[2.2]paracyclophane-derived chiral P,N-ligands: Design, synthesis, and application in palladium-catalyzed asymmetric allylic alkylation

Article abstract of DOI:10.1021/jo801373r

(Chemical Equation Presented) With the idea of tuning structural flexibility and rigidity, several [2.2]paracyclophane-derived P,N-ligands were designed and synthesized. A full investigation of the relationship between the ligands' structures and their ab

Full text of DOI:10.1021/jo801373r

on ferrocene derivatives.8 However, the full potential of
substituted [2.2]paracyclophanes for asymmetric synthesis has
only been realized since ca. the 1990s.9,10 These compounds
are not only highly rigid, but also stable during exposure to
high temperatures (up to 200 °C), light, acids, and bases.9,11
PhanePHOS achieved higher activity and enantioselectivity than
BINAP in the preparation of the HIV protease inhibitor
Crixivan.12 N,O-ligands derived from FHPC, AHPC, and BHPC
have also been successfully applied to the addition of organozinc
reagents to aldehydes and imines.13 Compared to these suc-
cessful analogues, P,N-[2.2]paracyclophane ligands are still at
an early stage. Pseudo-gem-phosphinyl-oxazolinyl[2.2]para-
cyclophane14 was the first to be reported, and the pseudo-ortho-
and ortho-counterparts15 were subsequently prepared. All of
these ligands were employed in the Pd-catalyzed allylic
substitution of 1,3-diphenyl-2-propenyl acetate with dimethyl
malonate and exhibited widely differing activities and enanti-
oselectivities, among which the pseudo-ortho-ligand gave the
best result.
[2.2]Paracyclophane-Derived Chiral P,N-Ligands:
Design, Synthesis, and Application in
Palladium-Catalyzed Asymmetric Allylic
Alkylation
Biao Jiang,* Yang Lei, and Xiao-Long Zhao
Laboratory of Modern Synthetic Organic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy
of Sciences, Shanghai 200032, People’s Republic of China
jiangb@mail.sioc.ac.cn
ReceiVed June 30, 2008
We reasoned that if the structural rigidity and flexibility could
be further regulated,16 the performance of the ligands might be
improved. Thus P,N-[2.2]paracyclophane ligands 1-6, which
use the pyridine or quinoline nitrogen as a donor atom, were
(4) (a) Matt, P. v.; Pfaltz, A. Angew. Chem., Int. Ed. 1993, 32, 566–568. (b)
Matt, P. v.; Loiseleur, O.; Koch, G.; Pfaltz, A.; Lefeber, C.; Feucht, T.; Helmchen,
G. Tetrahedron: Asymmetry 1994, 5, 573–584. (c) Matt, P. V.; Lloyd-Jones,
G. C.; Minidis, A. B. E.; Pfaltz, A.; Macko, L.; Neuburger, M.; Zehnder, M.;
Ru¨egger, H.; Pregosin, P. S. HelV. Chim. Acta 1995, 78, 265–284. (d) Sprinz,
J.; Helmchen, G. Tetrahedron Lett. 1993, 34, 1769–1772. (e) Sprinz, J.; Kiefer,
M.; Helmchen, G.; Reggelin, M.; Huttner, G.; Walter, O.; Zsolnai, L. Tetrahedron
Lett. 1994, 35, 1523–1526.
(5) For examples, see: (a) Mino, T.; Saito, A.; Tanaka, Y.; Hasegawa, S.;
Sato, Y.; Sakamoto, M.; Fujita, T. J. Org. Chem. 2005, 70, 1937–1940. (b) Mino,
T.; Sato, Y.; Saito, A.; Tanaka, Y.; Saotome, H.; Sakamoto, M.; Fujita, T. J.
Org. Chem. 2005, 70, 7979–7984. (c) Jiang, B.; Huang, Z.-G.; Cheng, K.-J.
Tetrahedron: Asymmetry 2006, 17, 942–951.
With the idea of tuning structural flexibility and rigidity,
several [2.2]paracyclophane-derived P,N-ligands were de-
signed and synthesized. A full investigation of the relation-
ship between the ligands’ structures and their abilities to
induce asymmetry in palladium-catalyzed asymmetric allylic
alkylations of malonates with 1,3-diphenyl 2-propenyl acetate
was carried out, and high yields and enantioselectivities (i.e.,
99% yield, 97% ee) were observed while using ligands
bearing matched planar and central chirality.
