Cyclopropylmethyl- and cyclobutylmethyllithium by an arene-catalyzed lithiation. Stability and reactivity

Article abstract of DOI:10.1016/j.tet.2010.02.090

The reaction of (chloromethyl)cyclopropane 5 and (bromomethyl)cyclobutane 8 with lithium and a substoichiometric amount of DTBB, in the presence of different carbonyl compounds as electrophiles, in THF at -78 °C leads, after hydrolysis, to the corresponding cycloalkyl alcohols 6 and 9, respectively. However, when the same starting materials are lithiated using naphthalene as catalyst in diethyl ether and at higher temperature (0 or 25 °C), and then react with the same electrophiles, the final hydrolysis yields the corresponding unsaturated alcohols 7 and 10, respectively.

Full text of DOI:10.1016/j.tet.2010.02.090

Tetrahedron 66 (2010) 2928–2935
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Cyclopropylmethyl- and cyclobutylmethyllithium by an arene-catalyzed
lithiation. Stability and reactivity
*
*
Itziar Pen˜afiel, Isidro M. Pastor , Miguel Yus
´
´
´
Departamento de Qu´ımica Organica, Facultad de Ciencias and Instituto de Sıntesis Organica (ISO), Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of (chloromethyl)cyclopropane 5 and (bromomethyl)cyclobutane 8 with lithium and
a substoichiometric amount of DTBB, in the presence of different carbonyl compounds as electrophiles, in
THF at ꢀ78 ꢁC leads, after hydrolysis, to the corresponding cycloalkyl alcohols 6 and 9, respectively.
However, when the same starting materials are lithiated using naphthalene as catalyst in diethyl ether
and at higher temperature (0 or 25 ꢁC), and then react with the same electrophiles, the final hydrolysis
yields the corresponding unsaturated alcohols 7 and 10, respectively.
Received 2 February 2010
Received in revised form
23 February 2010
Accepted 24 February 2010
Available online 1 March 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Cyclopropylmethyllithium
Cyclobutylmethyllithium
Homoallyllithium
Bishomoallyllithium
DTBB and naphthalene catalyzed lithiation
SE reaction
Lithium
1. Introduction
allowed the cycloisomerization of different alkenyl primary, secon-
dary, tertiary, and aryl iodides to the corresponding cyclic isomer
The formation of carbon–carbon bonds constitutes a key step
during the synthesis of many organic products, and organometallic
reagents are versatile reagents for carrying out this trans-
formation.1 Among organometallic compounds, functionalized
organolithium compounds constitute a unique class due to their
characteristic reactivity.1c,2 Regarding the lithiation agent
employed for the preparation of organolithium intermediates, two
different methodologies can be considered.3 The first one consists
in the use of another organolithium reagent, and the second is the
reductive lithiation using lithium metal. For the latter, the use of
a substoichiometric amount of an arene to facilitate the electron
transfer from the lithium to the substrate has shown to be very
useful under different reaction conditions and for several types of
starting materials.4
The intramolecular carbolithiation of carbon–carbon double
bonds is an interesting procedure to prepare functionalized
carbocyclic and heterocyclic compounds.5 Thus, the carbanionic cy-
clization reaction of different alk-5-enyllithium intermediates has
been extensively studied.6–8 Bailey et al. reported a very interesting
methodology employing a catalytic amount of phenyllithium that
iodides, and the mechanism of this procedure being substrate
dependent.6 Ourlaboratoryreportedtheintramolecularcyclizationof
different hex-5-enyllithium derivatives prepared by chlorine/lithium
exchange employing lithium metal.8a,b On the other hand, organo-
lithium intermediates having in
a-position a small cycloalkane
(three- or four-membered rings) undergo rapidly a transformation to
the more stable homoallyl- or bishomoallyllithium intermediates.
Thus, cyclopropylmethyllithium 1 is an unstable intermediate even at
low temperature, giving the corresponding homoallyllithium 2 with
less than 1 h half-life time (Scheme 1).9 Intermediates of type 1 and 2
have been prepared employing: (a) an organolithium reagent by
iodine–lithium exchange,9,10 selenium–lithium exchange,11 or sili-
con–lithium exchange (involving a Brook-type process),12 and (b)
lithium metal in a mercury–lithium transmetallation process.13
Regarding the stability of the cyclobutylmethyllithium intermediate
* Corresponding authors. Fax: þ34 965 903549; e-mail addresses: ipastor@ua.es
Scheme 1.
(I.M. Pastor), yus@ua.es (M. Yus).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.02.090

I. Pe˜nafiel et al. / Tetrahedron 66 (2010) 2928–2935
2929
3, which rearranges to the bishomoallyllithium intermediate 4
(Scheme 2), it has been less considered. Thus, organolithium 3 has
been prepared by bromide–lithium14 or iodine–lithium exchange15
using t-BuLi or n-BuLi, respectively. Cyclobutylmethyllithium
intermediate has shown lower stability than the corresponding
magnesium derivatives.16
amount of an arene [i.e., 4,40-di-tert-butylbiphenyl (DTBB) or
naphthalene; 5 mol %] in the presence (Barbier-type conditions)18
or absence (Grignard-type conditions) of 3-pentanone as the elec-
trophile. Different reaction conditions were assayed giving after
hydrolysis a mixture of the corresponding alcohols 6a and 7a
resulting from the SE reaction of the intermediates 1 and 2,
respectively (Table 1).
The cyclopropyl derivative 6a was exclusively formed perform-
ing the reaction at ꢀ78 ꢁC, in THF as solvent, under Barbier-type
conditions (Table 1, entries 1 and 3). The use of DTBB as electron
carrier gave better yield of the product 6a than using naphthalene
(Table 1, compare entries 1 and 3). Any change in the temperature
(Table 1, entry 2) or solvent (Table 1, entry 4) gave poorer results. In
contrast, the best yield for obtaining exclusively the unsaturated
alcohol 7a was observed by working under Grignard-type condi-
tions at 0 ꢁC in diethyl ether and using naphthalene as electron
carrier (Table 1, entry 14). This result was not improved by
performing the reaction at lower temperatures (Table 1, entries
6–9, 11 and 16), using DTBB as electron carrier (Table 1, entries
6–12) or employing other solvents (Table 1, entries 6–13 and 15).
Additionally, we investigated the importance of using an arene in
the selective preparation of either organolithium intermediate 1 or
2, and there was no formation of the final products when
performing the reaction under the optimal conditions but in the
absence of the arene (Table 1, entries 5 and 17). The use of
n-butyllithium, instead of the combination lithium/arene to per-
form the chlorine–lithium exchange, gave neither of the expected
alcohols (6a and/or 7a), but the alcohol derived from the addition of
butyllithium to the 3-pentanone.
Scheme 2.
Recently, we have preliminary reported that the arene-catalyzed
lithiation methodology allowed the selective generation either the
intermediate type 1 or type 2 from the same starting material.17
Herein, we describe the study of the lithiation reaction of (chloro-
methyl)cyclopropane and (bromomethyl)cyclobutane by means of
the mentioned arene-catalyzed lithiation reaction, the stability of
the generated organolithium intermediates being also studied
under these reaction conditions.
2. Results and discussion
To investigate the scope of the process, different carbonyl
compounds were subjected to the optimal conditions for
obtaining exclusively either the cyclopropyl alcohol 6 or the
unsaturated alcohol 7 (Table 2). Thus, compounds 6 were isolated
2.1. Lithiation of (chloromethyl)cyclopropane
The lithiation of (chloromethyl)cyclopropane 5 was performed
employing a slightexcess of lithium powder and a substoichiometric
Table 1
Arene-catalyzed lithiation of (chloromethyl)cyclopropane and SE reaction with 3-pentanonea
Method
Entry
T (ꢁC)
Timeb (min)
Arene
Solvent
Yieldc (%)
6a
7a
Total
Barbier-type
conditions
1
2
3
ꢀ78
0
ꢀ78
ꢀ78
ꢀ78
60
60
60
60
60
DTBB
DTBB
Naphthalene
Naphthalene
THF
THF
THF
Et2O
THF
87
4
65
1
0
85
0
0
0
87
89
65
1
4
5d
0
0
Grignard-type
conditions
6
7
8
ꢀ78
60þ30
90þ30
180þ30
60þ30
60þ30
60þ30
60þ30
60þ30
60þ30
60þ30
60þ30
60þ30
DTBB
DTBB
DTBB
DTBB
DTBB
DTBB
DTBB
Naphthalene
Naphthalene
Naphthalene
Naphthalene
THF
THF
THF
THF
THF
THF
THP
THF
Et2O
THP
Et2O
Et2O
19
3
1
4
0
0
7
0
0
0
2
0
53
66
50
90
84
87
44
54
97
51
3
72
69
51
94
84
87
51
54
97
51
5
ꢀ78
ꢀ78
9
ꢀ45
10
11
12
13
14
15
16
17d
0
ꢀ78 to 0
0
0
0
0
ꢀ78
0
6
6
a
Reactions performed with (chloromethyl)cyclopropane (2 mmol), Li (7.1 mmol), arene (0.1 mmol), solvent (10 mL), and 3-pentanone (2.2 mmol).
