Organocatalytic enantioselective synthesis of 2,3-dihydropyridazines

Article abstract of DOI:10.1039/c2cc17370k

We have developed an efficient procedure for the easy and straightforward preparation of functionalized dihydropyridazines as highly enantiopure materials by reaction of pyruvaldehyde 2-tosyl hydrazone with a variety of α,β-unsaturated aldehydes using a c

Full text of DOI:10.1039/c2cc17370k

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COMMUNICATION
Organocatalytic enantioselective synthesis of 2,3-dihydropyridazinesw
´
´ ´
Maitane Fernandez, Jose L. Vicario,* Efraım Reyes, Luisa Carrillo and Dolores Badıa
Received 25th November 2011, Accepted 9th December 2011
DOI: 10.1039/c2cc17370k
We have developed an efficient procedure for the easy and
straightforward preparation of functionalized dihydropyridazines
as highly enantiopure materials by reaction of pyruvaldehyde
2-tosyl hydrazone with a variety of a,b-unsaturated aldehydes
using a chiral secondary amine as catalyst. The overall process
consists of a cascade reaction involving an initial aza-Michael
reaction, in which the stereocentre is installed, followed by an
intramolecular aldol reaction/dehydration step.
Scheme 1 Organocatalytic enantioselective synthesis of 2,3-dihydro-
pyridazines by aza-Michael reaction/aldol condensation cascade
through iminium/enamine activation.
Pyridazines belong to a family of heterocyclic compounds that
possess remarkable pharmaceutical activities and have also shown
important applications in materials science. For example, several
members of this class of compounds have been utilised in the
development of therapeutic agents that have been employed as
analgesic and anti-inflammatory,1 antibacterial,2 antihypertensive,3
antidiabetic4 or antihistaminic5 agents and have also been
incorporated into semi-conductor materials as well as in substances
with non-linear optical properties.6 Among this wide range of
different applications and activities displayed, chirality also plays a
crucial role, which is exemplified with the case of levosimendan
(Fig. 1), an inotropic commercial drug with vasodilatory activity in
which only the (R) enantiomer is pharmacologically active.7
In this context, and as part of the continuing efforts of our
group directed towards the development of new synthetic
methodologies for the preparation of chiral heterocycles, we
have found that the pyridazine framework can be easily
accessed from a,b-unsaturated aldehydes and a functionalized
hydrazone of type 2 by means of a cascade reaction consisting
of an initial aza-Michael reaction followed by intramolecular
aldol condensation (Scheme 1). Moreover, we have also
investigated generation of the target compounds in an enantio-
selective manner by using the iminium/enamine activation
manifold,8 thus employing a chiral secondary amine as catalyst
for this transformation. In this context, the chiral catalyst would
play a crucial role in the initial aza-Michael reaction step
proceeding under iminium activation by providing the desired
stereocontrol. The subsequent enamine-mediated intramolecular
aldol reaction/dehydration step would provide the required
driving force for the reaction to proceed to completion, pushing
forward all of the equilibriums participating in the catalytic cycle
and avoiding the problems associated with the inherent reversible
character of the aza-Michael reaction, which would eventually
lead to low conversions and/or lack of enantiocontrol.9
According to this reaction design, we decided to use the
tosyl hydrazone 2 assuming that this compound would have
an enhanced profile (compared to alternative protecting
groups) to undergo the initial aza-Michael reaction step, since
the high acidity of the NH moiety would presumably favour
its deprotonation under the neutral or slightly basic conditions
associated with iminium catalysis.10 It should be pointed out
that even though the use of aza-Michael/aldol condensation
cascades exploiting the iminium/enamine manifold for the
construction of different classes of nitrogen heterocycles is
well documented in the literature,11 there are no examples
that explore the use of functionalized hydrazones in cascade
reactions. Moreover, there is only one example in which
hydrazones were used as nitrogen-centered pro-nucleophiles
for the aza-Michael reaction with enones, using a chiral
Brønsted base catalyst.12 Therefore, this is the first example
demonstrating that hydrazones can be successfully employed
as nitrogen-centered nucleophiles for the enantioselective
conjugate addition reaction under iminium catalysis.
