Chiral phosphaalkene - Oxazoline ligands for the palladium-catalyzed asymmetric allylic alkylation

Article abstract of DOI:10.1021/ol1020652

Enantioselective catalysis in moderate to excellent yields and ee's has been accomplished using a phosphaalkene-based ligand system. Specifically, the palladium-catalyzed allylic alkylation of 1,3-diphenyl-2-propenyl acetate using a chiral P(sp²

Full text of DOI:10.1021/ol1020652

ORGANIC
LETTERS
2010
Vol. 12, No. 20
4667-4669
Chiral Phosphaalkene-Oxazoline
Ligands for the Palladium-Catalyzed
Asymmetric Allylic Alkylation
Julien Dugal-Tessier, Gregory R. Dake,* and Derek P. Gates*
Department of Chemistry, 2036 Main Mall, UniVersity of British Columbia,
VancouVer, B.C., Canada, V6T 1Z1
gdake@chem.ubc.ca; dgates@chem.ubc.ca
Received August 30, 2010
ABSTRACT
Enantioselective catalysis in moderate to excellent yields and ee’s has been accomplished using a phosphaalkene-based ligand system.
Specifically, the palladium-catalyzed allylic alkylation of 1,3-diphenyl-2-propenyl acetate using a chiral P(sp2),N(sp2) ligand proceeds with a
variety of malonate nucleophiles in 73-95% yield (79-92% ee).
Innovations in the design of nonconventional ligand frame-
works can serve as a foundation for the discovery of new
reactivities in synthetic organic chemistry. To these ends,
there has been considerable interest in the development of
nonconventional phosphaalkene (PhAk) ligands that contain
P(sp2) moieties for catalytic applications.1,2 Such ligands offer
novel σ-donating and π-accepting properties and consequently
have been employed successfully in numerous achiral trans-
formations.3 The application of enantiomerically pure versions
of PhAk ligands in asymmetric catalysis remains at a primitive
stage. Although chiral aromatic phosphaferrocene and phos-
phinine ligands have successfully been used in asymmetric
catalysis,4 the current state-of-the-art catalysis with acyclic PhAk
ligands involves a singular example of Pd-catalyzed asymmetric
hydroamination (21% ee).5
the Pd-catalyzed asymmetric allylic alkylation. Our results
demonstrate that this novel ligand gives synthetically useful
yields and high ee’s using a range of functionalized ꢀ-di-
carbonyl nucleophiles.
(3) Examples of reactivity include allylic alkylation, conjugate addition,
cycloadditions, dehydrogenative silylation, hydroamination, hydrogenation,
isomerization, and polymerization and sigmatropic rearrangements. See, for
example: (a) Hayashi, A.; Yoshitomi, T.; Umeda, K.; Okazaki, M.; Ozawa,
F. Organometallics 2008, 27, 2321–2327. (b) Hayashi, A.; Okazaki, M.;
Ozawa, F. Organometallics 2007, 26, 5246–5249. (c) Dugal-Tessier, J.;
Dake, G. R.; Gates, D. P. Organometallics 2007, 26, 6481–6486. (d)
Katayama, H.; Nagao, M.; Nishimura, T.; Matsui, Y.; Umeda, K.; Akamatsu,
K.; Tsuruoka, T.; Nawafune, H.; Ozawa, F. J. Am. Chem. Soc. 2005, 127,
4350–4353. (e) Thoumazet, C.; Gru¨tzmacher, H.; Deschamps, B.; Ricard,
L.; Le Floch, P. Eur. J. Inorg. Chem. 2006, 3911–3922. (f) Ionkin, A.;
Marshall, W. Chem. Commun. 2003, 710–711. (g) Ozawa, F.; Okamoto,
H.; Kawagishi, S.; Yamamoto, S.; Minami, T.; Yoshifuji, M. J. Am. Chem.
Soc. 2002, 124, 10968–10969. (h) Daugulis, O.; Brookhart, M.; White, P. S.
