Conversion of Medium-Sized Lactams to α-Vinyl or α-Acetylenyl Azacycles via N,O-Acetal TMS Ethers

α-Vinyl or α-acetylenyl azacycles were easily synthesized from 7- to 9-membered lactams and 6- to 9-membered lactams via N,O-acetal trimethylsilyl (TMS) ethers. Organocopper and organostannane reagents afforded reasonable yields for the respective N-acyliminium ion vinylation and acetylenylation intermediates generated from N,O-acetal TMS ethers in the presence of a Lewis acid.


Introduction
The conversion of lactams to their corresponding azacycles is an efficient route for the preparation of functionalized azacycles. It involves amide bond manipulations, however, the nucleophilic addition to amides is limited due to the poor electrophilicity of amide carbonyls. Therefore, α-amidoalkylation of reactive iminium ions derived from amides is an effective method for providing azacycles with scaffold diversity [1,2]. Many 5-and 6-membered lactams and azacycles exist in Nature, and the conversion of these lactams via α-amidoalkylation has been extensively studied. For instance, approaches involving thioamides [3][4][5], sulfonyl amides [6], N-alkoxylactams [7], formamidines [8], enamine triflates/phosphates [9,10] and N,O-acetals [11][12][13] have been developed for conversion to α-vinyl and α-acetylenyl azacycles. Moreover, these methods have been used for the preparation of key intermediates for the assembly of structurally diverse azacycles, ranging from a simple bicyclic to complex polycyclic systems [1] in combination with various synthetic methods including metathesis [6] and aza-Claisen rearrangements [14]. Recent developments in organometallic chemistry also have enabled concise and efficient synthesis of α-vinyl and α-acetylenyl azacycles from cycloalkylamines as surrogates for lactams via direct C-H activation [15] and photoredox reactions [16]. However, most of the reported methods have been limited to the synthesis of 5-and 6-membered azacycles. In contrast, the conversion of medium-to macrocyclic lactams to their corresponding azacycles has not been extensively investigated. Thus, a lack of concise and efficient methods for such conversions has been a major challenge in the synthesis of azacycles in which the high ring strain energy might give rise to undesirable ring openings. Conventional methods generate unstable intermediates from medium-to macrocyclic lactams, resulting in imines or enamines which would be readily hydrolyzed to the corresponding amino aldehyde [17]. In addition, a series of synthetic steps were required for the preparation of medium-sized 2-vinylazacycles even after extensive attempts to apply the reported methods [14]. In this regard, there is growing demand for efficient methods to convert medium-sized lactams to their corresponding azacycles with α-vinyl or α-acetylenyl functionality. Herein, we report a novel synthetic method for the conversion of medium-sized lactam rings to α-vinyl and α-acetylenyl azacycles using N,O-acetal trimethylsilyl (TMS) ethers as N-acyliminium ion precursors.
The conversion of lactams to α-substituted azacycles involves the partial reduction and addition of a given nucleophile. The order of the two reactions is likely an important factor. For the conversion of medium-sized lactams, the introduction of a vinyl or acetylene nucleophile after the partial reduction of the lactam is likely to be more effective than the reverse sequence because of ring opening at the hemiaminal intermediate of medium-sized lactam. Considering the stability of the hemiaminal intermediate, N,O-acetal TMS ethers have been shown to be excellent precursors for reactions with medium-to macrocyclic azacycles that proceed via intermediate N-acyliminium ions [17]. Thus, we expected that α-vinyl and α-acetylenyl azacycles 4 and 5 could be prepared using N,O-acetal TMS ether 2 with proper nucleophiles via N-acyliminium ions 3 in the presence of a Lewis acid, as shown in Scheme 1.
Molecules 2018, 23, x 2 of 9 macrocyclic lactams to their corresponding azacycles has not been extensively investigated. Thus, a lack of concise and efficient methods for such conversions has been a major challenge in the synthesis of azacycles in which the high ring strain energy might give rise to undesirable ring openings. Conventional methods generate unstable intermediates from medium-to macrocyclic lactams, resulting in imines or enamines which would be readily hydrolyzed to the corresponding amino aldehyde [17]. In addition, a series of synthetic steps were required for the preparation of mediumsized 2-vinylazacycles even after extensive attempts to apply the reported methods [14]. In this regard, there is growing demand for efficient methods to convert medium-sized lactams to their corresponding azacycles with α-vinyl or α-acetylenyl functionality. Herein, we report a novel synthetic method for the conversion of medium-sized lactam rings to α-vinyl and α-acetylenyl azacycles using N,O-acetal trimethylsilyl (TMS) ethers as N-acyliminium ion precursors. The conversion of lactams to α-substituted azacycles involves the partial reduction and addition of a given nucleophile. The order of the two reactions is likely an important factor. For the conversion of medium-sized lactams, the introduction of a vinyl or acetylene nucleophile after the partial reduction of the lactam is likely to be more effective than the reverse sequence because of ring

