Highly regio- and enantioselective Pd-catalyzed allylic alkylation and amination of monosubstituted allylic acetates with novel ferrocene P,N-ligands [25]

Full text of DOI:10.1021/ja016121w

J. Am. Chem. Soc. 2001, 123, 7471-7472
7471
Highly Regio- and Enantioselective Pd-Catalyzed
Allylic Alkylation and Amination of Monosubstituted
Allylic Acetates with Novel Ferrocene P,N-Ligands
Shu-Li You, Xia-Zhen Zhu, Yu-Mei Luo,
Xue-Long Hou,* and Li-Xin Dai*
Figure 1. Transition-metal catalyzed allylic alkylation with unsym-
metrical monosubstituted π-allyl intermediate.
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences, 354 Fenglin Lu
Shanghai 200032, China
High regio- and enantioselectivity were realized in Pd-catalyzed
allylic alkylation and amination of monosubstituted allylic acetates
employing these chiral ligands. In this paper, we would like to
report the preliminary results of our studies.
ReceiVed May 2, 2001
ReVised Manuscript ReceiVed June 18, 2001
Ligands 8-11 were synthesized as shown in Scheme 1. A new
chiral center was formed on the P atom during the reaction with
BINOL, and all diastereoisomers were easily isolated as orange
solids by column chromatography. The preparation of these
ligands is fairly easy even in gram quantity although the structure
is seemingly rather complex. They are very stable in air, and no
change in NMR spectra was observed after 2 months. The absolute
configuration at the phosphorus atom was determined by X-ray
diffraction analysis.12 Although Pfaltz7 and Hayashi6 have also
developed ligands by incorporating a binaphthyl skeleton on the
P-atom, ligands 8-11 are entirely different from them. A cyclic
phosphite structure was found in that of Pfaltz, while in our
ligands, a new chiral center was introduced to the P-atom, and a
free OH functionality was retained, which is crucial in these
reactions, particularly in the amination reaction (vide infra).
For the allylic alkylation reaction of 1a or 2a, all ligands gave
branched product 5a in good regioselectivity, among which
(S,Sphos,R)-8d was the best. Under the optimized condition by
using ligand 8d, wide ranges of substrates were investigated (eq
1). All results are summarized in Table 1.
All reactions provided the branched products 5 with high regio-
and enantioselectivity, except the substrate 1g with 2-thienyl
group, which gave a relatively lower regio- and enantioselectivity
(entry 8, Table 1). In the literature, the regioselectivity was
dramatically reduced or even reversed to the achiral linear product
for substrates with electron-withdrawing groups on aryl rings, and
it was claimed that it was controlled by electronic factors.7 In
our case, 94/6 regioselectivity in favor of 5 (94% ee) was recorded
for 1e with p-chlorophenyl group (entry 6, Table 1). Even with
a very strong electron-withdrawing group such as CN group in
1f, the reaction still gave a 90/10 regioselectivity in favor of 5
(95% ee, entry 7, Table 1). Despite the fact that high regiose-
lectivity in Pd-catalyzed allylic substitution reactions of 1h
containing a methyl substituent has been reported with N9 or S13
nucleophile, no satisfactory results for 1h in the alkylation reaction
have ever been reported. However, with ligand 8d the alkylation
Palladium-catalyzed allylic substitution reaction is one of the
brightest focuses in asymmetric synthesis during the past decades
because of its great potential in organic synthesis.1 Various ligands
have been synthesized and used in this reaction, especially with
1,3-symmetrically disubstituted substrates, and high ee is realized.2
Despite this, little success was achieved with the unsymmetrical
substrate such as 1 or 2, and achiral linear product 4 was usually
given (Figure 1).3
High regio- and enantioselectivity for certain substrates in
allylic alkylation reactions were, however, achieved by employing
other chiral metal complexes such as W, Mo, and Ir.4 Even so,
the use of palladium aiming at the asymmetric reaction of the
monosubstituted substrates has never been abandoned,5 and
several specially designed ligands have been tested accordingly.
