A highly enantioselective overman rearrangement through asymmetric counteranion-directed palladium catalysis

Article abstract of DOI:10.1002/anie.201103843

The chiral TRIP anion combined with a simple commercially available palladacycle furnishes a highly active catalyst for the enantioselective rearrangement of allylic imidates to the corresponding amide products in high yields (see scheme). The stereoselectivity is induced entirely by the chiral phosphate anion although the catalyst complex contains a chiral palladacycle (see scheme). Copyright

Full text of DOI:10.1002/anie.201103843

Communications
DOI: 10.1002/anie.201103843
Asymmetric Catalysis
A Highly Enantioselective Overman Rearrangement through
Asymmetric Counteranion-Directed Palladium Catalysis**
Gaoxi Jiang, Rajkumar Halder, Yewen Fang, and Benjamin List*
The Overman rearrangement is an important method for the
construction of allylic amine derivatives from allylic imidates
and has found widespread application in organic synthesis.[1]
Since the first enantioselective version of this PdII-catalyzed
aza-Claisen-type rearrangement appeared in 1997,[2] signifi-
cant progress has been marked by the introduction of the
oxazoline-based palladacycle catalysts COP-X[3] and FOP-
X[4] (Scheme 1). The success of these catalysts is based on
soft Pd–p-Lewis acid complex may be easily generable in situ
from an achiral Pd halide through anion metathesis with
readily available chiral C2-symmetric phosphate anions. Such
an approach would provide a complementary strategy to the
existing ligand-dependent protocols based on planar chiral
cobalt and iron sandwich complexes.
Indeed, our initial studies focused on identifying a
palladium species capable of catalyzing the desired enantio-
selective rearrangement using the chiral TRIP counteranion,
À
which is easily introduced by reacting its silver salt with a Pd
Cl species. As a model, we looked at the reaction of N-(p-
methoxyphenyl)trifluoroacetimidate (1a), which was previ-
ously shown to undergo facile Overmann rearrangements by
Overman et al.[3b,4a] and Peters et al.[4c,d] Indeed, when 1a was
treated with 1 mol% of [PdCl2(CH3CN)2] (Pd1) and 2 mol%
of (S)-TRIP-Ag in CHCl3 at 358C for 40 h, the rearranged
allylic amide 2a was obtained in low yield (20%) but with
non-negligible enantioselectivity (53:47 e.r.) (Table 1,
entry 1).
While far from satisfactory, this initial result nonetheless
indicated that our chiral counteranion strategy may indeed be
feasible. Encouraged, we screened several simple pallada-
cycles. Using oxazoline-containing palladacycle Pd2, efficient
rearrangement can be achieved, albeit in still moderate
enantioselectivity (Table 1, entry 2). Further investigations
led to the discovery that cyclopalladated benzyl amines Pd3–
Pd5 are efficient and highly enantioselective catalysts
(Table 1, entries 3–6).
Compared to Pd3 and Pd4, the commercially available
palladacycle (S)-Pd5 gave excellent results in terms of
reactivity and enantioselectivity (Table 1, entry 5). The cor-
responding mismatched complex generated from (R)-Pd5
gave product 2a in 94:6 e.r. (Table 1, entry 6). In the absence
of TRIP-Ag, (S)-Pd5 accelerated the rearrangement of 1a to
give racemic 2a in near-quantitative yield, similar to the
previous result reported by Overman and co-workers[11]
(Table 1, entry 7). As expected, (S)-TRIP-Ag alone is com-
pletely inactive for the rearrangement (Table 1, entry 8).
These results suggest that the PdII complex is indeed
responsible for promoting the reaction, and more importantly,
that the enantioselectivity is induced mostly by the chiral
phosphate counteranion.
