Hydroboration of terpenes—VIII: Cyclic hydroboration of d-(+)-limonene. A stereoselective synthesis of d-(−)-(1R, 2R, 4R)-limonene-2,9-diol and d-(−)-(1R, 2R, 4R)-carvomenthol

d-(+)-Limonene can be converted into the corresponding bicyclic organoborinate intermediate, B-methoxy-4,8-dimethyl-2-borabicyclo[3.3.1]nonane, by cyclic hydroboration with borane in THF, followed by methanolysis, and distillation of the product. Alternatively, cyclic hydroboration of d-(+)-limonene with thexylborane provides the related bicyclic organoborane intermediate, B-thexyl-4,8-dimethyl-2-borabicyclo[3.3.1]nonane. Oxidation of the respective intermediates produces d-(?)-(1R, 2R, 4R)-limonene-2,9-diol. Protonation of the bicyclic thexyl intermediate, followed by oxidation, provides d-(?)-(1R, 2R, 4R)-carvomenthol. These results suggest that the cyclic hydroboration of dienes can provide a valuable means for controlling the exact site of hydroboration, leading to a stereoselective synthesis of alcohols.     

Stereodivergent Hydroboration of Allenes

Full details of a stereodivergent hydroboration of allenes are reported. While hydroboration of an allene with 9‐BBN provided a thermodynamically stable (E)‐allylic alcohol after oxidative work‐up, the reaction of an identical allene with HB(Sia)₂ (disiamylborane) formed a (Z)‐allylic alcohol as the kinetic product. The developed conditions allowed for the synthesis of trisubstituted olefins in a highly stereoselective fashion, which is known to be challenging. The method was also applied to the stereodivergent synthesis of structural motifs such as skipped dienes and allylbenzenes, which are often embedded in biologically active natural products.     

Mechanistic Insight into Hydroboration of Imines from Combined Computational and Experimental Studies

Boron Lewis acid-catalyzed and catalyst-free hydroboration reactions of imines are attractive due to the mild reaction conditions. In this work, the mechanistic details of the hydroboration reactions of two different kinds of imines with pinacolborane (HBpin) are investigated by combining density functional theory calculations and some experimental studies. For the hydroboration reaction of N-(α-methylbenzylidene)aniline catalyzed by tris[3,5-bis(trifluoromethyl)phenyl]borane (BAr^F₃), our calculations show that the reaction proceeds through a boron Lewis acid-promoted hydride transfer mechanism rather than the classical Lewis acid activation mechanism. For the catalyst- and solvent-free hydroboration reaction of imine, N-benzylideneaniline, our calculations and experimental studies indicate that this reaction is difficult to occur under the reaction conditions reported previously. With a combination of computational and experimental studies, we have established that the commercially available BH₃ ⋅ SMe₂ can serve as an efficient catalyst for the hydroboration reactions of N-benzylideneaniline and similar imines. The hydroboration reactions catalyzed by BH₃ ⋅ SMe₂ are most likely to proceed through a hydroboration/B−H/B−N σ-bond metathesis pathway, which is very different from that of the reaction catalyzed by BAr^F₃.     

The hydroboration of propargyl bromide. Simple one-Pot three-component routes to (Z)-1-bromoalk-1-en-4-ols and to anti-homoallylic alcohols

The hydroboration of propargyl bromide with dialkylboranes takes place regioselectively to give 3-bromoprop-1-en-1-yl dialkylboranes 13 which, upon quaternization with bromide ion, undergo a series of transformations into a number of allylic boron species. By a suitable choice of the experimental conditions it is possible to trap the reaction intermediates with aldehydes and to steer the process toward either the synthesis of (Z)-1-bromoalk-1-en-4-ols 6 or anti-homoallylic alcohols 8. Two one-pot three-component processes were developed based on a sequence of four reactions; preparation of dialkylborane and hydroboration of propargyl bromide are the first steps. Then, quaternization with TEBABr may be carried out either in the presence of the aldehyde when (Z)-1-bromoalk-1-en-4-ols 6 are requested, or in the absence of the aldehyde in order to allow the formation of gamma-substituted allyl borane 18 which, successively, adds to the aldehyde affording anti-homoallylic alcohols 8.     

