Highly functionalized alkenes produced from base-free organocatalytic Wittig reactions: (E)-3-benzyl­idenepyrrolidine-2,5-dione, (E)-3-benzyl­idene-1-methyl­pyrrolidine-2,5-dione and (E)-3-benzyl­idene-1-tert-but­yl­pyrrolidine-2,5-dione

Carbon–carbon double bonds are ubiquitous functional groups in chemistry. They are important feedstocks as well as synthetic targets in their own right. The Wittig reaction is one of the fundamental transformations for the preparation of alkenes from carbonyl compounds and phospho­nium ylides and is even used on an industrial scale (Parker et al., 2016). The ylides have to be prepared prior to the olefination step from the respective phospho­nium salts by deprotonation utilizing strong bases (Wittig & Geissler, 1953). We are inter­ested in phospho­rus-based organocatalysis and reported the first base-free catalytic Wittig reaction (Schirmer et al., 2015). Our aim was to prepare highly functionalized alkenes as useful building blocks for organic synthesis. The first protocol was based on tri­butyl­phosphane as the catalyst. Most recently we developed a system employing readily available phospho­lene oxide as a pre-catalyst and tri­meth­oxy­silane as reducing agent which operates under milder conditions (Schirmer et al., 2016). We used this new system to prepare the three title compounds, namely (E)-3-benzyl­idenepyrrolidine-2,5-dione, (I), (E)-3-benzyl­idene-1-methyl­pyrrolidine-2,5-dione, (II), and (E)-3-benzyl­idene-1-tert-butyl­pyrrolidine-2,5-dione, (III). [OK?]

Benzaldehyde (1.00 mmol), male­imide derivative (1.10 mmol), PhCO₂H (5 mol%) and (MeO)₃SiH (3.00 mmol) were added successively to a solution of 3-methyl-1-phenyl-2-phospho­lene 1-oxide (5 mol%) in toluene (2 ml) in a reaction vial. The vial was flushed with argon and the reaction mixture was stirred for 14 h at 373 K.

According to the general procedure, 3-methyl-1-phenyl-2-phospho­lene 1-oxide (9.9 mg, 0.052 mmol), benzaldehyde (106 mg, 1.00 mmol), 1H-pyrrole-2,5-dione (109 mg, 1.12 mmol), PhCO₂H (6.1 mg, 0.050 mmol) and (MeO)₃SiH (386 mg, 3.16 mmol) were converted in toluene (2 ml). After cooling the reaction vial to 255 K and keeping it for 2 d at this temperature, the resulting precipitate was filtered off and washed with toluene (3 × 2 ml). After removal of all volatiles in vacuum, the desired product, i.e. (I) (yield: 171 mg, 0.914 mmol, 91%, E/Z = 99:1) was obtained as a brown solid. Single crystals suitable for X-ray crystal stucture analysis were obtained from a 1:1 (v/v) mixture of ethanol and cyclo­hexane. ¹H NMR (300 MHz, CDCl₃, 299 K): E isomer: δ 3.58 (d, J = 2.5 Hz, 2H), 7.38–7.52 (m, 4H), 7.53–7.63 (m, 2H), 9.04 (s, NH). ¹³C{¹H} NMR (75 MHz, CDCl₃, 299 K): E isomer: δ 35.9 (CH₂), 127.4 (C), 123.0 (2 × CH), 130.9 (CH), 131.2 (2 × CH), 133.5 (CH), 135.3 (C), 172.2 (C═O), 175.7 (C═O). Elemental analysis calculated for C₁₁H₉NO₂: C 70.58, H 4.85, N 7.48%; found: C 70.72, H 4.73, N 7.31%.

