DBU-catalyzed dearomative annulation of 2-pyridylacetates with α,β-unsaturated pyrazolamides for the synthesis of multisubstituted 2,3-dihydro-4H-quinolizin-4-ones

Abstract

The reaction of 2-pyridylacetates and α,β-unsaturated pyrazolamides with DBU as the catalyst has been developed. A range of unexplored multisubstituted 2,3-dihydro-4H-quinolizin-4-ones are obtained with satisfactory yields (up to 94%) and excellent diastereoselectivities (all cases >20 : 1 dr) via a dearomative [3 + 3] annulation process. This practical method also features transition metal free, mild reaction conditions, wide functional group tolerance, easy scale-up synthesis, and versatile further derivatization.

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Functionalized heterocyclic scaffolds are attractive and interesting synthetic targets for the preparation of diversity-oriented compound libraries in medicinal and pharmaceutical applications.¹ In particular, almost all of the small-molecule drugs approved by the FDA contain at least one heterocyclic moiety.² The development of new synthetic strategies for the construction of functionalized heterocycles with structural diversification has always been a hot spot and main focus of research in organic synthesis. 4H-Quinolizin-4-one and its derivatives, as a type of N-containing heterocyclic compound, have been considered as important components in modern pharmaceuticals and versatile building blocks for drug and natural product synthesis.³ Consequently, an increasing number of creative methods have been developed for the preparation of 4H-quinolizin-4-one and its diverse derivatives.⁴ Despite the significant progress, inspired by their intriguing structural features and potential biological and pharmaceutical applications, the synthesis of diverse 4H-quinolizin-4-ones with innovative structures is not only of high value, but is also arousing much research attention from medical and synthetic organic chemists to develop novel and efficient methodologies.

Dearomatization of heteroarenes involving an annulation process represents an attractive strategy to access non-aromatic heterocycles from readily available raw materials in a very straightforward manner.⁵ In this research area, the possible involvement of 2-pyridylacetates for the construction of heterocyclic structures containing a dearomatized-pyridine moiety via a dearomative annulation process has been widely reported.⁶ Actually, from a reaction point of view, in these methods, the intrinsic 1,3-dinucleophilic character of 2-pyridylacetates makes them a type of C1–N3 synthon that reacts with appropriate 1,n-dielectrophilic partners to access aza-heterocycles via a dearomative [3 + n] annulation (Scheme 1). To the best of our knowledge, the majority of the existing reports on this aspect mainly focus on the formal [3 + 2] annulation to generate various indolizines and their derivatives (Scheme 1, left).⁷ However, the reaction involving 2-pyridylacetates as 1,3-dinucleophilic partners reacting with possible 1,3-dielectrophilic components for dearomative [3 + 3] annulation is relatively underdeveloped, and only a few scattered examples of the construction of 4H-quinolizin-4-one scaffolds have been reported (Scheme 1, right).⁸ Therefore, it is still highly desirable to develop feasible approaches for the synthesis of 4H-quinolizin-4-one derivatives with structural diversification.

Scheme 1 Profile of 2-pyridylacetates acting as 1,3-dinucleophiles for the dearomative annulation.

The employment of α,β-unsaturated pyrazolamides as 1,3-dielectrophilic reactants for the construction of various carbonyl-containing heterocycles has been reported.⁹ With comprehensive consideration of the 1,3-dinucleophilic character of 2-pyridylacetates and 1,3-dielectrophilic character of α,β-unsaturated pyrazolamides, we envisioned that the reaction of these two reactants would result in the formation of 4H-quinolizin-4-one scaffolds via a dearomative [3 + 3] annulation process (Scheme 2). As a continuation of our research interest in the development of new methodologies for the construction of various heterocycles,¹⁰ recently, we have discovered that one molecule of 2-pyridylacetate could react with two molecules of α,β-unsaturated pyrazolamide using DBU as the catalyst, affording a wide range of unexplored multisubstituted 2,3-dihydro-4H-quinolizin-4-ones with satisfactory yields and excellent diastereoselectivities (Scheme 2). Moreover, this practical method also features transition metal free, mild reaction conditions, wide functional group tolerance, easy scale-up synthesis, and versatile further functionalizations. Herein, we wish to report our research on this subject.

