Redox-Neutral Manganese(I)-Catalyzed C?H Activation: Traceless Directing Group Enabled Regioselective Annulation

Article abstract of DOI:10.1002/anie.201707396

A strategy is reported in which traceless directing groups (TDGs) are used to promote the redox-neutral Mn^I-catalyzed regioselective synthesis of N-heterocycles. Alkyne coupling partners bearing a traceless directing group, which serves as both the chelator and internal oxidant, were used to control the regioselectivity of the annulation reactions. This operationally simple approach is highly effective with previously challenging unsymmetrical alkyne systems, including unbiased dialkyl alkynes, with perfect regioselectivity. The simple conditions and the ability to carry out synthesis on a gram scale underscore the usefulness of this method. The application of this strategy in the concise synthesis of the bioactive compound PK11209 and the pharmaceutical moxaverine is also described.

Full text of DOI:10.1002/anie.201707396

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Accepted Article
Title: Redox-Neutral Manganese(I)-Catalyzed C-H Activation:
Traceless Directing Group Enabled Regioselective Annulation
Authors: Qingquan Lu, Steffen Greßies, Sara Cembellín, Felix Klauck,
Constantin Daniliuc, and Frank Glorius
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201707396
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10.1002/anie.201707396
Angewandte Chemie International Edition
COMMUNICATION
Redox-Neutral Manganese(I)-Catalyzed C–H Activation: Traceless
Directing Group Enabled Regioselective Annulation
Qingquan Lu+, Steffen Greßies+, Sara Cembellín, Felix J. R. Klauck, Constantin G. Daniliuc and Frank
Glorius*
Dedicated to Prof. Qi-Lin Zhou on the occasion of his 60th birthday
Abstract: An unprecedented strategy using traceless directing
groups (TDG) to promote the redox-neutral Mn(I)-catalyzed
regioselective synthesis of N-heterocycles is reported. Alkyne
coupling partners bearing traceless directing group, which serve as
both chelator and internal oxidant, were used to control the
regioselectivity of the annulation reactions. This operationally simple
approach is highly effective with previously challenging
unsymmetrical alkyne systems, including unbiased dialkyl alkynes,
featuring switchable regioselectivity, simple conditions, and gram-
scale synthesis. The application of this strategy in the concise
synthesis of bioactive compound PK11209 and pharmaceutical
moxaverine is also described.
and unexpected side products, which is a major drawback for any
synthetic application. To address this issue, a directing group
which can be removed directly in situ has been developed.[5]
Although the installation of catalyst-directing groups to direct
selective C–H activation has been widely applied, the use of a
directing group in the coupling partner to control the
regioselectivity has been seldom studied, especially with
traceless directing groups.[6] In principle, the problem of the
regioselectivity in oxidative annulations arises from the alkyne
insertion step, which is controlled mainly by an orbital interaction
of the occupied M−C σ bonding orbital with an unoccupied π*
orbital of the alkyne.[7] Therefore, in almost all cases, the
intermediate generated from the alkyne insertion cannot be
exclusively obtained and the regioselectivity problem remains
unsolved (Scheme 1a). Inspired by the well-developed
methodologies for directed ortho metalation, we questioned
whether a traceless directing group located in an alkyne can be
used to control the regioselectivity of oxidative annulation
(Scheme 1b), an approach which has not been realized to date.
Theoretically, such a group would have to precoordinate to the
metal catalyst and enable a regioselective alkyne insertion.
Afterwards, the resulting transient intermediate would also have
to selectively undergo -TDG elimination rather than-hydride
elimination or reductive elimination, furnishing the active allene
intermediate. Furthermore, a highly selective intramolecular
cyclization has to be ensured to circumvent potential side
reactions. On the basis of this hypothesis, control over the
regioselectivity and ease of removal would be the important
criteria for the efficiency of such a directing group.
Over the past few decades, catalytic C–H activation has
emerged as one of the most powerful and attractive methods for
the construction of new carbon–carbon and carbon–heteroatom
bonds using readily available hydrocarbon starting materials.[1] In
particular, unsaturated hydrocarbons have seen extensive use as
coupling partners in the synthesis of valuable cyclic compounds,
which are frequently found in natural product, pharmaceutical and
material frameworks.[2] Arguably, annulation reactions with
alkynes are one of the most popular methods of this type, which
have been extensively explored with Pd, Rh, Ir, Ru, Cu, Ni etc.[2,3]
Despite great progress in this area, essentially almost all the
methods reported to date suffer from uncontrolled regioselectivity,
leading inevitably to mixtures of positional isomers, especially
when unbiased unsymmetrical alkynes were utilized (Scheme
1a).[2,3] Furthermore, the application of unpolarized aliphatic
alkynes in this field has become a significant challenge, possibly
due to their weaker coordination and low boiling points.
Considering these issues, the development of new surrogates for
alkynes is of high interest.
