Highly regio- and enantioselective palladium-catalyzed allylic alkylation and amination of dienyl esters with 1,1′-P,N-ferrocene ligands

Article abstract of DOI:10.1021/ol051882f

(Chemical Equation Presented) Pd-catalyzed asymmetric allylic alkylation of dienyl acetates 1 and amination of allyl acetates 2 provides the corresponding chiral products in high regio- and enantioselectivities using 1,1′-P,N-ferrocenes L1a and L2d as ligands, respectively.

Full text of DOI:10.1021/ol051882f

ORGANIC
LETTERS
2005
Vol. 7, No. 23
5151-5154
Highly Regio- and Enantioselective
Palladium-Catalyzed Allylic Alkylation
and Amination of Dienyl Esters with
1,1′-P,N-Ferrocene Ligands
Wen-Hua Zheng,† Na Sun,‡ and Xue-Long Hou*,†,‡
State Key Laboratory of Organometallic Chemistry and Shanghai-Hong Kong Joint
Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
xlhou@mail.sioc.ac.cn
Received August 5, 2005
ABSTRACT
Pd-catalyzed asymmetric allylic alkylation of dienyl acetates 1 and amination of allyl acetates 2 provides the corresponding chiral products
in high regio- and enantioselectivities using 1,1 -P,N-ferrocenes L1a and L2d as ligands, respectively.
′
The past decades have witnessed great success in Pd-
catalyzed asymmetric allylic substitution reactions using a
variety of substrates and reagents to form diversified types
of bonds with excellent enantioselectivity. Today, this
reaction is one of the most important carbon-carbon bond-
forming processes in asymmetric catalysis and a powerful
tool in organic synthesis.1 Although significant progress has
been made recent years in obtaining good regio- and
enantioselectivity of Pd-catalyzed allylic substitution reac-
tions of monosubstituted allyl substrates,2,3 reaction of
polyenyl esters, a special variant of monosubstituted allylic
esters, mainly provided linear products.4 Many efforts have
been made to address the issue of regioselectivity as well as
enantioselectivity of allylic substitution reactions of polyenyl
esters employing other metal complexes. The first example
was provided by Trost.5 When a chiral Mo complex was
used, high regio- and enantioselectivities were achieved; the
ratio of branched and linear products 4 and 5 was (6-49):1
with 86-99% ee for 4 (eq 1).5 Takeuchi realized perfect
† State Key Laboratory of Organometallic Chemistry.
‡ Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis.
(1) For some reviews: (a) Trost, B. M.; van Vranken, D. L. Chem. ReV.
1996, 96, 395. (b) Pfaltz, A.; Lautens, M. In ComprehensiVe Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-
Verlag: Berlin, 1999; Vol. 2, Chapter 24. (c) Trost, B. M.; Crawley, M. L.
Chem. ReV. 2003, 103, 2921.
regioselectivity in the same reaction using [Ir(COD)Cl]2 and
P(OPh)3 as catalyst; in most cases, the reaction afforded
branched product 4 only.6 Recently, Helmchen reported an
10.1021/ol051882f CCC: $30.25
© 2005 American Chemical Society
Published on Web 10/19/2005

asymmetric version of Ir-catalyzed alkylation and amination
reaction.7 Excellent regioselectivity in favor of branched
products 4 with 96% ee in the alkylation reaction and up to
99:1 for the ratio of 4 and 5 with 97% ee for 4 in the
amination reaction was obtained. To the best of our
knowledge, there is no report on the asymmetric allylic
alkylation and amination reactions of polyenyl esters using
chiral Pd complex as catalyst.
