3-chloropropyl and 4-chlorobutyl phenyl ethers as sources of 1,3-dilithiopropane and 1,4-dilithiobutane: Sequential reaction with carbonyl compounds

Article abstract of DOI:10.1021/jo000039m

The reaction of 3-chloropropyl and 4-chlorobutyl phenyl ethers (1) with lithium powder and a catalytic amount of DTBB (5% molar) in THF at - 78 °C followed by successive treatment with a carbonyl compound [R¹R²CO = Bu^tCHO, Me₂CO, (CH₂)₅CO, (-)-menthone] at -78 to 20 °C and, after 1.5 h at this temperature, with a second one [R³R⁴CO = Bu¹CHO, PhCHO, Me₂CO, MeCOPrⁿ, (CH₂)₅CO, (-)-menthone] at -78 °C leads, after hydrolysis with water, to the corresponding 1,5-and 1,6-diols (2). Because of the competition of two different reductive cleavages, 1,4- and 1,5-diols 3 were also obtained as side-reaction products.

Full text of DOI:10.1021/jo000039m

3478
J . Org. Chem. 2000, 65, 3478-3483
3-Ch lor op r op yl a n d 4-Ch lor obu tyl P h en yl Eth er s a s Sou r ces of
1,3-Dilith iop r op a n e a n d 1,4-Dilith iobu ta n e: Sequ en tia l Rea ction
w ith Ca r bon yl Com p ou n d s†
Francisco Foubelo,* Sadiq A. Saleh,‡ and Miguel Yus*
Departamento de Quı´mica Orga´nica, Facultad de Ciencias, Universidad de Alicante, Apdo. 99,
03080 Alicante, Spain
Received J anuary 11, 2000
The reaction of 3-chloropropyl and 4-chlorobutyl phenyl ethers (1) with lithium powder and a
catalytic amount of DTBB (5% molar) in THF at -78 °C followed by successive treatment with a
carbonyl compound [R1R2CO ) ButCHO, Me2CO, (CH2)5CO, (-)-menthone] at -78 to 20 °C and,
after 1.5 h at this temperature, with a second one [R3R4CO ) ButCHO, PhCHO, Me2CO, MeCOPrn,
(CH2)5CO, (-)-menthone] at -78 °C leads, after hydrolysis with water, to the corresponding 1,5-
and 1,6-diols (2). Because of the competition of two different reductive cleavages, 1,4- and 1,5-diols
3 were also obtained as side-reaction products.
In tr od u ction
be prepared by bromine-lithium exchange in moderate
yield,2 the process has been widely used for the genera-
tion of cyclobutane derivatives by a δ-elimination using
both 1,4-dibromo or 1,4-diiodo compounds.10 In all cases,
when the 1,3- or 1,4-dilithioalkane is generated, the same
electrophilic fragment is introduced at the lithiated
centers, being impossible to discriminate both carbanionic
atoms in order to introduce two different electrophiles
in the molecule. In the past few years, we have been
using an arene-catalyzed lithiation reaction4,5 for the
preparation of very unstable functionalized organo-
lithium compounds11 startingfrom chlorinated materials,12a
thioethers,12b sulfones,12c or heterocyclic derivatives.12d,13,14
Recently, we discovered that this methodology can be
applied to the generation of alkyllithiums from alkyl
phenyl ethers.15 In this paper, we report the preparation
The problem of introducing two electrophilic fragments
in a 1,3- or 1,4-position in a hydrocarbon chain is the need
of using 1,3- or 1,4-dianionic synthons. This type of
species is normally exemplified by the corresponding
organometallic compounds, dilithio derivatives being very
representative in this context.1 1,3-Dilithioalkanes cannot
be generated directly from the corresponding dihalides2
because the 3-halogenlithioalkane initially formed under-
goes spontaneous γ-elimination, even at very low tem-
peratures, giving the corresponding cyclopropane deriva-
tives.3 Only in special cases [for instance, starting from
3-chloro-2-(chloromethyl)propene] and reaction conditions
[combining an arene-catalyzed lithiation4,5 with carrying
out the reaction in the presence of the electrophile
(Barbier-type conditions)6] was it possible to introduce
as many electrophilic fragments as there were chlorine
atoms present in the starting materials.7,8 Except in the
mentioned case, a mercury-lithium transmetalation is
the only way to generate nonstabilized 1,3-dilithiated
intermediates.9 For 1,4-dilithioalkanes, although they can
(7) (a) Ramo´n, D. J .; Yus, M. Tetrahedron Lett. 1992, 33, 2217-
2220. (b) Go´mez, C.; Ramo´n, D. J .; Yus, M. Tetrahedron 1993, 49,
4117-4126. (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.
(8) Previous paper on the generation of polylithiated synthons from
our laboratory: Go´mez, C.; Huerta, F. F.; Yus, M. Tetrahedron 1998,
54, 1853-1866.
* Address correspondence to M.Y. Fax: +34-965-903549. E-mail:
yus@ua.es. URL: http://www. ua.es/dept.quimorg/.
† This paper is dedicated to Prof. R. D. Rieke on occasion of his 60th
birthday.
(9) See, for instance: (a) Seetz, J . W. F. L.; Schot, G.; Akkerman,
D. S.; Bickelhaupt, F. J . Am. Chem. Soc. 1982, 104, 6848-6849. (b)
Barluenga, J .; Villaman˜a, J .; Fan˜ana´s, F. J .; Yus, M. J . Chem. Soc.,
Chem. Commun. 1982, 355-356. (c) Barluenga, J .; Villaman˜a, J .;
Fan˜ana´s, F. J .; Yus, M. J . Chem. Soc., Perkin Trans. 1 1984, 2689-
2692.
‡ On leave (J une-August, 1999) from Yarmouk University, Irbid,
J ordan.
(1) For reviews, see: (a) Maerker, A.; Theis, M. Top. Curr. Chem.
