Tri-Substituted Triazole-Enabled C-H Activation of Benzyl and Aryl Amines by Iron Catalysis

Article abstract of DOI:10.1021/acs.orglett.7b01672

The design of trisubstituted triazoles set the stage for proximity-induced iron-catalyzed C-H activation of benzyl and aryl amines with ample scope. Thereby, C-H alkylations and C-H arylations proved viable with high levels of chemo and positional selectivities by means of racemization-free iron catalysis with the reusable triazole being removed in a traceless fashion.

Full text of DOI:10.1021/acs.orglett.7b01672

Letter
pubs.acs.org/OrgLett
Tri-Substituted Triazole-Enabled C−H Activation of Benzyl and Aryl
Amines by Iron Catalysis
Zhigao Shen,† Gianpiero Cera,† Tobias Haven, and Lutz Ackermann*
Institut fur Organische und Biomolekulare Chemie, Georg-August-Universitat, Tammannstraße 2, 37077 Gottingen, Germany
̈
̈
̈
S
* Supporting Information
ABSTRACT: The design of trisubstituted triazoles set the stage for
proximity-induced iron-catalyzed C−H activation of benzyl and aryl
amines with ample scope. Thereby, C−H alkylations and C−H
arylations proved viable with high levels of chemo and positional
selectivities by means of racemization-free iron catalysis with the
reusable triazole being removed in a traceless fashion.
Scheme 1. Iron-Catalyzed C−H Activations on Electron-
enzylamines represent the key molecular motif of various
1
Rich Benzylamines by Fully-Substituted Triazoles
Bnatural products and bioactive compounds.
As a
consequence, the development of flexible strategies for their
selective functionalization continues to be in high demand. A
step-economical approach toward this goal exploits the
activation of otherwise inert C−H bonds.2 In this context,
major advances have been achieved by means of precious, toxic
transition metals.3 In sharp contrast, the use of inexpensive,
environmentally benign base metals4 only recently emerged as a
viable alternative for selective C−H activation chemistry.
Despite considerable progress,5 the direct functionalization of
benzylamines remains particularly challenging because of their
electron-rich nature and their geometrical flexibility within the
chelation-assisted C−H metalation. In recent years, iron
catalysis has been identified as an increasingly powerful tool
in C−H activation chemistry.6 However, the potential of iron-
catalyzed C−H activation has thus far been largely limited to
the modification of electron-deficient benzamides.7,8 Contrast-
ingly, we became attracted to developing an unprecedented
iron-catalyzed C−H functionalization by triazole9 assistance on
inherently electron-rich benzylamines. To this end, we designed
a set of novel tri-substituted 1,2,3-triazoles (TST), which set
the stage for versatile iron-catalyzed C−H activations on
electron-rich benzylamines including the direct installation of
the medicinally relevant10 methyl group (Scheme 1).
2,3-dichlorobutane7b was used as a mild oxidizing agent (entry
7).
With the optimized reaction conditions in hand, we explored
the influence exerted by the TST substitution pattern on the
catalytic efficacy. Thus, the iron catalysts tolerated various
benzylamines, with the sterically congested gem-disubstituted
benzylamine 1b being efficiently converted (Scheme 2). The
iron-catalyzed C−H activation proved amenable to differently
N-substituted triazoles including alkyl and aryl-decorated
derivatives 1c,d. The tertiary amide 1e failed to undergo
C−H methylation, probably due to an anionic bidentate
coordination mode on iron. It is particularly noteworthy that
the frequently used, powerful picolinic acid-derived12 benzyl-
amine 1f was significantly less effective under otherwise
identical reaction conditions.
Thereafter, we probed the versatility of our iron-catalyzed
C−H activation with differently substituted benzylamines 1. To
our delight, ortho-functionalized substrates furnished the
products 2g−l in good-to-excellent yields while tolerating
both electron-donating and electron-withdrawing groups
(Scheme 3). Also, the aromatic naphthalene-derivative 1m
At the outset of our studies, we probed the TST benzylamide
1a for the envisioned iron-catalyzed C−H methylation
manifold.11 Preliminary results revealed that nitrogen or
NHC ligands fell short in enabling the desired C−H
methylation (Table 1, entries 1−3). The bidentate dppe ligand
gave only unsatisfactory results, which could be rationalized