Scheme 1. The ACDC approach for the Overman rearrangement.
their planar chiral sandwich motif, a drawback of which is
their required multistep synthesis. Considering the well-
established PdII-p-Lewis acid mediated cyclization-induced
mechanism,[3,4] we were quickly attracted to extending and
capitalizing on the potential of our asymmetric counteranion-
directed catalysis (ACDC) concept.[5–10] We have recently
applied this approach to Pd-catalyzed Tsuji–Trost-type reac-
tions that bear some mechanistic resemblance.[8] Potentially,
an ACDC strategy could ultimately be used to develop
simplified and yet highly enantioselective catalysts. Here we
report significant progress towards this goal with the develop-
ment of a simple palladacyle catalyst that incorporates our
chiral TRIP counteranion and catalyzes the Overman rear-
rangement with high enantioselectivity.
We anticipated that an ACDC strategy for the Overman
rearrangement could take advantage of the fact that a chiral
[*] Dr. G. Jiang,[+] Dr. R. Halder,[+] Dr. Y. Fang,[+] Prof. Dr. B. List
Max-Planck-Institut fꢀr Kohlenforschung
Kaiser Wilhelm-Platz 1, 45470 Mꢀlheim an der Ruhr (Germany)
E-mail: list@mpi-muelheim.mpg.de
[+] These authors contributed equally to this work.
We next explored other substrates. As summarized in
Table 2, the present method is particularly suited for n-alkyl-
substituted allylic imidates. For instance, imidates 1b–g
underwent efficient rearrangement in high yields and enan-
tioselectivities (Table 2, entries 1–6). Even with branched
substituents, the rearrangement proceeded readily in high
yields and enantioselectivity with only slightly higher catalyst
loadings (Table 2, entries 7 and 8).
[**] Generous support by the Max Planck Society is acknowledged. We
also thank our HPLC and GC departments for their support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201103843.
9752
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 9752 –9755

Table 1: Development of suitable reaction conditions.[a]
Table 2: Substrate scope of the rearrangement of N-PMP imidates.[a]
Entry
1
Substrate
Product
Yield [%][b]
92
e.r.[c]
2b
96.5:3.5
2
3
2c
2d
96
92
98:2
98:2
4
2e
2 f
2g
97
92
93
94.5:5.5
98.5:1.5
98:2
Entry
Cat.
Yield [%][b]
e.r.[c]
1
2
3
4
5
6
Pd1
Pd2
Pd3
Pd4
(S)-Pd5
(R)-Pd5
(S)-Pd5
–
20
94
93
94
93
96
53:47
68:32
93:7
97:3
99:1
94:6
50:50
–
5
6[d]
7[d]
2h
2i
91
90
92:8
92:8
7[d]
8[e]
99
n.r.[f]
8[d]
[a] Reactions performed on 0.3 mmol scale. [b] Yield of isolated product.
[c] Determined by HPLC after hydrolysis of 2a to the corresponding
amine (see the Supporting Information). [d] No Ag salt used. [e] Only Ag
salt used. [f] No reaction.
9
X=H
X=F
X=Cl
X=Me
2j
2k
2l
92
90
93
97
95:5
96:4
99:1
92:8
10
11
12
Importantly, we were pleased to find that in the case of
challenging aryl-substituted trifluoroacetimidates, our new
catalyst system gave significantly higher enantioselectivities
than those obtained with FOP-X. Excellent enantioselectiv-
ities were achieved with all four cinnamyl alcohol derivatives
1j–m studied (Table 2, entries 9–12).[4c] With these substrates
we observe electronic effects on the enantioselectivity. For
example, the introduction of electron-withdrawing groups
such as p-F and p-Cl to the parent phenyl-substituted imidate
leads to an increase in enantioselectivity. A mildly electron-
donating group such as p-Me has a small negative effect on
the enantioselectivity. The lower enantioselectivity previously
obtained with such aryl-substituted trifluoroacetimidates has
been explained with a non-enantioselective thermal back-
ground rearrangement.[4h] The high catalytic activity of our
catalyst system may effectively outperform this uncatalyzed
process. A b,b-disubstituted imidate was also investigated; it
smoothly provided the allylic amide product 2n, which has a
quaternary stereogenic center, in high yield and with reason-
ably good enantioselectivity (Table 2, entry 13).
