|
|
Example 10Second Alternative Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde(1); A 0.05 g sample of morpholin-3-ylideneamine (2) (0.5 mmol, purity 70-80% by NMR) was stirred with 0.03 g of bromoaldehyde (0.15 mmol) at 30 C. for 30 to 60 minutes in 1.2 mL of an organic solvent. 1 mmol of base was added and the reaction heated to 70 C. for 30 minutes. The reaction was sampled and analyzed by HPLC using a C18 column, with a mobile phase gradient from 95% 10 mM ammonium carbonate and 5% acetonitrile to 100% acetonitrile over 9 minutes at a flow rate of 1.0 mL/min, and using UV detection at 220 nm and 264 nm. The product appeared as two broad peaks at 264 nm and 3.45 and 4.20 minutes, and the regioisomer appeared as a single peak at 264 nm and 5.75 minutes. Alternatively, the same weights of starting materials were used with 85 to 95% pure morpholin-3-ylideneamine (2) and 0.4 mmol of base. In all of the reaction mixtures, excess bromoaldehyde remained after heating. The organic solvents screened included acetone, N,N-DMAc, THF, ethyl acetate, ethyleneglycol diethyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, NMP, DMF, acetonitrile, DMSO, toluene, sulfolane, and ethanol, all of which yielded detectable amounts of product (1) and its regioisomer (16) in ratios ranging from about 0.4 to about 60. The bases screened with these solvents included lithium carbonate, cesium carbonate, 4-methylmorpholine, triethylamine, 2,6-lutidine, 2,2,6,6-tetramethyl-piperidine, diaminocyclohexane, N,N'-diethylaniline, DBN, pyridine, diethylamine, and ethanolamine; these bases had a small effect on the ratio of product (1) to its regioisomer (16). An absence of base also yielded product (1). |
|
|
Example 10Second Alternative Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde(1); A 0.05 g sample of morpholin-3-ylideneamine (2) (0.5 mmol, purity 70-80% by NMR) was stirred with 0.03 g of bromoaldehyde (0.15 mmol) at 30 C. for 30 to 60 minutes in 1.2 mL of an organic solvent. 1 mmol of base was added and the reaction heated to 70 C. for 30 minutes. The reaction was sampled and analyzed by HPLC using a C18 column, with a mobile phase gradient from 95% 10 mM ammonium carbonate and 5% acetonitrile to 100% acetonitrile over 9 minutes at a flow rate of 1.0 mL/min, and using UV detection at 220 nm and 264 nm. The product appeared as two broad peaks at 264 nm and 3.45 and 4.20 minutes, and the regioisomer appeared as a single peak at 264 nm and 5.75 minutes. Alternatively, the same weights of starting materials were used with 85 to 95% pure morpholin-3-ylideneamine (2) and 0.4 mmol of base. In all of the reaction mixtures, excess bromoaldehyde remained after heating. The organic solvents screened included acetone, N,N-DMAc, THF, ethyl acetate, ethyleneglycol diethyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, NMP, DMF, acetonitrile, DMSO, toluene, sulfolane, and ethanol, all of which yielded detectable amounts of product (1) and its regioisomer (16) in ratios ranging from about 0.4 to about 60. The bases screened with these solvents included lithium carbonate, cesium carbonate, 4-methylmorpholine, triethylamine, 2,6-lutidine, 2,2,6,6-tetramethyl-piperidine, diaminocyclohexane, N,N'-diethylaniline, DBN, pyridine, diethylamine, and ethanolamine; these bases had a small effect on the ratio of product (1) to its regioisomer (16). An absence of base also yielded product (1). |
|
|
Example 10Second Alternative Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde(1); A 0.05 g sample of morpholin-3-ylideneamine (2) (0.5 mmol, purity 70-80% by NMR) was stirred with 0.03 g of bromoaldehyde (0.15 mmol) at 30 C. for 30 to 60 minutes in 1.2 mL of an organic solvent. 1 mmol of base was added and the reaction heated to 70 C. for 30 minutes. The reaction was sampled and analyzed by HPLC using a C18 column, with a mobile phase gradient from 95% 10 mM ammonium carbonate and 5% acetonitrile to 100% acetonitrile over 9 minutes at a flow rate of 1.0 mL/min, and using UV detection at 220 nm and 264 nm. The product appeared as two broad peaks at 264 nm and 3.45 and 4.20 minutes, and the regioisomer appeared as a single peak at 264 nm and 5.75 minutes. Alternatively, the same weights of starting materials were used with 85 to 95% pure morpholin-3-ylideneamine (2) and 0.4 mmol of base. In all of the reaction mixtures, excess bromoaldehyde remained after heating. The organic solvents screened included acetone, N,N-DMAc, THF, ethyl acetate, ethyleneglycol diethyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, NMP, DMF, acetonitrile, DMSO, toluene, sulfolane, and ethanol, all of which yielded detectable amounts of product (1) and its regioisomer (16) in ratios ranging from about 0.4 to about 60. The bases screened with these solvents included lithium carbonate, cesium carbonate, 4-methylmorpholine, triethylamine, 2,6-lutidine, 2,2,6,6-tetramethyl-piperidine, diaminocyclohexane, N,N'-diethylaniline, DBN, pyridine, diethylamine, and ethanolamine; these bases had a small effect on the ratio of product (1) to its regioisomer (16). An absence of base also yielded product (1). |
