Overcoming the Limitations of C?H Activation with Strongly Coordinating N-Heterocycles by Cobalt Catalysis

Article abstract of DOI:10.1002/anie.201603260

Strongly coordinating nitrogen heterocycles, including pyrimidines, oxazolines, pyrazoles, and pyridines, were fully tolerated in cobalt-catalyzed C?H amidations by imidate assistance. Structurally complex quinazolines are thus accessible in a step-economic manner. Our findings also establish the relative powers of directing groups in cobalt(III)-catalyzed C?H functionalization for the first time.

Full text of DOI:10.1002/anie.201603260

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201603260
German Edition: DOI: 10.1002/ange.201603260
À
C H Activation
À
Overcoming the Limitations of C H Activation with Strongly
Coordinating N-Heterocycles by Cobalt Catalysis
Hui Wang+, Mꢀlanie M. Lorion+, and Lutz Ackermann*
Abstract: Strongly coordinating nitrogen heterocycles, includ-
ing pyrimidines, oxazolines, pyrazoles, and pyridines, were
À
fully tolerated in cobalt-catalyzed C H amidations by imidate
assistance. Structurally complex quinazolines are thus acces-
sible in a step-economic manner. Our findings also establish
the relative powers of directing groups in cobalt(III)-catalyzed
À
C H functionalization for the first time.
À
M
ethods for C H functionalization have emerged as an
increasingly powerful platform in modern organic synthesis.[1]
Despite tremendous advances during the past decade,
strongly coordinating N-heterocycles continue to pose major
challenges to transition-metal catalysts, often resulting in the
inhibition of catalytic turnover. More importantly, biologi-
cally relevant N-heterocycles, such as pyrazoles, oxazolines,
pyrimidines, or pyridines, strongly coordinate to the active
À
transition-metal catalyst, resulting in proximity-induced C H
activation in the ortho position (Figure 1a),[2] which severely
limits the application of these methods in medicinal[1e] and
pharmaceutical[3] chemistry or the materials sciences.[4] Posi-
À
tion-selective C H functionalizations of substrates with
strongly coordinating N-heterocycles have only very recently
been accomplished by means of palladium(II) catalysis with
N-methoxy benzamides, as elegantly devised by Dai, Yu, and
co-workers (Figure 1b).[5]
À
Figure 1. C H activation in the presence of strongly coordinating
heterocycles. a) Challenges. b) Palladium(II) catalysis.[5] c) Heterocycle-
tolerating cobalt catalysis.
À
In the past few years, the focus in C H activation
chemistry has shifted towards the use of naturally abundant
first-row transition metals.[6] Considerable progress was
accomplished by the development of high-valent cobalt(III)
[7]
À
À
catalyzed C H functionalizations, with notable contribu-
selectivity-ensuring entities in cobalt(III)-catalyzed C H
tions by the groups of Matsunaga/Kanai,[8] Ellman,[9]
Chang,[10] Glorius,[11] Shi,[12] Jiao,[13] and Ackermann,[14]
amidations,[20] on which we report herein.[21] Notable features
À
of our findings include 1) efficient imidate-assisted C H
among others.[15] Despite these major advances, cobalt C H
nitrogenation by cost-effective base-metal catalysis, 2) expe-
dient access to unique heterocycle-decorated quinazolines,
and 3) first detailed insight into the potencies of various
À
activation catalysts that fully tolerate strongly coordinating
heterocycles have unfortunately proven elusive. Within our
program on base-metal catalysis,[16] we have recently reported
directing groups in cobalt-catalyzed[22] C H activation, which
À
[17]
À
À
on cobalt(III)-catalyzed C H amidations
with dioxazo-
4) enabled the development of a C H amidation method that
fully tolerates strongly coordinating pyrazoles, oxazolines,
pyrimidines, and pyridines (Figure 1c).
lones[18] by the assistance of cyclic imidates.[19] Consequently,
we became intrigued by probing acyclic imidates as the site-
We initiated our studies by exploring reaction conditions
À
for the envisioned C H nitrogenation of benzimidate 1a by
[*] H. Wang,[+] Dr. M. M. Lorion,[+] Prof. Dr. L. Ackermann
Institut fꢀr Organische und Biomolekulare Chemie
Georg-August-Universitꢁt Gçttingen
cobalt catalysis (Table 1; see also the Supporting Information,
Table S1).[23] Preliminary studies indicated the facile forma-
tion of quinazoline 3aa, even in the absence of Cu(OAc)2 or
NaOAc additives (entries 1–4). The reaction temperature and
catalyst loading could be significantly reduced, which also set
the stage for the adjustment of the substrate ratio (entries 4–
7). Among a variety of cocatalytic silver(I) additives, optimal
results were obtained with AgSbF6 (entries 7–12). The robust-
ness of the cobalt(III) catalysis was reflected by the high
Tammannstrasse 2, 37077 Gçttingen (Germany)
E-mail: Lutz.Ackermann@chemie.uni-goettingen.de
Homepage: http://www.ackermann.chemie.uni-goettingen.de/
[+] These authors contributed equally to this work.
