another column containing solid supported amine that scavenged excess acid chloride from the reaction stream:71 (Scheme 2.14) Scheme 2.14 – Synthesis of oxazole 104 from isocyanides using a microreactor71 Using this procedure, oxazole 104 could be synthesised in 92 % yield from acid chloride 102 and isocyanide 101. Using the methodology, 34 different oxazoles were synthesised in yields ranging from 83-94 %, and none of the materials required further purification. Ley et al. also report a reaction to synthesise thiazole 108 from thioisocyanate 105 and isocyanide 106. The reagents were pumped separately through a microreactor to initiate the reaction and again were passed through a column containing solid-supported base 107 that promoted cyclisation. After elution of thiazole 108, alkyl bromide 109 was passed through the solid-supported base yielding imidazole 110 as the sole product:72 (Scheme 2.15) Scheme 2.15 – Synthesis of thiazole 108 and imidazole 110 using a microreactor72 Using this procedure thiazole 108 could be synthesised in 58 % yield from thioisocyanate 105 and isocyanide 106. After elution of thiazole 108, alkyl bromide 109 was passed through the solid-supported base 107 yielding imidazole 110 in 38 % yield. It was speculated that prior to passing through the solid-supported base 107, the reaction stream contained a mixture of vinyl thiolate 111 and 4-thioimidazole 112. 111 spontaneously cyclised to give thiazole 108 while 112 remained bound to the column. Alkyl bromide 109 released 112 from the column yielding 110: (Scheme 2.16) Scheme 2.16 – Mechanistic rationale for the two products72 Summary of the chemistry of isocyanides The unusual structure of isocyanides and tendency to participate in a variety of different reactions make them an intriguing functional group. Isoelectronic with carbon
Initial reaction between catalyst 127 and methyl formate leads to ionic intermediate 128 where one nitrogen atom is formylated. Deprotonation of the secondary amine by the methoxyl anion leads to intermediate 129 with methanol evolved. Nucleophilic attack by an amine followed by proton transfer regenerates catalyst 127 and evolves the formylated amine. Batch reactions, following the procedure outlined by Deutsch et al. were performed using cyclopropylamine 119, 10 mol % 127 and 4 equivalents of the formylating reagent. The reaction was heated to reflux for 24 hours, yielding formamide 123 in 72 % yield after 24 hours: (Scheme 4.5) Scheme 4.5 – batch synthesis of formamide 123 with catalyst 127 The reaction conditions were then applied to the flow reactor. The system was primed with toluene and a 100 psi back-pressure regulator fitted. A was loaded with a solution of 0.1 M cyclopropylamine 119 and 0.4 M methyl formate in toluene, and input B was loaded with a solution of 0.01 M TBD 127 in toluene. The low concentration of reagents used was due to the poor solubility of catalyst 127 in toluene. Reactions were performed at different flow rates and with different reactor temperatures: (Table 4.2) Table 4.2 – Synthesis of formamide 123 with catalyst 127 in toluene Residence time [min] Reactor temperature [oC] Yield [%]a 10 30 5 10 40 13 10 50 23 20 60 70 20 70 94 20 80 90 20 90 91
Scheme 4.12 – reaction of phosphorus oxychloride with triethylamine89 Phosphorus oxychloride and triethylamine were pre-mixed before being injected into the flow machine to avoid the formation of precipitate. A 0.5 M solution of formamide 125 in dichloromethane was injected into input A and the pre-mixed solution of 0.55 M triethylamine and 0.55 M phosphorus oxychloride in dichloromethane was injected into input B. Reactions were performed at different flow rates and reactor temperatures: (Table 4.7) Table 4.7 – Synthesis of isocyanide 157 using phosphorus oxychloride and triethylamine Residence time [min] Reactor temperature [oC] Yield [%]a 10 30 9 10 40 24 10 50 57 10 60 0b 15 40 0b 15 50 0b 15 20 20 60 30 40 0b 0b 0b a of isolated product b – precipitate blocked the reactor Highest yields were obtained at a combined flow rate of 1 (residence time of 10 minutes) and a reactor temperature of 50 oC giving isocyanide 157 in 57 % yield. The reaction generated stoichiometric amounts of triethylammonium chloride as a by-product that blocked the reactor. Above 50 oC the precipitate blocked the reactor, and reactions performed at a flow rate below 1 mL/min also caused the reactor to block. The yield obtained therefore is a compromise between obtaining a reasonable yield and creating a repeatable procedure. The conditions were applied to several formamides, but again yields were either moderate or the reaction was unsuccessful: (Table 4.8)
0.1 M amine (0.5 mmol) and 0.4 M methyl formate (123 µL, 2.0 mmol) in toluene, solution B contained 0.01 M 127 (7 mg, 0.05 mmol) in toluene. Both solutions were injected into 5 mL sample loops then pumped through the reactor. The solutions combined at a T-piece and passed through the 10 mL flow reactor heated to 80 oC at a combined flow rate of 0.5 mL/min, resulting in a residence time of 20 minutes. The output stream of the reactor was collected and solvent removed under vacuum. Purification by column chromatography yielded the titled N-formamide. flow preparation of N-formamides using methyl formate and solution-phase 127 in methanol (method D) The Vapourtec R-series system was fitted with a 10 mL reactor, a 100 psi back-pressure regulator and primed with methanol. Two 2 mL solutions were prepared: solution A contained 1 M amine (2 mmol) and 4 M methyl formate (0.5 mL, 8 mmol) in methanol, solution B contained 0.1 M 127 (28 mg, 0.2 mmol) in methanol. Both solutions were injected into 2 mL sample loops then pumped through the reactor. The solutions combined at a and passed through the 10 mL flow reactor heated to 110 oC at a combined flow rate of 0.5 mL/min, resulting in a residence time of 20 minutes. The output stream of the reactor was collected and solvent removed under vacuum. Purification by column chromatography yielded the titled N-formamide. flow preparation of N-formamides methyl formate and 127 in methanol (method E) The Vapourtec R-series system was fitted with a portex column containing 1 gram of polystyrene-supported 127 (3 mmol/gram catalyst loading), a 100 psi back-pressure phase
Isolated as an oil. Following method F, 155 mg used (64 mg, 47 %). Following method G, 0.11 mL N-(2-(thiophen-2-yl)ethyl)formamide used (77 mg, 56 %). Rf (1:19 ethyl acetate:hexanes) = 0.8; ν max (film/cm-1) = 3110, 3075, 2925, 2150, 1735, 1450, 1435; 1H NMR (250 MHz, CDCl3) δ = 7.25-7.21 (1H, m), 7.01-6.97 (2H, m), 3.66 (2H, t J = 7 Hz), 3.23 (2H, t J = 7 Hz); 13C NMR (400 MHz, CDCl3) δ = 151.4, 138.4, 127.2, 126.2, 124.7, 43.2, 30.0; HRMS (ES) found 137.0298 C7H7NSH+ requires 137.0299. ethyl 2-isocyanoacetate 165127 Isolated as an oil. Following method G, 131 mg ethylformylglycinate used (14 mg, 12 %). Rf (1:19 ethyl acetate:hexanes) = 0.8; ν max (film/cm-1) =3050, 3035, 2145, 1740; 1H NMR (400 MHz, CDCl3) δ = 4.31 (2H, q J = 7 Hz), 4.24 (2H, s), 1.34 (3H, t J = 7 Hz); HRMS (ES) found 114.0555 C7H11NH+ requires 114.0550; Data is in accordance with literature.127 Experimental data for chapter 5 Experimental procedures for the synthesis of preparation of imidazo-[1,2α]-pyrimidines (method J)