Synthesis of MAPA Reagents and 2-Alkyl(aryl)aminopyridines from 2-Bromopyridine Using the Goldberg Reaction
Abstract
:1. Introduction
2. Results and Discussion
2.1. Synthesis of MAPA Reagents 1 and 2
2.2. One-Pot Synthesis of 2-Alkyl(aryl)aminopyridines from 2-Bromopyridine and Secondary Formamides
2.3. Use of DMEDA as an Alternative Ligand for the above Goldberg Reactions
3. Materials and Methods
3.1. General Information
3.2. Preparation of MAPA Compounds
3.2.1. N-Methyl-N-(pyridin-2-yl)acetamide (2a)
3.2.2. N-Methyl-N-(pyridin-2-yl)benzamide (2b)
3.2.3. N-Methyl-N-(pyridin-2-yl)formamide (1)
3.3. Preparation of 2-Alkyl(aryl)aminopyridines
3.3.1. N-Butylpyridin-2-amine (3b)
3.3.2. N-Benzylpyridin-2-amine (3c)
3.3.3. N-(p-Tolyl)pyridine-2-amine (3e)
3.3.4. N-(tert-Butyl)pyridine-2-amine (3d)
3.3.5. N-Methylpyridin-2-amine (3a)
3.4. Preparation of MAPA Compounds from 2-Bromopyridine Using DMEDA as Ligand
4. Conclusions
Supplementary Materials
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
References
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Entry a | Amide (R) | CuI/phen (mol%) b | Solvent | Base (Equiv.) | Time c (h) | Yield d (%) |
---|---|---|---|---|---|---|
1 | H | 2 | t-AmOH | K3PO4 (2) | 8 | 1, 65 (28) e |
2 | H | 2 | PhMe/ t-AmOH (9:1) | K2CO3 (1.3) | 8 | 1, 93 |
K3PO4 (0.1) | ||||||
3 | H | 1 | PhMe | K2CO3 (1.3) | 8 | 1, 92 |
K3PO4 (0.05) | ||||||
4 | H | 0.5 | PhMe | K2CO3 (1.3) | 8 | 1, 88 |
5 | H | 2 | PhMe | K2CO3 (2) | 12 | 1, 85 f |
K3PO4 (0.1) | ||||||
6 | Me | 2 | t-AmOH | K3PO4 (2) | 24 | 2a, 75 (10) e |
7 | Me | 2 | PhMe/ t-AmOH (9:1) | K3PO4 (2) | 24 | 2a, 84 |
8 | Me | 2 | 5% t-AmOH/ PhMe | K3PO4 (2) | 36 | 2a, 92 (88) g |
9 | Ph | 2 | t-AmOH | K3PO4 (2) | 36 | 2b, 68 (11)e |
10 | Ph | 2 | PhMe/ t-AmOH (9:1) | K3PO4 (2) | 36 | 2b, 85 |
11 | Ph | 2 | PhMe | K3PO4 (2) | 36 | 2b, 88 (80) g |
Entry a | Formamide R | CuI/phen (mol%) b | Solvent, Base; 1st Step | Time c (h) 1st Step | Time c (h) 2nd Step | Yield d (%) |
---|---|---|---|---|---|---|
1 | Me | 2 | PhMe | 12 | 4 | 3a, 89 e |
K3PO4 (2) | ||||||
2 | Bu | 2 | PhMe | 14 | 6 | 3b, 90 f |
K3PO4 (2) | ||||||
3 | Bn | 2 | PhMe | 18 | 4 | 3c, 89 g |
K3PO4 (2) | ||||||
4 | t-Bu | 3 | 5% t-AmOH/ PhMe | 48 h | 6 i | 3d, 85 f |
K3PO4 (2) | ||||||
5 | p-tol | 1 | PhMe | 10 | 3 | 3e, 88 f |
K2CO3 (1.5) | ||||||
K3PO4 (0.5) |
Entry a | Amide R1, R2 | CuI/DMEDA mol%, Ratio | Solvent | Base (Equiv.) | Time b (h) | Yield c (%) |
---|---|---|---|---|---|---|
1 | Me, H | 2/4 | PhMe | K2CO3 (1.3) | 8 | 1, 92 |
K3PO4 (0.1) | ||||||
2 | Me, H | 2/2 | PhMe | K2CO3 (1.3) | 8 | 1, 91 |
K3PO4 (0.1) | ||||||
3 | Me, H | 2 (no ligand) | PhMe | K2CO3 (2) | 8 | 1, 16 |
K3PO4 (0.1) | ||||||
4 | Me, Me | 2/4 | PhMe | K3PO4 (2) | 24 | 2a, 8 |
5 | Me, Me | 2/2 | 5% t-AmOH/ PhMe | K3PO4 (2) | 24 | 2a, 10 |
6 | Me, Ph | 5/10 | PhMe | K3PO4 (2) | 36 | 2b, 81 |
7 | Bn, H | 2/4 | PhMe | K2CO3 (2) | 18 | 2c, 80 |
8 | Bn, H | 2/4 | PhMe | K3PO4 (2) | 18 | 2c, 84 |
9 | t-Bu, H | 5/10 | 5% t-AmOH/ PhMe | K3PO4 (2) | 24 | 2d, 12 |
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Comins, D.L. Synthesis of MAPA Reagents and 2-Alkyl(aryl)aminopyridines from 2-Bromopyridine Using the Goldberg Reaction. Molecules 2022, 27, 1833. https://doi.org/10.3390/molecules27061833
Comins DL. Synthesis of MAPA Reagents and 2-Alkyl(aryl)aminopyridines from 2-Bromopyridine Using the Goldberg Reaction. Molecules. 2022; 27(6):1833. https://doi.org/10.3390/molecules27061833
Chicago/Turabian StyleComins, Daniel L. 2022. "Synthesis of MAPA Reagents and 2-Alkyl(aryl)aminopyridines from 2-Bromopyridine Using the Goldberg Reaction" Molecules 27, no. 6: 1833. https://doi.org/10.3390/molecules27061833