Cobalt(III)-Catalyzed C-H/N-O Functionalizations: Isohypsic Access to Isoquinolines

Article abstract of DOI:10.1002/chem.201503624

C-H/N-O functionalizations by cobalt(III) catalysis allowed the expedient synthesis of a broad range of isoquinolines. Thus, internal and challenging terminal alkynes proved to be viable substrates for an isohypsic annulation, which was shown to proceed by a facile C-H cobaltation.

Full text of DOI:10.1002/chem.201503624

DOI: 10.1002/chem.201503624
Communication
&
CÀH Activation
Cobalt(III)-Catalyzed CÀH/NÀO Functionalizations: Isohypsic
Access to Isoquinolines
Hui Wang, Julian Koeller, Weiping Liu, and Lutz Ackermann*[a]
Abstract: CÀH/NÀO functionalizations by cobalt(III) cataly-
sis allowed the expedient synthesis of a broad range of
isoquinolines. Thus, internal and challenging terminal al-
kynes proved to be viable substrates for an isohypsic an-
nulation, which was shown to proceed by a facile CÀH co-
baltation.
Transition-metal-catalyzed
CÀH
functionalizations
have
Figure 1. Expedient cobalt-catalyzed CÀH aminocarbonylation.
emerged as increasingly powerful tools for sustainable organic
syntheses.[1] Alkyne annulations by CÀH/NÀO functionalizations
have proven to be particularly instrumental for the step-eco-
nomical assembly of various heterocycles with activities of rele-
vance to medicinal chemistry and biology.[2] Despite these un-
disputed advances, isohypsic alkyne annulations were thus far
only realized with costly 4d or 5d transition-metal catalysts.[2,3]
In light of the beneficial features of naturally abundant 3d
transition metals, focus has shifted in recent years to the use
of environmentally benign and less expensive base metal cata-
lysts for CÀH activation processes.[4] Versatile cobalt catalysts
have been applied for chemoselective CÀH transformations,[5]
with notable progress being accomplished with cobalt(III) com-
plexes as reported by Matsunaga/Kanai,[6] our group,[7] Glo-
rius,[8] Ellman,[9] and Chang[10] among others.[11] Within our re-
search program on cobalt-catalyzed CÀH functionalizations,[12]
we now report on cobalt-catalyzed CÀH/NÀO functionaliza-
tions for the redox-neutral preparation of isoquinolines
(Figure 1). Notable features of our cobalt catalysis strategy in-
clude i) short reaction times of 15 min, ii) aromatic and aliphatic
CÀH activation, and iii) isohypsic CÀH functionalizations that al-
lowed cobalt-catalyzed alkyne annulations in the absence of
external oxidants.
Table 1. Optimization of cobalt-catalyzed CÀH/NÀO functionalization.[a]
Entry
[Co]
Additive 1
Additive 2
Yield [%][b]
1
2
3
4
5
6
7
8
[Cp*CoI2(CO)]
[Cp*CoI2(CO)]
[Cp*CoI2(CO)]
[Cp*CoI2(CO)]
[Cp*CoI2(CO)]
[Cp*CoI2(CO)]
[Cp*CoI2(CO)]
[Cp*CoI2(CO)]
–
[Cp*CoI2(CO)]
[Cp*CoI2(CO)]
[Cp*CoI2(CO)]
[Cp*CoI2(CO)]
–
NaOAc
NaOAc
NaOAc
NaOAc
HOPiv
CsOAc
KOAc
NaOPiv
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
12
29
55
54
48
46
62
74
AgPF6
AgBF4
AgOTf
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
9
–
10
11
12
13
87
86[c]
60[d]
63[e]
[a] Reaction conditions: 1a (0.50 mmol), 2a (0.75 mmol), [Co] (10 mol%),
additive 1 (20 mol%), additive 2 (20 mol%), DCE (2.0 mL), under air,
1208C, 16 h. [b] Yields of isolated product. [c] Under N2. [d] 1008C.
[e] [Cp*CoI2(CO)] (5 mol%). DCE=1,2-dichloroethane.
At the outset of our studies, we explored various reaction
conditions for the envisioned isohypysic cobalt-catalyzed annu-
lation of alkyne 2a (Table 1, and Table S-1 in the Supporting In-
formation).
Preliminary experiments indicated 1,2-dicholoroethane (DCE)
to be the reaction medium of choice among a set of represen-
[a] H. Wang, J. Koeller, W. Liu, Prof. Dr. L. Ackermann
Institut für Organische und Biomolekulare Chemie
Georg-August-Universität Gçttingen
tative solvents (toluene, 1,4-dioxane, MeOH, H2O), while
[Cp*CoI2(CO)][13] was the most powerful catalyst.
Tammannstraße 2, 37077 Gçttingen (Germany)
E-mail: Lutz.Ackermann@chemie.uni-goettingen.de
Homepage: http://www.ackermann.chemie.uni-goettingen.de/
The CÀH/NÀO functionalization proceeded most efficiently
with AgSbF6 and NaOAc as the additives (Table 1, entries 1–10).
This finding can be rationalized in terms of a carboxylate-as-
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201503624.
Chem. Eur. J. 2015, 21, 15525 – 15528
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Communication
Scheme 1. Scope of cobalt(III)-catalyzed CÀH/NÀO functionalization.
[a] 15 min reaction time. [b] In HFIP.
Scheme 2. Isohypsic annulation of alkynes 2. [a] 15 min reaction time.
sisted[14] CÀH activation by a cationic cobalt(III) catalyst. The
robust nature of the cobalt(III)-catalyzed alkyne annulation was
reflected by successfully performing the CÀH activation under
a most user-friendly atmosphere of ambient air, but the reac-
desired product 3ka with a comparable catalytic efficacy. Intra-
molecular competition experiments with meta-substituted sub-
strates were largely governed by steric interactions through
tion also proved viable under
(entry 11). Notably, the reaction
temperature and the catalyst
loading could be reduced as
well (entries 12 and 13). The cat-
ionic cobalt(III) catalyst was not
limited to O-acetyl oxime 1a.
Indeed, oxime derivatives 4a–6a
were found to be amenable sub-
