Applications of pentafluorophenyl boron reagents in the synthesis of heterocyclic and aromatic compounds.

Volume 50 Number 10 7 February 2014 Pages 1149–1272

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FEATURE ARTICLE Rebecca L. Melen Applications of pentafluorophenyl boron reagents in the synthesis of heterocyclic and aromatic compounds

Published on 22 November 2013. Downloaded by Heinrich Heine University of Duesseldorf on 02/01/2014 17:58:11.

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Applications of pentafluorophenyl boron reagents in the synthesis of heterocyclic and aromatic compounds Rebecca L. Melen Recently, main group reagents have attracted a lot of attention in bond-forming reactions in organic synthesis. This article highlights the use of pentafluorophenyl substituted boron reagents in their reactions with CQC and CRC p-bonds for the synthesis of heterocyclic and aromatic compounds.

Received 18th October 2013, Accepted 21st November 2013 DOI: 10.1039/c3cc48036d

These cyclisation reactions fall into four general classes although there is some overlap between classes and often combinations of these different types of reactivity are observed in the formation of the final heterocyclic product: (i) 1,2- (and 1,4-) additions of nucleophile and Lewis-acidic boron centre, (ii) 1,1-carboboration, (iii) carbocation rearrangements and (iv) cycloaddition chemistry. In addition, the prospect of using such boron reagents catalytically in the synthesis of aromatic compounds such as

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oxazoles and dibenzopentalene derivatives is emphasised.

1. Introduction Bond-forming reactions using main group elements have attracted a lot of interest in recent years and the use of main group reagents as reactants in the development of novel compounds has become increasingly important.1 In particular Lewis acidic organoboranes have been widely used in synthetic Department of Chemistry, 80 St. George Street, Toronto, Ontario M5S 3H6, Canada. E-mail: [email protected]

Dr Rebecca Melen was born in Nottingham (UK) in 1985. She undertook her Bachelors and Masters degrees in Cambridge (2004–2008, Magdalene College) and, having won a University Scholarship, she became a PhD student in Prof. Dominic Wright’s group working on main group metal mediated dehydrocoupling reactions. She subsequently moved to Toronto, Canada as a postdoctoral fellow with Prof. Rebecca L. Melen Douglas Stephan investigating novel synthetic routes to, and reactivity of, Frustrated Lewis Pairs. She gained the RSC Dalton Young Researcher Award (2013) and was recently awarded a Humboldt Fellowship to study at the University of Heidelberg, Germany.

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organic chemistry both as reagents and as catalysts.2 The incorporation of electron-withdrawing C6F5 groups increase the Lewis acidity at boron and one of the most studied examples is the strongly Lewis acidic borane tris(pentafluorophenyl)borane [B(C6F5)3].3 This was first reported4 in 1963 and was shown to be between BF3 and BCl3 in terms of its Lewis acidity.5,6 However, several properties of B(C6F5)3 give it significant advantages over boron trihalides and allow a wealth of different reactivity patterns. For example, along with its high Lewis acidity, the presence of three pentafluorophenyl groups can lead to increased stability and chemical selectivity.6 Since its discovery it has been used in both stoichiometric and catalytic reactions across a range of organic and organometallic transformations.7 Applications include its use as a Lewis acid activator in homogeneous Ziegler–Natta chemistry,8 in organic chemistry (e.g. in hydrosilylation,9 hydroalumination10 or hydrogermylation11 reactions)12 and as a Lewis acid in Frustrated Lewis Pair (FLP) Chemistry.6,13 The latter supports the simultaneous presence of a Lewis acid and base without adduct formation and constitutes a major advance in the area of main group synthetic reagents. The first example was reported in 2006 by Stephan et al. who prepared the zwitterionic

Scheme 1

The first example of an FLP capable of reversibly activating H2.

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salt [(C6H2Me3)2PH(C6F4)BH(C6F5)2] which is a rare example of a main group molecule that contains both protic and hydridic hydrogen fragments and was shown to reversibly activate H2 (Scheme 1).14,15 In addition to the reversible activation of H2, these FLPs were shown to have applications in hydrogenation catalysis, in which they have been shown to hydrogenate an array of substrates. The subsequent evolution of FLP chemistry has resulted in an extended range of FLP reactions. The increasing interest in this area is reflected in several comprehensive reviews in recent years.13 The diverse range of reactivity of FLPs suggests broader applications of FLPs across synthetic organic chemistry. In this review the synthesis of heterocycles and aromatics from the boron-mediated activation of C–C p bonds to nucleophilic attack from amines, phosphines, thiols, amides and/or other C–C p bonds will be explored. In these reactions the Lewis acidic boron reagent and Lewis base (nucleophile) undergo a 1,2-(or 1,4-) addition across the p-bond. In many cases we shall see that these nucleophile and electrophile combinations are FLPs. In addition, in several cases additional reactivity is often observed, e.g. reactions of electrophilic boron reagents such as those bearing C6F5 groups may undergo C6F5 group migrations or 1,1-carboboration reactions.16 This has become increasingly useful in the preparation of alkenylboranes and also more recently in the (often ‘one-pot’) synthesis of functionalised heterocycles. Finally, the cycloaddition chemistry of C6F5-functionalised boron azides and related systems will be discussed which is an emerging area in boron-mediated heterocyclic synthesis.

