Metal-templated enantioselective enamine/H-bonding dual activation catalysis

Article abstract of DOI:10.1039/c4cc04636f

An octahedral bis-cyclometalated iridium(III) complex catalyzes the enantioselective α-amination of aldehydes with catalyst loadings down to 0.1 mol%. In this metal-templated design, the metal serves as a structural center and provides the exclusive source of chirality, whereas the catalysis is mediated through the organic ligand sphere. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc04636f

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Metal-templated enantioselective enamine/
H-bonding dual activation catalysis†
Haohua Huo,a Chen Fu,a Chuanyong Wang,a Klaus Harmsa and Eric Meggers*ab
Cite this: Chem. Commun., 2014,
50, 10409
Received 18th June 2014,
Accepted 21st July 2014
DOI: 10.1039/c4cc04636f
www.rsc.org/chemcomm
An octahedral bis-cyclometalated iridium(III) complex catalyzes the result in a limited conformational flexibility which is not only
enantioselective a-amination of aldehydes with catalyst loadings advantageous for entropic reasons but also simplifies an intuitive
down to 0.1 mol%. In this metal-templated design, the metal serves and rational catalyst optimization. Herein, we now wish to demon-
as a structural center and provides the exclusive source of chirality, strate how a chiral-at-metal octahedral iridium(III) complex can serve
whereas the catalysis is mediated through the organic ligand sphere. as a scaffold for the straightforward rational design of a low loading
asymmetric enamine/H-bonding dual activation catalyst (Fig. 1).5
Dual activation by multifunctional catalysts has emerged as a
We started our study by designing the substitutionally and
powerful concept for the design of high performance asymmetric configurationally inert bis-cyclometalated octahedral iridium(III)
metal-based catalysts and asymmetric organocatalysts.1 A typical complex L-Ir1 as our first generation bifunctional enamine cata-
bifunctional catalyst individually interacts with both the nucleo- lyst.1e,6 In L-Ir1, a coordinated 2-pyridyl-5,6-dihydro-4H-pyrrolo-
phile and electrophile (dual activation) through at least overall two [3,4-d][1,3]oxazole ligand7 contains a secondary amine for performing
functional groups (bi- or multifunctional catalysis). However, enamine catalysis, while a hydroxyl substituent at the 5-position of
although appealing as a concept, the design of high performance the benzoxazole ligands is supposed to serve as a hydrogen bonding
multifunctional catalysts remains challenging since it relies on a donor for the activation and positioning of an electrophile. As a
distinct positioning of carefully chosen functional groups within model reaction we chose the direct catalytic a-amination of aldehydes
the chiral catalyst template in order to gain a maximum advantage with azodicarboxylates as the nitrogen source, since it represents one
from functional group cooperativity. Hence, one can assume that of the simplest methods for the construction of a nitrogen-connected
most multifunctional, dual activation catalysts do not reach the stereogenic carbon and provides a convenient access to many classes
theoretically possible rate acceleration and asymmetric induction.
Recently, we reported octahedral chiral-at-metal iridium(III) com-
plexes as low-loading asymmetric catalysts which mainly rely on
three defined hydrogen bonds between substituents on the peri-
phery of the metal complexes and the substrates, and in which the
iridium center serves as an unreactive bystander fulfilling a purely
structural role.2–4 We hypothesize that inert octahedral metal com-
plexes are general, powerful templates for the efficient design of
multifunctional catalysts since octahedral stereocenters allow the
straightforward construction of molecular entities with high shape
and stereochemical complexity. Furthermore, steric crowding
around the metal stereocenter combined with chelate effects often
a
¨
Fachbereich Chemie, Philipps-Universitat Marburg, Hans-Meerwein-Straße,
35043 Marburg, Germany. E-mail: meggers@chemie.uni-marburg.de
b College of Chemistry and Chemical Engineering, Xiamen University,
Xiamen 361005, People’s Republic of China
† Electronic supplementary information (ESI) available: Experimental details and
analytical data, including chiral HPLC traces and X-ray crystallographic data.
CCDC 1006275. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c4cc04636f
Fig. 1 Organic versus metal-templated (this study) bifunctional asym-
metric enamine catalysts with indicated sources of chirality. BArFÀ
tetrakis[(3,5-di-trifluoromethyl)phenyl]borate.
