English

• Spiro-cyclopropyl oxindole is a prevalent pharmacophore in medicinal chemistry due to its significant biological activities, including antiviral and anti-HIV properties [1-6], as well as its distinctive structural characteristics (Scheme 1). These interesting and important properties have made the synthesis of spirocyclopropyl oxindoles an attractive target for new synthetic method development. To our knowledge, most of the synthetic methods of these compounds started from either indolinone derivatives by transition-metal catalyzed cyclopropanation based on Simmons-Smith and carbene transfer reactions [7-14] or cyclopropane precursors via transition-metal (TM) catalyzed cyclization [15-21], which required multiple reaction steps to construct the indolinone and cyclopropane ring one by one under harsh conditions.

  Scheme 1

  

  Scheme 1.  Chemical structures of some bioactive spirocyclopropyl oxindole.

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  Due to the existence of the extremely strained cyclopropane containing a spiroquaternary carbon stereocenter, it is particularly challenging to synthesize such spirocompounds enantioselectively (Scheme 2a) [22-26]. Up to now, the synthetic methods for enantiopure P₁ have been well developed [27-35]. Bencivenni [27], Kanger [28], Yu [29], Feng [30-32], and other research groups [33-37] have made many outstanding contributions to the synthesis of such structures. Furthermore, there are rare publications (Aria [38], Xu [39], Zhou [40,41]) on the synthesis of enantiopure P₂, although such cyclopropane rings are very valuable, which are shown to alter drug binding activities [42] and improve metabolic stability [43]. And the aforementioned synthetic strategies of P2 suffer from such as lower enantioselectivity, harsh reaction conditions, costly and the requirement of active diazo partners. Considering these limitations, investigations for alternative strategies that avoid usage of explosive diazo compounds for the highly stereoselective synthesis of these scaffolds are still in great demand.

  Scheme 2

  

  Scheme 2.  The strategies for the synthesis of spirocyclopropyl oxindoles.

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  Additionally, we have seen an increase in diastereo- and enantioselective cyclopropanation procedures based on ammonium ylide in recent years [44-49]. For example, in 2003, Gaunt group reported a seminal and practical cyclopropanation process mediated by a tertiary amine via an ammonium ylide intermediate. One year later, the same group developed the enantioselective organocatalytic cyclopropanation reaction by using quinine or quinidine-based cinchona alkaloid catalysts (Scheme 2b) [44-46]. Furthermore, Waser group reported a variety of cycloaddition reactions using various ammonium ylide intermediates [47-49]. And the addition of sulfonium ylides to Michael acceptors is also a successful method for obtaining (chiral) cyclopropanes [50-53].

  Inspired by these leading research results, we envisioned that the spirocyclopropyl oxindole skeleton 3 or 4 might be constructed starting form bromoketones 1 and N-(2-iodoaryl)-N-methylacryl amides 2 (Scheme 2c), three new carbon-carbon bonds and two new cycles would be constructed efficiently by an atom- and step-economic one-pot procedure under mild conditions. The challenge for this novel reaction is the identification of suitable reaction conditions not only to form the desired products with excellent enantioselectivities and diastereoselectivities but also to prevent constructed starting from readily available linear α- the formation of olefin dimer byproducts [54-57], and make this two-step, one-pot reaction working properly.

  We initiated our work by investigating the reaction between bromo-1-phenylethanone 1a and N-(2-iodophenyl)-N-2-acrylamide 2a using triethylenediamine (DABCO) as tertiary amine in the presence of Pd(OAc)₂ for promoting the conversion of 2a to spirocyclopropyl oxindole 3a (Table 1). To our delight, a moderate yield could be achieved in the presence of NaOH at 80 ℃ (entry 1). The effect of temperatures, bases and palladium catalysts on the processes were evaluated next (entries 3–7). In general, the reaction was found to be promoted by K₂CO₃ as base and Pd(OAc)₂ as catalyst to furnish the product with 88% yield at 70 ℃ (entry 5). Then, focusing on the development of an asymmetric protocol, a variety of commercially available cinchona alkaloids A-H were examined (entries 8–11, see Supporting information for details). To our pleasant, the employment of quinine A provided the desired product 3a (1S, 2S) in 80% yield with 96% ee and 97:3 dr (entry 8). However, neither quinine A, quinidine B, nor hydroquinine C exhibited favorable catalytic performance in these reactions (entries 10 and 11). The further screening including the other cinchona alkaloids, solvents, reaction times etc., did not make any improvements (see Supporting information for details).

