Arene-promoted lithiation of 1,n-dihaloalkanes (n=2-6): a comparative study

Article abstract of DOI:10.1016/j.tet.2006.08.064

The reaction of 1,n-dichloroalkanes 3a (n=2-6) with an excess of lithium powder and a catalytic amount of 4,4′-di-tert-butylbiphenyl (DTBB; 2.5 mol %) in the presence of different carbonyl compounds [Bu^tCHO, PhCHO, Et₂CO, (CH₂

Full text of DOI:10.1016/j.tet.2006.08.064

Tetrahedron 62 (2006) 10417–10424
Arene-promoted lithiation of 1,n-dihaloalkanes (n¼2–6):
a comparative study
*
Abdeslam Abou, Francisco Foubelo and Miguel Yus
´
Departamento de Quımica Organica, Facultad de Ciencias, and Instituto de Sıntesis Organica (ISO), Universidad de Alicante,
ꢀ
´
ꢀ
Apdo. 99, 03080 Alicante, Spain
Received 21 March 2006; revised 7 August 2006; accepted 18 August 2006
Available online 11 September 2006
Abstract—The reaction of 1,n-dichloroalkanes 3a (n¼2–6) with an excess of lithium powder and a catalytic amount of 4,40-di-tert-butylbi-
phenyl (DTBB; 2.5 mol %) in the presence of different carbonyl compounds [ButCHO, PhCHO, Et2CO, (CH2)4CO, (CH2)5CO, (CH2)7CO,
(ꢀ)-menthone], in THF at ꢀ78 ꢁC leads, after hydrolysis with water, to the expected 1,(n+2)-diols 4, yields being <25% for n¼2, 3 and in the
range of 45–79% for n¼4–6. When the same protocol is applied to 1,n-bromochloroalkanes 3b and 1,n-dibromoalkanes 3c (n¼2–6), diols 4
are obtained in general with lower yields.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
organolithium compound can be trapped under mild reaction
conditions.6 For intermediates 2 with n¼4–6 the elimination
can be avoided partially under controlled reaction condi-
tions,7 which in general consist in performing the lithiation
using an arene as electron carrier8 at low temperature and
in the presence of the corresponding electrophile (Barbier-
type reaction conditions9). In the frame of our continuous in-
terest on the lithiation of compounds of type 310 (Chart 1) we
report here the 4,40-di-tert-butylbiphenyl (DTBB)-catalysed
lithiation of different 1,n-dihaloalkanes 3a–c11 and their use
as 1,n-dianionic synthetic equivalents in the reaction with
different carbonyl compounds as electrophiles.
From a synthetic point of view, the generation of dilithio
compounds1 of the type 1 (Chart 1) would be of great interest
because their reaction with two molecules of an electrophile
would allow the simultaneous introduction of two electro-
philic fragments in the starting molecule through a single
synthetic operation. The halogen–lithium exchange2 is the
most commonly used method to generate these intermedi-
ates, but this methodology cannot be applied in this case
because the initially formed halogen-lithium compound 2
(Chart 1) is extremely unstable and suffers spontaneous
elimination of lithium halide, thus preventing the second
lithiation step.3 Thus, 2 with n¼1, the so-called lithium
carbenoids, undergo a-elimination giving a carbene, which
either decompose or can be trapped by an appropriate re-
agent.4 Probably, the most dramatic situation appears for 2
with n¼2, where the b-elimination affording an olefin occurs
rapidly, even at very low temperatures (<ꢀ100 ꢁC),5 mak-
ing impossible to prepare this type of intermediates and,
consequently, the corresponding 1,2-dilithio compounds.
In the case of n¼3, it has been shown that the g-elimination
that gives a cyclopropane derivative works not so easily,
so in some cases, the corresponding g-functionalised
2. Results and discussion
2.1. Lithiation of 1,n-dihaloalkanes 3 under Barbier-
type reaction conditions (Method A)
The reaction of commercially available 1,n-dichloroalkanes
3a with an excess of lithium (1:10 molar ratio; theoretic 1:4
molar ratio) and a catalytic amount of DTBB (1:0.1 molar
ratio, 2.5 mol %) in the presence of different carbonyl
compounds (1:3 molar ratio) in THF at ꢀ78 ꢁC for ca. 3 h,
followed by hydrolysis with water at temperatures ranging
between ꢀ78 ꢁC and room temperature (Method A), led to
the diols 4 (Scheme 1 and Table 1).
X
Cl
( )n
X
Li
Li
Li
( )n
2 (X = Cl, Br, I)
( )n
3 [X = Hal (Cl, Br), RO, RS, R2N]
1
Chart 1.
As expected, yields are low for compounds 4 with n¼2, 3
due to the above commented elimination side reaction prob-
lems, which gave ethylene and cyclopropane, respectively
(Table 1, entries 1–6). However, in the other cases (4 with
n¼4–6) this problem was extensively overcome, so the
Keywords: DTBB-catalysed lithiation; Halogen–lithium exchange; Electro-
philic substitution; Symmetric diols.
