A General Way to Spiro-Annulated 2-Benzoxepines via Rh₂(esp)₂-Catalyzed [5+2] Cycloaddition of Diazo Arylidene Succinimides to Ketones

Abstract

The formation of spirocyclic 2-benzoxepines by Rh₂(esp)₂-catalyzed decomposition of diazo arylidene succinimides in the presence of ketones was investigated. This transformation, which is a formal [5+2] cycloaddition of styryl rhodium carbenes to the carbonyl group, occurs in high yields under mild conditions, with high carbonyl substrate tolerance and diastereoselectivity. The developed general method opens access to rare spiro (hetero)cyclic scaffolds with great potential in drug discovery.

Spiro (hetero)cyclic motifs are widely represented in various natural compounds[1] and are of great importance in medicinal chemistry.[2] The high demand for spirocycles in drug discovery[3] can be explained by their three-dimensional spatial structure [as opposed to planar (hetero)aromatic rings], which allows peripheral groups to be located in the space required for binding to target proteins. At the same time, they possess a successful combination of conformational rigidity and flexibility, which allows, on the one hand, to avoid entropy losses during binding, and, on the other hand, to provide fine tuning of the geometry of the molecule for the most efficient interaction with the protein’s active site.

However, the construction of a spirocyclic fragment of a given geometry, as a rule, is associated with certain difficulties: a large number of synthetic steps, the use of non-conventional procedures, and the need to control the configuration of multiple stereocenters. In recent years, numerous effective approaches to spirocyclic scaffolds have appeared in the literature. One of the promising ones is the use of diazo reagents at the key step of the spirocycle construction. This approach opens up access to a wide range of spiro­cyclic frameworks, due to the remarkable variety of chemical transformations of the diazo group.[4]

Diazo arylidene succinimides (DAS, 1; Scheme [1]) represent one of the interesting and unique classes of diazocarbonyl compounds from the point of view of structure and reactivity. Recently it was shown that they can be used to synthesize spirocyclic tetrahydropyrans (as a result of the formal introduction of carbenoid into the C–O bond of tetrahydrofuran),[5] spiro-oxiranes (via Ag-catalyzed epoxidation of aldehydes),[6] as well as 2-benzazepines[7] and 2-benz­oxepines[8] (under Rh(II)-catalyzed decomposition of DAS in the presence of nitriles and aldehydes, respectively). The aim of this work is to study the interaction of DAS with ketones. The reaction of formal [5+2] cycloaddition of DAS to cyclic ketones opens access to spirocyclic 2-benzoxepines 2 (Scheme [1]).

Methods for the preparation of spiro-2-benzoxepines are very scarcely presented in the literature. Until now, 2-benzoxepine derivatives spiro-annelated at position 1 with three-, four-, and seven-membered rings have not been known. Some examples of the preparation of 2-benzoxepines spiro-annelated with six-membered rings are described. They include the coupling reaction of α-stanno- or α-boro-modified dihydropyrans with 3-(2-bromophenyl)propanol followed by cyclization[9] [10] (Scheme [2a]); addition of a lithium derivative obtained from 2′-bromocinnamaldehyde acetal to the carbonyl group of 4-piperidone, followed by the formation of a spirocyclic acetal[11] (Scheme [2b]); multistep conversion of 1-cyanobenzoxepine into amino alcohol followed by the formation of spiro-N,O-acetal upon condensation with aldehydes[12] (Scheme [2c]); an unusual three-component reaction between 1-phenyldihydroisoquinoline, benzaldehyde, and phenyl vinyl ketone, catalyzed by a cobalt(III) complex[13] (Scheme [2d]). The only example of the preparation of 2-benzoxepines spiro-annelated with a five-membered ring, as a result of the decomposition of vinyl diazo compounds in the presence of indan-1,2,3-trione, was reported by Hamaguchi and Tamura[14] (Scheme [2e]).

All of the above methods, as a rule, are multistep, time consuming, and are characterized by a limited substrate scope. Thus, in the scientific literature, there has been no convenient and general method for the preparation of 1-spiro-2-benzoxepines with the ability to vary the size of the spiro-annulated ring. It can be assumed that this is precisely the reason for the insufficient knowledge of the biological profile of spiro-2-benzoxepine derivatives (only one study investigated the σ₁- and σ₂-receptor affinity of particular representatives of the class[11a]). Aiming to fill this void, we studied the reaction of DAS with cyclic (as well as acyc­lic) ketones, to develop a general approach to the synthesis of spiro-annulated 2-benzoxepins.

Decomposition reactions of diazocarbonyl compounds can be carried out by photolysis, thermolysis, or under the action of catalysts. Taking into account the relatively high thermal stability of DAS (most compounds decompose at temperatures noticeably higher than 100 °C), and to minimize side processes, we chose a catalytic decomposition method that allows the studied reactions to be carried out under mild conditions (at room temperature). As a model reaction, we chose the interaction of DAS 1а with cyclohexanone in the presence of bis[rhodium(α,α,α′,α′-tetramethyl-1,3-benzenedipropionic acid)] [Rh₂(esp)₂] as a catalyst (Scheme [3]). Additional screening of catalytic systems was not carried out, since, at that point, Rh₂(esp)₂ had already proved to be one of the most effective catalysts for the decomposition of DAS.[7] [8] The reactions were carried out in an anhydrous DCM solution at room temperature. Immediately after the complete conversion of DAS was achieved, the reaction mixture was subjected to flash column chromatography on silica gel without additional treatment. Already in preliminary experiments (using 0.1 mol% catalyst), the target compound 2а was obtained in good yield (69%). Its structure was confirmed by single-crystal X-ray analysis data. When the ratio 1a/cyclohexanone was varied from 1:1.1 to 1:1.5, the yield of spiro-2-benzoxepine 2а increased insignificantly (from 69 to 72%). Subsequently, this observation gave us some freedom to vary the amount of the carbonyl compounds in a wide range. For instance, highly volatile ketones were used in a larger excess (1.5 or 3.0 equiv), and high-boiling ketones were used in only 10% excess (1.1 equiv), to avoid difficulties with their removal during the purification. In the model reaction, along with the target product 2a, the formation of side product 3a (the product of formal insertion into the O–H bond of the cyclohexanone enol form) was observed (estimated yield by ¹H NMR: 8%); its structure was proposed on the basis of NMR spectroscopy data. It was also found that enol ether 3а was slowly converted (presumably via a Claisen rearrangement) into compound 4а, even at room temperature. To establish the structure of the latter, a mixture of products 2а and 3а obtained after preliminary flash chromatography was kept at 50 °С for 12 h, until complete conversion of 3а into 4a. Thereafter, compound 4a was isolated in an individual state by HPLC and its characterization data were found to be consistent with the proposed structure. The mechanistic rationale for the formation of 3a and 4a will be discussed below.

The scope of the newly established spirocyclization was investigated while varying the substituents in the DAS starting materials as well as the ring size of the starting ketone (Scheme [4]). A number of examples have shown that the replacement of the benzyl substituent (2a) at the nitrogen atom by a phenyl group (2b) does not significantly affect the yield of the target product, while the introduction of a strong donor substituent into the arylidene fragment of the diazo substrate leads to a sharp drop in the yield of 2 (77% and 72% for 2b and 2c vs. 23% for 2d, Scheme [4]). This may be due to a decrease in the electrophilicity of the intermediate carbenoid in the case of methoxy-substituted DAS, which leads to a less efficient interaction with the carbonyl group.

When cyclic ketones with a ring size of four to eight units were introduced into the reaction, no significant effect on the yield of the target spirocycle (compounds 2a,e–h) was observed (Scheme [4]). Even for sterically demanding ketones such as 2-adamantanone and d-camphor, spiro-annulation products 2i,j and 2m were obtained in good yields. The structure of compound 2i was confirmed by X-ray analysis data (see SI). The configuration of the product 2m was assigned according to the NOESY data (see SI). The repeated synthesis of compound 2i was carried out (1.5 mmol scale) with a reduced amount of catalyst [Rh₂(esp)₂ (0.033 mol%)] and without using chromatographic methods of isolation. After crystallization of the reaction mixture, spirocycle 2i was isolated in 85% yield.

In some cases, the spiro-annulation reaction (for compounds 2b,c and 2k) was accompanied by a side process –the formation of small amounts of enol ether of type 3.

