Catalytic enantioselective Friedel-Crafts reactions of aromatic compounds with glyoxylate: A simple procedure for the synthesis of optically active aromatic mandelic acid esters

Article abstract of DOI:10.1021/ja002593j

The first catalytic highly enantioselective Friedel-Crafts reaction of aromatic compounds with glyoxylate catalyzed by chiral Lewis acids is presented. The reaction has been developed for mainly aromatic amines reacting with ethyl glyoxylate in the presence of chiral bisoxazoline-copper(II) complexes as the catalyst. A series of chiral bisoxazoline-copper(II) complexes have been tested as catalysts for the reaction with N,N-dimethylaniline and it has been found that a highly regio- and enantioselective Friedel-Crafts reaction takes place in the presence of especially tert-butyl bisoxazoline-copper(II). This reaction proceeds with the formation of exclusively the para-substituted isomer in up to 95% yield and 94% ee. The reaction has been investigated for N,N-dimethylaniline under different reaction conditions and has been developed to be a catalytic highly enantioselective reaction for meta-substituted N,N-dimethylanilines, containing either electron-withdrawing or electron-donating substituents. The catalytic enantioselective Friedel-Crafts reaction also proceeds well for cyclic aromatic amines such as N-methylindoline, N-methyltetrahydroquinoline, and julolidine, where up to 91% yield and 93% ee are obtained. For polyaromatic amines high yields, but moderate ee values, of the Friedel-Crafts products are obtained. To enhance the potential of the reaction the N,N-dimethyl- and N-methyl substituents can be removed successfully leading to either the mono-N-methyl product or the free amine. The latter class of products allow for the introduction of a variety of other substituents on the aromatic nucleus. The catalytic enantioselective reaction also proceeds for heteroaromatic compounds such as 2-substituted furans which react with glyoxylate as well as trifluoropyruvates, giving up to 89% ee of the Friedel-Crafts products. Furthermore, ethyl trifluoropyruvate reacts in a highly enantioselective reaction with m-methoxyanisole to give the corresponding Friedel-Crafts product in good yield. On the basis of the experimental results and the absolute configuration of the products, the mechanism for this catalytic highly enantioselective Friedel-Crafts reaction is presented.

Full text of DOI:10.1021/ja002593j

J. Am. Chem. Soc. 2000, 122, 12517-12522
12517
Catalytic Enantioselective Friedel-Crafts Reactions of Aromatic
Compounds with Glyoxylate: A Simple Procedure for the Synthesis
of Optically Active Aromatic Mandelic Acid Esters
Nicholas Gathergood, Wei Zhuang, and Karl Anker Jørgensen*
Contribution from the Center for Metal Catalyzed Reactions, Department of Chemistry, Aarhus UniVersity,
DK-8000 Aarhus C, Denmark
ReceiVed July 14, 2000
Abstract: The first catalytic highly enantioselective Friedel-Crafts reaction of aromatic compounds with
glyoxylate catalyzed by chiral Lewis acids is presented. The reaction has been developed for mainly aromatic
amines reacting with ethyl glyoxylate in the presence of chiral bisoxazoline-copper(II) complexes as the
catalyst. A series of chiral bisoxazoline-copper(II) complexes have been tested as catalysts for the reaction
with N,N-dimethylaniline and it has been found that a highly regio- and enantioselective Friedel-Crafts reaction
takes place in the presence of especially tert-butyl bisoxazoline-copper(II). This reaction proceeds with the
formation of exclusively the para-substituted isomer in up to 95% yield and 94% ee. The reaction has been
investigated for N,N-dimethylaniline under different reaction conditions and has been developed to be a catalytic
highly enantioselective reaction for meta-substituted N,N-dimethylanilines, containing either electron-withdrawing
or electron-donating substituents. The catalytic enantioselective Friedel-Crafts reaction also proceeds well
for cyclic aromatic amines such as N-methylindoline, N-methyltetrahydroquinoline, and julolidine, where up
to 91% yield and 93% ee are obtained. For polyaromatic amines high yields, but moderate ee values, of the
Friedel-Crafts products are obtained. To enhance the potential of the reaction the N,N-dimethyl- and N-methyl
substituents can be removed successfully leading to either the mono-N-methyl product or the free amine. The
latter class of products allow for the introduction of a variety of other substituents on the aromatic nucleus.
The catalytic enantioselective reaction also proceeds for heteroaromatic compounds such as 2-substituted furans
which react with glyoxylate as well as trifluoropyruvates, giving up to 89% ee of the Friedel-Crafts products.
Furthermore, ethyl trifluoropyruvate reacts in a highly enantioselective reaction with m-methoxyanisole to
give the corresponding Friedel-Crafts product in good yield. On the basis of the experimental results and the
absolute configuration of the products, the mechanism for this catalytic highly enantioselective Friedel-Crafts
reaction is presented.
