Intramolecular carbolithiation promoted by a DTBB-catalysed chlorine-lithium exchange

Tetrahedron 59 (2003) 8525–8542

Intramolecular carbolithiation promoted by a DTBB-catalysed

chlorine–lithium exchange

†

*

Miguel Yus, Rosa Ortiz and Fernando F. Huerta

´ ´

Departamento de Quımica Organica, Facultad de Ciencias, Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain

Received 22 July 2003; revised 21 August 2003; accepted 9 September 2003

Dedicated to Professor Reinhard W. Hoffmann on occasion of his 70th birthday

Abstract—The reaction of 6-chlorohex-1-ene 1 with lithium powder and a catalytic amount of 4,4⁰-di-tert-butylbiphenyl (DTBB, 5% molar)

in THF at 2788C gives the corresponding organolithium intermediate 2, which by reaction with different electrophiles affords, after

hydrolysis with diluted hydrochloric acid, the expected products 3. The same reaction performed at 2308C gives cyclopentyl derivatives 5,

probably by cyclisation of the open-chain intermediate 2 to give the cyclic organolithium compound 4. When the double bond in the starting

material contains an alkyl substituent, for instance compounds 6 and 9, the corresponding cyclisation is inhibited, so the corresponding

acyclic products 8 and 11 are respectively, obtained. However, when the substituent at the same positions is a phenyl group, like in starting

materials 12 and 15, the cyclised products 14 and 17 were respectively, isolated. In the case of the secondary starting chlorinated material 18,

the reaction can be directed to both, the acyclic products 20 or the cyclic ones 22, working at 278 or 2308C, respectively, as it happens in the

case of the unsubstituted chlorinated material 1. For the tertiary chloro derivative 23, only the cyclic compound 27 could be isolated at 2308C

due to the great instability of the corresponding tertiary organolithium intermediate 24, which undergoes a proton abstraction even at 2788C.

From allyl 2-chlorophenyl ether 28 or N,N-diallyl-2-chloroaniline 32, only the corresponding cyclic compounds 31 and 33, respectively, are

isolated either at 278 or at 2308C. In all cases a carbanionic cyclisation, better than a radical one, is postulated to occur as mechanistic

pathway.

1. Introduction

methodologies to generate unsaturated organolithiums,

which are necessary starting materials for the intramolecular

cyclisation, we can cite: (a) bromine- or iodine–lithium

exchange using an alkyllithium reagent;⁴(b) sulphur–

lithium exchange⁵starting from phenyl thioethers using a

lithium–arene;⁶(c) tin–lithium transmetallation from tri-n-

butylstannanes and n-butyllithium;⁷and (d) cyano-lithium

exchange using a lithium–arene in especial cases.⁸

However, to the best of our knowledge, the most general

way (a) has never been applied to the most accessible and

stable chlorinated unsaturated materials due to the difﬁculty

of performing the corresponding lithiation (chlorine–

lithium exchange) at low temperatures by using conven-

tional methodologies. We found some years ago⁹that the

use of an excess of lithium powder a₀nd a catalytic amount of

an arene [naphthalene and 4,4 -di-tert-butylbiphenyl

(DTBB) being the most commonly used¹⁰] is an adequate

procedure to carry out chlorine–lithium exchange under

very mild reaction conditions.^11–14Thus, this methodology

(arene-catalysed lithiation) has been intensively used for

performing new reactions such as the generation of simple

organolithium reagents from non-halogenated materials,¹⁵

the preparation of very unstable functionalised organo-

lithium intermediates¹⁶(by halogen–lithium exchange¹⁷or

by reductive ring opening of different heterocycles¹⁸), the

generation of dilithium synthons,¹⁹and the activation of

Organolithium reagents usually react as nucleophiles

towards polarised multiple bonds, the addition to carbonyl

compounds being a classical example of this process.¹As

a consequence of that, the addition to a non-polarised

carbon–carbon double bond, the so-called carbolithiation,²

is not a simple reaction. However, from a synthetic point of

view, the carbolithiation is an interesting process because a

new organolithium reagent is formed, which can react with a

typical electrophile to introduce an electrophilic fragment in

the new backbone. It means that through the mentioned

process it is possible to modify both the carbon chain and

the functionality in only one methodological operation. In

addition, two possibilities are opened concerning the inter-

and intramolecular fashion of the carbolithiation reaction, in

the second case allowing the generation of cyclic systems

during the creation of the new carbon–carbon s-bond, so

making possible the preparation of functionalised carbo-

cyclic compounds in a direct manner.³Among the different

Keywords: chlorine–lithium exchange; intramolecular carbolithiation;

DTBB-catalysed lithiation; cyclisation.

*

Corresponding author. Tel.: þ34-965-903548; fax: þ34-965-903549;

e-mail: yus@ua.es

Present address: AstraZeneca R & D, 15185 Sodertalje, Sweden.

†

¨

doi:10.1016/j.tet.2003.09.012

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M. Yus et al. / Tetrahedron 59 (2003) 8525–8542

other metals,²⁰especially nickel²¹and copper.²²In this

paper we describe the application of the mentioned arene-

catalysed lithiation to the generation of unsaturated

organolithium compounds by chlorine–lithium exchange

in order to study their possible intramolecular carbolithi-

ation reaction.²³

addition, when naphthalene was used as the electron carrier

agent under catalytic^9,11–14or stoichiometric²⁵conditions

(Table 1, entries 4 and 5, as well as footnotes d and e,

respectively) the corresponding yields were not improved;

however, in the catalytic version with naphthalene the

results are comparable to those obtained with DTBB, so

both electron-carrier agents can be used. A ﬁnal remark has

to do with the use of longer reaction times, either in the

lithiation or in the S_Ereaction steps, which did not improve

the corresponding yields (Table 1, entries 1 and 3). On the

other hand, concerning the use of the corresponding

brominated starting material, we obtained comparable

results (Table 1, entry 2 and footnote b), so we decided to

continue in the rest of this study with the cheaper and more

stable chlorinated materials (see below).

2. Results and discussion

The reaction of commercially available 6-chlorohex-1-ene

(1) with a slight excess of lithium powder (1:2.8 molar ratio;

theoretical 1:2) and a catalytic amount of DTBB (5 mol%)

in THF at 2788C led to a solution of the corresponding

organolithium intermediate 2, which by treatment with

different electrophiles [E¼Bu^tCHO, PhCHO, Et₂CO,

(CH₂)₅CO, PhCOMe] and ﬁnal hydrolysis with 2 M HCl,

both at the same temperature, gave the expected products 3

(Scheme 1 and Table 1). Pentan-3-one was used as the

standard electrophile in order to ﬁnd the best reaction

conditions (Table 1, entries 1–5). Thus, using 5 mol% of

DTBB as the catalyst, we found that working at 2788C the

best reaction time for the lithiation and the reaction with the

electrophile were 45 and 15 min, respectively (Table 1,

entry 1), these reaction conditions being applied to the other

electrophilic reagents (Table 1, entries 6–9). On the other

hand, the use of Barbier-type reaction conditions (lithiation

in the presence of the electrophile)²⁴did not improve the

obtained results (Table 1, entry 2 and footnote c). In

When the above mentioned reaction was carried out at

2308C, the cyclic intermediate 4 was the only one

generated [probably through intermediate 2 initially formed

via an intramolecular carbolithiation process (see below)],

which by reaction with the same electrophiles as for

compound 2 [E¼Bu^tCHO, PhCHO, Et₂CO, (CH₂)₅CO,

PhCOMe] gave compounds 5, after hydrolysis with 2 M

HCl, both steps being performed at the same temperature

(Scheme 1 and Table 2). The following remarks are

pertinent: (a) although the reaction can be performed at

temperatures ranging between 278 and 08C (Table 2, entry

3 and footnote d), the best results were obtained at 2308C,

so this temperature was chosen as the standard one for

all electrophiles (Table 2, entries 1, 2 and 4–10); (b) the

amount of the catalyst (DTBB) can be decreased until about

1% (Table 2, entries 5 and 6, and footnotes f and g), working

in any case nicely. Even in absence of the catalyst the

reaction worked well (Table 2, entry 2 and footnote c), this

behaviour being observed in other cases at 2308C;⁹

however, in this case the reaction time is longer and the

process is not so clean, a careful puriﬁcation being

necessary; (c) when 6-bromohex-1-ene was used as starting

material under the same reaction conditions a lower yield

was obtained (Table 2, entry 1 and footnote b).

Scheme 1. Reagents and conditions: (i) Li powder, DTBB (5 mol%), THF;

(ii) 2788C; (iii) E¼Bu^tCHO, PhCHO, Et₂CO, (CH₂)₅CO, PhCOMe,

2788C; (iv) 2 M HCl, 2788C to room temperature; (v) 2308C;

(vi) E¼Bu^tCHO, PhCHO, Et₂CO, (CH₂)₅CO, PhCOMe, 2308C; (vii) 2 M

HCl, 2308C to room temperature.

We then studied the inﬂuence of the substitution on the

double bond in the cyclisation process shown in Scheme 1.

Thus, 6-chloro-2-propylhex-1-ene (6) was submitted to the

DTBB-catalysed lithiation at temperatures ranging between

Table 1. Preparation of compounds 3

Entry

Reaction time (min)

Electrophile

E

Product

X

Lithiation

S_Ereaction

No

Yield (%)^a

1

2

3

4

5

6

7

8

9

45

75^b

70

30

60

45

15

Et₂CO

3a

3b

3c

3d

3e

Et₂COH

95

90^b(85)^c

64

30

15

30

15

89^d

33^e

91

Et₂CO

Et₂COH

Bu^tCHO

PhCHO

(CH₂)₅CO

PhCOMe

Bu^tCHOH

PhCHOH

(CH₂)₅COH

PhC(OH)Me

97

90

77

a

Isolated yield of $95% pure (300 MHz ¹H NMR and/or GLC) compounds 3 after column chromatography (silica gel, hexane/ethyl acetate) based on the

starting material 1.

Yield corresponding to the reaction starting from 6-bromohex-1-ene instead of compound 1 under the same reaction conditions.

The lithiation reaction was performed in the presence of the electrophile (Barbier-type conditions).

Naphthalene (5 mol%) was used as the electron-carrier catalyst.

b

c

d

e

Lithium naphthalenide was used as the lithiating agent (stoichiometric version).

M. Yus et al. / Tetrahedron 59 (2003) 8525–8542

8527

Table 2. Preparation of compounds 5

2788C resulted very clean, so we decided to prepare

compounds 8 at this temperature and using the catalyst in

5 mol% amount. In addition, when the reaction was carried

out with pentan-3-one as electrophile and under Barbier-

type reaction conditions the yield was lower (Table 3, entry

2 and footnote b), so we worked in all cases in a two-step

reaction manner (Grignard-type conditions).

Entry

Reaction time

(min)

Lithiation S_Ereaction

Electrophile

E

Product

X

No

Yield

(%)^a

1

2

3

4

5

6

7

8

9

10

45

50

90

60

45

15

30

15

30

15

Et₂CO

5a Et₂COH

5b Bu^tCHOH

5c PhCHOH

95 (74)^b

83^c

53^d

The starting material 6²⁷was prepared by Wittig methyl-

enation of 8-chlorooctan-4-one,²⁸which was obtained from

commercially available 5-chlorovaleronitrile by addition

of n-propylmagnesium chloride and further hydrolysis,

following literature procedures.

80^e

83^f

Et₂CO

93 ^g

75

Bu^tCHO

PhCHO

(CH₂)₅CO

PhCOMe

87

5d (CH₂)₅COH 95

5e PhC(OH)Me 81

When the substitution in the unsaturated chlorinated

material was at the ﬁrst carbon atom we obtained the

same results as indicated in Scheme 2. Thus, (Z)-8-

chlorooct-3-ene (9) was submitted to the same protocol as

it was described in Scheme 2 (2788C, DTBB 5 mol%)

giving products 11, after reaction of intermediate 10 with

different electrophiles [E¼Bu^tCHO, PhCHO, Et₂CO,

(CH₂)₅CO, PhCOMe, Me₃SiCl] and ﬁnal hydrolysis with

diluted 2 M HCl (Scheme 3 and Table 4). As it happened

for the starting material 6, different changes in temperature,

co-solvents and additives (see above) did not produce the

possible cyclisation to give the corresponding cyclic

organolithium intermediates and products. Also here, the

lithiation in the presence of the electrophile (Barbier-type

reaction conditions) did not improve the results obtained in

the two-step process (Table 4, entry 2 and footnote b).

a

Isolated yield of $95% pure (300 MHz ¹H NMR and/or GLC)

compounds 5 after column chromatography (silica gel, hexane/ethyl

acetate) based on the starting material 1.

Yield corresponding to the reaction starting from 6-bromohex-1-ene

instead of compound 1.

The lithiation reaction was performed in the absence of the electron-

carrier arene.

The lithiation was carried out at 2788C allowing the temperature to rise

to 08C before S_Ereaction and the corresponding hydrolysis with 2 M HCl.

The whole process was performed at 08C.

b

c

d

e

f

2.5 mol% of DTBB was used as the catalyst.

1 mol% of DTBB was used as the catalyst.

g

2788C and room temperature, giving in all cases the

corresponding ‘open’ intermediate 7 and the ﬁnal products

8, after successive reaction with different electrophiles

[E¼Bu^tCHO, PhCHO, Et₂CO, (CH₂)₅CO, PhCOMe,

Me₃SiCl] and ﬁnal hydrolysis with 2 M HCl (Scheme 2

and Table 3). Even using mixtures of other solvents

(pentane, ether) with THF or some additives (TMEDA or

PMDTA)²⁶we never got the corresponding cyclised

intermediates and products. Anyhow, the process at

The starting material 9 was prepared by reaction of

commercially available (Z)-5-octen-1-ol with triphenylphos-

phane in carbon tetrachloride.²⁹

A very different behaviour was observed when the

substitutent at the double bond was a phenyl group. For

Scheme 2. Reagents and conditions: (i) Li powder, DTBB (5 mol%), THF,

2788C; (ii) E¼Bu^tCHO, PhCHO, Et₂CO, (CH₂)₅CO, PhCOMe, Me₃SiCl,

2788C; (iii) 2 M HCl, 2788C to room temperature.

Scheme 3. Reagents and conditions: (i) Li powder, DTBB (5 mol%), THF,

2788C; (ii) E¼Bu^tCHO, PhCHO, Et₂CO, (CH₂)₅CO, PhCOMe, Me₃SiCl,

2788C; (iii) 2 M HCl, 2788C to room temperature.

Table 3. Preparation of compounds 8

Table 4. Preparation of compounds 11

Entry

Reaction time

(min)

Lithiation S_Ereaction

Electrophile

E

Product

X

Entry

Reaction time

(min)

Electrophile

E

Product

X

No

Yield

(%)^a

Lithiation

S

_Ereaction

No

Yield

(%)^a

1

2

3

4

5

6

7

40

60^b

40

30

Et₂CO

8a Et₂COH

63

43^b

74

62

76

1

2

3

4

5

6

7

30

90^b

30

20

Et₂CO

11a Et₂COH

11b Bu^tCHOH

11c PhCHOH

11d (CH₂)₅COH

77

48^b

67

76

77

8a Et₂COH

30

Bu^tCHO

PhCHO

(CH₂)₅CO

PhCOMe

Me₃SiCl

8b Bu^tCHOH

8c PhCHOH

8d (CH₂)₅COH

20

Bu^tCHO

PhCHO

(CH₂)₅CO

PhCOMe

Me₃SiCl

8e PhC(OH)Me 60

8f Me₃Si 63

11e PhC(OH)Me 72

11f Me₃Si 72

a

Isolated yield of $95% pure (300 MHz ¹H NMR and/or GLC)

compounds 8 after column chromatography (silica gel, hexane/ethyl

acetate) based on the starting material 6.

The lithiation reaction was performed in the presence of the electrophile

(Barbier-type conditions).

Isolated yield of $95% pure (300 MHz ¹H NMR and/or GLC)

compounds 11 after column chromatography (silica gel, hexane/ethyl

acetate) based on the starting material 9.

The lithiation reaction was performed in the presence of the electrophile

(Barbier-type conditions).

b

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M. Yus et al. / Tetrahedron 59 (2003) 8525–8542

Scheme 5. Reagents and conditions: (i) Li powder, DTBB (5 mol%),

E¼PhCHO, Et₂CO, Me₃SiCl, THF, 2308C; (ii) 2 M HCl, 2308C to room

Scheme 4. Reagents and conditions: (i) Li powder, DTBB (5 mol%), THF,

2788C; (ii) E¼Bu^tCHO, PhCHO, Et₂CO, 2788C; (iii) 2 M HCl, 2788C to

room temperature.

temperature.