Under Grignard conditions the given times correspond to the two steps (lithiation and reaction with the electrophile).
Yields of compounds 6a and 7a were calculated by GLC using an internal standard (1-decanol).
The starting material was recovered.
b
c
d

2930
I. Pe˜nafiel et al. / Tetrahedron 66 (2010) 2928–2935
with satisfactory yields performing the lithiation reaction, with
5 mol % of DTBB, under Barbier-type conditions at ꢀ78 ꢁC in
THF as solvent, the corresponding alcohols 7 being not detected
in any case (Table 2, Method A). However, carrying out the
reaction under the optimal conditions for generating the
intermediate 2 (naphthalene, Grignard-type conditions, 0 ꢁC,
Et2O) the process gave exclusively, after SE (electrophilic
substitution) and hydrolysis, compounds 7 with satisfactory
yields (Table 2, Method B).
2.2. Lithiation of (bromomethyl)cyclobutane
Then we studied the arene-catalyzed lithiation of (bromo-
methyl)cyclobutane 8, trying to find reaction conditions for the
selective generation of the intermediate 3 or 4 (Scheme 2). Thus,
commercially available compound 8 was treated with an excess
of lithium metal and a substochiometric amount of an arene
(DTBB or naphthalene; 5 mol %) under Barbier-type or Grignard-
type conditions, and employing 3-pentanone as electrophile.
Different reaction conditions were tested and, after hydrolysis,
the mixture of the corresponding alcohols 9a and 10a was
Table 2
Preparation of cyclopropyl alcohols 6 and unsaturated alcohols 7
obtained from the reaction of the intermediates
3 and 4,
respectively (Table 3). As previously observed for the cyclopropyl
derivatives, the alcohol 9a was exclusively obtained performing
the reaction under Barbier-type conditions at ꢀ78 ꢁC in THF and
using DTBB as electron carrier (Table 3, entry 1). The optimal
conditions to obtain exclusively the alcohol 10a were performing
the reaction under Grignard-type conditions at room tempera-
ture, using naphthalene as electron carrier, in diethyl ether (Table
3, entry 3).
Entry
Methoda
R1
R2
Product
Yieldb (%)
1
2
3
4
5
6
7
8
A
A
A
A
A
A
A
A
B
B
B
B
B
B
B
B
Et
Et
n-Pr
c-C3H5
6a
6b
6c
6d
6e
6f
6g
6h
7a
7b
7c
7d
7e
7f
67
61
53
71
63
53
52
62
77
70
51
65
63
51
63
50
The scope of the reaction was studied employing different
carbonyl compounds under the optimal conditions for the
exclusive generation of intermediate 3 (i.e., DTBB, THF, ꢀ78 ꢁC
and Barbier-type conditions), and also for the exclusive genera-
n-Pr
c-C3H5
(CH2)5
Ph
t-Bu
i-Pr
Me
H
H
H
Et
tion of
4
(i.e., naphthalene, Et2O, 25 ꢁC and Grignard-type
conditions). Both procedures are general for aldehydes and
ketones giving the corresponding alcohols (9 or 10, respectively)
in satisfactory isolated yields and as the only reaction products
(Table 4).
Ph
Et
9
10
11
12
13
14
15
16
n-Pr
c-C3H5
(CH2)5
Ph
t-Bu
i-Pr
n-Pr
c-C3H5
Me
H
H
2.3. Stability of cyclopropylmethyl- and cyclobutyl
methyllithium intermediates
7g
7h
Ph
H
a
Method A: (a) (chloromethyl)cyclopropane, Li (1.8 equiv), DTBB (5 mol %),
electrophile (1.1 equiv), THF, ꢀ78 ꢁC, 60 min; (b) H2O. Method B: (a) (chloro-
methyl)cyclopropane, Li (1.8 equiv), naphthalene (5 mol %), Et2O, 0 ꢁC, 60 min;
(b) electrophile (1.1 equiv), 0 ꢁC, 30 min; (c) H2O.
Isolated yield of pure (>95%) products 6 and 7 after column chromatography
(silica gel, hexane/ethyl acetate).
Finally, we studied the stability of cyclopropylmethyllithium 1
and cyclobutylmethyllithium 3 under the lithiation reaction
conditions employed. For that purpose, the silane derivatives 11
and 12 were prepared by means of the optimal conditions
described previously employing PhMe2SiCl as electrophile
b
Table 3
Arene-catalyzed lithiation of (bromomethyl)cyclobutane and SE reaction with 3-pentanonea
Method
Entry
T (ꢁC)
Timeb (min)
Arene
Solvent
Yieldc (%)
9a
10a
Total
Barbier-type
conditions
1
2
ꢀ78
60
60
DTBB
DTBB
THF
THF
88
44
0
34
88
78
0
Grignard-type
conditions
3
4
5
6
25
0
0
60þ30
90þ30
60þ30
60þ30
Naphthalene
Naphthalene
DTBB
Et2O
Et2O
THF
THF
0
0
13
7
89
78
35
34
89
78
48
41
0
Naphthalene
a
Reactions performed with (bromomethyl)cyclobutane (2 mmol), Li (7.1 mmol), arene (0.1 mmol), solvent (10 mL), and 3-pentanone (2.2 mmol).
Under Grignard conditions the given times correspond to the two steps (lithiation and reaction with the electrophile).
Yields of compounds 9a and 10a were calculated by 1H NMR using an internal standard (benzene).
b
c

I. Pe˜nafiel et al. / Tetrahedron 66 (2010) 2928–2935
2931
Table 4
Preparation of cyclobutyl alcohols 9 and unsaturated alcohols 10
Table 5
Formation of silyl derivatives 11–14 under different reaction conditionsa
Entry
Substrate
T (ꢁC)
Time (min)
Products
Ratiob
1
2
3
4
5
6
7
8
5
5
5
5
5
8
8
8
8
8
8
8
8
8
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ50
ꢀ50
ꢀ50
0
5
10
15
20
30
10
20
30
10
20
30
10
20
30
11/12
11/12
11/12
11/12
11/12
13/14
13/14
13/14
13/14
13/14
13/14
13/14
13/14
13/14
86:14
33:67
26:74
9:91
5:95
Entry
Methoda
R1
R2
Product
Yieldb (%)
>99:1
>99:1
>99:1
91:9
86:14
75:25
76:24
66:34
58:42
1
2
3
4
5
6
7
8
A
A
A
A
A
A
A
A
B
B
B
B
B
B
B
B
Et
Et
n-Pr
c-C3H5
9a
9b
9c
9d
9e
9f
9g
9h
10a
10b
10c
10d
10e
10f
10g
10h
74
58
52
70
49
46
47
70
59
69
49
62
28
55
60
35
n-Pr
c-C3H5
(CH2)5
Ph
t-Bu
i-Pr
9
10
11
12
13
14
Me
H
H
H
Et
0
0
Ph
Et
9
a
(Chloromethyl)cyclopropane or (bromomethyl)cyclobutane (1 mmol), Li
(1.8 equiv), DTBB (5 mol %), THF, then PhMe2SiCl (1.1 equiv).
10
11
12
13
14
15
16
n-Pr
c-C3H5
(CH2)5
Ph
t-Bu
i-Pr
n-Pr
c-C3H5
b
Ratio was determined by GLC.
Me
H
H
3. Conclusions
Ph
H
a
In summary, we have described herein that the arene-catalyzed
lithiation is an effective methodology for the selective generation of
cyclopropylmethyllithium 1 or but-3-enyllithium 2 intermediates
as well as cyclobutylmethyllithium 3 or pent-4-enyllithium 4
intermediates, by a chlorine–lithium exchange. In all cases, these
organolithiums react with different carbonyl compounds affording
the expected alcohols. The cycloalkylmethyllithium intermediates
have to be generated under milder reaction conditions [thus low
temperatures and an arene with high reduction potential
(i.e., DTBB)] than for the corresponding acyclic systems. In any
case, intermediates 1 and 3, even under these mild conditions, have
a short life time and give better results reacting immediately
with the corresponding electrophiles present in the reaction
medium (Barbier-type conditions). Additionally, in a comparative
experiment we have shown that cyclopropylmethyllithium is
less stable than the corresponding cyclobutylmethyllithium,
the former suffering almost complete rearrangement in 30 min
at ꢀ78 ꢁC.
