The first facile synthesis of some 1,2a,3,8b-tetrahydro-2H- cyclobuta[c] chromenes through intramolecular alkylation of an aromatic ring by a cyclobutanone

Article abstract of DOI:10.1055/s-2002-25355

Starting from cyclobutanones several new chromenes containing a cyclobutane ring are prepared. Ring fission of these derivatives gives easy access to functionalized 3-isoflavenes.

Full text of DOI:10.1055/s-2002-25355

796
LETTER
The First Facile Synthesis of Some 1,2a,3,8b-Tetrahydro-2H-Cyclobuta[c]
Chromenes Through Intramolecular Alkylation of an Aromatic Ring by a
Cyclobutanone
F
irst Facile Synthe
n
sis of 1, 2a,3,
g
8b-Tetrahyd
e
ro-2
H
-Cyclobuta[c
a
]
Chromenes M. Bernard, Costantino Floris, Angelo Frongia, Pier P. Piras*
Dipartimento di Scienze Chimiche, Università di Cagliari, Complesso Universitario di Monserrato, S.S. 554, Bivio per Sestu,
I-09042 Monserrato (Cagliari), Italy
Fax +39(70)6754388; E-mail: pppiras@unica.it
Received 7 February 2002
We now report a new use of the cyclobutanone ring as an
Abstract: Starting from cyclobutanones several new chromenes
intramolecular alkylating reagent of an oxygen substitut-
ed aromatic ring, to give access to a new versatile class of
containing a cyclobutane ring are prepared. Ring fission of these de-
rivatives gives easy access to functionalized 3-isoflavenes.
benzopyrans. As a matter of fact the cyclobutanones 3
Key words: cyclopropanes, cyclobutanones, electrophilic aromatic
have been prepared by lithium iodide induced ring
substitutions, ring opening, kinetic resolution
enlargement5 of the oxaspiropentane 2,6 obtained by ep-
oxidation of the easily accessible7 alkylidenecyclopro-
panes 1 (Scheme 1). Treating 3a–f with PTSA in
Cyclobutanones are the basic structure of several natural
refluxing benzene for 6 h the new derivatives 4a–f were
products and are useful intermediates in the synthesis of
obtained in 30–70% yields (Table) probably through pro-
many natural products and different molecules.1,2 While
tonation of the oxygen atom of the cyclobutanone and
they are mostly synthesized by [2+2] cycloaddition reac-
consequent alkylation of the activated aromatic ring.8 Ac-
tions between ketene and olefins, much effort is now be-
tivation of the aromatic ring is necessary as demonstrated
ing devoted to methods that use as starting material
by the unreactivity of the cyclobutanone 3g lacking the
suitably substituted cyclopropanes.2,3 The most common
oxygen atom. The stereochemistry of the R and the OH
reactions using cyclobutanones as useful intermediates in-
group in the derivatives 4a–f was demonstrated to be cis
clude their transformation into - lactones, pyrrolidones,
by NOE experiments.