Finally, attempts were made towards isolating and struc-
turally characterizing our proposed ion-pair catalyst. Accord-
ingly, treating the (S)-Pd5 dimer with 2.0 equivalents of (S)-
TRIP-Ag in CHCl3 at room temperature led to the rapid
formation of a AgCl precipitate. After filtration and evapo-
ration, a yellow foam was obtained in quantitative yield. The
31P NMR spectrum of this compound shows a singlet reso-
nance at 6.88 ppm in [D6]DMSO (Scheme 2). This assignment
is supported by the mass spectrum, which displays a signal
corresponding to a fragmentation product that has lost one of
the two bridging phosphates. Similar fragmentation patterns
2m
13[d]
91
90:10
[a] Reactions performed on 0.3 mmol scale. [b] Yield of isolated product.
[c] Determined by HPLC or GC with a chiral stationary phase (see the
Supporting Information). [d] 2.0 mol% of (S)-Pd5, 4.0 mol% of (S)-TRIP-
Ag, reaction time 60 h.
are also observed with the analogous acetate- and chloride-
bridged dimers.[4i] Complex Pd-A indeed catalyzes the
rearrangement of imidate 1b to product 2b and also that of
substrate 1g to amide 2g; the yields and enantioselectivities
are identical to those obtained with the in situ procedure.
After many unsuccessful attempts to obtain single crystals of
Pd-A suitable for X-ray structure determination, we found
that when N-methylimidazole in Et2O was added, an air-
stable colorless precipitate formed rapidly and quantitatively.
This material could be characterized as the monomeric Pd
complex Pd-B; it displays a singlet at 8.19 ppm in [D6]DMSO
in the 31P NMR spectrum and a [M]+ signal at m/z 1087 in its
mass spectrum. Moreover, suitable single crystals of Pd-B
could be obtained and analyzed (Scheme 2). In the corre-
sponding X-ray structure, it is noteworthy that the Pd1–N1
bond (2.034(4) ꢀ) is slightly shorter than the Pd1–N3 bond ,
which suggests a stronger complexation between Pd and the
imidazole ligand.[12] It is also apparent that the phosphate acts
as an anionic Pd ligand (Pd1—O1 2.149(3) ꢀ) rather than a
Angew. Chem. Int. Ed. 2011, 50, 9752 –9755
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
9753

Communications
Obviously, our X-ray-structure-based model is speculative.
Nonetheless, it qualitatively explains the observed stereose-
lectivity.
In summary, we have successfully extended the asymmet-
ric counteranion-directed catalysis (ACDC) concept to the Pd
catalysis of the asymmetric Overman rearrangement. Inter-
estingly, the enantioselectivity was induced by the chiral
phosphate anion even though the catalyst incorporates a
chiral palladacycle. The X-ray structure of Pd-B can be used
to create reasonable transition-state models that explain the
origin of enantioselectivity. Further studies on the potential
applications of this unique Pd complex are in progress.
Experimental Section
Under argon, (S)-Pd5 (1.74 mg, 1.0 mol%) and (S)-TRIP-Ag
(5.16 mg, 2.0 mol%) were stirred and dissolved in CHCl3 (0.30 mL)
in the absence of light. The mixture was stirred vigorously for 1 h at
room temperature, then a solution of 1a (109.0 mg, 0.30 mmol) in
CHCl3 (0.30 mL) was added at room temperature by syringe. The
reaction flask was sealed under argon, protected from light, and
maintained at 358C. After 40 h, the residue was diluted with CH2Cl2,
filtered through a short Celite column, and concentrated. Purification
of the residue by column chromatography on silica gel (hexane/
EtOAc 10:1) afforded 2a (101.3 mg; 93% yield) with 99:1 e.r. as
determined by HPLC analysis after hydrolysis to the corresponding
secondary amine.
Scheme 2. Preparation of Pd-A and its derivative Pd-B. ORTEP repre-
sentation of Pd-B (hydrogen atoms are omitted for clarity; ellipsoids
are set at 30% probability).
