Friedel-Crafts/Michael Addition Reactions
for bioactive compounds but also their high reactivity and
stereoselectivity. In this work, a monocyclic system such as
N-methylpyrrole (5) did not afford a good ee%. The lower ee%
observed for 5 probably arises from less effective steric
interaction of 5 with chiral ligand-Cu(II) and the ethenetricar-
boxylate 1 complex. For the reaction of indoles, the parallel
overlap of two π-faces may cause high stereoselection although
the reaction center C2 of 1-Cu(II)-3a does not reside near
the ligand chirality.
The reaction of benzilidene malonate and enolsilanes was
explained as a nucleophilic attack to the si-face of benzylidene
malonates supported by X-ray structure.5 However, Friedel-
Crafts reaction of benzylidene malonates can be also possibly
explained by the diastereomeric approach of indole (2a) to
prochiral C2 of benzylidene malonates. The structure of dimethyl
benzilidene malonate (7)-Cu(II)-3a was optimized by UB3LYP/
LANL2MB (Figure S2 in the Supporting Information), and it
shows the distorted square-planar (but also distorted tetrahedral)
geometry similar to that of 1o-Cu(II)-3a. Calculated O5-
Cu-N7-C9 and O6-Cu-N8-C10 dihedral angles are 27.3°
and 26.3°, respectively. They are larger than those of the X-ray
structure of 7-Cu(II)-3a‚(SbF6)2 (13.6° and 17.4°). The
calculated structure also shows that both π-faces of 7-Cu(II)-
3a are not obviously sterically differentiated, unlike the X-ray
structure. However, the re-facial selectivity can be explained
by the diastereomeric approach of 2a with secondary orbital
interactions, similar to Schemes 2 and 3 (Schemes S1 and S2)
(note that the re- and si-face nomenclature of 1o and benzilidene
malonate is opposite). The facial selectivity is in agreement with
the reaction of benzilidene malonates and indole catalyzed by
3a-Cu(II) reported by Jørgensen and co-workers.4a
Complete reversal of π-facial selectivity by solvents or
substituents in ligands 3 has not been observed in the reaction
of ethenetricarboxylates 1. Thus, although in some reactions of
alkylidene malonates various factors such as solvent, ligand
structures, and counterions are important and they cause reversal
of π-facial selectivity, the observed enantioselectivity in this
reaction can be explained by the diastereomeric approach of
indole toward â-substituents.
In summary, we have shown that the reaction of 1 with
indoles 2 in the presence of catalytic amounts of chiral
bisoxazoline 3-Cu(II) complex gives alkylated products 4 in
high ee. The present reaction provides an efficient enantiose-
lective Friedel-Crafts alkylation of indoles for diversely
substituted compounds. The highly functionalized products are
suitable for further elaboration. A new utility of ethenetricar-
boxylates in organic synthesis has been demonstrated in this
study. Further elaboration of the products and development to
use ethenetricarboxylates in other catalytic asymmetric reaction
are under investigation.
Experimental Section
Typical Procedure (Table 1, Entry 1). A powdered mixture
of Cu(OTf)2 (18 mg, 0.05 mmol) and 3a (16 mg, 0.054 mmol)
was dried under vacuum for 1 h. THF (1 mL) was added under
N2, and the solution was stirred for 1 h. Compound 1a (0.122 g,
0.5 mmol) in THF (0.4 mL) was added and stirred for 15 min,
followed by addition of 2a (65 mg, 0.55 mmol). After 20 h, the
reaction mixture was filtered through a plug of silica gel, washed
with Et2O, and dried (MgSO4), and the solvent was removed. The
residue was purified by column chromatography over silica gel,
eluting with CH2Cl2 to give 4a (173 mg, 96%). 4a (Rf 0.1 (CH2-
Cl2)): Pale brown oil; HPLC (CHIRALPAK AS-H, hexane/iPrOH
) 9:1) minor peak tR1 11.3 mim, major peak tR2 12.4 min, 68% ee;
[R]27D -99° (c 1.73, CHCl3); 1H NMR (400 MHz, CDCl3) δ (ppm)
0.851 (t, J ) 7.1 Hz, 3H), 1.18 (t, J ) 7.1 Hz, 3H), 1.29 (t, J )
7.1 Hz, 3H), 3.79-3.92 (m, 2H), 4.01-4.09 (m, 1H), 4.16-4.31
(m, 3H), 4.37 (d, J ) 11.8 Hz, 1H), 4.64 (dd, J ) 11.8, 0.5 Hz,
1H), 7.11-7.20 (m, 3H), 7.33 (d-like, J ) 7.9 Hz, 1H), 7.74 (d-
like, J ) 7.9 Hz, 1H), 8.21 (bs, 1H); 13C NMR (100.6 MHz, CDCl3)
δ (ppm) 13.6 (q), 14.1 (q), 42.4 (d), 55.0 (d), 61.38 (t), 61.43 (t),
61.9 (t), 109.8 (s), 111.2 (d), 119.5 (d), 120.0 (d), 122.4 (d), 123.3
(d), 126.4 (s), 136.1 (s), 167.6 (s), 168.3 (s), 172.5 (s); IR (neat)
3404, 2983, 1732, 1458, 1370, 1301, 1174, 1029 cm-1; MS (EI)
m/z 361 (M+, 39%), 287 (32%), 202 (43%), 170 (100%); exact
mass M+ 361.1530 (calcd for C19H23NO6 361.1525).
Theoretical Calculations. Density functional theory calculations
of 1o-Cu(II)-3a and 7-Cu(II)-3a were carried out by UB3LYP/
LANL2MB.9,10 Geometries were fully optimized. Vibrational
analyses were also performed to check whether the obtained
geometries are either at the energy minima or at the saddle points.
All calculations were conducted by the use of Gaussian03 installed
at the Information Processing Center (Nara University of Educa-
tion).
Acknowledgment. This work was supported by the Ministry
of Education, Culture, Sports, Science, and Technology of the
Japanese Government. We are grateful to Prof. S. Umetani
(Kyoto University) and Prof. K. Kakiuchi (Nara Institute of
Science and Technology) for mass spectra and elemental
analysis. We also thank Prof. S. Yamabe (Nara University of
Education) for theoretical calculations and Dr. S. Takaoka
(Tokushima Bunri University) for X-ray analysis.
Supporting Information Available: Additional experimental
procedures and spectral data, Figures S1 and S2, X-ray crystal-
lographic data, Schemes S1 and S2, and computational data. This
materialisavailablefreeofchargeviatheInternetathttp://pubs.acs.org.
JO052041P
J. Org. Chem, Vol. 71, No. 2, 2006 743
Yamazaki, Shoko
