1-Iodo-1-selenoalkenes as versatile alkene 1,1-dianion equivalents. Novel connective approach towards the tetrahydropyran subunit of polycavernoside A

Tetrahedron 62 (2006) 2331–2349

1-Iodo-1-selenoalkenes as versatile alkene 1,1-dianion equivalents.

Novel connective approach towards the tetrahydropyran

subunit of polycavernoside A

*

´

´ ´

Carlos Perez-Balado and Istvan E. Marko

´

ˆ

Departement de Chimie, Universite catholique de Louvain, Batiment Lavoisier, Place Louis Pasteur 1, B-1348 Louvain-la-Neuve, Belgium

Received 31 August 2005; revised 14 November 2005; accepted 1 December 2005

Available online 9 January 2006

Abstract—syn-Hydroalumination of 2,4,6-triisopropylphenylselanyl-1-alkynes with DIBAL-H followed by Al/I exchange with I₂afforded

exclusively (E)-1-iodo-1-selenoalkenes in good yields. 1-Iodo-1-selenopropene 10 proved to be a convenient 1,1 dianion equivalent, leading

to the stereodivergent synthesis of allylsilanes (Z)-6 and (E)-6. Adduct 3, an intermediate in the synthesis of the tetrahydropyran subunit of

polycavernoside A, was efﬁciently synthesised from allylsilane (Z)-6 and aldehyde 7 via an intramolecular Sakurai cyclisation.

SOPh

1. Introduction

O

In April 1991, the ingestion of the red alga gracilaria tsudae

caused a severe human intoxication in the island of Guam.

Thirteen people were affected; three of them died.¹This alga,

documented only from the west coast of Guam, is a local

gastronomic speciality that develops seasonal toxic properties

for still unknown reasons. In 1993, Yasumoto and co-workers

reportedtheisolation,fromthe causativealga, ofpolycaverno-

sides A and B, which were identiﬁed as the responsible toxins

for fatal poisoning.²Three other analogs (A2, A3, B2) were

reported by Yasumoto in 1995.³Polycavernoside A 1 is the

main member of a growing family of polycavernoside

congeners. Since the elucidation of its planar structure, 1 has

attracted the attention of several synthetic groups, undoubt-

edly due to its challenging architectural features and its

biological activities. Polycavernoside A possesses an unusual

13-membered keto-lactone ring and an interesting ﬁve-

membered hemiketal function connected to the C₉ketone

group. Moreover, a labile triene moiety is linked to C₁₅

(Scheme 1). The ﬁrst total synthesis of 1 was reported by

Murai and co-workers in 1998. They established at the same

time its absolute stereochemistry.⁴Two other total synthesis

have been reported so far.⁵

O

5

O

OH

4

O

13

15

HO ¹⁰O

O

1

9

O

5

S

S MeO

O

MeO

O

OMe

O

OMe

OH

1

OH

2

Polycavernoside A

S

OH

Our retrosynthetic analysis of 1 is depicted in Scheme 1.

Disconnection of the C₁–O and C₉–C₁₀bonds leads to three

fragments of approximately the same molecular complexity.

O

MeO

O

OMe

SPh

O

OMe

OH

OMe

Keywords: Alkenes; Carbanions; Polycavernoside A; Sakurai cyclisation;

Selenium.

3

*

Corresponding author. Tel.: C32 10 47 8773; fax: C32 10 47 2788;

e-mail: marko@chim.ucl.ac.be

Scheme 1. Retrosynthetic analysis of polycavernoside A.

doi:10.1016/j.tet.2005.12.005

´ ´

C. Perez-Balado, I. E. Marko / Tetrahedron 62 (2006) 2331–2349

2332

The northern subunit consists of the ﬁve-membered lactone

4, bearing the trienyl side chain, and the southern moiety 2

embodies a tetrasubstituted tetrahydropyran core. The

disaccharide residue has already been efﬁciently prepared

by Murai et al.⁶Our laboratory has previously disclosed an

expedient synthesis of 4 from the readily available

g-butyrolactone subunit 5.⁷Recently, we have reported

our preliminary results on a stereocontrolled approach to the

tetrahydropyran subunit 2, via an intramolecular Sakurai

cyclisation (IMSC).⁸In this article, we wish to present a full

account of our investigations directed towards a connective

and efﬁcient synthesis of the tetrahydropyran subunit of

polycavernoside A, using as a key intermediate, a novel

alkene 1,1-dianion equivalent.

C–C double bond of the allylsilane. According to this

model, the (Z)-allylsilane 6 is required to obtain the

tetrahydropyran possessing the correct stereochemistry

present in polycavernoside A.

Despite the number of procedures described in the literature

for the synthesis of alkenes, there are few, simple and

general methodologies that lead to the preparation of

trisubstituted allylsilanes with good stereocontrol of the

oleﬁn geometry.¹⁰In order to explore new strategies in this

ﬁeld, we decided to prepare allylsilane 6 from a synthetic

equivalent of an alkene 1,1-dianion. Several reports

describe the synthesis of alkene 1,1-bismetallic species.¹¹

Unfortunately, most of these reagents were found to suffer

from serious shortcomings, such as lack of reactivity,

difﬁculty in handling and, often, tedious preparation.

Therefore, it was deemed interesting to investigate the

reactivity of 1-halo-1-chalcogeno-alkenes 8 as equivalents

of alkene 1,1-dianions. Compounds such as 8 can be

handled without special precautions and can be transformed

easily into a variety of di- and tri-substituted oleﬁns via a

sequential functionalisation of both hetereoatom positions.

Interestingly, by inverting the sequence, the same precursor

8 should afford the opposite E/Z isomer of 6.

According to our strategy, the southern subunit 2 could be

derived from the tetrahydropyran 3 by a few functional

group transformations. Thus, the stereocontrolled pre-

paration of 3 became our prime objective. Our antithetic

analysis of 3 is shown in Scheme 2. Application of the

IMSC retron to 3 leads to the generation of two simple

fragments: the allylsilane 6 and the b-hydroxy aldehyde 7.

The condensation of these two fragments should afford

stereoselectively the requisite exo-methylene tetra-

hydropyran 3. The intramolecular Sakurai cyclisation is

believed to proceed via a two-step mechanism. The

coupling between an allylsilane such as 6 and an aldehyde

such as 7, in the presence of a Lewis acid, generates initially

an oxocarbenium cation intermediate, which undergoes

subsequent ring closure by intramolecular nucleophilic

addition of the pendant allylsilane function, to give a

tetrahydropyran ring possessing an exocyclic C–C double

bond. The relative conﬁguration of the three stereogenic

centres in the ﬁnal product is governed by the preference of

the substituents to occupy pseudoequatorial positions in the

chair-like transition-state during the ring closure step.⁹An

important parameter in the control of the relative orientation

of the substituents in the ﬁnal adduct is the geometry of the

The stereoselective synthesis of 1-halo-1-chalcogeno-

alkenes 8 was envisaged to be accomplished by the

hydrometallation of the C–C triple bond of 1-alkynyl

chalcogenides 10, followed by metal/halogen exchange of

the in situ generated 1-metallo-1-chalcogeno alkene species

9. Hydrometallation of hetero-substituted alkynes is usually a

highly regio- and stereoselective reaction and, in most cases,

the addition can be controlled to take place in a syn manner.

The C–C triple bond of 1-alkynyl chalcogenides is polarized

in such a way that the metal residue is typically positioned

on the carbon bearing the chalcogen substituent. The most

common hydrometallating agents are boron, aluminium and

zirconium mono hydrides. Among these, Cp₂Zr(H)Cl is the

most tolerant with regard to other functional groups.

S

OH

S

2. Results and discussion

O

OTBDMS

O

OH

+

H

2.1. Synthesis of 1-halogeno-1-chalcogeno-alkenes

7

(H₃C)₃Si

2.1.1. 1-Telluro-1-halogeno propenes. Attracted by the

broad range of interesting potential transformations that

organotellurides can undergo,¹²we began our investigations

by the preparation of 1-halo-1-telluro propenes, according

to the procedure described by Dabdoud et al.¹³Hydro-

zirconation of 1-butyltellanyl-propyne 11 with Cp₂Zr(H)Cl

generated in situ the 1-telluro-1-zircono alkene species

12,^14,15which was subsequently trapped with different

electrophiles giving the corresponding 1-alkenyl tellurides

13–16 (Scheme 3). In our hands, hydrozirconation of

11 afforded the 1-alkenyl tellurides in only moderate

yields. Besides the desired products, and in all cases, a

considerable amount of dibutyl ditelluride was formed. It

has been reported that 1-butyltellanyl alkynes undergo easy

tellurium–spC bond cleavage by treatment with hydrides,

such as DIBAL-H, LiAlH₄or NaBH₄, affording the

tellurium free alkyne and dibutyl ditelluride. It is believed

that hydride addition on the tellurium moiety generates

(Z)-6

3

X=Br, I

Y= Te, Se

R=alkyl, aryl

X

Y

R

8

X₂

L_nM

HML_n

Y

R

9

10

Scheme 2. Strategy for the synthesis of tetrahydropyran 3.

´ ´

C. Perez-Balado, I. E. Marko / Tetrahedron 62 (2006) 2331–2349

2333

11

H₃C

TeBu

Cp₂Zr(H)Cl (1.5 eq), THF, rt, 1hr

H₃C

H

TeBu

I₂, (1.5 eq),

THF, 0°C to rt

NBS (1.5 eq)

THF, 0°C to rt

Zr

Cl

12

D₂O

aq. NH₄Cl

H₃C

TeBu

H₃C

TeBu

H₃C

TeBu

I

Br

D

13 53%

E/Z ratio: 3/1

Scheme 3. Hydrozirconation–halogenation of telluroalkyne 11.

45%

53%

15

16

49%

14

E/Z ratio: 1/1

butyltellurol and an acetylide anion. Butyltellurol is

deprotonated by the hydride to give butyltellurate, which

rapidly oxidises to dibutyl ditelluride in the presence of

oxygen, during the work-up.¹⁵Our results indicate that the

hydrozirconation of 11 leads to the competitive formation of

dibutyl ditelluride via an analogous pathway.

hydrozirconation of other, more ameanable precursors.

Moreover, 1-iodo-1-butyltellanyl-propene 13 and

1-bromo-1-butyltellanyl propene 16 were always obtained

as an inseparable mixture of E/Z isomers.

2.1.2. 1-Seleno-1-halogeno alkenes. Searching for sub-

strates less prone to undergo heteroatom-spC cleavage

during the hydrozirconation step, and aware that the C–Se

bond is stronger than the C–Te bond, we elected to study the

hydrometallation of the corresponding alkynyl selenides. As

a model compound, hex-1-ynylselanyl-benzene 17 was

hydrozirconated with Cp₂Zr(H)Cl and the in situ generated

1-seleno-1-zircono-alkene intermediate 18 was quenched

with various electrophiles (Scheme 4).^17,18As expected, the

corresponding 1-alkenyl selenides 19–22 were obtained in

better yields (around 70%) as compared to the 1-alkenyl

tellurides. However, diphenyl diselenide was formed as

In our case, the optimised conditions for the hydrozirco-

nation of 11 were found to require 1.5 equiv of freshly

prepared Cp₂Zr(H)Cl. However, other groups reported

the use of 1.1^13band 2.0^13aequiv as the optimal number

of Cp₂Zr(H)Cl equivalents. The isolated yields of 1-alkenyl

tellurides also differ signiﬁcantly from one group to another,

indicating that the hydrozirconation of 1-alkynyl tellurides

is highly dependent upon the quality and the mode of

preparation of Cp₂Zr(H)Cl.¹⁶These results are thus difﬁcult

to reproduce and it was decided to investigate the

17

Bu

SePh

Cp₂Zr(H)Cl (1.2 eq), DCE, rt, 1hr

Bu

H

SePh

I₂, (1.3 eq),

DCE, -10°C to rt

NBS (1.3 eq)

DCE, 0°C to rt

Zr

Cl

18

D₂O

aq. NH₄Cl

Bu

SePh

Bu

SePh

71%

Bu

SePh

I

Br

D

19 70%

E/Z ratio: 4/1

Scheme 4. Hydrozirconation–halogenation of selenoalkyne 17.

71%

21

22

62%

20

E/Z ratio: 1.1/1

´ ´

C. Perez-Balado, I. E. Marko / Tetrahedron 62 (2006) 2331–2349

2334

the main by-product, indicating that the competitive Se–spC

cleavage could not be completely prevented. Trapping 18

with I₂or NBS, at low temperature, provided an inseparable

mixture of (E)- and (Z)-isomers of the corresponding

1-halo-1-selenoalkenes 19 and 22. Though the iodoalkene

19 was obtained in a fairly good yield, and a reasonable E/Z

ratio of 4:1, such a selectivity is clearly not adequate for

synthetic purposes.

was isolated in 95% yield. Diselenide 27 could not be

detected in the crude reaction mixture (Scheme 5). It thus

transpires that the steric hindrance of the TIPP group

dramatically inﬂuences the selectivity of the hydroalumina-

tion reaction by suppressing the competitive C–Se bond

cleavage. The formation of the diselenide by-product 27 is

prevented and the hydrometallation of the C–C triple bond

becomes essentially quantitative.

In order for our methodology to embrace broad synthetic

interest, it proved imperative to overcome three main

drawbacks; (i) to prevent completely the competitive

Se–spC bond cleavage; (ii) to avoid the isomerisation

during the metal/halogen exchange and (iii) if possible, to

replace the expensive and sensitive Cp₂Zr(H)Cl by another,

cheaper and easier to handle, hydrometallating agent.

Having discovered that the use of the TIPP group enabled

the efﬁcient hydroalumination of 24, we next turned our

attention to the metal/halogen exchange reaction. To our

delight, trapping of 25 with I₂, at low temperature, afforded

the corresponding 1-iodo-1-selenoalkene 28 in 95% yield.

Even more gratifyingly, only the (E)-isomer was isolated,

indicating that the replacement of Al by I took place

with retention of conﬁguration of the C–C double bond

(Scheme 6). In sharp contrast, bromination of 25, either with

Br₂or NBS, afforded a 1/1 mixture of (E)- and (Z)-1-bromo-

1-selenoalkenes 29. Although the yields were good, the

replacement of Al by Br occurred with complete scrambling

of the conﬁguration of the C–C double bond, even under

carefully controlled reaction conditions. These observations

suggest that bromination and iodination of 25 might follow

different mechanistic pathways.

Hydroalumination of hex-1-ynylselanyl-benzene 17 with

DIBAL-H,¹⁹followed by quenching with dilute HCl,

provided a mixture of 1-hexenyl selenide 20 (61% yield)

and diphenyl diselenide 23 (39% yield, Scheme 5).

