Regio- and stereoselective cyclopropanation of functionalised dienes. Novel methodology for the synthesis of vinyl- and divinyl-cyclopropanes

Article abstract of DOI:10.1016/S0040-4039(02)00242-3

Dienes, bearing an electron-withdrawing substituent at C-1, are cyclopropanated regio- and stereoselectively at the C-C double bond proximal to this electron-withdrawing group. The highest selectivity is observed in the case of dienylboronates. The cyclopropanation of these substrates affords almost exclusively the synthetically useful 1-boronato-2-vinyl-cyclopropanes.

Full text of DOI:10.1016/S0040-4039(02)00242-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2317–2320
Regio- and stereoselective cyclopropanation of functionalised
dienes. Novel methodology for the synthesis of vinyl- and
divinyl-cyclopropanes
Istva´n E. Marko´,* Thierry Giard, Shinichi Sumida and Anne-Elisabeth Gies
Universite´ catholique de Louvain, De´partement de Chimie, Unite´ de Chimie Organique et Me´dicinale, Baˆtiment Lavoisier,
Place Louis Pasteur 1, B-1348 Louvain-la-Neuve, Belgium
Received 22 November 2001; revised 24 January 2002; accepted 31 January 2002
Abstract—Dienes, bearing an electron-withdrawing substituent at C-1, are cyclopropanated regio- and stereoselectively at the CꢀC
double bond proximal to this electron-withdrawing group. The highest selectivity is observed in the case of dienylboronates. The
cyclopropanation of these substrates affords almost exclusively the synthetically useful 1-boronato-2-vinyl-cyclopropanes. © 2002
Elsevier Science Ltd. All rights reserved.
Numerous natural products contain, embedded in their
often complex architectural framework, one or more
vinylcyclopropane or divinylcyclopropane subunits
(Fig. 1).
Our interest in the total synthesis of some of the
above-mentioned natural products prompted us to
investigate a novel route towards vinylcyclopropane
and divinylcyclopropane residues based upon the direct,
regio- and stereocontrolled cyclopropanation of substi-
tuted dienes 3 (Fig. 2).
The unique physical and biological properties associ-
ated with this small ring system have stimulated enor-
mous interest in its preparation, theoretical studies and
subsequent transformations.1 Whilst the vast majority
of the reported synthetic methods allow the efficient
construction of diversely substituted cyclopropanes, few
reactions exist that produce directly, in a flexible and
concise manner, functionalised vinylcyclopropanes.2
Amongst the plethora of methods employed for the
preparation of three-membered rings,3 the Pd(OAc)2/
CH2N2-catalysed cyclopropanation of alkenes attracted
our attention.4 Whereas several publications describe
the successful cyclopropanation of olefins bearing
ketone,5 oxazolidine6 and boronate7 substituents with
this Pd(II) system, to the best of our knowledge, no
report has yet appeared on the direct cyclopropanation
of functionalised dienes.8
At the onset of our studies, several sorbate derivatives
were prepared and treated with 1 equiv. of CH2N2 in
the presence of 5 mol% of Pd(OAc)2. The results are
shown in Table 1.
As can be seen from Table 1, the regioselectivity of the
palladium-catalysed cyclopropanation of 3 increases
according to the electron-withdrawing ability of the
dienyl substituent. Thus, reaction of the oxazolidinone
derivative 3a with CH2N2/Pd(OAc)2 leads to a mixture
of the proximal vinylcyclopropane 4a and the distal
vinylcyclopropane 5a in a 2:1 ratio (entry 1). Ethyl
sorbate 3b also reacts smoothly, affording 4b and 5b in
a slightly improved ratio of 4:1 (entry 2). Finally,
ketone 3c gives rise to the expected cyclopropanation
Figure 1.
Keywords: dienylboronates; cyclopropanes; palladium; vinylcyclo-
propanes; Suzuki coupling.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00242-3

