Divergent construction of pyrazoles via Michael addition of n -arylhydrazones to 1,2-diaza-1,3-dienes

Article abstract of DOI:10.1021/acs.orglett.5b00776

The base (NaH)-promoted Michael addition of N-arylhydrazones (AHs) with 1,2-diaza-1,3-dienes (DDs) produces unprecedented β-azohydrazone adducts. Strategically, the use of AHs as acyl anion equivalents (d¹ synthon) and DDs as α-electrophiles (a

Full text of DOI:10.1021/acs.orglett.5b00776

Letter
pubs.acs.org/OrgLett
Divergent Construction of Pyrazoles via Michael Addition of
N‑Arylhydrazones to 1,2-Diaza-1,3-dienes
Serena Mantenuto, Fabio Mantellini, Gianfranco Favi,* and Orazio A. Attanasi
Department of Biomolecular Sciences, Section of Organic Chemistry and Organic Natural Compounds, University of Urbino “Carlo
Bo”, Via I Maggetti 24, 61029 Urbino PU, Italy
S
* Supporting Information
ABSTRACT: The base (NaH)-promoted Michael addition of
N-arylhydrazones (AHs) with 1,2-diaza-1,3-dienes (DDs)
produces unprecedented β-azohydrazone adducts. Strategi-
cally, the use of AHs as acyl anion equivalents (d1 synthon)
and DDs as α-electrophiles (a2 synthon) of carbonyl
compounds open the way to two important classes of pyrazole
compounds.
Scheme 1. Umpolung of the Reactivity of Carbonyl
Compounds: Michael Addition Reaction of AHs with DDs
he de novo construction of complex structures by use of
Tumpolung strategies represents an exciting area of study in
organic synthesis. In this regard, the umpolung1 concept,
introduced by Corey and Seebach, has been applied to
unconventional molecular assembly, providing flexibility,
chemoselectivity, and efficiency in the synthesis of biologically
active target molecules.2,3 Whereas the natural reactivity of an
aldehyde (a1 reactivity) requires a reaction with a ketone
enolate (d2 reactivity) and leads to the aldol addition product,4
we envisioned a conjugated addition in which a formal
umpolung of both reagents occurs (Scheme 1). For this
purpose, the transformation of a carbonyl group into a
hydrazone functionality (as masked carbonyl of aldehydes or
ketones) is one valuable tactic. It is well-known that hydrazones
and their derivatives can be employed as attractive system of
both acyl anion equivalents (i.e., arylhydrazones) and α-
electrophiles (i.e., 1,2-diaza-1,3-dienes).
The chemistry of arylhydrazones5 (AHs) and 1,2-diaza-1,3-
dienes6 (DDs) has been under study for a long time in various
fields ranging from organic chemistry to supramolecular
chemistry. Based on the multifaceted behavior of these reagents
and given our interest in the search of new strategies for the
construction of azaheterocycles, we became interested in
probing the reactivity of AHs with DDs. In a beautiful paper,
Glorius and co-workers developed intriguing NHC-catalytic
switchable reactions of enals with azoene to generate diazepines
and pyrazoles.6c To date, this work represents the sole example
of an umpolung reaction involving an azoene compound as
Michael acceptor. On the other hand, very few synthetic
strategies using the azaenamine character of monosubstituted
hydrazones has been exploited for the functionalization of
electrophiles (i.e., acrylate, acrylonitrile, α,β-unsaturated
aldehydes/ketones, nitroalkenes, α-keto esters, aldehydes)
leading to synthetically useful diazene compounds.7 Despite
the importance of NN bonds, the preparation of diazenes
containing the versatile hydrazone group still remains
challenging. Through polarity reversal, or “umpolung”, we
show here that ketone and aldehyde hydrazones can be used as
versatile precursors for the divergent assembly of pyrazole
structures after the conjugated addition to β-azohydrazone
compounds takes place. Specifically, DD serves as an a2
synthon, which formally installs an d1 synthon onto the original
α-carbon of an carbonyl compound, thus providing a
conceptually new way to form C−C bond. (Scheme 1)
Our investigations focused on the conjugate addition of AH
1a to DD 2a. Initially, we conducted the reaction in CH3CN at
Received: March 17, 2015
Published: April 9, 2015
© 2015 American Chemical Society
2014
DOI: 10.1021/acs.orglett.5b00776
Org. Lett. 2015, 17, 2014−2017

