Carbene-catalyzed enantioselective annulation of dinucleophilic hydrazones and bromoenals for access to aryl-dihydropyridazinones and related drugs

Article abstract of DOI:10.1039/d1sc01891d

4,5-Dihydropyridazinones bearing an aryl substituent at the C6-position are important motifs in drug molecules. Herein, we developed an efficient protocol to access aryl-dihydropyridazinone moleculesviacarbene-catalyzed asymmetric annulation between dinuc

Full text of DOI:10.1039/d1sc01891d

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Carbene-catalyzed enantioselective annulation of
dinucleophilic hydrazones and bromoenals for
access to aryl-dihydropyridazinones and related
drugs†
Cite this: Chem. Sci., 2021, 12, 8778
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
b
c
Bivas Mondal,c Rakesh Maiti,c Xing Yang,c Jun Xu,bc Weiyi Tian, Jia-Lei Yan,
*
a
ac
*
*
Xiangyang Li
and Yonggui Robin Chi
4,5-Dihydropyridazinones bearing an aryl substituent at the C6-position are important motifs in drug molecules.
Herein, we developed an efficient protocol to access aryl-dihydropyridazinone molecules via carbene-catalyzed
asymmetric annulation between dinucleophilic arylidene hydrazones and bromoenals. Key steps in this reaction
include polarity-inversion of aryl aldehyde-derived hydrazones followed by chemo-selective reaction with enal-
derived a,b-unsaturated acyl azolium intermediates. The aryl-dihydropyridazinone products accessed by our
protocol can be readily transformed into drugs and bioactive molecules.
Received 6th April 2021
Accepted 17th May 2021
DOI: 10.1039/d1sc01891d
rsc.li/chemical-science
One asymmetric example of these formal [4 + 2] reactions was
demonstrated using isothiourea as the organic catalyst to control
enantioselectivity at the C4-position.10a There is no success in
catalytic asymmetric access to C5 stereogenic center (Fig. 1a) of
these 4,5-dihydropyridazinones.
1. Introduction
4,5-Dihydropyridazinones and their derivatives, especially those
bearing aryl substituents at the 6-position, display a broad range of
pharmacological activities.1 Some members of this family have
already made their way into the market, such as Levosimendan2
and Pimobendan3 which are used for the treatment of heart disease
of humans and animals respectively (Fig. 1a). Other members of
this family, such as (ꢀ)-KCA 1490 (bonchodilatory and anti-
inammatory activity),4 Meribendan (potent PDE III inhibitor),5
and (R)-DNMDP (cancer cytotoxic modulator),6 have shown prom-
ising activities in biological studies (Fig. 1a). Traditionally, these
structural motifs can be accessed by condensation of substituted g-
keto carboxylic acids or their derivatives with hydrazines (Fig. 1b),
whereas asymmetric access relies on either chiral resolution of the
products4,5,7 or the use of optically enriched starting materials.8 It is
worth noting that access to chiral starting materials (1,4-dicarbonyl
compounds) used in these syntheses remains challenging in
organic chemistry.9 Another approach to construct these hetero-
cyclic moieties involves formal [4 + 2] cycloaddition between in situ
generated 3-aryl azoalkenes and two carbon synthons (Fig. 1b).10
We're interested in designing N-heterocyclic carbene-
catalyzed reactions for the preparation or modication of
bioactive molecules for medicinal and agriculture uses.11
Herein, we disclose carbene catalyzed asymmetric annulation
between N-monosubstituted arylidene hydrazones (precursor of
1,3-dinucleophile) and bromoenals12 (common 1,3-dinucleo-
philic hydrazones from triuoroacetaldehyde and glyoxal
derivatives13 have been explored in NHC-catalyzed reactions13c,d
as demonstrated in Fig. 1c) to afford highly enantiopure 6-aryl-
4,5-dihydropyridazinones (Fig. 1d). N-Monosubstituted hydra-
zones containing an electron-withdrawing group (e.g., –COR,
–CF3)13 at azomethine carbon have been used widely as 1,3-
dinucleophiles aer the pioneering study by Vicario14 in 2012.
In contrast, N-monosubstituted hydrazones from aryl aldehydes
rarely showed such character as 1,3-dinucleophiles. This is
probably because of the comparatively less stable anionic
character at azomethine carbon and an unfordable tendency for
proton transfer to regenerate a N-centered nucleophile (Fig. 1d).
