Fritsch–Buttenberg–Wiechell rearrangement of magnesium alkylidene carbenoids leading to the formation of alkynes

Introduction

Alkynes are important compounds in organic synthesis [1]. Electrophilic additions of alkynes give functionalized compounds, and cycloadditions such as the Huisgen reaction afford cyclic compounds. Weakly acidic terminal alkynes can be deprotonated, and the resulting acetylides are used as carbon nucleophiles. Terminal alkynes are also used for the Sonogashira coupling reaction with organic halides. The dehydrohalogenation of gem-dihaloalkanes, vic-dihaloalkanes, and haloalkenes with strong bases is often used for the synthesis of alkynes [2]. An alternative strategy for the synthesis of alkynes is the conversion of carbonyl compounds through one-carbon homologation [3]. Much effort has been devoted to developing a procedure for the synthesis of alkynes from carbonyl compounds, and the Corey–Fuchs method, the Seyferth–Gilbert method, and the Ohira–Bestmann modification have been developed (Scheme 1) [4-7]. These methods consist of the Wittig or Horner–Wadsworth–Emmons (HWE) reaction of carbonyl compounds with organophosphorus reagents containing carbene sources and the 1,2-rearrangement of alkylidene carbenes and related species, referred to as Fritsch–Buttenberg–Wiechell (FBW) rearrangement [8,9]. While alkynes are synthesized from carbonyl compounds with these methods, the use of butyllithium for the generation of lithium alkylidene carbenoids limits the range of usable substrates in the Corey–Fuchs method, and the Ohira–Bestmann method cannot be applied to the synthesis of internal alkynes from ketones [3].

Magnesium alkylidene carbenoids 3 are reactive intermediates in which both magnesium and chlorine atoms are attached to an alkene carbon atom (Scheme 2a) [10]. Magnesium alkylidene carbenoids 3 can be generated from isopropylmagnesium chloride and 1-chlorovinyl p-tolyl sulfoxides 2, which are prepared from carbonyl compounds 1 and chloromethyl p-tolyl sulfoxide, via the sulfoxide/magnesium exchange reaction [11]. During the course of our study on the ambiphilic reactions of magnesium alkylidene carbenoids 3 (Scheme 2b and 2c) [12-15], we found that the FBW rearrangement of magnesium alkylidene carbenoids 3 occurred to give alkynes 4 when magnesium alkylidene carbenoids 3 were left without reactants (Scheme 2d). Herein, we report the synthesis of alkynes 4 from carbonyl compounds 1 with one-carbon homologation via the FBW rearrangement of magnesium alkylidene carbenoids 3 as a key step. A mechanistic study on the FBW rearrangement of magnesium alkylidene carbenoids 3 by using ¹³C-labeled sulfoxides and by using DFT calculations is also described.

Results and Discussion

Synthesis of 1-heteroatom-substituted vinyl p-tolyl sulfoxides

As magnesium alkylidene carbenoid precursors, a series of 1-heteroatom-substituted vinyl p-tolyl sulfoxides 2, 5–7 and 1-unsubstituted sulfoxide 8 were prepared from carbonyl compounds 1 (Scheme 3). The 2,2-bis(4-methoxyphenyl)-substituted sulfoxides 2a, 5, and 8 were prepared via the nucleophilic addition of [(p-tolylsulfinyl)methyl]lithiums to 4,4'-dimethoxybenzophenone, acylation of the hydroxy group in the adducts, and β-elimination (Scheme 3a) [16]. The 1-bromovinyl p-tolyl sulfoxide 6 was prepared by the deprotonation of sulfoxide 8 with LDA followed by electrophilic bromination with 1,2-dibromo-1,1,2,2-tetrachloroethane. 1-Methoxyvinyl p-tolyl sulfoxide 7 was prepared by a Peterson olefination of 4,4'-dimethoxybenzophenone with methoxy(trimethylsilyl)methyl p-tolyl sulfide, and oxidation of the resulting 1-methoxyvinyl p-tolyl sulfide with mCPBA (Scheme 3b) [17]. The 1-chlorovinyl p-tolyl sulfoxides 2e–g were prepared through a one-pot procedure (Scheme 3c) [15]. The HWE reagent was generated in situ from chloromethyl p-tolyl sulfoxide, diethyl chlorophosphate, and LDA, and the reaction of the HWE reagent with carbonyl compounds gave sulfoxides 2e–g. The 2,2-disubstituted sulfoxides 2b–d, which could not be prepared by the one-pot HWE reaction, were prepared through a stepwise method (Scheme 3a). The 2,2-unsymmetrically substituted sulfoxides 2d–g were obtained as mixtures of geometric isomers that were separated by column chromatography on silica gel.

