Unusually Chemoselective Photocyclization of 2-(Hydroxyimino)aldehydes to Cyclobutanol Oximes: Synthetic, Stereochemical, and Mechanistic Aspects

Photocyclization of carbonyl compounds (known as the Norrish–Yang reaction) to yield cyclobutanols is, in general, accompanied by fragmentation reactions. The latter are predominant in the case of aldehydes so that secondary cyclobutanols are not considered accessible via the straightforward Norrish–Yang reaction. A noteworthy exception has been reported in our laboratory, where cyclobutanols bearing a secondary alcohol function were observed upon UV light irradiation of 2-(hydroxyimino)aldehydes (HIAs). This reaction is here investigated in detail by combining synthesis, spectroscopic data, molecular dynamics, and DFT calculations. The synthetic methodology is generally applicable to a series of HIAs, affording the corresponding cyclobutanol oximes (CBOs) chemoselectively (i.e., without sizable fragmentation side-reactions), diastereoselectively (up to >99:1), and in good to excellent yields (up to 95%). CBO oxime ether derivatives can be purified and diastereomers isolated by standard column chromatography. The mechanistic and stereochemical picture of this photocyclization reaction, as well as of the postcyclization E/Z isomerization of the oxime double bond is completed.


Photochemical setup
The photoreactor for NMR-scale experiments consists of a lab-made LED chip assembly equipped with a sample holder. ( Figure S1). The LED assembly is obtained by gluing a single LED chip (Nichia NVSU233A-D1 UV SMD-LED with PCB (10x10mm), λ = 365nm, 1030mW radiant flux or Nichia NVSU233B SMD-LED UV with PCB (10x10mm), λ = 365nm, 1450mW radiant flux, 3.75 V forward voltage from LUMITRONIX® LED-Technik GmbH) on an aluminum heat sink, using Fischer Elektronik heat-conducting adhesive WLK DK 4. The LED is powered with a constant current power supply (Meanwell LCM-40 Series, LUMITRONIX® LED-Technik GmbH). The sample holder consists of an aluminum block with a 7 mm housing to accommodate a 5mm NMR tube. The sample holder is screwed on top of the LED holder for easy replacement of the LED chip. The NMR tubing is placed in direct contact with the silicon lens that covers the light source and ensures a 60° viewing angle. Care should be taken not to damage the silicon lens. The system is kept at room temperature with the aid of a cooling fan. Figure S1. LED assembly for the photostimulation of samples for NMR studies. Schematic is not drawn to scale. S4 2. Synthetic procedures 2.1. General procedure for aldehydes synthesis via Albright-Onodera oxidation [1] To a solution of the alcohol (4.0 mmol, 1.0 equiv) in CH2Cl2 (10 mL) and DMSO (8.0 mmol, 2 equiv), P2O5 (7.2 mmol, 1.8 equiv) is added slowly to avoid overheating. The resulting slurry is stirred at room temperature for 1 h then cooled to 0 °C with an ice bath, then Et3N (14.0 mmol, 3.5 equiv) is added dropwise. The resulting clear solution is stirred at room temperature for about 30 min (reaction completion is monitored via GC-MS analysis), then quenched with cold (4 °C) 1 M HCl (15 mL). The organic layer is separated, then washed with H2O (1 x 15 mL) and brine (3 x 15 mL) and dried over Na2SO4. The solvent is removed by evaporation at reduced pressure and the residue is purified through column chromatography to afford the aldehydes as colorless liquids.

5-phenylpentanal.
Reaction performed on 1000 mg (6.10 mmol) of 5-phenylpentan-1-ol. Flash chromatography was performed with a mixture of pentane/Et2O in gradient from 30:1 to 15:1. Colorless oil, 834 mg (5.15 mmol), 83 % yield 1 H NMR (300 MHz, CDCl3) δ 9.76 (t, J = 1.7 Hz, 1H), 7.38 -7.10 (m, 5H), 2.66-2.64 (m, 2H), 2.54 -2.40 (m, 2H), 1.68 (m, 4H). Data are in agreement to those reported in the literature [4] . [4] 1.0 mmol of alcohol (1.0 equiv), 7 mL CH2Cl2 and 0.54 mL (4.0 mmol, 4.0 equiv) Et3N are introduced in a flame-dried two-necked round bottomed flask equipped with a nitrogen inlet and magnetic stirring. The flask is chilled in an ice bath, then a solution of 0.48 g (3.0 mmol, 3.0 equiv) SO3·Pyridine complex in 3 mL DMSO is added. Stirring is continued at 0°C for 1 h, then for 3 h at room temperature. The following workup procedure is aimed at minimizing product loss and maximizing removal of DMSO from the reaction crude. The reaction mixture is diluted with CH2Cl2 or Et2O and washed with a 1:1 (v/v) mixture of NH4Cl (sat) and brine. Most of the CH2Cl2 (if used) is removed by rotary evaporation and the residue is taken up with Et2O. The aqueous phase is extracted with fresh Et2O to minimize product loss. The combined organic phases are washed again S5 with the NH4Cl/ NaCl (sat), then with brine alone to remove as much DMSO as possible. After drying over anhydrous Na2SO4, the solvent is removed and the residue is purified by silica gel chromatography.

