Weakly Coordinating, Ketone-Directed (η5-Pentamethylcyclopentadienyl)cobalt(III)- and (η5-Pentamethylcyclopentadienyl)rhodium(III)-Catalyzed C?H Amidation of Arenes: A Route to Acridone Alkaloids

Article abstract of DOI:10.1002/chem.201805376

The weakly coordinating, ketone-directed, regioselective monoamidation of aromatic ketones, chalcone, carbazole, and benzophenones was achieved by employing high-valent cobalt and rhodium catalysis to access numerous biologically important molecular building blocks. This amidation proceeded smoothly with a variety of ketones and several amidating partners. The application of the products in the synthesis of various heterocycles, including acridones, indoles, quinoline, quinolones, quinolinones, and quinazolines, was also explored. The total synthesis of acridone-based alkaloids, namely, toddaliopsin A, toddaliopsin D, and arborinine, and the formal synthesis of acronycine and noracronycin were also accomplished by applying this method. A mechanistic study revealed this amidation reaction follows a base-assisted intermolecular electrophilic substitution pathway.

Full text of DOI:10.1002/chem.201805376

A Journal of
Accepted Article
Title: Weakly Coordinating Ketone-Directed Cp*Co(III)- and Cp*Rh(III)-
Catalyzed C–H Amidation of Arenes: A Route to Acridone
Alkaloids
Authors: Sourav Sekhar Bera, Md Raja Sk, and Modhu Sudan Maji
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To be cited as: Chem. Eur. J. 10.1002/chem.201805376
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10.1002/chem.201805376
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Weakly Coordinating Ketone-Directed Cp*Co(III)- and Cp*Rh(III)-
Catalyzed C–H Amidation of Arenes: A Route to Acridone
Alkaloids
Sourav Sekhar Bera, Md Raja Sk, and Modhu Sudan Maji*
Abstract: Weakly coordinating, ketone-directed, regioselective mono-amidation of aromatic ketones, chalcone, carbazole, and benzophenones
are achieved employing high-valent cobalt- and rhodium-catalysis to access numerous biologically important molecular building blocks. This
amidation proceeds smoothly with varieties of ketones as well as with several amidating partners. The application of the products to the
syntheses of heterocycles acridones, indoles, quinoline, quinolones, quinolinones, and quinazolines is also described. The total syntheses of
acridone based alkaloids, namely toddaliopsin A, toddaliopsin D, arborinine, and formal syntheses of acronycine and noracronycin have also
been accomplished applying this method. The mechanistic study reveals this amidation reaction follows a base assisted intermolecular
electrophilic substitution (BIES) pathway.
Introduction
Ortho amido aromatic ketones are important structural motif found
in many biologically active molecules1 and also used as a one of
the key intermediate for synthesizing diverse array of
heterocycles such as acridones, indoles, quinolines, quinolones,
quinolinones, quinazolines, etc (Figure 1).2 To this point,
installation of carbon-nitrogen bond in arenes has been a topic of
Scheme 1. Cobalt and Rhodium-Catalyzed Ketone-Directed Amidation with
Dioxazolones.
intensive research. Traditional approaches involve Photo-Fries
rearrangement of aryl acetamides3 and nitration of the aryl
In the past decades, with the incessant advancement in C–H
ketones followed by the reduction,4 suffers from harsh reaction
activation,6 considerable efforts have been devoted toward
conditions and poor regioselectivity, restricting their broad
directed C–H amidation on arenes using different transition
applicability. Though C–N-coupling reactions have been
metals like Rh,7 Ir,8 Ru,9 Pd10 and Cu.11 Although strongly
developed as a powerful protocol for the synthesis of aryl amines,
coordinating groups likes pyridyl, amide, imine, imidazole,
requirement of pre-functionalized aryl halides or aryl boronic acids
oxazoline have ample success for the amidations,7-11 the use of
has again led the chemists to search for other alternatives.5 In this
weakly coordinating directing groups are still rare.12,13 Among the
few reports on ketone-directed amidations, a palladium catalyzed
amidation12a using para-tolunesulphonamide as an amidating
context, transition-metal-catalyzed directed C–H amidation
represents a burgeoning field owing to its step- and atom-
economy, as well as rich with fixed regioselectivity.
