Disposable cartridge concept for the on-demand synthesis of turbo Grignards, Knochel–Hauser amides, and magnesium alkoxides

• Mateo Berton,
• Kevin Sheehan,
• Andrea Adamo and
• D. Tyler McQuade

Beilstein J. Org. Chem. 2020, 16, 1343–1356, doi:10.3762/bjoc.16.115

• fresh organomagnesium reagents on a discovery scale and will do so independent from the operator’s experience in flow and/or organometallic chemistry. Keywords: Knochel–Hauser base; lithium chloride; magnesium; on-demand; packed-bed reactors; plug and flow reactor; synthesizer; turbo Grignard reagent

• Knochel–Hauser base (TMPMgCl⋅LiCl), are also useful reagents for selective deprotonations due to their strong basicity and low nucleophilicity [47][48]. Knochel-type alkoxides [49], e.g., the 2-methyl-2-propoxymagnesium chloride–lithium chloride complex (tert-AmylOMgCl⋅LiCl), are less common in synthesis

• DMSO) [59] and TMPH due to its broad application in synthesis (Knochel–Hauser base, pKa = 37 in DMSO) [47][59][60][61][62][63][64][65][66][67][68][69]. Excellent yields were obtained: HMDSMgCl⋅LiCl 1.15 M (98%), Ph2NMgCl⋅LiCl 1.16 M (97%), and PhNHMgCl⋅LiCl (1.15 M, 96%, Table 4, entries 1–3). For TMPH

Formal preparation of regioregular and alternating thiophene–thiophene copolymers bearing different substituents

• Atsunori Mori,
• Keisuke Fujita,
• Chihiro Kubota,
• Toyoko Suzuki,
• Kentaro Okano,
• Takuya Matsumoto,
• Takashi Nishino and
• Masaki Horie

Beilstein J. Org. Chem. 2020, 16, 317–324, doi:10.3762/bjoc.16.31

• shown to proceed in a dehalogenative manner [3]. We have recently shown that the generation of the organometallic monomer species can alternatively also be achieved by deprotonation, using 2-halo-3-substituted thiophene 2 or 3 with a bulky magnesium amide Knochel–Hauser base (TMPMgCl⋅LiCl) [7], followed

• with monomer precursors 4 by deprotonation with Knochel–Hauser base followed by the addition of the nickel catalyst NiCl2(PPh3)IPr to initiate the polymerization of bithiophene. We first carried out the polymerization of chlorobithiophene 4a, bearing hexyl and methyl substituents at the 3- and 3

• result in much inferior solubility as compared to the alternating copolymer. Several chlorobithiophenes 4 were then similarly subjected to the polymerization. The results of the alternating copolymerizations are summarized in Scheme 4. The deprotonation by the Knochel–Hauser base was carried out at room

Functionalization of 4-bromobenzo[c][2,7]naphthyridine via regioselective direct ring metalation. A novel approach to analogues of pyridoacridine alkaloids

• Benedikt C. Melzer,
• Alois Plodek and
• Franz Bracher

Beilstein J. Org. Chem. 2019, 15, 2304–2310, doi:10.3762/bjoc.15.222

• hindered amide base TMPMgCl∙LiCl as crucial step, the Knochel–Hauser base was again the metalation reagent of our choice. Metalation of 4-bromobenzo[c][2,7]naphthyridine (9d) using 1.1 equivalents TMPMgCl∙LiCl at −40 °C, followed by the reaction with various electrophiles gave, in most cases, the expected

Aminomethylation/hydrogenolysis as an alternative to direct methylation of metalated isoquinolines – a novel total synthesis of the alkaloid 7-hydroxy-6-methoxy-1-methylisoquinoline

• Benedikt C. Melzer,
• Jan G. Felber and
• Franz Bracher

Beilstein J. Org. Chem. 2018, 14, 130–134, doi:10.3762/bjoc.14.8

• 7-benzyloxy-6-methoxyisoquinoline with Knochel–Hauser base, followed by cuprate-mediated methylation gives the target alkaloid directly, but separation from the educt is cumbersome. Quenching the metalated intermediate with Eschenmoser’s reagent gives an easy to clean tertiary benzylamine, which

• metalations of isoquinolines at C1 with sterically hindered amide bases like TMPMgCl∙LiCl (Knochel–Hauser base) [6]. For our present purpose, an appropriate 1-metalated isoquinoline species was to be converted into the corresponding 1-methyl product. Since the 7-hydroxy group of target alkaloid 1 is not

A novel approach to oxoisoaporphine alkaloids via regioselective metalation of alkoxy isoquinolines

• Benedikt C. Melzer and
• Franz Bracher

Beilstein J. Org. Chem. 2017, 13, 1564–1571, doi:10.3762/bjoc.13.156

• were inspired by Knochel’s reports on the direct metalation of isoquinoline [22] and 6,7-dimethoxyisoquinoline [23] as well as by our own results for the metalation of various alkoxyisoquinolines [13] at C-1 with the Knochel–Hauser base TMPMgCl·LiCl. Transmetalation of the intermediate organomagnesium

• 5,6,7-trimethoxyisoquinoline (7b) with 1.5 equivalents of the Knochel–Hauser base (TMPMgCl∙LiCl) exclusively occurs at C-1. Trapping with appropriate benzaldehydes opened an access to benzylisoquinoline and oxoaporphine-type alkaloids [13]. Here we describe the extension of this approach to the