Chemoselective lithiation of 1-Bromo-n-chloroalkanes

Article abstract of DOI:10.1002/ejoc.200500407

Reactions between different 1-bromo-n-chloroalkanes (1-3), lithium/naphthalene (1:2 molar ratio) and a carbonyl compound R ¹R²CO in THF at -78°C provide, after hydrolysis with water, the corresponding chlorinated alcohols 4 through s

Full text of DOI:10.1002/ejoc.200500407

FULL PAPER
DOI: 10.1002/ejoc.200500407
Chemoselective Lithiation of 1-Bromo-n-chloroalkanes
[a]
[a]
[a]
Francisco Foubelo,* Abdeslam Abou, and Miguel Yus
Dedicated to the memory of Professor Julio Rodríguez
Keywords: Selective lithiation / Diols / Chlorohydrins / Electrophilic substitution / 1-Bromo-n-chloroalkanes
Reactions between different 1-bromo-n-chloroalkanes (1–3),
ture before the hydrolysis, lithiation of the remaining carbon–
chlorine bond takes place. The addition of a second carbonyl
compound R R CO, followed by hydrolysis, affords the corre-
sponding diols 7.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
lithium/naphthalene (1:2 molar ratio) and a carbonyl com-
1
2
3 4
pound R R CO in THF at –78 °C provide, after hydrolysis
with water, the corresponding chlorinated alcohols 4 through
selective lithiation of the carbon–bromine bond. When an ex-
cess of lithium (1:7 molar ratio) is added to the reaction mix-
Introduction
this methodology. In the case of the corresponding bromo
compounds, tBuLi (as well as other organolithium com-
pounds) is not effective for performing the desired bro-
mine–lithium exchange with simple 1-bromo-n-chloroal-
kanes at low temperature. The selective metallation of 1-
Organolithium compounds are probably the most useful
carbanionic intermediates in synthetic organic chemistry,
due to their high reactivities even under mild reaction con-
[
1]
ditions. One special type of organolithium compounds in-
cludes species in which – as well as the carbon–lithium
bond – some further functional group is present in the
molecule: these functionalized organolithium compounds
are of interest because the functionality is transferred to the
electrophilic reagent in their reaction with an electrophile,
so polyfunctionalized molecules are accessible in only one
synthetic operation.[2] One such functionality not particu-
larly compatible with the presence of a carbon–lithium
bond, especially in aliphatic molecules, is a halogen (chlo-
rine, bromine or iodine).[ Two problems are inherent in the
existence of these halogenated organolithium compounds:
namely, (1) it is difficult to generate carbon–lithium bonds
in the presence of a halogen in the same molecule, because
the other carbon–halogen bond can obviously be lithiated
too, and (2) the elimination of lithium halide from the ini-
tially generated halogenated organolithium intermediate,
especially in intramolecular fashion, would self-destroy it,
giving a new, undesirable carbon–carbon bond. The litera-
ture offers a few examples of selective monolithiation of n-
chloro-1-iodoalkanes by use of tBuLi in diethyl ether as the
[6]
bromo-n-chloroalkanes 1–3 with magnesium in diethyl
ether to give the corresponding chloroalkylmagnesium bro-
mides is known, but no methodologies for the selective lithi-
ation of 1-bromo-n-chloroalkanes 1–3 have yet been re-
ported.
In this paper we describe the chemoselective lithiation of
a carbon–bromine bond in the presence of a carbon–chlo-
rine one by use of an arene-promoted lithiation. Advantage
of the differences in reactivities is taken in two versions of
this reaction: the stoichiometric (with a lithium arene rea-
3]
[7]
gent ) and the catalytic version (with a substoichiometric
[8]
amount of the arene and an excess of lithium metal ).
