bromomethallylalkyne 39 to cyclise to the

corresponding six-membered analogues (Scheme 4) under

them same conditions. These observations indicate that in

the presence of a protic solvent mixture,³³the rate of

proteodebromination of substrates 37–39 to give alkenes

40–42 is faster than that of cyclisation, and therefore it

seems likely that the reaction proceeds by a cyclic rather

than open transition state.

X

In

X

35

36

In the analogous intermolecular carboindinations of alkynes

it has been demonstrated that the two of the three allyl

groups are added across the alkyne carbon–carbon triple

bond, and the third acts as a ligand for the indium complex

in the reaction.³³Accordingly in the intermolecular case,

0.6 equiv of indium with respect to the alkyne substrate

(representing an effective 1.2 fold excess of allylindium

reagent over the alkyne) are typically used and one allyl

group per molecule of the organoindium complex is

sacriﬁced. However, in the case of intramolecular

Therefore, whilst the exact structure of this intermediate is

still unclear, the deuterium labelling results and consider-

ation of the geometries involved in the cyclisation suggests

that the reaction most likely proceeds through the (E)-form

In (1eq)

THF:H₂O (1:1)

Br

X

37 X=C(CO₂Me)

38 X=O

40 X=C(CO₂Me) (34%)

41 X=O (55% NMR yield)

CH₃

Br

In (1eq)

THF:H₂O (1:1)

MeO₂C CO₂Me

42 (67%)

39

Scheme 4. Attempted extension of the cyclisation reaction to six-membered systems.

3592

A. Goeta et al. / Tetrahedron 62 (2006) 3582–3599

In

H

MeO₂C

H

MeO₂C

In

H

9a-(Z)

9a-(E)

10a

MeO₂C

H

In

H

9a-(Z)

9a-(E)

H

In

Figure 2. Suggested structures for the cyclisation intermediate.

of the allylindium intermediate, generated either from the

action of indium on the (E)-allylic halide or from

isomerisation of the (Z)-allylindium. This then adds across

the alkyne in syn fashion with complete speciﬁcity, a

reaction mode which would be accommodated only by a

concerted carboindination of the triple bond and would not

be consistent with a radical mechanism (Fig. 2).

which is protonated in situ by the aqueous component of the

solvent system.

Not only is this protocol very attractive from a synthetic

standpoint due to operational simplicity, convenience and

cleanliness of the reactions, but is also provides a practical

contribution to the ﬁeld of Green Chemistry. The use of

aqueous media for organic synthesis is a ﬁeld of growing

importance²²and the development of environmentally benign

protocols by the minimisation of the use of organic solvents is

of considerable interest from both an economic and

environmental standpoint. We believe that the current method

represents a valuable addition to this important ﬁeld.

3. Conclusion

In summary, we have demonstrated a novel indium-

mediated cyclisation reaction of terminal haloallyl alkynes

which proceeds in THF/H₂O via intramolecular allylindina-

tion of the unactivated alkyne C–C triple bond. The

reactions, which occur smoothly under extremely mild

conditions without the need for the addition of NaI or KI, are

operationally simple and provide a quick and convenient

route to the synthesis of a variety of ﬁve-membered

heterocycles and carbocycles.

4. Experimental

4.1. General experimental procedure

¹H and ¹³C NMR data were recorded on a Brucker AM400

or AM360 spectrometer in deuterochloroform, referenced to

either TMS or residual CHCl₃as an internal standard.

Chemical shifts were measured in ppm and coupling

constants (J) were measured in Hz. Mass spectra were

obtained on a Jeol AX505W spectrometer using EI or CI. IR

spectra were recorded neat or from solution, as stated, on a

Perkin–Elmer paragon 1000 Fourier transform IR spec-

trometer. Analytical tlc was carried out on Merck 60 F₂₄₅

plastic backed silica gel plates. Short wave UV (245 nm) or

KMnO₄, were used to visualise components. Compounds

were puriﬁed by column chromatography using Merck silica

gel 60 (0.040–0.063 mm. Diethyl ether was dried over

sodium wire in a septum sealed Winchester under argon.

THF was distilled under N₂from sodium benzophenone

ketal NaH was freed of mineral oil by triturating three times

with 60–80 8C petroleum ether. Other chemicals were used

as obtained from commercial sources. All reactions were

carried out in oven dried glassware.

The reaction was facilitated by both In(0) and In(I) species

although not by the addition of either In(III) salts or Ga(0).

Generation of indium reagent by in situ reduction of In(III)

species with zinc allowed the use of catalytic quantities

(10 mol%) of indium. The presence of water in the reaction

medium was found to be essential for smooth and efﬁcient

cyclization, and although a 1:1 mixture of THF/H₂O was

established as the solvent system of choice, the reaction still

proceeds in O90% water without any serious detrimental

effect on the reaction.

Deuteration studies demonstrated that alkynylindium inter-

mediate is not involved in the reaction, but that the

intramolecular addition of the allylindium reagent to the

alkyne occurs via concerted syn speciﬁc carboindination of

the triple bond to generate a putative vinylindium species

A. Goeta et al. / Tetrahedron 62 (2006) 3582–3599

3593

4.2. Representative procedure for the synthesis of

carbon-centred haloenynes

4.4. Representative procedure for the cyclisation of

bromoallyl alkynes

4.4.1. Tetrahydro-3-methylene-4-vinylfuran 8a. To a

well-stirred solution of (E)-1-bromo-4-(prop-2-ynyloxy)-

but-2-ene 7a (1.89 g, 10 mmol) in dry THF (10 mL) and

distilled water (10 mL) at room temperature, was added

indium (Aldrich, 99.99%, 1.41 g, 10 mmol, 1 equiv). The

mixture was stirred for a further 16 h and then the reaction

mixture was poured onto a mixture of Et₂O and 2 M HCl.

The aqueous layer was extracted with Et₂O (2!25 mL) and

the combined organics were washed with water (2!

25 mL), saturated aqueous NaCl (1!25 mL) and dried

(MgSO₄). Filtration and removal of solvent gave a residue

which was puriﬁed by chromatography on silica (hexane/

Et₂O, 10:1) to give the cyclised product 8a (680 mg, 62%)

4.2.1. Dimethyl 2-((E)-4-bromobut-2-enyl)-2-(prop-2-

ynyl)malonate 9a. Sodium hydride (60% in oil, 2.40 g,

60 mmol) was washed with dry hexane (3!30 mL) and

dried in vacuo. The NaH was suspended in dry THF

(50 mL) and cooled to 0 8C. To this was added dimethyl-

(2-propynyl)malonate dropwise via syringe and after the

addition was complete the mixture was stirred and allowed

to come to room temperature over 30 min. This was then

added via a wide-bore cannula to a solution of (E)-1,4-

diromo-2-butene (15.67 g, 75 mmol) in THF (75 mL) at

0 8C over 5 min. The mixture was allowed to come to

room temperature and stirred for a further 2 h during

which time a white precipitate formed. The mixture was

quenched with a mixture of diethyl ether and water and

then partitioned between diethyl ether and 2 M HCl_(aq).

