The Aryne aza-Diels-Alder Reaction: Flexible Syntheses of Isoquinolines

Article abstract of DOI:10.1021/acs.orglett.5b01704

(Chemical Equation Presented). Two cascade reactions have been developed for the time-efficient preparation of a variety of functionalized aromatic heterocyclic products exhibiting an isoquinoline core. The approach is based on the normal electron-demand

Full text of DOI:10.1021/acs.orglett.5b01704

Letter
pubs.acs.org/OrgLett
The Aryne aza-Diels−Alder Reaction: Flexible Syntheses of
Isoquinolines
Juan-Carlos Castillo,† Jairo Quiroga,‡ Rodrigo Abonia,‡ Jean Rodriguez,*,† and Yoann Coquerel*,†
†Aix Marseille Universite,
́
Centrale Marseille, CNRS, iSm2 UMR 7313, 13397, Marseille, France
‡Universidad del Valle, Departamento de Química, A.A. 25360, Cali, Colombia
S
* Supporting Information
ABSTRACT: Two cascade reactions have been developed for the time-efficient preparation of a variety of functionalized
aromatic heterocyclic products exhibiting an isoquinoline core. The approach is based on the normal electron-demand [4 + 2]
aza-Diels−Alder cycloaddition of electron-rich N-aryl imines with arynes. Using this strategy, an expeditious total synthesis of the
naturally occurring benzo[c]phenanthridine alkaloid nornitidine was achieved.
soquinolines and their derivatives are important nitrogen-
containing heterocycles generally endowed with biological
properties, making them a privileged scaffold for applications in
medicinal chemistry and pharmaceuticals.1 Isoquinolines have
also found applications in material sciences because of their
interesting physicochemical properties.1 Synthetic approaches
to the isoquinolines (Figure 1) have largely relied on the
between 2-aza-dienes and arynes.7,8 However, an obstacle to
the development of this strategy is that benzyne is known to
react with imines and 2-aza-dienes essentially by [2 + 2]
cycloaddition reactions to provide the corresponding benzaze-
tidines.9 Moreover, the proposed aza-Diels−Alder reaction is a
normal electron-demand cycloaddition of a 2-aza-diene,
examples of which remain rare.10,11 Circumventing these
difficulties, the Stoltz group has reported an annulation reaction
between secondary eneamides and arynes as a viable route to
isoquinolines,12a,b and Huang has developed a pseudo four-
component approach involving 2 equiv of benzynes via a N-
allenyl aldimine intermediate generated in situ.12c The
realization of aza-Diels−Alder cycloadditions between arynes
and easily available 2-aza-dienes would open a direct and
practical synthetic approach to functionalized isoquinolines.
Herein, two distinct cascade reactions initiated by an aza-
Diels−Alder cycloaddition between N-aryl imines and arynes
are reported for the direct synthesis of a variety of
functionalized heterocycles with an isoquinoline core.13
At the origin of this work, it was hypothesized that electron-
rich N-aryl imines would be suitable candidates for aza-Diels−
Alder cycloadditions with arynes affording 1,2-dihydro-
isoquinolines, the oxidation of which would provide a direct
synthetic entry to isoquinolines (Scheme 1). In order to test
that idea, the prototypical electron-rich N-pyrazolyl aldimine 2a
(1.5 equiv) and benzyne, generated in situ by fluoride-induced
1,2 elimination from the ortho-silylated phenyltriflate 1a,14
were allowed to react in THF (Scheme 2).15 While 2a was
found to be almost unreactive at room temperature, a reaction
performed at 70 °C allowed the isolation of the 1,2-
dihydroisoquinoline 3a (34%), a significant amount of the N-
arylated over-reaction product 5a (31%),16 and 6% of the
I
Figure 1. Retrosynthetic strategies for isoquinolines.
