Synthetic Routes to 2-aryl-1H-pyrrolo[2,3-b]pyridin-4-amines: Cross-Coupling and Challenges in SEM-Deprotection
Abstract
:1. Introduction
2. Results
2.1. Route A: Amination Followed by Suzuki–Miyaura Cross-Coupling
2.2. Route B: Suzuki–Miyaura Cross-Coupling Followed by Amination
2.3. SEM-Deprotection
2.4. Enzymatic CSF1R Kinase Activity
3. Materials and Methods
3.1. Chemicals and Analysis
3.2. Synthesis
3.2.1. 4-Chloro-2-phenyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (14a)
3.2.2. 4-Chloro-2-(4-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (14b)
3.2.3. (4-(4-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)methanol (14c)
3.2.4. 2-(4-(((tert-Butyldimethylsilyl)oxy)methyl)phenyl)-4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (14d)
3.2.5. 4-Chloro-2-(4-(((2-(trimethylsilyl)ethoxy)methoxy)methyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (14e)
3.2.6. N-Benzyl-N-methyl-2-phenyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (13a) via 12
3.2.7. N-Benzyl-N-methyl-2-phenyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (13a) via 14a
3.2.8. N-Benzyl-2-(4-methoxyphenyl)-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]-pyridin-4-amine (13b)
3.2.9. (4-(4-(Benzyl(methyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)methanol (13c)
3.2.10. N-Benzyl-2-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (13d)
3.2.11. N-Benzyl-N-methyl-2-(4-(((2-(trimethylsilyl)ethoxy)methoxy)methyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (13e)
3.2.12. N-Benzyl-N-methyl-2-phenyl-1H-pyrrolo-[2,3-b]pyridin-4-amine (3a)
3.2.13. N-Benzyl-N-methyl-2-(4-methoxyphenyl-1H-pyrrolo-[2,3-b]pyridin-4-amine (3b)
3.2.14. (4-(4-(Benzyl(methyl)amino)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)methanol (3c)
3.2.15. 6-Methyl-1-phenyl-2,6,7,12-tetrahydro-2,3,6-triazabenzo[6,7]cycloocta[1,2,3-cd]indene (16a)
3.2.16. 1-(4-Methoxyphenyl)-6-methyl-2,6,7,12-tetrahydro-2,3,6-triazabenzo[6,7]cycloocta[1,2,3-cd]indene (16b)
3.2.17. (4-(6-Methyl-2,6,7,12-tetrahydro-2,3,6-triazabenzo[6,7]cycloocta[1,2,3-cd]inden-1-yl)phenyl)methanol (16c)
3.2.18. 3,3-Methylenebis(N-benzyl-N-methyl-2-phenyl-1H-pyrrolo[2,3-b]pyridin-4-amine (17a)
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Entry | Catalyst | Pd mol% | Temp. [°C] | Scale [mg] | Time [h] | Product Distribution (mol %) 1 | ||||
---|---|---|---|---|---|---|---|---|---|---|
14c | 15c 2 | Unk. 3 | 6 | IX 4 | ||||||
1 | Pd2(dba)3 | 7 | 100 | 100 | 1.75 | 92 | 4 | 4 | 0 | 0 |
2 | Pd2(dba)3 | 7 | 80 | 100 | 1.75 | 89 | 5 | 5 | 0 | 0 |
3 | Pd2(dba)3 | 7 | 60 | 50 | 2.5 | 87 | 6 | 7 | 0 | 0 |
4 | XPhos/ XPhos Pd G2 | 7 | 80 | 50 | 2.75 | 15 | 23 | 13 | 0 | 49 |
5 | Pd(OAc)2 | 5 | 80 | 50 | 2.75 | 68 | 7 | 17 | 2 | 6 |
6 | PEPPSITM-SIPr 5 | 5 | 80 | 50 | 0.3 | 44 | 17 | 13 | 9 | 18 |
7 | (Dppf)PdCl2 6 | 5 | 80 | 50 | 0.3 | 79 | 3 | 10 | 5 | 3 |
8 | Pd(PPh3)4 | 8 | 80 | 50 | 5 | 92 | 0 | 0 | 8 | 0 |
9 | Pd(PPh3)4 | 5 | 80 | 1233 | 9 | 95 | 0 | 0 | 5 | 0 |
10 | Pd(PPh3)4 | 5 | 90 | 2087 | 22 | 85 | 9 | 0 | 6 | 0 |
Entry | Subs. | R | Scale (mg) 1 | Time (h) | Conv. (%) 2 | Yield (%) 3 | Product |
---|---|---|---|---|---|---|---|
1 | 14a | H | 230 | 1 | >99 | 74 | 13a |
2 | 14b | OCH3 | 650 | 1 | >99 | 76 | 13b |
3 | 14c | CH2OH | 100 | 24 | ca 40 | - | 13c |
4 | 14d | CH2OTBDMS | 816 | 0.5 | >99 | 89 | 13d |
5 | 14e | CH2OSEM | 455 | 0.33 | >99 | 89 | 13e |
Inhibitor | X | Y | CSF1R IC50 1 | CSF1R IC50 2 |
---|---|---|---|---|
3c | CH | N | 3.1 | 105 |
1 3 | N | N | 1.0 | 5 |
2 3 | N | S | 707 | 450 |
PLX3397 3 | 5 | 20 |
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Merugu, S.R.; Selmer-Olsen, S.; Kaada, C.J.; Sundby, E.; Hoff, B.H. Synthetic Routes to 2-aryl-1H-pyrrolo[2,3-b]pyridin-4-amines: Cross-Coupling and Challenges in SEM-Deprotection. Molecules 2024, 29, 4743. https://doi.org/10.3390/molecules29194743
Merugu SR, Selmer-Olsen S, Kaada CJ, Sundby E, Hoff BH. Synthetic Routes to 2-aryl-1H-pyrrolo[2,3-b]pyridin-4-amines: Cross-Coupling and Challenges in SEM-Deprotection. Molecules. 2024; 29(19):4743. https://doi.org/10.3390/molecules29194743
Chicago/Turabian StyleMerugu, Srinivas Reddy, Sigrid Selmer-Olsen, Camilla Johansen Kaada, Eirik Sundby, and Bård Helge Hoff. 2024. "Synthetic Routes to 2-aryl-1H-pyrrolo[2,3-b]pyridin-4-amines: Cross-Coupling and Challenges in SEM-Deprotection" Molecules 29, no. 19: 4743. https://doi.org/10.3390/molecules29194743