(6) For examples, see: (a) Bourghida, M.; Widhalm, M. Tetrahedron:
Asymmetry 1998, 9, 1073–1083. (b) Imai, Y.; Zhang, W.; Kida, T.; Nakatsuji,
Y.; Ikeda, I. Tetrahedron Lett. 1998, 39, 4343–4346. (c) Stranne, R.; Vasse,
J. L.; Moberg, C. Org. Lett. 2001, 3, 2525–2528.
(7) Doucet, H.; Brown, J. M. Tetrahedron: Asymmetry 1997, 8, 3775–3784.
(8) For reviews, see: (a) Togni, A. In Metallocenes; Togni, A., Halterman,
R. L., Eds.; Wiley: New York, 1998; pp 685-721. (b) Atkinson, R. C. J.; Gibson,
V. C.; Long, N. J. Chem. Soc. ReV. 2004, 33, 313–328. (c) Colacot, T. J. Chem.
ReV. 2003, 103, 3101–3118.
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2003, 1, 1256–1269. (b) Rozenberg, V.; Sergeeva, E.; Hopf, H. In Modern
Cyclophane Chemistry; Gleiter, R., Hopf, H., Eds.; Wiley-VCH: Weinheim,
Germany, 2004; pp 435-462.
(10) Examples of chiral [2.2]paracyclophane structrues: (a) Rowlands, G. J.
Org. Biomol. Chem. 2008, 6, 1527-1534. (b) Vorontsova, N. V.; Rozenberg,
V. I.; Sergeeva, E. V.; Vorontsov, E. V.; Starikova, Z. A.; Lyssenko, K. A.;
Hopf, H. Chem. Eur. J. 2008, 14, 4600–4617.
(11) Reich, H. J.; Cram, D. J. J. Am. Chem. Soc. 1969, 91, 3505–3516.
(12) Pye, P. J.; Rossen, K.; Reamer, R. A.; Tsou, N. N.; Volante, R. P.;
Reider, P. J. J. Am. Chem. Soc. 1997, 119, 6207–6208.
Palladium-catalyzed asymmetric allylic alkylation has proven
to be a powerful tool for stereoselective C-C bond-formation.1
Among many chiral ligands designed for this reaction, chiral
P,N-ligands have played an important role owing to their steric
and electronic asymmetry.2,3
Extensive research has been conducted on centrally and
axially chiral P,N-ligands, of which representative examples are
the PHOX ligands,2,4 prolinol derived ligands,5 binaphthyl-based
ligands,6 and the QUINAP-type ligand.7 Most investigations
dealing with ligands possessing planar chirality have focused
(1) For reviews, see: (a) Pfaltz, A.; Lautens, M. In ComprehensiVe Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag:
Berlin, Germany, 1999; Vol. 2. (b) Trost, B. M.; Lee, C. In Catalytic Asymmetric
Synthesis; Ojima, I., Ed.; Wiley-VCH: New York, 2000; pp 593-649. (c)
Nishibayashi, Y.; Uemura, S. In ComprehensiVe Organometallic Chemistry;
Mingos, D. M. P., Crabtree, R. H., Eds.; Elsevier Science: Amsterdam, The
Netherlands, 2003; Vol. 11, pp 75-122. (d) Tsuji, J. In Palladium Reagents
and Catalysts; Wiley: Chichester, UK, 2004. (e) Zhan Lu, S. M. Angew. Chem.,
Int. Ed. 2008, 47, 258–297.
(2) Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33, 336–345.
(3) (a) Guiry, P. J.; Saunders, C. P. AdV. Synth. Catal. 2004, 346, 497–537.
(b) Pfaltz, A.; Drury, W. J., III. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5723–
5726. (c) Togni, A.; Burckhardt, U.; Gramlich, V.; Pregosin, P. S.; Salzmann,
R. J. Am. Chem. Soc. 1996, 118, 1031–1037.
(13) (a) Dahmen, S. Org. Lett. 2004, 6, 2113–2116. (b) Dahmen, S.; Bra¨se,
S. Tetrahedron: Asymmetry 2001, 12, 2845–2850. (c) Dahmen, S.; Bra¨se, S.
Org. Lett. 2001, 3, 4119–4122. (d) Dahmen, S.; Bra¨se, S. Chem. Commun. 2002,
26–27. (e) Dahmen, S.; Bra¨se, S. J. Am. Chem. Soc. 2002, 124, 5940–5941. (f)
Danilova, T. I.; Rozenberg, V. I.; Sergeeva, E. V.; Starikova, Z. A.; Bra¨se, S.