The aqueous layer was extracted with diethyl ether

(2!50 mL) and the combined organics washed with

water (1!50 mL), brine and dried (MgSO₄). Filtration

and removal of solvent gave a residue which was puriﬁed

by chromatography (SiO₂, hexane/EtOAc 5:1) to give the

required allyl bromide as a clear, colourless oil (8.10 g,

1

as a clear colourless oil: H NMR (360.13 MHz, CDCl₃) d

3.24 (1H, m), 3.48 (1H, dd, JZ8.5, 8.6 Hz), 4.03 (1H, dd,

JZ8.0, 8.1 Hz), 4.23 (1H, d, JZ13.3 Hz), 4.34 (1H, br d,

JZ13.1 Hz), 4.85 (1H, br s), 4.94 (1H, br s), 5.58 (1H, ddd,

JZ8.3, 10.1, 16.9 Hz); ¹³C NMR (100.62 MHz, CDCl₃) d

49.5, 71.8, 73.8, 105.6, 117.6, 136.8, 151.0; IR (thin ﬁlm):

3447, 3079, 2979, 2847, 1665, 1637 cm^K1; MS (EI): m/z

(%)Z110 (20.5) [M^C], 80 (100.0).

1

4.4.2. Tetrahydro-3-methylene-2-phenyl-4-vinylfuran

8b. 1-(1-((E)-4-Bromobut-2-enyloxy)prop-2-ynyl)benzene

7b (226 mg, 1 mmol), indium powder (114 mg, 1 mmol)

in 1:1 THF/H₂O (2 mL) were reacted and worked up

according to the general procedure. Chromatography on

silica (hexane/Et₂O 10:1) gave the cyclised product 10b as

2:1 mixture of diastereomers as a clear colourless oil

(82 mg, 50%): ¹H NMR (360.13 MHz, CDCl₃) d 3.52 (1H,

m, two diastereomers), 3.64 (1H, dd, JZ8.3, 10.2 Hz,

major), 3.88 (1H, dd, JZ6.7, 8.6 Hz, minor), 4.12 (1H, m,

two diastereomers), 4.15 (1H, dd, JZ8.6, 15.2 Hz, minor),

4.31 (1H, dd, JZ8.1, 16.1 Hz, major), 4.75 (1H, s, minor),

4.85 (1H, s, major), 4.97 (1H, s, major), 5.03 (1H, s, minor),

5.1–5.3 (2H, m, two diastereomers), 5.68 (1H, ddd, JZ8.3,

10.4, 16.1 Hz, major), 5.79 (1H, ddd, JZ8.2, 10.4, 16.2 Hz,

minor); ¹³C NMR (100.62 MHz, CDCl₃) d 49.5 (minor),

49.9 (major), 72.6 (minor), 72.9 (major), 83.9 (minor), 84.1

(major), 106 (major), 109.2 (minor), 117.2 (minor), 118.2

(major), 127.3, 127.7, 128.2, 128.3, 128.7, 128.8, 136.4,

137.6, 141.6 (minor), 141.9 (major), 154.3 (minor), 154.7

(major); IR (thin ﬁlm): 3079, 2929, 2851, 1718, 1663,

1637 cm^K1; MS (CI): m/z (%)Z204 [MNH₄^C] (100.0), 190

(6.8), 187 [MH^C] (5.5), 173 (6.3).

53%): H NMR (360.13 MHz, CDCl₃) d 2.05 (1H, brs),

2.81 (2H, m), 2.83 (2H, d, JZ7.7 Hz), 3.77 (6H, s), 3.91

(2H, d, JZ7.5 Hz), 5.63 (1H, dt, JZ7.5, 15.1 Hz), 5.86

(1H, dt, JZ7.5, 15.1 Hz); ¹³C NMR (100.62 MHz, CDCl₃)

d 23.4, 32.5, 35.3, 53.3, 57.3, 72.2, 78.9, 129.3, 131.9,

170.3; IR (thin ﬁlm): 3291, 2954, 2122, 1736, 1661 cm^K1

;

MS (EI): m/z (%)Z320 [MNH^C₄] (100.0), 223 (16.0),

162 (6.0).

4.3. Representative procedure for the synthesis of

heteroatom-centred haloenynes

4.3.1. (E)-1-Bromo-4-(prop-2-ynyloxy)but-2-ene 8a. Pro-

pargyl alcohol, (1.40 g, 1.45 mL, 25 mmol) was added

dropwise via syringe to a suspension of NaH (60% in oil

which had been removed by washing with dry hexane,

1.00 g, 1 equiv) in dry THF (25 mL) at 0 8C. The mixture

was stirred at ice point for 30 min and then (E)-1,4-

dibromo-2-butene (5.59 g, 1.1 equiv) in dry THF (25 mL)

was added via a cannula and the reaction was heated at

50 8C for 15 h. The mixture was allowed to cool and then

quenched with a mixture of diethyl ether and water

and then poured onto diethyl ether and 2 M HCl_(aq). The

aqueous layer was extracted with diethyl ether

(2!50 mL) and the combined organics washed with

water (1!50 mL), brine and dried (MgSO₄). Filtration

and removal of solvent gave a residue which was puriﬁed

by chromatography (SiO₂, hexane/EtOAc 5:1) to give the

required propargylic ether as a clear, colourless oil (1.6 g,

4.4.3. Tetrahydro-3-methylene-2-propyl-4-vinylfuran

8c. 3-((E)-4-Bromobut-2-enyloxy)hex-1-yne 7c (345 mg,

1.5 mmol), indium powder (180 mg, 1.57 mmol) in 1:1

THF/H₂O (1.5 mL) were reacted and worked up according

to the general procedure. Chromatography on silica

(hexane/Et₂O 10:1) gave the cyclised product 10b as 3.5:1

mixture of diastereomers as a clear colourless oil (128 mg,

1

34%): H NMR (360.13 MHz, CDCl₃) d 2.47 (1H, br s),

56%): H NMR (360.13 MHz, CDCl₃) d 0.94 (3H, m, two

4.03 (2H, d, JZ8.2 Hz), 4.16 (2H, br s), 4.21 (2H, dd, JZ

1.5, 6.5 Hz), 5.85 (1H, dt, JZ5.6, 15.3 Hz), 5.96 (1H, 6.5,

15.3 Hz); ¹³C NMR (100.62 MHz, CDCl₃) d 26.3,

57.4, 64.2, 74.9, 17.4, 129.3, 130.1; IR (thin ﬁlm):

3293, 2853, 2116, 1667 cm^K1; MS (CI): m/z (%)Z168

(27.0), 151 (100.0).

diastereomers), 1.40–1.70 (4H, m), 3.31 (1H, m), 3.44 (1H,

dd, JZ8.5, 8.6 Hz, major), 3.63 (1H, dd, JZ8.6, 8.7 Hz,

minor), 3.97 (1H, dd, JZ7.6, 8.6 Hz, minor), 4.12 (1H, dd,

JZ8.0, 8.1 Hz, major), 4.31 (1H, m, major), 4.35 (1H, m,

minor), 4.88 (1H, br s, two diastereomers), 4.91 (1H, br s,

two diastereomers), 5.12 (2H, m, two diastereomers), 5.61

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A. Goeta et al. / Tetrahedron 62 (2006) 3582–3599

1

(1H, ddd, JZ8.3, 9.7, 16.3 Hz, major), 5.65 (1H, m, minor);