Pomeranz−Fritsch synthesis involving the assembly of
benzaldehyde derivatives and aminoacetals.2 These reactions
typically require harsh acidic conditions, limiting their func-
tional diversity tolerance. More recently, Yamamoto described
an iodine-mediated electrophilic cyclization of elaborated 2-
alkynyl benzyl azides for the synthesis of polysubstituted
isoquinolines.3 Besides other stepwise approaches using single
bond-forming reactions, several metal-catalyzed multiple bond-
forming transformations have been developed in recent years to
prepare isoquinolines in a time-efficient manner.4 Notably, the
Larock group has established a general route to isoquinolines
from benzylidene amines and alkynes based on a palladium-
catalyzed cascade,5 and the groups of Fagnou,6a Lautens,6b and
Zhu6c have more recently used comparable approaches. All
these approaches rely at some point on a carbon−nitrogen
bond-forming event to assemble the desired bicyclic core. An
alternative inticing but largely unexplored strategy to prepare
isoquinolines would rely on the formation of two carbon−
carbon bonds by a metal-free aza-Diels−Alder cycloaddition
Received: June 11, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01704
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Letter
mode, a stepwise process, was found to be slightly kinetically
favored (by ca. 2 kcal.mol−1) and irreversible. In contrast, with a
N-pyrazolyl benzylidene imine of type 2 (Figure 2, bottom),
the [4 + 2] cycloaddition mode, a concerted asynchronous
process, was found kinetically preferred (by ca. 6 kcal·mol−1)
and irreversible. In the corresponding transition state TSGH, the
formation of the C−C bond between the pyrazolyl unit and
benzyne was found slightly in advance to the formation of the
C−C bond between the imine moiety and benzyne. From this
study, it was concluded that the relative nucleophilicities of the
nitrogen atom and the N-aryl moiety are essential factors that
govern the periselectivity of the cycloaddition reactions
between arynes and 2-aza-dienes.
Scheme 1. Aryne aza-Diels−Alder Strategy toward
Isoquinolines
Scheme 2. Aryne aza-Diels−Alder Reaction
Before the aryne aza-Diels−Alder reaction could be of any
synthetic utility to prepare isoquinolines, the issue of the
undesired formation of the N-arylation over-reaction product
5a had to be addressed. It was thus examined, if under oxidative
conditions, a rapid in situ oxidation of intermediate 3a could
occur prior to the unwanted N-arylation over-reaction. In
practice, several oxidizing agents were screened and the
reaction conditions optimized (see Supporting Information).
It was rapidly found that, in the presence of excess MnO2, the
isoquinoline 4a could be obtained in good yield from the 2-aza-
diene 2a and benzyne (Scheme 3). The scope of the reaction
was then examined with a variety of electron-enriched N-aryl
imines and arynes under similar conditions. In each case the
reaction was found productive, affording the isoquinoline
products 4a−l in good yields, and importantly, with good to
ultimately targeted isoquinoline 4a. Interestingly, no [2 + 2]
adduct or its derivatives could be identified in the crude
reaction mixture, which was considered possible.9
In order to rationalize the periselectivity ([2 + 2] vs [4 + 2])
of the cycloaddition of 2-aza-dienes with arynes, the reaction
between benzyne and model N-aryl imines was examined
theoretically by DFT calculations. In the case of N-phenyl
benzylidene imine (Figure 2, top), and in agreement with
previous experimental observations,9 the [2 + 2] cycloaddition
Scheme 3. Synthesis of Isoquinolines via the Oxidative
Aryne aza-Diels−Alder Reaction
Figure 2. Mechanism and energy profile of the cycloaddition reactions
between benzyne and N-aryl imines. The energy profiles were
obtained by DFT calculations at the B3LYP/6-311++G** level of
theory (free energies at 25 °C including ZPE corrections in kcal·mol−1
with the IEFPCM solvation model; see Supporting Information for
details).
a
b
1
With 20 equiv of MnO2, regioisomer ratio >15:1. The H NMR
analysis of the crude reaction mixture indicated the formation of the
other possible regioisomer in minor proportion (ca. 6:1). The
reported yield refers to the isolated 6:1 mixture of regioisomers.
B
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excellent regioselectivities with nonsymmetric arynes (in 4h, 4i,
and 4j; regioisomer ratios from 6:1 to >15:1). Notably, the
reaction with the hetaryne17 indol-4,5-yne regioselectively
afforded the expected isoquinoline product 4j bearing two
fused N-containing heterocycles and a free N−H group. Finally,
the scope of 2-aza-diene substrates was extended either to a N-
pyrrolyl imine leading to product 4k showing a 7-azaindole
moiety or to a N-isoxazolyl imine delivering the product 4l.
