Intramolecular carbolithiation of 2,6-dilithio-1,6-heptadienes: An experimental and theoretical study

Article abstract of DOI:10.1002/chem.200601863

2,6-Dilithio-1,6-heptadienes 3 undergo intramolecular carbolithiation in Et₂O/N,N,N′,N′-tetramethylethylenediamine (TMEDA) at the lithiated double bonds to afford 1,2-bis(lithiomethyl)cyclopentenes 5. Reaction of these dianions with electrophil

Full text of DOI:10.1002/chem.200601863

DOI: 10.1002/chem.200601863
Intramolecular Carbolithiation of 2,6-Dilithio-1,6-heptadienes:
An Experimental and Theoretical Study
Roberto Sanz,[b] JosØ M. Ignacio,[b] Miguel A. Rodríguez,[c] Francisco J. FaÇanµs,[a] and
JosØ Barluenga*[a]
Abstract: 2,6-Dilithio-1,6-heptadienes 3
undergo intramolecular carbolithiation
in Et2O/N,N,N’,N’-tetramethylethylene-
diamine (TMEDA) at the lithiated
double bonds to afford 1,2-bis(lithio-
methyl)cyclopentenes 5. Reaction of
these dianions with electrophiles af-
fords a number of 1,2-difunctionalized
cyclopentene derivatives 7–10. The
ease of carbolithiation of 2,6-dilithio-
1,6-heptadiene (3a) compared to that
of 2-lithio-1,6-heptadiene (14) has been
studied experimentally. A series of ab
initio molecular-orbital calculations on
the course of the reaction were carried
out and the results were compared to
those for the corresponding intramolec-
ular carbolithiation of an isolated
À
double bond. The Li C interactions
found in the transition state by this the-
oretical study support a carbolithiation
pathway for the cyclization of 2,6-dili-
thio-1,6-heptadienes.
Keywords: ab initio calculations ·
carbanions · carbolithiation · cycli-
zation · cyclopentenes
Introduction
achiral olefinic organolithiums in the presence of chiral li-
gands.[7]
Although simple alkenes are not generally thought of as
sites of nucleophilic attack, the formation of ring systems by
anionic cyclization of olefinic alkyl-,[1] aryl-,[2] and vinyllithi-
um compounds[3] is an interesting synthetic transformation
and provides a regiospecific and highly stereoselective route
to five-membered carbocycles and heterocycles.[4] Moreover,
enantioselective reactions of this kind[5] can be carried out
with enantiomerically enriched secondary lithium deriva-
tives[6] or by enantiofacially selective cycloisomerization of
The observed regioselectivities and stereoselectivities of
À
the intramolecular addition of a C Li bond to an unactivat-
ed alkene could be rationalized by recourse to a transition-
state model that resembles a cyclohexane chair in which
substituents preferentially occupy pseudoequatorial posi-
tions. Ab initio molecular-orbital calculations carried out by
Bailey et al. reveal that the regio- and stereochemistry of
the isomerization of substituted 5-hexen-1-yllithium com-
pounds is a consequence of an energetically favorable coor-
dination of the lithium atom of the substrate with the
remote p bond.[8] Lithiophilic Lewis bases, such as THF,
[a] Prof. Dr. F. J. FaÇanµs, Prof. Dr. J. Barluenga
Instituto Universitario de Química Organometµlica “Enrique Moles”
Unidad Asociada al C.S.I.C., Universidad de Oviedo
C/Juliµn Clavería 8, 33006-Oviedo (Spain)
Fax : (+34)985103450
N,N,N’,N’-tetramethylethylenediamine
(TMEDA),
and
N,N,N’,N’’,N’’-pentamethyldiethylenetriamine
(PMDTA),
have been found to increase the rate of cyclization of olefin-
ic organolithium compounds, and such additives do not
reduce the high stereoselectivity of these processes.[8]
E-mail: barluenga@uniovi.es
[b] Dr. R. Sanz, Dr. J. M. Ignacio
One of the major drawbacks of intramolecular carboli-
thiation of unactivated alkenes is that they are limited to
terminal double bonds (i.e. the alkenyl trap may only be
monosubstituted or 1,1-disubstituted). However, it has been
possible to obtain cyclized products for 1,2-disubstituted al-
kenes when the formed alkyllithium product is substituted
with a leaving group in a b position leading to an elimina-
tion reaction of the organolithium.[9] Also, terminally substi-
tuted 5-hexenyllithiums bearing a moderately activating
group, such as phenyl, trimethylsilyl,[10] arylthio,[11] tributyl-
Departamento de Química, rea de Química Orgµnica
Facultad de Ciencias. Universidad de Burgos
Pza. Misael BaÇuelos s/n, 09001-Burgos (Spain)
[c] Dr. M. A. Rodríguez
Departamento de Química, Grupo de Síntesis Química de La Rioja
Unidad Asociada al C.S.I.C., Universidad de La Rioja
Avda. Madre de Dios 51, 26006-LogroÇo (Spain)
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author. Calculated total
energies and Cartesian coordinates of all minima and transition struc-
tures 18, TS1, 19, 20, TS2, 21, 22, TS3, 23, 24, TS4, and 25.
4998
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Chem. Eur. J. 2007, 13, 4998 – 5008

FULL PAPER
tin,[3d] alkenyl, or alkynyl,[12] undergo totally regiospecific 5-
exo-cyclization reactions.
In recent years, we have developed an intramolecular car-
bolithiation reaction of lithiated double bonds, a conceptual-
ly new process that expands the scope of this kind of reac-
tion.[13] Initially, we described how N,N-bis(2-lithioallyl)-
ACHTREUNGamines, derived from readily prepared N,N-bis(2-bromoal-
lyl)amines, cyclize efficiently to afford 3,4-bis(lithiomethyl)-
dihydropyrrole derivatives that could be trapped with
electrophiles leading to functionalized N-heterocycles in
good yields. Until now, this new process was limited to N,N-
bis(2-lithioallyl)amines and to N-2-lithioallyl-2-lithioanilines.
Herein, we report that this cyclization is general with re-
spect to the moiety of the starting material and that simple
2,6-dilithio-1,6-heptadienes undergo this kind of process effi-
ciently. Moreover, we have carried out ab initio molecular
orbital calculations on the parent system, 2,6-dilithio-1,6-
heptadiene, and compared the results to those obtained for
2-lithio-1,6-heptadiene.
Scheme 1. Synthesis of 2,6-dibromo-1,6-heptadienes 1. Reagents and con-
À
ditions: i) (Et4N)+HBr2 (2 equiv), CH2Cl2, 4 80C; ii) for 2b and 2c:
1) LDA, À78 to 208C; 2) BrCH2C(Br)=CH2 (1 equiv), À408C to reflux;
iii) for 2d: BrCH2C(Br)=CH2 (2 equiv), K2CO3 (4equiv), MeCOEt,
reflux; iv) LiAlH4, Et2O, 0 to 20 8C; v) tBuMe2SiCl, 1H-imidazole, DMF,
208C; vi) Me2CACHTRE(UNG OMe)2 (excess), PPTS (cat.), 208C to reflux. LDA: lithi-
um diisopropylamide; PPTS: pyridinium p-toluene sulfonate.
Results and Discussion
ketalization afforded quantitatively dibromodiene 1e
Preparation of 2,6-dibromo-1,6-heptadienes1
:
To test
(Scheme 1).
whether intramolecular carbolithiation of lithiated double
bonds is a general process with regard to the dilithiated
starting product, we first synthesized some 2,6-dibromo-1,6-
Intramolecular carbolithiation of 2,6-dilithio-1,6-heptadienes
3: Treatment of 2,6-dibromo-1,6-heptadienes derivatives 1
with tBuLi (4equiv) in diethyl ether at À788C led to the ex-
pected dianions 3, which were characterized by deuteriolysis
or treatment with chlorotrimethylsilane to give compounds
heptadienes
1
by means of known methodologies
(Scheme 1). The parent 2,6-dibromo-1,6-heptadiene (1a)
was prepared by double hydrobromination of 1,6-heptadiyne
with tetraethylammmonium hydrogen dibromide in CH2Cl2
(Scheme 1).[14] Double alkylation of tert-butyl acetate,
phenyl acetate, or diethyl malonate with 2,3-dibromopro-
pene, followed by reduction with LiAlH4 afforded alcohols
2b–d in overall moderate-to-good yields (Scheme 1). Subse-
quent protection of the hydroxyl groups gave dienes 1b–d in
almost quantitative yield. Alternatively, protection of 2d by
4
(Scheme 2 and Table 1, entries 1–3). Although these
anions are stable in an ethereal solution at À788C, on addi-
tion of TMEDA they reacted with a number of different
electrophiles (D2O, silicon chlorides, tin chlorides, and 3-
pentanone) to afford the functionalized cyclopentene deriv-
atives 7 and 8 (Scheme 2 and Table 1, entries 4–14). The for-
Abstract in Spanish: Los 2,6-dilitio-1,6-heptadienos 3 experi-
mentan en Et2O/TMEDA la reacción de carbolitiación intra-
molecular de un doble enlace litiado, generando los 1,2-bis(li-
tiometil)ciclopentenos 5. La reacción de estos dianiones con
electrófilos permite la preparación de varios derivados de ci-
clopenteno 1,2-difuncionalizados 7–10. Se han realizado ex-
perimentos para comparar la facilidad de carbolitiación del
2,6-dilitio-1,6-heptadieno (3a) con respecto a la del 2-litio-
1,6-heptadieno (14). TambiØn se han llevado a cabo una serie
de cµlculos con orbitales moleculares, de tipo ab initio, sobre
el transcurso de la reacción y se ha comparado Østa con la
correspondiente carbolitiación intramolecular de un doble
enlace aislado. Las interacciones Li–C encontradas en el
estado de transición con este estudio teórico apoyan que la ci-
clación de los 2,6-dilitio-1,6-heptadienos tenga lugar mediante
un proceso de carbolitiación.
Scheme 2. Intramolecular carbolithiation of 2,6-dilithio-1,6-heptadienes 3.
Reagents and conditions: i) tBuLi (4equiv), Et 2O, À788C; ii) TMEDA
(4equiv), À78 to 208C; iii) 1) E+ (2.2 equiv), À78 to 208C, 2) H2O;
iv) 1) Ph2SiCl2 (1 equiv), À78 to 208C, 2) H2O; v) 1) iPrCO2Et (1 equiv),
À788C, 2) MeOH, À78 to 208C; vi) 1) iPrCO2Et (1 equiv), À78 to 208C,
2) H2O.
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4999

J. Barluenga et al.
Yield[%][a]
Table 1. Preparation of functionalized products 4, and 7–10.