¹³C NMR (100.62 MHz, CDCl₃) d 14.1, 19.6 (major),

19.1 (minor), 37.1 (minor), 37.8 (major), 49.5 (minor), 49.7

(major), 71.1 (minor), 71.9 (major), 80.7 (minor), 81.2

(major), 105.2 (major), 105.6 (minor), 116.4 (minor),

117.5 (major), 136.3 (major), 137.6 (minor), 154.4

(major), 154.5 (minor); IR (thin ﬁlm): 3309, 2958, 2871,

1663, 1640 cm^K1; MS (CI): m/z (%)Z151 (40.1) [MH^C],

137 (20.1), 123 (23.0), 111 (35.0), 97 (62.0), 83 (63.0), 69

(67.0), 57 (100.0).

isomer. H NMR (360.13 MHz, CDCl₃) d 0.86 (3H, t, JZ

6.8 Hz), 1.16–1.80 (8H, m), 2.42 (3H, s), 2.63 (1H, br dd,

JZ6.5, 10.1 Hz), 3.05 (1H, dd, JZ10.3, 12.2 Hz), 3.74 (1H,

dd, JZ8.4, 12.2 Hz), 4.25 (1H, br m), 4.80 (1H, s), 4.88

(1H, s), 4.93 (1H, d, JZ17.3 Hz), 5.07 (1H, d, JZ10.2 Hz),

5.45 (1H, ddd, JZ8.1, 10.2, 17.3 Hz), 7.28 (2H, d, JZ

8.2 Hz), 7.71 (2H, d, JZ8.2 Hz); ¹³C NMR (100.62 MHz,

CDCl₃) d 14.5, 21.9, 22.9, 24.7, 32.2, 36.0, 47.9, 52.6, 63.8,

108.4, 118.3, 127.7, 130.1, 136.3, 136.5, 143.8, 152.1; IR

(thin ﬁlm): 3080, 2953, 2929, 1653, 1640 cm^K1; MS (CI):

m/z (%)Z351 (32.5) [MNH^C₄], 334 [MH^C] (100.0).

4.4.4. Tetrahydro-3-methylene-2-pentyl-4-vinylfuran

8d. 3-((E)-4-Bromobut-2-enyloxy)oct-1-yne 7d (213 mg,

0.83 mmol), indium powder (94 mg, 0.83 mmol) in 1:1

THF/H₂O (2 mL) were allowed to react and then worked up

according to the general procedure. Chromatography on

silica (hexane/EtOAc 5:1) gave the desired carbocycle 8b as

3.6:1 mixture of diastereomers as a clear colourless oil

(77 mg, 52%): ¹H NMR (360.13 MHz, CDCl₃) d 0.88 (3H,

m, two diastereomers), 1.26–1.66 (8H, m), 3.30 (1H, m, two

diastereomers), 3.42 (1H, dd, JZ8.5, 9.8 Hz, major), 3.61

(1H, dd, JZ6.9, 8.7 Hz, minor), 3.96 (1H, dd, JZ7.5,

7.6 Hz, minor), 4.10 (1H, dd, JZ8.0, 8.1 Hz, major), 4.30

(1H, m, two diastereomers), 4.86 (1H, br s, two

diastereomers), 4.90 (1H, s, two diastereomers), 5.16

(2H, m, two diastereomers), 5.58 (1H, ddd, JZ8.6, 10.5,

16.2 Hz, major), 5.78 (1H, ddd, JZ8.2, 10.3, 16.1 Hz,

minor); ¹³C NMR (100.62 MHz, CDCl₃) d 13.0, 21.5

(minor), 21.6 (major), 24.0 (major), 24.58 (minor), 30.8

(minor), 30.9 (major), 33.9 (minor), 34.5 (major), 48.5

(minor), 48.7 (major), 70.1 (minor), 70.9 (major), 79.9

(minor), 80.4 (major), 104.1 (minor), 104.6 (major), 115.4

(minor), 116.5 (major), 135.3 (major), 136.6 (minor), 153.3

(minor), 153.5 (minor); IR (thin ﬁlm): 3079, 2932, 2859,

1663, 1641 cm^K1; MS (EI): m/z (%)Z180 (10.0) [M^C], 150

(19.0), 124 (45.0), 109 (100.0).

4.4.7.

N-tert-Butoxycarbonyl(3-methylene-4-vinyl-

pyrrolidine) 18c. N-(tert-Butoxycarbonyl)-(E)-4-bromo-

but-2-enylprop-2-ynylamine 13c (864 mg, 3 mmol),

indium powder (342 mg, 3 mmol) in 1:1 THF/H₂O (6 mL)

were allowed to react and worked up in accordance with the

general procedure. Puriﬁcation by chromatography on silica

(hexane/EtOAc 10:1) gave the N-protected pyrrolidine 18c

as a clear colourless oil (430 mg, 69%): ¹H NMR

(360.13 MHz, CDCl₃) d 1.45 (9H, s), 3.13 (1H, m), 3.30

(1H, br m), 3.75 (1H, m), 4.01 (1H, br d, JZ18.7 Hz), 4.08

(1H, br d, JZ18.3 Hz), 4.90 (1H, s), 5.00 (1H, br s), 5.14

(2H, m), 5.65 (1H, ddd, JZ8.6, 10.3, 16.3 Hz); ¹³C NMR

(100.62 MHz, CDCl₃) d 28.7 (rotamer), 47.5 (rotamer), 48.2

(rotamer), 50.6 (rotamer), 50.9 (rotamer), 51.2 (rotamer),

51.7 (rotamer), 79.8, 107.6 (rotamer), 107.8 (rotamer),

117.9, 136.8, 147.9 (rotamer), 148.8 (rotamer), 154.8; IR

(thin ﬁlm): 3466, 3081, 2977, 2868, 1701, 1644 cm^K1; MS

(EI): m/z (%)Z209 (2.2) [M^C], 154 (22.1), 108 (43.5), 79

(30.2), 57 (100.0).

4.4.8. N-(Benzyloxycarbonyl(3-methylene-4-vinylpyrro-

lidine)) 18d. N-(Benzyloxycarbonyl)-(E)-4-bromobut-2-

enylprop-2-ynylamine 13d (626 mg, 1.94 mmol), indium

powder (221 mg, 1.94 mmol) in 1:1 THF/H₂O (3 mL) were

reacted together and worked up according to the general

procedure. Chromatography on silica (hexane/EtOAc 5:1)

gave the N-protected pyrrolidine 18d as a clear colourless

4.4.5. 3-Methylene-1-tosyl-4-vinylpyrrolidine 18a. (E)-4-

Bromo-N-(prop-2-ynyl)-N-tosylbut-2-en-1-amine 13a

(105 mg, 0.31 mmol), indium powder (35 mg, 0.31 mmol)

in 1:1 THF/H₂O (1 mL) were allowed to react and then

worked up according to the general procedure. Chromatog-

raphy on silica (hexane/EtOAc 5:1) gave the pyrrolidine 18a

as a clear colourless oil (50 mg, 62%): ¹H NMR

(360.13 MHz, CDCl₃) d 2.44 (3H, s), 2.86 (1H, dd, JZ

8.9, 9.2 Hz), 3.25 (1H, m), 3.62 (1H, dd, JZ8.0, 9.3 Hz),

3.72 (1H, br d, JZ14.2 Hz), 3.99 (1H, br d, JZ14.2 Hz),

4.86 (1H, br s), 4.97 (1H, br d), 5.07–5.13 (2H, m), 5.50 (1H,

ddd, JZ8.2, 10.4, 16.5 Hz), 7.33 (2H, d, JZ8.0 Hz), 7.71

(2H, d, JZ8.0 Hz); ¹³C NMR (100.62 MHz, CDCl₃) d 21.9,

48.1, 52.3, 53.6, 108.7, 118.5, 128.2, 130.1, 133.1, 135.9,

144.1, 147.0; IR (thin ﬁlm): 3272, 3081, 2984, 2923, 2851,

1736, 1667, 1597, 1348, 1163 cm^K1; MS (EI): m/z (%)Z

263 (27.9), 222 (15.5), 155 (28.0), 108 (100.0).

