Synthesis of Some Fenchyl-Substituted Alkenes and Enol-Ethers Containing 3-Oxyphenyl Substituents by the Barton-Kellogg Reaction

Usando-se a reação de Barton-Kellogg, foram sintetizados um alceno e dois enóis-éteres fenchyl-substituídos, contendo grupos 3-oxifenila como substituintes. O fenchil-alceno aromático tri-substituído 1a foi preparado com rendimento de 53% a partir de tiofenchona e um diazoanisol. A abordagem inversa, baseada no acoplamento entre diazofenchona e tionoésteres aromáticos, foi utilizada para produzir os enóis-éteres 1b e 1c (rendimentos 95 e 75%, respectivamente). Em todos os casos foi obtida uma mistura dos isômeros E e Z; a atribuição e quantificação destes isômeros foram realizadas pela análise dos dados de espectroscopia de RMN assistida por cálculos teóricos (relação E/Z 1a = 0,72, 1b = 2,2, 1c = 1,8). A reação ocorre com baixa estereosseletividade, levando à formação preferencial dos diastereoisômeros das olefinas e enóis-éteres, nos quais o substituinte aromático está localizado ao lado dos dois grupos metila da porção fenchila.


Introduction
The chemistry of hindered olefins is a challenging topic for both synthetic and theoretical chemists. 1,2Strained alkenes containing the fenchone-type skeleton are chiral elements in asymmetric synthesis [3][4][5] and model compounds in the study of structural deformations on double bonds. 6he Barton-Kellogg (BK) reaction, or Barton-Kellogg (BK) olefination, [7][8][9] is the method of choice for the efficient preparation of such alkenes.The synthesis of 2-diphenylmethylenefenchane, 2-cyclohexylidenefenchane and bis-fenchylidene, one of the most hindered olefin yet synthesized, were accomplished with this method. 6,10,11The reaction consists of the 1,3-dipolar cycloaddition between a diazo and a thio or selenocarbonyl compound, furnishing the target alkene after two-fold extrusion of nitrogen and sulfur/selenium from D 3 -1,3,4-thia-or selenodiazolines. 9he synthesis of enol-ethers by the BK method has been scarcely investigated, 12,13 and derivatives bearing the fenchyl group have not yet been described.
The stabilization provided by the fenchyl group to these alkenes and enol-ethers, can bring new knowledge and possibilities to areas like organic synthesis and material science, as well as to chemiluminescence research, where Vol.][16] Therefore, herein we present: (i) the synthesis of the trisubstituted alkene 1a by conventional BK reaction from thiofenchone (5a) and diazoalkane 4a, and (ii) the synthesis of enol-ethers 1b and 1c using the inverse approach for the BK reaction, i.e., from diazofenchane (4b) and thionoesters 5b and 5c (Schemes 1 and 2).

