Utility of the iridium complex of the pybox ligand in regio- and enantioselective allylic substitution

Article abstract of DOI:10.1021/ol047915t

(Chemical equation presented) The viability of the iridium complex of pybox as chiral catalyst in allylic substitutions and the enantioselective synthesis of branched products was studied. Among several chiral ligands evaluated, the iridium complex of pybox having a phenyl group catalyzed the reaction with high activity to form the branched amines with good enantioselectivities when hydroxylamine, amine, and aniline were employed as a nucleophile. The allylic substitution with oximes proceeded smoothly to give the branched oxime ethers with good enantioselectivities.

Full text of DOI:10.1021/ol047915t

ORGANIC
LETTERS
2004
Vol. 6, No. 24
4631-4634
Utility of the Iridium Complex of the
Pybox Ligand in Regio- and
Enantioselective Allylic Substitution
Hideto Miyabe, Akira Matsumura, Katsuhiko Moriyama, and Yoshiji Takemoto*
Graduate School of Pharmaceutical Sciences, Kyoto UniVersity, Yoshida, Sakyo-ku,
Kyoto 606-8501, Japan
takemoto@pharm.kyoto-u.ac.jp
Received October 8, 2004
ABSTRACT
The viability of the iridium complex of pybox as chiral catalyst in allylic substitutions and the enantioselective synthesis of branched products
was studied. Among several chiral ligands evaluated, the iridium complex of pybox having a phenyl group catalyzed the reaction with high
activity to form the branched amines with good enantioselectivities when hydroxylamine, amine, and aniline were employed as a nucleophile.
The allylic substitution with oximes proceeded smoothly to give the branched oxime ethers with good enantioselectivities.
Chiral catalysts for allylic substitution have received con-
siderable attention.1 Traditionally, ligands with phosphorus
as donor atoms have been employed. In recent years, a
variety of nitrogen ligands have proven to be highly useful
as well.1
The box and pybox ligands are efficient nitrogen ligands
in numerous asymmetric reactions.2 The palladium complex
of the bidentate box ligand has been shown to induce high
stereoselectivity in the allylic substitution.1-3 In contrast, the
utility of the C2-symmetric pybox ligand in transition-metal-
catalyzed allylic substitution is largely unexplored, 4 although
the pybox ligand has the advantage of increased rigidity when
it behaves as a tridentate.2,5 We now report the results of
experiments to prove the utility of the pybox ligand in allylic
substitution. As shown below, the iridium complex of pybox
with a phenyl group catalyzed the reaction with high activity
to form the branched products with good enantioselectivities.6
The viability of the pybox ligand in iridium-catalyzed
allylic amination is the first focus of our efforts (Scheme
1). Takeuchi first reported that a high degree of regiocontrol
in allylic amination and alkylation was achieved by using
(3) (a) Muller, D.; Umbricht, G.; Weber, B.; Pfaltz, A. HelV. Chim. Acta
1991, 74, 232. (b) von Matt, P.; Lloyd-Jones, G. C.; Minidis, A. B. E.;
Pfaltz, A.; Macko, L.; Neuburger, M.; Zehnder, M.; Ruegger, H.; Pregosin,
P. S. HelV. Chim. Acta 1995, 78, 265. (c) Larock, R. C.; Zenner, J. M. J.
Org. Chem. 1995, 60, 482.
(4) (a) Bourguignon, J.; Bremberg, U.; Dupas, G.; Hallman, K.; Hagberg,
L.; Hortala, L.; Levacher, V.; Lutsenko, S.; Macedo, E.; Moberg, C.;
Que´guiner, C.; Rahm, F. Tetrahedron 2003, 59, 9583. (b) Chelucci, G.;
Deriu, S.; Pinna, G. A.; Saba, A.; Valenti, R. Tetrahedron: Asymmetry 1999,
10, 3803.
(5) Nishiyama, H.; Sakaguchi, H.; Nakamura, T.; Horihata, M.; Kondo,
M.; Itoh, K. Organometallics 1989, 8, 846.
(6) Recently, the iridium-idane-pybox catalyst was used in a reductive
aldol reaction. See: Zhao, C.-X.; Duffey, M. O.; Taylor, S. J.; Morken, J.
