Cycloaddition of in situ generated 1,2-diaza-1,3-dienes with simple olefins: Facile approaches to tetrahydropyridazines

Article abstract of DOI:10.1021/acs.orglett.5b00445

A catalyst-free [4 + 2] annulation process between in situ generated 1,2-diaza-1,3-butadienes and simple olefins has been developed. Under mild conditions, the reactions afforded 1,4,5,6-tetrahydropyridazines, which feature a wide range of bioactive compounds, with high yields (up to 99% yield).

Full text of DOI:10.1021/acs.orglett.5b00445

Letter
pubs.acs.org/OrgLett
[
4 + 2] Cycloaddition of in Situ Generated 1,2-Diaza-1,3-dienes with
Simple Olefins: Facile Approaches to Tetrahydropyridazines
Xingren Zhong, Jian Lv,* and Sanzhong Luo*
Beijing National Laboratory for Molecular Sciences (BNLMS), CAS Key Laboratory of Molecular Recognition and Function,
Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China
Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, China
*
S Supporting Information
ABSTRACT: A catalyst-free [4 + 2] annulation process between in situ
generated 1,2-diaza-1,3-butadienes and simple olefins has been developed.
Under mild conditions, the reactions afforded 1,4,5,6-tetrahydropyridazines,
which feature a wide range of bioactive compounds, with high yields (up to
99% yield).
yridazines and tetrahydropyridazines are versatile structural
Scheme 1. General Strategy for Tetrahydropyridazines
P
motifs in a number of natural products (e.g., Pyridazomy-
cin and Azamerone ) and pharmaceutically active compounds
Figure 1) such as nonsteroidal progesterone receptor
1
2
(
Previously, we developed an enantioselective hetero-Diels−
Alder reaction of a β,γ-unsaturated α-ketoester with various
12a
12b
olefins, including cyclopentadiene, enol ethers, and simple
12c
12d
olefins, catalyzed by asymmetric binary acids. In seeking
other electron-deficient dienes for the reactions with simple
olefins, we explored 1,2-diaza-1,3-dienes, generated in situ from
α-chloro hydrazones, e.g. α-chloro N-benzoyl hydrazone a1, as
potential targets (Scheme 1). Surprisingly, we found the
reactions with olefins proceeded smoothly by simple treatment
with a base in the absence of any catalysts. Herein, we present
this unprecedented [4 + 2] cycloaddition of 1,2-diaza-1,3-
dienes with simple olefins including those industrial olefins,
affording 1,4,5,6-tetrahydropyridazines with good to excellent
yields.
Figure 1. Examples of pyridazine and tetrahydro-pyridazine derivatives
in bioactive compounds.
3
4
regulators (e.g., I), neuro-transmitter inhibitors (e.g., II),
5
,6
and influenza neuraminidase inhibitors (e.g., III). The known
synthetic strategies for the tetrahydropyridazines have been
7
,8
Initially, we have examined the reaction between a1 and
ethylene (b1) in the presence of metal catalysts and no reaction
was observed. In this process, it was found that the use of a
stoichiometric amount of Na CO without any catalysts led to
limited to a few special substrates, and few general methods
3a,4,5
exist for their synthesis (Scheme 1).
Strategically, an
intermolecular [4 + 2] reaction between 1,2-diaza-1,3-dienes
and alkenes is one of the most effective and economic
approaches for the synthesis of tetrahydropyridazines (Scheme
2
3
the desired adduct c1 with 46% yield in CH Cl (Table 1, entry
2
2
1
). The base-mediated catalyst-free protocol was then
1
); however, such reactions are limited to those electron-rich
7
optimized in terms of solvents and bases, and the representative
alkenes and simple olefins remain challenging substrates. In
fact, [4 + 2] cycloaddition with simple olefins, especially for
industrial olefins, is generally difficult to achieve and requires
Received: February 11, 2015
9
−11
harsh conditions and long reaction times.
