One-pot synthesis of azacyclodiynes by reaction of α,ω-diacetylenes with 1,5,3-dioxazepanes using copper-containing catalysts

An effective method has been developed for the synthesis of cyclic propargylamines by aminomethylation of α,ω-diacetylenes with N-alkyl-substituted 1,5,3-dioxazepanes in the presence of copper-containing catalysts.

Azacycloalkynes have been previously obtained in reactions of primary amines with α,ω-dihaloalkadiynes,1 by intramolecular cyclization of diacetylenic gem-amino ethers under high dilution conditions,2 by a three-component cyclocondensation of terminal alkadiynes, aldehydes, and amines (A³-coupling) in the presence of СuCl catalyst,3 as well as by aminomethylation of α,ω-diacetylenes by using N,N-bis(ethoxymethyl)amines in the presence of СuBr₂ catalyst.4

It has been previously reported that 1,5,3-dioxazepanes5 can be effectively used as Mannich bases in aminomethylation reactions of β-keto esters6 and cyclopentanone.7 In the current work, we present data about the synthesis of azacycloalkadiynes by catalytic cycloaminomethylation of α,ω-diacetylenes using N-substituted 1,5,3-dioxazepanes.

The interest toward azacycloalkadiynes is motivated by their applications in organic synthesis, for example, in thermal intramolecular cyclization reactions of 1,6-diazacyclodeca-3,8-diynes8 or 1-thia-6-azacyclodeca-3,8-diynes.9

While continuing our exploration of aminomethylation reactions of terminal acetylenes using 1,5,3-dioxazepanes,10 as well as for the purpose of developing an effective method for the synthesis of azacyclodiynes, we studied the reaction of α,ω-diacetylenes with N-substituted 1,5,3-dioxazepanes 1a–с in the presence of copper-containing catalysts. The selection of catalysts on the basis of copper compounds was justified by their high activity in reactions between terminal acetylenes and N,N-bis(ethoxymethyl)amines.4

By using the model reaction of 3-butyl-1,5,3-dioxazepane (1b) with 1,7-octadiyne (2b), we screened catalysts that were either pure copper compounds (СuCl (5% yield of the product), CuBr (16%), CuI (25%), CuCl₂ (36%), CuBr₂ (65%), CuSO₄ (7%)) or immobilized copper catalysts on solid supports (CuCl₂·2Н₂О–γ-Al₂O₃ (25% yield of the product), CuBr₂–γ-Al₂O₃ (23%), CuBr₂–microSiO₂ (7%), CuBr₂–mesoSiO₂ (16%), CuBr₂–macroSiO₂ (15%), CuBr₂–ASM-40 (14%), CuBr₂–НY-BS (10%)). The highest yield (~65%) of 1-butyl-1-azacycloundeca-3,9-diyne (3d) was achieved by using 5 mol % of СuBr₂ catalyst at 80°С over 6 h in toluene under argon atmosphere. The reaction of α,ω-alkadiynes 2а–d with 1,5,3-dioxazepanes 1a–с under these conditions led to 1-alkyl-1-azacycloalkadiynes 3а–g in 42–72% yields (Scheme 1). The spectral characteristics of compounds 3c,d,e,g matched the literature data.4

Scheme 1.

Cycloalkyl(cyclopropyl,cyclopentyl,cyclohexyl)- and aryl-substituted 1,5,3-dioxazepanes did not react with α,ω-diacetylenes under the aforementioned conditions, because the indicated 1,5,3-dioxazepanes were converted to 1,3,5-triazines under the reaction conditions developed during our study. The α,ω-diacetylenes containing a heteroatom – (di(propyn-2-yl)ether and N,N-di(propyn-2-yl)amine) showed low activity in the reaction with alkyl-substituted 1,5,3-dioxazepanes, probably due to conformational rigidity caused by the effects of lone electron pairs of the heteroatom on the structure of α,ω-diacetylene.

Thus, we have developed a new one-pot method for the synthesis of azacyclodiynes by cycloaminomethylation of α,ω-diacetylenes using N-substituted 1,5,3-dioxazepanes in the presence of СuBr₂ catalyst.

