The Pummerer-type reaction mediated ring-opening of 2-alkyl substituted 1-[(2-methoxyethoxy)methoxy]-2-(phenylsulfinyl)cyclopropanes

Article abstract of DOI:10.1016/S0040-4039(01)00723-7

α-Lithiated 1-[(2-methoxyethoxy)methoxy]-2-(phenylsylfinyl)cyclopropane reacted smoothly with alkylating agents to afford the corresponding α-alkylated cyclopropylsulfoxides, which underwent the Pummerer-type reaction mediated ring-opening at low temperature (-78°C) by employing TFAA/Prⁱ₂NEt/CH₂Cl₂ to give mixtures of β-(phenylthio)-α,β- and γ,δ-unsaturated aldehydes.

Full text of DOI:10.1016/S0040-4039(01)00723-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4389–4391
The Pummerer-type reaction mediated ring-opening of
2-alkyl substituted 1-[(2-methoxyethoxy)methoxy]-
2-(phenylsulfinyl)cyclopropanes
Manat Pohmakotr,* Panawan Moosophon,† Somchai Pisutjaroenpong, Patoomratana Tuchinda and
Vichai Reutrakul
Department of Chemistry, Faculty of Science, Mahidol University, Rama 6 Road, Bangkok 10400, Thailand
Received 12 February 2001; revised 2 March 2001; accepted 1 May 2001
Abstract—a-Lithiated 1-[(2-methoxyethoxy)methoxy]-2-(phenylsylfinyl)cyclopropane reacted smoothly with alkylating agents to
afford the corresponding a-alkylated cyclopropylsulfoxides, which underwent the Pummerer-type reaction mediated ring-opening
at low temperature (−78°C) by employing TFAA/Pri2NEt/CH2Cl2 to give mixtures of b-(phenylthio)-a,b- and g,d-unsaturated
aldehydes. © 2001 Elsevier Science Ltd. All rights reserved.
Vicinally donor–acceptor substituted cyclopropanes are
of interest due to their synthetic utilities as three-carbon
building blocks via ring-opening reactions.1 Ring-cleav-
age of these types of cyclopropanes can be usually
accomplished by Lewis acid,2 thermal3 or oxidation
conditions.4 In connection with our ongoing interest in
developing new synthetic methods based on vicinally
O,S-disubstituted cyclopropanes,5 we report herein that
the a-sulfinyl carbanion 2 derived from trans-1-[(2-
methoxyethoxy)methoxy] - 2 - (phenylsulfinyl) - cyclopro-
pane (1)6 could be alkylated to give the corresponding
alkylated products 3, which smoothly underwent the
Pummerer-type mediated ring-opening reaction to give
mixtures of a,b- and g,d-unsaturated aldehydes 4 and 5
(Scheme 1).
The a-sulfinyl carbanion 2 could be generated from
trans-cyclopropylsulfoxide 1 (as a 1:1.5 mixture of
diastereomers) by treatment with either n-butyllithium
or lithium diisopropylamide in THF at −78°C for 1 h.
OMEM
H
O
O
Li
OMEM
OMe
LDA or n-BuLi
RCH2X/ THF
-78 oC to rt
CH2R
S Ph
THF, -78 oC, 30 min
S Ph
S Ph
O
O
O
1
2
3
MEM = -CH2OCH2CH2OCH3
TFAA/ CH2Cl2/
Pri2NEt/-78 oC
O
SPh
SPh
+
R
R
H
H
4
5
Scheme 1.
Keywords: Pummerer reactions; cyclopropanes; sulfoxides; lithiation; a-sulfinyl carbanions; unsaturated aldehydes; ring-cleavage.
* Corresponding author. Tel.: 066-02-2461358, ext. 1508; fax: 066-02-2477050; e-mail: scmpk@mahidol.ac.th
† Taken from an M.Sc. Thesis by P.M., Mahidol University, 2000.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00723-7