with the need for a more rigid coordination environment on
iron (entry 4). In good agreement with this hypothesis, dppz
and dppen led to the formation of the desired compound 2a in
synthetically useful yields (entries 5 and 6), particularly when
Received: June 2, 2017
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.7b01672
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Letter
Table 1. Iron-Catalyzed C−H Methylations of Benzylamine
Scheme 3. TST-Assisted Iron-Catalyzed C−H Methylation
a
1a
entry
ligand
oxidant
2a [%]
1
2
3
4
5
6
7
−
DCB
DCB
DCB
DCB
DCB
DCIB
DCB
−
−
−
21
45
53
86
dtbpy
IPrHCl
dppe
dppbz
dppen
dppen
a
Reaction conditions: 1a (0.20 mmol), FeCl3 (15 mol %), ligand (15
mol %), MeMgBr (1.40 mmol), ZnCl2·TMEDA (0.60 mmol), oxidant
(0.60 mmol), THF (0.5 M), 65 °C, 16 h. Isolated yields. dppe = 1,2-
bis(diphenylphosphino)ethane; dppbz = 1,2-bis(diphenylphosphino)-
benzene; dppen = 1,2-bis(diphenylphosphino)ethene. DCB = 2,3-
dichlorobutane. DCIB = 1,2-dichloro-2-methylpropane.
Scheme 2. Influence of the TST Substitution Pattern
Scheme 4. TST-Assisted Iron-Catalyzed C−H Ethylation
underwent a rather unusual peri-C−H methylation, which
thereby furnished the product 2m with excellent positional
selectivity. Para- and meta-substituted substrates directly
delivered the two-fold methylated products 2n−u. Importantly,
the robustness of this sustainable iron catalyst was highlighted
by synthesizing product 2s on a gram-scale with comparable
levels of efficacy. Given the practical importance of nitrogen-
containing heterocycles, it is noteworthy that pyridine 2v could
be obtained in synthetically useful yields as well. Likewise,
bicyclic substrate 1w delivered the desired product 2w featuring
the sertraline motif−an important pharmacophore in medicinal
chemistry.13
Scheme 5. TST-Assisted Iron-Catalyzed C−H Arylation
Our iron-catalyzed C−H activation strategy was not limited
to direct methylation reactions. Indeed, the versatility of our
approach was reflected by the high-yielding C−H ethylation14
of benzylamine 1h, with the best results being achieved by the
action of DCIB as the oxidant (Scheme 4).
Moreover, the robust nature of our iron catalyst also set the
stage for effective C−H arylations on benzylamines 1 under
otherwise identical reaction conditions (Scheme 5). Again,
DCIB proved to be the optimal oxidant, as was previously
found for iron-catalyzed C−H arylations.8e The observed
monoselectivity8e is likely due to increased steric interactions.
As to the catalyst mode of action, we conducted kinetic
studies through independent experiments. To this end, we
unraveled a kinetic isotope effect (KIE) of kH/kD = 1.7, which
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was suggestive of a kinetically relevant C−H activation step
In summary, we have reported on the design of a fully
trisubstituted triazole TST that has enabled the expedient C−H
functionalization of electron-rich benzyl and aryl amines by
sustainable iron-catalysis. Thus, hitherto unprecedented
triazole-assisted C−H methylations, alkylations, and arylations
are now viable with excellent positional selectivity under
racemization-free conditions, exploiting the versatile TST
group, which could be removed in a traceless fashion.
(Scheme 6) likely leading to two-state reactivity.15 The
Scheme 6. KIE Studies by Independent Experiments
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01672.
Experimental methods and data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: Lutz.Ackermann@chemie.uni-goettingen.de.
ORCID
Lutz Ackermann: 0000-0001-7034-8772
Author Contributions
†These authors contributed equally.
Notes
outstanding efficacy of this iron-catalyzed C−H activation was
further reflected by a 48% conversion of substrate 1k within
only 25 min reaction time.
The synthetic utility of our iron-catalyzed C−H activation
strategy was among others mirrored by the racemization-free
modification of the enantiomerically enriched benzylamine (S)-
1a (Scheme 7).16
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support by the Alexander von Humboldt-foundation (fellow-
ship to G.C.), the CSC (fellowship to Z.S.), and DFG (Leibniz
award) is gratefully acknowledged.
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Scheme 7. Racemization-Free C−H Methylation of
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■
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