Table 6. Preparation of compounds 17

Table 5. Preparation of compounds 14

Entry

Reaction time

(min)

Lithiation S_Ereaction

Electrophile

E

Product

Entry

Reaction time

(min)

Lithiation S_Ereaction

Electrophile

E

Product

X

No

X

Yield (%)^a

No

Yield

(%)^a

1

2

3

4

5

6

45

45^c

30

15

Et₂CO

PhCHO

Me₃SiCl

17a Et₂COH

17c PhCHOH

17f Me₃Si

38^b

c,d

–

d

1

2

3

4

5

6

60

90

60

15

Et₂CO

Bu^tCHO

PhCHO

14a Et₂COH

14b Bu^tCHOH

14c PhCHOH

38

35^b

35^c

20^d

25

30^c

63

70

80

15

a

25

Isolated yield of $95% pure (300 MHz ¹H NMR and/or GLC)

compounds 17 after column chromatography (silica gel, hexane/ethyl

acetate) based on the starting material 15.

a

Isolated yield of $95% pure (300 MHz ¹H NMR and/or GLC)

compounds 14 after column chromatography (silica gel, hexane/ethyl

acetate) based on the starting material 12.

The lithiation reaction was performed under Barbier-type conditions.

The reaction was performed at 2308C.

b

c

The reaction was performed at 2788C.

The lithiation reaction was performed under Barbier-type conditions at

2788C.

No reaction product was detected (GLC-MS).

b

c

d

The lithiation reaction was performed at 2308C and under Barbier-type

conditions.

(Table 6, entries 4–6). Also in this case, the corresponding

‘reduced’ product (17 with X¼H) was the main by-product

detected (GLC-MS).

6-chloro-2-phenylhex-1-ene (12) the DTBB-catalysed

lithiation even at 2788C gave already the cyclic inter-

mediate 13 (probably formed by an intramolecular carbo-

lithiation), which by reaction with some electrophiles

(E¼Bu^tCHO, PhCHO, Et₂CO) afforded, after hydrolysis

with 2 M HCl, the corresponding products 14 (Scheme 4

and Table 5). The conversion is total after about 1 h (the

starting material disappeared), so the rest of the starting

material was transformed into a mixture of compounds,

among them the ‘reduced’ product (14 with X¼H) resulting

from a lithium–hydrogen exchange by intermediate 13.

This hydrogen abstraction from the reaction medium,

probably from THF at the a-position, has already been

observed in other cases for very reactive organolithium

intermediates.³⁰Anyhow, we never detected (GLC-MS) in

the reaction mixture the product resulting from the reaction

of the ‘open’ intermediate with the electrophile. As Table 5

shows, the use of Barbier-type reaction conditions did not

improve the obtained results (Table 5, entries 2 and 4).

The starting material 15 was prepared in a two-step process:

(a) preparation of 6-chloro-1-phenylhex-1-yne by palladium

and copper catalysed coupling of iodobenzene with 6-chloro-

hex-1-yne³²and (b) Lindlar hydrogenation of the triple

bond to yield the cis chlorinated oleﬁn.³³

The next study on intramolecular carbolithiation of

substituted chlorohexenes involved the starting material

18. Its DTBB-catalysed lithiation at 2788C under Barbier

conditions led to the formation of the intermediate 19,

which reacting with the electrophile [E¼Bu^tCHO, PhCHO,

Et₂CO, (CH₂)₅CO, PhCOMe] present in the reaction

medium gave, after hydrolysis with 2 M HCl the expected

compounds 20 (Scheme 6 and Table 7). When the same

process was carried out in the absence of the electrophile

(two-step reaction) the corresponding cyclised product of

type 22 was exclusively obtained (see below). On the other

hand when the reaction was carried out under Barbier

conditions but at 2308C a mixture of both products 20 and

22, was obtained (Table 7, entry 2). In addition, and working

at 2788C under Barbier-type conditions, in some cases

yields are low due to decomposition of the intermediate and

the electrophile under the conditions assayed, none of the

products being the corresponding cyclic products 22 (Table

7, entries 3, 4 and 6). Concerning stereochemical aspects,

compounds 20 derived from prostereogenic carbonyl

compounds gave a ca. 1:1 mixture of diastereomers

(300 MHz ¹H NMR), which could not be separated by

column chromatography (Table 7, entries 3, 4 and 6, and

footnote d).

The starting material 12 was prepared by lithiation of

a-bromostyrene with n-butyllithium at 2788C followed by

reaction with 1-chloro-4-iodobutane.³¹

When (Z)-6-chloro-1-phenylhex-1-ene (15) was lithiated

under DTBB-catalysis, we always obtained the cyclised

products 17 either at 278 or at 2308C, so after the ﬁrst

chlorine–lithium exchange a carbolithiation took place to

yield the intermediate 16, which by reaction with some

electrophiles (E¼PhCHO, Et₂CO, Me₃SiCl) and ﬁnal

hydrolysis gave the mentioned products 17 (Scheme 5 and

Table 6). At 2788C the reaction under Barbier-type

conditions did not work (Table 6, entry 2). On the contrary,

at 2308C it was necessary to work under Barbier-type

conditions in order to achieve the expected products

On the other hand, when the DTBB-catalysed lithiation of

M. Yus et al. / Tetrahedron 59 (2003) 8525–8542

8529

Scheme 6. Reagents and conditions: (i) Li powder, DTBB (5 mol%), E¼Bu^tCHO, PhCHO, Et₂CO, (CH₂)₅CO, PhCOMe, THF, 2788C, then 2 M HCl; (ii) Li

powder, DTBB (5 mol%), E¼Bu^tCHO, PhCHO, Et₂CO, (CH₂)₅CO, PhCOMe, Me₂CO, THF, 2308C, then 2 M HCl.

addition times a mixture of both products 20 and 22 was

isolated (Table 8, entry 2). The corresponding two-step

Table 7. Preparation of compounds 20

Entry

Reaction time

(min)

Lithiation S_Ereaction

Electrophile

E

Product

X

process, either at 2308C (Table 8, entry 3), 08C (Table 8,

entry 4) or 2788C (Table 8, entry 5) gave any improvement

in the yields. An additional comment has to do with reaction

times under the same reaction conditions: we observed that

in some cases the lithiation step worked differently

depending on the carbonyl compound used as electrophile

(see, for instance, Table 8, entries 8 and 10) under Barbier

conditions. This fact has been already observed in our group

(for instance benzaldehyde usually works better as cyclo-

hexanone in lithiations under Barbier conditions³⁴) and

would suggest some participation of the carbonyl group in

the electron-carrying process. Finally, also in the case of

compounds 22, the use of prostereogenic carbonyl com-

pounds provokes the appearance of diastereomers as a ca.

1:1 diastereomers mixture (300 MHz ¹H NMR and/or

GLC; Table 8, entries 6, 7 and 9, and footnote e), which

in the case of the benzaldehyde derivatives could be

separated chromatographically (silica gel, hexane/ethyl

acetate).

No

Yield

(%)^a

1

2

3

4

5

6

70

30^b

70

Et₂CO

Bu^tCHO

PhCHO

(CH₂)₅CO

PhCOMe

20a Et₂COH

20b Bu^tCHOH

20c PhCHOH

20d (CH₂)₅COH

60

73^b,c

17^d

28^d

40

20e PhC(OH)Me 20^d

a

Isolated yield of $95% pure (300 MHz ¹H NMR and/or GLC) compound

20 after column chromatography (silica gel, hexane/ethyl acetate) based

on the starting material 18.

The lithiation reaction was performed in at 2308C.

A 1:1.7 mixture of compounds 20/22 was obtained (GLC).

A ca. 1:1 mixture of diastereomers was isolated (300 MHz ¹H NMR).

b

c

d

compound 18 above mentioned (Scheme 6) was carried out

also in the presence of the electrophile for 90 min but at

2308C the intermediate formed was the corresponding

cyclic one 21, so its reaction with electrophiles [E¼

Bu^tCHO, PhCHO, Et₂CO, (CH₂)₅CO, PhCOMe, Me₂CO]

followed by hydrolysis with 2 M HCl gave the correspond-

ing products 22 (Scheme 6 and Table 8). For shorter

In the case of compounds 22 we obtained only one

diastereomer concerning the two substituents at the ﬁve-

membered ring. In the literature, different stereochemical

results have been obtained depending on the reaction

conditions. For instance, starting from 6-iodohept-1-ene,

the lithiation with lithium at 08C gave mainly intermediate

cis-21 (cis/trans: 5/1 after protonation).^35aThe same results

were obtained when the same process was initiated by

phenyllithium as a catalyst at different temperatures (220 to

608C; cis/trans: 2.9–4.7/1), supporting in this case a radical

mechanism for the cyclisation.^4aIn addition, using tert-

butyllithium as the lithiating agent and starting from the

same material, the cis/trans ratio strongly depends from

Table 8. Preparation of compounds 22

Entry

Reaction time

(min)

Lithiation S_Ereaction

Electrophile

E

Product

X

No

Yield

(%)^a

1

2

90

30

Et₂CO

22a Et₂COH

22b Bu^tCHOH

22c PhCHOH

22d (CH₂)₅COH

68

73^b

62

3

4

5

6

7

8

9

10

20

10^c

80^d

90

120

90

10

10^c

45^d

Et₂CO

Bu^tCHO

PhCHO

(CH₂)₅CO

PhCOMe

Me₂CO

45^c

51^d

46^e

63^e

49

22e PhC(OH)Me 44^e

22 g Me₂COH 43

120

a

Isolated yield of $95% pure (300 MHz ¹H NMR and/or GLC)

compounds 20 after column chromatography (silica gel, hexane/ethyl

acetate) based on the starting material 18.

A 1:1.7 mixture of compounds 20/22 was obtained (GLC).

The lithiation reaction was performed at 08C.

The lithiation reaction was performed at 2788C.

b

c

d

e

A ca. 1:1 diastereomers mixture (at the carbon-hydroxy sterocenter) was

obtained (300 MHz ¹H NMR and/or GLC).

8530

M. Yus et al. / Tetrahedron 59 (2003) 8525–8542

Scheme 7. Reagents and conditions: (i) Li powder, DTBB (5 mol%), THF, 2788C; (ii) Et₂CO, 2788C; (iii) 2 M HCl, 2788C to room temperature; (iv) Li

powder, DTBB (5 mol%), THF, 2308C; (v) Et₂CO, 2308C; (vi) 2 M HCl, 2308C to room temperature.

the reaction conditions (cis/trans: 1.5/1 or ,1/44).^35b

Finally, a graphical simulation of the two possible topicities

shows that the trans representation (II) is more hindered

than the corresponding cis one (I).³⁶In our case, we

probably obtained the intermediate cis-21 and the corre-

sponding products cis-22, but at this moment the alternative

trans-structures can not be ruled out.³⁷

2308C (56%) the only compound isolated, after reaction

with pentan-3-one and ﬁnal hydrolysis, was the alcohol 31,

intermediates 29 (Y¼O) and 30 (Y¼O) being probably

involved in the process (Scheme 8). In this case, no

compound resulting from the reaction of intermediate 29

(Y¼O) with the electrophile was obtained. The moderate

yield obtained is probably due to by-reactions such as partial

deallylation³⁹or intramolecular deprotonation at the allylic

position⁴⁰followed by a Wittig rearrangement.⁴¹

The starting material 18 was prepared by addition of

4-pentenylmagnesium bromide to butanal, following by

hydroxy/chlorine exchange with triphenylphosphane and

carbon tetrachloride.²⁹

The starting ether 28⁴²was prepared by allylation of

commercially available 2-chlorophenol with allyl bromide

in the presence of sodium hydride.

When the carbolithiation reaction was applied to the tertiary

derivative 23 we found that at 2788C the corresponding

intermediate 24 initially formed was very unstable and

abstracts a proton from the reaction medium (probably from

THF),³⁰so after adding pentan-3-one as electrophile the

only reaction product detected (GLC-MS) was the ‘reduced’

compound 25, resulting from a lithium–hydrogen exchange

[two-step reaction/2788C: 61% (GLC); Barbier conditions/

2788C: 60% (GLC)]. It is worthy to note that even working

under Barbier conditions, only compound 25 was obtained

at 2308C [53% (GLC)]. However, at 08C under Barbier

conditions (76%) or at 2308C in a two-step process (75%),

the expected cyclic product 27 was the only one isolated

after reaction with pentan-3-one and ﬁnal hydrolysis with

2 M HCl at the same temperature, intermediate 26 being

probably involved in the lithiation step (Scheme 7).

When the starting material was the diallylamine 32, the

lithiation at 2788C under the reaction conditions described

above gave, after reaction with deuterium oxide, a mixture

of the cyclic product 34b and the acyclic one 35b in a 1.3:1

molar ratio. This behaviour is independent on the electro-

phile because using pentan-3-one under the same reaction

conditions we obtained the same ratio of compounds 33 and

35a, respectively (70–80% yield in both cases). However,

working at 2308C only the cyclic intermediate 30 (Y¼

NCH₂CH¼CH₂) was generated giving, after reaction with

pentan-3-one and ﬁnal hydrolysis with 2 M HCl, the

expected product 33 in 41% isolated yield, together with

the ‘reduced’ product 34a, resulting from a lithium–

hydrogen exchange from intermediate 30 (Y¼NCH₂CH¼

CH₂), either from tetrahydrofuran (see above) or from the

ketone at the a-position. The second possibility is the most

The starting material 23 was prepared from the correspond-

ing tertiary alcohol (obtained by lithiation of commercially

available 5-bromopent-1-ene followed by reaction with

pentan-3-one) by reaction with concentrated hydrochloric

acid.³⁸

Finally, we studied the DTBB-catalysed lithiation of

compound 28 ﬁnding that either at 2788C (ca. 45%) or at

Scheme 8. Reagents and conditions: (i) Li powder, DTBB (5 % molar), THF, 278 or 2308C; (ii) Et₂CO, same temperature as step i; (iii) 2 M HCl, 278 or

2308C to room temperature.

M. Yus et al. / Tetrahedron 59 (2003) 8525–8542

8531

from the reaction medium. At 2308C intermediate VIII

probably gives the most stable primary cyclic carbanion X.

As it was above commented, radical IX, resulting from the

radical VII by cyclisation, probably does not take part in the

reaction.

Finally, for aromatic chlorides, intermediates 29 suffer rapid

cyclisation to the corresponding primary organolithium

compounds of type 30, indicating again that the transfor-

mation V!VI (or III!IV, for the radical mechanism) is a

very favourable process.

Scheme 9.

probable, because when the same reaction was performed

using water or deuterium oxide as electrophiles, the

expected products 34a and 34b were isolated in 81 and

85% (95% deuterium incorporation), respectively.

3. Conclusion

In conclusion, we report in this paper the DTBB-catalysed

lithiation of 6-chlorohex-1-ene and related systems, which

can be in general controlled giving the corresponding open-

chain compounds or the cyclic derivatives, depending on the

substituents and the reaction conditions. We believe that in

the case of cyclisation processes an intramolecular carbo-

lithiation takes place transforming the initially formed

organolithium intermediate into the corresponding cyclic

one. Anyhow, the reported methodology can be useful from

a synthetic point of view, especially when functionalised

carbocycles are produced.

The diallylamine 32 was prepared by successive reaction of

commercially available 2-chloroaniline with n-butyllithium

and allyl bromide, this process being repeated twice.

Concerning the possible mechanism of the reaction, which

is illustrated in Scheme 9 for the simplest non-substituted

system derived from the starting material 1, we think that

radical of type III is initially formed, which could either

cyclise to the new radical IV or take a second electron

giving the carbanion V. Since the cyclisation of the radical

is much more rapid than that of the carbanion,⁴³we think

that once the radical III is formed at 2788C it is converted

rapidly to the anion V (k₂@k₁) whereas, at 2308C

cyclisation of intermediate V to the cyclic carbanion VI

probably occurs. Actually, the other possible pathway at

2308C, through intermediate VI can not be completely

ruled out. However, we observed that performing the

reaction in the presence of cumene as effective radical

scavenger,^4athe obtained results were not altered signiﬁ-

cantly, so we deduce that the half-live of radicals III and IV

should be very short. On the other hand, since the reaction

under Barbier-type conditions gives similar results as in

the two-step process, we conclude that the cyclisation

V!VI is faster than the S_Ereaction of carbanion V (k₃@k_E)

(Scheme 9).