Results and Discussion
We first studied the monolithiation of bromo chloro
[9]
compounds 1–3. Treatment of these starting materials
[7,10]
with lithium/naphthalene
in the presence of an excess
1
2
of a carbonyl compound [R R CO = tBuCHO, PhCHO,
Me CO, (n-C H ) CO, (CH ) CO, adamantanone] in THF
2
5
11 2
2 7
[
4]
lithiating reagent: 1-chloro-4-lithiobutane (I, n = 2) and
at –78 °C yielded, after hydrolysis with water at tempera-
tures ranging between –78 °C and room temperature, the
corresponding chlorinated alcohols 4 in moderate yields
-chloro-6-lithiohexane (I, n = 4)[ have been prepared by
5]
1
[
a] Departamento de Química Orgánica, Facultad de Ciencias and
Instituto de Síntesis Orgánica (ISO), Universidad de Alicante,
Apdo. 99, 03080 Alicante, Spain
(Scheme 1 and Table 1).
To provide compounds 4, the reaction shown in
Fax: +34-965-903549
Scheme 1 has to be performed under the indicated reaction
conditions. Most importantly, the only way to discriminate
between the two carbon–halogen bonds to be lithiated is
E-mail: foubelo@ua.es
URL: http://www.ua.es/dept.quimorg/index.html
http://www.ua.es/instituto/iso/index.htm
Eur. J. Org. Chem. 2005, 5089–5093
© 2005 Wiley-VCH Verlag GmbH & Co. KgaA, Weinheim
5089

F. Foubelo, A. Abou, M. Yus
FULL PAPER
Figure 1. Structures of compounds 4f, 4j, 5 and 6.
Scheme 1.
through the use of two equivalents of lithium/naphthalene,
because with the most active catalytic version of the reac-
tion both the bromine–carbon and the chlorine–carbon
bonds are cleaved. Thus, under the reaction conditions
shown in Scheme 1, but with use of excess lithium and a
catalytic amount of naphthalene (ca. 5 mol%) a mixture of
compound 4 and the corresponding diol 5 (Figure 1) was
obtained. On the other hand, the initially formed intermedi-
ate I is a very unstable species, which decomposes very eas-
ily even at low temperatures, probably through lithium chlo-
ride intramolecular elimination to give the corresponding
Scheme 2.
carbocycle 6 (Figure 1) or through intermolecular reac- ined the introduction of two different electrophiles in a one-
tions: these are the processes that occurred when the lithi- pot reaction. Thus, when compounds 1–3 were treated un-
ation was carried out in the absence of the electrophile der the same reaction conditions as shown in Scheme 1, but
(
Grignard conditions), so the two-step reaction (tandem with use of a slightly smaller amount of the first electro-
1
2
lithiation/reaction with the electrophile) never gave products phile [R R CO = tBuCHO, PhCHO; 1:0.95 molar ratio],
. Even in the presence of the electrophile (Barbier condi- the corresponding alkoxide II (precursor of the product 4
4
[
11]
tions ) such elimination takes place to some extent, this by hydrolysis) was again lithiated by addition of an excess
probably being one of the reasons for the moderate yields of lithium powder (1:7 molar ratio) to the reaction mixture.
generally obtained (Table 1), along with the possible forma- By this approach, the naphthalene-catalysed lithiation con-
[
8,13,14]
tion of a cyclic ether from the alkoxide II (Scheme 2), the ditions
produced a new organolithium intermediate
scale of the processes (1 mmol)[ and the difficulty of chro- III at temperatures between –78 and –50 °C. Subsequent
12]
3
4
matographic purification of chlorohydrins 4.
addition of a second carbonyl compound [R R CO =
Another control reaction, demonstrating the impossi- (CH ) CO, (CH ) CO] at –78 °C first gave dialkoxide IV
2
4
2 5
bility of discriminating between the same halogens, was car- and, after final hydrolysis with water at temperatures rang-
ried out with the use of 1,6-dibromohexane as starting ma- ing between –78 °C and room temperature, the differently
terial: in this case, both the stoichiometric and the catalytic substituted diols 7 (Scheme 2 and Table 2).
versions of the arene-promoted lithiation (benzaldehyde,
It is worth noting that the yields of compounds 7 were
Barbier conditions, THF, –78 °C) gave compound 5 with even higher than those of compounds 4, which is probably
1
2
R = H, R = Ph in 40–60% yields and as a ca. 1:1 mixture due to the chromatographic purification of the latter com-
of diastereomers. In the second part of this study we exam- pounds in the isolation process (see above).
