Organocatalyzed Formal [4+2] Cycloaddition of in situ Generated Azoalkenes with Arylacetic Acids: An Efficient Approach to the Synthesis of 4,5-Dihydropyridazin-3(2H)-ones

Article abstract of DOI:10.1002/adsc.201500645

An unprecedented [4+2] cycloaddition of in situ generated azoalkenes with arylacetic acids has been developed under the catalysis of isothiourea. The reaction provided an efficient approach to the synthesis of 4,5-dihydropyridazin-3(2H)-one derivatives in moderate to good yields (up to 95%).

Full text of DOI:10.1002/adsc.201500645

COMMUNICATIONS
DOI: 10.1002/adsc.201500645
Organocatalyzed Formal [4+2] Cycloaddition of in situ Generat-
ed Azoalkenes with Arylacetic Acids: An Efficient Approach to
the Synthesis of 4,5-Dihydropyridazin-3(2H)-ones
Xuanyi Li,a Kuo Gai,a Zhenbo Yuan,a Jie Wu,a Aijun Lin,a,* and Hequan Yaoa,*
a
State Key Laboratory of Natural Medicines (SKLNM) and Department of Medicinal Chemistry, School of Pharmacy,
China Pharmaceutical University, Nanjing 210009, Peopleꢀs Republic of China
Fax: (+86)-25-8327-1042; e-mail: ajlin@cpu.edu.cn or hyao@cpu.edu.cn
Received: July 6, 2015; Revised: September 7, 2015; Published online: November 18, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500645.
Abstract: An unprecedented [4+2] cycloaddition of
in situ generated azoalkenes with arylacetic acids
has been developed under the catalysis of isothiour-
ea. The reaction provided an efficient approach to
the synthesis of 4,5-dihydropyridazin-3(2H)-one de-
rivatives in moderate to good yields (up to 95%).
blocks with wide applications in the assembly of vari-
ous five-, six-, and seven-membered heterocyclic ring
systems.[8] In 2014, the Glorius group reported the
first example of NHC-catalyzed formal [4+3] and
[4+1] annulations of 1,2-diaza-1,3-dienes with enals,
providing a highly enantioselective access to the
chiral dihydrodiazepinones[9] (Scheme 1a). The Xiao
group[10] and the Luo group[11] achieved the [4+3] and
[4+2] annulations of the in situ generated 1,2-diaza-
1,3-dienes with 1,3-dipoles and olefins employing an
inorganic base, leading to the important building
blocks of the tetrazepine and tetrahydropyridazine
types (Scheme 1b, c). Inspired by these works, we en-
Keywords: 1,2-diaza-1,3-dienes; 4,5-dihydropyrida-
zin-3(2H)-ones; isothiourea catalysis
Dihydropyridazinones and pyridazinones are impor- visaged that the possible [4+2] cycloaddition between
tant six-membered aza-heterocycles, and are present a-halo hydrazones and arylacetic acids under the cat-
in a wide range of bioactive compounds with anti-in-
flammatory,[1] anti-platelet aggregation[2] and anti-con-
gestive heart failure activities (Figure 1). To the best
of our knowledge, the reported synthetic strategies
for the synthesis of dihydropyridazinones are normal-
ly limited to the condensation of costly substrate g-
oxo acids and hydrazine.[3] Therefore, the develop-
ment of a new strategy that allows rapid access to di-
hydropyridazinones from readily accessible starting
materials using a practical method is still highly desir-
able and an enduring goal of organic chemistry.
Organocatalysis is now a well established instru-
ment in the organic chemistsꢀ tool box due to the gen-
erally stability, high quality, inexpensive price, and
lower toxicity compared to transition metals. Iso-
thioureas,[4] one kind of frequently used organocata-
lyst, initially introduced by Birman[5] and Okamoto,[6]
could promote the in situ generation of ammonium
enolates from a carboxylic acid, introducing function-
alization to the carboxylic acid through a Michael–
lactonization sequence.[7]
1,2-Diaza-1,3-dienes, generated from the corre-
sponding a-halo hydrazones, have recently been iden-
tified as a robust and versatile synthetic building bioactive compounds.
Figure 1. Examples of dihydropyridazinone derivatives in
Adv. Synth. Catal. 2015, 357, 3479 – 3484
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3479