4. Experimental

4.1. General

All lithiation reactions were carried out under argon

atmosphere in oven-dried glassware. All commercially

available reagents (Acros, Aldrich, Fluka) were used

without further puriﬁcation, except in the case of electro-

philes, which were used freshly distilled. Commercially

available anhydrous THF (99.9%, water content #0.006%,

Acros) was used as solvent in all the lithiation reactions.

IR spectra were measured (ﬁlm) with a Nicolet Impact 400

D-FT Spectrometer. NMR spectra were recorded with a

Bruker AC-300 using CDCl₃as solvent and TMS as internal

standard; chemical shifts are given in ppm and coupling

constants (J) are given in Hz. ¹³C NMR assignments were

made on the basis of DEPT experiments. LRMS were

measured with Shimadzu GC/HS QP-5000 and Hewlett–

Packard EM/CG-5973A spectrometers, and HRMS were

measured with Finingan MAT95 S spectrometer, fragment

ions in m/z with relative intensities (%) in parentheses. The

purity of volatile products and the chromatographic

analyses (GLC) were determined with a Hewlett–Packard

HP-4890 instrument equipped with a ﬂame ionisation

detector and a 30 m capillary column (0.32 mm diam.,

0.25 mm ﬁlm thickness), using nitrogen (2 mL/min) as

carrier gas, T_injector¼2758C, T_detector¼3008C, T_column¼608C

(3 min) and 60–2708C (158C/min), P¼40 KPa. Thin layer

chromatography (TLC) was carried out on Merck plastic

sheets coated with silica gel 60 F₂₅₄. Lithium powder was

prepared from commercially available lithium granules

(99%, high sodium content, Aldrich) as it was already

reported by us.⁴⁴

For systems substituted at the double bond, we observed that

the cyclisation step of type III!IV (or V!VI) is highly

affected by stereoelectronic effects, so it did not take place

when the substituents at the double bond are alkyl groups

(see Schemes 2 and 3), thus supporting an anionic

cyclisation. However the cyclisation is the exclusive process

for the corresponding phenyl substituted systems, which

give either a primary (see intermediate 13) or a more stable

benzylic intermediate (see 16). For secondary intermediates

(see 19) the reaction can be directed to both acyclic and

cyclic products, involving intermediates of type V and VI,

respectively. Finally, in the case of the tertiary derivative

24, the radical VII evolves rapidly at 2788C to the

carbanion VIII, which is very unstable and takes a proton

8532

M. Yus et al. / Tetrahedron 59 (2003) 8525–8542

4.2. DTBB-catalysed lithiation of 6-chlorohex-1-ene (1)

11.6 Hz, 1H, CHHv), 5.00 (d, J¼17.7 Hz, 1H, CHHv),

5.81 (m, 1H, vCH); d_C22.2, 22.3, 25.8, 29.5, 33.7, 37.4,

42.2 (9C, 9£CH₂), 71.4 (COH), 114.3 (CH₂v), 138.9

(vCH); m/z 164 (M^þ218, 1%), 99 (100), 98 (30), 83 (25),

82 (11), 81 (69), 79 (14), 71 (13), 69 (17), 68 (15), 67 (21),

58 (18), 57 (17), 55 (79), 53 (13), 43 (44), 42 (14), 41 (71).

4.2.1.5. 2-Phenyloct-7-en-2-ol (3e).⁴⁹R_f0.3 (hexane/

ethyl acetate: 8/2); n (ﬁlm) 3438 (OH), 3074, 3026, 1640,

1601, 1494 cm²¹(CvC); d_H1.24 (m, 4H, 2£CH₂), 1.54

(s, 3H, CH₃), 1.79 (m, 2H, CH₂COH), 1.86 (s, 1H, OH),

1.97 (m, 2H, CH₂vCHCH₂), 4.89 (d, J¼10.4 Hz, 1H,

CHHv), 4.94 (d, J¼17.1 Hz, 1H, CHHv), 5.74 (m, 1H,

vCH), 7.31 (3m, 5H, ArH); d_C23.4, 29.1 (2£CH₂), 30.0

(CH₃), 33.6, 44.0 (2£CH₂), 74.6 (COH), 114.3 (CH₂v),

138.8 (vCH), 124.7, 126.4, 128.0, 148.0 (6C, ArC); m/z

204 (M^þ, 0.2%), 122 (119), 121 (100), 118 (12), 105 (15),

91 (12), 77 (13), 43 (96), 41 (22).

4.2.1. Preparation of compounds 3. To a stirred green

suspension of lithium powder (50 mg, 7.2 mmol) and DTBB

(26.6 mg, 0.1 mmol) in THF (4 mL) at 2788C was added

6-chlorohex-1-ene (1; 0.138 mL, 1.0 mmol) under an argon

atmosphere. The colour disappeared after the substrate

addition, the reaction mixture was stirred until the green

colour was recovered (45 min) and the corresponding

electrophile (1.1 mmol) was then added. The resulting

mixture was stirred for 15 min at the same temperature

(2788C), then it was hydrolysed with 2 M HCl (5 mL) and

stirred to room temperature for 10 min. The reaction

mixture was extracted with diethyl ether (3£15 mL), the

organic phase was dried over anhydrous magnesium

sulphate and was concentrated under vacuum (15 Torr).

Compounds 3 were isolated after column chromatography

(silica gel, hexane/ethyl acetate mixtures). Yields are given

in Table 1; physical and spectroscopic data, as well as

references for known compounds, follows.

4.2.2. Preparation of compounds 5. To a stirred green

suspension of lithium powder (50 mg, 7.2 mmol) and DTBB

(26.6 mg, 0.1 mmol) in THF (4 mL) at 2308C was added

6-chlorohex-1-ene (1; 0.138 mL, 1.0 mmol) under argon

atmosphere. The colour disappeared after the substrate

addition, the reaction mixture was stirred until the green

colour was recovered (45 min) and the corresponding

electrophile (1.1 mmol) was then added. The resulting

mixture was stirred for 15 min at the same temperature

(2308C), then was hydrolysed with 2 M HCl (5 mL) and

stirred to room temperature for 10 min. The reaction

mixture was extracted with diethyl ether (3£15 mL), the

organic phase was dried over anhydrous magnesium

sulphate and was concentrated under vacuum (15 Torr).

The compounds 5 were isolated after column chromatog-

raphy (silica gel, hexane/ethyl acetate mixtures). Yields are

given in Table 2; physical, spectroscopic and analytical

data, as well as references for known compounds, follows.

4.2.2.1. 1-Cyclopentyl-2-ethylbutan-2-ol (5a).^45aR_f0.4

(hexane/ethyl acetate: 8/2); n (ﬁlm) 3415 cm²¹(OH); d_H

0.79 (t, J¼7.6 Hz, 6H, 2£CH₃), 1.18 (m, 4H, 2£CH₂), 1.49

(m, 8H, 4£CH₂), 1.76 (m, 3H, CH and CH₂); d_C7.9

(2£CH₃), 24.9 (2£CH₂), 31.3 (2£CH₂), 34.5 (2£CH₂), 35.7

(CH), 44.3 (CH₂), 75.1 (COH); m/z 152 (M^þ218, 1.9%),

141 (44), 123 (16), 87 (100), 83 (24), 81 (34), 73 (28), 69

(38), 67 (23), 59 (14), 57 (43), 55 (41), 45 (69), 43 (34), 41

(71).

4.2.2.2. 1-Cyclopentyl-3,3-dimethylbutan-2-ol (5b). R_f

0.4 (hexane/ethyl acetate: 8/2); n (ﬁlm) 3329 cm²¹(OH);

d_H0.88 (s, 9H, 3£CH₃), 1.15 (m, 2H, CH₂), 1.38 (m, 2H,

CH₂), 1.58 (m, 4H, 2£CH₂), 1.82 (m, 2H, CH₂), 2.00 (m,

1H, CHCH₂CHOH), 3.24 (dd, J¼9.6 Hz, 2.3, 1H, CHOH);

d_C24.9, 25.1 (2£CH₂), 25.6 (3£CH₃), 31.9, 33.7 (2£CH₂),

34.8 [C(CH₃)₃], 37.2 (CH₂CH₂CH), 37.8 (CH₂), 79.0

(CHOH); m/z 155 (M^þ215, 0.3%), 152 (M^þ218, 0.6%),

113 (30), 112 (18), 96 (15), 95 (100), 87 (27), 83 (11), 81

(11), 70 (14), 69 (58), 68 (10), 67 (31), 57 (41), 56 (16), 55

(30), 45 (40), 43 (32), 42 (11), 41 (74). HRMS: M^þ2[H₂O],

found 152.1583. C₁₁H₂₀requires 152.1565.

Barbier type reaction. To a stirred green suspension of

lithium powder (50 mg, 7.2 mmol) and DTBB (26.6 mg,

0.1 mmol) in THF (4 mL) at 2788C was added a solution of

6-chlorohex-1-ene (1; 0.138 mL, 1.0 mmol) and pentan-3-

one in THF (1.5 mL) over a 30 min period, the reaction was

stirred for 15 additional minutes at the same temperature

and then quenched and worked-up as above.

4.2.1.1. 3-Ethylnon-8-en-3-ol (3a).⁴⁵R_f0.3 (hexane/

ethyl acetate: 8/2); n (ﬁlm) 3416 (OH), 3077, 1641 cm²¹

(CvC); d_H0.78 (t, J¼7.3 Hz, 6H, 2£CH₃), 1.31 (m, 11H,

5£CH₂and OH), 2.00 (m, 2H, CH₂vCHCH₂), 4.87 (d,

J¼10.4 Hz, 1H, CHHv), 4.93 (d, J¼17.4 Hz, 1H, CHHv),

5.74 (m, 1H, vCH); d_C7.7 (2£CH₃), 22.8, 29.5, 31.0, 31.3,

33.7, 38.0 (6£CH₂), 74.6 (COH), 114.3 (CH₂v), 138.9

(vCH); m/z 152 (M^þ218, 0.3%), 141 (15), 123 (15), 87

(91), 81 (18), 69 (31), 67 (14), 57 (100), 55 (40), 53 (10), 45

(67), 43 (42), 41 (74).

4.2.1.2. 2,2-Dimethylnon-8-en-3-ol (3b).⁴⁶R_f0.3 (hexane/

ethyl acetate: 8/2); n (ﬁlm) 3394 (OH), 3077, 1641 cm²¹

(CvC); d_H0.89 (s, 9H, 3£CH₃), 1.41 (m, 7H, 3£CH₂and

OH), 2.06 (m, 2H, CH₂vCHCH₂), 3.19 (m, 1H, CHOH),

4.94 (d, J¼11.0 Hz, 1H, CHHv), 5.00 (d, J¼17.1 Hz, 1H,

CHHv), 5.82 (m, 1H, vCH); d_C25.6 (3£CH₃), 26.6, 28.9,

31.3, 33.8 (4£CH₂), 34.9 [C(CH₃)₃], 79.9 (CHOH), 114.3

(CH₂v), 139.0 (vCH); m/z 152 (M^þ218, 0.2%), 113 (11),

95 (95), 87 (21), 71 (17), 70 (13), 69 (48), 68 (18), 67 (28),

57 (73), 56 (19), 55 (33), 45 (37), 44 (12), 43 (76), 42 (11),

41 (100).

4.2.1.3. 1-Phenylhept-6-en-1-ol (3c).⁴⁷R_f0.3 (hexane/

ethyl acetate: 8/2); n (ﬁlm) 3353 (OH), 3028, 3063, 3074,

1640 cm²¹(CvC); d_H1.43 (m, 4H, 2£CH₂), 1.74 (m,

4H, 2£CH₂), 4.63 (t, J¼6.7 Hz, 1H, CHOH), 4.92 (d, J¼

10.4 Hz, 1H, CHHv), 4.97 (d, J¼17.4 Hz, 1H, CHHv),

5.78 (m, 1H, CH₂vCH), 7.30 (m, 5H, ArH); d_C25.3, 28.7,

33.6, 38.9 (4£CH₂), 74.5 (CHOH), 114.3 (CH₂v), 125.8,

127.4, 128.4, 144.8 (6C, ArC), 138.8 (vCH); m/z 191

(M^þþ1, 0.4%), 190 (M^þ, 3%), 133 (15), 120 (19), 107

(100), 105 (11), 91 (11), 79 (69), 77 (39), 51 (14), 41 (24).

4.2.1.4. 1-(Hex-5-enyl)cyclohexanol (3d).⁴⁸R_f0.3

(hexane/ethyl acetate: 8/2); n (ﬁlm) 3394 (OH), 3076,

1641 cm²¹(CvC); d_H1.23 (m, 3H, CH₂and OH), 1.44 (m,

14H, 7£CH₂), 2.07 (m, 2H, CH₂vCHCH₂), 4.94 (d, J¼

4.2.2.3. 2-Cyclopentyl-1-phenyl-1-ethanol (5c).⁵⁰R_f0.3

(hexane/ethyl acetate: 8/2); n (ﬁlm) 3354 (OH), 3093, 3085,

3062, 3028 cm²¹(CvC); d_H1.54 (m, 11H, cycle and CH₂),

1.96 (s, 1H, OH), 4.67 (def. t, J¼6.4 Hz, 1H, CHOH), 7.28

(m, 5H, ArH); d_C24.9, 25.0, 32.6, 32.9 (4£CH₂), 36.7

(CHCH₂CHOH), 45.5 (CH₂CHOH), 74.1 (CHOH), 125.9,

M. Yus et al. / Tetrahedron 59 (2003) 8525–8542

8533

127.4, 128.4, 145.1 (6C, ArC); m/z 191 (M^þþ1, 0.7%), 190

(M^þ, 5%), 108 (12), 107 (100), 104 (12), 79 (55), 77 (31), 51

(11), 41 (24).

(3£20 mL). The organic phase was dried over anhydrous

magnesium sulphate and concentrated under vacuum

(15 Torr). The resulting oil was puriﬁed by simple

distillation and 6-chloro-2-propylhex-1-ene was isolated

with 60% yield (1.567 g, 9.8 mmol).

4.3.1.2. 6-Chloro-2-propylhex-1-ene (6). R_f0.7 (hexane);

n (ﬁlm) 3076, 1644 cm²¹(CvC); d_H0.90 (t, J¼7.3 Hz, 3H,

CH₃), 1.45 (m, 2H, CH₂), 1.59 (m, 2H, CH₂), 1.78 (m, 2H,

CH₂), 2.01 (m, 4H, CH₂vC(CH₂)₂), 3.55 (t, J¼6.4 Hz, 2H,

CH₂Cl), 4.72 (s, 2H, CH₂v); d_C13.8 (CH₃), 20.8, 24.9,

32.2, 35.1, 38.0 (5£CH₂), 45.0 (CH₂Cl), 109.2 (CH₂vC),

149.0 (CH₂vC); m/z 162 (M^þþ2, 3.83%), 160 (M^þ,

11.87%), 84 (31), 81 (11), 69 (34), 67 (13), 56 (100), 55

(54), 53 (12). HRMS: M^þ, found 160.1036. C₉H₁₇Cl

requires 160.1019.

4.2.2.4. 1-(Cyclopentylmethyl)cyclohexanol (5d). R_f0.3

(hexane/ethyl acetate: 8/2); n (ﬁlm) 3415 cm²¹(OH); d_H

1.29 (m, 20H, 2 cycles and OH), 1.80 (m, 2H, CH₂COH); d_C

22.2, 25.0, 25.8, 34.6 (7C, 7£CH₂), 35.2 (CH), 38.0, 48.6

(3C, 3£CH₂), 71.8 (COH); m/z 183 (M^þþ1, 0.1%), 182

(M^þ, 0.9%), 164 (13), 115 (16), 99 (100), 98 (14), 97 (27),

96 (21), 95 (11), 83 (22), 82 (29), 81 (84), 80 (10), 79 (27),

71 (24), 69 (26), 68 (18), 67 (47), 59 (16), 58 (22), 57 (12),

55 (84), 54 (11), 53 (18), 43 (38), 42 (15), 41 (83). HRMS:

M^þ, found 182.1668. C₁₂H₂₂O requires 182.1671.