Table 1. Pd-Catalyzed Regio- and Enantioselective Allylic
Substitution Reaction of 1a with Various Ligands L1 and L2a
yield (%) of
time (h) 4+5 or 7+8c
4a/5a or
7a/8ad
entry Sb
Lb
ee (%)e
1
2
3
4
5
6
7
8
9
1a L1a
1a L1b
1a L1c
1a L1d
2a L1a
3a L1a
1a L2a
2a L2d
2a L2a
2a L1b
1a L2d
0.5
72
72
10
80
77
41
92
81
77
87
85
88
83
NRf
98/2
96/4
94/6
98/2
96/4
95/5
60/40
>98/2
73/27
0/100
4a: 92
4a: 79
4a: 37
4a: 89
4a: 60
4a: 92
4a: 16
7a: 90
7a: 90
7a: -
7a: -
Recently, we developed several ferrocene-based chiral
ligands and used them successfully in asymmetric catalysis.3,8
High regio- and enantioselectivity were realized in Pd-
catalyzed allylic alkylation and amination reactions of
monosubstituted allyl substrates when 1,1′-P.N-ligands were
used.3 Further studies showed that they are also good ligands
in Pd-catalyzed allylic substitution reactions of polyenyl
esters. Herein, we report our preliminary results for these
Pd-catalyzed highly regio- and enantioselective allylic alkyla-
tion and amination reactions using polyenyl esters as
substrates.
0.5
0.5
0.5
3
3
3
10
11
36
a Molar ratio of [Pd(η3-C3H5)Cl]2/ligand/KOAc/substrate/NuH/BSA )
2/4/6/100/300/300. b S ) substrate, L ) ligand. c Isolated yield base on
1
substrate. d Determined by 300 MHz H NMR of the crude product after
preparative TLC. e Determined by chiral HPLC. f No reaction.
Initially, the reaction of pentadienyl acetate 1a with
dimethyl malonate was carried out using [Pd(η3-C3H5)Cl]2
and (S, Sphos, R)-ligands L13a,9,10 as catalyst because our
previous work demonstrated that 1,1′-P,N-ferrocene ligands
with such a combination of three chiral elements gave better
regio- and enantioselectivity in the allylic alkylation of
monosubstituted substrates (Scheme 1).3 The branched allyl
All reactions with substrates 1a-3a afforded branched and
linear products 4a and 5a with high regioselectivity in favor
of branched 4a (entries 1-7, Table 1). As a result of the
(3) (a) You, S. L.; Zhu, X. Z.; Luo, Y. M.; Hou, X. L.; Dai, L. X. J. Am.
Chem. Soc. 2001, 123, 7471. (b) Hou, X. L.; Na, S. Org. Lett. 2004, 6,
4399 (Corrections: Org. Lett. 2005, 7, 1435).
(4) Trost, B. M.; Bunt, R. C.J. Am. Chem. Soc. 1998, 120, 70.
(5) Trost, B. M.; Hildbrand, S.; Dogra, K. J. Am. Chem. Soc. 1999, 121,
10416.
(6) Takeuchi, R.; Tanabe, K. Angew. Chem., Int. Ed. 2000, 39, 1975.
(7) (a) Lipowsky, G.; Helmchen, G. Chem. Commun. 2004, 116. (b)
Lipowski, G.; Miller, N.; Helmchen, G. Angew. Chem., Int. Ed. 2004, 43,
4595.
Scheme 1
(8) (a) Dai, L. X.; Tu, T.; You, S. L.; Deng, W. P.; Hou, X. L. Acc.
Chem. Res. 2003, 36, 659. (b) Deng, W. P.; Hou, X. L.; Dai, L. X.; Dong,
X. W. Chem. Commun. 2000, 1483. (c) You, S. L.; Hou, X. L.; Dai, L. X.;
Cao, B. X.; Sun, J. Chem. Commun. 2000, 1933. (d) You, S.-L.; Hou, X.-
L.; Dai, L.-X.; Zhu, X.-Z. Org. Lett. 2001, 3, 149. (e) Tu, T.; Deng, W. P.;
Hou, X. L.; Dai, L. X.; Dong, X. C. Chem. Eur. J. 2003, 9, 3073. (f) Tu,
T.; Hou, X. L.; Dai, L. X. Org. Lett. 2003, 5, 3651.