|
|
Example 10Second Alternative Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde(1); A 0.05 g sample of morpholin-3-ylideneamine (2) (0.5 mmol, purity 70-80% by NMR) was stirred with 0.03 g of bromoaldehyde (0.15 mmol) at 30 C. for 30 to 60 minutes in 1.2 mL of an organic solvent. 1 mmol of base was added and the reaction heated to 70 C. for 30 minutes. The reaction was sampled and analyzed by HPLC using a C18 column, with a mobile phase gradient from 95% 10 mM ammonium carbonate and 5% acetonitrile to 100% acetonitrile over 9 minutes at a flow rate of 1.0 mL/min, and using UV detection at 220 nm and 264 nm. The product appeared as two broad peaks at 264 nm and 3.45 and 4.20 minutes, and the regioisomer appeared as a single peak at 264 nm and 5.75 minutes. Alternatively, the same weights of starting materials were used with 85 to 95% pure morpholin-3-ylideneamine (2) and 0.4 mmol of base. In all of the reaction mixtures, excess bromoaldehyde remained after heating. The organic solvents screened included acetone, N,N-DMAc, THF, ethyl acetate, ethyleneglycol diethyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, NMP, DMF, acetonitrile, DMSO, toluene, sulfolane, and ethanol, all of which yielded detectable amounts of product (1) and its regioisomer (16) in ratios ranging from about 0.4 to about 60. The bases screened with these solvents included lithium carbonate, cesium carbonate, 4-methylmorpholine, triethylamine, 2,6-lutidine, 2,2,6,6-tetramethyl-piperidine, diaminocyclohexane, N,N'-diethylaniline, DBN, pyridine, diethylamine, and ethanolamine; these bases had a small effect on the ratio of product (1) to its regioisomer (16). An absence of base also yielded product (1). |
|
|
Example 10Second Alternative Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde(1); A 0.05 g sample of morpholin-3-ylideneamine (2) (0.5 mmol, purity 70-80% by NMR) was stirred with 0.03 g of bromoaldehyde (0.15 mmol) at 30 C. for 30 to 60 minutes in 1.2 mL of an organic solvent. 1 mmol of base was added and the reaction heated to 70 C. for 30 minutes. The reaction was sampled and analyzed by HPLC using a C18 column, with a mobile phase gradient from 95% 10 mM ammonium carbonate and 5% acetonitrile to 100% acetonitrile over 9 minutes at a flow rate of 1.0 mL/min, and using UV detection at 220 nm and 264 nm. The product appeared as two broad peaks at 264 nm and 3.45 and 4.20 minutes, and the regioisomer appeared as a single peak at 264 nm and 5.75 minutes. Alternatively, the same weights of starting materials were used with 85 to 95% pure morpholin-3-ylideneamine (2) and 0.4 mmol of base. In all of the reaction mixtures, excess bromoaldehyde remained after heating. The organic solvents screened included acetone, N,N-DMAc, THF, ethyl acetate, ethyleneglycol diethyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, NMP, DMF, acetonitrile, DMSO, toluene, sulfolane, and ethanol, all of which yielded detectable amounts of product (1) and its regioisomer (16) in ratios ranging from about 0.4 to about 60. The bases screened with these solvents included lithium carbonate, cesium carbonate, 4-methylmorpholine, triethylamine, 2,6-lutidine, 2,2,6,6-tetramethyl-piperidine, diaminocyclohexane, N,N'-diethylaniline, DBN, pyridine, diethylamine, and ethanolamine; these bases had a small effect on the ratio of product (1) to its regioisomer (16). An absence of base also yielded product (1). |
|
|
Example 10Second Alternative Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde(1); A 0.05 g sample of morpholin-3-ylideneamine (2) (0.5 mmol, purity 70-80% by NMR) was stirred with 0.03 g of bromoaldehyde (0.15 mmol) at 30 C. for 30 to 60 minutes in 1.2 mL of an organic solvent. 1 mmol of base was added and the reaction heated to 70 C. for 30 minutes. The reaction was sampled and analyzed by HPLC using a C18 column, with a mobile phase gradient from 95% 10 mM ammonium carbonate and 5% acetonitrile to 100% acetonitrile over 9 minutes at a flow rate of 1.0 mL/min, and using UV detection at 220 nm and 264 nm. The product appeared as two broad peaks at 264 nm and 3.45 and 4.20 minutes, and the regioisomer appeared as a single peak at 264 nm and 5.75 minutes. Alternatively, the same weights of starting materials were used with 85 to 95% pure morpholin-3-ylideneamine (2) and 0.4 mmol of base. In all of the reaction mixtures, excess bromoaldehyde remained after heating. The organic solvents screened included acetone, N,N-DMAc, THF, ethyl acetate, ethyleneglycol diethyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, NMP, DMF, acetonitrile, DMSO, toluene, sulfolane, and ethanol, all of which yielded detectable amounts of product (1) and its regioisomer (16) in ratios ranging from about 0.4 to about 60. The bases screened with these solvents included lithium carbonate, cesium carbonate, 4-methylmorpholine, triethylamine, 2,6-lutidine, 2,2,6,6-tetramethyl-piperidine, diaminocyclohexane, N,N'-diethylaniline, DBN, pyridine, diethylamine, and ethanolamine; these bases had a small effect on the ratio of product (1) to its regioisomer (16). An absence of base also yielded product (1). |