FBW rearrangement of magnesium alkylidene carbenoids

Based on the results of DFT calculations, the degree of the vinylidene character of 1-heteroatom-substituted vinylmetals is dependent on the type of the metal and the heteroatom substituent [18,19]. The vinylidene character of 1-heteroatom-substituted vinylmetals is estimated to increase in the following order (1-methoxyvinyl)magnesium chloride, CH₂=C(OMe)MgCl < (1-halovinyl)magnesium chlorides, CH₂=CXMgCl (X = F, Cl, and Br) << (1-chlorovinyl)lithium, CH₂=CClLi. If the 1-heteroatom-substituted vinylmetal displays vinylidene characteristics, the FBW rearrangement occurs to give the alkyne. If not, the vinylmetal is simply protonated to give a heteroatom-substituted alkene. A series of 1-heteroatom-substituted vinyl p-tolyl sulfoxides 2a, 5–7, and 1-unsubstituted sulfoxide 8 were treated with organometallic reagents with the aim of finding the optimal combination of the metal and heteroatom substituent for the FBW rearrangement (Table 1). The 2,2-bis(4-methoxyphenyl)-substituted 1-chlorovinyl p-tolyl sulfoxide 2a was added to isopropylmagnesium chloride in toluene at −78 °C, and the mixture was warmed to 0 °C for 2 h (Table 1, entry 1). Excess isopropylmagnesium chloride (3.5 equivalents) was necessary for the complete consumption of the sulfoxide. As a result, isopropyl p-tolyl sulfoxide and alkyne 4a were obtained in 97% yield and 99% yield, respectively. This result shows that both the sulfoxide/magnesium exchange reaction and the FBW rearrangement occurred with high efficiency. A similar reaction of sulfoxide 2a with sec-butyllithium also gave alkyne 4a in 97% yield (Table 1, entry 2). On the other hand, the sulfoxide/zinc exchange reaction of sulfoxide 2a with isopropylzinc bromide did not proceed at all even under reflux conditions (Table 1, entry 3). In the case of the reaction of 1-fluorovinyl p-tolyl sulfoxide 5 with isopropylmagnesium chloride, the S_NV reaction of (1-fluorovinyl)magnesium chloride with isopropylmagnesium chloride competed with the FBW rearrangement to give a mixture of alkyne 4a and alkene 10 in 69% and 13% yield, respectively (Table 1, entry 4, Scheme 4a, and Scheme 2c) [20]. Both the sulfoxide/magnesium exchange reaction and bromine/magnesium exchange reaction occurred when 1-bromovinyl p-tolyl sulfoxide 6 was treated with isopropylmagnesium chloride, and debrominated sulfoxide 8 was obtained as a major product (Table 1, entry 5 and Scheme 4b). The reaction of the 1-methoxy-substituted sulfoxide 7 with isopropylmagnesium chloride gave the alkene 9d as the major product along with a small amount of alkyne 4a (Table 1, entry 6). Most of (1-methoxyvinyl)magnesium chloride, which is expected to have vinylidene characteristics to a lesser extent, remained without rearrangement [19]. The reaction of p-tolyl vinyl sulfoxide 8 having no leaving group with isopropylmagnesium chloride gave the desulfinylated product 9e in 79% yield, and the starting sulfoxide 8 was recovered in 10% yield (Table 1, entry 7). Considering the reaction efficiency, accessibility of precursors, and functional group tolerance, the use of isopropylmagnesium chloride and 1-chlorovinyl p-tolyl sulfoxide 2a was the optimal combination of organometallic reagent and carbenoid precursor.

