Reaction of ethyl 2,2-dimethoxycyclopropanecarboxylates with m-CPBA. Discovery of two new related degradative processes leading to β-hydroxyacid derivatives

Article abstract of DOI:10.1016/S0040-4039(00)01892-X

The reaction of the 3-alkyl-substituted and 3,3-dialkyl-substituted ethyl 2,2-dimethoxycyclopropanecarboxylates 1-3 with m-CPBA in CH₂Cl₂ leads to the formation of the β-hydroxyacid derivatives 4-6 via two related processes involving the scission of both the C₁-C₂ and C₂-C₃ bonds and consequently to the degradation of the original cyclopropane carbon skeleton (extrusion of the C-2 carbon). Cis- and trans-2-ethoxycyclopropanecarboxylic acid ethyl esters 9 and 10, respectively, structurally related to 1-3, are unreactive under the same conditions. A hypothesis explaining the observed reactivity is formulated.

Full text of DOI:10.1016/S0040-4039(00)01892-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 93–95
Reaction of ethyl 2,2-dimethoxycyclopropanecarboxylates with
m-CPBA. Discovery of two new related degradative processes
leading to b-hydroxyacid derivatives
Vincenzo Piccialli* and M. Liliana Graziano
Dipartimento di Chimica Organica e Biologica, Universita` degli Studi di Napoli ‘Federico II’,
Via Mezzocannone 16, 80134 Napoli, Italy
Received 24 July 2000; revised 18 October 2000; accepted 26 October 2000
Abstract—The reaction of the 3-alkyl-substituted and 3,3-dialkyl-substituted ethyl 2,2-dimethoxycyclopropanecarboxylates 1–3
with m-CPBA in CH2Cl2 leads to the formation of the b-hydroxyacid derivatives 4–6 via two related processes involving the
scission of both the C1ꢀC2 and C2ꢀC3 bonds and consequently to the degradation of the original cyclopropane carbon skeleton
(extrusion of the C-2 carbon). Cis- and trans-2-ethoxycyclopropanecarboxylic acid ethyl esters 9 and 10, respectively, structurally
related to 1–3, are unreactive under the same conditions. A hypothesis explaining the observed reactivity is formulated. © 2000
Published by Elsevier Science Ltd.
Vicinally substituted donor–acceptor cyclopropanes are
versatile building blocks in organic synthesis since they
are used for the preparation of many types of com-
pounds.1 We have recently undertaken a plan aimed at
testing the reactivity of some of these substances, namely
ethyl 2,2-dialkoxycyclopropanecarboxylates, under a va-
riety of oxidising conditions. Previous investigations
3,3-dialkyl substituted 2,2-dimethoxycyclopropanecar-
boxylic acid ethyl esters, e.g. 1–3 (Schemes 1 and 2), react
with m-CPBA4 in CH2Cl2 to give the methyl carbonate
derivatives 4 and 5 from 1 and 2, respectively, and the
m-chlorobenzoate derivative 6 from 3, through related
degradative processes. It is to be noted that the carbon
skeleton of the reaction products corresponds to that of
the original cyclopropane from which the C-2 carbon
has been extruded and is, in the case of compounds 4 and
5, the carbonyl carbon of the carbonate portion.
2
from our group have led to the finding that RuO4 and
3
Pb(OAc)4 are able to oxidatively cleave the reactive
C1ꢀC2 bond. We now report that 3-alkyl-substituted and
Scheme 1.
Scheme 2.
Keywords: m-CPBA; ethyl 2,2-dimethoxycyclopropanecarboxylates; methyl carbonates; b-hydroxyacid derivatives; degradative processes.
* Corresponding author. Tel.: 39-81-674111; fax: 39-81-674393; e-mail: vinpicci@unina.it
0040-4039/01/$ - see front matter © 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)01892-X