4.2.2.5. 1-Cyclopentyl-2-phenylpropan-2-ol (5e). R_f0.3

(hexane/ethyl acetate: 8/2); n (ﬁlm) 3449 (OH), 3086, 3059,

3026, 1602, 1494 cm²¹(CvC); d_H1.02 (m, 2H, CH₂), 1.50

(m, 8H, CH₃, CH and 2£CH₂), 1.81 (m, 5H, 2£CH₂and

OH), 7.32 (m, 5H, ArH); d_C24.8, 24.9 (2£CH₂), 30.9

(CH₃), 34.1 (2£CH₂), 36.2 (CHCH₂), 50.3 (CH₂COH), 75.1

(COH), 124.8, 126.3, 128.0, 148.4 (6C, ArC); m/z 205

(M^þþ1, 0.2%), 204 (M^þ, 1%), 122 (14), 121 (100), 118

(46), 117 (13), 105 (11), 91 (13), 78 (10), 77 (19), 51 (12),

43 (84), 41 (40). HRMS: M^þ, found 204.1560. C₁₄H₂₀O

requires 204.1560.

4.3.2. Lithiation of compound 6. To a stirred green

suspension of lithium powder (50 mg, 7.2 mmol) and DTBB

(13.3 mg, 0.05 mmol) in THF (4 mL) at 2788C was added

6-chloro-2-propylhex-1-ene (6; 0.080 g, 0.5 mmol) under

an argon atmosphere. The colour disappeared after the

substrate addition, the reaction mixture was stirred until the

green colour was recovered (ca. 40 min) and the corre-

sponding electrophile (0.55 mmol) was then added. The

resulting mixture was stirred for 15 min at the same

temperature (2788C), then was hydrolysed with 2 M HCl

(5 mL) and stirred to room temperature for 10 min.

The reaction mixture was extracted with diethyl ether

(3£15 mL), the organic phase was dried over anhydrous

magnesium sulphate and was concentrated under vacuum

(15 Torr). Compounds 8 were isolated after column

chromatography (silica gel, hexane/ethyl acetate mixtures).

Yields are given in Table 3; physical, spectroscopic and

analytical data follows.

4.3.2.1. 3-Ethyl-8-propylnon-8-en-3-ol (8a). R_f0.4

(hexane/ethyl acetate: 8/2); n (ﬁlm) 3401 (OH), 3077,

1644 cm²¹(CvC); d_H0.87 (m, 9H, 3£CH₃), 1.34 (m, 13H,

6£CH₂and OH), 2.01 [m, 4H, CH₂C(vCH₂)CH₂], 4.70

(s, 2H, vCH₂); d_C7.7 (2£COHCH₂CH₃), 13.8 (CH₃), 20.8,

23.1, 28.4, 31.0, 35.9, 38.0, 38.1 (8£CH₂), 74.5 (COH),

108.7 (CH₂vC), 149.7 (CH₂vC); m/z 194 (M^þ218,

0.45%), 165 (19), 123 (14), 110 (54), 109 (18), 97 (13),

95 (32), 87 (100), 85 (15), 83 (12), 81 (20), 69 (39), 67 (13),

57 (68), 55 (35). HRMS: M^þ2[H₂O], found 194.2058.

C₁₄H₂₅requires 194.2035.

4.3.2.2. 2,2-Dimethyl-8-propylnon-8-en-3-ol (8b). R_f

0.4 (hexane/ethyl acetate: 9/1); n (ﬁlm) 3383 (OH), 3072,

1644 cm²¹(CvC); d_H0.90 [m, 12H, CH₂CH₃and

C(CH₃)₃], 1.37 (m, 9H, 4£CH₂and OH), 2.00 [q, J¼

8.2 Hz, 4H, CH₂C(vCH₂)CH₂], 3.18 (d, J¼9.9 Hz, 1H,

CHOH), 4.70 (s, 2H, CH₂v); d_C13.8 (CH₂CH₃), 20.8, 26.9,

27.8, 31.3, 36.0, 38.1 (6£CH₂), 25.6 [3C, C(CH₃)₃], 34.9

[C(CH₃)₃], 79.9 (CHOH), 108.6 (CH₂v), 149.8 (Cv); m/z

213 (M^þþ1, 0.04%), 212 (M^þ, 0.14%), 137 (19), 123 (10),

110 (61), 97 (12), 96 (14), 95 (100), 87 (14), 83 (11), 81

(57), 71 (14), 70 (10), 69 (41), 68 (11), 67 (26), 57 (54), 56

(18), 55 (48). HRMS: M^þ2[H₂O], found 194.2043. C₁₄H₂₆

requires 194.2035.

4.3. DTBB-catalysed lithiation of 6-chloro-2-propylhex-

1-ene (6)

4.3.1. Preparation of compound 6. Preparation of

8-chlorooctan-4-one.²⁸To a solution of n-propylmag-

nesium chloride (2.0 M in diethyl ether, 15 mL, 30 mmol)

in dry diethyl ether (15 mL) under argon atmosphere was

added 5-chlorovaleronitrile (3.5 mL, 30 mmol), dropwise,

via syringe. The reaction mixture was stirred at room

temperature for 2 h. The reaction vessel was cooled on an

ice bath, and ice was added in portions to the reaction

mixture. Then the reaction mixture was acidiﬁed with 2 M

HCl and extracted with diethyl ether (3£30 mL). The

combined ether layers were washed (brine, 3£15 mL), dried

over anhydrous magnesium sulphate, ﬁltered and concen-

trated under vacuum (15 Torr) to afford a yellow oil. The

crude oil was puriﬁed by column chromatography (silica

gel, hexane/ethyl acetate mixtures), giving the title com-

pound in 55% yield (2.66 g, 16.4 mmol).

4.3.1.1. 8-Chlorooctan-4-one.²⁸R_f0.2 (hexane/ethyl

acetate: 9/1); n (ﬁlm) 1713 cm²¹(CvO); d_H0.92 (t, J¼

7.3 Hz, 3H, CH₃), 1.60 (q, J¼7.3 Hz, 2H, CH₂CH₃), 1.76

(m, 4H, ClCH₂CH₂CH₂), 2.42 (m, 4H, CH₂COCH₂), 3.54 (t,

J¼6.1 Hz, 2H, ClCH₂); d_C13.6 (CH₃), 17.2, 20.9, 31.9,

41.6, 44.5 (5£CH₂), 44.6 (COCH₂CH₂CH₃), 210.4 (CvO);

m/z 164 (M^þþ2, 0.8), 162 (M^þ, 2.5), 126 (14), 119 (28), 93

(11), 91 (34), 71 (100), 58 (12), 55 (69).

Preparation of 6-chloro-2-propylhex-1-ene.²⁷To a mixture

of methyltriphenylphosphonium bromide (8.80 g,

24.6 mmol) and sodium amide (1.26 g, 30.6 mmol) was

added dry THF (10 mL) under an argon atmosphere and the

mixture was stirred 15–20 min. A yellow salt was formed

and a solution of 8-chlorooctan-4-one (2.66 g, 16.4 mmol)

in dry THF (15 mL) was added. The reaction mixture was

stirred for 2 h, the reaction medium developing during this

period a tan colour. Finally, the reaction was hydrolysed

with 15% NaOH (15 mL) and extracted with diethyl ether

4.3.2.3. 1-Phenyl-6-propylhept-6-en-1-ol (8c). R_f0.2

(hexane/ethyl acetate: 9/1); n (ﬁlm) 3362 (OH), 3082, 3065,

3029, 1644 cm²¹(CvC); d_H0.88 (t, J¼7.3 Hz, 3H, CH₃),

1.35 (m, 6H, 3£CH₂), 1.73 (m, 2H, CH₂), 1.95 [def. t, J¼

7.0 Hz, 4H, CH₂C(vCH₂)CH₂], 2.28 (s, 1H, OH), 4.60 (t,

8534

M. Yus et al. / Tetrahedron 59 (2003) 8525–8542

J¼6.6 Hz, 1H, CHOH), 4.68 (s, 2H, CH₂v), 7.29 (m, 5H,

ArH); d_C13.8 (CH₃), 20.8, 25.5, 27.6, 35.8, 38.1, 38.9

(6£CH₂), 74.5 (CHOH), 108.6 (CH₂v), 125.8, 127.3,

128.3, 144.8 (6C, ArC), 149.7 (CvCH₂); m/z 232 (M^þ,

0.1%), 214 (M^þ218, 3.6%), 133 (13), 130 (32), 117 (10),

110 (24), 107 (100), 105 (12), 91 (11), 79 (56), 77 (28), 55

(19). HRMS: M^þ, found 232.1834. C₁₆H₂₄O requires

232.1827.

4.4.2. Lithiation of compound 9. To a stirred green

suspension of lithium powder (40 mg, 5.8 mmol) and DTBB

(26.6 mg, 0.1 mmol) in THF (4 mL) at 2788C was added

(Z)-8-chlorooct-3-ene (9; 0.146 g, 1.0 mmol) under an

argon atmosphere. The colour disappeared after the

substrate addition, the reaction mixture was stirred until

the green colour was recovered (ca. 40 min) and the

corresponding electrophile (1.1 mmol) was then added.

The resulting mixture was stirred for 15 min at the same

temperature (2788C), then it was hydrolysed with 2 M HCl

(5 mL) and stirred to room temperature for 10 min.

The reaction mixture was extracted with diethyl ether

(3£15 mL), the organic phase was dried over anhydrous

magnesium sulphate and the solvents were concentrated

under vacuum (15 Torr). Compounds 11 were isolated after

column chromatography (silica gel, hexane/ethyl acetate

mixtures). Yields are given in Table 4; physical, spectro-

scopic and analytical data follows.

4.4.2.1. (Z)-3-Ethylundec-8-en-3-ol (11a). R_f0.4 (hexane/

ethyl acetate: 9/1); n (ﬁlm) 3415 (OH), 3005 cm²¹(CvC);

d_H0.86 (t, J¼7.6 Hz, 6H, 2£COHCH₂CH₃), 0.96 (t, J¼

7.5 Hz, 3H, CHCH₂CH₃), 1.31 (m, 7H, CH₂CH₂CH₂COH),

1.46 (q, J¼7.5 Hz, 4H, 2£CH₂CH₃), 2.04 (m, 4H,

CH₂CHvCHCH₂), 5.35 (m, 2H, CHvCH); d_C7.7

(2£CH₂CH₃), 14.3 (CH₃), 20.5, 23.0, 27.0, 30.4, 30.9,

38.1 (7£CH₂), 74.6 (COH), 129.0 (vCHCH₂CH₂), 131.7

(vCHCH₂CH₃); m/z 180 (M^þ218, 1.1%), 169 (15), 151

(17), 110 (19), 109 (14), 97 (13), 96 (10), 95 (23), 87 (93),

85 (12), 82 (14), 81 (17), 69 (23), 67 (19), 57 (100), 55 (39).

HRMS: M^þ2[H₂O], found 180.1868. C₁₃H₂₄requires

180.1878.

4.4.2.2. (Z)-2,2-Dimethylundec-8-en-3-ol (11b). R_f0.4

(hexane/ethyl acetate: 9/1); n (ﬁlm) 3393 (OH), 3005,

1463 cm²¹(CvC); d_H0.89 (s, 9H, C(CH₃)₃), 1.91 (t, J¼

7.5 Hz, 3H, CH₃), 1.39 (m, 7H, 3£CH₂and OH), 2.04

(m, 4H, CH₂CHvCHCH₂), 3.18 (dd, J¼10.2 Hz, 1.5, 1H,

CHOH), 5.35 (m, 2H, CHvCH); d_C14.3 (CH₃), 20.4, 26.6,

27.0, 29.7, 31.3 (5£CH₂), 25.6 [3C, C(CH₃)₃], 34.8

[C(CH₃)₃], 79.8 (CHOH), 129.0 (vCHCH₂CH₂), 131.5

(vCHCH₂CH₃); m/z 180 (M^þ218, 3.1%), 141 (12), 137

(15), 124 (14), 123 (26), 110 (31), 109 (22), 97 (15), 96 (22),

95 (29), 87 (20), 85 (10), 83 (19), 82 (49), 81 (100), 71 (25),

70 (15), 69 (39), 68 (14), 67 (69), 57 (82), 56 (12), 55 (75),

54 (12), 53 (11). HRMS: M^þ2[H₂O], found 180.1876.

C₁₃H₂₄requires 180.1878.

4.3.2.4. 1-(5-Propylhex-5-enyl)cyclohexanol (8d). R_f

0.3 (hexane/ethyl acetate: 9/1); n (ﬁlm) 3385 (OH), 3076,

1644 cm²¹(CvC); d_H0.90 (t, J¼7.3 Hz, 3H, CH₃), 1.43

(m, 19H, 9£CH₂and OH), 2.00 [m, 4H, CH₂C(vCH₂)-

CH₂], 4.69 (s, 2H, CH₂v); d_C13.8 (CH₃), 20.8, 22.2, 22.6,

25.8, 28.3, 36.0, 37.3, 38.1, 42.3 (11£CH₂), 71.3 (COH),

108.6 (CH₂v), 149.7 (Cv); m/z 206 (M^þ218, 1.8%), 135

(12), 123 (18), 122 (52), 111 (11), 110 (94), 109 (18), 108

(10), 107 (18), 99 (89), 97 (10), 96 (11), 95 (100), 94 (13),

93 (21), 83 (17), 82 (14), 81 (84), 80 (10), 79 (33), 69 (27),

68 (14), 67 (41), 57 (11), 56 (14), 55 (75), 53 (16). HRMS:

M^þ2[H₂O], found 206.2039. C₁₅H₂₆requires 206.2035.

4.3.2.5. 2-Phenyl-7-propyloct-7-en-2-ol (8e). R_f0.3

(hexane/ethyl acetate: 9/1); n (ﬁlm) 3416 (OH), 3083,

3064, 3026, 1644 cm²¹(CvC); d_H0.87 (t, J¼7.3 Hz, 3H,

CH₂CH₃), 1.28 (m, 7H, 3£CH₂and OH), 1.54 (s, 3H,

COHCH₃), 1.81 (m, 2H, CH₂), 1.93 [t, J¼7.41 Hz, 4H,

CH₂C(vCH₂)CH₂], 4.64 (s, 2H, CH₂v), 7.22, 7.32, 7.42

(3m, 5H, ArH); d_C13.8 (CH₃), 20.8, 23.7, 28.1, 35.8, 38.1,

44.0 (6£CH₂), 30.4 (CH₃COH), 74.6 (COH), 108.6

(CH₂v), 124.7, 126.4, 128.0, 148.0 (6C, ArC), 149.7

(Cv); m/z 246 (M^þ, 0.03%), 228 (M^þ218, 2.0%), 144

(33), 131 (25), 129 (56), 121 (100), 118 (28), 117 (16), 115

(14), 105 (16), 91 (22), 77 (11), 55 (13). HRMS: M^þ, found

246.2011. C₁₇H₂₆O requires 246.1984.

4.3.2.6. Trimethyl(5-propylhex-5-enyl)silane (8f). R_f

0.8 (hexane); n (ﬁlm) 3071, 1644 cm²¹(CvC); d_H0.00

[s, 9H, Si(CH₃)₃], 0.52 (t, J¼8.3 Hz, 2H, CH₂Si), 0.93

(t, J¼7.3 Hz, 3H, CH₃), 1.32 (m, 2H, CH₂), 1.46 (m, 4H,

2£CH₂), 2.00 [m, 4H, CH₂C(vCH₂)CH₂], 4.72 (s, 2H,

CH₂vC); d_C21.65 [3C, Si(CH₃)₃], 13.9 (CH₃), 16.6, 20.9,

23.7, 31.7 (4£CH₂), 35.8, 38.2 [CH₂C(vCH₂)CH₂], 108.5

(CH₂v), 150.1 (CvCH₂); m/z 198 (M^þ, 0.03%), 114 (25),

73 (100), 59 (17). HRMS: M^þ2[CH₃], found 183.1572.

C₁₁H₂₃Si requires 183.1569.