|
|
Example 10Second Alternative Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde(1); A 0.05 g sample of morpholin-3-ylideneamine (2) (0.5 mmol, purity 70-80% by NMR) was stirred with 0.03 g of bromoaldehyde (0.15 mmol) at 30 C. for 30 to 60 minutes in 1.2 mL of an organic solvent. 1 mmol of base was added and the reaction heated to 70 C. for 30 minutes. The reaction was sampled and analyzed by HPLC using a C18 column, with a mobile phase gradient from 95% 10 mM ammonium carbonate and 5% acetonitrile to 100% acetonitrile over 9 minutes at a flow rate of 1.0 mL/min, and using UV detection at 220 nm and 264 nm. The product appeared as two broad peaks at 264 nm and 3.45 and 4.20 minutes, and the regioisomer appeared as a single peak at 264 nm and 5.75 minutes. Alternatively, the same weights of starting materials were used with 85 to 95% pure morpholin-3-ylideneamine (2) and 0.4 mmol of base. In all of the reaction mixtures, excess bromoaldehyde remained after heating. The organic solvents screened included acetone, N,N-DMAc, THF, ethyl acetate, ethyleneglycol diethyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, NMP, DMF, acetonitrile, DMSO, toluene, sulfolane, and ethanol, all of which yielded detectable amounts of product (1) and its regioisomer (16) in ratios ranging from about 0.4 to about 60. The bases screened with these solvents included lithium carbonate, cesium carbonate, 4-methylmorpholine, triethylamine, 2,6-lutidine, 2,2,6,6-tetramethyl-piperidine, diaminocyclohexane, N,N'-diethylaniline, DBN, pyridine, diethylamine, and ethanolamine; these bases had a small effect on the ratio of product (1) to its regioisomer (16). An absence of base also yielded product (1). |
|
|
Example 10Second Alternative Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde(1); A 0.05 g sample of morpholin-3-ylideneamine (2) (0.5 mmol, purity 70-80% by NMR) was stirred with 0.03 g of bromoaldehyde (0.15 mmol) at 30 C. for 30 to 60 minutes in 1.2 mL of an organic solvent. 1 mmol of base was added and the reaction heated to 70 C. for 30 minutes. The reaction was sampled and analyzed by HPLC using a C18 column, with a mobile phase gradient from 95% 10 mM ammonium carbonate and 5% acetonitrile to 100% acetonitrile over 9 minutes at a flow rate of 1.0 mL/min, and using UV detection at 220 nm and 264 nm. The product appeared as two broad peaks at 264 nm and 3.45 and 4.20 minutes, and the regioisomer appeared as a single peak at 264 nm and 5.75 minutes. Alternatively, the same weights of starting materials were used with 85 to 95% pure morpholin-3-ylideneamine (2) and 0.4 mmol of base. In all of the reaction mixtures, excess bromoaldehyde remained after heating. The organic solvents screened included acetone, N,N-DMAc, THF, ethyl acetate, ethyleneglycol diethyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, NMP, DMF, acetonitrile, DMSO, toluene, sulfolane, and ethanol, all of which yielded detectable amounts of product (1) and its regioisomer (16) in ratios ranging from about 0.4 to about 60. The bases screened with these solvents included lithium carbonate, cesium carbonate, 4-methylmorpholine, triethylamine, 2,6-lutidine, 2,2,6,6-tetramethyl-piperidine, diaminocyclohexane, N,N'-diethylaniline, DBN, pyridine, diethylamine, and ethanolamine; these bases had a small effect on the ratio of product (1) to its regioisomer (16). An absence of base also yielded product (1). |
|
|
Example 10Second Alternative Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde(1); A 0.05 g sample of morpholin-3-ylideneamine (2) (0.5 mmol, purity 70-80% by NMR) was stirred with 0.03 g of bromoaldehyde (0.15 mmol) at 30 C. for 30 to 60 minutes in 1.2 mL of an organic solvent. 1 mmol of base was added and the reaction heated to 70 C. for 30 minutes. The reaction was sampled and analyzed by HPLC using a C18 column, with a mobile phase gradient from 95% 10 mM ammonium carbonate and 5% acetonitrile to 100% acetonitrile over 9 minutes at a flow rate of 1.0 mL/min, and using UV detection at 220 nm and 264 nm. The product appeared as two broad peaks at 264 nm and 3.45 and 4.20 minutes, and the regioisomer appeared as a single peak at 264 nm and 5.75 minutes. Alternatively, the same weights of starting materials were used with 85 to 95% pure morpholin-3-ylideneamine (2) and 0.4 mmol of base. In all of the reaction mixtures, excess bromoaldehyde remained after heating. The organic solvents screened included acetone, N,N-DMAc, THF, ethyl acetate, ethyleneglycol diethyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, NMP, DMF, acetonitrile, DMSO, toluene, sulfolane, and ethanol, all of which yielded detectable amounts of product (1) and its regioisomer (16) in ratios ranging from about 0.4 to about 60. The bases screened with these solvents included lithium carbonate, cesium carbonate, 4-methylmorpholine, triethylamine, 2,6-lutidine, 2,2,6,6-tetramethyl-piperidine, diaminocyclohexane, N,N'-diethylaniline, DBN, pyridine, diethylamine, and ethanolamine; these bases had a small effect on the ratio of product (1) to its regioisomer (16). An absence of base also yielded product (1). |
