Asymmetric Iron-Catalyzed C?H Alkylation Enabled by Remote Ligand meta-Substitution

Article abstract of DOI:10.1002/anie.201709075

Highly enantioselective iron-catalyzed C?H alkylations by inner-sphere C?H activation were accomplished with ample scope. High levels of enantiocontrol proved viable through a novel ligand design that exploits a remote meta-substitution on N-heterocyclic

Full text of DOI:10.1002/anie.201709075

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Accepted Article
Title: Asymmetric Iron-Catalyzed C−H Alkylation Enabled by Remote
Ligand meta-Substitution
Authors: Joachim Loup, Daniel Zell, Joao Carlos Agostinho de Oliveira,
Helena Keil, Dietmar Stalke, and Lutz Ackermann
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201709075
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Asymmetric Iron-Catalyzed C−H Alkylation Enabled by Remote
Ligand meta-Substitution
Joachim Loup,[a] Daniel Zell,[a] João C. A. Oliveira,[a] Helena Keil,[b] Dietmar Stalke,[b] and Lutz
Ackermann[a]*
Abstract: Highly enantioselective iron-catalyzed C−H alkylations by
inner-sphere C−H activation were accomplished with ample scope.
High levels of enantiocontrol proved viable through a novel ligand
design that exploits a remote meta-substitution on N-heterocyclic
carbenes within a facile LLHT C−H cleavage.
The direct modification of otherwise inert C−H bonds has been
recognized as a transformative tool in molecular syntheses.[1]
While significant progress was realized with the aid of precious,
rather toxic 4d and 5d transition metals, recent focus has shifted
to earth-abundant 3d metals.[2] Despite major advances, full
Figure 1. Asymmetric iron-catalyzed C−H alkylation.
selectivity control in asymmetric C−H transformations continues
to heavily rely on noble 4d transition metals, mostly palladium[3]
and rhodium[4] complexes.[5] In sharp contrast, enantioselective
Preliminary studies identified imidazolinium salts to be superior
to phosphine and nitrogen ligands. Among a variety of NHCs,[15]
C−H activations with sustainable 3d metals are extremely scarce,
the importance of the meta-substitution pattern of the N,N’-
diarylated NHCs emerged, with best results being achieved with
the novel meta-1-adamantyl derivative L7.
with an elegant exception on phosphine ligand-enabled cobalt
catalysis by Yoshikai.[6] Within our program on less-toxic[7] iron-
catalysis for C−H activation,[8] we have developed the first
enantioselective iron-catalyzed C−H alkylation[9] by inner-
sphere[10] C−H activation. Notable features of our approach
include (i) asymmetric secondary indole C−H alkylations, (ii) low
reaction temperatures (45 °C), (iii) alkenylmetallocenes in C−H
alkylations, (iv) detailed mechanistic insights, and (v) the design
of novel meta-decorated N-heterocyclic carbene (NHC) ligands
for asymmetric iron-catalyzed C−H activation (Figure 1).
Table 1. Ligand optimization for asymmetric C−H alkylation.[a]
We initiated our studies by exploring a wealth of ligands in the
asymmetric C−H functionalization of indole 1a (Table 1 and
Tables S-1 – S-2 in the Supporting Information).[11] We selected
alkenylferrocenes 2 as substrates because of their unique
importance in asymmetric catalysis,[12] material sciences,[13] and
bioinorganic chemistry.[14]
Entry
Ligand
L1
3a Yield [%][b]
e.r.[c]
75:25[d]
46:54[d]
59:41
89:11
93:7
1
2
3
4
5
6
7
8
5.5
3.3
81
69
69
53
69
78
L2
L3
L4
L5
[*][a] J. Loup, Dr. D. Zell, Dr. J. C. A. Oliveira, Prof. Dr. L. Ackermann
Institut für Organische und Biomolekulare Chemie
Georg-August-Universität Göttingen
L6
95:5
L7
96:4
Tammannstrasse 2, 37077 Göttingen (Germany)
E-mail: Lutz.Ackermann@chemie.uni-goettingen.de
Homepage: http://www.ackermann.chemie.uni-goettingen.de
L8
88:12
[a] Reaction conditions: 1a (0.250 mmol), 2a (0.375 mmol), [Fe(acac)3] (10
mol %), ligand (20 mol %), CyMgCl (0.275 mmol), TMEDA (0.50 mmol), THF
(0.50 mL), 45 °C, 16 h. [b] Isolated yields. [c] Determined by HPLC. [d] 60 °C.
[b]
H. Keil, Prof. Dr. D. Stalke
Institut für Anorganische Chemie
Georg-August-Universität Göttingen
Tammannstrasse 4, 37077, Göttingen (Germany)
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Control experiments verified the importance of the TMEDA
additive and the iron catalyst, while manganese, cobalt or nickel
salts fell short in delivering the desired product 3a (Table 2).
Table 2. Variation of reaction parameters.[a]
Entry
1
Deviation from standard conditions
none
3a Yield [%][b]
e.r.[c]
96:4
95:5
---
69
53
---
26
33
---
55
---
39
---
50
2
L7 (10 mol %)
3
CyMgCl was omitted
4
CyMgCl (0.6 equiv)
96:4
96:4
---
5
PhMgCl instead of CyMgCl
TMSCH2MgCl instead of CyMgCl
iPrMgCl instead of CyMgCl
NaOtBu instead of CyMgCl
TMEDA was omitted
6
7
95:5
---
8
9
95:5
---
Scheme 1. Asymmetric C−H alkylation with alkenylmetallocenes 2.
10
11
[Fe(acac)3] was omitted
FeCl2 instead of [Fe(acac)3]
Rc = ruthenocenyl. [a] No hydrolysis.
