Synthesis of substituted 1,6-dioxaspiro[3.4]octanes from 3-Chloro- 2(chloromethyl)prop-1-ene

Article abstract of DOI:10.1055/s-2000-6289

The naphthalene-catalysed lithiation of 3-chloro-2-(chloromethyl)prop-1- ene, in the presence of symmetrically substituted ketones, led to the corresponding methylenic homoallylic diols, which upon treatment with iodine and silver(I) oxide in dioxane/wate

Full text of DOI:10.1055/s-2000-6289

PAPER
949
Synthesis of Substituted 1,6-Dioxaspiro[3.4]octanes from 3-Chloro-2-
(chloromethyl)prop-1-ene
Francisco Alonso,a Larry R. Falvello,#b,c Phillip E. Fanwick,c Emilio Lorenzo,a Miguel Yus*a
aDepartamento de Química Orgánica, Facultad de Ciencias, Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
Fax +34(96)5903549; E-mail: yus@ua.es; URL: http://www.ua.es/dept.quimorg/
bDepartamento de Química Inorgánica, Instituto de Ciencias de los Materiales de Aragón, Facultad de Ciencias, Universidad de Zaragoza-
CSIC, 50009 Zaragoza, Spain (permanent address)
cDepartment of Chemistry, Purdue University, West Lafayette IN 47907-1393, USA
Received 18 January 2000
Abstract: The naphthalene-catalysed lithiation of 3-chloro-2-(chlo-
romethyl)prop-1-ene, in the presence of symmetrically substituted
ketones, led to the corresponding methylenic homoallylic diols,
which upon treatment with iodine and silver(I) oxide in dioxane/-
water furnished a series of 1,6-dioxaspiro[3.4]octanes. These com-
pounds are structural units present in some natural compounds such
as clementeins and subexpinnatins.
Key words: 3-chloro-2-(chloromethyl)prop-1-ene, naphthalene-
catalysed lithiation, iodine/silver oxide induced cyclisation, 1,6-di-
oxaspiro[3.4]octanes
Although the 1,6-dioxaspiro[3.4]octane unit is scarcely
represented in nature, it is present in some series of ses-
quiterpene lactones with biological activity, isolated as
secondary metabolites from species of the Compositae
Figure 1
family,1ª such as clementeins1b or subexpinnatins1c,d (Fig-
ure 1). On the other hand, a few strategies have been de-
signed to access this particular skeleton, normally
These pure compounds were then treated with iodine and
involving a pre-formed tetrahydrofuran or oxetane ring,
and mostly leading to b- or g-lactones.2 Continuing with
silver(I) oxide in a 7:1 mixture of dioxane/water, to give
the corresponding 1,6-dioxaspiro[3.4]octanes 3, which
were >95% pure as a crude product and did not need fur-
ther purification (Scheme and Table).
our ongoing interest in the preparation of cyclic poly-
ethers,3 we describe here a direct two-step synthesis of the
above mentioned spiro moiety, starting from commercial-
ly available 3-chloro-2-(chloromethyl)prop-1-ene, using
as the key steps: (1) an arene-catalysed lithiation4,5 under
Barbier conditions,6 and (2) an iodine-mediated double in-
tramolecular cyclisation.7
The lithiation step has to be performed in the presence of
the electrophile, in order to avoid decomposition of the
initially formed intermediate of type I, which probably
gives first an alcoholate II and then, after a new tandem
lithiation-SE reaction yields the final diol 2, through a
functionalised organolithium compound9 of type IV. A
dilithiated intermediate of type III can not be ruled out.10
For the second step, the presence of silver(I) oxide is
necessary in order to achieve good yields, carbocation V
(or the precursor iodonium ion) being probably involved,
The reaction of 3-chloro-2-(chloromethyl)prop-1-ene (1)
with an excess of lithium powder and a catalytic amount
of naphthalene (5 mol%), in the presence of different ke-
tones in tetrahydrofuran, at a temperature ranging from
-78 to 20ºC led, after hydrolysis with water, to the expect-
ed unsaturated 1,5-diols 2 (56-72% isolated yield).8
R
R
R
R
R
R
R
R
Cl
Cl
i,ii
iii
O
O
OH
OH
1
3
2
Reagents and conditions: i) Li, C10H8 (5%), R2CO = Et2CO, (CH2)4CO, (CH2)5CO, O(CH2CH2)2CO, adamantan-2-one, THF, -78 to 20ºC;
ii) H2O; iii) I2, Ag2O, dioxane/H2O (7:1), 20ºC.