Method A: (a) (bromomethyl)cyclobutane, Li (1.8 equiv), DTBB (5 mol %), electro-
phile (1.1 equiv), THF, ꢀ78 ꢁC, 60 min; (b) H2O. Method B: (a) (bromomethyl)cyclo-
butane, Li (1.8 equiv), naphthalene (5 mol %), Et2O, 25 ꢁC, 60 min; (b) electrophile
(1.1 equiv), 0–25 ꢁC, 30 min; (c) H2O.
b
Isolated yield of pure (>95%) products 9 and 10 after column chromatography
(silica gel, hexane/ethyl acetate).
(Scheme 3). Subsequently, a set of lithiation reactions of com-
pound 5 were quenched at different times with PhMe2SiCl pro-
ducing mixtures of products 11 and 12 (Table 5). The
rearrangement of cyclopropylmethyllithium 1 showed to be very
rapid at low temperature, the ratio 11/12 being 86:14 in just
5 min (Table 5, entry 1). Additionally, we observed that in 30 min
the intermediate 1 was almost completely converted into the
homoallyllithium 2 (Table 1, entry 5). In the same way, the silyl
derivatives 13 and 14, which were prepared from (bromome-
thyl)cyclobutane as described above, were used in the study of
the stability of intermediate 3 (Scheme 3, Table 5). As expected,
intermediate 3 probed to be very stable at low temperature,
rearrangement of the organolithium being not observed after
30 min at ꢀ78 ꢁC (Table 5, entries 6–8). Then, higher tempera-
tures were needed to detect certain transformation of in-
termediate 3 into 4 (Table 5, entries 9–14).
4. Experimental section
4.1. General
All lithiation reactions were carried out under argon atmo-
sphere in oven-dried glassware. All commercially available re-
agents (Acros, Aldrich, Fluka) were used without further
purification, except in the case of liquid electrophiles, which were
used freshly distilled. Commercially available anhydrous THF
(99.9%, water content ꢂ0.006%, Fluka) was used as solvent in all the
lithiation reactions. Lithium powder was commercially available
(MEDALCHEMY S.L.). IR spectra were measured with a Nicolet Im-
pact 400 D-FT Spectrometer. NMR spectra were recorded on
a Bruker Avance 300 and Bruker Avance 400 (300 and 400 MHz for
1H NMR, and 75 and 100 MHz for 13C NMR) using, except otherwise
stated, CDCl3 as solvent and TMS as internal standard; chemical
shifts are given in d (ppm) and coupling constants (J) in hertz. Mass
spectra (EI) were obtained at 70 eV on an Agilent 5973 spectrom-
eter, fragment ions in m/z with relative intensities (%) in paren-
thesis and High Resolution Mass Spectra (HRMS) analyses were
Scheme 3.

2932
I. Pe˜nafiel et al. / Tetrahedron 66 (2010) 2928–2935
carried out on a Finnigan MAT95S spectrometer. The purity of
volatile and the chromatographic analyses (GLC) were determined
with an Agilent 6890 N instrument equipped with a flame ioniza-
tion detector and a 30 m capillary column (0.25 mm diameter,
(52), 55 (35), 53 (19). HRMS [MþꢀH2O] calcd for C10H18
154.1358, found 154.1352.
4.2.5. 1-Cyclopropyl-2-phenylpropan-2-ol (6e). Yellow oil; tR 10.06;
0.25
m
m film thickness), using nitrogen (2 mL/min) as carrier gas,
Rf 0.32 (hexane/EtOAc 10:1); n
(film) 3407 (OH), 3076 cmꢀ1 (cyclo-
Tinjector¼275 ꢁC, Tcolumn¼60 ꢁC (3 min) and 60–270 ꢁC (15 ꢁC/min);
retention times (tR) are given in minutes under these conditions.
Thin layer chromatography was carried out on TLC plastic sheets
with silica gel 60 F254 (Merck).
propyl); dH 0.01 (1H, m, CHH ring), 0.09 (1H, m, CHH ring), 0.40 (2H,
m, CH2 ring), 0.56 (1H, m, CH ring),1.53 (1H, m, CHHCOH),1.58 (3H, s,
CH3),1.97 (1H, dd, J¼14.2, 5.62, CHHCOH), 2.27 (1H, s, OH), 7.23, 7.35,
7.48 (1H, 2H and 2H, 3m, 5ꢃArH); dC 4.4 (2ꢃCH2 ring), 6.0 (CH ring),
29.8 (CH3), 48.5 (CH2COH), 75.4 (COH), 124.8, 126.4, 128.0, 148.3
(6ꢃArC); m/z 176 (Mþ, 0,03%), 158 (27), 143 (100), 141 (18), 129 (48),
128 (76), 127 (17), 121 (25), 115 (41), 91 (17), 77 (22); HRMS
[MþꢀH2O] calcd for C11H14 158.1095, found 158.1095.
4.2. General procedure for the preparation of the alcohols 6
(Chloromethyl)cyclopropane (0.38 mL, 4 mmol) and the elec-
trophile (4.4 mmol) were added to a suspension of lithium powder
(100 mg, 14.2 mmol) and DTBB (53.2 mg, 0.2 mmol) in dry THF
(15 mL) at ꢀ78 ꢁC. The mixture was stirred for 60 min at the same
temperature. The reaction mixture was hydrolyzed with water
(10 mL), extracted with ethyl acetate (3ꢃ10 mL), and the organic
phase was dried over anhydrous magnesium sulfate. After
removing the solvent, under reduced pressure (15 Torr), the
resulting crude was purified by column chromatography (pH¼6.7–
7.3 silica gel, mixtures of hexane and EtOAc). Yields are given in
Table 2; analytical, physical and spectroscopic data, as well as
literature references for known compounds, follow.
4.2.6. 1-Cyclopropyl-3,3-dimethylbutan-2-ol (6f). Colorless oil; tR
8.2; Rf 0.29 (hexane/EtOAc 10:1);
n
(film) 3407 (OH), 3076 cmꢀ1
(cyclopropyl); dH 0.01, 0.13, 0.43, 0.52 (1H, 1H, 1H and 1H, 4m,
2ꢃCH2 ring), 0.83 (1H, m, CH ring), 0.88 (9H, s, 3ꢃCH3), 1.29 (2H, t,
J¼4.8, CH2CHOH), 1.76 (1H, s, OH), 3.36 (1H, t, J¼4.8, CHOH); dC 3.3,
5.1 (2ꢃCH2 ring), 8.6 (CH ring), 25.7 (3ꢃCH3), 34.5 (CCHOH), 36.4
(CH2CHOH), 80.4 (CHOH); m/z 142 (Mþ, 0.15%), 124 (22), 109 (54),
95 (25), 91 (13), 87 (52), 86 (10), 85 (43), 84 (24), 83 (21), 82 (15), 81
(47), 70 (23), 69 (57), 57 (78), 57 (100), 56 (37), 55 (79), 53 (22).
4.2.7. 1-Cyclopropyl-3-methylbutan-2-ol (6g). Colorless oil; tR
4.2.1. 3-(Cyclopropylmethyl)pentan-3-ol (6a). Colorless oil; tR 7.12;
10.29; Rf 0.29 (hexane/EtOAc 10:1); n
(film) 3431 cmꢀ1 (OH); dH 0.01
Rf 0.31 (hexane/EtOAc 10:1);
n
(film) 3301 cmꢀ1 (OH); dH 0.08 (2H,
(1H, m, CHH ring), 0.11 (1H, m, CHH ring), 0.45 (2H, m, CH2 ring),
0.75 (1H, m, CH ring), 0.89 (6H, d, J¼6.8, 2ꢃCH3), 1.33 (2H, m,
CH2CHOH), 1.68 (1H, m, CHCHOH), 1.73 (1H, br s, OH), 3.46 (1H, m,
CHOH); dC 3.5, 4.6 (2ꢃCH2 ring), 7.8 (CH ring), 17.2, 18.8 (2ꢃCH3),
33.2 (CHCHOH), 38.9 (CH2CHOH), 69.8 (CHOH); m/z 110 (MþꢀH2O,
8%), 95 (42), 91 (24), 85 (26), 81 (18), 77 (20), 73 (87), 72 (21), 70
(17), 69 (28), 67 (54), 57 (32), 56 (44), 55 (100), 54 (27), 53 (24);
HRMS [MþꢀH2O] calcd for C8H14 110.1095, found 110.1102.
m, CH2 ring), 0.6 (2H, m, CH2 ring), 0.70 (1H, m, CH ring), 0.87 (6H, t,
J¼7.5, 2ꢃCH3), 1.37 (2H, d, J¼6.7, CH2COH),1.41 (1H, s, OH), 1.55 (4H,
m, 2ꢃCH2CH3); dC 4.1 (2ꢃCH2 ring), 5.5 (CH ring), 7.9 (2ꢃCH3), 31.0
(2ꢃCH2CH3), 42.9 (CH2COH), 75.4 (COH); m/z 113 (MþꢀEt, 17%), 87
(100), 69 (15), 57 (83), 55 (10); HRMS calcd for C7H13O 113.0966,
found 113.0984.
