Enantioselective synthesis of functionalized 1,4-dihydropyrazolo-[4′,3′:5,6]pyrano[2,3-: B] quinolines through ferrocenyl-phosphine-catalyzed annulation of modified MBH carbonates and pyrazolones

Article abstract of DOI:10.1039/d1cc00989c

An enantioselective synthesis of highly functionalized 1,4-dihydropyrazolo[4′,3′:5,6]pyrano[2,3-b]quinolines from modified MBH carbonates and pyrazolones via a chiral phosphine-mediated alkylation/annulation sequence has been realized. The chiral dihydropyrano[2,3-c]pyrazoles bearing bio-active condensed heterocycles were facilely formed in good chemical yields and with high to excellent enantioselectivity by utilizing low catalyst loading.

Full text of DOI:10.1039/d1cc00989c

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Enantioselective synthesis of functionalized 1,
0
0
4
-dihydropyrazolo-[4 ,3 :5,6]pyrano[2,3-
Cite this: Chem. Commun., 2021,
7, 4690
5
b]quinolines through ferrocenyl-phosphine-
catalyzed annulation of modified MBH carbonates
and pyrazolones†
Received 22nd February 2021,
Accepted 5th April 2021
DOI: 10.1039/d1cc00989c
ab
b
b
b
a
b
Xiao Xiao, Bingxuan Shao, Jingyi Li, Zehui Yang,
Yin-Jie Lu, Fei Ling
b
rsc.li/chemcomm
and Weihui Zhong
*
An enantioselective synthesis of highly functionalized 1,4- pyrazolone form plays a dominant role. Consequently, the most
0
0
dihydropyrazolo[4 ,3 :5,6]pyrano[2,3-b]quinolines from modified conventional applications of those scaffolds in organocatalyzed
MBH carbonates and pyrazolones via chiral phosphine- cyclization are shining the spotlight on [1+n] and [3+n] annula-
a
5
mediated alkylation/annulation sequence has been realized. The tion to achieve highly functionalized heterocycles. Despite the
chiral dihydropyrano[2,3-c]pyrazoles bearing bio-active con- extensive utility of pyrazolones as nucleophiles in asymmetric
densed heterocycles were facilely formed in good chemical yields organocatalysis, their utilization in phosphine-catalyzed
5
6
7
and with high to excellent enantioselectivity by utilizing low transformations, to the best of our knowledge, is rare. It
catalyst loading.
should be noteworthy that Lu and co-workers disclosed the
phosphine-mediated [4+1] annulation process to achieve an
The development of efficient annulation strategies for the enantioselective synthesis of spiropyrazolones from pyrazo-
7
construction of heterocycles, due to their peculiar features, lones and allenoate-derived MBH acetates (Scheme 1a). When
has been a longstanding interest of the chemical and pharma- it comes to asymmetric [3+3] annulation and related sequential
1
,2
8
ceutical communities. Pyrazolones and pyrazoles are signifi- reaction to construct high functionalized dihydropyrans, it has
cant heterocycles involving a broad range of valuable biological not been realized via chiral phosphine catalysis. A represented
1
e,2b
properties.
As an oxygen heterocycle, the dihydropyran strategy that amine-catalyzed asymmetric [3+3] annulations of
0
scaffold is also a general structural unit broadly existing in b -acetoxy allenoates and pyrazolone to enantioselective access
numerous biologically active natural products. Among a num- diversified 4H-pyrans was reported by Tong and co-workers
ber of dihydropyran and pyrazole derivatives, the skeletons of (Scheme 1b). At present, the related organocatalyzed cycliza-
,4-dihydropyrano[2,3-c]pyrazoles that possess both cores of tion of pyrazolones to form chiral dihydropyrano[2,3-c]pyra-
3
8
a
1
dihydropyran and pyrazole are peculiarly of synthetic and zoles bearing bio-active condensed heterocycles is unknown,
pharmaceutical interest because of their significant potential resulting in the need for efficient synthetic approaches to this
4
in pharmaceutical science (Fig. 1).
challenging structural motif, particularly for developing a ver-
Pyrazolones have been around for more than one century satile method via phosphine catalysis.
and have emerged as a commonly-used and versatile synthon to
furnish a series of potentially bioactive pyrazole and pyrazolone
2
b,5
derivatives.
The pyrazolone mostly serves as a brilliant
nucleophile in the reactions of carbon–carbon bond formation,
5a–c
especially the Michael addition reactions.
There is the
existence of either the carbonyl form or the aromatic pyrazole
form as a result of tautomerism. However, in solution, the
a
Institute of Pharmaceutical Science and Technology,
Zhejiang University of Technology, Hangzhou 310014, People’s Republic of China
b
College of Pharmaceutical Sciences, Zhejiang University of Technology,
Hangzhou 310014, People’s Republic of China
†
Electronic supplementary information (ESI) available. CCDC 1961004. For ESI
and crystallographic data in CIF or other electronic format, see DOI: 10.1039/
d1cc00989c
Fig. 1 Biologically active 1,4-dihydropyrano[2,3-c]pyrazole compounds.