Scheme
Synthesis 2000, No. 7, 949–952 ISSN 0039-7881 © Thieme Stuttgart · New York

950
F. Alonso et al.
PAPER
Table Substituted 1,6-Dioxaspiro[3.4]octanes 3
En- R2CO
try
Product
no.
Structure
Yield
(%)a
1
3a
60
Figure 2 X-Ray Crystal Structure of Compound 3e
2
3
3b
3c
57
63
using CDCl3 as solvent and TMS as internal reference. Chemical
shifts are given in d (ppm) and coupling constants (J) in Hz. Mass
spectra (EI) were obtained at 70 eV on a Shimadzu GC/HS QP-5000
spectrometer; fragment ions in m/z with relative intensitites (%) in
parentheses. High resolution mass spectrometry analyses (HRMS)
were performed on a Finningan MAT95S aparatus. The purity of
volatile and the chromatographic analyses (GLC) were determined
with a Hewlett Packard HP-5890 instrument equipped with a flame
ionization detector and a 12 m capillary column (0.2 mm i.d., 0.33
mm film thickness). N2 (2 mL/min) was used as carrier gas,
4
5
3d
3e
57
53
T
injector = 275 ºC, Tcolumn = 60 ºC (3 min) and 60-270 ºC (15 ºC/min);
retention times (tR) are given in minutes under these conditions.
Column chromatography was performed using silica gel 60 of 40-
60 microns. Thin layer chromatography was carried out on TLC
plastic sheets with silica gel 60 F254 (Merck). X-Ray diffraction
analysis of compound 3e: reflections were measured with a Nonius
KappaCCD diffractometer.
a Isolated crude yield of compound 3 (>95% from GLC and/or 300
MHz 1H NMR) based on the methylenic diol 2 (see references 3 and
8).
Preparation of Diols 3; General Procedure
A solution of 3-chloro-2-(chloromethyl)prop-1-ene (0.16 mL, 2
mmol) and the corresponding ketone (3.96 mmol) in THF (6 mL),
was added to a green suspension of lithium powder (100 mg, 14
mmol), and naphthalene (25 mg, 0.2 mmol) in THF (6 mL) at
-78 ºC. The mixture was allowed to reach r.t. continuing the stirring
for 8 h. Then it was hydrolysed with H2O (10 mL), extracted with
EtOAc (3 x 15 mL), and the organic phase was dried (Na2SO4). Af-
ter removal of the solvent under reduced pressure (15 Torr), the re-
sulting residue was purified by column chromatography (silica gel,
hexane/EtOAc) to yield compounds 2. Iodine (0.382 g, 1.5 mmol)
was then added to a solution of the corresponding diol 2 in dioxane/
H2O 7:1 (20 mL). The mixture was stirred for 5 min at r.t. and then
Ag2O (0.346 g, 1.5 mmol) was added with additional stirring for 24
h. The resulting suspension was filtered, H2O (10 mL) was added to
the filtrate, followed by extraction with EtOAc (3 x 10 mL). The or-
ganic phase was successively washed with sat. NaHSO3 (2 x 10 mL)
and H2O (2 x 10 mL), and dried (Na2SO4). The solvent was removed
under reduced pressure (15 Torr) to furnish pure compounds 3.
which suffers first cyclisation to an oxetane VI, and then
intramolecular SN type reaction affording the final spiro
compound 3.
R
R
Li
X
X
OLi
II: X = Cl
IV: X = Li
I: X = Cl
III: X = Li
R
R
R
R
R
R
R
+
R
O
I
:
:
HO
HO
OH
I
V
VI
2,2,7,7-Tetraethyl-1,6-dioxaspiro[3.4]octane (3a)
Colorless oil; tR 9.54; Rf 0.72 (hexane/EtOAc, 9:1).
Structures I-VI
IR (film): n = 1055 cm-1 (CO).