Similarly to the interaction with cyclic ketones, DAS reagents react with symmetric acyclic ketones (acetone, diethyl ketone) (Scheme [5]). All 2-benzoxepines 2n–x were obtained in high yields. In the case of 3-bromo-substituted DAS, the formation of two regioisomers (Scheme [5], compounds 2t and 2t′) in a ratio of 2:1 was observed. For DAS-containing electron-withdrawing substituents, the formation of insignificant amounts of isomeric fused maleimide 5 was observed. CF₃-substituted derivative 5a was isolated by HPLC and characterized. It can be assumed that an increase in the electron-withdrawing nature of the substituent at the DAS nitrogen atom (Boc, Ts, Ac, etc.) will lead to an increase of the percentage of isomeric benzoxepine 5. Such a trend can be observed upon going from 2o to 2w (0% and 8% of regioisomer 5, respectively, Scheme [5]).

To establish the diastereoselectivity of the formation of 2-benzoxepine derivatives 2, reactions were carried out with unsymmetrical methyl ketones (Scheme [6]). In all cases, the formation of a single diastereomer was observed, the structure of which was confirmed by the NOESY spectra (see SI). In the reaction with 2′-fluoroacetophenone, along with the target product 2аb, fused indene 6а, the product of the intramolecular C–H insertion transformation of the corresponding DAS, was isolated. A similar side product was previously observed by us in the reactions of DAS with nitriles.[7]

In the reaction of DAS with poorly nucleophilic ketones and chalcone, the formation of corresponding 2-benzoxepines 2 was not observed. In the case of phenyl trifluoromethyl ketone and fluorenone, the main product was quasi-dimer 7, which was isolated in 60% yield from the reaction with phenyl trifluoromethyl ketone (Scheme [7]). Its structure was established on the basis of single-crystal X-ray analysis data (see SI).

A plausible mechanism for the formation of 1,1-disubstituted 2-benzoxepines 2 is likely similar to that reported previously.[8] It involves the formation of conjugated carbonyl ylide 8, which is capable of undergoing a 1,7-electro­cyclization, followed by a 1,5-hydrogen shift (Scheme [8]). Side products 5, observed in some cases, are probably formed as a result of non-concerted migration of a hydrogen atom during aromatization of the electrocyclization product 9. It was shown that the thermal isomerization of compound 2u in 5а does not occur (50 °C, overnight).

An alternative pathway for the transformation of conjugated carbonyl ylide 8 consists of the migration of the α-proton of the ketone fragment (possibly intramolecular, Scheme [8]). Resulting enol ether 3 (in the case of reaction with cyclohexanone) is able to undergo [3,3]-sigmatropic Claisen rearrangement even at room temperature. Compound 4, as expected, is formed as a single diastereomer.

When comparing the reactions of DAS with aldehydes[8] and with ketones, it can be noted that in the latter case, the yields of the target 2-benzoxepines are generally higher, and the process is less dependent on the structure of the carbonyl component. In addition, no products of 1,3-dipolar cycloaddition of intermediate carbonyl ylide 8 to the double carbon–carbon bond of the starting diazo compound were detected in this work, whereas in the case of aldehydes, this reaction was observed as the principal side process. This can be explained by the increased steric requirement of carbonyl ylides formed from ketones.

In summary, as a result of a detailed study of the interaction of DAS with ketones of various nature, a general method was proposed for the first time for the preparation of 1-spiro-annulated 2-benzoxepines – products of Rh(II)-catalyzed formal [5+2] cycloaddition of styryl carbenoids to the CO double bond. The method is tolerant to the ring size and steric bulkiness of carbonyl substrates. With its help, under mild conditions in high yields, it is possible to obtain spirocyclic 2-benzoxepine derivatives of various structures. Reactions with unsymmetrical ketones proceed in high diastereoselectivity. In some cases, side processes were observed: the formation of enol ethers undergoing subsequent Claisen rearrangement, intramolecular cyclization of DAS to indene, and unusual DAS dimerization comprising a tandem of formal [5+2] cycloaddition and intramolecular CH insertion. These side transformations of DAS will become subjects of further research in our laboratory.

All commercial reagents were used without purification. NMR spectra of samples in CDCl₃ were recorded on a Bruker Avance III spectrometer (¹H: 400.13 MHz; ¹³С: 100.61 MHz; ¹⁹F: 376.50 MHz). The residual solvent peak (CHCl₃) was used as internal standard: 7.26 for ¹H and 77.16 ppm for ¹³C. Mass spectra were recorded on a Bruker microTOF spectrometer (ionization by electrospray, positive ions detection). Melting points were determined in open capillary tubes on a Stuart SMP50 Automatic Melting Point Apparatus. Analytical TLC was carried out on UV-254 silica gel plates using appropriate eluents. Compounds were visualized with short-wavelength UV light. Column chromatography was performed on a flash purification system Isolera^™ Prime (Biotage^®) using silica gel Merck grade 60 (0.040−0.063 mm), 230−400 mesh (gradient elution with n-hexane–acetone). HPLC was performed using an ECS28P00 instrument and YMC-Pack SIL-06 (250 × 20 mm) column. Diazo compounds 1 were synthesized according to previously described procedures.[15] Structural assignments for compounds 2m,y,z,aa,ab were made with additional information from NOESY experiments.

Fused Oxepines 2 by the Reaction of Diazo Compounds 1 with Ketones­; General Procedure

Diazo compound 1 (0.5 mmol) and the appropriate ketone (1.1 or 1.5 or 3.0 equiv) were dissolved in anhydrous DCM (1.8 mL); this was followed by the addition of the catalyst solution (2.5 mM Rh₂(esp)₂ in DCM, 200 μL, 0.1 mol%). The reaction mixture was stirred at r.t. for 0.5–1 h (controlled by TLC). The reaction mixture was diluted with n-hexane (2 mL) and the resulting solution was subjected to column chromatography (silica gel, n-hexane–acetone) to afford 2-benzoxepine 2.

In some cases, additional separation by HPLC was performed to isolate product 4a resulting from enol ether rearrangement and individual regioisomeric oxepines 2t and 2t′ or 2u and 5a.

2-Benzylspiro[benzo[5,6]oxepino[2,3-c]pyrrole-5,1′-cyclohexane]-1,3(2H,3aH)-dione (2a) and 1-Benzyl-3-((S/R)-((S/R)-2-oxocyclohexyl)(phenyl)methyl)-1H-pyrrole-2,5-dione (4a)

Prepared according to the general procedure from diazo compound 1a and cyclohexanone (78 μL, 0.75 mmol). After column chromatography (silica gel, n-hexane–acetone, 100:0 to 80:20) two fractions were obtained: pure oxepine 2a; yield: 110 mg (60%) and the mixture of oxepine and enol ether 3a; yield: 41 mg (2.5:1). The mixed fraction was kept at 50 °C as a solution in CDCl₃ for 12 h and subjected to HPLC separation (n-hexane–DCM, 50:50 to 0:100) to afford an additional amount of compound 2a and individual compound 4a.

Compound 2a

Total yield: 134 mg (72%); white solid; mp 174.8–176.6 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.51–7.44 (m, 4 H), 7.42 (dd, J = 7.6, 1.7 Hz, 1 H), 7.40–7.28 (m, 5 H), 4.95 (d, J = 2.2 Hz, 1 H), 4.83 (d, J = 14.0 Hz, 1 H), 4.78 (d, J = 14.0 Hz, 1 H), 2.40–2.34 (m, 1 H), 2.12–1.79 (m, 6 H), 1.65–1.54 (m, 2 H), 1.43–1.26 (m, 1 H).

¹³C NMR (101 MHz, CDCl₃): δ = 172.0, 167.2, 150.4, 136.3, 135.70, 135.68, 131.8, 131.1, 129.6, 129.2, 129.1, 128.7, 128.0, 127.1, 83.6, 68.3, 42.5, 40.9, 36.2, 25.4, 22.4, 20.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₄H₂₄NO₃: 374.1751; found: 374.1756.

Compound 4a

Yield: 8 mg (4%); amorphous white solid.

¹H NMR (400 MHz, CDCl₃): δ = 7.35–7.22 (m, 10 H), 6.31 (d, J = 1.2 Hz, 1 H), 4.65 (d, J = 14.8 Hz, 1 H), 4.62 (d, J = 14.8 Hz, 1 H), 4.30 (dd, J = 8.9, 1.3 Hz, 1 H), 3.46 (dddd, J = 11.8, 8.9, 5.2, 1.0 Hz, 1 H), 2.41–2.30 (m, 2 H), 2.10–2.04 (m, 1 H), 2.03–1.97 (m, 1 H), 1.94–1.88 (m, 1 H), 1.77–1.66 (m, 2 H), 1.49 (dtd, J = 13.0, 11.6, 3.7 Hz, 1 H).

