Rh(III)-Catalyzed Cascade Annulations to Access Isoindolo[2,1-b]isoquinolin-5(7H)-ones via C-H Activation: Synthesis of Rosettacin

Article abstract of DOI:10.1021/acs.orglett.7b03509

An efficient protocol for the synthesis of diversely substituted 7-hydroxyisoindolo[2,1-b]isoquinolin-5(7H)-ones from the reaction of N-(pivaloyloxy)benzamides with 2-alkynyl aldehydes has been developed, which proceeds through sequential alkyne insertion followed by addition of the amide nitrogen on to the aldehyde. This method provided the products with aminal functionality as a handle for further diversification. The synthetic utility of this strategy was successfully illustrated by the concise, two-step synthesis of an alkaloid, rosettacin, and a topoisomerase I inhibitor.

Full text of DOI:10.1021/acs.orglett.7b03509

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Rh(III)-Catalyzed Cascade Annulations To Access
Isoindolo[2,1‑b]isoquinolin-5(7H)‑ones via C−H Activation: Synthesis
of Rosettacin
Chada Raji Reddy*,†,‡ and Kathe Mallesh†,‡
†Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
‡Academy of Scientific and Innovative Research (AcSIR), New Delhi 110025, India
S
* Supporting Information
ABSTRACT: An efficient protocol for the synthesis of diversely substituted 7-hydroxyisoindolo[2,1-b]isoquinolin-5(7H)-ones
from the reaction of N-(pivaloyloxy)benzamides with 2-alkynyl aldehydes has been developed, which proceeds through
sequential alkyne insertion followed by addition of the amide nitrogen on to the aldehyde. This method provided the products
with aminal functionality as a handle for further diversification. The synthetic utility of this strategy was successfully illustrated by
the concise, two-step synthesis of an alkaloid, rosettacin, and a topoisomerase I inhibitor.
ndolizin-5(3H)-ones fused with aromatic or heteroaromatic
units are key structural frameworks embedded in various
natural products (Figure 1) such as camptothecin, rosettacin,
atom-economical method for the construction of complex
molecules.6 In particular, [Cp*RhIII]-catalyzed direct aryl C−H
functionalization toward the insertion of alkyne into aromatic
substances holding different directing groups is one of the
widely explored reactions, leading to diverse heterocyclic
compounds.7 Fagnou and co-workers discovered that the N-
pivaloyloxy group can act as a directing group as well as an
internal oxidant through N−O bond cleavage during the
synthesis of isoquinolones (Figure 2a).8 Later, this directing
group was extensively used in [Cp*RhIII]-catalyzed coupling
reactions with alkynes to access isoquinolone derivatives.9 In
2014, Lin and co-workers identified a novel cascade reaction of
O-substituted N-hydroxybenzamides with cyclohexadienone-
I
Figure 1. Representative compounds with an indolizin-5(3H)-one
structural motif.
22-hydroxyacuminatine, and synthetic compounds (camptothe-
cin analogues, e.g., topotecan, belotecan) that exhibit a wide
range of interesting biological and medicinal properties.1−3
Consequently, several strategies have been developed to
synthesize these important scaffolds4,5 including a recently
developed flexible strategy to various natural products by Gao
and co-workers.4a Nonetheless, conceptually different synthetic
approaches that provide an access to diversification are still of
great interest.
Figure 2. Rh(III)-catalyzed annulations of N-(pivaloyloxy)benzamide
with alkynes.
Transition-metal-catalyzed annulation reactions via C−H
activation have gained importance as a powerful step- and
Received: November 13, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03509
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Organic Letters
Letter
containing 1,6-enynes to obtain N-substituted isoquinolones
through alkyne insertion followed by aza-Michael addition
reaction (Figure 2b).10 Encouraged by these findings, we
envisioned a new cascade annulation of N-(pivaloyloxy)-
benzamides with 2-alkynyl aldehydes involving sequential
isoquinolone formation/addition of NH on to aldehyde (to
give the aminal). The successful development of this annulation
would lead to an unprecedented facile synthesis of 7-
hydroxyisoindolo[2,1-b]isoquinolin-5(7H)-ones (Figure 2c),
which could be readily transformed into polycyclic indolizin-
5(3H)-ones and their analogues. In continuation of our work
on alkyne-assisted annulations,11 herein we report the results of
the above proposed reaction and the total synthesis of
rosettacin via rhodium(III)-catalyzed C−H activation cascade
annulations. As far as we are aware, such a strategy comprising
alkyne insertion followed by the addition of NH on to aldehyde
(aminal formation) had not been reported. Very recently,
however, while our work was in progress, Chang’s research
group reported the annulation of N-pivaloyloxy benzamide with
conjugated enynones to access the tricyclic isoquinolinones
(Figure 2d).12 Nevertheless, there are sufficient differences
between the two methods to warrant a further communique on
the new work undertaken.