1

oil (310 mg, 66%): H NMR (360.13 MHz, CDCl₃) d 3.24

(1H, bs dd, JZ8.6, 10.2 Hz), 3.34 (1H, m), 3.85 (1H, br dd,

JZ8.7, 9.7 Hz), 4.08 (2H, m), 4.95 (1H, br s), 5.06 (1H, br

d, JZ14.9 Hz), 5.16 (4H, m), 5.68 (1H, br m),7.35 (5H, br

m); ¹³C NMR (100.62 MHz, CDCl₃) d 47.4 (rotamer), 48.2

(rotamer), 50.7 (rotamer), 51.1 (rotamer), 51.5 (rotamer),

51.7 (rotamer), 67.2 (rotamer), 67.5 (rotamer), 108.2, 118.2

(rotamer), 119.1 (rotamer), 128.3 (rotamer), 123.4

(rotamer), 128.8 (rotamer), 128.9 (rotamer), 136.5

(rotamer), 137.2 (rotamer), 155.1; IR (thin ﬁlm): 3080,

2979, 2948, 2867, 1953, 1704, 1542 cm^K1; MS (EI): m/z

(%)Z242 (14.8), 230 (6.5), 198 (8.6), 152 (48.7), 91

(100.0).

4.4.9. Dimethyl 3-methylene-4-vinylcyclopentane-1,1-

dicarboxylate 10a. (E)-2-(4-Bromobut-2-enyl)-(2-prop-2-

ynyl)-malonic acid dimethyl ester 9a (451 mg, 1.5 mmol),

indium powder (171 mg, 1.5 mmol) in 1:1 THF/H₂O

(1.5 mL) were allowed to react and worked up in

accordance with the general procedure. Puriﬁcation by

chromatography on silica (hexane/EtOAc 3:1) gave the

cyclised product 10a as a clear colourless oil (249 mg,

4.4.6. 3-Methylene-2-pentyl-1-tosyl-4-vinylpyrrolidine

18b. N-((E)-4-Bromobut-2-enyl)-N-tosyloct-1-yn-3-amine

13b (206 mg, 0.5 mmol), indium powder (57 mg,

0.5 mmol) in 1:1 THF/H₂O (1 mL) were allowed to react

and then worked up according to the general procedure.

Chromatography on silica (hexane/EtOAc 4:1) gave the

desired pyrrolidine 18b as a 14:1 mixture of diastereomers

as a clear colourless oil (139 mg, 83%). Data for major

1

74%): H NMR (360.13 MHz, CDCl₃) d 2.01 (1H, dd, JZ

11.0, 13.0 Hz), 2.57 (1H, dd, JZ8.0, 13.0 Hz), 2.95

A. Goeta et al. / Tetrahedron 62 (2006) 3582–3599

3595

(1H, ddd, JZ3.0, 6.0, 18.0 Hz), 3.08 (1H, br d, JZ18.0 Hz),

3.17 (1H, m), 3.73 (3H, s), 3.75 (3H, s), 4.82 (1H, s), 4.98

(1H, s), 5.05 (1H, br s), 5.08 (1H, m), 5.64 (1H, ddd, JZ8.0,

10.5, 13.0 Hz); ¹³C NMR (100.62 MHz, CDCl₃) d 40.7,

48.1, 53.2, 53.2, 58.9, 108.6, 116.5, 139.4, 150.8, 172.4,

172.6; IR (thin ﬁlm): 3660, 3471, 3078, 2953, 1731, 1714,

1659, 1642 cm^K1; MS (FAB): m/z (%)Z225 (73.2) [MH^C],

193 (36.5), 165 (65.1), 154 (74.3), 137 (68.1), 136 (61.7),

105 (100), 91 (49.7), 77 (49.1).

JZ12.2, 12.3 Hz, major), 2.59 (1H, ddd, JZ1.6, 7.2,

12.5 Hz, major), 2.80 (1H, dd, JZ8.6, 14.4 Hz, minor),

2.99 (1H, br m, major), 3.08 (1H, br d, JZ18.7 Hz, minor),

3.14 (1H, br d, JZ18.2 Hz, major), 3.21 (1H, d, JZ18.7 Hz,

major), 3.23 (1H, br d, JZ18.2 Hz, minor), 3.39 (1H, m,

minor), 3.62 (3H, s, minor), 3.66 (3H, s, major), 4.84 (1H, br s

two diastereomers), 5.00 (1H, br s, two diastereomers), 5.04

(1H, br s, two diastereomers), 5.07 (1H, m, two diaster-

eomers), 5.54 (1H, ddd, JZ8.2, 9.9, 15.9 Hz, minor), 5.64

(1H, ddd, JZ8.1, 10.2, 13.0 Hz, major), 7.54 (2H, dd, JZ7.5,

8.0 Hz, two diastereomers), 7.67 (1H, dd, JZ7.4, 7.6 Hz,

two diastereomers), 7.82 (2H, dd, JZ7.2, 7.5 Hz, two

diastereomers); ¹³C NMR (100.62 MHz, CDCl₃) d 38.1

(major), 38.3 (two diastereomers), 38.5 (minor), 47.6

(minor), 48.1 (major), 53.6 (minor), 53.8 (major), 77.3

(major), 77.7 (minor), 109.3 (minor), 109.8 (major), 129.3

(major), 130.0 (major), 130.3 (minor), 134.6 (major), 134.7

(minor), 136.6 (minor), 137.2 (major), 138.5 (major),

138.8 (minor), 148.5 (major), 149.3 (minor), 168.8 (major),

169.1 (minor); IR (thin ﬁlm): 3077, 2952, 1977, 1910, 1737,

1658, 1639 cm^K1; MS (FAB): m/z (%)Z324 (100.0)

[MNH^C₄].