Entry
Diene
R1
R2
E+/MCl2
Product
E/M
1
2
3
4
5
6
7
8
1a
1b
1d
1a
1a
1b
1b
1b
1c
1d
1d
1d
1e
1a
1a
1a
1b
1b
1d
1d
H
H
H
Me3SiCl
MeOD
MeOD
Me3SiCl
Et2CO
D2O
4a
4b
4c
7a
7b
7c
7d
7e
7 f
7g
7h
7i
SiMe3
D
D
SiMe3
Et2C(OH)
D
SnBu3
OH
D
D
SnBu3
OH
Et2C(OH)
SiPh2
–
–
–
–
–
–
89
93
91
82
77
90
83
64
92
90
81
67
81
80
67
72
50
52[f]
65
50
CH2OSi[b]
CH2OSi[b]
H
CH2OSi[b]
H
H
H
H
H
Ph
H
CH2OSi[b]
CH2OSi[b]
CH2OSi[b]
CH2OSi[b]
CH2OSi[b]
CH2OSi[b]
CH2OSi[b]
Bu3SnCl
[c]
[c]
B
A
9
D2O
D2O
Bu3SnCl
10
11
12
13
14
15
16
17
18
19
20
CH2OSi[b]
CH2OSi[b]
CH2OSi[b]
B
A
-CH2OC(Me)2OCH2-
Et2CO
Ph2SiCl2
7j
H
H
H
H
H
H
H
8a
9a
10a
9b
10b
9c
iPrCO2Et[d]
iPrCO2Et[e]
iPrCO2Et[d]
iPrCO2Et[e]
iPrCO2Et[d]
iPrCO2Et[e]
CH2OSi[b]
CH2OSi[b]
CH2OSi[b]
CH2OSi[b]
H
CH2OSi[b]
CH2OSi[b]
10c
[a] Yield of isolated product based on starting dibromides 1. [b] CH2OSi=CH2OSiMe2tBu. [c] After the treatment of dianions 5b, and 5d with trimethyl
borate, the resulting mixtures were oxidized in situ with alkaline hydrogen peroxide at 208C. [d] Carried out at À788C. [e] Carried out from À788C to
room temperature. [f] Obtained as a 1:1 mixture of diastereoisomers.
mation of these compounds seems to point to 1,2-bis(lithio-
methyl)cyclopentene derivatives 5 as intermediates. This
transformation, which involves the cycloisomerization of vi-
nyllithium to allyllithium moieties and the formation of a
monocyclic ketones or bicyclic alcohols can be prepared in a
selective manner, depending on the reaction conditions.
Effectson the cyclization rate : The role played by TMEDA
in this intramolecular carbolithiation process is shown in
Table 2. When TMEDA was added to the ethereal solution
À
new C C double bond, could be explained by assuming that
the first step is an intramolecular carbolithiation of one vi-
nyllithium moiety by the other one to afford a methylenecy-
clopentane moiety such as 6. Finally, these probable inter-
mediates could undergo an allylic rearrangement to give
dianions 5 (Scheme 2). Interestingly, different groups R1 and
R2 (alkyl, aryl, hydrogen) are tolerated at the central posi-
tion of the starting diene moiety, which indicates that the
process is general with respect to the structure of the start-
ing material.
Table 2. Effect of TMEDA and the dibromide 1 moiety on the cycliza-
tion rate.
Entry
Diene
TMEDA
T[8C]
t
A
4/7 ratio[a]
1
2
3
4
5
6
7
1a–e
1a
1a
1a
1a
yes
yes
no
no
no
no
no
1
20
0
0
20
20
20
20
50
90
150
360
50
0/1
0/1
1/0
0/1
9/1
2/1
1/5
In a study of the reactivity of the new organolithium com-
pounds generated after the carbolithiation reactions, we also
reported that treatment of 2,5-dihydro-3,4-bis(lithiomethyl)-
1-(4-methylphenyl)-1H-pyrrole derivatives with different
carboxylic esters gave rise to b,g-unsaturated ketones or bi-
cyclic alcohols, depending on the reaction conditions.[15] To
check whether this behavior was the same in the case of the
corresponding 1,2-bis(lithiomethyl)cyclopentene derivatives
5, we reacted some of these dianions 5 with ethyl isobuty-
rate. Treatment of dianions 5a, 5b, and 5d with such a car-
boxylic ester (1 equiv) at À788C afforded, after 1 h and fur-
ther hydrolysis with MeOH at this temperature, the b,g-un-
saturated ketones 9. Moreover, the addition of the ester at
À788C, stirring of the reaction mixture overnight at room
temperature, and aqueous hydrolysis led to 1,2,3,4,5,6-hexa-
hydro-2-hydroxypentalene derivatives 10 (Scheme 2 and
Table 1, entries 15–20). We have thus shown that the reactiv-
ity of these 1,2-bis(lithiomethyl)cyclopentene derivatives 5
with carboxylic esters is similar to that observed with the
corresponding 3,4-bis(lithiomethyl)dihydropyrroles, and that
1b
1d
50
50
[a] Ratio determined by H NMR analysis.
of intermediates 3, cyclization was complete in 50 min at
room temperature for all the dianions derived from dibro-
mides 1a–e (Table 2, entry 1). Moreover, the cyclizations
were monitored by GC-MS analysis of aliquots quenched
with MeOD at different temperatures. For 3a, we found
that the cyclization process begins at about À208C in the
presence of TMEDA; however, this reaction takes place
very slowly, and carbolithiation at 08C required 90 min to
go to completion (Table 2, entry 2). However, in the absence
of TMEDA, the reaction does not take place below room
temperature (Table 2, entry 3) and even at 208C the cycliza-
tion rate was much slower than in the presence of the di-
AHCTREaUNG mine (6 h were necessary to complete the reaction;
Table 2, entry 4). Thus, the addition of TMEDA allows the
reaction to proceed at lower temperatures and more quickly,
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Intramolecular Carbolithiation
FULL PAPER
which indicates that this lithium-coordinating diamine has a
strong accelerating effect. Table 2 also shows the effect of
substituents (R1 and R2) at the central carbon of the dibro-
modienes 1 on the cyclization rate. Compounds 1a, 1b, and
1d were reacted in the absence of TMEDA, and the reac-
tion mixture was quenched after 50 min at room tempera-
ture with deuterium oxide or chlorotrimethylsilane. When
the starting material was diene 1a (R1 =R2 =H), a 9:1 mix-
ture of uncyclized (4a) and cyclized products (7a) was ob-
tained (Table 2, entry 5). Diene 1b (R1 =H, R2 =
CH2OSiMe2tBu) gave a 2:1 mixture of the corresponding
deuteriated diene 4b and the cyclopentene derivative 7c
(Table 2,
entry 6).
Dibromodiene
1d
(R1 =R2 =
CH2OSiMe2tBu) gave a 1:5 mixture of the linear product 4c
and the corresponding cyclized product 7g (Table 2,
entry 7). These results indicate that the presence of substitu-
ents at C4in the starting 1,6-heptadienes 1 increases the cyc-
lization rate. This effect is more pronounced with diene 1d
in which two substituents are present. The acceleration of
the cyclization reaction indicates that the substitution of
alkyl groups for hydrogen atoms on the carbons in the chain
linking the two reactive centers allows a more efficient ap-
proach between the vinyllithium moieties in the correspond-
ing dilithiated derivatives 3. This “gem-dialkyl effect”[16] has
been explained by the compression of the internal angle
(“Thorpe–Ingold effect”),[17] by the reactive rotamer
effect,[18] and by the “facilitated transition” hypothesis.[19]
Scheme 3. Comparative intramolecular carbolithiation of dianion 3a and
monoanion 14. Reagents and conditions: i) tBuLi (4equiv), Et 2O,
À788C; ii) À78 to T[8C], t[min]; iii) 1) Me2PhSiCl, À78 to 208C, 2) H2O;
G
iv) tBuLi (2 equiv), Et2O, À788C.
that the addition of TMEDA increases the rate of carboli-
thiation of both lithiated and isolated double bonds, but in-
terestingly this acceleration is greater for lithiated double
bonds. In an effort to probe the factors responsible for these
differences in the rates of cyclization of both kinds of sub-
strates and also to increase our understanding of the carboli-
thiation reaction of lithiated double bonds, we carried out a
series of ab initio molecular-orbital calculations on the
course of these reactions.
Comparative study of the intramolecular carbolithiation of
2,6-dilithio-1,6-heptadiene (3a) and 2-lithio-1,6-heptadiene
(14): To compare the ease of cyclization in the intramolecu-
lar carbolithiation of a lithiated double bond with the corre-
sponding intramolecular carbolithiation of an isolated
double bond, by a vinyllithium in both cases, we carried out
two parallel reactions with dibromide 1a and monobromide
13 under identical conditions of temperature and reaction
time. Dienes 1a and 13 were treated with tBuLi (4equiv for
1a and 2 equiv for 13) in Et2O at À788C. The resulting solu-
tions of dianion 3a and monoanion 14 were warmed to 08C
and stirred at this temperature for 150 min. After the mix-
ture was cooled to À788C, chlorodimethylphenylsilane
(2 equiv for dibromide 1a and 1 equiv for monobromide 13)
was added to afford compound 11 in the first case, and a
11:1 mixture of compounds 16 and 17 in the second case
(Scheme 3).[20] This result shows that the intramolecular car-
bolithiation process for an isolated double bond begins at a
lower temperature than that of a lithiated double bond.
However, when the same set of experiments was carried
out in the presence of TMEDA (4equiv for dianion 3a and
2 equiv for monoanion 14) we observed a different result.
When the cyclizations of 3a and 14 were carried out with
TMEDA at 08C, the ratio of the cyclized product 12 derived
from dianion 3a is greater than the ratio of cyclized product
17 derived from monoanion 14 (Scheme 3).[21] Moreover, it
is interesting to note that for both 3a and 14, the addition of
TMEDA gave a higher ratio of cyclized products than the
reactions without the diamine. This leads to the conclusion
Computational details: All ab initio calculations on lithiated
compounds solvated with two water or one ethylenediamine
molecules per lithium atom (Scheme 4) were carried out
with the Gaussian98 program package.[22] The molecular ge-
ometries were first optimized without any molecular symme-
try constraints at the HF/6-31+G(d) level of theory. The
optimized structures were characterized as minima or saddle
Scheme 4. Lithiated model compounds 18–25 for ab initio calculations.