“true” counteranion. As expected, Pd-B is catalytically
inactive for the rearrangement of 1a to 2a as it lacks a
=
vacant coordination site for the activation of the C C bond of
the substrate.
Received: June 6, 2011
Published online: September 1, 2011
On the basis of the obtained structural information, we
have devised models to rationalize the observed enantiose-
lectivity. Accordingly, replacing the N-methylimidazole
ligand with the olefin portion of the two enantiomeric
precyclization conformations of substrate 1a provides two
diastereomeric transition states leading to the corresponding
product enantiomers (Figure 1). Unfavorable steric interac-
tions between the substituent of the coordinated olefin, and to
a lesser extent of the N substituent, with the bulky substituent
at the 3,3’-position of the phosphate moiety disfavor the
pathway leading towards the R enantiomer (Figure 1, left).
Similar destabilizing interactions are absent in the transition-
state model leading to the corresponding S product, which is
also experimentally the preferred product (Figure 1, right).
Keywords: aza-Claisen rearrangement · chiral counteranions ·
Overman rearrangement · palladium · phosphates
.
[1] a) A. M. M. Castro, Chem. Rev. 2004, 104, 2939 – 3002; b) L. E.
Overman, N. E. Carpenter in Organic Reactions, Vol. 66 (Ed.:
L. E. Overman), Wiley, Hoboken, 2005, pp. 1 – 107; c) U. Nub-
bemeyer in The Claisen Rearrangement (Eds.: M. Hiersemann,
U. Nubbemeyer), Wiley-VCH, Weinheim, 2007, pp. 461 – 523;
d) K. C. Majumdar, T. Bhattacharyya, B. Chattopadhyay, B.
Sinha, Synthesis 2009, 2117 – 2142; e) H. Nomura, C. J. Richards,
Chem. Asian J. 2010, 5, 1726 – 1740.
[2] M. Calter, T. Holis, L. E. Overman, J. Ziller, G. G. Zipp, J. Org.
Chem. 1997, 62, 1449 – 1456.
[3] For recent representative examples, with COP-X as catalyst, see:
a) C. E. Anderson, L. E. Overman, J. Am. Chem. Soc. 2003, 125,
12412 – 12413; b) L. E. Overman, C. E. Owen, M. M. Pavan, C. J.
Richards, Org. Lett. 2003, 5, 1809 – 1812; c) S. F. Kirsch, L. E.
Overman, M. P. Watson, J. Org. Chem. 2004, 69, 8101 – 8104;
d) R. S. Prasad, C. E. Anderson, C. J. Richards, L. E. Overman,
Organometallics 2005, 24, 77 – 81; e) H. Nomura, C. J. Richards,
Chem. Eur. J. 2007, 13, 10216 – 10224; f) M. P. Watson, L. E.
Overman, R. G. Bergman, J. Am. Chem. Soc. 2007, 129, 5031 –
5044.
[4] For recent representative examples, with FOP-X as catalyst, see:
a) C. E. Anderson, Y. Donde, C. J. Douglas, L. E. Overman, J.
Org. Chem. 2005, 70, 648 – 657; b) A. Moyano, M. Rosol, R. M.
Moreno, C. Lꢁpez, M. A. Maestro, Angew. Chem. 2005, 117,
1899 – 1903; Angew. Chem. Int. Ed. 2005, 44, 1865 – 1869;
c) M. E. Weiss, D. F. Fischer, Z.-q. Xin, S. Jautze, W. B.
Schweizer, R. Peters, Angew. Chem. 2006, 118, 5823 – 5827;
Angew. Chem. Int. Ed. 2006, 45, 5694 – 5698; d) R. Peters, Z.-q.
Xin, D. F. Fischer, W. B. Schweizer, Organometallics 2006, 25,
Figure 1. Reaction models rationalizing the observed enantioselectivity.
9754
www.angewandte.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 9752 –9755

2917 – 2920; e) S. Jautze, P. Seiler, R. Peters, Angew. Chem. 2007,
119, 1282 – 1286; Angew. Chem. Int. Ed. 2007, 46, 1260 – 1264;
f) D. F. Fischer, Z.-q. Xin, R. Peters, Angew. Chem. 2007, 119,
7848 – 7851; Angew. Chem. Int. Ed. 2007, 46, 7704 – 7707; g) Z.-q.
