Bidentate Directing-Enabled, Traceless Heterocycle Synthesis: Cobalt-Catalyzed Access to Isoquinolines

Article abstract of DOI:10.1021/acs.orglett.6b02870

Traceless heterocycle synthesis based on transition-metal-catalyzed C-H functionalization is synthetically appealing but has been realized only in monodentate directing systems. Bidentate directing systems allow for the achievement of high catalytic reactivity without the need for a high-cost privileged ligand. The first bidentate directing-enabled, traceless heterocycle synthesis is demonstrated in the cobalt-catalyzed synthesis of isoquinolines via 2-hydrazinylpyridine-directed C-H coupling/cyclization with alkynes. Convenient directing group installation through a ubiquitously present ketone group allows synthetic elaboration for complex molecules.

Full text of DOI:10.1021/acs.orglett.6b02870

Letter
pubs.acs.org/OrgLett
Bidentate Directing-Enabled, Traceless Heterocycle Synthesis:
Cobalt-Catalyzed Access to Isoquinolines
Shuguang Zhou, Mingyang Wang, Lili Wang, Kehao Chen, Jinhu Wang, Chao Song, 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: Traceless heterocycle synthesis based on transition-
metal-catalyzed C−H functionalization is synthetically appealing but
has been realized only in monodentate directing systems. Bidentate
directing systems allow for the achievement of high catalytic reactivity
without the need for a high-cost privileged ligand. The first bidentate
directing-enabled, traceless heterocycle synthesis is demonstrated in
the cobalt-catalyzed synthesis of isoquinolines via 2-hydrazinylpyridine-directed C−H coupling/cyclization with alkynes.
Convenient directing group installation through a ubiquitously present ketone group allows synthetic elaboration for complex
molecules.
ransition-metal-catalyzed directed C−H functionalization
Herein we report on the first demonstration of bidentate
directing-enabled, traceless synthesis of heterocycles (Scheme
1). In particular, isoquinolines have been efficiently synthesized
through cobalt-catalyzed, 2-hydrazinylpyridine-directed cou-
pling with both terminal and internal alkynes. Key to the
traceless synthesis reported herein is the use of the N−N bond in
the readily available hydrazone derivative (conveniently
synthesized through reaction between 2-hydrazinylpyridine and
a ubiquitously present ketone group) as a labile synthetic handle.
Significantly, the reaction protocol allows the performance of
synthesis in air (no need for an inert atmosphere protection)
with a low-cost commercially available salt and ready synthetic
elaboration for ketone-containing molecules, including natural
products and pharmaceutically important compounds.
Our synthetic efforts began with the examination of a reaction
between (E)-2-(2-(1-phenylethylidene)hydrazinyl) pyridine
(1a) and phenylacetylene (2a). Initial screening of the catalytic
systems showed the effectiveness of a variety of Cp*-free cobalt
salts in promoting the target transformation, demonstrating the
advantage of using a bidentate directing system. An isoquinoline
derivative 3a could be obtained, by using Co(acac)2 (10 mol %)
as the catalyst precursor and NaOAc (2 equiv) as the additive, in
a promising 26% yield when reacting in DCE at 80 °C, under air,
for 24 h. A change of solvent proved to be futile in boosting the
catalytic performance. Instead, a switch from NaOAc to an acidic
additive, PivOH, allowed an increase in yield to 67%. The yield
could be improved to 71% with the reduction of the PivOH
quantity to 1 equiv. Further tuning of the reaction temperature
revealed the highest yield of 78% at 70 °C. A control experiment
under nitrogen identifies only a trace amount of 3a, indicating
that air is crucial for maintaining an effective catalytic cycle.
