Rhodium(iii)-catalyzed intramolecular annulation through C-H activation: Concise synthesis of rosettacin and oxypalmatime

Article abstract of DOI:10.1039/c7cc06860c

A flexible and efficient rhodium(iii)-catalyzed intramolecular annulation of benzamides bearing tethered alkynes for the synthesis of indolizinones and quinolizinones is reported. This reaction shows a broad substrate scope and excellent functional-group tolerance, including different kinds of heterocyclic substrates, such as furan, thiophene, pyrrole, benzofuran, benzothiophene, indole and isonicotinamide substrates. This method also provides a practical and efficient approach for the synthesis of rosettacin and oxypalmatime.

Full text of DOI:10.1039/c7cc06860c

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Rhodium(III)-Catalyzed Intramolecular Annulation through C-H
Activation: Concise Synthesis of Rosettacin and Oxypalmatime†
Liangliang Song,a Guilong Tian,*a Yi Hea and Erik V. Van der Eycken*a,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A
flexible and efficient rhodium(III)-catalyzed intramolecular
OMe O
O
annulation of bearing alkyne-tethered benzamides for the
synthesis of indolizinones and quinolizinones is reported. This
reaction shows a broad substrate scope and excellent functional-
group tolerance, including different kinds of heterocyclic
substrates, such as furan, thiophene, pyrrole, benzofuran,
benzothiophene, indole and isonicotinamide substrates. This
method also provides a practical and efficient approach for the
synthesis of rosettacin and oxypalmatime.
MeO
N
N
N
OMe
OMe
rosettacin
oxypalmatime
O
N
O
N
O
O
N
HO
HN
norketoyobyrine
Me
camptothecin
The indolizinone and quinolizinone frameworks form the core
of lots of nature products with pharmacological relevance,
such as rosettacin,1 oxypalmatime,1a,2 camptothecin1a,3 and
norketoyobyrine1a,4 (Figure 1). Although several methods for
synthesizing these scaffolds have been reported, most of them
need harsh conditions or many steps.1-4 Thus developing easy
synthetic approaches still has significant value.
Figure 1 Representative examples of natural products with
indolizinone or quinolizinone scaffold.
alkenyl amides with different directing groups (Scheme 1a and
1b). However, most of the intermolecular annulations result in
the formation of a single ring and few cascade reactions to
build multiple ring are reported.8 When unsymmetrical alkynes
are utilized, the regioselectivity depends on the difference
between both substituents on the alkynes, often leading to
poor regioselectivity.7c,7d Obviously, intramolecular annulation
of alkynes with aryl or alkenyl amides can overcome these
limitations and can also allow the construction of multiple
rings existing in more complex scaffolds (Scheme 1c and 1d).9
Considering the advantages, we designed an intramolecular
annulation of alkyne-tethered benzamides, providing a flexible
synthesis of indolizinone and quinolizinone scaffolds (Scheme
1). Herein we report the construction of indolizinone and
In recent years, transition-metal catalyzed C-H bond
activation and functionalization plays an important role in
synthetic organic chemistry.5 One of the challenges is the
control of position selectivity. When a weakly coordinating
directing group is used for medicinally important heterocyclic
substrates, the heteroatoms can strongly coordinate with the
transition-metal catalyst, leading to either poisoning of the
catalyst or undesired selectivity.6 Therefore, new methods
should be explored to overcome these problems.
During the last decade, rhodium(III)-catalyzed C-H activation
has received great attention because of its high efficiency,
selectivity and functional-group tolerance.7 Many reports show
quinolizinone scaffolds based on
a rhodium(III)-catalyzed
intramolecular annulation. The generality of this approach is
demonstrated by accomplishing the synthesis of diverse
heterocyclic products including rosettacin and oxypalmatime.
We selected N-alkynylbenzamide 1a as our model substrate.
As revealed by the results in Table 1, [RhCp*Cl2]2 could easily
perform the construction of indolizinone 2a. We found that
treatment of 1a with [RhCp*Cl2]2 (5 mol%) and Cu(OAc)2 (2
equiv.) in t-AmOH at 110 °C gave 2a in 98% yield in 12 h (Table
1, entry 1). Screening of various solvents, such as 1,4-dioxane,
DMF and toluene, assured that t-AmOH was the most efficient
that rhodium(III)-catalyzed C-H activation is
a powerful
strategy to achieve intermolecular annulation of alkynes with
aryl or
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Table 1 Optimization of the reaction conditions.a
Entry
Solvent
t-AmOH
1,4-Dioxane
DMF
Toluene
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
Catalyst
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
Pd(OAc)2
t (h)
12
12
12
12
12
12
12
12
8
Yield (%)b
1
2
3
4
5
98
87
<5
<5
0
6
[Ru(p-cymene)Cl2]2
Ni(OAc)2·4H2O
[RhCp*Cl2]2
[RhCp*Cl2]2
83
0
7
8c
9d
<5
99(93)e
a
Condition: 1a (0.3 mmol), catalyst (0.015 mmol), Cu(OAc)2 (0.6
mmol), solvent (3.0 mL). Determined by 1H NMR analysis of the
b
c
d
e
crude reaction mixture. 90 °C. CsOAc (50 mol%) were added.
Isolated yield. t-AmOH tert-Amyl alcohol. Cp*
=
=