Organometallics 2002, 21, 5935–5943. (i) Minami, T.; Okamoto, H.; Ikeda,
S.; Tanaka, R.; Ozawa, F.; Yoshifuji, M. Angew. Chem., Int. Ed. 2001, 40,
4501–4503. (j) Ikeda, S.; Ohhata, F.; Miyoshi, M.; Tanaka, R.; Minami,
T.; Ozawa, F.; Yoshifuji, M. Angew. Chem., Int. Ed. 2000, 39, 4512–4513.
(4) For reviews, see: (a) Mu¨ller, C.; Vogt, D. Dalton Trans. 2007, 5505–
5523. (b) Fu, G. C. Acc. Chem. Res. 2006, 39, 853–860. For recent examples,
see: (c) Willms, H.; Frank, W.; Ganter, C. Organometallics 2009, 28, 3049–
3058. (d) Willms, H.; Frank, W.; Ganter, C. Chem.sEur. J. 2008, 14, 2719–
2729. (e) Sua´rez, A.; Downey, C. W.; Fu, G. C. J. Am. Chem. Soc. 2005,
127, 11244–11245. (f) Shintani, R.; Fu, G. C. Angew. Chem., Int. Ed. 2003,
42, 4082–4085. (g) Shintani, R.; Fu, G. C. J. Am. Chem. Soc. 2003, 125,
10778–10779. (h) Breit, B.; Winde, R.; Mackewitz, T.; Paciello, R.; Harms,
K. Chem.sEur. J. 2001, 7, 3106–3121.
Herein, we report a breakthrough in the evolution of low-
coordinate phosphorus ligands for catalysis, namely, the
application of an enantiomerically pure PhAk-oxazoline in
(1) For recent reviews highlighting the use of low-coordinate phosphorus
compounds in catalysis, see: (a) Le Floch, P. Coord. Chem. ReV. 2006,
250, 627–681. (b) Ozawa, F.; Yoshifuji, M. Dalton Trans. 2006, 4987–
4995. (c) Mathey, F. Angew. Chem., Int. Ed. 2003, 42, 1578–1604. (d)
Weber, L. Angew. Chem., Int. Ed. 2002, 41, 563–572
.
(2) Bates, J. I.; Dugal-Tessier, J.; Gates, D. P. Dalton Trans. 2010, 39,
3151–3159
.
10.1021/ol1020652  2010 American Chemical Society
Published on Web 09/23/2010

We have recently embarked on a program to develop chiral
P(sp2),N(sp2) ligands and have developed a modular route
to the air-stable and enantiomerically pure PhAk-oxazoline
ligand (PhAk-Ox, 1).6 The Pd-catalyzed alkylation of allylic
substrates using 1 was selected to assess the potential of these
ligands which bear resemblance to the highly successful
Pfaltz-Helmchen P(sp3),N(sp2) phosphinooxazoline (PHOX)
ligands.7,8 The successful implementation of PhAk-Ox in
catalytic asymmetric allylic alkylation provides an entry point
to broader application in asymmetric catalysis. Moreover,
these experiments also provide a benchmark for the develop-
ment of later-generation versions of the PhAk-Ox ligand
system.
Table 1. Initial Results Using PhAk-Ox Pd Complexes [2]X
and [4]X in Asymmetric Allylic Alkylation
entry
LG
catalyst
basea
NaH
% yieldb
% eec
1
2
3
4
5
6
OCO2Et
OCO2Et
OCO2Et
OCO2Et
OCO2Et
OAc
[2]OTf
[2]OTf
[2]OTf
[4]OTf
[4]BF4
[4]OTf
35
36
70
74
52
83
83
50
85
91
70
92
Cs2CO3
BSA/KOAc
BSA/KOAc
BSA/KOAc
BSA/KOAc
The Pd-catalyzed allylic alkylation necessitated the syn-
thesis of the PhAk-Ox-palladium allyl complex [2]OTf
from the reaction of [(C3H5)PdCl]2, AgOTf, and 1 in CH2Cl2.
Complex [2]OTf was isolated in high yield and was fully
a NaH (1 equiv); Cs2CO3 (1 equiv); BSA (1 equiv)/KOAc (0.01 equiv).