=
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Table 1 Development of a chiral-at-metal iridium(III) catalyst for the
enantioselective a-amination of aldehydes with azodicarboxylatesa
Table 2 Substrate scope of the enantioselective a-amination of alde-
hydes with iridium catalyst L-Ir4a
Entry R1
R2
Product t (h) Yieldb (%) eec (%)
1
2
3
4
5
6
7
8
tBu (1a)
nBu (1b)
iPr (1c)
nPr(1d)
Et (1e)
Allyl (1f)
nHex (1g)
C6H11 (1h)
Bn (2a)
Bn (2a)
Bn (2a)
Bn (2a)
Bn (2a)
Bn (2a)
Bn (2a)
Bn (2a)
(S)-3a
(S)-3b
(S)-3c
(S)-3d
(S)-3e
(S)-3f
(S)-3g
(S)-3h
(S)-3i
(S)-3j
12
15
14
15
15
14
15
15
15
15
15
15
96
81
89
78
73
87
75
77
75
91
91
88
97
94
95
96
93
92
95
95
91
89
96
95
Loading
(mol%)
Yieldb eec
Entry Cat
Cond
t (h) (%)
(%)
1
2
3
4
5
6
L-Ir1
4
4
4
4
1
1
2a (0.1 M), 0 1C
2a (0.1 M), 0 1C
2a (0.1 M), 0 1C
2a (0.1 M), 0 1C
2a (0.1 M), RT
2a (1.0 M), RT
2a (1.0 M), RT
2a (1.0 M), RT
2a (0.1 M), 0 1C
2a (1.0 M), RT, DMF
1.5 87
2.5 93
2.5 93
2.5 96
31
39
65
97
91
97
94
91
0
L-Ir2
L-Ir3
L-Ir4
L-Ir4
L-Ir4
36
92
96
91
89
88
78
13
9
BnOCH2 (1i) Bn (2a)
12
30
36
6
10
11
12
Bn (1j)
Bn (1j)
Bn (1j)
Bn (2a)
7
L-Ir4 0.2
L-Ir4 0.1
tBu (2b) (S)-4kd
Et (2c)
(S)-4ld
8
9
10
11
L-Ir5
L-Ir4
L-Ir4
4
1
1
8
28
9
a
Reaction conditions: to a mixture of azodicarboxylate 2a–c (0.2 mmol)
and L-Ir4 (1.0 mol%) in anhydrous toluene (0.2 mL, 1.0 M) at 0 1C was
added the aldehyde 1a–j (0.30 mmol, 1.5 M). After being stirred at RT
for 12–15 h, MeOH (0.2 mL) was added followed by the careful addition
of NaBH4 (10 mg, 0.26 mmol) at 0 1C. The products were isolated after
basic workup (except for entries 11 and 12) and chromatography.
2a (1.0 M), RT, MeOH 15
a
Reaction conditions: to a mixture of 2a (0.20 mmol) and iridium catalyst
L-Ir1–5 (0.1–4 mol%) in anhydrous toluene (2.0 mL for entries 1–5 and 9,
0.2 mL for entries 6–8), DMF (0.2 mL) or MeOH (0.2 mL) at 0 1C was added
the aldehyde 1a (0.30 mmol). After being stirred at 0 1C or room
temperature for 1.5–36 h under reduced light, MeOH (2.0 mL) was added,
followed by the careful addition of NaBH4 (0.26 mmol) at 0 1C. The
b
c
Isolated yields. Enantiomeric excess determined by chiral HPLC
d
analysis. No suitable chiral HPLC conditions to resolve the two
enantiomers were found for the corresponding cyclization products.
b
products were isolated after basic workup and chromatography. Iso-
lated yields. Enantiomeric excess determined by chiral HPLC analysis.
c
Under the assumption that the minor enantiomer is formed
from the uncatalyzed background reaction, for 0.1 mol%
catalyst loading one can calculate an impressive turnover
number of almost 103 with a rate acceleration of 1.0 Â 104.
Table 2 reveals the substrate scope of L-Ir4, providing the
corresponding b-hydroxyhydrazines (after in situ reduction of
the aldehyde) or oxazolidinones (after NaOH-induced cycliza-
tion of the b-hydroxyhydrazines) with satisfactory yields and
high enantioselectivities. Thus, rational design with just a few
rounds of optimization afforded the highly active chiral-only-at-
metal iridium catalyst L-Ir4 for the enantioselective a-amination
of aldehydes.
The mode of action of iridium complex L-Ir4 can be ratio-
nalized by a bifunctional, dual activation catalysis which con-
verts the aldehyde into a nucleophilic enamine, while at the
same time activating the azodicarboxylate electrophile through
hydrogen bonding with one OH-group (Fig. 2). The asymmetric
induction is then achieved by sterically enforcing the (E)-syn
enamine conformation through sterically preventing the unfavored
of nitrogen-containing optically active scaffolds.8,9 Accordingly, when
we reacted aldehyde 1a with dibenzyl azodicarboxylate (2a) in toluene
at 0 1C in the presence of 4 mol% of L-Ir1, we obtained the
configurationally stable N-(benzyloxycarbonylamino)oxazolidinone
(S)-3a after in situ reduction with NaBH4 and NaOH-induced cycliza-
tion in a yield of 87% with modest but encouraging 31% ee (Table 1,
entry 1).10 A repositioning of the hydrogen-bond donor by replacing
the phenolic OH by a hydroxymethyl group slightly improved the ee
value to 39% (L-Ir2; Table 1, entry 2). We next speculated that the low
enantiodifferentiation might be the result of a missing discrimination
between the two possible enamine conformations upon reaction of
the secondary amine of L-Ir2 with aldehyde 1a, so that the introduc-
tion of steric hindrance at the 5-position of the metalated phenyl
group would provide the necessary bias towards a single enamine
conformation. Indeed, L-Ir3, containing a 2,6-Me2Ph substituent at
the 5-position of the metalated phenyl group provided oxazolidinone
(S)-3a with a significantly improved ee value of 65% (Table 1, entry 3).