|
|
Example 10Second Alternative Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde(1); A 0.05 g sample of morpholin-3-ylideneamine (2) (0.5 mmol, purity 70-80% by NMR) was stirred with 0.03 g of bromoaldehyde (0.15 mmol) at 30 C. for 30 to 60 minutes in 1.2 mL of an organic solvent. 1 mmol of base was added and the reaction heated to 70 C. for 30 minutes. The reaction was sampled and analyzed by HPLC using a C18 column, with a mobile phase gradient from 95% 10 mM ammonium carbonate and 5% acetonitrile to 100% acetonitrile over 9 minutes at a flow rate of 1.0 mL/min, and using UV detection at 220 nm and 264 nm. The product appeared as two broad peaks at 264 nm and 3.45 and 4.20 minutes, and the regioisomer appeared as a single peak at 264 nm and 5.75 minutes. Alternatively, the same weights of starting materials were used with 85 to 95% pure morpholin-3-ylideneamine (2) and 0.4 mmol of base. In all of the reaction mixtures, excess bromoaldehyde remained after heating. The organic solvents screened included acetone, N,N-DMAc, THF, ethyl acetate, ethyleneglycol diethyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, NMP, DMF, acetonitrile, DMSO, toluene, sulfolane, and ethanol, all of which yielded detectable amounts of product (1) and its regioisomer (16) in ratios ranging from about 0.4 to about 60. The bases screened with these solvents included lithium carbonate, cesium carbonate, 4-methylmorpholine, triethylamine, 2,6-lutidine, 2,2,6,6-tetramethyl-piperidine, diaminocyclohexane, N,N'-diethylaniline, DBN, pyridine, diethylamine, and ethanolamine; these bases had a small effect on the ratio of product (1) to its regioisomer (16). An absence of base also yielded product (1). |
|
|
Example 10Second Alternative Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde(1); A 0.05 g sample of morpholin-3-ylideneamine (2) (0.5 mmol, purity 70-80% by NMR) was stirred with 0.03 g of bromoaldehyde (0.15 mmol) at 30 C. for 30 to 60 minutes in 1.2 mL of an organic solvent. 1 mmol of base was added and the reaction heated to 70 C. for 30 minutes. The reaction was sampled and analyzed by HPLC using a C18 column, with a mobile phase gradient from 95% 10 mM ammonium carbonate and 5% acetonitrile to 100% acetonitrile over 9 minutes at a flow rate of 1.0 mL/min, and using UV detection at 220 nm and 264 nm. The product appeared as two broad peaks at 264 nm and 3.45 and 4.20 minutes, and the regioisomer appeared as a single peak at 264 nm and 5.75 minutes. Alternatively, the same weights of starting materials were used with 85 to 95% pure morpholin-3-ylideneamine (2) and 0.4 mmol of base. In all of the reaction mixtures, excess bromoaldehyde remained after heating. The organic solvents screened included acetone, N,N-DMAc, THF, ethyl acetate, ethyleneglycol diethyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, NMP, DMF, acetonitrile, DMSO, toluene, sulfolane, and ethanol, all of which yielded detectable amounts of product (1) and its regioisomer (16) in ratios ranging from about 0.4 to about 60. The bases screened with these solvents included lithium carbonate, cesium carbonate, 4-methylmorpholine, triethylamine, 2,6-lutidine, 2,2,6,6-tetramethyl-piperidine, diaminocyclohexane, N,N'-diethylaniline, DBN, pyridine, diethylamine, and ethanolamine; these bases had a small effect on the ratio of product (1) to its regioisomer (16). An absence of base also yielded product (1). |
|
|
Example 10Second Alternative Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde(1); A 0.05 g sample of morpholin-3-ylideneamine (2) (0.5 mmol, purity 70-80% by NMR) was stirred with 0.03 g of bromoaldehyde (0.15 mmol) at 30 C. for 30 to 60 minutes in 1.2 mL of an organic solvent. 