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Article

BF3·Et2O-Promoted Decomposition of Cyclic α-Diazo-β-Hydroxy Ketones: Novel Insights into Mechanistic Aspects

by
Francesco Venturoni
1,2,
Bruno Cerra
1,
Maura Marinozzi
1,
Emidio Camaioni
1,
Antimo Gioiello
1,* and
Roberto Pellicciari
1,3
1
Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo 1, 06123 Perugia, Italy
2
Novartis Pharma AG, CH-4002 Basel, Switzerland
3
TES Pharma, Corso Vannucci 47, 06121 Perugia, Italy
*
Author to whom correspondence should be addressed.
Catalysts 2018, 8(12), 600; https://doi.org/10.3390/catal8120600
Submission received: 25 October 2018 / Revised: 20 November 2018 / Accepted: 21 November 2018 / Published: 2 December 2018
(This article belongs to the Section Catalysis in Organic and Polymer Chemistry)
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Abstract

:
We report novel insights into the cascade rearrangement of destabilized vinyl cations deriving from the BF3·Et2O-induced decomposition of cyclic α-diazo-β-hydroxy ketones in turn prepared by aldol-type condensation of cycloalkanones with diazoacetone. Complexation of the hydroxy group of the α-diazo-β-hydroxy compound with the Lewis acid is the first event, followed by the generation of the cycloalkanylidenediazonium salt that, after nitrogen loss, produces the highly reactive vinyl cation. The subsequent ring expansion results in the formation of a cycloalkenyl vinyl cation that affords the allylic cation by 1,2-methylene shift and ring contraction. The cation can then trap the solvent, the fluoride or the hydroxide released from the [BF3OH]− to afford different reaction products. The effect of both solvent and substrate ring size on products types and ratios were analyzed and discussed from a mechanistic point of view.

Graphical Abstract

1. Introduction

Since Curtius’s pioneering work on the diazotization of glycine in 1883 [1], α-diazocarbonyl compounds have represented versatile reagents for myriad chemical transformations including the homologation reaction of carbonyl compounds, cyclopropanation of olefins, aziridination, bond insertion reactions, sigmatropic rearrangements, 1,3-dipolar and Staudinger cycloaddition [2,3,4,5,6,7]. In most of these reactions, transition metals able to stabilize the highly reactive carbene intermediate are employed, including copper, rhodium, ruthenium, iridium, palladium, cobalt and iron species [8]. While the literature illustrates several examples and applications on α-diazo-β-hydroxy esters, especially in the homologation reaction of acyclic and cyclic ketones [2,3], only few reports concern the use of α-diazo-β-hydroxy ketones (Scheme 1). In 1981, we reported the Rh2(OAc)4-catalyzed decomposition of α-diazo-β-hydroxy ketones 3a, prepared from diazo lithioacetone (LiDAA, 1a) and aldehydes 2a, affording β-diketones 4 in 68–81% isolated yield (Scheme 1A) [9]. Notably, this two-step approach was adopted for the synthesis of the natural product β-damascone [9], and later for the preparation of β-diketones [10] and chiral N-protected α-amino-β-diketones [11].
More recently, López-Herrera and Sarabia-García studied the photochemical decomposition of α-diazo ketone 3b prepared from 2,3-O-isopropylidene-d-glyceraldehyde (2b) and diazoacetone (DAA, 1b) to determine those factors that favor the Wolf rearrangement over the 1,2-hydride shift (Scheme 1B) [12,13,14]. In line with this work, Wang and co-workers reported a mechanistic study on the decomposition reaction of β-(N-tosyl)amino diazocarbonyl compounds 3c [15,16,17]. With the aim to define the main factors affecting the formation of 1,2-aryl migration products (6 and 7) over the 1,2-hydride migration adduct (8) (Scheme 1C), the diazo ketone decomposition reaction is conducted under various catalytic systems and the results analyzed by means of Hammett correlation. In 2005, the same authors showed a novel decomposition process of β-thio-substituted α-diazo carbonyls (9) (Scheme 1D) [18]. Interestingly, the treatment of 9 with catalytic amounts of Rh2(OAc)4 in CH2Cl2 at 0 °C leads to only the 1,2-thio group migration products (Z)-10 and (E)-11 [18]. Similarly, β-trimethylsiloxy α-diazo carbonyls 3e are reacted with a stoichiometric amount of trimethylsilyl halides in CH2Cl2 at 0 °C affording a nearly equimolar mixture of α- and γ-halide substituted unsaturated carbonyl products (12 and 13) (Scheme 1E) [19]. To the best of our knowledge, only two research groups shed light on the mechanistic aspects of α-diazo-β-hydroxy ketones rearrangements. In 1981, Miyauchi et al. reported the acid-catalyzed decomposition of 3-aryl-2-diazo-3-hydroxy-1-phenylpropanones in different solvents [20]. Interestingly, more polar solvents favor the formation of aryl migration adducts over the products deriving from the hydrogen migration, while p-toluensulfonic acid (TsOH) is found to be an efficient catalyst for promoting the aryl shift. In 2017, Cleary et al. described the Lewis acid-catalyzed vinyl cation rearrangement of α-diazo-β-hydroxy ketones 1f by 1,2-shift and subsequent C–H insertion at non-activated γ C–H bond [21]. This reaction allows the preparation of synthetic versatile bicyclic cyclopentenones fused with seven- and eight-membered rings (14) (Scheme 1F) [21].
Herein, as a continuation of our interest in diazo chemistry [9,22,23,24,25,26,27,28,29,30,31], we investigated the cascade rearrangement of destabilized vinyl cations deriving from the BF3·Et2O-induced decomposition of α-diazo-β-hydroxy ketones, prepared by aldol-type condensation of cyclic ketones with DAA (1). In particular, the effect of solvent and ring size on products distribution and mechanism paths were analyzed and discussed.