4.2.2. 3-(Cyclopropylmethyl)heptan-4-ol (6b). Colorless oil; tR 9.59;
Rf 0.33 (hexane/EtOAc 10:1);
n
(film) 3397 (OH), 3076 cmꢀ1
4.2.8. 2-Cyclopropyl-1-phenylethanol (6h)19. Yellow oil; tR 9.23; Rf
(cyclopropyl); dH 0.05 (2H, m, CH2 ring), 0.43 (2H, m, CH2 ring), 0.65
(1H, m, CH ring), 0.90 (6H, t, J¼9.5, 2ꢃCH3), 1.30, 1.47 (6H and 5H,
2m, CH2COH, 2ꢃCH2CH2CH3); dC 4.1 (2ꢃCH2 ring), 5.6 (CH ring),
14.7 (2ꢃCH3), 16.8, 41.7 (2ꢃCH2CH2CH3), 43.9 (CH2COH), 75.2
(COH); m/z 152 (MþꢀH2O, 24%), 123 (24), 115 (40), 109 (51), 95 (37),
91 (26), 82 (18), 81 (100), 79 (40), 77 (21), 71 (33), 69 (38), 68 (17),
67 (57), 55 (75), 53 (19); HRMS [MþꢀH2O] calcd for C11H20
152.1565, found 152.1549.
0.32 (hexane/EtOAc 10:1); n
(film) 3364 (OH), 3076 cmꢀ1 (cyclo-
propyl); dH 0.01, 0.11, 0.44, 0.68 (1H, 1H, 2H and 1H, 2ꢃCH2 ring and
CH ring), 1.58–1.72 (2H, m, CH2CHOH), 2.17 (1H, s, OH), 4.76 (1H, dd,
J¼7.5, 5.8, CHOH), 7.25, 7.33 (1H and 4H, 2m, 5ꢃArH); dC 3.9, 4.4
(2ꢃCH2 ring), 7.6 (CH ring), 44.1 (CH2CHOH), 74.9 (CHOH), 125.8,
127.4, 128.3, 144.6 (6ꢃArC); m/z 162 (Mþ, 6.57%), 144 (29), 143 (24),
142 (21), 141 (23),129 (65), 128 (47), 115 (34), 107 (100), 105 (28), 79
(51), 77 (51), 51 (21).
4.2.3. 1,1,2-Tricyclopropylethanol (6c). Yellow oil; tR 9.26; Rf 0.38
(hexane/EtOAc 10:1);
4.3. General procedure for the preparation of the alcohols 7
n
(film) 3486 (OH), 3078 cmꢀ1 (cyclopropyl);
dH 0.11 (2H, m, CH2 ring), 0.36 (8H, m, 4ꢃCH2 ring), 0.46–0.51 (2H,
m, CH2 ring), 0.93 (3H, m, 3ꢃCH ring), 1.13 (1H, s, OH), 1.51 (2H, d,
J¼6.9, CH2COH); dC ꢀ0.6 (2ꢃCH2 ring), 0.8 (2ꢃCH2 ring), 4.4 (2ꢃCH2
ring), 6.0 (CH ring), 18.7 (2ꢃCH ring), 47.2 (CH2COH), 71.4 (COH);
m/z 166 (Mþ, 0.05%), 148.0 (10), 120 (26), 117 (22), 115 (15), 111 (33),
107 (13), 105 (16), 103 (10), 92 (29), 91 (100), 79 (67), 78 (19), 77
(40), 69 (21), 65 (17), 55 (10), 53 (11), 51 (11).
(Chloromethyl)cyclopropane (0.38 mL, 4 mmol) was added to
a suspension of lithium powder (100 mg, 14.2 mmol) and DTBB
(53.2 mg, 0.2 mmol) in THF (15 mL) at 0 ꢁC. The mixture was stirred
for 60 min and then, the corresponding carbonyl compound
(4.4 mmol) was added, continuing the stirring for 45 min at the
same temperature. The reaction mixture was hydrolyzed with
water (10 mL), extracted with ethyl acetate (3ꢃ10 mL), and the
organic phase was dried over anhydrous magnesium sulfate. After
removing the solvent, under reduced pressure (15 Torr), the
resulting crude was purified by column chromatography (pH¼6.7–
7.3 silica gel, mixtures of hexane and EtOAc). Yields are given in
Table 2; analytical, physical and spectroscopic data, as well as
literature references for known compounds, follow.
4.2.4. 1-(Cyclopropylmethyl)cyclohexanol (6d). Colorless oil; tR
10.53; Rf 0.29 (hexane/EtOAc 10:1);
n (film) 3386 (OH),
3073 cmꢀ1 (cyclopropyl); dH 0.07 (2H, m, CH2cyiclopropyl), 0.48
(2H, m, CH2 cyclopropyl), 0.77 (1H, m, CH cyclopropyl), 1.38 (2H,
d, J¼6.87, CH2COH), 1.21–1.31, 1.47–1.63, 1.68–1.77, 1.82–1.91,
2.32–2.36 (1H, 7H, 1H, 1H, and 1H, 5m, respectively, 5ꢃCH2
cyclohexyl and OH); dC 4.1 (2ꢃCH2 cyclopropyl), 5.3 (CH cyclo-
propyl), 22.2 (2ꢃCH2 cyclohexyl), 25.9 (CH2 cyclohexyl), 37.5
(2ꢃCH2 cyclohexyl), 47.1 (CH2COH), 72.3 (COH); m/z 154
(Mþ, 0.13%), 136 (44), 121 (28), 108 (17), 107 (40), 100 (42), 95
(56), 94 (37), 93 (62), 91 (35), 81 (64), 79 (100), 77 (32), 67
4.3.1. 3-Ethylhept-6-en-3-ol (7a)20. Colorless oil; tR 8.30; Rf 0.40
(hexane/EtOAc 10:1);
n
(film) 3437 (OH), 3077 cmꢀ1 (C]CH): dH
0.92 (6H, t, J¼7.5, 2ꢃCH3), 1.56 (4H, c, J¼7.5, 2ꢃCH2CH3), 1.59–
1.63 (2H, m, CH2COH), 1.90 (1H, s, OH), 2.09–2.17 (2H, m,
CH2CH]CH2), 4.98–5.12 (2H, m, CH]CH2), 5.94 (1H, ddt, J¼17.1,

I. Pe˜nafiel et al. / Tetrahedron 66 (2010) 2928–2935
2933
10.5, 6.3, CH]CH2); dC 8.2 (2ꢃCH3), 28.4 (CH2CH]CH2), 31.3
(2ꢃCH2CH3), 37.8 (CH2COH), 75.0 (COH), 114.6 (CH2]CH), 139.6
(CH2]CH); m/z 142 (Mþ, 0.02%), 124 (16), 95 (76), 87 (19), 67
(32), 57 (34), 55 (100).
(CH2]CH), 139.4 (CH2]CH); m/z 118 (Mþ, 0.04%), 109 (29), 87 (27),
85 (69), 84 (30), 83 (29), 81 (18), 71 (19), 70 (34), 69 (27), 68 (14), 67
(90), 57 (100), 56 (20), 55 (53).