Experimental

IR spectra were recorded on a Bruker Vertex 70v spectrometer for samples in the form of thin films. ¹Н and ¹³С NMR spectra were recorded on Bruker Avance 400 (400 and 100 MHz, respectively) and Bruker Ascend 500 (500 and 125 MHz, respectively) spectrometers in CDCl₃. Homonuclear (COSY) and heteronuclear (¹Н–¹³С HSQC, ¹Н–¹³С HMBC) two-dimensional NMR experiments for compounds 3а–e were performed on a Bruker Avance 500 spectrometer. The chemical shifts were determined relative to solvent signals (δ_Н 7.28 ppm and δ_С 77.1 ppm, respectively). GC/MS analyses were performed on a Shimadzu GC 2010 chromatograph with a Shimadzu GCMS-QP2010 Ultra mass selective detector. The gas chromatograph was equipped with a Supelco 5ms capillary column (60 m × 0.25 mm × 0.25 μm), carrier gas – helium, injector temperature 260°С, interface temperature 260°С, ion source temperature 200°С, EI ionization (70 eV). The content of С, Н, and N was determined with a Carlo Erba 1106 СHN-analyzer. Gas chromatography was performed on a Shimadzu GC-9A with a flame ionization detector, using SE-30 stationary phase (5%) on a Chromaton N-AW-HMDS support, 2000 × 3 mm packed steel column, temperature program 50–280°С, 8°C/min, the carrier gas was helium. Thin-layer chromatography was performed on Sorbfil PTSKh-AF-A plates, with visualization in iodine vapor. Individual compounds were isolated by chromatographic separation on KSK silica gel (50–160 μm). The eluent used for column chromatography is indicated for each compound.

The starting α,ω-diacetylenes 2а–d with ≥98% assay were commercially available from Acros Organics and were used without additional purification, while 1,5,3-dioxazepanes 1a–с were synthesized according to published procedures.5 Copper salts (CuBr, CuI, CuCl₂, CuBr₂, CuCl₂·2Н₂О, CuSO₄, and Cu(CH₃CO₂)₂) with ≥99% assay were commercially available from Acros Organics. The catalysts on solid support were obtained by coating copper salts on solid carriers. The procedure involved treatment of γ-Al₂O₃, micro-meso, meso, and macroporous silica gels, as well as acidic amorphous alumosilicate and micro-mesomacroporous zeolite HY (HY-BS) with the aforementioned copper salts as solutions in alcohol or ether, followed by drying at 110°С according to a published method.11 All samples contained 10–12 mass % of the respective copper salts.

Synthesis of 1-alkyl-1-azacycloalkadiynes 3а–g (General method). A Schlenk vessel was charged under argon atmosphere with the appropriate 1,5,3-dioxazepane 1a–с (1 mmol), toluene (3 ml), α,ω-diacetylene 2а–d (1 mmol), and СuBr₂ (0.01 g, 0.05 mmol). The reaction mixture was stirred at 80°С for 6 h and filtered through a layer of silica gel; the solvent was evaporated on a rotary evaporator. The product was isolated by column chromatography.

1-Propyl-1-azacyclododeca-3,10-diyne (3a). Yield 0.085 g (42%), yellow oil. R_f 0.53 (hexane–dichloromethane, 1:1). IR spectrum, ν, cm^–1: 1140 (C–N), 1432 (CH₃), 1457 (CH₂), 2258 (С≡C), 2860 (CH₂), 2934 (СН₃). ¹H NMR spectrum (500 MHz), δ, ppm (J, Hz): 0.93 (3H, t, J = 7.5, CH₃); 1.48–1.53 (8H, m, (C≡СCH₂СН₂)₂СН₂, CH₂CH₃); 2.21–2.23 (4H, m, N(CH₂С≡СCH₂)₂); 2.45 (2Н, t, J = 7.5, CH₃CH₂CH₂N); 3.38 (4Н, s, N(CH₂C≡C)₂). ¹³C NMR spectrum (125 MHz), δ, ppm: 12.0 (CH₃); 18.7 (2C≡CCH₂); 20.7 (CH₂СН₃); 28.3 ((C≡CCH₂CH₂)₂СН₂); 28.5 (2С≡СCH₂CH₂); 42.5 (N(CH₂C≡C)₂); 54.9 (CH₂CH₂N); 75.1 (N(CH₂C≡C)₂); 84.8 (N(CH₂C≡C)₂). Mass spectrum, m/z (I_rel, %): 203 [М]⁺ (11), 188 [М–CH₃]⁺ (3), 174 [M–CН₂СН₃]⁺ (100), 160 [М–CH₃(CH₂)₂]⁺ (9), 132 [M–N(CH₂)₃CH₃]⁺ (7). Found, %: С 82.76; Н 10.34; N 6.91. С₁₄Н₂₁N. Calculated, %: С 82.70; Н 10.41; N 6.89.

