An unusual four-step cascade reaction for accessing furo[3,4-c]pyridine-1,4-diones via rhodium catalysis

Abstract

The development of efficient cascade reactions is highly important and appealing because of their desirable step-economy and convenience in constructing multiple chemical bonds and complex molecules in one shot. Herein, we report a rare four-step tandem reaction between acrylamides and 4-hydroxy-2-alkynoates to prepare novel furo[3,4-c]pyridine-1,4-diones which are difficult to synthesize by traditional methods. This unique domino reaction includes C–H activation, Lossen rearrangement, annulation, and lactonization. Additionally, this protocol features good functional group tolerance, obtainment of products by simple filtration, room temperature, and air compatibility. DFT calculations were conducted to shed some light on the reaction mechanism.

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Introduction

The prevalence of heterocycles in natural products and pharmaceuticals has led to the importance and benefits of synthesizing such compounds efficiently. In the past decades, directing group (DG) assisted C–H activation/annulation reactions via transition-metal catalysis for the synthesis of heterocycles have achieved tremendous advances.^1,2 DGs play crucial roles in controlling chemical reactivity and regioselectivity in C–H activation reactions. On the other hand, DGs simply adhere to primordial positions and function as auxiliary groups in these reactions without other transformations. Amide-type DGs are frequently applied to C–H activation/annulation reactions for the synthesis of prevalent isoquinolones and 2-pyridones, where DGs remain static in most cases (Scheme 1a).^1,2a–f,3 The rearrangement or migration of DGs in C–H activation reactions provides an intriguing strategy to construct C–C/C–N bonds and also contributes to the synthesis of novel heterocyclic scaffolds.^4,5 Therefore, it is fascinating to apply this emerging strategy to organic synthesis. Nevertheless, the development of this emerging strategy involving DG rearrangement or migration still falls far behind when compared to the numerous reports of static DGs participating in C–H activation reactions.

Scheme 1 Transition-metal catalyzed C–H activation/annulation reactions.

Even though DGs could improve chemoselectivity and regioselectivity, they may be present as undesired moieties on products at times, and additional steps are required to remove unwanted DGs. If DGs undergo a rearrangement process, it will not only create a new and efficient avenue for synthesizing heterocycles, but also possibly generate novel heterocycles that traditional approaches can hardly furnish. By taking advantage of the strategy of directing group rearrangement, a series of intriguing spirooxindole pyrrolones were synthesized elegantly by Dai's group (Scheme 1b).⁶ Acrylamides involving the rearrangement of DGs undergo three processes: C–H activation, directing group rearrangement, and annulation. Recently, we developed an efficient rhodium-catalyzed domino C–H alkenylation, DG migration, and lactonization reaction between N-carbamoyl indoles and 4-hydroxy-2-alkynoates for the synthesis of the furan-2(5H)-one scaffold (Scheme 1c).⁷ Efficient cascade reactions are highly appealing due to their desirable step-economy and convenience in constructing complex molecules with multiple chemical bonds in one shot.^8–11

To our knowledge, the implementation of a multistep cascade reaction involving four distinct processes of C–H activation, directing group rearrangement, annulation, and lactonization has yet to be documented. In this study, we report a rare four-step tandem reaction between acrylamides and 4-hydroxy-2-alkynoates¹² to prepare novel furo[3,4-c]pyridine-1,4-diones which are difficult to synthesize by traditional methods. The four-step tandem reaction involves C–H activation, DG Lossen rearrangement, [4 + 2] annulation, and lactonization. The method can tolerate a variety of functional groups. Furthermore, the products can be easily purified by filtration and the reaction is compatible with both room temperature and air. These features contribute to the practicality and versatility of the protocol.

Results and discussion

We embarked on our studies with the optimization of the reaction conditions for the cyclization between acrylamide 1a and ethyl 4-hydroxy-4-phenylbut-2-ynoate 2a. No desired product 3a was obtained when catalyzed by MnBr(CO)₅, [RuCl₂(p-cym)]₂, Cp*Co(CO)I₂ and Pd(OAc)₂, respectively (Table 1, entries 1–6). Switching to [Cp*IrCl₂]₂ led to only 6% yield (entry 2). In contrast, the yield of 3a was improved to 73%, and 43% of the product could be obtained by simple filtration when using [Cp*RhCl₂]₂ (entry 5). The structure of 3a was confirmed using 1D-NMR and NOESY experiments as well as mass spectra. Solvent screening revealed that TFE outperformed other common solvents, such as THF (only trace), MeOH (15% yield), DCE (32% yield with 40% substrate not being consumed) and EA (20% yield) (entries 7–11). When using ethanol and adding Na₂CO₃ as a base, the yield of 3a was 0% (entry 12). After extensive screening of additives, such as Na₂CO₃, K₂CO₃, CsOAc, and KOAc, Na₂CO₃ was identified as the optimal one (entries 13–16). The control experiments confirmed that no desired reaction occurred in the absence of an additive or rhodium (entries 17 and 18).

