Synthesis of Bicyclo[4.1.0]tetrahydropyridazines by a Sequential [4 + 2] and [1 + 2] Annulation Reaction of Azoalkenes and Crotonate-Derived Sulfur Ylides

Article abstract of DOI:10.1021/acs.orglett.9b02661

The base-induced unprecedented tandem [4 + 2] and [1 + 2] annulation reaction of in situ formed 1,2-diaza-1,3-dienes and crotonate-derived sulfur ylides is reported. This protocol provides a novel and practical method for the synthesis of cyclopropane-fused tetrahydropyridazines with a quaternary carbon center in synthetically useful yield. In this tandem reaction, three new bonds were formed in one pot, and the crotonate-derived sulfur ylide serves as a C3 synthon.

Full text of DOI:10.1021/acs.orglett.9b02661

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Bicyclo[4.1.0]tetrahydropyridazines by a Sequential
[4 + 2] and [1 + 2] Annulation Reaction of Azoalkenes and
Crotonate-Derived Sulfur Ylides
Wenhao Yin,† Ling Fang,‡ Zhiyong Wang,† Fang Gao,† Zhefeng Li,*,† and Zhiyong Wang*,†
†School of Chemistry and Chemical Engineering, Chongqing University, Chongqing 401331, China
‡College of Environment and Resources, Chongqing Technology and Business University, Chongqing 400067, China
S
* Supporting Information
ABSTRACT: The base-induced unprecedented tandem [4 + 2] and [1 + 2] annulation reaction of in situ formed 1,2-diaza-1,3-
dienes and crotonate-derived sulfur ylides is reported. This protocol provides a novel and practical method for the synthesis of
cyclopropane-fused tetrahydropyridazines with a quaternary carbon center in synthetically useful yield. In this tandem reaction,
three new bonds were formed in one pot, and the crotonate-derived sulfur ylide serves as a C3 synthon.
oxide synthase inhibitors,2c and HIV-1 non-nucleoside reverse
yridazines and tetrahydropyridazines represent an im-
transcriptase inhibitors (Figure 1).2d
Pportant family of N−N bond-containing six-membered
To date, several efficient approaches have been developed
for the synthesis of the privileged tetrahydropyridazine
skeleton.1,3 The recently discovered [4 + 2] annulation of in
situ generated azoalkenes with alkenes is particularly attractive
because of the high efficiency and step economy (Scheme 1a,
pathway 1).4 Azoalkenes (1,2-diaza-1,3-dienes) can be mildly
heterocycles that show a broad range of pharmaceutical
activities,1 such as cannabinoid CB1 receptor antagonists1a and
influenza neuraminidase inhibitory activity (Figure 1).1b
Furthermore, as ubiquitous subunits, cyclopropanes, in
particular, cyclopropane-fused nitrogen heterocycles, are
found in various drug molecules.23-Azabicyclo[4.1.0]heptane
derivatives have shown potential in medicinal chemistry, such
as triple reuptake inhibitor (GSK1360707),2b inducible nitric
Scheme 1. Annulation Reactions Involving Azoalkenes
Figure 1. Biologically active tetrahydropyridazines and cyclopropane-
fused nitrogen heterocycles.
Received: July 29, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02661
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Letter
generated by treating α-halogeno hydrazones with a base,
which have been recognized as a class of powerful and versatile
four-atom building blocks for the synthesis of various valuable
multi-nitrogen-containing heterocycles.4−7 However, efficient
and economic methods for the construction of cyclopropane-
fused tetrahydropyridazines are limited so far. Great progress
has only been achieved for the synthesis of structurally diverse
bicyclo[4.1.0]tetrahydropyridazines through the dirhodium-
(II)-acetate-catalyzed [4 + 2] cycloaddition of azoalkenes with
enol diazoacetates by Doyle and Xu,8 and the resulting
cyclopropane-fused tetrahydropyridazines were converted to
tetrahydro-1,2-diazepines by ring expansion (Scheme 1a,
pathway 2). Therefore, the pursuit of practical approaches to
rapidly access intriguing cyclopropane-fused tetrahydropyrida-
zines is still highly desired. On the basis of these elegant studies
involving azoalkene as well as our continuous efforts on
tandem annulations9 involving sulfur ylides,6a herein we report
a novel transition-metal-free, tandem [4 + 2] and [1 + 2]
annulation reaction of in situ formed 1,2-diaza-1,3-dienes and
cronate-derived sulfur ylides,10,11 delivering valuable cyclo-
propane-fused tetrahydropyridazines. To the best of our
knowledge, this is the first example of a cronate-derived sulfur
ylide10 as a 1,2-C2 synthon as well as a C1 synthon in the
generation of a cyclopropane skeleton.
azoalkenes and sulfur ylides, cesium carbonate was initially
selected as the base in various solvents at room temperature.
