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Chapter 5

Unstable Intermediates as Keys to Synthesis with Organoboron Compounds Downloaded by MONASH UNIV on December 1, 2016 | http://pubs.acs.org Publication Date (Web): November 30, 2016 | doi: 10.1021/bk-2016-1236.ch005

Donald S. Matteson* Department of Chemistry, Washington State University, Pullman, Washington 99164-4630, United States *E-mail: [email protected]

The role of unstable intermediates is often the key to understanding and optimizing organoborane reactions. The examples described are selected from the author’s experience, with emphasis on reactions that were initially overlooked or not understood until an unstable intermediate was recognized. The topics chosen are Unsolvated Boranes in Hydroboration, (α-Haloalkyl)borate Rearrangements, (Halomethyl)lithiums, and (α-Aminoalkyl)boronic Esters. This brief review is not comprehensive but emphasizes the observations that enabled the original discoveries.

Introduction The theme that connects the diverse boron chemistry included in this brief review is the role of reactive intermediates that are not isolable in syntheses of boron compounds that were discovered in the author’s laboratory. In some cases the intermediates were understood before the research was undertaken, in others the results were a total surprise. It was my policy to encourage students and postdoctoral associates to try their own ideas in the lab. There were occasions where the professor could have told the student that his/her idea wouldn’t work, but trying the experiment produced an unexpected result that was useful after it was interpreted correctly. Some of my most important discoveries were made that way, and without revealing forgotten and possibly embarrassing ideas that led to the experiments, the pathway to these discoveries is described here.

© 2016 American Chemical Society Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Downloaded by MONASH UNIV on December 1, 2016 | http://pubs.acs.org Publication Date (Web): November 30, 2016 | doi: 10.1021/bk-2016-1236.ch005

Unsolvated Boranes in Hydroboration This section covers a convenient and useful method of hydroboration with haloboranes and silanes developed in our laboratory and how it was discovered. It has not been as widely publicized as other methods and it appears that few chemists have been aware of it. Brown and coworkers have provided convincing evidence that hydroboration of alkenes with 9-borabicyclo[3.3.1]nonane (9-BBN) dimer proceeds via dissociation to 9-BBN monomer (1, 2). If the alkene reacts rapidly with the 9-BBN monomer, the reaction is first-order in (9-BBN)2 and unaffected by the alkene concentration since every dimer that dissociates is consumed. However, a slower reacting alkene such as cyclohexene allows time for the monomer-dimer equilibrium to occur, the monomer concentration becomes proportional to the square root of that of the dimer, and the rate becomes half-order in (9-BBN)2 and first-order in alkene. The mechanism of the reaction of (9-BBN)2 with cyclohexene in carbon tetrachloride or other inert solvent to produce cyclohexyl-(9-BBN) (1) is illustrated in Scheme 1.

Scheme 1. Mechanism of reaction of (9-BBN)2 with cyclohexene The reaction of 9-BBN dimer with 2-methyl-1-pentene in carbon tetrachloride with THF is first-order in (9-BBN)2 and first-order in THF. It was concluded that the accelerating effect of ethers involves attack of the ether on the BH2B bridge bonded dimer, which liberates 9-BBN monomer and 9-BBN-THF, which then dissociates much faster than (9-BBN)2 does. The proposed mechanism that leads to 2-methylpentyl-(9-BBN) (2) is illustrated in Scheme 2.

Scheme 2. Mechanism of hydroboration with (9-BBN)2 in THF Wang and Brown extrapolated their results to all borane reactions, and concluded that free BH3 is the active hydroborating agent in borane-THF reactions (1). They attributed significance to a report by Klein et al. that pseudo-first-order 174 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