Introduction
diastereoselective reactions it has been found that glyoxylate
derivatives having a chiral auxiliary,6 chiral ketoesters,7 and
aldehydes8 can react with, e.g., phenolic substrates. There are
also few examples of Friedel-Crafts reactions with R-dicarbonyl
The Friedel-Crafts reaction of aromatic compounds with
carbonyl compounds is one of the most fundamental reactions
in organic chemistry.1 There are numerous examples of the
development and use of this reaction in chemistry; however,
the catalytic enantioselective version of the Friedel-Crafts
reaction is still an unexplored field, although the aromatic
optically active products formed are highly valuable.
This paper presents the catalytic enantioselective Friedel-
Crafts reaction of aromatic compounds 1 to R-dicarbonyl
compounds of the glyoxylate type 2 catalyzed by chiral Lewis
acids (eq 1).
(2) Reactions for benzaldehyde see e.g.: (a) Adams, S. R.; Kao, J. P.
Y.; Grynkeiwicz, G.; Minta, A.; Tsien, R. Y. J. Am. Chem. Soc. 1988, 110,
3212. (b) Sasakura, K.; Terui, Y.; Sugasawa, T. Chem. Pharm. Bull. 1985,
33, 1836. (c) Albrecht, K. Chem. Ber. 1888, 21, 3292.
(3) Reactions for chloral see e.g.: (a) Menegheli, P.; Rezende, M. C.;
Zucco, C. Synth. Commun. 1987, 17, 457. (b) Hebert, P. Bull. Soc. Chim.
Fr. 1920, 27, 52. (c) Casiraghi, G.; Casnati, G.; Sartori, G.; Catellani, M.
Synthesis 1979, 824. (d) Fritsch, P. Lieb. Ann. Chem. 1897, 296, 344. (e)
Menegheli, P.; Rezende, M. C.; Zucco, C. Synth. Commun. 1987, 17, 457.
(f) Dinesmann, A. C. R. Hebd. Seances Acad. Sci. 1905, 141, 201.
(4) Reactions for phenylglyoxyal derivatives see e.g.: (a)Fuson, R. C.;
Weinstock, H. H.; Ullyot, G. E. J. Am. Chem. Soc. 1935, 57, 1803. (b)
Arnold, R. T.; Fuson, R. C. J. Am. Chem. Soc. 1936, 58, 1295. (c) Fuson,
R. C.; Emerson, W. S.; Weinstock, H. H. J. Am. Chem. Soc. 1939, 61, 412.
(d) Fuson, R. C.; Armstrong, M. D.; Wallace, W. E.; Kneisley, J. W. J.
Am. Chem. Soc. 1944, 66, 1274. (e) Gualtieri, F.; Riccieri, F. M. Boll. Chim.
Farm. 1965, 104, 149. (f) Coan, S. B.; Trucker, D. E.; Becker, E. I. J. Am.
Chem. Soc. 1955, 77, 60. (g) Christy, M. E.; Colton, C. D.; MacKay, M.;
Staas, W. H.; Wong, J. B.; Engelhardt, E. L.; Torchiana, M. L.; Stone, C.
A. J. Med. Chem. 1977, 20, 421. (h) Bridge, A. W.; Fenton, G.; Halley, F.;
Hursthouse, M. B.; Lehmann, C. W.; Lythgoe, D. J. J. Chem. Soc., Perkin
Trans. 1 1993, 22, 2761. (i) Sohda, D. J.; Mizuno, K.; Imamiya, E.; Tawada,
H.; Meguro, K.; Kawamatsu, Y.; Yamamoto, Y. Chem. Pharm. Bull. 1982,
30, 3601.
Numerous examples of addition reactions of aromatic com-
pounds to activated carbonyl2,3 and R-dicarbonyl compounds4,5
in the presence of Lewis acids such as AlCl3 are known. For
(1) (a) Olah, G. A.; Khrisnamurti, R.; Surya Prakash, G. K. Compre-
hensiVe Organic Synthesis, 1st ed.; Pergamon: New York, 1991; Vol. 3,
pp 293-339. (b) Roberts, R. M.; Khalaf A. A. Friedel-Crafts Alkylation
Chemistry. A Century of DiscoVery, Marcel Dekker: New York, 1984.
(5) Reaction for tert-butyl glyoxal see e.g.: Hahn, B.; Kopke, B.; Voss,
J. Liebigs Ann. Chem. 1981, 1, 10.
10.1021/ja002593j CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/30/2000

12518 J. Am. Chem. Soc., Vol. 122, No. 50, 2000
Gathergood et al.