* Corresponding author. Tel.: +34 965 909672; fax: +34 965 903549;
e-mail: foubelo@ua.es
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.08.064

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A. Abou et al. / Tetrahedron 62 (2006) 10417–10424
i,ii
the chloro-lithio intermediate 2 with X¼Cl initially formed,
(Method A)
OH OH
which has a great tendency to undergo elimination of lithium
chloride (see above, especially for n¼2, 3), can also react
with the electrophile present in the reaction medium to
give the chloro-alkoxide 5. This new intermediate then suf-
fers a new chlorine–lithium exchange to afford the function-
alised organolithium species 6, which in the presence of the
electrophile gives the corresponding dialkoxide 7, precursor
of the diols 4 by final hydrolysis (Chart 2). On the other
hand, the participation of dilithium intermediates of the
X
Y
R1
R1
( )n
( )n
R2 R2
4
iii,iv,ii
(Method B)
3a (X = Y = Cl, n = 2-6)
3b (X = Cl, Y = Br, n = 2-6)
3c (X = Y = Br, n = 2-6)
Scheme 1. Reagents and conditions: (i) Li, DTBB (2.5 mol %), R1R2CO,
THF, ꢀ78 ꢁC; (ii) H2O, ꢀ78 to 20 ꢁC; (iii) Li, DTBB (2.5 mol %), THF,
ꢀ78 ꢁC; (iv) R1R2CO, ꢀ78 ꢁC.
expected diols were the main products isolated (Table 1, en-
tries 7–17). When aldehydes were used as prochiral electro-
philes, the corresponding ca. 1:1 mixtures of diastereomers
(NMR) were obtained (Table 1, entries 1, 5, 7, 14 and 15,
and footnote c). In the case of (ꢀ)-menthone, the attack of
the organolithium intermediate to the upper less hindered
face of the chiral electrophile12 was exclusively observed,
so the corresponding enantiomerically pure diol was the
only reaction product obtained (Table 1, entries 4, 6, 10,
13 and 17, and footnote d).
X
X
X
Li
X
Li
Li
Li
Li
X
2 (n = 2)
2 (n = 3)
2 (n = 4)
2 (n = 5)
2 (n = 6)
[X = Cl, Br]
OLi OLi
R1
( )n
OLi
( )n
OLi
Cl
Li
R1
R1
R1
( )n
R2
R2
R2
R2
5
6
7
Concerning a possible mechanistic pathway for the reaction
shown in the Scheme 1, we think that after the first lithiation,
Chart 2.
Table 1. Double lithiation of 1,n-dichloroalkanes 3a (preparation of compounds 4 (Method A))
Entry
n
2
2
2
2
3
3
4
4
Electrophile
Producta
Structure
No.
Yield (%)b
23c
OH
1
2
3
4
5
6
7
8
PhCHO
4a
OH
OH
OH
Et2CO
4b
4c
4d
4e
4f
18
OH
(CH2)7CO
(ꢀ)-Menthone
PhCHO
9
OH
OH
25d
20c
15d
79c
OH
OH
OH
(ꢀ)-Menthone
ButCHO
OH
OH
OH
4g
4h
OH
OH
Et2CO
45
OH
(continued)

A. Abou et al. / Tetrahedron 62 (2006) 10417–10424
10419
Table 1. (continued)
Entry
n
4
4
5
5
5
6
6
6
6
Electrophile
(CH2)4CO
(ꢀ)-Menthone
Et2CO
Producta
Structure
No.
Yield (%)b
OH
9
4i
62
OH
OH
10
11
12
13
14
15
16
4j
67d
46
OH
OH
OH
4k
4l
OH
OH
OH
(CH2)4CO
(ꢀ)-Menthone
ButCHO
57
4m
4n
4o
4p
4q
63d
64c
78c
65
OH
OH
OH
OH
PhCHO
OH
OH
(CH2)5CO
(ꢀ)-Menthone
OH
OH
OH
17
72d
All products 4 were >95% pure (GLC and/or 300 MHz 1H NMR) and were fully characterised by spectroscopic means (IR, 1H and 13C NMR, and LR and HR
mass spectrometry).
Isolated yields of compounds 4 after column chromatography (silica gel, hexane/ethyl acetate).
Obtained as a ca. 1:1 mixture of diastereomers (NMR).
The diastereomer shown in this table was exclusively obtained (see text).
a
b
c
d
type 1 could be ruled out because the second lithiation of the
the case of 1-bromo-n-chloroalkanes 3b, we think that after
the first lithiation, the choro-lithio intermediate 2 with X¼Cl
is formed due to the higher reactivity of the carbon–bromine
bond towards the lithiation reagent. We have reported
recently on the selective monolithiation of bromochloro-
alkanes (2, n¼4, 5 and 6) (carbon–bromine bond undergoes
reductive cleavage faster than carbon–chlorine bond) and
also on the one-pot tandem introduction of two different
electrophiles under careful reaction conditions.7
already chlorinated organolithium intermediate is much
more difficult than either the decomposition by elimination
or the reaction with the electrophile present in the reaction
medium.13 The reaction conditions [(a) low temperature,
(b) slow addition of the reagents (see Section 4.2) and (c)
Barbier-type conditions] are essential for the preparation
of diols 4 from the corresponding 1,n-dihaloalkane 3.