hydroboration of an aged sample of a methoxystyrene in excess THF-BH3 was delayed up to six half-lives by an undetected impurity but proceeded normally after the sample was distilled (3). However, the fact that hydroboration is not a chain reaction was overlooked in this interpretation. Several mols of the undetected impurity would be required to scavenge most of the free BH3 and delay hydroboration so long. The half-lives measured were only a few seconds, a flow system was used, and the likely explanation for the anomaly is an experimental error such as failure of mixing the rapidly reacting reagents. Otherwise, the normal kinetics first-order in styrene are in agreement with other observations, and citation of this work is merely a cautionary tale of Murphy’s Law. Although it is clear that ethers accelerate hydroboration by breaking the strong BH2B bridge bond in borane dimers and reducing the activation energy by delivering a single borane unit at a time to the alkene substrate, it is not clear whether borane etherates may also react directly with alkenes. Pasto and coworkers found that hydroboration of tetramethylethylene with BH3-THF in THF is first-order in BH3-THF as well as first-order in tetramethylethylene (4). The observed activation energy was 9.2±0.4 kcal/mol and the activation entropy -27±1 eu. These results are consistent with a direct reaction between BH3-THF and tetramethylethylene. If the mechanism involves irreversible dissociation of the BH3-THF and rapid reaction of the free BH3 with the alkene, the rate should be insensitive to the alkene concentration. The second mechanism allowed by the experimental data would be reversible dissociation of BH3-THF followed by reaction of the equilibrium concentration of free BH3 with the alkene. The half-order dependence of free BH3 on BH3-THF would be masked by the use of THF as solvent and measurement of pseudo-first-order rates exclusively. The activation energy for reaction of free BH3 with ethylene in the gas phase was estimated by Fehlner to be 2±3 Kcal-mol–1, not clearly distinguishable from zero (5). The BH3 was generated by thermolysis of BH3PF3 in a flow system with helium as carrier gas and the reaction products were identified by mass spectroscopy. Quantum mechanical calculations at the 6-31G** level (6) and more recently at the B3LYP/6-31G(d) level with corrections for solvation (7) have left unresolved the question of whether the active hydroborating agent is free BH3 or BH3-THF. The calculated results suggest that the activation energy is higher than the value measured by Pasto’s group, and leave open the possibility that hydroboration by BH3 might involve both pathways simultaneously. Several calculations are in accord in suggesting that the first step in hydroboration is formation of a borane–hydrocarbon π-complex, which subsequently forms the product-determining four-center transition state (6–8). Experimental evidence that hydroboration can involve direct transfer of borane from a complex with a base to an alkene is provided by Narayana and Periasamy, who found that hydroboration of a dihydrofuran with N-isobornyl-N-methylaniline-borane led to (R)-3-tetrahydrofuranol in up to 19% enantiomeric excess (ee) (9). This result requires that at least part of the reaction pathway involve the amine-borane directly reacting with the substrate, and since there is reason to expect that chiral induction would not be very high, allows the possibility that no free BH3 is involved. 175 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


In accord with the mechanistic data, hydroboration with HBCl2-THF is much slower than with BH3-THF, generally requiring hours at room temperature (10, 11). Addition of boron trichloride to a solution of an alkene and HBCl2-Et2O in pentane precipitates boron trichloride etherate and results in rapid hydroboration to form the alkylboron dichloride (12). Perhaps the hydroboration is so fast as unsolvated HBCl2 is liberated from its etherate that disproportionation does not occur, but as described in the following paragraph, the alkylboron dichloride will be the product as long as the proportion of chloride to hydride is at least 2:1. Hydroboration with HBCl2-SMe2 requires boron trichloride in order to proceed satisfactorily, but unexpectedly HBBr2-SMe2 alone is an efficient hydroborating agent in refluxing dichloromethane (13). My interest in hydroboration with unsolvated haloboranes arose when Raman Soundararajan tried a reaction of tributyltin hydride with catechol bromoborane and got a mixture of catechol butylboronate with catechol borane. Might the reaction with trialkylsilanes be more selective? It is, and it quickly developed that addition of a trialkylsilane or diethylsilane (which transfers only one hydride) to an equimolar mixture of boron trichloride and an alkene with no solvent or in an inert solvent resulted in immediate formation of the corresponding alkylboron dichloride (14, 15). Reaction of diethylsilane with approximately equimolar boron trichloride at –78 °C in an NMR tube and measurement of the 64 MHz 11B spectrum below –40 °C revealed a mixture of unchanged boron trichloride, both geometric isomers of (H2BCl)2, and ClB2H5. No clear evidence for HBCl2 or its dimer was seen, though a small amount could have been present. At –25 °C the mixture disproportionated to boron trichloride and B2H6. Checking the literature for precedent revealed that the Haszeldine group had already shown that enantiopure (methyl)(phenyl)(naphthyl)silane exchanges hydride for chloride with boron trichloride with retention of configuration at silicon (16). However, the reaction was not run under conditions that would allow observation of the borane products before total disproportionation to boron trichloride and diborane The most convenient procedure is to add an equimolar mixture of the alkene and either triethylsilane or diethylsilane dropwise to stirred boron trichloride either neat (bp 12 °C) or in an inert solvent such as dichloromethane or pentane. Trimethylsilane requires a cylinder for storage and is accordingly less convenient, but it transfers hydride very rapidly. It appears that trimethyl- and diethylsilane have comparable reactivities. Tributylsilane and triphenylsilane react more slowly. Chlorodimethylsilane transfers hydride very slowly to boron trichloride but could be useful at somewhat elevated temperature and pressure (15). An alternative is to mix the silane and boron trichloride first at –78 °C, then add the alkene. Either way, the product and yield are the same, even though HBCl2 is only a minor constituent of the preformed hydroborating agent, because redistribution of hydride and chloride between boranes is very rapid. Another alternative is the use of BBr3 in place of boron trichloride. One consequence of the rapid halide-hydride redistribution is that it makes no difference which alkyl group is joined to boron first for synthesis of a dialkylchloroborane, RR′BCl, having two different alkyl groups. Equilibrium control prevails at each step, in contrast to hydroboration with BH3-THF, which 176 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


