Fast, greener and scalable direct coupling of organolithium compounds with no additional solvents

Although the use of catalytic rather than stoichiometric amounts of metal mediator in cross-coupling reactions between organic halides and organometallic counterparts improves significantly the atom economy and waste production, the use of solvents and stoichiometric generation of main-group byproducts (B, Sn and Zn) hamper the ‘greenness' and industrial efficiency of these processes. Here we present a highly selective and green Pd-catalysed cross-coupling between organic halides and organolithium reagents proceeding without additional solvents and with short reaction times (10 min). This method bypasses a number of challenges previously encountered in Pd-catalysed cross-coupling with organolithium compounds such as strict exclusion of moisture, dilution and slow addition. Operational ease of this protocol combines the use of industrially viable catalysts loadings (down to 0.1 mol%), scalability of the process (tested up to 120 mmol) and exceptionally favourable environmental impact (E factors in several cases as low as 1).


Supplementary Tables
Supplementary Table 1. Pd-catalysed cross-coupling reaction of organolithium compounds and organic halides employing deep eutectic solvents (DES). Conditions: Commercial available PhLi (1.8 M in nBu 2 O) was added to a mixture of 1b (0.3 mmol, 56 mg) and Pd-PEPPSI-iPr ( atmosphere. However, we have repeated the synthesis (e.g. compound 2m) keeping the Schlenk flask open to the air and a similar selectivity (>99%) and isolated yield (95%) was obtained.

Supplementary Note 2:
The authors have not experienced significant problems of exothermicity in comparison to usual couplings (or other catalytic reactions). The synthesis of 2aa was performed on 6 mmol scale (1.25 g), with a small increase of temperature of 4 °C (from 25 °C to 28 °C) upon addition of the organolithium reagents.

Supplementary Note 3:
The authors have performed a cross coupling of 1-bromonaphthalene and dry MeLi, by removing the solvent under vacuum of a commercial organolithium reagent, and subsequent transferring to a glove box. The cross coupling works although, with strongly reduced selectivity in which 2aa was formed up to 15%. We do explicitly warn for the pyrophoric nature of dry organolithium species.

S40
Supplementary Note 4: The authors have performed a cross coupling of 1-bromonaphthalene and phenyl lithium under conditions given in general procedure A, however using 1 eq of the lithium species, rather than 1,2. Compound 2b was obtained in similar conversion and yield.

Supplementary Note 5:
We did not experience any problem with salt formation (for instance on stirring the reaction mixture) under any of the conditions we used.
Supplementary Note 6: Experimental procedure and calculation of the E-factor for the synthesis of 2ag, including aqueous work-up: The reaction mixture was quenched with 1 mL of water, extracted with 1 mL of AcOEt and the organic phase was dried with anhydrous Na 2 SO 4 . Evaporation of the solvent under reduced pressure afforded the crude product that was then filtered over a silica gel plug to afford the pure product. Yield 97%. The E factor including the water used for the work-up is 15.4. The E factor reported in literature for the Suzuki coupling is 84.

General Procedure A for the Cross-Coupling with (Hetero)aryllithium Reagents
The corresponding commercially available or homemade (hetero)aryllithium reagent was added over a mixture of substrate (1 mmol) and Pd-PEPPSI-iPr (1.5 mol %, 10.5 mg) at room temperature for 10 min. After the addition was completed a saturated solution of aqueous NH 4 Cl was added and the mixture was extracted with AcOEt or Et 2 O. The organic phases were combined and dried with anhydrous Na 2 SO 4 . Evaporation of the solvent under reduced pressure afforded the crude product that was then filtered over a silica gel plug.

General Procedure B for the Cross-Coupling with Alkyllithium Reagents
The corresponding commercially available alkyllithium reagent was added over a mixture of substrate (1 mmol) and Pd[P(t-Bu) 3 ] 2 (2 mol%, 10 mg) at room temperature for 10 min. After the addition was completed a saturated solution of aqueous NH 4 Cl was added and the mixture was extracted with AcOEt or Et 2 O. The organic phases were combined and dried with anhydrous Na 2 SO 4 . Evaporation of the solvent under reduced pressure afforded the crude product that was then filtered over a silica gel plug.

General Procedure C for Reactions Carried out in 120 mmol Scale
Commercially available n-BuLi (100 mL, 1.6 M solution in hexane) was added via cannula over a mixture of substrate (120 mmol, 27 g) and Pd[P(t-Bu) 3 ] 2 (0.4 mol%, 250 mg) at room temperature for 30 min, keeping the temperature between 20-25 °C with the use of an additional water bath. After the addition was completed water was slowly added and the mixture was extracted with AcOEt or Et 2 O. The organic phase were combined and dried with anhydrous Na 2 SO 4 and solvent was removed under reduced pressure affording the final product in reagent grade quality. 3 CAS Registry Number: 613-37-6. Synthesized using catalytic system A with 1-bromo-4-methoxybenzene (1 mmol, 187 mg) and 798 µL of PhLi. Catalytic system A: Reaction carried out at room temperature. White solid obtained after filtration over a silica plug (SiO 2 , n-pentane/ Et 2 O 100:1), 155 mg, 84% yield.