5-hexynal.
Reaction performed on 1.80 g (18.4 mmol) of 5-hexyn-1-ol. Flash chromatography was performed with a mixture of petroleum ether/Et2O in gradient from 20:1 to 8:1. Whereas Et2O was removed by distillation, the product could not be isolated from solvent hydrocarbons. After a first distillation through a Vigreux column, we held on to the product-rich residue and we submitted the richest distilled fraction to a second distillation in an attempt to further concentrate the product. We thus obtained two product-rich lightly yellow oily residues and the yield of 5hexynal was estimated by 1 H-NMR analysis. The residual solvent was assumed to be equivalent to hexane (C6H14), so that the integral of all signals below 1.8 ppm are worth 14H. Based on the amounts of the two fractions, we estimate 940 mg (9.79 mmol; 54% yield) as 73% (w/w) in hexanes. 1 H-NMR (300 MHz, CDCl3) δ 9.77 (t, J = 1.3 Hz, 1H); 2.58 (td, J = 7.2, 1.3 Hz, 2H); 2.24 (td, J = 6.8, 2.5 Hz, 2H); 1.96 (t, J = 2.5 Hz, 1H); 1.82 (m, 2H). Data are in agreement to those reported in the literature [6] .  [7] .

Synthesis of 3-propylhexanal
2-propylpentyl 4-methylbenzenesulfonate. 130 mg (1.0 mmol, 1.0 equiv) of 2-propyl-1pentanol and 286 mg (1.5 mmol, 1.5 equiv) of p-toluensulfonyl chloride are dissolved in 2 mL of CH2Cl2. The resulting solution is cooled to 0 °C, then Et3N (417 μL, 303 mg, 3.0 mmol, 3 equiv) is added dropwise and the reaction mixture is allowed to react at 25 °C. After 20 h the reaction is diluted with 13 mL of CH2Cl2 then the organic layer is washed with HCl 1 M (1 x 15 mL), water (1 x 10 mL), saturated aqueous NaHCO3 (1 x 15 mL) and brine (1 x 15 mL), dried over Na2SO4 and the solvent removed by evaporation at reduced pressure. The title compound is obtained as a colorless oil (278 mg, 0.98 mmol, 98 % yield) and used without further purification. . Data are in agreement to those reported in the literature [9] .

3-propylhexanal.
In a flame-dried two-necked round bottom flask 92 mg (0.66 mmol, 1.0 equiv) of 3-propylhexanenitrile are dissolved in 11 mL of anhydrous hexane then a 1 M solution of diisobutylaluminum hydride in heptane (DIBAL-H, 1.66 mL, 2.5 equiv) is added under an Ar atmosphere. After 3 h, 9 mL of 96 % EtOH and 5.5 mL of H2O are added dropwise to hydrolyze the excess of DIBAL-H and stirred for 1 h. The reaction mixture is then extracted with Et2O (3 x 10 mL), the organic layers washed with 3 M HCl (1 x 20 mL), H2O (1 x 20 mL), saturated NaHCO3 (1 x 20 mL), brine (1 x 20 mL) and dried over Na2SO4. The product is purified via flash chromatography using as eluant a mixture of pentane/Et2O in ratio 30:1. The product-containing fractions were distilled through a Vigreux column at ambient pressure to remove the solvents present, since evaporation with Rotavapor led to complete product loss. Although it was possible to remove all the Et2O this way, still accompanied with partial evaporation of the product, hydrocarbons were still present in the distillation residue. Given the 1 H-NMR ratio of the multiplets at δ = 1.32 -1.20 (comprising both 3-propylhexanal and hydrocarbon methylene hydrogens) and at δ = 0.92 -0.86 (representative of the terminal methyl protons), the solvent still present in the sample was assumed to be heptane. Therefore the clear colorless liquid obtained is estimated to be a 37 % (w/w) solution of 3-propylhexanal in heptane (118 mg of solution, estimated 44 mg of 3-propylhexanal, 0.31 mmol, 47 % yield). 1 H NMR (CDCl3, 300 MHz) δ 9.76 (t, J = 2.4 Hz, 1H), 2.33 (dd, J = 6.6, 2.4 Hz, 2H), 2.08 -1.85 (m, 1H), 1.38 -1.15 (m, 8H + 24H from heptane), 0.94 -0.80 (m, 6H + 14H from heptane). Data are in agreement to those reported in the literature [10] .