¹³C NMR (101 MHz, CDCl₃): δ = 210.3, 171.0, 170.1, 150.4, 139.1, 136.3, 128.8, 128.70, 128.67, 128.3, 127.7, 127.3, 127.3, 53.9, 43.1, 42.4, 41.6, 32.6, 28.1, 24.9.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₄H₂₄NO₃: 374.1751; found: 374.1750.

2-Phenylspiro[benzo[5,6]oxepino[2,3-c]pyrrole-5,1′-cyclohexane]-1,3(2H,3aH)-dione (2b)

Prepared according to the general procedure from diazo compound 1b and cyclohexanone (78 μL, 0.75 mmol). Column chromatography (silica gel, n-hexane–acetone, 100:0 to 75:25).

Yield: 139 mg (77%); white solid; mp 186.4–188.2 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.62 (d, J = 2.2 Hz, 1 H), 7.55–7.42 (m, 7 H), 7.40 (dd, J = 7.9, 1.7 Hz, 1 H), 7.34 (td, J = 7.4, 1.4 Hz, 1 H), 5.14 (d, J = 2.2 Hz, 1 H), 2.49–2.40 (m, 1 H), 2.16–1.86 (m, 6 H), 1.71–1.58 (m, 2 H), 1.39 (qt, J = 12.8, 3.9 Hz, 1 H).

¹³C NMR (101 MHz, CDCl₃): δ = 171.3, 166.5, 150.5, 137.3, 135.8, 131.8, 131.4, 131.2, 129.8, 129.3, 129.1, 128.6, 127.2, 126.3, 83.7, 68.3, 41.0, 36.3, 25.4, 22.4, 19.9.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₃H₂₂NO₃: 360.1594; found: 360.1600.

7-Chloro-2-phenylspiro[benzo[5,6]oxepino[2,3-c]pyrrole-5,1′-cyclohexane]-1,3(2H,3aH)-dione (2c)

Prepared according to the general procedure from diazo compound 1c and cyclohexanone (78 μL, 0.75 mmol). Column chromatography (silica gel, n-hexane–acetone, 100:0 to 75:25).

Yield: 143 mg (72%); white solid; mp 193.1–194.7 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.55 (d, J = 2.3 Hz, 1 H), 7.54–7.49 (m, 2 H), 7.47 (d, J = 2.1 Hz, 1 H), 7.46–7.42 (m, 3 H), 7.40 (d, J = 8.4 Hz, 1 H), 7.32 (dd, J = 8.3, 2.1 Hz, 1 H), 5.13 (d, J = 2.2 Hz, 1 H), 2.43 (br.d, J = 13.7 Hz, 1 H), 2.15–1.82 (m, 6 H), 1.71–1.57 (m, 2 H), 1.40 (qt, J = 13.0, 3.8 Hz, 1 H).

¹³C NMR (101 MHz, CDCl₃): δ = 170.9, 166.3, 152.3, 136.9, 136.0, 135.9, 131.8, 131.7, 129.7, 129.5, 129.1, 128.6, 127.5, 126.2, 83.5, 68.4, 40.8, 36.2, 25.3, 22.3, 19.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₃H₂₀ClNO₃: 394.1205; found: 394.1210.

7-Methoxy-2-phenylspiro[benzo[5,6]oxepino[2,3-c]pyrrole-5,1′-cyclohexane]-1,3(2H,3aH)-dione (2d)

Prepared according to the general procedure from diazo compound 1d and cyclohexanone (78 μL, 0.75 mmol). Column chromatography (silica gel, n-hexane–acetone, 100:0 to 75:25).

Yield: 46 mg (23%); white solid; mp 233.6–236.5 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.58 (d, J = 2.1 Hz, 1 H), 7.53–7.48 (m, 2 H), 7.46–7.40 (m, 4 H), 7.00 (d, J = 2.6 Hz, 1 H), 6.88 (dd, J = 8.5, 2.6 Hz, 1 H), 5.13 (d, J = 2.2 Hz, 1 H), 3.89 (s, 3 H), 2.46 (br.d, J = 14.4 Hz, 1 H), 2.14–1.84 (m, 6 H), 1.69–1.57 (m, 2 H), 1.43–1.33 (m, 1 H).

¹³C NMR (101 MHz, CDCl₃): δ = 171.5, 166.7, 160.6, 152.7, 138.0, 137.1, 131.9, 129.0, 128.5, 128.3, 126.3, 124.2, 116.5, 111.5, 83.5, 68.5, 55.5, 41.1, 36.3, 25.4, 22.4, 20.0.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₄H₂₃NNaO₃: 412.1519; found: 412.1526.

2-Benzylspiro[benzo[5,6]oxepino[2,3-c]pyrrole-5,1′-cyclopentane]-1,3(2H,3aH)-dione (2e)

Prepared according to the general procedure from diazo compound 1a and cyclopentanone (60 μL, 0.75 mmol). Column chromatography (silica gel, n-hexane–acetone, 100:0 to 80:20).

Yield: 150 mg (83%); white solid; mp 127.0–128.5 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.54 (d, J = 2.1 Hz, 1 H), 7.49–7.43 (m, 2 H), 7.43–7.39 (m, 1 H), 7.39–7.27 (m, 6 H), 4.86 (d, J = 2.1 Hz, 1 H), 4.81 (d, J = 14.1 Hz, 1 H), 4.77 (d, J = 14.1 Hz, 1 H), 2.44–2.34 (m, 1 H), 2.30–2.18 (m, 2 H), 2.20–1.80 (m, 5 H).

¹³C NMR (101 MHz, CDCl₃): δ = 171.9, 167.1, 148.6, 136.3, 135.6, 134.9, 132.1, 131.5, 129.6, 129.1, 129.0, 128.7, 128.0, 127.0, 93.7, 69.5, 45.5, 43.1, 42.5, 24.8, 24.5.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₃H₂₂NO₃: 360.1594; found: 360.1600.

2-Benzylspiro[benzo[5,6]oxepino[2,3-c]pyrrole-5,1′-cycloheptane]-1,3(2H,3aH)-dione (2f)

Prepared according to the general procedure from diazo compound 1a and cycloheptanone (65 μL, 0.55 mmol). Column chromatography (silica gel, n-hexane–acetone, 100:0 to 80:20).

Yield: 165 mg (85%); white solid; mp 130.1–131.4 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.51–7.43 (m, 3 H), 7.43 (dd, J = 8.0, 1.5 Hz, 1 H), 7.40 (dd, J = 7.7, 1.9 Hz, 1 H), 7.37–7.26 (m, 5 H), 4.96 (d, J = 2.2 Hz, 1 H), 4.82 (d, J = 14.0 Hz, 1 H), 4.77 (d, J = 14.0 Hz, 1 H), 2.48–2.40 (m, 1 H), 2.23 (ddd, J = 15.0, 11.1, 1.8 Hz, 1 H), 2.18–2.07 (m, 1 H), 2.08–1.80 (m, 5 H), 1.76–1.56 (m, 4 H).

¹³C NMR (101 MHz, CDCl₃): δ = 172.0, 167.2, 152.5, 136.2, 135.7, 135.4, 131.8, 130.4, 129.6, 129.08, 129.07, 128.7, 128.0, 126.9, 86.6, 68.6, 45.7, 42.5, 39.9, 28.0, 27.9, 23.6, 20.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₅H₂₆NO₃: 388.1907; found: 388.1912.

2-Benzylspiro[benzo[5,6]oxepino[2,3-c]pyrrole-5,1′-cyclooctane]-1,3(2H,3aH)-dione (2g)

Prepared according to the general procedure from diazo compound 1a and cyclooctanone (69 mg, 0.55 mmol). Column chromatography (silica gel, n-hexane–acetone, 100:0 to 80:20).

