One-pot synthesis of pyrrolo[3,2-d ]pyridazines and pyrrole-2,3-diones via zirconocene-mediated four-component coupling of Si-tethered diyne, nitriles, and azide

Article abstract of DOI:10.1021/ol200038n

A one-pot synthesis of pyrrolo[3,2-d]pyridazine derivatives via zirconocene-mediated four-component coupling of one Si-tethered diyne, two nitriles, and one azide is reported. When TMSN₃ was used, pyrrole-2,3-diones were formed in good yields.

Full text of DOI:10.1021/ol200038n

ORGANIC
LETTERS
2011
Vol. 13, No. 7
1626–1629
One-Pot Synthesis of Pyrrolo-
[3,2-d]pyridazines and Pyrrole-2,3-diones
via Zirconocene-Mediated
Four-Component Coupling of
Si-Tethered Diyne, Nitriles, and Azide
Shaoguang Zhang,† Jing Zhao,‡ Wen-Xiong Zhang,†,§ and Zhenfeng Xi*,†
Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of
Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of
Chemistry, Peking University, Beijing 100871, China, Institute of Chemistry, Chinese
Academy of Sciences, Beijing 100190, China, and State Key Laboratory of
Elemento-Organic Chemistry, Nankai University, Tianjin, 300071, China
zfxi@pku.edu.cn
Received January 6, 2011
ABSTRACT
A one-pot synthesis of pyrrolo[3,2-d]pyridazine derivatives via zirconocene-mediated four-component coupling of one
Si-tethered diyne, two nitriles, and one azide is reported. When TMSN3 was used, pyrrole-2,3-diones were formed in good
yields. Further condensation of these highly functionalized pyrrole-2,3-diones with hydrazine and hydroxylamine
afforded useful pyrrole-fused heterocycles.
Pyrrolo[3,2-d]pyridazines are a class of interesting and
useful N-heterocycles.1 However, synthetic methods for
such heterocyclic compounds have been very limited. Most
of the known pyrrolo[3,2-d]pyridazines are synthesized via
condensation of pyrrole-2,3-diones with hydrazine. There
are no reports on one-pot multicomponent synthesis of
pyrrolo[3,2-d]pyridazines.1,2 Moreover, synthetic methods
for pyrrole-2,3-diones are also very limited.2 On the other
hand, transition-metal-mediated reactions of azides are
of great importance and versatility in organic synthesis
because azides can be readily transformed into a wide
variety of valuable N-containing natural products and
† Peking University.
‡ Chinese Academy of Sciences.
§ Nankai University.
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r
10.1021/ol200038n
Published on Web 02/28/2011
2011 American Chemical Society