can only be paused cleanly after the first or second group is hydroborated if the group has sufficient steric bulk to slow further reaction. The facile hydroboration of 1-hexene to (dichloro)(1-hexyl)borane followed by subsequent reaction with cyclohexene to form (chloro)(cyclohexyl)(1-hexyl)borane (3) was reported as an example of the flexibility provided by hydroboration with haloboranes and silanes (Scheme 3) (15).

Scheme 3. Sequential hydroborations with BCl3 and Et3SiH Ethyldichloroborane was made in good yield by passing a slow stream of ethylene through a solution of boron trichloride in dichloromethane at –78 °C while adding triethylsilane dropwise. In spite of its high chlorine content (64%) the product is spontaneously flammable, though the flame did not char paper. Accordingly, methanol was added and dimethyl ethylboronate was isolated (15). Hydroboration of terminal alkynes with dichloroborane is easily controlled to produce the E-alkenyldichloroborane (4) or the 1,1-bis(dichloroboryl)alkane (5) by using the appropriate ratio of reactants, and 5 can be converted to the corresponding bis(boronic ester) (6) by treatment with an alcohol or reduced with excess silane to form the cyclic borane dimer (7). (Scheme 4).

Scheme 4. Product options from hydroboration of 1-hexyne with BCl3/Et3SiH Hydroboration of internal alkynes has yielded more complicated results. Brown and Gupta reported that catecholborane hydroborates alkynes stereospecifically cis to yield exclusively the Z-alkeneboronic esters (17), but when we tried to repeat that result with 3-hexyne and catecholborane we obtained gross mixtures of E- and Z-isomer (18). Reaction of 3-hexyne with boron trichloride and triethylsilane at –78 °C produced ~30% 3-(dichloroboryl)-4-chloro-3-hexene 177 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


(8) and very little hydroboration product. Efficient hydroboration was achieved with boron trichloride and the more reactive diethylsilane, and the NMR spectrum of the crude dimethyl 3-hexenyl-3-boronate obtained after methanolysis indicated that it was pure Z-isomer (9), but it partially isomerized to E-isomer (10) on distillation (18). Evidence that the Z/E isomerization is radical catalyzed includes an decreased proportion of 10 when the hydroboration with catecholborane was run in the presence of the radical inhibitor galvinoxyl and production of ~90% 10 when the free radical initiator AIBN was used. We did not find any way to obtain pure 9. These results are illustrated in Scheme 5.

Scheme 5. Results of hydroboration of 3-hexyne with BCl3 and Et3SiH or Et2SiH2 Addition of equimolar (+)-α-pinene and triethylsilane to neat boron trichloride stirred in a –78 °C bath resulted in complete conversion to dichloroisopinocampheylborane (11) within 5 minutes. The crude product was then mixed with a second mol of (+)-α-pinene and triethylsilane and was completely converted to diisopinocampheylchloroborane (12) at room temperature overnight (Scheme 6) (15).

