Selective Hydroboration–Oxidation of Terminal Alkenes under Flow Conditions

Abstract An efficient flow process for the selective hydroboration and oxidation of different alkenes using 9‐borabicyclo(3.3.1)nonane (9‐BBN) allows facile conversion in high productivity (1.4 g h−1) of amorpha‐4,11‐diene to the corresponding alcohol, which is an advanced intermediate in the synthesis of the antimalarial drug artemisinin. The in situ reaction of borane and 1,5‐cyclooctadiene using a simple flow generator proved to be a cost efficient solution for the generation of 9‐BBN.

Abstract: An efficient flow process for the selective hydroborationand oxidation of different alkenes using 9-borabicyclo (3.3.1)nonane (9-BBN)a llows facile conversion in high productivity (1.4 gh À1 )ofamorpha-4,11-diene to the corresponding alcohol, which is an advanced intermediate in the synthesis of the antimalariald rug artemisinin. The in situ reaction of borane and 1,5-cyclooctadiene using a simple flow generatorp rovedt ob eacost efficient solution for the generation of 9-BBN.
Alkenesa re very important entities in organic synthesis due to the diversity and wide availability of alkene substrates andt he large spectrum of chemical reactivities of doubleb onds. [1] Oxidation of alkenest ot he corresponding alcoholsi so ne of the fundamental chemical transformations and the hydroborationoxidation sequencei sa ni mportantt ool in this context. [2] In 2015, Souto et al. reported ah ighly efficient flow method for the hydroboration-oxidation of alkenes. [3] Their flow protocol presented several clear advantages over batchr eactionsi ncluding milder reactionc onditions, better selectivity and a high production rates of up to 120 mmol h À1 ,i na ddition to the facile continuousp rocessing of the produced biphasic mixture under flow conditions. Despite the efficiency,s calability and simplicity of this protocol, the use of boranep oses severe selectivity problems with substrates containingt erminala s well as internal double bonds. Limonene, for example,w as a challenging substrate that gave diol 2 in only 28 %y ield. The problem of ar egioselective reaction is alleviated in batch using bulkierh ydroboratingr eagents such as 9-BBN leadingt o compound 3 in 77 %y ield (Scheme1). [4] The selectiveo xidation of the terminal doubleb ondo f amorpha-4,11-diene 4 to the corresponding alcohol 5 as showni nS cheme 2i sakey step in the synthesis of the antimalariald rug artemisinin 6,w hichc an be achievedi nb atch using 9-borabicyclo(3.3.1)nonane (9-BBN). [5] As part of our ongoing research on the development of an efficient semi-synthetic approach to artemisinin, [6] we report hereascalable flow protocolf or the selective hydroboration-oxidationo ft erminal alkenes.
Initial investigationsw ere based on the optimised reaction conditions for the sequence of hydroboration and oxidation of alkenes in flow as published by Souto et al. [3] Using am odified reactions etup ( Figure 1) and replacing borane by 9-BBN,t he selectiveo xidation of the terminal alkene of (R)-(+ +)-limonene was investigated as ac heap ande asily accessible model substrate.
Under the optimal reaction conditions of Souto [3] (Table 1, entry 1), the desired alcohol (R)-3 wasf ormed in only 7% yield. The hydroboration step takes place in the first reactor (PFA coil, 1mmi .d.) while the oxidative work-upp roceeds in the second reactor (PFA coil, 2.4 mm i.d.). Coils with as maller internal diameter for the second reactor resulted in partial blockage of the reactor due to the formation of some solids whichw as also observed when borane wasu sed as ar eagent. [3] The flow rate of the NaOH solution was adjusted to deliver about 1.7 equivalents to the alkene and the stream of aqueous solu-Scheme1.Hydroboration-oxidation of limonene. [3,4] Scheme2.Hydroboration-oxidation of amorpha-4,11-diene 4 as ak ey step in the synthesis of artemisinin 6.
tion of hydrogen peroxide [20 %( v/v)] is adjusted to deliver 6.7 equivalents similar to the previously published optimisation. [3] Loweringt he concentration of limonene 1 to 0.5 m and increasingt he residence time in the first reactor to 1.0 min (entry 2) was not significant. Increasingt he reactor volume to 4mLa nd hence doubling the residence time to 2min led to a slight increase in yield (15 %, entry 3). Another increment of the reaction yield (27 %) was obtained by lowering the concentration of limonene to 0.25 m andi ncreasing the residence time to 5.3 min( entry 4). Using two equivalents of 9-BBN rather than one equivalent (entry 5) led to ad ramatic increase of the yield (65 %). Increasing the residence time further by increasingt