To our delight, an unprecedented product 3a was isolated in
56% yield when the reaction took place in acetonitrile (Table
1, entry 4), whose structure was elucidated from spectroscopic
data and verified unambiguously by X-ray diffraction analysis
(CCDC 1941157). This interesting result encouraged our
further exploration because there are few general methods for
the synthesis of bicyclo[4.1.0]tetrahydropyridazine derivatives.
Subsequently, various bases were tested. Unfortunately, other
inorganic bases, such as Na2CO3, K2CO3, t-BuOK, and NaOH
led to a decrease in yield (Table 1, entries 8−11). Organic base
Et3N seemed to be inefficient in this reaction. (Table 1, entry
12). Further optimization disclosed that an increase in the
amount of sulfonium salt and base has a beneficial effect and
resulted in 65% yield (Table 1, entry 13). Gratifyingly, the
yield was increased to 83% when the reaction was performed at
35 °C (Table 1, entry 14). No better results were obtained
whether the reaction was performed at higher or lower
temperature (Table 1, entries 15 and 16).
With the optimized reaction conditions in hand (Table 1,
entry 14), the generality and scope of the tandem [4 + 2]/[2 +
1] annulation reaction were investigated by reacting α-halo
hydrazones 1 with crotonate-derived sulfonium salts 2. The
results are summarized in Scheme 2. The investigation with
respect to the scope of the α-halo hydrazones revealed that not
only α-bromo-hydrazone 1a but also α-chloro-hydrazone 1a′ is
a suitable azoalkene precursor during the process of tandem
annulation. Various N-acetyl α-bromo hydrazones bearing
para, meta, or ortho substituents with both electron-deficient
and electron-rich character at the benzene rings were well
tolerated and furnished the bicyclo[4.1.0]tetrahydropyridazine
derivatives in moderate to good yield. In particular, α-bromo-
hydrazones bearing a functional group at the para position on
the aryl ring showed higher reactivity than their ortho- or
meta-substituted counterparts (3a vs 3h and 3l; 3c vs 3i). For
instance, sterically hindered o-chlorine-substituted congener 1l
led to the corresponding product 3l in 32% yield. In addition,
2-naphthyl-substituted α-bromo-hydrazone 1m also worked
well under the optimized reaction conditions, producing the
corresponding product 3m in 84% yield. More importantly,
cyclic α-bromo-hydrazones 1n and 1o derived from α-bromo-
1-tetralone and α-bromo-4-chromanone could successfully
take part in the tandem annulation reaction and afforded the
interesting polycyclic adducts 3n and 3o in 85 and 95% yield,
respectively. Besides aryl groups, a tert-butyl-substituted
hydrazone 1p was successfully converted into the correspond-
ing tetrahydropyridazine 3p in 92% yield. However, primary
and secondary alkyl-substituted hydrazones are not suitable
azoalkene precursors for this transformation, probably due to
the lower reactivity.12 Moreover, it was found that the
reactions proceeded efficiently when sulfonium salt 2b was
employed, leading to the desired products in excellent yield
(3q−s). Further screening revealed that the reactivity of the
reaction is significantly influenced by an N-protecting group on
the α-bromo-hydrazones 1: N-Boc α-bromo-hydrazone deliv-
ers the adduct 3t in 70% yield, whereas N-tosyl α-bromo-
hydrazone 1u does not participate in this transformation under
these initially developed reaction conditions. Additionally, the
reaction of a methyl-substituted crotonate-derived sulfonium
salt 2c with 1a under standard conditions led to complicated
mixtures. No desired product 3v was observed, which may be
Crotonate-derived sulfur ylides are a well-known class of
versatile building blocks and have been typically used as C1,
C2, or C3 synthons in various cascade annulation processes for
the synthesis of structurally diverse cyclic compounds.11 In our
preliminary screening, the α-bromo N-acetyl hydrazone 1a and