2. 1,2- and 1,4-additions to C–C p-bonds 1,2-Addition reactions of intramolecular and intermolecular (F)LPs to p-bonds have been used widely to synthesise zwitterionic heterocycles. In these reactions the nucleophilic centre can be a wide variety of atoms including hydrogen (hydride), carbon, nitrogen, oxygen, phosphorus or sulphur. The 1,2-addition of nucleophile–boron combinations to alkenes and alkynes could take place by two possible mechanisms: (i) concerted addition, or (ii) initial activation of the p-bond by boron followed by concerted 1,2-addition. Whilst many transition metals are able to interact with alkenes in a synergic manner through (M - L) bonding and (M ’ L) back-bonding this is not possible for boron. As a result, the corresponding boron–alkene or boron– alkyne adducts have not been isolated although van der Waals interactions have been observed.17 The nature of these two interactions are significantly different. In the former case formal donation of p-electron density to B is likely to lead to C–C bond lengthening and a distortion of the alkene (alkyne) geometry and a shortening of the C–C centroid B distance. In the latter case, no significant change in geometry is expected and the alkene B distance is expected to be close to the sum of the van der Waals’ radii. Previous computational studies have shown that an ‘‘encounter complex’’ forms between B(C6F5)3, PtBu3 and ethylene. In the transition state the alkene interacts with both components of the FLP in an antarafacial fashion.18 Calculations showed that, although the mechanism

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is concerted, it is asynchronous with C–B bond formation occurring slightly before P–C bond formation.18 In other calculations, the reaction of the same FLP–ethylene combination was found to occur via an initial association of ethylene with B(C6F5)3 followed by the concerted 1,2-addition of the phosphine and borane.19 However, when studying the reactions of tBu2P(CH2)3CHQCH2 with B(C6F5)3 a concerted addition process occurred with simultaneous C–B and C–P bond formation.19 The inter- and intra-molecular addition reactions of Lewis pairs to C–C p-bonds are described below. 2.1

Intramolecular addition reactions of Lewis pairs

The formation of heterocycles from the 1,2-addition of intramolecular Lewis pairs (in which both the Lewis acid and base are contained in the same molecule) proceeds through the initial activation of the alkyne by the boron centre followed by nucleophilic attack of the Lewis base which is held in close proximity to the activated alkyne. Indeed, the regioselectivity of the reactions are generally consistent with boron activation of the alkyne followed by attack at the carbon atom better able to stabilise a positive charge.20 For example, the intramolecular FLP (C6F5)2P–CH(Et)–B(C6F5)2 (1) was found to undergo a regioselective 1,2-addition to both alkenes (H2CQCH2) and alkynes (nPrCRCH, p-tol-CRCH) to give zwitterionic P/B-containing five-membered heterocycles with the phosphorus atom adding to the internal carbon atom of the acetylene and boron adding to the terminal carbon atom of the acetylene (Scheme 2).21,22 Equivalent reactivity was also observed with the structurally similar FLP (C6F5)2P–C[QC(H)Me]–B(C6F5)2 (2) with 1-pentyne and phenylacetylene (PhCRCH).23 Similarly, the FLP (C6F5)2P–CH(Me)–CH2–B(C6F5)2 (3) also underwent 1,2-addition to p-tol-CRCH (Scheme 2).22 In a similar fashion, the intramolecular FLP Mes2PCH2CH2B(C6F5)2 (4) was found to form new zwitterionic heterocycles when reacted with alkenes. When 4 was reacted with ethyl vinyl ether then the reaction afforded the zwitterionic six-membered heterocyclic product in high yield in a highly regioselective reaction (Scheme 3).24 4 was also found to add to norbornene under

Scheme 2

1,2-B/P additions affording zwitterionic heterocycles.

Scheme 3

Reactions of 4 with alkenes.


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ambient conditions to give a single product in >70% yield.24 Although several possible addition products are conceivable, the one isolated from the reaction was the exo-2,3-adduct (Scheme 3). The identification of this product indicated that the reaction is taking place under kinetic control. Computational studies suggest that the reaction takes place by an asynchronous but concerted 1,2-addition of the FLP to the CQC bond in norbornene (in the transition state the B–C bond is formed to a greater extent than the P–C bond).24 As well as P/B FLP additions to alkynes, S/B FLP cyclisations are also known.25,26 This has been exemplified by the reactivity of the sulfur–boron compound, PhSCH2B(C6F5)2 (5). Compound 5 was found to exist as a dimer in the solid state (by X-ray crystallography) and in solution at low temperatures (by NMR spectroscopy).26 At room temperature it was found to be in equilibrium with its monomeric FLP form which was able to undergo 1,2-synaddition with the alkynes EtCRCEt, PhCRCPh, HCRCPh, HCRCnBu and PhCRCnBu to afford novel zwitterionic boron– sulfur heterocyclopentene species (PhSCH2B(C6F5)2)(R 0 CQCR) (6, Scheme 4).26 Reactions of intramolecular FLPs with conjugated p-systems have also been explored. These substrates potentially allow a variety of different products to be formed depending upon the selectivity of the reaction. This, for example, could include selectivity for one p-bond over another or it could include selectivity between 1,2-addition and 1,4-addition in conjugated alkynes and alkenes. Reaction of the FLP 4 with ynones can afford either 6- or 8-membered rings depending upon the ynone starting material.27 If it is not possible to enolise the

Scheme 4

1,2-Addition reactions of 5 with alkynes.

Scheme 5

1,2- and 1,4-additions to ynones.


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Scheme 6

Synthesis of a cyclic cumulene.

ynone at R2 (Scheme 5) then the product obtained in the reaction is the 8-membered ring (7) containing a cyclic allene formed from the 1,4-addition of the FLP to the ynone.27 In the case of 1-phenylbut-2-yn-1-one this zwitterionic 8-membered cyclic allene (7d) initially formed from the 1,4-addition was observed at 40 1C but readily converted to the structurally characterised 6-membered product (8) after heating under reflux in CH2Cl2. This product can be viewed as the net 1,2-addition product of the FLP to the alkyne in the ynone.27 A different product was also observed when the substituent at R2 was a methyl group. In this instance it is assumed that initially the 8-membered product is formed from the 1,4-addition of the FLP to the ynone which subsequently undergoes a tautomerisation reaction to afford the final product (9, Scheme 5).27 The intramolecular FLP 4 (Scheme 6) was also found to undergo 1,4-addition (as opposed to 1,2-addition) when reacted with a conjugated diyne (4,6-decadiyne) to afford a novel eightmembered heterocycle (10) which was found structurally to be a cyclic cumulene containing a 1,2,3-butatriene sub-unit.28 Recent work has also looked at the reactivity of FLPs with enynes. Reaction of 4 with 2-methyl-1,3-butenyne afforded the eight-membered heterocyclic allene (11) as the major product via the 1,4-addition of the FLP to the enyne (Scheme 7).28 If the similar FLP (3) was reacted with 2-methyl-1,3-butenyne then a different outcome was observed in which the FLP added in a 1,2-fashion to the alkyne giving a 6-membered zwitterionic heterocycle (12, Scheme 7).22 The regioselectivity of the reaction is consistent with boron activation of the CRC bond followed by nucleophilic attack at the internal carbon atom with is better able to stabilise the build-up of positive charge during the reaction. Clearly, the selectivity for 1,2- versus 1,4-addition is important in these reactions and may be sensitive to the

Scheme 7

1,2- versus 1,4-addition with enynes.