1987, 138, 1-61. (b) Maerker, A. In Lithium Chemistry; Sapse, A.-M.,
Schleyer, P. v. R., Eds.; J . Wiley & Sons: New York, 1995; pp 477-
577. (c) Foubelo, F.; Yus, M. Trends Org. Chem. 1998, 7, 1-26.
(2) (a) West, R.; Rochow, E. G. J . Org. Chem. 1953, 18, 1739-1742.
(b) See, also: Shimp, L. A.; Lagow, R. J . Org. Chem. 1979, 44, 2311-
2312.
(3) See, for instance: (a) Barluenga, J .; Flo´rez, J .; Yus, M. Synthesis
1983, 647-649. (b) Barluenga, J .; Ferna´ndez-Simo´n, J . L.; Concello´n,
J . M.; Yus, M. Synthesis 1987, 584-586.
(4) First account: Yus, M.; Ramo´n, D. J . J . Chem. Soc., Chem.
Commun. 1991, 398-400.
(5) For reviews, see: (a) Yus, M. Chem. Soc. Rev. 1996, 155-161.
(b) Ramo´n, D. J .; Yus, M. Eur. J . Org. Chem., in press (Microreview).
For a polymer supported arene-catalyzed version of this reaction, see:
(c) Go´mez, C.; Ruiz, S.; Yus, M. Tetrahedron Lett. 1998, 39, 1397-
1400. (d) Go´mez, C.; Ruiz, S.; Yus, M. Tetrahedron 1999, 55, 7017-
7026.
(6) (a) Blomberg, C. The Barbier reaction and related one step
processes; Springer-Verlag: Berlin, 1993. (b) Alonso, F.; Yus, M. Recent
Res. Devel. Org. Chem. 1997, 1, 397-436.
(10) See, for instance: (a) Bailey, W. F.; Garnier, R. P.; Patricia, J .
J . J . Org. Chem. 1984, 49, 2098-2107. (b) Ramig, K.; Dong, Y.; van
Arnum, S. D. Tetrahedron Lett. 1996, 37, 443-446.
(11) For reviews, see: (a) Na´jera, C.; Yus, M. Trends Org. Chem.
1991, 2, 155-181. (b) Na´jera, C.; Yus, M. Recent Res. Devel. Org. Chem.
1997, 1, 67-96.
(12) Previous paper on this topic from our laboratory: (a) Ortiz, J .;
Guijarro, A.; Yus, M. Tetrahedron 1999, 55, 4831-4842. (b) Foubelo,
F.; Gutie´rrez, A.; Yus, M. Synthesis 1999, 503-514 (Feature Article).
(c) Alonso, D. A.; Alonso, E.; Na´jera, C.; Ramo´n, D. J .; Yus, M.
Tetrahedron 1997, 53, 4835-4856. (d) Soler, T.; Bachki, A.; Falvello,
L. R.; Foubelo, F.; Yus, M. Tetrahedron: Asymmetry 1998, 9, 3939-
3943.
(13) For a review, see: Yus, M.; Foubelo, F. Rev. Heteroatom Chem.
1997, 17, 73-107.
(14) This methodology has shown to be useful for the preparation
of simple organolithium compounds starting from nonhalogenated
materials. (a) For a review, see: Guijarro, D.; Yus, M. Recent Res.
Devel. Org. Chem. 1998, 2, 713-744. (b) Previous paper on this topic
from our laboratory: Alonso, E.; Guijarro, D.; Mart´ınez, P.; Ramo´n,
D. J .; Yus, M. Tetrahedron 1999, 55, 11027-11038.
10.1021/jo000039m CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/04/2000

Sources of 1,3-Dilithiopropane and 1,4-Dilithiobutane
Ta ble 1. P r ep a r a tion of Diols 2
J . Org. Chem., Vol. 65, No. 11, 2000 3479
a
b
All compounds 2 were >95% pure (GLC and/or 300 MHz 1H NMR). Isolated overall yield of pure compounds after column
chromatography (silica gel, hexane/ethyl acetate) based on the starting chloroether 1. c Ca. 1/1 diastereomeric mixture (75 MHz 13C NMR).
Compounds 3a was isolated as a side reaction product in less than 15% yield. e Compound 3b was isolated as a side reaction product in
d
less than 15% yield. f 4-5/1 diastereomeric mixture (75 MHz 13C NMR). Compound 3c was isolated as a side reaction product in less
g
h
i
than 15% yield. Compound 3d was isolated as a side reaction product in less than 15% yield. Compound 3e was isolated as a side
reaction product in less than 15% yield. Compound 3f was isolated as a side reaction product in less than 15% yield.
j
Sch em e 1
of new 1,3- and 1,4-dilithioalkane synthons, taking
advantage of the different reactivity of both carbon-
chlorine and carbon-oxygen bonds toward an arene-
catalyzed lithiation, making it possible to introduce two
different electrophilic fragments in the 1,3- or 1,4-
positions of the saturated hydrocarbon skeleton.16
a carbonyl compound [R1R2CO ) ButCHO, Me2CO,
(CH2)5CO, (-)-menthone] at the same temperature to
Resu lts a n d Discu ssion
form an alcoholate of type II. After 1.5 h of stirring at
20 °C, a second lithiation took place, leading to a inter-
mediate of type III, which reacted with a second carbonyl
compound [R3R4CO ) ButCHO, PhCHO, Me2CO, MeCO-
Prn, (CH2)5CO, (-)-menthone] at -78 °C to yield a
dialcoholate of type IV which, after hydrolysis with water
at -78 to 20 °C, gave the expected 1,5-diols 2 (Scheme
1, Chart 1 and Table 1, entries 1-12). When 4-chloro-
butyl phenyl ether (1b, prepared by treatment of 1-bromo-
4-chlorobutane with potassium phenolate in methanol in
95% yield) was submitted to the same protocol as 1a , 1,6-
diols 2 were obtained, the same intermediates I-IV being
involved (Scheme 1, Chart 1, and Table 1, entries 13-
19). In the case of using (-)-menthone as electrophile, a
The reaction of 3-chloropropyl phenyl ether (1a , easily
prepared by treatment of 1-bromo-3-chloropropane with
potassium phenolate in methanol in 90% yield) with a
dark green suspension of an excess of lithium powder
(1:10 molar ratio; theoretical amount, 1:4) and a catalytic
amount of 4,4′-di-tert-butylbiphenyl (DTBB; 1:0.1 molar
ratio; 5 mol %) in THF at -78 °C for 30 min gave a
solution of an intermediate of type I, which reacted with
(15) Bachki, A.; Foubelo, F.; Yus, M. Tetrahedron Lett. 1998, 39,
7759-7762.