Scheme 6. Hydroboration of 2 mols of (+)-α-pinene with BCl3/ 2Et3SiH Dhokte, Kulkarni, and Brown subsequently reported that the reaction of trimethylsilane with 11 is “...extremely slow in pentane, probably proceeding to the formation of a small equilibrium concentration of IpcBHCl (19)...” However, their data require that the equilibration not be slower than that with triethylsilane reported previously (15), since 3-methyl-2-butene was hydroborated by 11 and trimethylsilane in pentane at 0 °C in 24 h (19). The thermodynamic balance is shifted in diethyl ether, and IpcBHCl-Et2O was formed within minutes. It was also noted that equimolar amounts of 11, (+)-α-pinene, and trimethylsilane in diethyl ether were converted to 12 within 15 minutes at 0 °C. Hydroboration of 1-(1-cyclohexenyl)naphthalene with boron trichloride and triethylsilane in dichloromethane has provided clean alkyldichloroborane rac-13, 178 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


which was resolved via crystallization of the (–)-menthone complex of (R,R)-13 as illustrated in Scheme 7. In Diels-Alder reactions of esters the BCl2 group complexes with the ester carbonyl oxygen and the naphthalene substituent orients the remainder of the ester while blocking access of the diene to one side, making (R,R)-13 a highly effective asymmetric Diels-Alder catalyst (20).

Scheme 7. Preparation of (R,R)-1-(α-naphthyl)-2-dichloroborylcyclohexane The reaction of boron trichloride with silanes was not explored with any functionalized alkenes as hydroboration targets. A very brief investigation has shown that cyclohexylboron dichloride, derived from defluoridation of the trifluoroborate, does react with diethylsilane in refluxing THF and hydroborates alkenes rather slowly to form trialkylboranes (21). The reaction with 1-hexene does not stop cleanly at the dialkylchloroborane stage but proceeds to the trialkylborane. Reaction of diethylsilane with 1,5-cyclooctadiene in the presence of (dimethylamino)naphthalene produced cyclohexyl-(9-BBN) (1) (Scheme 8) (21).

Scheme 8. Hydroboration with RBCl2/Et2SiH2 in the presence of THF

(α-Haloalkyl)borate Rearrangements Synthetic organoboron chemistry in 1958 presented numerous obstacles that may be difficult for younger chemists to imagine. Normant’s discovery that vinyl Grignard reagents could be made in THF was recent (22), and the synthesis of a vinylboronic ester (14) became possible (23, 24). Free radical addition of bromotrichloromethane to dibutyl vinylboronate provided the first example of an (α-haloalkyl)boronic ester (15) (24, 25). With a very naive idea of what might be done with the product, I suggested to Raymond Mah, my first graduate student, that he phenylate the boron atom of 15 with the Grignard reagent (26), a well known process (27). The elemental analysis of his product did not yield the expected percentages, but repeated attempts to purify the material produced consistent numbers. The work of Kuivila on the 179 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


mechanism of the peroxidic oxidation of phenylboronic acid (28, 29) as well as the familiar Wagner-Meerwein rearrangement suggested that a rearrangement of intermediate anion 16 via phenyl migration to form boronic ester 17 might have occurred (26). The commercial analytical service could not distinguish between chlorine and bromine, and an inquiry about whether the halogen determination was titrimetric or gravimetric was needed to verify the result. Norman Bhacca of Varian Associates took the NMR spectrum, which was too poorly resolved for interpretation by novices, and assured us that it was consistent with our postulated structure. The mechanism was definitively proved by acidification of the cold reaction mixture prior to rearrangement, which did yield the expected borinic ester 18, and also by an alternative synthesis of 18 via radical addition of bromotrichloromethane to (butoxy)(phenyl)(vinyl)borane (19) (Scheme 9) (26, 30).

Scheme 9. Evidence for the rearrangement of an (α-bromoalkyl)borate anion

The first (α-bromoalkyl)boronic ester was an interesting curiosity for reaction mechanism studies but not much else. It was obvious that the rearrangement process ought to proceed with stereospecific retention at the migrating carbon and inversion at the displacement site, but without a general route to other structures, let alone to a pure single enantiomer, the potential synthetic utility was inaccessible. Radical addition is limited to a few unusual reagents. Radical addition of bromomalononitrile to dibutyl vinylboronate (14) yielded the (α-bromoalkyl)boronic ester 20, but the only reaction found with the few nucleophiles tested was deprotonation and closure to (cyclopropyl)boronic ester 21 (Scheme 10) (31).