According to the general procedure, 3-methyl-1-phenyl-2-phospho­lene 1-oxide (9.9 mg, 0.052 mmol), benzaldehyde (106 mg, 1.00 mmol), 1-methyl-1H-pyrrole-2,5-dione (125 mg, 1.13 mmol), benzoic acid (6.1 mg, 0.050 mmol) and tri­meth­oxy­silane (386 mg, 3.16 mmol) were converted in toluene (2 ml). The mixture was subsequently cooled to room temperature. All volatiles were removed in vacuum and the crude product was purified by column chromatography (SiO₂, cyclo­hexane–EtOAc = 20:1 v/v). The desired product, i.e. (II) (yield: 191 mg, 0.949 mmol, 95%, E/Z = 99:1) was obtained as white solid. Single crystals suitable for X-ray crystal stucture analysis were obtained from a 1:1 (v/v) mixture of ethanol and cyclo­hexane. R_F (SiO₂, cyclo­hexane–EtOAc = 2:1v/v) = 0.32. ¹H NMR (300 MHz, CDCl₃, 299 K): E isomer: δ 3.13 (s, 3H), 3.58 (d, J = 2.3 Hz, 2H), 7.38–7.54 (m, 5H), 7.63 (t, J = 2.3 Hz, 1H). ¹³C{¹H} NMR (75 MHz, CDCl₃, 299 K): E isomer: δ 25.1 (CH₃), 34.2 (CH₂), 123.6 (C), 129.3 (2 × CH), 130.3 (3 × CH), 134.2 (C), 134.4 (CH), 171.3 (C═O), 174.2 (C═O). Elemental analysis calculated for C₁₂H₁₁NO₂: C 71.63, H 5.51, N 6.96%; found: C 71.79, H 5.42, N 6.93%.

According to the general procedure, 3-methyl-1-phenyl-2-phospho­lene 1-oxide (9.9 mg, 0.052 mmol), benzaldehyde (106 mg, 1.00 mmol), 1-tert-butyl-1H-pyrrole-2,5-dione (174 mg, 1.14 mmol), PhCO₂H (6.1mg, 0.050 mmol) and (MeO)₃SiH (386 mg, 3.16 mmol) were converted in toluene (2 ml). After removal of all volatiles, the product was precipitated from EtOH. After cooling the flask to 255 K for 2 d, the precipitate was filtered off and washed with EtOH (3 × 2 ml) to yield the desired product, i.e. (III) (yield: 242 mg, 0.995 mmol, ≥99%, E/Z = 96:4) as a white solid. Single crystals suitable for X-ray crystal stucture analysis were obtained from an 1:1 (v/v) mixture of ethanol and cyclo­hexane. ¹H NMR (300 MHz, CDCl₃, 299 K): E isomer: δ 1.66 (s, 9H), 3.48 (d, J = 2.5 Hz, 2H), 7.35–7.49 (m, 5H), 7.53 (t, J = 2.5 Hz, 1H). ¹³C{¹H} NMR (75 MHz, CDCl₃, 299 K): E isomer: δ 28.7 (3 × CH₃), 34.9 (CH₂), 58.8 (C), 124.22 (C), 129.1 (2 × CH), 129.9 (CH), 130.1 (2 × CH), 133.0 (CH), 134.6 (C), 172.2 (C═O), 175.2 (C═O). Elemental analysis calculated for C₁₅H₁₇NO₂: C 74.05, H 7.04, N 5.76%; found: C 74.12, H 6.93, N 5.84%.

Crystal data, data collection and structure refinement details are summarized in Table 1. Atom H1 in compound (I) could be found in a difference Fourier map and was refined freely. All other H atoms were placed in idealized positions with C—H = 0.95 (methine), 0.99 (methyl­ene) and 0.98 Å (methyl) and refined using a riding model with U_iso(H) = 1.5 U_eq(C) for methyl H atoms and 1.2U_eq(C) otherwise.

