Macrocyclic ferrocenyl-bisimidazoline palladacycle dimers as highly active and enantioselective catalysts for the Aza-Claisen rearrangement of Z-configured N-para-methoxyphenyl trifluoroacetimidates

Article abstract of DOI:10.1002/anie.200603568

(Chemical Equation Presented) In just four steps from ferrocene, macrocyclic ferrocenyl bispalladacyles have been synthesized by using a diastereoselective biscyclopalladation reaction as the key step. The complexes not only possess a fascinating structur

Full text of DOI:10.1002/anie.200603568

Communications
DOI: 10.1002/anie.200603568
Asymmetric Rearrangements
Macrocyclic Ferrocenyl–Bisimidazoline Palladacycle Dimers as Highly
Active and Enantioselective Catalysts for the Aza-Claisen
Rearrangement of Z-Configured N-para-Methoxyphenyl
Trifluoroacetimidates**
Sascha Jautze, Paul Seiler, and RenØ Peters*
Dedicated to Professor Yoshito Kishi on the occasion of his 70th birthday
The PdII-catalyzed aza-Claisen (Overman) rearrangement[1]
of allylic trichloro-[2] and N-para-methoxyphenyl trifluoro-
acetimidates[3] enables the transformation of achiral allyl
imidates 2, readily prepared from allyl alcohols 1 in a single
high-yielding step, to chiral enantioenriched allyl amides 3
(Scheme 1). Since the trihaloacetamide and the N-para-
spectator ligand which is the key
structural element responsible for
both the high catalytic activity and
the excellent enantioselectivity.[4,5]
We assume that the enormous
increase of the catalytic activity
attributed to the CpF spectator
ligand can be explained at least in
part by the electron-withdrawing
nature of the five phenyl substituents, which should enhance
the Lewis acidity of 5. Complex 5 showed contrastingly very
low catalytic activity for the rearrangement of Z-configured
imidates.
The electron density on the PdII center would be further
decreased in a ferrocenyl–bisimidazoline system. The ligand
preparation can take advantage of the possible C2 symmetry
and starts from parent ferrocene,[6] which is first transformed
into the bisthioamide 6 by using a modified literature
procedure (Scheme 2).[7]
Scheme 1. The aza-Claisen (Overman) rearrangement.
methoxyphenyl (PMP) protecting groups can be easily
removed, the overall transformation leads to allyl amines 4,
valuable building blocks for the synthesis of important
compound classes such as unnatural amino acids.[2a]
Recently, we reported the first highly active chiral catalyst
for the rearrangement of E-configured trifluoroacetimidates
to provide allylic trifluoroacetamides with excellent enantio-
selectivities while tolerating a broad substrate scope. The
catalyst 5 is a planar-chiral ferrocenyl imidazoline pallada-
cycle (FIP) bearing a pentaphenylcyclopentadienyl (CpF)
[*] S. Jautze, P. Seiler, Prof. Dr. R. Peters
Laboratory of Organic Chemistry
ETH Zürich
Wolfgang-Pauli-Strasse 10, Hönggerberg HCI E 111
8093 Zürich (Switzerland)
Scheme 2. Synthesis of the C2-symmetric ligands 8.
Fax: (+41)44-633-1226
E-mail: peters@org.chem.ethz.ch
Homepage: http://www.peters.ethz.ch
Activation of the thioamide groups by S-alkylation
followed by treatment of the solution of the resulting
bisiminium thioether with (R,R)-1,2-diphenylethane-1,2-di-
amine (7) and subsequent sulfonylation provides the ligands
8. These ligands possess strongly pyramidalized sulfonylated
N atoms similar to the sulfonylated ferrocenyl–monoimidazo-
lines, as shown by X-ray structure analysis (Figure 1).[8,9]
[**] This work was financially supported by F. Hoffmann-La Roche. We
thank Raphal Rochat for skillful experimental work and Dr. Martin
Karpf and Dr. Paul Spurr (both F. Hoffmann-La Roche, Basel) for
critically reading this manuscript.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Chemie
Figure 1. ORTEP representation of ligand 8a (R=p-Tol) with ellipsoids
set at 30% probability; C black, N blue, O red, Syellow, Fe light green.