Synthesis of 3-octyltridecanal 3-octyltridecanal.
Under Ar atmosphere and at 0 °C, t-BuOK (0.94 g, 8.4 mmol) was added to a solution of CH3OCH2PPh3Cl (2.9 g, 8.3 mmol) in anhydrous THF (30 mL). The mixture was kept under magnetic stirring at room temperature for 4 h. 2-octyldodecanal (0.83 g, 2.8 mmol) dissolved in anhydrous THF (5 mL) was added at 0 °C and the mixture was kept under magnetic stirring at room temperature for 17 h. The mixture was filtered and the solvent evaporated under reduced pressure. The crude was dissolved in Et2O (20 mL), washed with saturated NH4Cl solution, dried over Na2SO4 and the solvent evaporated at reduced pressure. The residue was dissolved in THF (9 mL), then an aqueous HCl solution (1 M, 2.1 mL) was added and the mixture was stirred for 2 h at 75 °C. Et2O (10 mL) was added and the mixture was washed with H2O (5 mL). The aqueous phase was extracted with Et2O (15 mL); the organic phases was washed successively with saturated NaHCO3 and brine and dried over anhydrous Na2SO4. White solid, 0.35 g (1.1 mmol), 40 % yield. 1 H NMR (CDCl3, 300 MHz) δ 9.76 (t, J = 2.4 Hz, 1H); 2.32 (dd, J = 6.6, 2.5 Hz, 2H); 1.94 (m, 1H); 1.37 (m, 32H); 0.88 (t, J = 6.5 Hz, 6H). Data are in agreement to those reported in the literature [10] . S7 2.5. General procedure for α-oximation of aldehydes [12] In a two-necked round bottom flask equipped with magnetic stirring are introduced in this order, under a N2 atmosphere, 10 mL DMF, pyrrolidine (0.6 mmol, 0.2 equiv), p-toluenesulfonic acid (0.6 mmol, 0.2 equiv) and the aldehyde (3.0 mmol, 1.0 equiv). Then NaNO2 (3.0 mmol, 1.0 equiv) is added, followed by FeCl3·6H2O (3.0 mmol, 1.0 equiv) in small portions to avoid excessive heating. The reaction is stirred for 4-6 h at room temperature (completion is monitored by TLC using hexane/ethyl acetate 5:1 as eluant). The mixture is diluted with 30 mL EtOAc and 20 mL of a 1:1 (v/v) mixture of NH4Cl (sat) and brine and stirred for 20 minutes at room temperature. The organic layer is set aside and the aqueous phase is extracted with 20 mL fresh EtOAc to minimize product loss. The pooled organic solutions are washed once more with 20 mL of NH4Cl (sat)/brine mixture, then three times with brine. After drying over anhydrous Na2SO4, EtOAc is removed by rotary evaporation. The product is purified by silica gel chromatography.   [13] .  [13] .  [12] .  [11] .

CBO C=N double bond E/Z isomerization
Scheme S1. Suggested mechanism of E/Z isomerization of CBO 2e.

Methods
The simulation box consists of a single oxime molecule surrounded by 163 solvent molecules. Different oxime isomers were here considered: cis-endo-E-2j, cis-endo-Z-2j, cis-exo-E-2j, cis-exo-E-2j as well as a cis-endo-E-2i CBOs. Simulations are carried out using leap-frog algorithm with a time-step of 0.5 fs. UFF force field is adopted for the purpose [14] . Long range electrostatic interactions are considered using PME method while a cut-off scheme with cut-off distance 1 nm is applied for Van der Waals interactions. Initial configuration minimization is carried out using conjugate gradient method; further MD simulations lasting 90 ns were performed for each system in order to guarantee equilibrium. Canonical ensembles (NVT) are obtained through V-rescale thermostat with coupling constant T=0.1 ps and reference temperature 298.15 K. Periodic boundary conditions were applied in the three spatial directions. Data were collected during 30000000 step lasting simulations (20000000 in the case of DCM).

Discussion
In order to better highlight the crucial role of the solvent polarity in oxime double bond isomerization, the radial distribution functions (RDFs) of DCM chlorine with respect to the oxime oxygen for both cis-endo-E-2j and cis-endo-Z-2j isomers is reported in Figure S7. In the case of DCM solvent, we did not observe the appreciable differences between the two curves as in the case of DMSO solvent ( Figure 8). The lower intensity of the radial distribution functions in Figure S8 suggests a weaker interaction of the alcoholic OH group with the DMSO.  In Figure S10, distribution function of the dihedral angle  (defined by atoms 24-21-8-5, Figure S9) related to alcoholic OH group rotating around the oxygen-carbon bond of cis-endo-E-2j is reported. This distribution suggests that the most probable dihedral angles correspond to the conformations ( = -89 and  = 156), which have the alcoholic OH group near to the alkylic H (20, Figure S9). This observation is compatible with the S63 observed contact in the NOESY experiment in Figure S3 and the distance distribution function reported in Figure S11. Figure S9. Snapshot of cis-endo-E-2j isomer with dihedral angle (defined by atoms 24-21-8-5) corresponding to  = -95° in Figure S5.  Figure S4) related to alcoholic OH group rotating around the oxygen-carbon bond of cis-endo-E-2j.  = 0 corresponds to syn conformation. Positive angles define the counterclockwise rotation of the OH group. Figure S11. Distance distribution function between alcoholic H (atom 24 in Figure S4) and alkylic hydrogen (atom 20 in Figure S4) of cis-endo-E-2j and cis-exo-E-2j isomers in DMSO.