Scheme 2 The strategy for the construction of multisubstituted 2,3-dihydro-4H-quinolizin-4-ones with 2-pyridylacetates and α,β-unsaturated pyrazolamides via dearomative [3 + 3] annulation.

Our optimization studies began with the reaction between 2-pyridylacetate 1a and α,β-unsaturated pyrazolamide 2a in DMF at room temperature. As shown in Table 1, in the presence of 1.0 equivalent of TMG as a base, it was found that one molecule of 1a actually reacted with two molecules of 2avia a dearomative [3 + 3] annulation process, leading to the formation of 3aa in 33% yield with a >20 : 1 diastereoselectivity ratio (dr) (entry 1). Using 1.0 equivalent of DBU resulted in product 3aa in 65% yield with a 16 : 1 dr (entry 2). DIPEA or TEA led to the failure of the reaction (entries 3 and 4). The inorganic base KOH could afford 3aa in 35% yield with an 8 : 1 dr (entry 5). After DBU was chosen as the optimal base, various solvents were examined (entries 6–10). It was found that the reaction did not occur in nonpolar solvents such as CH₂Cl₂, THF, and toluene (entries 6–8), but DMSO and MeCN could yield 3aa in moderate levels with a 12 : 1 dr (entries 9 and 10). However, relatively favorable results were still obtained in DMF (entry 2). On reducing the loading of DBU to 30 mol%, the reaction furnished 3aa in 69% yield with a >20 : 1 dr (entry 11), whereas 20 mol% of DBU promoted the reaction to generate 3aa in 71% yield with a >20 : 1 dr (entry 12). Increasing the reactant concentration led to a slight enhancement in the yield (entry 13). Ultimately, on changing the molar ratio of 1a and 2a from 1 : 2.5 to 1 : 3.5, product 3aa was obtained in 79% yield with a >20 : 1 dr (entry 14). Disappointingly, on changing the base from DBU to TBD or DBN, no improved results were obtained (entries 15 and 16).

Table 1 Optimization of reaction conditions^a

Entry	Base	x	Solvent	Time (h)	Yield^b (%)	dr^c
a Unless otherwise noted, the reactions were carried out with 1a (0.4 mmol), 2a (1.0 mmol, 2.5 equiv.), and a base (x mol%) in 4.0 mL of solvent at room temperature. b Isolated yield. c Determined by ^1H NMR analysis. d 2.0 mL of DMF was used. e 1a : 2a = 1 : 3.5. TMG = 1,1,3,3-tetramethylguanidine, DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene, DIPEA = N,N-diisopropylethylamine, TEA = triethylamine, TBD = 1,5,7-triazabicyclo[4.4.0]dec-5-ene, DBN = 1,5-diazablcyclo[4.3.0]non-5-ene and nr = no reaction.
1	TMG	100	DMF	12	33	>20 : 1
2	DBU	100	DMF	12	65	16 : 1
3	DIPEA	100	DMF	12	nr	—
4	TEA	100	DMF	12	nr	—
5	KOH	100	DMF	12	35	8 : 1
6	DBU	100	CH2Cl2	12	nr	—
7	DBU	100	THF	12	nr	—
8	DBU	100	Toluene	12	nr	—
9	DBU	100	DMSO	12	52	12 : 1
10	DBU	100	MeCN	12	38	12 : 1
11	DBU	30	DMF	24	69	>20 : 1
12	DBU	20	DMF	24	71	>20 : 1
13^d	DBU	20	DMF	24	76	>20 : 1
14^d^,^e	DBU	20	DMF	24	79	>20 : 1
14^d^,^e	TBD	20	DMF	24	12	18 : 1
15^d^,^e	DBN	20	DMF	24	33	19 : 1