Fig. 1 The structure of the pharmacologically active enantiomer of
pyridazine-containing drug Simendan.
Department of Organic Chemistry II, UPV/EHU, P.O. Box 644,
48080 Bilbao, Spain. E-mail: joseluis.vicario@ehu.es;
Fax: +34 94 601 2748; Tel: +34 94 601 5454
w Electronic supplementary information (ESI) available: Experimental
procedures, characterisation of all new compounds, copies of 1H
and 13C-NMR spectra and chiral HPLC traces. CCDC 855796. For
ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c2cc17370k
c
2092 Chem. Commun., 2012, 48, 2092–2094
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Table 1 Screening for the best experimental conditions using the
reaction between 1a and 2 as a model systema
Table 2 Scope of the reactiona
Entry Aldehyde R
Product Yieldb (%) eec (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
1i
1j
1k
1l
1m
n-Bu
Me
Et
n-Pr
n-C8H17
4a
4b
4c
4d
4e
84
91
74
72
63
68
61
69
19
49
52
60
72
55
96
89
96
96
97
97
97
96
86
89
95
85
94
90
Yieldb
Solvent T/1C (%)
Entry Catalyst Additive
eec (%)
Z-EtCHQCH(CH2)2 4f
CH(OMe)2
BnOCH2
Ph
4g
4h
4i
4i
4j
4k
4l
4m
1
2
3
4
5
6
7
8
3a
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
PhCOOH
PhCOOH
4-(NO2)C6H4COOH Toluene rt
Toluene rt
Toluene rt
54
60
31
42
48
—
24
30
13
18
84
82
98
n.d.d
98
9
10d
11d
12d
13d
14d
Ph
AcOH
(Ph)2CHCOOH
DABCO
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
Toluene rt
Toluene rt
Toluene rt
CHCl3 rt
CH2Cl2 rt
p-(NO2)C6H4
p-(MeO)C6H4
p-(CN)C6H4
5-(NO2)-Furyl
98
—
94
94
9
10
11e
THF
rt
n.d.d
n.d.d
96
a
Reactions performed on a 0.6 mmol scale of 2 and 0.3 mmol
b
scale of 1 using 20 mol% of catalyst 3b in 6.0 mL of toluene. Isolated
EtOH rt
Toluene rt
c
yield. Determined by HPLC on a chiral stationary phase (see ESI).
d
a
Reactions performed on a 0.3 mmol scale of 1a and 2 using 20 mol%
Reactions performed on a 0.6 mmol scale of 1 and 0.3 mmol scale of 2.
b
c
of catalyst in 3.0 mL of solvent. Isolated yield. Determined by
d
HPLC (see ESI). Not determined. Reaction carried out using
e
2 equiv. of 2 in 6.0 mL of toluene.
Slightly more polar solvents like chloroform or dichloromethane
yielded the desired adduct still in high enantioselectivities but
with an accentuated drop in isolated yield (entries 7 and 8), while
the incorporation of strongly polar solvents like THF or EtOH
resulted in very poor conversion after the same reaction time
(entries 9 and 10). Finally, we succeeded in improving the yield
of the reaction by increasing the amount of hydrazone reagent,
reaching an 84% yield of dihydropyridazine 4a and a 96% ee
(entry 11).
With these precedents in mind, we started our work by
surveying the viability of the projected cascade process using
the reaction between 2-heptenal (1a) and tosylhydrazone 2, the
later being synthesized by direct condensation of commercially
available pyruvic aldehyde and tosylhydrazine,13 as a repre-
sentative model system (Table 1). We first tested diarylprolinol
derivatives 3a and 3b as chiral secondary amine catalysts,
which have already demonstrated their performance in many
other examples of conjugate addition reactions under iminium
activation,14 working in toluene at room temperature. We
incorporated benzoic acid as Brønsted acid co-catalyst since
its ability to accelerate the formation of the activated iminium
ion intermediate is also well known. In this context,
O-trimethylsilyl protected diphenylprolinol 3a delivered the
desired product 4a in moderate isolated yield albeit with high
enantiocontrol. When the bulkier catalyst 3b was employed,
enantioselectivity improved significantly and also a slight increase
in the yield of the process was observed (entries 1 and 2).
