TEMPO-mediated Aza-diels-alder reaction: Synthesis of tetrahydropyridazines using ketohydrazones and olefins

Article abstract of DOI:10.1021/acs.orglett.6b00702

A novel, facile, and efficient method for the synthesis of tetrahydropyridazines by a one-pot tandem reaction of easily accessible ketohydrazones and olefins in the presence of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) has been successfully developed. The reaction involves the initial generation of azoalkenes from direct oxidative dehydrogenation of ketohydrazones using TEMPO as the commercially available oxidant, followed by a subsequent aza-Diels-Alder reaction with olefins.

Full text of DOI:10.1021/acs.orglett.6b00702

Letter
pubs.acs.org/OrgLett
TEMPO-Mediated Aza-Diels−Alder Reaction: Synthesis of
Tetrahydropyridazines Using Ketohydrazones and Olefins
Xiu-Long Yang, Xie-Xue Peng, Fei Chen, and Bing Han*
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou
730000 P. R. China
S
* Supporting Information
ABSTRACT: A novel, facile, and efficient method for the
synthesis of tetrahydropyridazines by a one-pot tandem
reaction of easily accessible ketohydrazones and olefins in
the presence of 2,2,6,6-tetramethylpiperidine-1-oxyl
(TEMPO) has been successfully developed. The reaction
involves the initial generation of azoalkenes from direct
oxidative dehydrogenation of ketohydrazones using TEMPO
as the commercially available oxidant, followed by a subsequent aza-Diels−Alder reaction with olefins.
zoalkenes, also known as 1,2-diaza-1,3-dienes (DDs), have
been established as valuable synthetic building blocks and
efficient metal-, halogen-, and additive-free approach for the in
situ formation of azoalkenes by the reaction of hydrazones with
2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)5 via a hydra-
zonyl radical-involved process.6,7 By means of this protocol,
tetrahydropyridazines have been successively synthesized by the
subsequent reaction of the in situ-generated azoalkenes with
olefins via an aza-Diels−Alder reaction.
A
have found broad applications in cyclization and cycloaddition
reactions with a wide variety of partners for the preparation of
various nitrogen-containing heterocyclic compounds.1 Because
azoalkenes are unstable and highly reactive, their generation
and use usually proceeds by in situ transformation of the
corresponding hydrazone derivatives. In general, there are two
pathways for this transformation: one is elimination of
hydrogen halide from α-halo ketohydrazones under basic
conditions (Scheme 1a),2 and the other is pyrolysis of hardly
Tetrahydropyridazines, as an important class of six-
membered heterocycles, are widely found in many natural
products and pharmaceutically active compounds.8 To date,
several efficient methods for the synthesis of tetrahydropyr-
idazine motifs have been developed. Among them, the inverse-
electron-demand hetero-Diels−Alder (IEDDA)9 reaction of
electrophilic azoalkenes with electron-rich alkenes is arguably
one of the most effective and facile approaches for the synthesis
of tetrahydropyridazines (Scheme 1a). Several normal aza-
Diels−Alder reactions of electron-rich azoalkenes with alkenes
have also been developed.3 For example, Boeckman explored a
normal aza-Diels−Alder reaction of alkenes with electron-rich
azoalkenes generated through the pyrolysis of hardly acquired
heterocyclic precursors (Scheme 1b).3a In this context, the
present protocol provides a novel, mild, and efficient method
for the synthesis of structurally important tetrahydropyridazines
using ketohydrazones and olefins as easily accessible substrates
and TEMPO as the commercially available oxidant as well as
the first example of a TEMPO-mediated hydrazonyl radical-
involved tandem oxidative dehydrogenation/aza-Diels−Alder
reaction procedure.
Scheme 1. Strategies for in Situ Generation of Azoalkenes
and Their Application in the Aza-Diels−Alder Reaction
We commenced our studies by the reaction of acetophenone
phenylhydrazone (1a) with methyl acrylate (2a) (5 equiv) in
the presence of TEMPO (3 equiv) in toluene under an argon
atmosphere at 80 °C. To our delight, the desired product,
methyl 2,6-diphenyl-2,3,4,5-tetrahydropyridazine-3-carboxylate
acquired heterocyclic precursors 2,5-dihydro-1,2,3-thiadiazole-
1,1-dioxides, 3,6-dihydro-1-oxa-3,4-diazin-2-ones, and their
sulfur analogues under harsh conditions (Scheme 1b).3
However, the generation of azoalkenes by direct oxidative
dehydrogenation of the most common hydrazones has rarely
been documented.4 In view of the aspects of atom economy
and sustainable chemistry, herein we present a novel and
Received: March 10, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00702
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ab
,
(3a) was obtained in 65% yield (Table 1, entry 1). Significantly,
increasing the amount of 2a to 10 equiv improved the yield of
Scheme 2. Scope of Ketohydrazones
a
Table 1. Optimization Investigation
b
entry
oxidant
TEMPO
additive
solvent
yield (%)
c
1
−
−
−
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
neat
65
81
76
41
34
70
42
73
75
62
52
81
70
50
2
TEMPO
d
3
TEMPO
4
5
6
7
TEMPO
K3PO4
Cs2CO3
K2CO3
HOAc
HOAc
−
−
−
−
−
TEMPO
TEMPO
TEMPO
e
8
TEMPO
9
10
11
12
13
14
TEMPO
TEMPO
DMF
TEMPO
DMSO
toluene
toluene
toluene
a
4-HO-TEMPO
4-acetamido-TEMPO
4-oxo-TEMPO
Reaction conditions: a mixture of hydrazone 1 (0.5 mmol), 2a (5
mmol), and TEMPO (1.5 mmol) in toluene (1 mL) was stirred under
b
−
Ar at 80 °C for 48−72 h. Isolated yields are shown.
