Rh(Ⅲ)-Catalyzed annulative aldehydic C-H functionalization for accessing ring-fluorinated benzo[<i>b</i>]azepin-5-ones

Citation: Qiuyun Li, Kelu Yan, Yannan Zhu, Gang Qi, Yining Wang, Wen-Juan Hao, Bo Jiang. Rh(Ⅲ)-Catalyzed annulative aldehydic C-H functionalization for accessing ring-fluorinated benzo[b]azepin-5-ones[J]. Chinese Chemical Letters, 2023, 34(6): 108014. doi: 10.1016/j.cclet.2022.108014 shu

Rh(Ⅲ)-Catalyzed annulative aldehydic C-H functionalization for accessing ring-fluorinated benzo[b]azepin-5-ones

English

Rh(Ⅲ)-Catalyzed annulative aldehydic C-H functionalization for accessing ring-fluorinated benzo[b]azepin-5-ones

a.
School of Chemistry and Chemical Engineering, Yancheng Institute of Technology, Yancheng 224051, China
b.
Key Laboratory of Life-Organic Analysis of Shandong Province, School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, China
c.
School of Chemistry & Materials Science, Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, Jiangsu Normal University, Xuzhou 221116, China
^* Corresponding authors.
E-mail addresses: liqiuyun@ycit.edu.cn (Q.Y. Li). yining.wang@ycit.cn (Y.N. Wang). jiangchem@jsnu.edu.cn (B. Jiang).
Received Date: 26 August 2022
Accepted Date: 20 November 2022
Revised Date: 11 November 2022
Available Online: 15 June 2023

Abstract: A new Rh(Ⅲ)-catalyzed aldehydic C-H activation/[4 + 3] annulation cascade of N-sulfonyl-2-aminobenzaldehydes with gem-difluorocyclopropenes is reported for the first time, and used to produce a range of hitherto unreported precedented β-monofluorinated benzo[b]azepin-5-ones with good yields and complete regioselectivity. This approach features a broad substrate scope, good functional group tolerance, and high regioselectivity, which may include Rh(Ⅲ)-catalyzed aldehydic C−H activation, tandem site-/regioselective insertion, defluorinated ring-scission, and 1, 2-elimination.

Key words:

A new Rh(Ⅲ)-catalyzed aldehydic C-H activation/[4 + 3] annulation cascade of N-sulfonyl 2-aminobenzaldehydes with gem-difluorocyclopropenes is reported for the first time, and used to produce a range of hitherto unreported precedented β-monofluorinated benzo[b]azepin-5-ones with good yields and complete regioselectivity.

The past two decades have witnessed the rapid development of Rh(Ⅲ)-catalyzed C(sp²)−H activation reactions as powerful synthetic tools for fabricating valuable medicinally active substances and natural products with step- and atom-economy [1-5]. Among them, Rh(Ⅲ)-catalyzed annulative C(sp²)−H functionalization has been recognized as a versatile platform for forming heterocyclic amides or ketones. A survey of the literature shows that there are two main modes in the direct activation of C(sp²)−H bonds for the synthesis of these compounds, one is Rh(Ⅲ)-catalyzed annulative amide-oriented C(sp²)−H activation with various coupling reagents toward lactam derivatives, which include [3 + 3] [6], [4 + 1] [7-15,22], [4 + 2] [16-33], or [4 + 3] [34-38] annulations (Scheme 1a), and the other is Rh(Ⅲ)-catalyzed annulative aldehydic C(sp²)−H activations with different coupling reagents by using a β-amino group as the directing group [39], providing a direct protocol for heterocyclic ketone synthesis. However, the latter only allows [4 + 1] [40,41] and [4 + 2] [42,43] annulation processes for constructing normal 5- and 6-numbered N-heterocyclic ketones; in sharp contrast, a catalytic [4 + 3] annulation of these C—H substrates with three-carbon donors to give 7-numbered benzannulated N-heterocyclic ketones has rarely been explored.

Scheme 1

Scheme 1. Profiles of Rh(Ⅲ)-catalyzed C(sp²)−H activation.

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Benzannulated medium-sized N-heterocycles are widely distributed in bioactive natural products and pharmaceutical agents [44]. In particular, representing a unique class of seven-member N-heterocycles, compounds featuring a benzoazepinone skeleton [45-49], such as benzazepinediones [46], Tolvaptan [47] and Lotensin [48], demonstrate a wide range of biological activities (Fig. 1). On the other hand, organic molecules with fluorine or fluorine-containing groups usually enhance the solubility and lipophilicity to improve membrane permeability and bioavailability, especially those with ring-fluorinated heterocycles [50-60]. Consistent with these findings, we think that developing new methods for synthesizing compounds incorporating both benzoazepine and fluoro fragments is a required technology. This can be understood, on the one hand, by the existence of such a skeleton in natural products with biological activities [45-49], and on the other hand, by the potential of using these molecules for downstream studies in chemical biology and medicinal chemistry. Very recently, Zhou [61] and He [62] independently reported an elegant rhodium-catalyzed [4 + 3] annulation reaction of N-methoxybenzamides and gem–difluorocyclopropenes, leading to the straightforward formation of ring-fluorinated 2H-azepin-2-ones (Scheme 1c). Inspired by these impressive reports [61,62] and as part of ongoing efforts in developing metal catalysis [63-67], we questioned whether Rh(Ⅲ)-catalyzed aldehyde C(sp²)−H activation could be harnessed to establish a new [4 + 3] annulation with gem–difluorocyclopropenes for the synthesis of ring-fluorinated benzo[b]azepin-5-ones. Unfortunately, synthesizing this skeleton faces several challenges such as precise site-selective activation, control of the regiochemistry and unfavorable transannular interactions of medium-sized rings. To our delight, a Rh(Ⅲ)-catalyzed [4 + 3] annulation of N-sulfonyl-2-aminobenzaldehydes with gem-difluorocyclopropenes proceeded smoothly through an aldehydic C-H activation process, leading to the formation of the hitherto unreported β-monofluorinated benzo[b]azepin-5-ones in good yields, with complete regiochemistry control (Scheme 1d). Herein we elaborate on this attractive observation.

