Enantioselective indole Friedel-Crafts alkylations catalyzed by bis(oxazolinyl)pyridine-scandium(III) triflate complexes

Article abstract of DOI:10.1021/ja036985c

A highly enantioselective Friedel-Crafts alkylation of electron-rich aromatic nucleophiles catalyzed by scandium(III) triflate-pyridyl(bis)oxazoline complexes has been accomplished. The reaction involves α,β-unsaturated acyl phosphonates as electrophiles and primarily substituted indoles as nucleophiles. The reactive acyl phosphonate product is converted to the corresponding ester or amide in good overall yield by adding an alcohol or amine directly to the reaction mixture. Copyright

Full text of DOI:10.1021/ja036985c

Published on Web 08/13/2003
Enantioselective Indole Friedel-Crafts Alkylations Catalyzed by
Bis(oxazolinyl)pyridine-Scandium(III) Triflate Complexes
David A. Evans,* Karl A. Scheidt,† Keith R. Fandrick, Hon Wai Lam, and Jimmy Wu
Department of Chemistry and Chemical Biology, HarVard UniVersity, Cambridge, Massachusetts 02138
Received June 30, 2003; E-mail: evans@chemistry.harvard.edu
Table 1. Scandium-Catalyzed Alkylations of N-Methylindole with
Representative R,â-Unsaturated Acyl Phosphonates 2a
The Lewis acid-promoted addition of aromatic nucleophiles to
electron-deficient alkenes is a powerful bond-forming reaction in
organic chemistry.1 While the development of asymmetric catalytic
versions of this reaction provides access to important enantioen-
riched aryl-substituted products, only a few examples of this process
have been reported.2 Previous reports from this laboratory have
demonstrated that bis(oxazolinyl)pyridine (pybox)-scandium(III)
triflate complexes are effective chiral Lewis acid catalysts exhibiting
good chelating potential.3,4 In this Communication, we describe the
utility of the chiral scandium complex 15 in the catalyzed additions
of electron-rich aromatic substrates to R,â-unsaturated acyl phos-
phonates6 2 (eq 1). These intermediate acyl phosphonates are
effective active esters that may be employed in subsequent acyl-
transfer reactions. Accordingly, these intermediates may be further
transformed without isolation into product esters or amides.7
mol %
1
time
(h)
ee
(%)b
yield
(%)
entry
phosphonate
R
1c
2
3
2a
2a
2a
2a
2b
2c
2d
2e
Me
Me
Me
Me
Et
10
10
5
4
4
93
97
98
95
97
99
94
80
79 (4a)
75 (4a)
88 (4a)
72 (4a)
65 (4b)
82 (4c)
57 (4d)
85 (4e)
20
48
17
20
17
48
4
3
5d
6
10
10
10
20
i-Pr
CH2OTBDPS
Ph
7e
8
a All reactions were carried out in CH2Cl2 at -78 °C (0.2 M), except
where noted. b Enantiomeric excess determined by chiral HPLC using
Chiracel OD-H columns. c Reaction carried out at -20 °C. d Reaction
carried out at -50 °C. e Morpholine quench: 94% ee, 73% yield.
Table 2. Scandium-Catalyzed Alkylation of Substituted Indoles
with Crotonyl Acyl Phosphonate (2a)a
Since the indole skeleton is an important substructure in both
natural products and therapeutic agents,8 N-methylindole (3) was
selected for this study. A series of Sc(OTf)3-pybox complexes were
evaluated in the illustrated reaction, and pybox complex 1 emerged
as the most promising Lewis acid catalyst. For the purpose of
product analysis and characterization, the intermediate â-indolyl
acyl phosphonates were converted to the corresponding methyl
esters by direct addition of MeOH and an amine to the reaction
mixture (DBU, room temperature, 30 min).7
The Friedel-Crafts alkylation of N-methylindole (3) with
representative acyl phosphonates 2 is provided in Table 1.9 Entry
1 indicates that the reaction may be conducted at temperatures up
to -20 °C without deleterious effect on selectivity. High enanti-
oselectivities may be maintained at catalyst loadings as low as 3
mol % (95% ee, 72% yield, entry 4). The reaction is also tolerant
of a selection of â-alkyl substitutents on the unsaturated acyl
phosphonate (2) (entries 5-8). Even the encumbering isopropyl
substituent does not adversely affect the yield or enantioselectivity
(entry 6, 99% ee, 82% yield).