2. Results and Discussion

Preparation and decomposition reaction of hydroxycycloalkyl diazoacetones. Although DAA (1) can be easily obtained by acylation of diazomethane (15) with acetylchloride (16), its isolation from the crude reaction mixture is shown to be inefficient following the poor detailed experimental procedure reported in the original paper [32]. Indeed, the removal of the excess of ethereal diazomethane results in the loss of most highly volatile DAA (1). To overcome this problem, we first distilled off diethyl ether and the excess of diazomethane (15) under atmospheric pressure and the resulting residue was then distilled under reduced pressure. Thus, a solution of 16 was added dropwise to an ethereal solution of 15 at −10 °C affording DAA (1) in nearly quantitative conversion. Et2O and the excess of diazomethane (15) were then distilled off (50 °C, 760 mmHg) through a glass spheres-packed (silver shell) column connected to a Friedrich condenser (Figure 1) [33]. DAA (1) was isolated in 81% yield and high purity after re-distillation (49 °C, 13 mmHg).
DAA (1) was readily submitted to aldol-type condensations with cyclobutanone (17, n = 0), cyclopentanone (18, n = 1), and cyclohexanone (19, n = 2) in presence of lithium diisopropylamide (LDA) as the base. The corresponding 1-diazo-1-(1-hydroxycycloalkyl)propan-2-ones 20–22 were obtained in moderate to good yields after purification of the crude reaction mixture by aluminum oxide (Brockmann activity IV) flash chromatography (Scheme 2).
The lowest yield (57%) was observed for the cyclobutyl adduct 17 (n = 0), probably because of its relative instability also under weak acidic media, e.g., during chromatography (a partial decomposition was observed also in CDCl3 during the NMR analysis). The freshly synthesized α-diazo-β-hydroxy ketones 20–22 thus obtained were dissolved in the solvent chosen for the decomposition (freshly distilled n-pentane, acetonitrile or benzene) and the resulting solution was added dropwise at room temperature to a solution of freshly distilled BF3·Et2O (1.5 equivalents) in the same solvent.
Cyclobutyl derivatives. While the treatment of cyclobutyl analog 20 with BF3·Et2O in n-pentane resulted in a complex mixture of products, the same reaction performed in acetonitrile afforded N-(2-acetylcyclopent-1-en-1-yl)acetamide (23) (77%) as the major product accompanied by small amounts of 1-(2-fluorocyclopent-1-en-1-yl)ethanone (24) (2%) and 2-acetylcyclopentanone (25) (5%) (Scheme 3). A similar product distribution was observed using benzene as the solvent. Indeed, also in this case, the adduct 26 derived from the solvent addition resulted to be the main reaction product (55%), while compounds 24 and 25 were isolated in 13% and 15% yields, respectively (Scheme 3).
Cyclopentyl derivatives. Exposure of 1-diazo-1-(1-hydroxycyclopentyl)propan-2-one (21) to freshly distilled BF3·Et2O in n-pentane afforded a complex and inseparable mixture of products (Scheme 4). When the reaction was carried out in acetonitrile, β-enamino ketone 27, 1-(1-methyl-5,6-dihydrocyclopenta[c]pyrrol-2(4H)-yl)ethan-1-one (28) and 1-(3-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrrol-1-yl)ethanone (29) were isolated in 26%, 36% and 16% yields, respectively, while adducts deriving from fluorine trapping were not observed (Scheme 4). Solvent-adducts, namely 1-(2-benzylcyclopent-1-en-1-yl)ethanone (30) and 1-(2-phenylcyclohex-1-en-1-yl)ethanone (31); 1-cyclopentylidene-1-fluoropropan-2-one (32); and the inseparable mixture of 1-(2-fluorocyclohex-1-en-1-yl)ethanone (33) and 1-cyclopentylidene-1-phenylacetone (34) were isolated using benzene as the solvent (Scheme 4).
Cyclohexyl derivatives. Reaction of 1-diazo-1-(1-hydroxycyclohexyl)propan-2-one (22) with BF3·Et2O in n-pentane resulted again in a complex crude mixture whose purification allowed the exclusive isolation of 1-(2-hydroxycyclohept-1-en-1-yl)ethanone (35) in 12% yield (Scheme 5). When the same reaction was performed in acetonitrile, the enamino ketone 36 was obtained in 42% yield along with minor amounts of 35 (5% isolated yield) and the isomeric products deriving from the fluoride addition, namely 1-cyclohexylidene-1-fluoroacetone (37) and 1-(2-fluorocyclohept-1-en-1-yl)ethanone (38) (Scheme 5). Finally, decomposition of 22 in benzene gave 1-(2-benzylcyclohex-1-en-1-yl)ethanone (39) (45% isolated yield) as the main reaction product with poor amounts of fluorinated adducts 37 and 38, and the ketoenol 35 (Scheme 5).
Proposed reaction mechanism. A mechanism which nicely accommodates the various products isolated in the diverse reactions is outlined in Scheme 6. The complexation of the alcohol functionality of α-diazo-β-hydroxy ketones 20–22 with BF3·Et2O occurs first, followed by the generation of the cycloalkanylidenediazonium salt, which after loss of nitrogen produces the highly reactive and destabilized vinyl cation 40. Rearrangement of 40 via 1,2-methylene shift results in a ring expansion and in the formation of a cyclic vinyl cation 41 that, after 1,2-methylene shift and ring contraction, affords the allylic cation 42 (Scheme 6). As previously reported for α-diazo-β-hydroxy esters [28], these cations can trap solvent, fluoride or hydroxide from the [BF3OH]− specie, generating the corresponding derivatives 43, 44 and 45 (Scheme 6).
It is worth noting that the main differences in terms of reactivity between α-diazo-β-hydroxy esters and ketones are related to the different stabilizing/destabilizing effects of carbonyl in comparison to carboxyl group in the vinyl cation cascade [28]. In general, α-carbonyl vinyl cations result less stable and, therefore, more reactive with respect to α-carboxyl vinyl cations, thus resulting in a more complex array of products. However, in presence of more polar solvents such as acetonitrile, the stabilization of the cation intermediate and the subsequent trapping of the solvent results to be the favored process, with the exception of compound 20, for which the presence of a highly constrained four-membered vinyl cation gives rise of the ring expansion as the exclusive rearrangement process.
A further discussion is needed to explain the formation of tetrahydrocyclopenta[c]pyrroles 28 and 29 by BF3·Et2O-promoted decomposition of 21 in acetonitrile (Scheme 7). The formation of 28 is driven by acetonitrile trapping of the allyl cation intermediate 46, followed by an intramolecular cyclization involving the carbonyl group and the adjacent nitrogen. The obtained hydroxypyrrolidine 48 undergoes dehydration and aromatization leading to tetrahydrocyclopenta[c]pyrrole 28 (Scheme 7). Similarly, the α-carbonyl cation intermediate 50, generated from the 1,3-hydride shift of the linear vinyl cation 49, undergoes a dipolar cycloaddition with acetonitrile, resulting in the formation of 51. Deprotonation and aromatization of the cycloadduct 51 finally leads the product 29 (Scheme 7).
With the aim to support this mechanistic hypothesis and exclude the formation of 29 by 1,2-acetyl shift of 28 (Scheme 7), the decomposition reaction of 21 was carried out in CD3CN. According to Scheme 4, three deuterated derivatives 27-d3, 28-d3 and 29-d3 were obtained. Next, 1H-13C Heteronuclear Multiple-Quantum Correlation (HMQC) experiments were carried out evidencing that singlets at 2.52 and 2.34 ppm correspond to the methyl at C-3 position and the acetyl at C-1 position, respectively. The comparison of the 1H-NMR spectra of 29 and 29-d3 clearly confirms the structure and mechanistic hypothesis as derived from dipolar cycloaddition of CD3CN to cation 50 (Figure 2).

