Synthesis of [4.6] spirocarbocycles: a base-promoted ring-expansion and subsequent I₂-mediated regioselective spirocyclization protocol

Abstract

An efficient protocol for the synthesis of [4.6] spirocarbocycles has been developed. This process is realized through the sequential K₂CO₃-promoted C–C σ-bond cleavage of cyclic ketoesters and an I₂-mediated selective 5-exo spirocyclization reaction at room temperature. Atom economy, C–C σ bond cleavage, regioselective spirocyclization, and mild and transition-metal-free reaction conditions are the advantages of this procedure.

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Introduction

Spirocyclic compounds have attracted more and more attention because they are common structures existing in a number of bioactive natural products and privileged ligand scaffolds;¹ thus the construction of these spirocycles is of great significance in synthetic chemistry.² So far, many approaches have been developed to generate [4.4] or [4.5] spirocycles.³ [4.6] spirocycles are important structural units, distributed in the structures of some bioactive molecules and natural products (Fig. 1),⁴ attracting a great deal of attention. Of particular interest are [4.6] spirocarbocycles containing two rings of all carbon atoms and bearing a quaternary carbon, which are difficult to prepare, and such [4.6] spirocarbocycles are seldom reported in the literature. There are several ways for the synthesis of [4.6] spirocarbocycles.⁵

Fig. 1 Examples of bioactive spirocycles containing seven-membered rings.

One of the most straightforward and efficient methods is transition metal-catalyzed reactions, which are very appealing synthetic strategies to generate functionalized spirocyclic scaffolds. Transition metals such as Ru,^3e Pd,^6a–f Au,^6g,h and Ni^5c have been typically employed. For instance, in 2021, Tang and coworkers described the first enantioselective α-carbonylative arylation catalyzed by palladium, affording a series of spiro β,β′-diketones containing various ring sizes in high yields, in which one example of spiro[4,6] tetracyclic β,β′-diketone was prepared^6f (Scheme 1a). In addition, Brønsted acids and nonmetal organocatalysts also work well in spirocyclization.^5a,b,g,7 In 2009, Tu and coworkers constructed spirocyclic diketones bearing chiral all-carbon quaternary stereocenters for the first time by an unprecedented organocatalytic enantioselective vinylogous α-ketol rearrangement reaction. However, there are only two examples of [4.6] spirocarbocycles reported^7b (Scheme 1b). In 2022, Wang and coworkers reported a visible-light-mediated [3 + 2] cycloaddition of arylcyclopropylamines with olefins, constructing some structurally diverse cyclopentane-based spiro[4.n] skeletons, among which a spiro[4,6] skeleton was forged.⁸ In spite of the advances, these reactions were mainly restricted to the synthesis of [4.4] or [4.5] spirocycles, and only a few examples rather than a series of [4.6] spirocarbocycles have been constructed in the contexts. Besides, some reactions suffer from the complicated pre-preparation of precursors and the use of noble metals. The systematic synthesis of [4.6] spirocarbocycles has not been reported to the best of our knowledge. Thus, the development of new synthetic approaches for the efficient and systematic construction of all-carbon [4.6] spirocyclic skeletons under non-transition metal-catalyzed reaction conditions is in great demand.

Scheme 1 Approaches for synthesizing [4.6] spirocarbocycles.

Recently, our group has reported the base-induced C–C σ-bond cleavage reaction of β-diketones with alkynones.⁹ It provides a platform where various seven-membered ring compounds with multifunctional groups could be synthesized in a highly efficient way. We envisioned that when alkynones bearing an ortho-alkynyl-substituted aryl ring are used, the newly formed seven-membered ring may react with the tethered triple bond somehow to synthesize [4.6] spirocarbocycles (Scheme 1c), which are otherwise difficult to prepare. As part of our continuing interest in the spirocyclization reaction,¹⁰ herein, we report a base-promoted C–C cleavage reaction of cyclic β-ketoesters with aryl-fused 1,6-diyn-3-ones and a subsequent I₂-mediated spirocyclization reaction, furnishing a series of single (E)-benzo-fused iodospiro[4.6] tricyclic β,β′-diketones with multiple functional groups.

