General acid-mediated aminolactone formation using unactivated alkenes

Spirocyclic butyrolactones and butenolides are widespread structural motifs in bioactive substances. Despite their prevalence, a simple method ensuring their direct preparation from exocyclic alkenes, ideally in a late-stage context, remains elusive. Herein, we report direct aminolactone formation using unactivated alkenes which addresses this gap, employing cheap and readily available reactants. The method relies on the hijacking of a cationic aminoalkylation pathway and affords (spiro)aminolactones with excellent functional group tolerance and chemoselectivity. The synthetic versatility of the products is demonstrated through a range of transformations, notably exploiting stereospecific rearrangement chemistry to produce sterically congested scaffolds.


General information
All glassware was oven dried at 100 °C before use. All solvents were distilled from appropriate drying agents prior to use or directly taken from commercial sealed bottles under an atmosphere of argon. All reagents were used as received from commercial suppliers unless otherwise stated. Neat infrared spectra were recorded using a Perkin-Elmer Spectrum 100 FT-IR spectrometer. Wavenumbers (ν) are reported in cm -1 . Mass spectra were obtained using a Finnigan MAT 8200 or (70 eV) or an Agilent 5973 (70 eV) spectrometer, using electrospray ionization (ESI). All 1 H NMR, 13 C NMR, and 19 F NMR experiments were recorded using Bruker AV-400, AV-600 and AV-700 spectrometers at 300 K. Chemical shifts (δ) are quoted in ppm and coupling constants (J) are quoted in Hz. The 7.26 ppm resonance of residual CHCl3 for 1 H NMR spectra and 77.16 ppm resonance for 13 C NMR spectra were used as internal references. 1 H-NMR splitting patterns were designated as singlet (s), doublet (d), triplet (t), quartet (q), quintet (quint) or combinations thereof, as well as broad signal (br). Splitting patterns that could not be interpreted were designated as multiplet (m).
Spatial long-range contacts were determined by 1 H, 1 H NOESY experiments. CDCl3 was dried over 3Å molecular sieves prior to the measurements. Reaction progress was monitored by thin layer chromatography (TLC) performed on aluminum plates coated with kieselgel F254 with 0.2 mm thickness. Visualization was achieved by a combination of ultraviolet light (254 nm) and acidic potassium permanganate. Flash column chromatography was performed using silica gel 60 (230-400 mesh, Merck and co.). Aminal A -ethyl 2,2bis(dimethylamino)acetatewas prepared according to the literature. [1] S4

Preparation of the starting materials. General procedure A
Unless mentioned explicitly below, the starting materials were obtained from commercial sources and used as received.
Those alkenes that were not commercially available were synthesized using the following general procedure.
A suspension of methyltriphenylphosphonium bromide (1.0 eq., 5.0 mmol) in anhydrous Et2O (50 mL, 0.1 M) was cooled to 0 °C, after which tBuOK (2.0 eq., 10 mmol) was added. The resulting mixture was stirred at the same temperature for 30 min, with a noticeable color change. After that time, a solution of the ketone (1.0 eq., 5 mmol) in anhydrous Et2O (10 mL, precooled to 0 °C), was added to the reaction mixture, after which it was allowed to warm to 23 °C over the course of 14 h. The reaction was monitored by TLC and gently heated if little conversion was observed. After completion, excess base was quenched by the addition of a saturated aqueous solution of NH4Cl, and extracted with Et2O (3 × 20 mL). The pooled organic layers were dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, pentane) to obtain alkenes 1. S5

Methylenecycloheptane (1b)
The title compound was prepared using general procedure A for the synthesis of exocyclic alkenes. After flash chromatography, the compound was isolated in 72% yield as a colorless oil. All spectral data was found to be in accordance with the literature. [2] Methylenecyclooctane (1d) The title compound was prepared using general procedure A for the synthesis of exocyclic alkenes. After flash chromatography, the compound was isolated in 53% yield as a colorless oil. All spectral data was found to be in accordance with the literature. [3]