entry
indole
R
X
Y
time (h)
ee (%)b
yield (%)
1
2
3
4
5
6
7
8e
5a
5b
5c
5d
5e
5f
H
H
H
H
Br
Cl
H
H
H
H
H
H
H
Cl
3
5
83
98
99
>99
>99
97
83 (6a)
76 (6b)
85 (6c)
64 (6d)
66 (6e)
68 (6f)
67 (6g)
51 (6h)
allyl
Bn
Bn
Bn
Bn
Bn
Bn
20
19
19
16
19
48
CO2Me
OMe
H
5g
5h
97
90
a All reactions carried out in CH2Cl2 at -78 °C (0.2 M in substrate).
b Enantiomeric excess determined by chiral HPLC using Chiracel OD-H
columns. c 20 mol % catalyst.
(Table 2). Although the parent indole reacted with diminished
selectivity (entry 1, 83% ee), the other N-alkyl-substituted indoles
(methyl, allyl, and benzyl) afford alkylated products with higher
selectivity (90-99% ee, entries 2-8).
Indole derivatives with either electron-withdrawing or electron-
donating substituents at C(5) are competent substrates (entries
4-7).10 While a C(4) chlorine substituent lowers conversion (51%
yield), a good level of enantioselectivity is still observed (90% ee)
(entry 8).
A representative selection of indole derivatives was next evalu-
ated in the Friedel-Crafts alkylation with acyl phosphonate 2a
† Present address: Department of Chemistry, Northwestern University, Evanston,
IL 60208.
9
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J. AM. CHEM. SOC. 2003, 125, 10780-10781
10.1021/ja036985c CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Figure 1. Crystal structure of the complex 1‚hydrate. Model of the [Sc((S,S,S,S)-Inda-pybox)(OTf)(crotonyl-acyl phosphonate 2a)]2+ complex.
Acknowledgment. Support has been provided by the NSF, the
NIH (GM 33328-18), Merck, Amgen, and NSC Technologies.
K.A.S. acknowledges the receipt of an NIH postdoctoral fellowship.
J.W. thanks the ASEE for a NDSEG predoctoral Fellowship.
The procedure may be altered to afford amide reaction products
directly (eq 4). In this instance, the reaction is carried out as reported
in Table 1 (entry 1) and quenched with morpholine (room
temperature) to afford 7 (96% ee, 88% yield).11 In addition, these
reactions are not limited to indole alkylations. For example, the
electron-rich 3-dimethylaminoanisole (8) is also an effective
nucleophile (eq 5).
Supporting Information Available: Experimental procedures,
spectral data for all new compounds, crystallographic data, and
stereochemical proof (PDF, CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
References
(1) For a general review of Friedel-Crafts reactions, see: Olah, G. A.;
Krishnamurti, 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) (a) For Cu(II)-catalyzed additions of aromatic systems to unsaturated ester
derivatives, see: Jensen, K. B.; Thorbauge, J.; Hazell, R. G.; Jorgensen,
K. A. Angew. Chem., Int. Ed. 2001, 40, 160-163. Zhou, J.; Tang, Y. J.
Am. Chem. Soc. 2002, 124, 9030-9031. (b) For additions of electron-
rich benzenes and indoles to R,â-unsaturated aldehydes catalyzed by chiral
secondary amines, see: Paras, N. A.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2001, 123, 4370-4371. Austin, J. F.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2002, 124, 1172-1173.
(3) (a) Evans, D. A.; Sweeney, Z. K.; Rovis, T.; Tedrow, J. S. J. Am. Chem.
