Asymmetric addition of dimethylzinc to N-tosylarylimines catalyzed by a rhodium-diene complex toward the synthesis of chiral 1-arylethylamines

Article abstract of DOI:10.1021/ol060213e

A rhodium complex coordinated with a chiral diene, (R,R)-2,5- diphenylbicyclo[2.2.2]octa-2,5-diene (Ph-bod*), catalyzed the asymmetric addition of dimethylzinc to N-tosylarylimines to give high yields of chiral 1-aryl-1-ethylamines with high enantioselectivity (94-98% ee).

Full text of DOI:10.1021/ol060213e

ORGANIC
LETTERS
2006
Vol. 8, No. 5
979-981
Asymmetric Addition of Dimethylzinc to
N-Tosylarylimines Catalyzed by a
Rhodium−Diene Complex toward the
Synthesis of Chiral 1-Arylethylamines
Takahiro Nishimura, Yuichi Yasuhara, and Tamio Hayashi*
Department of Chemistry, Graduate School of Science, Kyoto UniVersity,
Sakyo-ku, Kyoto 606-8502, Japan
thayashi@kuchem.kyoto-u.ac.jp
Received January 25, 2006
ABSTRACT
A rhodium complex coordinated with a chiral diene, (R,R)-2,5-diphenylbicyclo[2.2.2]octa-2,5-diene (Ph-bod*), catalyzed the asymmetric addition
of dimethylzinc to N-tosylarylimines to give high yields of chiral 1-aryl-1-ethylamines with high enantioselectivity (94 98% ee).
−
The enantioselective preparation of R-chiral amines is one
of the most important objectives in organic synthesis because
they are known to play important roles for their bioactivity
in several chiral drugs and natural products.1 Of several
approaches recently developed for the synthesis of R-chiral
amines, the catalytic enantioselective alkylation of imines
using dialkylzinc reagents is most attractive if high enantio-
selectivity as well as high catalytic activity is realized.2-8 In
this context, most of the studies reported so far are on the
catalytic ethylation of imines using diethylzinc because of
its high reactivity and selectivity. On the other hand, efficient
methods for the asymmetric methylation of imines are still
few in number due to the lower reactivity of dimethylzinc,
where a large amount of dimethylzinc is often used in order
to obtain the methylation product in high yield. The leading
studies of the asymmetric methylation of imines with
dimethylzinc have been developed by Hoveyda/Snapper,2
Tomioka,3 and Charette.8 They reported promising results,
for example, in copper-catalyzed asymmetric methylation of
N-tosylimines with an amidophosphine ligand (Tomioka)3b
and of N-phosphinoylimines with a chiral bis(phosphine)
monoxide ligand (Charette)8b and in the methylation-
catalyzed by a Lewis acid complexed with chiral amino acid
based ligands (Hoveyda/Snapper).2d
(1) (a) Bloch, R. Chem. ReV. 1998, 98, 1407. (b) Kobayashi, S.; Ishitani,
H. Chem. ReV. 1999, 99, 1069.
(2) (a) Porter, J. R.; Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L. J.
Am. Chem. Soc. 2001, 123, 984. (b) Porter, J. R.; Traverse, J. F.; Hoveyda,
A. H.; Snapper, M. L. J. Am. Chem. Soc. 2001, 123, 10409. (c) Akullian,
L. C.; Snapper, M. L.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2003, 42,
4244. (d) Akullian, L. C.; Porter, J. R.; Traverse, J. F.; Snapper, M. L.;
Hoveyda, A. H. AdV. Synth. Catal. 2005, 347, 417.
(3) Fujihara, H.; Nagai, K.; Tomioka, K. J. Am. Chem. Soc. 2000, 122,
12055. (b) Soeta, T.; Nagai, K.; Fujihara, H.; Kuriyama, M.; Tomioka, K.
J. Org. Chem. 2003, 68, 9723.
(4) Wang, C.-J.; Shi, M. J. Org. Chem. 2003, 68, 6229.