4.4. DTBB-catalysed lithiation of (Z)-8-chloro-3-octene

(9)

4.4.2.3. (Z)-1-Phenylnon-6-en-1-ol (11c). R_f0.2 (hexane/

ethyl acetate: 9/1); n (ﬁlm) 3371 (OH), 3085, 3062, 3027,

3003, 1602, 1493 cm²¹(CvC); d_H0.93 (t, J¼7.6 Hz, 3H,

CH₃), 1.33 (m, 4H, 2£CH₂), 1.72 (m, 2H, CH₂), 2.01 (m,

4H, CH₂CHvCHCH₂), 2.34 (s, 1H, OH), 4.61 (t, J¼6.6 Hz,

1H, CHOH), 5.33 (m, 2H, CHvCH), 7.29 (m, 5H, ArH); d_C

14.3 (CH₃), 20.4, 25.4, 26.9, 29.6, 38.9 (5£CH₂), 74.6

(CHOH), 125.8, 127.4, 128.3, 144.8 (6C, ArC), 128.9

(vCHCH₂CH₂), 131.7 (vCHCH₂CH₃); m/z 219 (M^þþ1,

0.20%), 218 (M^þ, 1.22%), 144 (15), 133 (15), 130 (12), 117

(11), 107 (100), 105 (13), 104 (12), 91 (11), 79 (52), 77 (25).

HRMS: M^þ, found 218.1658. C₁₅H₂₂O requires 218.1671.

4.4.2.4. 1-[(Z)-Oct-5-enyl]-1-cyclohexanol (11d). R_f0.3

(hexane/ethyl acetate: 9/1); n (ﬁlm) 3383 (OH), 3004,

1462 cm²¹(CvC); d_H0.96 (t, J¼7.5 Hz, 3H, CH₃), 1.50

(m, 17H, 8£CH₂and OH), 2.04 (m, 4H, CH₂CHvCHCH₂),

5.35 (m, 2H, CHvCH); d_C14.3 (CH₃), 20.4, 22.2, 22.5,

25.8, 27.0, 30.3, 37.3, 42.2 (10£CH₂), 71.4 (COH), 129.0

4.4.1. Preparation of compound 9.²⁹A mixture of (Z)-5-

octen-1-ol (15.4 mL, 100 mmol) and triphenylphospane

(28.87 g, 110 mmol) in carbon tetrachloride was reﬂuxed

for 48 h. Then, the reaction mixture was concentrated under

vacuum (15 Torr) and the residue was puriﬁed by column

chromatography (silica gel, hexane) to give 14.7 g of

compound 9 (99%).

4.4.1.1. (Z)-8-Chlorooct-3-ene (9).⁵¹R_f0.7 (hexane); n

(ﬁlm) 3005, 1655 cm²¹(CvC); d_H0.96 (t, J¼7.5 Hz, 3H,

CH₃), 1.49 (m, 2H, CH₂), 1.78 (m, 2H, CH₂), 2.04 (m, 4H,

CH₂CHvCHCH₂), 3.53 (t, J¼6.6 Hz, 2H, CH₂Cl), 5.35

(m, 2H, CHvCH); d_C14.3 (CH₃), 20.5, 26.2, 26.9, 32.1

(4£CH₂), 44.9 (CH₂Cl), 128.2 (vCHCH₂CH₂), 132.2

(vCHCH₂CH₃); m/z 148 (M^þþ2, 9.4%), 146 (M^þ,

29.2%), 104 (26), 91 (10), 81 (36), 70 (13), 69 (53), 68

(37), 67 (30), 56 (45), 55 (100), 54 (16), 53 (19).

M. Yus et al. / Tetrahedron 59 (2003) 8525–8542

8535

(vCHCH₂CH₂), 131.6 (vCHCH₂CH₃); m/z 192 (M^þ218,

4.53%), 149 (17), 135 (13), 111 (14), 110 (17), 109 (14), 99

(100), 96 (19), 95 (12), 83 (11), 82 (20), 81 (69), 79 (16), 69

(17), 67 (29), 55 (22). HRMS: M^þ2[H₂O], found 192.1889.

C₁₄H₂₄requires 192.1878.

4.4.2.5. (Z)-2-Phenyldec-7-en-2-ol (11e). R_f0.3 (hexane/

ethyl acetate: 9/1); n (ﬁlm) 3435 (OH), 3086, 3060, 3024,

3003, 1602, 1494, 1462 cm²¹(CvC); d_H0.92 (t, J¼

7.5 Hz, 3H, CH₃CH₂), 1.22 (m, 4H, 2£CH₂), 1.55 (s, 3H,

CH₃COH), 1.79 (m, 3H, CH₂COH), 1.98 (m, 4H,

CH₂CHvCHCH₂), 5.29 (m, 2H, CHvCH), 7.23, 7.33,

7.43 (3m, 5H, ArH); d_C14.3 (CH₃CH₂), 20.4, 23.6, 26.9,

30.0, 44.1 (5£CH₂), 30.03 (CH₃COH), 74.7 (COH), 124.7,

126.4, 128.1, 148.0 (6C, ArC), 128.9 (vCHCH₂CH₂),

131.6 (vCHCH₂CH₃); m/z 232 (M^þ, 0.05%), 121 (100),

105 (12). HRMS: M^þ, found 232.1874. C₁₆H₂₄O requires

232.1827.

4.4.2.6. Trimethyl-[(Z)-oct-5-enyl]silane (11f). R_f0.8

(hexane); n (ﬁlm) 3005, 1462 cm²¹(CvC); d_H20.03

[s, 9H, Si(CH₃)₃], 0.49 (m, 2H, CH₂Si), 0.96 (t, J¼

7.5 Hz, 3H, CH₃), 1.32 (m, 4H, 2£CH₂), 2.04 (m, 4H,

CH₂CHvCHCH₂), 5.35 (m, 2H, CHvCH); d_C21.7 [3C,

Si(CH₃)₃], 14.4 (CH₃), 16.6, 20.5, 23.6, 26.8, 33.7 (5£CH₂),

129.2 (vCHCH₂CH₂), 131.5 (vCHCH₂CH₃); m/z 185

(M^þþ1, 0.09%), 184 (M^þ, 0.56%), 99 (11), 73 (100), 59

(17). HRMS: M^þ, found 184.1657. C₁₁H₂₄Si requires

184.1647.

until the green colour was recovered (ca. 30 min) and the

corresponding electrophile (0.55 mmol) was added. The

resulting mixture was stirred for 15 min at the same

temperature (2788C), then it was hydrolysed with 2 M

HCl (5 mL) and stirred to room temperature for 10 min. The

reaction mixture was extracted with diethyl ether

(3£15 mL), the organic phase was dried over anhydrous

magnesium sulphate and was concentrated under vacuum

(15 Torr). Compounds 14 were isolated after column

chromatography (silica gel, hexane/ethyl acetate mixtures).

Yields are given in Table 5; physical, spectroscopic and

analytical data follows.

4.5.2.1. 3-[(1-Phenylcyclopentyl)methyl]pentan-3-ol

(14a). R_f0.4 (hexane/ethyl acetate: 9/1); n (ﬁlm) 3591,

3585, 3485 (OH), 3085, 3057, 3022, 1600 cm²¹(C¼C);

d_H0.69 (t, J¼7.4 Hz, 6H, 2£CH₃), 1.27 (q, J¼7.5 Hz,

4H, 2£CH₂CH₃), 1.67 (m, 6H, 3£CH₂), 1.99 (s, 2H,

CCH₂COH), 2.18 (m, 2H, CH₂), 7.17 (t, J¼7.3 Hz, 1H,

ArH), 7.33 (m, 2H, 2£ArH), 7.42 (d, J¼1.38 Hz, 2H,

2£ArH); d_C7.9 (2£CH₃), 22.5, 31.7, 40.1 (6£CH₂), 49.7

(CCH₂COH), 50.2 (CCH₂COH), 76.1 (COH), 125.8, 127.1,

128.2, 147.1 (6£ArC); m/z 228 (M^þ218, 0.14%), 146 (12),

145 (100), 91 (50), 87 (46). HRMS: M^þ2[H₂O], found

228.1903. C₁₇H₂₄requires 228.1878.

4.5.2.2. 3,3-Dimethyl-1-(1-phenylcyclopentyl)butan-2-

ol (14b). R_f0.2 (hexane/ethyl acetate: 9/1); n (ﬁlm) 3584,

3500 (OH), 3084, 3057, 3023, 1600, 1495 cm²¹(CvC); d_H

0.76 (s, 9H, 3£CH₃), 1.79 (m, 11H, 5£CH₂and OH), 3.08

(dd, J¼8.8 Hz, 0.8, 1H, CHOH), 7.26 (m, 5H, ArH); d_C

22.7, 23.0, 36.9, 39.0 (4£CH₂), 25.5 (3£CH₃), 34.8

[C(CH₃)₃], 44.0 (CH₂CHOH), 50.3 (CCH₂), 77.2

(CHOH), 125.9, 126.9, 128.4, 148.2 (6C, ArC); m/z 247

(M^þþ1, 0.11%), 246 (M^þ, 0.59%), 146 (36), 145 (100), 91

(35). HRMS: M^þ, found 246.1974. C₁₇H₂₆O requires

246.1984.

4.5.2.3. 1-Phenyl-2-(1-phenylcyclopentyl)ethanol (14c).

R_f0.2 (hexane/ethyl acetate: 9/1); n (ﬁlm) 3417 (OH), 3083,

3058, 3026 1600, 1494 cm²¹(CvC); d_H1.30 (m, 4H,

2£CH₂), 1.69 (m, 4H, 2£CH₂), 2.05 (m, 3H, CH₂and OH),

4.44 (dd, J¼8.3 Hz, 7.8, 1H, CHOH), 7.27 (m, 10H,

2£ArH); d_C22.7, 22.9, 37.7, 38.9 (CH₂of the cyclopentyl),

50.4 (CCH₂), 51.4 (CH₂COH), 72.5 (CHOH), 125.6, 125.9,

126.9, 127.1, 128.3, 128.4, 145.6, 147.7 (10£ArC); m/z 266

(M^þ, 0.21%), 147 (12), 146 (100), 145 (31), 129 (11), 117

(15), 115 (15), 107 (63), 104 (11), 91 (64), 79 (32), 77 (25).

HRMS: M^þ, found 266.1646. C₁₉H₂₂O requires 266.1671.

4.5. DTBB-catalysed lithiation of 6-chloro-2-phenylhex-

1-ene (12)

4.5.1. Preparation of compound 12.³¹To a solution of

a-bromostyrene (3.0 mL, 20.7 mmol) in dry THF (45 mL)

at 2788C was slowly added n-BuLi (13.0 mL of a solution

1.6 M in hexane, 20.8 mmol), and the mixture was stirred

for 1 h at the same temperature (2788C). Then 1-chloro-4-

iodobutane (2.5 mL, 20.0 mmol) was added and the solution

was allowed to warm to room temperature. After 4 h stirring

at room temperature the reaction mixture was hydrolysed

with H₂O (40 mL) and extracted with ethyl acetate

(3£25 mL). The organic layer was dried with anhydrous

magnesium sulphate and was concentrated under vacuum

(15 Torr). The crude oil was puriﬁed by column chroma-

tography (silica gel, hexane) to give 2.13 g (53%) of the title

compound.

4.5.1.1. 6-Chloro-2-phenylhex-1-ene (12). R_f0.5 (hex-

ane); n (ﬁlm) 3081, 3056, 3024, 1600, 1494 cm²¹(CvC);

d_H1.59 (m, 2H, CH₂), 1.79 (m, 2H, CH₂), 2.53 (m, 2H,

CH₂CvCH₂), 3.50 (t, J¼6.6 Hz, 2H, CH₂Cl), 5.06

(d, J¼1.4 Hz, 1H, CvCHH), 5.28 (d, J¼1.4 Hz, 1H,

CvCHH), 7.30 (m, 5H, ArH); d_C25.3, 32.1 (2£CH₂),

34.5 (CH₂vCCH₂), 44.8 (CH₂Cl), 112.6 (CH₂vC), 126.0,

127.4, 128.3, 140.9 (6C, ArC), 147.8 (CH₂vC); m/z 196

(M^þþ2, 1.2%), 194 (M^þ, 3.9%), 131 (13), 119 (10), 118

(100), 117 (29), 115 (18), 103 (13), 91 (17), 77 (10). HRMS:

M^þ, found 194.0872. C₁₂H₁₅Cl requires 194.0862.

4.6. DTBB-catalysed lithiation of (Z)-6-chloro-1-phenyl-

hex-1-ene (15)

4.6.1. Preparation of compound 15. Preparation of

6-chloro-1-phenylhex-1-yne.³²To a solution of PdCl₂(PPh₃)₂

(3.5 mg, 0.005 mmol) and CuI (1.9 mg, 0.01 mmol) in

dry THF (3 mL) were successively added iodobenzene

(0.056 mL, 0.5 mmol), 6-chlorohex-1-yne (0.074 mL,

0.6 mmol) and tetrabutylamonium ﬂuoride (TBAF; 1 mL

of solution 1.0 M in THF, 1 mmol) under an argon

atmosphere. The reaction mixture was stirred for 3 h at

room temperature and then was passed through a Celite pad.

The ﬁltrate was concentrated under vacuum and subjected to

column chromatography on silica gel (hexane/ethyl acetate)

to give 0.094 g (98%) of the title compound.

4.5.2. Lithiation of compound 12. To a stirred green

suspension of lithium powder (45 mg, 6.5 mmol) and DTBB

(13.3 mg, 0.05 mmol) in THF (4 mL) at 2788C was added

6-chloro-2-phenylhex-1-ene (12; 0.097 g, 0.5 mmol) under

an argon atmosphere. The colour disappeared after the

substrate addition, the reaction mixture was then stirred

4.6.1.1. 6-Chloro-1-phenylhex-1-yne.⁵²R_f0.3 (hexane);

8536

M. Yus et al. / Tetrahedron 59 (2003) 8525–8542

n (ﬁlm) 3056, 1598, 1489 cm²¹(C¼C); d_H1.75 (m, 2H,

CH₂), 1.95 (m, 2H, CH₂), 2.45 (t, J¼6.7 Hz, 2H, CuCCH₂),

3.59 (t, J¼6.7 Hz, 2H, CH₂Cl), 7.26, 7.38 (2m, 5H, ArH);

d_C18.7, 25.8, 31.6 (3£CH₂), 44.5 (CH₂Cl), 81.1 (PhCuC),

89.2 (PhCuC), 123.7, 127.6, 128.2, 131.5 (6£ArC); m/z

194 (M^þþ2, 4.4%), 193 (M^þþ1, 1.9%), 192 (M^þ, 13.5%),

156 (14), 143 (15), 130 (21), 129 (40), 128 (41), 127 (12),

117 (40), 116 (13), 115 (100), 102 (11), 91 (24), 89 (12), 63

(11).

4.6.2.2. 2-Cyclopentyl-1,2-diphenylethanol (17b). R_f

0.3 (hexane/ethyl acetate: 9/1); n (ﬁlm) 3563, 3440 (OH),

3084, 3060, 3027, 1602, 1493 cm²¹(CvC); d_H(mixture of

diastereomers) 1.63 (m, 20H, 2£cycle and 2£OH), 2.69 (dd,

J¼9.6 Hz, 5.1, 1H, CHOHCHCH, ﬁrst diastereomer), 2.92

(dd, J¼9.8 Hz, 5.6, 1H, CHOHCHCH, second diastereo-

mer), 5.04 (2d, J¼5.6 Hz, 5.1, 2H, 2£CHOH), 7.00 (4m,

20H, ArH); d_C(mixture of diastereomers) 24.5, 24.7,

25.0, 25.5, 31.2, 31.7, 31.8, 32.1 (8£CH₂), 41.2, 41.6

(2£CHCH₂), 58.8, 59.5 (2£CHCHCH₂), 76.1, 76.6

(CHOH), 126.18, 126.24, 126.4, 127.0, 127.1, 127.2,

127.4, 127.5, 127.8, 127.9, 129.7, 130.0, 139.7, 140.1,

142.0, 143.5 (24C, ArC); m/z 266 (M^þ, 0.08%), 161 (12),

160 (100), 129 (10), 117 (19), 115 (18), 107 (84), 105 (12),

92 (72), 91 (87), 79 (37), 77 (27). HRMS: M^þ2[H₂O],

found 248.1559. C₁₉H₂₀requires 248.1565.