The double lithiation under the same reaction conditions
(Method A) of other starting materials, such as 1-bromo-n-
chloroalkanes 3b and 1,n-dibromoalkanes 3c (both commer-
cially available), was also studied. The results of this
comparative study are summarised in Table 2. In general,
yields are lower for compounds 3b and 3c, dichloro deriva-
tives 3a being the best substrates in this kind of processes. In
2.2. Lithiation of 1,n-dihaloalkanes 3 under Grignard-
type reaction conditions (Method B)
In order to determine the stability of the intermediates 2
(X¼Cl, Br; Chart 2), we studied the lithiation of compounds
3a–c in the absence of the electrophile (Grignard-type

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A. Abou et al. / Tetrahedron 62 (2006) 10417–10424
Table 2. Double lithiation of 1,n-dihaloalkanes 3a–c (preparation of compounds 4)
Entry
Electrophile
Producta
No.
Starting material [X–(CH2)n–Y]
Yield (%)b
Structure
No.
X
Y
n
Method A
Method B
OH
1
2
3
3a
3b
3c
Cl
Cl
Br
Cl
Br
Br
2
2
2
18
12
2c
0
0
0
Et2CO
PhCHO
Et2CO
4b
4e
4h
OH
OH
OH
4
5
6
3a
3b
3c
Cl
Cl
Br
Cl
Br
Br
3
3
3
20
7
23
0
0
0
OH
7
8
9
3a
3b
3c
Cl
Cl
Br
Cl
Br
Br
4
4
4
45
31
22
3c
2c
0
OH
OH
OH
10
11
12
3a
3b
3c
Cl
Cl
Br
Cl
Br
Br
5
5
5
46
30
16
4c
0
Et2CO
4k
4o
0
OH
13
14
15
3a
3b
3c
Cl
Cl
Br
Cl
Br
Br
6
6
6
78
67
53
23
17
0
PhCHO
OH
All products 4 were >95% pure (GLC and/or 300 MHz 1H NMR) and were fully characterised by spectroscopic means (IR, 1H and 13C NMR, and LR and HR
mass spectrometry).
Isolated yields of compounds 4 after column chromatography (silica gel, hexane/ethyl acetate).
Yield determined by GLC analysis.
a
b
c
conditions). So, there would be a correlation between the
entries 7–9 and 10–12). This indicates that 4-halo- and
5-haloalkyllithium intermediates (2, n¼4, 5, X¼Cl, Br) were
not stable species under these reaction conditions. Finally,
when benzaldehyde was used as electrophile, low yields of
diol 4o were obtained from 1,6-dichloro- and 1-bromo-6-
chlorohexanes 3a and 3b (n¼6) (Table 2, entries 13 and
14), meanwhile, diol 4o was not detected when starting
from 1,6-dibromohexane (3c, n¼6) (Table 2, entry 15). Pay-
ing attention to these experimental results, we can assume
that the 6-chloro derivative (2, n¼6, X¼Cl) is more stable
than the 6-bromoalkyllithium intermediate 2 (n¼6, X¼Br)
under the commented reaction conditions. The best yields
of 1,4-, 1,6-, 1,7- and 1,8-diols 4 were obtained from
dichloroalkanes 3a (n¼2, 4, 5 and 6). The preparation of
1-chloro-4-lithiobutane14 (2, n¼4, X¼Cl) and 1-chloro-6-
lithiohexane15 (2, n¼6, X¼Cl) by monolithiation of the
corresponding n-chloro-1-iodoalkanes with butyllithium has
been previously reported.
yield of compounds 4 and the stability of the corresponding
intermediates 2. The reaction of compounds 3a–c with an
excess of lithium (1:10 molar ratio; theoretic 1:4 molar ratio)
and a catalytic amount of DTBB (1:0.1 molar ratio,
2.5 mol %) in THF at ꢀ78 ꢁC for 1 h, followed by addition
of 2.2 equiv of a carbonyl compound at the same tempera-
ture and final hydrolysis with water at temperatures ranging
between ꢀ78 ꢁC and room temperature (Method B), would
lead to the expected diols 4 (Scheme 1 and Table 2).
In the case of 1,2-dihalo derivatives 3a–c (n¼2, entries 1–3,
Table 2), intermediates 2 (n¼2) decomposed rapidly before
a second lithiation took place, so, after the addition of 3-pen-
tanone as electrophile, nothing of the expected diol 4b was
isolated or detected by tandem GC–MS analysis. This indi-
cates, as previously commented, that intermediates of type 2
(n¼2, 3) show a high tendency to undergo elimination. Such
elimination takes place almost exclusively (Scheme 1, Table
2, entries 1–3) even in the presence of the electrophile (Barb-
ier-type conditions), this probably being the main reason for
the low yields. The possible participation of b-haloradicals in
the synthesis of 1,4-diols 4 cannot be completely ruled out.