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00445
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Optimization of the Reaction Conditions
Table 2. Substrate Scope for Hydrazones
b
entry
solvent
CH Cl
base
yield (%)
1
2
3
4
5
6
7
8
9
Na CO
46
2
2
2
3
3
3
3
CH CN
Na CO
23
3
2
Et O
2
Na CO
trace
NR
50
2
H O
2
Na CO
2
CH Cl
Cs CO
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
3
CH Cl
K CO
68
2
2
3
CH Cl
K PO ·3H O
62
2
3
4
2
CH Cl
Na PO ·12H O
52
2
3
4
2
CH Cl
CH COONa
16
2
3
10
11
12
13
14
15
16
17
CH Cl
DIPEA
13
2
CH Cl
Et N
3
trace
NR
71
2
CH Cl
Pyridine
K CO
2
c
c
c
c
c
CH Cl
2
2
3
3
3
3
3
,
,
,
,
d
e
f
CH Cl
K CO
73
2
2
CH Cl
K CO
47
2
2
CH Cl
K CO
35
2
2
g
CH Cl
K CO
trace
2
2
a
General conditions: a1 (0.40 mmol), b1 (16 atm), base (1.0 equiv),
b
1
a
solvent (0.1 M), room temperature, 16 h. Determined by H NMR
analysis with an internal standard, 1,3,5-trimethoxybenzene. K CO
General conditions: a (0.40 mmol), b1 (16 atm), K CO (2.0 equiv)
2 3
b
c
and CH Cl (0.2 M), room temperature, 24 h. Isolated yield.
2 2
2
3
d
e
f
g
(2.0 equiv). CH Cl (0.2 M). b1 (10 atm). b1 (5 atm). b1 (in
2 2
balloon). DIPEA = N,N-diisopropylethylamine, NR = No reaction
and 48% yield, respectively (Table 2, entries 7−8). Variations
1
of the R group were also tested, and an electron-withdrawing
results are summarized in Table 1. First, screening of various
solvents was carried out with Na CO (1.0 equiv) at room
group was preferred to an electron-donating group (Table 2,
entries 9 vs 10). In addition, alkyl substituted hydrazone a11
worked well, leading to a 97% yield (Table 2, entry 11).
To further expand the substrate scope, we next tested other
simple olefins. As seen from Scheme 2, styrenes bearing either
electron-donating or -withdrawing moieties could be equally
applied in the reaction with the former giving slightly better
yields (Scheme 2, c12−19). Propylene b10 and heteroaromatic
2-vinylthiophene b11 were tolerated with 62% and 91% yields,
respectively (c20 and c21). α-Methylstyrene and 1,1-diphenyl-
ethylene could also be incorporated to give acceptable results
by increasing the dosage and prolonging the reaction time (c22
and c23). Moreover, norbornene and cyclic dienes such as
norbornadiene and cyclopentadiene worked well to give the
desired adducts as single diastereoisomers with high yields
(c24, c25, and c26). An acyclic diene, isoprene, has also been
examined, and the reaction afforded regioisomeric adducts c27
and c28 in a 1.6:1 ratio with good yields.
2
3
temperature. The best result was obtained in CH Cl (Table 1,
2
2
entry 1), whereas others resulted in either low activity or no
reaction (Table 1, entry 1 vs entries 2−4). With respect to
bases, K CO and K PO ·3H O displayed better performance
2
3
3
4
2
with improved yields (Table 1, entries 6−7), while the use of
other inorganic bases resulted in a drop of the yield (Table 1,
entries 1, 5, and 8−9). Organic bases, such as DIPEA, Et N,
3
and pyridine, were ineffective (Table 1, entries 10−12). Further
increasing the amount of K CO (2.0 equiv) and the
2
3
concentration of reaction (0.2 M) led to a slight improvement
Table 1, entries 13 and 14). The yield was significantly
(
decreased when reducing the pressure of ethylene b1 (Table 1,
entries 15−17), and dimerization of the in situ generated 1,2-
diaza-1,3-butadiene was observed under this condition. On the
basis of these results, the combination of 0.4 mmol of a1, 16
atm of ethylene, and 0.8 mmol of K CO in 2 mL of CH Cl
2
2
3
2
was identified as the optimal reaction conditions.
With p-methoxy-styrene, we also examined different α-chloro
N-acylhydrazones, and the results are shown in Table 3.
Hydrazones bearing either electron-donating (Table 3, entries
1−2) or electron-withdrawing groups (Table 3, entries 3−4)
could be applied to give good yields. It is worth mentioning
that the reaction with alkyl-substituted hydrazone a12 also
proceeded smoothly to give the desired adduct c33 in 75%
yield (Table 3, entry 5).