4.3.8. 2-Methylhept-6-en-3-ol (7h)24. Yellow oil; tR 11.5; Rf 0.31
4.3.2. 4-Propyloct-7-en-4-ol (7b). Colorless oil; tR 10.18; Rf 0.4
(hexane/EtOAc 10:1); n
(film) 3348 (OH), 3064 cmꢀ1 (C]CH); dH
(hexane/EtOAc 10:1);
n
(film) 3394 (OH), 3077 cmꢀ1 (C]CH); dH
1.78 (2H, m, CH2CHOH), 2.08 (2H, m, CH2CH]CH2), 2.50 (1H, s, OH),
4.59 (1H, t, J¼5.8, CHOH), 5.02 (2H, m, CH]CH2), 5.79 (1H, ddt,
J¼17.0, 10.3, 6.6, CH2CH]CH2), 7.22–7.30 (5H, m, 5ꢃArH); dC 29.9,
37.9 (CH2CH2), 73.8 (CHOH), 114.8 (CH2]CH), 125.8, 127.4, 128.3,
144.5 (6ꢃArC), 138.1 (CH2]CH); m/z 162 (Mþ, 0.35%), 144 (39), 143
(22), 129 (100), 128 (56), 127 (14), 115 (38), 107 (22), 91 (17), 79 (14),
77 (17), 65 (14).
0.92 (6H, t, J¼7.0, 2ꢃCH3), 1.25–1.46, 1.51 (8H and 2H, respectively,
2m, 2ꢃCH2CH2CH3 and CH2COH), 2.07 (2H, m, CH2CH]CH2), 5.00
(2H, m, CH]CH2), 5.84 (1H, ddt, J¼16.9, 10.1, 6.5, CH]CH2); dC 15.3
(2ꢃCH3), 17.4 (2ꢃCH2CH3), 28.9 (CH2CH]CH2), 39.0 (CH2COH),
42.2 (2ꢃCH2 CH2CH3), 75.0 (COH), 114.9 (CH2]CH), 139.7
(CH2]CH); m/z 158 (Mþ, 0.01%), 152 (19), 127 (13), 123 (28), 115
(21), 110 (56), 109 (57), 95 (19), 82 (23), 81 (54), 79 (22), 77 (14), 71
(33), 69 (100), 67 (80), 55 (87), 53 (15); HRMS [MþꢀH2O] calcd for
152.1565, found 152.1481.
4.4. General procedure for the preparation of the alcohols 9
(Bromomethyl)cyclobutane (0.34 mL, 3 mmol) and the electro-
phile (3.3 mmol) were added to a suspension of lithium powder
(100 mg, 14.2 mmol) and DTBB (53.2 mg, 0.2 mmol) in THF (15 mL)
at ꢀ78 ꢁC. The mixture was stirred for 60 min at the same tem-
perature. The reaction mixture was hydrolyzed with water (10 mL),
extracted with ethyl acetate (3ꢃ10 mL), and the organic phase was
rinsed with brine solution (10 mL) and dried over anhydrous
magnesium sulfate. After removing the solvent under reduced
pressure (15 Torr), the resulting crude was purified by column
chromatography (pH¼6.7–7.3 silica gel, mixtures of hexane and
EtOAc). Yields are given in Table 4; analytical, physical and
spectroscopic data, as well as literature references for known
compounds, follow.
4.3.3. 1,1-Dicyclopropylpent-4-en-1-ol (7c). Yellow oil; tR 10.72; Rf
0.31 (hexane/EtOAc 10:1);
n
(film) 3382 (OH), 3073 cmꢀ1 (C]CH);
dH 0.26–0.43 (8H, m, 4ꢃCH2 ring), 0.80 (2H, m, 2ꢃCH ring), 0.92
(1H, s, OH), 1.64 (2H, m, CH2COH), 2.27 (2H, m, CH2CH]CH2), 5.01
(2H, m, CH2CH]CH2), 5.87 (1H, ddt, J¼17.0, 10.4, 6.4, CH]CH2); dC
0.6 (2ꢃCH2 ring), 0.7 (2ꢃCH2 ring), 18.5 (2ꢃCH ring), 28.3
(CH2CH]CH2), 41.5 (CH2COH), 70.7 (COH), 114.1 (CH2]CH), 139.4
(CH2]CH); m/z 166 (Mþ, 0.05%), 148 (25), 111 (20), 107 (16), 105
(44), 92 (18), 91 (90), 79 (100), 78 (15), 77 (41), 69 (14), 65 (18);
HRMS [MþꢀH2O] calcd for C11H16 148.1252, found 148.
4.3.4. 1-(But-3-enyl)cyclohexanol (7d)21. Yellow oil; tR 8.10.20; Rf
0.30 (hexane/EtOAc 10:1);
n
(film) 3423 cmꢀ1 (OH); dH 1.32–1.42,
1.44–1.60 (4H and 8H, 2 m, 5ꢃCH2 cyclohexyl and CH2COH), 2.12
(2H, m, CH2CH]CH2), 5.00 (2H, m, CH]CH2), 5.86 (1H, ddt, J¼17.0,
10.3, 6.6, CH]CH2); dC 22.1, 25.8, 37.4 (5ꢃCH2 ring), 27.4
(CH2CH]CH2), 41.9 (CH2COH), 71.3 (COH), 114.2 (CH2]CH), 139.3
(CH2]CH); m/z 154 (Mþ, 0.07%), 136 (44), 121 (26), 107 (24), 99
(27), 95 (100), 94 (33), 93 (34), 91 (24), 81 (32), 80 (17), 79 (52), 77
(24), 67 (70), 55 (36).
4.4.1. 3-(Cyclobutylmethyl)pentan-3-ol (9a). Yellow oil; tR 7.12; Rf
0.31 (hexane/EtOAc 10:1);
n
(film) 3457 (OH), 3060 cmꢀ1 (cyclo-
butyl); dH 0.84 (6H, t, J¼7.4, 2ꢃCH3), 1.35 (1H, s, OH), 1.42 (4H, m,
2ꢃCH2CH3), 1.52 (2H, d, J¼6.7, CH2COH),1.65–1.90, 2.01 (4H and 2H,
2m, 3ꢃCH2 ring), 2.44 (1H, m, CH ring); dC 7.8 (2ꢃCH3), 19.4 (CH2
ring), 29.7 (CH2), 31.3 (2ꢃCH2), 31.9 (CH), 45.5 (CH2), 75.2 (C); m/z
138 (MþꢀH2O, 17%), 127 (29), 87 (100), 69 (14), 57 (55), 55 (23).
4.3.5. 2-Phenylhex-5-en-2-ol (7e). Colorless oil; tR 11.60; Rf 0.30
4.4.2. 4-(Cyclobutylmethyl)heptan-4-ol (9b). Colorless oil; tR 10.5;
(hexane/EtOAc 10:1);
n
(film) 3405 (OH), 3062 cmꢀ1 (C]CH); dH
Rf 0.33 (hexane/EtOAc 10:1); n
(film) 3452 (OH), 2954 cmꢀ1
1.54 (3H, s, CH3), 1.89, 2.03 (3H and 1H, 2m, CH2CH2), 2.57 (1H, s,
OH), 4.93 (2H, m, CH]CH2), 5.77 (1H, m, CH2CH]CH2), 7.21, 7.31,
7.43 (1H, 2H and 2H, 3m, 5ꢃArH); dC 28.4 (CH2CH]CH2), 30.2
(CH3), 42.9 (CH2COH), 74.5 (COH), 114.0 (CH2]CH), 126.4, 128.2,
128.6, 147.6 (6ꢃArC), 138.6 (CH2]CH); m/z 176 (Mþ, 0.16%), 158
(43), 143 (100), 141 (19), 130 (20), 129 (65), 128 (84), 127 (16), 11
(24), 117 (13), 116 (13), 115 (61), 103 (13), 91 (31), 77 (24); HRMS
calcd for C12H16O 176.1201, found 176.1273.
(cyclobutyl); dH 0.90 (6H, t, J¼9.3, 2ꢃCH3), 1.12 (1H, s, OH), 1.24–
1.38 (8H, m, 2ꢃCH2CH2CH3), 1.54 (2H, d, CHCH2COH), 1.66–1.79,
1.83–1.92, 2.01–2.08 (3H, 1H and 2H, 3 m, 3ꢃCH2 ring), 2.44 (CH
ring); dC 14.6 (2ꢃCH3), 16.8 (2ꢃCH2CH3), 19.3 (CH2CH2CH2 ring),
30.11 (2ꢃCH2 ring), 31.9 (CH ring), 41.8 (2ꢃCH2CH2CH3), 46.5
(CH2COH), 74.9 (COH); m/z 166 (MþꢀH2O, 11%), 141 (15), 138
(15), 123 (14), 115 (46), 109 (16), 97 (15), 96 (16), 95 (100), 91
(10), 82 (13), 81 (45), 79 (21), 77 (27), 69 (20), 67 (58), 55 (79),
53 (18).