H atoms are omitted for clarity.
Steric repulsion between the phenyl group at the imidazoline
5-position and the sulfonyl group is assumed to trigger a
transfer of chirality to the sulfonylated N atoms, thus resulting
in a preferred conformation in which the sulfonyl residues
point away from the ferrocenyl core.
This preferred conformation allowed us to perform a
diastereoselective direct biscyclopalladation (Table 1), which
Table 1: Preparation of bispalladacycles 9.
Figure 2. ORTEP representations of the dimeric bispalladacycle 9a
with ellipsoids set at 30% probability; C black, N blue, O red, Syellow,
Fe light green, Pd bronze, Cl green. H atoms are omitted for clarity.
macrocycles comprising two ferrocenyl units and four chlo-
ride-bridged palladium ions. The dimeric nature of 9 forces
two chloride-bridged palladium square planes to be arranged
in an almost coplanar fashion. The high diastereoselectivity is
remarkable, since in theory, seven different diastereomeric
dimers could have been formed.[14] To our knowledge these
are the first reported examples of enantio- and diastereo-
merically pure dimeric ferrocenyl bispalladacycles.[15]
In contrast to ferrocenyl–monoimidazoline palladacycle
complexes and most other ferrocenyl palladacycles, the
coordination sphere about the square-planar PdII center is
dictated in the present case by the planar chirality of the
bisimidazolines, which means that the (Sp,S’p,S*p,S*’p)-config-
ured complexes 9 must adopt a trans,trans configuration for
geometric reasons.
Entry
Product
R
Yield[a] [%]
d.r.[b]
1
2
3
4
9a
9b
9c
9d
p-Tol
C6F5
mesityl
p-Ph-C6H4
56
34
40
40
>100:1
>100:1
>100:1
>100:1
[a] Yield of isolated product after purification by silica-gel filtration.
[b] Diastereomeric ratio of the product after silica-gel filtration as
determined by H NMR spectroscopy.[12]
1
to our knowledge is the first reaction of this kind reported in
the literature.[10] Previous nonracemic ferrocenyl bispallada-
cycles were accessible by double ortho lithiation, iodination,
and subsequent oxidative addition of the Pd0 centers to the
diiodoferrocenes.[11]
The resulting complexes 9 are C2-symmetric dimers with
an (Sp,S’p,S*p,S*’p) configuration[13] as indicated by X-ray
analysis (Figure 2).[9] The complexes can be regarded as
Bispalladacycle 9a was examined in the aza-Claisen
rearrangement of Z-configured trifluoroacetimidates 10
since no highly active enantioselective catalyst so far existed
for substrates with Z configuration.[16] Since the chloride-
bridged dimers turned out to be unreactive as catalysts for
model substrate 10a,[17] silver trifluoroacetate was employed
as an activating agent. With two equivalents of AgO2CCF3
(relative to dimer 9a), the rearrangement proceeded very
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slowly in CH2Cl2 even in the presence of 5 mol% of the
bispalladacycle, yet provided (S)-11a in high yield and with
91% ee (Table 2, entry 1). Increasing the amount of
ments indicate that at least the bulk of the bispalladacycle is
not oxidized by AgOTs, since the formation of a para-
magnetic species is not observed even with an excess of the
silver salt (6 equiv relative to 9a). However, we cannot
exclude that a ferrocenium species is formed in minute
amounts and catalyzes the rearrangement. By virtue of the
modified catalyst activation procedure, it was possible to
reduce the catalyst amount to 0.5 mol% (Table 2, entry 10)
while still obtaining reasonable conversions, whereas the
reaction became very sluggish at room temperature with only
0.1 mol% catalyst activated by 0.6 mol% AgOTs (entry 11).