4390
M. Pohmakotr et al. / Tetrahedron Letters 42 (2001) 4389–4391
Quenching of the pale yellow solution of the expected
carbanion 2 with a saturated aqueous ammonium chlor-
ide solution led to the recovery of trans-cyclopropylsul-
foxide 1 in good yield.7 The retention of the configura-
tion at the a-carbon adjacent to the sulfinyl group
implied that the structure of the anion 2 was as shown
in Scheme 1, in which the complexation between
lithium and oxygen atoms of the MEM group was
assumed to occur. The reaction of the anion 2 with
methyl iodide (1.1 equiv.) at −78°C at room tempera-
ture overnight provided the expected methylated cyclo-
propylsulfoxide 3a in 70% yield as a 1:1 mixture of
diastereomers, due to the chirality on sulfur. The trans-
stereochemistry of 3a was determined unambiguously
by NOE experiments.8 The alkylation of the anion 2
with other alkylating agents afforded moderate yields
of the alkylated products 3b–g as diastereomeric mix-
tures, as listed in Table 1.
Treatment of 3a with 2 equiv. of trifluoroacetic anhy-
dride (TFAA) in dichloromethane in the presence of
N,N-diisopropylethylamine at −78°C for 30 min fol-
lowed by quenching of the reaction mixture with an
aqueous saturated sodium hydrogen carbonate solution
Table 1. Preparation of compounds 3 and their Pummerer-type mediated ring-opening employing TFAA/Pri2NEt/CH2Cl2 at
−78°C
3
4 and 5
Ratio of 4 (E:Z): 5 (E:Z)b,d
RCH2X
3 (diastereomeric ratio)a,b
% Yieldc
% Yieldc
CH3I
3a, R=H (1:1)
70
62
59
60
60
65
63
4a, 100 (70:30)
62
83
75
84
77
69
n-C6H13Br
n-C7H15Br
n-C11H23Br
n-C15H31Br
PhCH2Br
3b, R=C5H11 (1:1:3)
3c, R=C6H13 (1:1:4)
3d, R=C10H21 (1:3.7)
3e, R=C14H29 (1:1.3)
3f, R=Ph (1:1.3)
4b, 79 (63:37):5b, 21 (20:80)
4c, 86 (79:21):5c, 14 (35:65)
4d, 78 (78:22):5d, 22 (26:74)
4e, 74 (75:25):5e, 26 (12:88)
4f, 84 (68:32):5f, 16 (36:64)
e
e
PhCHꢀCHCH2Br
3g, R=PhCHꢀCH (1:1.2)
–
–
a Determined by integration of the -OCH2O- resonances in the 1H NMR spectra (300 MHz) of the isolated products.
b All products were fully characterized by spectral data (IR; 1H and 13C NMR; MS) and elemental analyses.
c Yields of purified products by preparative thin-layer chromatography (PLC, SiO2).
d Measured by the integration of the resonances of the aldehyde protons. The stereochemistries of (E)- and (Z)-isomers of both compounds 4 and
5 were determined by NOE experiments.
e A complex mixture of products was obtained.
..
MEMO
H
CH2R
+
S Ph
MEMO
H
TFAA/ Pri2NEt/ CH2Cl2
-78 oC/ 30 min
CH2R
S Ph
O
C CF3
O
O
3
6
+
OMEM
+
Pri2NEt
(a)
H2O
H
OMEM
SPh
CH2R
SPh
O
R
H
C
H
H
CH2R
H
(a)
(b)
S Ph
+
4
7
Pri2NEt
SPh
(b)
+
H2O
SPh
OMEM
O
R
R
H
H
5
Scheme 2.