180 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Scheme 10. Products from bromomalononitrile and dibutyl vinylboronate

(α-Haloalkyl)boronic esters that could be made by hydrogen halide addition to unsaturated boronic esters were limited to adducts of a vinylboronic ester or of (sec-alkenyl)boronic esters (31, 32). Otherwise polar hydrogen halide addition puts the halogen in the β-position, where the only known reaction with nucleophiles (except iodide ion) is elimination of boron and halide, as illustrated with the synthesis and decomposition of 22 (Scheme 11).

Scheme 11. Formation and β-elimination of a (β-bromoalkyl)boronic ester

Attempted chlorination of di-t-butyl methylboronate with t-butyl hypochlorite resulted in very little chlorination of the B-methyl group (33). Light-initiated bromination of secondary alkylboronic esters has proved successful (34). Secondary alkylboronic anhydrides are more reactive in radical bromination, and tri(bromoisopropyl)boroxine is produced very efficiently (35). Dibutyl (iodomethyl)boronate, (BuO)2BCH2I, was first made via reaction of boron tribromide with (iodomethyl)mercuric iodide (36, 37), not a reaction anyone would want to repeat. The first practical synthesis of pinacol (iodomethyl)boronate, reaction of pinacol (phenylthiomethyl)boronate with methyl iodide and sodium iodide in acetonitrile (38), was based on the homologation of alkyl iodides by Corey and Jautelat (39). The lithiation of pinacol (phenylthiomethyl)boronate to 23 and alkylation with benzyl bromide to 24 enabled extension of this approach to a potential general synthesis of (α-iodoalkyl)boronic esters such as 25 (Scheme 12) (40, 41). That route was quickly superseded by the discovery of homologation of boronic esters with (dihalomethyl)lithiums described in the following section.

Scheme 12. Preparation of an (α-iodoalkyl)boronic ester via a thioether

181 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

(Halomethyl)lithiums


Precursor One-Carbon Chain Extensions (Dichloromethyl)lithium, LiCHCl2, was discovered by Köbrich and coworkers and shown to react with triphenylborane, Ph3B, with rearrangement to (diphenyl)(α-chlorobenzyl)borane, Ph2BCHClPh (42, 43). Ultimately this reagent became the key to useful syntheses with (α-chloroalkyl)boronic esters, but we reached this goal via a roundabout route. Our interests at that time were centered on boron substituted carbanions, beginning with deboronation of a tetraborylmethane ester, C[B(OMe)2]4 (44), and a triborylmethane ester (45). Deprotonation of a (methylene)diboronic ester, CH2[BO2(CH2)3]2, followed (46). Preparation these di-, tri-, and tetraboronic esters was hazardous, involving lithium dispersion, dichloromethane, and dimethoxyboron chloride in THF, and yields varied for no known reason. Unstable (chloromethyl)lithium intermediates with several combinations of halogen and boronic ester substitution are no doubt involved in these reactions, but our ignorance of what relations there are between their rates of formation and borylation precludes meaningful discussion. Dimethoxyboron chloride was the only successful borylating agent found. Cyclic boron substrates did not work, and transesterification of tetramethyl (methylene)diboronate with 1,3-propanediol was required for preparation of an improved substrate 26 for lithiation to 27 and typical carbanion reactions such as alkylation to 28 (Scheme 13).

Scheme 13. Alkylation of a lithiated methylenediboronic ester

The deboronation of triboronic ester 29 to lithiated derivative 30 and reaction with acetaldehyde yielded trans-propenylboronic ester 31 (Scheme 14) (47). The E/Z ratio was 93:7, and bulkier aldehydes yielded higher E/Z ratios.

Scheme 14. Reaction of a lithiated methylenediboronic ester with acetaldehyde 182 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


The reaction of 30 with a highly functionalized aldehyde was used in an essential step in the Kishi group’s famous palytoxin synthesis after it had been found that hydroboration of the corresponding alkyne resulted in reduction of a urethane function that was faster than the hydroboration (48). Perhaps Morken’s recently reported catalytic preparation of a diboronic ester from dibromomethane and pinacol diborate, B2(O2C2Me4)2, will make this chemistry more accessible and useful (49). We turned our attention to easier carbanion sources to prepare, such as the [(trimethylsilyl)methyl]boronic ester 32 (50). Alkylation of the lithiated species 33 provided the expected (α-trimethylsilylalkyl)boronic esters, for example 34 (Scheme 15).