(16) Preliminary communication: Foubelo, F.; Yus, M. Tetrahedron
Lett. 1999, 40, 743-746.

3480 J . Org. Chem., Vol. 65, No. 11, 2000
Foubelo et al.
Ta ble 2. Isola tion of Diols 3
a
b
All compounds 3 were >95% pure (GLC and/or 300 MHz 1H NMR). Isolated overall yield of pure compounds after column
chromatography (silica gel, hexane/ethyl acetate) based on the starting chloroether 1.
Ch a r t 1
cleavage of carbon-oxygen bond of the alkyl group, and
the minor one, giving dialcoholates V, by cleavage of
the oxygen-phenyl bond. Trying to take advantage of
this undesired process, we attempted to improve the
yield for the preparation of diols 3 starting from the
chloroalkyl phenyl ethers 1a ,b. Thus, after chlorine-
lithium exchange and addition of the first carbonyl
compound [R1R2CO ) n-C11H23CHO, Ph(CH2)2CHO,
MeCOPrn, (n-C5H11)2CO, (CH2)7CO], water was used as
electrophile after the second lithiation instead of a new
carbonyl compound. Isolated yields of compouds 3 were
always lower than 25% in all cases, compounds 4 being
the major reaction products, which were characterized
by tandem MS-GC. All attempts to improve the yield in
diols 3 by changing the reaction temperatures during the
second lithiation step and the lithium-DTBB ratio failed
(Table 2). Even though the process for compounds 3 pro-
duces low yields, the reaction can be interesting from a
synthetic point of view due to the easy separation of the
diols 3 from the corresponding “reduced” compound 4.
As a conclusion, we describe here a new way to
generate the equivalents of the 1,3-dianion of propane
and the 1,4-dianion of butane and the introduction of two
different electrophiles in a sequential manner. This is
possible due to the different reactivities of the carbon-
chlorine and carbon-oxygen bond toward an arene-
catalyzed lithiation: carbon/chlorine exchange takes
place at -78 °C and carbon/oxygen reductive cleavage
needs temperatures above -40 °C to occur. When car-
bonyl compounds were used as electrophiles, 1,5- and 1,6-
diols were obtained. Compounds of this type have proven
to be appropriate starting materials for cyclic ethers by
intramolecular dehydration.17
4-5/1 mixture of diastereoisomers was obtained, due to
the two possible approaches of the organolithium especies
to the carbonyl group, the major isomers being those
shown in Table 1 (entries 10-12 and 19), which result
from the attack to the less sterically hindered face. On
the other hand, when two prostereogenic carbonyl com-
pounds were used as electrophiles, a ca. 1/1 diastereo-
meric mixture was obtained (Table 1, entries 1 and 13).
Benzaldehyde cannot be used as electrophile after the
first lithiation step because the corresponding formed
alcoholate of type II undergoes a benzylic cleavage
together with the expected ether cleavage, leading finally
to a complex mixture of products. In all cases, diols 3a -f
were obtained as side reaction products in less than 15%
yield, based on the starting material 1. An explanation
for this result comes from the fact that two reductive
cleavages in intermediates II can occur under the reac-
tion conditions during the second lithiation step (20 °C,
1.5 h): the major one leads to species of type III, after
Exp er im en ta l Section
Gen er a l Meth od s. Melting points are uncorrected. IR
spectra were recorded using NaCl plates for liquids or KBr
pellets for solid samples. 1H and 13C NMR spectra were
(17) See, for instance: (a) Almena, J .; Foubelo, F.; Yus, M. Tetra-
hedron 1995, 51, 3351- 3364. (b) Almena, J .; Foubelo, F.; Yus, M.
Tetrahedron 1995, 51, 3365-3374.

Sources of 1,3-Dilithiopropane and 1,4-Dilithiobutane
recorded at 300 and 75 MHz, respectively, using CDCl3 as
J . Org. Chem., Vol. 65, No. 11, 2000 3481
1640 cm-1; H NMR δ 0.86 (s, 9H), 1.25-1.84 (m, 8H), 3.11-
3.17 (m, 1H), 4.63-4.68 (m, 1H), 7.19-7.34 (m, 5H); 13C NMR
δ 23.2, 25.6, 30.85, 31.2, 34.8, 38.9, 74.3, 74.6, 79.6, 79.7, 125.8,
127.4, 128.3, 144.9; MS m/z 218 (M+-H2O, 2), 57 (100); HRMS
calcd for C15H22O 218.1670, found 218.1684.
1
1
solvent and TMS (0.00 ppm, H) and CDCl3 (77.00 ppm, 13C)
as internal standards; chemical shifts are given in δ (ppm)
and coupling constants (J ) are given in Hz. 13C NMR assign-
ments were made on the basis of DEPT experiments. Mass
spectra (EI) were obtained at 70 eV, fragment ions given in
m/z with relative intensities in parentheses. Elemental analy-
ses were performed by the Microanalyses Service at the
University of Alicante. High-resolution mass spectra were
performed by the corresponding service at the University of
Alicante. The purity of volatile products and the chromato-
graphic analyses (GLC) were determinated with a flame
ionization detector and a 12 m capillary column (0.2 mm diam,
0.33 mm film thickness), using nitrogen (2 mL/min) as carrier
gas, Tinjector) 275 °C, Tcolumn) 80 °C (3 min) and 80-270 °C
(15 °C/min). Thin-layer chromatography (TLC) was carried out
on Schleicher & Schuell F1500/LS 254 plates coated with a
0.2 mm layer of silica gel; Rf values are given under these
condtions. Column chromatography was performed using silica
gel 60 of 35-70 mesh. All starting materials were com-
mercially available (Acros, Aldrich, Fluka) of the best grade
and were used without further purification. THF was dried
over benzophenone ketyl under an argon atmosphere and
distilled before use.