M. Pohmakotr et al. / Tetrahedron Letters 42 (2001) 4389–4391
4391
at the same temperature provided 4a in 62% yield after
preparative thin-layer chromatography (PLC) as a
70:30 mixture of (E)- and (Z)-isomers. On the other
hand, the reaction of 3b with TFAA/Pri2NEt in CH2Cl2
under the same conditions afforded a mixture of the
expected a,b- and b,g-unsaturated aldehydes 4b and 5b,
respectively, in 83% isolated yield as a mixture of (E)-
and (Z)-isomers. Likewise, under the standard condi-
tions, the cyclopropylsulfoxides 3c–f furnished mixtures
of 4c–f and 5c–f in moderate to good yields (Table 1).
PLC separation of the mixtures of 4b–f and 5b-f gave
pure 4b–f in 57–66% yields.9 Unfortunately, b,g-unsatu-
rated aldehydes 5b–f could not be obtained in pure
forms.
2. (a) Shimada, S.; Hashimoto, Y.; Saigo, K. J. Org. Chem.
1993, 58, 5226–5234 and references cited therein; (b) Sug-
ita, Y.; Kawai, K.; Hasoya, H.; Yokoe, I. Heterocycles
1999, 51, 2029–2033; (c) Graziano, M. L.; Iesce, M. R.;
Cermola, F. Synthesis 1994, 1944–1950; (d) Horiguchi, Y.;
Suehiro, I.; Sasaki, A.; Kuwajima, I. Tetrahedron Lett.
1993, 34, 6077–6080; (e) Davies, H. M. L.; Hu, B. J. Org.
Chem. 1992, 57, 3186–3190.
3. (a) Reissig, H.-U.; Buchert, M. Liebigs Ann. 1996, 2007–
2013; (b) Barluenga, J.; Tomas, M.; Lopez-Pelegrin, J. A.;
Rubio, E. J. Chem. Soc., Chem. Commun. 1995, 665–666;
(c) Lee, P. H.; Kim, J. S.; Kim, Y. C.; Kim, S. Tetrahedron
Lett. 1993, 34, 7583–7586; (d) Davies, H. M. L.; Hu, B. J.
Org. Chem. 1992, 57, 4309–4312.
4. (a) Piccialli, V.; Graziano, M. L. Tetrahedron Lett. 2001,
42, 93–95; (b) Graziano, M. L.; Piccialli, V. Tetrahedron
Lett. 1999, 40, 8469–8470; (c) Graziano, M. L.; Lasalvia,
M.; Piccialli, V.; Sica, D. Tetrahedron Lett. 1996, 37,
527–530.
5. (a) Pohmakotr, M.; Takampon, A.; Ratchataphusit, J.
Tetrahedron 1996, 52, 7149–7158; (b) Pohmakotr, M.;
Takampon, A. Tetrahedron Lett. 1996, 37, 4585–4588; (c)
Pohmakotr, M.; Ratchataphusit, J. Tetrahedron 1993, 49,
6473–6482; (d) Pohmakotr, M.; Pisutjaroenpong, S. Tetra-
hedron Lett. 1985, 26, 3613–3616.
A probable mechanistic pathway for the formation of
unsaturated aldehydes 4 and 5 depicted in Scheme 2
was proposed involving the Pummerer-type reaction
mediated ring-opening of cyclopropyl-sulfoxide 3.
Thus, trifluoroacetylation of 3 gave an intermediate 6,
which underwent spontaneous ring-cleavage at −78°C
leading to a thionium intermediate 7. Subsequent
deprotonation of 7 with N,N-diisopropylethylamine via
pathways (a) and (b) afforded the a,b- and b,g-unsatu-
rated aldehydes 4 and 5, respectively, with the thermo-
dynamically more stable isomer 4 as the major product.
6. The starting cyclopropylsulfoxide
1 could be readily
obtained by oxidation (NaIO4/MeOH/H2O, 0°C to room
temperature, overnight) of trans-1-[(2-methoxyethoxy)-
methoxy]-2-(phenylsufanyl)cyclopropane, which was pre-
pared according to the known procedure: Tanaka, K.;
Uneme, H.; Matsui, S.; Kaji, A. Bull. Chem. Soc. Jpn.
1982, 55, 2965–2972.
In summary, we have demonstrated the Pummerer-type
reaction mediated ring-opening of a-alkylated 1-[(2-
methoxyethoxy)methoxy]-2-(phenylsulfinyl)cyclopro-
panes 3, which are vicinally donor–acceptor cyclo-
propanes, to give mixtures of unsaturated aldehydes 4
and 5. To our knowledge, this is the first report for the
ring-opening of the cyclopropane ring containing vici-
nal O,S-substituents under the Pummerer conditions at
low temperature (−78°C).
7. Comparable yields of the recovered starting material 1
obtained from both lithiation conditions were observed.
Occasionally, bond-cleavage of the phenylsulfinyl group
leading to butyl phenyl sulfoxide occurred when com-
pound 1 was lithiated by employing butyllithium at −78°C.
8. Irradiation of the methyl groups alpha to the phenylsulfi-
nyl group of each diastereomer resulted in 2.8 and 3.5%
enhancements of the cyclopropyl protons (l 0.77 and 0.87
ppm) cis to the methyl groups, as well as 2.3 and 1.8%
enhancements of one proton of -OCH2O- group of each
diastereomer.
Acknowledgements
We thank the Higher Education Development Project:
Postgraduate Education and Research Program in
Chemistry for partial support. P.M. is grateful to the
Development and Promotion of Science and Technol-
ogy Talent Project (DPST) for a scholarship. V.R.
thanks the Thailand Research Fund for the award of a
Senior Research Scholar.
H H
O
O
O
CH3
1.8 and 2.3%
H
CH3
H
S Ph
O
H
References
3.5 and 2.8%
1. (a) For a review, see: Reissig, H.-U. Top. Curr. Chem.
1988, 144, 73–135; (b) Marino, J. P.; Long, J. K. J. Am.
Chem. Soc. 1988, 110, 7916–7917; (c) Tanaka, K.; Matsu-
ura, H.; Funaki, I.; Suzuki, H. J. Chem. Soc., Chem.
Commun. 1991, 1145–1146; (d) Tanaka, K.; Minami, K.;
Funaki, I.; Suzuki, H. Tetrahedron Lett. 1990, 31, 2727–
2730.
9. For the preparation of 3-(phenylthio)-2-alkenal, see:
Ogawa, A.; Takeba, M.; Kawakami, J.; Ryu, I.; Kambe,
N.; Sonoda, N. J. Am. Chem. Soc. 1995, 117, 7564–7565
and Kuniyasu, H.; Ogawa, A.; Sonoda, N. Tetrahedron
Lett. 1993, 34, 2491–2494.
.