Iron-Catalyzed C?H Alkynylation through Triazole Assistance: Expedient Access to Bioactive Heterocycles

Article abstract of DOI:10.1002/chem.201700587

Triazole assistance enabled the first iron-catalyzed C?H alkynylation of arenes, heteroarenes, and alkenes. The modular TAM directing group set the stage for a sequential C?H alkynylation/annulation strategy with ample scope, enabling the iron-catalyzed assembly of isoquinolones, pyridones, pyrrolones, and isoindolinones with high levels of chemo-, site-, and regioselectivity.

Full text of DOI:10.1002/chem.201700587

A Journal of
Accepted Article
Title: Iron-Catalyzed C-H Alkynylation through Triazole Assistance:
Expedient Access to Bioactive Heterocycles
Authors: Gianpiero Cera, Tobias Haven, and Lutz Ackermann
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Iron-Catalyzed C–H Alkynylation through Triazole Assistance:
Expedient Access to Bioactive Heterocycles
Gianpiero Cera, Tobias Haven and Lutz Ackermann*[a]
Abstract: Triazole assistance enabled the first iron-catalyzed C–H
In recent years, our group has exploited iron catalysts as a
powerful alternative to 4d and 5d transition metals in C–H
functionalization methodologies.[88] Indeed, iron is inexpensive,
enviromentally benign, earth-abundant and allows for new C–C
bond forming reactions under exceedingly mild conditions.[9,10] It
is particularly noteworthy that the toxicity of iron compounds
compares favorably with their nickel, cobalt or copper
counterparts.[11] Within our program on sustainable C–H
functionalizations,[12] we have now devised an unprecedented
strategy for iron-catalyzed C–H alkynylations by triazole
assistance (Scheme 1b).[13] The present approach enables a
versatile and regioselective approach to valuable heterocycles,
such as isoquinolones, pyridones, pyrrolones and isoquinolones,
through the judicious choice of the reaction parameters enabled
by the modular nature of the triazolyldimethylamine (TAM) group.
alkynylation of arenes, heteroarenes and alkenes. The modular TAM
directing group set the stage for
a
sequential C–H
alkynylation/annulation strategy with ample scope, enabling the iron-
catalyzed assembly of isoquinolones, pyridones, pyrrolones and
isoindolinones with high levels of chemo-, site- and regioselectivity.
Alkynes are versatile building blocks in organic synthesis.[1,2] As
a consequence, the development of efficient strategies for the
construction of alkynes continues to be an important goal, often
being achieved by the conventional Sonogashira-Hagihara
cross-coupling reaction.[3] However, over the last decade,
transition-metal catalyzed C–H functionalization has emerged as
a powerful alternative for the direct introduction of the alkynyl
moiety.[4] Thus, efficient and valuable methods have been
realized with the aid of expensive 4d and 5d transition metals.[5]
Very recently, the earth abundant 3d transition metals nickel,
copper and cobalt,[6] were identified as a viable alternative when
exploiting bidentate directing groups.[7] However, these
approaches continue to be largely restricted to the use of the
difficult to modify 8-aminoquinoline (8-AQ) bidentate directing
group (Scheme 1a).
Table 1. Optimization of iron-catalyzed aalkynylation.[a]
Entry
Ligand
dppe
ZnX2
ZnBr2
ZnBr2
ZnBr2
ZnCl2
--
Yield 3aa [%]
1
2
3
4
5
6
7
46
33
dppbz
dppen
dppen
dppen
dppen
dppen
59
66
--
ZnCl2
ZnCl2
--[b]
54[c]
[a] Reaction conditions: 1a (0.20 mmol)), [Fe(acac)3] (10 mol %), Ligand (15
mol %), PhMgBr (0.60 mmol), ZnX2·TMMEDA (0.40 mmol), 2a (0.50 mmol),
THF (0.1 M), 65 °C, 60 min; yields of iisolated product. [b] Reaction without
[Fe]. [c] Reaction with 8-AQ as the biidentate directing-group. dppe = 1,2-
bis(diphenylphosphino)ethane; dppbz == 1,2-bis(diphenylphosphino)benzene;
dppen = 1,2-bis(diphenylphosphino)etheene.