Although DIBAL-H produced more diphenyl diselenide

than Cp₂Zr(H)Cl, it was envisioned that the competitive

spC–Se bond cleavage could probably be suppressed by

selectively hindering the selenium atom, thereby impeding

the coordination between the selenium substituent and

the aluminium reagent and hence, thwarting the delivery

of hydride on selenium. In order to verify our hypothesis,

1-(2,4,6)-triisopropylphenyl-selenyl-hex-1-yne 24, bearing

the voluminous 2,4,6-triisopropylphenyl (TIPP) substituent

instead of the phenyl group, was prepared.²⁰When 24 was

treated with DIBAL-H, followed by quenching of the

intermediate vinyl alane 25 with dilute HCl (under the same

conditions than 18), we were delighted to observe the

exclusive formation of the (Z)-alkenyl selenide 26, which

Bu

SeTIPP

24

DIBAL-H, hexane/toluene, 0°C

I₂, (2.5eq),

THF, -78°C to rt

NBS (2.5 eq)

THF, -78°C to rt

Bu

H

SeTIPP

Al (i-Bu)₂

25

R= Ph

17

Bu

SeR

R=TIPP 24

DIBAL-H (1eq)

hexane, toluene, 0° to rt

Br₂(2.5 eq)

THF, -78°C to rt

Bu

SeTIPP

I

Bu

SeTIPP

Br

Bu

H

SeR

R= Ph

18

28 95%

exclusively E

29

90%

R=TIPP 25

Al(i-Bu)₂

E/Z ratio: 1/1

Scheme 6. Hydroalumination–halogenation of selenoalkyne 24.

1M HCl

In order to verify that this sequence could constitute a new

method for the synthesis of (E)-1-iodo-1-selenoalkenes, this

procedure was applied to other 1-alkynyl selenides bearing

the TIPP group. The results of our investigations are shown

in Table 1. In all cases, the corresponding (E)-1-iodo-1-

selenoalkenes 32 were obtained in good to excellent yields

and as a single isomer. Only the phenyl acetylene derivative

30f refused to react (entry 6). In this case, the addition of

DIBAL-H to the triple bond did not occur, even when the

reaction was attempted in hexane at reﬂux. This lack of

reactivity could be due to prohibitive steric repulsions that

gradually build up between the phenyl and the SeTIPP

groups during the addition of the aluminium hydride.

Bu

H

SeR

+

(RSe)₂

H

R= Ph

R=TIPP

20 (61%)

26 (95%)

23 (29%)

27 (0%)

TIPP = 2,4,6-triisopropylphenyl =

Scheme 5. Effect of the TIPP group on the hydroalumination of

selenoalkynes.

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C. Perez-Balado, I. E. Marko / Tetrahedron 62 (2006) 2331–2349

2335

Table 1. Synthesis of (E)-1-iodo-1-selenoalkenes via hydroalumination–iodination

R

SeTIPP

R

H

SeTIPP

I

I₂

DIBAL-H

R

SeTIPP

H

Al(i-Bu)₂

hexane/toluene

THF

30

0°C to rt

-78°C to rt

32

31

Entry

1

Substrate

Product

Yield (%)^a

SeTIPP

30a

92

95

H

I

32a

SeTIPP

2

3

SeTIPP

H

I

30b

32b

SeTIPP

O

H

I

96

82

30c

30d

32c

SeTIPP

4

SeTIPP

H

I

32d

SeTIPP

I

5

6

91

0

30e

30f

32e

—

^aIsolated yield after puriﬁcation by column chromatography.

The Al/I exchange requires a careful control of the reaction

conditions in order for the iodination to be complete. If the

reaction mixture is stirred longer than 1 h at room

temperature, some degradation occur, accompanied by the

appearance of the (Z)-isomer.

labile C–I bond was selectively replaced by a C–C bond,

either via the intermediacy of the 1-seleno-1-lithio-alkene

species 33 or via a palladium-catalysed cross-coupling

with organozinc derivatives. Subsequently, the selenium

substituent was replaced by a second C–C bond, either via

the generation of the disubstituted 1-alkenyl lithium species

35 or via nickel-catalysed cross-coupling with Grignard

reagents. No loss of the C–C double bond integrity was

observed in this overall process, indicating that 1-iodo-1-

selenoalkenes 32 are convenient 1,1-dianion equivalents for

the stereoselective synthesis of trisubstituted alkenes.

It did not escape us that the 1-alumino-1-seleno-alkene

intermediate 25 (Scheme 6) could be an interesting

precursor for the stereodeﬁned synthesis of alkenes, since

it is readily accessible from 24 via a simple and selective

hydroalumination. Unfortunately, 25 proved to be rather

unreactive towards various carbon electrophiles.

2.1.4. Functionalisation of the iodo position. 1-Iodo-1-

selenoalkene 32a underwent smooth I/Li exchange when

reacted with n-BuLi or t-BuLi, to give the 1-seleno-1-

alkenyllithium intermediate 33a.²¹Subsequent treatment

with various electrophiles, including acylating agents,

2.1.3. Functionalisation of 1-iodo-1-selenoalkenes. With

an efﬁcient access to (E)-1-iodo-1-selenoalkenes in hand,

we turned our attention to the sequential functionalisation of

both heteroatom positions (Scheme 7). Initially, the more

R²

R¹

R

Li

R

SeTIPP

I

R

SeTIPP

R¹

R²X

R¹X

R

SeTIPP

Li

BuLi

LDBB

R¹

35

34

32

37

+

33

Pd(PPh )

LiSeTIPP

36

1

R ZnI,

3 4

R²MgBr, Ni(acac)₂

Scheme 7. Functionalisation of 1-iodo-1-selenoalkenes.

´ ´

C. Perez-Balado, I. E. Marko / Tetrahedron 62 (2006) 2331–2349

2336

aldehydes, epoxides or alkyl halides, afforded the corres-

ponding functionalised 1-alkenyl selenides 34 in good

yields (Table 2). The I/Li exchange was carried out with

1 equiv of n-BuLi, either in THF at K78 8C or in hexane at

room temperature. The choice of the best conditions

depends strongly upon the electrophile. In the case of

valeraldehyde (entry 7), better yields were obtained when

the I/Li exchange was performed in hexane, at room

temperature.²²On the contrary, benzoyl chloride (entry 4)

gave better results when the metallation was performed in

THF, at K78 8C. In order to prevent the formation of

butylated by-products, when alkyl halides (entries 10 and

11) were used as electrophiles, the exchange was performed

with 2 equiv of t-BuLi in THF, at K78 8C. In the case of the

allysilane 34k (entry 11), an interesting improvement was

observed when the alkenyl lithium intermediate 33a was

generated by reverse addition, that is, by adding 1-iodo-1-

selenoalkene 32a to a solution of t-BuLi in THF, cooled at

K78 8C. Subsequent treatment of 33a with iodomethyl-

trimethylsilane afforded 34k in 78% yield. Normal addition

(t-BuLi added to a THF solution of 33a at K78 8C) gave

34k in only 41% yield.

able to insert into the sterically hindered C–Se bond. More

encumbered organomagnesium derivatives, such as phenyl-

magnesium bromide or (trimethylsilylmethyl)magnesium

chloride, in the presence of Ni(acac)₂, did not afford the

expected products.

2.1.6. Synthesis of the (Z)- and (E)-allylsilanes 6. As

previously discussed, the construction of the tetra-

hydropyran core of polycavernoside A was envisioned

from the (Z)-allylsilane 6 and the aldehyde 7, via an IMSC

condensation. The (Z)-allylsilane 6 was readily assembled

from the (E)-1-iodo-propenyl selenide 32a by sequential

replacement of the heteroatom substituents (Scheme 9).

Opening of the dithianylmethyl oxirane 43, by the vinylic

anion derived from 32a by I/Li exchange with n-BuLi, in the

presence of BF₃$OEt₂, resulted in the formation of the

homoallylic alcohol 34i in 50% yield based upon 32a (100%

based upon oxirane 43). In the absence of the Lewis acid,

this vinyl lithium species proved to be rather unreactive

towards oxirane 43. The moderate yield in the presence

of BF₃$OEt₂is due to the concomitant formation of

an unreactive vinyl ﬂuoroborate intermediate,²⁸which

consumes 50% of the vinyl lithium reagent. By employing

two equivalents of vinylselenide 32a, a quantitative yield of

adduct 34i was obtained.

Treatment of 32a with 2 equiv of isopropylmagnesium

chloride, in THF, at room temperature led to the I/Mg

exchange.²³However, the resulting 1-seleno-1-alkenyl

magnesium chloride intermediate did not react with carbon

electrophiles. This Grignard reagent only underwent

protonolysis and deuterolysis.

After treatment of 34i with methylmagnesium bromide, in

order to deprotonate the homoallylic hydroxy function, the

alkenyl C–Se bond was reductively cleaved with LDBB,

generating the carbanion 45 and lithium selenoate 36

(Scheme 7). Whilst it is reasonable to assume that the

lithium salt 45 is initially formed under these reductive

conditions, it is quite plausible that metal exchange might

take place under the reaction conditions, leading either to 46

or an equilibrating mixture of 45 and 46, with the latter

reagent being the active species in the subsequent coupling

step. In this regard, using n-BuLi to perform the

deprotonation of alcohol 34i, followed by LDBB treatment,

led to signiﬁcant erosion in the yields of 44 (Scheme 10).

The palladium-catalysed cross coupling of 1-iodo-1-

selenoalkene 32b with organozinc species (Scheme 8)

enabled the direct formation of a C–C bond from the C–I

bond. However, only moderate yields were obtained so far.

2.1.5. Functionalisation of the seleno position. The vinylic

C–Se bond of several functionalised 1-alkenyl selenides was

reductively cleaved in the presence of 2 equiv of LDBB

(lithium 4,4⁰-di-tert-butylbiphenyl),²⁴generating in situ

lithium 2,4,6-triisopropylphenylselenoate 36 and the corres-

ponding 1-alkenyl lithium 35 (Scheme 7).²⁵Trapping of the

1-alkenyl lithium derivatives with various electrophiles, at

low temperature, afforded the expected trisubstituted

alkenes 37–42 in good yields and with complete retention

of the C–C double bond geometry (Table 3). The selenoate

36, generated as a by-product, proved to be a better

nucleophile than the 1-alkenyl lithium species. In the

reactions of 35 with alkylating agents, the selective

quenching of selenoate 36 with 1 equiv of MeI (to give

1 equiv of 2,4,6-triisopropylphenyl methyl selenide), was

routinely performed prior to the addition of the electrophile.

Attempts to react the organometallic derivatives 45/46 with

various alkylating agents, in order to introduce directly the

CH₂TMS moiety failed, probably owing to the lack of

reactivity of these silyl-containing electrophiles. Quenching

of 45/46 with I₂led to the vinyl iodide 44 in excellent yield.

It is noteworthy that 1 equiv of MeI has to be added to the

lithiated species 45/46, before the iodine quench, in order to

obtain good yields of 44. Cross-coupling of 44 with

trimethylsilylmethyl magnesium chloride, catalysed by

Pd(PPh₃)₄, ultimately generated the requisite (Z)-allylsilane

6 in 55% overall yield from 34i (Scheme 6). The (Z)-

conﬁguration of the C–C double bond was established by

NOE experiments and subsequently conﬁrmed by the

independent synthesis of the (E)-isomer, indicating that

the transformation of 32a to (Z)-6 took place with retention

of conﬁguration.

It has been described that the vinyl C–Se bond of 1-alkenyl

selenides undergoes cross-coupling with organomagnesium

derivatives in the presence of nickel complexes as

catalyst.²⁶This coupling led to a straightforward construc-

tion of tri- and tetrasubstituted allylsilanes.²⁷In our case,

probably due to the steric hindrance of the TIPPSe group,

only methylmagnesium bromide could be coupled to 34

(Table 3, entries 5 and 6) using Ni(acac)₂as catalyst. When

nickel complexes bearing phosphino ligands were

employed, only the starting material was recovered. This

observation indicates that only ligandless Ni(0) species are

To demonstrate the versatility of our methodology, the

opposite (E)-allylsilane 6 was synthesised from the same

precursor 32a by simply inverting the heteroatom exchange/

alkylation sequence. Thus, vinyl selenide 34k was obtained

in 78% yield by alkylation of the vinyl anion, derived from

´ ´

C. Perez-Balado, I. E. Marko / Tetrahedron 62 (2006) 2331–2349

2337

Table 2. Stereocontrolled iodine replacement in 32a

SeTIPP

I

SeTIPP

R¹

1. BuLi

H

1

2. R

32a

34

Entry

1

Conditions

Electrophile

H₂O

Product

Yield (%)^a

SeTIPP

n-BuLi (1 equiv), THF, K78 8C

n-BuLi (1 equiv), hexane, rt

91

92

34a

SeTIPP

2

3

D₂O

D

34b

SeTIPP

O

N

n-BuLi (1 equiv), THF, K78 8C

t-BuLi (2 equiv), THF, K78 8C

67

72

78

82

34c

SeTIPP

O

4

5

6

Cl

34d

SeTIPP

O

F₃C

CF₃

F₃C

34e

SeTIPP

O

OH

H

34f

SeTIPP

O

7

n-BuLi (1 equiv), hexane, rt

65

H

O

HO

34g

SeTIPP

.

, BF₃OEt₂

8

n-BuLi (1 equiv), THF, K78 8C

50

C₆H₁₃

HO

C₆H₁₃

34h

SeTIPP

S

O

.

, BF₃OEt₂

9

n-BuLi (1 equiv), THF, K78 8C

50

HO

S

34i

SeTIPP

10

11

t-BuLi (2 equiv), THF, K78 8C

Mel

93

78

34j

SeTIPP

t-BuLi (2 equiv), THF, K78 8C, reverse

addition

Si(CH₃)₃

I

Si(CH₃)₃

34k

^aIsolated yield after puriﬁcation by column chromatography.

´ ´

C. Perez-Balado, I. E. Marko / Tetrahedron 62 (2006) 2331–2349

2338

Bu SeTIPP

PhZnBr

Pd(PPh₃)₄(10 mol %),

THF, rt

Bu

SeTIPP

I

34l

(35%)

32b

IZnCH₂Si(CH₃)₃

Bu

SeTIPP

Pd(PPh₃)₄(10 mol %),

THF, rt

Si(CH₃)₃

(38%)

34m

Scheme 8. Negishi coupling of 32b.