pentamethylcyclopentadienyl. p-cymene = 4-isopropyltoluene.
Table 2 Scope for aryl and heteroaryl substrates.a,b
Scheme 1 Towards the synthesis of rosettacin and
oxypalmatime.
one (Table 1, entries 2-4). We also evaluated the performance
of other metals, confirming [RhCp*Cl2]2 as the best choice.
Pd(OAc)2 and Ni(OAc)2·4H2O did not work, while with [Ru(p-
cymene)Cl2]2 83% yield was obtained (Table 1, entries 5-7).
Further investigation showed that a lower temperature was
deleterious for the reaction, leading to a very poor conversion
(Table 1, entry 8). We also tested [RhCp*Cl2]2 in combination
with CsOAc, resulting in an acceleration of the reaction,
yielding 2a in 99% yield in 8 h when 50 mol% CsOAc was added
(Table 1, entry 9).
With the optimized reaction conditions in hand, we next
examined various substrates to evaluate the scope of the
protocol. The annulation reactions proceeded smoothly to
afford indolizinones and quinolizinones in good to excellent
yields (Table 2). Substrates with electron-donating or electron-
withdrawing groups at the para position of the aryl moiety of
benzamide performed well under the reaction conditions (2b-
2e). The meta-methyl benzamide was totally selective to give the
corresponding indolizinone 2f in good yield. We also tested the
reactions with substrates containing a methyl or fluoro group in the
ortho position of the benzamide. Both gave the corresponding
products 2g and 2h in excellent yields. Naphthylbenzamide was an
a
Condition:
(0.6 mmol), t-AmOH (3.0 mL), CsOAc (0.15 mmol). Isolated
1 (0.3 mmol), [RhCp*Cl2]2 (0.015 mmol), Cu(OAc)2
b
yield.
2 | J. Name., 2012, 00, 1-3
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acceptable substrate, leading to the cycloadduct 2i in excellent
yield. The annulation reaction also tolerated electron-donating and
electron-withdrawing groups in the phenyl substituent of the alkyne
like methyl and trifluoromethyl groups (2j and 2k). When we
replaced the aryl groups of the alkyne by a cyclohexyl, cyclopropyl
or a tert-butyldimethylsiyl (TBS) group, the reaction smoothly
proceeded to give the cycloadducts 2m, 2n and 2l. Finally we tested
substrates containing electron-donating or electron-withdrawing
groups in the phenyl substituent of the benzylamine. Both gave the
corresponding products 2o and 2p in excellent yields.
Scheme 2 Synthesis of rosettacin (5a) and oxypalmatime (5b).
Interestingly, we found that the cycloaddition worked with
substrates bearing
a longer carbon chain between the
benzamide and the alkyne, leading to interesting products
containing either a six- (2q-2r) or seven-membered ring (2s) in
good yields. Considering that heterocycles are widely present
in many drug candidates,6 we extended the cycloaddition to
heteroaryl carboxamides, such as furan, thiophene, pyrrole,
benzofuran, benzothiophene and indole. They all smoothly
afforded the corresponding cycloadducts in moderate to
excellent yields (2t-2y). Even an isonicotinamide substrate
delivered the cycloadduct in moderate yield (2z).
[(Cp*RhCl2)2]
O
O
2 CsOAc
N
N
H
2 CsCl
Ph
Ph
2a
1a
Cp*Rh(OAc)2
2 CuOAc
2 Cu(OAc)2
O
N
O
To further demonstrate the synthetic utility, we used this
intramolecular annulation as a key ring-forming step for the
N
Rh
Cp*
Rh
Cp*
concise synthesis of rosettacin (5a) and oxypalmatime (5b
)
A
Ph
C
Ph
(Scheme 2). Cycloadduct 4a could be obtained from
benzamide 3a using the optimized conditions in 71% yield.
Removal of the TBS-group afforded rosettacin (5a) in good
overall yield. To our surprise, oxypalmatime (5b) could be
directly obtained in 66% yield from benzamide 3b in one step
employing the standard condition.
O
N
Rh
Cp*
Ph
B
Scheme 3 Plausible mechanism.
Based on the above results, we proposed a possible
mechanism (Scheme 3).9,10 First, an irreversible C-H bond
cleavage occurs to afford
intermediate with simultaneous loss of acetic acid. Next,
coordination of the alkyne furnishes intermediate , which
undergoes insertion into the Rh-C bond to produce seven-
membered rhodacycle . Subsequent reductive elimination
a five-membered rhodacycle
Conflicts of interest
A
There are no conflicts to declare.
B
C
Notes and references
gives the desired product, followed by reoxidation of Rh(I) by
Cu(OAc)2 to regenerate the catalyst.
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catalyzed intramolecular annulation of benzamides bearing N-
tethered alkynes for the synthesis of indolizinones and
quinolizinones. This reaction features a broad substrate scope
and excellent functional-group tolerance, including annulation
of different heterocyclic substrates, such as furan, thiophene,
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reliable and highly efficient approach for the synthesis of
rosettacin and oxypalmatime.
We thank the FWO [Fund for Scientific Research-Flanders
(Belgium)] and the Research Fund of the University of Leuven
(KU Leuven) and the Ministry of Education and Science of the
Russian Federation (agreement number 02.a03.0008).
Liangliang Song, Guilong Tian and Yi He appreciate the China
Scholarship Council (CSC) for providing a doctoral scholarship.
This journal is © The Royal Society of Chemistry 20xx
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