agent and Ru-catalyzed amidation12b,c employing tosyl azide as
nitrogen source are notable. Recently the field has perceived a
substantial shift toward earth abundant first-row transition metals,
e.g., cobalt catalysis, because of their higher abundance, lower
prices and less-toxicity.14-16 However, where low Lewis basicity of
the ketones was itself a drawback, inferior reactivity of the base-
metal cobalt makes the process more challenging for generating
a durable metallacycle. Additionally, enolizable alpha proton is
also an issue for promoting simple ketones in directed ortho C–H
functionalizations. Recently, we have developed a simple ketone-
directed allylation for the first time, using the base metal cobalt
catalyst.17 Here, inspired by the Chang’s pioneering dioxazolone
chemistry,18 we also wish to reveal our result on ketone-directed
Figure 1. 2-Amino-Ketone Derived Bioactive Molecules.
C–H amidation of aromatic ketones, chalcone, carbazole and
benzophenones (Scheme 1). To compare the reactivity of
Cp*Co(III)-catalyst with its Rh-congener, we also developed an
alternative amidation method by employing Cp*Rh(III)-catalyst
and found a complementary reactivity for several ketones. The
importance of this C–H amidation strategy is further demonstrated
by the construction of several key heterocycles and the total
syntheses of acridone based five alkaloids.
[a]
S. S. Bera, M. R. Sk, and Dr. M. S. Maji
Department of Chemistry, Indian Institute of Technology
Kharagpur, Kharagpur 721302, W. B., India.
E-mail: msm@chem.iitkgp.ac.in
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Results and Discussion
Table 1. Optimization of the Reaction Conditions[a]
Entry
Solvent
Catalyst
Additive
Temp Yield [%][b]
1
2[c]
DCE
DCE
DCE
dioxane
DCE
DCE
DCE
DCE
DCE
DCE
DCE
Cp*Co(CO)I2
Cp*Co(CO)I2
Cp*Co(CO)I2
Cp*Co(CO)I2
Cp*Co(CO)I2
Cp*Co(CO)I2
Cp*Co(CO)I2
Cp*Co(CO)I2
Cp*Co(CO)I2
Cp*Co(CO)I2
Cp*Co(CO)I2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
none
80
80
80
80
80
80
80
100
26
19
36
28
38
45
40
49
24
49
56
65
72
59
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
NaOAc
3
4
5
6
KOAc
7
AgOAc
8
KOAc
9
Mn(OAc)2·4H2O 100
Zn(OAc)2·2H2O 100
10
11[d]
KOAc
100
100
100
100
12[d],[e] DCE
13[d],[e],[f] DCE
14[d],[e],[f]
KOAc
Cu(OAc)2·H2O
NaOAc
DCE
Scheme 2. Scope of Different Ketone Derivatives.[a],[b] [a] Isolated yields. [b] 15
mol% of Cp*Co(CO)I2 was used.
[a] Reaction conditions: 1a (0.25 mmol), 2a (0.375 mmol) and 1.0 mL of DCE
were used. [b] Isolated yields. [c] 1.0 equiv additive. [d] 2.5 equiv 2a was
used. [e] 5 mol% [Cp*RhCl2]2 and 12 h reaction time. [f] 15 mol% additive
was used.
catalysis, while rhodium failed to provide encouraging result.
Acetophenones bearing electron withdrawing groups responded
only under cobalt catalysis to afford 3e to 3f in 36-38% yields. On
introduction of electron-donating amino group, ketone showed
excellent reactivities to provide 3g with 76% and 88% yields under
both the catalysis. Simple acetophenone afforded 36% of 3h
under rhodium catalysis. n-Butyl ketone 1i and ketone bearing a
coordinating ester group 1j furnished the corresponding amides
3i and 3j in 37-69% yields. Chalcones, an important structural
motif found in many natural products and bioactive molecules,
converted to the corresponding amide 3k in good to moderate
yields (Co: 68%, Rh: 40%). Gratifyingly, conjugated dienone also
survived under both the reaction conditions and provided 3l in
comparable yields (68–74%). Though Co-catalyzed amidation of
3-acetyl-carbazole was quite efficient to provide 3m in 66% yield,
but did not react well under rhodium catalysis. Surprisingly 2-
acetyl-thiophene was not reactive enough and 2-tert-butyl
thiophene provided 3n in only 35% yield under Rh-catalysis.