The substrate scope was explored with a variety of sulfoxides 2b–g (Table 2). The 2,2-diphenyl-substituted sulfoxide 2b was converted into alkyne 4b by treatment with isopropylmagnesium chloride in 99% yield (Table 2, entry 1). In contrast, the treatment of 2,2-dialkyl-substituted sulfoxide 2c with isopropylmagnesium chloride gave a complex mixture including alkene 11 with an isopropyl group, which arose from the S_NV reaction, in 35% yield (Table 2, entry 2, and Scheme 5). To compare the difference in reactivity between geometric isomers, the reaction of 2,2-unsymmetrically substituted sulfoxides 2d–g with isopropylmagnesium chloride was carried out (Table 2, entries 3–10). There was no significant difference in the reactivity between the geometric isomers of 2-alkynyl-2-phenyl-substituted sulfoxide 2d (Table 2, entries 3 and 4). The reaction of a mixture comprising the geometric isomers L-2d and M-2d with isopropylmagnesium chloride gave alkyne 4d in 83% yield. On the other hand, there was a difference in the reactivity between geometric isomers of 2-methyl-substituted sulfoxides 2e and 2f (Table 2, entries 5–8). The reaction of (Z)-sulfoxides (Z)-2e and (Z)-2f, in which the methyl group and chloro group were located trans to each other, tended to give alkynes 4 with low efficiency (Table 2, entries 6 and 8). The terminal alkyne 4g was obtained from both geometric isomers of 2-monoaryl-substituted sulfoxide 2g in good yields (Table 2, entries 9 and 10).

Reaction mechanism

The substrate scope results suggest that aryl and alkynyl groups are migratable, whereas alkyl groups are not. The FBW rearrangement of magnesium alkylidene carbenoids seems to be an anionotropic rearrangement because the trend of migratory aptitude (aryl, alkynyl >> alkyl) follows the trend of the stability of carbanions [21,22]. The trans-relationship between the chloro group and the migrating substituent appears to be of importance for a successful 1,2-rearrangement [8]. Given the difference in reactivity between geometric isomers, the formation of alkynes via the 1,2-rearrangement of free alkylidene carbenes is unlikely. To gain insight into the reaction mechanism, ¹³C-labeled sulfoxides [¹³C]-(E)-2e and [¹³C]-(Z)-2e were prepared from acetophenone-α-¹³C and HWE reagent (Scheme 6a), and each geometric isomer was subjected to the reaction with isopropylmagnesium chloride [23-26]. Alkyne 4e, having a ¹³C-labeled carbon atom at the 2-position of the propy-1-ynyl group, was exclusively formed in both cases (Scheme 6b and c) [27]. These results demonstrated that the C–Ph bond was cleaved and that the C–Me bond was maintained during the reaction.

Based on these results, we propose the reaction mechanism as outlined in Scheme 7. When substituent R¹ with a high migratory aptitude, such as an aryl group and alkynyl group, is located trans to the chloro group, the 1,2-rearrangement smoothly occurs to give alkynes 4 because substituent R¹ can readily approach the C–Cl antibonding orbital (Scheme 7a). On the other hand, when substituent R¹ is located cis to the chloro group and a nonmigratable alkyl group R² occupies the trans position, the 1,2-rearrangement does not occur directly. Geometric isomers of magnesium alkylidene carbenoids are in equilibrium [16], and the 1,2-rearrangement occurs giving the alkynes 4 when the substituent R¹ is located trans to the chloro group (Scheme 7b). An exchange of halogen atoms was observed in the reaction of a 1-chlorovinyl p-tolyl sulfoxide with ethylmagnesium bromide (Scheme 7c) [16]. The nucleophilic substitution of the halide on the magnesium atom with the carbenoid carbon atom having a halogen substituent is a plausible mechanism for the isomerization.

