One pot synthesis of cyclobutanols by ring expansion of oxaspiropentanes induced by Grignard reagents

Article abstract of DOI:10.1055/s-1998-1730

Aromatic, aliphatic and vinylic Grignard reagents efficiently catalyze the ring expansion of oxaspiropentanes 2a,b to give, in one pot, good yields of cyclobutanols 3a, 3b-7b. Benzyl magnesium chloride gives a mixture of cyclobutanols and the cyclopropanol 8, probably coming from a direct nucleophilic attack on the epoxide part of the oxaspiropentane.

Full text of DOI:10.1055/s-1998-1730

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One Pot Synthesis of Cyclobutanols by Ring Expansion of Oxaspiropentanes Induced by
Grignard Reagents
Angela M. Bernard, Costantino Floris, Angelo Frongia, Pier P. Piras*
Dipartimento di Scienze Chimiche, Università di Cagliari, Via Ospedale 72, 09124 CAGLIARI (Italy)
Fax (19) 70 6758605; E mail: pppiras@vaxca1.unica.it
Received 4 February 1998
Abstract : Aromatic, aliphatic and vinylic Grignard reagents efficiently
catalyze the ring expansion of oxaspiropentanes 2a,b to give, in one pot,
good yields of cyclobutanols 3a, 3b-7b. Benzyl magnesium chloride
gives a mixture of cyclobutanols and the cyclopropanol 8, probably
coming from a direct nucleophilic attack on the epoxide part of the
oxaspiropentane.
group. In this way they can trigger the ring expansion of the
oxaspiropentane to the corresponding cyclobutanones 9a, b that,
reacting with the Grignard reagent give the final cyclobutanols. (Scheme
4)
Cyclobutanols are important intermediates in the synthesis of interesting
target molecules and can undergo many useful transformations. Their
synthesis is carried out mainly by two different reaction protocols : a)
through cyclobutanones by reduction with various hydrides or
1
1, 2
enzymes, or by reaction with organometallic reagents. b) by [2 + 2]
Scheme 2
3
photoaddition of enol ethers with olefins. Among these methods the
direct reaction of cyclobutanones with organometallic reagents leads to
1
the very interesting tertiary cyclobutanols, that have been used in the
synthesis of biologically important products. In this way an amino acid
antimetabolite present in an unidentified Streptomyces species X-1029
4
was prepared from an α-dibenzylaminocyclobutanone, and, through an
anionic oxy-Cope rearrangement of vinyl cyclobutanols, the synthesis of
5
AB taxoid models has been reported. On the other hand
1
cyclobutanones are frequently obtained by ring expansion of
oxaspiropentanes with acidic reagents like protonic acids or lithium or
6
7
europium salts or by thermal treatment. Following this synthetic
approach, the overall sequence for preparing cyclobutanols implies a
two step synthesis as indicated in Scheme 1.
Scheme 3
Scheme 1
In this paper we report that the synthesis of cyclobutanols 3a, 3b-7b can
be carried out, in one pot, by reaction of the oxaspiropentanes 2a,b with
Grignard reagents.
8
As a matter of fact the oxaspiropentanes 2a,b, prepared by oxidation of
9
the already reported 2-cyclopropylidene-aryloxypropanes 1a,b
(Scheme 2) react very smoothly with a set of Grignard reagents at low
temperature to give good yields of cyclobutanols 3a, 3b-7b, as mixtures
10
of diastereoisomers separable by column chromatography. In the case
of 4b only the (E)-4b was isolated from the reaction mixture while the
diastereoisomer (Z)-4b was isolated always as an enriched mixture,
from which the proton NMR data were worked out. The separation of
(E)-7b from its diastereoisomer (Z)-7b was better carried out from a
mixture obtained from the reaction of the cyclobutanone 9b with
benzylmagnesium chloride in the same experimental conditions. As it
can be seen from Scheme 3 and from the data reported in the Table,
aromatic, aliphatic and vinylic Grignard reagents give cyclobutanols,
whereas the reaction with benzyl magnesium chloride leads to a 60 :40
mixture of cylobutanols (diastereoisomeric ratio 6 : 4) and the
cyclopropanol 8, probably coming from a nucleophilic attack on the
epoxide ring of the oxaspiropentane. We believe that due to their
electrophilic character on the metallic atom, the Grignard reagents can
coordinate with the oxygen atoms of the epoxide and of the aryl ether
Scheme 4
This hypothesis is supported by the fact that cyclobutanols 3b, 6b and
7b are also obtained, in the same diastereoisomeric ratio, by reaction of
cyclobutanone 9b with the corresponding Grignard reagents.
We can say nothing about the stereoselectivity of the ring expansion,
while the attack of the intermediate cyclobutanone is occurring with
moderate diastereoselectivity, probably as a consequence of a chelation
of the magnesium with the oxygen atom of the ether group. This
chelation leads to a preferential attack of the cyclobutanone, from the
same side of the ether group, to give the cyclobutanols with the E
geometry, except in the case of methyl magnesium iodide, that gives the
corresponding cyclobutanols 3b with practically no selectivity. The

