Exploiting the Electrophilic and Nucleophilic Dual Role of Nitrile Imines: One-Pot, Three-Component Synthesis of Furo[2,3-d]pyridazin-4(5H)-ones

Article abstract of DOI:10.1021/acs.orglett.5b01798

An expeditious multicomponent reaction to synthesize tetrasubstituted furo[2,3-d]pyridazin-4(5H)-ones is reported. In brief, hydrazonoyl chlorides react with isocyanoacetamides, in the presence of TEA, to give 1,3-oxazol-2-hydrazones which, without being isolated, can react with dimethylacetylene dicarboxylate to afford furo[2,3-d]pyridazin-4(5H)-ones with an unprecedented level of complexity in a triple domino Diels-Alder/retro-Diels-Alder/lactamization reaction sequence.

Full text of DOI:10.1021/acs.orglett.5b01798

Letter
pubs.acs.org/OrgLett
Exploiting the Electrophilic and Nucleophilic Dual Role of Nitrile
Imines: One-Pot, Three-Component Synthesis of
Furo[2,3‑d]pyridazin-4(5H)‑ones
Mariateresa Giustiniano,*,† Valentina Mercalli,‡ Jussara Amato,† Ettore Novellino,†
and Gian Cesare Tron*,‡
†Dipartimento di Farmacia, Universita
̀
degli Studi di Napoli “Federico II”, via D. Montesano 49, 80131 Napoli, Italy
‡Dipartimento di Scienze del Farmaco, Universita
Novara, Italy
̀
degli Studi del Piemonte Orientale “A. Avogadro”, Largo Donegani 2, 28100
S
* Supporting Information
ABSTRACT: An expeditious multicomponent reaction to
synthesize tetrasubstituted furo[2,3-d]pyridazin-4(5H)-ones is
reported. In brief, hydrazonoyl chlorides react with isocyanoa-
cetamides, in the presence of TEA, to give 1,3-oxazol-2-
hydrazones which, without being isolated, can react with
dimethylacetylene dicarboxylate to afford furo[2,3-d]pyridazin-
4(5H)-ones with an unprecedented level of complexity in a triple
domino Diels−Alder/retro-Diels−Alder/lactamization reaction
sequence.
can be simultaneously useful both as electrophilic partners for
isocyanides and as nucleophilic terminus of reaction.
he importance of the pyridazinone nucleus in medicinal
Tchemistry is well validated by a plethora of biological
activities as recently reviewed.1 The bioactivity profiles range
from cardiovascular and heart diseases2 to antihypertensive,
antithrombotic, antiinflammatory, and antiulcer activities.3
Furthermore, some pyridazinone derivatives have shown
potential as anticancer agents.4 Although the syntheses of the
pyridazinone nucleus per se are robust and well validated,5 the
syntheses of pyridazinones fused with other heterocycles still
require efforts and improvements. For example, furo[2,3-
d]pyridazin-4(5H)-one derivatives have shown potential in
medicinal chemistry as immunomodulator, antiasthmatic, and
thromboxane A2 synthase inhibitors,6 but despite their
pharmaceutical relevance, the reported synthetic approaches
required several reaction steps followed by chromatographic
purifications.
Stimulated by our first results with nitrile imines and in
connection with our ongoing studies on the reactivity of α-
isocyanoacetamides,11 we envisaged a multicomponent syn-
thesis of fully substituted furo[2,3-d]pyridazin-4(5H)-ones (4),
starting from readily available hydrazonoyl chlorides 1 and α-
methylisocyanoacetamides 2 (Scheme 1). The intermediate α-
Scheme 1. General Reaction Sequence To Obtain Furo[2,3-
d]pyridazin-4(5H)-ones
Over the last decades, the use of multicomponent reactions
to build functionalized heterocyclic rings starting from acyclic
precursors has received growing attention.7 Indeed, the use of a
multicomponent convergent process versus a divergent syn-
thesis can be advantageous toward reducing the number of
synthetic steps and sometimes allowing for the obtainment of
never reported heterocyclic rings.7f,g
Recently, we have shown, for the first time, the productive
use of the 1,3-dipolar species nitrile imine, generated in situ
from hydrazonoyl chlorides, in a three-component reaction
with carboxylic acids and isocyanides to afford the peptidomi-
metic aminocarbonyl N-acylhydrazones,8 a class of compounds
difficult to obtain with other strategies.9 Despite their long
history,10 in our opinion, nitrile imines are still an unexplored
class of compounds in multicomponent reactions. Indeed, they
hydrazono-oxazole 3 obtained is then reacted in situ with
dimethylacetylene dicarboxylate (DMAD), which should be
able to trigger a triple-domino process consisting of a Diels−
Alder cyclization, a [4 + 2]cycloreversion, and an intra-
molecular lactamization.
According to Scheme 2, 2-isocyano-1-morpholinopropan-1-
one12 (5) and the hydrazonoyl chloride (6) were mixed in
Received: June 22, 2015
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.5b01798
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Letter
Scheme 2. Synthetic Scheme for the Synthesis of Furo[2,3-
d]pyridazin-4(5H)-one (8)
Scheme 3. Proposed Reaction Mechanism for the One-Pot