Selective Hydroboration–Oxidation of Terminal Alkenes under Flow Conditions

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.     

Organoboranes : XXV. Hydridation of dialkylhaloboranes. New practical syntheses of dialkylboranes under mild conditions

Practical methods for the synthesis of dialkylboranes (R₂BH) via the hydridation of dialkylhaloboranes (R₂BX) have been developed. Convenient methods available for the preparation of R₂BX via the hydroboration of alkenes with monohaloborane complexes (H₂BX · SMe₂) make this approach valuable for the preparation of various dialkylboranes, R₂BH, many of which are not available by direct hydroboration of alkenes with borane itself. The suitability of various hydriding agents, such as borane derivatives, complex metal hydrides, and alkoxy metal hydrides, for the hydridation of R₂BX was examined, utilizing B-halo-9-borabicyclo[3.3.1]nonane as a representative dialkylhaloborane. In this case, the unusual stability of the resulting dialkylborane, 9-BBN, permits direct estimation of the reaction products by ¹¹B NMR spectroscopy. The generality of the procedure has been demonstrated.     

Synthesis of Cyclic Amine Boranes through Triazole‐Gold(I)‐Catalyzed Alkyne Hydroboration

The first catalytic alkyne hydroboration of propargyl amine boranecarbonitriles is accomplished with triazole‐Au^I complexes. While the typical [L‐Au]⁺ species decomposes within minutes upon addition of amine boranecarbonitriles, the triazole‐modified gold catalysts (TA‐Au) remained active, and allowed the synthesis of 1,2‐BN‐cyclopentenes in one step with good to excellent yields. With good substrate tolerability and mild reaction conditions (open‐flask), this new method provides an alternative route to reach the interesting cyclic amine borane with high efficiency.     

Enantioselective C3-Allylation of Pyridines via Tandem Borane and Palladium Catalysis

Herein, we report a one-pot method for enantioselective C−H allylation of pyridines at C3 via tandem borane and palladium catalysis. This method involves borane-catalyzed pyridine hydroboration to generate dihydropyridines, then palladium-catalyzed enantioselective allylation of the dihydropyridines with allylic esters, and finally air oxidation of the allylated dihydropyridines to afford the products. This method enables the introduction of an allylic group at C3 with excellent regio- and enantioselectivities.     

Amine-directed hydroboration: scope and limitations

Iodine activation induces intramolecular hydroboration of homoallylic and bis-homoallylic amine boranes with good to excellent control of regiochemistry compared to control experiments using excess THF*BH 3. Deuterium labeling and other evidence confirm that the iodine-induced hydroboration reaction of homoallylic amine boranes occurs via an intramolecular mechanism equivalent to the classical 4-center process and without competing retro-hydroboration. Longer carbon chain tethers result in lower regioselectivity, whereas the shorter tether in allylic amines results in a switch to dominant intermolecular hydroboration. Regioselectivity in THF*BH 3 control experiments is higher for the allylic amine boranes compared to the iodine activation experiments, whereas the reverse is true for homoallylic amine borane activation.     

Preparation of Trans-β-Acyl Cyclopentanols and Cyclohexanols

The utility of organoboranes in the synthesis of a wide variety of functional groups is now well established.¹ There have been, however, only a limited number of reports where an organoborane containing a β-functionalized carbon was utilized in organic synthesis. Part of the reason for this is the difficulty in preparing β-functional organoboranes and their tendency to undergo elimination under a variety of reaction conditions.² Those β-functionalized organoboranes utilized synthetically, which we could find in the literature are the β-ethoxy³, 1, and β-carboethoxyvinyl-boranes⁴, 2, of Zweifel and coworkers and the trans-β-tert-butyldimethylsilyloxy organoborane, 3, of Corey and Ravindranathan,⁵ who proposed this system as a potential precursor to prostanoids.     