1-Methyl-4-methylenecyclohexane (1h)
The title compound was prepared using general procedure A for the synthesis of exocyclic alkenes. After flash chromatography, the compound was isolated in 15% yield as a volatile colorless oil. All spectral data was found to be in accordance with the literature. [4]

1-(tert-Butyl)-4-methylenecyclohexane (1i)
The title compound was prepared using general procedure A for the synthesis of exocyclic alkenes. After flash chromatography, the compound was isolated in 90% yield as a colorless oil. All spectral data was found to be in accordance with the literature. [4][5] (4-Methylenecyclohexyl)benzene (1j) The title compound was prepared using general procedure A for the synthesis of exocyclic alkenes. After flash chromatography, the compound was isolated in 75% yield as a colorless oil. All spectral data was found to be in accordance with the literature. [5] S6

1-Methylene-4-(trifluoromethyl)cyclohexane (1k)
The title compound was prepared using general procedure A for the synthesis of exocyclic alkenes. After flash chromatography, the compound was isolated in 39% yield as a volatile colorless oil. All spectral data was found to be in accordance with the literature. [6] (2-Methylenecyclohexyl)benzene (1l) The title compound was prepared using general procedure A for the synthesis of exocyclic alkenes. After flash chromatography, the compound was isolated in 32% yield as a colorless oil. All spectral data was found to be in accordance with the literature. [7] 2-Methylene-1,1'-bi(cyclohexane) (1m) The title compound was prepared using general procedure A for the synthesis of exocyclic alkenes. After flash chromatography, the compound was isolated in 67% yield as a colorless oil.

8-Methylene-1,4-dioxaspiro[4.5]decane (1n)
The title compound was prepared using general procedure A for the synthesis of exocyclic alkenes. After flash chromatography, the compound was isolated in 65% yield as a colorless oil. All spectral data was found to be in accordance with the literature. [8]

tert-Butyldimethyl((4-methylenecyclohexyl)oxy)silane (1o)
The title compound was prepared using general procedure A for the synthesis of exocyclic alkenes. After flash chromatography, the compound was isolated in 86% yield as a volatile colorless oil. All spectral data was found to be in accordance with the literature. [4] S7

1-Ethoxy-2-methylenecyclohexane (1p)
The title compound was prepared using general procedure A for the synthesis of exocyclic alkenes. After flash chromatography, the compound was isolated in 23% yield as a volatile colorless oil. All spectral data was found to be in accordance with the literature. [9] Ethyl 4-methylenecyclohexane-1-carboxylate (1q) The title compound was prepared using general procedure A for the synthesis of exocyclic alkenes. After flash chromatography, the compound was isolated in 83 % yield as a volatile colorless oil. All spectral data was found to be in accordance with the literature. [5]

N-(4-Methylenecyclohexyl)benzamide (1r)
The title compound was prepared using general procedure A for the synthesis of exocyclic alkenes. After flash chromatography, the compound was isolated in 37% yield as an off-white solid.