(9) Procedures for the synthesis of ligand L1a and L2a.10 (a) Synthesis
of 1-Diethylaminophosphino-1′[(S)-4-benzyl-2,5-oxazolinyl]ferrocene.
1-Bromo-1′-[(S)-4-benzyl-2,5-oxazolinyl]ferrocene (2.54 g, 6 mmol)11 was
dissolved in freshly distilled THF (40 mL) under argon and cooled to -78
°C. At this tempreture, n-BuLi (4.2 mL, 6.6 mmol, 1.6 M in n-hexane) was
added, and the resulting deep red solution was stirred for 20 min. Then,
chlorodiethylaminophosphine (1.7 mL, 8 mmol) was added, and the resulting
mixture was continually stirred and warmed to room temperature over 30
min. The reaction mixture was diluted with ether (20 mL), washed with
distilled water and brine, and dried over Na2SO4. The solvent was removed
under reduced pressure, and the resulting residue was purified by flash
chromatography on silica gel with ethyl acetate/petroleum/Et3N (1:10:1)
as eluent to give 2.02 g of 1-diethylaminophosphino-1′-[(S)-4-benzyl-2,5-
oxazolinyl]ferrocene (65%) as a deep red oil: [R]20 ) +2.9 (c 0.85,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.04 (t, J ) D7.0 Hz, 12H), 2.68
(dd, J ) 9.2, 13.8 Hz, 1H), 2.96-3.11 (m, 8H), 3.23 (dd, J ) 4.6, 13.7 Hz,
1H), 4.04 (dd, J ) 7.5, 8.0 Hz, 1H), 4.21-4.25 (m, 5H), 4.34 (m, 2H),
4.38-4.45 (m, 1H), 4.73 (m, 2H), 7.22-7.33 (m, 5H); 31P NMR (161.92
MHz, CDCl3) δ 89.32; MS (EI) m/z (rel) 519 (M+, 12), 447 (100), 374
(43), 313 (28), 242 (28), 91 (10); IR (KBr) 2966 (m), 2930 (w), 1653 (s),
1481 (m), 1375 (m), 1187 (m), 1022 (s). Anal. Calcd for C28H38N3OPFe:
C, 64.74; H, 7.37; N, 8.09. Found: C, 65.18; H, 7.44; N, 8.43. (b) Synthesis
of (S)-1-Diethylamino[(R)-binaphthol]phosphite-1′-[(S)-4-benzyl-2,5-ox-
azolinyl]ferrocene L1a and (R)-1-Diethylamino[(R)-binaphthol]phos-
phite-1′-[(S)-4-benzyl-2,5-oxazolinyl]ferrocene L2a. 1-Diethylaminophos-
phino-1′-[(S)-4-benzyl-2,5-oxazolinyl]ferrocene (519 mg, 1 mmol) and (R)-
binaphthol (286 mg, 1 mmol) were dissolved in freshly distilled THF (40
mL) under argon. The reaction was completed after being refluxed for 12
h. The reaction mixture was condensed in vacuo, and the crude product
was purified by flash chromatography on silica gel with ethyl acetate/
petroleum/Et3N (1:10:1) as an eluent to give (S, Rphos, R)-L2a (329
substrate 2a and pentadienyl carbonate 3a were also inves-
tigated. The results are given in Table 1.
(2) (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. (c) Pre´toˆt, R.; Pfaltz, A. Angew. Chem., Int. Ed. 1998, 37, 323.
(d) Hilgraf, R.; Pfaltz, A. Synlett 1999, 1814. (e) Hilgraf, R.; Pfaltz, A.
AdV. Synth. Catal. 2005, 347, 61. (f) Trost, B M.; Jiang, C. J. Am. Chem.
Soc. 2001, 123, 12907. (g) Faller, J. W.; Wilt, J. C.; Parr, J. Org. Lett.
