Copper-catalyzed electrophilic amination of heteroarenes and arenes by C-H zincation

Article abstract of DOI:10.1002/anie.201311029

Direct amination of heteroarenes and arenes has been achieved in a one-pot C-H zincation/copper-catalyzed electrophilic amination procedure. This amination method provides an efficient and rapid approach to access a diverse range of heteroaromatic and aromatic amines including those previously inaccessible using C-H amination methods. The mild reaction conditions and good functional-group compatibility demonstrate its great potential for the synthesis of important and complex amines. Direct amination of heteroarenes and arenes has been achieved in a one-pot zincation/Cu(OAc)₂-catalyzed amination sequence using O-acylhydroxylamines. The method provides a rapid and efficient approach to a range of aromatic and heteroaromatic amines, including those which were previously inaccessible by using C-H amination methods. tmp=2,2,6,6- tetramethylpiperidide.

Full text of DOI:10.1002/anie.201311029

Angewandte
Chemie
DOI: 10.1002/anie.201311029
Synthetic Methods
Copper-Catalyzed Electrophilic Amination of Heteroarenes and
À
Arenes by C H Zincation**
Stacey L. McDonald, Charles E. Hendrick, and Qiu Wang*
Abstract: Direct amination of heteroarenes and arenes has
2-aminooxazoles.[3] Simultaneously, effective metal-catalyzed
À
À
been achieved in a one-pot C H zincation/copper-catalyzed
C H aminations have also been achieved by various tran-
electrophilic amination procedure. This amination method
provides an efficient and rapid approach to access a diverse
range of heteroaromatic and aromatic amines including those
sition metals.[4,5] Despite these significant advances, the
current methods often suffer from a limited arene scope and
poor efficiencies, particularly on important skeletons includ-
ing benzimidazoles, benzothiazoles, and thiazoles (Scheme
1A). This limitation is largely due to the challenging metal-
À
previously inaccessible using C H amination methods. The
mild reaction conditions and good functional-group compat-
ibility demonstrates its great potential for the synthesis of
important and complex amines.
H
eteroaromatic amines, especially 2-aminoazoles, are key
structural motifs which are widely found in biologically
important molecules and medicines.[1] For example, the 2-
piperazinylbenzimidazole derivative lerisetron is currently in
clinical trials for the treatment of nausea associated with
cancer chemotherapy (Figure 1).[1a] Other classes of hetero-
À
Scheme 1. Direct C H amination to access heteroaromatic amines.
Bz=benzoyl, TEMPO=2,2,6,6-tetramethyl-1-piperidinyloxy.
ation step associated with the inherently high dissociation
energy of sp2 C H bonds, and also leads to the common
Figure 1. Selected examples of bioactive heteroaromatic amines.
À
requirement of harsh reaction conditions (high temperatures,
strong oxidants, and acidic or basic additives). A more general
aryl amines, such as anti-HIVagent HM13N,[1d] WRC-0571,[1b]
and linagliptin,[1c] are also extensively used in drug discovery.
Therefore, efficient methods for the synthesis of these
important heteroaryl amines are highly valuable.
À
C H amination method is needed to access those highly
valuable aminated heteroarenes (Figure 1). Mild reaction
conditions are desirable to broaden the scope of its applica-
tions.[6]
Complementary to the Buchwald–Hartwig amination
from aryl halides,[2] direct C H amination provides a new
Herein we report a C H zincation and copper-catalyzed
À
À
À
and potentially more effective C N bond-formation
electrophilic amination as a modular and facile amination
approach to rapidly access a broad scope of important
heteroaromatic and aromatic amines (Scheme 1B). Our
approach is built on the use of strong and non-nucleophilic
zinc bases,[7] such as Zn(tmp)2 (tmp = 2,2,6,6-tetramethylpi-
peridide, pKa of the conjugate acid = 37),[8] to generate the
corresponding organozincates from a wide range of hetero-
arenes. Importantly, the resulting organozinc intermediates
approach for the synthesis of heteroaromatic amines. Several
À
À
metal-free C H/N H coupling methods have been developed
by an oxidative rearomatization pathway for the synthesis of
[*] S. L. McDonald, C. E. Hendrick, Prof. Dr. Q. Wang
Department of Chemistry, Duke University
Durham, NC 27708-0346 (USA)
À
can serve as a more reactive surrogate of C H bonds toward
E-mail: qiu.wang@duke.edu
amination.[9] Thus, this strategy will overcome the narrow
substrate scope and harsh reaction conditions of the previous
[**] Financial support was provided by a Duke University Fellowship
from the Burroughs Wellcome Endowment (S.L.M.) and the Duke
University Pharmacological Sciences Training Program (C.E.H.).
