Chiral bis(pyridylimino)isoindoles: A highly modular class of pincer ligands for enantioselective catalysis

Article abstract of DOI:10.1002/anie.200801150

(Chemical Equation Presented) Protect your back: Chiral wedges (red, see scheme) at the wingtips of bis(2-pyridylimino) isoindole (bpi) pincer ligands with an appropriate protective hedge (green), to block the metal center from backside attack, in the backbone represent a new class of efficient 3d-metal catalysts. These catalysts gave excellent enantioselectivities in the iron-catalyzed hydrosilylation of arylketones and in the cobalt-catalyzed cyclopropanation of alkenes.

Full text of DOI:10.1002/anie.200801150

Communications
DOI: 10.1002/anie.200801150
Asymmetric Catalysis
Chiral Bis(pyridylimino)isoindoles: A Highly Modular Class of Pincer
Ligands for Enantioselective Catalysis**
Björn K. Langlotz, Hubert Wadepohl, and Lutz H. Gade*
The control of stereoselective catalytic transformations that
use metal complexes rests upon the development of efficient
structural platforms for ancillary stereodirecting ligands.[1]
Essential for the rapid identification of an optimized system
for a given lead structure and catalytic reaction is modularity
of the ligand and thus, catalyst assembly.[2] Apart from the
ubiquitous chiral chelates, monoanionic, meridionally coor-
dinating tridentate ligand systems are expected to enhance
catalyst stability and to offer a structural platform for the
construction of efficient stereodirecting elements.
Figure 1. Construction principle of chiral bpi ligands: stereodirecting
units attached to the pyridyl wings of the meridionally coordinating
Whereas Nishiyamaꢀs phebox ligands (phebox = bis(oxa-
zolinyl)phenyl) have been proven to act as efficient stereo-
ligand (red) and substituents within the ligand backbone to control
directing ligands in a variety of applications,[3] the majority of
access fromthe backside of the metal center (green).
the known pincer-type chiral systems perform relatively
poorly in enantioselective catalysis.[4] This poor selectivity
may be in part due to a certain lack of control of the substrate
orientation for reactions that proceed by backside attack at
the metal center; that is, the stereodirection by the chiral units
in the wing positions may be ineffective.
available terpenes. Starting from myrtenal, the corresponding
bpi derivatives 2a–b (denoted myrbpi) were synthesized by
using 2-aminopyridine derivative 1a, which was first reported
by von Zelewsky and co-workers.[9] A series of constitutional
isomers of 2a–c, compounds 3a–c (denoted pinbpi), was
obtained by using 1b, which was derived from (À)-b-
pinene,[10] and the (+)-2-carene-derived series (4a–c; denoted
carbpi) was prepared from 1c, which was synthesized from the
corresponding 2-triflatopyridine (see the Supporting Infor-
mation).[11]
The bpi ligands for each of the three series were used for
the preparation of iron(II) and cobalt(II) acetato complexes
5a–9c (Scheme 2) by either direct complexation of the metal
diacetate or by reaction with the corresponding dichloride
with subsequent anion exchange. All metal compounds are
assumed to adopt distorted octahedral coordination geo-
metries with one solvent molecule (MeOH or THF) occupy-
ing the sixth coordination site as indicated by the mass
spectrometric and analytical data. An X-ray diffraction study
has established this type of coordination geometry for a
related Co complex bearing an achiral bpi ligand (see the
Supporting Information).
Bis(2-pyridylimino)isoindoles (bpi) are highly modular
and readily accessible pincer ligands.[5] These compounds
were first employed as ligands for the cobalt-catalyzed
aerobic oxidation of hydrocarbons three decades ago,[6] and
their coordination chemistry with 3d metals in particular has
been studied in some detail.[7] However they have not been
studied as new lead structures for enantioselective catalysts.
Herein we report the synthesis of a series of chiral bpi
ligands. Whereas the chirally modified pyridyl units act as
stereodirecting elements,[8] the appropriate substitution pat-
tern in the backbone will provide a protective hedge for
backside attack on the metal center (Figure 1). Their versa-
tility as efficient stereodirecting ligands will be demonstrated
for the iron-catalyzed asymmetric hydrosilylation of ketones
and the cobalt-catalyzed enantioselective inter- and intra-
molecular cyclopropanation of alkenes.