2,7,7-Tr im et h yl-2,6-oct a n ed iol (2b): Rf 0.16 (silica gel;
hexane/ethyl acetate 2/1); IR (film) 3500-3100, 2934, 1440
cm-1; 1H NMR δ 0.89 (s, 9H), 1.22 (s, 6H), 1.26-1.69 (m, 8H),
3.21 (dd, J ) 8.6, 1.8 Hz, 1H); 13C NMR δ 21.7, 25.7, 27.6,
29.1, 29.3, 34.9, 43.6, 49.55, 71.0, 79.8; MS m/z 152 (M+
2H2O, 2), 43 (100); HRMS calcd for C11H20 152.1565, found
152.1591.
-
5-Meth yl-1-p h en yl-1,5-h exa n ed iol (2c): Rf 0.15 (silica gel;
hexane/ethyl acetate 2/1); IR (film) 3600-3180, 3019, 2932,
1643 cm-1; 1H NMR δ 1.24 (s, 3H), 1.33 (s, 3H), 1.36-1.74 (m,
6H), 2.85 (br s, 2H), 4.67 (dd, J ) 8.0, 5.5 Hz, 1H); 13C NMR
δ 29.25, 31.9, 39.45, 43.4, 48.45, 71.7, 74.3, 125.8, 127.4, 128.4,
144.85; MS m/z 190 (M+ - H2O, 5), 56 (100); HRMS calcd for
C13H18O 190.1357, found 190.1362.
2,6-Dim eth yl-2,6-n on a n ed iol (2d ): Rf 0.10 (silica gel;
hexane/ethyl acetate 2/1); IR (film) 3450-3080, 2932, 1443
cm-1; 1H NMR δ 0.92 (t, J ) 6.7 Hz, 3H), 1.16 (s, 3H), 1.22 (s,
6H), 1.20-1.42 (m, 10H), 1.98 (br s, 2H); 13C NMR δ 14.6, 18.5,
26.8, 27.7, 29.2, 31.85, 42.2, 44.3, 71.0, 72.8; MS m/z 152 (M+
- 2H2O, 3), 43 (100); HRMS calcd for C11H20 152.1565, found
152.1550.
1-(4-Hyd r oxy-4-m eth ylp en tyl)cycloh exa n ol (2e): Rf 0.12
(silica gel; hexane/ethyl acetate 2/1); IR (film) 3650-3120,
2921, 1640 cm-1; 1H NMR δ 1.14 (s, 6H), 1.17-1.54 (m, 16H),
2.08 (br s, 2H); 13C NMR δ 17.55, 22.2, 25.75, 29.2, 37.4, 42.6,
44.3, 70.95, 71.4; MS m/z 182 (M+ - H2O, 1), 43 (100); HRMS
calcd for C12H22O 182.1670, found 182.1668.
P r ep a r a tion of Ch lor oa lk yl P h en yl Eth er s 1. Gen er a l
P r oced u r e. Phenol (1.98 g, 21.0 mmol) was added to a
solution of KOH (1.25 g, 22.5 mmol) in methanol (40 mL) at
20 °C. After 10 min, the corresponding 1-bromo-n-chloroalkane
(20.0 mmol) was added, and stirring was continued at 60 °C
for 2 h. Then, the solvent was removed in a rotary evaporator,
and the residue was hydrolyzed with water and extracted with
ethyl acetate. The organic layer was dried over anhydrous Na2-
SO4 and evaporated (15 mmHg). The residue was purified by
column chromatography (silica gel; hexane) to yield pure
products 1. Yields and physical and spectroscopic data as well
as literature references follow.
1-(4-Hyd r oxy-5,5-d im eth ylh exyl)cycloh exa n ol (2f): Rf
0.18 (silica gel; hexane/ethyl acetate 2/1); IR (film) 3700-3120,
2940, 1446 cm-1; 1H NMR δ 0.89 (s, 9H), 1.23-1.66 (m, 18H),
3.21 (dd, J ) 10.4, 1.8 Hz, 1H); 13C NMR δ 20.3, 22.3, 25.7,
25.8, 31.6, 31.9, 37.3, 37.6, 71.5, 79.9; MS m/z 210 (M+ - H2O,
3-Ch lor op r op yl p h en yl eth er (1a ):18 98% yield; Rf 0.21
(silica gel; hexane); IR (film) 3064, 3042, 2965, 2942, 1603,
2), 55 (100); HRMS calcd for
228.2090.
C14H28O2 228.2089, found
1
1245 cm-1; H NMR δ 2.21 (quintet, J ) 6.1 Hz, 2H), 3.72 (t,
J ) 6.1 Hz, 2H), 4.09 (t, J ) 6.1, 2H), 6.88-6.96 (m, 3H), 7.24-
7.30 (m, 2H); 13C NMR δ 32.3, 41.5, 64.1, 114.5, 120.9, 129.45,
158.7; MS m/z 172 (M+, 13), 94 (100).