cyclopentanones and cyclohexanones.1 They undergo eas-
ily the Favorskii4 rearrangement to give cyclopropanecar-
boxylic acids and react very easily with vinyl metals to
give the corresponding 1-vinylcyclobutanols that can un-
dergo many useful transformations.1
In the case of derivative 3e the corresponding compound
4e was formed together with some amount of the isofla-
vene 5e carrying a two carbon chain with a terminal tosyl-
oxy group, probably coming from the ring fission of the
Scheme 1
Synlett 2002, No. 5, 03 05 2002. Article Identifier:
1437-2096,E;2002,0,05,0796,0798,ftx,en;G03802ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
First Facile Synthesis of 1,2a,3,8b-Tetrahydro-2H-Cyclobuta[c] Chromenes
797
Table Reaction of Cyclobutanones 3a–g with PTSA.
Derivative 3d gave the two possible regioisomers 4d and
4d in roughly the same quantities, accompanied by small
quantities of the chromene 5d coming from the cyclobutyl
ring fission of the derivative 4d (Scheme 3).
3
a
b
c
d
e
f
X
R
R
H
R
Yield 4 (%)a
O
H
CH3
50
70
65
70b
60
30c
0
Derivative 3f prepared as a mixture (60:40) of the two
possible diastereoisomers, is particularly interesting for
what concerns the stereochemistry of the corresponding
ring closure product. In fact using catalytic amounts of
PTSA in refluxing benzene, after 6 h it was possible to
isolate from the reaction mixture only the cyclobutanol 4f
accompanied by small amounts of the chromene 5f and
the most abundant unreacted diastereoisomer of the start-
O
H
p-OCH3 CH3
O
H
p-Cl
m-CH3
H
CH3
CH3
C6H5
CH3
CH3
O
H
O
H
O
CH3
H
H
ing cyclobutanone, through
(Scheme 4).
a
kinetic resolution
g
CH2
H
a Isolated yield.
b Yields referred to the two regioisomers 4d and 4d formed in the 4:5
ratio.
The stereochemistry of the cyclobutanol 4f, assigned on
the basis of NOE experiments, shows that the relative po-
sition of the two methyl groups is trans, while the apical
methyl group, at 1.24 ppm, and the alcoholic OH are in
relative cis position. On the basis of the steric constraints
present during the cyclization step only the diastereoiso-
mer with the SR configuration, and of course its RS enan-
tiomer can give rise to the chromene 4f with the found
stereochemistry. The unreacted recovered 3f will there-
fore have the SS and RR stereochemistry and its unreactiv-
c Only one diastereoisomer has undergone cyclization, (vide infra).
intermediate cyclobutyl cation A by PTSA (Scheme 2).
Using an equimolar amount of PTSA, derivatives 3b and
3e were completely transformed, after 30 min into 5b and
5e in satisfactory yields (50% and 60% respectively)
(Scheme 2).
Scheme 2
Scheme 3
Synlett 2002, No. 5, 796–798 ISSN 0936-5214 © Thieme Stuttgart · New York