The FBW rearrangement of magnesium alkylidene carbenoids was studied by using DFT calculations (Figure 1) [28-32]. The calculations were performed using the 6-311G++(d,p) basis set at the B3LYP level of theory [33-36]. Bis(dimethyl ether)-solvated (1-chloro-2-phenylprop-1-enyl)magnesium chlorides (E)-3e and (Z)-3e were used as model compounds. The 1,2-shift of both the phenyl group and methyl group to the carbenoid carbon atom was examined for each geometric isomer to locate the transition state [37]. While appropriate transition state structures were not found for the 1,2-shift of the methyl group in (E)-3e and the 1,2-shift of substituents in magnesium alkylidene carbenoid (Z)-3e, transition state structure (E)-3e^‡ was found for the 1,2-shift of phenyl group in magnesium alkylidene carbenoid (E)-3e. The geometry around the carbenoid carbon atom in magnesium alkylidene carbenoids (E)-3e (C–Cl: 1.86 Å, C=C–Cl: 115°, C=C–Mg: 135°) significantly deviated from that of the standard sp²-hybridized carbon atom, suggesting that magnesium alkylidene carbenoids (E)-3e have partial vinylidene characteristics [19]. In the transition state structure (E)-3e^‡, the ipso carbon atom (C3) of the phenyl group was located at the middle between the C=C bond (C2–C3: 1.72 Å, C1–C3: 1.70 Å), and the C1–Cl bond (C1···Cl: 3.22 Å) was cleaved. The activation energy for this reaction was estimated to be 14.9 kcal/mol. The IRC calculation revealed that the chlorine atom gradually dissociated from the carbenoid carbon atom as the phenyl group approached the carbenoid carbon atom [38,39]. Then, three carbon atoms (C1, C2, and C3) were arranged linearly to give alkyne 4e.

Conclusion

We studied the FBW rearrangement of magnesium alkylidene carbenoids. The use of isopropylmagnesium chloride and 1-chlorovinyl p-tolyl sulfoxides was found to be the optimal combination for the generation of magnesium alkylidene carbenoids and the subsequent FBW rearrangement. Because 1-chlorovinyl p-tolyl sulfoxides can be readily prepared from carbonyl compounds and chloromethyl p-tolyl sulfoxides, the FBW rearrangement of magnesium alkylidene carbenoids generated from 1-chlorovinyl p-tolyl sulfoxides provides a convenient route to the synthesis of alkynes from carbonyl compounds through one-carbon homologation. The trans relationship between the substituent with a high migratory aptitude and the chloro group was of importance for the successful 1,2-rearrangement.

Experimental

All reactions involving air- or water-sensitive compounds were conducted under an argon atmosphere. Argon gas was dried by passage through P₂O₅. Anhydrous THF and toluene were purchased and used as supplied. Silica gel 60N containing 0.5% fluorescence reagent 254 and a quartz column were used for column chromatography, and the products that absorbed UV light were detected by UV irradiation. The melting points were measured using a Yanaco MP-S3 apparatus and are uncorrected. IR spectra were recorded on a Perkin–Elmer Frontier FTIR in the ATR mode. NMR spectra were recorded in CDCl₃ solutions using a JEOL JNM-LA 300, JEOL JNM-LA 500, Bruker AVANCE DPX 300, and Bruker AVANCE DPX 400 spectrometers. Mass spectrometry (MS) experiments were conducted at 70 eV by direct injection with a HITACHI M-80B mass spectrometer. Fast atom bombardment (FAB) mass spectra were obtained with a mixture of m-nitrobenzyl alcohol and glycerol as the matrix. Chloromethyl p-tolyl sulfoxide was prepared according to the procedure described in the literature [40]. Alkyne 4a is a known compound, and the characterization data were in agreement with those reported in the literature [41].