With the optimized conditions in hand, we next explored the
substrate scope of the heterodienes. As shown in Table 2, an
array of α-chloro-N-benzoyl hydrazones a1−11 were tested,
resulting in the expected 1,4,5,6-tetrahydropyridazines c1−11
in good to excellent yields. The significant electronic effect of
2
R on the aromatic ring has been observed. Electron-neutral
and -donating groups gave similar results (Table 2, entries 1−
3
), while electron-withdrawing groups gave relatively lower
The developed cycloaddition could be performed on a gram
scale. The reaction of α-chloro N-benzoyl hydrazone a1 with
ethylene b1 afforded c1 (1.12 g) as a nonsteroidal progesterone
yields (Table 2, entries 5−6). An ortho-substituted derivative
such as a4 also worked well, providing a much better yield than
its para-substituted counterpart (Table 2, entries 4 vs 5).
Gratifyingly, the heteroaromatic 2-thiophene hydrazone a7 and
N-tosylhydrazone a8 could react with ethylene, giving a 51%
3
receptor regulator in 85% yield (Scheme 3). Treatment of c1
with LiAlH in THF led to the reduction of the CO bond,
4
providing benzyl tetrahydropyridazine d in 64% yield (Scheme
B
DOI: 10.1021/acs.orglett.5b00445
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Substrate Scope for Simple Alkenes ,
a b
Table 3. Substrate Scope for Hydrazones with b2
a
b
entry
a
R
adduct
yield (%)
1
2
3
4
a2
4-CH OC H
4
c29
c30
c31
c32
c33
99
99
90
66
75
3
6
a3
4-CH C H
3 6 4
a4
2-ClC H4
6
a6
4-BrC H4
6
c
5
a12
n-C H
23
11
a
General conditions: a (0.40 mmol), b2 (3.0 equiv), K CO (2.0
2
3
b
equiv), and CH Cl (0.2 M), room temperature, 24 h. Isolated yield.
2
2
c
b2 (5.0 equiv), 36 h.
Scheme 3. Synthesis of c1 on a Gram Scale
Scheme 4. Transformation of c1
asymmetric version of this reaction and the extension of the
methodology to other types of alkenes are ongoing.
ASSOCIATED CONTENT
Supporting Information
■
a
*
S
General conditions: a1 (0.40 mmol), b (3.0 equiv), K CO (2.0
2
3
b
equiv) and CH Cl (0.2 M), room temperature. Isolated yield.
General experimental procedures, characterization details, and
2
2
c
d
1
13
Propene b10 (3 atm) was used. 10.0 equiv of olefin were used.
H and C NMR spectra, IR spectra, and HRMS for new
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
4
). Direct hydrogenation of the CN bond of c1 could be
successfully performed using Pd/C as the catalyst to give the
hexahydropyridazine e in 78% yield, which could be further
converted to a pharmaceutically important 1,4-diamine adduct f
AUTHOR INFORMATION
Corresponding Authors
■
*
*
E-mail: luosz@iccas.ac.cn.
E-mail: lvjian@iccas.ac.cn.
1
3
(
Scheme 4). Finally, we focused on the preparation of a
pyridazine derivative through an external oxidant. When c1 was
treated with n-Bu NI and TBHP in CH CN at room
temperature, the desired pyridazine g was isolated in 40%
yield (Scheme 4).
Notes
4
3
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
In summary, we reported herein a mild and catalyst-free [4 +
■
2
] cycloaddition between in situ generated 1,2-diaza-1,3-dienes
We thank the Natural Science Foundation of China (21390400,
21025208, 21202170, and 21472193) and the National Basic
Research Program of China (2012CB821600) for financial
support. S.L. is supported by the National Program of Top-
with simple olefins. This protocol provides facile and atom-
economic access to tetrahydropyridazines with good to
excellent yields. Further investigations into a catalytic
C
DOI: 10.1021/acs.orglett.5b00445
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
notch Young Professionals and CAS Youth Innovation
Promotion Association.
(10) For selected examples: (a) Williams, C. L.; Chang, C.-C.; Do,
P.; Nikbin, N.; Caratzoulas, S.; Vlachos, D. G.; Lobo, R. F.; Fan, W.;
Dauenhauer, P. J. ACS Catal. 2012, 2, 935. (b) Do, P. T. M.; McAtee,
J. R.; Watson, D. A.; Lobo, R. F. ACS Catal. 2013, 3, 41. (c) Chang,
C.-C.; Green, S. K.; Williams, C. L.; Dauenhauer, P. J.; Fan, W. Green
Chem. 2014, 16, 585. (d) Pacheco, J. J.; Davis, M. E. Proc. Natl. Acad.