1 mmol of base was added and the reaction heated to 70 C. for 30 minutes. The reaction was sampled and analyzed by HPLC using a C18 column, with a mobile phase gradient from 95% 10 mM ammonium carbonate and 5% acetonitrile to 100% acetonitrile over 9 minutes at a flow rate of 1.0 mL/min, and using UV detection at 220 nm and 264 nm. The product appeared as two broad peaks at 264 nm and 3.45 and 4.20 minutes, and the regioisomer appeared as a single peak at 264 nm and 5.75 minutes. Alternatively, the same weights of starting materials were used with 85 to 95% pure morpholin-3-ylideneamine (2) and 0.4 mmol of base. In all of the reaction mixtures, excess bromoaldehyde remained after heating. The organic solvents screened included acetone, N,N-DMAc, THF, ethyl acetate, ethyleneglycol diethyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, NMP, DMF, acetonitrile, DMSO, toluene, sulfolane, and ethanol, all of which yielded detectable amounts of product (1) and its regioisomer (16) in ratios ranging from about 0.4 to about 60. The bases screened with these solvents included lithium carbonate, cesium carbonate, 4-methylmorpholine, triethylamine, 2,6-lutidine, 2,2,6,6-tetramethyl-piperidine, diaminocyclohexane, N,N'-diethylaniline, DBN, pyridine, diethylamine, and ethanolamine; these bases had a small effect on the ratio of product (1) to its regioisomer (16). An absence of base also yielded product (1). |
|
|
Example 10Second Alternative Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde(1); A 0.05 g sample of morpholin-3-ylideneamine (2) (0.5 mmol, purity 70-80% by NMR) was stirred with 0.03 g of bromoaldehyde (0.15 mmol) at 30 C. for 30 to 60 minutes in 1.2 mL of an organic solvent. 1 mmol of base was added and the reaction heated to 70 C. for 30 minutes. The reaction was sampled and analyzed by HPLC using a C18 column, with a mobile phase gradient from 95% 10 mM ammonium carbonate and 5% acetonitrile to 100% acetonitrile over 9 minutes at a flow rate of 1.0 mL/min, and using UV detection at 220 nm and 264 nm. The product appeared as two broad peaks at 264 nm and 3.45 and 4.20 minutes, and the regioisomer appeared as a single peak at 264 nm and 5.75 minutes. Alternatively, the same weights of starting materials were used with 85 to 95% pure morpholin-3-ylideneamine (2) and 0.4 mmol of base. In all of the reaction mixtures, excess bromoaldehyde remained after heating. The organic solvents screened included acetone, N,N-DMAc, THF, ethyl acetate, ethyleneglycol diethyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, NMP, DMF, acetonitrile, DMSO, toluene, sulfolane, and ethanol, all of which yielded detectable amounts of product (1) and its regioisomer (16) in ratios ranging from about 0.4 to about 60. The bases screened with these solvents included lithium carbonate, cesium carbonate, 4-methylmorpholine, triethylamine, 2,6-lutidine, 2,2,6,6-tetramethyl-piperidine, diaminocyclohexane, N,N'-diethylaniline, DBN, pyridine, diethylamine, and ethanolamine; these bases had a small effect on the ratio of product (1) to its regioisomer (16). An absence of base also yielded product (1). |
|
|
Example 10Second Alternative Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde(1); A 0.05 g sample of morpholin-3-ylideneamine (2) (0.5 mmol, purity 70-80% by NMR) was stirred with 0.03 g of bromoaldehyde (0.15 mmol) at 30 C. for 30 to 60 minutes in 1.2 mL of an organic solvent. 1 mmol of base was added and the reaction heated to 70 C. for 30 minutes. The reaction was sampled and analyzed by HPLC using a C18 column, with a mobile phase gradient from 95% 10 mM ammonium carbonate and 5% acetonitrile to 100% acetonitrile over 9 minutes at a flow rate of 1.0 mL/min, and using UV detection at 220 nm and 264 nm. The product appeared as two broad peaks at 264 nm and 3.45 and 4.20 minutes, and the regioisomer appeared as a single peak at 264 nm and 5.75 minutes. Alternatively, the same weights of starting materials were used with 85 to 95% pure morpholin-3-ylideneamine (2) and 0.4 mmol of base. In all of the reaction mixtures, excess bromoaldehyde remained after heating. The organic solvents screened included acetone, N,N-DMAc, THF, ethyl acetate, ethyleneglycol diethyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, NMP, DMF, acetonitrile, DMSO, toluene, sulfolane, and ethanol, all of which yielded detectable amounts of product (1) and its regioisomer (16) in ratios ranging from about 0.4 to about 60. The bases screened with these solvents included lithium carbonate, cesium carbonate, 4-methylmorpholine, triethylamine, 2,6-lutidine, 2,2,6,6-tetramethyl-piperidine, diaminocyclohexane, N,N'-diethylaniline, DBN, pyridine, diethylamine, and ethanolamine; these bases had a small effect on the ratio of product (1) to its regioisomer (16). An absence of base also yielded product (1). |
|
|