However, the high robustness of the catalyst allowed us to
perform the rearrangement at higher temperatures and
concentrations (entries 12–13): at 558C, the product was
formed with 95% ee in almost quantitative yield after three
days.
Under the optimized conditions for the model reaction,
we compared the four bispalladacycles 9a–d, which differ in
the sulfonyl residue R (0.1 mol% 9, 0.6 mol% AgOTs, 46 h
catalyst activation, CHCl3, 558C, 24 h reaction time). While
9a (78% yield, 96% ee) and 9b (77% yield, 92% ee) gave
similar catalyst activities and enantioselectivities, thereby
demonstrating that the electronic influence of R is negligible,
the bulkier mesityl- and biphenylsulfonyl groups in 9c (37%
yield, 90% ee) and 9d (21% yield, 92% ee) reduced the
catalyst activity considerably while still maintaining high
enantioselectivities.
After the optimization of the reaction conditions, the
scope of the rearrangement of Z-configured imidates 10 was
studied by using catalyst precursor 9a (Table 3). The rate of
the rearrangement depends primarily on the steric bulk of the
residue R’. With a-unbranched substituents (R’ = Me, nPr,
(CH2)2Ph, iBu), (S)-11 was formed in excellent yield and
enantioselectivity with 1.0 mol% catalyst at room temper-
ature (Table 3, entries 1, 4, 6, and 9). By decreasing the
catalyst amount to 0.1 to 0.2 mol% and increasing the
reaction temperature to 558C, yields and enantioselectivities
were only marginally affected owing to the high robustness of
the catalyst against decomposition (Table 3, entries 2, 5, 7,
and 10). The rearrangements were performed by using 25 mg
of substrates 10, however, working on a larger scale (2.6 to
11.6 mmol) provided similar results (Table 3, entries 3, 8, and
11).
Particularly noteworthy is the excellent enantioselectivity
obtained with imidate 10b, which bears the small methyl
substituent (94–96% ee; Table 3, entries 4–5). The highest
literature value so far was 86% for this specific example.[3a]
For the first time Z-configured trifluoroacetimidates
bearing a-branched substituents were also tolerated as
substrates, as demonstrated for 10e (R’ = iPr; Table 3,
entry 12), thus providing 11e in 64% and with 93% ee. In
this case 1 mol% of catalyst and a temperature of 558C were
employed to obtain preparatively useful conversions. The
lower yield as compared to the a-unbranched substrates
reflects the lower reaction rate, since neither substrate nor
catalyst decomposition were significant issues.[19]
Table 2: Screening of conditions for the rearrangement of model
substrate (Z)-10a.
[a]
Entry mol% AgX (mol%)
T
Solvent tact
t
Yield[b] ee[c]
9a
[8C]
[h]
[h] [%]
[%]
1[e]
2[e]
3[e]
4[d,e]
5[e]
6[f]
5
5
5
5
5
5
5
5
5
AgO2CCF3 (10) 20 CH2Cl2
AgO2CCF3 (20) 20 CH2Cl2
AgO2CCF3 (30) 20 CH2Cl2
AgO2CCF3 (30) 20 CH2Cl2
3
3
3
3
3
3
91 87
44 80
20 94
89 87
18 95
24 18
24 76
24 83
24 77
24 72
24 14
72 80
72 98
91
89
89
91
94
94
96
95
95
97
96
94
95
AgOTs (30)
AgOTs (30)
AgOTs (30)
AgOTs (30)
AgOTs (30)
AgOTs (3)
20 CH2Cl2
20 CHCl3
20 CHCl3 22
20 CHCl3 46
7[f]
8[f]
9[f,h]
20 CHCl3
3
10[g] 0.5
11[g] 0.1
12[g] 0.1
13[g] 0.1
20 CHCl3 45
20 CHCl3 45
40 CHCl3 46
55 CHCl3 46
AgOTs (0.6)
AgOTs (0.6)
AgOTs (0.6)
[a] Activation time. [b] The reactions were performed on an 8-mg scale
and the yields were determined by 1H NMR spectroscopy. 10a contained
2% of the E isomer. [c] ee determined by chiral HPLC (Daicel OD-H) after
hydrolysis of 11a to the corresponding secondary amine (see the
Supporting Information). [d] Reaction in the presence of 20 mol%
proton sponge. [e] 200 mL of solvent was used. [f] 50 mL of solvent was
used. [g] 10 mL of solvent was used. [h] The catalyst was activated at
408C.