Therefore, aryl aldehyde-derived N-monosubstituted hydra-
zones were barely used as precursors of effective 1,3-dinucleo-
philes in asymmetric catalysis.13g,15 Key steps in our reaction
involve the Umpolung of arylidene hydrazone (2) to form
intermediate II followed by chemo-selective 1,4-addition to
NHC-bound a,b-unsaturated acyl azolium I to form interme-
diate III. Intermediate III upon intramolecular proton transfer
leads to intermediate IV that undergoes cyclization to form 6-
aryl-4,5-dihydropyridazinone products with good yields and
aState Key Laboratory Breeding Base of Green Pesticide and Agricultural
Bioengineering, Key Laboratory of Green Pesticide and Agricultural Bioengineering,
Ministry of Education, Guizhou University, Huaxi District, Guiyang 550025, China.
E-mail: xyli1@gzu.edu.cn
bGuizhou University of Traditional Chinese Medicine, Guiyang 550025, China. E-mail:
tianweiyi@gzy.edu.cn
cDivision of Chemistry & Mathematical Science, School of Physical & Mathematical
Sciences, Nanyang Technological University, Singapore 637371, Singapore. E-mail:
robinchi@ntu.edu.sg
† Electronic supplementary information (ESI) available. CCDC 2062761. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/d1sc01891d
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Table 1 Reaction condition optimizationa
Entry
Conditions
Yieldb (%)
e.r.c
1
2
3
4
5
6
7
8
A, TMEDA
B, TMEDA
C, TMEDA
D, TMEDA
E, TMEDA
F, TMEDA
E, TMEDA, solventsd
E, K2CO3
44
21
74
64
72
48
32–77
72
78.5 : 21.5
90 : 10
71 : 29
87 : 13
95 : 5
89.5 : 10.5
92.5 : 7.5–94 : 6
94 : 6
9
E, K3PO4
67
90
93.5 : 6.5
93 : 7
95 : 5
10
11
12
E, Cs2CO3
E, TMEDA
E, TMEDA
72(71)e,f
57g
95 : 5
a
Reaction conditions: 1a (0.1 mmol.), 2a (0.05 mmol), NHC precat.
(20 mol%), base (2.5 equiv.), solvent (0.05 M), 4A MS (100 mg mlꢀ1) at
˚
RT for 72 h. Yields determined by 1H NMR analysis with 1,3,5-
b
c
trimethoxybenzene as the internal standard. The e.r. value was
determined via chiral-phase HPLC analysis. See ESI. Isolated yield
was given in parentheses. 10 mol% precatalyst and 0.075 mmol of 1a
d
e
f
g
were used. 5 mol% precatalyst was used. MS ¼ molecular sieves,
TMEDA ¼ tetramethylethylenediamine.
model substrates to search for suitable precatalysts and reac-
tion conditions, with key results briefed in Table 1 (and also see
ESI†). The aminoindanol-derived precatalyst with an N-phenyl
substituent (A)16 led to the formation of the desired product
3a in moderate yield and enantioselectivity (Table 1, entry 1).
Installing a nitro (–NO2) group in the aminoindanol moiety of
precatalyst A (to get precatalyst B)17 improved the enantiose-
lectivity, albeit with poor yield (Table 1, entry 2). Replacing the
N-phenyl substituent of precatalyst A with an electron-rich and
bulky N-mesityl substituent (to get precatalyst C)18 gave the
product in improved yield (74%), although the e.r. value drop-
ped down to 71 : 29 (Table 1, entry 3). As expected, switching to
more sterically hindered NHC precatalyst D19 with a bromo
atom on the aminoindanol motif further boosted the e.r. value,
although a diminishing yield was obtained (Table 1, entry 4).
Ultimately, we found out that the use of nitro (–NO2) substituted
aminoindanol scaffold containing NHC precatalyst E19 could
give the desired product in 72% yield and 95 : 5 e.r (Table 1,
entry 5). In the hope for further improvement, we replaced the
mesityl group of E with the bulky 1,3,5-triisopropyl phenyl
group (to get precatalyst F).19 However, poorer enantioselectivity
and yield were detected (Table 1, entry 6). Screening of other
solvents showed no additional encouraging improvement in the
Fig. 1 Strategies to access 6-aryl-4,5-dihydropyridazinones.
high enantioselectivities. A broad range of hydrazones from aryl
and heteroaryl aldehydes were well tolerated under our reaction
conditions. Straightforward transformations of our products
lead to clinically approved drugs (Levosimendan and Pimo-
bendan) and several other bioactive molecules without any
erosion of the e.r. values (Scheme 3). It is worth mentioning that
previously reported procedures to access these drugs and
bioactive molecules comprised longer steps and used chiral
resolutions or chiral starting materials.4–6,7c–f,8e
2. Results and discussion
We initiated our studies using readily available a-bromo cin-
namaldehyde 1a and p-nosyl protected hydrazone 2a as the
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enantioselectivity of our reaction (Table 1, entry 7 and see ESI†). phenyl rings [such as halogens, –OAc, –N(Boc)2 and methyl
Both organic and inorganic bases were efficient in providing the groups at the ortho, meta, and para positions] at the azomethine
desired product (Table 1, entries 8–10 and also see ESI†). Aer carbon of hydrazones were all tolerated and gave the desired
further screening of the precatalyst loading parameter, we products in good yields and excellent e.r. values (3a–h). Inter-
established that the optimal conditions consist of ethyl acetate estingly, gram-scale synthesis of 3b with 1 mol% precatalyst
as the solvent and TMEDA as the base in the presence of loading could furnish the product in 74% yield and 96 : 4 e.r.