crotonate-derived sulfonium salt 2a were employed as the
model substrates to optimize the reaction conditions (Table
1). Because the base plays a vital role in the formation of the
a
Table 1. Optimization of Reaction Conditions
b
entry
base
solvent
3a, yield (%)
1
2
3
4
5
6
7
8
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Na2CO3
K2CO3
t-BuOK
NaOH
toluene
CH2Cl2
CHCl3
CH3CN
DMF
DMSO
CH3OH
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
trace
15
52
56
50
44
trace
trace
20
15
45
9
10
11
12
13
14
15
16
Et3N
trace
c
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
65
cd
,
83
53
e
f
trace
a
Unless otherwise noted, reactions were conducted with 1a (0.20
mmol), 2a (0.30 mmol), and base (0.60 mmol) in solvent (2.0 mL) at
b
c
rt under Ar for 8 h. Isolated yield based on 1a. 2.5 equiv of 2a and
4.0 equiv of Cs2CO3 were used. At 35 °C, 8 h. At 50 °C, 8 h. At 0
°C, 24 h.
d
e
f
B
DOI: 10.1021/acs.orglett.9b02661
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
,
Scheme 2. Substrate Scope
Scheme 3. Gram-Scale Experiment
conducted under the optimal reaction conditions, which still
afforded bicyclo[4.1.0]tetrahydropyridazine 3a in 72% yield.
On the basis of our deuterium exchange experiment results
(see the Supporting Information) and the previous reports, a
plausible reaction mechanism for this novel tandem reaction is
depicted in Scheme 4. Initially, crotonate-derived sulfonium
Scheme 4. Proposed Plausible Mechanism
salt 2a underwent deprotonation in the presence of cesium
carbonate to generate an allylic ylide with two resonance
structures A and B, which then reacted with in situ formed 1,2-
diaza-1,3-diene C to generate ylide E via Michael addition and
intramolecular nucleophilic addition, sequentially. Finally, a
proton transfer was followed by an intramolecular SN2
nucleophilic substitution to deliver the bicyclo[4.1.0]-
tetrahydropyridazine 3f.
In summary, the efficient construction of a challenging
cyclopropane-fused tetrahydropyridazine is developed through
an unprecedented sequential [4 + 2] and [1 + 2] annulation
reaction of 1,2-diaza-1,3-dienes and cronate-derived sulfur
ylides. This protocol provides a novel transition-metal-free
method for the synthesis of value bicyclo[4.1.0]-
tetrahydropyridazines possessing a quaternary carbon center
in one step. The development of an asymmetric version of this
tandem reaction is ongoing in our laboratory.
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.9b02661.
a
Unless noted otherwise, reactions were conducted with 1 (0.20
mmol), 2 (0.50 mmol), and Cs2CO3 (0.80 mmol) in CH3CN (2.0
b
c
mL) at 35 °C under Ar for 8 h. Isolated yield based on 1. α-Chloro
hydrazones were used.
Experimental procedures and compound characteriza-
tion data (PDF)
Accession Codes
due to the steric hindrance of 2c, showing the limitation of this
reaction.
As indicated in Scheme 3, a gram-scale reaction of α-bromo-
hydrazone 1a (1.44 g, 5 mmol) and sulfonium salt 2a was
CCDC 1941157 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
C
DOI: 10.1021/acs.orglett.9b02661
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
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*E-mail: zhefeng@cqu.edu.cn (Z.L.).
*E-mail: zwang@cqu.edu.cn (Z.W.).
ORCID
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Fang Gao: 0000-0003-1214-2754
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
Financial support from the National Natural Science
Foundation of China (nos. 21602025 and 21302236),
Fundamental Research Funds for the Central Universities
(2018CDXYHG0028, 2019CDXYHG0013), and Natural
Science Foundation of Chongqing, China (cstc2018jcy-
jAX0423) is gratefully acknowledged. We thank the Analytical
and Testing Center of Chongqing University for assistance
with the X-ray crystallographic analysis.
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D
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