Three types of chiral bpi derivatives, depicted in
Scheme 1, were prepared by the established one-pot proce-
dure with chiral aminopyridines derived from commercially
To gain insight into the structural details of this new class
of stereodirecting ligands, single crystal X-ray structure
analyses of carbpi (4a) (Figure 2a) and [Cu(tetraphenyl-
pinbpi)(OAc)] (12) (Figure 2b) were obtained. The latter has
been the only transition-metal complex with this type of
ligand to give X-ray quality crystals.[12] Whereas the structures
of both the ligand precursor and the metal complex illustrate
the orientation of the chiral wedges of the pyridyl units, which
are introduced as stereodirecting elements, the tetrapheny-
lated backbone of the Cu complex (Figure 2b) nicely depicts
the protective hedge on the backside of the reactive metal
center.
[*] B. K. Langlotz, Prof. Dr. H. Wadepohl, Prof. Dr. L. H. Gade
Anorganische-Chemisches Institut
Universität Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
Fax: (+49)6221-545-609
E-mail: lutz.gade@uni-hd.de
[**] This work was supported by the Deutsche Forschungsgemeinschaft
(SFB 623). We also acknowledge the award of a doctoral scholarship
by the Studienstiftung des Deutschen Volkes (to B.K.L.)
Supporting information for this article is available on the WWW
under http://www.angewandte.org or fromthe author.
4670
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Chemie
Figure 2. Molecular structure of: a) carbpi 4a and b) [Cu(tetraphenyl-
pinbpi)(OAc)] (12); hydrogen atoms omitted for clarity. Selected bond
lengths [Š] and angles [8] of carbpi (4a): N(1)–C(1) 1.391(2), N(1)–
C(4) 1.393(2), C(1)–N(2) 1.282(3), C(4)–N(4) 1.280(3), N(2)–C(9)
1.403(2), N(4)–C(21) 1.403(3), C(9)–N(3) 1.338(2), C(21)–N(5)
1.338(2); N(1)-C(1)-N(2) 131.2(2), N(1)-C(4)-N(4) 131.5(2); selected
bond length [Š] and angles [8] of [Cu(tetraphenyl-pinbpi)(OAc)] 12:
N(61)–Cu(2) 1.883(3), N(63)–Cu(2) 2.098(3), N(65)–Cu(2) 2.089(3),
O(61)–Cu(2) 2.480(3), O(62)–Cu(2) 1.945(2), O(61)–C(117) 1.226(4),
O(62)–C(117) 1.283(4); N(61)-Cu(2)-O(62) 155.0(1), N(63)-Cu(2)-
N(65) 156.7(1), N(61)-Cu(2)-O(61) 97.2(1), N(61)-Cu(2)-N(63)
90.7(1), N(61)-Cu(2)-N(65) 90.5(1).
soxazoline (pybox) and bis(oxazolinyl)diphenylamine (bopa)
ligands and reported enantioselectivities of up to 79% for
highly substituted aryl(alkyl)ketones.[16] Recently Beller and
co-workers have extended the scope of this reaction by using
Scheme 1. Modular assembly of chiral bis(2-pyridylimino)isoindole
ligand (precursors) by condensation of a substituted phthalonitrile and
two molar equivalents of a chiral 2-aminopyridine derivative. The
acronyms are derived from the underlying terpene structures and a
prefix designating the substitu-
tion pattern of the isoindole
backbone.
There has recently been
a
burgeoning interest in
replacing established
noble-metal catalysts by
systems containing nonpre-
cious metals.[13] Much of the
focus has been on catalysts
containing iron, a transition
metal still comparatively
underdeveloped in molecu-
lar catalysis.[14] In the first
report on the application of
iron catalysts in asymmetric
hydrosilylations
of
ketones,[15] Nishiyama and
Furuta employed pyridylbi-
Scheme 2. Synthesis of a series of chiral FeII–bpi and CoII–bpi complexes containing three different classes of
stereodirecting bpi ligands.