Hayashi found that 2-(diphenylphosphino)-2′-methoxy-1,1′-bi-
naphthyl ligand (MeO-MOP) gave good regio- and enantiose-
lectivity in palladium-catalyzed alkylation of 2, but a very low
regioselectivity for substrate 1.6 Pfaltz developed phosphite-
oxazoline ligands and used them to control the regio- and
enantioselectivity in the palladium-catalyzed allylic alkylation of
1 or 2.7 High regio- and enantioselectivity were achieved for 3-(1-
naphthyl)-3-allylic acetate. However, only moderate to low
regioselectivity was obtained for other aryl- and alkyl-substituted
substrates.7 For the regio- and enantioselective allylic amination
reactions,8 pioneering work has been done by Hayashi and Ito
with butenyl acetate as the only substrate.9 Therefore, the regio-
and enantioselectivity of monosubstituted substrates in palladium-
catalyzed allylic substitution reaction remain to be solved.
On the basis of our previous results10 and those of others,6,7,11
we designed and synthesized a series of novel ferrocene ligands.
(1) Reviews: (a) Trost, B. M.; Van Vranken, D. L. Chem. ReV. 1996, 96,
395. (b) ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. 2.
(2) For examples, see: (a) Trost, B. M. Acc. Chem. Res. 1996, 29, 355.
(b) Von Matt, P.; Pfaltz, A. Angew. Chem., Int. Ed. Engl. 1993, 32, 566. (c)
Kudis, S.; Helmchen, G. Angew. Chem., Int. Ed. 1998, 37, 3047.
(3) Some exceptional examples: (a) Goux, C.; Massacret, M.; Lhoste, P.;
Sinou, D. Organometallics 1995, 14, 4585. (b) Trost, B. M.; Toste, F. D. J.
Am. Chem. Soc. 1998, 120, 9074. (c) Blacker, A. J.; Clarke, M. L.; Loft, M.
S.; Williams, J. M. J. Org. Lett. 1999, 1, 1969.
(4) Examples of other metal-catalyzed allylic substitutions: (a) W: Lloyd-
Jones, G. C.; Pfaltz, A. Angew. Chem., Int. Ed. Engl. 1995, 34, 462. (b) Mo:
Trost, B. M.; Hildbrand, S.; Dogra, K. J. Am. Chem. Soc. 1999, 121, 10416.
(c) Ir: Bartels, B.; Helmchen, G. Chem. Commun. 1999, 741. (d) Fe: Xu,
Y.; Zhou, B. J. Org. Chem. 1987, 52, 974. (e) Rh: Evans, P. A.; Nelson, J.
D. J. Am. Chem. Soc. 1998, 120, 5581. (f) Ru: Kondo, T.; Ono, H.; Satake,
N.; Mitsudo, T.; Watanable, Y. Organometallics 1995, 14, 1945. (g) Pt:
Blacker, A. J.; Clarke, M. L.; Loft, M. S.; Mahon, M. F.; Humphries, M. E.;
Williams, J. M. J. Chem. Eur. J. 2000, 6, 353.
(5) (a) Palladium Reagents and Catalysts: InnoVations in Organic
Synthesis; Tsuji, J., Ed.; VCH: Wiley: England, 1995. (b) Tenaglia, A.;
Heumann, A. Angew. Chem., Int. Ed. 1999, 38, 2180.
(6) (a) Hayashi, T.; Kawatsura, M.; Uozumi, Y. Chem. Commun. 1997,
561. (b) Hayashi, T.; Kawatsura, M.; Uozumi, Y. J. Am. Chem. Soc. 1998,
120, 1681.
(7) (a) Pre´toˆt, R.; Pfaltz, A. Angew. Chem., Int. Ed. 1998, 37, 323. (b)
Hilgraf, R.; Pfaltz, A. Synlett 1999, 1814.
(8) Selected examples for regioselective Pd-catalyzed allylic amination
reaction: (a) Johnson, B. F. G.; Raynor, S. A.; Shephard, D. S.; Mashmeyer,
T.; Thomas, J. M.; Sankar, G.; Bromley, S.; Oldroyd, R.; Gladden, L.; Mantle,
M. D. Chem. Commun. 1999, 1167. (b) Trost, B. M.; Bunt, R. C.; Lemoine,
R. C.; Calkins, T. L. J. Am. Chem. Soc. 2000, 122, 5968. (c) Trost, B. M.;
Keinan, E. J. Org. Chem. 1979, 44, 3451.
