Pyridazine N-Oxides as Precursors of Metallocarbenes: Rhodium-Catalyzed Transannulation with Pyrroles

Article abstract of DOI:10.1021/acs.orglett.5b03064

Pyridazine N-oxides are used for the first time as precursors of metallocarbenes. These nitrogen-rich heterocycles led to the discovery of a novel acceptor and donor-acceptor enalcarbenoids. The synthetic utility of these metallocarbenes was demonstrated in the rhodium-catalyzed denitrogenative transannulation of pyridazine N-oxides with pyrroles to the valuable alkyl, 7-aryl, and 7-styryl indoles. The transannulation strategy was applied to the synthesis of a potent anticancer agent.

Full text of DOI:10.1021/acs.orglett.5b03064

Letter
pubs.acs.org/OrgLett
Pyridazine N‑Oxides as Precursors of Metallocarbenes: Rhodium-
Catalyzed Transannulation with Pyrroles
Vinaykumar Kanchupalli, Desna Joseph, and Sreenivas Katukojvala*
Department of Chemistry, Indian Institute of Science Education & Research, Bhopal, Madhya Pradesh 462066, India
S
* Supporting Information
ABSTRACT: Pyridazine N-oxides are used for the first time as
precursors of metallocarbenes. These nitrogen-rich heterocycles led to
the discovery of a novel acceptor and donor−acceptor enalcarbenoids.
The synthetic utility of these metallocarbenes was demonstrated in the
rhodium-catalyzed denitrogenative transannulation of pyridazine N-
oxides with pyrroles to the valuable alkyl, 7-aryl, and 7-styryl indoles.
The transannulation strategy was applied to the synthesis of a potent
anticancer agent.
ecently, nitrogen-rich heterocyclic compounds have
emerged as valuable precursors of metallocarbenes and
Scheme 1. Nitrogen Rich Heterocycles as Precursors of
Metallocarbenes or Metallacycles
R
metallacycles in various transition-metal-catalyzed reactions.1−3
It has been shown that 1,2,3-triazoles and 1,2,3-triazines
containing a labile nitrogen triad undergo facile denitrogenative
metalation.1−3 The triazole 1 derived aza-vinylcarbene 3,
discovered by Gevorgyan and Fokin, led to significant
developments in the metallocarbene chemistry.1,2 On the
other hand, the Murakami group discovered that 1,2,3-
benzotriazine 4 serves as a valuable precursor to aza-
metallacycle 5 (Scheme 1b) in various transannulations.3
Inspired by these seminal works and in continuation of our
ongoing studies on the design of new metallocarbenes,4 we
investigated nitrogen-rich pyridazines as the source of novel
carbene precursors. Electron-deficient N-alkoxypyridazinium
salts are susceptible to nucleophilic ring opening resulting in
the vinyldiazo compounds.5 We envisioned that the (E)-
enaldiazo compound 7 obtained by the mild hydroxide
mediated ring opening of N-alkoxypyridazinium salt 6 could
serve as a precursor for the novel acceptor and donor−acceptor
rhodium enalcarbenoids 8 (Scheme 1c) which are otherwise
difficult to access. In comparison to our recently designed
diacceptor enalcarbenoids,4,6 the pyridazine derived acceptor
and donor−acceptor enalcarbenoids are expected to offer
complementary reactivity, leading to divergent products.7
Herein, we disclose the first application of pyridazine N-oxide
9 as a precursor to metallocarbenes in the rhodium-catalyzed
transannulation with pyrroles to the valuable alkyl, 7-aryl, and
7-alkenyl indoles (Scheme 1c).
The diverse pyridazinium salts 6 required for our studies
were prepared by O-alkylation of the readily accessible
pyridazine N-oxides 9.8 The (E)-enaldiazo compound 7 was
instantly generated at 0 °C upon exposure of a solution of 6 to
aq KOH. Although the parent enaldiazomethane 7a (R1−3 = H)
could be isolated, the substituted enaldiazo compounds were
highly unstable for isolation.8 Our initial studies on trans-
annulation of N-methoxypyridazinium salt 6a with pyrrole via
enaldiazomethane 7a, in the presence of 0.5 mol % dirhodium-
(II)acetate and Brønsted acid diphenyl phosphate (DPP, 11),
proceeded rapidly under mild conditions and furnished indole
Received: October 22, 2015
© XXXX American Chemical Society
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10aa in 62% yield (eq 1).8−10 Other rhodium(II) catalysts such
as Rh2(oct)4, Rh2(S-DOSP)4, Rh2(TFA)4, and Rh2(esp)2 were
also effective toward the reaction. Among the solvents,
chlorinated solvents (DCM, chloroform, and DCE) were
found to be compatible while nonpolar (hexane) and
oxygenated solvents (ether, THF, ethyl acetate) gave poor
yields. An optimal yield of 73% was obtained with 0.3 mol % of
the Rh2(esp)2 in DCM solvent.