Example 10Second Alternative Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde(1); A 0.05 g sample of morpholin-3-ylideneamine (2) (0.5 mmol, purity 70-80% by NMR) was stirred with 0.03 g of bromoaldehyde (0.15 mmol) at 30 C. for 30 to 60 minutes in 1.2 mL of an organic solvent. 1 mmol of base was added and the reaction heated to 70 C. for 30 minutes. The reaction was sampled and analyzed by HPLC using a C18 column, with a mobile phase gradient from 95% 10 mM ammonium carbonate and 5% acetonitrile to 100% acetonitrile over 9 minutes at a flow rate of 1.0 mL/min, and using UV detection at 220 nm and 264 nm. The product appeared as two broad peaks at 264 nm and 3.45 and 4.20 minutes, and the regioisomer appeared as a single peak at 264 nm and 5.75 minutes. Alternatively, the same weights of starting materials were used with 85 to 95% pure morpholin-3-ylideneamine (2) and 0.4 mmol of base. In all of the reaction mixtures, excess bromoaldehyde remained after heating. The organic solvents screened included acetone, N,N-DMAc, THF, ethyl acetate, ethyleneglycol diethyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, NMP, DMF, acetonitrile, DMSO, toluene, sulfolane, and ethanol, all of which yielded detectable amounts of product (1) and its regioisomer (16) in ratios ranging from about 0.4 to about 60. The bases screened with these solvents included lithium carbonate, cesium carbonate, 4-methylmorpholine, triethylamine, 2,6-lutidine, 2,2,6,6-tetramethyl-piperidine, diaminocyclohexane, N,N'-diethylaniline, DBN, pyridine, diethylamine, and ethanolamine; these bases had a small effect on the ratio of product (1) to its regioisomer (16). An absence of base also yielded product (1). |
|
|
Example 10Second Alternative Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde(1); A 0.05 g sample of morpholin-3-ylideneamine (2) (0.5 mmol, purity 70-80% by NMR) was stirred with 0.03 g of bromoaldehyde (0.15 mmol) at 30 C. for 30 to 60 minutes in 1.2 mL of an organic solvent. 1 mmol of base was added and the reaction heated to 70 C. for 30 minutes. The reaction was sampled and analyzed by HPLC using a C18 column, with a mobile phase gradient from 95% 10 mM ammonium carbonate and 5% acetonitrile to 100% acetonitrile over 9 minutes at a flow rate of 1.0 mL/min, and using UV detection at 220 nm and 264 nm. The product appeared as two broad peaks at 264 nm and 3.45 and 4.20 minutes, and the regioisomer appeared as a single peak at 264 nm and 5.75 minutes. Alternatively, the same weights of starting materials were used with 85 to 95% pure morpholin-3-ylideneamine (2) and 0.4 mmol of base. In all of the reaction mixtures, excess bromoaldehyde remained after heating. The organic solvents screened included acetone, N,N-DMAc, THF, ethyl acetate, ethyleneglycol diethyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, NMP, DMF, acetonitrile, DMSO, toluene, sulfolane, and ethanol, all of which yielded detectable amounts of product (1) and its regioisomer (16) in ratios ranging from about 0.4 to about 60. The bases screened with these solvents included lithium carbonate, cesium carbonate, 4-methylmorpholine, triethylamine, 2,6-lutidine, 2,2,6,6-tetramethyl-piperidine, diaminocyclohexane, N,N'-diethylaniline, DBN, pyridine, diethylamine, and ethanolamine; these bases had a small effect on the ratio of product (1) to its regioisomer (16). An absence of base also yielded product (1). |
|
|
Example 10Second Alternative Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde(1); A 0.05 g sample of morpholin-3-ylideneamine (2) (0.5 mmol, purity 70-80% by NMR) was stirred with 0.03 g of bromoaldehyde (0.15 mmol) at 30 C. for 30 to 60 minutes in 1.2 mL of an organic solvent. 1 mmol of base was added and the reaction heated to 70 C. for 30 minutes. The reaction was sampled and analyzed by HPLC using a C18 column, with a mobile phase gradient from 95% 10 mM ammonium carbonate and 5% acetonitrile to 100% acetonitrile over 9 minutes at a flow rate of 1.0 mL/min, and using UV detection at 220 nm and 264 nm. The product appeared as two broad peaks at 264 nm and 3.45 and 4.20 minutes, and the regioisomer appeared as a single peak at 264 nm and 5.75 minutes. Alternatively, the same weights of starting materials were used with 85 to 95% pure morpholin-3-ylideneamine (2) and 0.4 mmol of base. In all of the reaction mixtures, excess bromoaldehyde remained after heating. The organic solvents screened included acetone, N,N-DMAc, THF, ethyl acetate, ethyleneglycol diethyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, NMP, DMF, acetonitrile, DMSO, toluene, sulfolane, and ethanol, all of which yielded detectable amounts of product (1) and its regioisomer (16) in ratios ranging from about 0.4 to about 60. The bases screened with these solvents included lithium carbonate, cesium carbonate, 4-methylmorpholine, triethylamine, 2,6-lutidine, 2,2,6,6-tetramethyl-piperidine, diaminocyclohexane, N,N'-diethylaniline, DBN, pyridine, diethylamine, and ethanolamine; these bases had a small effect on the ratio of product (1) to its regioisomer (16). An absence of base also yielded product (1). |
|
|
