MnCl2-Catalyzed C?H Alkylations with Alkyl Halides

Article abstract of DOI:10.1002/chem.201703191

C?H alkylations with challenging β-hydrogen-containing alkyl halides were accomplished with sustainable MnCl₂ as the catalyst under phosphine-ligand-free conditions. The proximity-induced benzamide C?H activation occurred with ample substrate s

Full text of DOI:10.1002/chem.201703191

A Journal of
Accepted Article
Title: MnCl2-Catalyzed C-H Alkylations with Alkyl Halides
Authors: Weiping Liu, Gianpiero Cera, João C. A. Oliveira, Zhigao
Shen, and Lutz Ackermann
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To be cited as: Chem. Eur. J. 10.1002/chem.201703191
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MnCl2-Catalyzed C–H Alkylations with Alkyl Halides
Weiping Liu,‡ Gianpiero Cera,‡ João C. A. Oliveira, Zhigao Shen and Lutz Ackermann*[a]
Abstract: C–H alkylations with challenging β-hydrogen-containing
alkyl halides were accomplished with sustainable MnCl2 as the
catalyst under phosphine-ligand free conditions. The proximity-
induced benzamide C–H activation occurred with ample substrate
scope through rate-determining C–H metalation, also setting the
stage for manganese-catalyzed oxidative C–H methylations.
The direct transformation of otherwise inert C−H bonds has
emerged as an increasingly powerful tool in molecular
synthesis.[1] While major progress has been achieved with noble
transition metals in C−H functionalizations with electrophilic alkyl
halides,[2,3] recent focus has shifted towards the use of less
expensive base[4] metal catalysis.[5] In this context, earth
abundant manganese is particularly attractive - not only because
of its cost-effective nature, but also due to its low toxicity.[6]
Figure 1. Manganese-catalyzed C–H activation.
However, despite of considerable advances,[7,8] manganese-
catalyzed organometallic C–H activations continue to be limited
to substrates that contain multiple bonds through migratory
insertion as the essential elementary step (Figure 1a). In sharp
We initiated our studies by a thorough optimization of the
contrast, manganese-catalyzed C–H activations with organic
halides have unfortunately thus far proven elusive. Within our
program on sustainable C–H functionalizations,[9] we have now
developed the unprecedented manganese-catalyzed substitutive
C–H activation with challenging organic halides, on which we
report herein. Notable features of our findings include (i)
versatile C–H alkylations with β-hydrogen-containing alkyl
halides, (ii) occurring – in contrast to iron catalysis –[10] under
zinc- and phosphine-free reaction conditions, (iii) a removable[11]
triazolylmethyl (TAM)-group[11b] approach and (iv) mechanistic
insights into novel low-valent manganese-catalyzed C–H
alkylations (Figure 1b).
envisioned manganese-catalyzed C–H alkylation of TAM-
substituted benzamide 1a (Table 1 and Tables S1–S6 in the
Supporting Information).[12] The desired C–H alkylation was
accomplished in the presence of expensive bisphosphine
ligands that are typically required in iron-catalyzed C–H
activation (entries 1–5).[13] In sharp contrast, we observed that a
phosphine was not required here (entries 6–8), highlighting the
unique features of the manganese regime. Contrarily, under
otherwise identical reaction conditions, typical iron catalysts fell
short in enabling effective C–H activation even at higher catalyst
loading (entry 9). Furthermore, control experiments verified the
essential role of the manganese catalyst (entry 10).
Table 1. Optimization of manganese-catalyzed C–H alkylation.[a]
Entry
TM
ligand
THF (M)
Yield [%]
1
2
3
4
5
6
7
MnCl2
MnCl2
MnBr2
Mn(OAc)2
MnCl2
MnCl2
MnCl2
PPh3
dppe
dppe
dppe
dcpe
---
0.2
0.2
0.2
0.2
0.2
0.2
1.0
36[b]
57[b]
49[b]
33[b]
47[b]
51[b]
80
[a]
Dr. W. Liu,‡ Dr. G Cera,‡ , Dr. J. C. A. Oliveira, Z. Shen, Prof. Dr. L.
Ackermann
Institut für Organische und Biomolekulare Chemie
Georg-August-Universität
Tammannstraße 2, 37077 Göttingen (Germany)
E-mail: Lutz.Ackermann@chemie.uni-goettingen.de
Homepage: http://www.org.chemie.uni-goettingen.de/ackermann/
These authors contributed equally to this work.
[‡]
---
Supporting information for this article is available on the WWW under
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8
MnCl2
FeCl3
---
---
---
---
2.0
2.0
2.0
82[c]
18
9
10
---
[a] Reaction conditions: 1a (0.2 mmol), 2a (0.6 mmol), MnCl2 (20 mol %),
Ligand (20 mol %), iPrMgBr (3.5 equiv), TMEDA (0.4 mmol), THF, 65 °C, 16 h,
isolated yields. [b] Conversion by 1H-NMR with CH2Br2 as the internal standard.
[c] MnCl2 (10 mol %). dppe = 1,2-bis(diphenylphosphino)ethane; dcpe = 1,2-
bis(dicyclohexylphosphino)ethane; TMEDA = N1,N1,N2,N2-tetramethylethane-
1,2-diamine.
Thereafter, we tested the influence exerted by the benzamide
directing group on the catalytic efficacy of the C–H alkylation
process (Scheme 1). Thus, triazoles bearing N-alkyl groups
proved highly effective for the chelation-assisted C–H
functionalization, while the previously employed[10b] benzyl-
substituted analog led to significantly lower yields of product 3ca.
The gem-disubstitution within the TAM group proved mandatory
(3ea), as was the acidic nature of the secondary amide (3fa). It
is particularly noteworthy that the 8-aminoquinoline directing
group did not allow for any synthetically useful C–H alkylation.[12]
Scheme 2. Manganese-catalyzed C−H alkylation of benzamides 1.
Likewise,
a representative set of alkyl bromides 2 were