Chem. Eur. J. 2007, 13, 4998 – 5008
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5001

J. Barluenga et al.
points (representing transition structures) by the evaluation
of force constants. Single-point calculations were carried out
at the MP2/6-31+G(d) and MP2/6-311+GACHTREU(NG 2df) level of
theory to introduce electron correlation and basis set effects
into the energy estimation. For a complementary modeling
of the solvation effect, single-point calculations were carried
out with the Onsager model, as implemented within a self-
consistent reaction field (SCRF) method in Gaussian98,
with a dielectric constant of Et2O (e=4.34).
barrier at the MP2/6-311+GACHTERUN(G 2df)+SCRF level for the eth-
ylenediamine/dilithiated model TS2, was calculated to be
17.4kcalmol À1, which indicates that conversion from 20 to
21 should be quicker than conversion from 18 to 19 at the
same temperature. Indeed, this is observed experimentally:
cyclization of dibromides 1 (T=208C, t=50 min) is more ef-
fective in the presence than in the absence of TMEDA
(Table 2, entry 1 vs. entries 5–7). The latter requires a reac-
tion time of 360 min to obtain the same result (Table 2,
entry 1 vs. entry 4).
Theoretical results: The relative energies of 18, TS1, 19, 20,
TS2, 21, 22, TS3, 23, 24, TS4, and 25 (Scheme 4) are given
in Tables 3 and 4. We first tried to mimic the different be-
havior observed when the reaction is carried out without or
with TMEDA. According to our calculations, the cyclic
model 19 is the most stable structure at all the computed
levels. The water/dilithiated model 18 should be 35.1 kcal
molÀ1 more stable than TS1 at the HF/6-31+G(d) level
(Table 3). Inclusion of correlation gives a value of 24.4 kcal
molÀ1, [MP2/6-31+G(d)], which supposes a relative stabili-
zation for the transition structure TS1 compared to 18. The
same tendency is predicted with the improved basis set 6-
This result may be explained by looking at the optimized
geometries. Figure 1 shows a computer plot of the structures
311+GACHTREUNG
(2df) at the MP2 level (DH=23.4kcalmol À1). How-
ever, the solvation effect calculated with the Onsager model
appears to have little influence because it gave a value of
24.6 kcalmolÀ1 [MP2/6-31+G(d)+SCRF]. To obtain
a
more accurate energy difference, we considered that the
Gibb free energy and SCRF correction to the MP2/6-31+
G(d) energy should be additive: our best level of calculation
Figure 1. Computer plot of the HF/6-31+G(d)-optimized structures for
À
TS1, and TS2. Selected bond lengths[Š] for model TS1: Li1 C1 2.551,
À
À
À
À
À
À
Li1 C2 2.391, Li1 C3 2.071, Li1 C4 2.986, Li2 C1 2.614, Li2 C2 2.093, Li2
[MP2/6-311+GACHTREUNG(2df)+SCRF] indicated an energy barrier of
À
À
À
À
C3 2.357, Li2 C4 2.109, C1 C2 1.344, C2 C3 2.058, C3 C4 1.470. For model
24.3 kcalmolÀ1 (Table 3). To account for the faster cycliza-
tion of dianion 3a versus monoanion 14 in the presence of
TMEDA, we decided to carry out a similar theoretical study
with the ethylenediamine/dilithiated model 20. The energy
À
À
À
À
À
TS2: Li1 C1 2.244, Li1 C2 2.263, Li1 C3 2.106, Li1 C4 2.953, Li2 C1 2.893,
À
À
À
À
À
À
Li2 C2 2.143, Li2 C3 2.259, Li2 C4 2.128, C1 C2 1.374, C2 C3 1.912, C3 C4
1.411.
Table 3. Calculated relative energies[kcalmolÀ1] for solvated dilithiated minima 18–21 and transition struc-
tures TS1 and TS2.[a]
of TS1 and TS2 optimized at
the HF/6-31+G(d) level of
theory. The bond lengths in
18
TS1
19
20
TS2
21
À
À
TS1 [Li1 C2 2.391 Š, Li1 C3
HF/6-31+G(d)
MP2/6-31+G(d)
MP2/6-31+G(d)+SCRF
0.0
0.0
0.0
0.0
0.0
+35.1
+24.4
+24.6
+23.4
+24.3
À14.7
À30.2
À30.0
À32.9
À30.40.0
0.0
0.0
0.0
0.0
+33.8
+15.7
+17.7
+12.9
+17.4
À11.7
À28.0
À25.7
À30.8
À26.4
À
À
2.071 Š, Li2 C2 2.093 Š, Li2
À
C3
2.357 Š,
2.109 Š] and in TS2 [Li1 C1
2.244 Š, Li1 C2 2.363 Š, Li1
C3 2.106 Š, Li2 C2 2.143 Š,
and
Li2 C4
MP2/6-311+G
ACHTREUNG
À
MP2/6-311+GACHTREUNG
À
À
[a] All calculations at the HF/6-31+G(d)-optimized geometries. [b] Based on MP2/6-311+GACHTRE(UGN 2df) energies
and modified by additive corrections obtained from Gibb free energies [thermochemical analysis at the HF/6-
31+G(d) level for T=298 K] and MP2/6-31+G(d)+SCRF.
À
À
À
Li2 C3 2.259 Š, and Li2 C4
2.128 Š]
represent
typical
À
values for Li C interactions.
Table 4. Calculated relative energies[kcalmolÀ1] for solvated monolithiated minima 22–25 and transition struc-
tures TS3 and TS4.[a]
À
This seems to indicate that Li
C
interactions complete the
lithium coordination sphere. In
22
TS3
23
24
TS4
25
À
HF/6-31+G(d)
MP2/6-31+G(d)
MP2/6-31+G(d)+SCRF
0.0
0.0
0.0
0.0
0.0
+25.5
+14.7
+14.1
+13.7
+12.4
À9.0
0.0
+25.8
+12.0
+12.3
+10.6
+11.7
À8.6
addition, if we consider the C
À13.40.0
À14.8
À13.8
À15.0
À13.9
À15.5
À14.4
À14.7
C distances, it can be observed
that the geometry of transition
state TS2 has a closer resem-
blance to the cyclic product
0.0
0.0
0.0
MP2/6-311+G
ACHTREUNG
MP2/6-311+GACHTREUNG
[a] All calculations at the HF/6-31+G(d)-optimized geometries. [b] Based on MP2/6-311+GACHTRE(UGN 2df) energies
and modified by additive corrections obtained from Gibb free energies [thermochemical analysis at the HF/6-
31+G(d) level for T=298 K] and MP2/6-31+G(d)+SCRF.
À
(C1 C2
À
1.374Š,
C 2 C3
À
1.912 Š, and C3 C4 1.411 Š)
5002
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 4998 – 5008

Intramolecular Carbolithiation
FULL PAPER
À
À
À
than that of TS1 (C1 C2 1.344 Š, C2 C3 2.058 Š, and C3 C4
1.470 Š), which explains the lower energy barrier for the
former.
Conclusion
In conclusion, we have shown that intramolecular carboli-
thiation of lithiated double bonds is not restricted to bis(2-
lithioallyl)amines and that this reaction thus is general for
2,6-dilithio-1,6-heptadienes moieties. In addition, ab initio
molecular-orbital calculations reveal that the transition state
For the monolithiated structures, Table 4and Figure 2
show the calculated energies for 22–25, TS3, and TS4 as
À
for this process presents typical values for Li C interactions,
thus supporting a carbolithiation pathway for this reaction.
We also showed, both experimentally and theoretically, that
this carbolithiation of lithiated double bonds is slightly
slower than the corresponding carbolithiation of isolated
double bonds. Interestingly, we found that the accelerating
effect of TMEDA as cosolvent in these reactions is greater
for carbolithiation of lithiated double bonds than for carbo-
lithiation of isolated double bonds.
Figure 2. Computer plot of the HF/6-31+G(d)-optimized structures for
À
TS3, and TS4. Selected bond lengths[Š] for model TS3: Li C1 2.621,
Experimental Section
À
À
À
À
À
À
Li C2 2.150, Li C3 2.334, Li C4 2.118, C1 C2 1.331, C2 C3 2.121, C3 C4
À
À
À
À
1.405. For model TS4: Li C1 2.870, Li C2 2.163, Li C3 2.334, Li C4
General: All reactions were carried out under a nitrogen atmosphere in
oven-dried glassware with magnetic stirring. Temperatures are reported
as bath temperatures. Et2O and THF were continuously refluxed and
freshly distilled from sodium under nitrogen. CH2Cl2 was distilled over
P2O5. TMEDA was refluxed over potassium under nitrogen using benzo-
phenone as indicator, and distilled under reduced pressure. Solvents used
in extraction and purification were distilled prior to use. TLC was per-
formed on Al-backed plates coated with silica gel60 with F254 indicator;
the chromatograms were visualized under UV light (254nm) and/or by
staining with a Ce/Mo reagent, anisaldehyde, or phosphomolybdic acid
solution and subsequent heating. Rf values refer to silica gel. Flash
column chromatography was carried out on silica gel60, 230–400 mesh.
Melting points (uncorrected) were obtained on a Büchi–Tottoli apparatus
with open capillary tubes. 1H and 13C NMR spectra were recorded on a
Varian Inova-400, Varian Mercury-plus 300, or Varian Gemini VXR-200
spectrometers. 1H NMR data are reported as follows: chemical shift, mul-
tiplicity (s: singlet, brs: broad singlet, d: doublet, t: triplet, dd: doublet of
doublets, dt: doublet of triplets, q: quartet, qt: quintet, sept: septet, m:
multiplet), coupling constants (J in Hz) and integration. Chemical shifts
(d) are given as ppm relative to the residual solvent peak (CDCl3 7.16/
76.95 ppm). FT-IR spectra were recorded on a Nicolet Impact 410 spec-
trometer. Low-resolution electron-impact mass spectra (EI-LRMS) were
obtained at 70 eV on a HP5987 A instrument or Micromass Autospec
spectrometer and only the molecular ions and/or base peaks in the spec-
tra are given. The intensities are reported as a percentage relative to the
base peak after the corresponding m/z value. High-resolution mass spec-
tra (HRMS) were obtained with a Micromass Autospec spectrometer. El-
emental analyses were carried out with Perkin Elmer and LECO elemen-
tal analyzers. All commercially available reagents were used without fur-
ther purification, unless otherwise indicated, and were purchased from
Aldrich Chemical Co. or Acros Organics. tBuLi was used as a 1.5m solu-
tion in pentane, and nBuLi was used as 1.6m or 2.5m solutions in hexane.
À
À
À
2.109, C1 C2 1.329, C2 C3 2.092, C3 C4 1.408.
well as the selected geometrical parameters for TS3 and
TS4, respectively. The energy values deserve a comment. At
the MP2/6-311+GACHTREUNG(2df)+SCRF level, the energy barrier for
the water/dilithiated TS1 model is 11.9 kcalmolÀ1 higher
than that obtained for TS3. This energy gap should be
enough to cause different experimental behaviors. This was
indeed observed for both reactions described in Scheme 3.
