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C2-Symmetric Bicyclo[2.2.2]octadienes as Chiral Ligands: Their High
Performance in Rhodium-Catalyzed Asymmetric Arylation of
Norihito Tokunaga, Yusuke Otomaru, Kazuhiro Okamoto, Kazuhito Ueyama, Ryo Shintani, and Department of Chemistry, Graduate School of Science, Kyoto UniVersity, Sakyo, Kyoto 606-8502, Japan Received August 29, 2004; E-mail: Recent developments on the chiral diene ligands have opened Table 1. Rhodium-Catalyzed Asymmetric Arylation of Imines 3
the door to an exciting new research area of catalytic asymmetric with Arylboroxines 4a
reactions.1 The C2-symmetric bicyclo[2.2.1]heptadienes (nbd*), which we have reported in 2003,2 are highly enantioselective chiral boroxine 4
ligands for rhodium-catalyzed asymmetric addition of organoboronic acids to R, -unsaturated ketones2 and fumaric and maleic com- pounds.3 More recently, Carreira reported C [2.2.2]octadienes and their successful use for iridium-catalyzed kinetic resolution of allyl carbonates.4 We have continued our studies on the preparation of new chiral diene ligands and their application to catalytic asymmetric reactions. Here we wish to report our new C2-symmetric bicyclo[2.2.2]octadienes (bod*), which have a clear superiority over chiral phosphorus ligands in both enantio- selectivity and catalytic activity in the rhodium-catalyzed arylation of N-tosylarylimines giving diarylmethylamines.
octadienes is straightforward as shown in Scheme 1. Enantiomeri- cally pure (1R,4R)-bicyclo[2.2.2]octa-2,5-dione ((R,R)-1)5 was
obtained by optical resolution of racemic diketone 1 through
a Reaction was carried out in dioxane at 60 °C for 6 h with 1.2 equiv of fractional recrystallization of its dihydrazone of (R)-5-(1-phenyl- boroxine 4 in the presence of 20 mol % KOH, 1 equiv (with respect to
boron) of H
ethyl)semioxamazide.6 Ditriflate formation with excess LDA and 2O, and 3 mol % the catalyst generated from [RhCl(C2H4)2]2 and a chiral ligand. b Isolated yields by column chromatography on silica N-(2-pyridyl)triflimide followed by cross-coupling of (R,R)-ditriflate gel (hexane/ethyl acetate ) 2/1). c Determined by HPLC analysis with a 2 with PhCH
chiral stationary phase column (Chiralcel OD-H: hexane/2-propanol ) 80/ 2MgBr and PhMgBr in the presence of PdCl2(dppf) 20 for 5am, 5bm, 5cm, 5dm, 5em, 5fm, 5hn, 5ho, 5hp, and 5cn; hexane/
as a catalyst7 gave the 2,5-disubstituted (1R,4R)-bicyclo[2.2.2]- 2-propanol ) 90/10 for 5gm). d Absolute configuration of 5am was
octadienes, (R,R)-Bn-bod* and (R,R)-Ph-bod*, respectively.8 It determined by conversion into known free amine (S)-phenyl(4-chlorophen- should be noted that the 2,5-diphenyl diene, Ph-bod*, is a stable yl)methylamine. The configurations of other amines were assigned by compound, while its [2.2.1] (nbd) analogue readily undergoes consideration of the stereochemical reaction pathway.
decomposition in the air under light.
ylboroxine (4m).12 Thus, a rhodium catalyst13 generated from
Scheme 1 a
[RhCl(C2H4)]2]2 (3 mol % Rh), Ph-bod* (1.1 equiv with respect to
Rh), and aqueous KOH (20 mol %) in dioxane was added to a
solution of imine 3a and boroxine 4m (1.2 equiv with respect to
3a) in dioxane, and the mixture was heated at 60 °C for 6 h.