compounds attached to a chiral auxiliary giving chiral products.9
Catalytic enantioselective Friedel-Crafts reactions have been
found for chloral reacting with anisole derivatives catalyzed by
chiral alkoxyaluminum chlorides,10 and very recently the
reaction of fluoral with anisole using BINOL-TiX2 catalysts
yielding products with up to 90% ee.11 This group also reported
the enantioselective Friedel-Crafts-type reaction of aromatic
methyl vinyl ethers with fluoral catalyzed by BINOL-TiX2
catalysts.12
Table 1. Results for the Catalytic Enantioselective Friedel-Crafts
Reaction of N,N-Dimethylaniline 1a with Ethyl Glyoxylate 2a
Catalyzed by Chiral Bisoxazoline-Metal(II) Complexes as the
Catalysts in Various Solventsa
The Friedel-Crafts products formed in this paper are potential
starting materials for many biologicaly active compounds, e.g.,
p-aminomandelic acid derivatives.13 Antibacterial properties
have been shown in several mandelic amide compounds,14 and
many substituted mandelic acid compounds show pharmaco-
logical activity.15
temp
2a
yieldb eea
entry
catalyst solvent (°C) (equiv)
(S)-4a-Cu(OTf)2 CH2Cl2 rt
(%)
(%)
1
2
3
4
5
6
7
8
9
1.5
1.5
1.5
10
5
5
5
1.5
1.5
1.5
1.5
81
78
72
90
71
32
36
70
76
81
41
80
89
90
82
74
18
0
54
42
22
12
(S)-4a-Cu(OTf)2 Et2O
(S)-4a-Cu(OTf)2 THF
rt
rt
(S)-4a-Cu(OTf)2 CH2Cl2 rt
Results and Discussion
(S)-4a-Cu(OTf)2 THF
(S)-4a-Cu(OTf)2 MeNO2
(S)-4a-Cu(SbF6)2 THF
-30
0
rt
Several different chiral bisoxazoline metal(II) complexes16,17
can catalyze the catalytic enantioselective Friedel-Crafts reac-
tion of N,N-dimethylaniline 1a with ethyl glyoxylate 2a (eq 2).
(R)-4b-Cu(OTf)2 CH2Cl2 rt
(R)-4b-Cu(OTf)2 Et2O
(R)-4b-Cu(OTf)2 THF
rt
rt
10
11
(R)-4b-Zn(OTf)2 CH2Cl2 rt
a For experimental details see Supporting Information. b Isolated
yield.
The results in Table 1 show that the combination of the t-Bu-
BOX (S)-4a ligand and copper(II) gives the best results,
(17) For the use of C2-symmetric BOX complexes to Mukaiyama-aldol
reactions see e.g.: Evans, D. A.; Kozlowski, M. C.; Murry, J. A.; Burgey,
C. S.; Campos, K. R.; Connell, B. T.; Staples, R. J. J. Am. Chem. Soc.
1999, 121, 669 and references therein. Evans, D. A.; Burgey, C. S.;
Kozlowski, M. C.; Tregay, S. W. J. Am. Chem. Soc. 1999, 121, 686 and
references therein. Diels-Alder reactions see e.g.: Evans, D. A.; Barnes,
D. M.; Johnson, J. S.; Lectka, T.; von Matt, P.; Miller, S. J.; Norcross, R.
D.; Shaughnessy, E. A.; Campos, K. R. J. Am. Chem. Soc. 1999, 121, 7582
and references therein. Evans, D. A.; Miller, S. J.; Lectka, T.; von Matt, P.
J. Am. Chem. Soc. 1999, 121, 7559 and references therein. 1,3-Dipolar
cycloaddition reactions see e.g.: Gothelf, K. V.; Hazell, R. G.; Jørgensen,
K. A. J. Org. Chem. 1996, 61, 346. Jensen, K. B.; Hazell, R. G.; Jørgensen,
K. A. J. Org. Chem. 1999, 64, 2353. Cyclopropanation reactions see e.g.:
Lowenthal, R. E.; Masamune, S. Tetrahedron Lett. 1991, 32, 7373. Evans,
D. A.; Worpel, K. A.; Hinman, M. M.; Faul, M. M. J. Am. Chem. Soc.
1991, 113, 726. Evans, D. A.; Woerpel, K. A.; Scott, M. J. Angew. Chem.,
Int. Ed. Engl. 1992, 31, 430. Gant, T. G.; Noe, M. C.; Corey, E. J.
Tetrahedron Lett. 1995, 36, 8745. Allylic substituton reactions see e.g.:
von Matt, P.; Lloyd-Jones, G. C.; Minidis, A. B. E.; Pfaltz, A.; Macko, L.;
Neuburger, M.; Zehnder, M.; Ru¨egger, H.; Pregogin, P. S. HelV. Chim.
Acta 1995, 78, 265. Allylation and addition reactions see e.g.: Wu, J. H.;
Radinov, R.; Porter, N. A. J. Am. Chem. Soc. 1995, 117, 11029. Sibi, M.
P.; Ji, J.; Wu, J.-H.; Gurtler, S.; Porter, N. A. J. Am. Chem. Soc. 1996, 118,
9200. Evans, D. A.; Rovis, T.; Kozlowski, M. C.; Tedrow, J. S. J. Am.
Chem. Soc. 1999, 121, 1994. Aziridination reactions see e.g.: Evans, D.