T
represents a promising strategy for the synthesis of diverse
organic structures.1 Key to the successful reaction development
is the achievement of electronic and steric activation of the
catalytic center via an appropriate coordination environment.2 In
this regard, electronic and steric control can be implemented in
two modalities depending on the directing group: through a
combination of ligand on the catalyst precursor and the directing
group on the substrate,3 and solely through the directing group
on the substrate.4 The former modality is typically in use when
the directing group is monodentate (Scheme 1).5 This modality
has witnessed tremendous success for both the attachment of
appendages and synthesis of heterocycles via the involvement of
a high-cost privileged ligand (e.g., tightly bound Cp*) on the
metal center.6 The latter modality alleviates the electronic and
steric constraints of the catalyst system through the use of a
bidentate directing group (Scheme 1). The relaxation of
requirement for a privileged ligand enables the achievement of
high catalytic activity for a diverse set of catalyst precursors,
especially low-cost metal salts.7 In addition, an important
advantage for the bidentate directing systems is the overriding
of otherwise interfering coordination of competing monodentate
binding sites when synthetic elaboration of complex molecules is
in demand.4e,8 However, despite the high reactivity, the bidentate
directing strategy is primarily used for appendage attachment,
and method development in heterocycle synthesis is largely
lagging behind, in part due to the limited available choice of
directing groups.9 Most importantly, mechanistically distinct,
traceless heterocycle synthesis, an approach featuring in situ
elimination of an unwanted portion of a directing group along
the catalytic process and important for improving step economy
as well as functional group compatibility, remains elusive for this
supposedly versatile strategy. Indeed, the undesired auxiliary is
removed thus far exclusively as a separate step, many through
harsh conditions, following the heterocycle formation process.10
Received: September 23, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02870
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Letter
Scheme 1. C−H Activation-Based Synthetic Strategies for the
Generation of Heterocycles
Scheme 2. Substrate Scope for (E)-2-(2-(1-
a b
,
Arylalkylidene)hydrazinyl)pyridines
a
Conditions: (E)-2-(2-(1-arylalkylidene)hydrazinyl)pyridine (0.5
b
mmol), 2a (0.75 mmol), DCE (2 mL). Isolated yields.
The broad substrate scope for (E)-2-(2-(1-arylalkylidene)-
hydrazinyl)pyridine prompted us to further examine the
substrate scope for alkynes (Scheme 3), with 1a used as the
coupling partner. Similarly observed was the compatibility of a
Oxygen is the working component of air, as a comparable yield
(81%) was observed under this atmosphere.
The optimized synthetic conditions allowed us to explore the
substrate scope for (E)-2-(2-(1-arylalkylidene)hydrazinyl)-
pyridines by employing 2a as the reacting partner (Scheme 2).
The synthetic efficiency is inversely correlated with the bulkiness
of the alkylidene group. Thus, variation from ethylidene (1a) to
propylidene (1b) and iso-butylidene (1c) leads to a decrease in
the yield to 62% and 31%, respectively. The synthetic versatility is
highlighted by the compatibility of a diverse set of electron-
donating (Me, 1d; Ph, 1e; OMe, 1f) and electron-withdrawing
(F, 1g; Cl, 1h; Br, 1i; I, 1j; CF3, 1k; CN, 1l; COOMe, 1m) groups
as a para-substituent on the phenyl ring. The ortho substitution,
irrespective of the electronic character (Me, 1n; OMe, 1o; F, 1p),
invariably affords a relatively low yield. This phenomenon most
likely derives from disfavored C−H activation due to steric
interaction-engendered placement of the cobalt catalytic center
in a nonideal geometry. In support of this, the reactivity can be
partially recovered by linking the ortho-substituent and
alkylidene group into a steric interaction-free cyclic moiety
(1q). The reaction proceeds smoothly for meta-substituted
substrates (Me, 1r; OMe, 1s; F, 1t), with regioselectivity favoring
C−H activation at the less hindered site. Disubstitution poses no
significant synthetic hurdle for the delivery of the target product
(1u−1w). A noteworthy observation is that regioselectivity is
primarily dictated by the steric factor, as electronically similar
substituents (1u, 1w) exhibit distinct preferred reaction sites in
C−H coupling. (E)-2-(2-(1-(Thiophen-2-yl)ethylidene)-
hydrazinyl)pyridine (1x) is also sufficiently reactive for the
transformation, yielding a fused bicyclic heterocycle as the target
product.
a b
,
Scheme 3. Substrate Scope for Alkynes
a
Conditions: 1a (0.5 mmol), alkyne (0.75 mmol), DCE (2 mL).
Isolated yields.
b
B
DOI: 10.1021/acs.orglett.6b02870
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Letter
broad range of electron-donating (Me, 2b; nPr, 2c; Ph, 2d; OMe,
2e) and electron-withdrawing (F, 2f; Cl, 2g; Br, 2h; CN, 2i;
COOMe, 2j) functional groups at the para position of
arylacetylene. The shift of substituent position from para to
ortho witnesses different consequences for different groups. The
negative impact for a methyl substituent (2k) is apparent, but the
effect for the fluoro (2l) and chloro (2m) substituents is not
noticeable. The reaction proceeds well in general for a meta-
substituted arylacetylene (Me, 2n; OMe, 2o; F, 2p; Cl, 2q; Br, 2r;
COOMe, 2s). In addition, 2- and 3-thiophenylacetylene (2t, 2u)
are compatible with the synthetic system reported herein. The
bulky ferrocenylacetylene (2v) is also a viable substrate for the
transformation, generating a readily crystallizable product for
structure confirmation with single-crystal X-ray diffraction
analysis. Gratifyingly, further experimental survey revealed the
synthetic compatibility of both unsymmetrically (2w, 2x) and
symmetrically (2y) substituted internal alkynes.