3. Materials and Methods

All the chemicals were purchased from Sigma-Aldrich (Saint Louis, MO, US). All dry solvents were distilled under argon immediately prior to use. Acetonitrile was distilled from P2O5. Benzene and n-pentane were distilled from sodium. N,N-diisopropylamine and BF3·Et2O were distilled from CaH2. Cyclobutanone (17), cyclopentanone (18) and cyclohexanone (19) were distilled in vacuo from molecular sieves (4 Å). All reactions were conducted in flame-dried glassware under a positive pressure of argon. NMR spectra were recorded on a Bruker AC 400 MHz spectrometer (Bruker, Madison, WI, USA) in the indicated solvent. Chemical shifts are reported in parts per million (ppm) using tetramethylsilane (TMS) as internal standard and are relative to CDCl3 (7.26 and 77.0 ppm) or acetone-d6 (2.05, 29.84, and 206.26 ppm). The abbreviations used are as follows: s, singlet; brs, broad singlet; d, doublet; dd, double of doublets; dt, doublet of triplets; t, triplet; q, quartet; qui, quintet; m, multiplet; and brm, broad multiplet. Coupling constants (J) are reported in Hertz (Hz). Flash column chromatography was performed using silica gel (40–63 μm, Merck, Darmstadt, Germany). Thin-layer chromatography (TLC) was performed on aluminum backed silica plates (silica gel 60 F254, Merck, Darmstadt, Germany). Spots were visualized by UV detector (λ = 254 nm) and/or by staining and warming with potassium permanganate. GC-MS analyses were performed using an Agilent Technologies 6890N GC system (Santa Clara, CA, USA) interfaced with a 5973N mass selective detector. An Agilent J&W capillary column (30 m length, 0.32 mm diameter, 0.25 μm film) was employed with a splitless injection (250 °C inlet, 8.8 psi), an initial 70 °C hold (2 min) and ramped for 15 min to 230 °C.