Tetrahedron: Asymmetry 2003, 14, 2013–2019. (g) Danilova, T. I.; Rozenberg,
V. I.; Starikova, Z. A.; Bra¨se, S. Tetrahedron: Asymmetry 2004, 15, 223–229.
(h) Hermanns, N.; Dahmen, S.; Bolm, C.; Bra¨se, S. Angew. Chem., Int. Ed.
2002, 41, 3692–3694. (i) Rozenberg, V. I.; Danilova, T. I.; Sergeeva, E. V.;
Shouklov, I. A.; Starikova, Z. A.; Hopf, H.; Ku¨hlein, K. Eur. J. Org. Chem.
2003, 432–440.
(14) Wu, X.-W.; Yuan, K.; Sun, W.; Zhang, M.-J.; Hou, X.-L. Tetrahedron:
Asymmetry 2003, 14, 107–112.
(15) Whelligan, D. K.; Bolm, C. J. Org. Chem. 2006, 71, 4609–4618.
10.1021/jo801373r CCC: $40.75
Published on Web 08/23/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 7833–7836 7833

SCHEME 3. Synthesis of Silylated Phosphino-Pyridine
Ligands
FIGURE 1. Designed [2.2]paracyclophane P,N-chiral ligands.
SCHEME 1. Synthesis of Phosphino-Pyridine Ligands
SCHEME 4. Synthesis of Silylated Phosphino-Quinoline
Ligands
Modifying (Rp,R)-1 and (Rp,S)-1 by silylation with use of
TBSOTf/lutidine smoothly generated (Rp,R)-2 in 95% yield and
(Rp,S)-2 in 97% yield (Scheme 3).19
SCHEME 2. Synthesis of Phosphino-Quinoline Ligands
Silylation of the quinoline ligands also provided the corre-
sponding compounds. However, only (Sp,S)-6 was isolated
because (Sp,R)-6 was unstable (Scheme 4).
Direct alkylation of the hydroxyl group of 1 with MeI was
not successful due to ylide formation at phosphorus. Thus, the
diphenylphosphine group was first protected with sulfur in
dicholoromethane, producing (Rp,R)-8 and (Rp,S)-8 in high yield.
After respective alkylation with MeI/NaH followed by
desulfurization with Raney-Ni of (Rp,R)-8 and (Rp,S)-8, the
alkylated P,N-ligands (Rp,R)-3 and (Rp,S)-3 were obtained.
(Scheme 5).17,20
With these chiral P,N-ligands in hand, we set out to study
their application in the Pd-catalyzed asymmetric allylic substitu-
tion of 1,3-diphenyl-2-propenyl acetate 10 with dimethyl
malonate 11 in the presence of BSA/LiOAc.21 (Rp,R)-1 and
(Rp,S)-1 were first employed to explore the reaction conditions
and the influence of the planar and central chirality (Table 1,
entries 1-8). While the yields are comparable, reactions run in
CH2Cl2 gave higher enantioselectivities than those in THF.
Temperature was not influential since lower temperatures did
not provide improved selectivity. A key issue was the configu-
rations of the product 12, which reversed when the central
chirality of the ligand was changed. This reminded us of a
matched-mismatched effect. Thus, planar chiral ligand (Rp)-4
was used to determine the role played by the planar chirality
(Table 1, entry 9). (R)-12 with an 86% ee was produced in 55%
yield, which showed us that planar chirality could not induce
good results alone. The central chiral carbon residing in the
ligands was a critical component.
designed (Figure 1).17 We conjectured that if the pyridine or
quinoline ring was attached to the benzylic carbon, which was
also a chiral carbon, these structures with adjusted side chains
might meet the requirements. Herein, we report the synthesis
of ligands 1-6. Matched-mismatched effects were observed
when applying them in Pd-catalyzed asymmetric allylic alky-
lkation reactions.
The synthesis started from enantiopure monophosphino [2.2]-
paracyclophane 7.18 Thus, the treatment of (Rp)-7 with n-BuLi
followed by the addition of 2-pyridinecarboxaldehyde led to
two diastereoisomers, (Rp,R)-1 (68%) and (Rp,S)-1 (32%), which
could be readily separated by chromatography (Scheme 1). The
relative stereochemistry of (Rp,R)-1 was confirmed by X-ray
analysis. Pd/C-catalyzed dehydroxylation of (Rp,R)-1 produced
(Rp)-4, a structure possessing only planar chirality in 42% yield
(Scheme 1).