Domino Formation of Furo[2,3-d]pyridazin-4(5H)-ones 4
dichloromethane in the presence of 1 equiv of TEA overnight
at room temperature. Addition of isocyanide to nitrile imine is
stereoselective, affording the Z-isomer.13 Due to the low energy
barrier required for the Z to E isomerism of this class of
hydrazones, we detected a Z/E mixture of 1,3-oxazole-2-
hydrazone (7) obtained in 75% yield after chromatographic
column.14 Subsequent reaction of 7 with 1 equiv of DMAD in
toluene at reflux overnight afforded a novel fluorescent spot on
TLC which, after purification and spectroscopic investigation,
was shown to be the desired furo[2,3-d]pyridazin-4(5H)-one
(8) obtained in 51% yield (Scheme 2).
After demonstrating the feasibility of this novel trans-
formation, in a further advancement, we evaluated the
possibility to perform the whole transformation in a one-pot,
two-step domino fashion without isolating the 1,3-oxazole-2-
hydrazone intermediate 7. Indeed, after monitoring its
formation by TLC, the dichloromethane was evaporated and
the crude reaction mixture was dissolved in toluene: by simply
adding DMAD the reaction proceeded smoothly toward the
formation of the furo[2,3-d]pyridazin-4(5H)-one (4). When
different DMAD equivalents (1, 1.2, 1.5, and 2 equiv) were
screened, a satisfactory yield of 45% was obtained when 2 equiv
was used.
The proposed reaction mechanism is reported in Scheme 3.
The hydrazonoyl chloride 6 formed in situ the dipolar nitrile
imine 9, which was then attacked by the isocyanide carbon
atom of isocyanoacetamide 5. Once the nitrilium ion 10
formed, it was intramolecularly intercepted by the oxygen of
the tertiary amide to give the 1,3-oxazole-2-hydrazone 7. The
latter was then able to attack the DMAD (11) triple bond to
give the oxa-bridged intermediate 12 via Diels−Alder reaction,
which after acetonitrile loss by means of a [4 + 2]
cycloreversion and methanol loss by means of intramolecular
lactamization gave the desired furo[2,3-d]pyridazin-4(5H)-one
(8).
Figure 1. Building blocks used.
in order to get a library of furo[2,3-d]pyridazin-4(5H)-ones
(24−34) (Figure 2). Hydrazonoyl chlorides were readily
synthesized in two steps starting from commercial carboxylic
acids and aryl hydrazines (see the Supporting Information).
Yields ranged from 22 to 50% and were shown to be
unaffected by the hydrazonoyl chloride substitution pattern as
With these optimized one-pot reaction conditions in hand,
we started to evaluate the scope of this transformation using
different hydrazonoyl chlorides (6, 13−19) and isocyanoace-
tamides (5, 20−23) (Figure 1) and randomly combining them
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DOI: 10.1021/acs.orglett.5b01798
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Letter
Scheme 4. Synthesis of the Furo[2,3-d]pyridazin-3-
carboxylic Acid 35
postcondensation domino processes. This method constitutes a
significant advancement over previously reported strategies16
and is likely to facilitate deeper medicinal chemistry studies of
this class of compounds.
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.5b01798.
Experimental procedures, spectroscopic data, copies of
1H and 13C spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Figure 2. Library of synthesized furo[2,3-d]pyridazin-4(5H)-ones.
*E-mail: mariateresa.giustiniano@unina.it.
*E-mail: giancesare.tron@pharm.unipmn.it.
Notes
both electron-withdrawing chlorine or iodine atoms (14, 17,
and 19, Figure 2), and electron-donor methoxy or phenoxy
groups gave good yields (15, 18, and 19, Figure 2).
Isocyanoacetamides with an additional alkyne function,
amenable to further derivatization (21, Figure 2) or a basic
amine group (22, Figure 2), also worked well, allowing for the
generation of widely decorated heterocyles. Notably, the yields
are referred to a sequence of four different reactions (the
formation of 1,3-oxazol-2-hydrazone, the Diels−Alder cycliza-
tion with DMAD, the [4 + 2] cycloreversion with the extrusion
of acetonitrile, and the intramolecular lactamization with loss of
methanol), indicating an average yield of 84−67% for each
synthetic step. It is important to highlight that, to date, the
chemistry of isocyanoacetamides coupled with domino
sequences has been mainly explored using aldehydes, imines,
and acyl chlorides as electrophilic partners.15 In this case, the
use of hydrazonoyl chlorides allowed for the incorporation of
one more nitrogen atom in the forming heterocyclic ring, giving
access to a furo[2,3-d]pyridazinone scaffold not synthesizable
with the previous strategies.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from Universita
Novara, and Universita
acknowledged.
■
̀
del Piemonte Orientale,
degli Studi “Federico II” Napoli, Italy, is
̀
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