Manganese-Catalyzed Carbonylative Annulations for Redox-Neutral Late-Stage Diversification

Article abstract of DOI:10.1002/anie.201801111

An inexpensive, nontoxic manganese catalyst enabled unprecedented redox-neutral carbonylative annulations under ambient pressure. The manganese catalyst outperformed all other typically used base and precious-metal catalysts. The outstanding versatility o

Full text of DOI:10.1002/anie.201801111

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Accepted Article
Title: Manganese-Catalyzed Carbonylative Annulations for Redox-
Neutral Late-Stage Diversification
Authors: Yu-Feng Liang, Ralf Steinbock, Annika Münch, Dietmar
Stalke, and Lutz Ackermann
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201801111
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10.1002/anie.201801111
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COMMUNICATION
Manganese-Catalyzed Carbonylative Annulations for Redox-
Neutral Late-Stage Diversification
Yu-Feng Liang, Ralf Steinbock, Annika Münch, Dietmar Stalke, and Lutz Ackermann*[a]
Abstract: An inexpensive, non-toxic manganese catalyst enabled
unprecedented redox-neutral carbonylative annulations under
ambient pressure. The manganese catalyst outperformed all other
typically used base and precious metal catalysts. The outstanding
versatility of the manganese catalysis manifold was reflected by
ample substrate scope, setting the stage for effective late-stage
manipulations under racemization-free conditions on a wealth of
marketed drugs and natural products, including alkaloids, amino
acids, steroids and carbohydrates.
a]pyrimidin-4-ones under ambient pressure and (iv) powerful
late-stage diversifications of structurally complex natural
products and drugs. It is furthermore noteworthy that the unique
performance of the manganese[15] catalysis manifold was
reflected by outperforming typically used noble rhodium,
ruthenium, palladium, and iridium catalysts – a strong testament
to the outstanding power of sustainable manganese catalysis
with the third most earth abundant transition metal.
Transition metal-catalyzed carbonylations of organic compounds
with cost-effective carbon monoxide have emerged as a step-
economical strategy to access carbonyl-containing molecules.[1]
Among a variety of carbonylative transformations, chelation-
assisted dehydrogenative annulations have been identified as
an atom-economical approach for the synthesis of bioactive
heterocycles.[2] To this end, oxidative carbonylative annulations
have been accomplished with various heteroatom-containing
groups, including imines,[3] amines,[4] anilines,[5] amides,[6]
phenols,[7] or pyridines.[8] Despite these undisputable advances,
major challenges remain to be addressed in order to unleash the
full potential of this strategy. First, carbonylative alkyne
annulations were thus far predominantly accomplished with the
aid of precious transition metals, such as rhodium, palladium,
iridium, and ruthenium, while the use of more sustainable earth-
abundant 3d metal catalysts continues to be scarce.[9] Second,
the oxidative nature of the dehydrogenative annulations calls for
sacrificial oxidants, largely requiring (super)stoichiometric
amounts of toxic metal oxidants. Third, the prerequisite directing
groups are normally not integral part of the target molecules,
translating into multi-step protocols for the directing group
installation, manipulation and removal.[10] In sharp contrast, we
Scheme 1. Manganese-catalyzed carbonylative annulations.
We initiated our studies by probing various reaction conditions
for the envisioned carbonylative annulation of 2-pyridyl
hydrazone 1a and alkyne 2a (Table 1, and Table S1 in the
Supporting Information). Thus, among a variety of transition
metal compounds, Mn2(CO)10 emerged as the only catalytically
competent complex. In sharp contrast, commonly used catalysts
based on cobalt, ruthenium, rhenium, iron, molybdenum,
rhodium, nickel, palladium or iridium fell short in providing the
desired product 3aa, illustrating the unique performance of the
manganese catalysis regime. Toluene proved to be the solvent
of choice for the thermal[16] annulation, and the connectivity of
the product 3aa was unambiguously established by single-
crystal X-ray diffraction. A set of control experiments confirmed
the essential nature of the manganese catalyst.