Beginning with (Sp)-7, quenching with 2-quinoline carbox-
aldehyde after treatment with n-BuLi yielded two structurally
similar ligands, (Sp,S)-5 (54%) and (Sp,R)-5 (19%), which were
also separable by chromatography (Scheme 2).
To obtain more evidence about the mechanism, the other
ligands were investigated. The reaction carried out with (Rp,R)-2
(16) (a) Hou, X.-L.; Wu, X.-W.; Dai, L.-X.; Cao, B.-X.; Sun, J. Chem.
Commun. 2000, 1195–1196. (b) Wu, X.-W.; Zhang, T.-Z.; Yuan, K.; Hou, X.-
L. Tetrahedron: Asymmetry 2004, 15, 2357–2365.
(17) Ferrocene based ligands with similar structure: Cheemala, M. N.;
Knochel, P. Org. Lett. 2007, 9, 3089–3092.
(18) Focken, T.; Raabe, G.; Bolm, C. Tetrahedron: Asymmetry 2004, 15,
1693–1706.
(19) Askin, D.; Angst, C.; Danishefsky, S. J. Org. Chem. 1987, 52, 622–
635.
(20) Zhang, W.; Xu, Q.; Shi, M. Tetrahedron: Asymmetry 2004, 15, 3161–
3169.
(21) (a) Leutenegger, U.; Umbricht, G.; Fahrni, C.; von.Matt, P.; Pfaltz, A.
Tetrahedron 1992, 48, 2143–2156. (b) Gihani, E. T. M.; Heaney, H. Synthesis
1998, 35, 7–375.
7834 J. Org. Chem. Vol. 73, No. 19, 2008

SCHEME 5. Synthesis of Alkylated Phosphino-Pyridine Ligands
TABLE 1. Results of the Pd-Catalyzed Asymmetric Allylic
Alkylation with [2.2]Paracyclophane-Derived Chiral P,N-Ligands
entry ligands solvent temp
time yield (%) conf.b ee (%)c
1
2
3
4
5
6
7
8
9
(Rp,R)-1 THF
(Rp,R)-1 THF
(Rp,S)-1 THF
(Rp,S)-1 THF
rt
-10°C 16 h
rt 3.5 h
-10°C 8 h
8 h
(Rp,R)-1 CH2Cl2 -10°C 8 h
(Rp,S)-1 CH2Cl2 rt 8 h
3.5 h
97
98
99
99
98
96
99
81
55
99
79
84
99
98
99
67
S
S
R
R
S
80
86
89
75
94
94
88
87
86
97
96
99
71
96
22
98
(Rp,R)-1 CH2Cl2 rt
S
R
R
R
S
R
S
R
R
S
(Rp,S)-1 CH2Cl2 -10°C 48 h
(Rp)-4
CH2Cl2 rt
48 h
5 min
48 h
10 (Rp,R)-2 CH2Cl2 rt
11 (Rp,S)-2 CH2Cl2 rt
12 (Rp,R)-3 CH2Cl2 rt
13 (Rp,S)-3 CH2Cl2 rt
14 (Sp,S)-5 CH2Cl2 rt
15 (Sp,R)-5 CH2Cl2 rt
16 (Sp,S)-6 CH2Cl2 rt
FIGURE 2. Proposed reaction intermediates of the Pd-catalyzed allylic
alkylation with ligands (Rp,R)-1 and (Rp,S)-1.
72 h
20 min
30 min
30 min
24 h
chelation, the pyridine ring rotates to the inner site of the
[2.2]paracyclophane to coordinate with palladium, while the
hydroxyl group should be away from the [2.2]paracyclophane
due to steric considerations. Thus, (Rp,R)-1-A and (Rp,S)-1-A
are more favored intermediates than (Rp,R)-1-B and (Rp,S)-1-
B, and (S)-12 and (R)-12 are generated from them, respectively.
In summary, a series of phosphine-pyridine ligands derived
from [2.2]paracyclophane were found to be good candidates
for asymmetric catalysis. They can easily be prepared from a
known enantiopure intermediate. Our pilot study disclosed the
high stereoselectivity achieved with these ligands in Pd-
catalyzed asymmetric allylic alkylation reactions. The structural
flexibility brought by the long side chain and the rigidity
originating from the rigid paracyclophane skeleton cooperate
to provide a fixed chiral environment, which is supported by
analysis of the intermediate π-allyl complexes. Further studies
to explore the scope of these ligands in more asymmetric
catalytic reactions are currently in progress.