Table 1. Preparation of compounds 4.
Entry
Starting
material
Electrophile
Product[a]
R1
No.
n
R2
Ph
Yield (%)[b]
1
2
3
4
5
6
7
8
9
1
1
1
2
2
2
3
3
3
3
PhCHO
4a
4b
4c
4d
4e
4f
2
2
2
3
3
3
4
4
4
4
H
33
24
27
37
39
41
48
37
42
51
(n-C
5
H
11
)
2
CO
n-C
5
H
11
n-C
5
H
11
(CH
2
)
7
CO
(CH
2
)
7
4
tBuCHO
PhCHO
adamantanone
tBuCHO
H
H
tBu
Ph
–[c]
4g
4h
4i
H
Me
tBu
Me
Me
(CH
adamantanone
2
CO
2
)
4
CO
(CH
2
)
[c]
10
4j
–
1
[
[
a] All products 4 were Ն95% pure (GLC and/or 300 MHz H NMR) and were fully characterised spectroscopically and spectrometrically
1 13
IR, H and C NMR, MS (LR and HR)]. [b] Isolated yield after column chromatography (silica gel, hexane/ethyl acetate) based on the
starting materials 1–3. [c] For structures 4f and 4j see Figure 1.
5090
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2005, 5089–5093

Chemoselective Lithiation of 1-Bromo-n-chloroalkanes
Table 2. Preparation of compounds 7.
FULL PAPER
Entry
Starting
material
First
Second
Product[a]
R2
electrophile
electrophile
No.
n
R1
R -R
3
4
Yield (%)[b]
1
2
3
4
5
6
1
1
2
2
3
3
tBuCHO
PhCHO
tBuCHO
PhCHO
tBuCHO
PhCHO
(CH
(CH
(CH
(CH
(CH
(CH
2
2
2
2
2
2
)
5
)
5
)
5
)
4
)
5
)
5
CO
CO
CO
CO
CO
CO
7a
7b
7c
7d
7e
7f
2
2
3
3
4
4
H
H
H
H
H
H
tBu
Ph
tBu
Ph
tBu
Ph
(CH
(CH
(CH
(CH
(CH
(CH
2
2
2
2
2
2
)
5
5
5
4
5
5
45
35
43
38
41
64
)
)
)
)
)
1
[
[
a] All products 4 were Ն95% pure (GLC and/or 300 MHz H NMR) and were fully characterised spectroscopically and spectrometrically
1 13
IR, H and C NMR, MS (LR and HR)]. [b] Isolated yield after column chromatography (silica gel, hexane/ethyl acetate) based on the
1
2
first electrophile (R R CO).
water (5 mL), and the system was allowed to reach room tempera-
ture. The reaction mixture was extracted with ethyl acetate
Conclusions
In conclusion, in this paper we report discrimination be- (2×20 mL), dried with anhydrous sodium sulfate and evaporated
tween bromine and chlorine in the lithiation of aliphatic (15 Torr). The resulting residue was purified by column chromatog-
bromo chloro compounds for the first time, thus making raphy (silica gel, hexane/ethyl acetate, 40:1) to yield pure products
4
. Yields are given in Table 1; spectroscopic data and literature ref-
possible either the monolithiation (by cleavage only of the
carbon–bromine bond) and the introduction of only one
erences follow.
