Copper-catalyzed carboxamide-directed ortho amination of anilines with alkylamines at room temperature

Article abstract of DOI:10.1021/ol500464x

In this report, a highly efficient method for the room temperature installation of alkyl amino motifs onto the ortho position of anilines via Cu-catalyzed carboxamide-directed amination with alkylamines is described. This method offers a practical solution for the rapid synthesis of complex arylamines from simple starting materials and enables new planning strategies for the construction of arylamine-containing pharmacophores. A single electron transfer (SET)-mediated mechanism is proposed.

Full text of DOI:10.1021/ol500464x

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Carboxamide-Directed Ortho Amination of
Anilines with Alkylamines at Room Temperature
Qiong Li, Shu-Yu Zhang, Gang He, Zhaoyan Ai, William A. Nack, and Gong Chen*
Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, United States
S
* Supporting Information
ABSTRACT: In this report, a highly efficient method for the
room temperature installation of alkyl amino motifs onto
the ortho position of anilines via Cu-catalyzed carboxamide-
directed amination with alkylamines is described. This method
offers a practical solution for the rapid synthesis of complex
arylamines from simple starting materials and enables new plan-
ning strategies for the construction of arylamine-containing
pharmacophores. A single electron transfer (SET)-mediated mechanism is proposed.
rylamines and heteroarylamines are important structural
units in pharmaceutical agents and organic materials.1
Scheme 1. Cu-Catalyzed PA-Directed Ortho Amination of
Arenes
A
Over the past decade, transition-metal-catalyzed amination of
C−H bonds has emerged as an attractive new strategy for Ar−
N bond construction.2 In particular, reactivity enabled by cheap
and abundant copper catalysts has attracted great interest.3−12
In 2006, the laboratory of Yu5 reported a Cu-catalyzed inter-
molecular amination of the nonacidic ortho C−H bonds of
2-phenylpyridine with tosylamine.6 Recently, the laboratory of
Daugulis11a has shown that the nonacidic ortho C−H bonds of
N-quinolyl benzocarboxamides can be directly coupled with
alkylamines, providing a useful Cu-catalyzed C−H amination
method facilitated by a removable auxiliary. Herein, we describe
a highly efficient and broadly applicable method for the room
temperature installation of cyclic alkylamino motifs onto the
ortho position of aniline substrates via Cu-catalyzed carbox-
amide-directed amination.13
Recently, our laboratory has focused on investigating the pi-
colinamide (PA) directing group, first introduced by Daugulis,
for use in palladium-catalyzed C−H functionalization reac-
tions.14−16 In these studies, we found that the ortho C(sp2)−H
bonds of N-benzyl picolinamides (e.g., 1 in Scheme 1A) can be
readily transformed into a variety of functional groups under
palladium catalysis. We postulated that N,N-PA-chelated 5-
membered palladacycle intermediates (analogous to organo-
metallic Cu complex 4) were involved in these Pd-catalyzed
C−H functionalization reactions. In contrast with N-quinolyl
benzocarboxamides, N-benzyl picolinamides seemed to be
much more challenging substrates for Cu-catalyzed C−H amin-
ation. In a prior report by Daugulis, only two examples of
conformationally constrained α-gem-dimethyl benzylamine
substrates (e.g., 11) could be aminated in moderate yield
(Scheme 1B).11a Our own attempts with unsubstituted
benzylamine 1 did not afford any γ ortho-aminated product
under the same reaction conditions. This disparate reactivity
between AQ (aminoquinoline) and PA-coupled substrates led us
to reexamine the mechanistic model for this Cu-catalyzed PA-
directed ortho functionalization reaction. While 5-membered
N,N-PA-chelated metallacycle intermediates (e.g., 4) have been
invoked in many Pd- and Cu-catalyzed C−H functionalization
reactions, we suspected that the imidate O-atom of the
Cu-chelated PA moiety might also be able to bind Cu to
Received: February 12, 2014
Published: March 4, 2014
© 2014 American Chemical Society
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Letter
effect ortho C−H amination (see 6).17,18 In comparison with
ortho amination of benzylamine through a 7-membered
metallacycle intermediate (e.g., 6),19 ortho C−H functionaliza-
tion of aniline substrates (see 2) may proceed more easily
through a 6-membered O-ligated metallacycle (e.g., 9). In addi-
tion to organometallic pathways, electron-transfer-mediated
mechanisms could also provide viable pathways for PA-directed
ortho amination of anilines (see 8, 10), as invoked in Yu’s
2-phenylpyridine system.5,20 If so, ortho amination of anilines
may be favored due to the more compact conformation of
the reaction intermediates (see 3 vs 8, 5 vs 10)21 and their
electron-rich arene moiety.
Scheme 2. Evaluation of PA Analogues As Directing
Groups
a
Prompted by our new mechanistic model, we attempted the
Cu-catalyzed amination of 2 with morpholine (eq 2, Scheme
1C; see Supporting Information (SI) for the detailed screening
conditions). We were delighted to find that 2 equiv of phenyl-
iodonium diacetate PhI(OAc)2,22 2 equiv of morpholine, and
20 mol % of Cu(OAc)2·H2O in dioxane at 90 °C gave desired
product 13 in 86% yield. An ortho-diaminated product was
formed in trace quantities. Lowering the catalyst loading to
10 mol % Cu(OAc)2·H2O provided a decreased yield (72%).
Interestingly, the addition of 20 mol % MgCl2 largely restored
the amination yield.23 To our surprise, the amination reaction
also proceeded very quickly at rt to give a 72% yield in 2 min