1
characterized by 31P, H, and 13C NMR spectroscopy, and
b Isolated yields. c ee was determined using chiral SFC-HPLC.
satisfactory elemental microanalysis was obtained.
lectivities.10 The presence of gem-dialkyl groups influences
i
the positioning of the Pr methyl moieties with respect
to the metal center, thus increasing the enantioselectivity.
Therefore, ligand 3 and the palladium-allyl [4]OTf were
prepared following procedures analogous to those outlined
above. Attempts to ascertain the orientation of the iPr methyl
moieties in [4]OTf through X-ray diffraction were unsuc-
cessful since suitable crystals could not be obtained. Thus,
3·PdCl2 was prepared and analyzed crystallographically to
reveal three conformational forms in the asymmetric unit
(Figure 1). In the solid state, two of the three isomers (b
The Pd complex [2]OTf showed considerable potential.
For example, the reaction between racemic 1,3-diphenyl-2-
propenyl ethyl carbonate and dimethyl malonate in the
presence of [2]OTf (5 mol %) afforded the substituted
malonate (A) with a very promising 83% ee, albeit in modest
isolated yield (35%) (Table 1, entry 1). Efforts to optimize
the performance of [2]OTf by employing different base
systems resulted in a major breakthrough with bis(trimeth-
ylsilyl)acetamide (BSA) and potassium acetate which im-
proved the yield of A to 70% while maintaining enantiose-
lectivity (85% ee).9
In an effort to improve the enantioselectivity of this process
further, modifications to the ligand skeleton were undertaken.
In the PHOX ligand series, the addition of a gem-dialkyl
moiety at C5 of the 4-iPr-Ox results in higher enantiose-
Figure 1. Molecular structures showing the three conformations
(5) Takita, R.; Takada, Y.; Jensen, R. S.; Okazaki, M.; Ozawa, F.
Organometallics 2008, 27, 6279–6285.
of 3·PdCl2 in the solid state: (a) 40%, (b) 37%, and (c) 23% (50%
probability ellipsoids). All hydrogen atoms are omitted for clarity.
(6) Dugal-Tessier, J.; Dake, G. R.; Gates, D. P. Angew. Chem., Int. Ed.
2008, 47, 8064–8067.
(7) (a) Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33, 336–345.
For initial publication, see: (b) von Matt, P.; Pfaltz, A. Angew. Chem., Int.
Ed. 1993, 32, 566–568. (c) Sprinz, J.; Helmchen, G. Tetrahedron Lett. 1993,
34, 1769–1772. (d) Dawson, G. J.; Frost, C. G.; Williams, M. J.; Coote,
and c, 60%) have the methyl groups on the isopropyl moiety
projecting toward the Pd atom in 3·PdCl2. This contrasts with
1·PdCl2 in which the methyl groups on the isopropyl unit
are oriented away from the Pd atom in the solid state (see
Supporting Information).
S. J. Tetrahedron Lett. 1993, 34, 3149–3150
.
(8) For reviews of Pd-catalyzed allylic alkylation, see: (a) Trost, B. M.
J. Org. Chem. 2004, 69, 5813–5837. (b) Trost, B. M.; Crawley, M. L. Chem.
ReV. 2003, 103, 2921–2943. (c) Lu, Z.; Ma, S. M. Angew. Chem., Int. Ed.
2008, 47, 258–297. (d) Braun, M.; Meier, T. Synlett 2006, 661–676
.
4668
Org. Lett., Vol. 12, No. 20, 2010

Importantly, the use of the modified catalyst [4]OTf led
to improved performance in allylic alkylation. Malonate A
was obtained in high enantioselectivity (91%; cf. 85% for
[2]OTf) and good yield (74%; cf. 70% with [2]OTf) (Table
1, entry 4). Changing the catalyst counterion to [BF4]- gave
poorer results (entry 5). In the midst of these optimization
experiments, it was observed that product mixtures were
often contaminated with 1,3-diphenyl-2-propenyl ethyl ether.
This undesired side product results from the addition of
propenyl acetate, was produced in 88% ee but only in 40%
yield. Importantly, ꢀ-dicarbonyl compounds that contain
ether or alkene functions are also well tolerated in reactions
catalyzed by [4]OTf, giving alkylated malonates F-I in good
yields with excellent enantioselectivities.