COMMUNICATIONS
Xuanyi Li et al.
Scheme 1. Non-metal-catalyzed cycloaddition reactions of azoalkenes.
alysis of isothiourea would provide an efficient access the benzene ring of the aromatic acetic acid. As
to dihydropyridazinone derivatives. Herein, we report shown in Table 2, a variety of functional groups at the
the first example of isothiourea-catalyzed formal 4-position, such as electron-donating and electron-
[4+2] annulation reactions of in situ generated azoal- withdrawing groups, and halogen atoms were all com-
kenes with arylacetic acids, constructing 4,5-dihydro- patible under the optimized conditions, providing the
pyridazin-3(2H)-one derivatives in moderate to excel- desired products in moderate to excellent yields. The
lent yields (Scheme 1d).
substrates bearing methyl or methoxy groups afforded
We started our investigation with the reaction be- the corresponding products 3ab and 3ac in 89% and
tween readily available a-chloro N-Boc-hydrazone 1a 71% yield, respectively. The substrate with an elec-
and phenylacetic acid 2a. When the reaction was per- tron-withdrawing group (CF3) gave 3ad in 45% yield.
formed in DCE at ambient temperature, compound In addition, the halogen-substituted substrates could
1a could indeed react with compound 2a under the also be converted into the desired products 3ae–3ag
catalysis of C1,[12–13] giving 4,5-dihydropyridazin- in moderate to good yields. Also, the reaction was
3(2H)-one 3aa in 58% yield (Table 1, entry 1). En- compatible with the sterically hindered C-2 bromo,
couraged by this result, various solvents and catalysts methyl and C-3 methoxy groups on the phenyl ring of
were then evaluated to optimize the reaction condi- the aromatic acetic acid, giving rise to the correspond-
tions. Screening of solvents revealed that the yield of ing products 3ah–3ak in 63–95% yields. 2-Naphthyl-,
3aa was increased to 84% when DME was employed 1-naphthyl-, 2-thienyl- and biphenylacetic acids could
as a solvent (Table 1, entries 2–5). Screening of cata- also participate in this transformation, resulting in the
lysts showed that DBU, TBD, 4-PPy and DMAP coupling products 3al–3ao in 50–73% yields. Investi-
failed to offer the desired product (Table 1, entries 6– gations on the substituent effect on the aromatic ring
9). A control experiment indicated that C1 was neces- in the hydrazone part revealed that a range of substi-
sary to promote the reaction (Table 1, entry 10). Fi- tuted aromatic hydrazones could also generate the
nally, we were delighted to find that the yield of 3aa functionalised 4,5-dihydropyridazin-3(2H)-ones 3ba–
could be further improved to 91% by increasing the 3ja in 40–94% yields. When R1 or R2 was an alkyl
ratio of 2a to 1.5 (Table 1, entry 11).
group, the reaction failed to offer the desired product.
With the optimized conditions in hand, we next
According to the literature,[14] we proposed the re-
probed the substrate scope and the generality of this action mechanism as shown in Figure 2. N-Acylation
reaction. We first examined the substituent effect on of DHPB (C1) with anhydride I, which was formed
3480
asc.wiley-vch.de
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2015, 357, 3479 – 3484