Yield: 132 mg (66%); white solid; mp 148.2–149.4 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.51–7.44 (m, 4 H), 7.41 (dd, J = 7.5, 1.8 Hz, 1 H), 7.38–7.27 (m, 5 H), 4.98 (d, J = 2.1 Hz, 1 H), 4.81 (d, J = 14.0 Hz, 1 H), 4.76 (d, J = 14.0 Hz, 1 H), 2.43 (dd, J = 14.7, 9.7 Hz, 1 H), 2.30–2.06 (m, 3 H), 2.04–1.95 (m, 2 H), 1.89–1.53 (m, 8 H).

¹³C NMR (101 MHz, CDCl₃): δ = 172.0, 167.2, 151.8, 136.2, 135.7, 135.7, 131.8, 130.4, 129.5, 129.1, 128.8, 128.7, 128.0, 127.0, 85.7, 68.5, 42.5, 40.4, 35.5, 27.8, 27.7, 23.2, 21.5, 18.9.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₆H₂₈NO₃: 402.2064; found: 402.2066.

2-Benzylspiro[benzo[5,6]oxepino[2,3-c]pyrrole-5,1′-cyclobutane]-1,3(2H,3aH)-dione (2h)

Prepared according to the general procedure from diazo compound 1a and cyclobutanone (55 μL, 0.75 mmol). Column chromatography (silica gel, n-hexane–acetone, 100:0 to 80:20).

Yield: 126 mg (73%); white solid; mp 145.0–146.1 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.72 (d, J = 2.3 Hz, 1 H), 7.68 (dd, J = 7.8, 1.2 Hz, 1 H), 7.51–7.35 (m, 5 H), 7.37–7.29 (m, 3 H), 4.82 (s, 2 H), 4.68 (d, J = 2.2 Hz, 1 H), 2.87–2.75 (m, 1 H), 2.62–2.46 (m, 2 H), 2.24–2.14 (m, 1 H), 2.07 (dtt, J = 11.2, 9.9, 5.2 Hz, 1 H), 1.69 (dddd, J = 16.5, 11.3, 8.9, 7.5 Hz, 1 H).

¹³C NMR (101 MHz, CDCl₃): δ = 172.1, 166.9, 145.2, 137.2, 135.6, 133.4, 132.6, 130.8, 129.9, 128.8, 128.7, 128.0, 127.9, 127.8, 83.8, 70.0, 42.5, 39.7, 35.1, 14.1.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₂H₂₀NO₃: 346.1438; found: 346.1443.

(1r,3r,5r,7r)-2′-Benzylspiro[adamantane-2,5′-benzo[5,6]oxepino[2,3-c]pyrrole]-1′,3′(2′H,3a′H)-dione (2i)

Prepared according to the general procedure from diazo compound 1a and 2-adamantanone (83 mg, 0.55 mmol). Column chromatography (silica gel, n-hexane–acetone, 100:0 to 80:20).

Yield: 201 mg (94%); white solid; mp 192.9–193.8 °C.

The synthesis of compound 2i was also performed on a 1.5 mmol scale, using anhydrous DCM (5.8 mL) and the catalyst solution [2.5 mM Rh₂(esp)₂ in DCM, 200 μL, 0.033 mol%]. After stirring for 30 min, the reaction mixture was evaporated, crystallized from n-hexane/acetone, and washed with Et₂O; this afforded pure 2i; yield: 542 mg (85%).

¹H NMR (400 MHz, CDCl₃): δ = 7.92 (d, J = 2.2 Hz, 1 H), 7.76 (d, J = 7.9 Hz, 1 H), 7.50–7.43 (m, 1 H), 7.43–7.36 (m, 4 H), 7.35–7.26 (m, 3 H), 4.83 (d, J = 14.3 Hz, 1 H), 4.78 (d, J = 14.3 Hz, 1 H), 4.40 (d, J = 2.1 Hz, 1 H), 2.72–2.62 (m, 2 H), 2.63–2.52 (m, 1 H), 2.22–2.08 (m, 2 H), 1.89–1.76 (m, 2 H), 1.72–1.58 (m, 4 H), 1.51–1.40 (m, 2 H), 0.85–0.76 (m, 1 H).

¹³C NMR (101 MHz, CDCl₃): δ = 172.2, 166.9, 142.8, 139.5, 136.1, 135.6, 130.9, 130.6, 129.6, 129.2, 128.7, 128.4, 127.9, 127.5, 83.0, 69.5, 42.3, 38.4, 37.6, 36.6, 35.9, 34.4, 33.4, 33.3, 27.1, 26.3.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₈H₂₈NO₃: 426.2064; found: 426.2066.

(1r,3r,5r,7r)-9′-Methoxy-2′-phenylspiro[adamantane-2,5′-benzo[5,6]oxepino[2,3-c]pyrrole]-1′,3′(2′H,3a′H)-dione (2j)

Prepared according to the general procedure from diazo compound 1e and 2-adamantanone (83 mg, 0.55 mmol). Column chromatography (silica gel, cyclohexane–acetone, 100:0 to 75:25).

Yield: 130 mg (59%); white solid; mp 190.8–192.1 °C.

¹H NMR (400 MHz, CDCl₃): δ = 8.42 (d, J = 2.1 Hz, 1 H), 7.55–7.48 (m, 2 H), 7.48–7.36 (m, 5 H), 6.95 (d, J = 8.1 Hz, 1 H), 4.60 (d, J = 2.1 Hz, 1 H), 3.92 (s, 3 H), 2.77–2.72 (m, 1 H), 2.70–2.65 (m, 1 H), 2.64–2.56 (m, 1 H), 2.34–2.28 (m, 1 H), 2.25–2.17 (m, 1 H), 1.89–1.82 (m, 2 H), 1.74–1.62 (m, 4 H), 1.60–1.47 (m, 3 H).

¹³C NMR (101 MHz, CDCl₃): δ = 171.7, 166.3, 158.8, 144.4, 137.4, 131.8, 130.5, 129.1, 128.6, 128.4, 126.5, 124.5, 122.7, 110.0, 83.3, 69.3, 55.7, 38.3, 37.6, 36.7, 36.3, 34.5, 33.6, 33.5, 27.2, 26.4.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₈H₂₈NO₄: 442.2013; found: 442.2014.

2-Cyclopropyl-7-fluorospiro[benzo[5,6]oxepino[2,3-c]pyrrole-5,1′-cyclopentane]-1,3(2H,3aH)-dione (2k)

Prepared according to the general procedure from diazo compound 1f and cyclopentanone (133 μL, 1.5 mmol). After column chromatography (silica gel, cyclohexane–acetone, 100:0 to 75:25), two fractions were obtained: pure oxepine 2k: 85 mg (52%) and a mixture of oxepine and the corresponding enol ether: 43 mg (2:1).

Compound 2k

Yield: 85 mg (52%); amorphous solid.

¹H NMR (400 MHz, CDCl₃): δ = 7.45 (d, J = 2.2 Hz, 1 H), 7.40 (dd, J = 8.6, 6.1 Hz, 1 H), 7.06 (dd, J = 11.0, 2.6 Hz, 1 H), 7.03–6.96 (m, 1 H), 4.76 (d, J = 2.1 Hz, 1 H), 2.78–2.70 (m, 1 H), 2.43–2.33 (m, 1 H), 2.29–2.21 (m, 1 H), 2.21–1.82 (m, 6 H), 1.11–0.96 (m, 4 H).

¹³C NMR (101 MHz, CDCl₃): δ = 172.4, 167.9, 162.8 (d, ¹ J _C-F = 252.3 Hz), 151.7 (d, ³ J _C-F = 6.7 Hz), 137.0 (d, ³ J _C-F = 8.8 Hz), 134.7, 130.7 (d, ⁵ J _C-F = 2.5 Hz), 128.5 (d, ⁴ J _C-F = 3.1 Hz), 116.1 (d, ² J _C-F = 23.1 Hz), 114.5 (d, ² J _C-F = 21.5 Hz), 93.3 (d, ⁴ J _C-F = 1.9 Hz), 69.1, 45.5, 42.9, 24.7, 24.4, 22.5, 5.0, 4.9.

¹⁹F NMR (376 MHz, CDCl₃): δ = –109.21.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₉H₁₉FNO₃: 328.1344; found: 328.1345.

2-(4-Chlorophenyl)spiro[benzo[5,6]oxepino[2,3-c]pyrrole-5,1′-cycloheptane­]-1,3(2H,3aH)-dione (2l)

Prepared according to the general procedure from diazo compound 1g and cycloheptanone (65 μL, 0.55 mmol). Column chromatography (silica gel, cyclohexane–acetone, 100:0 to 75:25).