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Table 2: Scope of the [Fe(tetraphenyl-carbpi)(OAc)]-catalyzed asymmet-
chiral diphosphine-based catalysts which were optimized in
ric hydrosilylation of ketones.[a]
an extensive screening process.[17]
Yield [%][b]
T [8C]
t [h]
ee [%][c]
The first test of iron complexes 8a and b, and 9a–c as
catalysts in the asymmetric hydrosilylation of acetophenone
(Table 1) established carene derivatives 9a–c as the most
Entry
1
ketone
91
80
65
40
16
40
75
86 (S)
Table 1: Chiral FeII–complex catalysts for asymmetric hydrosilylation of
acetophenone.[a]
92
79
65
40
16
40
73
85 (S)
2
Entry Catalyst
Yield T [8C] t [h] ee [%][c]
[%][b]
92
83
65
40
48
40
85
93
3
4
5
6
1
2
3
4
5
6
7
8
[Fe(myrbpi)(OAc)] (8a)
[Fe(diMe-myrbpi)(OAc)] (8b)
[Fe(carbpi)(OAc)] (9a)
[Fe(carbpi)(OAc)] (9a)
[Fe(diMe-carbpi)(OAc)] (9b)
[Fe(diMe-carbpi)(OAc)] (9b)
93
92
94
84
95
86
65
65
65
40
65
40
65
40
16
16
16
40
16
40
16
40
27 (R)
28 (R)
77 (S)
84 (S)
77 (S)
84 (S)
78 (S)
86 (S)
87
77
65
40
16
40
71
83 (S)
[Fe(tetraphenyl-carbpi)(OAc)] (9c) 91
[Fe(tetraphenyl-carbpi)(OAc)] (9c) 85
88
72
65
40
16
40
75
85 (S)
[a] General conditions: FeII-complex (5 mol%), acetophenone (1 equiv),
(diethoxy) methyl silane (2 equiv) in THF (2 mL). Work-up with K2CO3
(1% in methanol). [b] Yield of isolated pure product. [c] Determined by
chiral GC analysis on a b-PM column; absolute configuration of the
secondary alcohol was determined by comparison with literature.
89
72
65
40
16
40
74
80 (S)
65
50
65
40
16
40
50
56 (S)
7
8
selective systems, which gave the reaction product in enan-
tioselectivities of up to 86% (Table 1, entry 8); this result was
superior to previously reported iron catalysts that were tested
for this reference reaction.[16,17] Notably, the reaction is
relatively insensitive to the backbone substitution, but the
type of chiral pyridyl unit seems to determine the stereose-
lectivities.
67
51
65
40
16
40
54
59 (S)
[a] General conditions: FeII-complex 9c (5 mol%), ketone (1 equiv),
(diethoxy) methyl silane (2 equiv) in 2 equiv THF (2 equiv). Work-up with
K2CO3 (1% in methanol). [b] Yield of isolated pure product. [c] Deter-
mined by chiral GC or HPLC analysis; absolute configuration of the
secondary alcohol was determined by comparison with literature.
By using the optimized iron-based system (9c) for the
hydrosilylation of a range of aryl(alkyl) ketones, the reaction
products were determined to have enantiomeric excesses of
up to 93% (Table 2). In contrast, dialkyl ketones appeared to
be reduced with somewhat lower selectivities (55–60% ee),
mirroring the behavior of most of the established precious-
metal-based systems.
Table 3: Various CoII-complex catalysts for asymmetric cyclopropanation
of styrene.[a]
The importance of controlling a potential backside attack
at the active site of the molecular catalyst should be apparent
in catalytic reactions in which the key stereochemically
determining step involves a side-on approach of the substrate,
which should be sensitively dependent upon the backbone
structure. This aspect has been probed in the cobalt-catalyzed
asymmetric cyclopropanation of alkenes with diazoalkanes
previously developed in the groups of Katsuki and Yamada.[18]
A major advantage of the cobalt system is the complete
suppression of diazoalkane dimerization (giving the unde-
sired corresponding alkenes), a problem that complicates the
use of copper (and most of the Ru and Rh) catalysts and
necessitates the use of syringe pumps or similar devices.[19]
Cobalt complexes 5a–c, 6a–c, and 7a and 7b were first
tested in the reference reaction of styrene with ethyl
diazoacetate. The results displayed in Table 3 are instructive
as to how the different structural elements in the bpi ligand
platform influence the catalyst performance. Complexes 7a
and 7b, both of which contain the chiral units at the pyridyl
groups oriented furthest away from the active site, gave the
cyclopropane products in both low diastereo- and enatiose-
Entry Catalyst
Yield
[%][b]
trans:cis[c] ee
[%][d]
1
2
[Co(myrbpi)(OAc)] (7a)
96
80:20
81:19
45
(1S,2S)
44
[Co(diMe-myrbpi)(OAc)] (7b) 95
(1S,2S)
63(1S,2S)
62
3
4
[Co(pinbpi)(OAc)] (5a)
[Co(diMe-pinbpi)(OAc)] (5b)
94
96
91:9
91:9
(1S,2S)
68
(1S,2S)
84
(1R,2R)
84
(1R,2R)
90
5
6
7
8
[Co(tetraphenyl-pinbpi)(OAc)] 95
(5c)
94:6
92:8
91:9
95:5
[Co(carbpi)(OAc)] (6a)
95
94
[Co(diMe-carbpi)(OAc)] (6b)
[Co(tetraphenyl-carbpi)(OAc)] 97
(6c)
(1R,2R)
[a] General conditions: CoII-complex (2 mol%), styrene (1 equiv), ethyl
diazoacetate (1.2 equiv) in toluene (2 mL) for a reaction time of 16 h.