4.4.10. Diethyl 3-methylene-4-vinylcyclopentane-1,1-

dicarboxylate 10b. (E)-2-(4-Bromobut-2-enyl)-(2-prop-2-

ynyl)-malonic acid diethyl ester 9b (660 mg, 2 mmol),

indium powder (228 mg, 2 mmol) in 1:1 THF/H₂O (2 mL)

were allowed to react and worked up in accordance with the

general procedure. Puriﬁcation by chromatography on silica

(hexane/Et₂O 10:1) gave the cyclised product 10b as a clear

colourless oil (360 mg, 71%): ¹H NMR (360.13 MHz,

CDCl₃) d 1.25 (3H, m), 2.05 (1H, dd, JZ10.8, 12.9 Hz),

2.58 (1H, dd, JZ8.0, 12.9 Hz), 2.93 (1H, ddd, JZ2.9, 6.0,

17.8 Hz), 3.09 (1H, br d, JZ17.8 Hz), 3.18 (1H, m), 4.19

(2H, m), 4.83 (1H, s), 4.99 (1H, s), 5.06 (1H, br s), 5.11 (1H,

m), 5.64 (1H, ddd, JZ8.0, 10.3, 12.9 Hz); ¹³C NMR

(100.62 MHz, CDCl₃) d 14.4, 40.6, 48.1, 58.9, 61.9, 108.4,

116.4, 139.6, 151.0, 171.9, 172.2; IR (thin ﬁlm): 3079, 2982,

1732, 1658, 1640 cm^K1. MS (FAB): m/z (%)Z253 (2.3)

[MH^C], 252 (4.5), 207 (10.1), 178 (57.8), 105 (100.0).

4.4.13. Ethyl 1-(dimethylcarbamoyl)-3-methylene-4-

vinylcyclopentanecarboxylate 10f. (E)-Ethyl 2-(dimethyl-

carbamoyl)-6-bromo-2-(prop-2-ynyl)hex-4-enoate

9f

(330 mg, 1 mmol), indium powder (114 mg, 2 mmol) in

1:1 THF/H₂O (1.5 mL) were allowed to react and worked up

in accordance with the general procedure. Puriﬁcation by

chromatography on silica (hexane/Et₂O 3:1 gradient to 1:1)

gave the cyclised product 10e as a 1.3:1 mixture of

4.4.11. Ethyl-tert-butyl 3-methylene-4-vinylcyclo-

pentane-1,1-dicarboxylate 10c. (E)-Ethyl-tert-butyl-2-(4-

bromobut-2-enyl)-(2-prop-2-ynyl)-malonate diethyl ester

9c (344 mg, 1 mmol), indium powder (114 mg, 1 mmol)

in 1:1 THF/H₂O (1 mL) were allowed to react and worked

up in accordance with the general procedure. Puriﬁcation by

chromatography on silica (hexane/Et₂O 10:1) gave the

cyclised product 10b as a 1:1 mixture of diastereomers in

1

diastereomers as a clear colourless oil (210 mg, 84%): H

NMR (360.13 MHz, CDCl₃) d 1.23 (3H, t, JZ7.2 Hz,

diastereotopic), 1.92 (1H, dd, JZ11.3, 12.6 Hz, major),

2.23 (1H, dd, JZ11.5, 13.2 Hz, minor), 2.40 (1H, dd, 7.7,

13.2 Hz, minor), 2.58 (1H, dd, JZ7.8, 12.6 Hz, major), 2.80

(3H, br s, two diastereomers), 2.85 (1H, m), 2.94 (3H, br s,

two diastereomers), 3.20 (1H, m, two diastereomers), 4.19

(2H, q, JZ7.0 Hz, two diastereomers), 4.77 (1H, br s, two

diastereomers), 4.92 (1H, br s, two diastereomers), 5.06

(1H, br s, two diastereomers), 5.09 (1H, m, two

diastereomers), 5.66 (1H, ddd, JZ8.5, 10.5, 13.3 Hz, two

diastereomers); ¹³C NMR (100.62 MHz, CDCl₃) d 14.6

(minor), 15.6 (major), 37.2 (broad, two diastereomers),

41.1 (minor), 41.5 (minor), 41.6 (major), 41.8 (major), 47.7

(minor), 48.6 (major), 57.7 (major), 58.0 (minor), 60.8

(major), 61.9 (minor), 107.4 (major), 107.6 (minor), 116.4

(minor), 116.6 (major), 139.4 (major), 139.6 (minor),

151.4 (minor), 151.6 (major), 170.6 (minor), 172.2

(major), 173.9 (major), 174.3 (minor); IR (thin ﬁlm):

3501, 3077, 2980, 2934, 1729, 1650 cm^K1. MS (FAB):

m/z (%)Z269 (3.2) [MNH^C₄], 252 (100.0) [MH^C].

1

the form of a clear colourless oil (150 mg, 56%). H NMR

(360.13 MHz, CDCl₃) d 1.45 (4.5H, s, diastereotopic), 1.46

(4.5H, s, diastereotopic), 1.98 (1H, m, two diastereomers),

2.53 (1H, m, two diastereomers), 2.96 (1H, ddd, JZ3.0, 5.9,

17.8 Hz, two diastereomers), 3.11 (1H, br d, JZ17.8 Hz,

two diastereomers), 3.16 (1H, br m, two diastereomers),

3.73 (1.5H, s, diastereotopic), 3.75 (1.5H, s, diastereotopic),

4.81 (1H, s, two diastereomers), 4.98 (1H, s, two

diastereomers), 5.06 (1H, br s, two diastereomers), 5.09

(1H, m, two diastereomers), 5.66 (1H, ddd, JZ7.9, 8.2,

13 Hz, two diastereomers); ¹³C NMR (100.62 MHz, CDCl₃)

d 28.17, 28.19, 40.51, 40.55, 48.03, 48.15, 52.88, 52.93,

59.58, 59.76, 82.14, 108.22, 116.25, 116.33, 139.65, 151.15,

151.19, 170.84, 171.08, 172.76, 173.00; IR (thin ﬁlm):

3079, 2980, 1731, 1658, 1640 cm^K1. MS (FAB): m/z (%)Z

284 (52.7) [MNH^C₄], 267 (14.4), 228 (100.0), 211 (12.1).

4.4.12. Methyl 3-methylene-1-(phenylsulfonyl)-4-vinyl-

cyclopentanecarboxylate 10e. (E)-Methyl 6-bromo-2-(phe-

nylsulfonyl)-2-(prop-2-ynyl)hex-4-enoate 9e (258 mg,

0.67 mmol), indium powder (100 mg, 0.87 mmol) in 1:1

THF/H₂O (1.5 mL) were allowed to react and worked up in

accordance with the general procedure. Puriﬁcation by

chromatography on silica (hexane/EtOAc 3:1) gave the

cyclised product 10b as a 4.5:1 mixture of diastereomers in

the form of a clear colourless oil (91 mg, 44%):¹H NMR

(360.13 MHz, CDCl₃) d 2.23 (1H, m, minor), 2.29 (1H, dd,

4.4.14. Ethyl 1-(pyrrolidinylcarbamoyl)-3-methylene-4-

vinylcyclopentanecarboxylate 10g. (E)-Ethyl 2-(pyrroli-

dinylcarbamoyl)-6-bromo-2-(prop-2-ynyl)hex-4-enoate 9g

(355 mg, 1 mmol), indium powder (114 mg, 2 mmol) in

1:1 THF/H₂O (1 mL) were allowed to react and worked up

in accordance with the general procedure. Puriﬁcation by

chromatography on silica (hexane/EtOAc 3:2) gave the

cyclised product 10f as a 1:1 mixture of diastereomers as a

clear colourless oil (212 mg, 77%): ¹H NMR (360.13 MHz,

CDCl₃) d 1.26 (3H, m, diastereotopic), 1.88 (4.5H, m, two

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A. Goeta et al. / Tetrahedron 62 (2006) 3582–3599