Supporting information and the ORCID identification numbers for
the authors of this article can be found under http://dx.doi.org/10.
1002/anie.201603260.
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Table 1: Optimization of the cobalt-catalyzed C H amidation of imidate
1a.[a]
Entry
Catalyst (mol%)
Ag salt (mol%)
T [8C]
Yield [%]
1[b,c,d]
2[c,d]
3[d]
4[d]
5[d]
6[d]
7
8
9
10
11
Cp*CoI2(CO) (10)
Cp*CoI2(CO) (10)
Cp*CoI2(CO) (10)
Cp*CoI2(CO) (5)
Cp*CoI2(CO) (5)
Cp*CoI2(CO) (5)
Cp*CoI2(CO) (5)
Cp*CoI2(CO) (5)
Cp*CoI2(CO) (5)
Cp*CoI2(CO) (5)
Cp*CoI2(CO) (5)
Cp*CoI2(CO) (5)
Cp*CoI2(CO) (5)
Co(OAc)2 (5)
Co(acac)3 (5)
–
AgSbF6 (20)
AgSbF6 (20)
AgSbF6 (20)
AgSbF6 (10)
AgSbF6 (10)
AgSbF6 (10)
AgSbF6 (10)
AgBF4 (10)
AgPF6 (10)
AgOTf (10)
AgNTf2 (10)
AgOTs (10)
–
120
120
120
120
100
80
100
100
100
100
100
100
100
100
100
120
100
100
81
85
99
99
99
83
99
96
99
80
88
19
56
–
12
13
14
15
AgSbF6 (10)
AgSbF6 (10)
AgSbF6 (10)
–
–
–
94
96
16
17[e]
18
4 (5)
4 (5)
–
À
Scheme 1. Cobalt-catalyzed C H nitrogenation of imidates 1.
[a] Reaction conditions: 1a (0.25 mmol), 2a (1.2 equiv), DCE (1.0 mL),
T, 13 h; yields of isolated products are given. [b] Cu(OAc)2 (2.0 equiv).
[c] NaOAc (20 mol%). [d] 2a (2.0 equiv). [e] Under N2.
N-heterocyclic directing groups (Scheme 2). Surprisingly,
the cobalt(III) catalyst 4 set the stage for a chemoselective
À
catalytic efficiency under an atmosphere of ambient air.
C H nitrogenation by imidate assistance, delivering quinazo-
lines 6 as the sole products. Thus strongly coordinating
À
Interestingly, the C H amidation even occurred with
Cp*CoI2(CO) as the sole catalyst component in the absence
of silver(I) salts, albeit with reduced efficacy (entry 13). In
contrast, other typically used cobalt(II) or cobalt(III) salts
failed short in delivering the desired quinazoline 3aa
(entries 14–16). In consideration of the user-friendly nature
of single-component catalysts in homogenous catalysis,[24] we
heterocycles that are themselves usually employed for
directed C H functionalization strategies, such as pyrazoles,
pyrimidines, pyrazines, and even pyridines, were fully toler-
ated by the cobalt(III) catalyst. These observations should
prove instrumental for further applications to drug design in
medicinal chemistry.
À
À
were delighted that C H nitrogenation was highly efficient
The unique chemoselectivity with the difunctional sub-
strates 5, which bear strongly coordinating N-heteroarenes,
was further reflected by intermolecular competition experi-
ments with benzimidate 1a and arenes 7a–17a (Scheme 3). It
is noteworthy that in all intermolecular settings, the X-type
imidate outcompeted the strongly coordinating L-type car-
bamate, pyrazole, oxazoline, pyrimidine, and pyridine direct-
ing groups.
with the well-defined complex [Cp*Co(CH3CN)3](SbF6)2 (4)
as the catalyst in the absence of any additives (entries 17 and
18).
With the optimized single-component catalyst 4 in hand,
we initially probed its versatility in the silver-free C H
À
nitrogenation of benzimidates 1 (Scheme 1). Diversely dec-
orated arenes 1 underwent the desired reaction to yield
quinazolines 3 with excellent chemoselectivity, which was
highlighted by the reaction fully tolerating a broad range of
electrophilic functional groups, such as fluoro, chloro, ester,
Based on these competition experiments, the potencies of
À
various directing groups in cobalt(III)-catalyzed C H func-
tionalization were established for the first time, and decrease
in the order:
À
ketone, and nitro substituents. The C H nitrogenation
reactions proceeded with excellent levels of positional
À
selectivity at the less hindered C H bond. Catalyst 4 enabled
imidate ꢀ pyridine ꢁ pyrazole > oxazoline > pyrimidine
not only the transformation of carbocyclic aromatic benzimi-
dates, but thiophene imidate 1n proved viable as well.
Likewise, various benzyl-, alkyl-, aryl-, and even heteroaryl-
substituted dioxazolones 2 proved amenable to the cobalt-
catalyzed syntheses of quinazolines 3aa–3ak.