À
C H amination methods. In comparison to organozinc
intermediates prepared from the heteroaryl halides and
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201311029.
Grignard reagents,[10] our approach using the direct H–Zn
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Table 2: Amination of heteroarenes and arenes.[a]
exchange will make use use of various arenes and hetero-
arenes as more convenient starting materials, and offer
a better functional-group compatibility.[11] Based on this
hypothesis, we have developed an operationally convenient
À
one-step C H amination procedure and examined its effi-
ciency on a wide scope of heteroarenes and arenes, including
both electron-rich and electron-deficient substrates. Partic-
ularly useful is its high efficacy for those substrates, such as
benzimidazoles, pyridines, benzothiophenes, and less acidic
À
C H bonds, which were isolated in poor yields under previous
amination conditions.[4b–k,12] The application of our chemistry
has been demonstrated in the preparation of a diverse range
of important heteroaromatic amines, including the potent
antiemetic lerisetron.
Our studies began with the amination of N-methyl
benzimidazole (1a) with the hydroxylamine 2 via the
formation of its organozinc intermediate using Zn(tmp)2
(Table 1). We focused on O-acylhydroxylamines as the
Table 1: Optimization studies for copper-catalyzed amination of benz-
imidazole (1a) and 2.[a]
Entry
1a
(equiv)
Zn(tmp)2
(equiv)
Copper
catalyst
t[a]
[h]
Yield
[%][b]
1
2
3
4
5
6
7
8
2.1
2.1
2.1
2.1
2.1
2.1
1.4
1.05
1.0
1.0
1.0
1.0
1.0
1.0
0.6
0.5
–
CuCl
24[c]
4
4
3.5
5
0
88
71
89
76
99
56
40
CuOTf·tol
CuCl2
Cu(OTf)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
5
72[c]
72[c]
[a] Time required for complete consumption of 2 in step 2. [b] Yields
1
determined by H NMR spectroscopy with CH2Br2 as a quantitative
internal standard. [c] 2 not fully consumed after 72 h. THF=tetra-
hydrofuran.
electrophilic nitrogen source because of their easy availability
and previous use in the electrophilic amination of different
organometallic reagents.[9a–c,13] To our delight, the aminated
product 3a was formed upon treating the diarylzinc inter-
mediate with 2 and a copper catalyst, among which Cu(OAc)2
was most effective (entries 2–6). Without a copper catalyst, no
aminated product was observed (entry 1). Furthermore,
a stoichiometric amount of the diarylzinc intermediate was
needed to fully convert 2 into 3a, thus suggesting that the
resulting monoarylzinc benzoate was ineffective for the
amination under these reaction conditions (entries 7 and
8).[14]
One of the important attributes of this new amination
approach is its potential to directly access a broad array of
heteroaromatic amines, including those inaccessible from
[4b–k,12]
[a] Reactions typically run on 0.2 mmol scale. 1 (2.1 equiv), 2 (1.0 equiv,
0.08m), Zn(tmp)2 (1.0 equiv). [b] Reaction time for deprotonation and
amination step respectively. [c] Yield of isolated product. [d] Zn-
(tmp)2·LiCl·MgCl2[4g] was used as base to form stable zincate inter-
mediates. [e] Deprotonation step run in CH2Cl2 because of the poor
solubility of 1m in THF. [f] Amination step run at 508C.
À
other C H amination methods.
Toward this end, we
examined the amination reactions of different heteroarenes
and arenes using 2 (Table 2). We first looked into simple
heteroarenes, including both the electron-deficient benzo-
thiazole 1b and benzoxazole 1c, and electron-rich benzofuran
2
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1d and benzothiophene 1e. All the reactions successfully
provided the aminated products (entries 2–5). Analogous
reactions with the imidazole 1 f, oxazole 1g, and thiazole 1h
also occurred in excellent yields (entries 6–8). Next we
examined the amination of functionalized arenes (entries 9–
14), including the bromobenzoxazole 1i, bromothiazoles 1j–
k, disubstituted oxazole 1l, caffeine 1m, and 1,3,4-oxadiazole
1n. These reactions gave the corresponding aminated azoles
in 82–96% yields. In the examination of this method on
Recognizing that the use of Zn(tmp)2 would require the
sacrifice of an additional equivalent of the arene moiety, we
next exploited the amination of an alternative monoarylzinc
intermediate using arenes as the limiting reagent and
tmpZnCl·LiCl[15] in the C H metalation (Table 4). Encourag-
À
Table 4: Direct amination using a tmpZnCl·LiCl-mediated metalation.[a]
À
pyridinyl C H bonds, the reactions of the pyridines 1o–r all
proceeded smoothly, thus affording the aminated products
3o–r, albeit at an elevated amination temperature (508C;
entries 15–18). Lastly, the amination of the arene 1s also
proceeded smoothly (entry 19). The high regioselectivity
observed in these aminated products is presumably derived
from the selective zinc metalation. It is noteworthy that many
functionalities were well tolerated, and include halide, ester,
nitro, and nitrile groups. Many of these groups would be
À
incompatible with the amination conditions by C H lithiation
to form organozinc intermediates.[13] Such a broad scope
demonstrates the value of our amination protocol, which
À
proceeds by C H zinc metalation in comparison to other
amination strategies.