For the reaction at T=08C (t=150 min), cyclization was ob-
served for the monolithiated compound, 14, but not for its
dilithiated counterpart, 3a.[23] Thus, there is excellent agree-
ment between the experimental and theoretical results. On
the other hand, the barrier for dilithiated TS2 is
5.7 kcalmolÀ1 higher than that calculated for ethylenedi-
ACHTREUNGamine/monolithiated TS4 at the same level of calculation.
Therefore, the conversion from 24 to 25 should be quicker
than the conversion from 20 to 21 at the same temperature.
However, our experiments showed that cyclization of di-
ACHTREUNGanion 3a was quicker than cyclization of monoanion 14 in
the presence of TMEDA (Scheme 3). Although the theory
is not in agreement with the experimental outcome in this
case, our calculations have shown that the presence of a dia-
mine solvating the dianion has a large stabilization effect
and explains the facile carbolithiation of lithiated double
bonds. If we compare the calculated values for TS1 and
TS2 at the MP2/6-31+G(d)+SCRF level, a decrease of
about 7 kcalmolÀ1 is observed when the calculation is per-
formed with the diamine-solvated dianion model. However,
looking at the calculated values for monoanion models TS3
2,6-Dibromo-1,6-heptadiene (1a): This compound was prepared by hy-
drobromination of 1,6-heptadiyne following an established procedure.[14]
HBr, generated by adding PBr3 (5.23 mL, 55 mmol) dropwise to water
(2.97 mL, 165 mmol), was bubbled through Et4N+BrÀ (31.50 g,
150 mmol) in CH2Cl2 (150 mL) at 08C. The weight of the resulting solu-
tion showed that 10.12 g of HBr (125 mmol) had been absorbed by the
Et4N+BrÀ solution. 1,6-Heptadiyne (7.16 mL, 62.5 mmol) was added. The
mixture was heated at 408C overnight and then cooled to 08C. Et2O
(300 mL) was added, and the mixture was filtered. Vacuum distillation
(94–958C/20 Torr) gave 11.11 g (70%) of 1a as a colorless oil. 1H NMR
(400 MHz, CDCl3): d=5.59 (dt, J=1.7 and 1.1 Hz, 2H), 5.43 (d, J=
1.7 Hz, 2H), 2.44 (dq, J=7.3 and 1.1 Hz, 4H), 1.84ppm (qt, J=7.3 Hz,
À
and TS4, the C2 C3 distance is almost identical (2.121 and
2.092 Š, respectively, Figure 2) and, consistently, only a sta-
bilization of 0.7 kcalmolÀ1 is observed.
Chem. Eur. J. 2007, 13, 4998 – 5008
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5003

J. Barluenga et al.
2H); 13C NMR (100.6 MHz, CDCl3): d=133.5, 117.2, 39.7, 25.8 ppm;
LRMS (70 eV, EI): m/z (%): 175 (8) [MÀBr+2]+, 173 (8) [MÀBr]+, 93
(100); elemental analysis calcd (%) for C7H10Br2 (254.0): C 33.11, H 3.97;
found: C 33.05, H 3.96.
a mixture of unreacted initial compound and ethyl 4-bromo-2-(2-bro-
moallyl)-2-phenyl-4-pentenoate. Distillation under vacuum gave 5.2 g
(18.4mmol) of the initial compound. Without further purification, the
residue of ethyl 4-bromo-2-phenyl-4-pentenoate (5.91 g, 14.7 mmol,
40%) was reduced with LiAlH4 (0.56 g, 14.7 mmol) in dry THF (20 mL)
under nitrogen. After the reaction mixture was stirred for 24h at room
temperature, the reaction was quenched by pouring the mixture into ice.
The organic compound was extracted with EtOAc (3”30 mL). After
usual work-up, the crude product was purified by column chromatogra-
phy (hexane/EtOAc) to afford 4-bromo-2-(2-bromoallyl)-2-phenyl-4-
penten-1-ol (2c, 2.84g, 54%) as a clear brown oil. Rf =0.36 (hexane/
EtOAc, 4:1); 1H NMR (200 MHz, CDCl3): d=7.40–7.17 (m, 5H), 5.48–
5.43 (m, 2H), 5.31–5.25 (m, 2H), 4.13 (d, J=5.6 Hz, 2H), 3.08 (d, J=
15.4Hz, 2H), 2.98 (d, J=15.4Hz, 2H), 2.33 ppm (t, J=5.6 Hz, 1H);
13C NMR (50.3 MHz, CDCl3): d=141.3, 128.1, 127.7, 126.7, 126.5, 121.4,
47.4, 46.4 ppm; LRMS (70 eV, EI): m/z (%): 331 (1) [MÀCH2OH+4]+,
333 (2) [MÀCH2OH+2]+, 331 (1) [MÀCH2OH]+, 91 (100). A mixture of
2c (2.84g, 7.9 mmol), tBuMe2SiCl (1.2 g, 9.52 mmol), and 1H-imidazole
(1.33 g, 19.83 mmol) in DMF (12 mL) was stirred under nitrogen over-
night. After water was added (20 mL), the mixture was extracted with
CH2Cl2 (3”20 mL), the combined organic layers were dried over anhy-
drous Na2SO4, and the solvents were removed under vacuum to afford
2,6-dibromo-4-(tert-butyldimethylsilyloxymethyl)-4-phenyl-1,6-heptadiene
2,6-Dibromo-4-(tert-butyldimethylsilyloxymethyl)-1,6-heptadiene (1b): A
solution of LDA (100 mmol), prepared by addition of nBuLi (40 mL,
100 mmol) over a solution of iPr2NH (14.0 mL, 100 mmol) in dry THF
(40 mL) at 08C, was added dropwise to a solution of tert-butyl acetate
(12.14mL, 90 mmol) in THF (40 mL) under nitrogen at À788C. When
addition was complete, the cooling bath was removed, and the mixture
was stirred at room temperature for 15 min. After cooling to À408C, a
solution of 2,3-dibromopropene (20.0 g, 100 mmol) in THF (10 mL) was
added. The reaction mixture was then heated to reflux for 8 h. Water
(40 mL) was added and the mixture was transferred to a separatory
funnel. The organic layer was separated and the aqueous phase was ex-
tracted with Et2O (2”20 mL). The combined organic layers were dried
over anhydrous Na2SO4, and the solvent was removed under vacuum to
afford 19.5 g (92%) of tert-butyl 4-bromo-4-pentenoate, which was not
purified. Alkylation of the crude product with 2,3-dibromopropene under
the same reaction conditions as before afforded 24.77 g (85%) of tert-
butyl 4-bromo-2-(2-bromoallyl)-4-pentenoate. The crude product was dis-
solved in Et2O (20 mL), and the solution was added dropwise to a sus-
pension of LiAlH4 (2.68 g, 70.4mmol) in Et 2O (70 mL) at 08C. The reac-
tion mixture was stirred for 24h at room temperature. The mixture was
hydrolyzed by pouring it over ice. The organic compound was extracted
with EtOAc (3”30 mL). After usual work-up, the crude product was sub-
jected to column chromatography (hexane/EtOAc) to afford 16.39 g
(82%) of 4-bromo-2-(2-bromoallyl)-4-pentenol (2b) as a colorless oil.
Rf =0.26 (hexane/EtOAc, 3:1); 1H NMR (200 MHz, CDCl3): d=5.67–
5.63 (m, 2H), 5.51–5.46 (m, 2H), 3.70–3.58 (m, 2H), 2.64–2.26 (m, 5H),
1.72–1.62 ppm (brs, 1H); 13C NMR (50.3 MHz, CDCl3): d=132.2, 118.6,
62.4, 41.9, 36.7 ppm; LRMS (70 eV, EI): m/z (%): 205 (10) [MÀBr+2]+,
203 (10) [MÀBr]+, 83 (100). A mixture of 2b (14.20 g, 50 mmol), tBu-
Me2SiCl (9.0 g, 60 mmol) and 1H-imidazole (8.42 g, 125 mmol) in DMF
(75 mL) was stirred under nitrogen overnight. Addition of water was fol-
lowed by extraction with CH2Cl2 (3”30 mL). The combined organic
layers were dried over Na2SO4, and the solvents were removed under
vacuum to afford 18.71 g (94%) of 2,6-dibromo-4-( tert-butyldimethylsily-
loxymethyl)-1,6-heptadiene (1b) as a colorless oil. Rf =0.30 (hexane);
1H NMR (200 MHz, CDCl3): d=5.62–5.58 (m, 2H), 5.48–5.44 (m, 2H),
3.55 (d, J=3.4Hz, 2H), 2.64–2.19 (m, 5H), 0.88 (s, 9H), 0.02 ppm (s,
6H); 13C NMR (50.3 MHz, CDCl3): d=132.7, 118.3, 61.8, 42.1, 36.6, 25.8,
18.1, À5.6 ppm; LRMS (70 eV, EI): m/z (%): 343 (2) [MÀtBu+4]+, 34 1
(4) [MÀtBu+2]+, 339 (2) [MÀtBu]+, 105 (100).
(1c, 3.41 g, 91%) as
a
colorless oil. Rf =0.35 (hexane); 1H NMR
(200 MHz, CDCl3): d=7.42–7.16 (m, 5H), 5.46–5.41 (m, 2H), 5.30–5.25
(m, 2H), 4.08 (s, 2H), 3.10 (d, J=15.4Hz, 2H), 2.97 (d, J=15.4Hz, 2H),
0.92 (s, 9H), 0.05 ppm (s, 6H); 13C NMR (50 MHz, CDCl3): d=141.7,
128.4, 128.0, 126.8, 126.4, 120.8, 63.9, 47.16, 46.7, 25.8, 18.1, À5.6 ppm;
LRMS (70 eV, EI): m/z (%): 419 (1) [MÀtBu+4]+, 417 (2) [MÀtBu+2]+,
415 (1) [MÀtBu]+, 73 (100).