1H NMR: d = 0.75-0.91 (m, 12H, 4CH3), 1.44-1.81 (m, 8H, 4
CH2CH3), 1.90, 2.19 (2H, AB system, JAB = 13.5, CCH2C, THF
ring), 2.37 (s, 2H, CH2, oxetane ring), 3.87, 4.05 (2H, AB system,
The structures of compounds 3 were assigned by NMR
experiments (NOESY, HETCOR, COLOC) and X-ray
analysis in the case of the solid compound 3e (Figure 2).
J
AB = 9.9, CH2O).
In conclusion, we believe that the herein described meth-
odology represents a useful way to prepare substituted
1,6-dioxaspiro[3.4]octanes in a simple two-step proce-
dure starting from commercially available materials.
13C NMR: d = 7.6 (4CH3), 29.45, 29.75, 31.5, 31.6 (4CH2CH3),
39.5 (CH2 oxetane ring), 49.6 (CCH2C, THF ring), 78.35 (CH2O),
82.05, 86.2 (2CCH2CH3), 84.5 (OCH2CO).
MS: m/z = 197 (M+-29, 22%), 125 (13), 111 (31), 107 (30), 81 (10),
69 (36), 57 (93), 55 (63), 43 (91), 41 (58), 40 (100).
HRMS: Calc for C14H26O2 226.1932, (M+-C2H6) 196.1463. Found:
196.1435.
All solvents were treated prior to use by standard methods.11 Mps
were measured with a Reichert Thermovar apparatus. NMR spectra
were recorded on a Bruker AC-300 and a Bruker Avance DRX-500
Synthesis 2000, No. 7, 949–952 ISSN 0039-7881 © Thieme Stuttgart · New York

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Synthesis of Substituted 1,6-Dioxaspiro[3.4]octanes from 3-Chloro-2-(chloromethyl)prop-1-ene
951
Trispiro[cyclopentane-1, 2¢-oxacyclobutane-4¢, 3¢¢-oxacyclopen-
tane-5¢¢,1¢¢¢-cyclopentane] (3b)
monochromated Mo-Ka radiation (rotating anode generator),
l = 0.71073 Å, Z = 2, Dc = 1.241 Mg·m-3, F(000) = 388, very
weakly diffracting colorless crystals, m(Mo-Ka) = 0.076 mm-1,
Nonius KappaCCD diffractometer, 8 < 2q < 42.5º, 3277 data inte-
grated, 1982 unique reflections. The structure was solved by direct
methods (SIR-92) and refined by full-matrix least-squares
(SHELXL-97). All hydrogen atoms were placed at calculated posi-
tions and treated as riding atoms with Uiso set equal to 1.2 times the
equivalent isotropic U of their respective parent carbon atoms. The
two enantiomers of compound 3e are located at the same crystallo-
graphic site, with the terminal groups and the chiral carbon atom or-
dered, and with disorder involving the atoms bridging the central
carbon atom and the terminal groups. All carbon- and oxygen-atom
sites were located in difference Fourier maps, and appropriate con-
straints were used to model the disorder and partial occupancy. Sim-
ilarity restraints were applied to the disordered congeners. The final
least-squares refinement fitted 252 parameters to all 1982 data and
39 restraints, giving wR2 = 0.2210 (for all data) and R1 = 0.1374
(for 1200 reflections with I > 2·s(I)).
Colorless oil; tR 10.82; Rf 0.74 (hexane/EtOAc, 9:1)
IR (film): n = 971, 1058 cm-1 (CO).
1H NMR: d = 1.53-2.14 [m, 16H, 2(CH2)4], 2.05, 2.28 (2H, AB
system, JAB = 13.4, CCH2C, THF ring), 2.58 (s, 2H, CH2, oxetane
ring), 3.83, 3.97 (2H, AB system, JAB = 9.7, CH2O).
13C NMR: d = 23.15, 23.3, 23.65, 25.9, 37.9, 38.1, 40.1, 40.15 (10
¥
CH2), 78.0 (CH2O), 84.65, 91.25 [2(CH2)4CO], 87.15
(OCH2CO).
MS: m/z = 222 (M+, 1%), 141 (18), 111 (15), 82 (50), 54 (19), 41
(51).
HRMS: Calc for C14H22O2 222.1620. Found: 222.1646.