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stereochemical assignments have been made on the basis of the different
chemical shifts of the methyl and the methylene hydrogens of the
geometric isomers of the cyclobutanols. As a matter of fact, it is well
known that a phenyl group exerts shielding effects on groups cis to such
a phenyl group in four-membered rings while a hydroxy group is
(6) Trost, B. M., Bogdanowicz, M. J. J. Am. Chem. Soc. 1973, 5321 ;
Trost, B. M., Topics in Curr. Chem. 1986, 133, 3, Salaun, J. Topics
in Curr. Chem. 1988, 144, 1. Chevtchouk, T., Ollivier, J., Salaun,
J. Tetrahedron : Asymmetry 1997, 8, 1011.
(7) Johnson, C. R. Acc. Chem. Res. 1973, 6, 341 ; Trost, B. M. Acc.
Chem. Res. 1974, 7, 85.
11
expected to exert an opposite effect.
In conclusion we have reported a new way of inducing the ring
expansion of some oxaspiropentanes by using Grignard reagents as
electrophilic catalysts. This reaction is very useful as it allows the
synthesis of tertiary cyclobutanol derivatives saving one step compared
to the other methods involving the use of oxaspiropentanes. Further
studies are in progress for the assessment of the general character and
the stereoselectivity of this interesting transformation.
(8) Occasionally variable amounts of cyclobutanone 9b are
sometimes obtained if an excess of MCPBA is used. 9b has also
been prepared, in 84% yield, by treating the oxaspiropentane2b
with TsOH in CH Cl at reflux temperature for 24h.
2
2
(9) Bernard, A. M., Piras, P. P. Synlett 1997, 585.
(10) Typical procedure for the synthesis of cyclobutanols 3a, 3b- 7b :
To a stirred THF (10 ml) solution of the oxaspiropentane 2 (1.6
mmol), prepared under argon in a Schlenk apparatus, a solution of
Grignard reagent (2.5 mmol) is added at -70 °C. The solution is
allowed to reach room temperature under stirring for 20h, and then
is quenched with brine. Extraction with diethyl ether, drying with
Acknowledgments. Financial support from CNR (Rome) and Murst is
gratefully acknowledged.
Na SO and evaporation of the solvent leads to an oil that is
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All new compounds have been fully characterized by H NMR
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13
(300 MHz), C NMR (75.4 MHz). Selected spectral data for
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1
2a: H NMR (CDCl ) δ : 0.93-1.10 (m, 4H), 1.60 (s, 3H), 3.76 ( s,
3
13
3H), 4.07 (s, 2H), 6.80-6.89 (m, 4H). C NMR (CDCl ) δ : 1.82,
3
2.77, 17.75, 55.65, 62.03, 62.86, 72.95, 114.13, 116.25, 152.88,
1
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3
13
4.08 (s, 2H), 6.89-7.29 (m, 5H). C NMR (CDCl ) δ : 1.68, 2.62,
3
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1
3a : H NMR (CDCl ) δ : 1.43 (s, 3H), 1.79-1.87 (m, 2H), 2.09-
3
2.19 (m, 1H), 2.41 (br s, 1H), 2.72-2.81 (m, 1H), 3.20, 3.28 ( ABq,
13
2H, J = 9.0 Hz), 3.63 (s, 3H), 6.42-7.40 (m, 9H). C NMR
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3
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1
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3
2.12-2.35 (m, 2H), 2.75-2.85 (m, 1H), 3.21 (br s, 1H), 3.75 (s,

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1
3H), 3.96, 4.20 ( ABq, 2H, J = 9.3 Hz), 6.83-7.52 (m, 9H).
C
(data worked out from an unseparated reaction mixture) :
H
NMR (CDCl ) δ : 21.81, 25.02, 30.88, 46.99, 55.66, 73.66, 80.62,
NMR (CDCl ) δ : 0.58-0.68 (m, 4H), 0.65 (s, 3H), 2.35 (br s, 1H),
3
3
114.66, 115.64, 126.15, 127.01, 128.00, 129.41, 143.41, 152.92,
3.08, 3.22 ( ABq, 2H, J = 13.5 Hz), 3.91, 3.95 ( ABq, 2H, J = 9.0
1
13
154.01. (E)-7b : H NMR (CDCl ) δ : 1.27 (s, 3H), 1.50-1.61 (m,
3
Hz), 6.92-7.22 (m, 10H). C NMR (CDCl ) : 9.78, 10.62, 18.32,
3
1H), 1.81-2.02 (m, 2H), 2.25-2.30 (m, 1H), 2.35 (br s, 1H), 2.90
39.97, 40.89, 60.65, 74.37, 114.54, 121.21, 126.03, 127.85,
(s, 2H), 3.99, 4.11 ( ABq, 2H, J = 9.0 Hz), 6.89-7.30 (m, 10H).
1
129.50, 130.80, 138.14, 158.31. 9b : H NMR (CDCl ) δ : 1.20 (s,
3
13
C NMR (CDCl ) δ : 19.45, 24.47, 31.43, 42.42, 46.37, 73.06,
3
3H), 1.81-1.90 (m, 1H), 2.34-2.44 (m, 1H), 2.99- 3.20 (m,2H),
76.58, 114.60, 120.88, 126.30, 128.04, 129.39, 130.45, 137.32,
13
3.83, 4.04 ( ABq, 2H, J = 9.0 Hz), 6.78-7.22 (m, 4H). C NMR
1
158.89. (Z)-7b : H NMR (CDCl ) δ : 1.35 (s, 3H), 1.61-1.98 (m,
3
(CDCl ) : 17.85, 21.76, 43.39, 63.80, 70.13, 114.32, 120.85,
3
3H), 1.80 (br s), 2.25-2.32 (m, 1H), 2.92, 3.01 ( ABq, 2H, J = 13.5
129.20, 158.44, 212.83.
13
Hz), 3.88, 4.02 ( ABq, 2H, J = 9.3 Hz), 6.92-7.32 (m, 10H).
C
(11) Miller, D. D., Hsu, Fu-L., Salman, K. N., Patil, p. N. J. Med.
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NMR (CDCl ) δ : 18.80, 24.25, 30.82, 41.47, 46.29, 72.47, 76.68,
114.49, 120.65, 126.36, 128.15, 129.36, 130.33, 137.24, 159.06. 8
3