In the presence of 5 mol% 3-methyl-1-phenyl-2-phospho­lene 1-oxide as pre-catalyst and benzoic acid as co-catalyst, 3-benzyl­idenepyrrolidine-2,5-dione compounds (I), (II) and (III) were synthesized by the conversion of benzaldehyde with male­imides (see Scheme 1 showing the base-free catalytic Wittig reaction, conditions A). Full conversion was achieved after 14 h at 373 K and the desired products were obtained in excellent E selectivity and yields >90% (Schirmer et al., 2016). In contrast, if those substrates are converted in the presence of tri­butyl­phosphane as the catalyst significant lower yields (<30 %) were obtained (Scheme 1, conditions B). We propose the formation of the products (I)–(III) according to the mechanism depicted in Scheme 2. Initially an enolate is formed by the Michael addition of the catalyst to a male­imide. ¹H NMR experiments for the Bu₃P-catalyzed system revealed that this step is reversible (Schirmer et al., 2015). The ylide is subsequently formed by a proton shift, which might also be mediated by the benzoic acid present in the reaction mixture (Liang et al., 2008; Xia et al., 2007). Notably, this allows the generation of the ylide bypassing the commonly required preparation of a phospho­nium salt inter­mediate and subsequent preparation of the ylide. As mentioned above, the phospho­lene catalyst gives much higher yields than the Bu₃P-based system, which might be explained by the reactivity and stability of the formed yilde, respectively. In the case of the phospho­lene catalyst, the phospho­nium cation is stabilized by conjugation which in turn increases the nucleophilicity of the carbanion and thus increases reactivity of the ylide. The desired highly functionalized alkenes are formed and the precatalyst is liberated. Finally, the phosphane oxide is reduced by tri­meth­oxy­silane to regenerate the active catalyst, thus closing the catalytic cycle.

¹H NMR experiments to obtain evidence for the initial Michael addition step were performed with di­methyl maleate (Fig. 1, bottom spectra, t = 0 min). After ≤ 15 min, complete isomerization to the respective fumarate was observed in the presence of tributlyphosphane, as well as 3-methyl-1-phenyl-2-phospho­lene. Moreover, in the case of tributlyphosphane, the formation of the phospho­rus ylide was observed (Fig. 1, top spectra, ≤15 min). This was indicated by a characteristic doublet at 3.14 p.p.m. for the methyl­ene protons which showed a specific ³J_P–H coupling constant of 15.9 Hz. As expected the decoupling from ³¹P led to a single resonance at 3.14 p.p.m. However, the formation of the ylide in a 1:1 mixture of the phopholene and di­methyl maleate could not be observed in the ¹H NMR even at prolonged reaction times of 24 h. This indicates the lower stability and thus higher reactivity of the respective ylide. Independently from the substituent R of the employed male­imides, the products (I)–(III) were obtained in excellent yields of ≥90% and E/Z selectivities up to 99:1.

Herein we present X-ray crystallographic studies of the corresponding E isomers of the compounds (I), (II) and (III), respectively (Fig. 2–4). The bond lengths and angles of the title compounds are within the expected ranges. Selected torsion angles could be used to describe the conformation of the molecule: C2—C5—C6—C7 = 3.03 (18)° for (I), C2—C6—C7—C8 = 6.08 (19)° for (II), and C2—C9—C10—C15 = 10.9 (2)° and C17—C24—C25—C30 = -5.4 (2)° for the two molecules of (III). The angles between the planes of the succinimide group (plane defined by the ring atoms) and the phenyl ring of 9.26° for (I), 5.47° for (II) and 8.66 and 16.82° for (III) were observed.

In the crystal of (I), molecules are linked into centrosymmetric dimers via pairs of N—H···O hydrogen bonds (Tbale 2 and Fig. 5). In the crystal packing, molecules are arranged as rods along the a axis (Fig. 6). In the crystal structure of (III), two molecules are present in the asymmetric unit. In Fig. 7, the crystal packing of (II) along the a axis and in Fig. 8 the crystal packing of (III) along the b axis are depicted. Examples of similar N-substituted pyrrolidine-2,5-dione derivatives are reported for 2-aryl-3-methyl-4-oxo-3,4-di­hydro­quinazolines (Voitenko et al., 1999), bi­spiro­oxindoles (Xu et al., 2014) and 1,6-methano­[10]annulene-3,4-dicarboximides (Oda et al., 2014).