diastereomers), 1.96 (1H, dd, JZ11.0, 12.9 Hz, dia-

stereomer), 2.21 (1H, dd, JZ11.6, 13.1 Hz, diastereomer),

2.47 (1H, dd, JZ7.3, 12.9 Hz, diastereomer), 2.62 (1H, dd,

JZ8.0, 13.0 Hz, diastereomer), 3.00 (1H, dd, JZ2.2,

16.8 Hz, diastereomer), 3.25 (3H, m, diasteromers), 4.21

(2H, m, two diastereomers), 4.79 (1H, br s, two

diastereomers), 4.95 (1H, br s, two diastereomers), 5.06

(1H, br s, two diastereomers), 5.12 (1H, m, two

diastereomers), 5.66 (1H, ddd, JZ8.5, 10.5, 13.1 Hz, two

diastereomers); ¹³C NMR (100.62 MHz, CDCl₃) d 16.6

(two diastereomers), 26.0 (rotamer), 28.93 (rotamer), 42.6

(diastereomer), 42.9 (diastereomer), 43.2 (diastereomer),

43.3 (diastereomer), 48.5 (diastereomer and rotamer), 48.6

(diastereomer and rotamer), 49.5 (diastereomer and rota-

mer), 49.6 (diastereomer and rotamer), 49.9 (diastereomer),

50.6 (diastereomer), 60.6 (diastereomer), 61.0 (dia-

stereomer), 63.9, 109.4 (diastereomer), 109.7 (dia-

stereomer), 118.3 (diastereomer), 118.6 (diastereomer),

141.6 (diastereomer), 141.8 (diastereomer), 153.6 (dia-

stereomer), 153.9 (diastereomer), 171.1 (diastereomer),

171.5 (diastereomer), 176.1 (diastereomer); IR (thin ﬁlm):

3076, 2977, 2877, 1730, 1637 cm^K1; MS (FAB): m/z (%)Z

278 (100.0) [MH^C], 179 (5.6).

work-up and puriﬁcation by chromatography on silica

(hexane/EtOAc 10:1) gave the carbocyclic product 10i as

1

a light yellow oil (78 mg, 49%): H NMR (360.13 MHz,

CDCl₃) d 1.25 (3H, m), 2.22 (1H, dd, JZ10.7, 13.1 Hz),

2.76 (1H, dd, JZ7.7, 13.1 Hz), 3.11 (1H, d JZ17.9 Hz),

3.25 (1H, br d, JZ17.9 Hz), 3.42 (1H, m), 5.08 (1H, br s),

5.23 (1H, m), 5.67 (1H, ddd, JZ8.2, 9.3, 16.5 Hz); ¹³C

NMR (100.62 MHz, CDCl₃) d 32.6, 44.2, 44.7, 47.0, 112.7,

116.1, 116.3, 118.7, 136.8, 145.2; IR (thin ﬁlm): 3084, 2985,

2252, 1849, 1660, 1640 cm^K1; MS (FAB): m/z (%)Z158

(100) [M^C], 143 (30.4), 130 (56.9), 116 (66.0), 104 (21.5),

79 (85.5).

4.4.17. (E)-Dimethyl 3-ethylidene-4-vinylcyclopentane-

1,1-dicarboxylate 30. Dimethyl 2-((E)-4-bromobut-2-

enyl)-2-(but-2-ynyl)malonate 25 (316 mg, 1 mmol) and

indium powder (114 mg, 1mmol) were placed in a round-

bottomed ﬂask under N₂and dry DMF (1 mmol) was added.

The mixture was heated at 100 8C for 1.25 h and then

allowed to cool. The mixture was partitioned between 2 M

HCl and diethyl ether and the aqueous layer was extracted

with Et₂O (2!10 mL) and the combined organics were

washed with water (2!10 mL), saturated aqueous NaCl

(10 mL) and dried (MgSO₄). Filtration and removal of

solvent gave a residue which was puriﬁed by chromatog-

raphy on silica (hexane/EtOAc, 6:1) to give the carbocyclic

product 30 (154 mg, 65%) as a clear colourless oil as

4.4.15. Ethyl 1-(morpholinocarbamoyl)-3-methylene-4-

vinylcyclopentanecarboxylate 10h. (E)-Ethyl 2-(morpho-

linocarbamoyl)-6-bromo-2-(prop-2-ynyl)hex-4-enoate 9h

(323 mg, 0.868 mmol), indium powder (100 mg,

0.877 mmol) in 1:1 THF/H₂O (0.8 mL) reacted and worked

up following the general procedure. Puriﬁcation by on silica

(hexane/EtOAc 2:1) gave the carbocyclic product 10g as a

1:1 mixture of diastereomers as a clear colourless oil

(159 mg, 63%) which crystallised on standing (mp 87.7–

1

essentially a single diastereomer: H NMR (360.13 MHz,

CDCl₃) d 1.60 (3H, d, JZ6.7 Hz), 1.95 (1H, dd, JZ11.5,

12.8 Hz), 2.53 (1H, ddd, JZ1.6, 8.7, 12.9 Hz), 2.84 (1H, d,

JZ17.2 Hz), 3.02 (1H, d, JZ17.3 Hz), 3.09 (1H, m), 3.73

(3H, s), 3.75 (3H, s), 5.01 (2H, m), 5.2 (1H, m), 5.56 (1H,

ddd, JZ8.3, 11.2, 15.8 Hz); ¹³C NMR (100.62 MHz,

CDCl₃) d 15.0, 37.2, 40.9, 48.2, 53.2, 53.2, 59.0, 116.3,

118.4, 140.0, 141.6, 172.6, 172.7; IR (thin ﬁlm): 2954, 1716,

1661, 1644 cm^K1; MS (CI): m/z (%)Z256 (100.0)

[MNH^C₄], 239 [MH^C] (48.0).

1

89.4 8C): H NMR (360.13 MHz, CDCl₃) d 1.28 (3H, m,

diastereotopic), 1.95 (1H, dd, JZ11.4, 12.4 Hz, major),

2.27 (1H, dd, JZ11.4, 13.2 Hz, minor), 2.42 (1H, dd, JZ

7.6, 13.2 Hz, minor), 2.62 (1H, dd, JZ7.8, 12.6 Hz,

diastereomer), 3.00 (1H, dd, JZ2.2, 16.8 Hz, diastereomer),

3.21 (1H, br m, diastereomers, 3.30 (3H, br m, diaster-

eomers), 3.66 (6H, br s, diasteromers), 4.23 (2H, m, two

diastereomers), 4.81 (1H, br s, two diastereomers), 4.96

(1H, br s, two diastereomers), 5.08 (1H, br s, two

diastereomers), 5.13 (1H, m, two diastereomers), 5.66

(1H, ddd, JZ8.3, 10.7, 15.0 Hz, two diastereomers); ¹³C

NMR (100.62 MHz, CDCl₃) d 14.6 (two diastereomers),

41.1 (diastereomer), 41.4 (diastereomer), 41.6 (diaste-

reomer), 41.8 (diastereomer), 47.6 (diastereomer), 48.6

(diastereomer), 57.6 (diastereomer), 57.9 (diastereomer),

62.2 (two diastereomers), 66.0–68.0 (broad peak, diaste-

romers and rotamers), 107.8 (diastereomer), 107.9 (diaste-

reomer), 116.6 (diastereomer), 116.8 (diastereomer), 139.2

(diastereomer), 139.4 (diastereomer), 151.0 (diastereomer),

151.2 (diastereomer), 169.6 (diastereomer), 169.9 (diaste-

reomer), 173.8 (diastereomer), 174.2 (diastereomer); IR

(thin ﬁlm): 3076, 2978, 2919, 2856, 1730, 1653 cm^K1; MS

(EI): m/z (%)Z293 (47.8) [M^C], 239 (64.2), 220 (100.0,

205 (25.1), 179 (13.8), 133 (28.4).