10 mol% precatalyst loading, providing the corresponding The phenyl ring of 2a could also be replaced with 1-napthyl and
product without any change in the reaction outcomes 2-napthyl without affecting the yield and e.r. value of the
(comparing entry 5 and entry 11). Further decrease in the pre- products (3i–j) signicantly. A diverse set of heteroaryls such as
catalyst loading (5 mol%) resulted in low yield without affecting 2-benzothiophenyl, 2-thiophenyl, 3-thiophenyl and 3-pyridyl at
the enantioselectivity (Table 1, entry 12).
the azomethine carbon of hydrazones afforded the desired
With the optimized reaction conditions in hand (Table 1, products in excellent yield and e.r. (3k–3n). The absolute
entry 11), we moved to evaluate the generality of this reaction. conguration of 3n was conrmed by X-ray analysis.20 Most of
The scope of various hydrazones was examined rst with a- the time p-nosyl (p-Ns) protected hydrazones gave our desired
bromo cinnamaldehyde (1a) as the model substrate and the products in excellent outcomes; unfortunately, similar hydra-
results are shown in Scheme 1. Different kinds of substituted zones bearing a highly electron-decient phenyl ring at the
azomethine position were degraded under our catalytic condi-
tions. Thus, tosyl protected hydrazones (2o–2p) were used in our
reaction, giving the products (3o–3p) in good yields and excel-
lent enantioselectivities. Surprisingly, vinyl substituted
Scheme 2 Scope of a-bromoenal substrates.aReaction conditions as
in Table 1, entry 11. Yields (after silica gel chromatography purification)
based on 2. Reaction time 72–84 h. The e.r. value was determined via
chiral-phase HPLC analysis. SO2Ar1 ¼ p-nosyl, SO2Ar2 ¼ tosyl, SO2Ar3
Scheme 1 Scope of hydrazone substrates.aReaction conditions as in ¼ o-nosyl. bNaOAc and THF were used as the base and solvent,
Table 1, entry 11. Yields (after silica gel chromatography purification) respectively. cReagents were added in a glovebox. The reaction was
based on 2. Reaction time 72–84 h. The e.r. value was determined via carried out at 0 ꢁC for 24 h with 20 mol% precatalyst and 0.2 mmol
chiral-phase HPLC analysis. SO2Ar1 ¼ p-nosyl, SO2Ar2 ¼ tosyl.
bromoenal. d0.2 mmol bromoenal was used.
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hydrazone 2q was also compatible to provide the corresponding
product (3q) in 75% yield and 98.5 : 1.5 e.r.
We next examined the scope of bromoenals, and the results
are summarized in Scheme 2. Different kinds of electron-
donating and withdrawing substituents at the b-phenyl ring
(such as methyl, halogens, and methoxyl at the ortho, meta, and
para positions) of the bromoenal worked well under our reac-
tion conditions and gave the annulated products in good to
excellent yields and high enantioselectivities (4a–4g). The b-
phenyl ring of the bromoenal could also be replaced with the 2-
napthyl ring without affecting the result signicantly (4h). As
a 5-methyl substituent in 6-aryl-4,5-dihydropyridazinone is
crucial from the viewpoint of existing drugs and bioactive
molecules2–6 (Fig. 1a), we further examined the reaction of a-
bromocrotonaldehyde with some hydrazones. For example,
hydrazone containing 2-uoro phenyl for azomethine substi-
tution was coupled with a-bromocrotonaldehyde to obtain the
product 4i in moderate yield and excellent enantioselectivity.
With the aim to prepare precursors of clinical drugs and
bioactive molecules utilizing our methodology, products 4j and
4k were obtained in moderate to good yields and excellent
enantioselectivities by coupling corresponding hydrazones with
a-bromocrotonaldehyde. Notably, in the case of 4j o-nosyl pro-
tected hydrazone was used over p-nosyl protected hydrazone
due to its instability under our reaction conditions and the
reagents were added inside a glove box, as we found the
hydrazone decomposed under our reaction conditions and
hence resulted in lower yield, when the reagents were added
outside. Higher homologues of a-bromocrotonaldehyde, for
example, b-ethyl substituted bromoenal have also been used to
couple with hydrazone derived from 4-nitrobenzaldehyde to
give product 4l in good yield and excellent enantioselectivity.