798
A. M. Bernard et al.
LETTER
Scheme 4
(6) It has not been possible to isolate the oxaspiropentane 2e, as
it is transformed to the corresponding cyclobutanone 3e
during the epoxidation reaction.
ity could be explained with the unfavorable steric
hindrance present in the generation of the other possible
chromene, that should have all the three groups in relative
cis position.
(7) Some derivatives have been previously reported. For 1a–e, g
see: (a) Bernard, A. M.; Piras, P. P. Synth. Commun. 1997,
27, 709. (b) Bernard, A. M.; Piras, P. P. Synlett 1997, 5,
585. (c) Brandi, A.; Carli, S.; Goti, A. Heterocycles 1988,
27, 17. (d) For 2a,b, 3a see: Bernard, A. M.; Floris, C.;
Frongia, A.; Piras, P. P. Synlett 1998, 668. (e) For 3b see:
Bernard, A. M.; Floris, C.; Frongia, A.; Piras, P. P.
Tetrahedron 2000, 56, 4555.
(8) Typical procedure for the preparation of chromenes 4a–f: A
stirred solution of cyclobutanone 3 (2.7 mmol) and p-
toluenesulfonic acid (0.27 mmol, 0.046 g) in benzene (10
mL) was refluxed for 6 h. The reaction mixture was diluted
with CH2Cl2 and washed with 10% NaHCO3 and brine, dried
(Na2SO4) and evaporated to remove the solvent. The residue
was purified by chromatography on silica gel with Et2O–
light petroleum (1:1) as eluent.
In conclusion we have reported a synthesis of a new class
of chromenes containing the cyclobutane ring that is sus-
ceptible to be opened as a consequence of its strain to new
functionalized chromenes. This transformation is particu-
larly important as it represents a versatile access to the
family of the isoflav-3-enes bearing a 2H-1-benzopyran
nucleus that are gaining increasing importance for their
antiestrogen activity.9 Chiral non racemic version of this
reaction is being studied and the results will be presented
in due course.
Acknowledgement
All new compounds have been fully characterized by 1H
NMR (300 MHz), 13C NMR (75.4 MHz) and mass spectra
(70 eV). Analytical data for some representative derivatives
are reported. 1f: colorless oil; yield: 70%. 1H NMR (CDCl3)
: 1.00–1.22 (m. 4 H), 1.52 (d, 3 H, J = 6.6 Hz), 1.84 (s, 3
H), 5.05 (q, 1 H, J = 6.6 Hz), 6.90–7.28 (m, 5 H). 13C NMR
(CDCl3) : 1.14, 2.76, 15.10, 19.71, 78.56, 115.65, 118.76,
120.65, 124.74, 129.12, 158.16. 3e: yellow oil; yield: 85%.
1H NMR (CDCl3) : 2.48–2.58 (m, 1 H), 2.73–2.82 (m, 1 H),
2.98–3.10 (m, 1 H), 3.18–3.30 (m, 1 H), 3.97, 4.23 (AB q, 2
H, J = 9 Hz), 7.22–7.44 (m, 10 H). 13C NMR (CDCl3) :
21.09, 44.09, 72.06, 72.54, 114.58, 121.25, 126.58, 127.50,
128.69, 129.43, 137.83, 158.43, 210.17. IR (neat, cm–1) :
1782. MS m/z: 252 [M+ (0.4)], 209(5), 195(9), 159(100),
131(23), 117(60). 4e: yellow oil; yield 60%. 1H NMR
(CDCl3) : 2.13–2.27 (m, 1 H), 2.19 (br s, 1 H), 2.26–2.33
(m, 2 H), 2.54–2.61 (m, 1 H), 4.05,4.14 (AB q, 2 H, J = 11.4
Hz), 6.85–7.65 (m, 9 H). 13C NMR (CDCl3) : 19.94, 36.76,
52.91, 71.74, 72.68, 117.29, 122.08, 127.22, 127.32, 127.58,
128.57, 128.79, 129.73, 138.37, 154.17. IR (neat, cm–1) :
3450. MS m/z: 252 [M+(6)], 234(5), 224(8), 121(100). 5e:
red oil; yield 56%. 1H NMR (CDCl3) : 2.41 (s, 3 H), 2.81 (t,
2 H, J = 7.5 Hz), 3.99 (t, 2 H, J = 7.5 Hz), 4.78 (s, 2 H), 6.81–
7.64 (m, 10 H). 13C NMR (CDCl3) : 21.55, 26.98, 68.19,
69.39, 116.19, 121.51, 122.60, 123.25, 124.00, 127.69,
127.78, 128.02, 128.77, 128.91, 129.69, 132.69, 134.34,
13.44, 144.54, 153.89. IR (neat, cm–1): 1160,1350.
(9) (a) Gauthier, S.; Caron, B.; Cloutier, J.; Dory, Y. L.; Favre,
A.; Larouche, D.; Mailhot, J.; Ouellet, C.; Schwerdtfeger,
A.; Leblanc, G.; Martel, C.; Simard, J.; Merand, Y.;
Belanger, A.; Labrie, C.; Labrie, F. J. Med. Chem. 1997, 40,
2117. (b) Varma, R. S.; Dahiya, R. J. Org. Chem. 1998, 63,
8038.
Financial support from the Ministero dell’Università e della Ricerca
Scientifica e Tecnologica, Rome, and by the University of Cagliari
(National Project ‘Stereoselezione in Sintesi Organica. Metodolo-
gie ed Applicazioni’) and from C.N.R. (Italy) is gratefully acknow-
ledged.
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Synlett 2002, No. 5, 796–798 ISSN 0936-5214 © Thieme Stuttgart · New York