Yield: 95 mg (47%); white solid; mp 182.1–183.8 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.61 (d, J = 1.6 Hz, 1 H), 7.50–7.37 (m, 7 H), 7.33 (t, J = 7.3 Hz, 1 H), 5.13 (d, J = 1.5 Hz, 1 H), 2.54–2.45 (m, 1 H), 2.33–2.23 (m, 1 H), 2.22–2.09 (m, 1 H), 2.09–1.98 (m, 2 H), 1.98–1.82 (m, 3 H), 1.78–1.58 (m, 4 H).

¹³C NMR (101 MHz, CDCl₃): δ = 171.1, 166.22, 153.0, 137.7, 135.7, 134.3, 131.0, 130.29, 130.28, 130.0, 129.3, 129.2, 127.5, 127.0, 86.9, 68.6, 45.8, 40.0, 28.0, 27.9, 23.6, 20.8.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₄H₂₂ClNNaO₃: 430.1180; found: 430.1181.

(1′S,3aS,4′R,5R)-2-Benzyl-1′,7′,7′-trimethylspiro[benzo[5,6]oxepino[2,3-c]pyrrole-5,2′-bicyclo[2.2.1]heptane]-1,3(2H,3aH)-dione (2m)

Prepared according to the general procedure from diazo compound 1a and D-camphor (84 mg, 0.55 mmol). Column chromatography (silica gel, n-hexane–acetone, 100:0 to 80:20).

Yield: 109 mg (51%); amorphous solid.

¹H NMR (400 MHz, CDCl₃): δ = 7.91 (d, J = 2.1 Hz, 1 H), 7.87–7.80 (m, 1 H), 7.42–7.34 (m, 3 H), 7.36–7.27 (m, 6 H), 4.82 (d, J = 14.2 Hz, 1 H), 4.75 (d, J = 14.2 Hz, 1 H), 4.32 (d, J = 2.3 Hz, 1 H), 2.58 (ddd, J = 13.7, 4.8, 2.2 Hz, 1 H), 1.98 (t, J = 9.8 Hz, 1 H), 1.64 (t, J = 4.3 Hz, 1 H), 1.62–1.48 (m, 3 H), 1.43 (s, 3 H), 1.04 (s, 3 H), 0.89 (s, 3 H), 0.73–0.63 (m, 1 H).

¹³C NMR (101 MHz, CDCl₃): δ = 171.9, 166.5, 144.5, 139.3, 137.7, 135.7, 132.7, 130.1, 129.5, 128.7, 128.5, 127.9, 127.9, 127.0, 88.9, 69.2, 53.7, 53.5, 50.7, 44.6, 42.2, 32.1, 26.8, 22.1, 21.5, 13.5.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₈H₃₀NO₃: 428.2220; found: 428.2225.

2-Benzyl-5,5-dimethyl-3a,5-dihydro-1H-benzo[5,6]oxepino[2,3-c]pyrrole-1,3(2H)-dione (2n)

Prepared according to the general procedure from diazo compound 1a and acetone (111 μL, 1.5 mmol). Column chromatography (silica gel, n-hexane–acetone, 100:0 to 80:20).

Yield: 152 mg (91%); white solid; mp 107.1–108.1 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.50 (d, J = 2.2 Hz, 1 H), 7.50–7.40 (m, 3 H), 7.43–7.27 (m, 7 H), 5.04 (d, J = 2.2 Hz, 1 H), 4.82 (d, J = 14.2 Hz, 1 H), 4.77 (d, J = 14.2 Hz, 1 H), 1.85 (s, 3 H), 1.69 (s, 3 H).

¹³C NMR (101 MHz, CDCl₃): δ = 171.9, 167.1, 149.7, 136.1, 135.6, 135.4, 131.5, 130.7, 129.8, 129.1, 129.0, 128.7, 128.0, 127.3, 82.7, 69.6, 42.5, 32.6, 30.3.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₁H₂₀NO₃: 334.1438; found: 334.1443.

5,5-Dimethyl-2-phenyl-3a,5-dihydro-1H-benzo[5,6]oxepino[2,3-c]pyrrole-1,3(2H)-dione (2o)

Prepared according to the general procedure from diazo compound 1b and acetone (111 μL, 1.5 mmol). Column chromatography (silica gel, n-hexane–acetone, 100:0 to 75:25).

Yield: 137 mg (86%); white solid; mp 172.0–173.4 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.64 (d, J = 2.2 Hz, 1 H), 7.54–7.46 (m, 3 H), 7.46–7.38 (m, 5 H), 7.38–7.32 (m, 1 H), 5.23 (d, J = 2.2 Hz, 1 H), 1.91 (s, 3 H), 1.75 (s, 3 H).

¹³C NMR (101 MHz, CDCl₃): δ = 171.2, 166.5, 149.8, 137.1, 135.6, 131.7, 131.1, 130.7, 130.0, 129.12, 129.10, 128.6, 127.4, 126.3, 82.8, 69.6, 32.6, 30.4.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₀H₁₈NO₃: 320.1281; found: 320.1285.

5,5,7-Trimethyl-2-phenyl-3a,5-dihydro-1H-benzo[5,6]oxepino[2,3-c]pyrrole-1,3(2H)-dione (2p)

Prepared according to the general procedure from diazo compound 1h and acetone (111 μL, 1.5 mmol). Column chromatography (silica gel, cyclohexane–acetone, 100:0 to 75:25).

Yield: 138 mg (83%); white solid; mp 189.5–190.8 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.61 (d, J = 2.1 Hz, 1 H), 7.54–7.48 (m, 2 H), 7.45–7.40 (m, 3 H), 7.38 (d, J = 7.9 Hz, 1 H), 7.22 (s, 1 H), 7.17 (d, J = 7.8 Hz, 1 H), 5.22 (d, J = 2.1 Hz, 1 H), 2.43 (s, 3 H), 1.90 (s, 3 H), 1.75 (s, 3 H).

¹³C NMR (101 MHz, CDCl₃): δ = 171.4, 166.6, 149.9, 140.5, 137.1, 135.8, 131.8, 129.9, 129.10, 128.6, 128.2, 128.0, 126.35, 82.8, 69.6, 32.6, 30.4, 21.7.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₁H₂₀NO₃: 334.1438; found: 334.1439

2-Benzyl-7-fluoro-5,5-dimethyl-3a,5-dihydro-1H-benzo[5,6]oxepino[2,3-c]pyrrole-1,3(2H)-dione (2q)

Prepared according to the general procedure from diazo compound 1i and acetone (111 μL, 1.5 mmol). Column chromatography (silica gel, cyclohexane–acetone, 100:0 to 75:25).

Yield: 162 mg (92%); white solid; mp 131.9–132.6 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.48–7.39 (m, 1 H), 7.37–7.26 (m, 1 H), 7.11–6.99 (m, 1 H), 5.05 (d, J = 2.2 Hz, 1 H), 4.81 (d, J = 14.1 Hz, 1 H), 4.77 (d, J = 14.1 Hz, 1 H), 1.82 (s, 1 H), 1.69 (s, 1 H).

¹³C NMR (101 MHz, CDCl₃): δ = 171.7, 167.0, 162.9 (d, C-F, ¹ J _C-F = 252.8 Hz), 152.6 (d, ³ J _C-F = 6.6 Hz), 137.6 (d, ³ J _C-F = 8.8 Hz), 135.6, 134.9, 130.8 (d, ⁵ J _C-F = 2.6 Hz), 129.0, 128.7, 128.0, 127.1 (d, ⁴ J _C-F = 3.2 Hz), 116.3 (d, ² J _C-F = 23.2 Hz), 114.6 (d, ² J _C-F = 21.5 Hz), 82.3, 69.7, 42.5, 32.4, 30.1.

¹⁹F NMR (376 MHz, CDCl₃): δ = –108.70 (s).

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₁H₁₉FNO₃: 352.1344; found: 352.1343

2-Benzyl-8-bromo-5,5-dimethyl-3a,5-dihydro-1H-benzo[5,6]oxepino[2,3-c]pyrrole-1,3(2H)-dione (2t) and 2-Benzyl-6-bromo-5,5-dimethyl-3a,5-dihydro-1H-benzo[5,6]oxepino[2,3-c]pyrrole-1,3(2H)-dione (2t′)

Prepared according to the general procedure from diazo compound 1l and acetone (111 μL, 1.5 mmol). After column chromatography (silica gel, cyclohexane–acetone, 100:0 to 75:25) a mixture of two regioisomers was obtained; total yield: 192 mg (93%); 2t/2t′ 2:1. Individual compounds were obtained by HPLC (DCM–MeOH, 100:0 to 50:50).

