BF 3 · Et 2 O-Promoted Decomposition of Cyclic α -Diazo- β -Hydroxy Ketones: Novel Insights into Mechanistic Aspects

: We report novel insights into the cascade rearrangement of destabilized vinyl cations deriving from the BF 3 · Et 2 O-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 [BF 3 OH] − 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.


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 Scheme 1. Main synthetic applications of α-diazo-β-hydroxy ketones and analogs.

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. Et 2 O 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). 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 αdiazo-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  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 αdiazo-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 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 CDCl 3 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 BF 3 ·Et 2 O (1.5 equivalents) in the same solvent.

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

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 BF 3 ·Et 2 O 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 [BF 3 OH] − specie, generating the corresponding derivatives 43, 44 and 45 (Scheme 6).

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 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 BF 3    With the aim to support this mechanistic hypothesis and exclude the formation of 29 by 1,2acetyl 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, 1 H-13 C 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 1 H-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).

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.

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

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 P 2 O 5 . Benzene and n-pentane were distilled from sodium. N,N-diisopropylamine and BF 3 ·Et 2 O were distilled from CaH 2 . 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 CDCl 3 (7.26 and 77.0 ppm) or acetone-d 6 (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.

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 Et 2 O. 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. To a stirred solution of freshly distilled BF 3 ·Et 2 O (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 NaHCO 3 (75 mL), extracted with EtOAc (3 × 25 mL), dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure. The reaction crude was purified by flash chromatography.   -1-en-1-yl) Hydroxycyclohept-1-en-1-yl)

Conclusions
We studied the mechanistic hypotheses of the BF 3 ·Et 2 O-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].