3. Conclusions
In conclusion, we report here for the first time the controlled
lithiation of 1,n-dihaloalkanes under DTBB-promoted con-
ditions, which allows the preparation of symmetrically
substituted diols 4 by using carbonyl compounds as electro-
philes. The reaction is especially of interest for n¼2, 3 (even
working with low yields in all cases)16 due to the outstanding
problems concerning the decomposition of the halogen-
lithio intermediates by elimination, which are partially
overcome in this study. The best yields are always obtained
starting from 1,n-dichloroalkanes 3a.
Intermediates 2 with n¼3 seem to be also highly unstable
because 1,5-diol 4e was not observed after addition of
benzaldehyde as electrophile (Table 2, entries 4–6).
Very low yield was also obtained from 1,4- and 1,5-dihalo-
alkanes 3a–c (n¼4, 5) when 3-pentanone was used as elec-
trophile, the expected reaction products 4h and 4k not
being isolated but detected by tandem GC–MS (Table 2,

A. Abou et al. / Tetrahedron 62 (2006) 10417–10424
10421
4. Experimental
4.2.1.3. 1-[2-(1-Hydroxycyclooctyl)ethyl]cyclooctanol
(4c).19 White solid; mp 118–119 ꢁC (dichloromethane/
hexane); Rf 0.16 (hexane/ethyl acetate: 2/1); n (KBr)
3470–3230 (OH), 2932, 2919, 2852, 1460 cmꢀ1; dH 1.25–
1.78 (34H, m, 16ꢃCH2, 2ꢃOH); dC 22.4, 25.0, 28.25,
34.2, 36.3 (CH2), 74.65 (COH); m/z 264 (M+ꢀH2O, 5%),
193 (42), 180 (29), 127 (100), 122 (46), 110 (54), 109
(56), 95 (29), 81 (63), 67 (51), 55 (59).
4.1. General
All reactions were carried out under an atmosphere of argon
in oven-dried glassware. All reagents were commercially
available (Acros, Aldrich) and were used without further pu-
rification. Commercially available anhydrous THF (99.9%,
water contentꢂ0.006%, 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 or a Bruker ADVANCE
DRX-500 using CDCl3 as the solvent. LRMS and HRMS
were measured with Shimadzu GC/HS QP-5000 and
Finingan MAT95 S spectrometers, respectively. The purity
of volatile products and the chromatographic analyses
(GLC) were determined with a flame ionisation detector
and a 12 m capillary column (0.2 mm diameter, 0.33 mm
film thickness), using nitrogen (2 mL/min) as carrier gas,
Tinjector¼275 ꢁC, Tdetector¼300 ꢁC, Tcolumn¼60 ꢁC (3 min)
and 60–270 ꢁC (15 ꢁC/min), P¼40 kPa. Specific rotations
weredeterminedwitha Perkin–Elmer341digitalpolarimeter.
4.2.1.4. (1S,2S,5R,10S,20S,50R)-1-[2-(10-Hydroxy-20-iso-
propyl-50-methylcyclohexyl)ethyl]-2-isopropyl-5-methyl-
cyclohexanol (4d). White solid; mp 122–123 ꢁC
(dichloromethane/hexane) (found: C, 77.96; H, 12.37.
C22H42O2 requires: C, 78.05; H, 12.50); Rf 0.64 (hexane/
ethyl acetate: 2/1); n (KBr) 3510–3280 (OH), 2965, 2954,
2868, 1455, 1371 cmꢀ1; dH 0.85–1.00 (20H, m, 6ꢃCH3,
2ꢃCH), 1.05–1.67 (13H, m), 1.70–1.81 (6H, m), 1.90–2.15
(3H, m); dC 18.1 (CH3), 19.9 (CH3), 20.4 (CH2), 22.5, 23.5
(CH3), 24.3 (CH2), 24.7, 25.25, 25.3 (CH), 25.8 (CH2),
28.0, 29.85 (CH), 33.9, 35.05, 46.8, 47.1 (CH2), 47.4, 54.4
(CH), 75.2, 75.4 (COH); m/z 320 (M+ꢀH2O, 8%), 236
(17), 235 (100), 217 (18), 166 (21), 155 (64), 150 (51), 138
(51), 136 (31), 123 (30), 109 (21), 108 (17), 95 (51), 81
(42), 69 (38), 55 (29). [a]2D0 ꢀ15.9 (c 0.80, dichloromethane).