3.1. Preparation of DAA (1)

A 1 L single-neck round bottom flask, equipped with a magnetic stirring bar and a 25 mL pressure-equalizing dropping funnel fitted with an argon inlet, was charged a freshly prepared etheral solution of diazomethane (15, title: 2.3% w/v, 427 mmol, 780 mL) [33]. The flask was cooled to −10 °C and acetyl chloride (16, 143 mmol, 10 mL) was added dropwise over 2 h. After the addition was complete, the reaction mixture was stirred at −10 °C for additional 30 min. Then, the dropping funnel was removed and the flask was fitted with a vacuum-insulated silvered column (20 cm length, 1 cm i.d.) packed with glass helices (size 2.3 mm) and connected to a water-cooled Friedrich condenser (Figure 1). The cooling bath was removed and replaced by a heating mantel. The temperature was gently increased up to 50 °C. A first yellow fraction, containing the excess of 15, was collected (ca. 100 mL) followed by clear Et2O. The residue yellow liquid was transferred to a 25 mL single-neck round bottom flask and redistilled in vacuo (49 °C, 13 mmHg) cooling at −10 °C, with both the collecting flask (pig adapter) and the two traps placed between the vacuum pump and the distillation head. Thus, DAA (1) (9.7 g, 115 mmol, 81% yield) was obtained in high purity.

3.2. General Procedures for the Preparation of 1-Diazo-1-(1-hydroxycycloalkyl)acetone Derivatives 20–22

A solution of LDA was prepared by addition of n-BuLi (2.5 M in n-hexane, 1.2 mmol) to a solution of freshly distilled N,N-diisopropylamine (1.4 mmol) in freshly distilled tetrahydrofurane (THF) (3 mL) at −78 °C under nitrogen atmosphere. This cold solution was added, during 30 min, to a stirred solution of the appropriate distilled ketone 17–19 (1 mmol) and freshly prepared diazoacetone (1) (1 mmol) in dry THF (3 mL) at −78 °C. The mixture was stirred at −78 °C for 2 h, and then quenched with an aqueous saturated solution of NH4Cl (30 mL) and extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed with aqueous saturated solution of NaHCO3 (30 mL) and brine (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography (Eluent: n-hexane/EtOAc, from 100:0 to 90:10, v/v) affording the corresponding 1-diazo-1-(1-hydroxycycloalkyl)acetone derivatives 20–22.
1-Diazo-1-(1-hydroxycyclobuthyl)acetone (20): Obtained in 57% yield as yellow oil. 1H-NMR (400 MHz, acetone-d6) δ: 1.67–1.71 (m, 2H), 1.75–1.95 (m, 2H), 2.19 (s, 3H), 2.37–2.43 (m, 2H), 4.60 (brs, 1H).
1-Diazo-1-(1-hydroxycyclopenthyl)acetone (21): Obtained in 90% yield as yellow oil. 1H-NMR (400 MHz, acetone-d6) δ: 1.66–1.69 (m, 2H), 1.80–1.96 (m, 6H), 2.22 (s, 3H), 4.35 (s, 1H). 13C-NMR (100.6 MHz, acetone-d6) δ: 22.9 (2x), 25.9, 38.5 (2x), 77.2, 190.8.
1-Diazo-1-(1-hydroxycyclohexyl)acetone (22) [34]: Obtained in 82% yield as yellow oil. 1H-NMR (400 MHz, CDCl3) δ: 1.42–1.47 (m, 2H), 1.57–1.60 (m, 4H), 1.68–1.74 (m, 2H), 1.84–1.92 (m, 2H), 2.22 (s, 3H), 4.28 (brs, 1H). 13C-NMR (100.6 MHz, CDCl3) δ: 21.6 (2x), 25.2, 26.3, 36.1 (2x), 70.8, 193.6.