required 0.5 mol % of the rhodium catalyst. As shown in the
Scheme 3, diverse 7-arylindoles12,13 were obtained by the
Scheme 3. Scope of the Transannulation toward 7-
a b
,
Arylindoles
With the optimized conditions, the scope of the trans-
annulation was examined toward the synthesis of diverse alkyl
substituted indoles (Scheme 2), involving an acceptor type
Scheme 2. Scope of the Transannulation toward
a b
,
Alkylindoles
a
Reaction conditions: 9/pyrrole/11/Rh2(esp)2 = 1.1 mmol:0.5
mmol:0.5 mmol:1.5 μmol. See the Supporting Information for details.
Isolated yields.
b
enalcarbenoid 8 (R1 = H, alkyl).8 The transannulation of parent
pyridazine N-oxide 9 (R1−3 = H) with methyl substituted
pyrroles proceeded smoothly leading to 1-, 2-, and 3-
methylindoles in good yield (10ab−10ad). With respect to
substituted pyridazines, the reaction of 3- and 4- alkylpyridazine
N-oxides with pyrrole proceeded regioselectively leading to 7-
and 6-alkylindoles (10ba−10da). The moderate yields of 10ca
and 10da are due to the highly unstable nature of the
corresponding enaldiazo intermediates. It is noteworthy that a
potential competitive 1,2-hydride shift in the alkyl substituted
rhodium carbenoids was not observed in the transannulation
reactions of 3-alkylpyridazine N-oxides.9,11 In the case of 5-
methylpyridazine N-oxide, the transannulation to 10ea was
inefficient probably due to the prevailing steric crowding during
the reaction. Overall, the reaction allowed alkyl substituents at
as many as six out of seven available positions on the indole
nucleus.
a
Reaction conditions: 9/pyrrole/Rh2(esp)2 = 0.93 mmol:0.37
b
mmol:1.85 μmol. See the Supporting Information for details. Isolated
yields.
regioselective transannulation with pyrroles involving an
important class of donor−acceptor rhodium enalcarbenoid 8
(R1 = Ar). The electronic nature of the aryl group has marginal
influence on the transannulation. In general neutral, alkyl
substituted and electron-deficient aryl groups gave comparable
yields (10fa−10ka and 10ma). The electron-rich aryl group
The transannulation reaction was next evaluated with the 3-
arylpyridazine N-oxides 9 (R1 = Ar).8 Interestingly, the reaction
proceeded rapidly even without Brønsted acid 11; however, it
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gave a slightly lower yield (10la) due to the highly unstable
nature of the diazoenal intermediate. Polar groups such as F,
CF3, NO2, and OMe (10ia−10la) are well tolerated. The
reaction was sensitive to C-4 and C-5 substituents on the
pyridazine. Although a C-4 methyl substituent was partially
tolerated leading to 6,7-disubstituted indole 10na, a C-5 methyl
substituent severely hampered the transannulation (10oa)
likely due to steric crowding. The ortho-methyl group on the
aryl substituent was well tolerated (10pa). With respect to
pyrroles, C-2 and C-3 alkyl pyrroles gave higher yields (10fc−
10ic, 10mb, 10fd, 10hd) compared to N-alkyl pyrrole (10fb
and 10hb).14 N-Benzyl and electron-deficient pyrroles (N-Boc,
N-Ts, 3-acetyl) remained unreactive in the transannulation
reaction.
a variety of human cancer cell lines, including MDR resistant
KB-vin10 lines with IC50 values ranging from 17 to 32 nM.
As shown in Scheme 6, a plausible mechanism for the
transannulation was proposed. Initially, base-mediated ring
Scheme 6. Proposed Mechanism of Transannulation
Interestingly, 3-vinylpyridazine N-oxides 9r−t allowed us to
investigate the reactivity of an unusual donor−acceptor type
vinyl substituted rhodium enalcarbenoid 8 (R1 = vinyl) sharing
the features of both a vinylcarbenoid and an enalcarbenoid.