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Scheme 9 Scheme 8

Synthesis of 20.

Synthesis of macrocycles.

reaction conditions and FLP used. The more nucleophilic and bulky phosphine present in 4 favours a rapid 1,4-addition, in preference to 1,2-addition, leading to the less thermodynamically stable eight-membered heterocyclic allene. Macrocyclic compounds can also be synthesised when 1,2-addition to the same C–C p bond is not possible, e.g. where structural rigidity of the FLP backbone precludes intramolecular addition. In such cases 1,2-addition across the p-bond still takes place although now the addition is not from within the same FLP but between two different FLPs. For example, the reaction of the intramolecular FLP Mes2PC6F4B(C6F5)2 (13) with PhCRCH generates [(H)CQC(Ph)Mes2PC6F4B(C6F5)2]2 (14, Scheme 8).29 The analogous alkynyl phosphonium borates also afford macrocycles when reacted with alkenes or alkynes; reactions of the alkyne-bridged FLP R2P–CRC–B(C6F5)2 [R = Mes (15), R = tBu (16)] with PhCRCH or nBuC(H)QCH2 led to the macrocyclic products {[Mes2PCRCB(C6F5)2](CHQCPh)}2 (17) and {[tBu2PCR CB(C6F5)2](nBuCHCH2)}2 (18) respectively (Scheme 8).30 Notably these alkynyl-bridged FLPs do not appear to act as alkyne sources themselves presumably due to steric crowding of the alkyne group by R2P and B(C6F5)2 groups. If however, only one equivalent of alkene is used then interesting reactivity is observed. The reaction of two equivalents of the alkyne-bridged FLP 16 with 1-hexene afforded [tBu2P–CRC–B(C6F5)2]2(BuCH2CH) (19, Scheme 9), which can be viewed as a possible intermediate en route to forming the macrocycle. However since the FLP is in excess then the reaction of 19 with a second equivalent of alkene is not possible.31 Instead, when 19 is heated at 80 1C for 10 h a new compound is formed which was found to be the di-zwitterion [(tBu2P)C6F4BF(C6F5)C4B(C6F5)2(BuCHCH2)(PtBu2)] (20).31 This compound contains two separate 5-membered phosphonium borate rings linked by a four carbon butatriene unit. The transformation from 19 to 20 is clearly complex, occurring via a series of reaction steps involving intramolecular attack, rearrangements and a nucleophilic aromatic substitution

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reaction at the ortho position of one of the C6F5 rings with transfer of the fluoride anion to the boron atom (Scheme 9).31 An interesting example of a cyclisation reaction when the Lewis acid, Lewis base and alkyne are within the same molecule, is in the synthesis of zwitterionic ladder p-conjugated materials.32

2.2

Intermolecular additions of Lewis pairs

Additions of intermolecular FLPs can also afford heterocycles. Here the chemistry typically affords selectively the 1,2-addition product. The components of these reactions come in three different classes: (i) when the Lewis base and the p-bond are within the same molecule or (ii) when the Lewis acid and the p-bond are within the same molecule or (iii) when all components are discrete from one another and are added in the same pot. These three classes shall be considered below. Heterocyclic compounds have been synthesised by activation of carbon p-bonds by the Lewis acid B(C6F5)3 towards intramolecular attack by a Lewis base. The B(C6F5)3-promoted addition cyclisation of alkenes and alkynes to afford N-containing heterocycles (including indoles) has been reported by Erker and Stephan et al.33 The intramolecular cyclisation reactions of the alkyne containing compounds o-(pentynyl)-N,N-dimethyl toluidine (21a) and o-(phenylethynyl)-N,N-dimethyl toluidine (21b) or the alkene compound o-(2-propenyl)-N,N-dimethylaniline (22) with B(C6F5)3 led to indole derivatives C6H3Me(NMe2)(C(B(C6F5)3)CR) [R = nPr (23a), Ph (23b)] and C6H4(NMe2)(CH2CH(CH2B(C6F5)3)) (24) respectively (Scheme 10).33 In this reaction the Lewis acidic B(C6F5)3 activates the C–C p-bond to intramolecular nucleophilic attack resulting in a net 1,2-addition of the amine and borane to the p-bond. Notably, the B(C6F5)3 appears to react selectively with the p-bond rather than forming a donor–acceptor adduct with the mildly-protected tertiary amine. Moreover the reaction appears to work even when the nitrogen lone pair is conjugated to an aromatic system and is not, therefore, as strongly nucleophilic. These reactions occur via a 5-endo-dig cyclisation for alkynes whereas with the alkene substrate this is a 5-exo-trig


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Scheme 12 5-Alkylidene-4,5-dihydrooxazolium borate products from the reactions of propargyl amides with B(C6F5)3.