Scheme 15. Alkylation of a lithiated [(trimethylsilyl)methyl]boronic ester

However, condensation with aldehydes or ketones unexpectedly resulted in elimination of the trimethylsilyl group and not the boronic ester function. The second surprise was that heptanal yielded predominantly the Z-alkenylboronic ester 35, Z/E ratio ~70:30 (Scheme 16), and the only other aldehyde tested, benzaldehyde, produced a similar Z/E ratio.

Scheme 16. Reaction of a lithiated silyl boronic ester with an aldehyde

Considering the possible lability of the Z/E ratios of alkenylboronic esters noted much later (see isomerization of 9 to 10) (18) and that these were distilled samples, it might be worthwhile to check whether the initial Z/E ratios were higher. It is also possible that higher Z/E ratios could result from different combinations of boronic ester and trialkylsilyl groups. It has been noted in the preceding section that pinacol (α-phenylthiomethyl)boronate is easy to make, lithiate to 23, and alkylate with benzyl bromide to 24, which can be converted to the (α-iodoalkyl)boronic ester 25. It is also easy to make bis(phenylthio)boronic esters, deprotonate them with LDA, and react the anion with a carbonyl compound to make a 1,1-bis(phenylthio)alkene, as illustrated with the conversion of 36 to 37 (Scheme 17). 183 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Scheme 17. A bis[(phenylthio)methyl]boronic ester and reaction with a ketone In the hope that we might be able to alkylate the boron atom of 36, methylate sulfur, and rearrange the borate complex with displacement of PhSMe, Abel Mendoza tried treatment of 36 with butyllithium, then methyl iodide, but only obtained (PhS)2CHCH3 and BuB(O2C3H6). He then tried the reaction of 36 with methyl fluorosulfonate followed by butyllithium and obtained ~30% of what the NMR spectrum indicated was the desired product 38 in a gross mixture with (PhS)2CH2 (erroneously called “diphenylmethane” in our publication) (Scheme 18) (51). At that point a tragic fatality from an accidental spill of methyl fluorosulfonate was reported (52), and we immediately quit using that exceedingly dangerous reagent.

Scheme 18. Replacement of a phenylthio of a bis(phenylthio) boronic ester (Dichloromethyl)lithium A methylthio group would be easier to methylate than phenylthio, and perhaps the methylthio analogue of 36 could be methylated with methyl iodide and an efficient way to carry out a reaction analogous to the conversion of 36 to 38 could be found. Debesh Majumdar didn’t like that idea and wanted to try reaction of a boronic ester with (dichloromethyl)lithium. I unwisely tried to discourage that approach, doubting both the feasibility and the novelty of it. Köbrich and Merkle required –100 °C to prepare the reagent, not the most practical of reaction conditions, and had inserted the CHCl group into triarylboranes (43). Rathke, Chao, and Wu had already made diisopropyl (dichloromethyl)boronate, alkylated the boron with butyllithium, and rearranged the intermediate to insert the CHCl group and make an (α-chloropentyl)boronic ester (53). The intermediate was the same as would result from adding LiCHCl2 to an alkylboronic ester. The Rathke group had used several different (dichloromethyl)boronic esters and different organometallic partners but had oxidized all the other (α-chloroalkyl)boronic esters to aldehydes, with consistent 75% yields. Fortunately Debesh had learned that the professor is not always right, and he went ahead and tried the experiment. He immediately got consistent 80-90% isolated yields of (α-chloroalkyl)boronic esters (54, 55). We already knew that the α-halide could be displaced by a variety of nucleophiles (26). The products are, of course, boronic esters, and the reaction with LiCHCl2 could be repeated to produce a new (α-chloroalkyl)boronic ester. The rearrangement of the intermediate borate complex was slowed and yields were lower but still good when an α-alkoxy or a 184 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

remote carboxylic ester or dioxolane substituent was present. We also found the literature method of generating and capturing LiCHCl2 in situ (56), which allows temperatures as high as –30 °C. The homologation of pinacol butylboronate to 39 on a 0.1-mole scale using convenient dry ice cooling is illustrated in Scheme 19 (55).