With the broad substrate scope demonstrated, a series of
experiments were then performed to gain mechanistic insight
into this versatile reaction system. A high kinetic isotope effect
value (kH/kD = 2.45) was observed for a reaction between 1a/1a-
d3 and 2a. Two competition experiments, one involving 1f/1m
and 2a and the other involving 1a and 2e/2j, identified the
preferred reaction for electron-rich 1f (1f/1m = 1.33) and
virtually no electronic preference in the case of alkyne (2e/2j =
0.98). These results support that C−H activation is the turnover-
limiting step and proceeds through an electrophlic aromatic
substitution pathway. An attempt at the cyclization of a formal
alkenylation product (3-hsac, from 1a and 2a assuming the
occurrence of proto-demetalation after C−H activation and
migratory insertion steps) under standard catalytic conditions
yielded no target product 3a (eq 1), ruling out the detachment of
formation reported herein is that the reaction is negatively
impacted by an excessive amount of Co(acac)2 (e.g., 1 or 2
equiv), reflecting partial trapping of catalytically active species
into an inert state under this condition. Taken together, the
above data are consistent with the following mechanistic
proposal: reaction of oxygen with Co(acac)2 to generate a
catalytically active species, coordination of catalytically active
species with (E)-2-(2-(1-arylalkylidene)hydrazinyl)pyridine,
turnover-limiting ortho−C-H cobaltation and release of proton,
migratory insertion of alkyne to generate an alkenylcobalt
intermediate, simultaneous nucleophilic attack of alkenylcobalt
on a N atom (linked to the C atom via a double bond), N−N
bond cleavage, electrophilic attack of a N atom (linked to the 2-
pyridinyl group) on the released proton, and regeneration of the
cobalt catalyst.
As a demonstration of the synthetic utility of the reaction
protocol developed herein, synthetic transformations of ketone-
containing molecules were performed (Scheme 4). The ketone
Scheme 4. Synthetic Transformations for Natural Product
(Chromanone) and Pharmaceutically Important Compound
(Iloperidone) Using the Synthetic Protocol Developed
Herein
the cobalt center prior to the cyclization process. Key evidence
for the internal oxidation mechanism (based on the use of an N−
N bond) came from the identification of 2-aminopyridine as a
side product (eq 2). Importantly, this side product does not
significantly inhibit the catalytic reactivity for the cobalt center
even though it is supposed to be strongly coordinating, which
highlights the unique synthetic advantage conferred by the
bidentate directing systems. A systematic study of catalytic and
stoichiometric reactivity for Co(acac)2 and Co(acac)3 under
nitrogen suggests that oxygen most likely changes the
coordination environment for the generation of a more reactive
cobalt catalytic center (instead of simple oxidation of Co(II) to
Co(III)) at an early stage of the catalytic cycle (prior to the C−H
activation step): (1) catalytic amount of both Co(acac)2 and
Co(acac)3 exhibits minimal reactivity under nitrogen; (2)
addition of a stoichiometric amount of either Co(acac)2 or
Co(acac)3 under nitrogen does not allow the achievement of a
similar reactivity for the catalytic amount of respective salt under
oxygen; (3) preliminary oxygen uptake experiments reveal the
consumption of the catalytic amount of oxygen during the
reaction. A noteworthy phenomenon for the synthetic trans-
group is a ubiquitously present moiety in natural products and
pharmaceutically important compounds. Chromanones are
naturally present in many different plants, and tremendous
efforts have been devoted to their synthetic elaboration for
medicinal purposes.11 With 4-chromanone as the model
substrate, the 2-hydrazinylpyridine directing group could be
efficiently installed as expected and provided the desired cyclized
product 7. A second example used for synthetic potential
validation is a structurally more complex, pharmaceutically active
compound, iloperidone.12 Significantly, the directing bidentate
allowed overriding of otherwise interfering coordination of two
competing N atom sites and furnished target product 10 in an
efficient manner.
In conclusion, a bidentate directing-enabled, traceless hetero-
cycle synthesis protocol has been developed. The protocol
features convenient installation of a 2-hydrazinylpyridine
directing group through hydrazone formation with a ubiq-
uitously existing ketone group and a low-cost cobalt salt-
catalyzed C−H coupling with both terminal and internal alkynes,
allowing the generation of isoquinolines with a diverse set of
substitution patterns. The synthetic utility of the bidentate
C
DOI: 10.1021/acs.orglett.6b02870
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Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b02870.
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AUTHOR INFORMATION
Corresponding Author
■
*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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DOI: 10.1021/acs.orglett.6b02870
Org. Lett. XXXX, XXX, XXX−XXX