A.; Faul, M. M.; Bilodeau, M. T.; Anderson, B. A.; Barnes, D. M. J. Am.
Chem. Soc. 1993, 115, 5328. Hansen, K. B.; Finney, N. S.; Jacobsen, E. N.
Angew. Chem., Int. Ed. Engl. 1995, 34, 676. Carbonyl-ene reactions see
e.g.: Evans, D. A.; Burgey, C. S.; Paras, N. A.; Vojkovsky, T.; Tregay, S.
W. J. Am. Chem. Soc. 1998, 120, 5824. Reichel, F.; Fang, X.; Yao, S.;
Ricci, M.; Jørgensen, K. A. Chem. Commun. 1999, 1505. Gathergood, N.;
Jørgensen, K. A. Chem. Commun. 1999, 1869. Hetero-Diels-Alder reactions
see e.g.: Johannsen, M.; Jørgensen, K. A. J. Org. Chem. 1995, 60, 5757.
Johannsen, M.; Jørgensen, K. A. Tetrahedron 1996, 52, 7321. Johannsen,
M.; Jørgensen, K. A. J. Chem. Soc., Perkin Trans. 2 1997, 1183. Johannsen,
M.; Yao, S.; Jørgensen, K. A. J. Chem. Soc., Chem. Commun. 1997, 2169.
Yao, S.; Johannsen, M.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem.
1998, 63, 118. Yao, S.; Johannsen, M.; Audrain, H.; Hazell, R. G.;
Jørgensen, K. A. J. Am. Chem. Soc. 1998, 120, 8599. Ghosh, A. K.;
Mathivanan, P.; Cappiello, J.; Krishnan, K. Tetrahedron: Asymmetry 1996,
7, 2165. Thorhauge, J.; Johannsen, M.; Jørgensen, K. A. Angew. Chem.,
Int. Ed. Engl. 1998, 37, 2404. Evans, D. A.; Olhava, E. J.; Johnson, J. S.;
Janey, J. M. Angew. Chem., Int. Ed. Engl. 1998, 37, 3372. Evans, D. A.;
Johnson, J. S.; Olhava, E. J. J. Am. Chem. Soc. 2000, 122, 1635. Audrian,
H.; Thorhauge, J.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2000, 65,
4487. Zhuang, W.; Thorhauge, J.; Jørgensen, K. A. Chem. Commun. 2000,
459.
Some representative examples for the reaction using the t-Bu-
BOX (S)-4a and Ph-BOX (R)-4b (BOX ) bisoxazoline) and
Lewis acids catalysts are presented in Table 1.
(6) (a) Bigi, F.; Bocelli, G.; Maggi, R.; Satori, G. J. Org. Chem. 1999,
64, 5004. (b) Bigi, F.; Sartori, G.; Maggi, R.; Cantarelli, E.; Galaverna, G.
Tetrahedron: Asymmetry 1993, 4, 2411. (c) Bigi, F.; Casnati, G.; Sartori,
G.; Dalprato, C.; Bortolini, R. Tetrahedron: Asymmetry 1990, 1, 861.
(7) Casiraghi, G.; Bigi, F.; Casnati, G.; Sartori, G.; Soncini, P.; Gasparri,
G.; Fava, G.; Belicchi, M. F. J. Org. Chem. 1988, 53, 1779.
(8) (a) Bigi, F.; Casnati, G.; Sartori, G.; Araldi, G. Gazz. Chim. Ital.
1990, 120, 413. (b) Bigi, F.; Casnati, G.; Sartori, G.; Araldi, G.; Bocelli,
G. Tetrahedron Lett. 1989, 30, 1211.
(9) (a) Costa, P. R. R.; Cabral, L. M.; Alencar, K. G.; Schmidt, L. L.;
Vasconcellos, M. L. A. A. Tetrahedron Lett. 1997, 38, 7021. (b) El Kaim,
L.; Guyoton, S.; Meyer, C. Tetrahedron Lett. 1996, 37, 375.
(10) Bigi, F.; Casiraghi, G.; Casnati, G.; Sartori, G.; Gasparri Fava, G.;
Belicchi, M. F. J. Org. Chem. 1985, 50, 5018.
(11) Ishii, A.; Soloshohonok, V. A.; Mikami, K. J. Org. Chem. 2000,
65, 1597.
(12) Ishii, A.; Mikami, K. J. Fluorine Chem. 1999, 97, 51.
(13) (a) Nakamura, K.; Tsuji, K.; Kiyoshi, K.; Nobukiyo, M.; Matsuo,
M. Chem. Pharm. Bull. 1993, 41, 2050. (b) Kato, H.; Nakayama, K.; Takata,
Y.; Kurihara, J.; Sakai, T. Arzneim Forsch. 1985, 35, 1037. (c) Chem. Abstr.
1970, 74, 53563. (d) Chem. Abstr. 1976, 86, 5665. (e) Chem. Abstr. 1970,
74, 88185.