3.3. General Procedure for BF3·Et2O-Induced Decomposition of 1-Diazo-1-(1-hydroxycycloalkyl)acetone 20–22

To a stirred solution of freshly distilled BF3∙Et2O (1.66 mmol) in the selected anhydrous solvent (5 mL), a solution of 20–22 (1.11 mmol) in the same solvent (30 mL) was added at room temperature by using a syringe-pump (0.02 mmol min−1). After the complete addition, the reaction mixture was stirred for an additional 30 min at room temperature and then poured into a saturated aqueous solution of NaHCO3 (75 mL), extracted with EtOAc (3 × 25 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The reaction crude was purified by flash chromatography.
N-(2-Acetylcyclopent-1-en-1-yl)acetamide(23): Amorphous solid. 1H-NMR (400 MHz, CDCl3) δ: 1.83–1.90 (m, 2H), 2.09 (s, 3H), 2.12 (s, 3H), 2.52–2.56 (m, 2H), 3.10–3.14 (m, 2H), 11.38 (brs, 1H). 13C-NMR (100.6 MHz, CDCl3) δ: 21.2, 24.7, 29.35, 29.36, 33.9, 115.2, 155.4, 169.1, 199.0. GC-MS: tR = 19.627 min; m/z (%) = 167.2 ([M+], 100).
1-(2-Fluorocyclopent-1-en-1-yl)ethan-1-one(24): Amorphous solid. 1H-NMR (400 MHz, CDCl3) δ: 1.94–2.02 (m, 2H), 2.36 (s, 3H), 2.42–2.54 (m, 4H). 13C-NMR (100.6 MHz, CDCl3) δ: 27.2 (d, JC-F = 30.62 Hz), 27.7, 28.4 (d, JC-F = 8.74 Hz), 34.7 (d, JC-F = 1.62 Hz), 126.4 (d, JC-F = 12.84 Hz), 144.6 (d, JC-F = 118.47 Hz), 194.6 (d, JC-F = 36.2 Hz). 19F-NMR (376 MHz, CDCl3) δ: −67.1. GC-MS: tR = 10.751 min; m/z (%) = 128.1 ([M]+, 42), 113.1 (100), 85.1 (18), 65.1 (20), 59.1 (12).
2-Acetylcyclopentan-1-one(25) [35]: Colorless liquid. 1H-NMR (400 MHz, CDCl3) δ: 2.13 (s, 3H), 2.13–2.40 (m, 6H), 2.92 (brs, 1H). 13C-NMR (100.6 MHz, CDCl3) δ: 20.2, 25.8, 30.2, 38.6, 62.8, 205.2, 212.8. GC-MS: tR = 21.216 min; m/z (%) = 126.1 ([M+], 100).
1-(2-Phenylcyclopent-1-en-1-yl)ethan-1-one (26) [36]: Colorless oil. 1H-NMR (400 MHz, CDCl3) δ: 1.91 (s, 3H), 1.96 (qui, J = 7.70 Hz, 2H), 2.81 (tt, J1 = 2.26 Hz, J2 = 7.78 Hz, 2H), 2.87 (tt, J1 = 2.23 Hz, J2 = 7.50 Hz, 2H), 7.22–7.24 (m, 3H), 7.32–7.39 (m, 2H). 13C-NMR (100.6 MHz, CDCl3) δ: 21.9, 29.9, 35.1, 41.7, 127.7, 128.3, 128.6, 138.1, 139.7, 153.1, 200.2. GC-MS: tR = 21.080 min; m/z (%) = 186.2 ([M + 1]+, 50), 185.2 ([M]+, 100), 171.2 (80), 143.2 (16), 128.1 (59), 115.1 (31), 91.2 (8), 77.1 (6), 63.1 (6), 50.1 (5).
N-(2-Acetylcyclohex-1-en-1-yl)acetamide (27) [37]: Amorphous solid. 1H-NMR (400 MHz, CDCl3) δ: 1.56–1.63 (m, 4H), 2.08 (s, 3H), 2.18 (s, 3H), 2.35–2.37 (m, 2H), 2.95–2.98 (m, 2H), 12.80 (brs, 1H). 13C-NMR (100.6 MHz, CDCl3) δ: 21.4, 22.0, 25.6, 26.3, 28.4, 28.9, 111.2, 152.8, 169.5, 202.5. GC-MS: tR = 17.059 min; m/z (%) = 181.2 ([M]+, 28), 139.2 (70), 138.2 (100), 124.1 (65), 111.1 (10), 96.2 (55), 79.1 (10), 68.1 (7), 54.1 (6).