Organic Letters
Letter
room temperature in the absence of any catalyst as a
background reaction. As a result, the TLC check revealed no
formation of products (Table 1, entry 1). Different solvents, for
Scheme 2, different AHs 1a−g and DDs 2a−e were found to be
tolerant of the reaction, providing the corresponding β-
Scheme 2. NaH-Promoted Conjugated Addition of AHs 1a−
a
Table 1. C versus N Selectivity in Reaction of AH 1a with
DD 2a
g to DDs 2a−e
a
b
b
temp
(°C)
3a yield
(%)
3a′ yield
entry catalyst (mol %)
1
solvent
(%)
CH3CN
CH3CN
CH3OH
Et2O
rt
rt
rt
rt
rt
2
3
4
5
TFA (20)
TFA (20)
TFA (20)
39
77
37
41
Amberlyst
15(H)
CH3CN
a
b
6
ZnCl2 (20)
DIPEA (10)
Na2CO3 (10)
CH3ONa (10)
t-BuOK (10)
NaH (10)
CH3CN
CH2Cl2
CH2Cl2
CH3OH
t-BuOH
CH3CN
CH3CN
rt
rt
rt
rt
rt
rt
0
86
20
27
47
Yield of pure isolated products. Reaction performed at 0 °C.
7
25
8
azohydrazone adducts 3a−k.11 Either electron-neutral (H)
and electron-withdrawing (3-Br, 4-Br, 4-Cl, 4-CN, 4-CO2Me,
2,4-Cl2) substituents on Ar1 and Ar2 groups are well tolerated
(Scheme 2, 45−100%). Also, a variety of azoene partners
having different substituents (R, R1, R2 = Me, Et, t-Bu, Bn)
worked well to give the corresponding carba-Michael adducts.
During the course of our study, we observed that upon
exposure to CDCl3, β-azohydrazone 3a quickly disappeared
9
c
10
11
12
18
83
70
NaH (10)
a
All reactions were performed at a 0.8 mmol scale 1a using 1.1 equiv
or 1.5 equiv of DD 2a upon acidic or basic catalysis, respectively.
Yields of isolated product. Starting 1a (45%) was also recovered.
b
c
1
along with a concurrent appearance of a new set of H NMR
example CH3CN, Et2O, CH2Cl2, CH3OH, and t-BuOH, in the
presence of various commonly and inexpensive acid and basic
catalysts were tested. Interestingly, when acidic conditions were
used, only corresponding N-adduct 3a′ (hydrazino form) was
recovered (Table 1, entries 2−6). Similar results were also
obtained by using bases such as Na2CO3 or CH3ONa (Table 1,
entries 8 and 9). When the reaction was conducted in the
presence of DIPEA, not only the N adduct 3a′ was formed in
20% yield but the C-adduct 3a was also obtained in 25% yield
(Table 1, entry 7). To our delight, the exposure of 1a and 2a to
NaH led to the exclusive formation of the C-adduct 3a in
excellent yields (83%) (Table 1, entry 11). The use of strong
base as t-BuOK or decreasing the reaction temperature to 0 °C
resulted in no increase in yield (Table 1, entries 10 and 12).
These results mirror the observations made by Deng and Mani
on reactions of N-monosubstituted hydrazones with nitro-
alkenes, who highlighted that the site selectivity (C versus N) is
strongly dependent on the reaction conditions.7g,8
signals, easily assignable to pyrazole structure 4a. We also found
that when the Michael reaction between AH 1a and DD 2a was
conducted in the presence of a stoichiometric amount of NaH,
a 32% of pyrazole 5a along with the expected Michael adduct
3a was isolated. Besides, direct conversion to pyrazole 4 was
registered when 4-(N,N′-dimethylamino)carbonyl-DD
(CONMe2 instead of CO2R2) was used as azoene substrate
upon exposure to catalytic amount of NaH. These findings
prompted us to consider suitable reaction conditions to ensure
the selectivity in the ring closure processes.
Thus, β-azohydrazones 3a−k were successfully converted to
pyrazoles 4a−j by means of a simple acid (Amberlyst 15(H))
catalyzed cyclization (54−100%) (Scheme 3).
Then, we examined the ability of NaH to promote the
formation of pyrazoles 5a−h (33−76%) (Scheme 4).
On the basis of the results obtained, a plausible mechanism
for the divergent synthesis of pyrazoles 4 and 5 is proposed
(Scheme 5). Assuming a stepwise pathway, deprotonated
hydrazone I′ would be responsible for the initial regioselective
C attack at the terminal carbon of the DD 2 to furnish β-
azohydrazone intermediate 3. Two different 5-exo-trig cycliza-
tions would then occur. When acidic conditions are used a
With these optimized reaction conditions in hand, the
substrate scope with respect to both hydrazones9 and DDs10
was then investigated in order to evaluate the performance of
this C-selective Michael addition reaction. As summarized in
2015
DOI: 10.1021/acs.orglett.5b00776
Org. Lett. 2015, 17, 2014−2017