(14) Khalaj, A.; Shadnia, H.; Sharifzadeh, M. Pharm. Pharmacol.
Commun. 1998, 4, 373.
(15) (a) Miersch, O.; Kramell, R.; Parthier, B.; Wasternack, C. Phyto-
chemistry 1999, 50, 353. (b) El-Nimr, A. E.; Salama, H. A.; Khalil, R. M.;
Kassem, M. A. Pharmazie 1983, 38, 728. (c) Nishihata, T.; Takahagi, H.;
Yamamoto, M.; Tomida, H.; Rytting, J. H.; Higuchi T. J. Pharm. Sci. 1984,
73, 109. (d) Yoshioka, M.; Yoshida, A.; Ichihashi, Y.; Saito, H. Chem.
Pharm. Bull. 1985, 33, 2145.
(16) For recent reviews dealing with the use of chiral bisoxazoline-
Lewis acids as catalysts see: (a) Ghosh, A. K.; Mathivanan, P.; Cappiello,
J. Tetrahedron: Asymmetry 1998, 9, 1. (b) Jørgensen, K. A.; Johannsen,
M.; Yao, S.; Audrain, H.; Thorhauge, J. Acc. Chem. Res. 1999, 32, 605.
(c) Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325. (d)
Jørgensen, K. A. Angew. Chem., Int. Ed. 2000, 39, 3558.

Friedel-Crafts Reactions of Aromatic Compounds with Glyoxylate
J. Am. Chem. Soc., Vol. 122, No. 50, 2000 12519
Table 2. The Catalytic Enantioselective Friedel-Crafts Reaction
of N,N-Dimethylaniline 1a with Ethyl Glyoxylate 2a Catalyzed by
(S)-4a-Cu(OTf)2 at 0 °C under Various Reaction Conditionsa
Table 3. The Catalytic Enantioselective Friedel-Crafts Reaction
of Meta-Substituted N,N-Dimethylanilines 1a-f Catalyzed by
(S)-4a-Cu(OTf)2 (10 mol %) at Room Temperature with Ethyl
Glyoxylate 2a (5 equiv)a
catalyst loading
(mol %)
2a
(equiv)
yieldb
(%)
eea
(%)
entry
solvent
1
2
3
4
5
6
7
10
10
10
10
10
5
CH2Cl2
Et2O
THF
1.5
1.5
1.5
5
5
5
85
92
82
94
91
74
45
61
90
94
86
82
88
87
Et2O
THF
THFc
THFc
1
5
a For experimental details see Supporting Information. b Isolated
yield. c Reaction performed at room temperature.
compared with the Ph-BOX (R)-4b ligand and copper(II) and
zinc(II) as the Lewis acid. For (S)-4a-Cu(OTf)2, the Friedel-
Crafts product 3a is obtained in high yield and up to 90% ee at
room temperature in various solvents (entries 1-4). It is notable
that lowering the reaction temperature to -30 °C and increasing
the amount of 2a to 5 equiv leads to a reduction in both yield
and ee of 3a (entries 3 and 5). The reaction using (S)-4a-
Cu(OTf)2 as the catalyst is dependent on the solvent and
counterion; in THF, CH2Cl2, and Et2O high yield and ee are
obtained of 3a, whereas in MeNO2 only 32% yield of 3a with
low ee is found (entry 6). To study the effect of the counterion
(S)-4a-Cu(SbF6)2 was used as the catalyst; this shows the
importance of the triflate as the counterion, as hexafluoro-
antimonate gives a racemic product in low yield (entry 7). The
Ph-BOX ligand (R)-4b and copper(II) and zinc(II) as the Lewis
acid also catalyze the reaction. The yield of 3a for these catalysts
is good; however, at room temperature only low ee is observed.
Changing the metal from copper(II) to zinc(II) (entries 8 and
11) gave poor results with low yield and ee. It is notable that
the same enantiomer of 3a is formed using either (S)-4a-
Cu(OTf)2 or (R)-4b-Cu(OTf)2 as the catalyst.18 To further refine
the catalytic reaction, it was decided to focus on the (S)-4a-
Cu(OTf)2 catalyst at 0 °C. Some representative results are
presented in Table 2.
reaction
entry subst time (d)
yieldb CH2Cl2/ eea CH2Cl2/
product
THF (%)
THF (%)
1c
2
3
4
5
6
1a
1b
1c
1d
1e
1f
1
1
2
4
1
1
(+)-(S)-3a
(+)-3b
(+)-3c
(+)-3d
(+)-3e
(+)-3f
81/72
80/58
84/41
68/36
77/76
21/19
80/90
85/81
93/95
88/89
80/92
77/86
a For experimental details see Supporting Information. b Isolated
yield. c 1.5 equiv of ethyl glyoxylate.