Scheme 10

Intramolecular reaction of amines with olefins using B(C6F5)3.

cyclisation (Scheme 10).33 Similarly, reaction of B(C6F5)3 with o-(3-butenyl)-N,N-dimethylaniline (25) or o-(2-propenyl)-N,Ndimethylbenzylamine (26) led to 6-exo-trig cyclisation reactions yielding the 6-membered heterocyclic ammonium borate isomers 27 and 28 respectively (Scheme 10).33 Similar results were observed in the activation of CRC p-bonds by B(C6F5)3 to nucleophilic attack by Lewis-basic amide oxygen atoms. The generation of aromatic oxazoles from propargyl amides using transition metal catalysts34 (Scheme 11) is very important in the synthesis of ligands, natural products, drug and pharmaceutical molecules.35,36 Yet the only metal-free synthesis, until recently, was limited to harshly basic conditions.37,38 Previously soft Lewis acidic metals (e.g. Ag, Au), which activate the CRC p-bond to nucleophilic attack from the amide oxygen, have been used to catalyse this cyclisation.34 Therefore it is perhaps not surprising that the Lewis acidic B(C6F5)3 can effect this same transformation given its ability to activate alkynes described above.39 The cyclisation of N-substituted propargyl amides using B(C6F5)3 also occurs via the 1,2-addition of the amide and B(C6F5)3 to the alkyne (Scheme 12).39 Whilst these reactions proceed smoothly to generate 5-membered C/N/O heterocycles re-aromatisation to generate the final oxazole ring does not

Scheme 11 Synthesis of oxazoles via methylene-oxazolines from the transition metal catalysed cyclisation reactions of propargyl amides.


occur. Nevertheless, several intermediates have been isolated which provide considerable insight into the reaction sequence. In this reaction the first species identified (by both X-ray crystallography and NMR spectroscopy) was the adduct between the carbonyl oxygen atom and the Lewis acidic boron atom which forms at ambient temperature. The adduct formation between highly electrophilic B(C6F5)3 and carbonyl Lewis bases has been extensively studied in solution and in the solid state by Piers.3,40,41 Studies showed that the amide donor N,N-diisopropylbenzamide was a much stronger Lewis base in the coordination of B(C6F5)3 than aldehydes (benzaldehyde) and ketones (acetophenone).40 Subsequent dissociation of B(C6F5)3 from the propargyl amide, by heating the reaction to 45 1C, leads to activation of the CRC p-bond, resulting in a 5-exo-oxo-boration cyclisation reaction affording the dihydrooxazolium borate products 29 (Scheme 12).39 The cyclisation reactions were found to be strongly dependent upon the functional group on the aromatic ring in the propargyl amide; the p-NO2 derivative showed the fastest reaction whereas the p-OMe derivative was the slowest. This implied that the rate determining step was the dissociation of B(C6F5)3 from the amideoxygen atom39 which can be expected due to strong adduct formation.40 The inability of 29 to aromatise typically inhibits generation of the oxazole ring. However, if the substituent at R2 (Scheme 13) is a proton then at elevated temperatures (45 1C) proton migration of the N–H proton to the vinyl-fragment occurs, releasing B(C6F5)3. Finally, aromatisation by tautomerisation generates the oxazole product (30). The N-donor nitrogen atom of the oxazole ring is a sufficiently strong donor to form an adduct with the B(C6F5)3 Lewis acid in the final product (Scheme 13).39 The migration of B(C6F5)3 in this reaction suggested that this reaction may become catalytic if B(C6F5)3 could be liberated from the resultant oxazole. In most cases the N - B dative bond in the product was found to be too strong to allow dissociation of B(C6F5)3.39 However, if the steric bulk of the substituent is increased (e.g. R = adamantyl), then the dative N - B bond is weakened, the B(C6F5)3 becomes labile and the reaction becomes catalytic in B(C6F5)3. When R = Ad then the oxazole could be formed in 83% yield after 10 days at 100 1C using 10 mol% B(C6F5)3.39

Scheme 13

Synthesis of oxazoles using B(C6F5)3.

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Scheme 14

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P/B 1,2-addition to alkenes.

In a similar fashion, activation of alkenes bearing sterically encumbered phosphines by B(C6F5)3 can occur. Thus R2P(CH2)3CHQCH2 (R = Mes 31a, tBu 31b) undergo a 1,2-addition by a 5-exo-trig cyclisation reaction in the presence of B(C6F5)3 to afford the phosphonium borate products, [R2PCH(C3H6)CH2B(C6F5)3] (32a,b, Scheme 14).42 This reaction is proposed to proceed via initial activation of the CQC double bond to electrophilic attack by B(C6F5)3 (such activation has been observed in BF3–alkene complexes reported by Herrebout previously43 and DFT calculations have suggested ethylene–borane interactions44) although no interaction was observed in this case between 1-hexene and B(C6F5)3 by variable temperature NMR spectroscopy. Finally, it should be noted that the two component reaction between (aryl)bis(enynyl)phosphanes and HB(C6F5)2 give five-membered heterocyclic zwitterionic borata–diene compounds. This reaction occurs by the regioselective hydroboration of the alkene of one of the enyne groups followed by intramolecular attack on the phosphine onto the newly formed boryldiene unit.45 In the next class of reactions, the reactivity of systems comprising both the Lewis acid and the p-bond within the same molecule is examined. For example, 1,2-additions were also observed when HB(C6F5)2 was reacted with either 1,3-butadiene or 1,4-pentadiene in the presence of a phosphine.17 This reaction proceeds with initial hydroboration of one of the alkenes using HB(C6F5)2 followed by 1,2-addition of the newly generated alkyl borane and phosphine across the remaining CQC affording 5-membered (33) or 6-membered (34) zwitterionic borates (Scheme 15).17 The Lewis base was found to add to the internal carbon atom of the olefin. Calculations and 2D heteronuclear NOE techniques have showed that the tethered borane initially interacts with the olefin in the form of a van der Waals olefin– borane complex before attack by the Lewis base.17 The reaction of the alkoxyborane (C6F5)2B[OC(CF3)2CH2C(H)QCH2] (35) with a variety of C-, N- and P-based nucleophiles afforded a range of 5- or 6-membered cyclic borates via 1,2-addition of the boron atom and the nucleophile to the olefin (Scheme 16).46 This reaction was found to be initiated by

Scheme 15 Hydroboration followed by 1,2-addition.