electrophile or, more interestingly, the one-pot tandem in- 5-Chloro-1-phenylpentan-1-ol (4a):[ R = 0.28 (silica gel; hexane/
15]
f
1
troduction of two electrophilic fragments in the molecule ethyl acetate, 5:1). H NMR (300 MHz, CDCl
3
, 25 °C): δ = 1.27–
1
.76 (m, 6 H), 1.88 (brs, 1 H), 3.42 (t, J = 6.7 Hz, 2 H), 4.57 (dd,
through careful choice of lithiation conditions: at –78 °C
the use of lithium/naphthalene (stoichiometric conditions)
allowed selective lithiation of the carbon–bromine bond, so
that, after treatment of the corresponding chlorinated
organolithium intermediate with a carbonyl compound, a
second lithiation by use of an excess of lithium (catalytic
conditions) allowed a secondary metallation of the remain-
ing carbon–chlorine bond, so that a second carbonyl com-
pound could be used as electrophile. It is remarkable that
1
3
J = 7.4, 5.8 Hz, 1 H), 7.20–7.27 (m, 5 H) ppm. C NMR (75 MHz,
CDCl , 25 °C): δ = 23.2, 32.4, 38.1, 44.8, 74.3, 125.8, 127.6, 128.4,
44.5 ppm. IR (film): ν˜ = 3550–3245, 3060, 3033 cm . MS (EI):
3
–
1
1
+
m/z (%) = 198 [M] (3), 107 (100), 79 (49), 77 (23).
-(4-Chlorobutyl)undecan-6-ol (4b): R = 0.47 (silica gel; hexane/
ethyl acetate, 5:1). H NMR (300 MHz, CDCl , 25 °C): δ = 0.89 (t,
J = 6.9 Hz, 6 H), 1.23–1.35 (m, 14 H), 1.39–1.45 (m, 9 H), 3.55 (t,
6
f
1
3
1
3
J = 6.7 Hz, 2 H) ppm. C NMR (75 MHz, CDCl
1
3
, 25 °C): δ =
4.0, 20.8, 22.6, 23.1, 32.4, 33.0, 38.3, 39.1, 44.9, 74.3 ppm. IR
the tandem double lithiation–S reaction worked with bet-
–1
+
E
(
film): ν˜ = 3610–3320 cm . MS (EI): m/z (%) = 244 [M – H
2
O]
ter yields (from the point of view of isolated yields) than
(
1), 193 (27), 191 (80), 83 (22), 71 (23), 69 (37), 57 (27), 55 (89), 43
the monolithiation–SE reaction to give the corresponding (100), 41 (74). HMRS (EI): calcd. for C H Cl 244.1958; found
15
29
chloro alcohols.
244.1956.
1
-(4-Chlorobutyl)cyclooctanol (4c): R
f
= 0.31 (silica gel; hexane/
1
ethyl acetate, 5:1). H NMR (300 MHz, CDCl , 25 °C): δ = 1.32–
3
13
Experimental Section
1
.80 (m, 23 H), 3.55 (t, J = 6.7 Hz, 2 H) ppm. C NMR (75 MHz,
CDCl , 25 °C): δ = 20.5, 22.3, 24.9, 28.2, 33.1, 36.2, 40.5, 45.0,
4.7 ppm. IR (film): ν˜ = 3590–3295 cm . MS (EI): m/z (%) = 200
3
General Methods: All reactions were carried out under nitrogen
in oven-dried glassware. All reagents were commercially available
–
1
7
+
[M – H
2
O] (4), 127 (46), 81 (27), 67 (43), 57 (26), 55 (100), 43
23ClO 218.1437; found
(Acros, Aldrich) and were used without further purification. Com-
(
34), 41 (69). HMRS (EI): calcd. for C12
H
mercially available anhydrous THF (99.9%, water content
Յ0.006%, 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,
2
18.1416.
