Oxadiazolone-Enabled Synthesis of Primary Azaaromatic Amines

Article abstract of DOI:10.1021/acs.orglett.6b02814

Despite their tremendous synthetic and pharmaceutical utility, primary azaaromatic amines remain elusive for access based on a generally applicable C-H functionalization strategy. An oxadiazolone-enabled approach is reported for convenient entry into N-unsubstituted 1-aminoisoquinolines through Co(III)-catalyzed redox-neutral, step-, atom-, and purification-economic C-H functionalization with alkynes. A ¹⁵N labeling experiment reveals the effectiveness of both oxadiazolone N atoms as directing sites. The installed primary amine can be harnessed as a synthetically useful handle for attachment of divergent appendages.

Full text of DOI:10.1021/acs.orglett.6b02814

Letter
pubs.acs.org/OrgLett
Oxadiazolone-Enabled Synthesis of Primary Azaaromatic Amines
Xiaolong Yu, Kehao Chen, Fan Yang, Shanke Zha, and Jin Zhu*
Department of Polymer Science and Engineering, School of Chemistry and Chemical Engineering, State Key Laboratory of
Coordination Chemistry, Nanjing National Laboratory of Microstructures, Collaborative Innovation Center of Chemistry for Life
Sciences, Nanjing University, Nanjing 210093, China
S
* Supporting Information
ABSTRACT: Despite their tremendous synthetic and pharmaceutical
utility, primary azaaromatic amines remain elusive for access based on a
generally applicable C−H functionalization strategy. An oxadiazolone-
enabled approach is reported for convenient entry into N-unsubstituted 1-
aminoisoquinolines through Co(III)-catalyzed redox-neutral, step-, atom-,
and purification-economic C−H functionalization with alkynes. A 15N
labeling experiment reveals the effectiveness of both oxadiazolone N atoms as directing sites. The installed primary amine can be
harnessed as a synthetically useful handle for attachment of divergent appendages.
eterocyclic compounds represent a ubiquitous class of
the existence of two competing reaction pathways but leading to
Horganic structures with applications in a wide range of a synthetically identical target product (termed synthetically
academia and industrial sectors.1 Transition-metal-catalyzed C−
symmetric, because two N atoms are indistinguishable as far as
synthetic target structure is concerned). In each of these
synthetic scenarios, to achieve ideal step, atom, and purification
economy, the masking group, generally required for eliminating
undesired coordination orientation, should possess the following
attributes: convenient installation during the substrate prepara-
tion process, efficient removal during the catalytic process, and
extrusion in the form of a small gaseous molecular fragment (e.g.,
through a process initiated by the cleavage of a labile bond).
As a first demonstration of the synthesis of primary
azaaromatic amines, the last scenario was examined based on
the use of 1,2,4-oxadiazol-5(4H)-one (abbreviated as oxadiazo-
lone herein). In using oxadiazolone as an effective synthon, we
take into consideration the following factors (Scheme 1a): (1)
the two N atoms for the azaaromatic ring and primary amine are
structurally inequivalent but can be synthetically symmetric (vide
infra), (2) the two N atoms are orchestrated into a single cyclic
moiety to completely eliminate the C−H activation-incapable
coordination orientation,6 and (3) a sufficiently labile N−O
bond exists as a trigger for the formation of a primary amine, with
the simultaneous extrusion of a small molecular fragment.7 In
fact, oxadiazolone is a masked form for the parent structure,
amidine,8 an n-π conjugated heteroallylic system, and a versatile
synthetic intermediate with a diverse range of applications.
Oxadiazolone has demonstrated its synthetic utility as a handy
precursor to amidine functionality (under hydrogenation
condition)9 but has never been recruited as a synthetic handle
in the C−H functionalization context. We hypothesized that
oxadiazolone featured a weak N−O bond, and after aza-
cyclization, a variety of chemical events (e.g., organometallic
oxidative addition process) could initiate a N−O bond cleavage/
carbamate formation/decarboxylative reaction sequence for the
H functionalization provides a synthetically efficient tool for the
generation of such important molecular skeletons.2 The high
efficiency derives from the docking of the transition metal by the
heteroatom-containing directing group in an appropriate
orientation for the achievement of a high C−H activation
reactivity. Simultaneous installation of a synthetically versatile
functional group is important for the expansion of structural
space,3 but can be challenging to implement in the case of a
strongly coordinating moiety, due to its capability of disrupting
the docking process for target reaction course. Indeed, the
accessible functional groups reported thus far are generally
restricted to those weakly coordinating moieties that exhibit, as
compared to the directing group, minimal competing docking
capability.4 Typically, these functional groups are located either
at a distal site from the directing group or on the corresponding
coupling partner.