P. Org. Lett. 2001, 3, 1829.
(1) For reviews, see: (a) Trost B. M.; Crawley, M. L. Chem. ReV. 2003,
103, 2921. (b) Trost, B. M.; Lee, C. B. In Catalytic Asymmetric Synthesis
II; Ojima, I. Ed.; Wiley-VCH: Weinheim, Germany, 2000; pp 593-650.
(c) Pfaltz, A.; Lautens, M. In ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz A., Yamamoto, H., Eds.; Springer: Berlin, 1999;
Vol. 2, pp. 833-884. (d) Trost B. M.; Van Vranken, D. L. Chem. ReV.
1996, 96, 2921.
(2) For recent reviews, see: (a) Sibi, M. P.; Manyem, S.; Zimmerman,
J. Chem. ReV. 2004, 103, 3263. (b) Desimoni, G.; Faita, G.; Quadrelli, P.
Chem. ReV. 2003, 103, 3119. (c) Ghosh, A. K.; Mathivanan, P.; Cappiello,
J. Tetrahedron: Asymmetry 1998, 9, 1.
10.1021/ol047915t CCC: $27.50
© 2004 American Chemical Society
Published on Web 10/29/2004

Among several evaluated ligands (entries 1-7), the iridium
complex of pybox 5 having a phenyl group catalyzed the
reaction with high activity to form the branched amine 3Aa
with 79% ee after being stirred at 20 °C for 1 h (entry 1).
Although other aryl pybox ligands having 4-fluorophenyl,
4-methoxyphenyl, and 3,4,5-trimethoxyphenyl groups were
also evaluated, the iridium-pybox 5 complex has shown the
best reactivity. The degree of regio- and enantioselectivities
was shown to be dependent on the reaction temperature; thus
changing the temperature from 20 to -40 °C led to an
increase in regioselectivity to 90:10 and enantioselectivity
to 92% ee (entry 3). The absolute configuration of 3Aa was
determined to be S by the zinc-mediated reduction of the
N-O bond of 3Aa to convert N-((S)-1-phenylallyl)benz-
amide 10.12 In regard to the solvent effect, the replacement
of CH2Cl2 with toluene or THF led to a decrease in the regio-
and enantioselectivities. Additionally, other achiral allylic
reagents were also tested under the optimized reaction
conditions. However, no reaction occurred when cinnamyl
methyl carbonate or cinnamyl acetate was employed; thus,
the linear phosphate such as cinnamyl phosphate 2a was a
reactive electrophile for the iridium-pybox-catalyzed reac-
tion.
Scheme 1. Iridium-Pybox-Catalyzed Allylic Substitution with
Hydroxylamine 1A
The base influenced the regio- and enantioselectivities of
the reaction of phosphate 2a with hydroxylamine 1A (Table
2). Good regio- and enantioselectivities were obtained when
an iridium catalyst.7 Therefore, the control of regio- and
enantioselectivities has been a subject of current interest.8-10
We recently reported that both nitrogen and oxygen atoms
on hydroxylamines having an N-electron-withdrawing sub-
stituent acted as reactive nucleophiles.11
On the basis of these results, we first investigated the
enantioselective iridium-catalyzed allylic amination with
hydroxylamine 1A under basic conditions. As a linear achiral
electrophile, the phosphate 2a was employed to prove the
efficiency of chiral ligands.10 Table 1 outlines the optimiza-
Table 2. Effect of Base on Reaction of Phosphate 2a with
Hydroxylamine 1Aa
entry
base
T (°C) time (h) % yieldb (ratioc) % ee
1
2
3
4
5
6
Et2Zn
K2CO3
Cs2CO3
Ba(OH)2‚H2O
Ba(OH)2‚H2O -20
Ba(OH)2‚H2O -40
20
20
20
20
1
3
1
1
1
88 (64:36)
91 (94:6)
66 (87:13)
92 (63:37)
92 (76:24)
91 (81:19)
31
39
66
70
90
92
10
Table 1. Reaction of Phosphate 2a with Hydroxylamine 1A by
Using CsOH‚H2Oa
a [IrCl(cod)]2 (4 mol %) was employed, and reactions were carried out
by using ligand 5 in CH2Cl2. b Combined yields of 3Aa and 4Aa. c Ratio
for 3Aa:4Aa.