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Scheme 16

Synthesis of 5- and 6-membered zwitterionic cyclic borates.

a weak intramolecular van der Waals interaction between boron and an olefin fragments in the alkoxyborane. Subsequent reaction with tBu3P or Me3P afforded the zwitterionic 6-membered cyclic borates (C6F5)2B(OC(CF3)2CH2CHCH2)(PR3) (R = tBu 36a, Me 36b). 36a and 36b are formed from the nucleophilic attack on the internal carbon of the olefin whereas treatment with more hindered amine nucleophiles [lutidine or tetramethylpiperidine (TMPH)] yield the zwitterionic 5-membered cyclic borates (C6F5)2B(OC(CF3)2CH2CHCH2)(NR2) (NR2 = TMPH 37a, 2,6-lutidine 37b) formed from the nucleophilic attack at the terminal carbon of the olefin.46 Carbon-based nucleophiles also showed reactivity at the internal olefin carbon yielding zwitterionic 6-membered cyclic borates 38a–b and 39a–b. In the case of the pyrroles as nucleophiles addition occurs at the b-carbon affording 38a and 38b, and in d6-DMSO a 2,1-proton migration from carbon to nitrogen occurs affording compounds 40a and 40b respectively.46 1,2-Addition of H and a Lewis acidic-B to the alkyne in alkoxyborane 35 is also possible. When 35 was reacted under an H2 atmosphere with 1,2,2,6,6-pentamethylpiperidine (PMP) and catalytic B(C6F5)3 (5 mol%), the cyclic borate [PMPH][(C6F5)2B(OC(CF3)2CH2CH2CH2)] 41 is formed as an ammonium salt. In this reaction the combination of PMP and B(C6F5)3 acts as an FLP activating H2 generating the intermediate [PMPH][HB(C6F5)3] which then delivers H to the alkoxyborane affording the product (Scheme 17).46 In the next section reactions which combine the Lewis acid, Lewis base and the alkyne substrate in one pot are considered. Whilst these reactions are well known, the absence of intramolecular combinations of Lewis-acid–alkyne or Lewis-base– alkyne do not typically lead to heterocycle generation but simple addition across the unsaturated CRC bond.20,47 Indeed heterocycle generation under these circumstances tends to arise only out of unexpected rearrangements of acyclic


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Scheme 17

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1,2-Addition of H/B to an alkene.

Scheme 19

Scheme 18

1,2-Addition of pyrrole–borane combinations.

1,2-addition products. For example, the 1,2-addition of pyrrole– borane combinations to alkynes has also been achieved in which the pyrrole adds via its b-carbon atom generating the 1,2-addition intermediate 42 (Scheme 18). This intermediate undergoes subsequent rearrangement reactions via a 1,2-C6F5 group migration followed by attack of the newly formed enamine onto the boron atom to afford bicyclic products 43 (Scheme 18).48 Similar reactions of dimethylaminofulvene (44) with RB(C6F5)2 and an alkyne also results in the 1,2-addition of the boron reagent and the fulvene (also through the b-carbon atom) affording the intermediate 45. This then subsequently undergoes a 1,5-hydride shift generating an electrophilic conjugated p-system 46 [both of these intermediates, (45 and 46) were spectroscopically characterised].49 Subsequent migration of the R group from boron to the adjacent carbon centre, which is the end of the conjugated iminium functionality, generates the dienamine 47.49 Attack of the dienamine at the Lewis acidic boron site forms the five-membered boron containing heterocycle 48 which was characterised by NMR spectroscopy.49 Finally 48 then isomerises to yield the heterobicyclic [3.3.0]borabicyclo-octane system 49 (Scheme 19). In this reaction sequence the combination of the boron compounds and the aminofulvene act as an FLP with the aminofulvene acting as a carbon-based Lewis base allowing the generation of new heterocyclic systems with the formation of new C–C bonds.49

1,2-Addition of RB(C6F5)2 and a fulvene to an alkyne.

boron reagents such as B(C6F5)3 with substrates containing more than one alkyne (diyne) often proceed via 1,1-carboboration reactions.16 1,1-Carboboration has been reviewed recently by Erker and will not be discussed in detail here. However, it is worth noting that a few of these reactions generate heterocyclic compounds. Group 14 diacetylide compounds have been reacted with boron reagents to afford heterocyclic, metal containing systems (Scheme 20) via carboboration reactions.52 In a similar manner phospholes could also be synthesised from a sequence of 1,1-carboboration reactions of arylbis(alkynyl)phosphanes with B(C6F5)3 after 1–2 h in toluene at 70 1C (Scheme 20).53 3.1

Cyclisation reactions involving 1,1-carboboration

Several reactions of intermolecular FLPs with diynes often proceed in a stepwise manner with an initial 1,1-carboboration reaction to generate an alkenyl-borane followed by a second 1,2-addition reaction. For example, when the non-conjugated diyne 1,6-heptadiyne was reacted with the intermolecular P(o-tolyl)3/B(C6F5)3 Lewis pair then an eight membered

3. 1,1-Carboboration reactions and rearrangements 1,1-Carboboration reactions are a useful tool in the synthesis of boron functionalised alkenes.50,51 The reactions of Lewis acidic


Scheme 20 Heterocyclic group 14 metallo-containing systems (top) and phospholes (bottom).