Results and discussion

To ensure the optimized conditions for this reaction, aryl-fused 1,6-diyn-3-one 1a and ethyl 2-oxocyclopentanecarboxylate 2a were used as model substrates and the experimental conditions were explored (Table 1). We initially chose DMF as the solvent, K₂CO₃ as the base, and 2.0 equiv. of I₂ to try out our ideas. It is interesting that only the 5-exo cyclization product 3a was obtained in 83% yield (Table 1, entry 1), and no 6-endo product was detected.¹¹ The structure of 3a was confirmed by X-ray crystallography.¹² Further study of the solvent effect using DMSO and CH₃CN showed that DMSO was the optimal candidate (Table 1, entries 2 and 3 vs. entry 1). As a polar solvent is favorable for the ionic reaction, and the stronger the polarity, the more favorable for the formation of products. Stimulated by the positive result, the screening of other bases was next performed, including Cs₂CO₃, K₃PO₄ and DBU, which all showed inferior reactivity compared with K₂CO₃ (Table 1, entries 4–6 vs. entry 2). It is possible that the organic base DBU was less favorable for the ring-expansion reaction. Decreasing or increasing the amount of base all resulted in lower efficiency with yields ranging from 81% to 83% (Table 1, entries 7 and 8). Also, the reaction was attempted with varying amounts of 2a and 2.0 equiv. were the best for the reaction (Table 1, entries 9 and 10 vs. entry 2). Subsequently, adjustments were made to the iodine loading as well as other halide sources and no increase in the yield of product 3a was observed (Table 1, entries 11–13 vs. entry 2). When the reaction was carried out at 40 °C, the yield of 3a was reduced to 75%, though the reaction time was shortened to only 1.5 h (Table 1, entry 14). It seems that the atmosphere has some influence on the reaction, for which 3a could be obtained in 91% and 67% yields under nitrogen and oxygen atmospheres, respectively (Table 1, entries 15 and 16). Some unidentified complexes appeared when the reaction was conducted under O₂. Thus, the optimal reaction conditions for the synthesis of 3a included 2.0 equiv. of K₂CO₃ and 2.0 equiv. of I₂ at room temperature in DMSO under N₂.

Table 1 Optimization studies for the synthesis of 3a ^a

Entry	Solvent	Base. (2.0 equiv.)	Halide source (2.0 equiv.)	Time (h)	Yield^b (%)
a Reaction conditions: 1a (0.2 mmol), solvent (2.0 mL), 2a (2.0 equiv.), rt, air. b Isolated yields. c 1.5 equiv. of K2CO3. d 2.5 equiv. of K2CO3. e 1.5 equiv. of 2a. f 2.5 equiv. of 2a. g 1.5 equiv. of I2. h 2.5 equiv. of I2. i 40 °C. j N2. k O2.
1	DMF	K2CO3	I2	4.0	83
2	DMSO	K2CO3	I2	2.5	88
3	CH3CN	K2CO3	I2	17.0	73
4	DMSO	Cs2CO3	I2	2.5	86
5	DMSO	K3PO4	I2	4.0	76
6	DMSO	DBU	I2	12.0	36
7^c	DMSO	K2CO3	I2	2.5	83
8^d	DMSO	K2CO3	I2	2.5	81
9^e	DMSO	K2CO3	I2	2.5	86
10^f	DMSO	K2CO3	I2	2.5	77
11^g	DMSO	K2CO3	I2	2.5	84
12^h	DMSO	K2CO3	I2	2.5	88
13	DMSO	K2CO3	NIS	2.5	59
14^i	DMSO	K2CO3	I2	1.5	75
15^j	DMSO	K2CO3	I2	2.5	91
16^k	DMSO	K2CO3	I2	2.5	67