1-(4-Hyd r oxy-4-p h en ylbu tyl)cycloh exa n ol (2g): Rf 0.19
(silica gel; hexane/ethyl acetate 2/1); IR (film) 3650-3130,
1
3030, 2925, 1436 cm-1; H NMR δ 1.21-1.78 (m, 16H), 2.25
4-Ch lor obu tyl p h en yl eth er (1b):19 95% yield; Rf 0.27
(silica gel; hexane); IR (film) 3062, 3036, 2968, 2944, 1602,
1240 cm-1; 1H NMR δ 1.90-1.99 (m, 4H), 3.60 (t, J ) 6.1 Hz,
2H), 3.98 (t, J ) 6.1, 2H), 6.86-6.95 (m, 3H), 7.22-7.29 (m,
2H); 13C NMR δ 26.6, 29.3, 44.7, 66.8, 114.4, 120.6, 129.4,
158.8; MS m/z 186 (M+, 4), 94 (100).
(br s, 2H), 4.64 (dd, J ) 7.9, 5.5 Hz, 1H); 13C NMR δ 19.1,
22.15, 25.7, 37.2, 37.4, 39.5, 71.5, 74.3, 125.8, 127.3, 128.3,
144.9; MS m/z 230 (M+ - H2O, 4), 79 (100); HRMS calcd for
C
16H22O 230.1670, found 230.1695.
1-(4-Hydr oxy-4-m eth ylh eptyl)cycloh exan ol (2h ): Rf 0.16
(silica gel; hexane/ethyl acetate 2/1); IR (film) 3720-3080,
P r ep a r a tion of Com p ou n d s 2 a n d 3 fr om Ch lor oa lk yl
P h en yl Eth er s (1). Gen er a l P r oced u r e. To a blue suspen-
sion of lithium powder (0.105 g, 15.0 g atoms) and a catalytic
amount of 4,4′-di-tert-butylbiphenyl (0.040 g, 0.15 mmol) in
THF (5 mL) at -78 °C was added the corresponding chloro-
alkyl phenyl ether 1 (1.5 mmol) under nitrogen, and the
mixture was stirred for 30 min at the same temperature. The
corresponding carbonyl compound (1.6 mmol) was added, and
the cold bath was removed. Stirring was continued at 20 °C
for 1.5 h. Then, the reaction mixture was cooled -78 °C, and
1
2953, 1446 cm-1; H NMR δ 0.92 (t, J ) 6.7 Hz, 3H), 1.16 (s,
3H), 1.17-1.92 (m, 22H); 13C NMR δ 14.6, 17.1, 17.2, 22.2,
25.8, 26.85, 37.4, 42.4, 48.5, 44.3, 71.5, 72.85; MS m/z 210 (M+
- H2O, 1), 55 (100); HRMS calcd for C14H26O 210.1983, found
210.1955.
1-[3-(1-Hyd r oxycycloh exyl)p r op yl]cycloh exa n ol (2i):20
Rf 0.17 (silica gel; hexane/ethyl acetate 2/1); mp 122-123 °C
(pentane/dichloromethane); IR (KBr) 3450-3220, 2934, 1445
cm-1; 1H NMR δ 1.24-1.64 (m, 26H), 2.05 (br s, 2H); 13C NMR
δ 22.2, 25.8, 34, 37.5, 42.8, 71.5; MS m/z 222 (M+ - H2O, 2),
67 (100). Anal. Calcd for C15H28O2: C, 74.95; H, 11.74. Found:
C, 74.32; H, 11.71.
a
second electrophile (1.6 mmol in the case of carbonyl
compounds, 0.5 mL in the case of H2O) was added. After 5
min of stirring, the reaction mixture was hydrolyzed with
water and extracted with ethyl acetate. The organic layer was
dried over anhydrous Na2SO4 and evaporated (15 mmHg). The
residue was purified by column chromatography (silica gel;
hexane/ethyl acetate) and recrystallized to yield pure products
2 and 3. Yields and structures are included in Tables 1 and 2;
physical, analytical, and spectroscopic data as well as litera-
ture references follow.
(1S,2S,5R)-1-[3-(1-H yd r oxycycloh exyl)p r op yl]-2-iso-
p r op yl-5-m eth ylcycloh exa n ol (2j): Rf 0.51 (silica gel; hex-
ane/ethyl acetate 2/1); IR (film) 3560-3130, 2940, 1440 cm-1
;
1H NMR δ 0.79 (d, J ) 6.7 Hz, 3H), 0.81 (d, J ) 6.7 Hz, 3H),
0.82 (d, J ) 7.3 Hz, 3H), 0.86-2.04 (m, 27H); 13C NMR δ 17.1,
18.0, 20.4, 21.6, 22.1, 23.5, 25.3, 25.7, 27.8, 35.0, 37.1, 37.4,
41.6, 42.8, 46.6, 47.7, 71.2, 75.0; MS m/z 278 (M+ - H2O, 2),
55 (100); HRMS calcd for C19H34O 278.2610, found 278.2614;
6,6-Dim eth yl-1-ph en yl-1,5-h eptan ediol (2a): Rf 0.20 (silica
gel; hexane/ethyl acetate 2/1); IR (film) 3550-3120, 3023, 2928,
[R]25 ) +6.2° [c ) 1.0 (CH2Cl2)].
D
(1S,2S,5R)-1-(4-Hyd r oxy-4-m eth ylp en tyl)-2-isop r op yl-
5-m eth ylcycloh exa n ol (2k ): Rf 0.36 (silica gel; hexane/ethyl
(18) Yakabe, S.; Hirano, M.; Morimoto, T. Org. Prep. Proced. Int.
1998, 30, 218-222.
(19) Ogawa, A.; Sumino, Y.; Nanke, T.; Ohya, S.; Sonoda, N.; Hirao,
T. J . Am. Chem. Soc. 1997, 119, 2745-2746.
(20) Kostas, I. D.; Screttas, C. G. J . Org. Chem. 1997, 62, 5575-
5577.

3482 J . Org. Chem., Vol. 65, No. 11, 2000
Foubelo et al.