A second option to prepare isoquinolines via the aryne aza-
Diels−Alder strategy would be the introduction of a sacrificial
group, which would trigger the rapid eliminative aromatization
of the intermediate cycloadduct. In line with this idea, a series
of formimidamides 6a−h bearing a potentially labile
dimethylamino group were allowed to react with representative
arynes (Scheme 4). Rewardingly, a series of diversely
Scheme 5. Total Synthesis of Nornitidine via Arynes
N-Boc-pyrrole and the functionalized benzyne derived from the
ortho-silylated phenyltriflate 1c to give the bridged compound
9,21a which then underwent a rhodium-catalyzed ring opening
reaction21b and a deprotection step22 to afford the primary
amine 10. The required 2-aza-diene 11 was obtained
quantitatively from the amine 10. The pivotal benzyne aza-
Diels−Alder reaction between 11 and the o-dimethoxy benzyne
precursor 1g directly afforded the target molecule 12 in 31%
yield. Overall, the natural product 12 was obtained in five steps
and 22% yield from N-Boc-pyrrole featuring two benzyne
Diels−Alder cycloadditions. This original aryne-based synthesis
of nornitidine (12) very favorably competes with existing
routes. This synthesis also constitutes a formal total synthesis of
nitidine, another benzo[c]phenanthridine alkaloid natural
product with topoisomerase inhibition and potent antimalaria
properties.20
Scheme 4. Synthesis of Isoquinolines via the Aryne aza-
Diels−Alder Reaction
In summary, two flexible cascade reactions have been
developed to prepare diversely functionalized heteropolycyclic
products with an isoquinoline core in a time-efficient manner.
The approach relies on the normal electron-demand aza-Diels−
Alder cycloaddition reactions between easily accessible
electron-rich 2-aza-dienes and arynes, and a subsequent
aromatization step. The substitution patterns available by the
described approach are nicely complementary to the ones
obtained by existing methods. It can be noted that
heteropolycyclic compounds closely related to products 4 and
7 are of current high interest for their biological properties.1d,23
The method was successfully applied to a concise total
synthesis of the natural product nornitidine (12), a
representative member of a class of naturally occurring
biologically active benzo[c]phenanthridine alkaloids. The
described aryne aza-Diels−Alder cycloaddition strategy is
expected to become a useful tool for the synthesis of
nitrogen-containing heterocyclic compounds and functional
polyaromatic systems.
a
1
The H NMR analysis of the crude reaction mixture indicated the
formation of the other possible regioisomer in minor proportion (8:1
for 7h, 10:1 for 7i and 7k). The reported yield refers to the isolated
pure major regioisomer.
substituted pyrazolo-, pyrrolo-, isoxazolo-, and pyrimido-
isoquinolines 7a−m could be prepared efficiently by this
original cascade reaction, still with good regioselectivities with
unsymmetrical arynes as in 7h, 7i, and 7k (regioisomer ratios
from 8:1 to 10:1).18 The structures of products 7i and 7j have
been secured by X-ray diffraction techniques,19 and alkaline
hydrolysis of the pyrimido-isoquinoline 7m afforded the
corresponding 3-amino-4-amido-isoquinoline 8m.
ASSOCIATED CONTENT
* Supporting Information
■
S
Details of the computational study, CIFs for compounds 7i and
7j, detailed experimental procedures, characterization data, and
1
copies of H and 13C NMR spectra for all compounds. The
Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.orglett.5b01704.
The robustness of the aryne aza-Diels−Alder route to
isoquinolines was evaluated in a concrete case, through the
expeditious total synthesis of the naturally occurring benzo[c]-
phenanthridine alkaloid nornitidine (12, Scheme 5).20 The
synthesis was initiated by a Diels−Alder cycloaddition between
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: jean.rodriguez@univ-amu.fr.
*E-mail: yoann.coquerel@univ-amu.fr.
C
DOI: 10.1021/acs.orglett.5b01704
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Mohanan, K.; Charles, L.; Rajzmann, M.; Bonne, D.; Chuzel, O.;
Rodriguez, J.; Coquerel, Y. Chem.Eur. J. 2013, 19, 17578.
(14) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983,
1211.
(15) Noncommercially available substrates and reagents were
prepared according to the procedures described in: (a) Bagley, M.;
Davis, T.; Dix, M.; Widdowson, C.; Kipling, D. Org. Biomol. Chem.
2006, 4, 4158. (b) Allegretti, M.; Anacardio, R.; Cesta, M. C.; Curti,
R.; Mantovanini, M.; Nano, G.; Topai, A.; Zampella, G. Org. Process
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Michel Giorgi (Aix-Marseille Universite)
X-ray structural analyses. Financial support from Aix-Marseille
́
for the
́
Universite and the Centre National de la Recherche
Scientifique (CNRS) is gratefully acknowledged.
́ ́
Res. Dev. 2003, 7, 209. (c) Pena, D.; Cobas, A.; Perez, D.; Guitian, E.
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J. Org. Chem. 2006, 71, 3198.
(17) Goetz, A. E.; Shah, T. K.; Garg, N. K. Chem. Commun. 2015, 51,
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