Trifluoroethanol Promoted Castagnoli–Cushman Cycloadditions of Imines with Homophthalic Anhydride

Lactams are essential compounds in medicinal chemistry and key intermediates in the synthesis of natural products. The Castagnoli–Cushman reaction (CCR) of homophthalic anhydride with imines is an exciting method for accessing cyclic densely substituted lactam products. Most CCRs need to be catalyzed or heated. Herein, we report a new, efficient, metal and catalyst-free CCR for the synthesis of poly-substituted 3,4-lactams utilizing the unique properties of trifluoroethanol (TFE). This procedure provides high-speed and smooth access to a broad range of densely substituted 3,4-lactams in good yields and a 100% atom-economical fashion.

Generally, the reaction of succinic IIa and glutaric Iib anhydrides with imines requires forcing conditions such as reflux in benzene, toluene, or p-xylene (140 • C) during 12-36 h [16]. While the reaction conditions were less harsh when more enolizable anhydrides Iva and IVb were employed, catalysts or heating or long reactions time were necessary to isolate the CC products Va and Vb in decent yields.
In addition, depending on the nature of the imine and the reaction conditions, the cycloaddition of homophthalic anhydride (HPA) IVa with imines affords the 3,4-cis product Va, 3,4-trans product Va, or a mixture of both predominantly [3].
Despite the considerable attention that CCRs have received over the past decades, the development of mild and practical methods is an ongoing challenge in organic synthesis. Therefore, further exploration of new catalyst-free, mild, efficient, and fast conditions is still desirable to access substituted γ, δ, and ε-lactams.
Fluorinated alcohols may be considered promising alternatives to address this synthetic challenge due to their unique properties such as high dielectric constant, polarity, high H-bond donor ability, and low nucleophilicity for cation stabilization [28,29].
Herein, we report a fast and powerful cycloaddition of imines 1 with HPA IVa in 2,2,2-trifluoroethanol (TFE), resulting in an efficient synthesis of lactams 2. 2 are promising scaffolds for the design of biologically active compounds and key intermediates in the synthesis of natural products (Scheme 1b).

Results and Discussion
We initially investigated the reaction of HPA IVa with imine 1a in different solvents (Table 1).

Results and Discussion
We initially investigated the reaction of HPA IVa with imine 1a in different solvents (Table 1).
This resulted in the formation of desired cis-lactam 2a with excellent diastereoselectivity (d.r. > 19:1). Interestingly, the reaction rate varied noticeably depending on the solvent and the temperature. In CH2Cl2, toluene, and CH3CN, the reaction takes several hours at −40 °C, even at room temperature. In polar solvents such as MTBE at −40 °C, the reaction also takes several hours, but the yield is higher (78%). To our delight, in TFE, the lactam 2a was obtained in 81% yield in 15 min at −40 °C and in 72% yield in 2 min at room temperature (entries 6 and 7). Catalytic amounts of TFE in CH2Cl2 at −40 °C lead to an 8-fold decrease in reaction time (i.e., entries 1 and 8; 24 h vs. 3 h) and an increase in yield (i.e., entries 1 and 8; 37% vs. 61%). Another fluorinated alcohol, hexafluoro-2-propanol (HFIP), could also be used, although the yield was lower compared with the result of TFE (i.e., entry 9). The reaction could not be performed at −40 °C (solidifying of HFIP), and some degradation was observed at 0 °C. The diastereomeric excess remains unchanged whatever the solvent. The substituents of the starting imine induce diastereoselectivity. This resulted in the formation of desired cis-lactam 2a with excellent diastereoselectivity (d.r. > 19:1). Interestingly, the reaction rate varied noticeably depending on the solvent and the temperature. In CH 2 Cl 2 , toluene, and CH 3 CN, the reaction takes several hours at −40 • C, even at room temperature. In polar solvents such as MTBE at −40 • C, the reaction also takes several hours, but the yield is higher (78%). To our delight, in TFE, the lactam 2a was obtained in 81% yield in 15 min at −40 • C and in 72% yield in 2 min at room temperature (entries 6 and 7). Catalytic amounts of TFE in CH 2 Cl 2 at −40 • C lead to an 8-fold decrease in reaction time (i.e., entries 1 and 8; 24 h vs. 3 h) and an increase in yield (i.e., entries 1 and 8; 37% vs. 61%). Another fluorinated alcohol, hexafluoro-2-propanol (HFIP), could also be used, although the yield was lower compared with the result of TFE (i.e., entry 9). The reaction could not be performed at −40 • C (solidifying of HFIP), and some degradation was observed at 0 • C. The diastereomeric excess remains unchanged whatever the solvent. The substituents of the starting imine induce diastereoselectivity.
Different mechanisms have been proposed for the CCR, including an iminolysis pathway and a concerted [4+2] cycloaddition [3,20]. The most plausible mechanism for the reaction of homophthalic anhydride IVa with simple imines 1 in TFE is shown in Scheme 2, proposal mechanism 1. The origin of the reaction's kinetic and yield increases in the presence of TFE might be attributed to a double activation of imine and carbonyl function of anhydride IVa via the H-bond network of TFE. The formation of hydrogen bonds between the anhydride and the TFE will decrease the pK a of the enolizable proton. This will facilitate the attack of the IVa enol on the imine carbon. In this case, one molecule of TFE can bind to both imine and the IVa enol. A probable concerted hydrogen transfer between activated imine and enol mediated by TFE could occur. This could explain the increase in reaction kinetics (Scheme 2). This scenario is supported by computational studies on closely related reactions of imines with α-cyanosuccinic anhydride [5] and is consistent with the relatively high acidity of IVa (pK a = 8.15). Interested in expanding the scope of the optimal conditions in hand, we next examine carboxylic acid anhydrides other than homophthalic anhydride IVa and a variety of imines ( Figure 2). Imine 1a didn't react in TFE with glutaric anhydride, 3-methoxy-1H-isochromen-1-one, 1,4-dioxane-2,6-dione and (3aR,7aS)-hexahydroisobenzofuran-1,3-dione at −40 • C (24 h) or at reflux (24 h) or under microwave irradiations at 150 • C (4 h).
The best yields have been obtained at room temperature. The diastereoselectivity was the same at −40 • C or room temperature for 2b, 2c, 2e, and 2f, whereas it changed for 2d. The lower d.r. value for 2d at room temperature may be due to the flexibility of the CH 2 -PMP group attached to the nitrogen atom of the imine. The formation of cis-diastereoisomer was observed in all cases except for 2h and 2j. The trans-diastereoisomer was major for 2h. 2j was obtained as trans-diastereoisomer solely.
The group's properties linked to the imine's carbon may explain these results. The presence of electron-rich groups promotes the formation of the cis-diastereoisomer, whereas electron-poor groups promote the synthesis of the trans-diastereoisomer. An ethylcarboxylate function being more electron-withdrawing than nitrobenzene may explain the exclusive formation of the trans-diastereoisomer 2j.
The CCR usually leads to the kinetic cis-diastereoisomer product without catalyst or adduct. The thermodynamic trans-diastereoisomer can be obtained by epimerization in good yield upon exposure to DBU [30]. The cis-3,4-lactam 2a was epimerized in trans-3,4lactam 2a' in 85% yield without loss of diastereoselectivity (Scheme 3).