Sci. U.S.A. 2014, 111, 8363.
REFERENCES
■
(
1
1) (a) Bockholt, H.; Beale, J. M.; Rohr, J. Angew. Chem., Int. Ed.
994, 33, 1648. (b) Grote, R.; Chen, Y.; Zeeck, A. J. Antibiot. 1988, 41,
(11) (a) Banks, R. E.; Harrison, A. C.; Haszeldine, R. N.; Orrell, K. G.
595.
Chem. Commun. 1965, 3, 41. (b) Chung, Y.; Duerr, B. F.; McKelvey, T.
A.; Nanjappan, P.; Czarnik, A. W. J. Org. Chem. 1989, 54, 1018.
(
2) Cho, J. Y.; Kwon, H. C.; Williams, P. G.; Jensen, P. R.; Fenical,
W. Org. Lett. 2006, 8, 2471.
3) (a) Combs, D. W.; Reese, K.; Phillips, A. J. Med. Chem. 1995, 38,
878. (b) Combs, D. W.; Reese, K.; Cornelius, L. A. M.; Gunnet, J.
(c) Kakiuchi, K.; Yamaguchi, B.; Kinugawa, M.; Ue, M.; Tobe, Y.;
(
4
Odaira, Y. J. Org. Chem. 1993, 58, 2797. (d) Takeshita, H.; Kawakami,
H.; Ikeda, Y.; Mori, A. J. Org. Chem. 1994, 59, 6490.
W.; Cryan, E. V.; Granger, K. S.; Jordan, J. J.; Demarest, K. T. J. Med.
Chem. 1995, 38, 4880. (c) Palmer, S.; Campen, C. A.; Allan, G. F.;
Rybczynski, P.; Haynes-Johnson, D.; Hutchins, A.; Kraft, P.; Kiddoe,
M.; Lai, M.-T.; Lombardi, E.; Pedersen, P.; Hodgen, G.; Combs, D. W.
J. Steroid Biochem. Mol. Biol. 2000, 75, 33.
(
12) (a) Lv, J.; Zhang, L.; Hu, S.; Cheng, J.-P.; Luo, S. Chem.Eur. J.
2
012, 18, 799. (b) Lv, J.; Zhong, X.; Cheng, J.-P.; Luo, S. Acta Chim.
Sin. 2012, 70, 1518. (c) Lv, J.; Zhang, L.; Luo, S.; Cheng, J.-P. Angew.
Chem., Int. Ed. 2013, 52, 9786. For a review, see: (d) Lv, J.; Luo, S.
Chem. Commun. 2013, 49, 847.
(
4) Rybczynski, P. J.; Combs, D. W.; Jacobs, K.; Shank, R. P.;
Dubinsky, B. J. Med. Chem. 1999, 42, 2403.
5) Zhang, L.; Williams, M. A.; Mendel, D. B.; Escarpe, P. A.; Chen,
(13) Sinha, M.; Dola, V. R.; Soni, A.; Agarwal, P.; Srivastava, K.; Haq,
W.; Puri, S. K.; Katti, S. B. Bioorg. Med. Chem. 2014, 22, 5950.
(
X.; Wang, K.-Y.; Graves, B. J.; Lawton, G.; Kim, C. U. Bioorg. Med.
Chem. Lett. 1999, 9, 1751.
(
6) Lange, J. H. M.; den Hartog, A. P.; van der Neut, M. A.; van Vliet,
B. J.; Kruse, C. G. Bioorg. Med. Chem. Lett. 2009, 19, 5675.
7) For a review, see: (a) Attanasi, O. A.; Crescentini, L. D.; Favi, G.;
(
Filippone, P.; Mantellini, F.; Perrulli, F. R.; Santeusanio, S. Eur. J. Org.
Chem. 2009, 3109. For recent examples, see: (b) Attanasi, O. A.; Favi,
G.; Filippone, P.; Perrulli, F. R.; Santeusanio, S. Org. Lett. 2009, 11,
309. (c) Attanasi, O. A.; Favi, G.; Filippone, P.; Mantellini, F.;
Moscatelli, G.; Perrulli, F. R. Org. Lett. 2010, 12, 468. (d) Attanasi, O.
A.; Favi, G.; Mantellini, F.; Moscatelli, G.; Santeusanio, S. Adv. Synth.