4.2. Double lithiation of compounds 3a–c in the presence
of a carbonyl compound as electrophile (Barbier-type
reaction conditions, Method A). Preparation of diols 4
4.2.1.5. 1,5-Diphenylpentane-1,5-diol (4e).20 Diastereo-
meric mixture. Colourless oil; Rf 0.19 (hexane/ethyl acetate:
2/1); n (film) 3530–3180 (OH), 3062, 3029, 2980, 2938,
4.2.1. Isolation of compounds 4. Method A: general pro-
cedure. To a blue suspension of lithium powder (0.070 g,
10 mmol) and a catalytic amount of DTBB (0.027 g,
0.1 mmol) in THF (3 mL), a solution of the corresponding
1,n-dihaloalkane 3a–c (1.0 mmol) and the corresponding
carbonyl compound (R1R2CO, 3.0 mmol) in THF (1.2 mL)
was slowly added (ca. 3 h) at ꢀ78 ꢁC. After the addition,
the reaction mixture was stirred for 15 min at the same tem-
perature. Then, it was hydrolysed with water (4 mL) and
extracted with ethyl acetate (3ꢃ10 mL). The organic layer
was dried over anhydrous magnesium sulfate and evaporated
(15 Torr). The residue was purified by column chromato-
graphy (silica gel; hexane/ethyl acetate) to yield pure prod-
ucts 4. Yields and structures are included in Tables 1 and 2.
Physical and spectroscopic data as well as literature refer-
ences follow.
2865, 1454 cmꢀ1
;
dH 1.43 (2H, quintet, J¼7.9 Hz,
CH2CH2CH2), 1.52–1.81 (4H, m, 2ꢃCH2CH), 2.56 (2H, br
s, 2ꢃOH), 4.58 (2H, t, J¼7.3 Hz, 2ꢃCHOH), 7.23–7.33
(10H, m, ArH); dC 22.05, 22.15, 38.6, 38.7 (CH2), 74.1, 74.3
(CHOH), 125.8, 127.4, 128.35, 144.7 (ArC); m/z 238
(M+ꢀH2O,4%), 129(22),105(20),104(100),91(18),77(21).
4.2.1.6.
(1S,2S,5R,10S,20S,50R)-1-[3-(10-Hydroxy-20-
isopropyl-50-methylcyclohexyl)propyl]-2-isopropyl-5-
methylcyclohexanol (4f). Colourless oil; Rf 0.71 (hexane/
ethyl acetate: 2/1); n (film) 3630–3340 (OH), 2952, 2868,
1464, 1373 cmꢀ1; dH 0.82–1.78 (42H, m), 2.06–2.11 (2H,
m); dC 18.0 (CH2), 18.15 (CH3), 20.5 (CH2), 22.4, 23.6
(CH3), 25.5, 28.0 (CH), 35.1, 41.9, 46.7 (CH2), 48.1 (CH),
75.0 (COH); m/z 334 (M+ꢀH2O, 1%), 165 (15), 164 (100),
163 (18), 149 (26), 137 (25), 135 (35), 121 (27), 109 (38),
107 (17), 95 (53), 93 (26), 83 (17), 81 (58), 69 (48), 67
(34), 55 (56), 43 (56), 41 (58); HRMS: M+ꢀH2O, found
334.3233. C23H42O requires 334.3236. [a]2D0 +4.2 (c 1.07,
dichloromethane).
4.2.1.1. 1,4-Diphenylbutane-1,4-diol (4a).17 Diastereo-
meric mixture. Colourless oil; Rf 0.19 (hexane/ethyl acetate:
2/1); n (film) 3580–3170 (OH), 3060, 3029, 2935, 2875,
1460 cmꢀ1; dH 1.43 (2H, quintet, J¼7.9 Hz, CH2CH2CH2),
1.75–1.81 (4H, m, CH2CH2), 2.94 (2H, br s, 2ꢃOH), 4.63–
4.67 (2H, m, 2ꢃCHOH), 7.23–7.31 (10H, m, ArH); dC 35.0,
35.9 (CH2), 74.05, 74.45 (CHOH), 125.8, 127.35, 127.4,
128.35, 144.45 (ArC); m/z 224 (M+ꢀH2O, 13%), 120 (73),
118 (100), 107 (38), 105 (22), 104 (16), 79 (48), 77 (44).
4.2.1.7. 2,2,9,9-Tetramethyldecane-3,8-diol (4g).10c
Diastereomeric mixture. White solid; mp 113–114 ꢁC (di-
chloromethane/hexane) (found: C, 72.70; H, 13.39.
C14H30O2 requires: C, 72.99; H, 13.39); Rf 0.44 (hexane/
ethyl acetate: 2/1); n (KBr) 3580–3220 (OH), 2972, 2865,
1470, 1390, 1371 cmꢀ1; dH 0.89 (18H, s, 6ꢃCH3), 1.26–
1.54 (10H, m, 4ꢃCH2, 2ꢃOH), 3.20 (2H, dd, J¼8.3,
2.1 Hz, 2ꢃCHOH); dC 25.6 (CH3), 26.9, 27.1, 31.4 (CH2),
34.9 (C), 79.7, 79.9 (CHOH); m/z 212 (M+ꢀH2O, 1%), 155
(24), 137 (100), 99 (17), 97 (25), 95 (49), 83 (24), 81 (69),
71 (31), 69 (46), 67 (17), 57 (77), 55 (19).