4
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a
Table 1 The optimization of the reaction conditions
b
c
Entry Cat. Solvent
X
Temp. (1C) Time (h) Yield (%) ee (%)
Scheme 1 Asymmetric annulations of pyrazolones.
1
2
3
4
5
6
7
8
9
PPh
P1
P2
P3
P4
P5
P6
P7
P8
P4
P4
P4
P4
P4
P4
3
Toluene 20
Toluene 20
Toluene 20
Toluene 20
Toluene 20
Toluene 20
Toluene 20
Toluene 20
Toluene 20
o-Xylene 20
25
25
25
25
25
25
25
25
25
25
25
25
20
96
96
96
96
96
96
96
96
96
96
96
36/56
72
72
88
50
52
48
60
55
Trace
18
50
62
73
48
86/84
83
—
98
97
98
98
98
n.d.
ꢀ93
ꢀ98
83
95
84
91/93
93
94
We envisioned that the complicated structural motifs might
be concisely assembled through a phosphine-mediated [3+3]
annulation or related sequential reaction. The equilibrium of
pyrazole and pyrazolone suggests that it may be a suitable
synthon in the proposed annulation. By utilizing a modified
Morita–Baylis–Hillman (MBH) carbonate 1 containing a leaving 10
11
12
13
o-DCB
TCM
o-DCB
o-DCB
o-DCB
20
20
20/10 40
5
5
group on the ortho-position as a reaction partner, the designed
0 0
1
,4-dihydropyrazolo[4 ,3 :5,6]pyrano[2,3-b]quinoline 3 could be
facilely achieved (Scheme 1c). In recent years, we have disclosed 14
40
40
d
15
70
a series of enantioselective processes promoted by ferrocene-
9
based chiral phosphines. Inspired by our continuous interest in
a
Reaction conditions: 1a (0.6 mmol), 2a (0.5 mmol), catalyst
CO (1.0 equiv.) in solvent (2.5 mL), 36–96 h, under
atmosphere. Isolated yield. Determined by chiral HPLC analysis.
Using the related MBH acetate to instead of 1a.
ferrocenyl-phosphine catalysis, we herein describe the straight- (5–20 mol%), Na
forward alkylation/annulation sequence of functionalized MBH
2
3
b
c
N
2
d
carbonates 1 and pyrazolones 2 to construct optically enriched
0
0
1
,4-dihydropyrazolo[4 ,3 :5,6]-pyrano[2,3-b]quinolines 3.
We first investigate the feasibility of our designed annulation (entries 13 and 14). Ultimately, decreasing the catalyst loading of
process. Toward this end, methyl 2-(((tert-butoxycarbonyl)oxy) the reaction did not inhibit the efficiency of forming the desired
2-chloroquinolin-3-yl)methyl)acrylate 1a and 5-methyl-2-phenyl- product, which could afford the compound 3aa in 83% yield and
,4-dihydro-3H-pyrazol-3-one 2a were treated with triphenylphos- with 93% ee (entry 14). Changing the reported MBH acetate as the
phine and Na CO in toluene at room temperature. Gratifyingly, substrate to this reaction, product 3aa could be obtained in
the cyclization took place smoothly, and the desired product 3aa moderate yield (entry 15).
(
2
2
3
was obtained in 88% yield (Table 1, entry 1). Then, our previously
With the optimized reaction conditions in hand, we next
designed bifunctional chiral ferrocenylphosphine P1 was sub- commenced to establish the scope of this sequential annula-
jected to the asymmetric annulation and the desired product tion process (Scheme 2). When it came to functionalized MBH
3aa was furnished in 50% yield and with excellent enantioselec- carbonates, the substituted quinolines bearing the functional
tivity (98% ee) (Table 1, entry 2). Next, to testify the efficiency of groups of fluoro, chloro, bromo, methyl, and methoxyl were
phosphine catalysts, various ferrocene-derived bifunctional phos- well-tolerated in this annulation, which could be transformed
phine catalysts were investigated (Table 1, entries 3–9). Phosphine to the corresponding products in good yields and with excellent
amide P4 proved to be a promising catalyst, leading to the enantioselectivity (3aa–3ga). The absolute configurations of the
formation of the corresponding product 3aa in 60% yield and desired products were confirmed based on a single-crystal X-ray
1
0
with 98% ee (Table 1, entry 5). In the presence of a sulfonamide- analysis of a derivative of 3aa. The substrate possessing
derived bifunctional ferrocenylphosphine, only trace annulation dimethyl substituent on the quinoline ring was smoothly con-
product 3aa was obtained, which demonstrated that the fragment verted to the product 3ha in 60% yield and with 95% ee (3ha).
of amide was essential (Table 1, entry 7). Having identified P4 as Even when the condensed heterocycle-substituted MBH carbo-
the best catalyst, solvent screening was then followed (Table 1, nate was used, the high ee was still secured (3ia, and 3id).