meta-substituent from hydrogen (90% ee, entry 1) to fluoro
(81% ee, entry 2), chloro (95% ee, entry 3), and then bromo
(89% ee, entry 3) led to a stepwise increase in the reaction time
Table 2 shows the effect of temperature and amount of 2a
on the catalytic enantioselective reaction of 1a. On comparison
of entries 1-3 in Table 2 with entries 1-3 in Table 1, a lowering
of the reaction temperature to 0 °C leads to an increase in the
ee of the reaction in THF and Et2O to 94% and 90%,
respectively. Studying entries 2 and 3 with entries 4 and 5 leads
to the conclusion that an increase in the yield of 3a is observed
in THF and Et2O when the amount of 2a is increased from 1.5
to 5 equiv. The ee unfortunately decreases slightly. Lowering
the catalyst loading did not affect the ee of the reaction, but a
reduction in yield to 74% and 45%, at 5 mol % and 1 mol %
catalyst, respectively, was observed. It is notable that the reaction
can be performed in gram scale giving the same high yield and
ee of product.
to maintain the high yield of product. This effect is probably
attributed to the increasing steric interaction of the meta-
substituent and the catalyst. The yield and ee of the halogen-
containing products were found to be independent of the halogen
substituent. m-Methyl-N,N-dimethylaniline 1e reacts with 2a in
the presence of (S)-4a-Cu(OTf)2 as the catalyst and in THF 3e
is obtained in high yield and with 92% ee (entry 5). For the
reaction of m-methoxy-N,N-dimethylaniline 1f, product 3f is
formed with good ee, but a low yield was obtained in both
solvents (entry 6). It is proposed that 3f, containing an alcohol
and methyl ether, binds to the catalyst, forming a favorable six-
member ring which inhibits the catalytic effect.
The catalytic enantioselective Friedel-Crafts reaction pro-
ceeds well for various meta-substituted N,N-dimethylanilines
(eq 3) in CH2Cl2 or THF and the results are presented in
Table 3.
N-Methylindoline 1g and N-methyltetrahydroquinoline 1h
react smoothly with 2a in the presence of (S)-4a-Cu(OTf)2 (10
mol %) as the catalyst (eq 4). The reaction of 1g with 2a in
Both electron-donating and electron-withdrawing substituents
are tolerated in the meta-position in the catalytic enantioselective
reaction of N,N-dimethylanilines 1a-e with 2a. For the fluoro-,
chloro-, and bromo-substituted N,N-dimethylanilines 1b-d, the
Friedel-Crafts products 3b-d are obtained in good yield and
high ee, and with up to 95% ee for 1c (entry 3). Changing the
(18) For a discussion of this observation in previous reactions see e.g.
ref 16.

12520 J. Am. Chem. Soc., Vol. 122, No. 50, 2000
Gathergood et al.
THF at 0 °C leads to the formation of 3g as the only isomer in
76% yield and 83% ee. The result for this reaction is notable
as 3g can easily be converted to optically active 5-indolyl-R-
hydroxy acids by oxidation of the indoline moiety.19 N-
Methyltetrahydroquinoline 1h also reacts in a highly selective
Friedel-Crafts reaction, with 76% isolated yield of 3h and an
excellent ee of 90%, while a slightly lower yield and an increase
to 93% ee was found at 0 °C (eq 4).
Scheme 1a
The C2-symmetric substrate julolidine 1i reacts with 2a
catalyzed by (S)-4a-Cu(OTf)2 in THF to give 3i in good yield
and ee (eq 5). The reaction of 1i is dependent on the temperature
as only 56% yield with 21% ee of 3i are obtained in THF at
room temperature.
a Conditions: (a) PHIO, TMSN3, CH2Cl2, -78 °C, 2 h; (b) saturated
NaHCO3(aq), THF (1:1), room temperature, 48 h, 7a 85%,7b 90% from
5; (c) 10% HCl/EtOH, 12 h, 8a 92%, 8b 95%.
The catalytic enantioselective Friedel-Crafts reactions have
also been performed for N,N-diethyl-, N,N-dibutyl-, and N,N-
diisopropylaniline 1j-l. Compound 1j reacts with 2a to give
the expected product in 53% yield and 80% ee in THF using
(S)-4a-Cu(OTf)2 as the catalyst. For the reaction of 1k and 1l,
a significant reduction in the yield and ee of the Friedel-Crafts
products 3k and 3l are found. The former compound is only
formed in 34% yield as a racemic product, while for the latter
no reaction occurred. We postulate that the inactivity of 1l
in the Friedel-Crafts reaction is due to the geometry of the
lone pair electrons on the nitrogen atom. The bulky i-Pr groups
clash with the o-hydrogen atoms, rotating the aryl-nitrogen
bond so that the nitrogen lone pair electrons contribution into
the π-system of the aromatic ring is diminished. This deactivates
1l to an aromatic electrophilic substitution reaction. Comparison
of the pKa values of 1a and 1l (5.16 and 8.25, respectively)20
shows that 1l is the stronger base, thus contributing less elec-
tron density to the aromatic ring. Further evidence for the
relationship between reactivity and the geometry of the nitrogen
lone pair electrons was gained by studying ortho-substituted
N,N-dimethylanilines. o-Fluoro-, o-chloro-, o-bromo-, and o-
methyl-substituted N,N-dimethylaniline derivatives failed to
react with 2a using (S)-4a-Cu(OTf)2 as the catalyst. The lack
of reactivity of ortho-substituted N,N-dimethylanilines in aro-
matic electrophilic substitution reactions has been observed
before.21
The reaction of 1m with 2a catalyzed by 10 mol % (S)-4a-
Cu(OTf)2 at room temperature in Et2O leads to 75% yield of
3m with 50% ee. Excellent yields were also obtained for 3m
when the reaction was performed in CH2Cl2; however, the best
enantioselectivity was found in ethereal solvents. The (S)-4a
ligand in combination with Cu(OTf)2 or (R)-4b-Zn(OTf)2
catalyzes this reaction and in CH2Cl2 93% and 97% yields are
obtained, respectively; however, the ee of 3m is 40% ee.