Trispiro[cyclohexane-1,2¢-oxacyclobutane-4¢,3¢¢-oxacyclopen-
tane-5¢¢, 1¢¢¢-cyclohexane] (3c)
Colorless oil; tR 14.32; Rf 0.15 (hexane/EtOAc, 9:1)
IR (film): n = 1073, 1022 cm-1 (CO).
1H NMR: d = 1.20-1.86 [m, 20H, 2(CH2)5], 1.84, 2.19 (2H, AB
system, JAB = 13.4, CCH2C, THF ring), 2.31 (s, 2H, CH2, oxetane
ring), 3.82, 4.02 (2H, AB system, JAB = 9.8, CH2O).
13C NMR: d = 22.7, 23.5, 23.65, 25.05, 25.65, 36.7, 37.4, 39.05,
39.35, 41.55, 51.75 (12CH2), 79.45, 84.55 [2(CH2)5CO], 82.95
(OCH2CO).
Acknowledgement
This work was generously supported by the DGICYT (no. PB94-
1514, PB97-0133 and PB98-1593) from the Spanish Ministerio de
Educación y Cultura (MEC). E. L. thanks the MEC for a pre-docto-
ral grant.
MS: m/z = 250 (M+, 5%), 155 (35), 111 (22), 96 (60), 95 (33), 82
(16), 81 (100), 68 (21), 67 (74), 55 (92), 41 (85).
References and Notes
HRMS: Calc for C16H26O2 250.1933. Found: 250.1941.
#
Author for correspondence concerning X-ray analysis.
Trispiro[1-oxacyclohexane-4, 2¢-oxacyclobutane-4¢, 3¢¢-oxacy-
clopentane-5¢¢,4¢¢¢-1¢¢¢-oxacyclohexane] (3d)
Colorless oil; tR 15.31; Rf 0.12 (EtOAc, 9:1).
IR (film): n = 1124, 1028 cm-1 (CO).
1H NMR: d = 1.52-2.43 (m, 12H, 4OCH2CH2, CH2, oxetane ring,
CCH2C, THF ring), 3.45-4.50 (m, 10H, 5CH2O).
13C NMR: d = 38.55, 39.4, 46.55, 48.95 (4CH2CH2O, CCH2C, THF
ring, CH2, oxetane ring), 63.35, 63.45, 63.7, 63.75, (4CH2CH2O),
69.55 (CH2O, THF ring), 77.05, 77.85, 81.2 (2CH2CH2CO,
OCH2CO).
(1) (a) Collado, I. G.; Macías, F. A.; Massanet, G. M.; Molinillo,
J. M.; Luis, F. R. J. Org. Chem. 1987, 52, 3323.
(b) Massanet, G. M.; Collado, I. G.; Macías, F. A.; Bohlmann,
F.; Jakupovic, J. Tetrahedron Lett. 1983, 24, 1644.
(c) González Collado, I.; Macías, F. A.; Massanet, G. M.;
Rodríguez Luis, F. Phytochemistry 1985, 24, 2107.
(d) González Collado, I.; Macías, I. A.; Massanet, G. M.;
Rodríguez Luis, F. Tetrahedron 1986, 42, 3611.
(2) For other syntheses of 1,6-dioxaspiro[3.4]octanes, see:
Jarosz, S.; Zamojski, A. Tetrahedron 1982, 38, 1453.
Arjona, O.; Fernández de la Pradilla, R.; Pérez, S.; Plumet, J.
Tetrahedron Lett. 1986, 27, 5505.
MS: m/z = 254 (M+, 3%), 157 (11), 68 (40), 53 (16), 44 (61), 40
(100).
Arjona, O.; Fernández de la Pradilla, R.; Pérez, S.; Plumet, J.
Tetrahedron 1988, 44, 1235.
Arjona, O.; Fernández de la Pradilla, R.; Plumet, J.; Viso, A.
Tetrahedron 1989, 45, 4565.
Hirama, M.; Noda, T.; Yasuda, S.; Ito, S. J. Am. Chem. Soc.
1991, 113, 1830.
HRMS: Calc for C14H22O4 254.1518. Found: 254.1518.