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With the optimized reaction conditions in hand, we explored the generality of the dearomative [3 + 3] annulation. Different 2-pyridylacetates were firstly examined by reacting with α,β-unsaturated pyrazolamide 2a under the standard conditions. As shown in Scheme 3, all of the reactions afforded their corresponding 2,3-dihydro-4H-quinolizin-4-one products with excellent diastereoselectivities (all cases >20 : 1 dr). The ester group of 1 could range from ethyl-ester to methyl-, propyl-, butyl-, or benzyl-ester, all of which reacted well with 2a to give their respective products 3ba–ea in good yields. On changing the ethyl-ester group of 1a to the sterically hindered isopropyl- or tertiary butyl-ester group, the corresponding products 3fa and 3ga were obtained in moderate yields. Moreover, cyclohexyl 2-(pyridin-2-yl)acetate also reacted with 2a to afford 3ha in 33% yield. In addition, trifluoro ethyl, allyl, and propargyl groups were also compatible with the reaction system to give the cycloadducts in good yields (for products 3ia–la). Furthermore, 2-((phenylsulfonyl)methyl)pyridine and 2-(pyridin-2-yl)acetonitrile were applicable to the reaction, providing the desired products 3ma and 3na in reasonable yields. Ultimately, it was found that substrates incorporating either an electron-donating or electron-withdrawing group at the C5-position of the pyridine ring also afforded the corresponding products but in low yields (for products 3oa–pa). Disappointedly, we also investigated the reaction of ethyl 2-(quinolin-2-yl)acetate, 1-phenyl-2-(pyridin-2-yl)ethan-1-one, 2-(pyridin-2-yl)acetaldehyde, and 2-(nitromethyl)pyridine with α,β-unsaturated pyrazolamide 2a under the standard conditions, respectively. It was found that these reactions got messy as monitored by TLC, and no main product could be obtained.

Scheme 3 Substrate scope of 2-pyridylacetates. Reaction conditions: the reactions were carried out with 1 (0.4 mmol), 2a (1.4 mmol), and DBU (20 mol%) in 2.0 mL of DMF at room temperature for 24 h. The yield refers to the isolated yield after column chromatography. The dr was determined by ¹H NMR analysis.

Next, various substituted α,β-unsaturated pyrazolamides were examined by their reactions with 2-pyridylacetate 1a under the standard conditions. As illustrated in Scheme 4, all of the reactions provided the corresponding cycloadducts with excellent diastereoselectivities (all cases >20 : 1 dr). On installing a chlorine atom at the m-position of the phenyl ring, product 3ab was smoothly obtained in 80% yield. Moreover, substrates with electron-withdrawing substituents, such as Cl–, F–, Br–, I–, CN–, and CF₃– at the p-position of the phenyl ring, were also tolerated in the dearomative [3 + 3] annulation, affording 3ac–ah in moderate to good yields with excellent diastereoselectivities. Likewise, on incorporating an electron-donating substituent (Me– or MeO–) into the phenyl ring, the reactions proceeded smoothly to give 3ai and 3aj in good yields. In addition, the bulkier naphthyl group was also tolerated in the reaction with 1a to furnish 3ak in 67% yield with a >20 : 1 dr. Moreover, the heteroaromatic substituted α,β-unsaturated pyrazolamide substrate also could react effectively with 1a, delivering 3al in 70% yield with a >20 : 1 dr. Disappointingly, using β-methyl substituted α,β-unsaturated pyrazolamide or β-unsubstituted N-pyrazole acrylic amide failed to afford the desired products, probably due to the lower reactivity than their aryl-substituted congeners.

Scheme 4 Substrate scope of α,β-unsaturated pyrazolamides. Reaction conditions: the reactions were carried out with 1a (0.4 mmol), 2 (1.4 mmol), and DBU (20 mol%) in 2.0 mL of DMF at room temperature for 24 h. The yield refers to the isolated yield after column chromatography. The dr was determined by ¹H NMR analysis.