amenable to the low-valent manganese-catalyzed C–H
functionalization, thereby providing the desired products 3ab–
3ah in a step-economical manner and with high mono-selectivity
(Scheme 3). Notably, 1-bromo-6-chlorohexane (2i) underwent
the C–H alkylation process with excellent chemo-selectivity to
afford the chloroalkylated arene 3ai as the sole product. Also,
synthetically meaningful alkenes were fully tolerated (3aj and
3ak), rendering a β-elimination/hydroarylation sequence unlikely
to be operative here (vide infra).
Scheme 1. Probing chelation-assisted C–H alkylation.
Subsequently, we explored the versatility of the optimized
manganese-catalyzed C–H alkylation using diversely substituted
TAM-benzamides 1 (Scheme 2). Hence, arenes 1g–1n smoothly
underwent the C–H alkylation with high levels of chemo-
selectivity. Furthermore, a heteroaromatic indole 1o proved,
among others, to be
a viable substrate. Intramolecular
competition experiments with meta-substituted arenes 1m/n
were largely dominated by steric interactions.
Scheme 3. Manganese-catalyzed C−H alkylation with alkyl bromides 2.
The manganese-catalyzed C–H activation regime was not
limited to redox-neutral C–H alkylations with organic halides 2.
Indeed, considering the profound magic methyl effect[14] in drug
discovery, we were delighted to unravel the selective mono-
methylation by the action of MeMgBr (Scheme 4). It is
particularly noteworthy that costly bidentate phosphine ligands[13]
were not required for the challenging C–H methylation.
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Scheme 4. Manganese-catalyzed oxidative C−H methylation.
Considering the versatility of the low-valent manganese-
catalyzed C–H activation, we became attracted to delineating its
mode of action. To this end, 1-octene (6f) gave under otherwise
identical reaction conditions only minor amounts of the
corresponding
product
3af,
again
rendering
a
β-
elimination/hydroarylation manifold unlikely to be of relevance
(Scheme 5a). The C–H alkylation with 6-bromo-1-hexene (2l)
led to a mixture of the linear and the cyclized[15] products 3al
and 3al’ (Scheme 5b), being indicative of a homolytic C–Br
cleavage event. In good agreement with this observation,
cyclopropylmethyl bromide (2m) selectively delivered the
homoallylated arene 3ak as the sole product. Intermolecular
competition experiments revealed electron-deficient arenes 1 to
be inherently more reactive (Scheme 5c), which is in good
agreement with a σ-bond metathesis C–H activation pathway.[16]
Furthermore, a significant primary kinetic isotopic effect (KIE)
observed within intramolecular and intermolecular KIE
experiments, suggested the C–H activation step to be rate-
determining (Scheme 5d and 5e).
Scheme 5. Summary of key mechanistic findings.
Subsequently, we explored the working mode of the oxidative
C−H methylation by density functional theory (DFT) at the
B3LYP-D3(BJ)/def2-TZVP+COSMO(THF)//TPSS-D3(BJ)/def2-
SVP level of theory.[12,17] These calculations suggest that the C–
H activation step proceeds as the rate-determining step via
σ-bond metathesis with an activation energy of 22 kcal mol-1
(Scheme 6a). Generally, the high-spin manganese complexes
are favored with considerable contributions from attractive
dispersion[18] interactions (Scheme 6b).
a)
60,0
50,0
40,0
52,3
42,8
26,5
43,6
22,0
36,0
23,4
30,0
20,0
10,0
0,0
-10,0
-20,0
-30,0
31,4
-1,8
28,1
28,4
6,1
25,0
6,8
0,0
-2,7
-7,3
-10,3
-19,1
-21,1
Inter.-spin
-22,3
High-spin
Low-spin
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Scheme 6. (a) Computed ΔG343.15 for manganese-catalyzed C−H methylation
with dispersion corrections. (b) Catalytic cycle calculated energetics (kcal mol-1)
with (blue) and without dispersion correction (red).
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same time providing access to substituted benzoic acids 7
(Scheme 7).
[5]
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Scheme 7. Removal of reusable TAM group to deliver benzoic acids.
In summary, we have reported on the first manganese-catalyzed
C–H activation with organic halides. The unprecedented low-
valent manganese-catalyzed C–H alkylation occurred under
zinc-free reaction conditions in the absence of any expensive
phosphine ligands, providing versatile access to C–H-alkylated
benzamides by assistance of the removable TAM group.
Mechanistic studies provided strong support for
a rate-
determining C–H activation, which also set the stage for
transformative oxidative C–H methylations.
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Acknowledgements
[7]
[8]
Generous by the CSC (fellowship to Z.S.), the Alexander von
Humboldt Foundation (fellowship to G.C.), the DFG (SPP 1807),
and the European Research Council under the Seventh
Framework
Program
of
the
European
Community
(FP720072013; ERC Grant Agreement No. 307535) is gratefully
acknowledged.
Keywords: C–H activation
• alkylation • manganese •
mechanism • selectivity
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Weiping Liu,‡ Gianpiero Cera,‡ João C.
A. Oliveira, Zhigao Shen and Lutz
Ackermann*
Page No. – Page No.
MnCl2-Catalyzed C–H Alkylation with
Alkyl Halides
No P: Sustainable MnCl2 enabled challenging C–H alkylations under phosphine-free conditions with ample scope
through rate-determining C–H metalation, also enabling manganese-catalyzed oxidative C–H methylations.
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