Xin, D. F. Fischer, R. Peters, Synlett 2008, 10, 1495 – 1499; h) S.
Jautze, P. Seiler, R. Peters, Chem. Eur. J. 2008, 14, 1430 – 1444;
i) D. F. Fischer, A. Barakat, Z.-q. Xin, M. E. Weiss, R. Peters,
Chem. Eur. J. 2009, 15, 8722 – 8741; j) R. Peters, Z.-q. Xin, F.
Maier, Chem. Asian J. 2010, 5, 1770 – 1774.
M. Mba, F. D. Toste, Science 2007, 317, 496 – 499; b) R. L.
LaLonde, Z. J. Wang, M. Mba, A. D. Lackner, F. D. Toste,
Angew. Chem. 2010, 122, 608 – 611; Angew. Chem. Int. Ed. 2010,
49, 598 – 601; c) M. Hatano, K. Moriyama, T. Maki, K. Ishihara,
Angew. Chem. 2010, 122, 3911 – 3914; Angew. Chem. Int. Ed.
2010, 49, 3823 – 3826; d) F. Drouet, C. Lalli, H. Liu, G. Masson, J.
Zhu, Org. Lett. 2011, 13, 94 – 97; e) Z. Zhang, W. Zheng, J. C.
Antilla, Angew. Chem. 2011, 123, 1167 – 1170; Angew. Chem. Int.
Ed. 2011, 50, 1135 – 1138; f) W. Zheng, Z. Zhang, M. J. Kaplan,
J. C. Antilla, J. Am. Chem. Soc. 2011, 133, 3339 – 3341; g) V.
Rauniyar, Z. J. Wang, H. E. Burks, F. D. Toste, J. Am. Chem. Soc.
2011, 133, 8486 – 8489. For recent review on combined chiral
phosphoric acid and metal catalysis, see: h) C. Zhong, X. Shi,
Eur. J. Org. Chem. 2010, 2999 – 3025.
[5] a) S. Mayer, B. List, Angew. Chem. 2006, 118, 4299 – 4301;
Angew. Chem. Int. Ed. 2006, 45, 4193 – 4195; b) N. J. A. Martin,
B. List, J. Am. Chem. Soc. 2006, 128, 13368 – 13369.
[6] X. Wang, B. List, Angew. Chem. 2008, 120, 1135 – 1138; Angew.
Chem. Int. Ed. 2008, 47, 1119 – 1122.
[7] P. Garcꢂa-Garcꢂa, F. Lay, P. Garcꢂa-Garcꢂa, C. Rabalakos, B. List,
Angew. Chem. 2009, 121, 4427 – 4430; Angew. Chem. Int. Ed.
2009, 48, 4363 – 4366.
[8] S. Mukherjee, B. List, J. Am. Chem. Soc. 2007, 129, 11336 –
11337.
[9] S. Liao, B. List, Angew. Chem. 2010, 122, 638 – 641; Angew.
Chem. Int. Ed. 2010, 49, 628 – 631.
[10] Other selected examples of the use of chiral phosphates in
asymmetric metal catalysis, see: a) G. L. Hamilton, E. J. Kang,
[11] T. K. Hollis, L. E. Overman, Tetrahedron Lett. 1997, 38, 8837 –
8840.
[12] Selected distances [ꢀ] and angles [8]: Pd1–O1 2.149(3), Pd1–N1
2.034(4), Pd1–N3 2.075(4), Pd1–C12 1.968(4); N1-Pd1-O1
90.06(13), N1-Pd1-N3 176.96(15), N3-Pd1-O1 92.91(13), C12-
Pd1-O1 174.72(15), C12-Pd1-N1 94.54(15), C12-Pd1-N3
82.54(16). For more crystallographic data, see the Supporting
Information.
Angew. Chem. Int. Ed. 2011, 50, 9752 –9755
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
9755