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Scheme 21 FLP additions to the non-conjugated diynes.

heterocycle containing two endocyclic alkenyl groups bound by a borate anion (50) resulted.54 This product was formed from an initial 1,1-carboboration at one of the alkyne functionalities succeeded by ring closure brought about by the concerted 1,2-addition of the phosphine and the alkenyl-borane across the remaining alkyne (Scheme 21).54 This should be contrasted to the reactions of 1,7-octadiyne with the intermolecular PR3/ B(C6F5)3 Lewis pair {PR3 = P(o-tolyl)3, PPh2[C6H3(CF3)2]} which directly undergoes addition of the phosphine and borane across the two alkynes concurrent with C–C coupling generating a cyclohexane derivative (51, Scheme 21).54 Similar reactivity was observed when FLPs were reacted with arene-diynes in the presence of weaker Lewis bases. Analogous to the 1,6-heptadiyne case described above, when 1,2-diethynylbenzene was reacted with P(C6F5)3/B(C6F5)3 a 1,1-carboboration reaction takes place followed by a 1,2-addition of the phosphine and the newly generated alkenyl-borane across the second alkyne generating a six-membered zwitterionic product (52, Scheme 22).55 Likewise, when the bis-alkyne 9,9-dipropargylfluorene was reacted with the Lewis pair P(o-tolyl)3 and B(C6F5)3 a zwitterionic eightmembered heterocycle (53) was generated from the same sequence of 1,1-carboboration followed by FLP 1,2-addition to the remaining alkyne (Scheme 22).55 In the stepwise addition of B(C6F5)3/tBu3P to acetylenes, 1,2-addition was not observed, but rather a novel

Scheme 22

FLP additions to the arene-diynes.

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Scheme 23 Synthesis of 5-membered boracyclic compounds from an electrophilic aromatic substitution reaction.

boracyclic compound 54 resulted. 1,1-Carboboration of the alkynes diphenylacetylene and phenylacetylene using B(C6F5)3 yielded phenyl-substituted alkenylboranes which, when reacted with tBu3P for 1 d at 80 1C, afforded 5-membered boracyclic compounds from an electrophilic aromatic substitution reaction (Scheme 23).56

3.2

Synthesis of boroles

Dicyclopropylacetylene starting materials 55 have been used to afford five-membered 2,3-dihydroborole heterocyclic compounds (56, 57) when reacted with B(C6F5)3. This reaction takes place via dienylborane intermediates (58, 59) formed from a 1,1-carboboration reaction.57 Cyclisation by a subsequent 1,1-carboboration reaction of the terminal alkene in the dienylborane afforded the dihydroborole products 56 and 57 (Scheme 24). In 56 the CH3 and C6F5 groups were found to be trans to each other.57 The observation of the dienylborane intermediate inferred the opening of one of the cyclopropyl groups in the starting material generating an enyne.57 Indeed, it was also found that by taking a conjugated enyne (60) with B(C6F5)3 then a similar 2,3-dihydroborole 61 was generated from two successive 1,1-carboboration reactions however, unlike in 56, the product in this case was found to be the isomer in which the CH3 and C6F5 groups lie cis to each other (Scheme 24).57 These are textbook examples of 1,1-carboboration as there are no obvious nucleophiles present to complicate matters through 1,2-addition.

Scheme 24

Synthesis of boroles via 1,1-carboboration.


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3.3 Applications in the synthesis of complex aromatic compounds C/B addition across alkynes are also known to produce complex aromatic compounds by 1,1-carboboration or carbocation rearrangement mechanisms.58–60,62 When the arene-diyne 1,2bis[(dimesitylphosphino)ethynyl]benzene 62, which bears more sterically encumbered phosphines, was reacted with B(C6F5)3 then a benzopentafulvene derivative 63 resulted from the addition of boron and carbon across the CRC triple bond.60 Again, the activation of the p-bond by B(C6F5)3 is a fundamental initial step in the reaction which then promotes C–C coupling between the two alkynes. This can then undergo a series of aryl migrations to generate the benzopentafulvene via (i) a migration of a C6F5 group from boron to phosphorus synchronised with (ii) the migration of a mesityl group from phosphorus to the exocyclic vinyl carbocation (Scheme 25).60 Compounds with extended p systems have attracted considerable interest owing to their interesting optical properties.61 B(C6F5)3 has been used to activate alkynes in arene-diynes for the synthesis of naphthalene derivatives.62 The diynes, 1,2-bis(trimethylsilylethynyl)benzene 64 and 1,2-bis(trimethylsilylethynyl)-3,4-dimethylbenzene 65 were heated under reflux in toluene with RB(C6F5)2 (Scheme 26). The products of these reaction were found to be the tetrasubstituted naphthalene derivatives 66 and 67 formed by a series of 1,1-carboboration reactions. The intermediates in these reactions were found spectroscopically to be the product of a 1,1-carboboration reaction of one of the alkynes. Reactions with the unsymmetrical arene-diyne 68 with B(C6F5)3 afforded an analogous reaction product (Scheme 26).62 The initial 1,1-carboboration reaction takes place almost exclusively on the

Scheme 25

Synthesis of benzopentafulvene derivative.

Scheme 26

Synthesis of naphthalene derivatives using B(C6F5)3.


Scheme 27 Synthesis of a dibenzopentalene compound from 1,2bis(phenylethynyl)-tetrafluorobenzene with B(C6F5)3.

alkyne bearing the trimethysilyl functional group with a mixture of E- to Z-isomers in a 15 : 1 ratio. Heating this intermediate to 50 1C for ca. 24 h resulted in the naphthalene product 69. In these reactions a three-coordinate arylborane species was produced and these were shown to be used in subsequent palladium catalysed cross-coupling reactions.62 Dibenzopentalene derivatives have previously been synthesised from the cyclisation reactions of arene-diynes using Lewis acidic transition metals such as gold.63 However, Erker recently reported similar transformations using Lewis acidic B(C6F5)3. The reaction of 1,2-bis(phenylethynyl)-tetrafluorobenzene 70 with B(C6F5)3 afforded the corresponding dibenzopentalene compound (71, Scheme 27).59 The reactions of the similar bis(phenylethynyl)benzene derivatives 72a and 72b with B(C6F5)3 however yielded several different products all of which were structurally characterised.59 Importantly, compound 73 (Scheme 28) was the expected dibenzopentalene compound formed from the isomerisation of the arene-diyne starting material, whereas 74 (Scheme 29), although it contains dibenzopentalene framework, has had a C6F5 group incorporated. In this process one alkyne is activated to nucleophilic attack by p-coordination of B(C6F5)3. The resultant 5-endo-dig cyclisation reaction afforded the carbocation intermediate 75. Intramolecular electrophilic aromatic substitution at the ortho position of the phenyl ring onto the reactive carbocation centre then affords tetra-cyclic 76.59 Rearomatisation generates the dibenzopentalene compound 73 via proton transfer and release

Scheme 28

Mechanism for the reactions of arene-diynes with B(C6F5)3.

