Palladium-catalysed stereoselective [3 + 2] annulation of vinylethylene carbonates and tryptanthrin-based ketones

Abstract

The palladium-catalysed [3 + 2] annulation of vinylethylene carbonates (VECs) and ketones remains challenging in organic synthesis. Herein, we successfully achieved the [3 + 2] annulation of tryptanthrin-based ketones and VECs for the efficient synthesis of indoloquinazolinone derivatives with generally excellent yields and good diastereoselectivity. Notably, the asymmetric version of this [3 + 2] annulation can also be achieved by using a chiral spiroketal-based diphosphine ligand. In addition, preliminary biological studies reveal that some of the products exhibit promising antibacterial activity.

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Introduction

Transition-metal-catalysed annulation processes are powerful tools for building diverse biologically important organic molecules.¹ In particular, stereoselective reactions involving zwitterionic π-allyl palladium species have stimulated great interest among synthetic chemists, and significant achievements have been made over the past decades.² As easily accessible and versatile building blocks, vinylethylene carbonates (VECs)³ can readily undergo decarboxylative activation in the presence of palladium catalysts and generate highly reactive zwitterionic π-allyl palladium complexes, thereby enabling a series of interesting chemical transformations.⁴ In 2014, Zhang and co-workers used aldehydes for the palladium-catalysed [3 + 2] annulation of VECs, and the zwitterionic π-allyl palladium generated in situ served as a 1,3-dipole to react with various aldehydes in a sequential 1,2-addition/cyclisation fashion.⁵ Since then, a series of palladium-catalysed [3 + 2] annulation reactions of VECs have been developed by using diverse unsaturated systems, such as imines,⁶ isocyanates,⁷ isothiocyanates⁸ and electron-deficient alkenes.⁹ However, using ketones, which are important carbonyl substrates, in [3 + 2] cyclisation remains challenging probably because they have low electrophilic properties, steric hindrance effect and two quaternary carbon centres that are difficult to construct in a single step (Scheme 1a).

Scheme 1 Research motivation: Pd-catalysed [3 + 2] annulation of VECs and ketones.

Therefore, catalytic systems that allow ketones to participate in the stereoselective annulation reactions of VECs are highly desirable.

Indoloquinazolinones are key structural motifs in a variety of natural products and biologically active compounds.¹⁰ Tryptanthrin and its analogues, such as phaitanthrin A and B and cruciferane, consist of indoloquinazolinone cores, which exhibit a broad spectrum of biological activities (Scheme 1b).¹¹ Therefore, substantial efforts have been made to develop various valuable transformations on the basis of tryptanthrin cores and enrich the structural diversity of biologically interesting scaffolds.¹² Encouraged by these achievements and our continuing interest in the construction and modification of biologically relevant frameworks,¹³ we envisioned that the unprecedented ketone-participated [3 + 2] annulation of VECs might be achieved by using tryptanthrins as a highly reactive electrophile. In this work, a method for the palladium-catalysed stereoselective [3 + 2] annulation of VECs and tryptanthrin-based ketones has been developed. With this method, a series of indoloquinazolinone compounds bearing two quaternary carbon centres can be easily synthesised with excellent yields and good diastereoselectivity. In addition, the asymmetric catalytic cyclisation has been achieved by using a chiral spiroketal-based diphosphine ligand, producing the target products with high enantioselectivity. Preliminary biological studies reveal that some of the obtained indoloquinazolinone molecules show promising antibacterial activity (Scheme 1c).

Results and discussion

Initially, attempts to verify the concept of Pd-catalysed [3 + 2] annulation of VECs and ketones were unsuccessful despite using several ketone substrates, such as trifluoroacetophenone and isatins. Then, we tested tryptanthrin 1a as a highly reactive ketone in the reaction with VEC 2a. As shown in Table 1, 1a triggered the target [3 + 2] cyclisation in the presence of Pd(PPh₃)₄ in toluene at ambient temperature, and the desired product 3a was obtained in 11% yield with 3.8 : 1 diastereoselectivity (Table 1, entry 1). With this encouraging result, we subsequently examined the effect of the solvent, and DCM was identified as the optimal solvent that could dramatically improve the yield and diastereoselectivity (Table 1, entries 2–7). We further evaluated ligand effects by using various phosphines in combination with Pd₂(dba)₃·CHCl₃. As shown in entries 8–11, inferior results were generally observed after monophosphine ligands L1–L3 and bisphosphine ligand L4 were screened. Although Xantphos L5 gave the product 3a in 99% yield, poor diastereoselectivity was observed (Table 1, entry 12).