a
Reaction conditions: a mixture of 1a (0.5 mmol), 2a (5 mmol), and
oxidant (1.5 mmol) in solvent (1 mL) was stirred under Ar at 80 °C
in moderate yields. However, propiophenone hydrazone was
inert in the reaction and hardly gave the desired product 3q,
probably because forming this kind of azoalkene via a Cope-like
elimination of the TEMPO-trapped intermediate is difficult.10
Having successfully achieved the tandem reaction with
various ketohydrazones, we then shifted our attention to
investigate the scope of olefins (Scheme 3). A series of
acrylates, such as Et, nBu, tBu, Bn, and phenyl esters, were well-
tolerated in the reaction with hydrazone 1a, giving rise to the
corresponding products 3r−v in good to excellent yields. N-
Phenylacrylamide also proved to be suitable for this trans-
formation, as demonstrated by the modest yield of 3w.
Remarkably, isobornyl acrylate also participated well in the
b
c
d
e
for 72 h. Isolated yields. 2a (5 equiv) was used. At 110 °C. HOAc
(0.2 equiv) was used.
product 3a to 81% (entry 2). In addition, a higher reaction
temperature (110 °C) neither accelerated the reaction nor
increased the yield of product 3a (entry 3). Moreover, additives
such as bases and acids did not further improve the yield of 3a
(entries 4−8). Furthermore, when the model reaction was
carried out under solvent-free conditions, the desired product
3a was obtained in 75% yield (entry 9). Unfortunately, the use
of polar solvents such as DMSO and DMF resulted in lower
yields of 3a (entries 10 and 11). TEMPO derivatives such as 4-
HO-TEMPO, 4-acetamido-TEMPO, and 4-oxo-TEMPO were
also suitable for the reaction as the oxidant (entries 12−14),
leading to the same or a slightly lower yield of 3a.
a b
,
Scheme 3. Scope of Alkenes
With the optimized conditions in hand (Table 1, entry 2), a
variety of ketohydrazones 1 were subjected to the reaction with
2a. The results are summarized in Scheme 2. N-Phenyl-
substituted acetophenone hydrazones with a broad range of
electronic properties participated smoothly in the reaction,
affording the corresponding tetrahydropyridazine derivatives
3a−g in moderate to excellent yields. N-Methyl- and N-
benzoyl-substituted acetophenone hydrazones were also tried.
However, neither of them was suitable for the reaction,
probably because of the lower stability of the in situ-generated
alkyl azoalkene derived from compound 1h and the strong N−
H bond of acyl hydrazone 1i to initiate the N-centered radical,
respectively. In addition, both aromatic- and aliphatic-
substituted N-phenyl ketohydrazones were also examined in
the reaction. Acetophenone hydrazones bearing substituents
such as p-MeO, p-NO2, o-Br, and p-Ph on the phenyl groups of
the ketone moieties furnished the corresponding products 3j−
m in 50−85% yield. 2-Acetylthiophene hydrazone participated
swimmingly in the reaction as well, delivering the expected
product 3n in 73% yield. Notably, simple aliphatic ketohy-
drazones such as acetone phenylhydrazone and 3,3-dimethyl-
butan-2-one phenylhydrazone, were also good candidates for
the reaction, providing the corresponding products 3o and 3p
a
Reaction conditions: a mixture of hydrazone 1a (0.5 mmol), olefin 2
(5 mmol), and TEMPO (1.5 mmol) in toluene (1 mL) was stirred
under Ar at 80 °C for 48−72 h. Isolated yields are shown. N-
Phenylacrylamide (5 equiv) was used. The diastereomeric ratio was
b
c
d
1
determined by H NMR analysis.