medicinal agents,3,4 such as aziridine,5a amide,5b-d
amine,5e,f nitrile,5g triazoles,6a-f tetrazoles,6g,h and other re-
lated N-heterocycles.7 Some nucleophilic reactions of organo-
metallic reagents to organic azides have also been reported.8
During our investigation of zirconocene-mediated mul-
ticomponent reactions involving Si-tethered diynes 1, ni-
triles, and other unsaturated substrates such as aldehyde,
formamide, and isocyanide,9,10 we were curious about
whether azides could be used in this reaction, expecting
formation of new types of N-heterocycles. Thus, herein we
report a one-pot synthesis of pyrrolo[3,2-d]pyridazine
derivatives 2 via zirconocene-mediated cyclization of one
Si-tethered diyne 1, two nitriles, and one azide. We also
reporthereanefficientsynthesistowardpyrrole-2,3-diones
via the zirconocene-mediated cyclization of Si-tethered
diyne 1, nitriles, and TMSN3 as a special azide. These
functionalized pyrrole-2,3-diones could be efficiently
further transformed into pyrrole-fused heterocycles.
Reactive organometallic intermediates 3 could be syn-
thesizedinsituinhighyieldsviaa one-potmulticomponent
Scheme 1. One-Pot Synthesis of Pyrrolo[3,2-d]pyridazine
Derivatives 2 via Zirconocene-Mediated Cyclization of One
Si-Tethered Diyne 1, Two Nitriles, and One Azide
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Baran, P. S. Angew. Chem., Int. Ed. 2010, 49, 1095. (b) Zeng, Y.; Aube, J.
J. Am. Chem. Soc. 2005, 127, 15712. (c) Griffin, R. J. The Medicinal
Chemistry of the Azido Group. In Progress in Medicinal Chemistry;
Ellis, G. P., Luscombe, D. K., Eds.; Elsevier Science B.V.: Amesterdam,
1994; Vol. 31, Chapter 3, pp 121.
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Ed. 2001, 40, 2004. (b) Dıez-Gonzalez, S.; Nolan, S. P. Angew. Chem.,
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coupling process from Cp2ZrBu2, Si-tethered diyne (1),
and nitriles, as we previously reported (see the Supporting
Information).9b-d Treatment of 3a (Ar = Ph, R1 = i-Pr)
with benzyl azide BnN3 at 50 °C for 1 h followed by
quenching with saturated aqueous NaHCO3 afforded a
yellow solid 2a in 54% isolated yield (Scheme 1). The
structure of product 2a was confirmed as a pyrrolo[3,2-d]-
pyridazine derivative by X-ray single-crystal structure
analysis (Figure 1). As given in Scheme 1, various aryl or
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Figure 1. Single-crystal X-ray structure of 2a. Hydrogen atoms
are omitted for clarity except polar N-H bonds. Selected bond
lengths (A): N1-C1 1.390(2), N1-C6 1.363(2), N2-N3
1.350(2), N2-C4 1.372(2), N3-C5 1.327(2), N4-N2 1.438(2).
Org. Lett., Vol. 13, No. 7, 2011
1627

benzyl azides with both electron-withdrawing groups (F)
and electron-donating groups (MeO) could be applied to
afford pyrrolo[3,2-d]pyridazine derivatives 2 in good iso-
lated yields.
CdN bond to afford 8.13 Dehydration and aromatization
of 8 led to the final product 2.
Scheme 3. One-Pot Synthesis of Pyrrole-2,3-diones 9 via Zirco-
nocene-Mediated Cyclization of Si-Tethered Diyne 1, Nitriles,
and TMSN3
Scheme 2. Proposed Mechanisms
Shown in Scheme 2 is a proposed mechanism for the
reaction of azides with the reactive organometallic inter-
mediate 3. The hydrolysis mechanism of the reaction mixture
affording the pyrrolo[3,2-d]pyridazine derivative product 2is
also given in Scheme 2. We suggest 1,1-insertion of an azide
into the C-Zr bond of 3 and delocalization would lead to
formation of triazenido-ligated zirconium intermediate 4.
According to the literature,11 a 1,3-insertion of an azide
into the C-Zr bond of 3 may be also possible to generate
the intermediate 5.12 Although it is not clear which one is
formed in this reaction, only one insertion organometallic
intermediate, either 4a or 5a, was obtained in 87% isolated
yield and characterized by NMR spectroscopy. Hydrolysis
of the insertion product, either 4 or 5, would afford pyrrole
derivatives 6 or 7. These intermediates 6 and/or 7 would
undergo cyclization of the triazene moiety with the imine
Unexpectedly, when TMSN3 was used as an azide in this
zirconocene-mediated reaction, pyrrole-2,3-diones 9 were
formed in good isolated yields (Scheme 3). The structure of
product 9a was determined by single-crystal X-ray struc-
tural analysis (Figure 2). Si-tethered diynes with functional
groups as well as bulky nitriles like t-BuCN could not lead
to products 9 because their corresponding intermediates 3
could notbe formed efficiently. On mechanistic aspects, we
proposed that after insertion of TMSN3 into the C-Zr
bond, hydrolytic cleavage of N-Si and N-Zr bonds
would give triazene 10 or 100. Hydrolysis of N-SiMe3 bond
followed by elimination of dinitrogen would afford the
(11) (a) Deng, L.; Chan, H.-S.; Xie, Z. J. Am. Chem. Soc. 2005, 127,
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Soc. 2009, 131, 14903. (b) Ugolotti, J.; Kehr, G.; Frohlich, R.; Grimme,
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Nakajima, K.; Negishi, E. J. Org. Chem. 1998, 63, 6802. (e) Zippel, T.;
Arndt, P.; Ohff, A.; Spannenberg, A.; Kempe, R.; Rosenthal, U.
Organometallics 1998, 17, 4429. (f) Hanna, T. A.; Baranger, A. M.;
Bergman, R. G. Angew. Chem., Int. Ed. Engl. 1996, 35, 653. For
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L. M.; Rheingold, A. L.; Winter, C. H. Polyhedron 1997, 16, 4017.
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Sorokoumov, V. N.; Balova, I. A. Tetrahedron Lett. 2009, 50, 6358.
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124, 1572. (c) Kimball, D. B.; Haley, M. M. Angew. Chem., Int. Ed. 2002,
41, 3338.
Figure 2. Single-crystal X-ray structure of 9a. Hydrogen atoms
are omitted for clarity except polar N-H bonds. Selected bond
lengths (A): C5-O1 1.224(3), C12-O2 1.200(3), N1-C1
1.368(3), N1-C4 1.340(3).
1628
Org. Lett., Vol. 13, No. 7, 2011