Organic Letters
Letter
a
Scheme 3. Cyclization of Adducts 3a−k to Pyrazoles 4a−j
Scheme 5. Plausible Mechanism
nucleophilic attack of the Ar1N nitrogen atom onto the
activated CN function would lead to pentacyclic inter-
mediate III, which could produce pyrazole 4 by loss of the
hydrazine residue and 1,3-H shift reaction (Scheme 3, path
a).12 On the other hand, NaH-mediated cyclization to pyrazole
5 would occur from intermediate 3 via preliminary 1,3-H shift
followed by intramolecolar nucleophilic attack of the Ar1N
nitrogen atom on a ester function (intermediate IV) and
alcohol elimination (Scheme 3, path b). It is important to note
that the presence of an ester group (CO2R2 instead of the
amide group CONMe2) is essential to ensure this cyclization
path, presumably due to its greater ability as leaving group.
The pyrazole ring system found in products 4 and 5 is a
heterocyclic core amenable to application in medicinal,
pesticide, and coordination chemistry. For example, N-aryl-
functionalized pyrazoles of type 4 are known to have diverse
biological activities, such as HIV protease inhibitors and anti-
inflammatory, antiobesity, analgesic, antidiabetic and antitumor
agents.13 A number of commercial drugs and pesticides such as
Celebrex, Eliquis, Acomplia, and Fipronil have been successfully
commercialized. In addition, 5-hydroxy-4-acylpyrazole hydra-
zones such as 5 are of interest as effective chelating/extracting
reagents for many metal ions and photochromic materials.14 In
view of the importance of these target molecules, we hope this
methodology may be of value for future applications.
a
Yield of pure isolated products.
a
Scheme 4. Cyclization of Adducts 3a−k to Pyrazoles 5a−h
In summary, we found that AHs 1 can react with DDs 2 in
the presence of NaH as a promoter. In this way, an intriguing β-
azohydrazone intermediate was obtained formally, inverting the
usual reactivity of carbonyl compounds (aldehyde and
ketones). The carbo-Michael adduct so prepared was shown
to be the key intermediate for subsequent chemoselective
cyclizations to functionalized pyrazole compounds. Further
studies are presently in progress in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and characterization data for all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
a
Yield of pure isolated products.
2016
DOI: 10.1021/acs.orglett.5b00776
Org. Lett. 2015, 17, 2014−2017

Organic Letters
Letter
(8) (a) Deng, X.; Mani, N. S. J. Org. Chem. 2008, 73, 2412. (b) Deng,
X.; Mani, N. S. Org. Lett. 2006, 8, 3505.
AUTHOR INFORMATION
Corresponding Author
■
(9) AHs 1a−g were synthesized via condensation reaction from
aldehydes and hydrazines (see the Supporting Information).
(10) DDs 2a−f were synthesized from the corresponding
halohydrazones by treatment with base (see the Supporting
Information).
*E-mail: gianfranco.favi@uniurb.it.
Notes
The authors declare no competing financial interest.
(11) Compounds 3a−k exhibit a pronounced tendency to undergo
isomerization and/or partial decomposition when exposed to DMSO-
d6 solution; for these reasons, all attempts to obtain their fully
characterization were unsuccessful.
(12) An alternative pathway in which CH/NH tautomerization may
precede the cyclization step should be excluded according to our
previous findings. See: Attanasi, O. A.; Filippone, P.; Fiorucci, C.;
Mantellini, F. Tetrahedron Lett. 1999, 40, 3891.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the financial support from the
University of Urbino “Carlo Bo” and the PhD Programs of
Ministry of Education of Italy.
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DOI: 10.1021/acs.orglett.5b00776
Org. Lett. 2015, 17, 2014−2017