SCHEME 9. Facial Approach of the Ylide on the Michael
Acceptor
hardly in question, since the respective pKa values are virtually
equal as extrapolated from cyano- or ester-substituted methyl-
enetrimethylammonium salts12 (pKa of 20.6 in DMSO for both
ammoniums). Two hypotheses can be proposed: First, a greater
mesomeric delocalization of the anion in the ester moiety results
in a lowering of the ylide’s nucleophilicity. Alternatively, the
1,4-addition is effective in both cases, but the ring closure might
be hampered by the “bulky” ester group, thus allowing the
enolate to react with another acrylate molecule, starting the
polymerization process.
SCHEME 10. Particular Approach with Cinnamate 34
Azetidinium ylides proved capable of effecting cyclopropa-
nation of Michael acceptors in good yields. Novel (aminoethyl)-
cyclopropane esters were prepared by this method. Enantiopure
azetidinum salts reacted with good to excellent diastereoselec-
tivities to provide tri- or tetrasubstituted cyclopropanes pos-
sessing one or two quaternary carbon centers along with one
or two tertiary centers as a major isomer among the eight
possible. Some critical parameters of this three-step transforma-
tion have been delineated. First, the ring strain present in the
substrate is essential to overcome the energetic barrier of the
final ring closure. Second, the nature of the functional group in
the ylide (a nitrile) is of great importance. Finally, a simple
facial approach model is proposed to account for the observed
stereochemistries. The reactivity of azetidinium ylides is cur-
rently under study to aim at biologically relevant targets.
SCHEME 11. Cyclopropanation with Ester 44
between the nitrile and the ester groups. Upon formation of the
C-C bond, the zwitterion 39 is produced. Finally, the reaction
is completed by nucleophilic substitution resulting from overlap
of the π-orbital of the enolate with the σ* orbital of the C-N+
bond. This model readily accounts for the absolute configurations
invariably Rsof the carbon bearing the cyano group in the
produced cyclopropane as well as for the trans relationship
between the two electron-withdrawing groups (depending on
the Si or Re nature of the attacked face of the alkene).
However, a problem remains: how can one explain the
formation of the major cis isomer when ethyl cinnamate (34)
is used? Here again, the ylide attacks the Michael acceptor from
the upper face, since the R configuration is retained, but the
position of the cyano and ester groups on the same side of the
cyclopropane indicates an Re face approach of the alkene. As
an explanation, we can postulate a favorable π-stacking interac-
tion between the phenyls of the cinnamate and of the azeti-
dinium, thus stabilizing the transition state 41 in this particular
case as depicted in Scheme 10.
Finally, the important dependency of the reactant character-
istics on the reaction’s outcome prompted us to determine
whether the nature of the stabilizing group on the ylide had an
influence on the cyclopropanation. Therefore, the ester-bearing
azetidinium 44, previously prepared in our laboratory,5 was
reacted with methyl acrylate using the same standard conditions.
The expected cyclopropane 45 was indeed detected in the crude
mixture, though contaminated with polymeric material 46,
Scheme 11.
Experimental Section
A solution of azetidinium salt 26a (0.80 mmol) in dry THF was
cooled to -78 °C, and cyclohexanone (0.97 mmol, 1.2 equiv) was
added, followed by lithium hexamethyldisilazane (c ) 2 mol‚L-1
)
in THF (1.70 mmol, 2 equiv). The mixture was stirred while being
allowed to warm to -30 °C over a 1 h period. The reaction was
then stopped by addition of 10 mL of a saturated solution of
ammonium chloride. Water was added, and the aqueous layer was
extracted three times with 15 mL of dichloromethane. After drying
over magnesium sulfate and evaporation, the crude material was
checked in proton NMR. Chromatographic purification using silica
gel (Et2O/pentane (4/6), Rf ) 0.48) gave the cyclopropane 31, 312
mg, 90% yield, as a white solid: mp 118 °C; [R]D20 ) +88.9 (c )
1
1.0, CHCl3); H NMR (300 MHz, CDCl3) δ 7.40-7.25 (m, 5H),
3.30-3.20 (m, 1H), 2.53-2.42 (m, 1H), 2.35 (s, 6H), 2.32-2.25
(m, 2H), 2.07-2.02 (m, 4H), 2.00-1.71 (m, 2H), 0.70 (d, 3H, J )
6.4 Hz); 13C NMR (75 MHz, CDCl3) δ 204.5 (Cq), 139.9 (Cq),
129.1 (CH), 128.7 (CH), 127.9 (CH), 120.0 (Cq), 62.0 (CH), 57.7
(CH), 40.5 (CH3), 38.9 (CH2), 34.0 (CH), 33.5 (CH), 32.0 (Cq),
24.6 (CH2), 20.0 (CH2), 9.0 (CH3); IR (KBr, cm-1) ν 3032, 2970,
2939, 2852, 2827, 2770, 2217, 1700, 1608, 1597; HRMS (ESI,
TOF MS) m/z calcd for [MH+] 297.1967, found 297.1972.
Acknowledgment. The CNRS is greatly acknowledged for
financial support. We also express our gratefulness to Dr. Karen
Wright for the language revision of this manuscript.
Attempts to isolate compound 45 were unsatisfactory, all
resulting in impure material. Ylide-induced polymerizations of
acrylate derivatives have been reported,14 but the factor govern-
ing this change of reactivity between the cyano- and ester-
stabilized ylides is rather unclear. The deprotonation step is
Supporting Information Available: Detailed procedures and
full characterization. This material is available free of charge via
pounds 27, 31, 33b, and 35a were deposited at the Cambridge
Crystallographic Data Centre with the numbers CCDC 625288-
625291, respectively.
(14) (a) Shukla, A. K.; Saini, S.; Kumar, P.; Nigam, S. K.; Srivastava,
A. K. Angew. Makromol. Chem. 1986, 141, 103-111. (b) Prajapati, K.;
Varshney, A. J. Polym. Res. 2006, 13, 97-105.
JO062221E
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