AgO2CCF3 to four or six equivalents (relative to 9a) signifi-
cantly enhanced the rate of conversion while maintaining the
high enantioselectivity (Table 2, entries 2 and 3). In contrast
to previous catalysts, the presence of proton sponge (1,8-
bis(dimethylamino)naphthalene) as an additive did not
significantly increase the ee value but considerably slowed
down the reaction (Table 2, entry 4). To improve the catalyst
activity, various silver salts were screened. Whereas AgOTf,
AgOMs, AgNO3, AgBF4, and AgSbF6 induced little or no
conversion even after extended periods of time, AgOTs led to
slightly increased catalyst activity and an improved enantio-
selectivity, providing (S)-11a with 94% ee (Table 2, entry 5).
By using CHCl3 as the solvent for the rearrangement it was
found that the catalyst activation time plays a fundamental
role (Table 2, entries 6–9) since the chloride-bridged dimeric
bispalladacycles are presumably kinetically much more inert
than standard chloride-bridged monopalladacycle dimers for
a counteranion exchange. The best results were obtained with
a catalyst activation time of two days at room temperature
(Table 2, entry 8) or of three hours at 408C (entry 9). Previous
reports have demonstrated that ferrocenyl–oxazoline and
ferrocenyl–imidazoline monopalladacycles can be oxidized
by silver salts to the corresponding ferrocenium salts, which
are the catalytically active species.[18,3c,e] 1H NMR experi-
In conclusion, we have developed a short synthesis of
enantiomerically pure ferrocenyl–bisimidazolines which have
been utilized for diastereoselective biscyclopalladation reac-
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Chemie
[4] For other applications of imidazoline ligands in asymmetric
Table 3: Screening of substrates 10 with different groups R’.
catalysis, see, for example: a) F. Menges, M. Neuburger, A.
Pfaltz, Org. Lett. 2002, 4, 4713; b) C. A. Busacca, D. Grossbach,
R. C. So, E. M. OꢀBrien, E. M. Spinelli, Org. Lett. 2003, 5, 595;
c) S. Bhor, G. Anilkumar, M. K. Tse, M. Klawonn, C. Dobler, B.
Bitterlich, A. Grotevendt, M. Beller, Org. Lett. 2005, 7, 3393.
[5] For the first preparation of chiral ferrocenyl–imidazolines, see:
R. Peters, D. F. Fischer, Org. Lett. 2005, 7, 4137.
[6] Reviews about applications of ferrocene in asymmetric catalysis:
a) Ferrocenes (Eds.: T. Hayashi, A. Togni), VCH, Weinheim,
1995; b) C. J. Richards, A. J. Locke, Tetrahedron: Asymmetry
1998, 9, 2377; c) R. C. J. Atkinson, V. C. Gibson, N. J. Long,
Chem. Soc. Rev. 2004, 33, 313.
[7] K. Hamamura, M. Kita, M. Nonoyama, J. Fujita, J. Organomet.
Chem. 1993, 463, 169. The original yield was 29% and the
product isolation required two purifications by column chroma-
tography and one by crystallization. By our modifications no
column chromatography is necessary and the product is formed
in 54% yield.
[8] The pyramidality at a given atom can be expressed by the
difference between 360o and the sum of the three bond angles at
that atom. For the present analysis, corresponding values at
N(13) and N(43) are 21o and 16o, respectively. For further
information of the X-ray analysis, see reference [9].