strates as well, while the N-tosyl
hydrazone 7a only furnished
traces of the desired product
3aa.
a nitrogen atmosphere
With the optimized cobalt cat-
alyst in hand, we evaluated its
generality with a representative
set
of
decorated
arenes
1 (Scheme 1). Thus, a variety of
para-substituted substrates 1a–
1j was converted in a chemose-
lective fashion, thereby tolerat-
ing valuable electrophilic func-
tional groups, such as chloro,
bromo, nitro, or cyano substitu-
ents. Likewise, more sterically
hindered ortho-substituted O-
acetyl oxime 1k delivered the Scheme 3. Summary of key mechanistic studies.
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Communication
the CÀH functionalization at the less hindered site,
unless secondary interactions dominated as in oxime
derivatives 1o and 1p. The alkyne annulation with
substituted arene 1q set the stage for the assembly
of the tricyclic product 3qa. It is noteworthy that also
heterocyclic substrate 1t proved to be suitable for
the isohypsic alkyne annulation, when employing
hexafluoroisopropanol (HFIP) as the solvent. The un-
usually high catalytic activity of the cationic cobalt(III)
catalyst was reflected by high-yielding CÀH/NÀO
functionalizations within—in many cases—only
15 min.
As to the alkyne scope, both aryl as well as alkyl-
substituted substrates 2 were found to be viable
(Scheme 2). In contrast to previously reported ruthe-
nium(II)-catalyzed CÀH/NÀO transformations,[15] the
broadly applicable cobalt(III)-catalyzed procedure en-
abled the challenging use of simple[16] terminal al-
kynes 2m and 2n as well.
Scheme 4. H/D exchange studies.
Intrigued by the versatility and efficacy of the cobalt(III)-cata-
lyzed CÀH/NÀO functionalizations, we conducted mechanistic
studies to delineate its mode of action. To this end, inter-
(Scheme 3a) and intramolecular (Scheme 3b) competition ex-
periments revealed electron-rich arenes 1 to be inherently
more reactive. This observation is in good agreement with
a base-assisted intramolecular electrophilic-type substitution
(BIES)[17] mechanism by a cationic cobalt catalyst. Moreover,
the high overall yield of the CÀH/NÀO functionalization with
the diastereomeric mixture of substrate 1u revealed that a Z-
configuration of the O-acetyl oximes 1 is not a prerequisite for
the alkyne annulation. As to the relative reactivity of alkynes 2,
aromatic substituents increased the inherent reaction rate
(Scheme 3c). In accordance with this hypothesis we
found a minor kinetic isotope effect (KIE) of kH/kD ꢀ1.5
(Scheme 3d),[18] being suggestive of the CÀH metalation not
being the rate-determining step.[19]
Scheme 5. Attempted cyclization of ortho-alkenylated arene 8aa.
Studies with isotopically labeled compounds highlighted
a considerable H/D exchange in the ortho-position of the re-
isolated substrate [Dn]-1c and the product [Dn]-3ca
(Scheme 4a). It is noteworthy that we also observed a signifi-
cant H/D exchange at the C(sp3)ÀH bonds, which was shown
to proceed by chelation assistance (Scheme 4b), thereby show-
casing the potential of cobalt(III) catalysis beyond aromatic CÀ
H functionalization.
To probe the viability of a potential reaction sequence com-
prising of intermolecular hydroarylation[20] and electrocyclic re-
action, we subjected the independently prepared ortho-alkeny-
lated substrate 8aa to the optimized reaction conditions
(Scheme 5). Thus, a thermal pericyclic reaction did not occur,
even after prolonged heating. Likewise, the attempted trans-
formation of substrate 8aa in the presence of the cobalt(III)
catalyst provided results being considerably inferior to the
ones observed for the isohypsic alkyne annulation, thus ren-
dering a hydroarylation/electrocyclization sequence unlikely to
be operative here.
Scheme 6. Proposed catalytic cycle.
sible CÀH activation, along with a proposed migratory alkyne
insertion, providing key intermediate 11 (Scheme 6). Next, the
CÀN formation is proposed to proceed, followed by a subse-
quent concerted acetate transfer to deliver the desired product
3, and regenerate the catalytically competent cobalt(III) com-
plex 9.
Based on our mechanistic studies we propose the cobalt(III)-
catalyzed CÀH/NÀO functionalization to commence by a rever-
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In summary, we have reported on a cobalt-catalyzed CÀH/
NÀO functionalization. Thus, the isohypsic alkyne annulation
has set the stage for an effective isoquinoline synthesis with
ample substrate scope. The step-economical direct functionali-
zation occurred by facile CÀH activation, and circumvented the
use of an external oxidant[21] for the regioselective alkyne func-
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Generous support by the European Research Council under
the European Community’s Seventh Framework Program (FP7
2007-2013)/ERC Grant agreement no. 307535, and the China
Scholarship Program (fellowship to H. W. and W. L.) is gratefully
acknowledged.
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Keywords: alkyne · CÀH activation · cobalt · isoquinoline · N-O
cleavage
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Received: August 19, 2015
Revised: September 10, 2015
Published online on September 30, 2015
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