  Table 1

  

  Table 1.  Optimization of reaction conditions.^a

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  Entry	NR3 (1 equiv.)	Yield of trans 3a (%)	trans: cis b
  1c	DABCO	63	86:14
  2c	Et3N	36	85:15
  3d	DABCO	70	90:10
  4e	DABCO	27	93:7
  5	DABCO	88	95:5
  6f	DABCO	83	95:5
  7g	DABCO	73	95:5
  8	A	80 (96 ee)	97:3
  9h	A	25 (88 ee)	87:13
  10h	B	18 (−85 ee)	89:11
  11h	C	21 (80 ee)	87:13
  a Standard conditions: 1a (0.2 mmol) stirred with NR3 in DMF (1 mL) for 20 min. Then Pd(OAc)2 (0.1 equiv.), base (2 equiv.), 2a (0.22 mmol), 70 ℃ for 4 h. Yield of isolated product, ee values were determined by chiral HPLC analysis.
  b dr values were determined by 1H NMR.
  c NaOH, 80 ℃.
  d NaOH.
  e NaOAc.
  f PdCl2.
  g Pd2(dba)3.
  h NR3 (0.2 equiv.).

  With the optimized reaction conditions in hand, the scope of the bromide substrates was first investigated (Scheme 3). Diverse substituents R (aryl, alkyl or heterocycle) attached to ketone moiety in 1 could react with 2a to produce the desired products in moderate to excellent yields (3a, 3c-i, 3m-q) except for 3b and 3l, which produced the desired products in lower yields when DABCO was used as the tertiary amine. Additionally, α-bromoacetophenones 1 bearing electron-donating or electron-withdrawing phenyl substituent R were all effective, readily producing the corresponding products in moderate to excellent yields with outstanding dr (typically > 95:5). When quinine was utilized as the tertiary amine, the yields, ee and dr values were increased when R was replaced with an electron-rich phenyl group (3c, 3d vs. 3i, 3j). The absolute configurations of the major enantiomers were determined by X-ray crystallographic analysis of the corresponding spirocyclopropyl oxindoles 3i (CDDC: 1999581) and 3i' (CDDC: 2006798). We also investigated the effect of the substrate's steric hindrance on the reaction by modifying the spatial size of the R group (3l, 3m, 3n, 3o), and it was found that as steric hindrance increases, the reaction yields were declined rapidly. It's worth noting that 3o could still be formed in 38% yield in the absence of quinine. The desired product was not generated when ethyl 2-bromo-3-oxobutanoate, a diketone bromide with smaller steric hindrance, was employed in place of 1o. The above results imply that the steric hindrance and instability of the ammonium ylide intermediates are crucial elements influencing the reaction [58-60].

  Scheme 3

  

  Scheme 3.  Substrate scope for the α-carbonyl bromides. ^a DABCO instead of quinine. dr was determined by ¹H NMR.