Table 1 Optimization of reaction conditions^a

Entry	Catalyst	Additive	Solvent	Yield^b^,^c (%)
a Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), catalyst (3 mol%), additive (0.2 mmol), under air, solvent (1.0 mL), room temperature, 6 h. b Total isolated yield. c Isolated yields obtained by simple filtration are shown in parenthesis. d Na2CO3 was not used. e [Cp*RhCl2]2 was not used.
1	MnBr(CO)5	NaOAc	TFE	0
2	[Cp*IrCl2]2	NaOAc	TFE	6
3	Cp*Co(CO)I2	NaOAc	TFE	0
4	[Ru(p-cym)Cl2]2	NaOAc	TFE	0
5	[Cp*RhCl2]2	NaOAc	TFE	73 (47)
6	Pd(OAc)2	NaOAc	TFE	0
7	[Cp*RhCl2]2	NaOAc	THF	Trace
8	[Cp*RhCl2]2	NaOAc	MeOH	15
9	[Cp*RhCl2]2	NaOAc	DCE	32
10	[Cp*RhCl2]2	NaOAc	CH3CN	0
11	[Cp*RhCl2]2	NaOAc	EA	20
12	[Cp*RhCl2]2	Na2CO3	EtOH	0
13	[Cp*RhCl2]2	Na2CO3	TFE	78 (53)
14	[Cp*RhCl2]2	K2CO3	TFE	19
15	[Cp*RhCl2]2	CsOAc	TFE	54 (37)
16	[Cp*RhCl2]2	KOAc	TFE	46 (33)
17^d	[Cp*RhCl2]2	—	TFE	0
18^e	—	Na2CO3	TFE	0

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With the optimal conditions in hand, we next examined the scope of this cyclization reaction (Scheme 2). Aryl-substituted propynol bearing electron-donating groups are all tolerated in this system, such as CH₃, t-Bu, OMe, and CH₂CH₃, and the corresponding products can be obtained in high yields by direct filtration (3a–3e). To our delight, electron-withdrawing groups including F, Cl, Br, and I were also tolerated well with the isolated yields ranging from 62% to 72% (3f–3i). Although the yield of the product dropped dramatically when the group was changed to cyclopentyl (3k), the reaction was compatible with other different rings (naphthalene, furan, and thiophene) and afforded the products smoothly (3j, 3l, and 3m). We also explored tertiary alkynol and obtained the desired product in a moderate yield (3n). Next, we investigated R¹ of acrylamide 1 bearing electron-donating and electron-withdrawing groups at the para position of the phenyl group, and the reactions proceeded well to generate the corresponding products. In comparison, when the phenyl group was changed to the benzyl and methyl group, the yield dropped to 47% and 20%, respectively (3o–3u). Additionally, the structures of 3h, 3n, 3p, and 3q were further confirmed by NOESY experiments.

Scheme 2 Substrate scope. Reaction conditions: 1 (0.2 mmol), 2 (0.24 mmol), [Cp*RhCl₂]₂ (3 mmol%), Na₂CO₃ (0.2 mmol), under air, trifluoroethanol (1.0 mL), rt, 6–12 h. Total yields are shown, and yields obtained by simple filtration are shown in parentheses.

Several experiments were conducted to probe the reaction mechanism. In the presence of 1a, Na₂CO₃, [Cp*RhCl₂]₂, and 1.0 ml methanol-d⁴, the experiment of H/D exchange occurring at the olefinic bond of acrylamide was performed (Scheme 3a). And no obvious deuterium incorporation was observed at this position (8% D). In addition, there was also almost no D at the olefinic bond of 3a after adding 2a. The result demonstrated that the cleavage of the C–H bond could be irreversible. Additionally, two parallel reactions were performed giving a KIE value of 0.98 (Scheme 3b), which suggested that the C–H activation step was less likely to be involved in the rate-determining step.

Scheme 3 Deuteration and KIE experiments.

