C O M M U N I C A T I O N S
0.26 M in substrate (eq 2): 1 mol % (98% ee); 10 mol % (90%
ee); 20 mol % (78% ee); 35 mol % (49% ee); 50 mol % (11% ee).
This trend was most evident when a stoichiometric amount of
catalyst 1 was used, resulting in a turnover in asymmetric induction
(-31% ee).
Reaction enantioselection in the presence of 5 mol % of 1 (-40
°
(
C) as a function of reaction molarity was also probed: 0.10 M
95% ee); 0.4 M (94% ee); 0.8 M (93% ee); 1.0 M (92% ee).
On the basis of these data and the fact that Sc(OTf) -pybox
3
complexes can adopt seven-coordinate pentagonal-bipyramidal
geometry,6 we speculate that the reaction might proceed through
a 1:1:1 substrate:product:catalyst complex that is favored at lower
catalyst loadings and is more enantioselective than the correspond-
ing 1:1 substrate:catalyst complex which would be favored at higher
catalyst loadings.
,9
In summary, R,â-unsaturated 2-acyl imidazoles are efficient
substrates for Friedel-Crafts alkylations. These substrates are easily
converted to a variety of useful functional groups and are easily
synthesized. Further studies to explain the catalyst loading profile
and expand the scope of the reactions of the R,â-unsaturated 2-acyl
imidazoles are in progress.
The 2-acyl imidazole residue may be transformed into a range
of carboxylic acid derivatives. Removal of the imidazole group
7
Acknowledgment. Support is provided by the NIH (GM-33328-
can be accomplished in one of two ways (eqs 7-9). First, the
imidazole group can be successively methylated then treated under
a variety of nucleophilic conditions to acquire esters, amides, and
carboxylic acids in good yields in one-pot operations (Table 3).
2
0), the NSF (CHE-9907094), and Merck Research Laboratories.
H.-J.S. acknowledges a Novartis fellowship.
Supporting Information Available: Experimental procedures,
spectral data for all new compounds, stereochemical determinations,
synthesis of R,â-unsaturated 2-acyl imidazoles, and complete ref 3b
(PDF, CIF). This material is available free of charge via the Internet at
http://pubs.acs.org.
Table 3. Conversion of Imidazole 4a to Carboxylic Acid
Derivatives (eq 7)
References
(
1) For a review of the Friedel-Crafts reactions see: Olah, G. A.; Krishna-
murti, R.; Prakash, G. K. S. Friedel-Crafts Alkylations. In ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press:
Oxford, 1991; Vol. 3, pp 293-339.
(
2) For examples of natural products which are relevant to the formed
stereocenter, see cycloaplysinopsin: (a) Mancini, I.; Guella, G.; Zibrowius,
H.; Pietra, F. Tetrahedron 2003, 59, 8757-8762. 10,11-Dimethoxynare-
line: (b) Kam, T.; Choo, Y. J. Nat. Prod. 2004, 67, 547-552.
Hapalindoles: (c) Kinsman, A. C.; Kerr, M. A. J. Am. Chem. Soc. 2003,
1
25, 14120-14125. (d) Huber, U.; Moore, R. E.; Patterson, G. M. L. J.
Nat. Prod. 1998, 61, 1304-1306.
(
3) For examples of potential medicinal agents relevant to the formed
stereocenter, see: (a) Rawson, D. J.; Dack, K. N.; Dickinson, R. P.; James,
K. Biorg. Med. Chem. Lett. 2002, 12, 125-128. (b) Dillard, R. D. et al.
J. Med. Chem. 1996, 39, 5119-5136. (c) Chang-Fong, J.; Rangisetty, J.
B.; Dukat, M.; Setola, V.; Raffay, T.; Roth, B.; Glennon, R. Biorg. Med.
Chem. Lett. 2004, 14, 1961-1964.
(
4) For Cu(II)-catalyzed additions of aromatic systems to R,â-unsaturated
R-keto esters, see: (a) Jensen, K. B.; Thorbauge, J.; Hazell, R. G.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2001, 40, 160-163. For additions
of electron-rich aromatics and indoles to R,â-unsaturated aldehydes
catalyzed by chiral secondary amines, see: (b) Paras, N. A.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2001, 123, 4370-4371. (c) Austin, J. F.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 1172-1173. For Cu-
(II)-catalyzed additions of indoles to alkylidene malonates, see: (d) Zhou,
J.; Ye, M.-C.; Huang, Z.-Z.; Tang, Y. J. Org. Chem. 2004, 69, 1309-
a
b
c
PhMgBr, THF, -78 to 0 °C. MeI, EtOAc, 50 °C. Benzene, 10 wt
e
%
Na2CO3, 50 °C. d NaBH4, MeOH, rt. Benzene, 0.1 M NaOH,
1
320. For Cu(II)-catalyzed additions of indoles and pyrroles to R′-hydroxy
H2N(CH2)5CO2Na, 80 °C.
enones, see: (e) Palomo, C.; Oiarbide, M.; Kardak, B. G.; Garcia, J. M.;
Linden, A. J. Am. Chem. Soc. 2005, 127, 4154-4155.
(
(
5) Itoh, K.; Kanemasa, S. J. Am. Chem. Soc. 2002, 124, 13394-13395.
6) Evans, D. A.; Scheidt, K. A.; Fandrick, K. R.; Lam, H. W.; Wu, J. J. Am.
Chem. Soc. 2003, 125, 10780-10781.
Second, the initial ketone moiety in 4a can be treated with a
Grignard reagent to give the tertiary alcohol 13 or reduced to the
secondary alcohol 14 with sodium borohydride (eqs 8 and 9). The
resulting imidazole groups can be methylated and subsequently
eliminated under basic conditions to liberate the ketone 15 or
aldehyde 16 in good yields.
(
7) For the transformation of 2-acyl benzimidazoles to esters, amides,
â-diketones, and â-ketoesters, see: (a) Miyashita, A.; Suzuki, Y.;
Nagasaki, I.; Ishiguro, C.; Iwamoto, K.-I.; Higashino, T. Chem. Pharm.
Bull. 1997, 45, 1254-1258. For the transformation of 2-acyl imidazoles
to ketones, â-diketones, â-ketoesters, and aldehydes, see: (b) Ohta, S.;
Hayakawa, S.; Nishimura, K.; Okamoto, M. Chem. Pharm. Bull. 1987,
35, 1058-1069.
Next, we turned our attention to the issue of the effect of catalyst
loading on enantioselectivity. As shown in Table 1, the addition of
N-methylindole to 2a afforded better selectivities with lower catalyst
loadings. To further explore this phenomenon, we conducted a series
of experiments with different catalyst loadings of 1 at -40 °C at
(
8) All substrates explored showed increased product enantioselection with
decreased catalyst loading.
(9) Evans, D. A.; Sweeney, Z. K.; Rovis, T.; Tedrow, J. S. J. Am. Chem.
Soc. 2001, 123, 12095-12096.
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