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  To further expand the substrate scopes, a series of Michael receptors 2 were examined with the findings shown in Scheme 4. The products were readily formed for the substrates bearing either electron-withdrawing groups, electron-donating groups, or halogens (4b-4g). The protecting groups R³ (such as benzyl, allyl, or acetophenone) at the nitrogen atom of oxindole frame work in 2 were tested as well, and the corresponding products were generated in good yields with satisfactory ee values (4j, 4k, 4l, 4m, 4n). A gram-scale reaction was also performed, the desired product 4j was smoothly produced in 80% yield (1.41 g) with 96% ee from 1a (5 mmol) and 2j (5.5 mmol). It is worth noting that we demonstrated quinine can be recycled and reused four times with similar yields and ee. The average recovery rate for quinine could typically reach a respectable yield of 80% (for more details, see Supporting information). Additionally, alkyne 4o, heterocycles 4p and 4q were also tolerated in this process. It is necessary to note that the unprotected spirocyclopropyl oxindole 4i, which is regarded as a more attractive structure [4], was also produced from 2i in 63% yield with 94% ee.

  Scheme 4

  

  Scheme 4.  Substrate scope for the Michael receptors. ^a DABCO instead of quinine. ^b KOAc instead of K₂CO₃. ^c DABCO instead of quinine. KOAc instead of K₂CO₃. ^d 5 mmol scale.

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  Furthermore, several derivatization studies were carried out to explore the applicability of the products. As shown in Scheme 5, a ring-opening reaction of 4j by treating with Pd/C gave product 5 in 92% yield. The Wittig reaction, reduction, and ring opening/bromination produced versatile oxindoles 6, 7 and 8 in excellent yields, respectively. Finally, the nucleophilic additon with alkenyl Grignard reagent or alkyne gave the tertiary alcohol 9 or 10, respectively.

  Scheme 5

  

  Scheme 5.  Further transformations.

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  To further understand the reaction process, a variety of control experiments were carried out (Scheme 6A). Based on previous literature studies, we suspect that the 3-alkenyl indolone intermediate Ⅳ or cyclopropane intermediate Ⅴ may be involved in the process. Unfortunately, the intermediate Ⅳ could not be separated under standard conditions due to the instability of 3-alkenyl indolone Ⅳ, which readily forms dimers or higher-order polymers [54-56]. But it is feasible to produce Ⅳ via Peterson's isatin olefination [57] as illustrated in Scheme 6A-ⅰ, after extraction with dichloromethane, the solution containing Ⅳ was concentrated and used promptly for the cycloaddition method in the absence of palladium acetate, generating 3a in 52% yield with 95:5 dr. Then we utilized 2r to generate the stable intermediate Ⅳ' in order to further confirm the existence of the 3-alkenyl indolone intermediate. And it only took half an hour to generate Ⅳ' from 2r, and stirring Ⅳ' with 1a for 4 h gave the cyclopropane product 4r in 38% yield without using palladium acetate, showing that the cyclopropanation may be a rate-limiting step which is also consistent with previous reports (Scheme 6A-ⅱ) [58]. Additionally, It was noted that the mixtures of Ⅴ (E: Z = 1:1) could be generated in 60% yield under standard conditions without Pd(OAc)₂. However, the final product 3a could not be obtained when we heated Ⅴ with Pd(OAc)₂ at 70 ℃, which indicated that the reaction may not undergo a transition-metal-promoted intramolecular cyclopropyl methine C(sp³)-H functionalization process (Scheme 6A-ⅲ) [22-26,61,62-64].

  Scheme 6

  

  Scheme 6.  Mechanism study.

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  In addition, density functional theory (DFT) calculations were performed in Gaussian 16 [65]. The reaction pathway is calculated to involve two key steps: (a) Michael addition of the ammonium ylide IN2 to the alkene IN4, leading to the intermediate IN3; and (b) cyclopropanation of IN3 leading to the final product 3a. The pathway involving quinine is displayed in Scheme 6B. Both of these two steps are with Gibbs free energy activation barriers of 13-17 kcal/mol, achievable at the given reaction temperature. And among these two steps, the cyclopropanation step is nonreversible. Besides, our calculations suggested that the Gibbs free energies for the transition state (TS1-Qu) of the Michael addition step and that (TS2-Qu) of the cyclopropanation step leading to the enantiomer (1R, 2R)−3a are indicating the formation of the (1R, 2R)−3a as the major enantiomer. The decreased energy of TS1-Qu is found to be attributed to the hydrogen bonding in the oxindole moiety, while the increased energy for TS1-Qu-ee could be derived from the steric hindrance. Therefore, our computational studies are in consistent with the experimental observation of the high stereo and enantioselectivity in this reaction.