[9] X-Ray crystal structure analyses. Bruker-Nonius Kappa CCD
diffractometer, MoKa radiation (l = 0.7107 Š). The structures
were solved by direct methods (SIR-97; A. Altomare, M. Burla,
M. Camalli, G. Cascarano, C. Giacovazzo, A. Guagliardi,
A. G. G. Moliterni, G. Polidori, R. Spagna, J. Appl. Crystallogr.
1999, 32, 115) and refined by full-matrix least-squares analysis
(SHELXL-97, G. M. Sheldrick, SHELXL-97, Program for the
Refinement of Crystal Structures, University of Göttingen,
Germany 1997), by using an isotropic extinction correction. All
non-H atoms were refined anisotropically, H atoms isotropically,
whereby H positions are based on stereochemical considera-
tions. 8a: Crystal data at 220(2) K for C54H46FeN4O4S2: Mr =
Entry 10
R’
mol% 9a T [8C] Yield[a] [%] ee[b] [%]
1[c]
2[c]
10a nPr
10a nPr
1.0
0.1
0.1
1.0
0.1
20
55
55
20
55
20
55
55
20
55
55
55
96
94
97
94
97
99
90
92
87
86
93
64
98
97
97
96
94
96
95
97
98
98
99
93
3[c,d] 10a nPr
4[e]
5[f]
10b Me
10b Me
10c
10c
10c
10d iBu
10d iBu
10d iBu
10e iPr
6[c]
(CH2)2Ph 1.0
(CH2)2Ph 0.2
(CH2)2Ph 0.2
7[c]
8[g]
9[c]
1.0
0.1
0.1
1.0
10[c]
11[h]
12[c]
[a] Yield of isolated product. The reactions were performed on a 25-mg
scale unless otherwise noted. [b] ee determined by chiral HPLC (Daicel
OD-H) after hydrolysis of 11 to the corresponding secondary amines
(see the Supporting Information). [c] Reaction time 3 d. [d] 3.5 g of
substrate 10a (11.6 mmol) was used. [e] Reaction time 1.5 d. [f] Reac-
tion time 1 d. [g] 0.94 g (2.59 mmol) of substrate 10c was used.
[h] 1.21 g of substrate 10d (3.83 mmol) was used.
tions, thereby giving access to structurally fascinating dimeric
macrocyclic PdII complexes. These are the first highly active
enantioselective catalysts for the aza-Claisen rearrangement
of Z-configured trifluoroacetimidates, requiring as little as
0.1 mol% of catalyst precursor for most of the substrates,
whereas the best catalyst systems so far required 5 mol%.
Even substrates with a-branched substituents, which could
previously not be applied, rearranged with high enantiose-
lectivity by action of only 1 mol% of catalyst precursor.
934.92, orthorhombic, space group P212121 (no. 19), 1calcd
=
1.386 gcmÀ3
,
Z = 4, a = 11.1108(2), b = 11.3676(2), c =
35.4662(7) Š, V= 4479.49(14) Š3, linear crystal dimensions
0.21 ” 0.19 ” 0.17 mm, m = 0.483 mmÀ1. Final R(F) = 0.042, wR-
(F2) = 0.097 for 635 parameters and 6264 reflections with I >
2s(I) and 2.49 < q < 26.018 (corresponding R values based on all
7194 reflections are 0.054 and 0.105, respectively). 9a: Crystal
data at 220(2) K for C108H88Cl4Fe2N8O8Pd4S4·7CHCl3: Mr =
Received: August 31, 2006
Revised: October 31, 2006
Published online: January 9, 2007
3268.91, monoclinic, space group P21 (no. 4), 1calcd
=
1.392 gcmÀ3
,
Z = 2, a = 15.5124(3), b = 30.3423(9), c =
15.8007(3) Š, b = 118.956(1)8, V= 6507.4(3) Š3, linear crystal
dimensions 0.14 ” 0.12 ” 0.10 mm, m = 1.392 mmÀ1. Final R(F) =
0.049, wR(F2) = 0.115 for 1499 parameters, 1 restraint, and
21058 reflections with I > 2s(I) and 2.95 < q < 26.028 (corre-
sponding R values based on all 23932 reflections are 0.059 and
0.122 respectively). CCDC-617968 (8a) and -617969 (9a) con-
tain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
Keywords: aza-Claisen rearrangement · cyclopalladation ·
.