General Information
Reagents and solvents were purchased from commercial sources and were purified by distillation or recrystallization prior to use. Reactions were run under an argon atmosphere unless stated otherwise. The purification of reaction products was carried out by flash column chromatography using silica gel (60 F 254 ) packed Redisep or Interchim columns (230-400 mesh). Preparative thin-layer chromatography was performed on Macherey-Nagel 0.25 mm silica gel (60 F 254 ) glass plates. Melting points were recorded on a B540 Büchi melting point apparatus and are uncorrected. Infrared spectra were recorded on a Perkin Elmer FT-IR 100 spectrum spectrometer. Proton nuclear magnetic resonance spectra ( 1 H-NMR) were recorded on Bruker Advance-300 or Bruker AC-500 machines and are reported in parts per million (ppm) using solvent as an internal standard (CDCl 3 at 7.26 ppm, DMSO-d 6 at 2.50 ppm, or CD 3 OD at 3.31 ppm). For 1 H NMR, the NMR spectroscopic data are given in parts per million (ppm). Coupling constants, usually denoted J, are given in the unit of Hertz (Hz). Multiplicities are designed by abbreviation: singlet (s), broad singlet (bs), doublet (d), doublet of doublet (dd), doublet of doublet of doublet (ddd), triplet (t), doublet of triplet (d), quartet (q), quintet (quint.), multiplet (m), etc. Proton-decoupled carbon nuclear magnetic resonance spectra ( 13 C-NMR) were recorded on Bruker Advance-300 or Bruker AC-500 machines and are reported in parts per million (ppm) using solvent as an internal standard (CDCl 3 at 77.1 ppm, DMSO-d 6 at 39.5 ppm, or CD 3 OD at 49.0 ppm). The d.r. was calculated with 1 H NMR. Mass data were obtained on an AUTOMASS ThermoFinnigan spectrometer with electrospray or electronebullization ionization and quadrupole mass filter. HRMS data were recorded either by LCT spectrometer (Waters) or LCT Premier XE (Waters) with ESI ionization and TOF analyzer. Reactions under microwave irradiation were performed in an Anton Parr MCP300 reactor.

General Procedure for Castagnoli-Cushman reaction (2a-2f).
A round-bottom flask under an argon atmosphere was charged with the corresponding imine 1 (0.100 mmol, 1.0 eq.) in TFE (3 mL) and then charged with homophthalic anhydride IVa (24.3 mg, 0.150 mmol, 1.5 eq.) at −40 • C. The reaction mixture was stirred at −40 • C until the starting material was consumed, as indicated by TLC analysis. The mixture was concentrated in vacuo, and the residue was purified by preparative TLC to afford the pure product. Purification: CH 2 Cl 2 /MeOH (95:5). Copies of 1 H and 13 C spectra for all prepared are available in the supplementary materials.