Table 1 Optimisation of the [3 + 2] cyclisation of ketone 1a and VEC 2a ^a

Entry	Pd source	Ligand	Solvent	Yield^b (%)	dr^c
a Reactions were performed with 0.10 mmol of 1a, 0.15 mmol of 2a and 5 mol% of Pd(PPh3)4 (or 2.5 mol% of Pd2(dba)3·CHCl3/10 mol% of ligand) in 1.0 mL solvent at room temperature for 12 h. b Isolated yields. c Determined by ^1H NMR analysis of the crude reaction mixture. ND: not determined; Cy: cyclohexyl.
1	Pd(PPh3)4	—	Toluene	11	3.8 : 1
2	Pd(PPh3)4	—	THF	<5	ND
3	Pd(PPh3)4	—	MeCN	58	3.5 : 1
4	Pd(PPh 3 ) 4	—	DCM	96	7.9 : 1
5	Pd(PPh3)4	—	CHCl3	63	7.6 : 1
6	Pd(PPh3)4	—	DCE	48	6.9 : 1
7	Pd(PPh3)4	—	PhCl	62	4.7 : 1
8	Pd2(dba)3·CHCl3	PCy3L1	DCM	<5	ND
9	Pd2(dba)3·CHCl3	L2	DCM	34	5.2 : 1
10	Pd2(dba)3·CHCl3	L3	DCM	35	7.2 : 1
11	Pd2(dba)3·CHCl3	L4	DCM	47	7.8 : 1
12	Pd2(dba)3·CHCl3	L5	DCM	99	4.7 : 1

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After establishing the optimal conditions, we then investigated the generality and limitations of the [3 + 2] annulation by using various tryptanthrin-based ketone substrates. As shown in Table 2, substrates 1 with diverse electronic and steric properties on the indole skeleton readily participated in the [3 + 2] annulation, affording the desired products 3a–3g in excellent yields (up to 99% yield) with reasonable diastereoselectivity. Electron-withdrawing and electron-donating substituents on the quinazolinone ring at different positions of 1 were well tolerated, providing the products 3h–3m in 80%–99% yields with up to 8.1 : 1 diastereoselectivity. Dimethyl-substituted 1 was also a suitable substrate and generated the product 3n in an excellent yield but with decreased diastereoselectivity.

Table 2 Substrate scope of the [3 + 2] cyclisation of VEC 1a with various tryptanthrin-based ketones 2 ^a,b

a Reactions were performed with 0.10 mmol of 1, 0.15 mmol of 2a and 5 mol% of Pd(PPh₃)₄ in 1 mL DCM at room temperature for 12 h. b Isolated yields; dr was determined by ¹H NMR analysis of the crude reaction mixture.

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Various substituted VECs 2 were subsequently investigated in the reaction with ketone 1a under the catalysis of Pd(PPh₃)₄ (Table 3). VECs 2 featuring either an electron-donating or electron-withdrawing group at the para-position of the benzene ring worked well under standard conditions, generating the corresponding products 3o–3s in 72%–99% yields with good diastereoselectivity. VECs bearing a fluorine or bromine atom at the meta-position of the benzene ring were also suitable substrates for the production of 3t and 3u in excellent yields. The reactions proceeded smoothly for the ortho-fluoro-substituted VEC, and 3v was obtained in 93% yield. The biphenyl VEC could also participate in the reaction, and the corresponding 3w was obtained in 95% yield with 5 : 1 dr. The reactions with disubstituted VECs smoothly provided products 3x and 3y in excellent yields. The reaction was compatible with naphthyl VEC, and afforded product 3z efficiently. Furthermore, the alkyl-substituted VEC was tested, and 3aa was produced in a good yield with decreased diastereoselectivity. The reaction with VEC bearing a single vinyl substituent generated the product in an extremely high yield, but the diastereoselective control remained a limitation for this method (3ab).

Table 3 Substrate scope of the [3 + 2] cyclization of various VECs 2 with ketone 1a ^a,b

a Reactions were performed with 0.10 mmol of 1a, 0.15 mmol of 2 and 5 mol% of Pd(PPh₃)₄ in 1 mL DCM at room temperature for 12 h. b Isolated yields; dr was determined by ¹H NMR analysis of the crude reaction mixture.