1-(1-Methyl-5,6-dihydrocyclopenta[c]pyrrol-2(4H)-yl)ethan-1-one (28): Amorphous solid. 1H-NMR (400 MHz, CDCl3) δ: 1.94 (qui, J = 7.42 Hz, 2H), 2.32 (s, 3H), 2.34 (s, 3H), 2.40–2.44 (m, 2H), 2.60–2.65 (m, 2H), 6.04–6.05 (m, 1H). 13C-NMR (100.6 MHz, CDCl3) δ: 11.4, 13.6, 23.4, 32.6, 33.4, 127.1, 132.0, 134.1, 142.9, 158.8. GC-MS: tR = 13.889 min; m/z (%) = 164.2 ([M + 1]+, 10), 163.2 ([M]+, 91), 162.1 (59), 149.1 (10), 148.1 (100), 120.1 (21), 107.1 (32), 91.1 (10), 79.1 (38), 65.1 (7), 51.1 (11).
1-(3-Methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrrol-1-yl)ethan-1-one (29) [38]: Amorphous solid. 1H-NMR (400 MHz, CDCl3) δ: 2.34 (s, 3H), 2.42 (qui, J = 7.39 Hz, 2H), 2.52 (s, 3H), 2.65 (t, J = 7.14 Hz, 2H), 2.80 (t, J = 6.81 Hz, 2H), 8.42 (brs, 1H). 13C-NMR (100.6 MHz, CDCl3) δ: 14.7, 25.1, 27.5, 28.5, 29.6, 117.2, 127.3, 133.7, 138.2, 195.4. GC-MS: tR = 18.953 min; m/z (%) = 164.1 ([M + 1]+, 7), 163.1 ([M]+, 56), 162.1 (9), 149.1 (11), 148.1 (100), 120.1 (19), 91.1 (6), 77.1 (9), 60.5 (4), 51.0 (3).
1-(2-Benzylcyclopent-1-en-1-yl)ethan-1-one (30): Amorphous solid. 1H-NMR (400 MHz, CDCl3) δ: 1.73–1.82 (m, 2H), 2.27 (s, 3H), 2.37–2.41 (m, 2H), 2.69–2.73 (m, 2H), 3.90 (s, 2H), 7.18–7.21 (m, 2H), 7.25–7.29 (m, 3H). 13C-NMR (100.6 MHz, CDCl3) δ: 21.5, 23.6, 34.6, 36.2, 37.9, 126.1, 128.4, 128.8, 136.9, 139.0, 155.6, 198.6. GC-MS: tR = 22.273 min; m/z (%) = 201.2 ([M + 1]+, 15), 200.2 ([M]+, 100), 185.1 (78), 167.1 (22), 157.1 (47), 141.1 (12), 129.1 (47), 118.1 (21), 109.1 (34), 91.1 (53), 77.1 (18), 65.1 (13), 51.1 (9).
1-(2-Phenylcyclohex-1-en-1-yl)ethan-1-one (31) [39]: Amorphous solid. 1H-NMR (400 MHz, CDCl3) δ: 1.22–1.44 (m, 2H), 1.68–1.76 (m, 2H), 1.68 (s, 3H), 2.38–2.44 (m, 4H), 7.16–7.32 (m, 5H). 13C-NMR (100.6 MHz, CDCl3) δ: 22.0, 22.6, 26.4, 30.2, 32.4, 127.6, 127.8, 128.2, 137.6, 142.6, 143.4, 206.2. GC-MS: tR = 21.135 min; m/z (%) = 200.2 ([M]+, 9), 157.2 (98), 142.1 (15), 129.1 (100), 115.1 (45), 91.1 (51), 77.1 (12), 65.1 (5), 51.1 (5).
1-Cyclopentylidene-1-fluoropropan-2-one (32): Colorless oil. 1H-NMR (400 MHz, CDCl3) δ: 1.67–1.76 (m, 4H), 2.26 (d, J = 4.80 Hz, 3H), 2.47–2.49 (m, 2H), 2.68–2.70 (m, 2H). 13C-NMR (100.6 MHz, CDCl3) δ: 25.5, 27.1, 27.2 (d, JC-F = 2.86 Hz), 30.7 (d, JC-F = 3.15 Hz), 31.3 (d, JC-F = 1.67 Hz), 140.0 (d, JC-F = 14.65 Hz), 149.3 (d, JC-F = 248.10 Hz), 193.3 (d, JC-F = 38.0 Hz). 19F-NMR (376 MHz, CDCl3) δ: −124.7. GC-MS: tR = 12.593 min; m/z (%) = 143.1 ([M + 1]+, 9), 142.1 ([M]+, 100), 141.1 (19), 127.1 (37), 113.1 (43), 107.1 (83), 99.1 (20), 91.1 (6), 85.1 (4), 79.1 (53), 73.1 (5), 67.1 (9), 59.1 (11), 51.1 (17).