Compound 2t

Amorphous solid.

¹H NMR (400 MHz, CDCl₃): δ = 7.56 (d, J = 2.2 Hz, 1 H), 7.49–7.43 (m, 3 H), 7.39 (d, J = 2.2 Hz, 1 H), 7.36–7.29 (m, 3 H), 7.25 (d, J = 8.6 Hz, 1 H), 5.03 (d, J = 2.2 Hz, 1 H), 4.81 (d, J = 14.1 Hz, 1 H), 4.77 (d, J = 14.1 Hz, 1 H), 1.81 (s, 3 H), 1.67 (s, 3 H).

¹³C NMR (101 MHz, CDCl₃): δ = 171.5, 166.7, 148.5, 137.4, 135.5, 134.5, 133.0, 132.7, 132.5, 130.6, 129.0, 128.7, 128.1, 120.8, 82.4, 69.51, 42.6, 32.4, 30.2.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₁H₁₉BrNO₃: 412.0543; found: 412.0546

Compound 2t′

Amorphous solid.

¹H NMR (400 MHz, CDCl₃): δ = 7.72 (dd, J = 7.9, 1.5 Hz, 1 H), 7.47–7.42 (m, 3 H), 7.39 (d, J = 2.2 Hz, 1 H), 7.37–7.30 (m, 3 H), 7.15 (t, J = 7.8 Hz, 1 H), 5.07 (d, J = 2.2 Hz, 1 H), 4.82 (d, J = 14.1 Hz, 1 H), 4.77 (d, J = 14.1 Hz, 1 H), 2.23 (s, 3 H), 1.91 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 171.8, 166.9, 149.8, 138.5, 136.4, 136.2, 135.5, 133.7, 133.5, 129.1, 128.7, 128.09, 128.08, 123.2, 84.4, 68.4, 42.6, 28.9, 28.7.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₁H₁₉BrNO₃: 412.0543; found: 412.0544

2-(4-Methoxyphenyl)-5,5-dimethyl-3a,5-dihydro-1H-benzo[5,6]oxepino[2,3-c]pyrrole-1,3(2H)-dione (2r)

Prepared according to the general procedure from diazo compound 1j and acetone (111 μL, 1.5 mmol). Column chromatography (silica gel, cyclohexane–acetone, 100:0 to 75:25).

Yield: 150 mg (86%); white solid; mp 178.3–179.8 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.62 (d, J = 2.2 Hz, 1 H), 7.50–7.47 (m, 1 H), 7.45–7.40 (m, 2 H), 7.39–7.31 (m, 3 H), 7.04–6.99 (m, 2 H), 5.21 (d, J = 2.2 Hz, 1 H), 3.86 (s, 3 H), 1.90 (s, 3 H), 1.75 (s, 3 H).

¹³C NMR (101 MHz, CDCl₃): δ = 171.5, 166.8, 159.5, 149.8, 136.9, 135.6, 131.2, 130.7, 129.9, 129.1, 127.6, 127.4, 124.4, 114.5, 82.8, 69.6, 55.5, 32.6, 30.4.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₁H₂₀NO₄: 350.1387; found: 350.1393

7-Chloro-2-isobutyl-5,5-dimethyl-3a,5-dihydro-1H-benzo[5,6]oxepino[2,3-c]pyrrole-1,3(2H)-dione (2s)

Prepared according to the general procedure from diazo compound 1k and acetone (111 μL, 1.5 mmol). Column chromatography (silica gel, cyclohexane–acetone, 100:0 to 75:25).

Yield: 117 mg (70%); amorphous solid.

¹H NMR (400 MHz, CDCl₃): δ = 7.39 (d, J = 2.2 Hz, 1 H), 7.35–7.32 (m, 2 H), 7.28–7.24 (m, 1 H), 5.01 (d, J = 2.2 Hz, 1 H), 3.47–3.36 (m, 2 H), 2.13–2.02 (m, 1 H), 1.80 (s, 3 H), 1.66 (s, 3 H), 0.90 (dd, J = 6.7, 2.2 Hz, 6 H).

¹³C NMR (101 MHz, CDCl₃): δ = 172.1, 167.4, 151.4, 136.5, 135.7, 134.2, 132.1, 129.4, 129.1, 127.5, 82.2, 69.4, 46.1, 32.3, 30.1, 27.2, 20.1, 20.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₈H₂₁ClNO₃: 334.1205; found: 334.1204.

5,5-Dimethyl-2-phenyl-7-(trifluoromethyl)-3a,5-dihydro-1H-benzo[5,6]oxepino[2,3-c]pyrrole-1,3(2H)-dione (2u) and 5,5-Dimethyl-2-phenyl-7-(trifluoromethyl)-5,10-dihydro-1H-benzo[5,6]oxepino[2,3-c]pyrrole-1,3(2H)-dione (5a)

Prepared according to the general procedure from diazo compound 1m and acetone (111 μL, 1.5 mmol). After column chromatography (silica gel, cyclohexane–acetone, 100:0 to 75:25), a mixture of two regioisomers 2u and 5a was obtained; yield: 178 mg (92%), ratio 3:1. Individual compounds were obtained by HPLC (n-hexane–DCM, 50:50 to 0:100)

Compound 2u

White solid; mp 145.0–146.2 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.66–7.63 (m, 1 H), 7.61 (d, J = 1.1 Hz, 1 H), 7.55–7.50 (m, 1 H), 7.48–7.40 (m, 2 H), 5.26 (d, J = 2.2 Hz, 1 H), 1.93 (s, 2 H), 1.79 (s, 2 H).

¹³C NMR (101 MHz, CDCl₃): δ = 170.6, 166.0, 150.5, 135.9, 135.1, 133.9, 133.7, 131.5, 131.1, 129.2, 128.8, 126.3, 125.7 (q, ³ J _C-F = 3.9 Hz), 124.1 (q, ³ J _C-F = 3.6 Hz), 123.6 (q, ¹ J _C-F = 272.7 Hz), 82.7, 69.7, 32.3, 30.2.

¹⁹F NMR (376 MHz, CDCl₃): δ = –62.99.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₁H₁₇F₃NO₃: 388.1155; found: 388.1156.

Compound 5a

Amorphous solid.

¹H NMR (400 MHz, CDCl₃): δ = 7.78 (s, 1 H), 7.61 (d, J = 7.9 Hz, 1 H), 7.50–7.33 (m, 6 H), 4.09 (s, 2 H), 2.06 (s, 6 H).

¹³C NMR (126 MHz, CDCl₃): δ = 170.0, 164.8, 152.7, 141.1, 141.0, 140.3, 131.7, 131.4, 129.9 (q, ² J _C-F = 32.6 Hz), 129.1, 127.7, 126.07 (q, ³ J _C-F = 7.3 Hz), 125.9, 124.0 (q, ³ J _C-F = 3.7 Hz), 123.8 (q, ¹ J _C-F = 272.3 Hz), 106.7, 84.8, 29.6, 28.1.

¹⁹F NMR (376 MHz, CDCl₃): δ = –62.62.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₁H₁₇F₃NO₃: 388.1155; found: 388.1155.

9-Fluoro-5,5-dimethyl-2-phenyl-3a,5-dihydro-1H-benzo[5,6]oxepino[2,3-c]pyrrole-1,3(2H)-dione (2v)

Prepared according to the general procedure from diazo compound 1n and acetone (111 μL, 1.5 mmol). After column chromatography (silica gel, cyclohexane–acetone, 100:0 to 75:25), two fractions were obtained: pure oxepine 2v: 108 mg (64%) and a mixture of oxepine and double-bond regioisomer: 28 mg (1.0:0.8).

Compound 2v

Amorphous solid.

¹H NMR (400 MHz, CDCl₃): δ = 8.04 (d, J = 2.2 Hz, 1 H), 7.53–7.45 (m, 2 H), 7.44–7.32 (m, 4 H), 7.21 (d, J = 8.1 Hz, 1 H), 7.07 (ddd, J = 10.1, 8.2, 1.1 Hz, 1 H), 5.22 (d, J = 2.3 Hz, 1 H), 1.87 (s, 3 H), 1.74 (s, 3 H).