Acyclic dialkenes H and I can be further synthetically
manipulated using catalytic amounts (5 mol %) of the Grubbs
II catalyst [(IMes)(PCy3)RuCl2(dCHPh)]. The ring-closing
metathesis of H and I proceeded smoothly to produce
cyclopentene H′ and cyclohexene I′ in good yields. Impor-
tantly, HPLC analysis of the starting materials and products
in this sequence demonstrated that no erosion of the
stereochemical configuration took place.
-
ethoxide (formed from EtOCO2 ) to the putative π-allyl
intermediate. This has been observed previously11 and is
avoided by employing acetate as the leaving group. To our
delight, racemic 1,3-diphenyl-2-propenyl acetate reacted
readily with dimethyl malonate using catalyst [4]OTf to
afford A in 83% yield and 92% ee (entry 6), an improvement
over the analogous carbonate (74%, 91% ee).
The scope of nucleophiles in allylic alkylations with 1,3-
diphenyl-2-propenyl acetate catalyzed by [4]OTf was ex-
plored further. Standard experimental conditions for these
studies were [4]OTf (5 mol %), BSA (1 equiv), and KOAc
(0.01 equiv) in CH2Cl2 at 20 °C. The results are summarized
in Figure 2 and generally show [4]OTf to be an effective
This work demonstrates the first application of a chiral
phosphaalkene (PhAk) derived ligand that supports metal-
catalyzed processes for organic chemistry in high yields and
enantioselectivities. The modular nature within the ligand
design bodes well for utility and optimization in other
applications involving metal catalysis. Importantly, it is
expected that the future reactivity studies will exploit the
unique capabilities of the PhAk fragment. Further studies
examining these possibilities are ongoing in our laboratories.
Acknowledgment. We gratefully acknowledge NSERC
of Canada (Discovery, Strategic and Research Tool grants
to G.R.D. and D.P.G. and a PGS D scholarship to J.D.-T.),
Merck & Co. Inc., and Merck-Frosst Canada Inc. for support
of this work. We acknowledge Doris Tang (UBC), Megan
Boyd (UBC), and Hyukin Kwon (UBC) for assistance in
molecule construction. We are grateful to Prof. Glenn
Sammis (UBC) and his research group for access to SFC-
HPLC equipment.
Figure 2. Preliminary investigation of the scope of enantioselective
allylic alkylation using PhAk-Ox catalyst [4]OTf showing func-
tional group tolerance (isolated yields, ee’s determined by chiral
SFC-HPLC).
Supporting Information Available: Experimental pro-
cedures, characterization data for all previously unreported
compounds, and CIF files. This material is available free of
charge via the Internet at http://pubs.acs.org.
catalyst. A few points merit comment. The dibenzyl malonate
C was formed in lower yield and enantioselectivity relative
to its dimethyl (A) or diethyl (B) congeners. Diketone E,
formed by the addition of acetylacetone to 1,3-diphenyl-2-
OL1020652
(10) (a) Be´langer, E.; Pouliot, M. F.; Paquin, J. F. Org. Lett. 2009, 11,
2201–2204. (b) Bull, S. D.; Davies, S. G.; Key, M.-S.; Nicholson, R. L.;
Savory, E. D. Chem. Commun. 2000, 1721–1722. (c) Bull, S. D.; Davies,
S. G.; Garner, A. C.; Kruchinin, D.; Key, M.-S.; Roberts, P. M.; Savory,
E. D.; Smith, A. D.; Thomson, J. E. Org. Biomol. Chem. 2006, 4, 2945–
2964.
(9) The absolute configuration of A-E was determined by comparison
of optical rotation values to literature data. The absolute configuration of
H and I was determined by comparison of the optical rotation data of the
RCM products H′ and I′ to literature data. Compounds F and G were
assigned by analogy. See Supporting Information for details.
(11) For recent examples, see: (a) Austeri, M.; Linder, D.; Lacour, J.
Chem.sEur. J. 2008, 14, 5737–5741. (b) Kuwano, R.; Kusano, H. Org.
Lett. 2008, 10, 1979–1982.
Org. Lett., Vol. 12, No. 20, 2010
4669