Overall, we can conclude that for the electron-donating substrates
both Rh- and Co-catalysis showed comparable reactivities, but
Rh-catalysis does not react well for electron-deficient substrates
rendering this cobalt-catalyst a more versatile one.
We have commenced our optimization using ketone 1a and
amidating agent 2a. Conducting the reaction in 1,2-
dichloroethane solvent by employing 10 mol% of Cp*Co(CO)I2
catalyst and 20 mol% of AgSbF6 afforded 3a in 26% yield
(Table 1, entry 1). Usages of Cu(OAc)2·H2O as an additive
improved the yield (entry 3). Among different acetate additives
(entries 5–10), KOAc and Zn(OAc)2·2H2O provided better
o
results at 100 C. To compensate the slow decomposition of
2a at 100 oC, 2.5 equiv of 2a was found to be optimal amount
providing 3a in 56% yield (entry 11). In contrast, benzoyl- and
tosyl-azide failed to provide any amidation products. Next, to
compare the reactivity of Co-catalysis with its Rh-congener, a
reaction was conducted using [Cp*RhCl2]2 under our optimized
conditions, and 65% of 3a was isolated (entry 12). Upon using
15 mol% of Cu(OAc)2·H2O, the best yield of 3a was isolated
under Rh-catalysis (72%, entry 13).
With both the optimized conditions in hand for cobalt and
rhodium catalysis, we applied this directed amidation on a
series of electronically and sterically diversified ketones. Aryl
moiety bearing electron-donating groups reacted efficiently to
give amides 3a-3c in 56-86% yields under the cobalt and
rhodium catalysis (Scheme 2). Acetophenone stitched with a
1,3-dioxole group at the 3,4-position reacted through the more
hindered C–H bond due to weak coordinating nature of the 1,3-
dioxole oxygen to provide 3d in 91% yield under cobalt
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Rh: 37%). Interestingly for dioxazolone bearing aliphatic group, a
reverse trend was observed as rhodium provided superior results
over cobalt (6h, 70% vs 37%). Alkenyl dioxazolone was also
reactive albeit lower yield of 6i.
Acridone derivatives, an important class of heterocycles, shows
versatile bioactivities such as anti-inflammatory, anticancer,
antimicrobial, antitubercular, antiparasitic, antimalarial, antiviral
and fungicidal activities.19a-c,2c The unique semi-planar structure
enables acridones to act as DNA intercalators and to inhibit
topoisomerase or telomerase enzymes. Reported synthesis of
acridone core structures mainly rely on the aniline
derivatives.19a,2c Arguably the best way to accomplish these
valuable alkaloids are via two-fold C−H amination of
benzophenones. Here, applying our method, using simple
benzophenones derivatives, a two-fold C−H amination strategy is
designed to achieve the total synthesis of acridone alkaloids such
as toddaliopsin and arborinine, demonstrating the applicability of
our amidation reaction (Scheme 5).19a,2c
Scheme 3. Scope of Benzophenone Derivatives.[a],[b] [a] Isolated yields, [b] 15
mol% of Cp*Co(CO)I2 was used.
After investigating acetophenones derivatives, we switched our
focus
to
benzophenones
(Scheme
3).
Symmetrical
benzophenones reacted smoothly under cobalt and rhodium
conditions to provide the products 5a and 5b with moderate to
good yields (40-73%). Unsymmetrical ketone 4c also responded
well to afford single regioisomeric amide 5c predominantly in 52-
54% yields arising from the C–H amidation of the electron-rich
arene. Another unsymmetrical ketone 4d was also introduced
under cobalt catalysis to achieve 5d and 5d′ in 5.2:1 ratio with the
overall yield of 68%. In contrary, in presence of rhodium, we got
the similar yield but with reduced selectivity (2.2:1). The amidating
agent 2g also reacted with 4a to provide 5e in modest yield.
Scheme 5. Total Syntheses of Toddaliopsin A, Toddaliopsin D and Arborinine.
Reagents and conditions: a) [Cp*RhCl)2]2 (5 mol%), AgSbF6 (20 mol%),
Cu(OAc)2·H2O (15 mol%), 20 h; b) 4 N NaOH in 9:1 dioxane:methanol; c)
KOtBu (4 equiv), DMSO; d) MOMCl (2 equiv), NaH (2.5 equiv); e) CH3I (2.5
equiv), NaH (5 equiv); f) water, 80 oC; g) CuI (2 mol%), bpy (2 mol%), DMAc,
O2 balloon; h) BBr3 in 1 M DCM (1.5 equiv).