¹³C NMR (101 MHz, CDCl₃): δ = 170.9, 166.1, 162.2 (d, ¹ J _C-F = 253.7 Hz), 151.5, 132.6 (d, ⁴ J _C-F = 1.4 Hz), 131.7, 131.3 (d, ³ J _C-F = 10.2 Hz), 129.1, 128.7, 127.2 (d, ² J _C-F = 13.3 Hz), 126.3, 124.6 (d, ³ J _C-F = 3.6 Hz), 119.8 (d, ³ J _C-F = 10.5 Hz), 114.1 (d, ² J _C-F = 23.8 Hz), 82.6 (d, ⁴ J _C-F = 1.6 Hz), 69.6, 32.5, 30.4.

¹⁹F NMR (376 MHz, CDCl₃): δ = –110.02.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₀H₁₇FNO₃: 338.1187; found: 338.1186.

5,5-Dimethyl-2-[4-(trifluoromethyl)phenyl]-3a,5-dihydro-1H-benzo[5,6]oxepino[2,3-c]pyrrole-1,3(2H)-dione (2w)

Prepared according to the general procedure from diazo compound 1o and acetone (111 μL, 1.5 mmol). After column chromatography (silica gel, cyclohexane–acetone, 100:0 to 75:25), a mixture of oxepine 2w and a regioisomer was obtained (189 mg, ratio 10:1). The mixture was recrystallized from Et₂O to give pure compound 2w.

Yield: 128 mg (66%); white solid; mp 179.0–181.0 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.79 (d, J = 8.5 Hz, 2 H), 7.67 (d, J = 2.1 Hz, 1 H), 7.62 (d, J = 8.4 Hz, 2 H), 7.53–7.33 (m, 4 H), 5.24 (d, J = 2.1 Hz, 1 H), 1.92 (s, 3 H), 1.75 (s, 3 H).

¹³C NMR (101 MHz, CDCl₃): δ = 170.9, 165.94, 149.9, 138.0, 135.8, 134.8, 130.52, 130.51, 130.5 (q, ² J _C-F = 32.8 Hz), 130.2, 129.2, 127.4, 126.5, 126.22 (q, ³ J _C-F = 3.8 Hz), 123.71 (q, ¹ J _C-F = 272.5 Hz), 83.0, 69.5, 32.6, 30.3.

¹⁹F NMR (376 MHz, CDCl₃): δ = –62.71.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₁H₁₆F₃NaNO₃: 410.0974; found: 410.0974.

5,5-Diethyl-2-(4-fluorophenyl)-3a,5-dihydro-1H-benzo[5,6]oxepino[2,3-c]pyrrole-1,3(2H)-dione (2x)

Prepared according to the general procedure from diazo compound 1p and diethyl ketone (160 μL, 1.5 mmol). Column chromatography (silica gel, n-hexane–acetone, 100:0 to 75:25).

Yield: 117 mg (64%); white solid; mp 170.9–172.4 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.62 (d, J = 2.2 Hz, 1 H), 7.51–7.38 (m, 4 H), 7.37–7.32 (m, 2 H), 7.20 (dd, J = 9.0, 8.3 Hz, 2 H), 5.10 (d, J = 2.2 Hz, 1 H), 2.41 (dq, J = 14.9, 7.5 Hz, 1 H), 2.29 (dq, J = 14.3, 7.2 Hz, 1 H), 2.18 (dq, J = 14.8, 7.4 Hz, 1 H), 1.74 (dq, J = 14.5, 7.3 Hz, 1 H), 1.22 (t, J = 7.4 Hz, 3 H), 0.58 (t, J = 7.3 Hz, 3 H).

¹³C NMR (101 MHz, CDCl₃): δ = 171.3, 166.5, 162.2 (d, C-F, ¹ J _C-F = 248.6 Hz), 149.0, 137.6, 135.6, 132.6, 130.9, 130.0, 129.4, 128.1 (d, C-F, ³ J _C-F = 8.8 Hz), 127.7 (d, C-F, ⁴ J _C-F = 3.3 Hz), 127.1, 116.1 (d, C-F, ² J _C-F = 23.0 Hz), 87.8, 68.6, 33.6, 33.5, 7.7, 6.5.

¹⁹F NMR (376 MHz, CDCl₃): δ = –112.27.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₂H₂₀FNNaO₃: 388.1319; found: 388.1319.

(3aS/R,5R/S)-2-Benzyl-5-(tert-butyl)-5-methyl-3a,5-dihydro-1H-benzo[5,6]oxepino[2,3-c]pyrrole-1,3(2H)-dione (2y)

Prepared according to the general procedure from diazo compound 1a and pinacolone (94 μL, 0.75 mmol). Column chromatography (silica gel, n-hexane–acetone, 100:0 to 80:20).

Yield: 173 mg (92%); white solid; mp 135.3–136.7 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.54–7.44 (m, 5 H), 7.40–7.28 (m, 5 H), 5.69 (d, J = 1.8 Hz, 1 H), 4.78 (s, 2 H), 1.72 (s, 3 H), 1.15 (s, 9 H).

¹³C NMR (101 MHz, CDCl₃): δ = 171.7, 167.1, 147.0, 136.8, 136.5, 135.7, 131.6, 130.0, 129.8, 129.2, 129.0, 128.7, 128.6, 128.0, 127.3, 89.3, 72.5, 42.4, 40.3, 26.9.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₄H₂₆NO₃: 376.1907; found: 376.1911.

(3aS/R,5R/S)-2-Benzyl-5-(4-chlorophenyl)-5-methyl-3a,5-dihydro-1H-benzo[5,6]oxepino[2,3-c]pyrrole-1,3(2H)-dione (2z)

Prepared according to the general procedure from diazo compound 1a and 4′-chloroacetophenone (71 μL, 0.55 mmol). Column chromatography (silica gel, n-hexane–acetone, 100:0 to 80:20); after column chromatography, the substance was recrystallized from n-hexane/Et₂O.

Yield: 112 mg (52%); white solid; mp 142.5–143.3 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.55 (dd, J = 7.2, 2.1 Hz, 1 H), 7.47–7.39 (m, 5 H), 7.36–7.26 (m, 8 H), 4.73 (d, J = 14.4 Hz, 1 H), 4.69 (d, J = 14.4 Hz, 1 H), 4.57 (d, J = 2.3 Hz, 1 H), 2.11 (s, 3 H).

¹³C NMR (101 MHz, CDCl₃): δ = 171.4, 166.9, 145.6, 143.7, 136.4, 135.5, 135.4, 134.5, 131.5, 131.5, 131.3, 130.0, 129.2, 129.0, 128.9, 128.7, 128.0, 86.9, 70.4, 42.5, 32.8.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₆H₂₀ClNNaO₃: 452.1024; found: 452.1027.

(3aS/R,5R/S)-7-Chloro-5-(3,4-dimethoxyphenyl)-2,5-dimethyl-3a,5-dihydro-1H-benzo[5,6]oxepino[2,3-c]pyrrole-1,3(2H)-dione (2aa)

Prepared according to the general procedure from diazo compound 1q and 3′,4′-dimethoxyacetophenone (99 mg, 0.55 mmol). Column chromatography (silica gel, n-hexane–acetone, 95:5 to 75:25).

Yield: 194 mg (94%); white solid; mp 181.2–182.9 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.48 (d, J = 7.9 Hz, 1 H), 7.43–7.36 (m, 3 H), 7.12 (d, J = 2.3 Hz, 1 H), 6.76 (d, J = 8.5 Hz, 1 H), 6.53 (dd, J = 8.3, 2.2 Hz, 1 H), 4.63 (d, J = 2.3 Hz, 1 H), 3.94 (s, 3 H), 3.87 (s, 3 H), 3.05 (s, 3 H), 2.13 (s, 3 H).

¹³C NMR (101 MHz, CDCl₃): δ = 171.9, 167.3, 149.7, 149.2, 147.8, 137.4, 137.0, 135.2, 133.6, 132.1, 131.3, 130.2, 128.1, 122.1, 110.2, 109.8, 87.0, 70.5, 56.1, 55.9, 32.6, 24.8.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₂H₂₀ClNNaO₅: 436.0922; found: 436.0924.