Example 10Second Alternative Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde(1); A 0.05 g sample of morpholin-3-ylideneamine (2) (0.5 mmol, purity 70-80% by NMR) was stirred with 0.03 g of bromoaldehyde (0.15 mmol) at 30 C. for 30 to 60 minutes in 1.2 mL of an organic solvent. 1 mmol of base was added and the reaction heated to 70 C. for 30 minutes. The reaction was sampled and analyzed by HPLC using a C18 column, with a mobile phase gradient from 95% 10 mM ammonium carbonate and 5% acetonitrile to 100% acetonitrile over 9 minutes at a flow rate of 1.0 mL/min, and using UV detection at 220 nm and 264 nm. The product appeared as two broad peaks at 264 nm and 3.45 and 4.20 minutes, and the regioisomer appeared as a single peak at 264 nm and 5.75 minutes. Alternatively, the same weights of starting materials were used with 85 to 95% pure morpholin-3-ylideneamine (2) and 0.4 mmol of base. In all of the reaction mixtures, excess bromoaldehyde remained after heating. The organic solvents screened included acetone, N,N-DMAc, THF, ethyl acetate, ethyleneglycol diethyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, NMP, DMF, acetonitrile, DMSO, toluene, sulfolane, and ethanol, all of which yielded detectable amounts of product (1) and its regioisomer (16) in ratios ranging from about 0.4 to about 60. The bases screened with these solvents included lithium carbonate, cesium carbonate, 4-methylmorpholine, triethylamine, 2,6-lutidine, 2,2,6,6-tetramethyl-piperidine, diaminocyclohexane, N,N'-diethylaniline, DBN, pyridine, diethylamine, and ethanolamine; these bases had a small effect on the ratio of product (1) to its regioisomer (16). An absence of base also yielded product (1). |
|
|
Example 10Second Alternative Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde(1); A 0.05 g sample of morpholin-3-ylideneamine (2) (0.5 mmol, purity 70-80% by NMR) was stirred with 0.03 g of bromoaldehyde (0.15 mmol) at 30 C. for 30 to 60 minutes in 1.2 mL of an organic solvent. 1 mmol of base was added and the reaction heated to 70 C. for 30 minutes. The reaction was sampled and analyzed by HPLC using a C18 column, with a mobile phase gradient from 95% 10 mM ammonium carbonate and 5% acetonitrile to 100% acetonitrile over 9 minutes at a flow rate of 1.0 mL/min, and using UV detection at 220 nm and 264 nm. The product appeared as two broad peaks at 264 nm and 3.45 and 4.20 minutes, and the regioisomer appeared as a single peak at 264 nm and 5.75 minutes. Alternatively, the same weights of starting materials were used with 85 to 95% pure morpholin-3-ylideneamine (2) and 0.4 mmol of base. In all of the reaction mixtures, excess bromoaldehyde remained after heating. The organic solvents screened included acetone, N,N-DMAc, THF, ethyl acetate, ethyleneglycol diethyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, NMP, DMF, acetonitrile, DMSO, toluene, sulfolane, and ethanol, all of which yielded detectable amounts of product (1) and its regioisomer (16) in ratios ranging from about 0.4 to about 60. The bases screened with these solvents included lithium carbonate, cesium carbonate, 4-methylmorpholine, triethylamine, 2,6-lutidine, 2,2,6,6-tetramethyl-piperidine, diaminocyclohexane, N,N'-diethylaniline, DBN, pyridine, diethylamine, and ethanolamine; these bases had a small effect on the ratio of product (1) to its regioisomer (16). An absence of base also yielded product (1). |
|
|
Example 10Second Alternative Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde(1); A 0.05 g sample of morpholin-3-ylideneamine (2) (0.5 mmol, purity 70-80% by NMR) was stirred with 0.03 g of bromoaldehyde (0.15 mmol) at 30 C. for 30 to 60 minutes in 1.2 mL of an organic solvent. 1 mmol of base was added and the reaction heated to 70 C. for 30 minutes. The reaction was sampled and analyzed by HPLC using a C18 column, with a mobile phase gradient from 95% 10 mM ammonium carbonate and 5% acetonitrile to 100% acetonitrile over 9 minutes at a flow rate of 1.0 mL/min, and using UV detection at 220 nm and 264 nm. The product appeared as two broad peaks at 264 nm and 3.45 and 4.20 minutes, and the regioisomer appeared as a single peak at 264 nm and 5.75 minutes. Alternatively, the same weights of starting materials were used with 85 to 95% pure morpholin-3-ylideneamine (2) and 0.4 mmol of base. In all of the reaction mixtures, excess bromoaldehyde remained after heating. The organic solvents screened included acetone, N,N-DMAc, THF, ethyl acetate, ethyleneglycol diethyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, NMP, DMF, acetonitrile, DMSO, toluene, sulfolane, and ethanol, all of which yielded detectable amounts of product (1) and its regioisomer (16) in ratios ranging from about 0.4 to about 60. The bases screened with these solvents included lithium carbonate, cesium carbonate, 4-methylmorpholine, triethylamine, 2,6-lutidine, 2,2,6,6-tetramethyl-piperidine, diaminocyclohexane, N,N'-diethylaniline, DBN, pyridine, diethylamine, and ethanolamine; these bases had a small effect on the ratio of product (1) to its regioisomer (16). An absence of base also yielded product (1). |
|
|