We have recently initiated a research program aimed at the
installation of a synthetically useful, albeit strongly coordinating,
functional group during the heterocycle formation process. In
particular, our initial target goal is to derivatize azaaromatic
compounds with a primary amine, an arguably most important
functional group that manifests a strikingly diverse set of utilities
in synthetic and pharmaceutical chemistry.5 In devising a
versatile strategy for the preparation of primary azaaromatic
amines, one can imagine three potentially viable synthetic
scenarios: two structurally equivalent N atoms (either one acting
as the directing N atom, for C−H activation and incorporation
into the azaaromatic ring, with the other as an amino N atom, for
the generation of primary amine) enabling the operation of a
single reaction pathway; two structurally inequivalent N atoms
(directing N atom and amino N atom serving respective roles)
leading to the dominance of a preferred reaction pathway; two
structurally inequivalent N atoms (either one acting as the
directing N atom, with the other as amino N atom) allowing for
Received: September 19, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02814
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Letter
With the combination of an additional acidic additive, adamantyl
carboxylic acid (AdCOOH), the yield could be boosted to 65%.
The acquisition of optimized reaction conditions allowed
examination of the substrate scope of 3-aryl-1,2,4-oxadiazol-
5(4H)-ones by employing 2a as the coupling partner (Scheme
2). A variety of 3-aryl-1,2,4-oxadiazol-5(4H)-ones, bearing
Scheme 1. Synthetic Strategies for the Preparation of Primary
Azaaromatic Amines (N-Unsubstituted, Reported Herein),
and N-Substituted 1-Aminoisoquinolines (Previous Work)
through C−H Activation
Scheme 2. Substrate Scope for 3-Aryl-1,2,4-oxadiazol-5(4H)-
ab
,
ones
a
Reaction conditions: 3-aryl-1,2,4-oxadiazol-5(4H)-one (0.2 mmol),
2a (0.24 mmol), [CoCp*(CO)l2] (10 mol %), KOAc (30 mol %),
b
AdCOOH (20 mol %), CF3CH2OH (2.0 mL). Isolated yield.
generation of a primary amine. Reaction development confirmed
the synthetic utility of this important structural motif, and herein,
we report on the oxadiazolone-enabled synthesis of primary
azaaromatic amines.
electron-donating (1b, 1c) and electron-withdrawing (1d−1g)
groups at the para position of directing group, proved to be viable
substrates for this process. The structure assignment for these
products was further confirmed by a single-crystal X-ray analysis
of 3e. The transformation is also effective for an ortho-substituted
substrate (1h). The regioselectivity for a meta-substituted
substrate (1i−1k) is independent of electronic character of the
substituent, allowing the smooth delivery of, likely through steric
control, a single isomer. Di- and trisubstitution (1l−1o) pose no
synthetic hurdle for the respective reaction. Interestingly, for
substrate 1m, C−H functionalization at the sterically more
hindered site was observed.10b 3-(Thiophen-2-yl)-1,2,4-oxadia-
zol-5(4H)-one (1p) is also compatible with the developed
protocol, furnishing a fused bicyclic heterocycle as the target
product.
The optimized catalytic system was then used for establishing
the substrate scope of alkynes by reacting with 1e (Scheme 3).
Satisfactorily, a variety of functional groups on diarylalkynes
(2b−2i), irrespective of the electronic character (electron-
donating or electron-withdrawing) and the location (para, ortho,
or meta), were tolerated. A switch to di(thiophen-2-yl)acetylene
(2j) does not cause apparent attenuation in the reactivity.
Further, the reaction can accommodate alkynes bearing aryl/
ester (2k) and aryl/ketone (2l) substituents. The regiospecificity
is dictated by the steric effect. Substitution with alkyls (2m) also
largely preserves the reactivity, and a slight adjustment of the
reaction conditions can be beneficial for the reaction.
Amidines bearing protecting groups on one or both of the N
atoms have been previously employed for synthetic access to 1-
aminoisoquinolines (Scheme 1b).10,11 However, in the majority
of reported protocols, the bulky group used for blocking the
disfavored coordination orientation was left intact on the amino
N atom.10 Only a single isolated case11 was briefly mentioned for
the synthesis of a N-unsubstituted 1-aminoisoquinoline deriva-
tive through the capping of an imino N atom with a hydroxyl
group, and no general applicability of the described trans-
formation was demonstrated. In that amidoxime-directed
reaction, a highly reactive cationic Rh(III) catalyst was resorted
to for, presumably, overriding competing coordination modes/
reaction pathways.12 Taken together, despite their tremendous
synthetic and pharmaceutical utility, primary azaaromatic amines
remain elusive for access based on a broadly applicable C−H
functionalization synthetic strategy. Indeed, forward reactivity
analysis and pathway inference, for a directing group in our
particular case, are critical for the increased chance of success in
target reaction development. The oxadiazolone approach
described herein provides convenient entry into N-unsubstituted
1-aminoisoquinolines through Co(III)-catalyzed C−H coupling
with alkyne partners.