4.3.6. 2,2-Dimethylhept-6-en-3-ol (7f)22. Colorless oil; tR 7.76; Rf
0.44 (hexane/EtOAc 10:1);
n
(film) 3386 (OH), 3072 cmꢀ1 (C]CH);
4.4.3. 2-Cyclobutyl-1,1-dicyclopropylethanol (9c). Yellow oil; tR
dH 0.89 (9H, s, 3ꢃCH3), 1.36 (1H, m, CHHCHOH), 1.61 (1H, m,
CHHCHOH), 1.79 (1H, s, OH), 2.10 (1H, m, CHHCH]CH2), 2.32 (1H,
m, CHHCH]CH2), 3.20 (1H, m, CHOH), 5.02 (2H, m, CH]CH2), 5.85
(1H, ddt, J¼17.1, 10.3, 6.7, CH]CH2); dC 25.7 (3ꢃCH3), 30.7, 31.2
(CH2CH2), 34.9 (CCHOH), 79.3 (CHOH), 114.7 (CH2]CH), 138.9
(CH2]CH); m/z 130 (Mþ, 0.01%), 109 (29), 87 (27), 85 (69), 84 (30),
83 (29), 81 (18), 71 (19), 70 (34), 69 (27), 68 (14), 67 (90), 57 (100),
56 (20), 55 (53).
9.26; Rf 0.38 (hexane/EtOAc 10:1); n
(film) 3206 (OH), 3087 cmꢀ1
(cyclobutyl); dH 0.23–0.28, 0.31–0.40 (2H and 6H, 2m, 4ꢃCH2
cyclopropyl), 0.72–0.79 (2H, m, 2ꢃCH cyclopropyl), 0.87 (1H, s, OH),
1.67 (2H, d, J¼5.2, CH2COH), 1.70–1.84, 1.86–1.91, 2.03–2.11 (3H, 1H
and 2H, 3 m, 2ꢃCH2 cyclobutyl), 2.65 (1H, m, J¼5.8, CH cyclobutyl);
dC ꢀ0.7 (2ꢃCH2 cyclopropyl), 0.8 (2ꢃCH2 cyclopropyl), 18.5 (2ꢃCH
cyclopropyl), 19.09 (CH2 cyclobutyl), 30.1 (2ꢃCH2 cyclobutyl), 31.9
(CH cyclobutyl), 49.7 (CH2COH), 71.0; (COH); m/z 162 (MþꢀH2O,
2.6%), 134 (45), 119 (32), 111 (43), 106 (21), 105 (32), 91 (100), 79
(26), 78 (20), 77 (38), 69 (24), 65 (16); HRMS [MþꢀOH] calcd for
C12H19 163.1486, found 163.1479.
4.3.7. 2-Methylhept-6-en-3-ol (7g)23. Colorless oil; tR 7.03; Rf 0.33
(hexane/EtOAc 10:1);
n
(film) 3382 (OH), 3073 cmꢀ1 (C]CH); dH
0.87 (6H, d, J¼9.2, 2ꢃCH3), 1.38–1.67 (4H, m, CH2CHOHCH), 2.00–
2.24 (2H, m, CH2CH]CH2), 3.33 (1H, m, CHOH), 4.99 (2H, m,
CH]CH2), 5.80 (1H, ddt, J¼17.0, 10.1, 6.7, CH]CH2); dC 17.2, 18.7
(2ꢃCH3), 31.1, 33.8 (CH2CH2), 34.2 (CHCHOH), 76.1 (CHOH), 115.3
4.4.4. 1-(Cyclobutylmethyl)cyclohexanol (9d). Colorless oil; tR
10.75; Rf 0.29 (hexane/EtOAc 10:1);
n (film) 3138 (OH),
2934 cmꢀ1 (cyclobutyl); dH 1.21 (2H, m, CH2 ring), 1.32–1.40 (2H,

2934
I. Pe˜nafiel et al. / Tetrahedron 66 (2010) 2928–2935
m, CH2 ring), 1.46 (4H, m, 2ꢃCH2 ring), 1.56 (4H, m, 2ꢃCH2 ring),
10.66–1.84, 1.86–1.93 (3H and 1H, 2m, 2ꢃCH2 ring), 2.06 (2H, def
d, CH2COH); dC 19.4 (CH2 cyclobutyl), 22.1 (2ꢃCH2 cyclohexyl),
25.7 (CH2 cyclohexyl), 30.2 (2ꢃCH2 cyclobutyl), 31.6 (CH cyclo-
butyl), 37.5 (2ꢃCH2 cyclohexyl), 49.9 (CH2COH), 72.0 (COH); m/z
168 (Mþ, 0.18%), 101 (23), 99 (100), 98 (10), 81 (50), 79 (13), 55
(30); HRMS [MþꢀH2O] calcd for C11H18 150.1409, found
150.1372.
5.81 (1H, ddt, J¼17.2, 10.3, 6.5, CH2CH]CH2); dC 7.7 (2ꢃCH3), 22.7
(2ꢃCH2CH3), 31.0 (CH2CH2COH), 34.2 (CH2CH]CH2), 37.6 (CH2COH),
74.5 (COH), 114.5 (CH2]CH), 138.7 (CH2]CH); m/z 156 (Mþ, 0,03%),
127 (28), 87 (96), 86 (11), 69 (15), 57 (19); HRMS [MþþH] calcd for
C10H21O 157.1586, found 157.1580.
4.5.2. 4-Propylnon-8-en-4-ol (10b). Yellow oil; tR 10.53; Rf 0.30
(hexane/EtOAc 10:1);
n
(film) 3468 cmꢀ1 (OH); dH 0.91 (6H, t, J¼5.4,
2ꢃCH3), 1.27–1.37, 1.42 (4H and 8H, 2m, 2ꢃCH2CH2CH3 and
2ꢃCH2CH2COH), 2.05 (2H, m, CH2CH]CH2), 4.98 (2H, m, CH]CH2),
5.83 (1H, ddt, J¼12.6, 7.8, 5.1, CH]CH2); dC 14.7 (2ꢃCH3), 16.7
(2ꢃCH2CH3), 22.8 (2ꢃCH2CH2CH3), 34.2 (CH2CH]CH2), 38.7
(CH2CH2CH2), 41.6 (CH2COH), 74.4 (COH), 114.5 (CH]CH2), 138.8
(CH]CH2); m/z 166 [MþꢀH2O] (4.4%), 141 (23), 123 (22), 115 (55),
110 (24), 95 (27), 91 (12), 84 (24), 83 (26), 82 (18), 81 (58), 79 (26),
77 (17), 71 (66), 69 (62), 67 (58), 55 (100), 53 (27); HRMS [MþꢀEt]
calcd for C10H19O 155.1435, found 155.1430.
4.4.5. 1-Cyclobutyl-2-phenylpropan-2-ol (9e). Yelow oil; tR 12.11; Rf
0.30 (hexane/EtOAc 10:1); n
(film) 3439 cmꢀ1 (OH); dH 1.50 (4H, m,
OH and CH3), 1.55–1.85 (6H, m, 3ꢃCH2 ring), 1.82 (2H, m, J¼6.7,
CH2COH), 2.30 (1H, m, CH ring), 7.18–7.25, 7.40–7.46 (2H and 3H,
2m, 5ꢃArH); dC 19.3 (CH3), 24.8 (2ꢃCH2 ring), 29.7 (CH2 ring), 32.7
(CH ring), 51.4 (CH2CHOH), 78.8 (CHOH), 124.7, 127.3, 128.0, 143.4
(6ꢃArC); m/z 176 (Mþ, 0,08%), 122 (10), 105 (12), 121 (100), 78 (15),
77 (23).
4.4.6. 1-Cyclobutyl-3,3-dimethylbutan-2-ol (9f). Yellow oil; tR: 9.34;
4.5.3. 1,1-Dicyclopropylhex-5-en-1-ol (10c). Yellow oil; tR 10.73; Rf
Rf 0.31 (hexane/EtOAc 10:1);
n
(film) 3411 cmꢀ1 (OH); dH 0.88 (9H, s,
0.29 (hexane/EtOAc 10:1); n
(film) 3488 cmꢀ1 (OH); dH 0.24–0.31,
3ꢃCH3), 1.01 (1H, s OH), 1.7, 1.5, 1.67, 1.77–1.94 (1H, 2H, 1H, 2H, m,
3ꢃCH2 ring), 2.03–2.12 (2H, m, CH2CHOH), 2.44–2.54 (1H, m, CH
ring), 3.16 (1H, m, CHOH); dC 18.6 (CH2 ring), 25.6 (3ꢃCH3), 28.0
(2ꢃCH2 ring), 29.5 (CH ring), 34.7 (CHCHOH), 38.7 (CH2CHOH), 78.3
(CHOH); m/z 156 (Mþ, 0.01%), 99 (47), 95 (6), 87 (60), 81 (100), 71
(14), 70 (36), 69 (30), 57 (36), 55 (53).