Hydroboration of Arynes with N‐Heterocyclic Carbene Boranes

Arynes were generated in situ from ortho‐silyl aryl triflates and fluoride ions in the presence of stable N‐heterocyclic carbene boranes (NHC? BH₃). Spontaneous hydroboration ensued to provide stable B‐aryl‐substituted NHC‐boranes (NHC? BH₂Ar). The reaction shows good scope in terms of both the NHC‐borane and aryne components and provides direct access to mono‐ and disubstituted NHC‐boranes. The formation of unusual ortho regioisomers in the hydroboration of arynes with an electron‐withdrawing group supports a hydroboration process with hydride‐transfer character.     

Rh-catalyzed enantioselective hydrogenation of vinyl boronates for the construction of secondary boronic esters

[reaction: see text] Rh-catalyzed hydrogenation of prochiral vinyl boronates occurs in an enantioselective fashion in the presence of the chiral ligand Walphos 1. This transformation provides access to chiral secondary organoboronates that are not available from alkene hydroboration reactions. The chiral reaction products should be useful in organic synthesis, and preliminary experiments suggest that they may participate in one-pot amination and homologation reactions.     

The boron-catalyzed polymerization of dimethylsulfoxonium methylide. A living polymethylene synthesis

Trialkyl and aryl organoboranes catalyze the polymerization of dimethylsulfoxonium methylide (1). The product of the polymerization is a tris-polymethylene organoborane. Oxidation affords linear telechelic alpha-hydroxy polymethylene. The polymer molecular weight was found to be directly proportional to the stoichiometric ratio of ylide/borane, and polydispersities as low as 1.01-1.03 have been realized. Although oligomeric polymethylene has been the most frequent synthetic target of this method, polymeric star organoboranes with molecular weights of 1.5 million have been produced. The average turnover frequency at 120 degrees C in 1,2,4,5-tetrachlorobenzene/toluene is estimated at >6 x 10(6) g of polymethylene (mol boron)(-1) h(-1). The mechanism of the polyhomologation reaction involves initial formation of a zwitterionic organoborane.ylide complex which breaks down in a rate-limiting 1,2-alkyl group migration with concomitant expulsion of a molecule of DMSO. The reaction was found to be first order in the borane catalyst and zero order in ylide. DMSO does not interfere with the reaction. The temperature dependence of the reaction rate yielded the following activation energy parameters (toluene, DeltaH(++) = 23.2 kcal/mol, DeltaS(++) = 12.6 cal deg/mol, DeltaG(++) = 19.5 kcal/mol; THF, DeltaH(++) = 26.5 kcal/mol, DeltaS(++) = 21.5 cal deg/mol, DeltaG(++) = 20.1 kcal/mol).     

Total synthesis of the antiinflammatory and proresolving protectin D1

Stereoselective total synthesis of protectin D1 was completed through construction of the Z,E,E-triene structure by using the Suzuki coupling between the vinyl borane (C13-C22) and the vinyl iodide (C1-C12). The Z-enyne, the acetylene precursor of the vinyl borane was synthesized from optically active γ-TMS allylic alcohol in a straightforward way. On the other hand, the vinyl iodide was prepared by using Wittig reaction between the C8-C12 aldehyde possessing the requisite iodo-olefin moiety and the C1-C7 phosphonium iodide.     

Regioselective Amine–Borane Cyclization: Towards the Synthesis of 1,2‐BN‐3‐Cyclohexene by Copper‐Assisted Triazole/Gold Catalysis

The combination of triazole/gold (TA‐Au) and Cu(OTf)₂ is identified as the optimal catalytic system for promoting intramolecular hydroboration for the synthesis of a six‐membered cyclic amine–borane. Excellent yields (up to 95 %) and regioselectivities (5‐exo vs. 6‐endo) were achieved through catalyst control and sequential dilution. Good functional‐group tolerance was attained, thus allowing the preparation of highly functionalized cyclic amine–borane substrates, which could not be achieved using other methods. Deuterium‐labeling studies support the involvement of a hydride addition to a gold‐activated alkyne with subsequent C?B bond formation.     