Chromatography on silica gel gave phenyl(4-chlorophenyl)meth-
ylamine tosylamide 5am in 96% yield, whose enantiomeric purity
a Reagents and conditions: (a) (i) LDA/THF, -78 °C; (ii) Tf2Npy-2, was determined to be 98% ee by HPLC analysis with a chiral -78 °Cfrt. Yield ) 70%. (b) RMgBr, PdCl2(dppf) (1 mol %), Et2O reflux.
stationary phase column (entry 1 in Table 1). Deprotection of Yield ) 59% for R ) PhCH2. Yield ) 78% for R ) Ph.
tosylamide 5am with SmI2 in HMPA gave free amine (S)-phenyl-
The asymmetric synthesis of diarylmethylamines by the catalytic (4-chlorophenyl)methylamine in 64% yield as a mixture with 14% asymmetric arylation9,10 has attracted growing attention due to their of diphenylmethylamine (not optimized). The enantioselectivity was importance in biological activity.11 Unfortunately, however, enan- still high but a little lower with benzyl-disubstituted diene ligands, tioselectivity as high as 95% has not been reported yet for the Bn-bod* and Bn-nbd*, which gave a high yield of tosylamide 5am
asymmetric synthesis of phenyl(4-chlorophenyl)methylamine, which in 94 and 92% ee, respectively (entries 2 and 3). On the contrary, is a potential key intermediate to Cetirizine hydrochloride,11 (R)-binap, which is a chiral bisphosphine ligand successfully used although considerable efforts have been made, for example, by steric for the rhodium-catalyzed asymmetric 1,4-addition to electron- tuning of aryl groups in arenesulfonamides of arylimines.9b,c deficient olefins,14 was a poor ligand in terms of both enantiose- It was found that the enantioselectivity as high as 98% was lectivity and catalytic activity in the present arylation reaction15 readily attained by use of chiral diene ligand (R,R)-Ph-bod* for (entry 4). Low efficiency was also observed with segphos16 and a the reaction of 4-chlorobenzaldehyde N-tosylimine 3a with phen-
phosphoramidite17 as a ligand (entries 5 and 6).
13584 9 J. AM. CHEM. SOC. 2004, 126, 13584-13585
10.1021/ja044790e CCC: $27.50 2004 American Chemical Society
using arylboroxines where the aryl groups are 4-chloro (4n),
4-methoxy (4o), and 2-methyl (4p) phenyls (entries 13-15). The
diarylmethylamines where both of the aryl groups are substituted
phenyls can be prepared as well by combination of substituted
arylimines and substituted arylboroxines. One example giving (R)-
4-chlorophenyl(4-methoxyphenyl)methylamine (5cn) with 99%
enantioselectivity is shown in entry 16.
In summary, asymmetric synthesis of diarylmethylamines with high enantioselectivity (95-99% ee) was realized for the first timeby use of a C2-symmetric diene ligand, Ph-bod*, for the rhodium-catalyzed asymmetric arylation of N-tosylarylimines.
Acknowledgment. This work has been supported in part by a
Grant-in-Aid for Scientific Research, the Ministry of Education,Culture, Sports, Science and Technology, Japan (21 COE on KyotoUniversity Alliance for Chemistry). N.T. thanks the Japan Societyfor the Promotion of Science for the award of a fellowship forgraduate students.
Supporting Information Available: Experimental procedures and
spectroscopic and analytical data for the products (PDF). This materialis available free of charge via the Internet at
(1) For a short review: Glorius, F. Angew. Chem., Int. Ed. 2004, 43, 3364.
(2) Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K. J. Am. Chem. Soc.
2003, 125, 11508.
(3) Shintani, R.; Ueyama, K.; Yamada, I.; Hayashi, T. Org. Lett. 2004, 6,
(4) Fischer, C.; Defieber, C.; Suzuki, T.; Carreira, E. M. J. Am. Chem. Soc.
2004, 126, 1628.
(5) Some other methods for the optical resolution have been reported: (a) Hill, R. K.; Morton, G. H.; Peterson, J. R.; Walsh, J. A.; Paquette, L. A.
J. Org. Chem. 1985, 50, 5528. (b) Naemura, K.; Takahashi, N.; Tanaka,
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Haga, K.; Ikai, K.; Takeuchi, K.; Okamoto, K. Tetrahedron Lett. 1990,
31, 4057. (d) Almqvist, F.; Ekman, N.; Frejd, T. J. Org. Chem. 1996, 61,
3794 and references therein.
(6) Optical resolution of ketones using (R)-5-(1-phenylethyl)semioxamazide has been reported: Leonard, N. L.; Boyer, J. H. J. Org. Chem. 1950, 15,
(7) Hayashi, T.; Konishi, M.; Kobori, Y.; Kumada, M.; Higuchi, T.; Hirotsu, K. J. Am. Chem. Soc. 1984, 106, 158.