2,6-Dibromo-4,4-bis(tert-butyldimethylsilyloxymethyl)-1,6-heptadiene
(1d): A mixture of diethyl malonate (8.0 g, 50 mmol), 2,3-dibromopro-
pene (20 g, 100 mmol), and anhydrous K2CO3 (30.43 g, 220 mmol) in 2-
butanone (100 mL) was heated to reflux for 48 h.[24] The mixture was fil-
tered, and the filtrate was concentrated under vacuum. The resulting
crude product was dissolved in Et2O (30 mL) and then added dropwise
to a suspension of LiAlH4 (3.76 g, 100 mmol) in dry Et2O (100 mL) at
08C. When the addition was complete, the ice bath was removed and the
mixture was stirred at room temperature for 16 h. The reaction was
quenched by pouring it into ice. After filtration, the organic product was
extracted with EtOAc (3”30 mL). The combined organic layers were
dried over anhydrous Na2SO4, and the solvent was removed under
vacuum. The crude product was subjected to flash column chromatogra-
phy (hexane/EtOAc 3:1) to give 2,2-bis(2-bromoallyl)-1,3-propanediol
(2d, 11.70 g, 75%) as a white solid. M.p. 56–588C; 1H NMR (200 MHz,
CDCl3): d=5.73–5.69 (m, 2H), 5.61–5.58 (m, 2H), 3.69 (s, 4H), 3.12 (s,
2H), 2.67 ppm (s, 4H); 13C NMR (50.3 MHz, CDCl3): d=127.8, 122.0,
65.3, 43.6, 42.7 ppm; LRMS (70 eV, EI): m/z (%): 235 (12) [MÀBr+2]+,
233 (12) [MÀBr]+, 95 (100). A mixture of 2d (7.8 g, 25 mmol), tBu-
Me2SiCl (9.0 g, 60 mmol) and 1H-imidazole (8.42 g, 125 mmol) in DMF
(75 mL) was stirred under nitrogen at room temperature overnight.
Water was added, and the mixture was extracted with CH2Cl2 (3”
40 mL). The combined organic layers were washed with water (5”
30 mL) and dried over anhydrous Na2SO4. The solvents were removed
under vacuum to afford 1d (12.6 g, 93%) as a colorless oil. Rf =0.76
(hexane); 1H NMR (200 MHz, CDCl3): d=5.70–5.67 (m, 2H), 5.60–5.57
(m, 2H), 3.61 (s, 4H), 2.73 (s, 4H), 0.90 (s, 18H), 0.04ppm (s, 12H);
13C NMR (50.3 MHz, CDCl3): d=128.9, 121.2, 63.8, 45.1, 42.3, 25.8, 18.1,
À5.6 ppm; LRMS (70 eV, EI): m/z (%): 73 (100).
2,6-Dibromo-4-(tert-butyldimethylsilyloxymethyl)-4-phenyl-1,6-hepta-
diene (1c): A solution of LDA (44 mmol), prepared by addition of
nBuLi (17.6 mL, 44 mmol) over iPr2NH (6.16 mL, 44 mmol) in dry THF
(25 mL) at 08C, was added dropwise to a solution of ethyl phenyl acetate
(6.56 g, 40 mmol) in THF (25 mL) under nitrogen at À788C. The mixture
was stirred at this temperature for 1 h before addition of a solution of
2,3-dibromopropene (8 g, 40 mmol) in THF (20 mL). After 15 min, the
cooling bath was removed and the reaction was stirred for 4h at room
temperature. The mixture was quenched with water, and the organic
compound was extracted with EtOAc (3”30 mL). After usual work-up,
the crude product was subjected to column chromatography (hexane/
EtOAc) to afford ethyl 4-bromo-2-phenyl-4-pentenoate (10.4 g, 92%) as
a
colorless oil. Rf =0.50 (hexane/EtOAc, 5:1); 1H NMR (200 MHz,
CDCl3): d=7.36–7.26 (m, 5H), 5.54–5.50 (m, 1H), 5.39–5.35 (m, 1H),
4.25–3.94 (m, 3H), 3.21 (dd, J=7.8 and 14.4 Hz, 1H), 2.81 (dd, J=14.4
and 7.8 Hz, 1H), 1.21 ppm (t, J=7.1 Hz, 3H); 13C NMR (50.3 MHz,
CDCl3): d=172.2, 137.4, 130.4, 128.5, 127.6, 127.3, 118.9, 60.7, 49.6, 44.8,
13.9 ppm; LRMS (70 eV, EI): m/z (%): 203 (100) [MÀBr]+. A solution
of LDA (40.4 mmol) in THF (20 mL) was added dropwise to a solution
of ethyl 4-bromo-2-phenyl-4-pentenoate (10.4 g, 36.8 mmol) in dry THF
(20 mL) at À788C. After stirring the mixture for 1 h at this temperature,
a solution of 2,3-dibromopropene (7.36 g, 36.8 mmol) in THF (10 mL)
was added dropwise and stirring at low temperature was continued for
15 min. The cooling bath was removed, and the mixture was heated to
reflux for 15 h before addition of water. Extraction and work-up afforded
5,5-Bis(2-bromoallyl)-2,2-dimethyl-[1,3]-dioxane (1e): A solution of 2,2-
bis(2-bromoallyl)-1,3-propanediol (2d, 1.56 g, 5 mmol), prepared as de-
scribed above, and a catalytic amount of PPTS in 2,2-dimethoxypropane
(15 mL) was stirred for 3 h at room temperature and heated to reflux for
1 h. Excess 2,2-dimethoxypropane was evaporated to afford 1e (1.77 g,
100%) as
a
yellow oil. Rf =0.45 (hexane/EtOAc, 10:1); 1H NMR
(200 MHz, CDCl3): d=5.75 (s, 2H), 5.65 (s, 2H), 3.81 (s, 4H), 2.82 (s,
4H), 1.42 ppm (s, 6H); 13C NMR (50.3 MHz, CDCl3): d=127.6, 122.1,
97.8, 65.9, 43.2, 36.6, 23.7 ppm; LRMS (70 eV, EI): m/z (%): 341 (14)
[MÀCH3+4]+, 339 (30) [MÀCH3+2]+, 415 (16) [MÀCH3]+, 43 (100).
5004
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 4998 – 5008

Intramolecular Carbolithiation
FULL PAPER
2-Bromo-1,6-heptadiene (13): This compound was prepared following an
established procedure.[25] Colorless oil. Rf =0.52 (hexane); 1H NMR
(400 MHz, CDCl3): d=5.85–5.74(m, 1H), 5.58–5.56 (m, 1H), 5.41–5.39
(m, 1H), 5.06–4.96 (m, 2H), 2.43 (t, J=7.6 Hz, 2H), 2.12–2.03 (m, 2H),
1.66 ppm (qt, J=7.6 Hz, 2H); 13C NMR (100.6 MHz, CDCl3): d=137.9,
134.3, 116.6, 105.5, 40.6, 32.3, 26.9 ppm; elemental analysis calcd (%) for
C7H11Br (175.1): C 48.02, H 6.33; found: C 47.95, H 6.35.
(qt, J=7.4Hz, 2H), 1.43 (s, 4H), 0.00 ppm (s, 18H);
13C NMR
(100.6 MHz, CDCl3): d=129.5, 38.2, 22.3, 19.1, À0.7 ppm; LRMS (70 eV,
EI): m/z (%): 240 (20) [M]+, 73 (100); HRMS (EI): m/z: calcd for
C13H28Si2: 240.1730; found: 240.1738.
1,2-Bis(2-ethyl-2-hydroxybutyl)cyclopentene (7b): Reaction of 1a
(254mg, 1 mmol) with tBuLi (2.67 mL, 4mmol) and TMEDA (0.6 mL,
4mmol) was followed by addition of 3-pentanone (189 mg, 2.2 mmol).
Work-up as above yielded 7b (207 mg, 77%) as a colorless oil. Rf =0.22
(hexane/EtOAc 5:1); 1H NMR (400 MHz, CDCl3): d=2.40 (t, J=7.3 Hz,
4H), 2.27 (s, 4H), 2.19 (brs, 2H), 1.76 (qt, J=7.3 Hz, 2H), 1.49 (q, J=
7.2 Hz, 8H), 0.87 ppm (t, J=7.2 Hz, 12H); 13C NMR (100.6 MHz,
CDCl3): d=136.4, 75.0, 38.7, 37.8, 31.3, 23.0, 8.1 ppm; LRMS (70 eV, EI):
m/z (%): 87 (100); elemental analysis calcd (%) for C17H32O2 (268.4): C
76.06, H 12.02; found: C 75.93, H 11.98.
General procedure for the preparation of dienes4 : A solution of the cor-
responding starting dibromodiene 1 (1 mmol) in dry Et2O (10 mL) was
treated with tBuLi (2.67 mL, 4mmol) at À788C under nitrogen. After
the reaction mixture was stirred for 30 min at this temperature, deuteri-
um oxide (excess) or chlorotrimethylsilane (240 mg, 2.2 mmol) was
added to the solution. The cooling bath was removed to allow the mix-
ture to reach room temperature. The mixture was quenched with water
and extracted with EtOAc (3”10 mL). The combined organic layers
were dried over anhydrous Na2SO4, and the solvents were removed
under vacuum. The resulting residue was purified by column chromatog-
raphy (silica gel, hexane) to afford 4a–c.
4-(tert-Butyldimethylsilyloxymethyl)-1,2-bis(deuteriomethyl)cyclopentene
(7c): Reaction of 1b (398 mg, 1 mmol) with tBuLi (2.67 mL, 4mmol) and
TMEDA (0.6 mL, 4mmol) was followed by addition of deuterium oxide
(excess). Work-up as above yielded 7c (218 mg, 90%) as a colorless oil.
Rf =0.25 (hexane); 1H NMR (400 MHz, CDCl3): d=3.46 (d, J=6.4Hz,
2H), 2.42–2.30 (m, 3H), 2.06–1.95 (m, 2H), 1.56 (s, 4H), 0.90 (s, 9H),
0.05 ppm (s, 6H); 13C NMR (50.3 MHz, CDCl3): d=129.5, 67.6, 41.2,
37.8, 25.9, 18.3, 13.4(t, J=19.5 Hz), À5.3 ppm; LRMS (70 eV, EI): m/z
(%): 185 (24) [MÀtBu]+, 109 (100); elemental analysis calcd (%) for
C14H26D2OSi (242.5): C 69.35, H/D 12.47; found: C 69.46, H/D 12.43.
2,6-Bis(trimethylsilyl)-1,6-heptadiene (4a): Reaction of 1a (254mg,
1 mmol) with tBuLi (2.67 mL, 4mmol) was followed by addition of chlor-
otrimethylsilane (240 mg, 2.2 mmol). Work-up as above yielded 4a
1
(214mg, 89%) as a colorless oil. Rf =0.60 (hexane); H NMR (400 MHz,
CDCl3): d=5.57–5.55 (dt, J=3.0 and 1.5 Hz, 2H), 5.33–5.30 (dt, J=3.0
and 1.0 Hz, 2H), 2.16–2.10 (m, 4H), 1.57–1.48 (m, 2H), 0.08 ppm (s,
18H); 13C NMR (100.6 MHz, CDCl3): d=152.2, 123.8, 36.0, 28.5,
À1.4ppm; LRMS (70 eV, EI): m/z (%): 240 (1) [M]+, 73 (100); HRMS
(EI): m/z: calcd for C13H28Si2: 240.1730; found: 240.1724.