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Subsequently, we turned our attention to the enantioselective synthesis and used a chiral ligand in the presence of a Pd₂(dba)₃·CHCl₃ pre-catalyst. After a large number of chiral phosphine ligands were screened for the [3 + 2] reaction,¹⁴L6 was selected as the optimal ligand to produce 3a′ with satisfactory results (99% yield, 6.7 : 1 dr and 96 : 4 er, see Scheme 2). This asymmetric catalytic system was found to be robust and exhibited good compatibility. As shown in Scheme 3, more than 10 examples of enantioenriched products were readily synthesised under the established catalytic system. The absolute configuration of 3r′ was determined through X-ray analysis.¹⁵ Notably, the optically pure products could be easily obtained through simple recrystallisation, as exemplified in 3d′, 3f′ and 3r′ in Scheme 3.

Scheme 2 Attempt at asymmetric catalysis.

Scheme 3 Scope of Pd-catalytic asymmetric synthesis. ^aThe data in parentheses refer to the results after recrystallisation.

In addition, the practicability and synthetic usefulness of the [3 + 2] annulation was further demonstrated with a scale-up experiment. Under the standard conditions, product 3d was produced on a 3 mmol scale without yield loss, and 0.68 g of the single diastereoisomer was obtained after recrystallisation. On treating the product 3d with K₂OsO₄ and NMO (4-methylmorpholine N-oxide), the 1,2-diol 4 could be smoothly synthesised through oxidative dihydroxylation of the terminal alkene moiety (Scheme 4).

Scheme 4 Further synthetic investigations.

The synthesised indoloquinazoline compounds were screened for in vitro antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA, clinic isolates), methicillin-sensitive Staphylococcus aureus (MSSA, clinic isolates), methicillin-resistant Staphylococcus epidermidis (MRSE, clinic isolates), methicillin-sensitive Staphylococcus epidermidis (MSSE, clinic isolates) and Staphylococcus aureus (ATCC25923) with the broth microdilution method.¹⁶ The preliminary experimental result indicated that compounds 3f, 3j, 3y and 3ab exhibited specific bioactivity against MRSE, with minimum inhibitory concentration (MIC) values ranging from 32 μg mL⁻¹ to 64 μg mL⁻¹. In addition, diol 4 showed promising inhibition effects on the tested bacteria, with the MIC value ranging from 4 μg mL⁻¹ to 32 μg mL⁻¹ (Fig. 1).

Fig. 1 The preliminary study of antibacterial activity. MRSA: Gram-positive, MIC of levofloxacin: 2 μg mL⁻¹ (positive control). MSSA: Gram-positive, MIC of levofloxacin: 0.06 μg mL⁻¹ (positive control). MRSE: Gram-positive, MIC of levofloxacin: 0.5 μg mL⁻¹ (positive control). MSSE: Gram-positive, MIC of levofloxacin: 0.06 μg mL⁻¹ (positive control). ATCC25923: Gram-positive, MIC of levofloxacin: 0.06 μg mL⁻¹ (positive control).

Conclusions

In summary, we have developed the first example of palladium catalysed [3 + 2] annulation of VECs and ketones. In this work, tryptanthrins have been found to be a reactive ketone substrate that allows the catalytic construction of the indoloquinazoline skeleton. Moreover, the asymmetric version of the [3 + 2] annulation was achieved by using a chiral spiroketal-based diphosphine ligand, and the products were obtained with satisfactory enantioselectivity. In addition, the indoloquinazoline compounds were also tested for in vitro antibacterial activity, and some of the compounds showed promising bioactivity against Staphylococcus. Investigation into the interesting transformations of tryptanthrins and related medicinal applications is currently underway in our laboratory, and the results will be reported in due course.

Conflicts of interest

The authors declare no conflict of interest.

Acknowledgements

Financial support from the NSFC (21871031 and 22071011), the Science & Technology Department of Sichuan Province (2021YJ0404), the Longquan Talents Program, and the start-up funding from Chengdu University is gratefully acknowledged.

Notes and references

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14. For detailed optimisation screening for asymmetric synthesis, see the ESI.†.
15. CCDC 2090813 (3r′) contains the supplementary crystallographic data for this paper, and for more details, see the ESI.†.
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Footnotes

† Electronic supplementary information (ESI) available: Experimental procedures, characterization data for new compounds. CCDC 2090813. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d1qo01543e

‡ These authors contributed equally.

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