(9) Hayashi, T.; Kishi, K.; Yamamoto, A.; Ito, Y. Tetrahedron Lett. 1990,
31, 1743.
(10) (a) You, S.-L.; Zhou, Y.-G.; Hou, X.-L.; Dai, L.-X. Chem. Commun.
1998, 2765. (b) You, S.-L.; Hou, X.-L.; Dai, L.-X.; Cao, B.-X.; Sun, J. Chem.
Commun. 2000, 1933. (c) You, S.-L.; Hou, X.-L.; Dai, L.-X.; Zhu, X.-Z. Org.
Lett. 2001, 3, 149. (d) Deng, W.-P.; Hou, X.-L.; Dai, L.-X.; Yu, Y.-H.; Xia,
W. Chem. Commun. 2000, 285.
(11) (a) Ferrocene; Hayashi, T., Togni, A., Eds.; VCH: Weiheim, Germany,
1995. (b) Richards, C. J.; Locke, A. J. Tetrahedron: Asymmetry 1998, 9,
2377 and references therein.
(12) The absolute configurations on P-atom in 8a, 8b, 9c, 8d, and 10 were
determined by X-ray diffraction (see Supporting Information).
(13) Trost, B. M.; Krische, M. J.; Radinov, R.; Zanoni, G. J. Am. Chem.
Soc. 1996, 118, 6297.
10.1021/ja016121w CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/10/2001

7472 J. Am. Chem. Soc., Vol. 123, No. 30, 2001
Scheme 1. Synthesis of Ligangs 8-11
Communications to the Editor
Table 2. Pa-catalyzed Allylic Amination with Ligand 9ca
entry substrate, R time h yield %b 12/13/14c B/Ld ee %e
1
2
3
4
5
6
7
2a, phenyl
7
8
8
6
3
8
4
94
87
86
89
76
85
78
95/3/2
94/6/-
87/13/- 85/15
94/6/-
86/9/5
90/9/1
94/6
96/4
98
97
94
95
97
98
84
2b, 1-naphthyl
2c, 4-Meo-Ph
2d, 4-Me-Ph
2e, 4-Cl-Ph
2g, 2-thienyl
2h, methyl
90/10
87/13
90/10
>97/3/- >97/3
Table 1. Pd-catalyzed Allylic Alkylation with Ligand 8da
a Proceeded at 0 °C in CH2Cl2 with molar ratio: [Pd(η3-C3H5)Cl]2/
9c/substrate/BnNH2 ) 2/4/100/300. b Isolated yield. c Determined by
GC of the crude product after column chromatography. d Determined
1
by 300 MHz H NMR of the crude product after column chromatog-
raphy, B/L represents ratio of 12/(13+14 × 2). e Determined by chiral
HPLC.
between these two sets of ligands in two reactions could possibly
be rationalized by the following considerations. In the amination
reaction, a hydrogen bond between the free OH group in the ligand
and the amine might be formed. Thus, the attack of the nucleophile
may probably happen in an intramolecular mode. The X-ray
structures of these ligands showed two types of disposition of
the OH group. For 8 and 10, the OH group is directed outwardly
from the metal center. For 9 and 11, the OH group is directed
inwardly to the reaction center. For 8 and 10, the intramolecular
attack of a nucleophile may favor the formation of the linear
product, while branched products with different configuration will
be derived from 9 and 11, which is consistent with the
experimental results. To verify the above notion, the free OH
group of 8a and 9a was converted to the Me-ether, and the
corresponding methylated ligands (S,Sphos,R)-15 and (S,Rphos,R)-
16 were prepared from 7a and (R)-2-(2′-hydroxy-1,1′-binaphthyl)
methyl ether. We therefore expected that the regioselectivity by
using 15 would be higher than that of 8a, and regioselectivity by
using 16 would be lower than that of 9a, accordingly. The results
are almost the same as we expected. The regioselectivity by 15
is 50/43/7 for 2a, which is higher than for 8a (3/81/16) and that
by 16 is 63/31/6, which is lower than for 9a (89/8/3). The reaction
rate by 15 and 16 was much slower (72 and 48 h, respectively)
as a result of intermolecular reaction instead of the original
intramolecular ones. It is therefore clear that the hydroxyl group
in the ligands is crucial and important in the palladium-catalyzed
allylic amination reaction.