Scheme 19. Homologation of an alkylboronic ester with (dichloromethyl)lithium The one glaring deficiency in the chemistry at that point was the lack of stereocontrol, which was needed in order to make it a truly useful procedure. Any organic chemist is well aware of the use of α-pinene as the source of asymmetric control in the first truly successful enantioselective synthesis, that of (–)-2-butanol via hydroboration of cis-2-butene by Brown and Zweifel (57). Both enantiomers of α-pinene are commercially available. The diol that results from osmium tetroxide oxidation of α-pinene seemed a possibility, but a catalytic route would be needed in order to make it practical, and hydrogen peroxide as the oxidizer destroys pinanediol (42). Rahul Ray found the Van Rheenen amine oxide procedure (58, 59), and since he did not have the recommended N-methylmorpholine N-oxide immediately available, tried the trimethylamine N-oxide he did have (60, 61). When he tried the less expensive N-methylmorpholine N-oxide, the yield was not as high. One necessary precaution with the t-butyl alcohol solvent used was that the reflux be very gentle, because the higher temperature reached with a more vigorous reflux decreased the yields. Recent unpublished work in our laboratory with K. S. Hanes has indicated that acetone is a better solvent for the reaction and provides nearly quantitative yields. A study of the kinetics suggests the catalytic cycle outlined, in which the amine oxide converts 40 to the Os(VIII) ester, which adds to a second molecule of α-pinene to form the stable Os(VI) ester 41, which liberates 40 + pinanediol (42) on oxidative hydrolysis (Scheme 20). Also, it should be noted that bis(pinanediol) osmate 41 is a very stable intermediate that remains at the end of the reaction (62), and it may be possible to distill the diol without intervening workup and recover the osmium from the residue, but this investigation has not yet been completed, and 41 has not been isolated for proof of the oxidation state of the osmium.

Scheme 20. Oxidation of (+)-α-pinene to (1S,2S,3R,5S)-pinanediol Pinanediol (42) as chiral director was just a wild guess, and it proved far more stereoselective than we had expected. Diastereomeric ratios near 10:1 were 185 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


generally achievable (63, 64). α-Pinene was only available as impure enantiomers, but 42 can be recrystallized from heptane (65), and our original route to pure enantiomers (64) is obsolete. The problem of epimerization of pinanediol (αchloroalkyl)boronates quickly became obvious. At first, the best option was to get the product away from lithium chloride as soon as the reaction was complete. Alkyl migrations generally required several hours, most conveniently overnight, but aryl migrations were done within an hour. Best results for alkylated derivatives seemed to be obtained when a Grignard reagent was added to the reaction mixture without isolation of the (α-chloroalkyl)boronic ester intermediate. We chose to make the four stereoisomers of 3-phenyl-2-butanol, which had been previously fully characterized and the absolute configurations assigned by Cram (66, 67), as a demonstration of the power of the method. The synthesis of the diastereomeric pair derived from (1S,2S,3R,5S)-pinanediol phenylboronate (43), called “(+)-” or “(s)-pinanediol” in our earlier publications, is illustrated. The first reaction with LiCHCl2 produced (1S,2S,3R,5S)-pinanediol (S)-(α-chlorobenzyl)boronate (44), and alkylation in situ with methylmagnesium bromide yielded ~86% of (S)-(1-phenylethyl)boronic ester 45a with the diastereomer ratio (dr) estimated to be 98% (64). Further homologation and methylation in situ produced 46a, which was oxidized in the usual manner with alkaline hydrogen peroxide to (2S,3S)-3-phenyl-2-butanol (47a). The yield of 47a from 43 was 67% and the dr was 94:6. Hydrolysis of the (1S,2S,3R,5S)-pinanediol ester 45a to produce (S)-1-(phenylethyl)boronic acid (48) is contrathermodynamic. The destruction of the pinanediol with boron trichloride that was resorted to has been superseded by the du Pont two-phase transesterification method for water-soluble boronic acids (65) or the conversion of the boronic acid to a cesium trifluoroborate salt (68). Conversion of 48 to (1R,2R,3S,5R)-pinanediol (S)-1-(phenylethyl)boronate (45b) and on to 46b and to (2R,3S)-3-phenyl-2-butanol, dr 96:4, was routine (Scheme 21) (64).