Results and Discussion
Treatment of (−)-fenchone (3a) with Lawesson's reagent in refluxing xylene afforded (−)-thiofenchone (5a) in 95% yield (Scheme 1). 17Alternatively, 5a was prepared by the reaction of 3a with a mixture of H 2 S/HCl gas in trimethyl orthoformate (88% yield, orange crystals).The diazo compound 4a was prepared by the Bamford-Stevens route from the corresponding tosylhydrazone 2a, using potassium tert-butoxide and pyridine in THF. 18his compound is highly unstable and therefore it was not isolated or characterized.Reaction yield was estimated in 75% from the stoichiometry of the subsequent reaction with thiofenchone (Scheme 1).The reaction of 5a with the deep red diazo compound 4a occurred immediately at room temperature affording a diastereoisomeric mixture of D 3 -1,3,4-thiadiazolinic intermediates 6a, as indicated by discoloration of the mixture and TLC analysis (Scheme 1).Warming up of the reaction mixture leads to nitrogen liberation and formation of thiirane 7a as a colorless solid.A solution of 7a in toluene was treated with triphenylphosphine and refluxed for 24 h, resulting, after sulfur extrusion, in a mixture of E/Z isomers of the alkene 1a (overall yield: 53% from 5a).The products were isolated and characterized by spectroscopic analysis.
Enol-ethers 1b and 1c were prepared by the coupling of diazofenchane (4b) with thionoesters 3b and 3c (Scheme 2). 12,13This inverse approach is required because the conventional BK reaction would require the difficult preparation of a methoxy-substituted diazomethane derivative. 19The Bamford-Stevens method was unsuccessful to convert the corresponding tosylhydrazone to diazofenchane (4b).Thus, 4b was prepared by oxidation of fenchylhydrazone (2b) with nickel peroxide and calcium oxide in dimethoxyethane at −78 °C. 20,21Again, due to the highly unstable nature of 4b, the yield of this transformation could only be estimated to be as high as 90% based on the stoichiometry of the subsequent reaction with the thionoesters.Thionoesters 5b and 5c were prepared from the corresponding esters with Lawesson's reagent in 84% (R = Me) and 45% (R = TBDMS) yields, 17,22 and stored at −20 °C after purification by column chromatography, to avoid polymerization. 23The reaction Scheme 1. Synthesis of fenchyl-substituted olefin 1a by the Barton-Kellogg reaction.Synthesis of Some Fenchyl-Substituted Alkenes and Enol-Ethers J. Braz.Chem.Soc.1898   between diazofenchane (4b) and thionoesters 5b or 5c was carried out in a similar manner as described previously for diazo compound 4a, except that the solution of 6c in toluene was refluxed with copper-bronze for 6 h after nitrogen extrusion (Scheme 2).Enol-ethers 1b and 1c were obtained as mixtures of isomers, with overall yields of 95 and 75%, respectively.
The fenchyl-substituted alkene 1a and enol-ethers 1b and 1c were obtained in better yields with the BK method that by other classical methods of carbon-carbon double-bond formation.For example, the methylenation of fenchone by an optimized Wittig reaction was reported to afford a yield of 5%. 24The same reaction using the very expensive Tebbe's reagent gives a yield of only 16%, showing that the preparation of fenchone-derived olefins generally occurs with low yields. 24Our own attempts to prepare these compounds using Wittig and Horner-Wadsworth-Emmons (HWE) methods failed or resulted in very poor yields.(−)-Fenchone showed to be not reactive in HWE conditions, independent of the base used (NaH, n-BuLi, sec-BuLi, LDA, LiHMDS), with no product formation detected at all, even after a 24 h reaction time.Also, the intermolecular McMurry cross-coupling 15,25 of methyl 3-methoxybenzoate and (−)-fenchone, in the presence of either TiCl 3 /LiAlH 4 /TEA or TiCl 4 /Zn, did not produce reproducible results. 26e attribution of NMR signals and quantification of the E and Z isomers of 1a and 1b was performed as follows.The 1 H NMR spectra of 1a featured two singlet signals at 6.15 and 6.16 ppm, which clearly indicate the existence of two different olefinic hydrogen atoms.The HSQC experiment (see Figure S1) shows that there are two different sets of signals corresponding to three methyl groups each: one group with 1 H shifts of 1.27, 1.04 and 0.98 ppm, and another group at 1.15, 1.14 and 0.95 ppm (Figure S2 and Figure S3).The integration of the corresponding carbon peaks in the 13 C spectrum showed a slight majority of the first set of methyl groups.The attribution of E and Z isomers could not be done by means of a straightforward 1D NOESY spectrum, because the irradiation intensity at the olefinic hydrogen had to be very high to produce any detectable nOe signal for the adjacent methyl groups, causing a broadening of the signal that prevented the selective excitation of just one hydrogen atom.The 2D NOESY experiments (see Figure S4) showed that the hydrogen atom at 6.15 ppm is located in the proximity of the region of the two methyl groups with signals at 1.15 and 1.14 ppm, an indication that these signals correspond to the E isomer.Contrarily, the hydrogen atom at 6.16 ppm is located in the proximity of only one methyl group at 1.27 ppm, therefore corresponding to the Z isomer (see spatial structures in Scheme 1).Consequently, the signals at 6.15 and 6.16 ppm were attributed to the Scheme 2. Synthesis of fenchyl-substituted enol-ethers 1b and 1c by the inverse Barton-Kellogg reaction.olefinic hydrogen atoms of isomers E and Z, respectively (E/Z ratio = 0.72).NMR spectra (HMBC, HSQC, NOESY, HSQC/HMBC) are given in Supplementary Information.
The evaluation of the 1 H NMR spectrum of 1b also suggests the presence of two isomers, because there are two different olefinic methoxy group signals at 3.09 and 3.08 ppm, but only one signal at 3.73 ppm, corresponding to the aromatic methoxy group of both isomers.The HSQC spectra (see Figure S5) also corroborate the presence of two isomers: methyl groups of the fenchyl moiety are observed at 1.45, 1.01 and 0.52 ppm for one isomer, and 1.23 (two signals together) and 0.56 ppm for the other isomer (Figure S2).With the methyl groups of different isomers localized, selective excitation 2D-and 1D-NOESY experiments were carried out to assert the attribution of E and Z isomers of 1b (see Figures S5 and S6).Selective excitation of the single methyl group at 1.45 resulted in the nOe enhancement of the methoxy group signal at 3.09 ppm, identifying it as belonging to the E isomer (Figure S7).Excitation of the two methyl groups at 1.23 ppm resulted in the NOE enhancement of the signal at 3.08 ppm, therefore belonging to the Z isomer (see structures in Scheme 2).The integration of the carbon peaks in the INVGATE 13 C NMR spectrum 27 revealed an E/Z ratio of 2.2.
The spectrum of 1c showed to be very similar to that of 1b, so E/Z attribution could be performed in analogy to the former compound.Two sets of three methyl groups could also be observed in the 1 H NMR spectrum, one set with peaks at 1.50, 1.06 and 0.60 ppm, and another one with two peaks together at 1.29 and one at 0.63 ppm.For 1b, the two CH 3 signals together correspond to the Z isomer; therefore it is assumed that this is also the case for 1c.An E/Z ratio of 1.8 could be obtained from the integration of these 1 H signals.
A quantum chemistry study was carried out in order to provide further structural evidence on E/Z attribution of 1a and 1b isomers from spectroscopic data.The equilibrium geometries, vibrational frequencies and thermochemical data were obtained using the hybrid generalized gradient approximation functional PBE1PBE 28 with the 6-311+G(d,p) basis set (see Supplementary Information). 29his functional was used because it produced excellent results in the calculation of bond angles in a dataset of 27 small organic molecules, when compared with other 37 density functionals, including the popular B3LYP. 302][33][34][35] The optimized structures of E/Z , 1a and 1b are depicted in Figure 1 and relevant geometry parameters are given in Table S1 (see Supplementary Information).The isotropic chemical shielding at H and C nuclei of 1a, 1b and TMS were calculated at the GIAO/IEFPCM/W04P/cc-pVDZ// pbe1pbe/6-311+G(d,p) level. 34This approach allowed us to calculate 1 H and 13 C chemical shifts of 1a and 1b, which were compared to the experimental data (Figure S8). 35he adjusted coefficients of determination (adj-R 2 > 0.99) indicate that the predicted d values for both 1 H and 13 C nuclei are in excellent agreement with experimental data.