3-(2-Methylenecyclohexyl)propanenitrile (1s)
The title compound was prepared using general procedure A for the synthesis of exocyclic alkenes. After flash chromatography, the compound was isolated in 89% yield as a volatile colorless oil. All spectral data was found to be in accordance with the literature. [10] (4aS*,8aR*)-1-Methylenedecahydronaphthalene (1t) The title compound was prepared using general procedure A for the synthesis of exocyclic alkenes. After flash chromatography, the compound was isolated in 78% yield as a colorless oil. [11] S8 (4aS*,8aS*)-1-Methylenedecahydronaphthalene (1u) The title compound was prepared using general procedure A for the synthesis of exocyclic alkenes. After flash chromatography, the compound was isolated in 75% yield as a colorless oil. [11] (1S,4R)-1-Isopropyl-4-methyl-2-methylenecyclohexane (1v) The title compound was prepared using general procedure for the synthesis of exocyclic alkenes. After flash chromatography, the compound was isolated in 85% yield as a volatile colorless oil. All spectral data was found to be in accordance with the literature. [12] 1-Allyl-2-methylenecyclohexane (1x) The title compound was prepared using general procedure A for the synthesis of exocyclic alkenes. After flash chromatography, the compound was isolated in 45% yield as a volatile colorless oil. All spectral data was found to be in accordance with the literature. [13] S9 2.2 Spectral data of the starting materials 2-Methylene-1,1'-bi(cyclohexane) (1m) S10 N-(4-Methylenecyclohexyl)benzamide (1r) S11 3. General procedure B for the formation of aminolactones from alkenes All reactions were performed on a 0.2 mmol scale.
To a flame-dried Schlenk flask charged with the aminal A (synthesized following the procedure reported in reference [1], 4.0 eq., 0.8 mmol) was added trifluoroacetic acid (0.33 mL, 0.6 M), then the mixture was cooled to 0 °C. After 5 min, the corresponding alkene 1 (1.0 eq., 0.2 mmol) was added as a solution in anhydrous 1,2-dimethoxyethane (0.33 mL). The reaction was heated to 50 °C and vigorously stirred for 20 h (unless otherwise stated), after which it was cooled to 0 °C. Then, an aqueous solution of NaOH (1.0 M) was added until a pH >7 was reached. The resulting biphasic mixture was separated and the aqueous phase was extracted with DCM (3 × 50 mL/mmol). The combined organic phases were then dried over anhydrous K2CO3 and filtered. The filtrate was concentrated under reduced pressure to afford the crude product, which was purified by flash column chromatography on silica gel with DCM-DMA (DMA = solvent mixture of dichloromethane, methanol, aq. NH4OH in the ratio 9:1:0.15) or heptane-EEA (EEA = solvent mixture of ethyl acetate, ethanol, aq. NH4OH in the ratio 3:1:0.08) to afford the analytically pure desired products 2.
as an off-white solid. Only the major diastereoisomer was characterized.

3-(Diallylamino)-1-oxaspiro[4.5]decan-2-one (5d)
The title compound was prepared from diallylamine using general To a stirred solution of spirolactone 2j (single diastereoisomer, 14 mg, 0.05 mmol, 1 eq.) in DCM (1 mL) was added mCPBA (17 mg, 0.075 mmol, 1.50 eq.) in one portion at 0 °C and the reaction mixture was stirred for 4 h at the same temperature. The reaction mixture was then treated with sat. aq. Na2CO3 solution (1 mL) and the mixture was stirred for 15 min. The phases were separated and the organic phase was dried over Na2SO4, concentrated, and purified by column chromatography on silica gel (heptane/EtOAc neat to 5:1) to afford the product 6 in 65% yield (7.4 mg) as a colorless oil.

Assessment of the reactivity of different classes of alkenes
As can be inferred from the scope presented within the manuscript, during the course of our investigations, we found 1,1-disubstituted alkenes to be privileged motifs for this aminolactonization reaction.
Below, we aim to showcase the less selective reactivity of other classes of alkenes and comment on the regioselectivity that was observed for substrates presented in the reaction scope (Scheme 1 of the manuscript).
As previously reported, monosubstituted terminal alkenes tend to favor formation of products derived from hydroaminoalkylation. [1] This preference, however, does not always preclude the formation of aminolactones, as 4-phenyl-1-butene was found to provide S1 in 23% NMR yield. A similarly non-selective reaction was observed for olefins embedded within a carbocycle, such as cycloheptene (giving product S2 in 42% yield alongside varying amounts of hydroaminoalkylation products) and 1-methylcyclohexene (S3 formed in 20% NMR yield).
Alkenes bearing electron-withdrawing substituents-such as methyl acrylate-were not found to undergo any sort of productive reaction under the reported conditions, while dienes-such as trans-1-phenyl-1,3-butadiene-underwent non-specific decomposition with no detectable product formation.
With regard to the chemoselectivity observed for products bearing multiple olefins, several factors might be at play. The result obtained for 2y can also be contrasted with 2w, which does result from the reaction of a trisubstituted double bond. However, in comparison with 1y, the olefin found in 1w is i) likely more sterically accessible and ii) its reactivity is not attenuated by the inductive effects invoked above. [14] In order to establish reproducibility of the previously reported transformation, a test reaction was performed, aiming to obtain the product of Run 6 ( Table 2). As shown below, the reaction was found to be reproducible in our hands.

