Activation of trimethylsilyl cyanide by potassium phthalimide for facile synthesis of TMS-protected cyanohydrins

Dekamin, Mohammad G.; Karimi, Zahra

doi:10.1016/j.jorganchem.2009.01.058

Cited by 26 publications

(4 citation statements)

References 54 publications

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“…22 Unfortunately, these conditions also did not afford the desired cyanohydrin. Finally, the use of potassium phthalimide as a catalyst in the absence of solvent provided mild enough conditions to allow for the formation of the desired cyanohydrin, 23 which was reduced immediately due to stability issues to yield amino alcohol 53 (Scheme 5). Treatment of 53 with the corresponding sulfonyl chlorides afforded final compounds 54 and 55.…”

Section: Table 1 Modifications In the Aromatic Ring (Ar)mentioning

confidence: 99%

Structure–Activity Relationship Studies of a Novel Class of Transmission Blocking Antimalarials Targeting Male Gametes

et al. 2019

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Malaria is still a leading cause of mortality among children in the developing world, and despite the immense progress made in reducing the global burden, further efforts are needed if eradication is to be achieved. In this context, targeting transmission is widely recognized as a necessary intervention towards that goal. After carrying out a screen to discover new transmission-blocking agents, herein we report our medicinal chemistry efforts to study the potential of the most robust hit, DDD01035881, as a male-gamete targeted compound. We reveal key structural features for the activity of this series and identify analogues with greater potency and improved metabolic 2 stability. We believe this study lays the groundwork for further development of this series as a transmission blocking agent. 3 130±30 6 128±10 34 > 1000 35 785±48 36 > 25000 37 > 10000 38 196±19 39 83±13 40 364±47 41 79±18 42 > 25000 43 > 25000 44 > 25000 45 > 25000 a Biological evaluation was carried out using the DGFA under the specific "add-in" format. Compounds were incubated at variable concentrations with fresh gametocytes, and their ability to impair exflagellation of male gametes determined. Values below 1 µM are expressed as the mean±SEM obtained from between three and eight biological replicates, each carried out in at least duplicate. All synthesised analogues resulted in a significant loss of activity, with the exception of fluorinated derivatives 38-41 (Table 2). Compounds 39 and 41 even show a slight improvement in potency over 6. Once again, these results suggest the binding site of this series within the target(s) to be reasonably confined. Indeed, in contrast to other substituents, fluorine is very similar in size to hydrogen, which could explain why analogues 38-41 retain activity. It should be highlighted that fluorine is widely used within drug discovery to improve permeability by increasing lipophilicity and to address pharmacokinetic issues such as oxidative metabolism, 21 the latter being interesting in the context of this work (vide infra).

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Section: Table 1 Modifications In the Aromatic Ring (Ar)mentioning

confidence: 99%

Structure–Activity Relationship Studies of a Novel Class of Transmission Blocking Antimalarials Targeting Male Gametes

et al. 2019

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“…This pattern of reactivity could be attributed to the vacant 3d-orbital in silicon atom. [57] The cyanide nucleophile can then add to the carbonyl compound, and the resulting alkoxide anion can coordinate to the silicon atom of the coordination sphere. Again a penta-or hexacoordinated intermediate (III or IV) is possible.…”

Section: Resultsmentioning

confidence: 99%

Organocatalytic synthesis of cyanohydrin trimethylsilyl ethers by potassium 4‐benzylpiperidinedithiocarbamate under solvent‐free conditions

Dekamin

Alizadeh

Naimi-Jamal

2009

Applied Organom Chemis

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Potassium 4-benzylpiperidinedithiocarbamate was found to be an efficient organocatalyst for facile addition of trimethylsilyl cyanide to a wide variety of aldehydes and ketones to afford corresponding cyanohydrin trimethylsilyl ethers in high to quantitative yields. The reaction proceeded smoothly by employing 2.0 mol% PBPDC loading under mild conditions at room temperature within a very short reaction time.

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“…Azides 18a and 18b were synthesized via a two step sequence. Following a known procedure, 56 ( E )-4-(4-methoxyphenyl)-2-((trimethylsilyl)oxy)but-3-enenitrile was isolated crude as an orange oil (698 mg, 88%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.37 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 6.77 (d, J = 15.7 Hz, 1H), 6.08 (dd, J = 15.7, 6.2 Hz, 1H), 5.12 (d, J = 6.2 Hz, 1H), 3.85 (s, 3H), 0.27 (s, 9H); 13 C NMR (100 MHz, CDCl 3 ) δ 160.1, 133.6, 128.3, 127.7, 121.3, 118.6, 114.2, 62.5, 55.3, 0.0; IR (KBr, thin film, cm −1 ) 2959, 2838, 1607, 1513, 1255, 1176, 845; HRMS (ESI-TOF) m / z [M + Na] + calcd for C 14 H 19 NO 2 Na + [M + Na] + : 284.1077, found 284.1067.…”

Section: Methodsmentioning

confidence: 99%

“…Azides 18a and 18b were synthesized via a two step sequence. Following a known procedure, 56 (E)-4-(4-methoxyphenyl)-2-((trimethylsilyl)oxy)but-3enenitrile was isolated crude as an orange oil (698 mg, 88%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.37 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 6.77 (d, J = 15.7 Hz, 1H), 6.08 (dd, J = 15.7, 6.2 Hz, 1H), 5.12 (d, J = 6.2 Hz, 1H), 3.85 (s, 3H), 0.27 (s, 9H); 13 Starting from (E)-4-(4-methoxyphenyl)-2-((trimethylsilyl)oxy)but-3-enenitrile and following the procedure above for the azide installation for compounds 15 and 16, a mixture of azides 18a and 18b (17 mg, 38%) was isolated as an oil.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

Evidence for a Sigmatropic and an Ionic Pathway in the Winstein Rearrangement

et al. 2018

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The spontaneous rearrangement of allylic azides is thought to be a sigmatropic reaction. Presented herein is a detailed investigation into the rearrangement of several allylic azides. A combination of experiments including equilibrium studies, kinetic analysis, density functional theory calculations, and selective N-isotopic labeling are included. We conclude that the Winstein rearrangement occurs by the assumed sigmatropic pathway under most conditions. However, racemization was observed for some cyclic allylic azides. A kinetic analysis of this process is provided, which supports a previously undescribed ionic pathway.

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Activation of trimethylsilyl cyanide by potassium phthalimide for facile synthesis of TMS-protected cyanohydrins

Cited by 26 publications

References 54 publications

Structure–Activity Relationship Studies of a Novel Class of Transmission Blocking Antimalarials Targeting Male Gametes

Structure–Activity Relationship Studies of a Novel Class of Transmission Blocking Antimalarials Targeting Male Gametes

Organocatalytic synthesis of cyanohydrin trimethylsilyl ethers by potassium 4‐benzylpiperidinedithiocarbamate under solvent‐free conditions

Evidence for a Sigmatropic and an Ionic Pathway in the Winstein Rearrangement

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