The scope of the amines is also crucial for extensive utility
of this amination method. Next we examined different O-
benzoyl hydroxylamines derived from simple dialkylamines
in the amination reactions with representative heteroarenes
and arenes (Table 3). We were pleased to find that all the
reactions proceeded smoothly in modest to excellent yields
(67–97%), thus allowing the introduction of a variety of cyclic
and acyclic alkylamino groups. Notably, the cleavage of the
benzyl group or allyl group can additionally afford either
a secondary amine or a primary amine (e.g., 13–17).
[a]Reactions typically run on 0.2 mmol scale. Yields given are those of the
isolated products. [b] Amination step run at 508C. [c] Deprotonation run
at 658C.
ingly, these reactions from both electron-deficient and
electron-rich substrates all provided the aminated products
in excellent yields, and included the azoles 4 and 19,
benzothiophene 20, pyridines 21–22, pyridazine 23, and
arenes 24–26. These preliminary results suggest that arylzinc
chloride was equally effective as a diarylzinc for electrophilic
amination under the current reaction conditions and extend
the synthetic utility of this amination with the flexibility of
using heteroarenes as the limiting reagent.
Table 3: Scope of O-benzoyl hydroxylamines.[a]
Given the broad generality and operational simplicity of
this amination reaction, its utility for the synthesis of
medicinally valuable agents was demonstrated by the rapid
synthesis of lerisetron (Scheme 2). This 5-HT3 receptor
antagonist was readily prepared from the simple benzimid-
azole 27 by using the standard amination conditions.
In summary, we have developed a direct and facile
amination reaction of heteroarenes and arenes, including
both electron-poor and electron-rich substrates. This trans-
À
formation was achieved by a one-pot C H zincation and
copper-catalyzed electrophilic amination using O-acylhydro-
xylamines. It features broad substrate scope, high efficiency,
mild reaction conditions, and good functional-group compat-
ibility. It demonstrates great potential as a rapid and powerful
way to access a variety of highly functionalized complex
[a] Reactions run on 0.2 mmol scale. Conditions: Ar-H (2.1 equiv),
Zn(tmp)2 (1.0 equiv), RT, 1 h; BzONR1R2 (1.0 equiv, 0.08m), Cu(OAc)2
(10 mol%), RT, 5 h. Yields given are those of the isolated products.
[b] Amination step run for 24 h. Boc=tert-butoxycarbonyl.
Scheme 2. A rapid synthesis of lerisetron.
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synthesis and drug discovery. Furthermore, this work also
À
provides insight into developing a modular C H zincation/
3
À
amination transformation for effective amination of sp C H
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[6] J. Wencel-Delord, T. Droge, F. Liu, F. Glorius, Chem. Soc. Rev.
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Received: December 19, 2013
Revised: February 21, 2014
Published online: && &&, &&&&
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À
Keywords: amination · C H functionalization · copper ·
heterocycles · synthetic methods
.
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Synthetic Methods
S. L. McDonald, C. E. Hendrick,
Q. Wang*
&&&& — &&&&
Copper-Catalyzed Electrophilic Amination
À
of Heteroarenes and Arenes by C H
Zincation
Direct amination of heteroarenes and
arenes has been achieved in a one-pot
zincation/Cu(OAc)2-catalyzed amination
sequence using O-acylhydroxylamines.
The method provides a rapid and efficient
approach to a range of aromatic and
heteroaromatic amines, including those
which were previously inaccessible by
À
using C H amination methods. tmp=
2,2,6,6-tetramethylpiperidide.
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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These are not the final page numbers!