Figure 1

Figure 1. Selected examples of bioactive benzoazepines.

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We commenced our investigation on the reaction with N-(2-formylphenyl)benzenesulfonamide (1a) and (3, 3-difluorocycloprop-1-en-1-yl)benzene (2a) in the presence of 5 mol% of [Cp*RhCl₂]₂ and 2.0 equiv. of CsOAc in DCE at 60 ℃ under N₂ atmosphere (Table 1). A preliminary attempt gave desired product 3a in 20% yield, and its structure was unambiguously confirmed by NMR spectra and single-crystal X-ray diffraction analysis (for details, see Supporting information). Further studies to improve the efficiency of this transformation were conducted. Swapping R substituents on the nitrogen atom from 4-methylbenzenesulfonyl to benzenesulfonyl (1b), 4-nitrobenzenesulfonyl (Ns, 1c) and t-butyloxy carbonyl (1d) revealed that 4-nitrobenzenesulfonyl 1c proved to be the better choice, giving 3a in 53% yield. The reaction did not work when free 2-aminobenzaldehyde (1e) was used. Subsequently, the reaction parameters, including the catalyst, solvent and base, were examined, as shown in Table 1. Other transition metal catalysts such as [Cp*IrCl₂]₂, [(p-cymene)RuCl₂]₂, Cp*Co(CO)I₂ and Cp*Rh(OAc)₂ were tested in the reaction of 1c with 2a (entries 1–4). The results indicated that the former three completely suppressed the reaction process, and no desired product was observed. Delightedly, the latter demonstrated a higher catalytic performance, enhancing the yield to 74% (entry 4). The yield was slightly increased when DCE was replaced with DCM, delivering product 3a in 77% yield (entry 5). Next, the effect of the solvent was further evaluated by exploiting several other solvents such as MeOH, DMF, dioxane, toluene, xylene, and CH₃CN (entries 6−11). However, none of these attempts gave positive results. The use of other bases such as NaOAc, KOAc, Cs₂CO₃ and CsF could make the reaction work, but less efficient than CsOAc (entries 12−15 vs. entry 5). Decreasing the amount of CsOAc to 1.0 equiv. resulted in a higher yield of 3a (85%, entry 16). Further reducing the amount of CsOAc is harmful for the reaction (entry 17). Without the Rh catalyst or the base, the reaction was ineffective (entries 18 and 19).

Table 1

Table 1. Optimization of reaction conditions.^a

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With the optimized reaction conditions in hand, we set out to examine the scope and limitations of this Rh(Ⅲ)-catalyzed [4 + 3] annulation by exploiting a variety of N-sulfonyl 2-aminobenzaldehydes with gem-difluorocyclopropenes. As shown in Scheme 2, first, the effects of changing the electronic properties and positions of substituents in the arene ring of gem-difluorocyclopropenes were investigated by repeatedly reacting with substrate 1c. Both electron-donating (methyl 2b-2d, tert-butyl 2e, methoxy 2f, and phenyl 2g) and electron-withdrawing (fluoro 2h, chloro 2i-2k and bromo 2l) groups located at various positions (ortho, meta, or para) of the phenyl ring were all compatible with the standard conditions, furnishing corresponding products 3b-3l in 63%−82% yields with complete regioselectivity. Of these functional groups, the more sterically demanding o-chloro and o-methyl substituents were examined to prove the compatibility of this transformation with high efficiency. Besides, 2-naphthyl group-substituted gem-difluorocyclopropene 2m was also feasible, giving the desired benzo[b]azepin-5-one 3m in 70% yield. Then, the scope of N-sulfonyl-2-aminobenzaldehydes was also investigated in this catalytic [4 + 3] annulation. In detail, various commonly encountered substituents, such as electronically rich (methyl, 1f−1g and methoxy, 1h and 1q), and poor (fluoro, 1i−1j; chloro, 1k−1l; bromo, 1m−1n; trifluoromethyl, 1o; nitro, 1p) at the 4- and 5-positions of the arene ring, could successfully participate in the [4 + 3] annulation, producing the corresponding benzo[b]azepin-5-ones 3n-3y in 70%−87% yields. Even challenging cases where the trifluoromethyl and nitro functionalities are strong electronically deficient groups at the 4-position were functional for this catalytic protocol, providing products 3w and 3x in 79% and 72% yields, respectively. Alternatively, disubstituted 2-aminobenzaldehyde 1q proved to be applicable (3y, 73%). Furthermore, naphthyl counterpart 1q was also suitable for this reaction, enabling the annulation to access 3z in 81% yield. Regrettably, the reaction of N-sulfonyl 2-aminobenzaldehydes bearing a methyl substituent at the 3-, or 6-position was unsuccessful, probably due to steric effects.