Once a catalyst that provided high enantiocontrol had been
identified (3b), we directed our efforts to the improvement of
the yield of the reaction, first studying the role of the Brønsted
acid co-catalyst by testing carboxylic acids of different acidity.
However, the incorporation of additives with higher or lower
pKa compared to PhCO2H led to a considerable loss in the
yield of the desired compound 4a (entries 3–5), although
enantioselectivities remained intact. The incorporation of a
base as a co-catalyst was also surveyed but in this case
formation of the desired product was not observed (entry 6).
We next studied the influence of the solvent (entries 7–10)
and, as shown in Table 1, toluene appeared to be the most
efficient one in terms of both conversion and enantioselectivity.
Once the best protocol for the reaction had been established,
we next proceeded to extend the reaction to the use of
a,b-unsaturated aldehydes with different substitution patterns
in order to determine the scope of the reaction and its
performance for the preparation of differently substituted
2,3-dihydropyridazines. From the results summarized in
Table 2 we observed that the hydrazone 2 reacted in a satisfactory
way in most of the cases studied, furnishing the adducts 4a–m in
moderate to very good yields and excellent enantioselectivities.
The reaction tolerates well the use of different b-substituted
a,b-unsaturated aldehydes containing linear alkyl chains of
different length and size (entries 1–5), also observing that the
yield of the process became only moderately affected when the size
of the chain was considerably increased (entry 5). Furthermore,
functionalized a,b-unsaturated aldehydes such as 1f, 1g or 1h
also performed well, furnishing the final adducts in good yield
and very high stereocontrol (entries 6–8).
On the other hand, cinnamaldehyde 1i showed a remarkably
lower reactivity and slightly decreased enantiocontrol under
the same reaction conditions (entry 9). This led us to survey
modified reaction conditions in order to improve this result
and, after several attempts, it was found that the reaction
proceeded more efficiently by simply changing the proportion
of reagents from using excess of hydrazone reagent to employing
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Chem. Commun., 2012, 48, 2092–2094 2093

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further manipulations, therefore anticipating the synthetic
utility of the methodology.
The authors thank the Spanish MICINN (CTQ2008-00136/
BQU), the Basque Government (Grupos IT328-10 and fellow-
ship to M. F.) and UPV/EHU (fellowship to E. R.) for
financial support.
Notes and references
1 (a) M. Gokce, S. Utku and E. Kupeli, Eur. J. Med. Chem., 2009,
44, 3760; (b) M. Y. Y. Khan and A. A. Siddiqui, Indian J. Chem.,
Sect. B, 2000, 39, 614; (c) F. Rohet, C. Rubat, P. Coudert and
J. Couquelet, J. Bioorg. Med. Chem., 1997, 5, 655.
2 M. Sonmez, I. Berber and E. Akbas, Eur. J. Med. Chem., 2006,
41, 101.
Fig. 2 Synthesis of compound 5j and its crystal structure.
3 S. Demirayak, A. C. Karaburun and R. Beis, Eur. J. Med. Chem.,
2004, 39, 1089.
4 I. G. Rathish, K. Javed, S. Bano, S. Ahmad, M. S. Alam and
K. K. Pillai, Eur. J. Med. Chem., 2009, 44, 2673.
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an excess of enal (entry 10). These conditions were further
extended to other b-aryl substituted a,b-unsaturated aldehydes
leading to the formation of the corresponding adducts in moderate
to good yields and high enantioselectivities (entries 11–14).
The absolute configuration of the cycloadducts obtained in
this cascade process was assigned by X-ray analysis of primary
alcohol 5j obtained after sodium borohydride reduction of 4j
(Fig. 2). This compound provided monocrystal structures
suitable for single-crystal X-ray analysis (see ESIw) showing
an (3R) absolute configuration. The absolute stereochemical
outcome for the rest of the adducts 4a–m synthesized was
established by analogy, assuming an identical configuration
based on mechanistic analogy for the reaction in all the cases.