and a 91% isolated yield in 4 h. No product was formed in the
absence of the Cu catalyst.
To probe the mechanism of this Cu-catalyzed C−H amin-
ation reaction and evaluate the scope of directing groups, we
next surveyed a range of ester and amide-linked auxiliary groups
under the standard conditions A at rt (eq 3, Scheme 2). Simple
benzamide 14, phenolic ester 15, N-methylated amide 16, and
sulfonamides (e.g., 17) did not undergo the desired C−H
amination reaction, indicating the critical roles of both amide
NH and the ortho pyridine N. On the other hand, the parent
picolinamide motif demonstrated remarkable tolerance for
substitution on the pyridine ring while still facilitating Cu-
catalyzed ortho amination. For instance, pyrimidines 18 and 20
as well as pyrazine 19 containing an additional N-atom on the
pyridine ring gave a good to excellent amination yield. Sterically
bulky substituents on the 3, 4, and 5 positions of the pyridine
ring are very well tolerated. In contrast, substrates bearing sub-
stituents at position 6 are unreactive under the standard con-
ditions (e.g., 29, 33, 37). All of these picolinic acid analogues
are available commercially and are frequently employed as
building blocks in structure and activity relationship (SAR)
studies in medicinal chemistry.
As shown in Scheme 3, anilines substituted with a variety of
functional groups such as OBn, NHBoc, ester, and all of the
halogens were well tolerated under the standard reaction con-
ditions. Even free OH groups are tolerated (see 54, 58). In
general, electron-rich substrates are more reactive. For example,
near-quantitative yields of 47 could be obtained at rt in 5 min
(conditions C). Electron-deficient substrates (e.g., 41, 48) and
even a pyridine substrate (e.g., 42) also worked well. The amin-
ation reactions were sensitive toward the sterics of the targeted
C−H bond; the less hindered ortho position was preferentially
aminated in the case of substrates bearing meta-substitutents
(see 44−46). As shown in Scheme 3B, 6-membered cyclic
secondary amines were excellent substrates for this reaction.
A variety of functional groups and substituents on the amine
substrate were well tolerated, including the sulfide group
on thiomorpholine (see 51). In comparison, 5-membered
a
Isolated yields on 0.2 mmol scale under the standard conditions A
b
(rt, 4 h). Conditions B: 90 °C, 4 h.
pyrrolidine, e.g. 53, and acyclic amines, e.g. diethylamine, were
unreactive (<10%) under these reaction conditions.24
The mechanistic details of these Cu-catalyzed ortho amin-
ation reactions are unclear. The differing reactivity of naph-
thalene substrate 65, which contains both β and γ′ C−H bonds,
in three different Cu-catalyzed C−H functionalization systems
may provide mechanistic insight (Scheme 4A). Subjecting 65 to
our room temperature PhI(OAc)2-oxidized conditions gave
exclusively β-aminated product 43, along with unreacted
starting material. No γ′-aminated product 70 was obtained.
Little conversion of 65 was observed under the previously
reported Cu-catalyzed, NMO-mediated, and Ag-promoted
amination conditions at 110 °C.11a In contrast, a recent
study11d by Daugulis reported that the C−H alkoxylation of 65
with phenols under Cu-catalyzed conditions gave primarily the
γ′ functionalized product 66.25 A recent study by Miura showed
that the C−H heteroarylation of 65 with benzoxazole under
Cu-facilitated conditions gave exclusively γ′ functionalized pro-
duct 67.12b In addition, our control experiments indicated that
the addition of radical scavengers, e.g. TEMPO or galvinoxyl,
inhibited the reaction (see SI). The lack of KIE (∼1.0) between
2 and D5-substituted substrate 70 indicates that C−H cleavage
is not the rate-limiting step (Scheme 4B). Whereas organo-
metallic pathways involving 5-membered N,N-bidentate metal-
lacycle intermediates (e.g., 68) have been proposed for Miura’s
C−H heteroarylation,12,20 an aromatic substitution-type path-
way mediated by stepwise single electron transfer (SET) is very
likely to be operative in our system (see 69).26 The exact
binding mode of the PA group and the oxidation state of the
reactive Cu species (CuII or CuIII)7,20,27 is still unclear.
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Letter
a
Scheme 3. Substrate Scope of Anilines and Amines
Scheme 4. Mechanistic Considerations
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, X-ray crystallographic analysis, and
1H and 13C NMR spectra for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
a
Isolated yields on a 0.2 mmol scale under the standard conditions. A:
rt, 4 h. B: 90 °C, 4 h. C: rt, 5 min.
*E-mail: guc11@psu.edu.
Notes
The PA group of the aminated products can be easily re-
moved under simple basic conditions due to the electron-
deficient pyridine ring. For example, treatment of 13 with
5 equiv of NaOH in EtOH at 70 °C gave aniline 73 in high
yield (eq 5).
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully thank the Pennsylvania State University, NSF
(CAREER CHE-1055795), and ACS-PRF (51705-DN11) for
financial support of this work.
REFERENCES
■
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In summary, we have developed a highly efficient method to
selectively install alkyl amino motifs onto the ortho position of
aniline substrates via Cu-catalyzed and carboxamide-directed
amination at rt. These reactions are operationally simple and
robust, avoid the use of sensitive and expensive reagents, and
possess a broad substrate scope for both anilines and directing
groups. The picolinamide group can be used as a protecting
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