4-tert-Butyldimethylsilyloxymethyl-1,2-bis(tributylstannylmethyl)cyclo-
pentene (7d): Reaction of 1b (398 mg, 1 mmol) with tBuLi (2.67 mL,
4mmol) and TMEDA (0.6 mL, 4mmol) was followed by addition of trib-
utyltin chloride (0.61 mL, 2.2 mmol). Work-up as above yielded 7d
4-(tert-Butyldimethylsilyloxymethyl)-2,6-dideuterio-1,6-heptadiene (4b):
Reaction of 1b (398 mg, 1 mmol) with tBuLi (2.67 mL, 4mmol) was fol-
lowed by addition of deuterium oxide (excess). Work-up as above yielded
1
(679 mg, 83%) as a colorless oil. Rf =0.33 (hexane); H NMR (400 MHz,
CDCl3): d=3.46 (d, J=6.8 Hz, 2H), 2.37–2.20 (m, 3H), 2.02–1.89 (m,
2H), 1.60 (s, 4H), 1.55–1.38 (m, 12H), 1.36–1.19 (m, 12H), 0.99–0.70 (m,
39H), 0.04ppm (s, 6H); 13C NMR (50.3 MHz, CDCl3): d=128.0, 67.9,
41.3, 38.0, 29.2, 27.4, 25.9, 18.3, 13.7, 10.8, 9.8, À5.3 ppm.
4b (225 mg, 93%) as
a
colorless oil. Rf =0.36 (hexane); 1H NMR
(200 MHz, CDCl3): d=5.00 (s, 4H), 3.48 (d, J=5.6 Hz, 2H), 2.20–1.95
(m, 4H), 1.72–1.55 (m, 1H), 0.89 (s, 9H), 0.03 ppm (s, 6H); 13C NMR
(50.3 MHz, CDCl3): d=136.7 (t, J=23.4 Hz), 115.8, 64.5, 40.2, 34.8, 25.9,
18.2, À5.5 ppm; LRMS (70 eV, EI): m/z (%): 18h5 (14) [MÀtBu]+, 75
(100); elemental analysis calcd (%) for C14H26D2OSi (242.5): C 69.35,
H/D 12.47; found: C 69.22, H/D 12.51.
4-tert-Butyldimethylsilyloxymethyl-1,2-bis(hydroxymethyl)cyclopentene
(7e): Reaction of 1b (398 mg, 1 mmol) with tBuLi (2.67 mL, 4mmol)
and TMEDA (0.6 mL, 4mmol) was followed by addition of trimethylbo-
rate (0.26 mL, 22 mmol).at À788C. After the mixture was stirred for
30 min at this temperature, the cooling bath was removed, and stirring
was continued for 1 h at room temperature. The mixture was cooled to
08C and a solution of NaOH (1.33 mL of a 3m solution in water,
4mmol) and H 2O2 (0.4mL of a solution 10 m in water, 4mmol) was
added dropwise. The resulting mixture was heated to reflux for 30 min.
Work-up as above yielded 7e (174mg, 64%) as a white solid. M.p. 38–
408C (hexane); 1H NMR (400 MHz, CDCl3): d=4.17 (d, J=12.8 Hz,
2H), 4.12 (d, J=12.8 Hz, 2H), 3.48 (d, J=7.6 Hz, 2H), 3.42 (brs, 2H),
2.59–2.49 (m, 2H), 2.48–2.37 (m, 1H), 2.24–2.14 (m, 2H), 0.87 (s, 9H),
0.03 ppm (s, 6H); 13C NMR (50.3 MHz, CDCl3): d=136.7, 66.8, 58.9,
38.0, 37.8, 25.8, 18.2, À5.3 ppm; elemental analysis calcd (%) for
C14H28O3Si (272.5): C 61.72, H 10.36; found: C 61.59, H 10.38.
4,4-Bis(tert-butyldimethylsilyloxymethyl)-2,6-dideuterio-1,6-heptadiene
(4c): Compound 1c (543 mg, 1 mmol) was treated with tBuLi (2.67 mL,
4mmol) before adding deuterium oxide (excess) to the mixture. Work-up
as above afforded 4c (352 mg, 91%) as a colorless oil. Rf =0.64(hexane);
1H NMR (200 MHz, CDCl3): d=5.03 (s, 4H), 3.32 (s, 4H), 1.96 (s, 4H),
0.89 (s, 18H), 0.02 ppm (s, 12H); 13C NMR (50.3 MHz, CDCl3): d=134.2
(t, J=23.0 Hz), 117.1, 63.8, 43.1, 35.0, 25.9, 18.2, À5.6 ppm; LRMS
(70 eV, EI): m/z (%): 329 (2) [MÀtBu]+, 147 (100); anal. calcd (%) for
C21H42D2O2Si2 (386.8): C 65.22, H/D 11.99; found: C 65.05, H/D 11.96.
Intramolecular carbolithiation of 2,6-dilithio-1,6-dienes3 : General proce-
dure for the preparation of cyclopentene derivatives7 and 8 : TMEDA
(0.6 mL, 4mmol) was added at À788C to a solution of the corresponding
dianion 3 (1 mmol), which was generated by reaction of the correspond-
ing dibromodiene 1 (1 mmol) with tBuLi (2.67 mL, 4mmol), as described
above. The resulting mixture was stirred for 15 min at this temperature,
then the cooling bath was removed to allow the reaction to reach room
temperature. Stirring was continued for 50 min. The ethereal solution of
the resulting dianion 5 was cooled to À788C, and 2.2 equiv (2.2 mmol) of
an electrophile (deuterium oxide, chlorotributyltin, trimethylborate, 3-
pentanone, or chlorotrimethylsilane) or 1 equiv (1 mmol) of dichlorodi-
phenylsilane was added. The mixture was allowed to reach room temper-
ature and stirring was continued for 3 h. The mixture was hydrolyzed
with water and extracted with EtOAc (3”10 mL). The combined organic
layers were dried over anhydrous Na2SO4. The solvents were removed
under vacuum and the resulting residue was purified by flash column
chromatography to yield functionalized cyclopentenes 7 and 8.
4-tert-Butyldimethylsilyloxymethyl-1,2-bis(deuteriomethyl)-4-phenylcy-
clopentene (7 f): Compound 1c (474 mg, 1 mmol) was treated with tBuLi
(2.67 mL, 4mmol) and TMEDA (0.6 mL, 4mmol). Addition of deuteri-
um oxide (excess) followed by work-up as above yielded 7 f (293 mg,
92%) as a white solid. M.p. 56–588C; 1H NMR (200 MHz, CDCl3): d=
7.31–7.12 (m, 5H), 3.47 (s, 2H), 2.64 (d, J=14.6 Hz, 2H), 2.54 (d, J=
14.6 Hz, 2H), 1.60 (s, 4H), 0.79 (s, 9H), À0.23 ppm (s, 6H); 13C NMR
(50.3 MHz, CDCl3): d=148.5, 129.1, 127.5, 127.4, 125.3, 71.4, 49.8, 47.0,
25.8, 18.2, 13.5 (t, J=19.3 Hz), À5.9 ppm; LRMS (70 eV, EI): m/z (%):
261 (51) [MÀtBu]+, 186 (100); elemental analysis calcd (%) for
C20H30D2OSi (318.6): C 75.40, H/D 10.76; found: C 75.57, H/D 10.80.
4,4-Bis(tert-butyldimethylsilyloxymethyl)-1,2-bis(deuteriomethyl)cyclo-
pentene (7g): Compound 1d (543 mg, 1 mmol) was treated with tBuLi
(2.67 mL, 4mmol) and TMEDA (0.6 mL, 4mmol) before addition of
deuterium oxide (excess). Work-up as above afforded 7g (348 mg, 90%)
as a colorless oil. Rf =0.45 (hexane); 1H NMR (200 MHz, CDCl3): d=
3.44(s, 4H), 2.01 (s, 4H), 1.54(s, 4H), 0.88 (s, 18H), 0.02 ppm (s, 12H);
13C NMR (50.3 MHz, CDCl3): d=128.8, 65.8, 46.6, 46.9, 25.9, 18.3, 13.5
(t, J=19.1 Hz), À5.5 ppm; LRMS (70 eV, EI): m/z (%): 329 (2)
1,2-Bis(trimethylsilylmethyl)cyclopentene (7a): Reaction of 1a (254mg,
1 mmol) with tBuLi (2.67 mL, 4mmol) and TMEDA (0.6 mL, 4mmol)
was followed by addition of chlorotrimethylsilane (0.28 mL, 2.2 mmol).
Work-up as above yielded 7a (197 mg, 82%) as a colorless oil. Rf =0.75
(hexane); 1H NMR (400 MHz, CDCl3): d=2.22 (t, J=7.4Hz, 4H), 1.70
Chem. Eur. J. 2007, 13, 4998 – 5008
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5005

J. Barluenga et al.
[MÀtBu]+, 122 (100); elemental analysis calcd (%) for C21H42D2O2Si2
4-tert-Butyldimethylsilyloxymethyl-1-methyl-2-(2-oxo-2-isopropyl)cyclo-
pentene (9b): Reaction of 1b (398 mg, 1 mmol) with tBuLi (2.67 mL,
4mmol) and TMEDA (0.6 mL, 4mmol) followed by addition of ethyl
isobutyrate (116 mg, 1 mmol) and work-up as above yielded 9b (155 mg,
(386.8): C 65.22, H/D 11.99; found: C 65.46, H/D 12.03.
4,4-Bis(tert-butyldimethylsilyloxymethyl)-1,2-bis(tributylstannylmethyl)-
cyclopentene (7h): Compound 1d (543 mg, 1 mmol) was treated with
tBuLi (2.67 mL, 4mmol) and TMEDA (0.6 mL, 4mmol). Addition of
tributyltin chloride (0.61 mL, 2.2 mmol) and work-up as above yielded
50%) as
a
colorless oil. Rf =0.19 (hexane/EtOAc, 25:1); 1H NMR
(400 MHz, CDCl3): d=3.46-3.44 (m, 2H), 3.14 (s, 2H), 2.63 (sept, J=
7.0 Hz, 1H), 2.46–2.31 (m, 3H), 2.18–1.95 (m, 2H), 1.62 (s, 3H), 1.07 (d,
J=7.0 Hz, 6H), 0.87 (s, 9H), 0.02 ppm (s, 6H); 13C NMR (50.3 MHz,
CDCl3): d=212.6, 134.3, 127.0, 67.1, 41.1, 39.8, 39.3, 37.8, 25.9, 18.2, 14.0,
À5.4ppm; LRMS (70 eV, EI): m/z (%): 253 (27) [M+-tBu], 107 (100); el-
emental analysis calcd (%) for C18H34O2Si (310.6): C 69.62, H 11.04;
found: C 69.49, H 11.07.