Table 3. Stereocontrolled selenium substitution in 34

R

H

SeTIPP

R¹

R

H

R²

R¹

37-42

LDBB then E

or

Ni(acac) then Nu

34

2

Entry

Sustrate

Conditions

Electrophile/

nucleophile

Product

Yield (%)^a

Bu

SeTIPP

1

LDBB (2 equiv), THF, K78 8C

Mel

67

(H₃C)₃Si

34m

(H₃C)₃Si

37

Bu

SeTIPP

O

H

Bu

OH

2

LDBB (2 equiv), THF, K78 8C

62

(H₃C)₃Si

34m

(H₃C)₃Si

38

SeTIPP

S

(1) n-BuLi (1 equiv), THF,

K78 8C (2) LDBB (2 equiv)

S

HO

3

H₂O

92

HO

S

39

40

34i

S

SeTIPP

O

S

HO

4

5

LDBB (2 equiv), THF, K78 8C

85

60

34a

BF₃$OEt₂

SeTIPP

Ni(acac)₂(1 mol%), THF, room

temperature

MeMgBr

HO

C₆H₁₃

41

C₆H₁₃

34h

SeTIPP

Ni(acac)₂(1 mol%), THF, room

temperature

S

HO

6

MeMgBr

64

S

HO

S

42

34i

^aIsolated yield after puriﬁcation by column chromatography.

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C. Perez-Balado, I. E. Marko / Tetrahedron 62 (2006) 2331–2349

2339

O

S

OH

O

BF_3.OEt₂

+

S

SeTIPP

I

OTBDMS

H

CH₂Cl₂,

-78˚C to rt

43

S

7

TMS

d, 78%

32a

a, 100%

(Z)-6

SeTIPP

Si(CH₃)₃

TBDMSO

O

S

34k

34i

HO

S

Me₃Si

48

O

S

e, 50%

H₁

H₅

43

S

HO

81%

b

H₄

O

S

91%

H₂

H₃

S

I

S

J_1-2= 9.6 Hz

S

J_3-5=10 Hz J_4-5=3 Hz

HO

S

3

HO

(E)-6

44

Scheme 11. The IMSC condensation.

S

32a by I/Li exchange with t-BuLi, with iodomethyl-

trimethylsilane. Reductive lithiation of 34k with LDBB

generated in situ the corresponding 1-alkenyl lithium

species, which opened oxirane 43 in the presence of

BF₃$OEt₂, to give the (E)-allylsilane 6 in 39% overall

yield from 32a.

Me₃Si

H₃C

ClMg

Si(CH₃)₃

H

(Z)-6

H

S

OH

c, 68%

3.1%

2.1.7. Intramolecular Sakurai cyclisation. With a ready

supply of allylsilane (Z)-6 in hand, we next turned our

attention to the crucial intramolecular Sakurai cyclisation.

We were delighted to observe that the tetrahydropyran 3

could be readily obtained, in a 91% yield, when (Z)-6 and

aldehyde 7 were treated with 1 equiv of BF₃$OEt₂, at low

temperature. Interestingly, it was found that smooth

deprotection of the TBDMS group occurred concomitantly,

when the reaction mixture was allowed to warm up to room

temperature, affording in a single operation the free alcohol

3. The relative stereochemistry of 3 was unambiguously

established by careful analysis of its ¹H NMR spectrum. The

coupling constant values of 9.6 and 10 Hz for the H¹–H²and

H⁵–H³hydrogen pairs clearly indicate that the three

substituents occupy equatorial positions on the tetra-

hydropyran ring system (Scheme 11).

2%

N.O.E.

S

Scheme 9. Preparation of (Z)- and (E)-allysilanes 6. Conditions: (a) n-BuLi,

THF, K78 8C, 30 min, BF₃$OEt₂, then (G)-43, THF, K78 8C, 1 h;

(b) CH₃MgBr, THF, 0 8C, 15 min, LDBB (2 equiv), K78 8C, 30 min, MeI,

K78 8C, 15 min, then I₂, K78 8C, 1 h; (c) ClMgCH₂Si(CH₃)₃, Pd(PPh₃)₄,

THF, rt, 9 h; (d) t-BuLi (2 equiv), THF, K78 8C, 10 min, then

iodomethyltrimethylsilane, THF, K78 8C to rt; (e) LDBB (2 equiv),

THF, K78 8C, 30 min, MeI, K78 8C, 15 min, BF₃$OEt₂then (G)-43,

THF,K78 8C, 1 h.

SeTIPP

Li

MgBr

1. CH₃MgBr (1eq),

THF, 0°C

or

HO

S

BrMgO

LiO

46

2. LDBB (2 eq),

-78°C

45

The relative stereochemistry of adduct 3 can be easily

rationalised by examining the transition state invoked in the

ﬁnal cyclisation of the allylsilane residue onto the

oxocarbenium cation 48. In order to minimise steric

interactions, the substituents occupy pseudoequatorial

positions. The geometry of the allylsilane double bond

controls the C₂conﬁguration.

S

+

34i

LiSeTiPP

36

I

1. MeI (1 eq),

-78°C

HO

44 (81%)

S

2. I₂(2.5 eq),

3. Conclusions

-78°C

In summary, we have shown that racemic tetrahydropyran 3

could be efﬁciently synthesised from allylsilane (Z)-6 and

aldehyde 7, using the IMSC condensation as a key step. By

the judicious control of the allylsilane C–C double bond, the

relative stereochemistry of three stereogenic centres could be

+

MeSeTiPP 47 (86%)

Scheme 10. Selenium replacement in 34i.

´ ´

C. Perez-Balado, I. E. Marko / Tetrahedron 62 (2006) 2331–2349

2340

established in a single operation. We have also developed a

simple and efﬁcient procedure for the stereocontrolled

preparation of a range of 1-iodo-1-selenoalkenes and

demonstrated that they are useful precursors for the synthesis

of stereodeﬁned di- and tri-substituted alkenes, including the

important allylsilane 6. These interesting vinylselenides can

be considered as alkene-1,1-dianion equivalents.

solvents were removed under reduced pressure. The crude

material was puriﬁed by ﬂash chromatography (hexane as

eluent) affording 168 mg (53% yield) of the title compound

as an inseparable mixture of isomers (E/Z:3/1; brown oil).

¹H NMR (200 MHz, CDCl₃): dZ7.08 (q, JZ6.8 Hz, 1H),

6.70 (q, JZ6.4 Hz, 1H), 2.92 (t, JZ7.4 Hz, 2H), 2.88 (t, JZ

7.4 Hz, 2H), 1.90–1.72 (m, 4H), 1.75 (d, JZ6.3 Hz, 3H),

1.67 (d, JZ7.4 Hz, 3H), 1.50–1.33 (m, 4H), 0.94 (t, JZ

7.2 Hz, 6H) ppm. ¹³C NMR (50 MHz, CDCl₃): dZ150.6,

149.2, 78.6, 74.6, 34.0, 24.8, 20.8, 14.9, 14.1, 13.5, 6.9 ppm.

4. Experimental

4.1. Generalities

4.1.3. (Z)-1-Butyltellanyl-propene (14). To a suspension of

Cp₂Zr(H)Cl (198 mg, 0.76 mmol, 1.2 equiv) under argon in

THF (1.5 mL) was added a solution of 1-butyltellanyl-

propyne 11 (143 mg, 0.64 mmol) in THF (2 mL). The

yellow suspension was stirred at room temperature for

20 min until a clear red solution was obtained. H₂O (2 mL)

was added and the mixture was stirred for a further 15 min.

Hexane was added until a white precipitate was formed. It

was ﬁltered through a short path of silica and the solvents

were removed under reduced pressure. The crude material

was puriﬁed by column chromatography (hexane as eluent)

affording 56 mg (53% yield) of the title compound as a

Unless otherwise stated all the reactions were carried out

using anhydrous conditions and under an atmosphere of

1

argon. H and ¹³C NMR spectra were recorded on Varian

Gemini 200 and 300 instruments. Chemical shifts are

expressed as parts per million (ppm) downﬁeld from

tetramethylsilane or calibrated from CDCl₃. Mass spectra

were obtained using Varian MAT-44 and Finnigan MAT-

TSQ 70 spectrometers with electron impact (70 eV) and

chemical ionization (100 eV, ionization gas, isobutene). IR

spectra were taken with a BIO-RAD FTS 135 spectrometer.

¨

Microanalysis were performed in Professor V. Jager’s

analytical laboratory (Institut fu¨r Organishe Chemie,

¨

Universitat Stuttgart, Germany). High resolution mass

spectra were recorded in Professor R. Flamant’s laboratory

1

yellow oil. H NMR (200 MHz, CDCl₃): dZ6.58 (dd, JZ

9.3, 1.2 Hz, 1H), 6.24 (dq, JZ9.3, 6.4 Hz, 1H), 2.68 (t, JZ

7.4 Hz, 2H), 1.84–1.68 (m, 2H), 1.71 (dd, JZ6.4, 1.2 Hz,

2H), 1.45–1.30 (m, 2H), 0.92 (t, JZ7.3 Hz, 3H) ppm. ¹³C

NMR (50 MHz, CDCl₃): dZ142.4, 100.2, 34.1, 24.9, 13.9,

13.6, 9.9 ppm. IR (neat, NaCl): nZ3025, 2940, 2923, 2201,

1424, 1031, 1011 cm^K1. MS (EI): m/z (%): 226 [M^C%] (85).

Elemental analysis calcd for C₇H₁₄Te (225.78): C, 37.24; H,

6.25. Found C, 37.69; H, 6.47.

´

(Universite de Mons, Belgium).

4.1.1. 1-Butyltellanyl-propyne (11). Methylacetylene was

bubbled through a stirred solution of n-BuLi (6.25 mL,

10 mmol, 1.6 M in hexanes) in THF (7 mL) cooled at 0 8C,

until the initial yellow solution becomes a milky suspension.

Tellurium (1.3 g, 10 mmol) was added and the suspension

heated for 1 h at reﬂux. The heat source was removed,

1-iodobutane (1.1 mL, 10 mmol) was added and the mixture

was stirred overnight at room temperature. The reaction

mixture was diluted with petroleum ether (30 mL), washed

with brine (30 mL), dried over MgSO₄and the solvents

were removed under reduced pressure. The crude material

was puriﬁed by ﬂash chromatography (petroleum ether)

affording 1.63 g (73%) of the title compound as a yellow oil.

¹H NMR (200 MHz, CDCl₃): dZ2.79 (t, JZ7.4 Hz, 2H),

2.16 (s, 3H), 1.85 (m, 2H), 1.42 (d, JZ6.9 Hz, 2H), 0.94

(t, JZ7.3 Hz, 3H) ppm. ¹³C NMR (50 MHz, CDCl₃): dZ

189.3, 125.7, 33.7, 24.7, 13.3, 8.6, 5.8 ppm. IR (neat, NaCl):

nZ3027, 2936, 2197, 1423, 1030, 1011 cm^K1. MS (EI): m/z

(%): 224 [M^C%] (76), 168 [M^C%KC₄H₉] (41). Elemental

analysis calcd for C₇H₁₂Te (223.77): C, 37.57; H, 5.41.

Found C, 38.02; H, 5.63.

4.1.4. (Z/E)-1-Bromo-1-butyltellanyl-propene (16). To a

suspension of Cp₂Zr(H)Cl (240 mg, 0.93 mmol) in THF

(1 mL) under argon was added a solution of 1-butyltellanyl-

propyne 11 (137 mg, 0.62 mmol) in THF (1.5 mL). The

mixture was stirred at room temperature until a red solution

was obtained (ca. 15 min). The solution was cooled to

K40 8C and neat NBS (166 mg, 0.93 mmol) was added.

The mixture was stirred for 1 h at K40 8C and then it was

allowed to slowly reach K10 8C. Hexane (6 mL) was added

in order to precipitate the zirconium salts. The solids were

removed by ﬁltration through a path of silica and the

solvents were removed under reduced pressure. The crude

material was puriﬁed by ﬂash chromatography (hexane as

eluent) affording 92 mg (49% yield) of the title compound

as an inseparable mixture of isomers (Z/E:1/1; brownish

1

oil). H NMR (200 MHz, CDCl₃): dZ6.74 (q, JZ6.5 Hz,

1H), 6.59 (q, JZ6.9 Hz, 1H), 2.95 (t, JZ7.5 Hz, 4H), 1.94–

1.76 (m, 4H), 1.81 (d, JZ6.5 Hz, 3H), 1.72 (d, JZ6.9 Hz,

3H), 1.51–1.32 (m, 4H), 0.94 (t, JZ7.2 Hz, 6H) ppm. ¹³C

NMR (50 MHz, CDCl₃): dZ144.5, 138.2, 109.2, 106.5,

33.9, 24.7, 13.3, 12.5, 12.0, 7.0 ppm.

4.1.2. (Z/E)-1-Butyltellanyl-1-iodo-propene (13). To a

suspension of Cp₂Zr(H)Cl (348 mg, 1.35 mmol) in THF

(1.5 mL) under argon was added a solution of 1-butyltel-

lanyl-propyne 11 (201 mg, 0.9 mmol) in THF (2 mL). The

mixture was stirred at room temperature until a red solution

was obtained (ca. 15 min). The solution was cooled to 0 8C

and a solution of I₂(343 mg, 1.35 mmol) in THF (0.5 mL)

was added. The mixture was stirred for 1 h at 0 8C and was

then allowed to slowly reach room temperature. It was

diluted with hexane (10 mL), washed with a saturated

aqueous solution of Na₂S₂O₃(10 mL) and then with brine

(8 mL). The organic layer was dried over Na₂SO₄and the

4.1.5. Hex-1-ynylselanyl-benzene (17). To a solution of

1-hexyne (2.3 g, 27.5 mmol) in dry THF (35 mL) at 0 8C

was added dropwise n-BuLi (12.1 mL, 30.3 mmol, 2.5 M in

hexanes), and the mixture was stirred for 10 min at 0 8C. A

solution of phenyl selenyl bromide (6.5 g, 27.5 mmol) in

THF (16 mL) was added dropwise over a 5 min period. The

reaction mixture was then allowed to reach slowly room

temperature and was stirred overnight. It was poured into

´ ´

C. Perez-Balado, I. E. Marko / Tetrahedron 62 (2006) 2331–2349

2341

a saturated NH₄Cl solution (100 mL) and extracted with

petroleum ether (3!75 mL). The combined organic layers

were washed with brine, dried over MgSO₄and concen-

trated in vacuo. The crude product was puriﬁed by ﬂash

chromatography (petroleum ether as eluent) affording 6.3 g

analysis calcd for C₁₂H₁₆Se (239.22): C, 60.25; H, 6.74.

Found C, 60.41; H, 6.87.

4.1.8. (Z/E)-(1-Bromo-hex-1-enylselanyl)-benzene (22).

To a 10 mL round bottomed ﬂask containing Cp₂Zr(H)Cl

(304 mg, 1.17 mmol) under argon was added 1,2-dichloro-

ethane (2 mL). To this suspension was added a solution of

hex-1-ynylselanyl-benzene 17 (233 mg, 0.98 mmol) in

1,2-dichloroethane (1.5 mL) via syringe. The suspension

was stirred for 20 min until a clear red solution was obtained.