Scheme 1. Iron-catalyzed C–H alkynylation through triazole assistance
At the outset of our studies, we probed the use of triazolyl (TAM)
amide 1a for the envisioned iron-catalyzed C–H alkynylation with
alkynyl bromide 2a (Table 1, see also Tables S1 and S2 in the
Supporting Information).[14] The C–H alkynylation of substrate 1a
smoothly proceeded under rather mild reaction conditions when
using dppen as the ligand (Table 1, entries 1-4).[14] Interestingly,
zinc salts proved to be crucial in promoting the desired reaction
(Table 1, entry 5), while a test reaction in the absence of the iron
[a]
Dr. Gianpiero Cera, T. Haven, Prof. Dr. L. Ackermann
Institut für Organische und Biomolekulare Chemie
Georg-August-Universität
Tammannstraße 2, 37077 Göttingen (Germany)
E-mail: Lutz.Ackermann@chemie.uni-goettingen.de
Homepage: http://www.ackermann.chemie.uni-goettingen.de/
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author
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ut a base-mediated pathway (Table 1, entry 6).
phenylated substrate and the unreacted starting materials 1.[14]
Extended aromatic hydrocarbons and heteroarenes, such as
pyrroles 1p-q, were found to be suitable substrates for the C–H
transformation as well. Notably, the optimized catalytic system
proved applicable to the C–H alkynylation of alkenes (Scheme
2b), delivering highly substituted olefins 4ra-ta with excellent
levels of diastereo-selectivity as the single (Z)-isomers.
d auxiliary also proved to be amenable for
C–H alkynylation under otherwise identical
ons, albeit in diminished yields (Table 1, entry 7).
catalyst was found applicable to the direct
of different triazole-functionalized benzamides 1
rticularly N-alkylated or N-arylated triazoles
esired products with high efficacy (entries 2 and
iary benzamide 1e was not effective, highlighting
of the mono-anionic bidentate coordination motif.
of the TAM substitution pattern.
R1
R2
R3
Bn
3
Me
Me
Me
H
H
H
3aa: 66%
3ba: 64%
3ca: 56%
3da: --
PMP
nHex
nHex
Bn
H
H
Me
Me
3ea: --
tions: 1 (0.20 mmol), [Fe(acac)3] (10 mol %), dppen (15
0.60 mmol), ZnCl2·TMEDA (0.40 mmol), 2a (0.50 mmol),
60 min; yields of isolated product. PMP= p-methoxyphenyl
mized catalyst in hand, we probed differently
nyl halides 2. Thus, the versatile iron catalyst
itable for the conversion of iodo- and chloro-
C–H alkynylation, yet with somewhat reduced
cheme 1).
Scheme 2. Scope of iron-catalyzed C–HH alkynylation with alkynes 2a.
The versatility of the iron-catalyzed C–H alkynylation was further
tested with (bromoethynyl)trimethylsilane (2d). Hence, by the
judicious choice of the base in the iron-catalyzed C–H
alkynylation process, we were able to devise a two-step
procedure for the synthesis of synthetically meaningful
isoquinolones (Scheme 3).[15] Interestingly, the reaction
procedeed with high 6-endo regioselectivity, while the
desilylation occurred under basic conditions (Scheme 3).[16] The
synthetic utility of this protocol was further mirrored by
converting various benzamides
1
to the corresponding
isoquinolone derivatives 4. Here, the optimized catalytic system
displayed high functional group tolerance with respect to
diversely substituted benzamides. Indeed, products 5ad, 5fd,
5ud and 5id-jd were selectively obtained, while naphthalene
and heterocyclic derivatives, such as pyrroles and thiophenes,
were converted into the corresponding products 5pd, 5qd and
5vd with high chemo- and site-selectivity (Scheme 3a).
Moreover, the catalyst proved to be widely applicable, and thus
allowed for the C–H functionalization of alkene derivatives with
complete regio- and diastereo-control (Scheme 3b).
alyzed C–H alkynylation with alkynes 2.
explored the versatility of the iron catalyst by
tuted benzamides
1
(Scheme 2a). meta-
zamides 1f–i were efficiently converted to the
ts 3fa–ha with complete positional selectivity
para- and ortho-substituents were fully tolerated
orresponding products 3ia–oa. Here, the mass
nly accounted for by minor quantities of ortho-
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olone synthesis via iron-catalyzed alkynylation/deprotection
val of the TAM group on isoquinolones 5id was
n a traceless fashion, thereby delivering the
econdary amide 7id in high yield (Scheme 4).