1-Propyl-1-azacyclotrideca-3,11-diyne (3b). Yield 0.132 g (60%), yellow oil. Rf 0.45 (hexane–dichloromethane, 1:1). IR spectrum, ν, cm^–1: 1170 (C–N), 1433 (CH₃), 1461 (CH₂), 2118 (С≡C), 2859 (CH₂), 2933 (СН₃). ¹H NMR spectrum (500 MHz), δ, ppm (J, Hz): 0.93 (3H, t, J = 7.5, CH₃); 1.38–1.44 (4H, m, (C≡ССН₂CH₂СН₂)₂); 1.49–1.56 (6H, m, (C≡CСН₂CH₂CH₂)₂, CH₂СН₂N); 2.19–2.22 (4H, m, N(СН₂С≡СCH₂)₂); 2.47 (2Н, t, J = 7.5, CH₂CH₂N); 3.39 (4Н, s, N(CH₂C≡C)₂). ¹³C NMR spectrum (125 MHz), δ, ppm: 11.96 (CH₃); 18.7 (2C≡CCH₂); 20.7 (CH₂СН₃); 28.4 (2C≡CCH₂CH₂СН₂); 28.8 (2С≡СCH₂CH₂); 42.5 (N(CH₂C≡C)₂); 54.9 (CH₂CH₂N); 75.1 (N(CH₂C≡C)₂); 84.9 (N(CH₂C≡C)₂). Mass spectrum, m/z (I_rel, %): 217 [М]⁺ (10), 202 [М–CH₃]⁺ (3), 188 [M–CН₂СН₃]⁺ (100), 174 [М–CH₃(CH₂)₂]⁺ (3), 160 [M–N(CH₂)₃CH₃]⁺ (3), 91 [NH(CH₂C≡C)₂]⁺ (18). Found, %: С 82.94; Н 10.61; N 6.45. С₁₅Н₂₃N. Calculated, %: С 82.89; Н 10.67; N 6.44.

1-Butyl-3,4,8,9-tetradehydro-1,2,5,6,7,10-hexahydroazecine (3c). Yield 0.085 g (45%), yellow oil. R_f 0.53 (cyclohexane–ethyl acetate–CН₂Сl₂, 1:10:2). IR spectrum, ν, cm^–1: 1110 (C–N), 1432 (CH₃), 1455 (CH₂), 2220 (С≡C), 2861 (CH₂), 2931 (СН₃). ¹H NMR spectrum (500 MHz), δ, ppm (J, Hz): 0.94 (3H, t, J = 9.0, CH₃); 1.33–1.39 (2H, m, CH₂СН₃); 1.40–1.49 (2H, m, CH₂CH₂СН₃); 1.71–1.76 (2H, m, (C≡CCH₂)₂CH₂); 2.32–2.35 (4H, m, (С≡СCH₂)₂CH₂); 2.50 (2Н, t, J = 9.0, CH₂CH₂N); 3.38 (4Н, s, N(CH₂C≡C)₂). ¹³C NMR spectrum (125 MHz), δ, ppm: 14.0 (CH₃); 18.0 ((C≡CCH₂)₂CH₂); 20.6 (CH₂СН₃); 28.2 ((С≡СCH₂)₂CH₂); 29.6 (CH₂CH₂СН₃); 42.6 (N(CH₂C≡C)₂); 52.7 (CH₂CH₂N); 75.6 (N(CH₂C≡C)₂); 84.0 (N(CH₂C≡C)₂). Mass spectrum, m/z (I_rel, %): 188 [M–Н]⁺ (6), 174 [M–CН₃]⁺ (6), 146 [М–(CH₂)₂CH₃]⁺ (100), 117 [M–NH(CH₂)₃CH₃]⁺ (45), 103 [М–CH₃(CH₂)₃NHCH₂]⁺ (13), 91 [NH(CH₂C≡C)₂]⁺ (83). Found, %: С 82.53; Н 10.07; N 7.35. С₁₃Н₁₉N. Calculated, %: С 82.48; Н 10.12; N 7.40.