Preparation of N,O-Acetal TMS Ether
Our work commenced with the preparation of N,O-acetal TMS ethers. The requisite N,O-acetal TMS ethers were prepared from 6-to 9-membered lactams by using previously reported procedures [18], as shown in Scheme 2. In short, protected lactams 1a-d were reduced with DIBAL, and trapping of the resulting N,O-acetal with trimethylsilyl triflate (TMSOTf) afforded the desired N,O-acetal TMS ethers 2a-d in high yields. Scheme 1. Conversion of medium-sized lactams to α-vinyl and α-acetylenyl azacycles via N,O-acetal TMS ethers.

Preparation of N,O-Acetal TMS Ether
Our work commenced with the preparation of N,O-acetal TMS ethers. The requisite N,O-acetal TMS ethers were prepared from 6-to 9-membered lactams by using previously reported procedures [18], as shown in Scheme 2. In short, protected lactams 1a-d were reduced with DIBAL, and trapping of the resulting N,O-acetal with trimethylsilyl triflate (TMSOTf) afforded the desired N,O-acetal TMS ethers 2a-d in high yields.

Preparation of N,O-Acetal TMS Ether
Our work commenced with the preparation of N,O-acetal TMS ethers. The requisite N,O-acetal TMS ethers were prepared from 6-to 9-membered lactams by using previously reported procedures [18], as shown in Scheme 2. In short, protected lactams 1a-d were reduced with DIBAL, and trapping of the resulting N,O-acetal with trimethylsilyl triflate (TMSOTf) afforded the desired N,O-acetal TMS ethers 2a-d in high yields.

Optimization of α-Vinylation
The vinylation of the 9-membered N,O-acetal TMS ether 2d was performed using various vinyl metals as nucleophiles. As shown in Table 1, reaction of 2d with the vinylcopper reagent derived from vinylmagnesium bromide and CuBr·SMe 2 in the presence of BF 3 OEt 2 afforded the desired product 4d, while the use of vinyllithium or vinylsilane resulted in a mixture of side products. The yield was considerably higher in tetrahydrofuran than in diethyl ether solvent. Other copper salts such as CuI and CuOTf could not be used instead of CuBr·SMe 2 . The coordinating characteristics of the anion that accompanies the Cu(I) ion might be attributed to the reaction. Under the same conditions, the vinylcopper reagent was reacted with N,O-acetal TMS ethers of the 7-and 8-membered azacycles 2b and 2c affording the α-vinylated adducts 4b and 4c, respectively. The N,O-acetal TMS ether 2a did not undergo vinylation with the vinylcopper reagent. Previously, Neipp and Martin reported that an organocopper reagent derived from vinylmagnesium bromide could not produce a vinyl adduct from the 6-membered cyclic precursor of the N-acyliminium ion [6], whereas Collado et al. reported the highly efficient addition of Grignard-derived organocopper reagents to 5-membered cyclic N,O-acetals.