entry
ligand
T (°C)
time (h)
% yieldb (ratioc)
% ee
1
2
3
4
5
6
7
5
5
5
6
7
8
9
20
-20
-40
-20
-20
-20
-20
1
8
94 (76:24)
89 (86:14)
86 (90:10)
27 (74:26)
17 (51:49)
nr
79
92
92
33
43
a weak base such as CsOH‚H2O, Cs2CO3, or Ba(OH)2‚H2O
was employed (entries 4-6). In the presence of Ba(OH)2‚
H2O, the reaction proceeded smoothly at -40 °C to give a
17
50
50
50
50
56 (85:15)
-79
(8) For some examples, see: (a) Hayashi, T.; Kawatsura, M.; Uozumi,
Y. J. Am. Chem. Soc. 1998, 120, 1681. (b) Trost, B. M.; Toste, F. D. J.
Am. Chem. Soc. 1999, 121, 4546. (c) Evans, P. A.; Robinson, J. E.; Nelson,
J. D. J. Am. Chem. Soc. 1999, 121, 6761. (d) Trost, B. M.; Tsui, H.-C.;
Toste, F. D. J. Am. Chem. Soc. 2000, 122, 3534. (e) You, S.-L.; Zhu, X.-
Z.; Luo, Y.-M.; Hou, X.-L.; Dai, L.-X. J. Am. Chem. Soc. 2001, 123, 7471.
(9) For some related examples, see: (a) Tissot-Croset, K.; Polet, D.;
Alexakis, A. Angew. Chem., Int. Ed. 2004, 43, 2426. (b) Alexakis, A.: Polet,
D. Org. Lett. 2004, 6, 3529. (c) Shu, C.; Hartwig, J. F. Angew. Chem., Int.
Ed. 2004, 43, 4794. (d) Shu, C.; Leitner, A.; Hartwig, J. F. Angew. Chem.,
Int. Ed. 2004, 43, 4797. (e) Lipowsky, G.; Helmchen G. Chem. Commun.
2004, 116. (f) Fisher, C.; Defieber, C.; Suzuki, T.; Carreira, E. M. J. Am.
Chem. Soc. 2004, 126, 1629. (g) Lo´pez, F.; Ohmura, T.; Hartwig, J. F. J.
Am. Chem. Soc. 2003, 125, 3426. (h) Ohmura, T.; Hartwig, J. F. J. Am.
Chem. Soc. 2002, 124, 15164. (i) Fuji, K.; Kinoshita, N.; Tanaka K.;
Kawabata, T. Chem. Commun. 1999, 2289. (j) Bartels, B.; Helmchen, G.
Chem. Commun. 1999, 741.
a [IrCl(cod)]2 (4 mol %) was employed, and reactions were carried out
in CH2Cl2 in the presence of CsOH‚H2O. b Combined yields of 3Aa and
4Aa. c Ratio for 3Aa:4Aa.
tion of the pybox ligands 5-9. To a suspension of hydroxyl-
amine 1A and CsOH‚H2O in CH2Cl2 was added a solution
of phosphate 2a, [IrCl(cod)]2, and chiral ligand in CH2Cl2.
(7) (a) Takeuchi, R.; Ue, N.; Tanabe, K.; Yamashita, K.; Shiga, N. J.
Am. Chem. Soc. 2001, 123, 9525. (b) Takeuchi R.; Kashio, M. J. Am. Chem.
Soc. 1998, 120, 8647. For a review, see: (c) Takeuchi, R. Synlett 2002,
1954.
4632
Org. Lett., Vol. 6, No. 24, 2004

good yield of the branched oxime ether 3Aa with 92% ee
(entry 6).
To study the viability of the iridium-pybox 5 complex
in allylic amination, we next investigated the reaction of
phosphates 2a-c with amines 1A-E (Scheme 2). All
with good enantioselectivity (entry 6). In contrast to hy-
droxylamines 1A and 1B having N-electron-withdrawing
substituents, the reactions with basic amines 1C and 1E also
proceeded without base.