have now uncovered
a
chelation-enabled[11] traceless
carbonylative annulation by inexpensive manganese[12]
catalysts,[13] setting the stage for a redox-neutral strategy
towards pyrido[1,2-a]pyrimidin-4-ones (Scheme 1a) - ubiquitous
structural motifs of medicinally-relevant compounds (Scheme
1b).[14] Notable features of our findings include (i) first
manganese-catalyzed carbonylative alkyne annulations, (ii) a
traceless directing group approach for external oxidant-free
cyclizations, (iii) user-friendly syntheses of bioactive pyrido[1,2-
[*]
Dr. Y.-F. Liang, R. Steinbock, Prof. Dr. L. Ackermann
Institut für Organische und Biomolekulare Chemie
Georg-August-Universität Göttingen
Tammannstraße 2, 37077 Gottingen (Germany)
E-mail: Lutz.Ackermann@chemie.uni-goettingen.de
Homepage: http://www.ackermann.chemie.uni-goettingen.de/
A. Münch, Prof. Dr. D. Stalke,
Institut für Anorganische Chemie
Georg-August-Universität Göttingen
Tammannstraße 4, 37077 Göttingen (Germany)
E-mail: dstalke@chemie.uni-goettingen
Supporting information for this article is given via a link at the end of
the document.
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Table 1. Establishing carbonylative alkyne annulation.[a]
Entry
1
Deviation from standard conditions
S2–S9 instead of 1a
Yield of 3aa [%][b]
Listed below
2
Without Mn2(CO)10
0
3
MnCl2 instead of Mn2(CO)10
Mn(OAc)2 instead of Mn2(CO)10
Co2(CO)8 instead of Mn2(CO)10
Ru3(CO)12 instead of Mn2(CO)10
Re2(CO)10 instead of Mn2(CO)10
Cp2Fe2(CO)4 instead of Mn2(CO)10
Mo(CO)6 instead of Mn2(CO)10
Rh2Cl2(CO)4 instead of Mn2(CO)10
Pd(OAc)2 instead of Mn2(CO)10
Ni(COD)2 instead of Mn2(CO)10
[Cp*IrCl2]2 instead of Mn2(CO)10
1,4-Dioxane instead of PhMe
DMF instead of PhMe
0
4
0
5
0
6
0
7
0
8
0
9
0
10
11
12
13
14
15
16
17
18
0
0
0
0
86
0
PhCF3 instead of PhMe
54
75
91
80 oC instead of 100 oC
Reaction carried out in dark
Scheme 2. Redox-neutral carbonylative annulation of alkynes 2.
[a] Reaction conditions: 1a (0.50 mmol), 2a (1.00 mmol), Mn2(CO)10 (10
mol%), PhMe (1.0 mL), CO (1 atm), 100 °C, 16 h. [b] Yield of isolated
products.[20]
We were pleased to find that a variety of hydrazones 1 could be
efficiently employed in the redox-neutral alkyne annulation,
again featuring high functional group tolerance (Scheme 3). It is
particularly noteworthy that medicinally relevant purines[17] could
be functionalized to form the annulated product 3pa, the
molecular structure of which was unambiguously confirmed by
X-ray diffraction analysis.
With the optimized manganese catalyst in hand, we next tested
its versatility with diversely decorated alkynes 2 (Scheme 2).
The outstanding robustness of our carbonylative alkyne
annulation was thus mirrored by fully tolerating a wealth of
sensitive functional groups, including ester, chloro, thiophene,
pyridino or cyano substituents. The widely applicable
manganese catalyst was further amenable to both terminal and
internal alkynes with excellent levels of chemo-, positional- and
regio-selectivity control. In addition to aryl and alkyl alkynes,
diynes were identified as viable substrates, thereby delivering
the bispyrido[1,2-a]pyrimidin-4-one 3ai’ in a single step.