ferrocenes · imidazoline ligands · Overman rearrangement
[1] Review about enantioselective aza-Claisen rearrangements:
T. K. Hollis, L. E. Overman, J. Organomet. Chem. 1999, 576, 290.
[2] a) C. E. Anderson, L. E. Overman, J. Am. Chem. Soc. 2003, 125,
12412; b) S. F. Kirsch, L. E. Overman, M. P. Watson, J. Org.
Chem. 2004, 69, 8101.
[3] a) L. E. Overman, C. E. Owen, M. M. Pavan, C. J. Richards, Org.
Lett. 2003, 5, 1809; b) R. S. Prasad, C. E. Anderson, C. J.
Richards, L. E. Overman, Organometallics 2005, 24, 77;
c) C. E. Anderson, Y. Donde, C. J. Douglas, L. E. Overman, J.
Org. Chem. 2005, 70, 648; d) R. Peters, Z.-q. Xin, D. F. Fischer,
W. B. Schweizer, Organometallics 2006, 25, 2917; e) M. E. Weiss,
D. F. Fischer, Z.-q. Xin, S. Jautze, W. B. Schweizer, R. Peters,
Angew. Chem. 2006, 118, 5823; Angew. Chem. Int. Ed. 2006, 45,
5694.
[10] Only very few direct diastereoselective cyclopalladations of
chiral ferrocene derivatives are known; see references [3d,e]
and references therein.
[11] J. Kang, K. H. Yew, T. H. Kim, D. H. Choi, Tetrahedron Lett.
2002, 43, 9509.
[12] Prior to short-pad silica-gel filtration the 1H NMR spectra were
too complex for an accurate determination of the d.r. value.
[13] The stereodescriptors with regard to the planar chirality are used
according to K. Schlögl, Top. Stereochem. 1967, 1, 39. We employ
different superscripts to distinguish the four Cp ligands: (S’p)
Angew. Chem. Int. Ed. 2007, 46, 1260 –1264
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indicates the configuration of a bottom Cpligand while an
asterisk (*) indicates the second ferrocene unit.
[14] The seven diastereomers would have the following configura-
gave ee values upto 91% for E-configured model substrate 10a
(4 equiv AgNO3, CH2Cl2, RT, 1 d, 91% yield), but is less active
than 5 for E-configured substrates.
tions:
(Rp,S’p,R*p,S*’p),
(Rp,R’p,R*p,R*’p).
(Sp,S’p,S*p,S*’p),
(Rp,S’p,S*p,S*’p),
(Rp,R’p,S*p,S*’p),
and
[17] The same of 10a that was used for the catalyst-screening
experiments contained 2% of the E-configured isomer.
[18] T. P. Remarchuk, Ph.D. Dissertation, University of California,
Irvine, 2003, pp. 175–235 (Overman group).
[19] Like previous catalysts, 9a is not a suitable catalyst for the Z-
configured substrate bearing a phenyl substituent R’, since the
rearrangement is not only exceedingly slow, but also accompa-
nied by decomposition.
(Rp,S’p,S*p,R*’p), (Rp,R’p,R*p,S*’p),
[15] Previous nonracemic bispalladacycles are monomeric since
tridentate ligand motifs were used; see reference [11].
[16] With the same enantiomerically pure catalyst, E- and Z-
configured substrates generally give the opposite major enan-
tiomers. For that reason it is important to have isomerically pure
substrates to get maximum ee values. Precatalyst 9a (2.5 mol%)
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