COMMUNICATIONS
Organocatalyzed Formal [4+2] Cycloaddition
Table 1. Optimization of the reaction conditions.[a,b]
shown in Scheme 2, the tert-butyloxycarbonyl group
in compound 3aa could be removed easily by
CF3COOH in 68% yield (Scheme 2a). Subsequently,
the compound 4 could be further functionalized to
afford compound 5 and 6 in 51% and 61% yield, re-
spectively (Scheme 2b, c). It was noteworthy that
compound 5 is the core skelecton of a fungicide.[15]
Besides, the dihydropyridazinone could also be con-
verted into pyrdazinone 7 through a Br2 and AcOH-
mediated deprotection and oxidation step in 60%
yield (Scheme 2d). Furthermore, product 3ag could be
transformed to 3ao through a Suzuki coupling reac-
tion in 75% yield (Scheme 2e).
Encouragingly, preliminary studies showed that the
asymmetric version of this reaction was also feasible.
For example, when chiral catalyst C6[16] was em-
ployed, dihydropyridazinone 3aa could be obtained in
91% yield with 92% ee (Scheme 3).
In conclusion, we have developed the first organo-
catalyzed formal [4+2] cycloaddition between the in
situ generated 1,2-diaza-1,3-dienes and aromatic
acetic acids. This protocol provided a facile access to
the 4,5-dihydropyridazin-3(2H)-ones in moderate to
excellent yields with good functional group tolerance.
Studies have shown that asymmetric version was also
accessible with a chiral catalyst. Further efforts will
be devoted to understanding the reaction mechanism,
expanding the substrate scope, and developing a more
effective asymmetric process.
Entry
Catalyst
Solvent
1a:2a
Yield
1
2
3
4
5
6
7
8
C1
C1
C1
C1
C1
C2
C3
C4
C5
–
DCE
CH3CN
THF
1,4-dioxane
DME
DME
DME
DME
DME
DME
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1.5
58%
32%
62%
81%
84%
NR
NR
NR
NR
Experimental Section
General Procedure for the Formal [4+2]
Cycloaddition
9
10
11
NR
C1[c]
DME
93% (91%[d])
A
sealed tube was charged with phenylacetic acid 2
(0.3 mmol, 1.5 equiv.) in dry DME at 08C under an argon
atmosphere. (i-Pr)2NEt (0.45 mmol, 2.25 equiv.) and pivaloyl
chloride (0.45 mmol, 2.25 equiv.) were then added at 08C.
After 30 min, the corresponding catalyst (0.06 mmol,
[a]
Reaction conditions: 1a (0.2 mmol), 2a (0.2 mmol), cata-
lyst (0.04 mmol, 20 mol%), (CH3)3CCOCl (0.3 mmol,
1.5 equiv.), (i-Pr)2NEt (0.8 mmol, 4 equiv.) in solvent
(2.5 mL) at ambient temperature under an argon atmos-
phere.
30 mol%), a-chloro N-Boc-hydrazone
1
(0.2 mmol,
1.0 equiv.) and (i-Pr)2NEt (0.5 mmol, 2.5 equiv.) were added
and the reaction was warmed up to ambient temperature
and monitored by TLC until completion. The solvent was
then evaporated and the residue was purified by column
chromatography to afford the dihydropyridazinone as
a white solid.
[b]
Yield was determined by 1H NMR using dibromome-
thane as the internal standard.
[c]
[d]
The catalyst C1 amount is 0.06 mmol (30 mmol%).
Isolated yield.
from pivaloyl chloride and phenylacetic acid 2a, af-
forded acylisothiouronium II. Deprotonation generat-
ed isothiouronium enolate III, which underwent Mi-
chael addition of the in situ generated azoalkene V
from compound 1a and subsequent intramolecular
lactamization to generate the corresponding 4,5-dihy-
dropyridazin-3(2H)-one 3aa and regenerated DHPB
to complete this catalytic cycle.
Acknowledgements
Generous financial support from the National Natural Sci-
ence
Foundation
of
China
(NSFC21272276
and
NSFC21502232), the Natural Science Foundation of Jiangsu
Province (BK20140655) and the Foundation of State Key
Laboratory of Natural Medicines (ZZJQ201306) is gratefully
To gain insight into the utility of the reaction, the
dihydropyridazinones were further functionalized. As acknowledged.
Adv. Synth. Catal. 2015, 357, 3479 – 3484
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3481