Scheme 5. Summary of mechanistic finddings.
The lack of primary kinetic isotope effect (KIE) suggested that
the C–H activation is not involved in the rate-determining step
(Scheme 6).
ss removal of the TAM group.
anding selectivity features of the iron-catalyzed
n, we became attracted to delineating its mode
his end, intermolecular competition experiments
on-deficient derivatives 1 to be inherently more
me 5a). This finding can be accounted for by a
σ-bond metathesis (DBM) elementary step.
actions conducted in the presence of reagents
o probe radical intermediates did not fully shut
ytic activity (Scheme 5b). These observations
ype mechanism[17] unlikely to be operative in the
n.
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access to isoindolinones scaffolds 9 with excellent site- and
chemo-selectivity.[21] Thus, several benzamide derivatives 1
were converted to the corresponding isoindolinones 9ba and
9wa-ya showing good functional group tolerance with respect to
electron-donating and electron-withdrawing substituents. The
protocol was found to be also suitable for delivering pyrrolone
9za in good yields and excellent regioselectivities.
Based on our mechanistic studies we propose a plausible
catalytic cycle for the C–H alkynylation, which is initiated by the
reversible C–H metalation to generate metallacycle 11 (Scheme
9). A subsequent migratory insertion of alkyne 2 delivers the
proposed intermediate 12, which finally undergoes β-bromo-
elimination to deliver the final product 3a.
ndependent experiments.
synthetic utility of the iron-catalyzed C–H
tocol was illustrated by the late-stage diversifying
For instance, the alkynylsilane derivative 3ha
converted into the corresponding alkynylaryl
a via a direct C–Si functionalization (Scheme
due to the practical importance of the bioactive
caffold,[19] we developed
a step-economical
synthesis and functionalization of this structural
7b). Particularly, 3-iodo-isoquinolone 8fd could
h complete control of regio- and site-selectivity.
otential of this intermediate was highlighted by
ng the isoquinolone scaffold.
Scheme 8. Plausible catalytic cycle.
In conclusion, we have developed the first iron-catalyzed
organometallic C–H alkynylation. The C–H transformation was
enabled by triazole assistance. The highly versatile catalytic
system allowed for site-selective C–H functionalizations of
various arenes, heteroarenes and alkenes with high functional
group tolerance. Thereby, we demonstrated the unprecedented
facile access to several isoquinolones, pyridones, isoindolones
and pyrrolones by the judicious choice of the reaction conditions
utilizing the modular electronic features of the triazole group.
Sonogashira functionalization of alkynylbenzamide 3ha; b)
atization protocol; c) isoindolone synthesis via C–H
ection.
Acknowledgements
nd that through a fine tuning of the electronic
e triazole[20] it was possible to achieve a base-
ylative cyclization with complete 5-exo-dig
(Scheme 7c). This protocol provided a versatile
Generous support by the Alexander Von Humboldt Foundation
(fellowship to G. C.) and the European Research Council under
the Seventh Framework Program of the European Community
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lkynylations with TAM and 8-AQ derivatives, see the
nformation.
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10.1002/chem.201700587
Chemistry - A European Journal
ICATION
NICATION
Gianpiero Cera, Tobias Haven and Lutz
Ackermann*
Page No. – Page No.
Iron-Catalyzed C–H
Alkynylation/Annulation Strategy by
Triazole Assistance
O
TAM
TAM
N
O
TAM
Si
N
Fe
H
O
N
catalyzed C H alkynylation
conditions
tional group tolerant and ample scope
ctive synthesis of heterocycles
ensive, earth-abundant and no-toxic iron catalyst
ed C–H alkynylation: Triazole assistance enabled the selective C–H alkynylation
alkenes and heteroarenes with ample scope, providing step-economical access to
active heterocycles.
This article is protected by copyright. All rights reserved.