Enantioselective Friedel-Crafts alkylation reactions catalyzed by a chiral nonracemic C2-symmetric 2,2′-bipyridyl copper(II) complex

Article abstract of DOI:10.1021/ol050075d

(Chemical Equation Presented) Enantioselective Friedel-Crafts alkylation reactions of a series of substituted indoles with methyl trifluoropyruvate, catalyzed by a chiral nonracemic C₂-symmetric 2,2′-bipyridyl copper(II) triflate complex, are d

Full text of DOI:10.1021/ol050075d

ORGANIC
LETTERS
2005
Vol. 7, No. 5
901-904
Enantioselective Friedel−Crafts
Alkylation Reactions Catalyzed by a
Chiral Nonracemic C2-Symmetric
2,2′-Bipyridyl Copper(II) Complex
Michael P. A. Lyle, Neil D. Draper, and Peter D. Wilson*
Department of Chemistry, Simon Fraser UniVersity, 8888 UniVersity DriVe,
Burnaby, British Columbia V5A 1S6, Canada
pwilson@sfu.ca
Received January 13, 2005
ABSTRACT
Enantioselective Friedel
nonracemic C2-symmetric 2,2
propionic acid methyl esters were formed in good yield and in high enantiomeric excess (up to 90%). This is the first report of the use of a
chiral nonracemic 2,2 -bipyridyl ligand in catalytic and enantioselective Friedel Crafts alkylation reactions. The structural characterization of
a copper(II) chloride complex of the chiral 2,2 -bipyridyl ligand by X-ray crystallography is also presented.
−Crafts alkylation reactions of a series of substituted indoles with methyl trifluoropyruvate, catalyzed by a chiral
′
-bipyridyl copper(II) triflate complex, are described. The corresponding 3,3,3-trifluoro-2-hydroxy-2-indole-3-yl-
′
−
′
Many different types of chiral ligands have been developed
for catalytic asymmetric synthesis and of these, chiral
nonracemic 2,2′-bipyridines and 1,10-phenanthrolines have
received considerable attention.1,2 We have recently reported
an efficient synthesis of a low molecular weight, chiral
nonracemic C2-symmetric bipyridyl ligand (+)-1 and dem-
onstrated that it is an outstanding chiral director for use in
asymmetric copper(I)-catalyzed cyclopropanation reactions
of alkenes and diazoesters (Figure 1).3 The ligand (+)-1 was
prepared in a convergent manner using a notable and highly
enantioselective (90% ee) catalytic asymmetric dihydroxy-
lation reaction of the 2-chloropyrindine 2 as a key step. On
conversion to the corresponding 3-pentanone cyclic acetal,
a subsequent nickel-mediated homocoupling reaction af-
forded the desired 2,2′-bipyridyl ligand (+)-1 in greater than
99% enantiomeric excess. This indicated that a significant
(1) (a) Chelucci, G.; Thummel, R. P. Chem. ReV. 2002, 102, 3129. (b)
Fletcher, N. C. J. Chem. Soc., Perkin Trans. 1 2002, 1831. (c) Malkov, A.
V.; Kocˇovsky´, P. Curr. Org. Chem. 2003, 7, 1737.
(2) For discussions on the coordination chemistry of 2,2′-bipyridines and
1,10-phenanthrolines, see: (a) Reedijk, J. In ComprehensiVe Coordination
Chemistry; Wilkinson, G., Gillard, R. D., McCleverty, J. A., Eds.; Pergamon
Press: Oxford, 1987; Vol. 2, pp 73-98. (b) Kaes, C.; Katz, A.; Hosseini,
M. W. Chem. ReV. 2000, 100, 3553.
Figure 1. Chiral nonracemic C2-symmetric 2,2′-bipyridyl ligand
(+)-1.
(3) Lyle, M. P. A.; Wilson, P. D. Org. Lett. 2004, 6, 855.
10.1021/ol050075d CCC: $30.25
© 2005 American Chemical Society
Published on Web 02/10/2005