(5) Li, X.; Cun, L.-F.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z. Tetra-
hedron: Asymmetry 2003, 14, 3819.
(6) Wang, M.-C.; Liu, L.-T.; Hua, Y.-Z.; Zhang, J.-S.; Shi, Y.-Y.; Wang,
D.-K. Tetrahedron: Asymmetry 2005, 16, 2531.
(7) Dahmen, S.; Bra¨se, S. J. Am. Chem. Soc. 2002, 124, 5940.
(8) (a) Boezio, A. A.; Charette, A. B. J. Am. Chem. Soc. 2003, 125,
1692. (b) Boezio, A. A.; Pytkowicz, J.; Coˆte´, A.; Charette, A. B. J. Am.
Chem. Soc. 2003, 125, 14260. (c) Coˆte´, A.; Boezio, A. A.; Charette, A. B.
Angew. Chem., Int. Ed. 2004, 43, 6525. (d) Coˆte´, A.; Boezio, A. A.; Charette,
A. B. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5405. (e) Desrosiers, J.-N.;
Coˆte´, A.; Charette, A. B. Tetrahedron 2005, 61, 6186. (f) Charette, A. B.;
Boezio, A. A.; Coˆte´, A.; Moreau, E.; Pytkowicz, J.; Desrosiers, J.-N.;
Legault, C. Pure Appl. Chem. 2005, 77, 1259.
10.1021/ol060213e CCC: $33.50
© 2006 American Chemical Society
Published on Web 02/10/2006

Recently, it has been disclosed that rhodium complexes
coordinated with chiral diene ligands are highly active and
enantioselective catalysts for the asymmetric addition of
arylboronic acids to imines9,10 as well as to R,â-unsaturated
carbonyl compounds.11 Here, we report that the asymmetric
methylation of N-tosylimines with dimethylzinc proceeds
with high enantioselectivity in the presence of a chiral diene/
rhodium catalyst to give high yields of the corresponding
amines of 94-98% ee. To the best of our knowledge, this
is the first example of a rhodium-catalyzed methyl-transfer
reaction.
Our initial attempts to use methylboronic acid for the
asymmetric methylation of imines failed. Thus, the reaction
of N-tosylimine of benzaldehyde 1a with methylboronic acid
in the presence of a rhodium catalyst containing binap or a
chiral diene ligand under the reaction conditions similar to
those used for the asymmetric arylation using arylboronic
acids9a resulted in low yields (<10%) of the methylation
product. It was found that the use of dimethylzinc as a
methylating reagent in the presence of a chiral diene rhodium
catalyst greatly improved the asymmetric methylation (Scheme
1, Table 1).
Table 1. Effects of Ligands on the Asymmetric Addition of
Dimethylzinc to 1aa
entry
ligand
yieldb (%)
eec (%)
1
2
3
4
5
6
(R,R)-Ph-bod*
(R,R)-Bn-bod*
(R)-binap
(R)-segphos
(R)-MeO-mop
(R)-phosphoramidite
82
65
14
4
<1
6
97 (S)
62 (S)
52 (R)
4 (S)
5 (S)
a The reaction of 1a with Me2Zn (1.0 M in hexane, 1.5 equiv) was carried
out in dioxane at 50 °C for 3 h in the presence of 3 mol % of rhodium
catalyst generated from [RhCl(C2H4)2]2 and ligands (6 mol % of diene
ligands, 3.3 mol % of bisphosphine ligands, and 6 mol % of monophosphine
ligands, respectively). b Isolated yield after column chromatography on silica
gel. c Determined by HPLC. Absolute configuration of 2a was determined
by comparison of its specific rotation with the reported one (ref 3b).