1-(2-Hydroxycyclohept-1-en-1-yl)ethan-1-one (35): Yellow oil. 1H-NMR (400 MHz, CDCl3) δ: 1.58–1.64 (m, 6H), 2.24 (s, 3H), 2.36–2.38 (m, 2H), 2.48–2.56 (m, 2H), 15.86 (s, 1H). 13C-NMR (100.6 MHz, CDCl3) δ: 22.4, 24.2, 26.7, 27.2, 28.6, 38.4, 117.2, 138.4, 198.2. GC-MS: tR = 18.953 min; m/z (%) = 163.1 ([M]+, 100).
N-(2-Acetylcyclohept-1-en-1-yl)acetamide (36): Amorphous solid. 1H-NMR (400 MHz, CDCl3) δ: 1.49–1.54 (m, 2H), 1.60–1.65 (m, 2H), 1.72–1.76 (m, 2H), 2.08 (s, 3H), 2.23 (s, 3H), 2.46–2.49 (m, 2H), 3.05–3.07 (m, 2H), 12.46 (brs, 1H). 13C-NMR (100.6 MHz, CDCl3) δ: 24.2, 25.7, 26.4, 27.9, 29.2, 29.9, 31.5, 119.4, 158.1, 170.0, 201.6. GC-MS: tR = 17.500 min; m/z (%) = 195.2 ([M + 1]+, 9), 162.1 (4), 153.2 (19), 152.2 (100), 138.1 (31), 124.1 (14), 110.2 (39), 93.1 (7), 82.1 (10), 54.1 (6).
1-Cyclohexylidene-1-fluoropropan-2-one (37) [40]: Colorless oil. 1H-NMR (400 MHz, CDCl3) δ: 1.56–1.65 (m, 6H), 2.27–2.32 (m, 5H), 2.72–2.75 (m, 2H). 13C-NMR (100.6 MHz, CDCl3) δ: 26.0 (d, JC-F = 0.29 Hz), 27.2 (d, JC-F = 1.82 Hz), 27.3 (d, JC-F = 2.82 Hz), 27.4 (d, JC-F = 9.60 Hz), 27.5 (d, JC-F = 2.72 Hz), 28.3 (d, JC-F = 2.4 Hz), 134.8 (d, JC-F = 12.44 Hz), 148.3 (d, JC-F = 246.64 Hz), 194.7 (JC-F = 42.11 Hz). 19F-NMR (376 MHz, CDCl3) δ: −127.48. GC-MS: tR = 9.899 min; m/z (%) = 157.1 ([M + 1]+, 9), 156.1 ([M]+, 100), 141.1 (23), 135.1 (5), 127.1 (35), 121.1 (27), 113.1 (81), 102.1 (23), 93.1 (34), 85.1 (12), 77.1 (20), 67.1 (19), 59.1 (11), 51.1 (13).
1-(2-Fluorocyclohept-1-en-1-yl)ethan-1-one (38): Colorless oil. 1H-NMR (400 MHz, CDCl3) δ: 1.49–1.53 (m, 2H), 1.64–1.69 (m, 2H), 1.71–1.75 (m, 2H), 2.36–2.40 (m, 5H), 2.52–2.55 (m, 1H), 2.56–2.59 (m, 1H). 13C-NMR (100.6 MHz, CDCl3) δ: 23.98 (d, JC-F = 2.77 Hz), 24.03 (d, JC-F = 6.01 Hz), 26.1 (d, JC-F = 1.58 Hz), 31.1, 32.0 (d, JC-F = 9.60 Hz), 32.9 (d, JC-F = 29.42 Hz), 121.6 (d, JC-F = 7.11 Hz), 172.5 (d, JC-F = 281.68 Hz), 197.2. 19F-NMR (376 MHz, CDCl3) δ: −70.87. GC-MS: tR = 15.329 min; m/z (%) = 156.1 ([M]+, 46), 141.1 (100), 128.1 (4), 121.1 (7), 113.1 (22), 93.1 (20), 83.0 (10), 77.1 (15), 67.1 (7), 59.1 (6), 51.1 (7).
1-(2-Benzylcyclohex-1-en-1-yl)ethan-1-one (39) [41]: Amorphous solid. 1H-NMR (400 MHz, CDCl3) δ: 1.55–1.59 (m, 2H), 1.62–1.68 (m, 2H), 1.99–2.02 (m, 2H), 2.28 (s, 3H), 2.29–2.33 (m, 2H), 3.55 (s, 2H), 7.19–7.23 (m, 3H), 7.26–7.30 (m, 2H). 13C-NMR (100.6 MHz, CDCl3) δ: 22.0, 22.1, 26.9, 29.5, 29.6, 40.0, 125.9, 128.2, 128.7, 135.0, 139.6, 140.6, 204.8. GC-MS: tR = 23.0219 min; m/z (%) = 215.2 ([M + 1]+, 15), 214.2 ([M]+, 89), 199.2 (98), 181.2 (12), 171.2 (32), 157.1 (62), 141.2 (19), 129.6 (61), 115.2 (34), 105.2 (12), 91.2 (100), 77.2 (24), 65.2 (22), 51.2 (11).