enrichment in the enantiomeric purity of the chiral material
had occurred in this coupling reaction.
bipyridyl ligand (+)-1. Typically, the F-C reactions were
carried out in ether at 0 °C. These reaction conditions were
established on performing a series of optimization experi-
ments.7 Under the optimized reaction conditions, the
Cu(OTf)2‚ligand (+)-1 complex displayed excellent catalytic
activity and the F-C reactions reached completion within
16 h in all instances. The F-C reaction of indole 3a with
ethyl 3,3,3-trifluoropyruvate 4a afforded the known product
5a in good yield (68%) and in good enantiomeric excess
(74%) (entry 1). The absolute stereochemistry of product 5a
was assigned as S on comparison of the optical rotation with
a literature value.8 The F-C reaction of indole 3a with
methyl 3,3,3-trifluoropyruvate 4b afforded product 5b in
similar yield (77%) but in significantly higher enantiomeric
excess (90%) (entry 2). This result compares favorably with
the Cu(OTf)2‚(S)-t-BuBox-catalyzed reactions reported by
Jørgensen and co-workers for a range of substrates (83-
94% ee).6b Of note, we assume that the absolute stereochem-
istry of the reaction product 5b is S in that it is reasonable
to expect that the alternative use of the methyl ester of 3,3,3-
trifluoropyruvic acid 4b will not effect the stereochemical
outcome of the reaction. No further improvement in the
enantioselectivity of the reaction was achieved by repeating
the above experiment at a lower temperature (entry 3). Thus,
methyl 3,3,3-trifluoropyruvate 4b was used exclusively in
subsequent experiments, and the reactions were performed
at 0 °C.
The Friedel-Crafts (F-C) alkylation reaction is one of
the oldest known organic transformations to employ Lewis
acid catalysts, and it is a particularly versatile carbon-carbon
bond formation reaction.4,5 Recently, Jørgensen and co-
workers have pioneered the catalytic enantioselective F-C
alkylation reaction of activated aromatic compounds with
electron-deficient carbonyl compounds and alkenes using
chiral bisoxazoline copper(II) complexes as catalysts.6 In this
paper, in regard to the exploration of the versatility of our
new chiral nonracemic 2,2′-bipyridyl ligand (+)-1, we report
a study of the application of this ligand in copper(II)-
catalyzed asymmetric F-C alkylation reactions.
The 2,2′-bipyridine (+)-1 was evaluated in the copper(II)-
catalyzed F-C reaction of a series of commercially available
indoles 3a-f with the ethyl and methyl esters of 3,3,3-
trifluoropyruvic acid 4a,b (Table 1). To the best of our
Table 1. Asymmetric Friedel-Crafts Alkylation Reactions of
Indoles 3a-f
The F-C reaction of 2-methylindole 3b again afforded
the corresponding product 5c in good enantiomeric excess
(86%) (entry 4). The electron-rich substrate, 5-methoxyindole
3c, afforded the product 5d in 72% ee, whereas the electron-
poor substrate, 5-nitroindole 3d, afforded the product 5e in
slightly lower enantiomeric excess (60%). Surprisingly,
1-methylindole 3e and 1-methyl-2-phenylindole 3f afforded
the corresponding products 5f and 5g in low enantiomeric
excess (18%) (entries 7 and 8).9 Thus, it is evident that
substitution of the hydrogen atom of the indole nitrogen has
a detrimental effect on the enantioselectivity of the F-C
reaction. Further experimentation is required to determine
the origin of this effect. However, these results do suggest
that the indole N-H bond is involved in the reaction
transition state or that detrimental steric factors are at play
in these particular catalytic reactions.
entry
R1
R2
R3
R4 product yield (%)a ee (%)b
1
2
3
4
5
6
7
8
H
H
H
H
OMe
NO2
H
H
H
H
H
H
H
Me
H
H
H
Et
5a
5b
5b
5c
5d
5e
5f
68
77
62
79
69
75
74
65
74
90
90c
86
72
60d
18
18
Me
Me
Me Me
H
H
H
Me
Me
Me
H
Me Ph Me
5g
a Isolated yield after purification by flash chromatography. b Determined
by analytical chiral HPLC (Daicel Chiracel OD column). c The reaction
was performed at -10 °C. d The enantiomeric excess, in this instance, was
1
determined by H NMR analysis using the chiral shift reagent Eu(hfc)3.
We have also evaluated the 2,2′-bipyridine (+)-1 in the
conjugate addition reactions of the indole 3a and 3-meth-
oxyphenol 8 to (3E)-2-oxo-4-phenyl-3-butenoic acid methyl
ester 6 (Scheme 1).10,11 In the case of indole 3a, the conjugate
knowledge, this is the first report of the application of a 2,2′-
bipyridyl ligand in catalytic enantioselective F-C reactions.
The active copper(II) catalyst was generated in situ on
reaction of 10 mol % copper(II) triflate with 10 mol % 2,2′-
(7) The F-C reaction of indole 3a with methyl 3,3,3-trifluoropyruvate
4b afforded the product 5b in good yield in dichloromethane and in tetra-
hydrofuran. However, the enantioselectivities were lower (28 and 45% ee,
respectively) in these instances.
(8) The absolute stereochemistry of (2S)-2-(4-chloroindole-3-yl)-3,3,3-tri-
fluoro-2-hydroxy propionic acid ethyl ester has been assigned unambigu-
ously by X-ray crystallography, and the absolute stereochemistry of
compound 5a was assigned by analogy; see ref 6b.
(9) This result is in contrast to the bisoxazoline copper(II) complex-
catalyzed reactions in which substitution of the indole nitrogen does not
lower the enantioselectivity of the reaction; see ref 6b.
(10) Jensen, K. B.; Thorhauge, J.; Hazell, R. G.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2001, 40, 160.
(4) (a) Friedel, C.; Crafts, J. M. R. Hebd. Seances Acad. Sci. 1877, 84,
1392. (b) Friedel, C.; Crafts, J. M. R. Hebd. Seances Acad. Sci. 1877, 84,
1450.
(5) Olah, G. A.; Khrisnamurti, R.; Prakash, G. K. S. In ComprehensiVe
Organic Synthesis, 1st ed.; Pergamon: New York, 1991; Vol. 3, pp 293-
339.
(6) (a) Gathergood, N.; Zhuang, W.; Jørgensen, K. A. J. Am. Chem. Soc.
2000, 122, 12517. (b) Zhuang, W.; Gathergood, N.; Hazell, R. G.; Jørgensen,
K. A. J. Org. Chem. 2001, 66, 1009. (c) Jørgensen, K. A. Synthesis 2003,
1117. (d) For a recent review on the asymmetric F-C alkylation reaction,
see: Bandini, M.; Melloni, A.; Umani-Ronchi, A. Angew. Chem., Int. Ed.
2004, 43, 550.
(11) van Lingen, H. L.; Zhuang, W.; Hansen, T.; Rutjes, F. P. J. T.;
Jørgensen, K. A. Org. Biomol. Chem. 2003, 1, 1953.
902
Org. Lett., Vol. 7, No. 5, 2005