Trispiro[adamantane-2, 2¢-oxacyclobutane-4¢, 3¢¢-oxacyclopen-
tane-5¢¢,2¢¢¢-adamantane] (3e)
Colorless crystals; mp 120-122ºC; tR 29.78; Rf 0.51 (hexane/
EtOAc, 9:1).
IR (KBr): n = 916, 988, 1060 cm-1 (CO).
1H NMR: d = 1.47-2.18 (m, 28H, 10CH2CH, 8CHCH2), 2.00, 2.30
(2H, AB system, JAB = 13.4, CCH2C, THF ring), 2.36 (s, 2H, CH2,
oxetane ring), 3.81, 3.98 (2H, AB system, JAB = 10.8, CH2O).
Bouifraden, S.; Lavergne, J.-P.; Martínez, J.; Viallefont, P.
Riche, C. Tetrahedron: Asymmetry 1997, 8, 849.
(3) Alonso, F.; Lorenzo, E.; Yus, M. Tetrahedron Lett. 1997, 38,
2187.
Alonso, F.; Lorenzo, E.; Yus, M. Tetrahedron Lett. 1998, 39,
3303.
(4) First account: Ramón, D. J.; Yus, M. J. Chem. Soc., Chem.
Commun. 1991, 398.
13C NMR: d = 26.5, 26.65, 26.75, 35.7, 36.7, 37.7, 39.0, 39.25 (8
CH), 27.25, 31.85, 33.1, 33.35, 33.6, 35.65, 36.4, 37.2, 42.8, 50.95
(10CH2CH, CCH2C THF ring, CH2 oxetane ring), 82.9, 83.7
(2CHCO), 83.75 (OCH2CO).
MS: m/z = 356 (M++2, 0.13%), 355 (1), 354 (4), 336 (22), 206 (24),
175 (47), 148 (100), 79 (47), 67 (18), 55 (18).
Last paper on this topic from our laboratory: Ortiz, J.;
Guijarro, A.; Yus, M. Eur. J. Org. Chem. 1999, 3005.
(5) Reviews: Yus, M. Chem. Soc. Rev. 1996, 155.
Ramón, D. J.; Yus, M. Eur. J. Org. Chem. 2000, 225.
(6) Monograph: Blomberg, C. The Barbier Reaction and Related
Processes; Springer-Verlag: Berlin, 1993.
HRMS: Calc for C24H34O2 354.2559. Found: 354.2559.
Review: Alonso, F.; Yus, M. Recent Res. Devel. Org. Chem.
1997, 1, 397.
(7) Polniaszek, R. P.; Stevens, R. V. J. Org. Chem. 1986, 51,
3023.
X-Ray Structural Analysis of 3e
Crystal data: C24H34O2, M = 354.51, triclinic, a = 6.461 (3),
b = 10.762 (4), c = 13.949 (6) Å, a = 83.70 (2), b = 80.030 (19),
g = 87.11 (2)º, U = 949.0 (6) Å3, T = 173 (2) K, space groupP1
Synthesis 2000, No. 7, 949–952 ISSN 0039-7881 © Thieme Stuttgart · New York

952
F. Alonso et al.
PAPER
Last paper on this topic from our laboratory: Foubelo, F.;
Gutiérrez, A.; Yus, M. Tetrahedron Lett. 1999, 40, 8177.
(11) Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory
Chemicals; Pergamon Press: Oxford, 1988.
(8) Ramón, D. J.; Yus, M. Tetrahedron Lett. 1992, 33, 2217.
Gómez, C.; Ramón, D. J.; Yus, M. Tetrahedron 1993, 49,
4417.
(9) For rewiews on functionalised organolithium intermediates,
see: Nájera, C.; Yus, M. Trends Org. Chem. 1991, 2, 155.
Nájera, C.; Yus, M. Recent Res. Devel. Org. Chem. 1997, 1,
67.
Article Identifier:
Yus, M.; Foubelo, F. Rev. Heteroatom Chem. 1997, 17, 73.
(10) For a recent review on polylithiated intermediates, see:
Foubelo, F.; Yus, M. Trends Org. Chem. 1998, 7, 1.
1437-210X,E;2000,0,07,0949,0952,ftx,en;C00300SS.pdf
Synthesis 2000, No. 7, 949–952 ISSN 0039-7881 © Thieme Stuttgart · New York