Example 10Second Alternative Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde(1); A 0.05 g sample of morpholin-3-ylideneamine (2) (0.5 mmol, purity 70-80% by NMR) was stirred with 0.03 g of bromoaldehyde (0.15 mmol) at 30 C. for 30 to 60 minutes in 1.2 mL of an organic solvent. 1 mmol of base was added and the reaction heated to 70 C. for 30 minutes. The reaction was sampled and analyzed by HPLC using a C18 column, with a mobile phase gradient from 95% 10 mM ammonium carbonate and 5% acetonitrile to 100% acetonitrile over 9 minutes at a flow rate of 1.0 mL/min, and using UV detection at 220 nm and 264 nm. The product appeared as two broad peaks at 264 nm and 3.45 and 4.20 minutes, and the regioisomer appeared as a single peak at 264 nm and 5.75 minutes. Alternatively, the same weights of starting materials were used with 85 to 95% pure morpholin-3-ylideneamine (2) and 0.4 mmol of base. In all of the reaction mixtures, excess bromoaldehyde remained after heating. The organic solvents screened included acetone, N,N-DMAc, THF, ethyl acetate, ethyleneglycol diethyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, NMP, DMF, acetonitrile, DMSO, toluene, sulfolane, and ethanol, all of which yielded detectable amounts of product (1) and its regioisomer (16) in ratios ranging from about 0.4 to about 60. The bases screened with these solvents included lithium carbonate, cesium carbonate, 4-methylmorpholine, triethylamine, 2,6-lutidine, 2,2,6,6-tetramethyl-piperidine, diaminocyclohexane, N,N'-diethylaniline, DBN, pyridine, diethylamine, and ethanolamine; these bases had a small effect on the ratio of product (1) to its regioisomer (16). An absence of base also yielded product (1). |
|
|
Example 10Second Alternative Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde(1); A 0.05 g sample of morpholin-3-ylideneamine (2) (0.5 mmol, purity 70-80% by NMR) was stirred with 0.03 g of bromoaldehyde (0.15 mmol) at 30 C. for 30 to 60 minutes in 1.2 mL of an organic solvent. 1 mmol of base was added and the reaction heated to 70 C. for 30 minutes. The reaction was sampled and analyzed by HPLC using a C18 column, with a mobile phase gradient from 95% 10 mM ammonium carbonate and 5% acetonitrile to 100% acetonitrile over 9 minutes at a flow rate of 1.0 mL/min, and using UV detection at 220 nm and 264 nm. The product appeared as two broad peaks at 264 nm and 3.45 and 4.20 minutes, and the regioisomer appeared as a single peak at 264 nm and 5.75 minutes. Alternatively, the same weights of starting materials were used with 85 to 95% pure morpholin-3-ylideneamine (2) and 0.4 mmol of base. In all of the reaction mixtures, excess bromoaldehyde remained after heating. The organic solvents screened included acetone, N,N-DMAc, THF, ethyl acetate, ethyleneglycol diethyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, NMP, DMF, acetonitrile, DMSO, toluene, sulfolane, and ethanol, all of which yielded detectable amounts of product (1) and its regioisomer (16) in ratios ranging from about 0.4 to about 60. The bases screened with these solvents included lithium carbonate, cesium carbonate, 4-methylmorpholine, triethylamine, 2,6-lutidine, 2,2,6,6-tetramethyl-piperidine, diaminocyclohexane, N,N'-diethylaniline, DBN, pyridine, diethylamine, and ethanolamine; these bases had a small effect on the ratio of product (1) to its regioisomer (16). An absence of base also yielded product (1). |
|
|
Example 10Second Alternative Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde(1); A 0.05 g sample of morpholin-3-ylideneamine (2) (0.5 mmol, purity 70-80% by NMR) was stirred with 0.03 g of bromoaldehyde (0.15 mmol) at 30 C. for 30 to 60 minutes in 1.2 mL of an organic solvent. 1 mmol of base was added and the reaction heated to 70 C. for 30 minutes. The reaction was sampled and analyzed by HPLC using a C18 column, with a mobile phase gradient from 95% 10 mM ammonium carbonate and 5% acetonitrile to 100% acetonitrile over 9 minutes at a flow rate of 1.0 mL/min, and using UV detection at 220 nm and 264 nm. The product appeared as two broad peaks at 264 nm and 3.45 and 4.20 minutes, and the regioisomer appeared as a single peak at 264 nm and 5.75 minutes. Alternatively, the same weights of starting materials were used with 85 to 95% pure morpholin-3-ylideneamine (2) and 0.4 mmol of base. In all of the reaction mixtures, excess bromoaldehyde remained after heating. The organic solvents screened included acetone, N,N-DMAc, THF, ethyl acetate, ethyleneglycol diethyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, NMP, DMF, acetonitrile, DMSO, toluene, sulfolane, and ethanol, all of which yielded detectable amounts of product (1) and its regioisomer (16) in ratios ranging from about 0.4 to about 60. The bases screened with these solvents included lithium carbonate, cesium carbonate, 4-methylmorpholine, triethylamine, 2,6-lutidine, 2,2,6,6-tetramethyl-piperidine, diaminocyclohexane, N,N'-diethylaniline, DBN, pyridine, diethylamine, and ethanolamine; these bases had a small effect on the ratio of product (1) to its regioisomer (16). An absence of base also yielded product (1). |