Preparation of Functionalized Diorganomagnesium Reagents in Toluene via Bromine or Iodine/Magnesium-Exchange Reactions

Abstract

A wide range of polyfunctionalized di(hetero)aryl- and dialkenyl-magnesium reagents are prepared in toluene within 10 to 120 minutes between –78 °C and 25 °C via an I/Mg- or Br/Mg-exchange reaction using reagents of the general formula R₂Mg (R = sBu, Mes). Highly sensitive functional groups, such as triazene or nitro, are tolerated in these exchange reactions, enabling the synthesis of various functionalized (hetero)arene and alkene derivatives after quenching with several electrophiles including allyl bromides, acyl chlorides, aldehydes, ketones, and aryl iodides.

Key words

alkenes - apolar solvents - arenes - Grignard reaction - halogen/magnesium-exchange - heterocycles - magnesium

Publikationsverlauf

Eingereicht: 01. Juli 2021

Angenommen nach Revision: 15. Juli 2021

Accepted Manuscript online:
15. Juli 2021

Artikel online veröffentlicht:
04. August 2021

• References

• 1a McGrath NA, Brichacek M, Njardarson JT. J. Chem. Educ. 2010; 87: 1348
• 1b Brown DG, Boström J. J. Med. Chem. 2016; 59: 4443
• 1c Nishimura RH. V, Weidmann N, Knochel P. Synthesis 2020; 52: 3036
• 1d Tüllmann CP, Steiner S, Knochel P. Synthesis 2020; 52: 2357
• 1e Skotnitzki J, Kremsmair A, Kicin B, Saeb R, Ruf V, Knochel P. Synthesis 2020; 52: 873
• 1f Skotnitzki J, Kremsmair A, Knochel P. Synthesis 2020; 52: 189
• 1g Weidmann N, Nishimura RH. V, Harenberg JH, Knochel P. Synthesis 2021; 53: 557
• 1h Kremsmair A, Graßl S, Seifert CJ. B, Godineau E, Knochel P. Synthesis 2021; 53 in press; DOI:
• 2 Handbook of Functionalized Organometallics . Knochel P. Wiley-VCH; Weinheim: 2008
• 3a Kremsmair A, Harenberg JH, Schwärzer K, Hess A, Knochel P. Chem. Sci. 2021; 12: 6011
• 3b Lutter FH, Hofmayer MS, Hammann JM, Malakhov V, Knochel P. Org. React. 2019; 100: 63
• 4a Krasovskiy A, Knochel P. Angew. Chem. Int. Ed. 2004; 43: 3333 ; Angew. Chem. 2004, 116, 3396
• 4b Krasovskiy A, Straub BF, Knochel P. Angew. Chem. Int. Ed. 2006; 45: 159 ; Angew. Chem. 2005, 118, 165
• 4c Schnegelsberg C, Bachmann S, Kolter M, Auth T, John M, Stalke D, Koszinowski K. Chem. Eur. J. 2016; 22: 7752
• 5a Ziegler DS, Karaghiosoff K, Knochel P. Angew. Chem. Int. Ed. 2018; 57: 6701 ; Angew. Chem. 2018, 130, 6811
• 5b Ziegler DS, Wei B, Knochel P. Chem. Eur. J. 2019; 25: 2695
• 5c Desaintjean A, Haupt T, Bole LJ, Judge NR, Hevia E, Knochel P. Angew. Chem. Int. Ed. 2021; 60: 1513 ; Angew. Chem. 2021, 133, 1536
• 5d Bole LJ, Judge NR, Hevia E. Angew. Chem. Int. Ed. 2021; 60: 7626 ; Angew. Chem. 2021, 133, 7704
• 6 Balkenhohl M, Ziegler DS, Desaintjean A, Bole LJ, Kennedy AR, Hevia E, Knochel P. Angew. Chem. Int. Ed. 2019; 58: 12898 ; Angew. Chem. 2019, 131, 13030 features a related halogen/zinc exchange
• 7a Solvent Recovery Handbook . Smallwood IM. Blackwell Science; Oxford: 2002
• 7b Delhaye L, Ceccato A, Jacobs P, Köttgen C, Merschaert A. Org. Process Res. Dev. 2007; 11: 160
• 8 This reagent still contained 0.5 equivalents of Et₂O, having the formula sBu₂Mg·0.5Et₂O (determined by ¹H NMR analysis) that we have abbreviated as sBu₂Mg for the sake of clarity: Hess A, Prohaska JP, Doerrich SB, Trauner F, Lutter FH, Lemaire S, Wagschal S, Karaghiosoff K, Knochel P. Chem. Sci. 2021; 12: 8424
• 9 The same reactivity was observed after 5 days of storage of the sBu₂Mg toluene solution at –20 °C.
• 10 Knochel P, Yeh MC. P, Berk SC, Talbert J. J. Org. Chem. 1988; 53: 2390
• 11 Metzger A, Piller FM, Knochel P. Chem. Commun. 2008; 5824
• 12 Negishi E, Huang Z, Wang G, Mohan S, Wang C, Hattori H. Acc. Chem. Res. 2008; 41: 1474

When used in association with R₂Mg (1c, R = sBu; 1d, R = Mes), DMPU increases the exchange rate, thus improving conversions and diminishing side reactions:
• 13a Mukhopadhyay T, Seebach D. Helv. Chim. Acta 1982; 65: 385
• 13b Benischke AD, Le Corre G, Knochel P. Chem. Eur. J. 2017; 23: 778
• 13c Bengtsson M, Liljefors T. Synthesis 1988; 250
• 13d Riguet E, Klement I, Reddy CK, Cahiez G, Knochel P. Tetrahedron Lett. 1996; 37: 5865
• 13e Ellwart M, Makarov IS, Achrainer F, Zipse H, Knochel P. Angew. Chem. Int. Ed. 2016; 55: 10502 ; Angew. Chem. 2016, 128, 10658
• 14 Arylmetal reagents tolerate more functional groups than their alkyl counterparts: Benischke AD, Anthore-Dalion L, Kohl F, Knochel P. Chem. Eur. J. 2018; 24: 11103
• 15 The syntheses of all starting materials and the corresponding literature references are given in the Supporting Information.