95:5
[Co(acac)2], [Mn(acac)2] or [Ni(acac)2]
instead of [Fe(acac)3]
The versatile iron catalyst was not limited to metallocenyl
alkenes 2. Indeed, a variety of styrenes 4 smoothly underwent
the iron-catalyzed C−H activation with high levels of positional
and enantio selectivity likewise (Scheme 2). The asymmetric
iron-catalyzed C−H alkylation was again characterized by high
chemo-selectivity and broad substrate scope. The connectivity
and absolute configuration of the imine S-5a was collaborated
by X-ray diffraction analysis.[11,16] It is noteworthy that an
azaindole was also efficiently converted to the heterocycle 5s.
12
---
---
13
14
At 60 °C
At 23 °C
72
40
94:6
97:3
[a] Reaction conditions: 1a (0.250 mmol), 2a (0.375 mmol), [Fe(acac)3] (10
mol %), L7 (20 mol %), CyMgCl (0.275 mmol), TMEDA (0.50 mmol), THF
(0.50 mL), 45 °C, 16 h. [b] Isolated yields. [c] Determined by HPLC.
With the optimized iron catalyst in hands, we probed its
performance in the intermolecular asymmetric C−H alkylation
(Scheme 1). Thus, the desired carbaldehydes 3 were obtained
with excellent levels of enantiocontrol. The asymmetric C−H
alkylations occurred with excellent positional selectivity, and
enabled the preparation of highly enantiomerically-enriched
ferrocenyl and ruthenocenyl indoles. The absolute configuration
of product 3a was unambiguously established by X-ray
diffraction analysis.[11,16] In addition, synthetically meaningful
azaindoles were identified as viable substrates for the first time
in iron-catalyzed C−H alkylations as well.
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Scheme 3. Reactions with isotopically labeled substrate [D]1-1g.
Detailed kinetic studies showed the reaction rate to feature a
first order dependence on the concentration of indole 1g, while a
less common zeroth order was found for the alkene 4e (Scheme
4).
Scheme 2. Asymmetric C−H activation with alkenes 4. [a] No hydrolysis.
Given the unique selectivity of the iron-catalyzed C−H
activation, we became attracted to delineating its mode of action.
To this end, C−H alkylations with isotopically labeled substrates
provided support for an inner-sphere C−H activation, selectively
transferring the deuterium to the terminal position of the alkene
(Scheme 3a-c), which can be rationalized with the C−H cleavage
occurring by ligand-to-ligand H-transfer (LLHT) or C−H oxidative
addition.[17,18] C−H activations with isotopically labeled
compounds further revealed a kinetic isotope effect (KIE) of
kH/kD  1.0 (d).[11]
Scheme 4. Kinetic analysis of iron-catalyzed C−H alkylation.
Based on our mechanistic studies, we propose the catalytic
cycle to be initiated by the formation of the active iron catalyst
through the reduction[19] of the iron(III) precursor by the action of
CyMgCl via -hydrogen-elimination (Scheme 5). In consideration
of previous reports,[20] we propose the TMEDA additive to induce
deaggregation and coordinate to the Grignard reagent rather
than the active NHC-ligated iron(II)[20c] catalyst. The mono-NHC-
iron catalyst is then coordinated by the alkene in a reversible
fashion, leading to the zeroth order in the alkene. The
subsequent kinetically-relevant migratory insertion is induced by
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ligation of the substrate 1,[21] thus explaining its first order. Given
the facile inner-sphere C−H cleavage and the selective
deuterium transfer to the methyl group in product [D]1-5g
(Schemes 4), we propose the C−H metalation to occur through a
LLHT[17] manifold by the action of the coordinated substrate 1.
While we cannot rule out a rate-determining initial coordination
of substrate 1, along with subsequent C−H activation by
oxidative addition, preliminary computational studies provide
support for the LLHT regime.[11]
Scheme 7. Diversification of the products.
In conclusion, we report on the first enantioselective iron-
catalyzed C−H alkylations by organometallic C−H activation.
The
positional-selective
alkene
hydroarylation
was
accomplished with ample scope at low reaction temperature
through a LLHT C−H cleavage. Key to success was the
unravelling of a novel ligand design strategy that highlights the
crucial importance of remote meta-substitution on NHC ligands
in iron catalysis.
Acknowledgements
Generous support by the DFG (SPP 1807) is gratefully
acknowledged.
Keywords: C−H activation • iron • asymmetric catalysis • chiral
ligands • metallocene
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J. Loup, D. Zell, J. C. A. Oliveira, H. Keil,
D. Stalke, L. Ackermann*
Page No. – Page No.
Asymmetric Iron-Catalyzed C−H
Alkylation Enabled by Remote Ligand
meta-Substitution
Text for Table of Contents
Remote for Fe: Asymmetric iron-catalyzed C−H alkylations were realized through a novel ligand design featuring
remote meta-substitution for organometallic C−H activation.
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