To evaluate the synthetic potential of the methodology, we conducted a gram-scale reaction of 1a and 2a under the standard conditions. As shown in Scheme 5, the reaction proceeded smoothly to give 3aa in 71% yield with a >20 : 1 dr. This suggests that the developed catalytic system has good scalability. In addition, the structure and relative configuration of product 3aa was further confirmed by single crystal X-ray crystallographic study.¹¹ Then, different transformations of 3aa were carried out to showcase the synthetic utility of the products 2,3-dihydro-4H-quinolizin-4-ones.¹² Treating 3aa with DDQ in CH₂Cl₂ gave the product 4H-quinolizin-4-one 4 in 54% yield. The corresponding ester derivative 5 could be easily obtained in 90% yield with a >20 : 1 dr through the cleavage of the pyrazole moiety and then an esterification process. Similarly, on treating 3aa with BnNH₂ in THF at 70 °C, the corresponding amide product 6 was obtained in 60% yield without any loss in the diastereoselectivity. The reaction of 3aa with BnNH₂ in the presence of DBU led to the formation of product 7 in 77% yield with a 53 : 47 dr. Finally, 3aa was conveniently conversed into the thioesterification product 8 in 61% yield with a >20 : 1 dr.

Scheme 5 Gram-scale experiment and versatile transformations of 3aa.

We further conducted some control experiments to verify the importance of the N-acylpyrazole moiety of the α,β-unsaturated pyrazolamides for the above DBU-catalyzed dearomative [3 + 3] annulation (Scheme 6). As mentioned earlier, the reaction of 1a and 2a smoothly provided 3aa in 79% yield with a >20 : 1 dr. Under the standard conditions, the reaction of 1a and α,β-unsaturated pyrazolamide 11 gave the cycloadduct 12 only in a trace amount, but 12 was obtained in 34% yield with a >20 : 1 dr on raising the reaction temperature to 40 °C for 48 h. These two experiments revealed that the pyrazole moiety in α,β-unsaturated pyrazolamides is more conducive to the dearomative [3 + 3] annulation process than the 3,5-dimethyl pyrazole moiety. In addition, it was also found that both α,β-unsaturated ester 9 and α,β-unsaturated amide 10 failed to react with 1a under the standard conditions. These control experiments revealed that the N-acylpyrazole moiety in α,β-unsaturated pyrazolamides is crucial for the dearomative annulation reaction.

Scheme 6 Control experiments.

In conclusion, we have developed a dearomative [3 + 3] annulation of 2-pyridylacetates and α,β-unsaturated pyrazolamides with DBU as the catalyst. A wide range of unexplored multisubstituted 2,3-dihydro-4H-quinolizin-4-ones were obtained in satisfactory yields (up to 94%) with excellent diastereoselectivities (all cases >20 : 1 dr). The developed protocol takes full advantage of the 1,3-dinucleophilic character of 2-pyridylacetates and 1,3-dielectrophilic character of α,β-unsaturated pyrazolamides to realize the dearomative annulation process. The N-acylpyrazole moiety of the α,β-unsaturated pyrazolamides was demonstrated to be crucial for the reaction. This practical method also features transition metal free, mild reaction conditions, wide functional group tolerance, easy scale-up synthesis, and versatile further derivatization.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We are grateful to the National Natural Science Foundation of China (No. 22171029, 21901024, 21871252, 21801024, and 21801026), the Sichuan Science and Technology Program (2021YFS0315), and the Talent Program of Chengdu University (2081919035 and 2081921038).

Notes and references

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11. CCDC 2103427 (3aa) contains the supplementary crystallographic data for this paper. †.
12. For details, see the ESI.†.

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, spectral data of new compounds, and crystallographic data. CCDC 2103427. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d1qo01414e

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