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Scheme 3. Hydrazones 1 for traceless alkyne annulation.[20]
The late-stage manipulation of natural products and synthetic
drugs is of key importance for the identification of bioactive
compounds with improved properties.[18] Hence, we were
particularly delighted to find that the outstanding versatility of our
manganese-catalyzed carbonylative annulation set the stage for
the late-stage diversification of structurally complex drug
molecules of prominence in pharmaceutical industries and
medicinal chemistry (Scheme 4). Specifically, the estrogen
prodrug Mestranol chemo-selectively underwent the redox-
neutral alkyne annulation without racemization of the
stereogenic centers, as confirmed by single-crystal X-ray
diffraction analysis. Yet, the manganese catalysis regime was
not restricted to Mestranol modifications. Indeed, a wealth of
structurally complex drugs and natural products could be
smoothly converted to the desired products 4–12 in a traceless
fashion. To this end, progesterone drug Norethindrone,
endogenous steroid Pregnenolone, orally-active estrogen
Ethynylestradiol, monoamine oxidase inhibitor Pargyline,
carbohydrate glucofuranose, α-amino acid tryptophan, oral
contraceptive Desogestrel, and tyrosine kinase inhibitor Erlotinib
were identified as viable substrates. The structural diversity of
the thus obtained products within a variety of natural product
Scheme 4. Late-stage diversification of structurally complex natural products
and drugs.[20]
Given the unique versatility of the manganese-catalyzed
carbonylative alkyne annulation, we became intrigued by
delineating its mode of action. To this end, mass spectrometric
analysis provided support for a bidentate coordination of the
hydrazones 1 (Figure S-1 in the Supporting Information). The
traceless nature of our chelation assisted manifold was
confirmed by careful analysis of the crude reaction mixture,
revealing the formation of by-products 13 and 14 (Scheme 5a),
the latter of which being formed by C–H/N–H functionalization.[12l]
These observations were then exploited for the development of
an unprecedented complexity-increasing double alkyne
annulation, which provided atom-economical access to
isoquinolines and pyridopyrimidinones in a single reaction
(Scheme 5b). The use of typical radical scavengers indicated
homolytic bond cleavages not to be operative (Scheme 5c),
which was further supported by the complete conservation of the
cyclopropyl motif in the radical clock-type substrates 2j’ and 2k’
(Scheme 5d). Detailed kinetic analysis by in-operando infrared-
spectroscopy did not reveal a significant induction period, but
classes is
a strong testament to the robustness of the
manganese-catalyzed alkyne annulation, with major potential for
applications to medicinal chemistry and biomolecular sciences
as well as pharmaceutical and agrochemical industries.
rather
a sigmoidal curve (Figure S-2 in the Supporting
Information). In addition, the kinetic profile of the carbonylative
alkyne annulation was not affected by the CO pressure (Figure
S-3 in the Supporting Information), being indicative of the CO
insertion not to be rate-determining. Experiments with
isotopically 18O-labeled CO clearly showed that the carbonyl
moiety in the products largely originated from gaseous CO
(Scheme 5e). Based on our mechanistic studies, we propose a
plausible catalytic cycle to commence by an initial coordination
of the manganese catalyst by the hydrazone 1 to afford the
complex A (Scheme 5f), as was supported by high resolution
mass spectrometry. Subsequently, facile insertion of CO
generates key intermediate B, while migratory insertion of
alkyne 2 delivers the eight-membered metalacycle C. Then, the
key C–N formation is enabled by imine extrusion, with proto-
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demetalation regenerating the catalytically active manganese
complex A.
Finally, the synthetic utility of our manganese-catalyzed
carbonylative annulation was highlighted by ruthenium(II)-
catalyzed C‒H activation of the thus obtained products 3 in a
bifurcating ortho- or remote meta-fashion[19] (Scheme 6).
Scheme 6. Post modification by ortho- and meta-C–H functionalizations.
In summary, we have devised the unprecedented manganese-
catalyzed carbonylative alkyne annulation in a redox-neutral
fashion. The traceless approach avoids the use of stoichiometric
toxic metal oxidants and enables the assembly of bioactive
pyridopyrimidinones in a modular fashion. Detailed mechanistic
studies have provided support for a facile CO insertion. The
manganese catalyst outperformed all other typically used
catalysts based on base and precious transition metals. The
outstanding synthetic utility of our manganese catalysis was
reflected by the versatile late-stage diversification of numerous
marketed drugs and natural products, including steroids,
alkaloids, amino acids and carbohydrates.
Acknowledgements
Generous support by the Alexander von Humboldt Foundation
(fellowship to Y.L.), and the DFG (Gottfried-Wilhelm-Leibniz
prize) is gratefully acknowledged.
Conflict of interest
The authors declare no conflict of interest.
Keywords: carbonylation • traceless • annulation • manganese •
late-stage
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Yu-Feng Liang, Ralf Steinbock, Annika
Münch, Dietmar Stalke, and Lutz
Ackermann*
Page No. – Page No.
Text for Table of Contents
Manganese-Catalyzed Carbonylative
Annulations for Redox-Neutral Late-
Stage Diversification
Smart Man: Traceless carbonylative annulations by sustainable manganese catalysis set the stage for enabling
late-stage diversification in a redox-neutral fashion.
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