Scheme 1. Conjugate Addition Reactions of Indole 3a and
3-Methoxyphenol 8 to the â,γ-Unsaturated R-Ketoester 6
Figure 2. ORTEP representation of the CuCl2‚ligand (+)-1
complex 10. The thermal ellipsoids are drawn at a 25% probability
level for clarity.
addition product 7 was formed in excellent yield (97%) and
in good enantiomeric excess (59%). In the case of the
reaction of 3-methoxyphenol 8, the product of the initial
conjugate addition reaction undergoes a subsequent intra-
molecular F-C reaction to afford the novel chromane
derivative 9 (as a single diastereoisomer) in moderate
enantiomeric excess (42%) and in good yield (62%). The
absolute stereochemistry of the major conjugate addition
product 7 was assigned as S on comparison of the optical
rotation with a literature value.12 The absolute stereochem-
istry of the chromane derivative 9 is not known. However,
we assume that the major product of this reaction has the
same absolute stereochemistry (at C2) as that observed for
the major conjugate addition product 7.
3a-f with the methyl ester of 3,3,3-trifluoropyruvic acid 4b,
we postulate that the relatively small R-ketoester 4b coor-
dinates in a bidentate fashion to the copper center of the
Cu(OTf)2‚ligand (+)-1 complex in an approximately square-
planar geometry (Figure 3). The indoles 3a-f would then
To gain insight into the structure of the active catalyst in
the above reactions, a copper(II) chloride complex 10 was
prepared from the 2,2′-bipyridine (+)-1 and anhydrous
copper(II) chloride. Yellow crystals that were suitable for
X-ray crystallography were obtained on recrystallization, by
the slow evaporation of the solvent, from a mixture (2:1) of
dichloromethane and ethanol. An ORTEP representation of
the CuCl2‚ligand (+)-1 complex 10 is provided below (Figure
2). It was found that, in the solid state, the ligands adopt a
geometry that lies between square-planar and tetrahedral
around the copper atom. In this structure, the chloride ligands
are tilted away from the large cyclic acetal moieties of the
C2-symmetric bipyridyl ligand (+)-1. Similar structural
observations have been recorded for several bisoxazoline
copper(II) complexes such as CuCl2‚t-BuBox, CuCl2‚PhBox,
and CuCl2‚1-NpBox, as well as for other chiral bipyridyl
copper(II) complexes.13,14
Figure 3. Square-planar and tetrahedral coordination of the
R-ketoester reaction substrates 4b and 6 to the chiral catalyst.
be expected to attack the more sterically accessible Re-face
of the carbonyl moiety. To rationalize the opposite facial
selectivity for the reaction of indole 3a (or the assumed facial
selectivity for the reaction of 3-methoxyphenol 8) with the
â,γ-unsaturated R-ketoester 6, we postulate that this larger
â,γ-unsaturated R-ketoester coordinates in a bidentate fashion
to the copper center in an approximately tetrahedral geometry
and that the â,γ-unsaturated R-ketoester moiety adopts an
s-cis conformation. The indole 3a (or the phenol 8) would
then be expected to attack the â,γ-unsaturated R-ketoester
moiety from the more sterically accessible Si-face of the
complex.15 The lower enantioselectivity of the latter two
reactions can be attributed to the conformational flexibility
of â,γ-unsaturated R-ketoester moiety or, more simply, to
the fact that reaction center is located further from the chiral
pocket of the catalytic entity.
To rationalize the stereochemical outcome of the cop-
per(II)-catalyzed asymmetric F-C reactions of the indoles
(12) See the supporting information for ref 10.
(13) Thorhauge, J.; Roberson, M.; Hazell, R. G.; Jørgensen, K. A. Chem.
Eur. J. 2002, 8, 1888 and references therein.
(14) (a) Kwong, H.-L.; Lee, W.-S.; Ng, H.-F.; Chiu, W.-H.; Wong, W.-
T. J. Chem. Soc., Dalton Trans. 1998, 1043. (b) Malkov, A. V.; Bella, M.;
Langer, V.; Kocˇovsky´, P. Org. Lett. 2000, 2, 3047. (c) Lo¨tscher, D.;
Rupprecht, S.; Stoeckli-Evans, H.; von Zelewsky, A. Tetrahedron: Asym-
metry 2000, 11, 4341.
Org. Lett., Vol. 7, No. 5, 2005
903