The Rh(III)-catalyzed, ketone-directed, C−H amidation of 4f,
provide the key amides 5f and 5f′ as a 3:1 mixture which upon
hydrolysis under heating conditions afforded anilines 7 and 7′ in
t
a combined yield of 43%. The BuOK mediated second C−H
amination of the mixture of 7 and 7′ delivered the toddaliopsin A
8 in 56% yield.19b Further methoxymethyl-protection of 8 afforded
the other alkaloid toddaliopsin D 9 in 80% yield. Synthesis of
arborinine was also began with amides 5f and 5f′. The mixture of
amides 5f and 5f′ was first methylated using methyl iodide in the
presence of excess amount of sodium hydride. Pleasingly, though
the majority of the methylated products underwent hydrolysis
during workup to give 10 and 10′, heating at 80 oC was required
for complete conversion. The mixture of methylated amines 10
and 10′ were next subjected to the copper-catalyzed C−H
amination reaction to furnish the acridone core 11 in 71% yield.19c
Scheme 4. Scope of Different Amidating Agents.[a] [a] Isolated yields.
The scope of the amidating agent 2 was next investigated
(Scheme 4). Fluoro, chloro, and bromo substituted dioxazolones
2b-2d were all viable for the amidation giving 6b-6d in 51-80%
yields under the cobalt- and rhodium-catalysis. Incorporation of
electron donating substituent decreased the yield of the reaction
significantly for cobalt-conditions (6e, 39%), and was very
inefficient for Rh-conditions. Same trend was observed for the
amidating agent 2f bearing electron-rich thiophene ring (Co: 66%,
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Selective demethylation of 11 completed the synthesis of
arborinine 12 alkaloids in 74% yield.
also decrease the VEGF protein expression, was prepared in two
steps from 4-quinolone 16 using POCl3 and n-propyl amine
(Scheme 7b).20b In one step, using titanium-powder, the amide 3h
was converted to important 2,3-disubstituted indole 20 by
reductive coupling (Scheme 7c).20c Amide 5e was further
diversified through the synthesis of 3,4-diarylquinolinones 21 by
t
treatment with BuOK (scheme 7d). Synthesis of benzoxazinone
core 22, found in many drug molecules, was also accomplished
t
from 3h by reacting with iodine and BuOOH (Scheme 7e).20d
Finally, hydrolysis of 3h afforded 2′-amino acetophenone 23.
To understand the catalyst’s mode of action, we first examined
the competition between electron-rich and -deficient
benzophenones. The preferential conversion of 3a over 3e (4.5:1)
Scheme 6. Formal Synthesis of Acronycine and Noracronycin. Reagents and
conditions: a) CH3I (2.5 equiv), NaH (5 equiv); b) water, 80 oC; c) CuI (2 mol%),
bpy (2 mol%), DMAc, O2 balloon; d) BBr3 in 1M DCM (4 equiv).
hints toward
a base assisted intermolecular electrophilic
substitution (BIES) mechanism.21 A lacking of H/D scrambling at
the ortho-position of 1h with CD3OD and CD3CO2D indicates an
irreversible C–H activation step (Scheme 8b). The results from
intermolecular competition experiment and parallel experiment
(KIE = 4.6, kH/kD = 4.0, Scheme 8c) suggest that C–H activation
step involves in the rate determining step. Detection of the
intermediates B involved in the catalytic cycles have also been
achieved via LC-MS analysis (Scheme 8d).22
To show further applicability, formal synthesis of antitumor
alkaloids acronycine and noracronycine were accomplished using
our method. The products 5d and 5d′, obtained by Co(III)-
catalyzed C−H amidation of 4d, was first subjected to the
methylation followed by hydrolysis as described for the synthesis
of 10 afforded the mixture of N-methylated products 13 and 13′ in
50% combined yield (Scheme 6). In presence of CuI and bpy
under the oxygen atmosphere, the intramolecular C−H amination
provided acridone core 14 in 76% yield.19c Finally, treatment of 14
with BBr3 provided the advanced intermediate 15 which has been
previously utilized to synthesize acronycine and noracronycine
alkaloids.2a,19a
Scheme 8. Mechanistic Studies.