COMMUNICATIONS
Xuanyi Li et al.
Table 2. Substrate scope of the reaction.[a,b]
[a]
Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), C1 (0.06 mmol, 30 mol%), (CH3)3CCOCl (0.45 mmol,
2.25 equiv.), (i-Pr)2NEt (0.95 mmol, 4.75 equiv.), in DME (2.5 mL) at ambient temperature under an argon at-
mosphere.
Isolated yield.
[b]
3482
asc.wiley-vch.de
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2015, 357, 3479 – 3484

COMMUNICATIONS
Organocatalyzed Formal [4+2] Cycloaddition
Figure 2. Proposed reaction mechanism.
Scheme 2. Synthetic transformation of the products.
Adv. Synth. Catal. 2015, 357, 3479 – 3484
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3483

COMMUNICATIONS
Xuanyi Li et al.
land, T. J. C. OꢀRiordan, A. D. Smith, Org. Biomol.
Chem. 2014, 12, 9016–9027.
[8] a) J.-R. Chen, W.-R. Dong, M. Candy, F.-F. Pan, M.
Jçrres, C. Bolm, J. Am. Chem. Soc. 2012, 134, 6924–
6927; b) M.-C. Tong, X. Chen, J. Li, R. Huang, H. Tao,
C.-J. Wang, Angew. Chem. 2014, 126, 4768–4772;
Angew. Chem. Int. Ed. 2014, 53, 4680–4684; c) S. Gao,
J.-R. Chen, X.-Q. Hu, H.-G. Cheng, L.-Q. Lu, W.-J.
Xiao, Adv. Synth. Catal. 2013, 355, 3539–3544; d) O. A.
Attanasi, L. D. Crescentini, G. Favi, F. Mantellini, S.
Mantenuto, S. Nicolini, J. Org. Chem. 2014, 79, 8331–
8338.
[9] C. Guo, B. Sahoo, C. G. Daniliuc, F. Glorius, J. Am.
Chem. Soc. 2014, 136, 17402–17405.
[10] X.-Q. Hu, J.-R. Chen, S. Gao, B. Feng, L.-Q. Lu, W.-J.
Xiao, Chem. Commun. 2013, 49, 7905–7907.
[11] X. Zhong, J. Lv, S. Luo, Org. Lett. 2015, 17, 1561–1564.
[12] For a selection of dynamic kinetic resolutions employ-
ing isothiourea, see: a) X. Yang, G. Lu, V. B. Birman,
Org. Lett. 2010, 12, 892–895; b) X. Yang, V. B. Birman,
Angew. Chem. 2011, 123, 5667–5669; Angew. Chem.
Int. Ed. 2011, 50, 5553–5555.
[13] For a selection of asymmetric C-acylation and C-car-
boxylation reaction processes employing isothiourea or
tertiary amine, see : a) B. Viswambharan, T. Okimura,
S. Suzuki, S. Okamoto, J. Org. Chem. 2011, 76, 6678–
6685; b) E. R. T. Robinson, C. Fallan, C. Simal,
A. M. Z. Slawin, A. D. Smith, Chem. Sci. 2013, 4, 2193–
2200; c) C. Joannesse, C. P. Johnston, C. Concellón, C.
Simal, D. Philp, A. D. Smith, Angew. Chem. 2009, 121,
9076–9080; Angew. Chem. Int. Ed. 2009, 48, 8914–8918;
d) F. R. Dietz, H. Grçger, Synthesis 2009, 4208–4218;
e) J. E. Taylor, M. D. Jones, J. M. J. Williams, S. D. Bull,
Org. Lett. 2010, 12, 5740–5743.
[14] a) M. E. Abbasov, B. M. Hudson, D. J. Tantillo, D.
Romo, J. Am. Chem. Soc. 2014, 136, 4492–4495; b) D.
Belmessieri, L. C. Morrill, C. Simal, A. M. Z. Slawin,