We commenced our studies with the reaction between N-
(pivaloyloxy)benzamide (1a) and 2-(pent-1-yn-1-yl)-
benzaldehyde (2a). It was observed that the reaction proceeded
smoothly in the presence of [(Cp*RhCl2)2] (5 mol %) and
CsOAc (2 equiv) in acetone at room temperature to give 7-
hydroxyisoindolo[2,1-b]isoquinolin-5(7H)-one 3a in 83% yield
in 2 h (Scheme 1). A similar result was observed in other
solvents like CH3CN (2 h, 76%) as well as in tert-amyl alcohol
(4 h, 81%), while in MeOH a low yield (14%) of the product
3a was isolated along with starting materials. Having identified
the optimized conditions, the scope of this cascade annulation
approach was investigated, through the coupling of various N-
(pivaloyloxy)amides with alkynyl aldehyde 2a (Scheme 1).
Hydroxamic acids containing both electron-donating (3,4,5-
trimethoxy, 1b) as well as electron-withdrawing groups such as
4-chloro (1c), 4-trifluoromethyl (1d) and 4-nitro (1e)
smoothly participated in the double annulation without any
substantial effect on the outcome of the reaction to furnish the
corresponding 7-hydroxyisoindolo[2,1-b]isoquinolin-5(7H)-
ones 3b−e in 72−87% yield. It is noteworthy that the present
cascade process was not limited to N-(pivaloyloxy)benzamides,
but it could also be extended to N-(pivaloyloxy)heteroaryl
carboxamides. This was successfully tested by the reactions of
N-(pivaloyloxy)thiophene-2-carboxamide (1f) and benzofuran-
2-carboxamide (1g) with 2a to obtain the annulated products
3f (73%) and 3g (81%), respectively.
We also evaluated the scope of the reaction with respect to 2-
alkynyl aldehyde substrates (Table 1). The annulation reactions
of (2-alkynyl) benzaldehydes bearing n-butyl (2b), cyclopropyl
(2c), cyclohexyl (2d), 2-hydroxyethyl (2e), and phenyl (2f)
with 1a afforded the corresponding 12-substituted 7-
hydroxyisoindolo[2,1-b]isoquinolin-5(7H)-ones 3h−l in good
yields, indicating that neither the alkyl nor aryl group on the
alkyne functionality influenced the reaction outcome. Note in
a
Table 1. Reaction of 1a with Various 2-Alkynyl Aldehydes
Scheme 1. Optimization and Sope of N-
a,b
(Pivaloyloxy)amides
a
a
Unless otherwise specified, 1 (1.5 equiv), 2a (0.29 mmol),
[Cp*RhCI2]2 (5 mol %), and CsOAc (0.58 mmol) in acetone (2
Unless otherwise specified, 1a (0.3 mmol), 2 (0.2 mmol),
[Cp*RhCI2]2 (5 mol %), and CsOAc (0.4 mmol) in acetone (2
mL) was stirred for the given time at rt. Isolated yield.
b
b
mL) was stirred for the given time at rt. Isolated yields.
B
DOI: 10.1021/acs.orglett.7b03509
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Letter
particular that 2-ethynylbenzaldehyde (2g) participated in this
rhodium-catalyzed C−H activation and cascade annulation
reaction with 1a under the optimal conditions to afford 3m in
72% yield, which suggests that a terminal alkyne group is well
tolerated. 2-(Pent-1-yn-1-yl)benzaldehyde containing OMe
substitution on the phenyl ring 2h successfully underwent the
reaction to give 3n in 93% yield. Additionally, when the phenyl
group was replaced by a heteroaromatic ring, the corresponding
products were still obtained in high yield. For instance, 2-(pent-
1-yn-1-yl)nicotinaldehyde (2i) and 2-(pent-1-yn-1-yl)-
quinoline-3-carbaldehyde (2j) furnished the corresponding
annulated products 3o (82%) and 3p (85%), respectively. To
our delight, a cyclohexene ring (2k) could be used instead of
the benzene ring in the alkynyl aldehyde, leading to the
corresponding isoquinolin-5(7H)-one 3q in 78% yield. Based
on the results obtained, we believe that the reaction proceeds
(Figure 3) via alkyne insertion into the five-membered
in several bioactive natural products) 4a in 94% yield. Likewise,
the treatment of 3h with other nucleophiles such as propargylic
alcohol, TMS-N3 and allyltrimethyl silane under BF3.Et2O (10
mol %)/CH2Cl2 conditions offered the functionalized
isoindolo[2,1-b]isoquinolin-5(7H)-ones 4b (92%), 4c (91%),
and 4d (95%) via C−O, C−N, and C−C bond formations,
respectively.