2004, 6, 1301. (h) Pa`mies, O.; Die´guez, M.; Claver, C. J. Am. Chem. Soc.
2005, 127, 3646. (i) Miyabe, H.; Takemoto, Y. Synlett 2005, 1641.
5152
Org. Lett., Vol. 7, No. 23, 2005

Table 2. Pd-Catalyzed Allylic Substitution Reactions of 1 and 2a
a Molar ratio of [Pd(η3-C3H5)Cl]2/ligand/KOAc/substrate/NuH/BSA ) 2/4/6/100/300/300. b Isolated yield based on substrate. c Determined by 300 MHz
1H NMR of the crude product after preparative TLC. d Determined by chiral HPLC. e L1a was used. f L2d was used.
reactions of monosubstituted allyl substrates,3a linear acetate
1a and carbonate 3a gave better regio- and enantioselectivi-
ties (entries 1 and 6, Table 1), while branched acetate 2a
afforded the product with only 60% ee although the regio-
selectivity remains good (entry 5, Table 1). Ligand (S,
Rphos, R)-L2a3a was also tested. It can be seen from Table 1
that both regio- and enantioselectivity of the reactions using
ligands (S, Sphos, R)-L1a-d are better than that using ligand
(S, Rphos, R)-L2a (entries 1-4 vs entry 7, Table 1). Among
the ligands tested, ligand L1a with benzyl as the substituent
on the oxazoline ring provided better results for both the
regio- and enantioselectivity (entries 1, Table 1). It should
be pointed out that the reaction using L1a proceeded faster
than that using ligands L1b-d (entry 1 vs entries 2-4). The
study of the effect of additives showed that the reaction using
LiCl7 and Bu4NF as additive gave almost the same regio-
selectivity but lower enantioselctivity (4a/5a ) 96:4, 88%
ee for 4a using LiCl as additive, 4a/5a ) 94:6, 68% ee for
4a using TBAF).
mg, 45% yield) and (S, Sphos, R)-L1a (263 mg, 36% yield) by turn. (S,
S
phos, R)-L1a as an orange solid: mp 154-155 °C; [R]20D ) -357 (c, 0.33,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 0.76 (t, J ) 7.0 Hz, 6H), 2.67 (dd,
J ) 9.1, 13.7 Hz, 1H), 2.86 (m, 4H), 3.18 (dd, J ) 4.7, 13.7 Hz, 1H), 3.39
(m, 1H), 3.73 (m, 1H), 3.88 (m, 1H), 3.94 (m, 1H), 4.01 (t, J ) 7.8 Hz,
1H), 4.05-4.13 (m, 2H), 4.18 (t, J ) 8.6 Hz, 1H), 4.34-4.42 (m, 2H),
4.52 (m, 1H), 5.24 (br, 1H), 7.21-7.39 (m, 12H), 7.82-8.05 (m, 5H); 31
P
NMR (161.92 MHz, CDCl3) δ 127.86; MS (EI) m/z (rel) 732 (M+, 2), 659
(42), 541 (100), 447 (20), 315 (27), 286 (74); IR (KBr) 3055 (w), 2966
(w), 1641 (s), 1588 (m), 1504 (m), 1458 (m), 1226 (s), 1023 (s). Anal.