4.6.2.3. Cyclopentyl(phenyl)methyl(trimethyl)silane

(17c). R_f0.7 (hexane); n (ﬁlm) 3081, 3060, 3022, 1600,

1495 cm²¹(CvC); d_H20.07 [s, 9H, Si(CH₃)₃], 1.29 (m,

7H, 3£CH₂and CHH), 1.83 (d, J¼11.2 Hz, 1H, CHSi), 1.93

(m, 1H, CHH), 2.31 (m, 1H, CHCHSi), 7.04, 7.21 (2m, 5H,

ArH); d_C21.3 [3C, Si(CH₃)₃], 24.1, 25.5 (2£CH₂), 32.3,

34.3 (2£CH₂), 42.6, 43.8 (2£CH), 124.1, 127.9, 128.0,

145.5 (6C, ArC); m/z 233 (M^þþ1, 1.7%), 232 (M^þ, 8.32%),

158 (56), 135 (12), 91 (14), 73 (100). HRMS: M^þ, found

232.1647. C₁₅H₂₄Si requires 232.1647.

Preparation of (Z)-6-chloro-1-phenylhex-1-ene.³³A mixture

of 6-chloro-1-phenylhex-1-yne (0.46 g, 2.4 mmol) and the

Lindlar catalyst (0.24 g) in ethanol (13 mL), containing 3

drops of quinoline was hydrogenated at atmospheric

pressure for 16 h. Then, the suspension was ﬁltered through

a Celite pad and it was washed with ethanol. The ethanol

was concentrated (15 Torr) and the residue was diluted in

diethyl ether and was washed with diluted 1 M HCl and

water. The organic phase was dried over anhydrous

magnesium sulphate and the solvent was concentrated

under vacuum (15 Torr) to give 0.44 g (95%) of the title

compound.

4.6.1.2. (Z)-6-Chloro-1-phenylhex-1-ene (15).⁵³R_f0.5

(hexane); n (ﬁlm) 3080, 3055, 3023, 3008, 1643 cm²¹

(CvC); d_H1.59 (m, 2H, CH₂), 1.79 (m, 2H, CH₂), 2.35

(m, 2H, vCHCH₂), 3.50 (t, J¼6.6 Hz, 2H, CH₂Cl), 5.63

(m, 1H, vCHCH₂), 6.44 (d, J¼11.7 Hz, 1H, PhCH), 7.27

(m, 5H, ArH); d_C27.0, 27.7 (2£CH₂), 32.1 (vCHCH₂),

44.8 (CH₂Cl), 126.5, 128.1, 128.7, 129.4, 132.0, 137.5 (8C,

ArC and CHvCH); m/z 196 (M^þþ2, 4.36%), 195 (M^þþ1,

1.53%), 194 (M^þ, 12.26%), 118 (10), 117 (100), 116 (10),

115 (34), 104 (21), 91 (30).

4.7. DTBB-catalysed lithiation of 6-chloronon-1-ene (18)

4.7.1. Preparation of compound 18. Preparation of non-8-

en-4-ol. Magnesium powder (378 mg, 15.6 mmol) was

warmed under vacuum for 20 min. Then, dry THF

(33 mL) was added under an argon atmosphere. 5-Bromo-

pent-1-ene (1.94 mL, 15.6 mmol) was dissolved in THF

(7 mL) and a few drops of this solution were added at room

temperature to start the reaction. The reaction mixture was

then cooled to 2158C by means of an ice-salt bath. The

rest of the solution of the mentioned bromide was added

dropwise over 1.5 h using a syringe-pump. The resultant

grey solution was stirred for 30 min and then butyraldehyde

(1.38 mL, 15.6 mmol) was added dropwise and the reaction

mixture was stirred overnight. The mixture was cooled in an

ice bath and ice portions were added to hydrolyse the

reaction. Then 2 M HCl was added to acidify the resulting

mixture and it was extracted with diethyl ether (3£30 mL).

The organic phase was dried with anhydrous magnesium

sulphate, and concentrated under vacuum (15 Torr). The

residue was puriﬁed by column chromatography (silica gel,

hexane/ethyl acetate) to give 1.77 g (80%) of the title

compound.

4.6.2. Lithiation of compound 15. To a stirred green

suspension of lithium powder (35 mg, 5.0 mmol) and DTBB

(6 mg, 0.02 mmol) in THF (4 mL) at 2308C was added

6-chloro-1-phenylhex-1-ene (15; 0.050 g, 0.2 mmol) and

the corresponding electrophile in THF (1.5 mL) under an

argon atmosphere. The reaction was ﬁnished in 30 min (the

solution recovered the green colour) and then it was

hydrolysed with 2 M HCl (5 mL) at the same temperature

(2308C), and then it was stirred for 10 min allowing the

temperature to rise to room temperature. The reaction

mixture was extracted with diethyl ether (3£15 mL), the

organic phase was dried over anhydrous magnesium

sulphate and was concentrated under vacuum (15 Torr).

Compounds 17 were isolated after column chromatography

(silica gel, hexane/ethyl acetate mixtures). Yields are given

in Table 5; physical, spectroscopic and analytical data

follows.

4.6.2.1. 3-Cyclopentyl(phenyl)methylpentan-3-ol

(17a). R_f0.4 (hexane/ethyl acetate: 9/1); n (ﬁlm) 3584,

3493 (OH), 3084, 3059, 3023 1602, 1494 cm²¹(CvC); d_H

0.80 (t, J¼7.4 Hz, 3H, CH₃), 0.88 (t, J¼7.4 Hz, 3H, CH₃),

1.31 (m, 12H, OH, 5£CH₂and CHH), 1.97 (m, 1H, CHH),

2.32 (m, 1H, CHCH₂), 2.68 (d, J¼7.8 Hz, 1H, CHCOH),

7.23 (m, 5H, ArH); d_C7.8, 8.1 (2£CH₃), 24.2, 24.9, 29.3,

29.4, 32.4, 33.3 (6£CH₂), 41.0 (CHCH₂), 56.7 (CHCOH),

77.2 (COH), 126.0, 127.6, 130.3, 142.3 (6C, ArC); m/z 228

(M^þ218, 1.4%), 160 (49), 159 (20), 131 (12), 129 (11), 117

(27), 115 (15), 92 (75), 91 (53), 87 (100), 69 (19), 57 (12).

HRMS: M^þ2[H₂O], found 228.1865. C₁₇H₂₄requires

228.1878.

4.7.1.1. Non-8-en-4-ol.⁵⁴R_f0.3 (hexane/ethyl acetate:

9/1); n (ﬁlm) 3355 (OH), 3077, 1641 cm²¹(CvC); d_H0.93

(t, J¼6.8 Hz, 3H, CH₃), 1.42 (m, 8H, 4£CH₂), 1.66 (s, 1H,

OH), 2.06 (m, 2H, CH₂CHvCH₂), 3.59 (m, 1H, CHOH),

4.95 (d, J¼11.7 Hz, 1H, vCHH), 5.01 (d, J¼19.2 Hz, 1H,

vCHH), 5.81 (m, 1H, CHvCH₂); d_C14.0 (CH₃), 18.8,

24.9, 33.7, 36.8, 39.6 (5£CH₂), 71.5 (CHOH), 114.5

(vCH₂), 138.7 (CHvCH₂); m/z 124 (M^þ218, 0.83%),

99 (18), 82 (17), 81 (69), 73 (26), 57 (23), 55 (100), 54 (25).

Preparation of 6-chloronon-1-ene. A mixture of non-8-en-

4-ol (2.77 g, 19.5 mmol) and triphenylphosphane (10.24 g,

39.0 mmol) in carbon tetrachloride (50 mL) was reﬂuxed

M. Yus et al. / Tetrahedron 59 (2003) 8525–8542

8537

for 48 h. Then, the reaction mixture was concentrated and

the residue was puriﬁed by column chromatography (silica

gel, hexane) to give 3.1 g (99%) of the title compound.

4.7.1.2. 6-Chloronon-1-ene (18). R_f0.8 (hexane); n

(ﬁlm) 3078, 1641 cm²¹(CvC); d_H0.92 (t, J¼7.3 Hz, 3H,

CH₃), 1.52 (m, 4H, 2£CH₂), 1.74 (m, 4H, 2£CH₂), 2.07

(m, 2H, CH₂CHvCH₂), 3.91 (m, 1H, CHCl), 4.97 (d, J¼

11.7 Hz, 1H, vCHH), 5.02 (d, J¼19.1 Hz, 1H, vCHH),

5.80 (m, 1H, CHvCH₂); d_C13.6 (CH₃), 19.7, 25.7, 33.2,

37.8, 40.6 (5£CH₂), 63.7 (CHCl), 114.8 (vCH₂), 138.3

(CHvCH₂); m/z 162 (M^þþ2, 0.18%), 160 (M^þ, 0.5), 96

(31), 95 (35), 83 (16), 82 (53), 81 (49), 69 (35), 68 (37), 67

(51), 56 (24), 55 (89), 54 (100), 53 (22). HRMS: M^þ, found

160.1020. C₉H₁₇Cl requires 160.1019.

0.85 (m, 6H, 2£CH₃), 1.29 (m, 18H, 2£OH, 8£CH₂), 1.71

(m, 2H, 2£CHCHOH), 1.99 (m, 4H, 2£CH₂CHvCH₂),

4.65 (m, 2H, 2£CHOH), 4.94 (m, 4H, 2£CH₂v), 5.77 (m,

2H, 2£CHv), 7.30 (m, 10H, 2£ArH); d_C(mixture of

diastereomers) 14.4, 14.5 (2£CH₃), 20.0, 20.1, 26.2,

26.3, 28.1, 29.5, 30.9, 32.2 (8£CH₂), 34.0, 34.1 (2£

CH₂CHvCH₂), 44.6, 44.7 (2£CHCHOH), 76.20, 76.22

(2£COH), 114.28, 114.33 (2£CH₂v), 126.4, 127.2, 128.2,

143.88, 143.94 (12£ArC), 138.9, 139.0 (2£CHvCH₂); m/z

233 (M^þþ1, 0.23%), 232 (M^þ, 1.39%), 214 (M^þ218,

0.26%), 107 (100), 79 (21), 77 (10). HRMS: M^þ, found

232.1835. C₁₆H₂₄O requires 232.1827.

4.7.2.4. 1-(1-Propyl-5-hexenyl)cyclohexanol (20d). R_f

0.3 (hexane/ethyl acetate: 9/1); n (ﬁlm) 3478 (OH), 3076,

1641 cm²¹(CvC); d_H0.90 (t, J¼7.1 Hz, 3H, CH₃),

1.36 (m, 20H, 9£CH₂, CH and OH), 2.06 (m, 2H,

CH₂CHvCH₂), 4.94 (d, J¼10.1 Hz, 1H, CHHvCH),

5.00 (d, J¼17.4 Hz, 1H, CHHvCH), 5.82 (m, 1H, CHv);

d_C14.6 (CH₃), 21.9, 22.6, 25.9, 28.8, 29.7, 32.5, 34.4, 34.5

(10C, 10£CH₂), 48.8 (CH), 74.2 (COH), 114.3 (CH₂v),

139.0 (CHv); m/z 224 (M^þ, 0.02%), 99 (100), 98 (13), 81

(35), 55 (20). HRMS: M^þ, found 224.2127. C₁₅H₂₈O

requires 224.2140.

4.7.2.5. 2-Phenyl-3-propyloct-7-en-2-ol (20e). R_f0.4

(hexane/ethyl acetate: 9/1); n (ﬁlm) 3479 (OH), 3061, 3026,

1640 cm²¹(CvC); d_H(mixture of diastereomers) 0.84

(m, 6H, 2£CH₂CH₃), 1.36 (m with s at 1.52, 26H, 8£CH₂,

2£CH and 2£COHCH₃), 1.95 (m, 4H, 2£CH₂CHvCH₂),

4.92 (m, 4H, 2£CH₂v), 5.73 (m, 2H, 2£CHvCH₂), 7.23,

7.32, 7.42 (3m, 10H, 2£ArH); d_C(mixture of diastereomers)

14.5, 14.6 (2£CH₂CH₃), 22.0, 22.3, 26.9, 27.0, 30.0, 30.1,

32.8, 32.9, 34.17, 34.25 (10C, 10£CH₂), 28.3, 28.5

(2£COHCH₃), 48.78, 48.82 (2£CH), 77.6 (2£COH),

114.2, 114.3 (2£CH₂v), 125.3, 126.4, 127.9, 148.4 (12C,

12£ArC), 138.87, 138.93 (2£CH₂vCH); m/z 228 (M^þ218,

0.9%), 131 (28), 121 (100), 105 (13), 91 (12). HRMS:

M^þ2[C₅H₉] ﬁrst diastereomer, found 177.1259. C₁₂H₁₇O

requires 177.1279. M^þ2[C₅H₉] second diastereomer, found

177.1248. C₁₂H₁₇O requires 177.1279.

4.7.2. Lithiation of compound 18. Preparation of

compounds 20. To a stirred green suspension of lithium

powder (40 mg, 5.8 mmol) and DTBB (13.3 mg,

0.05 mmol) in THF (3 mL) at 2788C was added a mixture

of 6-chloronon-1-ene (18; 0.080 g, 0.5 mmol) and the

corresponding electrophile (0.55 mmol) in THF (1 mL)

under an argon atmosphere. When the addition ﬁnished the

mixture was stirred for 30 additional minutes (the solution

recovered the green colour), then it was hydrolysed with

2 M HCl (5 mL) at the same temperature (2788C), and it

was stirred allowing the temperature to rise to room

temperature. The reaction mixture was extracted with

diethyl ether (3£15 mL), the organic phase was dried over

anhydrous magnesium sulphate and then was concentrated

under vacuum (15 Torr). Compounds 20 were isolated after

column chromatography (silica gel, hexane/ethyl acetate

mixtures). Yields are given in Table 7; physical, spectro-

scopic and analytical data follows.

4.7.2.1. 3-Ethyl-4-propylnon-8-en-3-ol (20a). R_f0.3

(hexane/ethyl acetate: 9/1); n (ﬁlm) 3493 (OH), 3076,

1641 cm²¹(CvC); d_H(in benzene-d₆) 0.63 (s, 1H, OH),

0.80 (def. t, J¼7.5 Hz, 6H, 2£COHCH₂CH₃), 0.91 (def. t,

J¼7.0 Hz, 3H, CH₂CH₂CH₃), 1.28 (m, 13H, CH, 6£CH₂),

2.02 (m, 2H, vCHCH₂), 5.04 (m, 2H, vCH₂), 5.81 (m,

1H, CHv); d_C(in benzene-d₆) 7.8 (2£COHCH₂CH₃), 15.0

(CH₂CH₂CH₃), 23.0, 28.8, 29.3, 30.3, 33.2, 34.9 (7C,

7£CH₂), 44.7 (CH), 76.4 (COH), 114.6 (CH₂v), 139.2

(vCH); m/z 194 (M^þ218, 0.09%), 87 (100), 69 (17), 57

(48), 55 (20). HRMS: M^þ2[CH₂CH₃], found 183.1767.

C₁₂H₂₃O requires 183.1749.

4.7.2.2. 2,2-Dimethyl-4-propylnon-8-en-3-ol (20b). R_f

0.5 (hexane/ethyl acetate: 9/1); n (ﬁlm) 3491 (OH), 3076,

1641 cm²¹(CvC); d_H(mixture of diastereomers) 0.91 (m,

24H, 8£CH₃), 1.29 (m, 20H, 8£CH₂, 2£CH and 2£OH),

2.04 (m, 4H, 2£vCHCH₂), 3.23 (m, 2H, 2£CHOH), 4.94

(d, J¼12.2 Hz, 2H, 2 £vCHH), 5.00 (d, J¼17.2 Hz, 2H,

2 £vCHH), 5.82 (m, 2H, 2 £vCH); d_C(mixture of

diastereomers) 14.3, 14.6 (2£CH₂CH₃), 20.5, 21.4, 26.8,

27.7, 28.7, 31.3, 33.7, 34.1, 34.3, 36.5 (10C, 10£CH₂), 26.6

[6C, 2£C(CH₃)₃], 35.8, 35.9 [2£C(CH₃)₃], 38.3, 38.4

(2£CHCH₂), 81.0 (2£CHOH), 114.3, 114.4 (2 £vCH₂),

138.9, 139.0 (2 £vCH); m/z 197 (M^þ215, 0.12%), 137

(27), 97 (10), 95 (48), 87 (100), 85 (13), 83 (19), 81 (55), 71

(40), 70 (14), 70 (55), 67 (23), 57 (72), 56 (14), 55 (52).

HRMS: M^þ, found 212.2189. C₁₄H₂₈O requires 212.2140.