R
a [Pd(η3-C3H5)Cl]2/ligand/LiOAc/BSA/10/11 ) 2/6/3/300/100/300.
b Determined by comparison of the retention time of products with that
reported by references. c Determined by chiral HPLC, ChiralPAK AD-H,
0.8 mL/min, hexane/iPrOH ) 80/20.
was very rapid, proceeding to completion within 5 min in high
yield (99% yield) and enantioselectivity (97% ee, Table 1, entry
10). In contrast, the reaction with (Rp,S)-2 as ligand was much
slower, although the ee was still high (Table 1, entry 11). Using
(Rp,R)-3 gave 84% yield and 99% ee after 72 h (Table 1, entry
12). When using (Rp,S)-3, it took 20 min to furnish a 99% yield
and 71% ee (Table 1, entry 13). Quinoline ligands (Sp,S)-5 and
(Sp,R)-5 afforded comparable yields (98% and 99%) in short
times (Table 1, entry 14 and 15), but the ee values were
dramatically different (96% ee and 22% ee). The asymmetric
induction of (Sp,R)-5 was obviously much lower than that of
its diastereoisomer (Sp,S)-5. Finally, (Sp,S)-6 was tested, and
the reaction was slow compared the reaction with unsilylated
(Sp,S)-5, with only 67% yield achieved after 24 h, but the ee
value was still satisfactory (98% ee).
Product configuration and enantioselectivities of all of these
reactions proved that both the planar chiral [2.2]paracyclophane
unit and the stereogenic center strongly influence the enanti-
oselectivities. Our attention was therefore drawn to the reaction
pathway. Two M-type π-allyl complexes1a were proposed to
be responsible for the different product configurations induced
by (Rp,R)-1 and (Rp,S)-1 (Figure 2). This model also suits other
ligands. Since the W-type complexes (Rp,R)-1-C and (Rp,S)-
1-C were assumed to have greater steric interference between
the two phenyl groups, M-type would be prefered. During
Experimental Section
Typical Procedure for the Asymmetric Allylic Alkylation.
Allyl palladium chloride dimer (2.3 mg, 7.0 µmol), ligand (21
µmol), and LiOAc (2 mg) were dissolved in solvent (2 mL), and
the solution was stirred at rt for 15 min before 1,3-diphenyl
2-propenyl acetate (88.3 mg, 0.35 mmol) was introduced. The
mixture was stirred at rt for another 15 min and changed to the
desired temperature before dimethyl malonate (139 mg, 1.05 mmol)
and BSA (0.26 mL, 1.05 mmol) were added. The reaction was
monitored by TLC. The mixture was quenched by the addition of
cold saturated aqueous NH4Cl (2 mL) and extracted with EtOAc.
The organic phase was dried over Na2SO4. After filtration and
concentration, the residue was purified by flash chromatography
J. Org. Chem. Vol. 73, No. 19, 2008 7835

on silica gel (petroleum ether/EtOAc ) 20/1) to give the product.
1H NMR (CDCl3, 300 MHz) δ 7.40-7.16 (m, 10H), 6.50 (d, J )
15.8 Hz, 1H), 6.35 (dd, J ) 15.8, 8.5 Hz, 1H), 4.29 (dd, J ) 10.8,
8.5 Hz, 1H), 3.98 (d, J ) 10.8 Hz, 1H), 3.72 (s, 3H), 3.53 (s, 3H).
The ee was determined by chiral HPLC with a ChiralPAK AD-H
column, with hexane/i-PrOH (80/20) as the mobile phase and a
flow rate of 0.8 mL/min (tR ) 12.6 min, tS ) 16.7 min).
20390053), and the Knowledge Innovation Program of the
Chinese Academy of Sciences and Shanghai Byelen Chemicals
Co., Ltd. for their financial support.
Supporting Information Available: General experimental
procedures, compound characterization data, the X-ray structure
1
of (Rp,R)-1 (CIF file) and copies of H NMR and 13C NMR
spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
Acknowledgment. We gratefully acknowledge the Shanghai
MunicipalCommitteeofScienceandTechnology(No.05DZ19344),
the National Natural Science Foundation of China (No.
JO801373R
7836 J. Org. Chem. Vol. 73, No. 19, 2008