[b] Yield of isolated pure product. [c] Determined by GC analysis.
[d] Determined by chiral GC analysis on a b-PM column; absolute
configuration of the secondary alcohol was determined by comparison
with literature.
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Table 5: Scope of the [Co(tetraphenyl-carbpi)(OAc)]-catalyzed asymmet-
ric intramolecular cyclopropanation.[a]
lectivities (ca. 45% ee, Table 3, entries 1 and 2). The rotation
of the chiral bicyclic terpene-derived unit towards the metal
center, as achieved in the pinbpi derivatives (5a–c) gives the
product with improved stereoselectivity. The introduction of
the tetraphenyl-substituted backbone significantly improves
the enantiomeric excess (compare Table 3, entries 5 and 4).
The highest enantio- and diastereoselectivities were obtained
by using the carene-derived catalysts (6a–c), in which the
chiral stereodirecting elements control the active chiral space
most effectively. Again, protection of the backside of the
metal center by the tetraphenyl-substituted isoindole groups
leads to an improved selectivity (compare Table 3, entries 8
and 7).
The optimized catalyst, [Co(tetraphenyl-carbpi)(OAc)]
(6c), has been employed in the cyclopropanation of a variety
of arylalkenes to give cyclopropane products with enantiose-
lectivities of up to 94% (Table 4). Not unexpectedly, the
system is somewhat less efficient for 1,1-disubstituted alkenes
(Table 4, entries 5 and 6). Dimerization of the diazoalkane
Entry
R1
R2
R3
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
H
H
H
H
Ph
H
H
H
H
H
H
H
H
83
81
84
79
83
74
64
42
93
93
94
93
93
88
77
65
p-ClC6H4
p-BrC6H4
p-MeOC6H4
p-MeC6H4
Ph
H
Me
Ph
Ph
Ph
H
[a] General conditions: CoII-complex 6c (2 mol%), diazo compound
(1 equiv) in toluene (2 mL) for a reaction time of 16–48 h. [b] Yield of
isolated pure product. [c] Determined by chiral GC or HPLC analysis.
the scope of this new lead structure and the potential strategy
it provides for discovering new catalysts is ongoing.
Table 4: Scope of the [Co(tetraphenyl-carbpi)(OAc)]-catalyzed asymmet-
ric inter molecular cyclopropanation.[a]
Received: March 10, 2008
Published online: May 14, 2008
Entry
Alkene
Yield [%][b]
97
trans:cis[c]
ee[%][d]
1
95:5
91
Keywords: cobalt · cyclopropanation · hydrosilylation · iron ·
.
ligand design
2
3
96
93
94:6
96:4
91
94
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Angew. Chem. Int. Ed. 2008, 47, 4670 –4674
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a = 12.9641(7),
b = 13.0908(7),
c = 15.3367(8) Š,
V=
2602.8(2) Š3, Z = 4, m = 0.057 mmÀ1, F000 = 1040. q range 2.1 to
30.58. Index ranges h, k, l (indep. set): 0…18, 0…18, 0…21.
Reflections measd.: 63065, indep.: 4413 [Rint = 0.0542], obsvd.
[I > 2s(I)]: 3844. Final R indices [Fo > 4s(Fo)]: R(F) = 0.0447,
wR(F2) = 0.1190, GooF = 1.088. 12 C58.35H51.70Cl0.70CuN5O2, mon-
oclinic, 7% pseudo-merohedral twin, space group P21, a =
15.8992(8), b = 18.4526(9), c = 16.1443(8) Š, b = 90.276(1)8,
V= 4736.4(4) Š3, Z = 4, m = 0.551 mmÀ1, F000 = 1975. q range
1.3 to 31.08. Index ranges h, k, l (indep. set): À23…23, À26…26,
4674 www.angewandte.org
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Angew. Chem. Int. Ed. 2008, 47, 4670 –4674