N,N-Dimethylamino-1-anthracene 1n reacts with 2a giving
3n in excellent yield; however, only 4% ee is obtained (eq 7).
An increase in ee was observed when (R)-4b-Zn(OTf)2 was used
as the catalyst.
An important synthetically useful aspect of the present
reaction is that the corresponding aniline and N-methylaniline
compounds can be easily prepared from e.g. 3a. Protection of
the alcohol in 3a as the TBS ether by reaction with TBSOTf
gave 5 in 91% yield (Scheme 1). Reaction of 5 with iodosyl-
benzene and TMSN3 afforded 6a in good yield,22 which was
converted into the TBS-protected N-methyl derivative 7a by
basic hydrolysis at room temperature in 85% overall yield. The
TBS group was removed by stirring with 10% HCl/EtOH. The
reaction temperature for the N,N-demethylation of 3a is critical
for the success of the procedure (Scheme 1). At room temper-
ature or 0 °C, the reaction proceeds within a few minutes, but
competing side reactions lead to a moderate yield of 6b.
However, when performing the reaction in CHCl3 at -50 °C
(45 min) or in CH2Cl2 at -78 °C (2 h), a clean quantitative
The reaction of N,N-(dimethylamino)-1-naphthalene 1m with
2a can proceed with several chiral bisoxazoline catalysts (eq 6).
(19) See e.g.: (a) Nicolaou, K. C.; Baran, P. S.; Zhong, Y.; Fong, K.
C.; He, Y.; Yoon, W. H.; Choi, H. Angew. Chem., Int. Ed. Engl. 1999,
38, 1676. (b) Takami, H.; Koshimura, H.; Kishibayashi, N.; Ishii, A.;
Nonaka, H.; Aoyama, S.; Kase, H.; Kumazawa, T. J. Med. Chem. 1996,
39, 5047.
(20) Graaf, B. van de; Hoefnagel, A. J.; Wepster, B. M. J. Org. Chem.
1981, 46, 653.
(21) (a) Tice, B. B. P.; Lee, I.; Kendall, F. H. J. Am. Chem. Soc. 1963,
85, 329. (b) Brown, W. G.; Widiger, A. H.; Letang, N. J. J. Am. Chem.
Soc. 1939, 61, 2597.
(22) Magnus, P.; Lacour, J.; Weber, W. Synthesis 1998, 547.

Friedel-Crafts Reactions of Aromatic Compounds with Glyoxylate
J. Am. Chem. Soc., Vol. 122, No. 50, 2000 12521
Scheme 2
% (S)-4a-Cu(OTf)2 catalyst. Higher enantioselectivity was
observed when 1o was reacted with methyl trifluoropyruvate
2b at 0 °C catalyzed by (S)-4a-Cu(OTf)2 (10 mol %) to give
the corresponding hydroxy trifluoromethyl ester 3p in 89% ee
(eq 8). At room temperature (S)-4a-Cu(OTf)2 catalyzes the
Friedel-Crafts reaction of trimethylsilylfuran 1p with ethyl
trifluoropyruvate 2c to give the hydroxy trifluoromethyl ester
1q with good enantioselectivity as 76% ee was obtained at room
temperature (eq 8).
m-Methoxyanisole 1q also undergoes an enantioselective
Friedel-Crafts reaction with ethyl trifluoropyruvate 2c catalyzed
by 10 mol % (S)-4a-Cu(OTf)2. The 4-substituted hydroxy
trifluoromethyl ester aromatic product 3r was the only isomer
formed, in good yield and high enantioselectivity (eq 9).
conversion to the bis azide 6b was observed. Conversion of 6b
to p-aminophenyl-mandelic acid ethyl ester 8b was accom-
plished by basic hydrolysis followed by deprotection of the TBS
group in 85% overall yield from 5. The N,N-demethylation of
3a leads to the formation of the free amine product 7b which
can be easily converted into the diazonium-BF4 derivative. This
diazonium salt has the potential to be a useful intermediate for
the synthesis of e.g. para-substituted mandelic acid derivatives.