86 (c 0.71, CHCl3). (R,R)-Ph-bod*: [R]20D (9) Rhodium-catalyzed arylation. (a) With arylstannane: Hayashi, T.; Ishige- The high enantioselectivity observed with chiral diene ligands, dani, M. J. Am. Chem. Soc. 2000, 122, 976. (b) With arylboroxine:
Kuriyama, M.; Soeta, T.; Hao, X.; Chen, Q.; Tomioka, K. J. Am. Chem.
especially Ph-bod*, demonstrates that the chirality recognition Soc. 2004, 126, 8128. (c) With aryltitanium: Hayashi, T.; Kawai, M.;
ability brought about by two phenyl groups at the 2- and 5-positions Tokunaga, N. Angew. Chem., Int. Ed. 2004, 43, in press.
of the diene is substantially high and is higher for the N- (10) Addition of phenylzinc catalyzed by a chiral ketimine: Hermanns, N.; Dahmen, S.; Bolm, C.; Bra¨se, S. Angew. Chem., Int. Ed. 2002, 41, 3692.
tosylarylimine than the ability brought about by the face-and-edge (11) For examples: (a) Bishop, M. J.; McNutt, R. W. Bioorg. Med. Chem. orientation of four phenyl groups18 on the chelating bisphosphine Lett. 1995, 5, 1311. (b) Spencer, C. M.; Foulds, D.; Peters, D. H. Drugs
1993, 46, 1055. (c) Sakurai, S.; Ogawa, N.; Suzuki, T.; Kato, K.; Ohashi,
ligands represented by binap. The S configuration of the arylation T.; Yasuda, S.; Kato, H.; Ito, Y. Chem. Pharm. Bull. 1996, 44, 765. (d)
product 5am obtained with (R,R)-dienes is rationalized by the
Cetirizine is currently prepared as a racemate via an alkylation of apiperazine derivative with a benzhydryl chloride derivative: Baltes, E.; coordination of imine 3a to a rhodium with its si-face.19 The
De Lannoy, J.; Rodriguez, L. Eur. Patent Appl. 58146, 1982.
coordination with the other face is much less favorable due to the (12) Rhodium-catalyzed arylation of N-tosylimines with arylboron reagents has been reported by Tomioka (ref 9b) and by Miyaura: (a) Ueda, M.; steric repulsions caused by both of two phenyl groups on the diene Miyaura, N. J. Organomet. Chem. 2000, 595, 31. (b) Ueda, M.; Saito,
A.; Miyaura, N. Synlett 2000, 1637.
(13) We presume the formation of [Rh(OH)(Ph-bod*)] The scope of the present rhodium-catalyzed asymmetric arylation (14) For reviews: (a) Hayashi, T.; Yamasaki, K. Chem. ReV. 2003, 103, 2829.
using Ph-bod* as a chiral ligand is limited to aryl-derived imines (b) Fagnou, K.; Lautens, M. Chem. ReV. 2003, 103, 169. (c) Bolm, C.;
Hildebrand, J. P.; Mun˜iz, K.; Hermanns, N. Angew. Chem., Int. Ed. 2001,
but is tolerant of a range of functional groups. Phenylation of the aromatic imines substituted with trifluoromethyl (3b), methoxy (3c),
(15) Low enantioselectivity of binap in the rhodium-catalyzed asymmetric arylation of imines has been reported in refs 9b and 9c.
and dimethylamino (3d) at the 4-position of phenyl gave the
(16) Saito, T.; Yokozawa, T.; Ishizaki, T.; Moroi, T.; Sayo, N.; Miura, T.; corresponding sulfonamides of aryl(phenyl)methylamines (S)-5 in
Kumobayashi, H. AdV. Synth. Catal. 2001, 343, 264.
high yields with over 95% enantioselectivity (entries 7-9 in Table (17) Boiteau, J.-G.; Minnaar, A. J.; Feringa, B. L. J. Org. Chem. 2003, 68,
1). High enantioselectivity (98-99% ee) was also observed in the (18) Ozawa, F.; Kubo, A.; Matsumoto, Y.; Hayashi, T. Organometallics 1993,
phenylation of imines 3e, 3f, and 3g, which were derived from
12, 4188, and references therein.
(19) Insertion of imine into an aryl-rhodium bond forming an amido complex 2-methoxybenzaldehyde, 1-naphthaldehyde, and 2-furaldehyde, has been reported: Krug, C.; Hartwig, J. F. J. Am. Chem. Soc. 2004,
respectively (entries 10-12). The asymmetric arylation of benzal- dehyde imine 3h with substituted phenyl groups was also successful
J. AM. CHEM. SOC. 9 VOL. 126, NO. 42, 2004 13585



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