Increasing this steric hindrance with the more bulky 2,4,6-iPr3Ph
substituent (L-Ir4) further improved the enantioselectivity to 97% ee
at a yield of 96% with 4 mol% of L-Ir4 (Table 1, entry 4). Even with a
reduced catalyst loading of 1 mol% L-Ir4, the oxazolidinone (S)-3a
was obtained with 91% ee at room temperature (Table 1, entry 5).
Finally, upon optimization of the reaction conditions by increasing
the concentrations of aldehyde 1a (1.5 M) and azodicarboxylate 2a
(1.0 M), the reaction time was significantly decreased while improving
the enantiodifferentiation to 97% ee with 1 mol% L-Ir4 (entry 6). To
our delight, under these conditions, the catalyst loading could be
decreased further down to 0.2 (entry 7) and even 0.1 mol% (entry 8)
while retaining satisfactory enantioselectivities of 94% and 91% ee,
respectively.‡
Fig. 2 Proposed enamine/H-bonding mechanism of the a-amination of
aldehydes (blue) with azodicarboxylates (green) catalyzed by iridium
complex L-Ir4.
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of functional groups in the three-dimensional space, whereas
the limited flexibility of the metal scaffold provides entropic
benefits and promotes the rational catalyst design.
Notes and references
‡ The catalyst can be recycled several times without any significant loss
of enantioselectivity as determined for the conversion 1a + 2a - (S)-3a
catalyzed by L-Ir4 (1 mol%): cycle 1 (1.0 mmol scale) = 76% yield, 97% ee,
81% catalyst recovery; cycle 2 (0.81 mmol scale) = 71% yield, 95% ee,
78% catalyst recovery; cycle 3 (0.63 mmol scale) = 67% yield, 96% ee, 76%
catalyst recovery.
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ellipsoids). The iridium complex was crystallized as an iodide salt in its
racemic form. The iodide counterions and the D-isomer are omitted for
clarity (CCDC 1006275).
(E)-anti conformation induced by a bulky 2,4,6-iPr3Ph substituent,
in combination with a preference for the Si face approach of the
electrophile favored by a hydrogen bond between a hydroxymethyl
group of the benzoxazole moiety and a nitrogen or carbonyl oxygen
atom of the azodicarboxylate. The importance of this hydrogen
bond for catalysis rate and enantioselectivity is demonstrated
by the result with iridium complex L-Ir5, devoid of the hydroxyl
methyl substituent on the benzoxazole moiety, resulting in the
completely racemic formation of oxazolidinone 3a (Table 1,
entry 9). The importance of this key hydrogen bond for catalysis
also explains why the aprotic, nonpolar solvent toluene pro-
vides superior results to polar (28% ee in DMF, entry 10 in
Table 1) or protic (9% ee and low yield in MeOH, entry 11 in
Table 1) solvents in which competing hydrogen bonds disfavor
the proposed hydrogen bonded binary complex shown in Fig. 2.
A structure of the iridium complex cation of the catalyst L-Ir4,
derived from a crystal structure of racemic L/D-Ir4, is shown in
Fig. 3 and illustrates the local environment around the second-
ary amine with the steric interference of one close by isopropyl
group and a neighboring hydroxyl group for hydrogen bond
interactions, thereby supporting the above proposed rationale
for the observed efficient asymmetric induction.
In conclusion, we here presented an asymmetric enamine
catalyst build from an octahedral chiral-at-metal complex. With
respect to catalyst loading in asymmetric organocatalysis,8,9,11
iridium complex L-Ir4 constitutes one of the most efficient
catalyst for the enantioselective a-amination of aldehydes to
date. The high performance and straightforward design of the
developed enamine/H-bonding dual activation catalyst through
just a few cycles of ligand optimization indicates the power for
a metal-templated design of ‘‘organocatalysts’’, in which the
octahedral stereocenter orchestrates the tailored arrangement
´
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7 As an alternative, the thiazole analog of oxazole 8 can be employed
as the third bidentate ligand. See the ESI† for more details.
8 For pioneering work on the direct catalytic a-amination of aldehydes
through enamine catalysis, see: (a) A. Bøgevig, K. Juhl,
N. Kumaragurubaran, W. Zhuang and K. A. Jørgensen, Angew.
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¨
¨
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`
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a-hydrazino aldehydes, enantioselectivities were determined after
aldehyde reduction and subsequent base induced cyclization.
11 Low loading asymmetric organocatalysis: F. Giacalone,
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Chem. Commun., 2014, 50, 10409--10411 | 10411