In principle, the precoordination of a functional group with a
metal can guide the site selectivity, which is the vital step in
directed C–H activation.[4] However, the late stage removal of
directing groups may lead to labor-intensive multistep operations
[*]
Dr. Q. Lu,[+] S. Greßies,[+] S. Cembellín, F. J. R. Klauck, C. G.
Daniliuc and Prof. Dr. F. Glorius
Organisch-Chemisches Institut
Westfälische Wilhelms-Universität Münster
Corrensstraße 40, 48149 Münster (Germany)
E-mail: glorius@uni-muenster.de;
Scheme 1. TDG enabled regioselective annulation.
[+]
Dr. Q. Lu and S. Greßies contributed equally to this work
To probe the feasibility of our assumption, we selected 1-
phenylpentan-1-imine (1a) and tertiary propargylic carbonate (2a)
as model substrates under manganese catalysis.[8,9] It is
noteworthy that N-H imines are especially challenging substrates
[]
This work was supported by the Alexander von Humboldt Foundation
(Dr. Q.L.), the Deutsche Forschungsgemeinschaft (Leibniz Award)
and the Fonds der Chemischen Industrie (F.J.R.K.). We also thank
Dr. Michael J. James and Dr. Zackaria Nairoukh for helpful
discussions.
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10.1002/anie.201707396
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for C–H activation, since the possible enamine tautomerization,
the nucleophilicity of the nitrogen and the facile hydrolysis to the
ketone can lead to undesired side reactions.[10] Recently, the
wang group has successfully utilized N–H imines to couple with
alkynes, achieving an elegant dehydrogenative [4+2] annulation
in the presence of manganese.[9f] Through an extensive screening
(for details, see Table S1 in the Supporting Information (SI)), it
was found that the solvent has a significant impact on promoting
the reaction efficiency and the expected product 3a can be
isolated in 88% yield with exclusive selectivity when using
[MnBr(CO)5] as a catalyst with 20 mol% NaOAc as a base and
DMF as solvent at 100 oC. Further experiments showed that the
traceless directing group also plays a crucial role in this
transformation. Boc-protected propargylic alcohol 2d displayed
good reactivity while propargylic acetate 2c and propargylic
alcohol 2b showed low or inert reactivity (Scheme 2).
Scheme 3. Regioselective Synthesis of Isoquinolines. For details, see
Supporting Information. [a] BPh3 (10 mol%) and DME were employed.
Scheme 2. All reactions were carried out using 1a (0.10 mmol), 2 (0.15 mmol),
[MnBr(CO)5] (10 mol%) and NaOAc (20 mol%) in DMF (0.25 mL) under argon
for 14 h at 100 oC, GC-FID yields using mesitylene as internal standard.
With the optimized reaction conditions in hand, the scope of
imines was first investigated. As shown in Scheme 3, a variety of
alkyl aryl imines bearing either electron-donating groups (R =
OMe, OPh, Me) or electron-withdrawing groups (R = F, Cl, CF3)
on the aryl ring, reacted smoothly with 2a, affording the
corresponding isoquinolines 3a-3g in 63% to 92% yield. The less
sterically congested C–H bond was preferably annulated in the
meta-methyl imine, furnishing the desired product 3d in 63% yield.
When a sterically hindered ortho-fluoro substituted imine was
employed, the corresponding product 3g was obtained in 70%
yield. Furthermore, the scope of the reaction with respect to
propargylic carbonates was explored with 1a. The R1 group in the
propargylic carbonates was tolerated with aryl, heteroaryl or alkyl
groups (3a, 3h, 3i). The sterically hindered alkyl groups, such as
ethyl and cyclopentyl, located on the tertiary carbon of the
propargylic carbonate were found to marginally affect the
efficiency of these reactions, providing the products 3j and 3k in
73% and 77% yields respectively. Furthermore, diaryl ketimine,
as exemplified by diphenylmethanimine, could also serve as a
suitable reaction partner and gave the desired product 3l in 94%
yield. Importantly, arylimidates were also effective, affording the
corresponding desired products 3m-3p in good to excellent yield.
Notably, further extending this method to other heterocycles such
as thiophene and benzothiophene was also successful, giving the
expected products 3o and 3p in 95% and 73% yield respectively.
The regioselectivity of this protocol was unequivocally confirmed
by the X-ray crystallography of 3a and 3m.[11]
Scheme 4. Regioselective switching synthesis of isoquinolines. For details, see
Supporting Information. [a] BPh3 (10 mol%) and DME were employed.
Encouraged by these promising results, we further attempted
to apply our developed protocol to secondary propargylic
carbonates. To our delight, a variety of secondary and even
primary propargylic carbonates were applicable to this procedure,
affording the desired products in good to excellent yields (Scheme
4). Intriguingly, complementary to the challenging use of aliphatic
alkynes or terminal alkynes in C–H activation, dialkyl-substituted
and monoalkyl-substituted propargyl carbonates were compatible
as well and delivered the corresponding products 3r-3y in 62% to
91% yield. It should be noted that a C3 building block, methyl
prop-2-yn-1-yl carbonate, can also be applied to this annulation
reaction and gave the expected product 3s in 65% yield, while its
C3 surrogate, propyne, is a gas and is therefore difficult to utilize.