7h (780 mg, 81%) as
a
colorless oil. Rf =0.63 (hexane); 1H NMR
(400 MHz, CDCl3): d=3.44 (s, 4H), 1.97 (s, 4H), 1.58 (s, 4H), 1.55–1.20
(m, 24H), 0.95–0.77 (m, 48H), 0.03 ppm (s, 12H); 13C NMR (50.3 MHz,
CDCl3): d=127.3, 65.8, 46.5, 44.0, 29.2, 27.4, 25.9, 18.3, 13.7, 10.8, 9.8,
À5.5 ppm.
4,4-Bis(tert-butyldimethylsilyloxymethyl)-1,2-bis(hydroxymethyl)cyclo-
pentene (7i): Reaction of 1d (543 mg, 1 mmol) with tBuLi (2.67 mL,
4mmol) and TMEDA (0.6 mL, 4mmol) was followed by addition of tri-
methylborate (0.26 mL, 2.2 mmol).at À788C. After the mixture was
stirred for 30 min at this temperature, the cooling bath was removed and
stirring was continued for 1 h at room temperature. The mixture was
cooled to 08C, and a solution of NaOH (1.33 mL of a 3m solution in
water, 4mmol) and H 2O2 (0.4mL of a solution 10 m in water, 4mmol)
was added dropwise. The resulting mixture was heated to reflux for
30 min. Work-up as above yielded 7i (279 mg, 67%) as a white solid.
M.p. 86–888C (hexane); 1H NMR (200 MHz, CDCl3): d=4.19 (s, 4H),
3.47 (s, 4H), 2.22 (s, 4H), 2.09 (brs, 1H), 1.62 (brs, 1H), 0.87 (s, 18H),
0.02 ppm (s, 12H); 13C NMR (50.3 MHz, CDCl3): d=136.0, 65.4, 59.1,
46.9, 40.7, 25.8, 18.2, À5.5 ppm; elemental analysis calcd (%) for
C21H44O4Si2 (416.7): C 60.52, H 10.64; found: C 60.31, H 10.67.
4,4-Bis(tert-butyldimethylsilyloxymethyl)-1-methyl-2-(2-oxo-2-isopropyl)-
cyclopentene (9c): Diene 1d (543 mg, 1 mmol) was treated with tBuLi
(2.67 mL, 4mmol) and TMEDA (0.6 mL, 4mmol). Addition of ethyl iso-
butyrate (116 mg, 1 mmol) and work-up as above afforded 9c (296 mg,
65%) as
a
colorless oil. Rf =0.19 (hexane/EtOAc, 25:1); 1H NMR
(400 MHz, CDCl3): d=3.43 (s, 4H), 3.11 (s, 2H), 2.64 (sept, J=6.8 Hz,
1H), 2.08 (s, 2H), 2.03 (s, 2H), 1.60 (s, 3H), 1.06 (d, J=6.8 Hz, 6H), 0.86
(s, 18H), 0.01 ppm (s, 12H); 13C NMR (50.3 MHz, CDCl3): d=212.7,
133.7, 126.3, 65.6, 46.9, 43.7, 42.0, 41.3, 39.6, 25.8, 18.3, 14.2, À5.5 ppm;
LRMS (70 eV, EI): m/z (%): 397 (53) [MÀtBu]+, 71 (100); elemental
analysis calcd (%) for C25H50O3Si2 (454.8): C 66.02, H 11.08; found: C
65.87, H 11.11.
General procedure for the preparation of hydroxylic derivatives10 : The
suspension of the corresponding dianion 5, generated by reaction of the
corresponding starting diene 1 (1 mmol) with tBuLi (2.67 mL, 4mmol)
and TMEDA (0.6 mL, 4mmol) as described above, was treated with
ethyl isobutyrate (1 mmol) at À788C. The mixture was allowed to reach
room temperature and was then stirred overnight. The mixture was hy-
drolyzed with water and extracted with EtOAc (3”10 mL). The com-
bined organic layers were dried over anhydrous Na2SO4. The solvent was
removed under vacuum, and the resulting residue was purified by flash
column chromatography (silica gel, hexane/EtOAc, 15:1) to afford the bi-
cyclic alcohols 10.
2,3-Bis(2-ethyl-2-hydroxybutyl)-8,8-dimethyl-7,9-dioxaspiroACTHRE[UNG 4,5]-2-decene
(7j): Compound 1e (354mg, 1 mmol) was treated with tBuLi (2.67 mL,
4mmol) and TMEDA (0.6 mL, 4mmol). Addition of 3-pentanone
(189 mg, 2.2 mmol) and work-up as above yielded 7j (313 mg, 81%) as a
white solid. M.p. 84–868C; 1H NMR (200 MHz, CDCl3): d=3.65 (s, 4H),
2.53 (brs, 2H), 2.33 (s, 4H), 2.21 (s, 4H), 1.46 (q, J=7.6 Hz, 8H), 1.40 (s,
6H), 0.83 ppm (t, J=7.6 Hz, 12H); 13C NMR (50.3 MHz, CDCl3): d=
134.1, 97.7, 74.9, 69.2, 45.8, 39.8, 37.8, 31.4, 23.7, 8.1 ppm; LRMS (70 eV,
EI): m/z (%): 353 (3) [MÀCH3]+, 87 (100); elemental analysis calcd (%)
for C22H40O4 (368.6): C 71.70, H 10.94; found: C 71.48, H 10.98.
2-Isopropyl-1,2,3,4,5,6-hexahydropentalen-2-ol (10a): Reaction of 1a
(254mg, 1 mmol) with tBuLi (2.67 mL, 4mmol) and TMEDA (0.6 mL,
4mmol) was followed by addition of ethyl isobutyrate (116 mg, 1 mmol).
Work-up as above yielded 10a (120 mg, 72%) as a colorless oil. Rf =0.27
(hexane/AcOEt, 10:1); 1H NMR (400 MHz, CDCl3): d=2.40 (d, J=
15.2 Hz, 2H), 2.29–2.14(m, 6H), 2.10 (d, J=15.2 Hz, 2H), 1.81 (sept, J=
6.8 Hz, 1H), 1.61 (brs, 1H), 0.95 ppm (d, J=6.8 Hz, 6H); 13C NMR
(100.6 MHz, CDCl3): d=142.9, 90.5, 43.1, 37.3, 29.6, 27.3, 17.3 ppm;
LRMS (70 eV, EI): m/z (%): 166 (28) [M]+, 71 (100); HRMS (EI): m/z:
calcd for C11H18O: 166.1358; found: 166.1361.
2,2-Diphenyl-1,2,3,4,5,6-hexahydro-2-silapentalene (8a): Compound 1a
(254mg, 1 mmol) was treated with tBuLi (2.67 mL, 4mmol) and
TMEDA (0.6 mL, 4mmol). Addition of dichlorodiphenylsilane (253 mg,
1 mmol) and work-up as above yielded 8a (221 mg, 80%) as a white
1
solid. M.p. 81–838C; H NMR (400 MHz, CDCl3): d=7.64–7.59 (m, 4H),
7.47–7.38 (m, 6H), 2.33 (t, J=7.2 Hz, 4H), 2.10 (qt, J=7.2 Hz, 2H),
1.77 ppm (s, 4H); 13C NMR (100.6 MHz, CDCl3): d=141.9, 136.6, 134.5,
129.3, 127.8, 34.4, 24.9, 15.5 ppm; LRMS (70 eV, EI): m/z (%): 276 (31)
[M]+, 183 (100); HRMS (EI): m/z calcd for C19H2Si: 276.1334; found:
276.1324.
5-(tert-Butyldimethylsilyloxymethyl)-2-isopropyl-1,2,3,4,5,6-hexahydro-
pentalen-2-ol (10b): Reaction of diene 1b (398 mg, 1 mmol) with tBuLi
(2.67 mL, 4mmol) and TMEDA (0.6 mL, 4mmol) was followed by addi-
tion of ethyl isobutyrate (116 mg, 1 mmol). Work-up as above yielded
10b as a 1:1 mixture of diastereoisomers 10b1 and 10b2 (162 mg, 52%
combined yield for the two diastereoisomers).
General procedure for the preparation of carbonyl derivatives9 : The sus-
pension of the corresponding dianion 5, generated by reaction of the cor-
responding starting diene 1 (1 mmol) with tBuLi (2.67 mL, 4mmol) and
TMEDA (0.6 mL, 4mmol) as described above, was treated with ethyl
isobutyrate (1 mmol) at À788C. The mixture was stirred for 1 h at this
temperature. It was then quenched with MeOH and extracted with
EtOAc (3”10 mL). The combined organic layers were dried over anhy-
drous Na2SO4. The solvent was removed under vacuum and the resulting
residue was purified by flash column chromatography (silica gel, hexane/
EtOAc, 25:1) to yield the monocyclic ketones 9.
10b1: Colorless oil. Rf =0.23 (hexane/EtOAc, 10:1); 1H NMR (400 MHz,
CDCl3): d=3.55 (d, J=7.2 Hz, 2H), 2.86–2.74(m, 1H), 2.54–2.34(m,
2H), 2.31–2.20 (m, 2H), 2.11–1.93 (m, 4H), 1.79 (sept, J=6.8 Hz, 1H),
1.63 (brs, 1H), 0.93 (d, J=6.8 Hz, 6H), 0.88 (s, 9H), 0.04ppm (s, 6H);
13C NMR (100.6 MHz, CDCl3): d=141.5, 90.1, 67.5, 44.6, 43.2, 37.3, 32.8,
25.9, 18.3, 17.3, À5.3 ppm; LRMS (70 eV, EI): m/z (%): 292 (8)
[MÀH2O]+, 161 (100).
1-Methyl-2-(3-methyl-2-oxobutyl)cyclopentene (9a): Diene 1a (254mg,
1 mmol) was treated with tBuLi (2.67 mL, 4mmol) and TMEDA
(0.6 mL, 4mmol). Addition of ethyl isobutyrate (116 mg, 1 mmol) fol-
lowed by work-up as above gave 9a (111 mg, 67%) as a colorless oil.