4. Conclusions

We studied the mechanistic hypotheses of the BF3·Et2O-promoted decomposition reaction of cycloalkyl α-diazo-β-hydroxy ketones in various solvents. In line with previous findings on α-diazo-β-hydroxy esters [28], vinyl cation formation, rearrangement and carbenium ion trapping accommodate both products structure and distribution deriving from the different reaction pathways. Although ab initio computational studies are needed to confirm our mechanistic hypothesis, it is likely that the driving force for vinyl cations rearrangement is basically determined by the formation of a more stable carbenium ion. Interestingly, it can be ruled out that the main difference in reactivity between α-diazo-β-hydroxy esters and ketones derived from the different electronic characteristics of the carbonyl versus the carboxyl group. Indeed, they behaved differently in the stabilization/destabilization of the cation intermediates that, in turn, drive products type and distribution. It is worth noting that a novel reaction pathway was identified, yielding tetrahydrocyclopenta[c]pyrroles 28 and 29, which represent relevant structural frameworks for the synthesis of biologically active compounds [42,43,44,45].

Supplementary Materials

The following are available online at https://www.mdpi.com/2073-4344/8/12/600/s1: NMR and GC-MS spectra of compounds 20–39, and semiempirical, quantum mechanical calculations for intermediates 40–42.

Author Contributions

F.V., R.P. and A.G. conceived and designed the experiments; F.V. and B.C. performed the experiments; F.V., M.M. and A.G. analyzed the data; E.C. contributed reagents/materials/analysis tools; B.C. contributed with publication fees; and F.V. and A.G. wrote the paper.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

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Catalysts 08 00600 sch001 550
Scheme 1. Main synthetic applications of α-diazo-β-hydroxy ketones and analogs.
Scheme 1. Main synthetic applications of α-diazo-β-hydroxy ketones and analogs.
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Catalysts 08 00600 g001 550
Figure 1. Apparatus used for the preparation and isolation of diazoacetone (1).
Figure 1. Apparatus used for the preparation and isolation of diazoacetone (1).
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Catalysts 08 00600 sch002 550
Scheme 2. Synthesis of 1-diazo-1-(1-hydroxycycloalkyl)acetones 20–22.
Scheme 2. Synthesis of 1-diazo-1-(1-hydroxycycloalkyl)acetones 20–22.
Catalysts 08 00600 sch002
Catalysts 08 00600 sch003 550
Scheme 3. BF3·Et2O-induced decomposition of 1-diazo-1-(1-hydroxycyclobutyl)propan-2-one (20).
Scheme 3. BF3·Et2O-induced decomposition of 1-diazo-1-(1-hydroxycyclobutyl)propan-2-one (20).
Catalysts 08 00600 sch003
Catalysts 08 00600 sch004 550
Scheme 4. BF3·Et2O-induced decomposition of 1-diazo-1-(1-hydroxycyclopentyl)propan-2-one (21).
Scheme 4. BF3·Et2O-induced decomposition of 1-diazo-1-(1-hydroxycyclopentyl)propan-2-one (21).
Catalysts 08 00600 sch004
Catalysts 08 00600 sch005 550
Scheme 5. BF3·Et2O-induced decomposition of 1-diazo-1-(1-hydroxycyclohexyl)propan-2-one (22).
Scheme 5. BF3·Et2O-induced decomposition of 1-diazo-1-(1-hydroxycyclohexyl)propan-2-one (22).
Catalysts 08 00600 sch005
Catalysts 08 00600 sch006 550
Scheme 6. Carbocation cascade in the BF3·Et2O-promoted decomposition of α-diazo-β-hydroxy ketones 20–22.
Scheme 6. Carbocation cascade in the BF3·Et2O-promoted decomposition of α-diazo-β-hydroxy ketones 20–22.
Catalysts 08 00600 sch006
Catalysts 08 00600 sch007 550
Scheme 7. Proposed reaction mechanism for the formation of tetrahydrocyclopenta[c]pyrrole derivatives 28 and 29 from the BF3·Et2O-promoted decomposition of 1-diazo-1-(1-hydroxycyclopentyl)propan-2-one (21) in acetonitrile.
Scheme 7. Proposed reaction mechanism for the formation of tetrahydrocyclopenta[c]pyrrole derivatives 28 and 29 from the BF3·Et2O-promoted decomposition of 1-diazo-1-(1-hydroxycyclopentyl)propan-2-one (21) in acetonitrile.
Catalysts 08 00600 sch007
Catalysts 08 00600 g002 550
Figure 2. Comparison of the 1H-NMR spectra of 29 and 29-d3.
Figure 2. Comparison of the 1H-NMR spectra of 29 and 29-d3.
Catalysts 08 00600 g002

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Venturoni, F.; Cerra, B.; Marinozzi, M.; Camaioni, E.; Gioiello, A.; Pellicciari, R. BF3·Et2O-Promoted Decomposition of Cyclic α-Diazo-β-Hydroxy Ketones: Novel Insights into Mechanistic Aspects. Catalysts 2018, 8, 600. https://doi.org/10.3390/catal8120600

AMA Style

Venturoni F, Cerra B, Marinozzi M, Camaioni E, Gioiello A, Pellicciari R. BF3·Et2O-Promoted Decomposition of Cyclic α-Diazo-β-Hydroxy Ketones: Novel Insights into Mechanistic Aspects. Catalysts. 2018; 8(12):600. https://doi.org/10.3390/catal8120600

Chicago/Turabian Style

Venturoni, Francesco, Bruno Cerra, Maura Marinozzi, Emidio Camaioni, Antimo Gioiello, and Roberto Pellicciari. 2018. "BF3·Et2O-Promoted Decomposition of Cyclic α-Diazo-β-Hydroxy Ketones: Novel Insights into Mechanistic Aspects" Catalysts 8, no. 12: 600. https://doi.org/10.3390/catal8120600

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