8-Chloro-2,2-dimethyloctan-3-ol (4d): R
f
= 0.44 (silica gel; hexane/
ethyl acetate, 5:1). H NMR (300 MHz, CDCl , 25 °C): δ = 0.89
(s, 9 H), 1.25–1.59 (m, 6 H), 1.79 (quintet, J = 6.9 Hz, 2 H), 3.15–
1
3
3
in CDCl as solvent. LRMS and HRMS were measured with Shim-
1
3
adzu GC/HS QP-5000 and Finnigan MAT95 S spectrometers,
respectively. The purities of volatile products and the chromato-
graphic analyses (GLC) were determined with a flame ionisation
detector and a 12-m capillary column (0.2 mm diam., 0.33 µm film
3.19 (m, 1 H), 3.54 (t, J = 6.7 Hz, 2 H) ppm. C NMR (75 MHz,
CDCl , 25 °C): δ = 25.2, 25.9, 26.5, 30.8, 32.1, 34.4, 44.6, 79.4 ppm.
IR (film): ν˜ = 3580–3275 cm . MS (EI): m/z (%) = 135 [M – tBu]
(38), 117 (26), 87 (34), 81 (65), 57 (86), 55 (57), 43 (57), 41 (100).
3
–
1
+
–1
thickness), with nitrogen (2 mLmin ) as carrier gas, Tinjector
=
HMRS (EI): calcd. for C10
H
19Cl 174.1175; found 174.1157.
2
75 °C, Tdetector = 300 °C, Tcolumn = 60 °C (3 min) and 60–270 °C
[16]
6
-Chloro-1-phenylhexan-1-ol (4e):
R
f
= 0.34 (silica gel; hexane/
, 25 °C): δ = 1.25–
1.47 (m, 4 H), 1.67–1.78 (m, 4 H), 2.12 (brs, 1 H), 3.49 (t, J =
naphthalene (0.7 , 3.0 mL, 2.1 mmol) was added dropwise at 6.7 Hz, 2 H), 4.63 (dd, J = 7.2, 5.9 Hz, 1 H), 7.23–7.34 (m, 5
–1
(15 °Cmin ), P = 40 kPa.
1
ethyl acetate, 5:1). H NMR (300 MHz, CDCl
3
General Procedure for Compounds 4: A THF solution of lithium/
1
3
–78 °C over 45 min to a stirred THF solution (3 mL) of the corre-
H) ppm. C NMR (75 MHz, CDCl
3
, 25 °C): δ = 25.0, 26.7, 32.4,
sponding 1-bromo-n-chloroalkane 1–3 (1.0 mmol) and a carbonyl
compound (R R CO, 1.5 mmol). Stirring was continued for 10 ad-
ditional min, the reaction mixture was carefully hydrolysed with
38.7, 44.9, 74.4, 125.8, 127.5, 128.4, 144.6 ppm. IR (film): ν˜ =
3570–3285, 3060, 3035 cm . MS (EI): m/z (%) = 212 [M] (2), 107
(100), 79 (42), 77 (18).
1
2
–1
+
Eur. J. Org. Chem. 2005, 5089–5093
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5091

F. Foubelo, A. Abou, M. Yus
FULL PAPER
2
-(5-Chloropentyl)adamantan-2-ol (4f): R
f
= 0.49 (silica gel; hexane/
(2), 41 (100). HMRS (EI): calcd. for C11
H28O 224.2140; found
1
ethyl acetate, 5:1). H NMR (300 MHz, CDCl , 25 °C): δ = 1.39– 224.2154.
3
1
2
2
=
.80 (m, 21 H), 2.13 (brs, 1 H), 2.17 (brs, 1 H), 3.54 (t, J = 6.7 Hz,
[18]
1
-(5-Hydroxy-5-phenylpentyl)cyclohexanol (7b):
R
f
= 0.25 (silica
, 25 °C):
δ = 1.21–1.82 (m, 18 H), 2.23 (brs, 2 H), 4.62 (dd, J = 7.3, 5.5 Hz,
H) ppm. 13C NMR (75 MHz, CDCl
, 25 °C): δ = 21.3, 27.2, 27.3,
3
1
gel; hexane/ethyl acetate, 2:1). H NMR (300 MHz, CDCl
3
7.5, 32.6, 32.8, 34.5, 36.8, 38.0, 38.2, 45.0, 74.9 ppm. IR (film): ν˜
–1
+
3555–3260 cm . MS (EI): m/z (%) = 238 [M – H
2
O] (2), 151
13
1
H), 7.23–7.33 (m, 5 H) ppm. C NMR (75 MHz, CDCl
3
, 25 °C):
(100), 55 (16), 41 (30) ppm. HMRS (EI): calcd. for C15H23Cl
δ = 22.1, 22.6, 25.7, 26.3, 37.2, 37.3, 38.95, 71.4, 74.3, 125.8, 127.3,
238.1488; found 238.1475.