Calcd for C44H41N2O3PFe: C, 72.13; H, 5.64; N, 3.82. Found: C, 71.73;
H, 5.94; N, 3.69. (S, Rphos, R)-L2a as an orange solid: mp 68-70 °C; [R]20
D
The amination reaction of pentadienyl acetate 1a and
branched allyl acetate 2a with benzylamine was also carried
out. As in the amination reaction of monosubstituted allyl
substrates,3a better regio- and enantioselectivities were
1
) 403 (c, 0.57, CHCl3); H NMR (400 MHz, CDCl3) δ 0.53 (t, J ) 7.0
Hz, 6H), 2.41-2.62 (m, 4H), 2.67 (dd, J ) 8.9, 13.8 Hz, 1H), 3.17 (dd, J
) 5.0, 13.7 Hz, 1H), 3.74 (m, 1H), 3.92 (m, 1H), 4.07 (dd, J ) 7.2, 8.1
Hz, 1H), 4.29-4.33 (m, 3H), 4.41 (m, 1H), 4.57 (t, J ) 1.2 Hz, 1H), 4.59-
4.64 (m, 1H), 5.09 (t, J ) 1.2 Hz, 1H), 7.11-7.41 (m, 12H), 7.79-8.03
(m, 5H), 9.25 (br, 1H); 31P NMR (161.92 MHz, CDCl3) δ 119.50; MS (EI)
m/z (rel) 732 (M+, 1), 659 (9), 541 (19), 447 (11), 315 (5), 286 (100); IR
(KBr) 3055 (w), 2967 (w), 1639 (s), 1589 (m), 1504 (m), 1461 (m), 1232
(s), 1023 (s). Anal. Calcd for C44H41N2O3PFe: C, 72.13; H, 5.64; N, 3.82.
Found: C, 72.00; H, 5.66; N, 3.85.
(10) For the synthesis of other ligands, see the Supporting Information
of ref 3a.
(11) Chesney, A.; Bryce, M. R.; Chubb, R. W. J.; Batsanov, A. S.;
Howard, J. A. K. Synthesis 1998, 413.
Org. Lett., Vol. 7, No. 23, 2005
5153

provided when branched allyl acetate 2a was used as
substrate (entry 8 vs entry 11, Table 1). Among the ligands
tested, ligand (S, Rphos, R) L2d3a is best (entry 8 vs entries 9
and 10, Table 1), while L2a was better than L1b (entry 9 vs
entry 10, Table 1).
On the basis of the above results, alkylation reactions using
(S, Sphos, R) L1a and amination reaction using (S, Rphos, R)
L2d with a wide range of substrates 1 and 2 were carried
out (Scheme 2, Table 2). All substrates, not only with
Table 2).3b The substituent on the distal double bond has no
effect on the regio- and enantioselectivities of the reactions
(entries 2, 3, and 9, Table 2). When the reaction of 1a
proceeded at 0 °C, the ee value of 4a increased from 92%
to 94%, and it increased further to 97% if the reaction was
run at -20 °C. However, the reaction of all other substrates
proceeded very slow at 0 °C.
In summary, high regio- and enantioselctivities were
realized in palladium-catalyzed allylic alkylation and ami-
nation reactions of dienyl acetate using 1,1′-P,N-ferrocene
derivatives as ligands. These results demonstrated the useful-
ness of the ligands in further control of regio- and enantio-
selectivities of allylic substitution reactions.3,8 Investigations
on that why the alkylation and amination need different
ligands and on the applications of these ligands in asymmetric
catalysis are in progress.
Scheme 2
Acknowledgment. This research was financially sup-
ported by the Major Basic Research Development Program
(Grant No. G 200077506), National Natural Science Founda-
tion of China, Chinese Academy of Sciences, and Shanghai
Committee of Science and Technology. N.S. gratefully
acknowledges the Hong Kong Croucher Foundation for a
Studentship.
aromatic substituents but also with alkyl substituents at the
terminal position gave branched products in high regio- and
enantioselectivities in both alkylation and amination reac-
tions. The regioselectivity is between 92/8 and >98/2 in favor
of branched products 4 and 7 with an ee value of 87-94%
for 4 and 7 (Table 2). The only except is substrate 1g, which
gave product 4g containing chiral quaternary carbon center
and 5g in the ratio of 92:8 with 56% ee for 4g (entry 7,
Supporting Information Available: General procedure
for allylic alkylation and amination and spectral data for
4a-g and 7a-d. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL051882F
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Org. Lett., Vol. 7, No. 23, 2005