This solution was transferred via cannula to a ﬂask containing

a suspension of NBS (227 mg, 1.27 mmol) in 1,2-dichloro-

ethane (2 mL) cooled to 0 8C. The reaction mixture was

stirred at 0 8C for 1 h and then it was allowed to slowly reach

room temperature. Petroleum ether was added until a white

precipitate was formed. The precipitate was removed by

ﬁltration through a short path of ﬂorisil and the ﬁltrate was

concentrated in vacuo. The crude material was puriﬁed by

ﬂash chromatography (petroleum ether as eluent) affording

189 mg (61% yield) of the title compound as an inseparable

mixture of isomers (E/Z:1.1/1; colourless oil). ¹H NMR

(300 MHz, CDCl₃): dZ7.54–7.47 (m, 4H), 7.36–7.28 (m,

6H), 6.61 (t, JZ7.2 Hz, 1H), 6.52 (t, JZ7.1 Hz, 1H), 2.28 (q,

JZ7.2 Hz, 2H), 2.23 (q, JZ7.1 Hz, 2H), 1.50–1.28 (m, 8H),

0.92 (t, JZ7.0 Hz, 3H), 0.91 (t, JZ7.1 Hz, 3H) ppm. ¹³C

NMR (50 MHz, CDCl₃): dZ145.7, 143.8, 132.4, 132.3,

129.3, 127.8, 127.6, 107.1, 105.8, 33.5, 33.1, 30.8, 30.1, 22.2,

22.1, 13.8 ppm. IR (neat, NaCl): nZ3023, 2957, 2871, 2858,

1

(92% yield) of the title compound as a colourless oil. H

NMR (300 MHz, CDCl₃): dZ7.55–7.45 (m, 2H), 7.35–7.15

(m, 3H), 2.45 (t, JZ7.0 Hz, 2H), 1.65–1.40 (m, 4H), 0.93

(t, JZ7.1 Hz, 3H) ppm. ¹³C NMR (50 MHz, CDCl₃): dZ

129.3, 128.6, 126.6, 104.6, 67.4, 30.8, 21.9, 20.2, 13.6 ppm.

IR (neat, NaCl): nZ3059, 2957, 2931, 2871, 2180, 1578,

1477, 1439, 1325 cm^K1. MS (EI): m/z (%): 238 [M^C%] (94),

194[M^C%KC₃H₈] (24). Elemental analysis calcd for

C₁₂H₁₄Se (237.19): C, 60.76; H, 5.95. Found C, 61.23; H,

6.03.

4.1.6. (Z/E)-(1-Iodo-hex-1-enylselanyl)-benzene (19). To

a ﬂask containing Cp₂Zr(H)Cl (274 mg, 1.06 mmol) under

argon was added 1,2-dichloroethane (2 mL). To this suspen-

sion was added a solution of hex-1-ynylselanyl-benzene 17

(210 mg, 0.88 mmol) in 1,2-dichloroethane (1.5 mL) via

syringe. The suspension was stirred for 20 min until a clear

red solution was obtained. The solution was cooled to K10 8C

and a solution of I₂(290 mg, 1.14 mmol) in 1,2-dichloro-

ethane (1.5 mL) was added dropwise. The reaction mixture

was stirred at K10 8C for 30 min and then it was allowed to

slowly reach room temperature. It was diluted with petroleum

ether (15 mL), washed with a saturated Na₂S₂O₃solution

(10 mL) and brine (10 mL). The organic layer was dried over

MgSO₄and concentrated in vacuo. The crude material was

puriﬁed by ﬂash chromatography (petroleum ether as eluent)

affording 225 mg (70% yield) of the title compound as an

1578, 1477, 1439, 1022 cm^K1. MS (EI): m/z (%): 318 [M^C%

]

(14), 81 [Bu–C^C^C%] (100). HRMS (EIC, MC) calcd for

C₁₂H₁₅BrSe, 317.9522; found 317.9699.

1

inseparable mixture of isomers (E/Z:4/1; brownish oil). H

4.1.9. 2,4,6-Ditriisopropylphenyl diselenide. To a solution

of

NMR(300 MHz, CDCl₃): dZ7.60–7.30(m, 10H), 7.03(t, JZ

7.4 Hz, 1H), 6.40 (t, JZ6.9 Hz, 1H), 2.30–2.10 (m, 4H), 1.50–

1.30 (m, 8H), 0.95 (t, JZ7.1 Hz, 6H) ppm. ¹³C NMR

(50 MHz, CDCl₃): dZ153.3, 148.5, 132.6, 132.4, 129.3,

129.2, 128.8, 127.6, 79.4, 74.5, 38.2, 35.1, 35.0, 30.6, 22.2,

13.9 ppm. IR (neat, NaCl): nZ3030, 2936, 1480, 1427,

1027, 1010 cm^K1. MS (EI): m/z (%): 366 [M^C%] (26), 239

[M^C%KI] (5).

1-bromo-2,4,6-triisopropylbenzene

(11.67 g,

41.23 mmol) in THF (134 mL) cooled at K78 8C was

added t-butyllithium (48 mL, 82.47 mmol, 1.7 M in

pentane) dropwise. The mixture was stirred for 15 min at

K78 8C until a yellow milky solution was formed. Selenium

(3.58 g, 45.35 mmol) was added. The reaction mixture was

allowed to reach room temperature slowly and was stirred

overnight. A saturated aqueous NH₄Cl solution (40 mL)

was added and the whole was stirred in the presence of

atmospheric oxygen for 15 min. The reaction mixture was

extracted with Et₂O (3!75 mL). The combined organic

layers were washed with brine (75 mL), dried over MgSO₄

and concentrated in vacuo. The crude material was

recrystalized from ethanol/petroleum ether to yield 9.76 g

(84%) of the title compound as an orange crystalline solid.

¹H NMR (300 MHz, CDCl₃): dZ6.89 (s, 4H), 3.53 (hep,

JZ6.9 Hz, 4H), 2.82 (hep, JZ6.9 Hz, 2H), 1.19 (d, JZ

6.9 Hz, 12H), 0.99 (d, JZ6.9 Hz, 24H) ppm. ¹³C NMR

(50 MHz, CDCl₃): d_CZ153.6, 150.3, 129.0, 121.6, 34.4,

34.0, 23.9, 23.8 ppm. IR (neat, NaCl): nZ3043, 2958, 2926,

2866, 1594, 1382, 1361, 1166, 1154 cm^K1. MS (EI): m/z

(%): 564 [M^C%] (100), 282 [SeTIPP^C] (16). Elemental

analysis calcd for C₃₀H₄₆Se₂(564.61): C, 63.82; H, 8.21.

Found C, 63.96; H, 8.16.

4.1.7. (Z)-Hex-1-enylselanybenzene (20). To a 10 mL

round bottomed ﬂask, containing Cp₂Zr(H)Cl (286 mg,

1.1 mmol) under argon, was added freshly distilled

1,2-dichloroethane (1.5 mL). To this suspension was

added via cannula a solution of hex-1-ynylselanyl-benzene

17 (219 mg, 0.92 mmol) in 1,2-dichloroethane (1.5 mL).

The mixture was stirred for 20 min at room temperature and

quenched by the addition of a saturated NH₄Cl solution

(0.5 mL). Petroleum ether was added dropwise until a white

precipitate was formed. The precipitate was removed by

ﬁltration over ﬂorisil and washed with petroleum ether. The

crude material was puriﬁed by column chromatography

(petroleum ether as eluent) affording 157 mg (71% yield) of

the title compound as a colourless oil. ¹H NMR (300 MHz,

CDCl₃): dZ7.55–7.40 (m, 2H), 7.35–7.20 (m, 3H), 6.43 (dt,

JZ8.9, 1.2 Hz, 1H), 6.05 (dt, JZ8.9, 7.1 Hz, 1H), 2.19 (qd,

JZ7.2, 7.1 Hz, 2H), 1.50–1.25 (m, 4H), 0.92 (t, JZ7.1 Hz,

3H) ppm. ¹³C NMR (50 MHz, CDCl₃): dZ135.4, 131.7,

129.2, 126.8, 120.1, 31.1, 22.3, 13.9 ppm. IR (neat, NaCl):

nZ3043, 2960, 2870, 2850, 1579, 1456 cm^K1. MS (EI): m/z

(%): 240 [M^C%] (100), 197 [M^C%KC₃H₈] (18). Elemental

4.2. General procedure for the preparation

of 1-(2,4,6)-triisopropylphenyl-1-alkynyl selenides

To a solution of di-2,4,6-triisopropyldiselenide (23.7 mmol)

in THF (400 mL) at 0 8C was added a solution of Br₂

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C. Perez-Balado, I. E. Marko / Tetrahedron 62 (2006) 2331–2349

2342

(24.9 mmol) in benzene (23 mL) over a period of 15 min,

using an addition funnel. The dark brown solution was

allowed to reach room temperature and was stirred for a

further 30 min. In parallel, to a solution of the corresponding

terminal alkyne (49.8 mmol) in THF (60 mL) at 0 8C was

added n-BuLi (49.7 mmol, 1.6 M in hexanes). This solution

was transferred via cannula to the solution of selenyl

bromide cooled to 0 8C. The clear solution obtained was

stirred for 2 h at room temperature. The reaction mixture

was diluted with petroleum ether (300 mL) and washed with

H₂O (300 mL) and brine (300 mL), dried over MgSO₄and

concentrated in vacuo. The crude material was puriﬁed by

column chromatography to give pure 1-TIPP-1-alkynyl

selenides.

(hep, JZ6.9 Hz, 2H), 2.89 (hep, JZ6.9 Hz, 1H), 2.15 (d,

JZ6.9 Hz, 2H), 1.76 (non, JZ6.9 Hz, 1H), 1.28 (d, JZ

6.9 Hz, 6H), 1.27 (d, JZ6.9 Hz, 12H), 0.93 (d, JZ6.9 Hz,

6H) ppm. ¹³C NMR (75 MHz, CDCl₃): dZ152.5, 150.2,

126.2, 122.4, 107. 3, 62.2, 34.9, 34.7, 30.1, 28.7, 24.8, 24.5,

22.5 ppm. IR (neat, NaCl): nZ2999, 2943, 2860, 2246, 1657,

1562, 1471, 1112 cm^K1. MS (EI): m/z (%): 364 [M^C%] (34),

349 [M^C%KCH₃] (13), 321 [M^C%KC₃H₇] (12). Elemental

analysiscalcdfor C₂₁H₃₂Se(363.44): C, 69.40;H, 8.87. Found

C, 69.52; H, 8.63.

4.2.5. 2-Cyclohexylethynylselanyl-1,3,5-triisopropyl-

benzene (30e). The title compound was obtained as a

yellow oil in 86% yield following the general procedure. ¹H

NMR (300 MHz, CDCl₃): dZ7.02 (s, 2H), 3.90 (hep, JZ

6.6 Hz, 2H), 2.88 (hep, JZ6.6 Hz, 1H), 2.90–2.79 (m, 1H),

1.80–1.23 (m, 10H), 1.26 (d, JZ6.6 Hz, 6H), 1.25 (d, JZ

6.6 Hz, 12H) ppm. ¹³C NMR (75 MHz, CDCl₃): dZ152.1,

150.1, 125.9, 122.0, 101. 5, 61.0, 34.3, 34.2, 32.7, 30.7,

25.9, 24.9, 24.3, 24.0 ppm. IR (neat, NaCl): nZ2997, 2953,

2898, 2546, 1653, 1565, 1476 cm^K1. MS (APCI): m/z (%):

390 [M^C%] (97). Elemental analysis calcd for C₂₃H₃₄Se

(389.48): C, 70.93; H, 8.80. Found C, 70.99; H, 8.54.

4.2.1. (1,3,5)-Triisopropyl-2-prop-1-ynylselanyl-benzene

(30a). The title compound was obtained as a light yellow oil

1

in 87% yield following the general procedure. H NMR

(300 MHz, CDCl₃): dZ7.04 (s, 2H), 3.88 (hep, JZ6.9 Hz,

2H), 2.89 (hep, JZ6.9 Hz, 1H), 1.90 (s, 3H), 1.27 (d, JZ

6.9 Hz, 12H), 1.25 (d, JZ6.9 Hz, 6H) ppm. ¹³C NMR

(50 MHz, CDCl₃): dZ152.2, 150.3, 125.7, 122.1, 92.8,

60.1, 34.3, 34.2, 24.2, 23.9, 5.2 ppm. IR (neat, NaCl): nZ

3043, 2960, 2926, 2867, 2243, 1594, 1383, 1314, 1168 cm^K

¹. MS (EI): m/z (%): 322 [M^C%] (100), 280 [M^C%KC₃H₇]

(16). Elemental analysis calcd for C₁₈H₂₆Se (321.36): C,

67.36; H, 8.11. Found C, 67.28; H, 8.16.

4.2.6. 1-(2,4,6)-Triisopropylphenylselenyl-1-phenyl-

acetylene (30f). The title compound was obtained as a

yellow crystalline solid in 95% yield following the general

procedure. ¹H NMR (300 MHz, CDCl₃): dZ7.41–7.31 (m,

2H), 7.27–7.23 (m, 5H), 7.06 (s, 2H), 3.89 (hep, JZ6.6 Hz,

2H), 3.87–3.79 (m, 1H), 3.95 (hep, JZ6.6 Hz, 2H), 2.88

(hep, JZ7.2 Hz, 1H), 1.30 (d, JZ6.6 Hz, 12H), 1.26 (d, JZ

7.2 Hz, 6H) ppm. ¹³C NMR (50 MHz, CDCl₃): dZ152.6,

150.9, 131.7, 128.4, 128.4, 125.6, 123.8, 122.5, 96.7, 73.3,

34.7, 34.4, 24.5, 24.1 ppm. IR (neat, NaCl): nZ3057, 2963,

2932, 2866, 2240, 1567, 1383, 1321, 1163 cm^K1. MS (EI):

m/z (%): molecular peak not observed, 204 [TIPP^C].

Elemental analysis calcd for C₂₃H₂₈Se (383.43): C, 71.92;

H, 7.35. Found C, 71.80; H, 7.36.

4.2.2. 2-Hex-1-ynylselanyl-(1,3,5)-triisopropyl-benzene

(30b). The title compound was obtained as a colourless oil

1

in 93% yield following the general procedure. H NMR

(300 MHz, CDCl₃): dZ7.03 (s, 2H), 3.88 (hep, JZ6.9 Hz,

2H), 2.88 (hep, JZ6.9 Hz, 1H), 2.24 (t, JZ7.0 Hz, 2H),

1.50–1.30 (m, 4H), 1.26 (d, JZ6.9 Hz, 12H), 1.25 (d, JZ

6.9 Hz, 6H), 0.85 (t, JZ7.1 Hz, 3H) ppm. ¹³C NMR

(50 MHz, CDCl₃): dZ152.2, 150.4, 126.0, 122.2, 97.8,

61.1, 34.6, 34.5, 31.0, 24.5, 24.2, 22.2, 20.4, 13.9 ppm. IR

(neat, NaCl): nZ2960, 2931, 2869, 2346, 1653, 1560,

1472, 1104 cm^K1. MS (EI): m/z (%): 364 [M^C%] (34), 349

[M^C%KCH₃] (13). Elemental analysis calcd for C₂₁H₃₂Se

(363.44): C, 69.51; H, 8.89. Found C, 69.32; H, 8.86.