Remarkably, transannulation of 9r−t with pyrrole proceeded
regio- and chemoselectively leading to 7-vinylindoles 10ra−
10ta (Scheme 4), through the preferential reactivity of the
Scheme 4. Scope of the Transannulation toward 7-
a b
,
Vinylindoles
a
Reaction conditions: 9/pyrrole/Rh2(esp)2 = 0.93 mmol:0.37
opening of pyridazinium salt 6 followed by Z/E enal
isomerization and loss of methoxide in 13 leads to the (E)-
enaldiazo compound 7.5 Rhodium-catalyzed denitrogenation of
7 to the transient (E)-enalcarbenoid 8 followed by rapid
regioselective C-2 functionalization of pyrrole gives the
zwitterion 14. Subsequent proto-demetalation of 14 leads to
the isomeric (E)- and (Z)-4-pyrrolyl-3-butenal intermediates
15a,b.8 Intramolecular Friedel−Crafts reaction of the reactive
isomer 15a either by the assistance of a rhodium catalyst or by
DPP 11 gives dihydroindole 17. Finally, dehydration of 17
delivers the indole 10. In the case of 3(H)- and 3-
alkylpyridazines (R1= H, alkyl), the sterically less hindered
unreactive isomer 15b predominates. Hence, the DPP assisted
isomerization to the strained reactive isomer 15a facilitates the
transannulation. However, in the case of 3-aryl and 3-
styrylpyridazines (R1 = Ar, styryl), both 15a and 15b will be
in rapid equilibrium as they experience similar 1,3-allylic strain
due to the sterically crowded pyrrole and aryl/styryl
substituents on the allylic C-1 carbon. Therefore, relief of
strain due to the intramolecular cyclization of the strained
reactive isomer 15a accelerates the transannulation reactions of
the 3-aryl and 3-styrylpyridazines, without the need for 11. An
alternative mechanism involving 6π-electrocyclization of trienol
16 also leads to 10.4a
b
mmol:1.85 μmol. See the Supporting Information for details. Isolated
yields.
enalcarbenoid moiety.8,15 The moderate yields could be
attributed to the rapid decomposition of the highly unstable
vinyldiazoenal intermediate. The transannulation developed
here constitutes a direct approach toward the 7-vinylindole core
of biologically active raputindole B, luteorides A−C, and DG-
041.16
The transannulation was successfully employed in the
synthesis of 7-arylindoline based anticancer agents 12a,b
(Scheme 5).8,17 Transannulation of 9f and 9q (R = H, CN)
with pyrrole followed by reduction and N-sulfonylation gave
indolines 12a and 12b respectively. It is noteworthy that 4-(1-
((4-methoxyphenyl)sulfonyl)indolin-7-yl)benzonitrile 12b (R
= CN) is known to have potent antiproliferative activity against
Scheme 5. Synthetic Applications of Transannulation
In summary, we have demonstrated that pyridazine N-oxides
are versatile precursors for the metallocarbenes. The synthetic
importance of the novel acceptor and donor−acceptor rhodium
enalcarbenoids has been successfully demonstrated in the
rhodium-catalyzed transannulation of pyridazine N-oxides with
pyrrole to diverse alkyl, 7-aryl, and 7-vinyl substituted indoles.
C
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Murakami, M. Angew. Chem., Int. Ed. 2010, 49, 4955. (d) Miura, T.;
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Transannulation was used in the synthesis of a potent
anticancer agent. Complementary to our recently reported
diacceptor enalcarbenoids, the pyridazine derived acceptor and
donor−acceptor enalcarbenoids are expected to impart unique
reactivity in various metal-catalyzed carbene transfer reactions.
We hope that the new pyridazine derived diverse enalcarbe-
noids, and the transannulation reaction will find wide
applications in synthetic chemistry.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03064.
Optimization studies, experimental procedures, charac-
1
terizations, and copies of the H and 13C NMR spectra
(PDF)
X-ray data for 10fc (CIF)
AUTHOR INFORMATION
Corresponding Author
■
(8) See the Supporting Information for optimization studies,
experimental details, and characterization.
(9) For an intramolecular reaction of triazole with pyrrole, see: Yang,
J. M.; Zhu, C. Z.; Tang, X. Y.; Shi, M. Angew. Chem., Int. Ed. 2014, 53,
5142.
*E-mail: sk@iiserb.ac.in.
Notes
The authors declare no competing financial interest.
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(c) Miura, T.; Funakoshi, Y.; Murakami, M. J. Am. Chem. Soc. 2014,
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H. D.; Jia, Z. H.; Xu, K.; Zhou, H.; Shen, M. H. Org. Lett. 2015, 17, 66.
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ACKNOWLEDGMENTS
■
We are grateful for the financial support from IISER Bhopal.
V.K. is a recipient of a research fellowship from the CSIR, New
Delhi. We thank Mr. Rajbeer Singh (NMR facility) for the high
field NMR data.
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