1
1
acetate 2/1); IR (film) 3600-3100, 2945, 1442 cm-1; H NMR
δ 0.87 (d, J ) 6.7 Hz, 3H), 0.89 (d, J ) 6.7 Hz, 3H), 0.90 (d, J
) 6.6 Hz, 3H), 1.22 (s, 6H), 0.94-2.06 (m, 17H); 13C NMR δ
18.6, 20.5, 22.4, 23.6, 25.5, 29.0, 35.1, 41.7, 44.5, 46.7, 47.9,
70.95, 75.1; MS m/z 220 (M+ - 2H2O, 4), 69 (100); HRMS calcd
1/1); IR (film) 3630-3120, 2945, 1454 cm-1; H NMR δ 0.88
(d, J ) 7.3 Hz, 3H), 0.89 (d, J ) 6.7 Hz, 3H), 0.91 (d, J ) 7.3
Hz, 3H), 0.96-2.14 (m, 15H), 3.62-3.67 (m, 2H); 13C NMR δ
18.1, 20.55, 22.4, 23.6, 25.4, 27.0, 28.0, 35.0, 37.4, 46.5, 48.6,
63.4, 74.8; MS m/z 214 (M+, 1), 111 (100); HRMS calcd for
for C16H28 220.2191, found 220.2195; [R]25 ) +9.1° [c ) 0.8
C
13H26O2 214.1933, found 214.1941; [R]25 ) +19.0° [c ) 0.6
D
D
(CH2Cl2)].
(CH2Cl2)].
2,2,9,9-Tet r a m et h yl-3,8-d eca n ed iol (2l): Rf 0.46 (silica
gel; hexane/ ethyl acetate 2/1); IR (film) 3450-3150, 2944, 1430
cm-1; 1H NMR δ 0.89 (s, 18H), 0.92-1.62 (m, 10H), 3.18-3.21
(m, 2H); 13C NMR δ 25.6, 26.9, 27.1, 31.4, 34.9, 79.7, 79.9; MS
m/z 194 (M+ - 2H2O, 1), 67 (100); HRMS calcd for C14H26
194.2034, found 194.2038.
2,8,8-Tr im eth yl-2,7-n on a n ed iol (2m ): Rf 0.28 (silica gel;
hexane/ethyl acetate 2/1); IR (film) 3600-3150, 2945, 1430
cm-1; 1H NMR δ 0.89 (s, 9H), 1.21 (s, 3H), 1.23 (s, 3H), 1.18-
1.64 (m, 8H), 2.22 (br s, 2H), 3.18 (dd, J ) 10.5, 1.2 Hz, 1H);
13C NMR δ 25.7, 27.6, 29.1, 29.25, 31.4, 32.0, 43.9, 49.5, 71.0,
79.8; MS m/z 184 (M+ - H2O, 1), 43 (100); HRMS calcd for
6,6-Dim eth yl-1,5-h ep ta n ed iol (3d ):23 Rf 0.20 (silica gel;
hexane/ethyl acetate 1/1); IR (film) 3630-3110, 2938, 1435
cm-1; H NMR δ 0.88 (s, 9H), 1.19-1.68 (m, 6H), 2.75 (br s,
1
2H), 3.18 (dd, J ) 9.8, 1.2 Hz, 1H), 3.63 (t, J ) 6.1 Hz, 2H);
13C NMR δ 23.1, 25.7, 30.8, 32.4, 34.9, 62.3, 79.7; MS m/z 127
[M+ - (CH3, H2O), 3], 57 (100).
1-(4-Hyd r oxybu tyl)cycloh exa n ol (3e):24 Rf 0.15 (silica
gel; hexane/ethyl acetate 1/1); IR (film) 3650-3120, 2943, 1436
cm-1; H NMR δ 1.18-1.56 (m, 16H), 2.24 (br s, 2H), 3.57 (t,
1
J ) 6.7 Hz, 2H); 13C NMR δ 18.9, 22.2, 25.8, 33.0, 37.35, 41.6,
62.4, 71.5; MS m/z 154 (M+ - H2O, 3), 55 (100).
(1S,2S,5R)-1-(4-H yd r oxyb u t yl)-2-isop r op yl-5-m et h yl-
cycloh exa n ol (3f): Rf 0.46 (silica gel; hexane/ethyl acetate
C
12H24O 184.1827, found 184.1806.
1
1/1); IR (film) 3600-3130, 2942, 1438 cm-1; H NMR δ 0.80
1-(5-Hyd r oxy-6,6-d im eth ylh ep tyl)cycloh exa n ol (2n ): Rf
0.39 (silica gel; hexane/ ethyl acetate 2/1); IR (film) 3620-3160,
2932, 1431 cm-1; 1H NMR δ 0.88 (s, 9H), 1.27-1.64 (m, 20H),
3.17 (dd, J ) 9.7, 4.2 Hz, 1H); 13C NMR δ 22.2, 22.8, 25.7,
27.6, 31.4, 34.9, 37.2, 37.5, 42.3, 71.4, 79.8; MS m/z 224 (M+-
H2O, 2), 41 (100); HRMS calcd for C15H28O 224.2140, found
224.2154.
(d, J ) 7.0 Hz, 3H), 0.82 (d, J ) 6.7 Hz, 3H), 0.83 (d, J ) 6.7
Hz, 3H), 0.86-1.71 (m, 16H), 1.98-2.04 (m, 1H), 3.59 (t, J )
6.7 Hz, 2H); 13C NMR δ 18.1, 20.1, 20.5, 22.4, 23.6, 25.5, 28.0,
33.3, 35.1, 40.9, 46.7, 47.8, 62.7, 75.1; MS m/z 210 (M+ - H2O,
6), 69 (100); HRMS calcd for C14H26O 210.1984, found 210.1999;
[R]25 ) +19.0° [c ) 0.6 (CH2Cl2)].