A. D. Smith, J. Am. Chem. Soc. 2011, 133, 2714–2720;
c) G. Liu, M. E. Shirley, K. N. Van, R. L. McFarlin, D.
Romo, Nat. Chem. 2013, 5, 1049–1057; d) Y. Fukata, K.
Asano, S. Matsubara, J. Am. Chem. Soc. 2015, 137,
5320–5323; e) C.-E. Yeom, M. J. Kim, B. M. Kim, Tetra-
hedron 2007, 63, 904–909; f) J. E. Murtagh, S. H.
McCooey, S. J. Connon, Chem. Commun. 2005, 41,
227–229; g) E. Bappert, P. Müller, G. C. Fu, Chem.
Commun. 2006, 42, 2604–2606.
Scheme 3. Preliminary asymmetric studies.
References
[1] B. ÖkÅelik, S. Ünlü, E. Banoglu, E. Küpeli, E. Yes¸ilada,
M. F. S¸ahin, Arch. Pharm. Pharm. Med. Chem. 2003,
336, 406–412.
[2] G. Yang, L. Liu, J. Xu, T. Li, J. Cardiovasc. Pharmacol.
2006, 47, 751–757.
[3] a) B. A. Provencher, K. J. Bartelson, Y. Liu, B. M.
Foxman, L. Deng, Angew. Chem. 2011, 123, 10753–
10757; Angew. Chem. Int. Ed. 2011, 50, 10565–10569;
b) W. Hu, H. R. Ranaivo, S. M. Roy, H. A. Behanna,
L. K. Wing, L. Munoz, L. Guo, L. J. V. Eldik, D. M.
Watterson, Bioorg. Med. Chem. Lett. 2007, 17, 414–418;
c) J. D. Albright, F. J. McEvoy, D. B. Moran, J. Hetero-
cycl. Chem. 1978, 15, 881–892; d) H. Cousse, G.
Mouzin, J.-P. Rieu, A. Delhon, F. Bruniquel, F. Fauran,
Eur. J. Med. Chem. 1987, 22, 45–57.
[4] J. E. Taylor, S. D. Bull, J. M. J. Williams, Chem. Soc.
Rev. 2012, 41, 2109–2121.
[5] V. B. Birman, H. Jiang, X. Li, L. Guo, E. W. Uffman, J.
Am. Chem. Soc. 2006, 128, 6536–6537.
[6] M. Kobayashi, S. Okamoto, Tetrahedron Lett. 2006, 47,
4347–4350.
[7] For a selection of isothiourea-catalyzed Michael-lacto-
nization sequences, see: a) L. C. Morrill, J. Douglas, T.
Lebl, A. M. Z. Slawin, D. J. Fox, A. D. Smith, Chem.
Sci. 2013, 4, 4146–4155; b) D. Belmessieri, L. C. Morrill,
C. Simal, A. M. Z. Slawin, A. D. Smith, J. Am. Chem.
Soc. 2011, 133, 2714–2720; c) C. A. Leverett, V. C. Pur-
ohit, D. Romo, Angew. Chem. 2010, 122, 9669–9673;
Angew. Chem. Int. Ed. 2010, 49, 9479–9483; d) D. Bel-
messieri, L. C. Morrill, C. Simal, A. M. Z. Slawin, A. D.
Smith, J. Am. Chem. Soc. 2011, 133, 2714–2720;
e) L. C. Morrill, D. G. Stark, J. E. Taylor, S. R. Smith,
J. A. Squires, A. C. A. D’Hollander, C. Simal, P. Shap-
[15] R. R. Jamison, S. H. S. Horsharm, U.S. Patent
005763440A, 2000.
[16] a) I. Shiina, K. Nakata, K. Ono, Y.-S. Onda, M. Itagaki,
J. Am. Chem. Soc. 2010, 132, 11629–11641; b) I. Shiina,
K. Nakata, Y.-S. Onda, Eur. J. Org. Chem. 2008, 5887–
5890; c) I. Shiina, K. Nakata, K. Ono, Y.-S. Onda, M.
Itagaki, J. Am. Chem. Soc. 2010, 132, 11629–11641;
d) V. B. Birman, X. Li, Org. Lett. 2006, 8, 1351–1354.
3484
asc.wiley-vch.de
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2015, 357, 3479 – 3484