entries 10–12). To our delight, when 1,2-dichlorobenzene (o-DCB) Subsequently, the modified MBH carbonates bearing different
was utilized as the solvent, the yield was improved to 73% and the ester groups on the side chain proceeded smoothly under the
enantioselectivity could reach 95% ee (Table 1, entry 12). Next, the standard conditions (3ja–3ma). It was noteworthy that the ee
excellent results in terms of the yield and enantioselectivity could value of the dihydropyran 3ma derived from benzyl acrylate was
also be achieved by increasing the reaction temperature to 40 1C the lowest among the products 3ja to 3ma, probably owing to
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0
0
a
Scheme 2 Asymmetric synthesis of 1,4-dihydropyrazolo[4 ,3 :5,6]pyrano[2,3-b]quinolines 3. Reaction condition: 1 (0.6 mmol), 2 (0.5 mmol),
b
c
2 3 2
P4 (5.0 mol%), Na CO (1.0 equiv.) in o-DCB (2.5 mL), 72–168 h, under N atmosphere. Isolated yields. Values of ee were determined by using chiral HPLC.
d
e
P4 (10 mol%) was added. P4 (20 mol%) was added.
the p–p interaction influence from the substrate and phosphine
P4. We further investigated the scope of pyrazolones. Increas-
ing steric hindrance of the groups adjoined to the nucleophilic
site of the pyrazolones led to lower enantioselectivity (3ab–3ad).
Variation of the N substituent on pyrazolone showed that both
electron-rich and -deficient aryl groups were well-tolerated
(
3ae–3ak). The N-tert-butyl-substituted pyrazolone was then
utilized to smoothly afford product 3al in 70% yield and with b]quinoline derivatives.
6% ee. Significantly, this strategy could also facilitate the
0
0
Fig. 2 The bioactivity of chiral 1,4-dihydro pyrazolo[4 ,3 :5,6]pyrano[2,3-
8
0
0
generation of the 1,4-dihydropyrazolo[4 ,3 :5,6]thiopyrano
2,3-b]quinolone derivatives with high efficiency (3am and
fm). To further test the practical utility, gram-scale operation of designed MBH carbonates and pyrazolones is shown in
[
3
A tentative mechanism for this sequential annulation reaction
was performed by utilizing 6.9 mmol of 1a and 5.8 mmol of 2a, Scheme 3. Initially, the chiral phosphine P4 attacks the MBH
which furnished the desired product 3aa in good yield (75%, carbonate 1a to generate the phosphonium I with the release of
1.7 grams) and with 91% ee (Scheme 2, 3aa).
tert-butoxide anion and carbon dioxide, followed by a Michael
Moreover, the investigations on the potential bioactivity of addition of species II to I via the transient state A and then leading
0
0
selected chiral 1,4-dihydropyrazolo[4 ,3 :5,6]pyrano[2,3-b]qui- to generation of intermediate III. A deprotonation is subsequently
noline derivatives 3 were carried out by testing their cytotoxicity conducted to generate anion IV. An intramolecular S Ar substitu-
utilizing the MDA-MB-231 breast cancer cell line, A549 human tion ultimately took place, resulting in the formation of highly
N
0
0
non-small cell lung carcinoma cell line and HT-29 colorectal enantioselective 1,4-dihydropyrazolo[4 ,3 :5,6]pyrano[2,3-b]quino-
cancer cell line (for details, see page S35 of the ESI†). Among line derivative 3aa. In order to illuminate the high yield and
these compounds (Fig. 2), 3fa possessed the highest cytotoxicity enantioselectivity of this transformation, a probable transient state
toward both the MDA-MB-231 (IC50 = 3.00 mM) and A549 (IC50
=
A was proposed. Firstly, the phosphine core would be to control the
1
.90 mM) cell line. Notably, the derivative 3ba served as a high- reactivity of MBH carbonate. Secondly, both the H-bonding inter-
efficacy agonist with low micromolar activities in the HT-29 action with the N–H of the amide and the p–p interaction with the
colorectal cancer cell line (IC50 = 4.06 mM). These results benzothiophene on catalyst P4 to the species II would be increasing
0
0
indicated that these 1,4-dihydropyrazolo[4 ,3 :5,6]pyrano not only the reaction enantioselectivity but also the reactivity of
2,3-b]quinoline scaffolds have the potential for drug discovery. pyrazolone.
[
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3
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2
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0
0
nalized chiral 1,4-dihydro pyrazolo[4 ,3 :5,6]pyrano[2,3-b]qui-
noline derivatives from the newly modified MBH carbonates
and pyrazolones via ferrocene-derived bifunctional phosphine-
catalyzed asymmetric alkylation/annulation sequence. With
this strategy, numerous chiral heterocyclic compounds bearing
bio-active pyrazoles and quinolines are facilely furnished by
utilization of low catalyst loading. The gram-scale operation
and potential bioactivity investigation make this synthetic route
more useful for pharmaceutical discovery. A more systematic
study of both the mechanism and cytotoxicity testing is ongoing.
This work was supported by the National Natural Science
Foundation of China (No. 22078298, 21978271, 21706234 and
1
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7
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M. S ´a nchez-Rosell ´o , P. Barrio and A. Sim ´o n-Fuentes, Chem. Rev., 10 CCDC 1961004 contains the supplementary crystallographic data for
011, 111, 6984. this paper†.
2
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