0.33–0.45 (3H and 5H, 2m, 4ꢃCH2 ring),0.81 (2H, m, 2ꢃCH ring),
0.90 (1H, s, OH), 1.58 (2H, m, CH2COH), 2.07 (2H, m, CH2CH]CH2),
4.98 (2H, m, CH2CH]CH2), 5.84 (1H, ddt, J¼17.0,10.1, 6.7, CH]CH2);
dC ꢀ0.7 (2ꢃCH2 ring), 0.7 (2ꢃCH2 ring), 18.4 (2ꢃCH ring), 23.1
(CH2CH2CH2), 34.3 (CH2CH]CH2), 42.1 (CH2COH), 70.7 (COH), 114.3
(CH2]CH), 138.9 (CH2]CH); m/z 162 [MþꢀH2O] (3%), 121 (57), 111
(60), 105 (17), 93 (53), 92 (10), 91 (67), 80 (12), 79 (100), 78 (16), 77
(60), 69 (39), 67 (88), 65 (25), 55 (36); HRMS [MþꢀH2O] calcd for
C12H18 162.1409, found 162.1447.
4.4.7. 1-Cyclobutyl-3-methylbutan-2-ol (9g). Colorless oil; tR 10.29;
Rf 0.29 (hexane/EtOAc 10:1);
n
(film) 3383 cmꢀ1 (OH); dH 0.88 (6H,
d, J¼7.2, 2ꢃCH3), 1.45–1.58, 1.66–1.72, 1.73–1.79 (2H, 2H and 2H,
3m, 3ꢃCH2 ring), 1.83–1.92 (2H, m, CH2CHOH), 1.94–2.07 (1H, m,
CHCHOH), 2.4–2.7 (1H, m, CH ring); dC 18.5, 18.8 (2ꢃCH3), 20.21,
31.4, 31.8 (3ꢃCH2 ring), 34.4 (CH ring), 34.6 (CHCHOH), 43.0
(CH2CHOH), 70.2 (CHOH); m/z 142 (Mþ, 11%), 141 (100), 97 (37), 95
(13), 81 (16), 71 (45), 70 (45), 67 (12), 55 (39); HRMS [MþꢀH] calcd
for C9H17O 141.1274, found 141.1280.
4.5.4. 1-(Pent-4-enyl)cyclohexanol (10d)25. Yellow oil; tR 10.12; Rf
0.28 (hexane/EtOAc 10:1);
n
(film) 3392 cmꢀ1 (OH); dH 1.28–1.38,
1.44–1.60 (2H and 12H, 2m, 5ꢃCH2 cyclohexyl, CH2CH2COH and
CH2COH), 2.05 (2H, m, CH2CH]CH2), 4.97 (2H, m, CH]CH2), 5.81
(1H, ddt, J¼17.0,10.2, 6.6, CH]CH2); dC 22.1, 25.8, 37.4 (5ꢃCH2 ring),
22.2 (CH2CH2CH2), 34.2 (CH2CH]CH2), 41.8 (CH2COH), 71.3 (COH),
114.4 (CH2]CH), 138.8 (CH2]CH); m/z 168 (M), 141 (18), 124 (11),
123 (23), 115 (41), 110 (34), 95 (28), 84 (33), 83 (36), 82 (19), 81 (57),
79 (22), 77 (14), 71 (50), 69 (73), 67 (58), 55 (100), 53 (22); HRMS
[MþꢀOH] calcd for C11H19 151.1486, found 151.1488.
4.4.8. 2-Cyclobutyl-1-phenylethanol (9h)19. Yellow oil; tR 13.7; Rf
0.29 (hexane/EtOAc 10:1);
n
(film) 3358 (OH), 3029 cmꢀ1 (cyclo-
butyl); dH 1.54–2.07 (9H, m, 3ꢃCH2 ring, CH ring, and CHHCHOH),
2.57 (1H, s, OH), 2.31 (1H, m, CHHCHOH), 4.55 (1H, t, J¼6.9, CHOH),
7.21–7.32 (5H, m, CHAr); dC 18.6 (CH2 ring), 28.3 (2ꢃCH2 rin), 32.6
(CH ring), 46.2 (CH2CHOH), 72.9 (CHOH), 125.8, 127.2, 128.2, 144.8
(6ꢃArC); m/z 176 (Mþ, 3.81%), 107 (100), 79 (37), 77 (20), 51 (21);
HRMS calcd for C12H16O 176.1196, found 176.1197.
4.5.5. 2-Phenylhept-6-en-2-ol (10e). Colorless oil; tR 11.77; Rf 0.30
(hexane/EtOAc 10:1);
n
(film) 3405 (OH), 3062 cmꢀ1 (C]CH); dH
1.18–1.42 (2H, m, CH2CH2CH2), 1.53 (3H, s, CH3), 1.79 (2H, m,
CH2CHOH), 1.98 (3H, m, CH2CH]CH2 and OH), 4.88–4.97 (2H, m,
CH]CH2), 5.65 (1H, ddt, J¼17.1, 10.3, 6.7, CH]CH2), 7.17–7.21,
7.22–7.36, 7.37–7.42 (1H, 1H and 3H, 3m, 5ꢃArH); dC 23.2
(CH2CH2CH2), 33.8 (CH2CH]CH2), 43.5 (CH2COH), 74.5 (CHOH),
114.5 (CH2]CH), 138.5 (CH2]CH), 124.7, 126.4, 128.0, 147.9
(6ꢃArC); m/z 176 (Mþ, 0.06%), 144 (8), 131 (15), 121 (100), 115
4.5. General procedure for the preparation of the alcohols 10
(Bromomethyl)cyclobutane (0.34 mL, 3 mmol) was added to
a suspension of lithium powder (100 mg, 14.2 mmol) and DTBB
(53.2 mg, 0.2 mmol) in THF (15 mL) at 0 ꢁC. The mixture was stirred
for 60 min and then, the corresponding carbonyl compound
(3.3 mmol) was added, continuing the stirring for 45 min at the
same temperature. The reaction mixture was hydrolyzed with
water (10 mL), extracted with ethyl acetate (3ꢃ10 mL), and the
organic phase was dried over anhydrous magnesium sulfate. After
removing the solvent, under reduced pressure (15 Torr), the
resulting crude was purified by column chromatography (pH¼6.7–
7.3 silica gel, mixtures of hexane and EtOAc). Yields are given in
Table 4; analytical, physical and spectroscopic data, as well as lit-
erature references for known compounds, follow.
(12), 105 (20), 91 (31), 77 (24); HRMS [Mþ] calcd for C13H18
190.1358, found 190.1358.
O
4.5.6. 2,2-Dimethyloct-7-en-3-ol (10f)22. Colorless oil; tR 8.25; Rf
0.32 (hexane/EtOAc 10:1);
(film) 3420 (OH), 3064 cmꢀ1 (C]CH);
n
dH 0.89 (9H, s, 3ꢃCH3), 1.18–1.29, 1.40, 1.52, 1.66 (1H, 1H, 1H and 1H,
4m, CH2CH2CHOH), 2.01–2.13 (2H, m, CH2CH]CH2), 3.14–.3.19 (1H,
m, CHOH), 5.83–5.04 (2H, m, CH]CH2), 5.81 (1H, ddt, J¼17.1, 10.5,
6.6, CH]CH2); dC 25.6 (3ꢃCH3), 26.3 (CH2CH2CH2), 30.8 (CCHOH),
31.2 (CH2CHOH), 33.7 (CH2CH]CH2), 79.8 (CHOH), 114.5
(CH2]CH),138.8 (CH2]CH); m/z 156 (Mþ, 0.02%),141 (49),113 (12),
99 (50), 89 (48), 81 (100) 69 (43), 67 (41), 55 (53); HRMS
[MþꢀH2OꢀH] calcd for C10H17 137.1330, found 137.1337.