4.7.2.3. 1-Phenyl-2-propylhept-6-en-1-ol (20c). R_f0.3

(hexane/ethyl acetate: 9/1); n (ﬁlm) 3415 (OH), 3074, 3063,

3028, 1640 cm²¹(CvC); d_H(mixture of diastereomers)

4.7.3. Preparation of compounds 22. To a stirred green

suspension of lithium powder (40 mg, 5.8 mmol) and DTBB

(13.3 mg, 0.05 mmol) in THF (3 mL) at 2308C was added a

mixture of 6-chloronon-1-ene (18; 0.080 g, 0.5 mmol) and

the corresponding electrophile (0.55 mmol) in THF (1 mL)

under an argon atmosphere. When the addition was ﬁnished

(1 h), the mixture was stirred one more hour (the solution

recovered the green colour) and then it was hydrolysed with

2 M HCl (5 mL) at the same temperature (2308C), and

stirred allowing the temperature to rise to room temperature.

The reaction mixture was extracted with diethyl ether

(3£15 mL), the organic phase was dried over anhydrous

magnesium sulphate and then was concentrated under

vacuum (15 Torr). Compounds 22 were isolated after

column chromatography (silica gel, hexane/ethyl acetate

mixtures). Yields are given in Table 8; physical, spectro-

scopic and analytical data follows.

4.7.3.1. 3-(2-Propylcyclopentylmethyl)pentan-3-ol

(22a). R_f0.3 (hexane/ethyl acetate: 9/1);

n (ﬁlm)

3471 cm²¹(OH); d_H0.85 (def. t, J¼6.8 Hz, 3H,

CH₂CH₂CH₃), 0.87 (t, J¼7.3 Hz, 3H, COHCH₂CH₃), 0.89

(t, J¼7.3 Hz, 3H, COHCH₂CH₃), 1.35 (m, 17H, 2£CH,

7£CH₂and OH), 1.78 (m, 1H, CHH), 1.96 (m, 1H, CHH);

8538

M. Yus et al. / Tetrahedron 59 (2003) 8525–8542

d_C7.7, 8.1 (2£COHCH₂CH₃), 14.4 (CH₂CH₂CH₃), 21.7,

24.0, 30.9, 31.1, 31.6, 34.2, 37.0 (7£CH₂), 41.4, 43.4

(2£CH), 46.9 (CH₂), 75.1 (COH); m/z 194 (M^þ218,

0.14%), 183 (13), 109 (13), 87 (100), 69 (32), 67 (12), 57

(14), 55 (19). HRMS: M^þ, found 212.2193. C₁₄H₂₈O

requires 212.2140.

(2£CHCH₂COH), 46.6, 46.7 (2£CHCH₂CH₂CH₃), 49.3,

49.7 (2£CH₂COH), 74.8, 75.4 (2£COH), 124.8, 126.3,

126.4, 127.95, 127.98, 148.2, 148.7 (12C, ArC); m/z (ﬁrst

diastereomer) 246 (M^þ, 0.23%), 121 (100), 118 (20);

(second diastereomer) 231 (M^þ215, 0.38%), 121 (100),

118 (20). HRMS ﬁrst diastereomer: M^þ2[CH₃], found

231.1735. C₁₆H₂₃O requires 231.1749. HRMS second

diastereomer: M^þ2[CH₃], found 231.1744. C₁₆H₂₃O

requires 231.1749.

4.7.3.2. 3,3-Dimethyl-1-(2-propylcyclopentyl)butan-2-

ol (22b). R_f0.4 (hexane/ethyl acetate: 9/1); n (ﬁlm)

3472 cm²¹(OH); d_H(mixture of diastereomers) 0.91 (m,

24H, 8£CH₃), 1.51 (m, 30H, 12£CH₂, 4£CH and 2£OH),

3.24 (m, 2H, 2£CHOH); d_C(mixture of diastereomers) 14.4,

14.5 (2£CH₂CH₃), 21.6, 21.7, 23.5, 24.2, 31.8, 32.2, 33.9,

36.9, 37.2, 37.7, 38.2 (12£CH₂), 25.7 [6C, 2£C(CH₃)₃],

34.8, 35.0 [2£C(CH₃)₃], 42.6, 43.9, 45.5, 46.3 (4£CH),

78.5, 79.7 (2£COH); m/z (ﬁrst diastereomer) 197 (M^þ215,

0.13%), 194 (M^þ218, 0.48%), 155 (28), 137 (64), 111 (32),

110 (44), 109 (29), 95 (100), 87 (18), 83 (11), 82 (11), 81

(92), 70 (16), 69 (91), 67 (40), 57 (42), 56 (10), 55 (49);

(second diastereomer) 197 (M^þ215, 0.18%), 194 (M^þ218,

0.55%), 155 (30), 137 (65), 111 (33), 110 (45), 109 (29), 96

(10), 95 (100), 87 (17), 83 (11), 82 (12), 81 (92), 70 (16), 69

(94), 67 (40), 57 (43), 56 (10), 55 (47). HRMS ﬁrst

diastereomer: M^þ2[CH₃], found 197.1903. C₁₃H₂₅O

requires 197.1905. HRMS second diastereomer: M^þ2

[CH₃], found 197.1907. C₁₆H₂₃O requires 197.1905.

4.7.3.3. 1-Phenyl-2-(2-propylcyclopentyl)ethanol (22c,

ﬁrst diastereomer). R_f0.3 (hexane/ethyl acetate: 9/1); n

(ﬁlm) 3383 (OH), 3085, 3062, 3028 cm²¹(CvC); d_H0.88

(t, J¼7.1 Hz, 3H, CH₃), 1.54 (m, 15H, 2£CH, 6£CH₂and

OH), 4.71 (dd, J¼9.7 Hz, 3.5, 1H, CHOH), 7.30 (m, 5H,

ArH); d_C14.4 (CH₃), 21.6, 23.6, 32.0, 32.1, 37.2 (5£CH₂),

42.5 (CH), 45.1 (CH₂), 46.1 (CH), 73.6 (COH), 125.7,

127.4, 128.4, 145.6 (6C, ArC); m/z 233 (M^þþ1, 0.04%),

232 (M^þ, 0.20%), 108 (13), 107 (100), 79 (21), 77 (11).

HRMS: M^þ, found 232.1810. C₁₆H₂₄O requires 232.1827.

4.7.3.4. 1-Phenyl-2-(2-propylcyclopentyl)ethanol (22c,

second diastereomer). R_f0.2 (hexane/ethyl acetate: 9/1); n

(ﬁlm) 3371 (OH), 3084, 3062, 3028 cm²¹(CvC); d_H0.85

(t, J¼7.1 Hz, 3H, CH₃), 1.49 (m, 15H, 2£CH, 6£CH₂and

OH), 4.68 (dd, J¼7.7 Hz, 6.7, 1H, CHOH), 7.30 (m, 5H,

ArH); d_C14.4 (CH₃), 21.5, 23.9, 31.8, 32.6, 37.2 (5£CH₂),

42.5 (CH), 44.5 (CH₂), 46.0 (CH), 74.4 (COH), 126.2,

127.6, 128.5, 144.6 (6C, ArC); m/z 233 (M^þþ1, 0.04%),

232 (M^þ, 0.20%), 108 (10), 107 (100), 79 (23), 77 (11).

HRMS: M^þ, found 232.1834. C₁₆H₂₄O requires 232.1827.

4.7.3.5. 1-(2-Propylcyclopentylmethyl)cyclohexanol

4.7.3.7. 2-Methyl-1-(2-propylcyclopentyl)propan-2-ol

(22f). R_f0.2 (hexane/ethyl acetate: 9/1);

n (ﬁlm)

3401 cm²¹(OH); d_H0.89 (def. t, J¼7.1 Hz, 3H,

CH₂CH₃), 1.54 [m with s at 1.23, 21H, COH(CH₃)₂,

6£CH₂, 2£CH and OH]; d_C14.4 (CH₂CH₃), 21.7, 24.1,

31.3, 34.4, 36.9, 49.1 (6£CH₂), 29.6, 30.2 [COH(CH₃)₂],

42.2, 46.9 (2£CH), 71.5 (COH); m/z 169 (M^þ215, 2.3%),

166 (M^þ218, 0.48%), 110 (17), 69 (17), 67 (21), 59 (100),

55 (14). HRMS: M^þ2[H₂O], found 166.1741. C₁₂H₂₂

requires 166.1722.

4.8. DTBB-catalysed lithiation of 6-chloro-6-ethyloct-1-

ene (23)

4.8.1. Preparation of compound 23. Preparation of

3-ethyloct-7-en-3-ol. To a stirred green suspension of

lithium powder (50 mg, 7.2 mmol) and DTBB (26 mg,

0.1 mmol) in THF (4 mL) at 2788C was added 5-bromo-

pent-1-ene (0.125 mL, 1.0 mmol). The colour disappeared

after the substrate addition, the reaction mixture was stirred

until the green colour was recovered (45 min), and pentan-

3-one (1.1 mmol) was then added. The resulting mixture

was stirred for 15 min at the same temperature (2788C),

then it was hydrolysed with 2 M HCl (5 mL) and stirred to

room temperature for 10 min. The reaction mixture was

extracted with diethyl ether (3£15 mL), the organic phase

was dried over anhydrous magnesium sulphate and was

concentrated under vacuum (15 Torr). 0.13 g (82%) of the

title compound were isolated after column chromatography

(silica gel, hexane/ethyl acetate mixtures).

4.8.1.1. 3-Ethyloct-7-en-3-ol.⁵⁵R_f0.3 (hexane/ethyl

acetate: 8/2); n (ﬁlm) 3404 (OH), 3076, 1641 cm²¹

(CvC); d_H0.86 (t, J¼7.3 Hz, 6H, 2£CH₃), 1.13 (s, 1H,

OH), 1.46 (m, 8H, 4£CH₂), 2.06 (m, 2H, vCHCH₂), 4.96

(d, J¼9.8 Hz, 1H, CHHv), 5.02 (d, J¼17.1 Hz, 1H,

CHHv), 5.82 (m, 1H, vCH); d_C7.7 (2£CH₃), 22.7,

31.0, 34.2, 37.6 (5£CH₂), 74.5 (COH), 114.5 (CH₂v),

138.7 (vCH); m/z 138 (M^þ218, 0.7%), 127 (20), 109 (13),

87 (83), 69 (22), 67 (16), 57 (100), 55 (50), 53 (11), 45 (68),

43 (43), 41 (60).

(22d). R_f0.3 (hexane/ethyl acetate: 9/1);

n (ﬁlm)

3466 cm²¹(OH); d_H0.89 (t, J¼7.1 Hz, 3H, CH₃), 1.52

(m, 25H, 11£CH₂, 2£CH and OH); d_C14.5 (CH₃), 21.7,

22.2, 22.3, 24.1, 25.8, 31.2, 34.6, 37.0, 37.6, 38.4 (11C,

11£CH₂), 41.0, 46.9 (2£CH), 71.9 (COH); m/z 206

(M^þ218, 1.5%), 115 (11), 111 (10), 110 (85), 109 (13),

99 (100), 98 (11), 95 (12), 82 (15), 81 (45), 79 (13), 69 (34),

67 (47), 55 (34). HRMS: M^þ, found 224.2076. C₁₅H₂₈O

requires 224.2140.

Preparation of 6-chloro-6-ethyloct-1-ene. 3-Ethyloct-7-en-

3-ol (0.934 g, 6.0 mmol) and concentrated HCl (10 mL)

were shaken vigorously in a separation funnel for 10 min.

The product was extracted with pentane (3£15 mL). The

organic layer was dried over anhydrous sodium sulphate

and then was concentrated under vacuum (15 Torr) to give

1.05 g (.99%) of the title compound after puriﬁcation by

distillation at normal pressure.

4.8.1.2. 6-Chloro-6-ethyloct-1-ene (23). R_f0.8 (hexane),

n (ﬁlm) 3076, 1642 cm²¹(CvC); d_H0.95 (t, J¼7.3 Hz, 6H,

2£CH₃), 1.51 (m, 2H, CH₂), 1.76 (m, 6H, 3£CH₂), 2.07

(m, 2H, vCHCH₂), 4.97 (d, J¼9.8 Hz, 1H, CHHv), 5.03

(d, J¼17.1 Hz, 1H, CHHv), 5.81 (m, 1H, vCH); d_C8.7

4.7.3.6. 2-Phenyl-1-(2-propylcyclopentyl)propan-2-ol

(22e). R_f0.2 (hexane/ethyl acetate: 9/1); n (ﬁlm) 3452

(OH), 3086, 3059, 3026, 1602 cm²¹(C¼C); d_H(mixture of

diastereomers) 1.29 (m with 2 s at 1.55 and 1.57, 40H,

4£CH₃, 12£CH₂and 4£CH), 7.32 (3m, 10H, 2£ArH); d_C

(mixture of diastereomers) 14.39, 14.42 (2£CH₂CH₃),

21.5, 21.6, 23.9, 24.0, 30.99, 31.06 (6£CH₂), 30.3, 31.2

(2£COHCH₃), 33.8, 33.9, 36.5, 36.8 (4£CH₂), 41.76, 41.79

M. Yus et al. / Tetrahedron 59 (2003) 8525–8542

8539

(2£CH₃), 23.5, 33.3, 33.8, 39.6 (5£CH₂), 79.4 (CCl), 114.8

(CH₂v), 138.4 (vCH); m/z 176 (M^þþ2, 0.3%), 174 (M^þ,

0.8%), 109 (33), 97 (17), 96 (23), 84 (48), 83 (22), 81 (15),

69 (61), 68 (14), 67 (53), 56 (20), 55 (98), 54 (20), 53 (21),

43 (42), 42 (15), 41 (100).

4.9.1.1. Allyl 2-chlorophenyl ether (1-allyloxy-2-chloro-

benzene) (28).⁵⁶R_f0.4 (hexane/ethyl acetate: 9/1); n (ﬁlm)

3068, 1649 cm²¹(CvC); d_H4.61 (dd, J¼5.2 Hz, 1.5, 2H,

OCH₂), 5.31 (d, J¼10.4 Hz, 1H, CHHv), 5.47 (d, J¼

1.8 Hz, 1H, CHHv), 6.07 (m, 1H, CHvCH₂), 6.90, 7.21,

7.36 (3m, 4H, ArH); d_C69.6 (OCH₂), 113.8, 121.5, 123.0,

127.6, 130.3, 154.1 (6C, ArC), 117.8 (vCH₂), 132.7

(CHvCH₂); m/z 170 (M^þþ2, 10.5%), 169 (M^þþ1,

3.5%), 168 (M^þ, 32%), 133 (30), 128 (28), 99 (15), 75

(13), 73 (12), 64 (12), 63 (17), 41 (100).

4.8.2. Lithiation of compound 23. To a stirred green

suspension of lithium powder (50 mg, 7.2 mmol) and DTBB

(26.6 mg, 0.1 mmol) in THF (4 mL) at 2308C was added

6-chloro-6-ethyloct-1-ene (23; 0.175 g, 1.0 mmol) under an

argon atmosphere. The colour disappeared after the

substrate addition, the reaction mixture was stirred until

the green colour was recovered (30 min) and pentan-3-one

(0.118 mL, 1.1 mmol) was added. The resulting mixture

was stirred for 15 min at the same temperature (2308C),

then it was hydrolysed with 2 M HCl (5 mL) and stirred to

room temperature for 10 min. The reaction mixture was

extracted with diethyl ether (3£15 mL), the organic phase

was dried over anhydrous magnesium sulphate and then

was concentrated under vacuum (15 Torr). 0.17 g (75%) of

compound 27 were isolated after column chromatography

(silica gel, hexane/ethyl acetate mixtures).

4.9.2. Lithiation of compound 28. To a stirred green

suspension of lithium powder (50 mg, 7.2 mmol) and DTBB

(26.6 mg, 0.1 mmol) in THF (4 mL) at 2788C or 2308C

was added allyl 2-chlorophenyl ether (28; 0.169 g,

1.0 mmol) under an argon atmosphere. The colour dis-

appeared after the substrate addition, the reaction mixture

was stirred until the green colour was recovered (30 min)

and pentan-3-one (0.118 mL, 1.1 mmol) was added. The

resulting mixture was stirred for 15 min at the same

temperature (2788C or 2308C), then it was hydrolysed

with 2 M HCl (5 mL) and stirred to room temperature.