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I. E. Marko´ et al. / Tetrahedron Letters 43 (2002) 2317–2320
Figure 2.
products 4c and 5c with a high selectivity (18:1) in
favour of 4c (entry 3). In all cases, variable amounts of
bis-cyclopropanes were observed (Table 1, caption). It is
noteworthy that only the trans cyclopropanes were
obtained with virtually complete stereocontrol. The
increasing preference for proximal cyclopropanation
over distal addition as a function of the electron-with-
drawing ability of the dienyl substituent, prompted us
to investigate the reaction of the analogous
dienylboronates.
With a variety of differently substituted dienylboronates
9 and 10 in hand, we next turned our attention to the
crucial cyclopropanation reaction. Addition of CH2N2
to a cold solution of substrates 9–10, containing 5 mol%
of Pd(OAc)2 resulted in their smooth conversion to the
corresponding boron-containing vinylcyclopropanes.
Some selected results are collected in Table 2.
As can be seen from Table 2, the palladium-catalysed
cyclopropanation of 9–10 proceeds in all cases with
good to excellent yields. The reaction tolerates a range
of functionalities and protecting groups such as esters
and silyl ethers (entries 3 and 4). It is noteworthy that,
in all cases studied, cyclopropanation occurs with
exquisite regio- and stereoselectivity on the CꢀC double
bond proximal to the boron atom. Even more remark-
able is the observation that simple alkenes are unaf-
fected under these conditions; chemoselective
cyclopropanation of the dienylboronate taking place
even in the presence of highly reactive (Z)-olefins11
(entry 5). Finally, the procedure tolerates a variety of
substitution on the boron atom (entries 1, 6 and 7).
The requisite starting dienes were readily prepared
according to the procedure of Yates,9 as shown in Fig.
3. Thus, Wittig olefination of aldehydes 6, using the
trimethylsilyl-protected ylid 7, afforded, after desilyla-
tion, the corresponding (E)-enynes 8 in essentially quan-
titative yields. Hydroboration with catecholborane
generated dienylboronates 9, possessing almost exclu-
sively the (E,E)-configuration. Finally, ligand exchange
at the boron centre was readily accomplished by stirring
9 with pinacol or 1,3-propanediol, affording boronates
10 in 45–55% overall yields.10
Table 1. Palladium-catalysed cyclopropanation of electron-deficient dienes 3
a
All reactions were carried out using 1 equiv. of CH2N2 and 5 mol% of Pd(OAc)2 in Et2O at 0°C. The ratios of isomers have been measured
by 1H NMR spectroscopy and by capillary gas chromatography on the crude reaction mixtures.
b Conversion=90%; the bis-cyclopropane is obtained in 20% yield (see text).
c
Conversion=93%; the bis-cyclopropane is formed in 10% yield.
Conversion=50%; the bis-cyclopropane is formed in 2% yield.
d

I. E. Marko´ et al. / Tetrahedron Letters 43 (2002) 2317–2320
2319
Figure 3.
Table 2. Palladium-catalysed cyclopropanation of dienylboronates
a
All the reactions were conducted using 5 mol% of Pd(OAc)2 and 1.5 equiv. of CH2N2 in Et2O, at 0°C. Unless otherwise stated, all yields are
for pure, isolated products. In all cases, only traces of the regioisomeric cyclopropane could be detected in the crude NMR spectrum. The
conversions are quantitative but some decomposition occurs during the silica gel column chromatography.
Obtained as a 1:1 mixture of diastereoisomers.
This compound is unstable and hydrolyses rapidly, precluding complete purification.
Isolated as the corresponding boronic acid after basic hydrolysis.
b
c
d