4.5.1. 3-Ethyloct-7-en-3-ol (10a). Colorless oil; tR 8.57; Rf 0.32 (hex-
ane/EtOAc 10:1); n
(film) 3365 (OH), 3068 cmꢀ1 (C]CH); dH 0.86 (6H,
t, J¼7.5, 2ꢃCH3), 1.17 (1H, s, OH), 1.40–1.50 (8H, m, 2ꢃCH2CH3 and
4.5.7. 2,2-Dimethyloct-7-en-3-ol (10g)26. Colorless oil; tR 7.03; Rf
CH2CH2CHOH), 2.06 (2H, CH2CH]CH2), 5.00 (2H, m, CH2CH]CH2),
0.30 (hexane/EtOAc 10:1);
n
(film) 3420 (OH), 2959 cmꢀ1 (C]CH);

I. Pe˜nafiel et al. / Tetrahedron 66 (2010) 2928–2935
2935
dH 0.91 (6H, d, J¼5.3, 2ꢃCH3),1.38–1.67 (4H, m, CH2CHOHCH), 2.00–
2.24 (2H, m, CH2CH]CH2), 3.33 (1H, m, CHOH), 4.99 (2H, m,
CH]CH2), 5.80 (1H, ddt, J¼17.0, 10.1, 6.7, CH]CH2); dC 17.2, 18.7
(2ꢃCH3), 31.1, 33.8 (CH2CH2), 34.2 (CHCHOH), 76.1 (CHOH), 115.3
(CH2]CH), 139.4 (CH2]CH); m/z 118 (Mþ, 0.04%), 109 (29), 87 (27),
85 (69), 84 (30), 83 (29), 81 (18), 71 (19), 70 (34), 69 (27), 68 (14), 67
(14), 121 (25), 105 (8); HRMS [MþꢀMe] calcd for C12H17Si 189.1100,
found 189.1122.
Acknowledgements
This work was generously supported by the Spanish Ministerio
(90), 57 (100), 56 (20), 55 (53); HRMS [Mþ] calcd for C9H18
142.1358, found 142.1357.
O
´
de Educacion y Ciencia [CTQ2004-01261, CTQ2007-65218, and
CONSOLIDER INGENIO 2010 (CSD2007-00006)], the Generalitat
Valenciana (GRUPOS 03/135, GV05/52, GV/2007/036, GVPRE/2008/
278 and PROMETEO 2009/039) and the Universidad de Alicante. I.P.
4.5.8. 1-Phenylhex-5-en-1-ol (10h). Yellow oil; tR 11.5; Rf 0.30 (hex-
ane/EtOAc 10:1);
(film) 3368 (OH), 3063 cmꢀ1 (C]CH); dH 1.32,
n
´
thanks the Spanish Ministerio de Educacion y Ciencia for a pre-
1.36–1.50, 1.52–1.81 (1H, 1H and 2H, 3m, CH2CH2CHOH), 1.98–2.07
(2H, m, CH2CH]CH2), 2.55 (1H, s, OH), 4.58 (1H, m, CHOH), 4.90–5.00
(2H, m, CH]CH2), 5.75 (1H, ddt, J¼17.1,10.2, 6.6, CH2CH]CH2), 7.21–
7.33 (5H, m, ArH); dC 33.5 (CH2CH2CH2), 38.4 (CH2CH]CH2), 65.3
(CH2CHOH), 74.7 (CHOH), 114.6 (CH2]CH), 140.8 (CH2]CH), 127.6,
128.4, 128.5, 144.9 (6ꢃArC); m/z 176 (Mþ, 0.16%), 158 (43), 143 (100),
141 (19),130(20),129(65),128(84),127 (16),11 (24),117 (13),116 (13),
doctoral fellowship. We also thank Medalchemy S.L. for a gift of
chemicals, especially lithium powder.
References and notes
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115 (61), 103 (13), 91 (31), 77 (24); HRMS [Mþ] calcd for C12H16
176.1201, found 176.1209.
O
2. (a) Na´jera, C.; Yus, M. Trends Org. Chem. 1991, 2, 155–181; (b) Na´jera, C.; Yus, M.
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´
(f) Najera, C.; Yus, M. Curr. Org. Chem. 2003, 7, 867–926; (g) Chinchilla, R.;
Following the same procedures as described for the preparation
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follow.
Na´jera, C.; Yus, M. Chem. Rev. 2004, 104, 2667–2722; (h) Chinchilla, R.; Na´jera,
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2005, 61, 3125–3450; (j) Brandsma, L.; Zwikker, J. W. Sci. Synth. 2006, 8a, 243–
252; (k) Foubelo, F.; Yus, M. Chem. Soc. Rev. 2008, 37, 2620–2633.
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n
(film) 3069 cmꢀ1 (CH
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ring); dH 0.10 (1H, m, CHH ring), 0.33 (1H, m, CHH ring), 0.37 (2H, m,
CH2 ring), 0.42 (6H, s, 2ꢃCH3), 0.46 (1H, m, CH ring), 0.92 (2H, d,
J¼6.4, CH2Si), 7.34–7.61 (5H, m, 5ꢃArH); dC 0.7 (2ꢃCH3), 0.82
(2ꢃCH2 ring), 6.1 (CH ring), 31.3 (CH2Si), 126.6, 127.7, 133.0, 149.9
(6ꢃArC); m/z 190 (Mþ, 2.3%),175 (8),136 (14),135 (100),121 (8),107
(6), 105 (8), 91 (8).
4.6.2. (But-3-en-1-yl)dimethyl(phenyl)silane (12). Yield 94%; yel-
low oil; tR 10.60; Rf 0.30 (hexane/EtOAc 10:1);
n
(film) 2986 cmꢀ1
(C]CH); dH 0.25 (6H, s, 2ꢃCH3), 0.85 (2H, m, CH2Si), 2.06 (2H, m,
CH2CH]CH2), 4.94 (2H, m, CH]CH2), 5.86 (1H, ddt, J¼17.0,10.1, 6.2,
CH2CH]CH2), 7.33, 7.50 (3H and 2H, 2m, 5ꢃArH); dC 0.8 (2ꢃCH3),
14.8 (CH2Si), 27.9 (CH2CH]CH2), 112.8 (CH2]CH), 127.7, 128.8,
132.9, 141.4 (6ꢃArC), 139.2 (CH2]CH); m/z 190 (Mþ, 5.4%), 175 (16),
162 (13), 136 (14), 135 (100), 121 (25), 105 (10).
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4.6.3. (Cyclobutylmethyl)dimethyl(phenyl)silane (13). Yield 73%;
colorless oil; tR 10.60; Rf 0.27 (hexane);
n
(film) 2955 cmꢀ1 (CH
ring); dH 0.25 (6H, s, 2ꢃCH3), 0.98 (2H, d, J¼7.5, CH2Si), 1.53–1.68
(2H, m, CH2 ring), 1.7–1.8 (2H, m, CH2 ring), 2.0–2.09 (1H, m, CH
ring), 7.34, 7.45 (3H and 2H, 2 m, 5ꢃArH); dC 0.8 (2ꢃCH3), 18.5 (CH2
ring), 24.8 (CH2Si), 32.4 (CH ring), 32.8 (2ꢃCH2 ring), 127.6, 127.9,
133.5, 139.9 (6ꢃArC); m/z 204 (Mþ, 0.05%), 176 (5), 161 (4), 136 (14),
135 (100), 107 (11), 105 (16), 91 (10); HRMS [Mþ] calcd for C13H20Si
204.1334, found 204.1321.
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4.6.4. (Dimethyl)pent-4-en-1-yl(phenyl)silane (14). Yield 84%; yel-
low oil; tR 11.60; Rf 0.29 (hexane/EtOAc 10:1);
n
(film) 2958 cmꢀ1
(C]CH); dH 0.32 (6H, s, 2ꢃCH3), 0.83 (2H, m, CH2Si), 1.47 (2H, m,
CH2CH2CH2), 2.12 (2H, m, CH2CH]CH2), 5.01 (2H, m, CH]CH2),
5.82 (1H, m, CH2CH]CH2), 7.39, 7.55 (3H and 2H, 2m, 5ꢃArH); dC
3.1 (2ꢃCH3), 15.3 (CH2Si), 23.4 (CH2CH2CH2), 37.5 (CH2CH]CH2),
114.5 (CH2]CH), 127.7, 128.7, 133.5, 139.5 (6ꢃArC), 138.8
(CH2]CH); m/z 204 (Mþ, 0.04%), 161 (9), 136 (14), 135 (100), 126
25. Hu, N. X.; Aso, Y.; Otsubo, T.; Ogura, F. J. Org. Chem. 1989, 54, 4391–4397.
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