On the basis of our mechanistic studies and previous reports,23
we proposed a plausible catalytic cycle where the neutral cobalt
catalyst is assumed to be converted initially into a cationic species
A in presence of a silver salt (Scheme 9). Species A commences
a kinetically relevant, in situ generated acetate-assisted C−H
cobaltation in acetophenone to generate metallacycle B which
was further supported by LC-MS analysis (Scheme 8d). After the
subsequent co-ordination with dioxazolones 2a, species C
undergoes CO2 extrusion to form an amido inserted species D.
Finally, in the presence of AcOH, proto-demetalation occurs to
afford amidated product 3a and regenerate active catalyst A.
Scheme 7. Applications of Amidation Products.
The importance of the products amide was further demonstrated
by converting them to several important heterocycles. 2-Phenyl-
4-quinolone derivatives are the subject of extensive research as
potent cardiovascular protectors, cytotoxic antimitotic, anti-
diabetic, and antibacterial agents.20a-b Employing this amidation
reaction, an effective 4-quinolone based anti-tumor agent 17 was
synthesized from 3c with an overall yield of 59% (Scheme 7a).20a
The 4-amino quinoline derivative 19 which exhibits potent
cytotoxicity against HCT-116 cells (IC50 value = 0.97 μM) and can
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20.0 mol%) were added successively to the reaction mixture and was
stirred for 5 min at the room temperature. After that, the amidating agent 2
(0.375 mmol, 2.5 equiv) was added to the reaction mixture and the
resultant reaction mixture was allowed to stir at 100 °C for 16 h. After
completion of the reaction as indicated by TLC, the crude product was
directly purified by silica gel column chromatography using petroleum
ether/ ethylacetate eluent.
General Procedure for Cp*Rh(III)-Catalyzed Ketone-Directed
Amidation: (GP II)
The aryl/heteroaryl ketone 1 (0.15 mmol, 1.0 equiv) was taken in a 15.0
mL screw capped sealed tube and 1.0 mL of 1,2-dichloroethane was
added. Then catalyst [Cp*RhCl2]2 (4.65 mg, 0.0075 mmol, 5.0 mol%),
AgSbF6 (10.3 mg, 0.03 mmol, 20.0 mol%) and Cu(OAc)2·H2O (4.5 mg,
0.0225 mmol, 15.0 mol%) were added successively to the reaction mixture
and was stirred for 5 min at the room temperature. After that, the amidating
agent 2 (0.375 mmol, 2.5 equiv) was added to the reaction mixture and the
resultant reaction mixture was allowed to stir at 100 °C for 12 h. After
completion of the reaction as indicated by TLC, the crude product was
directly purified by silica gel column chromatography using petroleum
ether/ ethylacetate eluent.
Scheme 9. Proposed Mechanism.
Conclusions
Acknowledgements
In summary, we have developed weakly co-ordinating ubiquitous
ketone-directed, high-valent cobalt and rhodium catalyzed C–H
amidation using dioxazolnes as an amidating agents. The
successful response from varieties of ketones and dioxazoles
made the method suitable for practical applications. Total
synthesis of toddaliopsin alkaloids and formal synthesis acronysin
alkaloids have been achieved using amidation as key C−N bond
forming step. Supremacy of this methodology was further shown
by accomplishing the synthesis of important heterocycles like
indole, quinoline, quinolone, quinolinone, and benzoxazinone.
M.S.M. gratefully acknowledges SERB, Department of Science
and Technology, New Delhi, India (Sanction No. EMR/2015/
000994) for funding. S.S.B. thanks CSIR, India and M.R.S. thanks
IIT Kharagpur for fellowships.
Keywords: cobalt • ketone • C–H functionalization • amidation •
acridone.
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General Procedure for Cp*Co(III)-Catalyzed Ketone-Directed
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The aryl/heteroaryl ketone 1 (0.15 mmol, 1.0 equiv) was taken in a 15.0
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* Co(III)- and Rh(III)-catalyzed ketone directed amidation. * Regioselective mono-amidation * Total synthesis of toddaliopsin A,
toddaliopsin D and arborinine. * Formal synthesis of acronycine and isoacronycine. * Direct access to potent antitumor agent *
Detection of reactive intermediates via LC-MS analysis.
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