4.4.18. (E)-Dimethyl 3-benzylidene-4-vinylcyclopentane-

1,1-dicarboxylate 31. Dimethyl 2-((E)-4-bromobut-2-

enyl)-2-(3-phenylprop-2-ynyl)malonate 26 (379 mg,

1 mmol) and indium powder (114 mg, 1 mmol) were placed

in a round-bottomed ﬂask and placed under a nitrogen

atmosphere, Dry DMF (1 mmol) was added and the mixture

was heated at 100 8C for 70 min and then allowed to cool.

The mixture was partitioned between 2 M HCl and diethyl

ether and the aqueous layer was extracted with Et₂O (2!

10 mL) and the combined organics were washed with water

(10 mL), saturated aqueous NaCl (10 mL) and dried

(MgSO₄). Filtration and removal of solvent gave a residue

which was puriﬁed by chromatography on silica (hexane/

EtOAc, 5:1) to give the carbocyclic product 31 (258 mg,

85%) as a clear colourless oil as a 3.6:1 mixture of

diastereomers: ¹H NMR (360.13 MHz, CDCl₃) d 1.94 (1H,

d, JZ11.6, 12.7 Hz, major), 2.15 (1H, dd, JZ4.4, 8.7 Hz,

minor), 2.54 (1H, ddd, JZ1.5, 10.4, 12.8 Hz, major), 2.65

(1H, dd, JZ8.7, 13.2 Hz, minor), 3.14 (1H, br d, JZ2.7,

17.8 Hz, two diastereomer), 3.26 (1H, m, two diastereo-

mers), 3.33 (1H, br d, JZ17.8 Hz, major), 3.65 (3H, s,

minor), 3.66 (6H, s, two diastereomers), 3.68 (3H, s, major),

4.92–5.10 (3H, m, two diastereomers), 5.62 (1H, ddd, JZ

8.3, 9.4, 17.6 Hz, major), 5.74 (1H, m, minor), 6.13 (1H, br

s, major), 6.41 (1H, br s, minor), 7.18–7.28 (5H, m, two

4.4.16. 3-Methylene-4-vinylcyclopentane-1,1-dicarbo-

nitrile 10i. 2-((E)-4-Bromobut-2-enyl)-2-(prop-2-ynyl)-

malononitrile 9i (236 mg, 1 mmol), indium powder

(114 mg, 1 mmol) in 1:1 THF/H₂O (1 mL) were allowed

to react according to the general procedure. Mild acidic

A. Goeta et al. / Tetrahedron 62 (2006) 3582–3599

3597

diastereomers); ¹³C NMR (100.62 MHz, CDCl₃) d 39.1

Supplementary data

(major), 40.0 (minor), 41.3 (minor), 43.2 (major), 44.4

(minor), 50.0 (major), 53.1 (minor), 53.2 (two diastereo-

mers), 53.3 (major), 58.2 (minor), 60.0 (major), 115.4

(diastereomer), 15.6 (diastereomer), 117.1 (diastereomer),

124.3 (diastereomer), 125.1 (diastereomer), 126.7 (diaster-

eomer), 126.8 (diastereomer), 128.4 (diastereomer), 128.5

(diastereomer), 128.6 (diastereomer), 128.8 (diastereomer),

132.0 (diastereomer), 138.0 (major), 138.8 (minor), 139.5

(major), 142.3 (minor), 143.5 (major), 172.2 (diastereo-

mers), 172.3 (diastereomer); IR (thin ﬁlm): 2952, 2843,

1732, 1635 cm^K1; MS (EI): m/z (%)Z300 (30.6) [M^C], 240

(100.0), 181 (93.7).

Supplementary data associated with this article can be found,

in the online version, at doi:10.1016/j.tet.2006.01.094

References and notes

1. For recent reviews on the subject of organoindium chemistry

see: (a) Cintas, P. Synlett 1995, 1087. (b) Li, C.-J. Tetrahedron

1996, 52, 5643. (c) Li, C.-J.; Chan, T.-H. Tetrahedron 1999,

55, 11149. (d) Chauhan, K. K.; Frost, C. G. J. Chem. Soc,

Perkin Trans. 1 2000, 3015. (e) Podlech, J.; Maier, T. C.

Synthesis 2003, 633. (f) Pacquette, L. A. Synthesis 2003, 765.

(g) Nair, V.; Ros, S.; Jayan, N.; Pillai, B. S. Tetrahedron 2004,

60, 1959.

4.4.19. (E)-Dimethyl 3-((methoxycarbonyl)methylene)-4-

vinylcyclopentane-1,1-dicarboxylate 32. (E)-Trimethyl

8-bromooct-6-en-1-yne-1,4,4-tricarboxylate 27 (114 mg,

0.32 mmol) and indium powder (36 mg, 0.32 mmol) in

THF/H₂O (1:1) were allowed to react together and worked

up in accordance with the general procedure. Puriﬁcation of

the crude reaction mixture on silica (hexane/EtOAc 2:1)

gave the desired cyclic triester 32 as a clear, colourless oil

(58 mg, 65%) as essentially a single diastereomer. Data for

major diastereomer. ¹H NMR (360.13 MHz, CDCl₃) d 2.01

(1H, dd, JZ12.6, 12.7 Hz),2.59 (1H, dd, JZ7.3, 12.9 Hz),

3.34 (2H, m), 3.69 (3H, s), 3.74 (3H, s), 3.75 (3H, s), 5.16

(2H, m), 5.57 (1H, ddd, JZ8.2, 10.1, 16.9 Hz), 5.67 (1H, s);

¹³C NMR (100.62 MHz, CDCl₃) d 39.7, 40.6, 50.1, 51.5,

53.3, 53.4, 59.1, 114.4, 118.7, 137.5, 165.0, 167.2, 172.0,

2. (a) Araki, S.; Butsugan, Y. J. Org. Chem. 1988, 53, 1831. (b)

Araki, S.; Butsugan, Y. J. Chem. Soc., Perkin Trans. 1 1991,

2395. (c) Li, C.-J.; Chen, D.-L. Synlett 1999, 735. (d) Lee,

J. G.; Choi, K. I.; Pae, A. N.; Koh, H. Y.; Kang, Y.; Cho, Y. S.

J. Chem. Soc., Perkin Trans. 1 2002, 1314. (e) Miao, W.;

Chan, T. H. Synthesis 2003, 785. (f) Foubelo, F.; Yus, M.

Tetrahedron: Asymmetry 2004, 15, 3823. (g) Lombardo, M.;

Gianotti, K.; Licciulli, S.; Trombini, C. Tetrahedron 2004, 60,

11725. (h) Babu, S. A.; Yasuda, M.; Shibata, I.; Baba, A.