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4. Boron azides in click chemistry

Scheme 29

Mechanism for the reactions of arene-diynes with B(C6F5)3.

of B(C6F5)3 (Scheme 28) or anionic borylated compound 77 by deprotonation (Scheme 29). 77 was prepared separately by reacting the starting material arene-diyne with B(C6F5)3 and TMP.59 In this instance the TMP deprotonates intermediate 76 affording [77][TMPH]. In the case that B(C6F5)3 is regenerated (Scheme 28) then this isomerisation reaction has the potential to be catalytic. If however, instead of deprotonation of 76, a C6F5 group migrates from B(C6F5)3 then intermediate 78 is formed which can eliminate HB(C6F5)2 generating the other product of the reaction, 74 (Scheme 29).59 In this case there is no possibility for a catalytic reaction as the B(C6F5)3 is consumed in the reaction. Evidence for the release of HB(C6F5)2 was found from the reaction of B(C6F5)3 with the arene-diyne 72c.59 This reaction proceeds in a similar way to that described above for the phenyl substituted arene-diyne in which a C6F5 group migrates from B(C6F5)3 affording 79 (Scheme 30) an analogue of 78. This can then eliminate HB(C6F5)2 generating 80 which then undergoes a 1,4-hydoboration reaction with the previously eliminated HB(C6F5)2 resulting in the isolated product 81 (Scheme 30).59

Scheme 30

Synthesis of 81.

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Previously we have seen that highly electrophilic boron reagents have been used in cyclisation reactions via 1,2-addition or rearrangement mechanisms. Here the new and emerging area of boron azide cycloaddition chemistry will be discussed. Click chemistry is a powerful synthetic reaction in organic chemistry allowing the efficient assembly of complex organic compounds in high yields with relatively few by-products and has widespread applications.64,65 The azide–alkyne Huisgen cycloaddition which selectively generates 1,2,3-triazoles is of particular importance since the triazole moiety is present in many drug molecules.66 Only a few boron azide compounds (R2BN3; R = alkyl or aryl) have been reported,67,68 but include (C6F5)2BN3 which has been found to be dimeric in the solid state.68 Nevertheless, the chemistry of boron azides and, in particular, their reactions with CQC and CRC bonds has only recently been realised.69–71 Importantly these reactions, unlike most azide click reactions, are uncatalysed. The need for metal-free click reactions, particularly for biological applications due to the concerns arising from the cytotoxicity of copper, has become much more important in the recent past.72 As a consequence, there has been an increasing number of reports of copper(I)-free azide–alkyne cycloadditions.72 Cycloaddition chemistry of boron azides was first reported by Curran who investigated the chemistry of the NHC-stabilised boron azide 83, prepared according to Scheme 31.69,73 This NHC-stabilised boron azide (83) reacts with a wide range of electron-deficient alkynes bearing carbonyl or ester functionalities.69 The reactions were generally performed between 80–180 1C with reaction times varying from 3 h–7 d (Table 1).69 Notably microwave synthesis has been shown to drastically reduce reaction times e.g. from 7 d to a few hours (Table 1).69 In the absence of an electron-withdrawing carbonyl group then little or no reactivity was observed although the reaction with (4-bromophenyl)ethyne yielded the corresponding triazole albeit in lower isolated yields.69 The click reactions of the NHC-stabilised boron azide (83) has also been applied to the reactions with electron deficient alkenes to generate triazolidene compounds.69 The reactions of 83 with methyl acrylate and perfluoro-1-heptene resulted in just one regioisomer (84 and 85 respectively) with the electronwithdrawing group in the 4-position on the triazolidene ring.69 The reaction with cyclopent-2-en-1-one also gave a single regioisomer and stereoisomer (cis) 86 (Scheme 32). Cycloaddition reactions with (trans)-dimethyl fumarate and (cis)-dimethyl maleate both yielded the same product 87 although the reaction with (cis)-maleate was slower.69

Scheme 31

Synthesis of an NHC-stabilised boron azide.


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Table 1 1,3-Cycloaddition reactions of the NHC-stabilised boron azide with substituted alkynes69

Regioisomer (%) Acetylene 0

R = H; R = CO2Me R = H; R 0 = COMe R = Me; R 0 = CO2Et R = Ph; R 0 = CO2Me R = Ph; R 0 = COMe R = H; R 0 = 4-BrC6H4 R = R 0 = CO2Me R = R 0 = CO2Et

Conditions

1,4-

1,5-

80 1C, 4 h 80 1C, 3.5 h 110 1C, 7 d 180 1C, 3 h (microwave) 110 1C, 7 d 110 1C, 7 d 180 1C, 2 h (microwave) 110 1C, 3 d 80 1C, 5 h 110 1C, 3 h 110 1C, 3 h

91 94 19 55 54 61 47 50

— — 67 23 27 28 39 8 96 84 92

Fig. 1

POV-ray depiction of the dimeric structure of 90.