he reactor volume from 4mLt o6mL (entry 6) or by lowering the flow rates (entry 7) did not result in an improve-ment of the reaction outcome. As mall improvement (76 %) was obtained by raising the temperature to 30 8C. Another increase of the reactiony ield to 92 %w as obtained using ar eaction temperature of 40 8C( entry 9). Raisingt he temperature furtherd id not improve the reactiony ield (entry 10). All yields were determined by 1 HNMR using 1,3,5-trimethoxybenzene as internal standard. Applying the optimum reaction conditions of entry 9t oareactiono nl arger scale (2.5 mmol, entry 11)l ed to the isolation of alcohol 3 in 90 %y ield. The reactionw as also scaled up further(15 mmol) to prove the efficiency and reliability of the developed flow protocol where 2.1 g( 90 %) of alcohol (R)-3 was obtained in 2h.
As mentioned above,t he main motivation of this work was the development of an efficient flow protocol for the conversion of amorpha-4,11-diene 4 to the corresponding alcohol 5, an advanced intermediate in the synthesis of the antimalarial drug artemisinin 6.W hen the optimal conditions (Table 1, entry 9) were used for amorpha-4,11-diene 4 as as tarting material, alcohol 5 was isolated in 85 %y ield. Performing the reaction on 15 mmol scale led to the production of 5 with ap roductionr ate of 1.4 gh À1 without ar eduction in yield. In addition, epi-amorpha-4,11-diene [5] was also successfully converted to the corresponding alcohol 7 in 85 %y ield under the same conditions. The method was also appliedt oo ther substrates to prove its general applicability( Scheme3). Both (+ +)-valencene and (À)-b-pineneg ave the corresponding alcohols 8 and 9 in excellent yields of 90 %a nd 95 %, respectively.U nder the same reaction conditions, both terminal double bonds of deca-1,9-diene reactedt og ive diol 10 in 91 %y ield. Slightly lower yields wereo btained in the case of 5-bromopent-1-ene and styrenew here the corresponding alcohols 11 and 12 were obtained in 81 %and 77 %yield, respectively.
As af urtherp roof of concept, the 9-BBN solution wasr eplacedw ith af low generatoro f9 -BBN from borane (BH 3 ·THF) and 1,5-cycloctadiene [7] (Figure 2) leading to thei solation of alcohol (R)-3 in 56 %y ield. Although the yield of (R)-3 was lower compared to using commercially available 9-BBN (Figure 1), the experiment shows clearly the feasibility of the flow genera-  [a] Reactionc onditions:S olvent: THF,f low rate of NaOH (0.53 m)i ss et to 1.7 equiv,f low rate of H 2 O 2 (20 %a q.) is set to 6.7 equiv. [b] Determined by tion of 9-BBN and the potential of af uture development of an efficient 9-BBN generatorfrom cheaper reagents.
In conclusion, an efficient and scalablep rotocol for the selective hydroboration-oxidation of terminal alkenesu sing 9-BBN under flow conditions was developed. This protocol is particularly useful for substrates containing terminal and internal double bonds such as limonene, amorpha-4,11-diene and valencene, where selective functionalisation of the terminal alkene is observedw ithouta ffecting the internal alkene, a problem that is encountered when borane is used. The methodw as efficientlya ppliedt ot he conversion of amorpha-4,11-diene 4 to dihydroartemisinic alcohol 5 (1.4 gh À1 ), an importanta dvanced intermediate in the synthesis of the antimalarial drug artemisinin 6.I na ddition, the flow generation of 9-BBN from borane and 1,5-cyclooctadieneu sing as imple generator was probeda nd the preliminaryr esults are promising. Development of an efficient fully integratedg enerator of 9-BBN is ongoing in our laboratories.

Experimental Section
Synthetic protocol:U sing the reaction setup shown in Figure 1, a solution of alkene (0.25 m)i nT HF and 9-BBN (0.5 m)i nT HF pumped at 0.5 mL min À1 each were combined using aT -piece and reacted in a4mL PFAc oil (R1, 1mmi .d.) at 40 8C. As econd stream formed by combining as olution of NaOH (0.53 m)i nam ixture of water and ethanol (52.5:47.5) at 0.4 mL min À1 and an aqueous solution of H 2 O 2 (20 % v/v)a t0 .1 mL min À1 was combined with the outlet of reactor R1 through aT -piece and the combined solutions reacted at room temperature in as econd PFAc oil (R2, 2.4 mm i.d., 4.4 mL). The reaction mixture was received in af lask containing saturated aqueous ammonium chloride solution to quench the reaction. The two phases were separated, and the aqueous layer was extracted three times with Et 2 O. The combined organic layers were washed with water then brine and dried over anhydrous MgSO 4 , filtered and evaporated under reduced pressure to give the crude reaction mixture which was then purified by flash column chromatography.