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With the optimized conditions in hand, the generality and limitation of this one-pot tandem reaction were explored. As shown in Table 2, a variety of substrates 1 were tested, and the corresponding products 3a–3v were smoothly synthesized in 74–97% yields. It is clear that both electron-withdrawing and electron-donating groups on the aromatic ring (R²) of 1 were well tolerated, resulting in the corresponding products 3a–3j in excellent yields (84–91%). Expectedly, substrates having 3-OMe and 4-Cl as R³ (1k and1l) were well incorporated, with products 3k and 3l being formed in 92% yield and 82% yield, respectively. Besides, substituents on the aromatic ring (R¹) of 1 were also explored, with the strong electron-withdrawing group –CF₃ affording 3m in 97% yield and the electron-donating group –OMe generating 3n in 84% yield. Meanwhile, the substrates containing other aryl groups such as naphthyl and thienyl groups (1o and1p) were also compatible with this reaction, affording the desired products in good to excellent yields (3o and3p). Methyl 2-oxocyclopentanecarboxylate also reacted smoothly to afford 3q in 87% yield. Interestingly, the 5-membered cyclic substrates could even extend to α-cyanoketone and β-diketone, affording 3r and 3s in 84% yields. Besides, it is worth mentioning that the reaction using 1,3-dichloro-5,5-dimethyl hydantoin could proceed smoothly as well, offering 3t in 81% yield. It showed that the chlorinated product could also be obtained. Finally, alkyl-substituted alkyne derivatives (1q and1r) were tested and the corresponding products 3u and 3v could be obtained in 83% and 74% yields, respectively.

Table 2 Substrate scope of the reaction^a

a Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), K₂CO₃ (0.4 mmol), DMSO (2.0 mL), I₂ (0.4 mmol), rt, N₂, isolated yields. b 1,3-Dichloro-5,5-dimethyl hydantoin was used as the halide source.

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We next explored the synthetic utility of the synthetic strategies; a 1 mmol scale reaction was performed and we obtained the expected product 3a in 90% yield (Scheme 2).

Scheme 2 1 mmol scale reaction.

To further demonstrate the synthetic application of the iodine-substituted [4.6] spirocarbocycles in organic synthesis, several transformations of 3a were carried out (Scheme 3). Sonogashira coupling and Suzuki coupling could be performed and the corresponding products 7 and 8 were obtained in 85% and 86% yields, respectively (Scheme 3, eqn (1) and (2)). The C–S coupling reaction of 3a with 4-methylbenzenethiol 6 proceeded successfully in 58% yield as well (Scheme 3, eqn (3)).

Scheme 3 Synthetic transformation of compound 3a.

To clarify the reaction mechanism, we carried out the radical trapping experiment by the addition of 2.0 equiv. of butylated hydroxytoluene (BHT) under the standard conditions, and almost negligible influence on the reaction yield was observed, indicating that the reaction probably did not undergo a radical pathway (Scheme 4, eqn (1)). The reaction of 1a with 2a was carried out under the optimized reaction conditions for the first step and product 1aa was obtained in 89% yield after 1.5 h (Scheme 4, eqn (2)). When the ring-expansion product 1aa was treated with the general reaction conditions for the second step, product 3a could be obtained in 96% yield, indicating that 1aa was the intermediate of the reaction (Scheme 4, eqn (3)).

Scheme 4 Mechanism investigation.

Based on the above experimental results and previous reports,^9,13 a plausible reaction mechanism has been proposed in Scheme 5. Initially, 1a was attacked by β-ketoester 2a to afford intermediate B in the presence of a base, which undergoes an intramolecular nucleophilic addition/ring-opening to generate the formal alkyne insertion product D. Tautomerization of D leads to product 1aa. Then, the triple bond of 1aa is activated by iodine to produce iodonium E. Upon proton abstraction with a base, E undergoes an intramolecular nucleophilic attack to afford the target compound 3a.

Scheme 5 Plausible reaction mechanism for the formation of 3a.

Conclusions

In summary, we have developed an efficient and atom-economical protocol for the one-pot synthesis of iodine-substituted [4.6] spirocarbocycles through the sequential C–C σ-bond cleavage and iodine-mediated spirocyclization reaction. A range of substituted aryl-fused 1,6-diyn-3-ones 1 were tolerated to prepare the corresponding products 3 in good to excellent yields, and alkenyl iodide may serve as a useful handle for a wide range of structurally diverse compounds.

Data availability

The data supporting this article have been included as part of the ESI.†

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We thank the National Natural Science Foundation of China (Grant No. 21871087) and the Open Research Fund of the Key Laboratory of Polar Materials and Devices, Ministry of Education for financial support.

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12. CCDC 2323439 (3a) contains the crystallographic data for this paper. For details concerning the crystal structure of 3a, see the ESI† as well.
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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures and characterization data of all compounds. CCDC 2323439 (3a). For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d4qo01632g

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