Conclusions
Sterically-hindered fenchyl-substituted aromatic alkene 1a can be prepared using the Barton-Kellogg method from thiofenchone and a diazoanisole; whereas enol-ethers 1b and 1c can be obtained from diazofenchane and aromatic thionoesters.This approach results in product formation in better yields than those obtained by classical methods and can be useful for the synthesis of encumbered alkenes.Reaction proceeds with low stereoselectivity leading to the preferential formation of diastereoisomeric olefins and enol-ethers where the aromatic substituent resides at the side of the two fenchyl methyl groups.

Experimental
All reactants were purchased at highest commercial quality and used without purification, except otherwise mentioned.Solvents were purified and dried as described by Armarengo and Perrin. 36Bulb-to-bulb distillations were made using a Kugelrohr apparatus (Büchi Glass Oven B-580).Melting points (°C) were determined in a Kofler hot-stage apparatus

CAUTION:
Although no accident occurred during the progress of this work, diazo compounds are known to decompose explosively. 37Therefore, all caution should be taken.
In the attributions of the 1 H and 13 C NMR spectra below, more than one chemical shift values have been assigned to several of the atoms, since a mixture of diastereoisomers has been obtained in the synthesis.
Triphenylphosphine (0.52 g, 2.0 mmol) was added to a solution of 7a (5.2 g, 1.8 mmol) in dry toluene (5 mL) and the resulting mixture refluxed for 24 h.The solution was cooled to room temperature and 1 mL of methyl iodide was added, and the resulting suspension kept at 50 °C for 1 h, filtered and the solvent removed in vacuo.The oily liquid obtained was purified by column chromatography (Al 2 O 3 , heptane), yielding 1a (0.24 g, 53%) as a clear oil.
In the attributions of the 1 H and 13 C NMR spectra below, more than one chemical shift values have been assigned to several of the atoms, since a mixture of diastereoisomers has been obtained in the synthesis. 1
In the attributions of the 1 H and 13 C NMR spectra below, two chemical shift values have been assigned to several of the atoms, since a mixture of two diastereoisomers has been obtained in the synthesis. 1

Computational details
Gaussian03 was used for all calculations. 40All geometries were optimized at the pbe1pbe/6-311+G(d,p) theoretical level. 28To model the solvent effect (chloroform), CPCM-SCRF (self-consistent reaction field) procedure was employed. 41Stationary points were characterized as minima by vibrational analysis.All reported energies include zero-point energy (ZPE) as well as thermal corrections (T = 298.15K) from frequency calculations.Gauge invariant atomic orbitals (GIAO) method was used to calculate isotropic chemical shielding. 42,43Calculations were carried out using the WP04 functional, a version of the B3LYP functional explicitly reparameterized for the calculation of chemical shifts in chloroform, 44 with Dunning's cc-pVDZ basis. 34WP04 functional was invoked by specifying the BLYP keyword and adding iop (3/76 = 1000001189, 3/77 = 0961409999, 3/78 = 0000109999) to the keyword line.The theoretical NMR chemical shifts were calculated as the difference isotropic shielding constants with respect to tetramethylsilane (GIAO/WP04/cc-pVDZ//pbe1pbe/6-311+G(d,p)) 1 H shielding = 31.79, 13C shielding = 188.78).Solvent effects in GIAO calculations were modeled by the IEFPCM-SCRF method. 45The IEFPCM-SCRF method was used to model solvent (chloroform) effects, which are known to be of great importance in such calculations. 34The IEFPCM was used because it has been successfully used in association with the W04P functional in the accurate prediction of 1 H and 13 C chemical shifts in chloroform. 34 -1a E/Z = 0.72 HC(OH) 3 H 2 S/HCl, 88% Lawesson's reagent (LR):

Figure 1 .
Figure 1.Optimized structures of E/Z isomers of 1a and 1b.