4.2.1.2. 3,6-Diethyloctane-3,6-diol (4b).18 Colourless
oil; Rf 0.21 (hexane/ethyl acetate: 2/1); n (film) 3520–3190
(OH), 2972, 2935, 2880, 1460 cmꢀ1; dH 0.86 (12H, t,
J¼7.5 Hz, 4ꢃCH3), 1.45 [4H, s, (CH2)2], 1.48 (8H, q,
J¼7.5 Hz, 2ꢃCH3CH2), 1.75 (2H, br s, 2ꢃOH); dC 7.8
(CH3), 30.9, 31.3 (CH2), 74.4 (COH); m/z 166 (M+ꢀ2H2O,
1%), 156 (11), 155 (100), 137 (52), 98 (33), 95 (18), 87
(56), 83 (26), 69 (31), 57 (91), 55 (30); HRMS: M+ꢀH2O,
found 184.1833. C12H24O requires 184.1827.
4.2.1.8. 3,8-Diethyldecane-3,8-diol (4h).21 White solid; mp
72–73 ꢁC (dichloromethane/hexane); Rf 0.25 (hexane/ethyl

10422
A. Abou et al. / Tetrahedron 62 (2006) 10417–10424
acetate: 2/1); n (KBr) 3520–3230 (OH), 2963, 2943, 2878,
1461 cmꢀ1; dH 0.85 (12H, t, J¼7.5 Hz, 4ꢃCH3), 1.27–1.40
[10H, m, (CH2)4, 2ꢃOH], 1.46 (8H, q, J¼7.5 Hz, 4ꢃCH2);
dC 7.75 (CH3), 24.0, 31.0, 38.15 (CH2), 74.6 (COH); m/z 194
(M+ꢀ2H2O, 1%), 183 (13), 165 (65), 109 (23), 97 (43), 95
(20), 87 (100), 85 (24), 69 (38), 57 (77), 55 (21).
137 (100), 123 (14), 109 (30), 97 (18), 95 (47), 81 (51), 69
(42), 55 (25). [a]2D0 +5.8 (c 0.91, dichloromethane).
4.2.1.14.
2,2,11,11-Tetramethyldodecane-3,10-diol
(4n).7 Diastereomeric mixture. White solid; mp 104–
105 ꢁC (dichloromethane/hexane) (found: C, 74.99; H,
13.81. C16H34O2 requires: C, 74.36; H, 13.26); Rf 0.58
(hexane/ethyl acetate: 2/1); n (KBr) 3580–3210 (OH), 2970,
2864, 1469, 1389, 1367 cmꢀ1; dH 0.89 (18H, s, 6ꢃCH3),
1.25–1.55 (14H, m, 6ꢃCH2, 2ꢃOH), 3.18 (2H, dd, J¼9.9,
2.0 Hz, 2ꢃCHOH); dC 25.7 (CH3), 27.1, 29.7, 31.4, 31.45
(CH2), 34.9 (C), 79.9, 79.95 (CHOH); m/z 240 (M+ꢀH2O,
1%), 183 (22), 165 (29), 109 (100), 97 (23), 95 (62), 83
(58), 81 (22), 71 (29), 69 (39), 67 (17), 57 (74), 55 (24).
4.2.1.9. 1-[4-(1-Hydroxycyclopentyl)butyl]cyclopenta-
nol (4i).22 White solid; mp 98–99 ꢁC (dichloromethane/
hexane) (found: C, 74.20; H, 11.75. C14H26O2 requires: C,
74.29; H, 11.58); Rf 0.13 (hexane/ethyl acetate: 2/1);
n (KBr) 3440–3180 (OH), 2957, 2869, 1434 cmꢀ1; dH 1.43–
1.81 (26H, m, 12ꢃCH2, 2ꢃOH); dC 23.7, 25.2, 39.55, 41.4
(CH2), 82.4 (COH); m/z 208 (M+ꢀH2O, 1%), 121 (14),
113 (13), 108 (100), 95 (15), 93 (31), 85 (28), 79 (12), 67
(31), 55 (18).
4.2.1.15. 1,8-Diphenyloctane-1,8-diol (4o).7 Diastereo-
meric mixture. White solid; mp 83–84 ꢁC (dichloromethane/
hexane); Rf 0.30 (hexane/ethyl acetate: 2/1); n (KBr) 3520–
3180 (OH), 3083, 3058, 3022 cmꢀ1 (ArH); dH 1.19–1.69
(14H, m, 6ꢃCH2, 2ꢃOH), 4.54 (2H, dd, J¼7.2, 6.1 Hz,
2ꢃCHOH), 7.21–7.29 (10H, m, 2ꢃArH); dC 25.1, 28.8,
38.4 (CH2), 73.9 (CHOH), 125.3, 126.8, 127.8, 144.3
(ArC); m/z 280 (M+ꢀH2O, 2%), 207 (37), 174 (64), 158
(15), 117 (52), 107 (100), 105 (26), 104 (83), 91 (30), 79
(61), 77 (36).