from [RhCl(C2H4)2]2 and a C2-symmetric chiral diene ligand
(R,R)-Ph-bod*,9a,11d in dioxane at 50 °C for 3 h gave, after
hydrolysis, 82% yield of N-tosyl-1-phenylethylamine (2a)
which is 97% ee (entry 1). The absolute configuration was
determined to be S by comparison of its specific rotation
with the reported value.12 It should be noted that this
rhodium-catalyzed methylation smoothly proceeded using
only 1.5 equiv of dimethylzinc. The use of another chiral
diene ligand (R,R)-Bn-bod*9a,11d leads to lower enantiose-
lectivity (62% ee) (entry 2). The higher catalytic activity of
the chiral diene-rhodium complexes than phosphine-rho-
dium complexes is demonstrated by the results obtained with
some chiral phosphine ligands under similar conditions. The
yields of 2a are very low with (R)-binap,13 (R)-segphos,14
(R)-MeO-mop,15 and (R)-phosphoramidite16 (entries 3-6).
The data in Table 2 illustrate that the methylation of
several N-tosylarylimines having different substituents on the
aromatic nuclei can be performed to afford the N-tosylamines
(2a-j) in good yields with high enantioselectivity. The
Scheme 1
Table 2. Rhodium-Catalyzed Asymmetric Methylation of 1
Thus, the reaction of 1a with dimethylzinc in the presence
of 3 mol % of a chiral rhodium catalyst, generated in situ
(9) (a) Tokunaga, N.; Otomaru, Y.; Okamoto, K.; Ueyama, K.; Shintani,
R.; Hayashi, T. J. Am. Chem. Soc. 2004, 126, 13584. (b) Otomaru, Y.;
Tokunaga, N.; Shintani, R.; Hayashi, T. Org. Lett. 2005, 7, 307.
(10) Other reports on the catalytic enantioselective arylation of
arylimines: (a) Hayashi, T.; Ishigedani, M. J. Am. Chem. Soc. 2000, 122,
976. (b) Hermanns, N.; Dahmen, S.; Bolm, C.; Bra¨se, S. Angew. Chem.,
Int. Ed. 2002, 41, 3692. (c) Kuriyama, M.; Soeta, T.; Hao, X.; Chen, Q.;
Tomioka, K. J. Am. Chem. Soc. 2004, 126, 8128. (d) Hayashi, T.; Kawai,
M.; Tokunaga, N. Angew. Chem., Int. Ed. 2004, 43, 6125. (e) Weix, D. J.;
Shi, Y.; Ellman, J. A. J. Am. Chem. Soc. 2005, 127, 1092.
(11) (a) Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K. J. Am.
Chem. Soc. 2003, 125, 11508. (b) Shintani, R.; Ueyama, K.; Yamada, I.;
Hayashi, T. Org. Lett. 2004, 6, 3425. (c) Otomaru, Y.; Kina, A.; Shintani,
R.; Hayashi, T. Tetrahedron: Asymmetry 2005, 16, 1673. (d) Otomaru,
Y.; Okamoto, K.; Shintani, R.; Hayashi, T. J. Org. Chem. 2005, 70, 2503.
(e) Shintani, R.; Kimura, T.; Hayashi, T. Chem. Commun. 2005, 3213. (f)
Shintani, R.; Okamoto, K.; Hayashi, T. Org. Lett. 2005, 7, 4757. (g)
Defieber, C.; Paquin, J.-F.; Serna, S.; Carreira, E. M. Org. Lett. 2004, 6,
3873. (h) Paquin, J.-F.; Defieber, C.; Stephenson, C. R. J.; Carreira, E. M.
J. Am. Chem. Soc. 2005, 127, 10850. (i) Paquin, J.-F.; Stephenson, C. R.
J.; Defieber, C.; Carreira, E. M. Org. Lett. 2005, 7, 3821.
entry
imine
1a: C6H5
1b: 4-ClC6H4
1c: 3-ClC6H4
1d: 4-FC6H4
1e: 4-CF3C6H4
1f: 3-MeOC6H4
1g: 4-MeC6H4
1h: 3-MeC6H4
1i: 2-MeC6H4
1j: 2-naphthyl
time (h) isolated yield (%) eea (%)
1
2
3
4
5
6
7
8
9b
10b
3
3
2a: 82
2b: 84
2c: 83
2d: 84
2e: 83
2f: 91
2g: 81
2h: 82
2i: 61
2j: 75
97 (S)
96 (S)
96 (S)
98 (S)
94 (S)
97 (S)
98 (S)
98 (S)
96 (S)
98 (S)
3
3
3
6
6
6
12
12
a The absolute configurations were assigned by consideration of the
stereochemical pathway. b 5 mol % of Rh with the ligand (10 mol %) was
used.