¨ ¨ ¨

Synlett 2004, 1223. (i) Kallstrom, S.; Erkkila, A.; Pihko, P. M.;

¨

¨¨

Sjoholm, R.; Sillanpaa, R.; Leino, R. Synlett 2005, 751.

(j) Hirayama, L. C.; Gamsey, S.; Knueppel, D.; Steiner, D.;

DeLaTorre, K.; Singaram, B. Tetrahedron Lett. 2005, 46,

2315.

172.3; IR (thin ﬁlm): 2998, 2953, 1737, 1659, 1640 cm^K1

;

MS (EI): m/z (%)Z282 (8.9) [M^C], 250 (98.7), 223 (47.5),

188 (100.0), 162 (47.9), 131 (22.7), 102 (36.5).

3. (a) Chappell, M. D.; Halcomb, R. L. Org. Lett. 2000, 2, 2003.

(b) Hirashita, T.; Kinoshita, K.; Yamamura, H.; Kawai, M.;

Araki, S. J. Chem. Soc., Perkin Trans. 1 2000, 825. (c)

Izquierdo, I.; Plaza, M. T.; Tamayo, J. A.; Mota, A. J.

Synthesis 2004, 1083. (d) Babu, S. A.; Yasuda, M.; Shibata, I.;

Baba, A. Org. Lett. 2004, 6, 4475.

4.4.20. 3-Benzylidene-tetrahydro-4-vinylfuran 33. 1-(3-

((E)-4-Bromobut-2-enyloxy)prop-1-ynyl)benzene (264 mg,

1 mmol) and indium powder (114 mg) in THF/H₂O (1:1)

were reacted together and worked up in accordance with the

general method. Puriﬁcation of the crude reaction mixture

on silica (hexane/EtOAc 10:1) gave the desired vinylic

furan 33 as essentially a single diastereomer as a yellowish

4. (a) With aldehydes: Lombardo, M.; Girotti, R.; Morganti, S.;

Trombini, C. Org. Lett. 2001, 3, 2981. Kang, H.-Y.; Kim,

Y.-T.; Yu, Y.-K.; Cha, J. H.; Cho, Y. S.; Koh, H. Y. Synlett

2004, 45. (b) With ketones: Alcaide, B.; Almendros, P.;

Rodriguez-Acebes, R. J. Org. Chem. 2002, 67, 1925. (c) With

imines: Beuchet, P.; Marrec, M. L.; Mosset, P. Tetrahedron

Lett. 1992, 33, 5959. Vilaivan, T.; Winotapan, C.; Shinada, T.;

Ohfune, Y. Tetrahedron Lett. 2001, 42, 9073. Hirashita, T.;

Hayashi, Y.; Mitsui, K.; Araki, S. J. Org. Chem. 2003, 68,

1309. (d) With sulfonimines: Lu, W.; Chan, T. H. J. Org.

Chem. 2001, 66, 3467. (e) With acyl cyanides: Yoo, B.-W.;

Lee, S.-J.; Choi, K.-H.; Keum, S.-R.; Ko, J.-J.; Choi, K.-I.;

Kim, J.-H. Tetrahedron Lett. 2001, 42, 7287. (f) With acyl

silanes: Chung, W. J.; Higashiya, S.; Oba, Y.; Welch, J. T.

Tetrahedron 2003, 59, 10031. (g) With acetals: Kwon, J. S.;

Pae, A. N.; Choi, K. I.; Koh, H. Y.; Kim, Y.; Cho, Y. S.

Tetrahedron Lett. 2001, 42, 1957. (h) With oxime ethers:

Ritson, D. J.; Cox, R. J.; Berge, J. Org. Biomol. Chem. 2004, 2,

1921. (i) With quinolines: Lee, S. H.; Park, Y. S.; Nam, M. H.;

Yoon, C. M. Org. Biomol. Chem. 2004, 2, 2170. Kumar, S.;

Kaur, P. Tetrahedron Lett. 2004, 45, 3413. (j) With

hydrazones: Cook, G. R.; Maity, B. C.; Kargbo, R. Org.

Lett. 2004, 6, 1741. (k) With epoxides: Yadav, J. S.;

Anjaneyulu, S.; Ahmed, M. M.; Subba Reddy, B. V.

Tetrahedron Lett. 2001, 42, 2557. Oh, B. K.; Cha, J. H.;

Cho, Y. S.; Choi, K. I.; Koh, H. Y.; Chang, M. H.; Pae, A. N.

1

oil (56 mg, 30%): H NMR (360.13 MHz, CDCl₃) d 3.32

(1H, m), 3.93 (1H, dd, JZ1.9, 11.2 Hz), 4.00 (1H, dd, JZ

1.9, 11.2 Hz), 4.32 (1H, dd, JZ2.3, 16.1 Hz), 4.42 (1H, dd,

JZ2.1, 16.1 Hz), 4.94 (1H, d, JZ17.2 Hz), 5.01 (1H, d, JZ

10.3 Hz), 5.79 (1H, ddd, JZ7.8, 10.3, 17.2 Hz), 7.30 (5H,

m); ¹³C NMR (100.62 MHz, CDCl₃) d 47.7, 59.6, 71.3,

117.8, 118.9, 127.9, 128.5, 128.8, 128.9, 132.2, 136.6,

137.7, 139.9; IR (thin ﬁlm): 3400, 3057, 2851, 1954, 1883,

1725, 1693, 1659 cm^K1; MS (CI): m/z (%)Z228 (100.0)

[MNaNH^C₄], 193 (26.3), 165 (54.1).

Acknowledgements

The authors would like to thank King’s College Chemistry

department for ﬁnancial support. MMS would also like to

thank Pﬁzer Ltd and Syngenta for small project grants. Also

the authors would like to thank Ms Soﬁa Sardo-Inﬁrri for

her input, Mr Jon Cobb for NMR support, and Dr Jon Steed

(University of Durham) for assistance with X-ray crystallo-

graphic measurements.

3598

A. Goeta et al. / Tetrahedron 62 (2006) 3582–3599

Tetrahedron Lett. 2003, 44, 2911. Hirashita, T.; Mitsui, K.;

Hayashi, Y.; Araki, S. Tetrahedron Lett. 2004, 45, 9184 and

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´

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30. Full crystallographic data is presented in the Supporting

Information supplied with the present paper. Alernatively,

crystallographic data (excluding structure factors) for the

structures in this paper have been deposited with the

Cambridge Crystallographic Data Centre as supplementary

publication numbers CCDC 279213. Copies of the data can be

obtained, free of charge, on application to CCDC, 12 Union

Road, Cambridge CB2 1EZ, UK [fax: C44 1223 336033 or

deposit@ccdc.cam.ac.uk].

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¹H NMR with that of compound 7d. The syn conﬁguration of

7d was in turn estabilshed by NOESY spectroscopy where a

small but real NOE was observed between H₃and H₆(arbitrary

numbering).

Me

CO₂Me

O

H₆

O

43

CH₃

O

37. Chan, T. H.; Yang, Y. J. Am. Chem. Soc. 1999, 121, 3228.

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H₃

7d

Article Doi

New indium-mediated cyclisation reactions of tethered haloenynes in aqueous solvent systems

DOI: 10.1016/j.tet.2006.01.094

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Article abstract of DOI:10.1016/j.tet.2006.01.094

Full text of DOI:10.1016/j.tet.2006.01.094

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