Optimization α-Acetylenylation
Next, various acetylene nucleophiles with N,O-acetal TMS ether 2d were reacted to afford α-acetylenyl azacycle 5d. As shown in Table 2, the organocopper, organomagnesium, and organolithium reagents yielded unsuccessful results (entries 1-3, respectively). Although the use of trimethylsilyl cyanide (TMSCN) as a nucleophile for the reaction of N,O-acetal TMS ethers to afford α-cyanated cycloalkylamines is reported by Suh et al. [17], the use of trimethylsilylacetylene could not provide the desired α-acetylenyl azacycle 5d (Entry 4). After extensive efforts, an organotin reagent was successful for the synthesis of α-acetylenyl azacycle 5d from N,O-acetal TMS ether 2d in the presence of a Lewis acid. Various solvents including dichloromethane, toluene, and diethyl ether except tetrahydrofuran (entries 5-8) were tolerable for the reaction. It was reported that tetrahydrofuran was not suitable for some reactions of N,O-acetal TMS ethers [19], even though tetrahydrofuran was the best solvent for vinylation of N,O-acetal TMS ethers in Table 1. BF 3 ·OEt 2 and TMSOTf were effective Lewis acids for the generation of the N-acyliminium ion, which readily reacted with the organotin reagent to afford the desired adduct 5d (entries 5,11). The treatment of N,O-acetal TMS ether 2d with the organotin reagent in the presence of SnCl 4 or TiCl 4 afforded a mixture of unidentified and possibly decomposed side products.   After optimizing the reaction conditions, we explored the scope of the reaction by using various substituted acetylenes. The required stannylacetylene reagents were purchased from commercial vendors or prepared as previously reported [20]. As shown in Table 3, N,O-acetal TMS ether 2 derived from 6-to 9-membered lactams 1 were easily reacted with various substituted stannylacetylenes to afford the corresponding α-acetylenyl azacycles 5-8 in reasonable yields. After optimizing the reaction conditions, we explored the scope of the reaction by using various substituted acetylenes. The required stannylacetylene reagents were purchased from commercial vendors or prepared as previously reported [20]. As shown in Table 3, N,O-acetal TMS ether 2 derived from 6-to 9-membered lactams 1 were easily reacted with various substituted stannylacetylenes to afford the corresponding α-acetylenyl azacycles 5-8 in reasonable yields.  Various substituents including hydrogen, alkylsilane, alkyl, and aryl groups were well tolerated. For the 7-to 9-membered cyclic N,O-acetal TMS ethers, stannylacetylenes with electron donating groups, including Me or Ph, efficiently provided the desired α-acetylenyl azacycles in high yields. The chemical yield was notably lower in reactions for the 6-membered azacycles (entries 1-4) compared to the others. Enamine formation might be attributed to the unexpected low yield in those cases, and which was supported by the isolation of N-Boc-1,2,3,4-tetrahydropyridine as a major side product. Spectral data of the isolated N-Boc-1,2,3,4-tetrahydropyridine was identical to the reported data [21].

General Information
Unless noted otherwise, all starting materials and solvents were used as obtained from commercial suppliers without further purification. Organic solvents used in this study were dried over appropriate drying agents and distilled prior to use. Thin layer chromatography was carried out using Merck silica gel 60 F 254 plates (Merck, Kenilworth, NJ, USA), and flash chromatography was performed automatically with Isolera (Biotage, Uppsala, Sweden) or manually using Merck silica gel 60 (0.040-0.063 mm, 230-400 mesh, Merck, Kenilworth, NJ, USA). 1 H-and 13 C-NMR spectra were recorded using JEOL-500 (JEOL, Tokyo, Japan) and AVANCE-500 (Brucker, Billerica, MA, USA) spectrometers. 1 H-and 13 C-NMR chemical shifts are reported in parts per million (ppm) relative to TMS, with the residual solvent peak used as an internal reference. 1 H-NMR data were reported in the order of chemical shift, multiplicity (br, broad signal; s, singlet; d, doublet; t, triplet; q, quartet; quint, quintet; m, multiplet and/or multiple resonances), number of protons, and coupling constant in Hertz (Hz). Infrared spectra were recorded on Cary 630 FT-IR spectrometer (Agilent, Santa Clara, CA, USA). Low-and high-resolution mass spectra were obtained with JMS-700 (JEOL, Tokyo, Japan) and Q TOF 6530 (Agilent, Santa Clara, CA, USA) instruments.