Soc. 2001, 123, 12095-12096. (b) Evans, D. A.; Masse, C. E.; Wu, J.
Org. Lett. 2002, 4, 3375-3378. (c) Evans, D. A.; Wu, J.; Masse, C. E.;
MacMillan, D. W. C. Org. Lett. 2002, 4, 3379-3382.
(4) For the application of a chiral scandium catalyst in Diels-Alder reactions,
see: (a) Kobayashi, S.; Araki, M.; Hachiya, I. J. Org. Chem. 1994, 59,
3758. (b) Quian, C.; Wang, L. Tetrahedron Lett. 2000, 41, 2203. For a
review of scandium(III) triflate-catalyzed reactions, see: Kobayashi, S.
Eur. J. Org. Chem. 1999, 15-27.
(5) Sc(S,S)-Ph-pybox ) [(S)-(R*,R*)]-2,6-bis(4,5-dihydro-4-phenyl-2-oxazolyl)-
pyridine. Davies, I. W.; Gerena, L.; Lu, N.; Larsen, R. D.; Reider, P. J.
J. Org. Chem. 1996, 61, 9629-9630.
(6) For the use of R,â-unsaturated acyl phosphonates in Lewis acid-catalyzed
reactions, see: (a) Telan, L. A.; Poon, C.-D.; Evans, S. A., Jr. J. Org.
Chem. 1996, 61, 7455-7462. (b) Evans, D. A.; Johnson, J. S.; Olhava,
E. J. J. Am. Chem. Soc. 2000, 122, 1635-1649.
(7) Dialkyl acyl phosphonates are highly effective acylating agents. Sekine,
M.; Kume, A.; Hata, T. Tetrahedron Lett. 1981, 22, 3617-3620.
(8) (a) Saxton, J. E. Nat. Prod. Rep. 1997, 14, 559-590. (b) Toyota, M.;
Ihara, N. Nat. Prod. Rep. 1998, 15, 327-340 and references therein.
(9) Only alkylation at the 3-position of the indole structure was observed.
(10) Substitution at the 2-position only slightly affects enantioselectivity, e.g.,
for 1,2-dimethylindole addition to 2a, 86% ee, 94% yield.
(11) For examples of additions to morpholine amides, see: Douat, C.; Heitz,
A.; Martinez, J.; Fehrentz, J.-A. Tetrahedron Lett. 2000, 41, 37-40 and
references therein.
The structure of the scandium-pybox complex 1, as its derived
monohydrate 1‚(H2O), was determined by X-ray crystallography
(Figure 1). The pentagonal bipyramidal geometry of this complex
is remarkably similar to that of a closely related X-ray structure,
Sc[(S,S)-Ph-pybox(H2O)](OTf)3, recently reported by us.3a A model
that rationalizes the observed sense of asymmetric induction (eq
1) is provided in Figure 1.12 All extraneous ligands in this model
have been removed for clarity. Placement of the sterically demand-
ing coordinating phosphonate oxygen in the more accessible apical
position orients the carbonyl oxygen toward the ligand plane. The
addition of nucleophiles from the indicated s-cis enoate diastereo-
face should be favored on the basis of resident nonbonding
interactions. At the present time, the issue of the coordination
number (6 or 7) of the catalyst-substrate complex remains
unresolved.
In summary, scandium-pybox complexes are efficient catalysts
for the Friedel-Crafts additions of electron-rich aromatic nucleo-
philes to R,â-unsaturated acyl phosphonates. Further studies of the
utility of these scandium complexes as chiral Lewis acids are in
progress.
(12) The stereochemical model was created from the crystal structure of 1‚
H2O as follows. The coordinates of 1‚H2O were accessed with ChemBats3D
Pro (version 7.0). The two vicinal triflates and water molecule were
replaced by the acyl phosphonate, and the molecular energy was minimized
(MM2) with the ligand-metal bonds held constant.
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J. AM. CHEM. SOC. VOL. 125, NO. 36, 2003 10781