To further obtain the mechanistic features of the unprecedented Rh(III)-catalyzed sequential C–H activation/Lossen rearrangement/[4 + 2] annulation/lactonization cascade, we next performed DFT calculations on the key reaction steps: alkyne insertion, Lossen rearrangement, [4 + 2] annulation and lactonization. As shown in Scheme 4, the five-membered rhodacycle INT-0 derived from C–H activation was rationally selected as the starting point, which coordinated with propargyl alcohol 2a and produced the intermediate INT-1 (ΔG^‡ = −11.3 kcal mol⁻¹) involving hydrogen-bonding between the hydroxyl group of 2a and the pivalate group. Then the C–C unsaturated bond of 2a was inserted into the Rh–C bond viaTS-1 (ΔG^‡ = −4.6 kcal mol⁻¹) to deliver INT-2 with a free energy of −35.8 kcal mol⁻¹. The subsequent facile coordination change viaTS-2 (ΔG^‡ = −28.1 kcal mol⁻¹) produced the unstable intermediate INT-3 which afforded different reaction paths. The concerted Lossen rearrangement/N–O bond cleavage from INT-3 occurred viaTS-3 (ΔG^‡ = −26.9 kcal mol⁻¹) which demanded an energy barrier of 8.9 kcal mol⁻¹ (from INT-2 to TS-3) to give the intermediate INT-4 along with a considerable quantity of heat. The relatively elongated N–O¹ bond (1.48 Å vs. 1.42 Å in INT-0) in the geometry of INT-3 and the significantly elongated N–O¹ bond (2.41 Å) and shortened C¹–N bond (1.98 Å) in the transition state TS-3 suggest that the Lossen rearrangement was assisted by the pivalate group and the rhodium center. Alternatively, classic C–N bond reductive elimination viaTS-3ii (ΔG^‡ = −14.7 kcal mol⁻¹) involved a higher energy barrier of 21.1 kcal mol⁻¹ (from INT-2 to TS-3ii). Moreover, the Rh(III)–Rh(V)–Rh(III) reaction path involving an oxidative addition process from INT-3 was also ruled out owing to the relatively high free energies of INT-4i/TS-4i. After low-barrier isomerization viaTS-4, INT-4 was transformed into the isocyanate intermediate INT-5 from which the direct C–C bond formation/annulation occurred viaTS-5i (ΔG^‡ = −50.2 kcal mol⁻¹) and required a barrier of 22.4 kcal mol⁻¹ (from INT-5 to TS-5i). However, the coordination change viaTS-5/TS-6 led to a more favorable C–C bond formation reaction viaTS-7 (ΔG^‡ = −55.1 kcal mol⁻¹) which only needs an activation energy of 17.5 kcal mol⁻¹. Afterwards, the protonolysis reaction viaINT-9/TS-8 was followed by lactonization viaTS-9 (ΔG^‡ = −81.0 kcal mol⁻¹). Alternatively, the metal-free lactonization without the rhodium complex goes through TS-9i (ΔG^‡ = −60.2 kcal mol⁻¹) which is of a much higher barrier and can be ruled out.

Scheme 4 DFT calculations of the reaction pathways.

In order to shed light on the driving force of the Lossen rearrangement, we examined closely the geometry change along the intrinsic reaction coordinate (IRC) corresponding to TS-3 (see the ESI for details†). The results revealed that at the beginning the N–O¹ bond distance increases which seems to drive the C¹ atom attack on the N atom. The reaction goes through TS-3 and then the N–O¹ bond breaks which is followed by C¹–N bond formation and C¹–C² bond cleavage. This gives a chance for the O¹ atom to attack the positively charged C² atom. With the assistance of the pivalate group and the rhodium center, the Lossen rearrangement involves multiple σ-bond metathesis processes.

Conclusions

In summary, we have developed a rare four-step tandem reaction between acrylamides and 4-hydroxy-2-alkynoates to prepare novel furo[3,4-c]pyridine-1,4-diones. This unique tandem reaction consists of C–H activation, Lossen rearrangement, [4 + 2] annulation, and lactonization. The protocol features good functional group tolerance, obtainment of pure products by simple filtration, room temperature, and air compatibility. In addition, DFT calculations were conducted to shed some light on the reaction mechanism.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

Financial support from the Basic and Applied Basic Research Foundation of Guangdong Province (2021A1515110468), Shanghai Pujiang Program (21PJ1415800), Natural Science Foundation of Guangdong Province (2019A1515010935), High-level New R&D Institute (2019B090904008), High-level Innovative Research Institute (2021B0909050003), and NSFC (21877020 and 22007020) is gratefully acknowledged. We also thank Wei Zhang from the Zhongshan Institute for Drug Discovery for X-ray crystallographic analysis.

References

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Footnotes

† Electronic supplementary information (ESI) available. CCDC 2281784. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d3qo00909b

‡ These authors contributed equally.

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