4.2.1.10. (1S,2S,5R,10S,20S,50R)-1-[4-(10-Hydroxy-20-
isopropyl-50-methylacyclohexyl)butyl]-2-isopropyl-
5-methylcyclohexanol (4j). White solid; mp 56–57 ꢁC
(dichloromethane/hexane) (found: C, 78.21; H, 12.54.
C24H46O2 requires: C, 78.63; H, 12.65); Rf 0.69 (hexane/
ethyl acetate: 2/1); n (KBr) 3610–3330 (OH), 2941, 2866,
1455, 1366 cmꢀ1; dH 0.83–0.98 (20H, m, 6ꢃCH3, 2ꢃCH),
1.06–1.52 (17H, m), 1.60–1.77 (6H, m), 1.86–2.17 (3H, m);
dC 18.1 (CH3), 20.5 (CH2), 22.4, 23.6 (CH3), 24.7 (CH2),
25.45, 28.0 (CH), 35.1, 41.3, 46.8 (CH2), 47.7 (CH), 75.05
(COH); m/z 348 (M+ꢀH2O, 25%), 330 (12), 196 (18), 194
(19), 178 (78), 163 (27), 155 (78), 137 (100), 135 (49), 95
(46), 83 (15), 81 (54), 69 (49), 55 (30). [a]2D0 +6.1 (c 0.84,
dichloromethane).
4.2.1.16. 1-[6-(1-Hydroxycyclohexyl)hexyl]cyclohexa-
nol (4p).23 White solid; mp 89–90 ꢁC (dichloromethane/
hexane) (found: C, 76.11; H, 12.36. C18H34O2 requires: C,
76.54; H, 12.13); Rf 0.35 (hexane/ethyl acetate: 2/1);
n (KBr) 3570–3240 (OH), 2945, 1442 cmꢀ1; dH 1.25–1.60
(34H, m, 16ꢃCH2, 2ꢃOH); dC 22.2, 22.7, 25.8, 30.2, 37.3,
42.3 (CH2), 71.3 (COH); m/z 246 (M+ꢀ2H2O, 13%), 166
(26), 109 (21), 99 (100), 96 (39), 95 (20), 94 (21), 83 (17),
82 (17), 81 (59), 67 (24), 55 (35).
4.2.1.11. 3,9-Diethylundecane-3,9-diol (4k). White
solid; mp 82–83 ꢁC (dichloromethane/hexane); Rf 0.27
(hexane/ethyl acetate: 2/1); n (KBr) 3450–3210 (OH),
2968, 2933, 2878, 1466 cmꢀ1; dH 0.85 (12H, t, J¼7.5 Hz,
4ꢃCH3), 1.25–1.42 [12H, m, (CH2)5, 2ꢃOH], 1.45 (8H, q,
J¼7.5 Hz, 4ꢃCH2); dC 7.7 (CH3), 23.3, 30.9, 30.95, 38.1
(CH2), 74.55 (COH); m/z 208 (M+ꢀ2H2O, 2%), 197 (17),
179 (64), 123 (21), 111 (42), 109 (28), 97 (20), 95 (28), 87
(100), 85 (31), 69 (45), 57 (90), 55 (26).
4.2.1.17. (1S,2S,5R,10S,20S,50R)-1-[6-(10-Hydroxy-20-
isopropyl-50-methylcyclohexyl)hexyl]-2-isopropyl-5-
methylcyclohexanol (4q). White solid; mp 54–55 ꢁC
(dichloromethane/hexane); Rf 0.77 (hexane/ethyl acetate:
2/1); n (KBr) 3590–3370 (OH), 2952, 2866, 1455,
1366 cmꢀ1; dH 0.86–0.91 (18H, m, 6ꢃCH3), 1.02–1.12
(4H, m), 1.22–1.49 (20H, m), 1.64–1.77 (6H, m), 2.05–
2.10 (2H, m); dC 18.1 (CH3), 20.4 (CH2), 22.45, 23.6
(CH3), 23.8 (CH2), 25.4, 27.95 (CH), 30.2, 35.1, 41.3, 46.8
(CH2), 47.5 (CH), 75.1 (COH); m/z 376 (M+ꢀH2O, 38%),
358 (18), 333 (65), 315 (18), 222 (13), 179 (36), 155 (81),
137 (100), 123 (20), 109 (30), 97 (21), 95 (49), 81 (55), 69
(43), 55 (25); HRMS: M+ꢀH2O, found 376.3707. C26H48O
requires 376.3705. [a]2D0 +6.3 (c 1.09, dichloromethane).
4.2.1.12.