In order to showcase the synthetic value of this Rh(III)-
catalyzed cascade reaction, we decided to carry out the total
synthesis of rosettacin (II). Rosettacin, one of the aromathecin
alkaloids, is used as camptothecin/luotonin A hybrid for
binding to the topo-I/DNA covalent binary complex.2e,f To
date, the total synthesis of rosettacin has been accomplished by
nine research groups.4,13 For instance, the groups of Glorius13a
and Park13b have independently reported the synthesis of II in
more than five steps employing an intramolecular annulation as
the key reaction. We have accomplished the synthesis of
rosettacin via the present intermolecular annulation between N-
(pivaloyloxy)benzamide (1a) and 2-ethynylquinoline-3-carbal-
dehyde (2l) in two steps (Scheme 3). The reaction of 1a with
Scheme 3. Total Synthesis of Rosettacin
Figure 3. Plausible reaction pathway.
2l, under the developed conditions, provided the corresponding
diannulated product 3r in 66% yield. The reduction of aminal
of 3r in the presence of BF3·Et2O (10 mol %)/Et3SiH in
CH2Cl2 afforded the rosettacin (II) in 74% yield (Scheme 3).
This approach was amenable to the synthesis of various
analogues of rosettacin through the acid-catalyzed substitution
reactions of the annulated product 3r with different
nucleophiles.
rhodacycle B, C−N bond reductive elimination with N−O
bond cleavage (C and D) and base-mediated addition of amide
NH on to aldehyde (E), similar to the cascade reactions
reported by Lin et al. and Chang et al.10,12 They have
extensively studied various experiments to understand and
support their proposed reaction pathway.
Additionally, the isoquinolin-5(7H)-one 3m was transformed
into the topoisomerase I inhibitor, isoindolo[2,1-b]isoquinolin-
5(7H)-one VI, in 94% yield (Scheme 4). It is important to
mention that there are four synthetic approaches known for the
synthesis of VI to date, each involving harsh conditions or
multistep reaction sequence.2c,4b,14
To exemplify the practical applicability of this protocol, a
gram-scale reaction under the standard conditions was
conducted to obtain 3h in 85% yield. Various transformations
of this 7-hydroxyisoindolo[2,1-b]isoquinolin-5(7H)-one were
also explored (Scheme 2). For example, the reaction of 3h with
Et3SiH in the presence of BF3·Et2O (10 mol %) in CH2Cl2
underwent the reduction of hemiaminal to give isoindolo[2,1-
b]isoquinolin-5(7H)-one (a commonly found structural motif
Scheme 4. Synthesis of Topoisomerase I Inhibitor
Scheme 2. Diversification of Aminal 3ha
In conclusion, we have developed a one-pot efficient method
for the synthesis of 7-hydroxyisoindolo[2,1-b]isoquinolin-
5(7H)-ones from N-(pivaloyloxy)amides and 2-alkynyl alde-
hydes by Rh(III)-catalyzed C−H functionalization. Both aryl
and heteroaryl substrates having different substituents were
found to be effective coupling partners. Moreover, the present
reactions are first examples of cascade Rh(III)-catalyzed alkyne
insertion/intramolecular amide nitrogen addition to aldehydes.
C
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73, 1975. (d) Zhou, H.-B.; Liu, G.-S.; Yao, Z.-J. J. Org. Chem. 2007, 72,
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The significance of the products having aminal functionality
was shown by further diversification through substitutions in
the five-membered ring. Additionally, the application of this
method in a short synthesis of rosettacin and topoisomerase I
inhibitor was also demonstrated. The flexibility and the
extensive scope of this cascade annulation approach should
find applications in the synthesis bioactive natural product-like
molecules.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03509.
(7) For selected refs, see: (a) Upadhyay, N. S.; Thorat, V. H.; Sato,
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Experimental procedures, characterization details, and 1H
and 13C NMR spectra of new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: rajireddy@iict.res.in.
ORCID
(8) (a) Guimond, N.; Gouliaras, C.; Fagnou, K. J. Am. Chem. Soc.
2010, 132, 6908. (b) Guimond, N.; Gorelsky, S. I.; Fagnou, K. J. Am.
Chem. Soc. 2011, 133, 6449.
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Glorius, F. J. Am. Chem. Soc. 2012, 134, 19592.
Chada Raji Reddy: 0000-0003-1491-7381
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
C.R.R. thanks the Science and Engineering Research Board
(SERB), Department of Science and Technology, New Delhi,
for funding the project (EMR/2016/006253). K.M. thanks the
Council of Scientific and Industrial Research (CSIR), New
Delhi, for a research fellowship.
(10) Fukui, Y.; Liu, P.; Liu, Q.; He, Z.-T.; Wu, N.-Y.; Tian, P.; Lin,
G.-Q. J. Am. Chem. Soc. 2014, 136, 15607.
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2017, 53, 1904. (b) Raji Reddy, C.; Rani Valleti, R.; Dilipkumar, U.
Chem. - Eur. J. 2016, 22, 2501. (c) Raji Reddy, C.; Panda, S. A.; Reddy,
M. D. Org. Lett. 2015, 17, 896. (d) Raji Reddy, C.; Dilipkumar, U.;
Damoder Reddy, M. Org. Lett. 2014, 16, 3792.
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