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I. E. Marko´ et al. / Tetrahedron Letters 43 (2002) 2317–2320
The powerful influence of the boron atom in directing
proximal cyclopropanation with such high regiocontrol
is difficult to reconcile by consideration of simple elec-
tronic effects. More work is required before any serious
mechanistic rationale can be suggested. However, the
results displayed in Tables 1 and 2 clearly reveal that the
active species generated by the reaction of diazomethane
with the palladium catalyst exhibits nucleophilic charac-
ter and reacts faster with electron-deficient alkenes.12
Pd, see: Maas, G.; Seitz, J. Tetrahedron Lett. 2001, 42,
6137 and references cited therein.
5. (a) Mende, U.; Radu¨chel, B.; Skuballa, W.; Vorbru¨ggen,
H. Tetrahedron Lett. 1975, 16, 629; (b) Ortuno, R. M.;
Ibarzo, J.; Alvarez-Larena, A.; Piniella, J. F. Tetrahedron
Lett. 1996, 37, 4059.
6. Abdallah, H.; Gre´e, R.; Carrie´, R. Tetrahedron Lett. 1982,
23, 503.
7. (a) Fontani, P.; Carboni, B.; Vaultier, M.; Carrie´, R.
Tetrahedron Lett. 1989, 30, 4815; (b) Fontani, P.; Car-
boni, B.; Vaultier, M.; Maas, G. Synthesis 1991, 605; (c)
Hildebrand, J. P.; Marsden, S. P. Synlett 1996, 893; (d)
Pietruszka, J.; Widenmeyer, M. Synlett 1997, 977; (e)
Pietruszka, J.; Witt, A. J. Chem. Soc., Perkin Trans. 1
2000, 4293.
8. For interesting discussion on the direct cyclopropanation
of dienes, see: (a) van Es, D. S.; Gret, N.; de Rijke, M.;
van Eis, M. J.; de Kanter, F. J. J.; de Wolf, W. H.;
Bickelhaupt, F.; Menzer, S.; Spek, A. L. Tetrahedron
2001, 57, 3557; (b) Cantrell, W. R., Jr.; Davies, H. M. L.
J. Org. Chem. 1991, 56, 723; (c) Dzhemilev, U. M.;
Dokichev, V. A.; Sultanov, S. Z.; Khusnutdinov, R. I.;
Tomilov, Y. V.; Nefedov, O. M.; Tolstikov, G. A. Izv.
Akad. Nauk. SSSR, Ser. Khim. 1989, 1861.
In summary, we have developed a simple and efficient
route to 1-boronato-2-vinylcyclopropanes from readily
available dienylboronates.13 The palladium-catalysed
cyclopropanation is highly regio- and stereoselective,
favouring almost exclusively the formation of the prox-
imal cyclopropane. Furthermore, the procedure displays
excellent tolerance towards a variety of functional
groups. Current efforts are now being directed towards
delineating the full scope of this novel methodology,
uncovering an enantioselective version of this cyclo-
propanation reaction and applying our approach to the
total synthesis of selected natural products. The results
of these investigations will be reported in due course.
9. Ahmed, M.; Barley, G. C.; Hearn, M. T. W.; Jones, E. R.
H.; Thaller, V.; Yates, J. A. J. Chem. Soc., Perkin Trans.
1 1974, 1981.
Acknowledgements
10. In all cases, quantitative conversions are observed. How-
ever, purification by silica gel column chomatography
induces significant decomposition of the dienylboronates,
resulting in only modest yields of the pure products.
11. Suda, M. Synthesis 1981, 714.
12. For some interesting discussions on the mechanism of
these palladium-catalysed cyclopropanation reactions,
see: (a) Denmark, S. E.; Stavenger, R. A.; Faucher, A. M.;
Edwards, P. E. J. Org. Chem. 1997, 62, 3375; (b)
Rodriguez-Garcia, C.; Oliva, A.; Ortuno, R. M.; Bran-
chadell, V. J. Am. Chem. Soc. 2001, 123, 6157.
Financial support of this work by the Universite´
catholique de Louvain, the Janssen Research Founda-
tion, the Actions de Recherche Concerte´es (convention
96/01-197), the Fonds de la Recherche Fondamentale
Collective (dossier n°2.4571.98) and the Fond National
de la Recherche Scientifique (FNRS) for S. Sumida
(Visiting
Scientist,
FNRS-JSPS)
is
gratefully
acknowleged.
13. Typical experimental procedure: Synthesis of 1-pinacolo-
boranyl-2-octenyl cyclopropane (Table 2, entry 1): N-
Methyl-N-nitrosourea (460 mg, 4.44 mmol, 4 equiv.) was
added portionwise to a stirred mixture of ether (2 mL)
and 50% KOH (1 mL), cooled to 0°C. The ether layer
rapidly became yellow and the reaction mixture was
stirred at 0°C for another 30 min. The ether phase
(containing the diazomethane) was separated and added
dropwise to a cold (0°C) solution of the dienylboronate
(293 mg, 1.11 mmol, 1 equiv.) and Pd(OAc)2 (5.5 mg, 5
mol%) in ether. At the end of the addition, the solution
was filtered through Celite and the solvent evaporated
under reduced pressure. The dark residue was further
purified by silica gel column chromatography, affording
the title compound as a yellow oil (216 mg, 70%).
1H NMR (CDCl3, 500 MHz) l: 5.53 (1H, dt, J1=15.2
Hz, J2=6.7 Hz), 4.92 (1H, dd, J1=15.2 Hz, J2=8.5 Hz),
2.0–1.9 (2H, m), 1.56 (1H, m), 1.40–1.15 (20H, m), 0.95–
0.85 (4H, m), 0.62 (1H, ddd, J1=9.7 Hz, J2=5.3 Hz,
J3=3.5 Hz), −0.11 (1H, ddd, J1=9.7 Hz, J2=6.7 Hz,
J3=5.3 Hz). 13C NMR (CDCl3, 125 MHz) l: 133.4,
128.7, 82.8, 32.4, 31.6, 29.5, 28.7, 24.6, 22.5, 20.2, 14.0,
12.2, 2.4. IR (neat) w: 1660, 1420, 1365, 1319, 1217, 1147
cm−1. MS (CI/CH4–N2O): 279 ([M+H]+). Anal. calcd for
C17H31BO2: C, 73.38; H, 11.23. Found: C, 73.45; H, 11.10.
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