We next investigated the utility of the iridium-pybox 5
complex in enantioselective allylic substitution with oxygen
nucleophiles. The oxygen nucleophile of choice was oxime,
since it has shown an excellent reactivity in our recent work
on allylic substitution (Scheme 3).13
Scheme 2. Iridium-Pybox-Catalyzed Allylic Amination
Scheme 3. Iridium-Pybox-Catalyzed Allylic Substitution with
Oximes 11A-11G
reactions were carried out in CH2Cl2 at -20 °C in the
presence of CsOH‚H2O. The reaction of phosphate 2b having
an electron-withdrawing substituent on the aromatic ring
proceeded slowly to give the product 3Ab with 87% ee
(Table 3, entry 1). Excellent regio- and enantioselectivities
Table 3. Allylic Amination of Phosphates 2a-c with Amine
1A-E in the Presence of CsOH‚H2Oa
entry amine phospate time (h) % yieldb (ratioc) % ee
1
2
3
4
5
6
1A
1A
1B
1C
1D
1E
2b
2c
2a
2a
2a
2a
20
30
12
1
20
3
75 (70:30)
95 (>95:5)
73 (73:27)
91 (71:29)
nr
87
96
87
95
The base also influenced the selectivity of the reaction of
phosphate 2a with oxime 11A (Table 4). The good regio-
and enantioselectivities were obtained when Ba(OH)2‚H2O
was employed at -20 °C to gave the oxime ether 12Aa with
95% ee and 90:10 ratio (entry 6).
86 (90:10)
88
a [IrCl(cod)]2 (4 mol %) was employed, and reactions were carried out
by using ligand 5 in CH2Cl2 at -20 °C in the presence of CsOH‚H2O.
b Combined yields of 3Aa-Ea and 4Aa-Ea. c Ratio for 3Aa-Ea:4Aa-Ea.
Several phosphates 2c-f having bulky 1-naphthyl or
2-naphthyl substituents and having an electron-withdrawing
were observed in the reaction of phosphate 2c having a bulky
1-naphthyl group with 1A (entry 2). The hydroxylamine 1B,
having two N-electron-withdrawing substituents, worked well
in the presence of CsOH‚H2O (entry 3). The reaction of 2a
with basic dibenzylamine 1C proceeded smoothly to give
the product 3Ca with 95% ee (entry 4). In contrast, the reac-
tion with benzylamine 1D having a N-electron-withdrawing
substituent did not take place (entry 5). Additionally, the
iridium-pybox complex was effective for the reaction of
2a with less reactive aniline derivative 1E to give the product
Table 4. Effect of Base on Reaction of Phosphate 2a with
Oxime 11Aa
entry
base
time (h)
% yieldb (ratioc)
% ee
1d
2d
3d
4d
5d
6e
7e
n-BuLi
K2CO3
CsOAc
Cs2CO3
Ba(OH)2‚H2O
Ba(OH)2‚H2O
CsOH‚H2O
3
3
3
2
1
40 (66:34)
64 (89:11)
18 (98:2)
80 (86:14)
81 (88:12)
87 (90:10)
52 (89:11)
80
73
40
80
81
95
85
20
20
(10) For our studies on the iridium-catalyzed reaction, see: (a) Kanayama,
T.; Yoshida, K.; Miyabe, H.; Takemoto, Y. Angew. Chem., Int. Ed. 2003,
42, 2054. (b) Kanayama, T.; Yoshida, K.; Miyabe, H.; Kimachi, T.;
Takemoto, Y. J. Org. Chem. 2003, 68, 6197.
(11) Miyabe, H.; Yoshida, K. Matsumura, A.; Yamauchi, M.; Takemoto,
Y. Synlett 2003, 567.
a [IrCl(cod)]2 (4 mol %) was employed, and reactions were carried out
by using ligand 5 in CH2Cl2. b Combined yields of 12Aa and 13Aa. c Ratio
for 12Aa:13Aa. d Reactions were carried out at 20 °C. e Reactions were
carried out at -20 °C.
(12) Castagnolo, D.; Armaroli, S.; Corelli, F.; Botta, M. Tetrahedron:
Asymmetry 2004, 15, 941.