The reaction mixture was extracted with diethyl ether

(3£15 mL), the organic phase was dried over anhydrous

magnesium sulphate and then was concentrated under

vacuum (15 Torr). Compound 31 was isolated after column

chromatography (silica gel, hexane/ethyl acetate mixtures)

obtaining 0.123 g (56%) and 0.10 g (45%) for the reaction at

230 and 2788C, respectively.

4.9.2.1. 3-(2-Ethyl-2-hydroxybutyl)dihydrobenzo[b]-

furan (31).⁵⁷R_f0.2 (hexane/ethyl acetate: 8/2); n (ﬁlm)

3453 (OH), 3080, 3073, 3060, 1598, 1478 cm²¹(CvC); d_H

0.905 (t, J¼7.3 Hz, 3H, CH₃), 0.913 (t, J¼7.3 Hz, 3H, CH₃),

1.26 (s, 1H, OH), 1.55 (m, 4H, 2£CH₂CH₃), 1.72 (dd, J¼

14.3 Hz, 2.1, 1H, CHCHH), 2.04 (dd, J¼14.7 Hz, 10.3, 1H,

CHCHH), 3.63 (m, 1H, CHCH₂), 4.27 (def. t, J¼8.9 Hz,

1H, CHHO), 4.77 (def. t, J¼8.9 Hz, 1H, CHHO), 6.82,

7.17 (2m, 4H, ArH); d_C7.6, 8.2 (2£CH₃), 30.5, 32.0

(2£CH₂CH₃), 37.6 (CHCH₂), 43.5 (CH₂COH), 74.7 (COH),

78.6 (OCH₂), 159.7, 131.4, 128.0, 120.3, 115.3, 109.4 (6C,

ArC); m/z 222 (M^þþ2, 0.3%), 221 (M^þþ1, 1.5%), 220

(M^þ, 9.6%), 202 (M^þ218, 9.3%), 173 (53), 131 (12), 119

(100), 118 (18), 91 (84), 65 (18), 57 (32), 55 (15), 45 (28),

43 (17), 41 (20).

Barbier type reaction. To a stirred green suspension of

lithium powder (50 mg, 7.2 mmol) and DTBB (26.6 mg,

0.1 mmol) in THF (4 mL) at 08C was added a solution of

6-chloro-6-ethyloct-1-ene (23; 0.175 mL, 1.0 mmol) and

pentan-3-one (0.118 mL, 1.1 mmol) in THF (1.5 mL) over a

30 min period, the reaction was stirred for 15 additional

minutes at the same temperature and then it was quenched

and worked-up as above, yielding 0.17 g (75%) of

compound 27.

4.8.2.1. 3-[(2,2-Diethylcyclopentyl)methyl]pentan-3-ol

(27). R_f0.3 (hexane/ethyl acetate: 8/2); n (ﬁlm) 3463 cm²¹

(OH); d_H0.83 (t, J¼7.3 Hz, 6H, 2£CH₃), 0.87 (t, J¼7.3 Hz,

6H, 2£CH₃), 1.06 (s, 1H, OH), 1.24 (m, 6H, 3£CH₂), 1.54

(m, 8H, 4£CH₂), 1.69 (d, J¼7.9 Hz, 2H, CH₂COH), 1.98 (m,

1H, CHCH₂COH); d_C7.7, 8.0 (2£CH₃), 8.6, 8.7 (2£CH₃),

22.0, 25.1, 28.4, 30.8, 31.7, 32.3, 32.6, 38.5 (8C, 8£CH₂),

41.1 (CH), 46.9 (CH₂CCH₂), 75.2 (COH); m/z 208 (M^þ2

18, 1.0%), 109 (14), 95 (28), 87 (100), 83 (21), 81 (15), 69

(59), 67 (20), 57 (31), 55 (50), 45 (49), 43 (28), 41 (58).

HRMS: M^þ2[H₂O], found 208.2160. C₁₅H₂₈requires

208.2191.

4.9. DTBB-catalysed lithiation of allyl 2-chlorophenyl

ether (1-allyloxy-2-chlorobenzene) (28)

4.10. DTBB-catalysed lithiation of N,N-diallyl-2-chloro-

aniline 32

4.9.1. Preparation of compound 28.⁴²NaH (0.186 g,

4.7 mmol, 60% in mineral oil) was washed with THF

(3£7 mL) at 08C and to the resulting solid was added a

solution of 2-chlorophenol (0.423 mL, 4 mmol) in dry THF

(1 mL). The mixture was stirred 2 h at room temperature

and after cooling at 08C allyl bromide (0.699 mL, 8 mmol)

was added. The resulting solution was stirred overnight,

washed with brine (20 mL) and the aqueous phase was

extracted with diethyl ether (4£3 mL). The organic layer

was washed with 10% NaOH (2£2 mL) and brine (2 mL)

and was dried over anhydrous magnesium sulphate. The

solvents were concentrated (15 Torr) and the yellow oil

obtained was puriﬁed by column chromatography (silica

gel, hexane/ethyl acetate) to give 0.60 g (90%) of compound

28.

4.10.1. Preparation of compound 32. 2-Chloroaniline

(0.537 mL, 5 mmol) was dissolved in dry THF (3 mL) under

an argon atmosphere. The ﬂask was introduced into a cooled

bath (2308C) and n-BuLi (3.13 mL of a 1.6 M solution

in hexane, 5 mmol) was added. After 15 min stirring allyl

bromide was added (0.524 mL, 6 mmol) and the solution

was stirred 1 h at 08C. The mixture was cooled to 2308C

and n-BuLi was again added (3.13 mL of a 1.6 M solution in

hexane, 5 mmol), the solution was stirred 15 min and allyl

bromide was added (0.524 mL, 6 mmol). The reaction

mixture was warmed to 08C and stirred 1 h and it was

hydrolysed with H₂O (15 mL). The product was extracted

with diethyl ether (3£15 mL), the organic layer was dried

over anhydrous magnesium sulphate and the solvents were

concentrated under vacuum (15 Torr). The residue was

8540

M. Yus et al. / Tetrahedron 59 (2003) 8525–8542

puriﬁed by column chromatography (silica gel, hexane/

ethyl acetate) to obtain 0.88 g (85%) of pure compound 32.

4.10.1.1. N,N-Diallyl-2-chloroaniline (32).⁵⁶R_f0.4

(hexane); n (ﬁlm) 3073, 3009, 1588, 1642, 1480 cm²¹

(CvC); d_H3.71 (d, J¼6.1 Hz, 4H, 2£NCH₂), 5.16 (dd, J¼

17.1 Hz, 10.4, 4H, 2£CH₂v), 5.81 (m, 2H, 2£CHvCH₂),

6.92, 7.02, 7.15, 7.34 (4m, 4H, ArH); d_C54.8 (2C,

2£NCH₂), 117.5 (2C, 2£CH₂v), 123.3, 123.5, 126.8,

129.6, 130.6, 147.6 (6C, ArC), 134.7 (2C, 2£CHvCH₂);

m/z 209 (M^þþ2, 16.6%), 208 (M^þþ1, 10.5%), 207 (M^þ,

50.3%), 206 (12), 182 (23), 180 (79), 178 (22), 173 (13), 172

(100), 166 (10), 164 (19), 144 (11), 140 (35), 139 (28), 138

(85), 131 (19), 130 (86), 113 (16), 111 (50), 77 (21), 75 (23),

51 (13).

(10), 146 (58), 144 (13), 143 (11), 132 (12), 131 (27), 130

(68), 118 (17), 117 (67), 115 (11), 103 (13), 91 (12), 77 (24).

4.10.2.3. N-Allyl-3-(deuteriomethyl)indoline (34b).⁵⁹

R_f0.4 (hexane/ethyl acetate: 9/1);

n (ﬁlm) 3073,

1595 cm²¹(CvC); d_H0.88 (m, 2H, CH₂D), 2.85 (t,

J¼8.5 Hz, 1H, NCHHCHCH₂D), 3.29 (m, 1H, CHCH₂D),

3.55 (t, J¼8.5 Hz, 1H, NCHHCHCH₂D), 3.61 (m, 1H,

NCHHCHv), 3.78 (m, 1H, NCHHCHv), 5.24 (dd,

J¼17.1 Hz, 9.8, 2H, vCH₂), 5.91 (m, 1H, CHvCH₂),

6.51, 6.69, 7.07 (3m, 4H, ArH); d_C18.0, 18.2, 18.5 (CH₂D),

35.0, 35.1 (CHCH₂D), 52.0 (CH₂CHvCH₂), 61.2 (NCH_2-

CHCH₂D), 107.4, 117.8, 123.1, 127.3, 135.2, 151.7 (ArC),

117.22 (CHvCH₂), 134.2 (CHvCH₂); m/z 176 (M^þþ2,

0.8%), 175 (M^þþ1, 12.1%), 174 (M^þ, 96.6%), 173 (36),

159 (15), 158 (100), 147 (54), 146 (13), 143 (12), 133 (12),

132 (21), 131 (39), 130 (47), 118 (25), 117 (68), 116 (11),

103 (10), 91 (12), 90 (10), 89 (10), 78 (13), 77 (20).

4.10.2.4. N,N-Diallyl-2-(1-ethyl-1-hydroxypropyl)ani-

line (35a). R_f0.3 (hexane/ethyl acetate: 8/2); n (ﬁlm) 3429

(OH), 3076, 1640 cm²¹(CvC); d_H0.79 (t, J¼7.3 Hz, 6H,

2£CH₃), 1.78 (m, 4H, 2£CH₂CH₃), 3.55 (m, 4H, 2£NCH₂),

5.15 (dd, J¼17.1 Hz, 11.0, 4H, 2£CHvCH₂), 5.92 (m, 2H,

2£CHvCH₂), 7.18 (m, 4H, ArH), 9.89 (s, 1H, OH); d_C8.5

(2£CH₃), 37.1 (2£CH₂CH₃), 59.0 (2£NCH₂), 80.6 (COH),

118.9 (2£CHvCH₂), 125.0, 126.1, 126.8, 128.1, 141.0,

149.7 (6C, Ar), 134.0 (2£CHvCH₂); m/z 260 (M^þþ1,

2.4%), 259 (M^þ, 9.0%), 231 (13), 230 (79), 218 (16), 212

(13), 201 (16), 200 (100), 190 (12), 175 (11), 174 (79), 172

(13), 171 (11), 170 (16), 160 (48), 158 (18), 156 (11), 146

(14), 144 (30), 143 (10), 134 (14), 133 (51), 132 (42), 131

(13), 130 (37), 120 (10), 118 (14), 117 (23), 115 (16), 91

(14), 77 (20), 57 (21). HRMS: M^þ, found 259.1920.

C₁₇H₂₅NO requires 259.1936.

4.10.2. Lithiation of compound 32. To a stirred green

suspension of lithium powder (50 mg, 7.2 mmol) and DTBB

(26.6 mg, 0.1 mmol) in THF (4 mL) at 2788C or 2308C

was added N,N-diallyl-2-chloroaniline (32; 0.210 g,

1.0 mmol) under an argon atmosphere. The colour dis-

appeared after the substrate addition, the reaction mixture

was then stirred until the green colour was recovered (1 h)

and pentan-3-one (0.118 mL, 1.1 mmol) or D₂O (0.050 mL,

2.5 mmol) were added. The resulting mixture was stirred for

1 h at the same temperature (278 or 2308C), then it was

hydrolysed with 2 M HCl (5 mL) and stirred to room

temperature for 10 min. The reaction mixture was extracted

with diethyl ether (3£15 mL), the organic phase was dried

over anhydrous magnesium sulphate and the solvents were

concentrated under vacuum (15 Torr). Compounds 33, 34a,

34b, 35a, 35b were isolated after column chromatography

(silica gel, hexane/ethyl acetate mixtures). Yields are given

in the text; physical, spectroscopic and analytical data, as

well as references for known compounds, follows.

4.10.2.1. N-Allyl-3-(2-ethyl-2-hydroxybutyl)indoline

(33). R_f0.2 (hexane/ethyl acetate: 8/2); n (ﬁlm) 3434

(OH), 3070, 3048, 3018, 1640 cm²¹(CvCH₂); d_H0.91 (t,

J¼7.3 Hz, 6H, 2£CH₃), 1.16 (s, 1H, OH), 1.57 (m, 4H,

2£CH₂CH₃), 2.08 (d, J¼15.9 Hz, 2H, COHCH₂CH),

3.00 (t, J¼9.2 Hz, 1H, NCHHCHCH₂), 3.34 (m, 1H,

NCHHCHCH₂), 3.59 (m, 1H, NCHHCHv), 3.70 (t, J¼

5.8 Hz, 1H, NCHHCHCH₂), 3.81 (m, 1H, NCHHCHv),

5.24 (dd, J¼17.1 Hz, 9.8, 2H, vCH₂), 5.57 (m, 1H,

CHvCH₂), 6.51, 6.69, 7.07 (3m, 4H, ArH); d_C7.7, 8.2

(2xCH₃), 30.6, 32.0 (2xCH₂CH₃), 36.3 (NCH₂CHCH₂),

42.6, 52.0 (2xCH₂), 61.5 (COH), 117.8 (CH₂v), 107.4,

123.1, 127.4, 134.0, 151.6 (6C, Ar) 134.5 (CHvCH₂); m/z

261 (M^þþ2, 0.5%), 260 (M^þþ1, 5.8%), 259 (M^þ, 25%),

170 (13), 159 (12), 158 (100), 157 (28), 156 (18), 130 (30),

118 (10), 117 (31). HRMS: M^þ, found 259.1911. C₁₇H₂₅NO

requires 259.1936.

4.10.2.5. N,N-Diallyl-2-deuterioaniline (35b). R_f0.3

(hexane); n (ﬁlm) 3070, 3048, 3023, 1644, 1606 cm²¹

(CvC); d_H3.92 (d, J¼3.05 Hz, 4H, 2£NCH₂), 5.18 (dd,

J¼17.1 Hz, 7.3, 4H, 2£CH₂v), 5.86 (m, 2H, 2£CHvCH₂),

6.69, 7.20 (2m, 4H, ArH); d_C52.7 (2C, 2£NCH₂), 112.3,

116.2, 128.9, 129.0, 148.7 (6C, ArC), 115.9 (2£CH₂vCH),

134.0 (2£CHvCH₂); m/z 176 (M^þþ2, 0.7%), 175 (M^þþ1,

9.8%), 174 (M^þ, 79%), 173 (30), 148 (12), 147 (100), 146

(26), 145 (27), 133 (10), 132 (15), 131 (47), 130 (17), 119

(14), 118 (21), 106 (31), 105 (67), 104 (18), 78 (63), 77 (18),

52 (14), 51 (17). HRMS: M^þ, found 174.1257. C₁₂H₁₄DN

requires 174.1266.

Acknowledgements

´

This work was generously supported by the Direccion

General de Ensen˜anza Superior (DGES) of the current

4.10.2.2. N-Allyl-3-methylindoline (34a).⁵⁸R_f0.5 (hex-

ane/ethyl acetate: 9/1); n (ﬁlm) 3048, 3023, 1604, 1486,

1658 cm²¹(CvC); d_H1.30 (d, J¼6.7 Hz, 3H, CH₃), 2.83

(t, J¼8.5 Hz, 1H, NCHHCHCH₃), 3.27 (m, 1H, CHCH₃),

3.56 (t, J¼8.5 Hz, 1H, NCHHCHCH₃), 3.63 (m, 1H,

NCHHCHv), 3.78 (m, 1H, NCHHCHv), 5.24 (dd,

J¼17.1 Hz, 10.4, 2H, vCH₂), 5.93 (m, 1H, CHvCH₂),

6.53, 6.71, 7.09 (3m, 4H, ArH); d_C18.5 (CH₃), 35.1

(CHCH₃), 51.9 (NCH₂CHv), 61.2 (NCH₂CHCH₃), 107.3,

117.6, 123.1, 127.3, 135.2, 151.7 (6C, Ar), 117.2 (vCH₂),

134.2 (CHvCH₂); m/z 175 (M^þþ2, 0.8%), 174 (M^þþ1,

12.5%), 173 (M^þ, 100), 172 (18), 159 (12), 158 (94), 156

´

Spanish Ministerio de Ciencia y Tecnologıa (MCyT; grant

no. BQU2001-0538). R. O. thanks the MCyT for a

scholarship.

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Article Doi

Intramolecular carbolithiation promoted by a DTBB-catalysed chlorine-lithium exchange

DOI: 10.1016/j.tet.2003.09.012

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