(3aS/R,5S/R)-5-(2-Fluorophenyl)-5,9-dimethyl-2-phenyl-3a,5-dihydro-1H-benzo[5,6]oxepino[2,3-c]pyrrole-1,3(2H)-dione (2ab) and 7-methyl-2-phenylindeno[1,2-c]pyrrole-1,3(2H,8H)-dione (6a)

Prepared according to the general procedure from diazo compound 1r and 2′-fluoroacetophenone (67 μL, 0.55 mmol). Oxepine 2ab and indene­ 6a were isolated after column chromatography (silica gel, n-hexane–acetone, 100:0 to 80:20).

Compound 2ab

Yield: 85 mg (41%); white solid; mp 169.6–171.0 °C.

¹H NMR (400 MHz, CDCl₃): δ = 8.14 (d, J = 2.1 Hz, 1 H), 7.52–7.46 (m, 2 H), 7.44–7.32 (m, 5 H), 7.27 (d, J = 6.9 Hz, 1 H), 7.23–7.14 (m, 3 H), 6.97 (d, J = 7.9 Hz, 1 H), 5.02 (d, J = 1.7 Hz, 1 H), 2.62 (s, 3 H), 2.09 (s, 3 H).

¹³C NMR (101 MHz, CDCl₃): δ = 170.6, 166.7, 161.0 (d, C-F, ¹ J _C-F = 251.8 Hz), 146.7, 140.8, 133.6, 132.6 (d, C-F, ² J _C-F = 10.7 Hz), 131.7, 131.4, 130.5, 130.42, 130.40, 130.3 (d, C-F, ³ J _C-F = 8.6 Hz), 129.5, 129.0, 128.5, 128.4, 126.3, 123.9 (d, ³ J _C-F = 3.5 Hz), 117.1 (d, C-F, ² J _C-F = 23.5 Hz), 85.4, 70.1 (d, C-F, ³ J _C-F = 3.5 Hz), 31.2 (d, C-F, ⁴ J _C-F = 3.0 Hz), 21.5.

¹⁹F NMR (376 MHz, CDCl₃): δ = –105.20.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₆H₂₀FNNaO₃: 436.1319; found: 436.1322.

Compound 6a

Yield: 42 mg (30%); yellow solid; mp 162.1–164.2 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.74 (d, J = 7.5 Hz, 1 H), 7.54–7.48 (m, 2 H), 7.46–7.37 (m, 4 H), 7.32–7.27 (m, 1 H), 3.72 (s, 2 H), 2.46 (s, 3 H).

¹³C NMR (101 MHz, CDCl₃): δ = 165.7, 164.6, 151.6, 148.5, 147.0, 134.9, 134.0, 132.1, 130.2, 129.1, 128.2, 127.6, 126.5, 120.6, 32.5, 18.8.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₈H₁₃NNaO₂: 298.0838; found: 298.0838.

(8bR/S,12bR/S,15aS/R,15bS/R)-2,14-Dibenzyl-8b,15b-dihydro-1H-dibenzo[2,3:4,5]azuleno[1,8a-c:7,8-c′]dipyrrole-1,3,13,15(2H,12bH,14H)-tetraone (7)

Prepared according to the general procedure using diazo compound 1a and 2,2,2-trifluoro-1-phenylethan-1-one (77 μL, 0.55 mmol). Column chromatography (silica gel, n-hexane–acetone, 95:5 to 70:30).

Yield: 83 mg (60%); white solid; mp 232.1–234.2 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.81 (d, J = 2.1 Hz, 1 H), 7.69–7.61 (m, 1 H), 7.44–7.38 (m, 2 H), 7.37–7.26 (m, 7 H), 7.27–7.14 (m, 5 H), 7.07–7.01 (m, 2 H), 6.70 (d, J = 7.9 Hz, 1 H), 5.10 (s, 1 H), 4.59 (s, 1 H), 4.34 (d, J = 14.1 Hz, 1 H), 4.22 (d, J = 14.4 Hz, 1 H), 4.08 (d, J = 12.5 Hz, 1 H), 4.04 (d, J = 12.2 Hz, 1 H), 3.36 (d, J = 2.2 Hz, 1 H).

¹³C NMR (101 MHz, CDCl₃): δ = 176.9, 174.8, 172.7, 167.5, 139.7, 139.3, 138.9, 136.4, 135.6, 135.1, 134.4, 130.4, 130.30, 129.3, 129.2, 129.0, 128.93, 128.89, 128.6, 128.4, 127.9, 127.8, 127.7, 127.5, 125.5, 71.2, 55.5, 52.8, 46.2, 41.97, 41.96.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₆H₂₇N₂O₄: 551.1965; found: 551.1973.

X-ray Crystal Structures

CCDC 2078096 (2a), 2112492 (2i), and 2112747 (7) contain the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We thank the Research Center for Magnetic Resonance, the Center for Chemical Analysis and Materials Research, and the Center for X-ray Diffraction Methods of Saint Petersburg State University Research Park for obtaining the analytical data.

• References

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  CrossrefSearch in Google Scholar
• 15a Chupakhin EG, Kantin GP, Dar’in DV, Krasavin M. Mendeleev Commun. 2021; 31: 36
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  Thieme ConnectSearch in Google Scholar

Corresponding Authors

Publication History

Received: 11 November 2021

Accepted after revision: 08 December 2021

Article published online:
26 January 2022

© 2022. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

• References

• 1 Chupakhin E, Babich O, Prosekov A, Asyakina L, Krasavin M. Molecules 2019; 24: 4165
  CrossrefPubMedSearch in Google Scholar
• 2 Hiesinger K, Dar’in D, Proschak E, Krasavin M. J. Med. Chem. 2021; 64: 150
  CrossrefPubMedSearch in Google Scholar
• 3 Zheng Y, Tice CM, Singh SB. Bioorg. Med. Chem. Lett. 2014; 24: 3673
  CrossrefPubMedSearch in Google Scholar
• 4 Solovyev I, Eremeyeva M, Zhukovsky D, Dar’in D, Krasavin M. Tetrahedron Lett. 2021; 62: 152671
  CrossrefSearch in Google Scholar
• 5 Dar’in D, Kantin G, Bakulina O, Inyutina A, Chupakhin E, Krasavin M. J. Org. Chem. 2020; 85: 15586
  CrossrefPubMedSearch in Google Scholar
• 6 Laha D, Bhat RG. Asian J. Org. Chem. 2020; 9: 918
  CrossrefSearch in Google Scholar
• 7 Inyutina A, Dar’in D, Kantin G, Krasavin M. Org. Biomol. Chem. 2021; 19: 5068
  CrossrefPubMedSearch in Google Scholar
• 8 Inyutina A, Kantin G, Dar’in D, Krasavin M. J. Org. Chem. 2021; 86: 13673
  CrossrefPubMedSearch in Google Scholar
• 9a Wurst JM, Liu G, Tan DS. J. Am. Chem. Soc. 2011; 133: 7916
  CrossrefPubMedSearch in Google Scholar
• 9b Liu G, Wurst JM, Tan DS. Org. Lett. 2009; 11: 3670
  CrossrefPubMedSearch in Google Scholar
• 10 Butkevich AN, Corbu A, Meerpoel L, Stansfield I, Angibaud P, Bonnet P, Cossy J. Org. Lett. 2012; 14: 4998
  CrossrefPubMedSearch in Google Scholar
• 11a Maier CA, Wünsch B. Eur. J. Org. Chem. 2003; 714
  Crossref
• 11b Maestrup EG, Wiese C, Schepmann D, Brust P, Wünsch B. Bioorg. Med. Chem. 2011; 19: 393
  CrossrefPubMedSearch in Google Scholar
• 12 Bohme H, Hitzel V. Arch. Pharm. 1974; 306: 948
  CrossrefPubMedSearch in Google Scholar
• 13 Boerth JA, Hummel JR, Ellman JA. Angew. Chem. Int. Ed. 2016; 55: 1
  CrossrefPubMedSearch in Google Scholar
• 14 Hamaguchi M, Takahashi K, Oshima T, Tamura H. Tetrahedron Lett. 2003; 44: 4339
  CrossrefSearch in Google Scholar
• 15a Chupakhin EG, Kantin GP, Dar’in DV, Krasavin M. Mendeleev Commun. 2021; 31: 36
  CrossrefSearch in Google Scholar
• 15b Chupakhin E, Gecht M, Ivanov A, Kantin G, Dar’in D, Krasavin M. Synthesis 2021; 53: 1292
  Thieme ConnectSearch in Google Scholar

• Supplementary Material