1-Butyl-1-azacycloundeca-3,9-diyne (3d). Yield 0.132 g (65%), yellow oil. R_f 0.60 (hexane–ethyl acetate, 1:2). IR spectrum, ν, cm^–1: 1111 (C–N), 1325 (C–N), 1385 (CH₃), 1432 (CH₃), 1458 (CH₂), 2230 (C≡C), 2863 (CH₂), 2931 (СН₃). ¹H NMR spectrum (400 MHz), δ, ppm (J, Hz): 0.94 (3H, t, J = 7.2, CH₃); 1.33–1.38 (2H, m, CH₂СН₃); 1.40–1.48 (2H, m, CH₂CH₂CH₃); 1.63–1.65 (4H, m, (С≡СCH₂CH₂)₂); 2.24 (4Н, br. s, (C≡CCH₂CH₂)₂); 2.50 (2H, t, J = 7.2, CH₂CH₂N); 3.38 (4Н, s, N(CH₂C≡C)₂). ¹³C NMR spectrum (100 MHz), δ, ppm: 14.0 (CH₃); 18.2 (2C≡CCH₂CH₂); 20.6 (CH₂СН₃); 27.9 (2С≡СCH₂CH₂); 29.6 (CH₂CH₂СН₃); 42.5 (N(CH₂C≡C)₂); 52.6 (CH₂CH₂N); 75.3 (N(CH₂C≡C)₂); 84.4 (N(CH₂C≡C)₂). Mass spectrum, m/z (I_rel, %): 202 [M–Н]⁺ (9), 160 [M–(CH₂)₂CН₃]⁺ (100), 117 [M–CH₂NH(CH₂)₃CH₃]⁺ (38), 91 [М–N(CH₂C≡C)₂]⁺ (51). Found, %: С 82.74; Н 10.45; N 6.92. C₁₄H₂₁N. Calculated, %: C 82.70; H 10.41; C 6.89.

1-Butyl-1-azacyclotrideca-3,11-diyne (3e). Yield 0.167 g (72%), yellow oil. R_f 0.45 (cyclohexane–ethyl acetate–CН₂Сl₂, 1:10:2). IR spectrum, ν, cm^–1: 1111, 1144 (C–N), 1361 (CH₃), 1436 (CH₂), 2261 (C≡C), 2857 (СН₂), 2930 (CH₃). ¹H NMR spectrum (500 MHz), δ, ppm (J, Hz): 0.94 (3H, t, J = 7.2 CH₃); 1.35–1.38 (2H, m, CH₂СН₃); 1.39–1.43 (4H, m, (С≡СCH₂CH₂CH₂)₂); 1.44–1.49 (2H, m, CH₂CH₂СН₃); 1.51–1.53 (4H, m, (С≡СCH₂CH₂СН₂)₂); 2.21 (4Н, t, J = 7.0 (С≡СCH₂CH₂СН₂)₂); 2.50 (2Н, t, J = 7.5, CH₂CH₂N); 3.38 (4Н, s, N(CH₂C≡C)₂). ¹³C NMR spectrum (125 MHz), δ, ppm: 14.0 (CH₃); 18.7 (2C≡CCH₂CH₂CH₂); 20.7 (CH₂СН₃); 28.4 (2С≡СCH₂CH₂СН₂); 28.8 (2С≡СCH₂CH₂СН₂); 29.6 (CH₂CH₂СН₃); 42.6 (N(CH₂C≡C)₂); 52.6 (CH₂CH₂N); 75.1 (N(CH₂C≡C)₂); 84.9 (N(CH₂C≡C)₂). Mass spectrum, m/z (I_rel, %): 231 [M]⁺ (6), 207 [M–C≡С]⁺ (27), 188 [M–(CH₂)₂CH₃]⁺ (87), 40 [CNCH₂]⁺ (100). Found, %: С 83.11; Н 10.92; N 6.01. С₁₆Н₂₅N. Calculated, %: С 83.06; Н 10.89; N 6.05.