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V. Piccialli, M. L. Graziano / Tetrahedron Letters 42 (2001) 93–95
The reactions have been performed by adding the
freshly prepared cyclopropane (typically 300 mg) to a
solution of m-CPBA (1.2 equiv. desiccated overnight
over P2O5) in anhydrous CH2Cl2 (1 mL) with stirring at
room temperature. The reaction was complete within a
1 h period in the case of 1 and 2 (TLC monitoring) but
required 9 days to proceed to completion for the less
reactive cyclopropane 3. Filtration of the reaction mix-
ture through a short silica gel plug (eluent hexane/Et2O,
95:5) followed by HPLC (hexane/EtOAc, 93:7) afforded
pure samples of compounds 4–6, as well as methyl
m-chlorobenzoate from the oxidations of 1 and 2. All
the isolated substances gave satisfactory spectral data5
in full agreement with the assigned structures. While the
reaction of compounds 1 and 2 with m-CPBA was
shown to be reproducible and rather clean, the oxida-
tion of 3 always produces, in addition to the main
product 6, variable amounts of various side-products
(unidentified). Worth mentioning, however, is that
among these, after a careful HPLC separation of the
reaction mixture, the carbonate derivative correspond-
ing to compounds 4 and 5 could not be identified,
although it would have been obtained if the oxidation
path followed by 3 had been the same as that for 1 and
2.
The formation of carbonates 4 and 5 can be explained
through the sequence shown in Scheme 3. In the first
step, the addition of the OH portion of the percar-
boxylic acid to the C1ꢀC2 bond of the cyclopropane, in
a manner similar to that observed for other nucleophilic
species (H2O, MeOH etc.), would generate intermediate
7. This species could rearrange in such a way that the
C2ꢀC3 bond shifts from C-2 to O-1 with the simulta-
neous expulsion of the m-chlorobenzoate anion and
formation of the stabilised C-2 cation species 8. This
latter would then collapse to the carbonate product via
a SN2 displacement at one of the two OMe groups by
the attack of the released m-chlorobenzoate, with for-
mation of methyl m-chlorobenzoate, a species in turn
obtained from the oxidative process. The net result of
the above route is that the C-2 carbon of the original
cyclopropane ring becomes the carbonyl carbon of a
carbonate function linked to the C-3 carbon of a b-hy-
droxyester derivative.
As for the formation of compound 6 from 3, it is likely
that an intermediate analogous to 7, obtained as hy-
pothesised above, could form in the first step through
the addition of m-CPBA across the C1ꢀC2 bond
(Scheme 4). We reasoned that, at this stage, the pres-
ence of two methyl groups at C-3 could favour a
fragmentation step that would occur with the expulsion
of dimethylcarbonate (DMC) and the m-chloroben-
zoate anion, as well as the formation of the C-3 tertiary
carbocation. Recombination of the two produced ionic
species would eventually give the diester product 6.
Definitive confirmation of the structures of diesters 4–6
was provided by synthesis. In particular, methyl car-
bonate 4 was obtained by borohydride reduction of
ethyl acetoacetate (NaBH4/EtOH, 25°C, 15 min, 80%)
followed by treatment of the resulting ethyl 3-hydroxy-
butyrate with methyl chloroformate in pyridine (25°C,
10 min, 90%). Similarly, methyl carbonate 5 was syn-
thesised by reaction of methyl chloroformate with ethyl
3-hydroxyvalerate in pyridine (25°C, 10 min, 95%); the
latter compound was in turn obtained via a Refor-
matsky reaction of ethyl bromoacetate with propanal,
as described.6 m-Chlorobenzoate derivative 6 was syn-
thesised by the reaction of m-chlorobenzoic acid chlo-
ride with ethyl 3-hydroxyisovalerate in pyridine (25°C,
24 h, 80%); ethyl 3-hydroxyisovalerate was in turn
synthesised by Reformatsky reaction of ethyl bromoac-
etate with acetone.6
In order to gain evidence supporting the latter mechanis-
tic hypothesis, the reaction of 3 with m-CPBA was
performed in CDCl3. The advancement of the process
was monitored by periodically recording the proton
spectrum of the reaction mixture. A singlet peak at l 3.78
attributable to DMC began to be detectable after some
7 h. Unequivocal assignment of the above resonance to
DMC was provided by addition of a trace amount of
pure DMC to the reaction mixture that produced the
enhancement of the sole peak at l 3.78. At this time peaks
diagnostic for diester 6 were also present.
Scheme 3.