Catal. 2011, 353, 1519. (e) Lopes, S. M. M.; Brigas, A. F.; Palacios, F.;
Lemos, A.; Pinho e Melo, T. M. V. D. Eur. J. Org. Chem. 2012, 2152.
(
f) Hu, X.-Q.; Chen, J.-R.; Gao, S.; Feng, B.; Lu, L.-Q.; Xiao, W.-J.
Chem. Commun. 2013, 49, 7905. (g) Hu, X.-Q.; Chen, J.-R.; Wei, Q.;
Liu, F.-L.; Deng, Q.-H.; Beauchemin, A. M.; Xiao, W.-J. Angew. Chem.,
Int. Ed. 2014, 53, 12163. (h) Attanasi, O. A.; Crescentinia, L. D.;
Filipponea, P.; Fringuelli, F.; Mantellinia, F.; Matteuccib, M.;
Piermattib, O.; Pizzo, F. Helv. Chim. Acta 2001, 84, 513. (i) D'Auria,
M.; Racioppi, R.; Attanasi, O. A.; Mantellini, F. Synlett 2010, 1363.
(
j) Lemos, A. In Targets in Heterocyclic Systems − Chemistry and
Properties, Vol. 14; Attanasi, O. A., Spinelli, D., Eds.; Societa Chimica
̀
Italiana: Rome, 2010; p 1. (k) Rossi, E.; Abbiati, G.; Attanasi, O. A.;
Rizzato, S.; Santeusanio, S. Tetrahedron 2007, 63, 11055. (l) Attanasi,
O. A.; Favi, G.; Mantellini, F.; Mantenuto, S.; Moscatelli, G.; Nicolini,
S. Synlett 2015, 26, 193. For an example of the use of electron-poor
alkenes, see: (m) Attanasi, O. A.; Bianchi, L.; D’Auria, M.; Mantellini,
F.; Racioppi, R. Curr. Org. Synth. 2013, 10, 631.
(
̋
8) (a) Chen, J.-R.; Dong, W.-R.; Candy, M.; Pan, F.-F.; Jorres, M.;
Bolm, C. J. Am. Chem. Soc. 2012, 134, 6924. (b) Gao, S.; Chen, J.-R.;
Hu, X.-Q.; Cheng, H.-G.; Lu, L.-Q.; Xiao, W.-J. Adv. Synth. Catal.
2
013, 355, 3539. (c) Tong, M.-C.; Chen, X.; Li, J.; Huang, R.; Tao, H.;
Wang, C.-J. Angew. Chem., Int. Ed. 2014, 53, 4680. (d) Guo, C.; Sahoo,
B.; Daniliuc, C. G.; Glorius, F. J. Am. Chem. Soc. 2014, 136, 17402.
(
9) (a) Rogiers, J.; Wu, X.; Toppet, S.; Compernolle, F.; Hoornaert,
G. J. Tetrahedron 2001, 57, 8971. (b) De Borggraeve, W. M.;
Rombouts, F. J. R.; Van der Eycken, E. V.; Toppet, S. M.; Hoornaert,
G. J. Tetrahedron Lett. 2001, 42, 5693. (c) Van der Eycken, E.;
Appukkuttan, P.; De Borggraeve, W.; Dehaen, W.; Dallinger, D.;
Kappe, C. O. J. Org. Chem. 2002, 67, 7904. (d) Stadler, A.; Yousefi, B.
H.; Dallinger, D.; Walla, P.; Van der Eycken, E.; Kaval, N.; Kappe, C.
O. Org. Process Res. Dev. 2003, 7, 707. (e) Rogiers, J.; De Borggraeve,
W. M.; Toppet, S. M.; Compernolle, F.; Hoornaert, G. J. Tetrahedron
2003, 59, 5047. (f) Kaval, N.; Dehaen, W.; Kappe, C. O.; Van der
Eycken, E. Org. Biomol. Chem. 2004, 2, 154. (g) Kamoune, L.; De
Borggraeve, W. M.; Verbist, B. M. P.; Broeck, J. V.; Coast, G. M.;
Compernolle, F.; Hoornaert, G. Tetrahedron 2005, 61, 9555.
(
h) Rodriguez, A. M.; Prieto, P.; de la Hoz, A.; Díaz-Ortiz, A. Org.
Biomol. Chem. 2011, 9, 2371.
D
DOI: 10.1021/acs.orglett.5b00445
Org. Lett. XXXX, XXX, XXX−XXX