“Batch and Continuous-Flow One-Pot Processes using Amine

Diazotization to Produce Silylated Diazo Reagents”

Audubert, C.; Gamboa Marin, O. J.; Lebel, H. Angew. Chem. Int. Ed. 2017, 56, 6294 –6297.

Leila Terrab

Wipf Group

06/10/2017

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Trimethylsilyldiazomethane

Lappert, M. F.; Lorberth, J. Chem. Comm. 1967, 16, 836–837.

Lappert- First report of covalent organometallic diazoalkanes:

Podlech, J. J. Prakt. Chem. 1998, 340, 679.

Shioiri, T. ; Aoyama, T. ; Snowden, T. Encyclopedia of Reagents for Organic Synthesis 2001.

DOI:10.1002/047084289X.rt298

Shioiri and Aoyama:

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Arndt-Eistert Homologation

TMSCHN2is known to be thermally stable due to the C-Si pπ__ dπ resonance:

TMSCHN2 , Proposed by Aoyama and Shioiri as an alternative to diazomethane

Seyferth:

Seyferth, D.; Menzel, A. ; Dow, A. W.; Flood, T. C. J. Organomet. Chem. 1972, 44, 279.

Aoyama, T.; Shioiri, T. Tetrahedron Lett. 1980, 21, 4461.

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Reactions with Trimethylsilyldiazomethane

Arndt-Eistert Homologation:

Shioiri, T. ; Aoyama, T. ; Snowden, T. Encyclopedia of Reagents for Organic Synthesis 2001. Leila Terrab @ Wipf Group Page 4 of 17 8/7/2017

5Shioiri, T. ; Aoyama, T. ; Snowden, T. Encyclopedia of Reagents for Organic Synthesis 2001.

Reactions with Trimethylsilyldiazomethane

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Previously reported, done by flow chemistry:

Trimethylsilylazide derivative:

Possible Strategies to Synthesize TMSCHN2

Rossi, D.; Woehl, P.; Maggini, M. Org. Process Res. Dev. 2012, 16, 1146−1149. Leila Terrab @ Wipf Group Page 6 of 17 8/7/2017

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Diazomethane:

Trimethylsilylazide derivative:

Possible Strategies to Synthesize TMSCHN2

Synthesis used:

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Possible strategies to synthesize TMSCHN2

.

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Continuous flow of trimethylsilylazide has not been reported

Martin, J. et al. Org. Lett. 2011, 13, 320.Leila Terrab @ Wipf Group Page 9 of 17 8/7/2017

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Flow Synthesis of Intermediate

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Screening of Reaction Conditions

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Proposed Flow Synthesis

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One-pot: Synthesis of Esters

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One-pot: Synthesis of Pyrazoles

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Work-up necessary for nitrite-sensitive reagents:

Rhodium-catalyzed methylenation

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Homologation of ketones

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Conclusion

• Batch and flow synthesis of TMSCHN2 from TMSCH2NH2 using propyldinitrite and acetic acid derivatives.

• TMSCH2NH2 used in the continuous flow reactions of carboxylic acid esterification and pyrazole formation from alkynes.

• Developed a work-up procedure of TMSCH2NH2 to be used for Rh-catalyzed methylenation and ketone homologation.

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