V. Piccialli, M. L. Graziano / Tetrahedron Letters 42 (2001) 93–95
95
Scheme 4.
144, 73–135.
2. Graziano, M. L.; Lasalvia, M.; Piccialli, V.; Sica, D.
Tetrahedron Lett. 1996, 4, 527–530.
3. Graziano, M. L.; Piccialli, V. Tetrahedron Lett. 1999, 40,
8469–8470.
4. For general accounts on m-CPBA reactions, see: (a)
Comprehensive Organic Synthesis; Trost, B. M.; Fleming,
I., Ed.; Vol. 7, pp. 357–372. (b) Paquette, L. Encyclope-
dia of Reagents for Organic Synthesis; John Wiley &
Sons: New York, Vol. 2, pp. 1192–1198.
Scheme 5.
For a comparative purpose, cis- and trans-2-ethoxycy-
clopropanecarboxylic acid ethyl esters (9 and 10,
Scheme 5) were synthesised as reported7 and subjected
to the same oxidising conditions described above for
1–3; they proved to be unreactive on prolonged treat-
ment (7 days). This result shows that a single alkoxy
group at C-2 is not sufficient to confer to the C1ꢀC2
bond the electronic characteristics that render it reac-
tive toward m-CPBA. Compounds 9 and 10 were also
shown to be unreactive towards RuO4 and Pb(OAc)4
that, on the contrary, are able to cleave cyclopropanes
1–3, as previously reported.2,3
5. Spectral data for compounds 4–6. Compound 4: FTIR
(film) wmax 1741 cm−1 (2×CO); 1H NMR (CDCl3, 200
MHz) l 5.13 (1H, sextet, J=6.5 Hz, H-3), 4.12 (2H, q,
J=7.1 Hz, OCH2), 3.75 (3H, s, OMe), 2.69 (1H, dd,
J=15.8, 7.6 Hz, Ha-1), 2.48 (1H, dd, J=15.8, 5.8 Hz,
Hb-1), 1.33 (3H, d, J=6.3 Hz, CH3 linked at C-3), 1.23
(3H, t, J=7.1 Hz, OCH2CH3). Compound 5: FTIR
(film) wmax 1752 cm−1 (2×CO); 1H NMR (CDCl3, 200
MHz) l 5.02 (1H, broad quintet, J=5.6 Hz, H-3), 4.12
(2H, q, J=6.9 Hz, OCH2), 3.75 (3H, s, OMe), 2.59 (2H,
AB system further coupled; A part J=15.9, 7.8 Hz, B
part J=15.9, 5.3 Hz, H2-1), 1.68 (2H, quintet, J=7.5
Hz, methylene protons of the Et linked at C-3), 1.22
(3H, t, J=6.9 Hz, OCH2CH3), 0.93 (3H, t, J=7.5 Hz,
methyl protons of the Et linked at C-3). Compound 6:
FTIR (film) wmax 1735 cm−1 (CO); 1H NMR (CDCl3,
200 MHz) l 7.95 (1H, bt, J=1.6 Hz, H-2 of the aro-
matic ring), 7.88 (1H, dt, J=8.0, 1.6, 1.6 Hz, H-4 or
H-6 of the aromatic ring), 7.50 (1H, dt, J=8.0, 1.6, 1.6
Hz, H-6 or H-4 of the aromatic ring), 7.35 (1H, dd,
J=8.0, 8.0 Hz, H-5 of the aromatic ring), 4.11 (2H, q,
J=7.3 Hz, OCH2), 2.97 (2H, s, H2-1), 1.69 (6H, s, 2×
CH3 linked at C-3), 1.18 (3H, t, J=7.0 Hz, OCH2CH3).
6. Rathke, M. W.; Lindert, A. J. Org. Chem. 1970, 35,
3966–3967.
As far as we know this is the first report of the
m-CPBA-induced scission of cyclopropyl compounds.
Acknowledgements
We are grateful to MURST, Italy (Prin 1999) for a
grant in support of this investigation, to the ‘Centro di
Metodologie Chimico-Fisiche dell’Universita` Federico
II di Napoli’ for NMR facilities, and to the ‘Servizio di
Spettrometria di Massa del CNR e dell’Universita` di
Napoli’ for mass spectral data.
References
7. Anciaux, A. J.; Hubert, A. J.; Noels, A. F.; Petiniot, N.;
Teyssie´, P. J. Org. Chem. 1980, 45, 695–702.
1. For a review, see Reißig, H.-U. Top. Curr. Chem. 1988,
.