D
1-(5-Hyd r oxy-5-p h en ylp en tyl)cycloh exa n ol (2o): Rf 0.25
(silica gel; hexane/ethyl acetate 2/1); IR (film) 3520-3100,
1,4-P en ta d eca n ed iol (3g): Rf 0.26 (silica gel; hexane/ethyl
1
acetate 1/1); IR (film) 3600-3110, 2941, 1436 cm-1; H NMR
1
2931, 1442 cm-1; H NMR δ 1.21-1.82 (m, 18H), 2.23 (br s,
δ 0.88 (t, J ) 6.7 Hz, 3H), 1.26-1.72 (m, 26H), 3.63-3.71 (m,
3H); 13C NMR δ 14.1, 22.7, 25.7, 29.1, 29.3, 29.6, 29.65, 29.7,
31.9, 34.3, 37.6, 63.1, 72.0; MS m/z 226 (M+ - H2O, 3), 71 (100);
HRMS calcd for C15H30O 226.2297, found 226.2302.
2H), 4.62 (dd, J ) 7.3, 5.5 Hz, 1H), 7.23-7.33 (m, 5H); 13C
NMR δ 22.1, 22.6, 25.7, 26.3, 37.2, 37.3, 38.95, 71.4, 74.3, 125.8,
127.3, 128.3, 144.9; MS m/z 244 (M+- H2O, 3), 130 (100);
HRMS calcd for C17H24O 244.1827, found 244.1831.
6-P h en yl-1,4-h exa n ed iol (3h ): Rf 0.17 (silica gel; hexane/
ethyl acetate 1/1); IR (film) 3580-3100, 3025, 2943, 1438 cm-1
;
1-(5-Hyd r oxy-5-m eth ylh exyl)cycloh exa n ol (2p ): Rf 0.18
(silica gel; hexane/ethyl acetate 2/1); IR (film) 3500-3110,
2942, 1432 cm-1; 1H NMR δ 1.20 (s, 6H), 1.23-1.61 (m, 20H);
13C NMR δ 22.2, 23.3, 24.9, 25.8, 29.15, 37.35, 43.85, 48.50,
70.95, 71.4; MS m/z 178 (M+ - 2H2O, 6), 82 (100); HRMS calcd
for C13H22 178.1721, found 178.1719.
1H NMR δ 1.40-1.71 (m, 6H), 2.51-2.74 (m, 2H), 3.20 (br s,
2H), 3.49-3.59 (m, 3H), 7.05-7.21 (m, 5H); 13C NMR δ 28.9,
32.05, 34.4, 39.1, 62.65, 71.0, 125.7, 128.3, 142.1; MS m/z 176
(M+ - H2O, 5), 44 (100); HRMS calcd for C12H16O 176.1201,
found 176.1211.
4-Meth yl-1,4-h ep ta n ed iol (3i):25 Rf 0.19 (silica gel; hexane/
1-[4-(1-Hyd r oxycycloh exyl)bu tyl]cycloh exa n ol (2q): Rf
0.29 (silica gel; hexane/ethyl acetate 2/1); mp 99-100 °C
(pentane/dichloromethane); IR (KBr) 3420-3180, 2941, 1438
1
ethyl acetate 1/1); IR (film) 3600-3125, 2940, 1441 cm-1; H
NMR δ 0.85 (t, J ) 7.3 Hz, 3H), 1.09 (s, 3H), 1.28-1.56 (m,
8H), 2.97 (br s, 2H), 3.55 (t, J ) 6.0 Hz, 2H); 13C NMR δ 14.6,
17.2, 26.6, 26.85, 38.3, 44.5, 63.0, 72.4; MS m/z 182 (M+ - H2O,
2), 43 (100).
1
cm-1; H NMR δ 1.22-1.68 (m, 30H); 13C NMR δ 22.2, 23.4,
25.7, 37.3, 42.2, 71.35; MS m/z 218 (M+ - 2H2O, 3), 122 (100).
Anal. Calcd for C16H30O2: C, 75.53; H, 11.88. Found: C, 75.21;
H, 11.62.
4-P en tyl-1,4-n on a n ed iol (3j): Rf 0.39 (silica gel; hexane/
1
ethyl acetate 1/1); IR (film) 3630-3130, 2942, 1431 cm-1; H
(1S,2S,5R)-1-(5-Hyd r oxy-5-m eth ylh exyl)-2-isop r op yl-5-
m eth ylcycloh exa n ol (2r ): Rf 0.42 (silica gel; hexane/ethyl
NMR δ 0.82 (t, J ) 6.7 Hz, 6H), 1.20-1.57 (m, 20H), 2.37 (br
s, 2H), 3.57 (t, J ) 6.1 Hz, 2H); 13C NMR δ 14.0, 22.6, 23.2,
26.6, 32.4, 36.05, 39.1, 63.3, 74.3; MS m/z 212 (M+ - H2O, 2),
43 (100); HRMS calcd for C14H28O 212.2140, found 212.2149.
1-(3-Hyd r oxyp r op yl)cycloocta n ol (3k ): Rf 0.20 (silica gel;
hexane/ethyl acetate 1/1); IR (film) 3580-3115, 2936, 1438
1
acetate 2/1); IR (film) 3620-3130, 2932, 1443 cm-1; H NMR
δ 0.88 (d, J ) 6.7 Hz, 3H), 0.90 (d, J ) 6.7 Hz, 3H), 0.91 (d, J
) 7.3 Hz, 3H), 1.23 (s, 6H), 0.95-2.21 (m, 19H); 13C NMR δ
18.2, 18.6, 20.5, 22.4, 23.6, 25.5, 28.0, 29.25, 35.1, 41.6, 44.5,
46.7, 47.9, 70.95, 75.15; MS m/z 252 (M+ - H2O, 1), 69 (100);
HRMS calcd for C17H32O 252.2453, found 252.2464; [R]25
+4.6° [c ) 1.1 (CH2Cl2)].
)
1
cm-1; H NMR δ 1.32-1.72 (m, 18H), 2.49 (br s, 2H), 3.57 (t,
D
J ) 6.1 Hz, 2H); 13C NMR δ 22.3, 25.0, 26.45, 28.2, 36.15, 38.0,
63.3, 74.65; MS m/z 212 (M+ - H2O, 2), 43 (100); HRMS calcd
for C11H20O 168.1514, found 168.1505.