–1
1
28.3, 144.9 ppm. IR (film): ν˜ = 3520–3100 cm . MS (EI): m/z (%)
+
9-Chloro-2,2-dimethylnonan-3-ol (4g): R
f
= 0.47 (silica gel; hexane/ = 244 [M – H
2 24
O] (3), 180 (100). HMRS (EI): calcd. for C17H O
1
ethyl acetate, 5:1). H NMR (300 MHz, CDCl
3
, 25 °C): δ = 0.88 244.1827; found 244.1831.
(
s, 9 H), 1.25–1.53 (m, 8 H), 1.67 (brs, 1 H), 1.77 (quintet, J =
1
-(6-Hydroxy-7,7-dimethyloctyl)cyclohexanol (7c): R
f
= 0.34 (silica
gel; hexane/ethyl acetate, 2:1). H NMR (300 MHz, CDCl , 25 °C):
δ = 0.89 (s, 9 H), 1.23–1.57 (m, 22 H), 3.15–3.20 (m, 1 H) ppm.
7
.5 Hz, 2 H), 3.14–3.19 (m, 1 H), 3.53 (t, J = 6.7 Hz, 2 H) ppm.
1
3
1
3
C NMR (75 MHz, CDCl
3
, 25 °C): δ = 25.2, 26.3, 26.4, 28.4, 30.8,
–1
3
2.1, 34.4, 44.6, 79.4 ppm. IR (film): ν˜ = 3565–3280 cm . MS (EI):
13
C NMR (75 MHz, CDCl
3
, 25 °C): δ = 22.2, 22.8, 25.7, 25.8, 27.1,
+
m/z (%) = 188 [M – H
5
1
2
O] (1), 149 (23), 95 (56), 87 (23), 69 (35),
3
0.3, 31.4, 34.9, 37.4, 42.3, 71.4, 79.9 ppm. MS (EI): m/z (%) = 238
7 (64), 43 (44), 41 (100) ppm. HMRS (EI): calcd. for C11
H21Cl
+
2
[M – H O] (3), 181 (22), 163 (78), 99 (100), 95 (57), 83 (41), 81
88.1332; found 188.1354.
–1
(
92), 67 (30), 55 (45) ppm. IR (film): ν˜ = 3615–3185 cm . HMRS
30O 238.2297; found 238.2303.
-Chloro-2-methyloctan-2-ol (4h):[
17]
R
f
= 0.23 (silica gel; hexane/
, 25 °C): δ = 1.14
8
(EI): calcd. for C16
H
1
ethyl acetate, 5:1). H NMR (300 MHz, CDCl
3
1
-(6-Hydroxy-6-phenylhexyl)cyclopentanol (7d): R = 0.20 (silica gel;
hexane/ethyl acetate, 2:1). H NMR (300 MHz, CDCl , 25 °C): δ
1.25–1.78 (m, 20 H), 4.63 (dd, J = 13.5, 7.4 Hz, 1 H), 7.22–7.34
f
(s, 6 H), 1.18–1.40 (m, 8 H), 1.71 (quintet, J = 6.9 Hz, 2 H), 1.94
1
3
13
(
brs, 1 H), 3.46 (t, J = 6.7 Hz, 2 H) ppm. C NMR (75 MHz,
=
CDCl
IR (film): ν˜ = 3595–3260 cm . MS (EI): m/z (%) = 163 [M – Me]
7), 59 (100), 43 (43), 41 (25).