980
Org. Lett., Vol. 8, No. 5, 2006

aromatic imines having electron-withdrawing substituents,
such as chloro, fluoro, and trifluoromethyl groups, smoothly
gave the corresponding amines 2 in high yields (83-84%)
with high ee values (94-98% ee) (entries 2-5). On the other
hand, in the reaction of imines with electron-donating
substituents, a longer reaction time (6 h) was required to
complete the reaction. Nevertheless, the corresponding
amines 2f-h were obtained in good yields with high
enantioselectivity (entries 6-8). The methylation of imines
with an ortho substituent (1i) and 2-naphthylimine 1j was
sluggish, and the increase of the catalyst loading was needed
to acquire the corresponding products sufficiently (entries 9
and 10). The p-toluenesulfonyl group was readily removed
from the 1-aryl-1-ethylamines by the standard method.10d For
example, treatment of 2a with lithium in liquid ammonia at
-78 °C gave (S)-1-phenylethylamine in 79% yield without
loss of its enantiomeric purity.
Scheme 2
The present rhodium-catalyzed methylation may proceed
via a methylrhodium species,17 which is formed by the
reaction of [RhCl(diene)] with dimethylzinc. Addition of the
methylrhodium to CdN bond forms an aminorhodium
species, which undergoes the σ-bond metathesis with
Me2Zn to regenerate the methylrhodium species and to
produce the methylated product as a zinc amide. The S
configuration of the product 2a obtained with (R,R)-Ph-Bod*
is rationalized by the coordination of imine 1a to a rhodium
with its si-face as shown in Scheme 2, which is similar to
the arylation of imine that we previously reported.9a
In summary, asymmetric synthesis of 1-aryl-1-ethylamines
with high enantioselectivity (94-98% ee) was accomplished
by use of a chiral diene ligand (Ph-bod*) for the rhodium-
catalyzed enantioselective methylation of N-tosylarylimines
with dimethylzinc.
(12) The specific rotation of 2a (97% ee): [R]20D -64.8 (c 1.02, EtOH).
See ref 3b.
(13) (R)-binap is successfully used for the asymmetric 1,4-addition of
activated alkenes. Hayashi, T.; Yamasaki, K. Chem. ReV. 2003, 103,
2829.
(14) Saito, T.; Yokozawa, T.; Ishizaki, T.; Moroi, T.; Sayo, N.; Miura,
T.; Kumobayashi, H. AdV. Synth. Catal. 2001, 343, 264.
(15) Hayashi, T. Acc. Chem. Res. 2000, 33, 354.
Acknowledgment. This work has been supported in part
by a Grant-in-Aid for Scientific Research from the Ministry
of Education, Culture, Sports, Science and Technology, Japan
(21 COE on Kyoto University Alliance for Chemistry).
Supporting Information Available: Experimental pro-
cedures and spectroscopic and analytical data for the sub-
strates and products. This material is available free of charge
via the Internet at http://pubs.acs.org.
(16) Boiteau, J.-G.; Minnaard, A. J.; Feringa, B. L. J. Org. Chem. 2003,
68, 9481.
(17) The methylrhodium complexes such as [RhMe(cod)]2 and
[RhMe(cod)L] are known, the former of which is thermally unstable. (a)
Schmidt, G. F.; Muetterties, E. L.; Beno, M. A.; Williams, J. M. Proc.
Natl. Acad. Sci. U.S.A. 1981, 78, 1318. (b) Kulzick, M. A.; Price, R. T.;
Andersen, R. A.; Muetterties, E. L. J. Organomet. Chem. 1987, 333, 105.
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