Spurred by these exciting results, we synthesized an array of
isoquinolines (3v-3y) with switchable regioselectivity, which have
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10.1002/anie.201707396
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not been successfully prepared as single isomer using previously
reported C–H activation methods, highlighting the unique
practical application of this catalytic system. This protocol was
also readily scaled up to gram quantities with high efficiency. For
example, 1.11 g of 3a was isolated with 73% yield (for details, see
SI), further demonstrating the synthetic utility of this method.
To gain insight into the reaction mechanism, a series of
experiments were conducted (Scheme 5). First, no oxidative
annulation product was detected when N-phenyl-2-pyridinamine
(4a) was employed, and the skipped diene 5a was isolated
instead in moderate yield [Eq. a], which might be formed from the
isomerization of the corresponding allene generated in situ. This
forming
a
five-membered manganacycle I. Afterwards,
coordination of the carbonyl oxygen of the carbonate 2a to I forms
manganacycle II, which is followed by a regioselective alkyne
insertion and subsequent selective β-oxygen elimination to deliver
the active allene intermediate IV and regenerate the active Mn(I)
complex. Finally, a highly selective intramolecular cyclization of
IV would give the desired isoquinoline 3a.[13]
Furthermore, the synthetic applications of our developed
method were demonstrated. Isoquinolones are indispensable and
ubiquitous structural motifs in bioactive compounds and natural
products.[2d,3] Although great efforts have been devoted for their
preparation, to date, the regioselective synthesis of isoquinolones
result revealed that an allene-species might be a key intermediate, is still a daunting challenge in C–H activation.[2d,3] Here, we
and that the N-H imine directing group plays a crucial role for the
selective intramolecular cyclization. Additionally, no chirality
transfer was observed when chiral carbonate (S)-2e (98% ee)
was applied, even when the reaction was conducted at a lower
synthesized a series of valuable isoquinolones with controlled
regioselectivity in two steps without isolation of the isoquinoline
intermediate, which cannot be achieved using the corresponding
alkynes (Scheme 7). The identity of product 6c was unequivocally
established by its X-ray single-crystal structure.[11]
o
reaction temperature (80 C) [Eq. b], implying the intramolecular
cyclization might be
a
nucleophilic addition process.[8]
Furthermore, a kinetic isotope effect (kH/kD = 1.62) was observed
from two parallel reactions of 1a or [D]-1a with 2a (for details, see
SI). Notably, a robustness screen was applied to demonstrate the
good functional group and heterocycle tolerance of this protocol
(for details, see SI).[12]
Scheme 7. Regioselective switching synthesis of isoquinolones. For details,
see Supporting Information.
Additionally, isoquinoline and its derivatives are common
motifs found in pharmaceuticals and natural products, such as
antitumor compound PK11209, the peripheral benzodiazepine
receptor ligand PK 11195, and the drug moxaverine, which was
used to treat functional gastrointestinal disorders.[14] Pleasingly,
these compounds were then concisely prepared using our
protocol (Scheme 8). Again, the regioselectivity plays a crucial
role in these processes.
Scheme 5. Mechanistic studies.
Scheme 6. Proposed mechanism.
Scheme 8. Application to the synthesis of bioactive compounds. For details,
see Supporting Information.[a] Yield is based on the purity of 1d.
Based on the aforementioned results and previous reports,[8,9]
a plausible mechanism was proposed in Scheme 6. The reaction
commences with base-assisted cyclomanganation of imine 1a,
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In conclusion, we have developed a general and scalable
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alkyne coupling partners with traceless directing group and an
earth abundant manganese-based catalyst. This protocol
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broaden scope and functional group tolerance. Related bioactive
compound and pharmaceutical were also readily synthesized
based on this methodology.
Keywords: C−H activation • regioselective annulation•
manganese • unpolarized alkyne • heterocycle
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COMMUNICATION
Qingquan Lu†, Steffen Greßies†, Sara
Cembellín, Felix J. R. Klauck,
Constantin G. Daniliuc and Frank
Glorius*
Page No. – Page No.
Redox-Neutral Manganese(I)-
Catalyzed C–H Activation: Traceless
Directing Group Enabled
Regioselective Annulation
Traceless Manganese Catalysis! An unprecedented strategy using traceless
directing groups (TDG) to promote the redox-neutral Mn(I)-catalyzed regioselective
synthesis of N-heterocycles is reported. This operationally simple approach is highly
effective with previously challenging unsymmetrical alkyne systems, including
unbiased dialkyl alkynes, featuring switchable regioselectivity, simple conditions, and
gram-scale synthesis.
This article is protected by copyright. All rights reserved.