3
, 25 °C): δ = 24.1, 26.8, 29.2, 29.7, 32.5, 43.7, 45.1, 71.0 ppm.
13
3
(m, 5 H) ppm. C NMR (75 MHz, CDCl , 25 °C): δ = 23.7, 24.5,
–1
+
2
1
5.6, 25.7, 39.0, 39.6, 41.3, 74.6, 82.6, 125.8, 127.4, 128.4,
(
–1
44.8 ppm. IR (film): ν˜ = 3535–3210 cm . MS (EI): m/z (%) = 244
+
[M – H
2
O] (3), 138 (59), 122 (55), 117 (30), 107 (100), 95 (31), 91
1
-(6-Chlorohexyl)cyclopentanol (4i): R
f
= 0.45 (silica gel; hexane/
1
(47), 79 (64), 77 (34), 67 (33) ppm. HMRS (EI): calcd. for C H O
244.1827; found 244.1824.
ethyl acetate, 5:1). H NMR (300 MHz, CDCl
1
3
, 25 °C): δ = 1.25–
17 24
.80 (m, 19 H), 3.53 (t, J = 6.7 Hz, 2 H) ppm. 13C NMR (75 MHz,
3
CDCl , 25 °C): δ = 23.7, 24.5, 26.8, 29.4, 32.5, 39.6, 41.3, 45.0,
1
-(7-Hydroxy-8,8-dimethylnonanyl)cyclohexanol (7e): R
f
= 0.42 (sil-
–1
8
2.4 ppm. IR (film): ν˜ = 3550–3265 cm . MS (EI): m/z (%) = 204
–1
ica gel; hexane/ethyl acetate, 2:1). IR (film): ν˜ = 3600–3215 cm .
+
[M] (0.5), 175 (18), 113 (18), 85 (100), 67 (20), 58 (17), 57 (16), 55
1
H NMR (300 MHz, CDCl
m, 24 H), 3.14–3.19 (m, 1 H) ppm. C NMR (75 MHz, CDCl
5 °C): δ = 22.2, 22.8, 25.6, 25.8, 27.0, 29.6, 30.2, 31.4, 34.8, 37.3,
3
, 25 °C): δ = 0.88 (s, 9 H), 1.21–1.65
(
21). HMRS (EI): calcd. for C11 21ClO 204.1281; found 204.1277.
H
13
(
2
3
,
2
-(6-Chlorohexyl)adamantan-2-ol (4j): R = 0.50 (silica gel; hexane/
ethyl acetate, 5:1). H NMR (300 MHz, CDCl , 25 °C): δ = 1.25–
.85 (m, 23 H), 2.14 (brs, 1 H), 2.18 (brs, 1 H), 3.53 (t, J = 6.7 Hz,
H) ppm. 13C NMR (75 MHz, CDCl
, 25 °C): δ = 21.8, 26.8, 27.1,
7.3, 29.4, 32.5, 32.8, 34.5, 36.8, 38.0, 38.2, 45.0, 74.8 ppm. IR
f
+
1
2
42.3, 71.4, 79.9 ppm. MS (EI): m/z (%) = 252 [M – H O] (2), 195
3
(
20), 177 (40), 135 (20), 121 (18), 109 (25), 99 (100), 95 (79), 81
1
2
2
(63), 69 (25), 57 (31), 55 (32) ppm. HMRS (EI): calcd. for C H O
17 32
3
252.2453; found 252.2461.
–1
+
(
(
2
film): ν˜ = 3570–3265 cm . MS (EI): m/z (%): 252 [M – H
0.5), 151 (100), 55 (20), 41 (30). HMRS (EI): calcd. for C16
52.1645; found 252.1639.
2
O]
25Cl hexane/ethyl acetate, 2:1).