  Based on the early findings mentioned above and in combination with the previous reports [44-57,58-60,66-68], we then proposed a plausible mechanism (Scheme 6C). Initially, the quaternary ammonium salt Ⅰ could be formed when the tertiary amine 4 displaces the bromide in 1a. The ammonium ylide Ⅱ would be generated by deprotonation with a mild base, an in-situ Heck reaction could product the alkene Ⅳ [54-57], and the ammonium ylide Ⅱ would be conjugated with Ⅳ to give Ⅲ [44-53]. Finally, cyclization slowly generates the cyclopropane 3a to form Ⅲ [58-60] and release the tertiary amine 4.

  In conclusion, a practical one-pot asymmetric cyclopropanation process mediated by recyclable (chiral) tertiary amine catalyst was developed. The valuable spirocyclopropyl oxindole cores with two adjacent stereo centres were prepared efficiently with high dr and ee from readily available substrates via an ammonium ylide intermediate. We anticipate that this ammonium ylide-mediated asymmetric annulation procedure would be employed in a number of ways to generate valuable and diverse enantiopure cyclopropane.

  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.

  CRediT authorship contribution statement

  Min Liu: Writing – original draft, Methodology, Investigation, Data curation, Conceptualization. Di Wang: Writing – original draft, Data curation. Zenghui Ye: Writing – original draft, Validation, Data curation. Donghao Jiang: Formal analysis, Data curation. Bencan Tang: Writing – original draft, Formal analysis. Yanqi Wu: Supervision, Project administration, Formal analysis. Fengzhi Zhang: Writing – review & editing, Supervision, Conceptualization.

  Supplementary materials

  Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.cclet.2025.110923.

  
  
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• 

  Scheme 1  Chemical structures of some bioactive spirocyclopropyl oxindole.

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  Scheme 2  The strategies for the synthesis of spirocyclopropyl oxindoles.

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  Scheme 3  Substrate scope for the α-carbonyl bromides. ^a DABCO instead of quinine. dr was determined by ¹H NMR.

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  Scheme 4  Substrate scope for the Michael receptors. ^a DABCO instead of quinine. ^b KOAc instead of K₂CO₃. ^c DABCO instead of quinine. KOAc instead of K₂CO₃. ^d 5 mmol scale.

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  Scheme 5  Further transformations.

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  Scheme 6  Mechanism study.

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  Table 1.  Optimization of reaction conditions.^a

  Entry	NR3 (1 equiv.)	Yield of trans 3a (%)	trans: cis b
  1c	DABCO	63	86:14
  2c	Et3N	36	85:15
  3d	DABCO	70	90:10
  4e	DABCO	27	93:7
  5	DABCO	88	95:5
  6f	DABCO	83	95:5
  7g	DABCO	73	95:5
  8	A	80 (96 ee)	97:3
  9h	A	25 (88 ee)	87:13
  10h	B	18 (−85 ee)	89:11
  11h	C	21 (80 ee)	87:13
  a Standard conditions: 1a (0.2 mmol) stirred with NR3 in DMF (1 mL) for 20 min. Then Pd(OAc)2 (0.1 equiv.), base (2 equiv.), 2a (0.22 mmol), 70 ℃ for 4 h. Yield of isolated product, ee values were determined by chiral HPLC analysis.
  b dr values were determined by 1H NMR.
  c NaOH, 80 ℃.
  d NaOH.
  e NaOAc.
  f PdCl2.
  g Pd2(dba)3.
  h NR3 (0.2 equiv.).

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