imine 11, which might be oxidized and hydrolyzed on the
silica gel during column chromatography to give the final
product pyrrole-2,3-dione 9 (see the Supporting Informa-
tion for more discussion). Although plenty of synthetic
methods for pyrrole derivatives have been developed,7d,14
synthetic methods for pyrrole-2,3-diones, which are highly
functionalized pyrroles, are very rare.2
However, surprisingly, condensation of 9a with hydroxy-
lamine hydrochloride in refluxing pyridine led to the
pyrrolo[2,3-c]pyridinone 13 as the single product. The
carbonyl group adjacent to the i-Pr group was untouched;
instead, the Csp3-H bond of i-Pr was coupled with the in
situ generated oxime moiety to form the pyridinone ring
via intramolecular nucleophilic substitution or 6π-electro-
cyclization (see the Supporting Information for
more discussion). The structure of product 13 was
determined by single-crystal X-ray structural analysis
(Figure 3).
Scheme 4. Preparation of Pyrrole-Fused N-Heterocyclic Com-
pounds via Annulation of Pyrrole-2,3-diones 9
Figure 3. Single-crystal X-ray structure of 13. Hydrogen atoms
are omitted for clarity except polar N-H bonds. Selected bond
lengths (A): C4-O1 1.229(5), N1-C1 1.410(5), N1-C7
1.387(5), N2-C5 1.434(5), N2-C6 1.291(5).
In conclusion, novel synthetic methods for pyrrolo[3,2-d]-
pyridazines and pyrrole-2,3-diones have been realized via
a zirconocene-mediated one-pot multicomponent coupling
process.
The two carbonyl groups on the pyrrole ring of 9 are
expected to be very useful for the preparation of other
valuable pyrrole-fused N-heterocyclic compounds via con-
ventional annulation methods.15 As a demonstration of
their further application, condensation of 9 with hydrazine
hydrate and hydroxylamine hydrochloride was carried
out, and the pyrrole-fused heterocycles pyrrolo[3,2-
d]pyridazine 12 and pyrrolo[2,3-c]pyridinone 13 were gener-
ated in high isolated yields, respectively (Scheme 4).
Acknowledgment. This work was supported by the
Natural Science Foundation of China, and the Major State
Basic Research Development Program (2011CB808705).
Supporting Information Available. Details for proposed
mechanisms, experimental details, characterization data,
copies of 1H and 13C NMR spectra for all isolated
compounds, and crystallographic data for 2a, 9a, 13
(CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
Condensation of 9 with hydrazine hydrate in ethanol at
80 °C gave pyrrolo[3,2-d]pyridazines 12 as products.1
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