5,5-Dim eth yl-1,4-h exa n ed iol (3a ):21 Rf 0.19 (silica gel;
hexane/ethyl acetate 1/1); IR (film) 3620-3100, 2940, 1444
cm-1; 1H NMR δ 0.88 (s, 9H), 1.70-1.74 (m, 2H), 1.87 (quintet,
J ) 6.1 Hz, 2H), 2.39 (br s, 2H), 3.23 (dd, J ) 10.4, 1.2 Hz,
1H), 3.69 (t, J ) 6.1 Hz, 2H); 13C NMR δ 25.7, 30.4, 31.6, 35.0,
63.0, 80.1; MS m/z 128 (M+ - H2O, 3), 71 (100); HRMS calcd
for C8H16O 128.1201, found 128.1189.
1,5-Hexa d eca n ed iol (3l): Rf 0.28 (silica gel; hexane/ethyl
1
acetate 1/1); IR (film) 3610-3130, 2938, 1442 cm-1; H NMR
δ 0.81 (t, J ) 6.6 Hz, 3H), 1.28-1.51 (m, 26H), 2.38 (brs, 2H),
3.55-3.59 (m, 3H); 13C NMR δ 14.1, 21.7, 22.65, 25.7, 29.3,
29.6, 29.65, 29.7, 31.9, 32.45, 36.8, 37.5, 62.5, 71.8; MS m/z
1-(3-Hyd r oxyp r op yl)cycloh exa n ol (3b):22 Rf 0.12 (silica
gel; hexane/ethyl acetate 1/1); IR (film) 3640-3110, 2938, 1442
222 (M+ - H2O, 1), 98 (100); HRMS calcd for C16H32
240.2453, found 240.2459.
O
1
cm-1; H NMR δ 1.13-1.59 (m, 14H), 3.47 (br s, 2H), 3.54 (t,
7-P h en yl-1,5-h ep ta n ed iol (3m ): Rf 0.18 (silica gel; hexane/
J ) 6.1 Hz, 2H); 13C NMR δ 22.2, 25.7, 25.9, 37.3, 38.5, 62.8,
71.0; MS m/z 140 (M+ - H2O, 4), 55 (100).
ethyl acetate 1/1); IR (film) 3620-3130, 3030, 2936, 1443 cm-1
;
1H NMR δ 1.38-1.55 (m, 6H), 1.70-1.78 (m, 2H), 2.59-2.82
(m, 4H), 3.58-3.64 (m, 3H), 7.14-7.29 (m, 5H); 13C NMR δ
(1S,2S,5R)-1-(3-Hyd r oxyp r op yl)-2-isop r op yl-5-m eth yl-
cycloh exa n ol (3c): Rf 0.36 (silica gel; hexane/ethyl acetate
(23) Hartung, J .; Gallou, F. J . Org. Chem. 1995, 60, 6707-6716.
(24) Canonne, P.; Foscolos, G. B.; Belanger, D. J . Org. Chem. 1980,
45, 1828-1835.
(25) Fujita,T.; Watanabe, S.; Suga, K.; Inaba, T. J . Chem. Technol.
Biotechnol. 1979, 29, 100-106. Chem. Abstr. 1980, 92, 58268j.
(21) Batey, R. A.; Smil, D. V. Angew. Chem., Int. Ed. Engl. 1999,
38, 1798-1800.
(22) J ohnson, R. C.; Mueller, R. H. J . Org. Chem. 1972, 37, 1947-
1950.

Sources of 1,3-Dilithiopropane and 1,4-Dilithiobutane
21.7, 32.0, 32.3, 36.9, 39.1, 62.3, 71.0, 125.7, 128.3, 142.1; MS
J . Org. Chem., Vol. 65, No. 11, 2000 3483
Ack n ow led gm en t. This work was financially sup-
portert by the DGICYT from the Spanish Ministerio de
Educacio´n y Cultura (project no. PB97-133) and by the
Generalitat Valenciana (project no. GV-C-CN-09-066-
96). S.A.S. thanks the University of Alicante for a
fellowship.
m/z 190 (M+ - H2O, 3), 91 (100); HRMS calcd for C13H18
O
190.1358, found 190.1376.
5-P en tyl-1,5-d eca n ed iol (3n ): Rf 0.40 (silica gel; hexane/
1
ethyl acetate 1/1); IR (film) 3600-3100, 2936, 1442 cm-1; H
NMR δ 0.87 (t, J ) 7.0 Hz, 6H), 1.25-1.58 (m, 22H), 1.85 (br
s, 2H), 3.64 (t, J ) 6.7 Hz, 2H); 13C NMR δ 14.0, 19.5, 22.6,
23.15, 32.4, 33.1, 38.8, 39.1, 62.6, 74.5; MS m/z 226 (M+ - H2O,
3), 43 (100); HRMS calcd for C15H30O 226.2297, found 226.2286.
1-(4-Hyd r oxybu tyl)cycloocta n ol (3o): Rf 0.18 (silica gel;
hexane/ethyl acetate 1/1); IR (film) 3610-3140, 2950, 1446
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H (300
MHz) and 13C (75 MHz) spectra of new compounds lacking
microanalyses (2a -h ,j-p ,r and 3c,f-h ,j-o). This material is
available free of charge via the Internet at http://pubs.acs.org.
1
cm-1; H NMR δ 1.29-1.72 (m, 20H), 2.36 (br s, 2H), 3.56 (t,
J ) 6.1 Hz, 2H); 13C NMR δ 19.1, 22.3, 25.0, 28.2, 32.95, 36.1,
40.7, 62.3, 74.9; MS m/z 182 (M+ - H2O, 5), 55 (100); HRMS
calcd for C12H22O 182.1670, found 182.1681.
J O000039M