= 1.18–1.79 (m, 22 H), 2.21 (brs, 2 H), 4.59 (dd, J = 13.1, 7.2 Hz,
1-(7-Hydroxy-7-phenylheptyl)cyclohexanol (7f): R = 0.29 (silica gel;
f
H
1
3
H NMR (300 MHz, CDCl , 25 °C): δ
1
3
1
H), 7.21–7.34 (m, 5 H) ppm. C NMR (75 MHz, CDCl
3
, 25 °C):
General Procedure for Compounds 7: A THF solution of lithium/
naphthalene (0.7 , 3.0 mL, 2.1 mmol) was added dropwise at
δ = 22.1, 22.6, 25.6, 25.7, 29.3, 29.9, 37.2, 38.95, 42.1, 71.5, 74.4,
1
3
25.8, 127.2, 128.2, 144.9 ppm. IR (film): ν˜ = 3545–3220, 3060,
035 cm . MS (EI): m/z (%) = 272 [M – H O] (2.5), 166 (21), 150
2
–78 °C over 45 min to a stirred THF (3 mL) solution of the corre-
–
1
+
sponding 1-bromo-n-chloroalkane 1–3 (1.0 mmol) and a carbonyl
1
2
(25), 130 (24), 129 (31), 117 (56), 115 (23), 107 (91), 104 (64), 99
compound (R R CO, 0.95 mmol). After 10 min, lithium metal
35 mg, 5.0 mmol) was added to the reaction mixture and stirring
was continued for 30 min at temperatures ranging from –78 to
50 °C. The system was then cooled down to –78 °C and a second
(
(
2
59), 94 (38), 91 (79), 81 (80), 79 (94), 77 (42), 67 (61), 55 (97), 43
52), 41 (100). HMRS (EI): calcd. for C19 28O 272.2140; found
72.2133.
(
H
–
3
4
carbonyl compound (R R CO, 1.4 mmol) was added. After 10 min,
the system was hydrolysed with water (5 mL) and allowed to reach
room temperature. The reaction mixture was extracted with ethyl
acetate (2×20 mL), dried over anhydrous sodium sulfate and evap-
orated (15 Torr). The resulting residue was purified by column
chromatography (silica gel, hexane/ethyl acetate, 5:1) to yield pure
products 7. Yields are given in Table 2; spectroscopic data and lit-
erature references follow.
Acknowledgments
This work was generously supported by the Dirección General de
Enseñanza Superior (DGES) of the Spanish Ministerio de Ciencia
y Tecnología (grant no. BQU2001–0538) and the Generalitat Va-
lenciana (grant no. GRUPOS03/135). A. A. thanks the University
of Alicante for financial support. We also thank MEDALCH-
EMY S. L. for a gift of chemicals, especially lithium powder.
18]
1
-(5-Hydroxy-6,6-dimethylheptyl)cyclohexanol (7a):[
f
R = 0.39
1
(silica gel; hexane/ethyl acetate, 2:1). H NMR (300 MHz, CDCl
3
,
2
4
2
5 °C): δ = 0.88 (s, 9 H), 1.27–1.64 (m, 20 H), 3.17 (dd, J = 9.7,
.2 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl
, 25 °C): δ = 22.2,
2.8, 25.7, 27.6, 31.4, 34.9, 37.2, 37.5, 42.3, 71.4, 79.8 ppm. IR
[
1] For general monographs, see: a) B. J. Wakefield, Organolithium
Methods; Academic Press, London, 1988; b) A.-M. Sapse, P.
von Ragué Schleyer (Eds.), Lithium Chemistry. A Theoretical
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3
–1
+
(film): ν˜ = 3620–3160 cm . MS (EI): m/z (%) = 224 [M – H
2
O]
5092
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2005, 5089–5093

Chemoselective Lithiation of 1-Bromo-n-chloroalkanes
FULL PAPER
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Published Online: October 12, 2005
Eur. J. Org. Chem. 2005, 5089–5093
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5093