1- tert -Butyl-3,4,8,9-tetradehydro-1,2,5,6,7,10-hexahydroazecine (3f). Yield 0.12 g (63%), yellow oil. R_f 0.38 (hexane–ethyl acetate–CН₂Сl₂, 1:2:1). IR spectrum, ν, cm^–1: 1018 (C–N), 1366 (СН₃), 1392 (СН₃), 1453 (CH₃), 2118 (С≡С), 2200 (С≡С), 2910 (CH₂), 2960 (СН₃). ¹H NMR spectrum (500 MHz), δ, ppm (J, Hz): 1.20 (9H, s, 3CH₃); 1.68–1.76 (2H, m, (C≡CСН₂)₂CH₂); 2.29–2.36 (4H, m, (С≡СCH₂)₂); 3.60 (4Н, s, N(CH₂C≡C)₂). ¹³C NMR spectrum (125 MHz), δ, ppm: 18.2 ((2C≡CCH₂)₂); 27.5 ((СН₃)₃); 28.0 ((С≡СCH₂)₂CH₂); 36.8 (N(CH₂C≡C)₂); 55.0 (C(СН₃)₃); 78.1 (N(CH₂C≡C)₂); 83.3 (N(CH₂C≡C)₂). Mass spectrum, m/z (I_rel, %): 189 [M]⁺ (9), 174 [M–CН₃]⁺ (100), 144 [М–3(CH₃)]⁺ (13), 132 [М–C(CH₃)]⁺ (30), 117 [M–NHC(CH₃)₃]⁺ (40), 91 [NH(CH₂C≡C)₂]⁺ (45). Found, %: С 82.61; Н 10.08; N 7.43. С₁₃Н₁₉N. Calculated, %: С 82.48; Н 10.12; N 7.40.

1-( tert- Butyl)-1-azacycloundeca-3,9-diyne (3g). Yield 0.103 g (51%), yellow oil. R_f 0.48 (hexane–ethyl acetate–CН₂Сl₂, 1:2:1). IR spectrum, ν, cm^–1: 1202 (С(СН₃)₃), 1262 (C–N), 1364 (CH₃), 1390 (CH₃), 1431 (CH₃), 1457 (CH₂), 2130 (C≡С), 2863 (CH₂), 2938 (CH₃). ¹H NMR spectrum (400 MHz), δ, ppm (J, Hz): 1.17 (9H, s, 3CH₃); 1.59–1.62 (4H, m, (CH₂CH₂)₂); 2.20 (4H, br. s, (CH₂CH₂)₂); 3.57 (4H, s, N(CH₂C≡C)₂). ¹³C NMR spectrum (100 MHz), δ, ppm: 18.5 (2C≡CCH₂CH₂); 27.5 (СН₃); 27.9 ((С≡СCH₂СН₂)₂); 36.7 (N(CH₂)₂); 54.9 (NC(CH₃)₃); 77.8 (N(CH₂C≡C)₂); 83.7 (N(CH₂C≡C)₂). Mass spectrum, m/z (I_rel, %): 203 [M]⁺ (7), 188 [M–СН₃]⁺ (100), 146 [М–C(CH₃)₃]⁺ (9), 117 [M–СН₂NНС(CH₃)₃]⁺ (16), 91 [NН(CH₂C≡C)₂]⁺ (29). Found, %: С 82.83; Н 10.52; N 6.84. С₁₄Н₂₁N. Calculated, %: С 82.70; Н 10.41; N 6.89.