In conclusion, we have evaluated our new low molecular
weight, chiral nonracemic C2-symmetric 2,2′-bipyridyl ligand
(+)-1 in the copper(II)-catalyzed asymmetric F-C alkylation
reactions of the substituted indoles 3a-f with the ethyl and
methyl esters of 3,3,3-trifluoropyruvic acid 4a,b. This is the
first report of the application of a chiral nonracemic 2,2′-
bipyridyl ligand in catalytic enantioselective F-C reactions.
When indole 3a and the methyl ester of 3,3,3-trifluoropyruvic
acid 4b were employed as reaction substrates and the reaction
was performed in ether at 0 °C, an enantioselectivitiy of 90%
ee was recorded. However, it was noted that substitution of
the hydrogen atom of the indole nitrogen has a detrimental
effect on the enantioselectivity of this Cu(OTf)2‚ligand (+)-1
complex-catalyzed F-C reaction. The copper(II)-catalyzed
asymmetric conjugate addition reactions of indole 3a and
3-methoxyphenol 8 to (3E)-2-oxo-4-phenyl-3-butenoic acid
methyl ester 6 were also demonstrated. Studies are currently
underway to improve the enantioselectivity of these cop-
per(II)-catalyzed F-C reactions by making structural modi-
fications to the cyclic acetal moieties of the 2,2′-bipyridine
(+)-1.3 Current investigations are also focused on the use
of this notable bipyridyl ligand (+)-1 in other catalytic
asymmetric processes.
Acknowledgment. We are grateful to the Natural Sci-
ences and Engineering Research Council of Canada (NSERC)
and Simon Fraser University for financial support. We also
wish to acknowledge the Canadian Foundation for Innovation
(CFI), the British Columbia Knowledge Development Fund
(BCKDF), and AstraZeneca Canada, Inc., for support of our
research program. M.P.A.L. thanks Simon Fraser University
for an entrance scholarship and graduate research fellowships.
Professors F. W. B. Einstein and D. B. Leznoff (SFU) are
also thanked for advice in regard to the X-ray structure
determination.
Supporting Information Available: Detailed experi-
mental procedures and full product characterization data for
all compounds synthesized, including a procedure for the
preparation and crystallization of the CuCl2‚ligand (+)-1
complex 10, as well as 1H and 13C NMR spectra for
compounds 5b-g (PDF), and X-ray crystallographic data
for complex 10 (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
(15) The reversal of facial selectivity observed in these reactions is not
unusual and has been observed in other closely related reactions that have
been catalyzed by C2-symmetric bisoxazoline copper(II) complexes; see:
(a) Jørgensen, K. A.; Johannsen, M.; Yao, S.; Audrain, H.; Thorhauge, J.
Acc. Chem. Res. 1999, 32, 605. (b) Johnson, J. S.; Evans, D. A. Acc. Chem.
Res. 2000, 33, 325. (c) Zhou, J.; Ye, M.-C.; Huang, Z.-Z.; Tang, Y. J. Org.
Chem. 2004, 69, 1309.
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Org. Lett., Vol. 7, No. 5, 2005