This configuration is also in good agreement with the sense of
the chirality induction provided by catalyst 3b in other conjugate
addition reactions in which this catalyst has been employed.14
In conclusion, we have demonstrated that hydrazone 2 can
efficiently be employed as a bifunctional reagent in the reaction
with a,b-unsaturated aldehydes in the presence of a chiral
secondary amine as catalyst in a cascade reaction operating
through the iminium/enamine manifold. This compound is able
to first behave as a N-nucleophile, initiating the process with
an aza-Michael-type reaction, in which the stereochemical
information is installed with very high stereocontrol. Secondly,
the enamine intermediate reacts intramolecularly with the
remaining formyl moiety through an aldol condensation.
According to the recent classification of organocatalytic
cascade/one-pot reactions made by Jørgensen,15 this reaction
can be classified as a TypeA-1-1C1X process with a YPBF
(yield per bond formed) of 70–95%, a YPMO (yield per manual
operation) of 49–91% and a Pf (purification factor) of 0.
As far as we know this is the first example of the use of a
hydrazone as a nitrogen-based pro-nucleophile in conjugate
addition reactions under iminium activation and also the first
case of a hydrazone reagent that is able to react bifunctionally
in an enantioselective manner in a cascade process under
iminium/enamine activation. This procedure also represents
an efficient way for building up the pyridazine scaffold, a
heterocyclic architecture of remarkable interest for medicinal
chemists. Moreover, this simple protocol allows the pre-
paration of chiral derivatives as highly enantiopure materials
which incorporate different functionalities with potential for
6 Y. Cheng, B. Ma and F. Wudl, J. Mater. Chem., 1999, 9, 2183.
7 For some reviews: (a) A. A. Rognoni, A. A. Lupi, M. M. Lazzero,
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(a) C. Grondal, M. Jeanty and D. Enders, Nat. Chem., 2010, 2, 167;
(b) A.-N. Alba, X. Companyo, M. Viciano and R. Rios, Curr. Org.
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K. A. Jørgensen, J. Am. Chem. Soc., 2005, 127, 15710.
9 For reviews about catalytic enantioselective aza-Michael reactions
see: (a) L.-W. Xu and C.-G. Xia, Eur. J. Org. Chem., 2005, 633;
(b) D. Enders, C. Wang and J. X. Liebich, Chem.–Eur. J., 2009,
15, 11058.
10 When other hydrazones related to
2 incorporating different
N-substituents were tested either the reaction did not take place
or, when it occurred, only a minor amount of the desired pyridazine
adduct was isolated.
11 (a) S.-J. Lee, S.-H. Youn and C.-W. Cho, Org. Biomol. Chem.,
2011, 9, 7734; (b) J.-Y. Bae, H.-J. Lee, S.-H. Youn, S.-H. Kwon
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C. Liu, L. Wang and R. Wang, Chem.–Eur. J., 2010, 16, 440;
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(e) Y. Yoshitomi, H. Arai, K. Makino and Y. Hamada,
Tetrahedron, 2008, 64, 11568; (f) H. Li, J. Wang, H. Xie, L. Zu,
W. Jiang, E. N. Duesler and W. Wang, Org. Lett., 2007, 9, 965;
(g) H. Sunden, R. Rios, I. Ibrahem, G.-L. Zhao, L. Eriksson and
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12 D. Perdicchia and K. A. Jørgensen, J. Org. Chem., 2007, 72,
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13 N. De Kimpe, Pyruvaldehyde 2-Phenylhydrazone, in e-EROS:
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Sons, New York, 2001, DOI: 10.1002/047084289X.rp305.
14 (a) K. L. Jensen, G. Dickmeiss, H. Jiang, L. Albrecht and
K. A. Jørgensen, Acc. Chem. Res., 2011, DOI: 10.1021/ar200149w;
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K. A. Jørgensen, Chem. Commun., 2010, 47, 632; (c) S. Bertelsen and
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2094 Chem. Commun., 2012, 48, 2092–2094
This journal is The Royal Society of Chemistry 2012