Thus the amino group in 7b allows for the introduction of
different electron-withdrawing and electron-donating substituents
on the aromatic nucleus. Furthermore, the TBS protecting group
is stable against a variety of reaction conditions which allows
for manipulation of the product without destroying the formed
stereogenic center (vide infra).
The reactions presented in eqs 8 and 9 show that this
new catalytic enantioselective Friedel-Crafts reaction of the
trifluoropyruvates can be used for the facile introduction of
chiral hydroxy trifluoromethyl ester substituent into various
aromatic compounds. These reactions lead to a simple synthetic
approach for the introduction of the important trifluoromethyl
group which has been found to have unique physical and
biological properties.23
To determine the absolute stereochemistry of 3a, compound
7b was transformed into mandelic acid ethyl ester in 86% overall
yield via the following three-step sequence: (i) diazotation by
NOBF4, (ii) H3PO2, and (iii) TBS deprotection. Chiral GC
showed no detectable racemization in the synthetically prepared
material (94% ee) and the optical rotation [(S)] established that
the reaction of 1a with 2a catalyzed by (S)-4a-Cu(OTf)2 gave
the (S)-configuration in the enantioselective step. A model for
the approach of 1a to 2a coordinated to (S)-4a-Cu(OTf)2 as a
square-planar complex is outlined in Scheme 2.
In summary, the first catalytic enantioselective Friedel-Crafts
reaction of aromatic amines with glyoxylate catalyzed by chiral
bisoxazoline-copper(II) complexes has been developed. The
reactions proceed as a regioselective reaction for N,N-dimethyl-
aniline and meta-substituted N,N-dimethylanilines in high yield
and high enantiomeric excess. Cyclic aromatic amines also react
in a highly regio- and enantioselective fashion, while for
polyaromatic amines high yields of the Friedel-Crafts products
are formed in moderate ee. A synthetic procedure for the
removal of the N,N-dimethyl and N-methyl substituents is also
presented giving successfully either the mono-N-methyl product
or the free amine. These derivatives allow the introduction of a
variety of other electron-donating or electron-withdrawing
substituents on the aromatic nucleus. The reaction has also been
shown to proceed for heteroaromatic compounds such as
2-substituted furans, and furthermore, trifluoropuruvates also
undergo a highly enantioselective Friedel-Crafts reaction as
illustrated by 2-substituted furans and m-methoxyanisole. This
development is a promising new synthetic procedure for the
synthesis of optically active mandelic acid derivatives as well
as the introduction of the chiral hydroxy trifluoromethyl ester
substituent in various aromatic compounds.
Other aromatic compounds can also undergo an enantio-
selective Friedel-Crafts reaction with both ethyl glyoxylate
2a and trifluoropyruvates, 2b,c, catalyzed by (S)-4a-Cu(OTf)2.
2-Methylfuran 1o reacts with ethyl glyoxylate 2a at room
temperature to give 3o in excellent yield with moderate ee (eq 8).
(23) (a) Organofluorine Chemistry-Principle and Commerical Applica-
tion; Banks, R. E., Smart, B. E., Tatlow, J. C., Eds.; Plenum Press: New
York, 1994. (b) Fluorine-Containing Molecules, Structure, ReactiVity,
Synthesis and Applications; Liebman, J. F., Greenberg, A., Dolbier, W. R.,
Jr., Eds.; VCH Publishers: Weinheim, 1988. (c) Biomedical Frontiers of
Fluorine Chemistry; Ojima, I., McCarthy, J. R., Welch, J. T., Eds.; ACS
Symp. Ser.; American Chemical Society: Washington, DC, 1996. (d)
Fluorine-containing Amino Acids, Synthesis and Properties; Kukhar’, V.
P., Soloshonok, V. A., Eds.; John Wiley & Sons Ltd.: New York, 1995.
(e) For a recent review of the synthesis of trifluoromethyl containing
compounds see e.g.: Lin, P.; Jiang, J. Tetrahedron 2000, 56, 3635. (f)
Soloshonok, V. A. Enantiocontrolled Synthesis of Fluoro-organic Com-
pounds, Stereochemical Challenges and Biomedical Targets; John Wiley
& Sons Ltd.: New York, 1999.
However, high catalyst loading (40 mol %) was required to
obtain good yields, as only 30% yield was formed with 10 mol

12522 J. Am. Chem. Soc., Vol. 122, No. 50, 2000
Gathergood et al.
Experimental Section
See Supporting Information.24
This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. This work was made possible by a grant
from the Danish National Research Foundation.
JA002593J
(24) General Information is provided in the Supporting Information.
The following are also included in the Supporting Information: specific
reaction conditions, characterization data, absolute stereochemical proofs.
Supporting Information Available: Complete experimental
procedure, characterization, and 1H and 13C NMR spectra (PDF).