Comparison with the Huang & Li procedure
For this reason, we set out to survey amines not bearing electron-depleting substituents. As can be seen below, the reaction of methylenecyclohexane, ethyl glyoxylate and dibenzylamine did not lead to the formation of quantifiable amounts of product.
We further wanted to probe the ability of the previously reported conditions to tolerate potentially sensitive functional groups. For this reason, 8-methylene-1,4dioxaspiro [4.5]decane (1n) was subjected to the reaction conditions using a suitable, electron-deficient amine.
Notably, this transformation also did not yield any of the anticipated product, leading only to non-specific decomposition on the acetal-containing starting material, which could not be recovered. This result further highlights the contrasts between the related previously reported procedure and the transformation shown herein.

Stereochemical assignments
An explanation of pseudosymmetry on lactone 2j is depicted in the following scheme.
The major diastereoisomer of 2j was crystallized from heptane/EtOAc and analyzed by X-ray crystallography showing a syn relationship between Cx and Ox.

S40
The five-membered lactone ring is disordered, likely due to pseudosymmetry on the spiroquaternary carbon center. Therefore, the relative configurations of compounds 2h, 2i, 2k, 2o, 2q, and 2r were assigned in analogy to have syn configuration at Cx-Ox of the major diastereoisomer.
The configuration of compounds 2l, 2m, 2p, 2s, 2v, and 2x having 1,2 substitution patterns on the cyclohexane ring and exhibiting no pseudochirality could not be analyzed by X-Ray crystallography. The NOESY experiment of the major diastereomer of 2p showed strong NOE cross-peaks between protons of the NMe2 group with the CH2 group neighboring the quaternary spiro center. Moreover, the proton adjacent to the NMe2 group showed cross-S41 peaks of medium to weak intensity with all of the protons of the EtO group, suggesting that the NMe2 group has a syn relationship with the spirocyclic oxygen atom. On the other hand, the chemical shifts of CH2 protons on the lactone ring are shifted up to 2.49 ppm, resulting from this proton's axial location. Additionally, the acidic proton adjacent to the NMe2 group is shifted significantly downfield, up to 3.95 ppm, which is likely a deshielding result of the quasihydrogen bond with the EtO group located in an equatorial position.
Therefore, the relative configuration of compounds 2l, 2m, 2s, 2v, and 2x were assigned in analogy. It is advisable to attempt to resolve as many as possible of the alerts in all categories. Often the minor alerts point to easily fixed oversights, errors and omissions in your CIF or refinement strategy, so attention to these fine details can be worthwhile. In order to resolve some of the more serious problems it may be necessary to carry out additional measurements or structure refinements.

X-Ray crystallographic data of 2j
However, the purpose of your study may justify the reported deviations and the more serious of these should normally be commented upon in the discussion or experimental section of a paper or in the "special_details" fields of the CIF.
checkCIF was carefully designed to identify outliers and unusual parameters, but every test has its limitations and alerts that are not important in a particular case may appear. Conversely, the absence of alerts does not guarantee there are no aspects of the results needing attention. It is up to the individual to critically assess their own results and, if necessary, seek expert advice.

Publication of your CIF in IUCr journals
A basic structural check has been run on your CIF. These basic checks will be run on all CIFs submitted for publication in IUCr journals (Acta

Crystallographica, Journal of Applied Crystallography, Journal of Synchrotron
Radiation); however, if you intend to submit to Acta Crystallographica Section C or E or IUCrData, you should make sure that full publication checks are run on the final version of your CIF prior to submission.