Synthesis of compounds 88 and 89.

selectively the 1,4-regio-isomer, 89 was formed as both the 1,4- and 1,5-products in a 19 : 32 ratio.70 Isolation of 88 and 89 under ambient conditions reflect higher activation energies for the second cycloaddition. Indeed, performing the reaction under more forcing conditions (6 h at 80 1C), formed a new product which has been tentatively assigned to the double ‘clicked’ product 90.70 More substantial differences in the reactivity of the NHCstabilised boron azide (83) and (Cy2BN3)2 were observed in the reactions with dialkyl acetylenedicarboxylates [RCO2CR CCO2R (R = Me, Et, tBu]. With 83 the expected triazole product was formed in high yields (84–96%, Table 1) when reacted with RCO2CRCCO2R (R = Me, Et).69 However, with (Cy2BN3)2 the product formed for all reactions with acetylenes of type RCO2CRCCO2R (R = Me, Et, tBu) was unexpectedly found to be a novel macrocyclic compound 90 (Fig. 1).70 This 14-membered macrocycle consists of an C8O4B2 core positioned around a crystallographic inversion centre with the entire hepta-cyclic framework being almost perfectly planar.70 The loss of the alkyl groups in these reactions is remarkable. The reaction is thought to proceed via an initial 1,3-dipolar cycloaddition reaction between the azide and the alkyne forming the expected triazole (inferred by in situ 1H NMR spectroscopy). However, the elimination of the alkyl group from the ester is unusual but arguably thermodynamically driven by the strength of the B–O bond formed (average B–O bond enthalpy is ca. 523 kJ mol1 cf. average C–O bond enthalpy at ca. 360 kJ mol1).70,74 One potential by-product is RN3. Whilst it was not detected by NMR, its high volatility or consumption in subsequent reactions may have prevented its observation.70 The dimeric boron azide [(C6F5)2BN3]2 originally reported by ¨tke68 has also been employed in attempted click reactions Klapo again affording unexpected products. The reaction of [(C6F5)2BN3]2 with the phosphine Ph2P–CRCp-tol in the presence of excess TMSN3 yielded the bicyclic compound Ph2P(QNH)(CQCp-tol)N3B(C6F5)2 (91, Fig. 2).71 The formation of the product involves the initial Staudinger reaction between the phosphine and the boron azide followed by a 1,3-dipolar cycloaddition between the azide and an alkyne and finally hydrolysis yielding Ph2P(QNH)(CQCp-tol)N3B(C6F5)2.71 Strong evidence for the intermediate Staudinger product is the


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Scheme 32 Synthesis of triazolidene compounds from click reactions using boron azides.

Shortly after the first report of the cycloaddition chemistry of boron azides, Stephan and coworkers reported the cycloaddition chemistry of the dimeric boron azide, (Cy2BN3)2.70 Notably the dimeric nature of the boron azide leads to somewhat different reactivity patterns to 83 when reacted with similar acetylenes. The boron azide (Cy2BN3)2 was unreactive towards unactivated terminal acetylenes but underwent cycloaddition reactions with the more electron deficient acetylenes such as EtCRCCOMe and Ph2P(QO)CRCH, affording the 1,2,3,triazole containing products 88 and 89 (Scheme 33) in which just one of the two azide moieties in the Cy2BN3 dimer has undergone cyclisation.70 Whilst the synthesis of 88 afforded

Scheme 33

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5-membered triazole ring formed by a click reaction between the boron azide and the alkyne, and a 7-membered C2P2O2B ring.71 Two of these monomer units associate via two dative PQO - B bonds to form a central C2N4O2B2P2 macrocycle (Fig. 3).71 It is clear from the structure that a click reaction has occurred to form the triazole. Yet the affinity of the Lewis acidic boron centre for O donors appears to favour migration and this is coupled with a similar alkyl abstraction from the phosphate ester in an analogous fashion to that previously observed for the carboxylate ester functionality.71

5. Conclusions

Fig. 2

Synthesis and structure of Ph2P(QNH)(CQCp-tol)N3B(C6F5)2 91.

isolation of compounds of the type (C6F5)2B–NQP(Ph)2–CRC– R from reactions of [(C6F5)2BN3]2 with the phosphines Ph2P– CRC–R (R = Ph, PPh2).71 An even more unexpected product was the formation of [(EtO)2P(O)CQCN3B(C6F5)2P(O)(OEt)]2 [(92)2, Fig. 3)] from the reaction of [(C6F5)2BN3]2 with (EtO)2P(O)CRCP(O)(OEt)2.71 92 comprises two fused rings: one

The Lewis acidic nature of C6F5 boron reagents and their ability to activate C–C p-bonds provides an efficient way to synthesise heterocyclic compounds. There are a variety of different reactions by which this is possible but perhaps the most common method is in the synthesis of zwitterionic heterocycles by 1,2addition of nucleophile and boron combinations to CQC or CRC p-bonds in which either the Lewis acid or Lewis base is intramolecularly bound to the unsaturated ene or yne bond. Importantly, these 1,2-additions have also been used to afford a variety of aromatic oxazoles which are useful moieties in organic chemistry. Under the right conditions these existing stoichiometric processes can be made catalytic in nature. Thus, by fine-tuning substituents on the oxazole and boron reagent this catalytic process has the potential to be improved. In addition, this methodology can be extended to the catalytic synthesis of other heterocyclic rings for example by replacement of NR by isolobal O or S. In addition, the synthesis of complex aromatic systems (as in the synthesis of dibenzopentalene derivatives) using B(C6F5)3 by a series of carbocation rearrangement reactions also has potential for driving a catalytic reaction as B(C6F5)3 is regenerated in the process. An emerging area of the use boron compounds is the synthesis of boron substituted triazoles using boron azides. The reaction of boron azides with alkynes is more complex than originally thought, ultimately resulting in the isolation of some unusual poly-cyclic compounds reflecting the necessity for further study to gain a better insight into the reaction chemistry.

Acknowledgements I would like to thank my previous supervisors for their guidance, contributions and constructive suggestions for this manuscript. In particular I am grateful to Prof. Douglas Stephan, for introducing me to the area of boron/phosphorus chemistry and for his continued support.

Notes and references

Fig. 3

Synthesis and structure of 92.

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1 P. P. Power, Nature, 2011, 463, 171. 2 See for example: A. Suzuki, Acc. Chem. Res., 1982, 15, 178; A. Pelter, Chem. Soc. Rev., 1982, 11, 191; H. C. Brown, M. C. Desai and P. K. Jadhav, J. Org. Chem., 1982, 47, 5065; E.-I. Negishi and M. J. Idacavage, Org. React., 1985, 33, 1; P. K. Jadhav, K. S. Bhat, P. T. Perumal and H. C. Brown, J. Org. Chem., 1986, 51, 432;


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