Typical procedure for the synthesis of sulfoxides 2

A solution of chloromethyl p-tolyl sulfoxide (4.16 g, 22.0 mmol) in THF (20 mL) was added dropwise to a solution of LDA (2.0 mol/L solution in THF/heptane/ethylbenzene, 12.0 mL, 24 mmol) in THF (30 mL) at −78 °C, and the mixture was stirred at −78 °C for 10 min. Then, a solution of 4,4'-dimethoxybenzophenone (4.85 g, 20.0 mmol) in THF (40 mL) was added dropwise to the mixture at −78 °C, and the reaction mixture was warmed to −20 °C over a period of 2 h. The reaction was quenched with sat. aq. NH₄Cl (20 mL), and the mixture was extracted with CHCl₃ (3 × 20 mL). The combined organic layers were washed with water (50 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/EtOAc 1:1) to give the alcohol [6.90 g, 16.7 mmol, 83%, R_f = 0.45 (hexane/EtOAc 1:1)] as a single diastereomer; yellow solid; mp 102.5–104.0 °C; IR (ATR) 3558, 3004, 2965, 2932, 2905, 2837, 1606, 1585, 1512, 1461, 1307, 1250, 1178, 1156, 1085, 1055, 1028, 838, 801, 754 cm⁻¹; ¹H NMR (301 MHz, CDCl₃) δ 2.42 (s, 3H), 3.76 (s, 3H), 3.82 (s, 3H), 4.19 (s, 1H), 5.23 (s, 1H), 6.83 (d, J = 8.9 Hz, 2H), 6.94 (d, J = 8.9 Hz, 2H), 7.29–7.42 (m, 6H), 7.55 (d, J = 8.9 Hz, 2H); ¹³C NMR (126 MHz, CDCl₃) δ 21.8, 55.2, 55.3, 80.8, 85.3, 113.6, 114.1, 124.6, 126.9, 127.4, 129.9, 135.2, 136.5, 138.0, 142.4, 158.9, 159.2; FABMS (m/z, %): 453 ([M + Na]⁺, 3), 431 ([M + H]⁺, 3), 413 (6), 274 (100), 227 (28); HRMS–FAB⁺ (m/z): [M + H]⁺ calcd for C₂₃H₂₄³⁵ClO₄S, 431.1084; found, 431.1085. A mixture of the alcohol (1.66 g, 3.84 mmol), acetic anhydride (7.5 mL), pyridine (16.0 mL), and DMAP (93 mg, 0.76 mmol) was stirred under reflux for 24 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane/EtOAc) to give sulfoxide 2a [1.38 g, 3.34 mmol, 87%, R_f = 0.50 (hexane/EtOAc 1:1)]. Colorless solid; mp 140.2–141.0 °C; IR (ATR) 3063, 3032, 3024, 2955, 2932, 2908, 2837, 1603, 1577, 1506, 1462, 1306, 1246, 1172, 1082, 1049, 1031, 829 cm⁻¹; ¹H NMR (399 MHz, CDCl₃) δ 2.42 (s, 3H), 3.79 (s, 3H), 3.85 (s, 3H), 6.84 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 7.23 (d, J = 8.8 Hz, 2H), 7.27–7.33 (m, 4H), 7.51 (d, J = 8.2 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 21.5, 55.3, 55.4, 113.4, 114.0, 125.0, 129.7, 130.9, 131.0, 131.5, 131.7, 135.0, 139.3, 141.5, 149.4, 160.1, 160.4; FABMS (m/z, %): 413 ([M + H]⁺, 100), 364 (20), 238 (22); HRMS–FAB⁺ (m/z): [M + H]⁺ calcd for C₂₃H₂₂³⁵ClO₃S, 413.0978; found, 413.0980.

Typical procedure for the reaction of sulfoxides 2 with iPrMgCl

A solution of sulfoxide 2a (207 mg, 0.501 mmol) in toluene (10 mL) was added dropwise to a solution of iPrMgCl (2.0 mol/L solution in Et₂O, 0.875 mL, 1.75 mmol) in toluene (15 mL) at −78 °C, and the reaction mixture was warmed to 0 °C over 2 h. The reaction was quenched with sat. aq. NH₄Cl (8 mL) and extracted with CHCl₃ (3 × 5 mL). The combined organic layers were washed with water (30 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/EtOAc 5:1) to give 4a [118 mg, 0.495 mmol, 99%, R_f = 0.4 (hexane/EtOAc 3:1)]. Colorless solid; mp 139.2–140.1 °C; IR (ATR) 2969, 2938, 2841, 1607, 1511, 1457, 1444, 1287, 1244, 1172, 1106, 1025, 834, 820 cm⁻¹; ¹H NMR (301 MHz, CDCl₃) δ 3.83 (s, 6H), 6.87 (d, J = 8.8 Hz, 4H), 7.45 (d, J = 8.8 Hz, 4H); ¹³C NMR (126 MHz, CDCl₃) δ 55.3, 88.0, 114.0, 115.7, 132.9, 159.4; EIMS (m/z, %): 238 ([M]⁺, 100), 223 (55); HRMS–EI (m/z): [M]⁺ calcd for C₁₆H₁₄O₂, 238.0994; found, 238.0997.