À
To estimate the positional selectivity of the key C H
activation step, we further performed stoichiometric reactions
À
with complex 4, and determined the extent of C H metal-
Intrigued by the excellent tolerance of functional groups,
we focused on the originally envisioned amidation of imidates
5, which also contain challenging, strongly coordinating
ation by subsequent treatment with CD3CO2D (Scheme 4).
These findings indicate that the selectivity is determined in
À
the C N bond-forming step.
2
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Scheme 2. Overriding the conventional selectivity dictated by strongly
coordinating heterocycles.
À
As to the reaction mechanism, the cobalt-catalyzed C H
amidation displayed a notable kinetic isotope effect (KIE) of
kH/kD ꢁ 2.4, did not show significant H/D scrambling, and
typical radical scavengers did not inhibit the reaction.[23]
Furthermore, intermolecular competition experiments
between differently substituted benzimidates 1d and 1e
revealed that electron-rich arenes react preferentially.[23]
These observations can be rationalized in terms of a rate-
À
determining C H metalation with an electrophilic, cationic
À
cobalt(III) catalyst. The elementary step of C H activation is
proposed to proceed by s-bond metathesis[25] by means of
ligand-to-ligand hydrogen transfer. Thereafter, selectivity-
determining migratory insertion occurs by CO2 extrusion
(Scheme 5), along with the liberation of amide 23, which was
detected by GC/MS analysis of the crude reaction mixture.
In summary, we have reported the first base-metal-
À
Scheme 3. Directing group powers in cobalt-catalyzed C H functional-
ization; yields of isolated products are given. Product ratios were
À
catalyzed C H functionalization that fully tolerates strongly
coordinating heterocycles. Biologically important oxazolines,
pyrazoles, pyrimidines, and pyridines were, among others,
1
determined by H NMR spectroscopy with 1,3,5-trimethoxybenzene as
the internal standard. Bz=benzoyl, 2-pym=2-pyrimidyl.
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Keywords: C H activation · cobalt · directing groups ·
heterocycles · imidates
À
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Scheme 5. Proposed catalytic cycle.
À
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À
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Acknowledgements
Generous support by the European Research Council under
the European Communityꢀs Seventh Framework Program
(FP7 2007–2013; ERC Grant agreement 307535), the DFG
(SPP 1807), and the Chinese Scholarship Program (fellow-
ships to H.W.) is gratefully acknowledged.
4
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128, 3205 – 3209; b) G. Cera, T. Haven, L. Ackermann, Angew.
Chem. Int. Ed. 2016, 55, 1484 – 1488; Angew. Chem. 2016, 128,
1506 – 1510; c) W. Liu, J. Bang, Y. Zhang, L. Ackermann, Angew.
Chem. Int. Ed. 2015, 54, 14137 – 14140; Angew. Chem. 2015, 127,
14343 – 14346.
reports on C H activation with benzimidates and N-sulfinyl
imines and silver(I) salts were disclosed; see: a) F. Wang, H.
Wang, Q. Wang, S. Yu, X. Li, Org. Lett. 2016, 18, 1306 – 1309;
b) T. X. Wang, A. Lerchen, F. Glorius, Org. Lett. 2016, 18, 2090 –
2093.
[22] L. V. Desai, K. J. Stowers, M. S. Sanford, J. Am. Chem. Soc. 2008,
130, 13285 – 13293.
[23] See the Supporting Information for details.
[24] For recent progress, see: a) D. Zell, S. Warratz, D. Gelman, S. J.
Garden, L. Ackermann, Chem. Eur. J. 2016, 22, 1248 – 1252; b) S.
Ge, J. F. Hartwig, Angew. Chem. Int. Ed. 2012, 51, 12837 – 12841;
Angew. Chem. 2012, 124, 13009 – 13013; c) L. Ackermann, P.
Novꢁk, R. Vicente, N. Hofmann, Angew. Chem. Int. Ed. 2009, 48,
6045 – 6048; Angew. Chem. 2009, 121, 6161 – 6164, and refer-
ences therein.
[25] L. Ackermann, Chem. Rev. 2011, 111, 1315 – 1345.
À
[17] For reviews on C H nitrogenation, see: a) H. Kim, S. Chang,
ACS Catal. 2016, 6, 2341 – 2351; b) S. Dana, M. R. Yadav, A. K.
Sahoo, Top. Organomet. Chem. 2016, 55, 189 – 215; c) Y. Park, S.
Jee, J. G. Kim, S. Chang, Org. Process Res. Dev. 2015, 19, 1024 –
Received: April 3, 2016
Revised: June 13, 2016
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
À
C H Activation
H. Wang, M. M. Lorion,
L. Ackermann*
&&&& — &&&&
À
Overcoming the Limitations of C H
Activation with Strongly Coordinating N-
Heterocycles by Cobalt Catalysis
Strongly coordinating nitrogen heterocy-
cles are fully tolerated by a versatile
complex quinazolines. The powers of
various directing groups in cobalt-cata-
À
À
cobalt-catalyzed C H amidation method,
which provides access to structurally
lyzed C H activation were thus
delineated.
6
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!