4.3. General procedure for the preparation

of (E)-1-iodo-1-selenoalkenes

4.2.3. 2-[6-(2,4,6-Triisopropyl-phenylselanyl)-hex-5-

ynyloxyl]-tetrahydro-pyrane (30c). The title compound

was obtained as a light yellow oil in 76% yield following the

general procedure. ¹H NMR (300 MHz, CDCl₃): dZ7.03 (s,

2H), 4.55 (t, JZ3.4 Hz, 1H), 3.89 (hep, JZ6.6 Hz, 2H),

3.87–3.79 (m, 1H), 3.71 (dt, JZ10.0, 6.0 Hz, 1H), 3.52–

3.44 (m, 1H), 3.36 (dt, JZ10.0, 6.0 Hz, 1H), 2.89 (hep, JZ

6.6 Hz, 1H), 2.29 (t, JZ7.0 Hz, 2H), 1.85–1.46 (m, 10H),

1.26 (d, JZ6.6 Hz, 12H), 1.25 (d, JZ6.6 Hz, 6H) ppm. ¹³C

NMR (75 MHz, CDCl₃): dZ152.3, 150.4, 125.9, 122.3,

98.9, 97.4, 67.1, 62.4, 61.6, 34.6, 34.5, 30.9, 29.1, 25.8,

25.7, 24.5, 24.2, 20.5, 19.8 ppm. IR (neat, NaCl): nZ3043,

2959, 2867, 2655, 1593, 1463, 1382, 1361 cm^K1. MS (EI):

m/z (%): 464 [M^C%] (2), 384 [M^C%KTHP] (2). Elemental

analysis calcd for C₂₆H₄₀O₂Se (463.55): C, 67.37; H, 8.70.

Found C, 66.64; H, 8.47.

To a solution of the corresponding 1-alkynyl selenide

(37.8 mmol) in hexane (80 mL) at 0 8C was added dropwise

DIBAL-H (39.6 mmol, 1.5 M in toluene). The colourless

solution was stirred at 0 8C for 1 h and then for 3 h at room

temperature. The mixture was cooled to K78 8C and a

solution of I₂(94.5 mmol) in THF (45 mL) was added

dropwise via cannula. The reaction was stirred at K78 8C

for 30 min, then it was allowed to slowly reach 0 8C and

ﬁnally it was stirred during 45 min at room temperature. It

was poured in a mixture of EtOH (215 mL)/EtOAc

(215 mL)/H₂O (108 mL) and treated with NaBH₄until the

solution became colourless or slightly yellow. The resulting

solution was washed with aqueous 1 M HCl (120 mL), a

saturated aqueous Na₂S₂O₃solution (100 mL), brine

(130 mL), dried over MgSO₄and concentrated in vacuo.

The crude material was puriﬁed by ﬂash chromatography to

give pure 1-iodo-1-selenoalkenes.

4.2.4. 1,3,5-Triisopropyl-2-(4-methyl-pent-1-ynylselanyl)-

benzene (30d). The title compound was obtained as a

light yellow oil in 91% yield following the general procedure.

¹H NMR (300 MHz, CDCl₃): dZ7.05 (s, 2H), 3.92

4.3.1. (E)-2-(Iodo-propenylselanyl)-1,3,5-triisopropyl-

benzene (32a). The title compound was obtained as a red-

brown oil in 92% yield following the general procedure. ¹H

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2343

NMR (300 MHz, CDCl₃): dZ7.04 (s, 2H), 6.83 (q, JZ

6.9 Hz, 1H), 3.67 (hep, JZ6.9 Hz, 2H), 2.91 (hep, JZ

7.0 Hz, 1H), 2.75 (d, JZ6.9 Hz, 3H), 1.27 (d, JZ7.0 Hz,

6H), 1.25 (d, JZ6.9 Hz, 12H) ppm. ¹³C NMR (50 MHz,

CDCl₃): dZ153.0, 150.7, 140.7, 125.8, 121.9, 82.1, 34.2,

33.9, 24.2, 23.8, 20.2 ppm. IR (neat, NaCl): nZ3041, 2959,

2926, 1701, 1462, 1382, 1361, 1168, 1069 cm^K1. MS (EI):

m/z (%): 450 [M^C%] (62), 324 [M^C%KI] (73). Elemental

analysis calcd for C₁₈H₂₇ISe (449.27): C, 48.12; H, 6.06.

Found C, 49.45; H, 6.23.

(hep, JZ6.9 Hz, 1H), 2.16 (t, JZ6.6 Hz, 2H), 1.76 (non,

JZ6.9 Hz, 1H), 1.26 (d, JZ6.9 Hz, 6H), 1.22 (d, JZ

6.6 Hz, 6H), 0.96 (d, JZ6.6 Hz, 6H) ppm. ¹³C NMR

(50 MHz, CDCl₃): dZ152.8, 152.0, 150.6, 130.3, 121.9,

79.5, 44.4, 34.3, 33.9, 32.1, 25.9, 25.7, 24.4, 24.0 ppm. IR

(neat, NaCl): nZ2958, 2959, 2920, 1594, 1463, 1382, 1168,

1061 cm^K1. MS (APCI): m/z (%): 518 [M^C%] (34), 391

[M^C%KI] (100). HRMS (CIC, MC) calcd for C₂₃H₃₅ISe,

518.0949; found 518.0943.

4.3.6. (Z)-1,3,5-Triisopropyl-2-propenylselanyl-benzene

(34a). To a solution of the vinyl iodide 32a (325 mg,

0.72 mmol) in THF (10 mL) at K78 8C was added n-BuLi

(470 mL, 0.75 mmol, 1.6 M in hexanes) dropwise. The

solution was stirred for 20 min at K78 8C and then it was

poured into a saturated aqueous solution of NH₄Cl (8 mL)

and extracted with petroleum ether (3!10 mL). The

combined organic layers were washed with brine (25 mL),

dried over MgSO₄and concentrated in vacuo. The crude

material was puriﬁed by ﬂash chromatography (PE) to

afford 212 mg (91% yield) of the title compound as a

slightly yellow oil. ¹H NMR (200 MHz, CDCl₃): dZ7.04 (s,

2H), 6.09 (dd, JZ8.8, 1.3 Hz, 1H), 5.90 (dq, JZ8.8, 6.6 Hz,

1H), 3.82 (hep, JZ6.9 Hz, 2H), 2.90 (hep, JZ6.9 Hz, 1H),

1.80 (dd, JZ6.6, 1.3 Hz, 3H), 1.25 (d, JZ6.9 Hz, 6H), 1.23

(d, JZ6.9 Hz, 12H) ppm. ¹³C NMR (50 MHz, CDCl₃): dZ

152.8, 149.3, 127.5, 125.3, 121.8, 121.6, 34.2, 34.1, 24.3,

23.9, 16.2 ppm. IR (neat, NaCl): nZ3041, 2962,

2860, 1685, 1762, 1595, 1381 cm^K1. MS (EI): m/z (%):

324 [M^C%] (100), 309 (27). Elemental analysis calcd for

C₁₈H₂₈Se (323.37): C, 66.86; H, 8.73. Found C, 66.89; H,

8.79.

4.3.2. (E)-2-(1-Iodo-hex-1-enylselanyl)-1,3,5-triisopro-

pyl-benzene (32b). The title compound was obtained as a

brown oil in 95% yield following the general procedure. ¹H

NMR (200 MHz, CDCl₃): dZ7.03 (s, 2H), 6.78 (t, JZ6.9 Hz,

1H), 3.68 (hep, JZ6.9 Hz, 2H), 2.91 (hep, JZ7.0 Hz, 1H),

2.27 (m, 2H), 1.50–1.32 (m, 4H), 1.27 (d, JZ7.3 Hz, 6H),

1.23 (d, JZ7.3 Hz, 12H), 0.94 (t, JZ7.0 Hz, 3H) ppm. ¹³C

NMR (75 MHz, CDCl₃): dZ152.9, 150.8, 146.7, 125.8,

122.0, 81.2, 34.6, 34.3, 33.9, 30.7, 24.3, 23.9, 22.2, 13.9 ppm.

IR (neat, NaCl): nZ3043, 2960, 2927, 1701, 1594, 1382,

1361, 1154 cm^K1. MS (EI): m/z (%): 492 [M^C%] (100), 365

[M^C%KI] (55). Elemental analysis calcd for C₂₁H₃₃ISe

(491.35): C, 51.33; H, 6.77. Found C, 52.17; H, 6.71.

4.3.3. 2-[6-Iodo-6-(2,4,6)-triisopropyl-phenylselanyl)-

hex-5-enyloxy]-tetrahydropyran (32c). The title com-

pound was obtained as a yellow oil in 96% yield following

1

the general procedure. H NMR (300 MHz, CDCl₃): dZ

7.03 (s, 2H), 6.78 (t, JZ7.2 Hz, 1H), 4.60 (dd, JZ6.0,

2.7 Hz, 1H), 3.94–3.81 (m, 1H), 3.77 (dt, JZ9.4, 6.0 Hz,

1H), 3.66 (hep, JZ6.7 Hz, 2H), 3.58–3.42 (m, 1H), 3.42 (dt,

JZ9.4, 6.0 Hz, 1H), 2.91 (hep, JZ6.6 Hz, 1H), 2.30 (q, JZ

7.2 Hz, 2H), 1.90–1.45 (m, 10H), 1.26 (d, JZ6.7 Hz, 6H),

1.22 (d, JZ6.6 Hz, 12H), 0.94 (t, JZ7.0 Hz, 3H) ppm.

¹³C NMR (50 MHz, CDCl₃): dZ153.0, 150.8, 146.3, 125.7,

122.1, 98.9, 81.9, 67.4, 62.5, 34.9, 34.5, 34.1, 31.0, 29.5,

25.7, 25.5, 24.5, 24.2, 19.9 ppm. IR (neat, NaCl): nZ3043,

2960, 2868, 2667, 1708, 1576, 1364, 1361, 1154 cm^K1. MS

(EI): m/z (%): 592 [M^C%] (100), 465 [M^C%KI] (61). HRMS

(EIC, MC) calcd for C₂₆H₄₁IO₂Se, 592.1316; found

592.1319.

4.3.7. (E)-4-(2,4,6 Triisopropylphenyl)seleno-2-methyl

hex-4-en-3-one (34c). To a solution of the vinyl iodide

32a (195 mg, 0.43 mmol) in THF (5 mL) at K78 8C was

added n-BuLi (282 mL, 0.45 mmol, 1.6 M in hexanes)

dropwise. The solution was stirred for 20 min at K78 8C

and then neat N-methoxy-N-methylamide (56 mg,

0.48 mmol) was added at once. The reaction mixture was

allowed to reach slowly room temperature. It was poured

into a saturated aqueous solution of NH₄Cl (5 mL) and

extracted with petroleum ether (3!10 mL). The combined

organic layers were washed with brine (20 mL), dried over

MgSO₄and concentrated in vacuo. The crude material was

puriﬁed by ﬂash chromatography (PE/Et₂O:30/1 as eluent)

to afford 110 mg (67% yield) of the title compound as a

yellowish oil. ¹H NMR (300 MHz, CDCl₃): dZ6.88 (s, 2H),

6.69 (q, JZ6.6 Hz, 1H), 3.64 (hep, JZ6.9 Hz, 2H), 2.98

(hep, JZ6.9 Hz, 1H), 2.76 (hep, JZ6.9 Hz, 1H), 1.66 (d,

JZ6.9 Hz, 3H), 1.13 (d, JZ6.9 Hz, 6H), 1.11 (d, JZ

6.9 Hz, 12H), 0.77 (d, JZ6.9 Hz, 6H) ppm. ¹³C NMR

(50 MHz, CDCl₃): dZ202.8, 153.7, 150.6, 139.8, 137.7,

127.1, 122.5, 36.6, 34.9, 34.8, 24.9, 24.5, 19.4, 17.6 ppm. IR

(neat, NaCl): nZ3045, 2962, 2869, 1685, 1595,

1463, 1361 cm^K1. MS (EI): m/z (%): 394 [M^C%] (45), 323

[M^C%KCOC₃H₇] (12). Elemental analysis calcd for

C₂₂H₃₄OSe (393.46): C, 67.16; H, 8.71. Found C, 67.19;

H, 8.65.

4.3.4. 2-(1-Iodo-4-methyl-pent-1-enylselanyl)-1,3,5-tri-

isopropyl-benzene (32d). The title compound was obtained

as a yellow oil in 82% yield following the general

1

procedure. H NMR (300 MHz, CDCl₃): dZ7.02 (s, 2H),

6.79 (t, JZ6.9 Hz, 1H), 3.66 (hep, JZ6.6 Hz, 2H), 2.90

(hep, JZ6.9 Hz, 1H), 2.16 (t, JZ6.6 Hz, 2H), 1.76 (non,

JZ6.9 Hz, 1H), 1.26 (d, JZ6.9 Hz, 6H), 1.22 (d, JZ

6.6 Hz, 6H), 0.96 (d, JZ6.6 Hz, 6H) ppm. ¹³C NMR

(50 MHz, CDCl₃): dZ153.3, 151.1, 145.9, 130.6, 122.4,

82.5, 44.4, 34.8, 34.4, 28.8, 24.9, 24.5, 22.9 ppm. IR

(neat, NaCl): nZ2958, 2959, 2920, 1594, 1463, 1382,

1168, 1061 cm^K1. MS (APCI): m/z (%): 492 [M^C%] (76),

365 [M^C%KI] (100). HRMS (CIC, MC) calcd for

C₂₁H₃₃ISe, 492.0792; found 492.0799.

4.3.5. 2-(2-Cyclohexyl-1-iodo-vinylselanyl)-1,3,5-triiso-

propyl-benzene (32e). The title compound was obtained

as a yellow oil in 91% yield following the general

4.3.8. (Z)-1-Phenyl-2-(2,4,6-triisopropyl-phenylselanyl)-

but-2-en-1-one (34d). To a solution of the vinyl iodide 32a

(250 mg, 0.55 mmol) in THF (6 mL) at K78 8C was added

1

procedure. H NMR (300 MHz, CDCl₃): dZ7.02 (s, 2H),

6.79 (t, JZ6.9 Hz, 1H), 3.66 (hep, JZ6.6 Hz, 2H), 2.90

´ ´

C. Perez-Balado, I. E. Marko / Tetrahedron 62 (2006) 2331–2349

2344

n-BuLi (362 mL, 0.58 mmol, 1.6 M in hexanes) dropwise.