B
DOI: 10.1021/acs.orglett.6b00702
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reaction, delivering 3x as an inseparable mixture of diaster-
eomers in a combined 75% yield. In addition, styrenes with a
range of electronic properties on the phenyl ring were also
employed as the partners in the reaction, affording the desired
products 3y−aa in moderate yields. Significantly, the product
3y was unequivocally determined to show ortho/para
regioselectivity by single-crystal X-ray structural analysis
(Figure 1). Furthermore, when 2-vinylpyridine and 4-vinyl-
performed on a gram scale without any difficulty, delivering
compound 3a in 71% yield (1.05 g) when 5 mmol of
acetophenone was used.
To account for the aforementioned results, the mechanism
shown in Scheme 5 is proposed. We believe that TEMPO
Scheme 5. Proposed Mechanism
Figure 1. X-ray structure of 3y (thermal ellipsoids are shown with 30%
probability).
initially abstracts the H atom from the N−H bond of
hydrazone 1 to produce the corresponding hydrazonyl radical.6
Our previous results demonstrated that hydrazonyl radical
serves as a π radical with the single electron spin density
delocalized on both the N atom adjacent to a phenyl ring and
the conjugated C atom of the ketone, which means that it can
be drawn with resonance structures I and II.6d,7g Thus, the
carbon-centered radical II would be trapped immediately by
TEMPO to produce intermediate III, which would sub-
sequently undergo Cope-like TEMPOH elimination to produce
azoalkene IV.10 Finally, the normal aza-Diels−Alder reaction of
IV with alkene 2 would give the desired tetrahydropyridazine 3.
In conclusion, a facile one-pot metal- and halogen-free
hydrazonyl radical-involved tandem oxidative dehydrogen-
ation/aza-Diels−Alder reaction has been successively devel-
oped for the synthesis of tetrahydropyridazines using
ketohydrazones and alkenes as the readily accessible substrates
and commercially available TEMPO as the cheap oxidant. To
the best of our knowledge, the reaction not only provides facile
one-pot access to the biologically important and synthetically
valuable tetrahydropyridazine derivatives under halide-free-
substrate conditions but also provides the first example of the
in situ generation of azoalkenes by direct oxidative dehydrogen-
ation of ketohydrazones employing TEMPO as the hydrazonyl
radical initiator as well as the β-hydrogen acceptor in the Cope-
like elimination. Further studies of the hydrazonyl radical-
promoted reaction are in progress in our laboratory.
pyridine were allowed to react with 1a, the reactions gave the
corresponding products 3ab and 3ac in moderate yields.
Unfortunately, the aliphatic olefin oct-1-ene, which is
commonly used in the IEDDA reaction as the electron-rich
dienophile, was inert in the reaction and gave only a trace
amount of the desired product 3ad. The phenomenon further
revealed that the reaction is a normal-electron-demand aza-
Diels−Alder reaction. The reaction was also successful with 1,1-
disubstituted alkenes, as demonstrated in the cases of 3ae and
3af. Unfortunately, when the 1,2-disubstituted alkene 1-phenyl-
1H-pyrrole-2,5-dione participated in the reaction, the corre-
sponding product 3ag was scarcely obtained.
Considering that hydrazones are very readily formed by the
condensation of ketones and hydrazines under acidic
conditions, we examined the aza-Diels−Alder reaction of
arylhydrazines, ketones, and alkenes with TEMPO in a one-
pot manner. First, the condensation of ketones and
arylhydrazines in the presence of 20% HOAc in EtOH almost
quantitatively yielded ketohydrazones 1. After removal of the
solvent, TEMPO and alkenes were added, and then the mixture
was stirred at 80 °C neat under argon for 48−72 h. As shown in
Scheme 4, some representative substrates were found to be
transformed into the desired products in comparable yields. It
is noteworthy that the improved one-pot procedure could be
Scheme 4. One-Pot Reaction of Arylhydrazines, Ketones,
a b
,
and Alkenes
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00702.
Detailed experimental procedures and spectral data (1H
and 13C NMR spectra) for all products (PDF)
Crystallographic data for 3y (CIF)
AUTHOR INFORMATION
■
Corresponding Author
a
Reaction conditions: ketone 4 (1.0 mmol), arylhydrazine (1.05
mmol), alkene 2 (10 mmol), and TEMPO (3 mmol), Ar, 48−72 h.
*hanb@lzu.edu.cn
Notes
b
c
Isolated yields are shown. The reaction was carried out on a gram
scale (5 mmol of ketone was used).
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.6b00702
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
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ACKNOWLEDGMENTS
■
We thank the NNSFC (21422205 and 21272106), the Program
for New Century Excellent Talents in University (NCET-13-
0258), the “111” Project, the Changjiang Scholars and
Innovative Research Team in University (IRT-15R28), and
the Fundamental Research Funds for the Central Universities
(lzujbky-2014-k03, lzujbky-2014-60) for financial support.
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