Scheme 21. Preparation of two diastereomers of 3-phenyl-2-butanol 186 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Although the preparations of diastereomers 47a and 47b produced high drs, other substrates usually yielded drs in the 90:10 to 95:5 range. The problem of epimerization of (α-chloroalkyl)boronic esters by chloride exchange was an obvious contributing factor, and we undertook a kinetic investigation of the epimerization of 44 in THF, which occurs at a rate convenient for following by polarimetric measurements (69). The kinetics indicated that free chloride ion attacked 44 in the rate determining step of the major pathway. Lithium chloride is an ion tetramer in THF, and if the ion cluster dissociates to Li2Cl+ + Cl–, half-order dependence is expected. At the lower concentrations of LiCl, 0.075-0.25 M, the measurements best fit 0.62-order, but increased to 0.75-order when concentrations up to 0.45 M were included in a least squares plot. This was considered consistent with half-order plus a salt effect. Very small amounts of added water greatly increased the epimerization rate, and zinc chloride or mercuric chloride strongly inhibited epimerization (69). In my application for an NSF grant renewal, I suggested that addition of a Lewis acid such as zinc chloride might catalyze the rearrangement step as well as inhibit epimerization, but the referee ratings were too low to allow funding, the only time that NSF failed to renew funding for my boron chemistry. In the meantime, Matthew Sadhu had tried adding 0.5 mol of rigorously anhydrous zinc chloride to the reaction of LiCHCl2 with pinanediol (isobutyl)boronate (49), one of the few homologations that had provided poor yields (30%) previously. The results were immediately spectacular: dr 99.5:0.5, yield 89% for (α-chloroalkyl)boronic ester 51 (Scheme 22) (70, 71). Catalysis of the rearrangement of intermediate borate 50 and sequestering of the chloride byproduct as ZnCl42– had solved the problem.

Scheme 22. Zinc chloride catalyzed homologation of a pinanediol boronic ester

Not surprisingly, the NSF funded my revised proposal at a higher level than the first request. We were lucky to have chosen to begin with pinanediol alkylboronates and (dichloromethyl)lithium rather than pinanediol (dichloromethyl)boronate (52) and alkyllithium or Grignard reagents. The latter pairing produces intermediate 53, a diastereomer of 50, and poor stereoselection between diastereomers 54a and 54b follows, as illustrated in Scheme 23 (72). Zinc chloride altered the various 54a:54b ratios but did not make the two that were tested useful, and work with 52 was terminated. 187 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Scheme 23. Poor diastereoselection with pinanediol (dichloromethyl)boronate

At first, we were cautious about adding too much zinc chloride, because our kinetic study had suggested that there was a term in the rate law that included (ZnCl2)(ZnCl3–) at high concentrations, consistent with a plausible push/pull mechanism for chloride exchange (69). However, in many years of subsequent work, much of which has involved homologations in the presence of polar functional substituents, no example in which an excess amount of zinc chloride had a deleterious effect on the dr has ever been encountered (73). What has been encountered is an absolute requirement for an increased amount of zinc chloride when substituents that coordinate with it are present, and a need to work up reaction mixtures in such a way that the (α-chloroalkyl)boronic ester product is never in the same phase with water and chloride salts (74). Adding pentane to the THF phase and beginning the extraction with saturated ammonium chloride rather than plain water is effective. It seems likely that the increased epimerization rates in concentrated solutions may have been an artifact caused by the difficulty of keeping lithium and zinc chlorides strictly anhydrous. C2-Symmetric chiral directors make the two faces of the boron atom identical and thus produce the same intermediate borate anion regardless of whether the dichloromethyl group is added to the boronic ester or an organometallic reagent is added to the (dichloromethyl)boronic ester. Our first example was (S,S)-diisopropylethanediol (DIPED), made initially via straightforward homologation of (1R,2R,3S,5R)-pinanediol isopropylboronate and appropriate subsequent steps (75), later in a synthesis beginning from tartaric acid (76). DIPED boronic esters produced higher drs than pinanediol boronic esters. How much higher was not realized until Pran Tripathy laboriously made (S,S)-DIPED (1S)-(1-chlorobutyl)boronate (55), the minor diastereomer (

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