1-[5-(1-Hydroxycyclopentyl)pentyl]cyclo-
pentanol (4l).23 Colourless oil; Rf 0.18 (hexane/ethyl ace-
tate: 2/1); n (film) 3530–3210 (OH), 2968, 2933, 2859,
1462 cmꢀ1; dH 1.26–1.82 (28H, m, 13ꢃCH2, 2ꢃOH); dC
23.8, 24.6, 30.7, 39.65, 41.4 (CH2), 82.6 (COH); m/z 222
(M+ꢀH2O, 1%), 204 (6), 136 (20), 135 (62), 123 (20), 122
(100), 121 (26), 108 (34), 95 (45), 93 (47), 85 (77), 81
(49), 80 (58), 67 (71), 57 (29), 55 (51).
4.2.1.13. (1S,2S,5R,10S,20S,50R)-1-[5-(10-Hydroxy-20-
isopropyl-50-methylcyclohexyl)pentyl]-2-isopropyl-5-
methylcyclohexanol (4m). White solid; mp 68–69 ꢁC
(dichloromethane/hexane) (found: C, 78.23; H, 12.60.
C25H48O2 requires: C, 78.88; H, 12.71); Rf 0.74 (hexane/
ethyl acetate: 2/1); n (KBr) 3560–3390 (OH), 2949, 2866,
2840, 1469, 1368 cmꢀ1; dH 0.86–0.91 (18H, m, 6ꢃCH3),
1.03–1.11 (4H, m), 1.22–1.49 (18H, m), 1.62–1.77 (6H,
m), 2.03–2.12 (2H, m); dC 18.1 (CH3), 20.45 (CH2), 22.45,
23.6 (CH3), 23.9 (CH2), 25.45, 28.0 (CH), 31.0, 35.1, 41.3,
46.8 (CH2), 47.6 (CH), 75.1 (COH); m/z 362 (M+ꢀH2O,
14%), 344 (13), 319 (26), 208 (19), 165 (45), 155 (64),
4.3. Double lithiation of compounds 3a–c followed by
reaction with carbonyl compounds as electrophiles
(Grignard-type reaction conditions, Method B).
Preparation of diols 4
4.3.1. Isolation of compounds 4. Method B: general pro-
cedure. To a blue suspension of lithium powder (0.070 g,
10 mmol) and a catalytic amount of DTBB (0.027 g,
0.1 mmol) in THF (3 mL) was added the corresponding
1,n-difunctionalised alkane 3a–c (1.0 mmol) at ꢀ78 ꢁC.
The reaction mixture was stirred for 1 h at the same temper-
ature and after that, the corresponding carbonyl compound

A. Abou et al. / Tetrahedron 62 (2006) 10417–10424
10423
ꢀ
Concellon, J. M. J. Chem. Soc., Perkin Trans. 1 1991, 2890
and references cited therein.
(2.2 mmol) was added dropwise and after 15 min it was
hydrolysed with water (4 mL) and extracted with ethyl ace-
tate (3ꢃ10 mL). The organic layer was dried over anhydrous
magnesium sulfate and evaporated (15 Torr). The residue
was purified by column chromatography (silica gel; hexane/
ethyl acetate) to yield pure products 4. Yields and structures
are included in Table 2. Physical and spectroscopic data as
well as literature references are shown above.
5. See, for example: (a) Schlosser, M.; Ladenberger, V. Angew.
Chem., Int. Ed. Engl. 1966, 5, 519. This b-elimination has
been used synthetically to prepare olefinic compounds; (b)
For the first account from our laboratory, see: Barluenga, J.;
Bernad, P.; Yus, M. J. Chem. Soc., Chem. Commun. 1978,
ꢀ
847; (c) See also: Barluenga, J.; Fernandez-Simon, J. L.;
Concellon, J. M.; Yus, M. Tetrahedron Lett. 1989, 30, 5927–
ꢀ
ꢀ
5928 and references cited therein.
ꢀ
6. See, for instance: (a) Ramon, D. J.; Yus, M. Tetrahedron Lett.
1992, 33, 2217–2220; (b) Ramon, D. J.; Yus, M. Tetrahedron
Acknowledgements
ꢀ
1993, 49, 10103–10110; (c) Alonso, F.; Lorenzo, E.; Yus, M.
Tetrahedron Lett. 1997, 38, 2187–2190; (d) Alonso, F.;
Lorenzo, E.; Yus, M. Tetrahedron Lett. 1998, 39, 3303–3306;
(e) Lorenzo, E.; Alonso, F.; Yus, M. Tetrahedron 2000, 56,
1745–1757; (f) Alonso, F.; Falvello, L. R.; Fanwick, P. E.;
Lorenzo, E.; Yus, M. Synthesis 2000, 949–952; For an applica-
tion of the g-elimination to generate cyclopropane derivatives,
This work was generously supported by the Spanish Minis-
ꢀ
terio de Educacion y Ciencia (MEC; grant no. CTQ2004-
01261) and the Generalitat Valenciana (GV; grants no.
GRUPOS05/052 and GRUPOS05/058). A.A. thanks the
University of Alicante for a predoctoral fellowship. We
also thank MEDALCHEMY S.L. for a gift of chemicals,
especially lithium powder.
ꢀ
see: (g) Barluenga, J.; Florez, J.; Yus, M. Synthesis 1983,
647–649.
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€

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