The solution was stirred for 20 min at K78 8C and then

a solution of benzoyl chloride (67 mL, 0.58 mmol) in THF

(2 mL) was added dropwise. The reaction mixture was

allowed to slowly reach room temperature. It was poured

into a saturated aqueous solution of NaHCO₃(5 mL) and

extracted with petroleum ether (3!10 mL). The combined

organic layers were washed with brine (20 mL), dried over

MgSO₄and concentrated in vacuo. The crude material was

puriﬁed by ﬂash chromatography (PE/Et₂O:25/1 as eluent)

to afford 169 mg (72% yield) of the title compound as a

The crude material was puriﬁed by ﬂash chromatography

(PE/Et₂O:4/1 as eluent) to afford 335 mg (82% yield) of the

allylic alcohol as a yellowish oil. ¹H NMR (300 MHz,

CDCl₃): dZ7.37–7.15– (m, 5H), 7.00 (s, 2H), 5.92 (qt, JZ

6.6, 0.9 Hz, 1H), 4.87 (s, 1H), 3.62 (hep, JZ6.9 Hz, 2H),

2.88 (hep, JZ6.9 Hz, 1H), 1.88 (dd, JZ6.6, 0.9 Hz, 3H),

1.26 (d, JZ6.9 Hz, 6H), 1.18 (d, JZ6.9 Hz, 6H), 1.16 (d,

JZ6.9 Hz, 6H) ppm. ¹³C NMR (50 MHz, CDCl₃): dZ

153.4, 150.1, 141.7, 138.3, 128.3, 127.7, 127.1, 126.9,

125.1, 122.0, 76.2, 34.4, 33.9, 24.6, 24.3, 24.1, 16.8 ppm. IR

(neat, NaCl): nZ3414, 3030, 3031, 2960, 1632, 1595, 1462,

1312 cm^K1. MS (EI): m/z (%): 430 [M^C%] (100), 323 [M^C%

KCH(OH)Ph] (89). Elemental analysis calcd for

C₂₅H₃₄OSe (429.50): C, 70.07; H, 8.04. Found C, 70.00;

H, 7.99.

1

yellowish oil. H NMR (300 MHz, CDCl₃): dZ7.70–7.65

(m, 2H), 7.03 (s, 2H), 7.01–6.90 (m, 3H), 6.15 (q, JZ

6.8 Hz, 3H), 3.97 (hep, JZ6.9 Hz, 2H), 2.68 (hep, JZ

6.9 Hz, 1H), 1.73 (d, JZ6.8 Hz, 3H), 1.28 (d, JZ6.9 Hz,

12H), 1.11 (d, JZ6.9 Hz, 6H) ppm. ¹³C NMR (50 MHz,

CDCl₃): dZ194.0, 153.5, 152.7, 149.7, 137.3, 136.9, 132.1,

129.2, 128.4, 127.8, 121.5, 34.1, 33.9, 24.3, 24.0, 17.2 ppm.

IR (neat, NaCl): nZ3045, 2961, 2869, 1722, 1662, 1596,

1382 cm^K1. MS (EI): m/z (%): 428 [M^C%] (12). HRMS

(EIC, MC) calcd for C₂₅H₃₂OSe, 428.1618; found

428.1614.

4.3.11. (Z)-3-(2,4,6-Triisopropyl-phenylselanyl-oct-2-en-

4-ol (34g). To a solution of the vinyl iodide 32a (325 mg,

0.72 mmol) in hexane (10 mL) at room temperature was

added n-BuLi (470 mL, 0.75 mmol, 1.6 M in hexanes)

dropwise. The solution was stirred at room temperature

for 10 min and neat valeraldehyde (92 mL, 0.86 mmol) was

added. The mixture was stirred for 1.5 h at room

temperature and then poured into a saturated aqueous

solution of NH₄Cl (8 mL). It was extracted with petroleum

ether (3!10 mL) and the combined organic layers were

washed with brine (25 mL), dried over MgSO₄and

concentrated in vacuo. The crude material was puriﬁed by

ﬂash chromatography (PE/Et₂O:2/1 as eluent) to afford

191 mg (65% yield) of the title compound as a colourless

oil. ¹H NMR (300 MHz, CDCl₃): dZ7.00 (s, 2H), 6.05 (qd,

JZ6.6, 0.9 Hz, 1H), 3.78 (hep, JZ6.9 Hz, 2H), 3.84–3.70

(m, 1H), 2.87 (hep, JZ6.9 Hz, 1H) 1.89 (dd, JZ6.6, 0.9 Hz,

3H), 1.60–1.10 (m, 6H), 1.24 (d, JZ6.9 Hz, 12H), 1.20 (d,

JZ6.9 Hz, 6H), 0.87 (t, JZ6.9 Hz, 3H) ppm. ¹³C NMR

(75 MHz, CDCl₃): dZ153.1, 149.9, 139.2, 125.5, 124.8,

122.0, 75.2, 36.5, 34.5, 34.2, 28.3, 24.7, 24.2, 22.8, 16.8,

14.3 ppm. IR (neat, NaCl): nZ3396, 3042, 2960,

2929, 1632, 1595, 1462, 1362 cm^K1. MS (EI): m/z (%):

409 [M^C%] (35). Elemental analysis calcd for C₂₃H₃₈OSe

(409.50): C, 67.46; H, 9.35. Found C, 67.17; H, 9.04.

4.3.9. (Z)-1,1,1-Triﬂuoro-3-(2,4,6-triisopropyl-phenylse-

lanyl)-pent-3en-2one (34e). To a solution of the vinyl

iodide 32a (200 mg, 0.45 mmol) in THF (5 mL) at K78 8C

was added n-BuLi (292 mL, 0.47 mmol, 1.6 M in hexanes)

dropwise. The solution was stirred for 20 min at K78 8C

and then a solution of triﬂuoroacetic anhydride (103 mg,

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

was allowed to slowly reach room temperature. It was

poured into a saturated aqueous solution of NaHCO₃(4 mL)

and extracted with petroleum ether (3!10 mL). The

combined organic layers were washed with brine (20 mL),

dried over MgSO₄and concentrated. The crude material was

puriﬁed by ﬂash chromatography (pure PE as eluent) to

afford 147 mg (78% yield) of the title compound as

1

a colourless oil. H NMR (200 MHz, CDCl₃): dZ7.12 (s,

2H), 6.87 (qq, JZ6.9, 1.3 Hz, 1H), 4.01 (hep, JZ6.9 Hz,

2H), 2.70 (hep, JZ6.9 Hz, 1H), 1.58 (d, JZ6.9 Hz, 3H),

1.28 (d, JZ6.9 Hz, 12H), 1.12 (d, JZ6.9 Hz, 6H) ppm. ¹³C

NMR (50 MHz, CDCl₃): dZ200.8, 154.2, 151.1, 139.8,

137.7, 132.5, 127.1, 122.5, 34.9, 34.8, 24.8, 24.3, 19.4 ppm.

IR (neat, NaCl): nZ3043, 2962, 2871, 1716, 1594,

1463, 1383 cm^K1. MS (EI): m/z (%): 420 [M^C%] (100),

377 [M^C%KC₃H₇] (25). Elemental analysis calcd for

C₂₀H₂₇F₃OSe (419.38): C, 57.28; H, 6.49. Found C,

57.74; H, 6.61.

4.3.12. (Z)-3-(2,4,6-Triisopropyl-phenylselanyl)-undec-

2-en-5-ol (34h). To a solution of the vinyl iodide 32a

(660 mg, 1.47 mmol) in THF (15 mL) at K78 8C was added

n-BuLi (920 mL, 1.47 mmol, 1.6 M in hexanes) dropwise.

The solution was stirred for 20 min at K78 8C and neat

epoxide (225 mL, 1.47 mmol) and then neat BF₃$OEt₂

(144 mL, 1.47 mmol) were added. The solution was stirred

at K78 8C for 30 min and then it was allowed to slowly

reach 0 8C. At this temperature a saturated aqueous solution

of NaHCO₃(8 mL) was added and the mixture was allowed

to warm up to room temperature. It was extracted with

EtOAc (3!10 mL), the combined organic layers were

washed with brine (25 mL), dried over MgSO₄and

concentrated in vacuo. The crude material was puriﬁed by

ﬂash chromatography (PE/Et₂O:2/1 as eluent) to afford

332 mg (50% yield) of the title compound as a colourless

4.3.10. (E)-2-(2,4,6-Triisopropylphenyl)seleno-1-phenyl-

but-2-ene-1-ol (34f). To a solution of the vinyl iodide 32a

(490 mg, 1.1 mmol) in THF (15 mL) at K78 8C was added

t-BuLi (750 mL, 2.3 mmol, 1.5 M in pentane). The solution

was stirred at K78 8C for 15 min and neat benzaldehyde

(122 mL, 1.2 mmol) was added. The mixture was stirred for

1 h at K78 8C and then it was allowed to slowly room

temperature. The reaction was quenched by the addition

of deuterated methanol (500 mL) and stirred for further

15 min. It was diluted with petroleum ether (15 mL) and

then poured into a saturated aqueous solution of NH₄Cl

(20 mL). It was extracted with petroleum ether (3!15 mL)

and the combined organic layers were washed with brine

(40 mL), dried over MgSO₄and concentrated in vacuo.

1

oil. H NMR (300 MHz, CDCl₃): dZ7.00 (s, 2H), 5.79 (q,

JZ6.6 Hz, 1H), 3.70 (hep, JZ6.9 Hz, 2H), 3.46 (m, 1H),

2.88 (hep, JZ6.9 Hz, 1H), 2.05 (d, JZ14.1 Hz, 1H), 1.94

(dd, JZ14.1, 9.0 Hz, 1H), 1.90 (d, JZ6.6 Hz, 3H), 1.70 (m,

1H), 1.24 (d, JZ6.9 Hz, 6H), 1.22 (d, JZ6.9 Hz, 6H), 1.17

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C. Perez-Balado, I. E. Marko / Tetrahedron 62 (2006) 2331–2349

2345

(d, JZ6.9 Hz, 3H), 1.39–098 (m, 10H), 0.85 (t, JZ6.9 Hz,

3H) ppm. ¹³C NMR (75 MHz, CDCl₃): dZ153.1, 149.9,

133.4, 126.5, 125.7, 121.9, 69.2, 46.0, 36.6, 34.4, 34.2, 32.0,

29.6, 25.7, 24.8, 24.2, 23.0, 17.1, 14.3 ppm. IR (neat, NaCl):

iodide 32a (225 mg, 0.46 mmol) and Pd(PPh₃)₄(53 mg,

0.046 mmol) in THF (4 mL) at room temperature was added

trimethylsilylzinc iodide²⁹(500 mL, 0.55 mmol, 1.0 M in

THF). The yellow solution thus obtained was stirred at

reﬂux for 10 h. It was diluted with petroleum ether (10 mL),

washed with aqueous 0.5 M HCl (8 mL) and extracted

several times with PE. The combined organic layers were

washed with brine (15 mL), dried over MgSO₄and

concentrated. The crude material was puriﬁed by ﬂash

chromatography (PE) affording 79 mg (38% yield) of the

title compound as a yellowish oil. ¹H NMR (300 MHz,

CDCl₃): dZ6.99 (s, 2H), 5.42 (t, JZ7.0 Hz, 1H), 3.79 (hep,

JZ6.9 Hz, 2H), 2.88 (hep, JZ6.9 Hz, 1H), 2.32 (dd, JZ

7.0, 7.0 Hz, 2H), 1.49 (s, 2H), 1.45–1.30 (m, 4H), 1.26 (d,

JZ6.9 Hz, 6H), 1.18 (d, JZ6.9 Hz, 12H), 0.93 (t, JZ

7.0 Hz, 3H), 0.03 (s, 9H) ppm. ¹³C NMR (75 MHz, CDCl₃):

dZ153.2, 149.3, 131.7, 128.8, 126.0, 121.6, 34.1, 33.6,

32.0, 31.5, 27.2, 24.2, 23.9, 22.4, 14.0, K1.4 ppm. IR (neat,

NaCl): nZ3042, 2959, 2927, 2870, 1762, 1595, 1562, 1462,

1422, 1382, 1247 cm^K1. MS (EI): m/z (%): 452 [M^C%] (92),

437 [M^C%KCH₃] (19), 379 [M^C%KSi(CH₃)₃] (20).

Elemental analysis calcd for C₂₅H₄₄SeSi (451.66): C,

66.48; H, 9.82. Found C, 66.73; H, 9.64.

nZ3410, 3043, 2960, 2868, 1630, 1595, 1462, 1361 cm^K1

.

MS (EI): m/z (%): 452 [M^C%] (100), 323 (11). Elemental

analysis calcd for C₂₆H₄₄OSe (451.59): C, 69.15; H, 9.82.

Found C, 69.05; H, 9.88.

4.3.13. (Z)-1,3,5-Triisopropyl-2-(1-methyl-propenyl-

selanyl)-benzene (34j). To a solution of vinyl iodide 32a

(355 mg, 0.79 mmol) in THF (4 mL) at K78 8C was added

t-BuLi (1.0 mL, 1.5 M in pentane, 1.58 mmol) dropwise. It

was stirred atK78 8C for 15 min and neat methyl iodide

(74 mL, 1.2 mmol) was added in three portions. The mixture

was stirred at K78 8C for 1 h, then it was allowed to slowly

reach room temperature It was diluted with petroleum ether

(10 mL), washed with H₂O, dried over MgSO₄and the

solvents were evaporated under reduced pressure. The crude

material was puriﬁed by ﬂash chromatography (pure

petroleum ether as eluent) to afford 251 mg of the title

compound (93% yield) as a yellow oil. ¹H NMR (300 MHz,

CDCl₃): dZ7.01 (s, 2H), 5.65 (qq, JZ6.6, 1.5 Hz, 1H), 3.79

(hep, JZ6.9 Hz, 2H), 2.88 (hep, JZ6.9 Hz, 1H), 1.82 (dq,

JZ6.6, 1.5 Hz, 3H), 1.67 (m, 3H), 1.25 (d, JZ6.9 Hz, 6H),

1.20 (d, JZ6.9 Hz, 12H) ppm. ¹³C NMR (75 MHz, CDCl₃):

dZ153.5, 149.8, 131.2, 125.3, 122.3, 121.7, 34.4, 34.3,

25.2, 24.4, 24.2, 16.8 ppm. IR (neat, NaCl): nZ2960, 2868,

1640, 1595, 1461, 1424, 1143 cm^K1. MS (EI): m/z (%): 338

[M^C%] (100), 323 [M^C%KCH₃] (28). Elemental analysis

calcd for C₁₉H₃₀Se (337.40): C, 67.64; H, 8.96. Found C,

68.08; H, 9.20.