We commenced our studies by examining the reaction
between 3-phenyl-1,2,4-oxadiazol-5(4H)-one (1a) and 1,2-
diphenylacetylene (2a). Preliminary experiments identified
[CoCp*(CO)I2] as the ideal catalyst source and also suggested
the necessity of using additives. The target 1-aminoisoquinoline
derivative 3a could be obtained in 51% yield in the presence of
KOAc when reacting in CF3CH2OH at 120 °C for 20 h. A silver
salt proved to be unnecessary for effecting the transformation.
A key mechanistic insight into the catalytic process came from
a
15N labeling experiment. A reaction between 1a-15N (15N
labeling for carbonyl-neighboring N atom) and 2a generated a
mixture of 3a-15N-R (15N located on the azaaromatic ring) and
3a-15N-A (15N located on the primary amine) (3a-15N-R: 39%;
3a-15N-A: 23%) (eq 1). This suggests the effectiveness of both N
atoms in directing C−H activation for subsequent coupling/
B
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Organic Letters
Letter
ab
,
Scheme 3. Substrate Scope for Alkynes
Scheme 4. Proposed Catalytic Mechanism
a
Reaction conditions: 1e (0.2 mmol), alkyne (0.24 mmol), [CoCp*-
(CO)l2] (10 mol %), KOAc (30 mol %), AdCOOH (20 mol %),
b
c
CF3CH2OH (2.0 mL). Isolated yield. 1e (0.2 mmol), 2m (0.4
mmol), [CoCp*(CO)I2] (15 mol %), KOAc (40 mol %), AdCOOH
(30 mol %).
cyclization reaction. Based on the structural characteristic of the
oxadiazolone group, the first step in the catalytic reaction
sequence likely involves the following processes (Scheme 4):
generation of a coordination-capable monoanionic N atom
(either one on the oxadiazolone due to the resonance
stabilization effect) through deprotonation, and coordination
of a N atom to Co(III). Indeed, minimal reactivity was observed
for two types of deprotonation-incapable species, a dioxazolone
(eq 2) and a methyl-protected oxadiazolone (eq 3). Further
mechanistic experimental results, the absence of H/D scrambling
on the aryl ring and favored reaction for an electron-deficient
oxadiazolone, suggest that C−H activation is irreversible and
proceeds through a concerted metalation−deprotonation
process. Following C−H activation, coordination of alkyne and
1,2-migratory insertion allows the generation of alkenylcobalt
species for the subsequent reductive elimination process (C−N
bond formation and release of Co(I) species). This is followed by
oxidative addition of Co(I) species to N−O bond/N−Co(III)
bond cleavage (demetalation as a result of protonation on O
atom-neighboring N atom)/O−Co(III) bond cleavage/decar-
boxylative process/protonation of carbonyl-neighboring N
atom/regeneration of Co(III) catalyst (stepwise or concerted).
The target N-unsubstituted 1-aminoisoquinoline derivative is
then generated by tautomerization.
Scheme 5. Diversified Synthetic Transformations for 3a
generation of N-unsubstituted 1-aminoisoquinolines with a
broad range of substitution patterns. The primary amine in 1-
aminoisoquinoline products can be harnessed as a synthetically
useful handle for attaching diverse appendages.
The synthetic utility of the reaction protocol developed herein
is highlighted by the amenability of a primary amine to diverse
functionalization (Scheme 5). A variety of halogenated
compounds can serve as the electrophile for derivatization on
the amino group (5a−5c). An extended fused ring system (5d)
can also be generated through a Rh(III)-catalyzed double C−H
activation and alkyne coupling pathway.12 Further, one can elect
to, with a primary amine intact, attach an appendage based on a
heterocycle-directed C−H activation process (5e).
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b02814.
Experimental and synthetic details (PDF)
1H and 13C NMR data (PDF)
Crystallographic data (CIF)
In summary, an oxadiazolone-enabled synthetic strategy has
been developed for access of primary azaaromatic amines.
Co(III)-catalyzed C−H functionalization with alkynes allows the
C
DOI: 10.1021/acs.orglett.6b02814
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AUTHOR INFORMATION
■
Corresponding Author
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(b) Li, J.; John, M.; Ackermann, L. Chem. - Eur. J. 2014, 20, 5403. (c) Li,
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*E-mail: jinz@nju.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge support from the National Natural
Science Foundation of China (21425415, 21274058) and the
National Basic Research Program of China (2015CB856303).
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Org. Lett. XXXX, XXX, XXX−XXX