Zinc-mediated carboxylations of allylic and propargylic halides in flow: synthesis of β-lactones via subsequent bromolactonization

Zinc-mediated carboxylation of allylic halides under flow conditions delivered β,γ-unsaturated carboxylic acids and subsequent bromolactonization provides a streamlined process for the synthesis of γ-bromo-β-lactones. The described process further demonstrates the utility of organozinc reagents prepared by passage of allylic halides through a metallic zinc column integrated into a flow process. Use of a tube-in-tube reactor for efficient CO2 introduction led to improvements in conversion compared to a batch process and improved overall yields of β-lactones. The described flow process was also applied to propargylic bromides for the synthesis of allenic and propargylic acids.


Optimization Studies
Batch Preparation of AllylZinc Halide Solution and Carboxylations in Flow (Table S1)  Organozinc Formation and Carboxylations in Flow (Table S2)   Table S2. Additional optimization experiments for the streamlined flow procedure Note: *20.0 mmol scale; yield refers to product isolated by an acid-base extraction procedure to avoid loss of polar carboxylic acid on silica gel.

Experimental Procedures
Titration of Allylzinc Bromide Solution (Table S3) Note: Titration studies were performed to determine how many times a packed zinccolumn could be used. Titrations were carried out following a known procedure described by Alcazar using iodine. 1 A solution of the simple allylzinc bromide was generated and collected in an oven-dried flask under argon following the protocol outlined by Alcazar. 1 3-bromooct-1-yne (5e): Prepared following the standard Appel conditions described above using oct-1-yn-3-ol (1.45 mL, 10.0 mmol), triphenylphosphine (3.15 g, 12.0 mmol), and NBS (2.14 g, 12.0 mmol), delivering the propargylic bromide as a colorless oil (1.33 g, 7.02 mmol, 70% yield).
Spectral data matched that previously reported. To an oven-dried, 500 mL round-bottomed flask, a stir bar and solid LiAlH4 (~1.5 g; 3 reagent grade 95% pellets, each weighing ~0.5 g; 39.5 mmol) was added before being fitted with a septum and purged with inert gas (argon or nitrogen). After 5-10 min of purging, the solid was dissolved in Et2O (90 mL) and stirred for 30 mins until a uniform, grey suspension was observed. The reagent mixture was cooled to -78 o C before the slow, dropwise addition of (R)-carvone (6.20 mL, 39.5 mmol). The reaction mixture stirred for 30 min at -78 o C, after which the excess LiAlH4 was carefully quenched by slow addition of a 10% H2SO4 solution (30 mL) added dropwise at -78 o C (flask was opened to air with nitrogen flowing through to avoid pressure build up and allow the release of H2). After complete addition of the H2SO4 solution and no further gas evolution, the reaction mixture was gradually warmed to 0 o C, and treated with a saturated solution of Rochelle's salt (potassium sodium tartrate, 30 mL). The biphasic mixture was vigorously stirred for 2 h until the layers were no longer cloudy and the mixture was transferred to a 500 mL separatory funnel where the two layers were separated. The aqueous layer was extracted using Et2O (3 x 50 mL), and the combined organic layers were washed with brine (1 x 50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to deliver ((-)-cis) carveol as an off yellow oil (99%, >19:1 dr) which was used without further purification. Spectral data matched that previously reported. 20 To an oven-dried, 250 mL round-bottomed flask equipped with a stir bar was added ((-)cis) carveol (2.4 mL, 15.0 mmol) before being fitted with a septum and purged with inert gas (argon or nitrogen). After 5-10 mins of purging, the starting material was dissolved in dropwise at 0 o C (flask was opened to air with nitrogen flowing through to avoid pressure build up and allow the release of gas). The biphasic solution was then transferred to a 250 mL separatory funnel and the two layers were separated. The organic layer was further washed with NaHCO3 (1 x 30 mL), brine (1 x 30 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to deliver an off-yellow oil. The bromide 1h was found to be unstable on various forms of chromatographic stationary phases (treated/untreated silica, basic/neutral alumina, and fluorosil) and thus was used directly in the next step without any further purification (2.91 g, 13.5 mmol, 90% yield, 6:1 dr).
Compound 1h was previously reported without spectral data 21 (crude NMR data included below). However, the authors determined the anti-bromide isomer to be the major diastereomer following subsequent Sn2 vs Sn2' transformations which were found to competitive mechanistic pathways (as shown at right).

Zinc-Mediated Carboxylation Flow Reaction Setup: Schematic, Picture, and Description
The Vapourtec flow system was equipped with an Ominfit glass column, a tube-in-tube (Gastropod) reactor, a CO2 inlet (6 bar), a 10 mL heated reactor coil (35 °C), and a backpressure regulator (Zaiput BPR-10, 3 bar). The glass column of metallic zinc was prepared and activated as described above using a solution of TMSCl and 1,2dibromoethane. The reaction mixture containing the allylic/propargylic bromide substrate was maintained under an argon atmosphere and dissolved in a 2.3% LiCl•THF solution (prepared following a known procedure 9 ). The allyl/propargyl bromide solution is drawn into the flow system under argon using perfluoroethylene tubing fitted with a needle through the zinc column and the tube-in-tube (CO2) reactor leading to the desired carboxylic acids.
Following the acid-base extraction procedure and concentration delivered the carboxylic acids 6d and 7d as a colorless oil (220 mg, 1.37 mmol, 30% yield) in a 2:1 inseparable mixture of allene and alkyne constitutional isomers.
Spectral data matched that previously reported.
Following acid-base extraction and concentration, the allenic acid 6f and propargylic acid 7f were obtained as a yellow oil (614 mg, 3.53 mmol, 50% yield) as an inseparable mixture (1:1.5) of allene and alkyne constitutional isomers. Spectral data for propargylic acid 7f matched that previously reported. 18 However, allene 6f was previously unreported, thus spectral data is included below and was extracted from NMR. Data for the mixture of alkyne 7e and allene 6e are provided below with non-overlapping peaks identified.