Regio- and enantiocontrol in the room-temperature hydroboration of vinyl arenes with pinacol borane

The catalyzed hydroboration of vinyl arenes was carried out using pinacol borane instead of catechol borane, as the former reagent and the product boronates are significantly easier to handle. By careful choice of catalyst, either the branched or the linear product can be obtained in greater than 96% selectivity. Interestingly, common ligands such as BINAP and Josiphos give opposite asymmetric induction with pinacol borane as compared with catechol borane, while P,N-ligands such as Quinap gave the same sense of induction. The hydroboration of 6-methoxynaphthalene proceeded with the greatest regio- (95:5) and enantioselectivity (94:6) of all vinyl arenes examined. The hydroboration product was then employed in a concise synthesis of the nonsteroidal antiinflammatory agent, Naproxen.     

Molecular addition compounds. 17. Borane and chloroborane adducts with organic sulfides for hydroboration

The following sulfides have been examined as borane carriers in comparison with dimethyl sulfide and 1,4-oxathiane: tert-butyl methyl sulfide, isoamyl methyl sulfide, ethyl isoamyl sulfide, tert-butyl isoamyl sulfide, diisoamyl sulfide, tetrahydrothiophene, tetrahydro-thiopyran, thioanisole, 3-ethylthiotetrahydrofuran, bis(3-tetrahydrofuryl) sulfide, and bis(2-methoxyethyl) sulfide. Their complexing ability toward borane increases in the following order: thioanisole < ether-sulfides < dialkyl sulfides < dimethyl sulfide. Borane adducts of the sulfides are liquids above 0 degrees C. The thioanisole adduct loses diborane at room temperature. The reactivity of the adducts toward 1-octene increases in the reversed order of the complexing ability of the sulfides. Diisoamyl sulfide has a mild, ethereal, agreeable aroma, its synthesis is economical and the borane adduct, 4.2 M in BH3, is stable over prolonged periods at room temperature. The sulfide can be recovered from hydroboration-oxidation products by distillation. Consequently, diisoamyl sulfide is a new promising borane carrier. Bis(2-methoxyethyl) sulfide, easily synthesized from the low cost thiodiethanol, is three times more soluble in water than 1,4-oxathiane. Its borane adduct is 6.0 M in BH3 and can substitute for more expensive borane-1,4-oxathiane in hydroboration reactions. Applications of these new borane adducts in the synthesis of mono- and dichloroborane adducts was also studied. The equilibrium ratios observed for the new chloroborane adducts were similar to that observed for dimethyl sulfide adducts. However, the hydroboration of 1-octene with these new chloroborane adducts are much faster than the corresponding adducts of dimethyl sulfide, which are currently used extensively.     

Formylborane Formation with Frustrated Lewis Pair Templates

Boranes R₂BH react with carbon monoxide by forming the respective borane carbonyl compounds R₂BH(CO). The formation of (C₆F₅)₂BH(CO) derived from the Piers borane, HB(C₆F₅)₂, is a typical example. Subsequent CO‐hydroboration does not take place, since the formation of the formylborane is usually endothermic. However, an “η²‐formylborane” was formed by CO‐hydroboration with the Piers borane at vicinal phosphane/borane frustrated Lewis pair (FLP) templates. Subsequent treatment with pyridine liberated the intact formylborane from the FLP framework, and (pyridine)(C₆F₅)₂B? CHO was then isolated as a stable compound. This product underwent typical reactions of carbonyl compounds, such as Wittig olefination.     

Studies on the total synthesis of sanglifehrin A: stereoselective synthesis of the C(29)-C(39) fragment

A highly stereoselective synthesis of the C(29)-C(39) fragment of the potent immunosuppressant sanglifehrin A has been accomplished by a sequence involving 16 steps (18% overall yield) from N-propionyloxazolidinone 9. Key steps are a diastereoselective hydroboration, and a diastereoselective epoxidation of an allylic alcohol followed by a 1,5-anti boron-mediated aldol reaction of methyl ketone 4 with chiral aldehyde 5.     

Intramolecular Cyclopropanation of 1,4‐Dienes through Hydroboration–Homologation: Easy Access to Bicyclo[3.1.0]hexanes

An intramolecular cyclopropanation reaction involving B‐(1‐chloroalkyl)catecholborane intermediates generated from 1,4‐dienes through hydroboration with catecholborane and Matteson homologation was developed. This sequential procedure leading to bicyclo[3.1.0]hexanes involves the formation of three new sigma C?C bonds at the same carbon atom. A mechanistic study supports the involvement of carbocationic intermediates.