Rf =0.32 (hexane/EtOAc, 20:1); 1H NMR (400 MHz, CDCl3): d=3.15 (s,
2H), 2.62 (sept, J=7.0 Hz, 1H), 2.32–2.20 (m, 4H), 1.75 (qt, J=7.5 Hz,
2H), 1.62 (s, 3H), 1.04ppm (d, J=7.0 Hz, 6H); 13C NMR (100.6 MHz,
CDCl3): d=212.8, 135.4, 128.1, 41.0, 39.8, 38.2, 36.4, 21.5, 18.2, 14.0 ppm;
LRMS (70 eV, EI): m/z (%): 166 (48) [M]+, 71 (100); HRMS (EI): m/z:
calcd for C11H18O: 166.1358; found: 166.1352; elemental analysis calcd
(%) for C11H18O (166.3): C 79.46, H 10.91; found: C 79.30, H 10.92.
10b2: Colorless oil. Rf =0.16 (hexane/EtOAc, 10:1); 1H NMR (400 MHz,
CDCl3): d=3.54(d, J=7.2 Hz, 2H), 2.89–2.78 (m, 1H), 2.43–2.27 (m,
4H), 2.17–2.03 (m, 2H), 1.96–1.85 (m, 2H), 1.80 (sept, J=6.9 Hz, 1H),
1.62 (brs, 1H), 0.94(d, J=6.9 Hz, 6H), 0.88 (s, 9H), 0.04ppm (s, 6H);
13C NMR (100.6 MHz, CDCl3): d=141.6, 90.1, 67.3, 44.7, 43.2, 37.3, 32.9,
25.9, 18.3, 17.3, À5.3 ppm; LRMS (70 eV, EI): m/z (%): 310 (1) [M]+,107
(100); HRMS (EI): m/z: calcd for C18H34O2Si: 310.2328; found: 310.2317.
5,5-Bis(tert-butyldimethylsilyloxymethyl)-2-isopropyl-1,2,3,4,5,6-hexahy-
dropentalen-2-ol (10c): Compound 1d (543 mg, 1 mmol) was treated
with tBuLi (2.67 mL, 4mmol) and TMEDA (0.6 mL, 4mmol). Addition
5006
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ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 4998 – 5008

Intramolecular Carbolithiation
FULL PAPER
of ethyl isobutyrate (116 mg, 1 mmol) and work-up as above afforded
10c (227 mg, 50%) as a colorless oil. Rf =0.16 (hexane/EtOAc, 25:1);
1H NMR (400 MHz, CDCl3): d=3.52 (s, 2H), 3.48 (s, 2H), 2.42–2.33 (m,
2H), 2.11–1.88 (m, 6H), 1.79 (sept, J=6.7 Hz, 1H), 1.64(brs, 1H), 0.93
(d, J=6.7 Hz, 6H), 0.88 (s, 9H), 0.87 (s, 9H), 0.03 (s, 6H), 0.02 ppm (s,
6H); 13C NMR (50.3 MHz, CDCl3): d=140.6, 89.9, 65.9, 54.7, 43.4, 37.3,
35.8, 25.8, 18.2, 17.3, À5.5 ppm; LRMS (70 eV, EI): m/z (%): 397 (2)
[MÀtBu]+, 159 (100); HRMS (EI): m/z: calcd for C21H41O3Si2 [MÀtBu]+:
397.2594; found: 397.2582.
1H), 4.77 (s, 1H), 2.37–2.23 (m, 3H), 1.86–1.80 (m, 1H), 1.73–1.62 (m,
1H), 1.45–1.40 (m, 1H), 1.22 (dd, J=14.8, 3.6 Hz, 1H) 1.16–1.03 (m,
1H),0.72 (dd, J=14.8, 11.2 Hz, 1H), 0.30 ppm (s, 6H); 13C NMR
(100.6 MHz, CDCl3): d=138.7, 133.5, 128.8, 127.7, 126.0, 103.5, 40.3, 35.3,
32.2, 23.9, 20.7, À2.0, À2.3 ppm.
Comparative study of the intramolecular carbolithiation of 2,6-dilithio-
1,6-heptadiene 3a and 2-lithio-1,6-heptadiene 14: A solution of dibromo-
diene 1a (254mg, 1 mmol) in dry Et 2O (10 mL) was treated with 4equiv
of tBuLi (2.67 mL, 4mmol) at À788C under nitrogen. The reaction mix-
ture was stirred for 30 min at this temperature. Depending on the experi-
ment, at this point TMEDA (0.60 mL, 4mmol) was added at À788C and
the resulting mixture was stirred for a further 15 min at low temperature.
The cooling bath was removed to allow the reaction to reach 08C. The
mixture was stirred for another 30 min if TMEDA had been added or it
was stirred for 150 min if TMEDA had not been added (see Scheme 3).
Acknowledgement
We are grateful for financial support received from Junta de Castilla y
León (BU012A06) and Ministerio de Educación y Ciencia (MEC) and
FEDER (CTQ2004-08077-C02-02/BQU and CTQ2004-03134). J.M.I.
thanks Junta de Castilla y León for a predoctoral fellowship.
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The mixture was cooled to À788C, and chloro
ACHTRE(UNG dimethyl)phenylsilane
(376 mg, 2.2 mmol) was added to the solution. The cooling bath was re-
moved to allow the mixture to reach room temperature. The mixture was
quenched with water and extracted with EtOAc (3”10 mL). The com-
bined organic layers were dried over anhydrous Na2SO4 and the solvents
were removed under vacuum. The resulting residue was purified by
column chromatography (silica gel, hexane) to afford a mixture (see
Scheme 3) of products 11 and 12 281 mg (77%) in the experiment with
TMEDA and 303 mg (83%) without TMEDA.
2,6-Bis(dimethylphenylsilyl)-1,6-heptadiene (11):[26] Colorless oil. Rf =
0.28 (hexane); 1H NMR (400 MHz, CDCl3): d=7.53–7.48 (m, 4H), 7.40–
7.33 (m, 6H), 5.64–5.60 (m, 2H), 5.40–5.37 (m, 2H), 2.10–2.04 (m, 4H),
1.48–1.39 (m, 2H), 0.35 ppm (s, 12H); 13C NMR (100.6 MHz, CDCl3):
d=150.1, 138.3, 133.8, 128.8, 127.6, 125.7, 35.7, 28.1, À3.0 ppm; LRMS
(70 eV, EI): m/z (%): 364(1) [ M]+, 135 (100); elemental analysis calcd
(%) for C23H32Si2 (364.7): C 75.75, H 8.84; found: C 75.54, H 8.87.
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1,2-Bis(dimethylphenylsilylmethyl)cyclopentene (12):[26] Colorless oil.
Rf =0.32 (hexane); 1H NMR (400 MHz, CDCl3): d=7.51–7.47 (m, 6H),
7.36–7.31 (m, 6H), 2.09 (t, J=7.4Hz, 4H), 1.65–1.57 (m, 6H), 0.25 ppm
(s, 12H); 13C NMR (100.6 MHz, CDCl3): d=140.0, 133.4, 129.7, 128.7,
127.6, 38.2, 22.3, 18.3, À2.2 ppm; LRMS (70 eV, EI): m/z (%): 364(18)
[M]+, 135 (100); HRMS (EI): m/z: calcd for C23H32Si2: 364.2043; found:
364.2056.
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379.
Parallel to this, a solution of bromodiene 13 (175 mg, 1 mmol) in dry
Et2O (10 mL) was treated with two equivalents of tBuLi (1.33 mL,
2 mmol) at À788C under nitrogen. The reaction mixture was stirred for
30 min at this temperature. Depending on the experiment, at this point
TMEDA (0.30 mL, 2 mmol) was added at À788C and the resulting mix-
ture was stirred for another 15 min at low temperature. The cooling bath
was removed to allow the mixture to reach 08C. Stirring was continued
for 30 min if TMEDA had been added or for 150 min if TMEDA had not
been added (see Scheme 3). The mixture was cooled to À788C, and
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chloroACHTREUNG(dimethyl)phenylsilane (188 mg, 1.1 mmol) was added to the solu-
tion. The cooling bath was removed to allow the mixture to reach room
temperature. The mixture was quenched with water and extracted with
EtOAc (3”10 mL). The combined organic layers were dried over anhy-
drous Na2SO4, and the solvents were removed under vacuum. The result-
ing residue was purified by column chromatography (silica gel, hexane)
to afford 171 mg (74%, with TMEDA) or 180 mg (78%, without
TMEDA) as a mixture (see Scheme 3) of products 16 and 17 as a color-
less oil, Rf =0.39 (hexane).
2-Dimethylphenylsilyl-1,6-heptadiene (16): 1H NMR (400 MHz, CDCl3):
d=7.59–7.48 (m, 2H), 7.36–7.24 (m, 3H), 5.78–5.65 (m, 2H), 5.43–5.36
(m, 1H), 4.98–4.85 (m, 2H), 2.14 (t, J=7.6 Hz, 2H), 2.02–1.97 (m, 2H),
1.43 (qt, J=7.6 Hz, 2H) 0.39 ppm (s, 6H); 13C NMR (100.6 MHz,
CDCl3): d=159.5, 150.1, 138.4, 133.9, 128.9, 127.7, 125.9, 114.4, 35.4, 33.3,
28.1, À2.9 ppm.
1-Dimethylphenylsilylmethyl-2-methylenecyclopentane (17): 1H NMR
(400 MHz, CDCl3): d=7.59–7.48 (m, 2H), 7.36–7.24 (m, 3H), 4.82 (s,
Chem. Eur. J. 2007, 13, 4998 – 5008
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5007

J. Barluenga et al.
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thus higher than the ratio of the cyclized product from the carboli-
thiation of a lithiated double bond.
[21] The cyclization of both 3a and 14 starts at much lower temperature
in the presence of TMEDA than in its absence. At about À208C, a
3.2:1 ratio of 11:12 was obtained from 3a and a 4.4:1 ratio of 16:17
was obtained from 14. This tendency was maintained when both
cyclizations were performed at
a slightly higher temperature
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(ꢀÀ108C): 1:1 ratio for 11:12 and 2.5:1 for 16:17.
[22] Gaussian98, versionA.7, Gaussian Inc., Pittsburgh, PA, 1998.
[23] Also, at T=11–168C and t=60 min (see ref. [20]), the ratio of the
cyclized product from 14 is higher than the ratio of the cyclized
product from 3a.
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11–168C for 60 min, a 17:1 mixture of compounds 11 and 12 and a
5:1 mixture of compounds 16 and 17 were obtained after treatment
of the corresponding mixtures of dianions 3a and 5a and monoan-
ions 14 and 15 with chlorodimethylphenylsilane. The ratio of the cy-
clized product from the carbolithiation of an isolated double bond is
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[26] Compounds 11 and 12 were prepared independently according to
the procedure to prepare compounds 4 and 7, respectively.
Received: December 12, 2006
Published online: March 20, 2007
5008
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ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 4998 – 5008