Org. Lett., Vol. 6, No. 24, 2004
4633

conditions, allowing facile incorporation of structural variety
(entries 8-10).
Table 5. Reaction of Phosphates 2a-f with Oximes 11A-G
in the Presence of Ba(OH)2‚H2Oa
The oxime ether 12Aa could be converted into 14-17 via
the selective reduction of CdC, CdN, or N-O bond of
12Aa. The absolute configuration of 12Aa was determined
to be S by comparison of 14 with authentic spectral data.14
These oxime ethers are an attractive substrate for the addition
of carbon radicals and organometallic nucleophiles.15
In conclusion, we have demonstrated that the iridium
complex of the pybox ligand acts as an effective chiral
catalyst in allylic substitution. The allylic substitution of
phosphates with amines and oximes gave the branched
amines and oxime ethers with good enantioselectivities.
entry oxime phosphate time (h) % yieldb (ratioc) % ee
1f
11A
11A
11A
11A
11B
11C
11D
11E
11F
11G
2c
2d
2e
2f
2a
2a
2a
2a
2a
2a
35
30
40
20
20
30
10
20
40
20
83 (94:6)
90
89
90
90
92
93
89
76
94
73
2e
81 (83:17)
89 (69:31)
84 (83:17)
91 (90:10)
85 (88:12)
94 (94:6)
81 (82:18)
64 (89:11)
52 (83:17)
3f
4d
5d
6e
7d
8d
9f
10d
Acknowledgment. This work was supported in part by
a Grant-in-Aid for Scientific Research (C) (Y.T.) and for
Young Scientists (B) (H.M.) from the Ministry of Education,
Culture, Sports, Science and Technology of Japan, the
Science Research Promotion Fund of the Japan Private
School Promotion Foundation for Reseach Grants, 21st
Century COE Program “Knowledge Information Infrastruc-
ture for Genome Science”, and Mitsubishi Chemical Cor-
poration Fund (H.M.).
a Reactions were carried out by using ligand 5 in CH2Cl2 at -20 °C.
b Combined yields of 12Aa-Ga and 13Aa-Ga. c Ratio for 12Aa-Ga:13Aa-
Ga. d [IrCl(cod)]2 (4 mol %) was employed. e [IrCl(cod)]2 (6 mol %) was
employed. f [IrCl(cod)]2 (8 mol %) was employed.
substituent on the aromatic ring worked well (Table V,
entries 1-3). Next, several oximes 11B-G were employed
(entries 5-10). The stability of conjugate base of oximes
would be important for the nucleophilic property of an
oxygen atom of oximes. The reaction of aldoximes 11B and
11D containing an electron-withdrawing substituent pro-
ceeded smoothly as a result of the extra stabilization of
conjugate base of oximes by an electron-withdrawing sub-
stituent (entries 5 and 7). The aldoxime 11C containing an
electron-donating substituent also produced an excellent yield
of product by using 6 mol % of [IrCl(cod)]2, after being
stirred for 30 h (entry 6). The aldoxime 11E containing a
basic 2-pyridinyl group, a bulky ketoxime 11F, and aliphatic
ketoxime 11G also worked well under similar reaction
Supporting Information Available: Experimental pro-
cedure and characterization data and 1H and 13C NMR spectra
of all obtained compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL047915T
(14) Yoshioka, M.; Kawakita, T.; Ohno, M. Tetrahedron Lett. 1989, 30,
1657.
(15) Oxime ethers have emerged as excellent radical acceptors. See: (a)
McNabb, S. B.; Ueda, M.; Naito, T. Org. Lett. 2004, 6, 1911. Diastereo-
seclective addition of organometallic reagents to oxime ethers: (b) Cooper,
T. S.; Laurent, P.; Moody, C. J.; Takle, A. K. Org. Biomol. Chem. 2004, 2,
265. (c) Gallagher, P. T.; Hunt, J. C. A.; Lightfoot, A. P.; Moody, C. J. J.
Chem. Soc., Perkin Trans. 1 1997, 2633.
(13) Miyabe, H.; Matsumura, A.; Yoshida, K.; Yamauchi, M.; Takemoto,
Y. Synlett 2004, 2123.
4634
Org. Lett., Vol. 6, No. 24, 2004