4.4. Preparation of Lithium 4,4⁰-di-tert-butyl

biphenylide (LDBB)

To a ﬂame-dried two necked ﬂask, equipped with a glass-

coated stirring bar, rubber septum and Ar inlet, were added

4,4⁰-di-tert-butyl-biphenyl (DBB) (1.6 g, 6.02 mmol) and

THF (20 mL). Lithium ribbon was prepared by scraping the

dark oxide coating off the surface while it was immersed in

mineral oil. The shiny metal was dipped in hexane in order

to remove the oil and then weighed (50 mg, 7.13 mmol) in a

tared beaker containing mineral oil. The metal was sliced

into small pieces while it was still immersed in mineral oil.

The lithium pieces were dipped again in hexane prior to

addition to the solution of DBB in THF, while the ﬂask was

rapidly being purged with Ar. The reaction mixture was

stirred at room temperature for 5 min until a dark green

colour appeared on the lithium surface, then it was cooled

down to 0 8C and stirred for 4–5 h. The resulting dark green

LDBB solution (6.02 mmol, 0.3 M in THF) was ready for

use in reductive lithiation. The actual amount of LDBB is

usually less than indicated due to impurities on the lithium

ribbon and decomposition of LDBB. The real concentration

can be calculated by titration with PhSCH₂Si(CH₃)₃. A

solution of this phenylthio ether in THF was added dropwise

to a known volume of solution of LDBB at K78 8C until the

colour of the solution changed from dark green to yellow-

red. The concentration of the LDBB solution was calculated

from the amount of phenylthio ether added.

4.3.14. (Z)-Trimethyl-[2-(2,4,6-triisopropyl-phenylsela-

nyl)-but-2-enyl]-silane (34k). To a 25 mL round bottomed

ﬂask, containing THF (2 mL) atK78 8C were added t-BuLi

(1.0 mL, 1.77 mmol, 1.7 M in pentane) and immediately

after, a solution of vinyl iodide 32a (361 mg, 0.8 mmol) in

THF (1 mL). The mixture was stirred for 5 min at K78 8C,

meanwhile the formation of a white precipitate was

observed. Neat iodomethyltrimethylsilane (275 mL,

1.9 mmol) was added and the mixture was stirred for 1 h

at K78 8C and then allowed to slowly reach room

temperature. It was poured into a mixture of PE (10 mL)/

H₂O (10 mL) and extracted with petroleum ether (3!

8 mL). The combined organic layers were washed with

brine (20 mL), dried over MgSO₄and concentrated. The

crude material was puriﬁed by ﬂash chromatography (pure

PE as eluent) to afford 256 mg (78% yield) of the title

compound as a colourless oil. ¹H NMR (300 MHz, CDCl₃):

dZ7.18 (s, 2H), 5.45 (q, JZ6.6 Hz, 1H), 4.12 (hep, JZ

6.9 Hz, 2H), 2.76 (hep, JZ6.9 Hz, 1H), 1.93 (d, JZ6.6 Hz,

3H), 1.61 (m, 2H), 1.32 (d, JZ6.9 Hz, 12H), 1.18 (d, JZ

6.9 Hz, 6H), 0.05 (s, 9H) ppm. ¹³C NMR (75 MHz, CDCl₃):

dZ153.6, 149.6, 133.1, 127.2, 123.0, 122.0, 34.6, 34.3,

27.8, 24.8, 24.6, 17.7, K0.8 ppm. IR (neat, NaCl): nZ3043,

2961, 2929, 2870, 1624, 1595, 1562, 1462, 1422,

1382, 1248 cm^K1. MS (EI): m/z (%): 410 [M^C%] (37), 395

[M^C%KCH₃] (12). Elemental analysis calcd for C₂₂H₃₈SeSi

(409.58): C, 64.51; H, 9.35. Found C, 64.03; H, 9.25.

4.4.1. (E)-Trimethyl-(2-methyl-hept-2-enyl)-silane (35).

To a freshly prepared solution of LDBB (4.3 mL, 1.3 mmol,

0.3 M in THF) at K78 8C was added a solution of selenide

34m (275 mg, 0.6 mmol) in THF (10 mL) dropwise. At the

end of the addition the dark green solution changed to pale

red. It was stirred for further 10 min at K78 8C and neat

methyl iodide (50 mL, 1.3 mmol) was added. The reaction

mixture was stirred for 30 min at K78 8C and then was

allowed to reach slowly 0 8C. It was diluted with petroleum

ether (10 mL), washed with aqueous 1 M HCl (10 mL)

4.3.15. (Z)-Trimethyl-[2-(2,4,6-triisopropyl-phenylsela-

nyl)-hept-2-enyl]-silane (34m). To a solution of vinyl

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C. Perez-Balado, I. E. Marko / Tetrahedron 62 (2006) 2331–2349

2346

and extracted with PE (3!10 mL). The combined organic

layers were washed with brine (20 mL), dried over MgSO₄

and concentrated in vacuo. The crude material was puriﬁed

by ﬂash chromatography (pure PE as eluent) to afford 74 mg

126.3, 67.7, 44.2, 42.0, 40.7, 30.3, 29.9, 25.9, 17.9 ppm. IR

(neat, NaCl): nZ3416, 3021, 2933, 2903, 2858, 1635, 1423,

1275 cm^K1. MS (EI): m/z (%): 219 [M^C%] (25). Elemental

analysis calcd for C₁₀H₁₈OS₂(218.38): C, 55.00; H, 8.31, S,

29.36. Found C, 55.00; H, 8.29; S, 29.36.

1

(67% yield) of the title compound as a colourless oil. H

NMR (300 MHz, CDCl₃): dZ5.16 (tt, JZ7.0, 1.0 Hz, 1H),

2.32 (d, JZ1.0 Hz, 2H), 2.07 (q, JZ7.0 Hz, 2H), 1.35 (s,

3H), 1.40–1.20 (m, 4H), 0.90 (t, JZ7.0 Hz, 3H), 0.08 (s,

9H) ppm. ¹³C NMR (50 MHz, CDCl₃): dZ132.6, 102.5,

36.8, 36.7, 30.8, 24.1, 22.3, 13.9, K1.3 ppm. IR (neat,

NaCl): nZ3417, 2959, 2985, 2870, 1595, 1562, 1462, 1422,

1382, 1247 cm^K1. MS (EI): m/z (%): 184 [M^C%] (63).

HRMS (EIC, MC) calcd for C₁₁H₂₄Si, 184.1647; found

184.1642.

4.4.4. (Z)-1-[1,3]Dithian-2-yl-1-hex-4-en-2-ol (38). To a

freshly prepared solution of LDBB (32 mL, 9.52 mmol,

0.3 M in THF) at K78 8C was added a solution of selenide

34a (1.53 g, 4.76 mmol) in THF (3 mL) dropwise. At the

end of the addition the dark green solution changed to pale

red. It was stirred for a further 10 min at K78 8C and neat

methyl iodide (100 mL, 4.76 mmol) was added. The reaction

mixture was stirred for 30 min at K78 8C and then a

solution of oxirane 41 (418 mg, 2.38 mmol) in THF

(1.5 mL) and neat BF₃$OEt₂(150 mL, 2.38 mmol) were

added. The reaction mixture was stirred for 2 h at K78 8C

and then quenched by addition of a saturated aqueous

solution of NaHCO₃(2 mL). The mixture was allowed to

reach room temperature and poured into a mixture PE

(40 mL)/H₂O (40 mL). It was extracted with petroleum

ether (2!40 mL) and the combined organic layers were

washed with brine (60 mL), dried over MgSO₄and

concentrated in vacuo. The crude material was puriﬁed by

ﬂash chromatography (PE/Et₂O:2/1 as eluent) to afford

441 mg (85% yield) of the title compound as a crystalline

white solid. ¹H NMR (300 MHz, CDCl₃): dZ6.22 (dq, JZ

9.1, 1.4 Hz, 1H), 5.99 (m, 1H), 4.25 (dd, JZ6.8, 6.7 Hz,

1H), 3.89 (m, 1H), 4.05 (m, 1H), 3.10–2.79 (m, 5H), 2.53

(dd, JZ12.9, 5.1 Hz, 1H), 2.30–2.02 (m, 4H), 1.72 (dd, JZ

6.2, 1.4 Hz, 3H) ppm. ¹³C NMR (75 MHz, CDCl₃): dZ

129.3, 106.6, 67.5, 44.2, 42.1, 34.9, 30.5, 30.2, 26.1,

18.5 ppm. IR (neat, NaCl): nZ3410, 3021, 2936, 2858,

1636, 1423, 1275 cm^K1. MS (EI): m/z (%): 219 [M^C%] (25).

Elemental analysis calcd for C₁₀H₁₈OS₂(218.38): C, 55.00;

H, 8.31, S, 29.36. Found C, 54.98; H, 8.34; S, 29.36.

4.4.2. (E)-6-Trimethylsilanylmethyl-undec-6-en-5-ol

(36). To a freshly prepared solution of LDBB (1.1 mL,

0.32 mmol, 0.3 M in THF) at K78 8C was added a solution

of selenide 34m (71 mg, 0.16 mmol) in THF (2.5 mL)

dropwise. At the end of the addition the dark green solution

changed to pale red. It was stirred for a further 10 min at

K78 8C and neat valeraldehyde (50 mL, 0.47 mmol) was

added. The reaction mixture was stirred for 30 min at

K78 8C and then was allowed to slowly reach 0 8C. It was

diluted with petroleum ether (10 mL), washed with aqueous

1 M HCl (10 mL) and extracted with PE (3!8 mL). The

combined organic layers were washed with brine (20 mL),

dried over MgSO₄and concentrated in vacuo. The crude

material was puriﬁed by ﬂash chromatography (PE/

EtOAc:30/1) to afford 25 mg (62% yield) of the title

compound as a colourless oil. ¹H NMR (300 MHz, CDCl₃):

dZ5.08 (t, JZ7.4 Hz, 1H), 4.49 (t, JZ6.9 Hz, 1H), 2.15–

1.90 (m, 4H), 1.63–1.15 (m, 10H), 0.90 (t, JZ6.9 Hz, 3H),

0.89 (t, JZ6.9 Hz, 3H), 0.03 (s, 9H) ppm. ¹³C NMR

(75 MHz, CDCl₃): dZ138.5, 126.0, 70.5, 35.3, 32.7, 28.2,

27.2, 22.7, 22.3, 19.9, 14.0, 13.9, K0.7 ppm. IR (neat,

NaCl): nZ3415, 2960, 2920, 2860, 1638, 1457, 1379,

1248 cm^K1. MS (EI): m/z (%): 256 [M^C%] (41). HRMS

(EIC, MC) calcd for C₁₅H₃₂OSi, 256.2222; found

256.2223.

4.4.5. (E)-Methyl-undec-2-en-5-ol (39). To a round

bottomed ﬂask containing Ni(acac)₂(10 mg, 0.03 mmol),

under argon, was added a solution of alcohol 34h (250 mg,

0.55 mmol) in THF (9 mL). The suspension was cooled

down to 0 8C and methylmagnesium bromide (424 mL,

1.28 mmol, 3.0 M in ether) was added dropwise. At the end

of the addition, the solution changed from green to red. The

reaction mixture was stirred 16 h at room temperature. It

was diluted with EtOAc (5 mL) and poured into a saturated

aqueous solution of NH₄Cl (10 mL). The aqueous phase was

extracted with EtOAc (3!8 mL) and the combined organic

layers were washed with brine (25 mL), dried over MgSO₄

and concentrated in vacuo. The crude material was puriﬁed

by ﬂash chromatography (PE/EtOAc:10/1 as eluent) to

afford 61 mg (60% yield) of the title compound as a

colourless oil. ¹H NMR (300 MHz, CDCl₃): dZ5.32 (q, JZ

6.9 Hz, 1H), 3.74–3.60 (m, 1H), 2.19 (d, JZ13.2 Hz, 1H),

1.98 (dd, JZ13.2, 9.6 Hz, 1H), 1.67 (s, 1H), 1.63 (s, 3H),

1.61 (d, JZ6.9 Hz, 3H), 1.52–1.14 (m, 10H), 0.88 (t, JZ

6.6 Hz, 3H) ppm. ¹³C NMR (75 MHz, CDCl₃): dZ133.5,

122.6, 68.7, 48.3, 37.3, 32.1, 29.7, 26.0, 22.9, 16.0, 14.4,

13.8 ppm. IR (neat, NaCl): nZ3411, 2958, 2928, 2858,

1638, 1457, 1379, 1125 cm^K1. MS (EI): m/z (%): 184 [M^C

^%] (4), 96 [M^C%KC₆H₁₅] (24). HRMS (EIC, MC) calcd for

C₁₂H₂₄O, 184.1827; found 184.1830.

4.4.3. (E)-1-[1,3]Dithian-2-yl-1-hex-4-en-2-ol (37). To a

solution of selenide 34i (275 mg, 0.55 mmol) in THF

(6 mL) at K78 8C was added n-BuLi (343 mL, 0.55 mmol,

1.6 M in hexanes) dropwise and then the solution was

allowed to warm up slowly to 0 8C. This solution was added

via cannula to a freshly prepared solution of LDBB (4.3 mL,

1.3 mmol, 0.3 M in THF). At the end of the addition the

dark green solution changed to pale red. It was stirred for a

further 10 min at K78 8C and neat methanol (1.5 mL) was

added. The reaction mixture was allowed to slowly reach

room temperature. It was diluted with petroleum ether

(15 mL), washed with aqueous 1 N HCl (10 mL) and

extracted with PE (3!10 mL). The combined organic

layers were washed with brine (25 mL), dried over MgSO₄

and concentrated in vacuo. The crude material was puriﬁed

by ﬂash chromatography (PE/Et₂O:1/1 as eluent) to afford

110 mg (92% yield) of the title compound as a coulorless

1

oil. H NMR (300 MHz, CDCl₃): dZ5.53 (dqt, JZ15.2,

6.2, 1.1 Hz, 1H), 5.39 (dqt, JZ15.2, 7.5, 1.2 Hz, 1H), 4.25

(dd, JZ6.8, 6.7 Hz, 1H), 3.89 (m, 1H), 2.94–2.75 (m, 4H),

2.30–2.08 (m, 3H), 1.96–1.81 (m, 4H), 1.67 (dd, JZ6.2,

1.2 Hz, 3H) ppm. ¹³C NMR (50 MHz, CDCl₃): dZ129.3,

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C. Perez-Balado, I. E. Marko / Tetrahedron 62 (2006) 2331–2349

2347

4.4.6. (E)-1-[1,3]Dithian-2-yl-4-methyl-hex-4-en-2-ol

(40). To a round bottomed ﬂask containing Ni(acac)₂

(2 mg, 0.008 mmol), under argon, was added a solution of

alcohol 34i (134 mg, 0.27 mmol) in THF (2.5 mL). The

suspension was cooled down to 0 8C and methylmagnesium

bromide (270 mL, 0.8 mmol, 3.0 M in ether) was added

dropwise. At the end of the addition, the solution changed

from green to red. The reaction mixture was stirred 20 h at

room temperature. It was diluted with EtOAc (5 mL) and

poured into a saturated aqueous solution of NH₄Cl (8 mL).