Scheme 2

Scheme 2. Substrate scope for the synthesis of products 3. Reaction conditions: 1 (0.15 mmol), 2a (0.18 mmol), Cp*Rh(OAc)₂ (8.0 mol%), CsOAc (0.15 mmol), DCM (1.5 mL), 60 ℃, N₂ atmosphere, 12 h, isolated yield. For 3p and 3y, Ts instead of Ns, 24 h.

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Further investigations were then performed to gain more insight into the mechanism of this transformation (Scheme 3). First, attempts to trace aldehydic C(sp²)-H activation of 1c by deuterium incorporation showed 14% deuteration at the aldehyde C-H bond (Scheme 3a), suggesting that amino-directed aldehyde C(sp²)−H activation may be involved in the reaction. Subsequently, the deuterium labeling experiment was conducted to display a significant kinetic isotope effect (KIE, KIE = 2.9) in an intermolecular competitive coupling of an equimolar mixture of 1c and [D]−1c with 2a (Scheme 3b), demonstrating that the rupture of C(sp²)-H bonds on the aldehyde fragment occurs at the rate-determining step. To understand the reactivity of N-sulfonyl 2-aminobenzaldehydes and gem-difluorocyclopropenes, two intermolecular competitive reactions were performed: 1) a competition reaction of 1f and 1p exclusively gave 3x in 65% yield with a trace amount of 3n (Scheme 3c), implying that the N-sulfonyl 2-aminobenzaldehyde with an electron-donating substituent is less reactive; and 2) the other competition reaction of 2f and 2h generated products 3f and 3h in almost the same yields (Scheme 3d), suggesting that there are no apparent electronic effects in gem-difluorocyclopropenes.

Scheme 3

Scheme 3. Mechanistic studies.

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Based on the literature survey [40-43] and our experimental observations, a plausible mechanism for this [4 + 3] annulation is outlined in Scheme 4. Initially, ligand exchange with N-sulfonyl 2-aminobenzaldehyde 1 via a similar concerted metallation-deprotonation (CMD) pathway affords rhodacycle A [40-43], owing to the steric factor and the stability of the intermediate, which prefers to undergo regioselective migratory insertion into gem-difluorocyclopropene 2 to deliver intermediate B without observation of its regioisomer B'. Then two successive ligand exchanges of B with HOAc release intermediate D and regenerate catalytically active Cp*Rh(OAc)₂ species for the next catalytic cycle. Subsequently, intermediate D undergoes defluorinated ring-opening of cyclopropane intermediate E to provide seven-membered intermediate F, followed by 1, 2-elimination [42] to give product 3 in the presence of the base. Although the detailed reaction process is not clear, the synergistic effect of rhodium and CsOAc is believed to accelerate the formation of product 3 via defluorinated ring-opening and 1, 2-elimination.

Scheme 4

Scheme 4. Proposed mechanism for forming product 3.

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In conclusion, by taking advantage of the unique reactivity of gem-difluorocyclopropenes and N-sulfonyl-2-aminobenzaldehydes, Rh(Ⅲ)-catalyzed aldehydic C−H activation/[4 + 3] annulation was developed, and used to produce a wide range of unreported β-monofluorinated benzo[b]azepin-5-ones with good yields and complete regioselectivity in one-pot manner. This redox-neutral protocol holds a broad substrate scope, good functional group tolerance, and high regioselectivity, which affords a conceptually new synthesis strategy capable of the integration of C−H activation with fluorine chemistry. Further investigation and application of these fluorinated 7-membered heterocycles is underway in our laboratory.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

We are grateful for financial support from the school-level research projects of Yancheng Institute of Technology (No. xjr2020044) and the National Natural Science Foundation of China (Nos. 22101151 and 21971090)

Supplementary materials

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.cclet.2022.108014.
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Scheme 1 Profiles of Rh(Ⅲ)-catalyzed C(sp²)−H activation.

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Figure 1 Selected examples of bioactive benzoazepines.

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Scheme 2 Substrate scope for the synthesis of products 3. Reaction conditions: 1 (0.15 mmol), 2a (0.18 mmol), Cp*Rh(OAc)₂ (8.0 mol%), CsOAc (0.15 mmol), DCM (1.5 mL), 60 ℃, N₂ atmosphere, 12 h, isolated yield. For 3p and 3y, Ts instead of Ns, 24 h.

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Scheme 3 Mechanistic studies.

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Scheme 4 Proposed mechanism for forming product 3.

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Table 1. Optimization of reaction conditions.^a

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