Organocatalytic Asymmetric SNAr Reactions
FIGURE 1. Concept of the organocatalytic direct SNAr reaction of â-keto ester showing the formation of a chiral ion pair by the interaction of a
cinchona alkaloid quaternary ammonium salt and the â-keto ester generating a chiral nucleophile in a “chiral pocket”.
alkaloids as the catalyst.6 In the present paper, we present the
scope and limitation of this novel asymmetric reaction, together
with various transformations of the optically active products
such as the synthesis of optically active spiro[pyrrolidone-3,3′-
oxoindoles], diastereoselective reductions, and an unusual
nucleophilic ring opening reaction of the products.
The organocatalytic direct SNAr reaction of â-ketoesters is
based on the concept outlined in Figure 1 with a cinchona
alkaloid quaternary ammonium salt as the chiral catalyst.7 A
base removes the acidic proton in the â-ketoester generating
FIGURE 2. Influence of the substituents R′, R′′, and R′′′ on the
an ambident nucleophile, which interacts with the chiral
quaternary ammonium salt forming a chiral ion pair. The idea
behind this chiral ion-pair formation is that the chiral cinchona
alkaloid salt and the â-ketoester generate a nucleophile in a
“chiral pocket” (Figure 1) in which one face is shielded by the
chiral cinchona alkaloid salt leading to an enantioselective
nucleophilic approach to the aromatic compound.
reaction course of the organocatalytic enantioselective SNAr reaction.
biphasic system consisting of toluene as the solvent and CsOH-
monohydrate as the base in the presence of an extensive number
of cinchona alkaloid quaternary ammonium salts 4 having a
diversity in substitution patterns (eq 1).8,9 The results from the
screening process are presented in Table 1.
It has been found that the regio- and stereoselectivity are very
dependent on the substituents R′ and R′′. For R′ ) Bn or 4-CF3-
Bn and R′′ ) allyl of the catalysts 4a and 4b, respectively, the
ambident nature of the nucleophile determines the C- vs
O-arylation selectivity, and mixtures of the C- and O-arylated
products are obtained in ratios of 1.5:1 to 1.0:1 and with very
low enantiomeric excess (entries 1 and 2). For the cinchona
alkaloid catalyst 4c having R′ ) R′′ ) Bn, a 1.0:1 ratio between
the C- and O-arylated products is also obtained and the desired
product 3a is formed as a racemate (entry 3). The functional-
ization of the catalyst turned out to solve both the regio- and
enantioselectivity problem of the SNAr reaction; an exchange
of the R′′-substituent from benzyl to benzoyl (catalyst 4d) leads
to a dramatic change in both regio- and enantioselectivity; at
room temperature, the desired product 3a is now formed as the
major product (C-/O-arylating ratio 4:1) and with an enantio-
meric excess of 46% ee (entry 4). Lowering the reaction
temperature to -40 °C leads to a significant improvement to
>20:1 in favor of 3a and now with 87% ee in toluene as the
solvent (entry 5). Although we lack a rigorous model to explain
the increase in enantiomeric excess, we can hypothesize that a
coordinating group near the 9-position (the R′′-position) is
Results and Discussion
Due to the ambident nature of the nucleophile formed in the
reaction, both a carbon and oxygen nucleophile can perform
the SNAr reaction, and the reaction course is very dependent
on the R′, R′′, and R′′′ substituents as outlined in Figure 2.
Our starting point is the reaction of 2-carbethoxycyclopen-
tanone 1a with 2,4-dinitrofluorobenzene (2,4-DNF) 2a in a
(5) For synthesis of asymmetric quaternary stereocenters starting from
R-dicarbonyl compounds, see, e.g.: Conjugate addition: (a) Hamashima,
Y.; Hotta, D.; Sodeoka, M. J. Am. Chem. Soc. 2002, 124, 11240. (b) Harada,
S.; Kumagai, N.; Kinoshita, T.; Matsunaga, S.; Shibasaki, M. J. Am. Chem.
Soc. 2003, 125, 2582. (c) Fanghui, W.; Hongming, L.; Hong, L.; Deng, L.
Angew. Chem., Int. Ed. 2006, 45, 947. Conjugate addition to alkynones:
(d) Bella, M.; Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126, 5672.
Amination: (e) Saaby, S.; Bella, M.; Jørgensen, K. A. J. Am. Chem. Soc.
2004, 126, 8120. Alkylation: (f) Park, E. J.; Kim, M. H.; Kim, D. Y. J.
Org. Chem. 2004, 69, 6897. (g) Ooi, T.; Miki, T.; Taniguchi, M.; Shiraishi,
M.; Takeuchi, M.; Maruoka K. Angew. Chem., Int. Ed. 2003, 42, 3796.
Halogenation: (h) Bartoli, G.; Bosco, M.; Carlone, A.; Locatelli, M.;
Melchiorre, P.; Sambri, L. Angew. Chem., Int. Ed. 2005, 44, 6219. (i)
Marigo, M.; Kumaragurubaran, N.; Jørgensen, K. A. Chem. Eur. J. 2004,
10, 2133. Fluorination: (j) Shibata, N.; Suzuki, E.; Asahi, T.; Shiro, M. J.
Am. Chem. Soc. 2001, 123, 7001. Pd-mediated arylation: (k) Ahman, J.;
Wolfe, J. P.; Troutman, M. V.; Palucki, M.; Buchwald, S. L. J. Am. Chem.
Soc. 1998, 120, 1918. (l) Hamada, T.; Chieffi, A.; A° hman, J.; Buchwald,
S. L. J. Am. Chem. Soc. 2002, 124, 1261. (m) Spielvogel, D. J.; Buchwald,
S. L. J. Am. Chem. Soc. 2002, 124, 3500.
(8) (a) O’Donnel, M. J.; Wu, S.; Huffman, J. C. Tetrahedron 1994, 50,
4507. (b) Corey, E. J.; Bo, Y.; Bush-Pedersen, J. J. Am. Chem. Soc. 1998,
120, 13000. (c) Dolling, U.-H.; Davis, P.; Grabowski, E. J. J. J. Am. Chem.
Soc. 1984, 106, 6; 446. For the modifications of cinchona alkaloid-derived
PTC catalysts, see: Kacprzak, K.; Gawronski, J. Synthesis 2001, 961.
(9) For the use of benzoylated quinine derivatives in asymmetric
synthesis, see, e.g.: France S.; Shah, M. H.; Weatherwax, A.; Wack, H.;
Roth, J. P.; Lectka, T. J. Am. Chem. Soc. 2005, 127, 1206 and references
therein.
(6) See, e.g.: (a) Halpern, M. E. Phase-Transfer Catalysis. Mechanism
and Synthesis; American Chemical Society: Washington, DC, 1997. (b)
Sasson Y.; Neumann, R. Handbook of Phase-Transfer Catalysis; Blackie
A&M: London, 1997.
(7) (a) Ooi, T.; Maruoka, K. Chem. ReV. 2003, 103, 3013. (b) Lygo, B.;
Andrews, B. I. Acc. Chem. Res. 2004, 37, 518. (c) O’Donnell, M. J. Acc.
Chem. Res. 2004, 37, 506.
J. Org. Chem, Vol. 71, No. 13, 2006 4981