The aqueous phase was extracted with EtOAc (3!10 mL)

and the combined organic layers were washed with brine

(25 mL), dried over MgSO₄and concentrated in vacuo. The

crude material was puriﬁed by ﬂash chromatography (PE/

EtOAc:10/1 as eluent) to afford 40 mg (64% yield) of the

quenched by the addition of a saturated aqueous solution of

NaHCO₃(15 mL). The mixture was allowed to slowly reach

room temperature. It was diluted with petroleum ether

(300 mL), washed with H₂O and extracted several times

with petroleum ether. The combined organic layers were

dried over MgSO₄and concentrated in vacuo. The

crude material was puriﬁed by ﬂash chromatography

(PE/Et₂O:2/1 as eluent) to afford 6.45 g (100% yield,

based upon oxirane) of the title compound as a white

1

crystalline solid. H NMR (300 MHz, CDCl₃): dZ6.99 (s,

2H), 5.81 (q, JZ6.6 Hz, 1H), 4.26 (dd, JZ9.4, 4.8 Hz, 1H),

3.95–3.80 (m, 1H), 3.70 (hep, JZ6.8 Hz, 2H), 2.90–2.78

(m, 5H), 2.05 (d, JZ6.5 Hz, 2H), 1.91 (d, JZ6.6 Hz, 3H),

2.15–1.72 (m, 2H), 1.70–1.55 (m, 2H), 1.25 (d, JZ6.8 Hz,

6H), 1.22 (d, JZ6.8 Hz, 6H), 1.17 (d, JZ6.8 Hz, 6H) ppm.

¹³C NMR (75 MHz, CDCl₃): dZ152.9, 149.4, 132.1, 127.2,

125.0, 121.5, 65.8, 45.6, 43.8, 41.7, 33.9, 33.7, 30.2, 29.7,

25.7, 24.3, 24.1, 23.8, 16.4 ppm. IR (neat, NaCl): nZ3347,

3042, 2959, 2907, 2867, 1594, 1560, 1462, 1382 cm^K1. MS

(EI): m/z (%): 499 [M^C%] (10), 217 [M^C%KSeTIPP] (100).

Elemental analysis calcd for C₂₅H₄₀OS₂Se (499.68): C,

60.10; H, 8.07; S, 12.83. Found C, 59.97; H, 8.04; S, 13.59.

1

title compound as a colourless oil. H NMR (300 MHz,

CDCl₃): dZ5.33 (qq, JZ6.6, 1.2 Hz, 1H), 4.30 (dd, JZ8.6,

6.9 Hz, 1H), 4.01 (m, 1H), 3.00–2.78 (m, 4H), 2.18 (dd, JZ

13.2, 4.5 Hz, 1H), 2.08 (dd, JZ13.2, 8.7 Hz, 1H), 2.20–2.08

(m, 1H), 1.96–1.81 (m, 4H), 1.63 (s, 3H), 1.61 (d, JZ

6.6 Hz, 3H) ppm. ¹³C NMR (75 MHz, CDCl₃): dZ132.5,

123.1, 65.5, 48.2, 44.5, 42.6, 30.6, 30.3, 26.2, 15.9,

13.7 ppm. IR (neat, NaCl): nZ3413, 2929, 2905,

2858, 1668, 1497, 1382, 1275 cm^K1. MS (EI): m/z (%):

232 [M^C%] (29), 161 [M^C%KC₅H₉S₂] (19). Elemental

analysis calcd for C₁₁H₂₀OS₂(232.40): C, 56.85; H, 8.67, S,

27.59. Found C, 56.89; H, 8.44; S, 28.36.

4.4.9. 1-[1,3]Dithian-2-yl-4-iodo-hex-4-en-2-ol (42). To a

solution of selenide 34i (130 mg, 0.26 mmol) in THF at 0 8C

under argon was added dropwise CH₃MgBr (130 mL,

0.39 mmol, 3.0 M in Et₂O). The reaction mixture was

stirred for 15 min at 0 8C. This solution was added to a

LDBB solution (2.5 mL, 0.3 M in THF) at K78 8C via

syringe. At the end of the addition, the solution colour

changed from dark green to clear red. It was stirred for

30 min at K78 8C, neat MeI (16 mL, 0.26 mmol) was added

and the mixture was stirred for a further 10 min. After the

addition, the solution became colourless. A solution of I₂

(165 mg, 0.65 mmol) in THF (2 mL) was added dropwise

and the reaction mixture was stirred for 1 h to K78 8C. It

was quenched by the addition of ethanol (2 mL) at K78 8C

and then it was allowed to reach room temperature. It was

diluted with petroleum ether (5 mL), washed with a

saturated aqueous solution of Na₂S₂O₃(5 mL) and the

aqueous layer extracted several times with petroleum ether.

The combined organic layers were dried over MgSO₄and

concentrated in vacuo. The crude material was puriﬁed by

ﬂash chromatography (PE/Et₂O:1/1 as eluent) to afford

73 mg (81% yield) of the title compound as a yellow oil. ¹H

NMR (300 MHz, CDCl₃): dZ5.73 (qt, JZ6.3, 1.1 Hz, 1H),

4.28 (dd, JZ8.4, 6.0 Hz, 1H), 4.35–4.20 (m, 1H), 2.99–2.80

(m, 4H), 2.62 (d, JZ6.5 Hz, 2H), 2.25–1.80 (m, 4H), 1.77

(d, JZ6.3 Hz, 3H) ppm. ¹³C NMR (75 MHz, CDCl₃): dZ

128.4, 106.3, 67.3, 53.3, 44.7, 42.4, 30.6, 30.2, 26.4,

22.5 ppm. IR (neat, NaCl): nZ3348, 2938, 2900, 2827,

1647, 1422, 1275, 1164, 1072 cm^K1. MS (EI): m/z (%): 219

[M^C%KI] (15), 205 (29), 188 (22), 145 (24). HRMS (CIC,

MC) calcd for C₁₀H₁₇IOS₂, 344.9765; found 344.9769.

4.4.7. (rac)-2-[1,3]Dithian-2-ylmethyl-oxirane (41). To a

solution of 1,3 dithiane (5.0 g, 41.6 mmol) in THF (100 mL)

at K78 8C was added n-BuLi (30 mL, 41.6 mmol, 1.6 M in

hexanes) dropwise via syringe. The reaction mixture

was warmed to K20 8C and stirred at that

temperature for 2 h. It was then cooled down to K78 8C

and neat (G)-epichlorohydrin (3.3 mL, 41.6 mmol) was

added. The mixture was allowed to slowly reach room

temperature and was stirred overnight at that temperature.

The solution was concentrated under reduced pressure to

75 mL, then washed with H₂O and extracted with petroleum

ether (4!40 mL). The combined organic layers were

washed with brine (150 mL), dried over MgSO₄and

concentrated in vacuo. The crude material was puriﬁed by

ﬂash chromatography (PE/Et₂O:2/1) to afford 6.68 g (92%

1

yield) of the title compound as a yellowish oil. H NMR

(300 MHz, CDCl₃): dZ4.26 (t, JZ7.0 Hz, 1H), 3.20–3.12

(m, 1H), 3.10–2.80 (m, 5H), 2.55 (dd, JZ5.1, 2.7 Hz, 1H),

2.20–2.08 (m, 1H), 1.97 (dd, JZ6.9, 6.0 Hz, 2H), 1.94–1.80

(m, 1H) ppm. ¹³C NMR (75 MHz, CDCl₃): dZ49.9, 47.3,

45.0, 38.9, 30.8, 30.6, 26.0 ppm. IR (neat, NaCl): nZ3348,

2992, 2901, 2827, 1687, 1480, 1277, 1258 cm^K1. MS (EI):

m/z (%): 176 [M^C%] (84). Elemental analysis calcd for

C₇H₁₂OS₂(176.30): C, 47.69; H, 6.86, S, 36.37. Found C,

47.61; H, 6.88; S, 36.07.

4.4.8. (Z)-1-[1,3]Dithian-2-yl-4-(2,4,6-triisopropyl-phe-

nylselanyl)-hex-4-en-2-ol (34i). To a solution of iodide

32a (23.2 g, 51.6 mmol) in THF (500 mL) at K78 8C was

added n-BuLi (34 mL, 51.6 mmol, 1.6 M in hexanes)

dropwise and the mixture was stirred for 15 min at

K78 8C. Neat BF₃$OEt₂(3.27 mL, 25.8 mmol) was added

and immediately after, a solution of the oxirane 41 (4.5 g,

28.5 mmol) in THF (10 mL) was added all at once. The

reaction mixture was stirred at K78 8C for 1 h and then

4.4.10. (Z)-1-[1,3]Dithian-2-yl-trimethylsilanylmethyl-

hex-4-en-2-ol ((Z)-6). To a solution of vinyl iodide 42

(462 mg, 1.35 mmol) and Pd(PPh₃)₄(80 mg, 0.07 mmol) in

THF (5 mL) was added trimethylsilylmagnesium chloride

(1.7 mL, 4.05 mmol, 2.3 M in THF) dropwise. The mixture

was stirred overnight at room temperature. It was then

poured into a saturated aqueous solution of NH₄Cl (10 mL)

and the aqueous layer extracted with EtOAc (4!10 mL).

´ ´

C. Perez-Balado, I. E. Marko / Tetrahedron 62 (2006) 2331–2349

2348

The combined organic layers were washed with brine

(30 mL), dried over MgSO₄and concentrated in vacuo. The

crude material was puriﬁed by ﬂash chromatography (PE/

Et₂O:1.5/1 as eluent) to afford 279 mg (68% yield) of the

in vacuo. The crude material was puriﬁed by ﬂash

chromatography (PE/Et₂O:2/1) affording 55 mg (91%

yield) of the title compound as a colourless oil. H NMR

1

(300 MHz, CDCl₃): dZ4.80 (d, JZ1.5 Hz, 1H), 4.73 (d,

JZ1.5 Hz, 1H), 4.23 (dd, JZ9.3, 4.8 Hz, 1H), 3.92–3.82

(m, 2H), 3.62 (tt, JZ10.0, 3.0 Hz, 1H), 3.18 (td, JZ9.6,

3.0 Hz, 1H), 3.00–2.66 (m, 4H), 2.30–1.60 (m, 9H), 1.99

(d, JZ6.9 Hz, 3H) ppm. ¹³C NMR (75 MHz, CDCl₃): dZ

148.3, 107.3, 83.2, 75.2, 60.9, 44.4, 42.5, 41.5, 41.4, 35.6,

30.8, 30.5, 26.1, 12.7 ppm. IR (neat, NaCl): nZ3332, 3084,

2935, 2899, 2859, 1647, 1423, 1364, 1324, 1191 cm^K1. MS

(EI): m/z (%): 288 [M^C%] (89). Elemental analysis calcd

for C₁₄H₂₄O₂S₂(288.47): C, 58.29; H, 8.39. Found C,

57.54; H, 8.35.

1

title compound as a colourless oil. H NMR (500 MHz,

CDCl₃): dZ5.20 (q, JZ7.0 Hz, 1H), 4.29 (dd, JZ9.2,

5.2 Hz, 1H), 3.98 (m, 1H), 2.86 (m, 4H), 2.11 (m, 2H), 2.01

(d, JZ2.4 Hz, 1H), 1.97 (dd, JZ13.1, 9.2 Hz, 1H), 1.88 (m,

1H), 1.82 (m, 2H), 1.62 (d, JZ14.4 Hz, 1H), 1.54 (d, JZ

7.0 Hz, 3H), 1.40 (d, JZ14.4 Hz, 1H), 0.02 (s, 9H) ppm.

¹³C NMR (75 MHz, CDCl₃): dZ134.3, 119.3, 65.1, 47.3,

44.2, 42.3, 30.3, 30.0, 25.9, 20.8, 13.9, K0.8 ppm. IR (neat,

NaCl): nZ3321, 2958, 2931, 2902, 1637, 1561, 1461, 1422,

1382, 1056 cm^K1. MS (EI): m/z (%): 304 [M^C%] (25), 233

[M^C%KSi(CH₃)₃] (39). Elemental analysis calcd for

C₁₄H₂₈OS₂Si (304.59): C, 55.31; H, 9.28, S, 21.09. Found

C, 55.59; H, 9.10; S, 21.14.

Acknowledgements

4.4.11. (E)-1-[1,3]Dithian-2-yl-trimethylsilanylmethyl-

hex-4-en-2-ol ((E)-6). To a freshly prepared solution of

LDBB (11.2 mL, 3.15 mmol, 0.28 M in THF) at K78 8C

was added a solution of allylsilane 34k (645 mg,

1.58 mmol) in THF (1 mL) dropwise. At the end of the

addition the dark green solution turned to pale red. It was

stirred for a further 10 min at K78 8C and neat methyl

iodide (98 mL, 1.58 mmol) was added. The reaction mixture

was stirred for 30 min at K78 8C and then a solution of

oxirane 41 (280 mg, 1.58 mmol) in THF (1 mL) and neat

BF₃$OEt₂(198 mL, 1.58 mmol) were added. The reaction

mixture was stirred for 2 h at K78 8C and then quenched by

the addition of a saturated NaHCO₃aqueous solution

(2 mL). It was allowed to reach room temperarture and was

poured into a mixture of PE (40 mL)/H₂O (40 mL).

The aqueous layer was extracted with petroleum ether

(2!40 mL) and the combined organic layers were washed

with brine (60 mL), dried over MgSO₄and concentrated in

vacuo. The crude material was puriﬁed by HPLC using

a reverse phase column (hexane/isopropanol:99/1) affording

240 mg (50% yield) of the title compound as a colourless

Financial support of this work by Chirotech Technology

´

Ltd, Cambridge, UK and the Universite catholique de

Louvain is gratefully acknowledged.

References and notes

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1

oil. H NMR (300 MHz, CDCl₃): dZ5.54 (q, JZ6.6 Hz,

1H), 4.27 (t, JZ7.0 Hz, 1H), 3.95 (m, 1H), 2.86 (m, 4H),

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Article Doi

1-Iodo-1-selenoalkenes as versatile alkene 1,1-dianion equivalents. Novel connective approach towards the tetrahydropyran subunit of polycavernoside A

DOI: 10.1016/j.tet.2005.12.005

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Article abstract of DOI:10.1016/j.tet.2005.12.005

Full text of DOI:10.1016/j.tet.2005.12.005

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