entry
substrate, R
T °C time h yield %b
5/4c
ee %d
1
2
3
4
5
6
7
8
9
1a, phenyl
1b, 1-naphthyl
1b, 1-naphthyl -43
1c, 4-Meo-Ph
1d, 4-Me-Ph
1e, 4-Cl-Ph
1f, 4-CN-Ph
1g, 2-thienyl
1h, methyl
0
0
2
1
7
2
9
1
1
1
2
98
95
97
97
91
97
96
95
83
95/5
>99/1
>99/1
93/7
98/2
94/6
90/10
80/20
>97/3
95
93
97
97
92
94
95
87
94
-20
0
0
0
0
0
a Molar ratio: [Pd(η3-C3H5)Cl]2/8d/KOAc/substrate/CH2(CO2Me)2/
BSA ) 2/4/3/100/300/300. CH2Cl2 and toluene were the solvents.
b Isolated yield. c Determined by 300 MHz 1H NMR of the crude
product after column chromatography. d Determined by chiral HPLC.
of 1h gave >97/3 regioselectivity in favor of 5 with 94% ee (entry
11, Table 1). For substrates 2a and 2b an excellent regioselectivity
but a slightly lower enantioselectivity were achieved (the data
were not showed).
The above ferrocene-based P,N-ligands were also applied
successfully to Pd-catalyzed allylic amination reactions, a more
challenging but very useful reaction to synthesize allylic amines.14
Benzylamine was chosen as the nucleophile. First, 1a or 2a was
used as the substrate, and the reaction was optimized by varying
the ligands, solvents, and temperature. It was surprising that all
the (S,Sphos,R)-8 and (S,Rphos,S)-10 ligands, which gave excellent
results in the alkylation reactions, provided the linear product with
high ratio. Fortunately, high regio- and enantioselectivity for 2
were given by utilizing (S,Rphos,R)-9 and (S,Sphos,S)-11 ligands;
products with opposite absolute configuration were obtained from
9 and 11. With (S,Rphos,R)-9c as ligand, 0 °C in CH2Cl2 was found
to be the best reaction condition, and wide ranges of substrates
were investigated (eq 2). The results are summarized in Table 2.
Substrates 2a-e gave excellent ee values and branched regio-
selectivity. It differed from the results of the allylic alkylation,
and high regio- and enantioselectivity were achieved in the
amination of 2g with a 2-thienyl group (12g/13g/14g: 90/9/1, ee
of 12g: 98%, entry 6, Table 2). High regio- and relatively lower
enantioselectivity for 2h with methyl as substituent were obtained
(entry 7, Table 2). However, only moderate regioselectivity was
achieved for substrate 1.
Highly regio- and enantioselective Pd-catalyzed allylic alky-
lation and amination of monosubstituted allylic acetates were
realized for a wide range of substrates for the first time. However,
the difference of regio- and enantioselectivity between two types
of substrates 1 and 2 in these two reactions is a problem that
remains to be solved.
Acknowledgment. Financially supported by the Major Basic Research
Development Program (G2000077506), the Natural Science Foundation
of China, Outstanding Youth Fund, the Chinese Academy of Sciences.
We thank Professor H. N. C. Wong for inspiring discussion. This paper
is dedicated to Professor Wei-Yuan Huang on the occasion of his 80th
birthday.
Supporting Information Available: Synthetic procedure and spectral
characterization for all ligands, X-ray crystallographic files (CIF) of
compound 8a, 8b, 9c, 8d, and 10, general procedure for allylic alkylation,
The favored ligands for these two reactions are entirely
different. Ligands 8 (S,Sphos,R) and 10 (S,Rphos,S) give better results
in alkylation reactions, while the ligands 9 (S,Rphos,R) and 11
(S,Sphos,S) are better in amination reactions. The contradiction
1
1H NMR and HPLC data for 5a-h, 12a-e, 12g-h; H NMR data for
13a-e, 13g, 14a-e, 14g (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
(14) Johannsen, M.; Jørgensen, K. A. Chem. ReV. 1998, 98, 1689.
JA016121W