Notably, in the case of 4l tosyl protected hydrazone instead of
nosyl protected hydrazone was used, to avoid the decomposi-
tion of the hydrazone under the reaction conditions.
Scheme 3 Synthesis of marketed-drugs and bioactive molecules.
and other bioactive molecules (Scheme 3). For example, inter-
mediate 5b, the precursor of Levosimendan (clinical drug), was
obtained without any degradation of the e.r. value from opti-
cally enriched 4j (96 : 4 e.r.) through thiophenol mediated nosyl
deprotection, followed by Pd/C-catalyzed hydrogenation
(Scheme 3a).7c Successive deprotection of the p-nosyl group and
two Boc groups of the product 4k (96 : 4 e.r.) gave the inter-
mediate 6b in high yield without any erosion of the e.r. value
(Scheme 3b). Intermediate 6b is the precursor for cancer cyto-
toxic modulator DNMDP6, drug Pimobendan8e,21 and bioactive
Meribendan5,21 (Scheme 3b).
A rationale for the reaction stereoselectivity is illustrated in
Fig. 2 for product 3n based on the absolute conguration of 3n.
The Si-face of the NHC-bound a,b-unsaturated acyl azolium is
blocked by the catalyst and specically the presence of the nitro
(–NO2) group on the catalyst makes the Si-face less available for
the nucleophile. So, it is more favourable to intercept the NHC-
bound a,b-unsaturated acyl azolium from the Re-face resulting
in the formation of the (R)-3a stereoselectively.
3. Conclusions
In summary, we have developed a carbene-catalyzed enantio-
selective formal [3 + 3] annulation strategy for the construction
of 6-aryl-4,5-dihydropyridazinones. The reaction proceeds via
the Umpolung of aryl aldehyde-derived hydrazones followed by
chemoselective 1,4-addition to the NHC-bound acyl azolium
intermediate. A broad scope of functional groups is well toler-
ated on both of the bromoenal and hydrazone substrates, with
all the corresponding products afforded in good to excellent
yields and enantioselectivities. Scalable synthesis with low
precatalyst loading (1 mol%) could also give the annulated
products in good results. Applications of our reaction products
allow enantiomeric access to marketed drugs and bioactive
molecules.
The chiral 4,5-dihydropyridazinone molecules from our
catalytic reaction were readily transformed to marketed drugs
Author contributions
B. Mondal conducted most of the experiments and wrote the
Fig. 2 Proposed TS model for stereoselectivity.
initial manuscript dra. R. Maiti, X. Yang, J. Xu, and J.-L. Yan
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performed part of the experiments. W. Tian and X. Li contrib-
uted to product design regarding potential bioactivities. Y. R.
Chi conceptualized and directed the project and nalized the
manuscript dra. All authors contributed to discussions.
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Conflicts of interest
There are no conicts to declare.
˜
F. X. Kleber, S. J. Pocock, R. Thakkar, R. J. Padley, P. Poder,
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We thank Dr Yongxin Li (NTU) for assistance with X-ray struc-
ture analysis. We acknowledge nancial support from the Sin-
gapore National Research Foundation under its NRF
Investigatorship (NRF-NRFI2016-06) and Competitive Research
Program (NRF-CRP22-2019-0002); the Ministry of Education,
Singapore, under its MOE AcRF Tier 1 Award (RG108/16, RG5/
19, RG1/18), MOE AcRF Tier 2 (MOE2019-T2-2-117), MOE
AcRF Tier 3 Award (MOE2018-T3-1-003); the Agency for Science,
Technology and Research (A*STAR) under its A*STAR AME IRG
Award (A1783c0008, A1783c0010); GSK-EDB Trust Fund;
Nanyang Research Award Grant, Nanyang Technological
University; the National Natural Science Foundation of China
(21772029, 21801051, 21807019, 21961006, 22071036,
22061007, 82360589, 81360589), Frontiers Science Center for
Asymmetric Synthesis and Medicinal Molecules, Department of
Education, Guizhou Province [Qianjiaohe KY number (2020)
004]; The 10 Talent Plan (Shicengci) of Guizhou Province ([2016]
5649); the Science and Technology Department of Guizhou
Province ([2018]2802, [2019]1020); the National Natural Science
Foundation of China (No. 31960546); the Program of Intro-
ducing Talents of Discipline to Universities of China (111
Program, D20023) at Guizhou University; the Guizhou Province
First-Class Disciplines Project [(Yiliu Xueke Jianshe Xiangmu)-
GNYL(2017)008], NSFC Grant (81360589), Guizhou University
of Traditional Chinese Medicine (China); and Guizhou
University.
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© 2021 The Author(s). Published by the Royal Society of Chemistry
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