Boron Trifluoride

Boron trifluoride, Et3Si+, or a proton binds with the phosphate analogue of (184) to form the trigonal bipyramidal transannulated phosphatrane having a POB, POSi, or POH bond, respectively 〈85JA7084, 90PS(49/50)163, 86JA4918〉.

From: Comprehensive Heterocyclic Chemistry II, 1996

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Boron trifluoride: Risk assessment, environmental, and health hazard

Ashwani Kumar, Nishant Khandelwal, in Hazardous Gases, 2021

Abstract

Boron trifluoride is a pungent, highly toxic, and corrosive gas which is frequently used as a Lewis acid. The vapors of boron trifluoride are heavier than air, therefore, the exposure of these vapors to fire or heat may bring out violent rupture. Boron trifluoride and its organic complexes are highly corrosive. They are found to be destructive to almost all tissues of the body. A risk assessment should be conducted and documented in each work area to measure the risks related to the use and to select the protective personal equipment that matches the related risk. This chapter gives a detailed overview of boron trifluoride along with its emphasis on risk assessment and risk management.

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Four-membered Rings, with all Fused Systems containing Four-membered Rings

Russell J. Linderman, in Comprehensive Heterocyclic Chemistry II, 1996

1.22.6.5.2.(ii) Al, Cu, and Si reagents

Boron trifluoride-catalyzed addition of a vinyl alane to oxetane has also been reported 〈89T6197〉. Aluminum acetylides readily add to substituted 2-oxetanones by nucleophilic attack at the ring carbon with concomitant displacement of the carboxylate 〈86TL87〉. This regioselectivity is noteworthy since most protic acid-catalyzed nucleophilic addition reactions with oxetanones occur at the acyl carbon.

Regioselective ring opening of 2-oxetanones can also be realized with organocuprates, phosphinestabilized organocopper reagents, and copper-catalyzed Grignard addition reactions 〈89T403〉. Only 3-substituted propionic acid derivatives are obtained in very good yield (Equation (9)). The reaction proceeds by an SN2 pathway with inversion of configuration at the β-carbon of the lactone. Di-Grignard reagents react with 2-oxetanone to provide α,ω-dicarboxylic acids 〈83BCJ345〉. Precursors of the natural products muscone and civitone were prepared by this method.

(9)

There are few examples of carbon–carbon bond-forming reactions of organosilicon reagents and oxetanes or oxetanones. Allylsilanes add to oxetane in the presence of titanium tetrachloride in moderate to good yields 〈85JOC2782〉. The reaction suffers from competitive ring cleavage of the oxetane by titanium tetrachloride. The allylsilane reaction occurred regioselectively at the γ-carbon. Allyl- and alkynic silanes also react with diketene in the presence of titanium tetrachloride to provide the acetoalkylation product 〈87S1092〉. Silyl enol ethers also served as the nucleophile for this reaction leading to the derived 3,5-diketo ester in modest yield. Attempted reaction of 3-methyl-2-oxetanone with the silyl enol ether of acetophenone led only to the O-alkylated product in low yield (Equation (10)).

(10)
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Ring Systems with at least Two Fused Heterocyclic Five- or Six-membered Rings with no Bridgehead Heteroatom

A. Graham, M. Robinson, in Comprehensive Heterocyclic Chemistry III, 2008

10.21.7.1.1 On the carbocyclic ring

Treatment of the tertiary alcohol 108 with either boron trifluoride–diethyl etherate in dichloromethane or concentrated hydrochloric acid in acetic acid leads to the formation of the spiro compond 109 by an intramolecular condensation reaction (Equation 27) <2001J(P1)740>. Both reagents generate a triarylmethyl cation which undergoes intramolecular electrophilic attack at the ortho-position of the terminal phenyl unit. Due to the stabilizing aryl units, the lifetime of the cation is sufficiently long for it to react intermolecularly at the α-thienyl position. Thus, independent of which dehydrating reagent is used, a dimeric material 110 is also produced, the yield of which is strongly dependent on the dilution of the reaction mixture. Thus, reactions utilizing boron trifluoride–diethyl etherate in dilute dichloromethane gave 109 with only trace amounts of the dimeric material.

(27)

Thiophene-fused benzoquinones, such as 23, can be easily alkylated to produce dialkoxybenzodithiophene compounds 111 on reaction with tosyl esters (Equation 28) <2002SM(130)139>.

(28)

The anhydride moiety of a rebeccamycin analogue 112 (where R = glycoside) is partially or totally reduced by reaction with a zinc–mercury amalgam to give lactones 113 and indolocarbazoles 114 as a mixture of regioisomers (Equation 29) <2004BMC1955>.

(29)

The carbonyl function of indolocarbazole 115 undergoes the expected range of reactions <2004EJO2593>.

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Synthesis and Activation of Carbohydrate Donors: Acetates, Halides, Phenyl selenides and Glycals

Benjamin G. Davis, ... David Gamblin, in Carbohydrates, 2003

3.2.2 Use of anomeric acetates as glycosyl donors

Under the influence of strong, hard Lewis acid catalysis, the anomeric acetate can serve as an effective leaving group and therefore allow glycosylation. Indeed, acetates act as glycosyl donors during the preparation of e.g. glycosyl bromides (vide infra, here HBr acts both a source of Br and as an acid catalyst) or thioglycosides (here BF3·OEt2 is used as the Lewis acid).

Clearly, the major consideration is the need for acid-stability in both glycosyl donor and acceptor. In fact, prolonged reaction times may lead to associated acid-catalysed AAc2 acetate hydrolysis in the acetylated donor or in the acetylated glycosylation products. Note too the use of a large excess of Lewis acid. Although the role of the Lewis acid is as a catalyst, peracetate glycosyl donors (and possibly glycosyl acceptors also) contain a large number of potentially Lewis basic sites that may sequester a given activator.

Method 4

The synthesis of 2-bromoethyl 2,3,4,6-tetra-O-acetyl-β-d-glucoside from D-glucose pentaacetate [10, 11].

Notes and discussion.

Note the use of 5 equiv. of boron trifluoride etherate in this procedure. Use of fewer equivalents (< 5 equiv.) results in a sluggish, low yielding reaction.

Here the glycosyl acceptor contains a group (bromide) that is incompatible with the use of a soft Lewis acid activator and so precludes the use of some alternative glycosylation donors, such as glycosyl bromides or thioglycosides. As a consequence of anchimeric assistance by the C-2 acetate group, the β-glucoside is the major product.

Materials.

d-Glucose pentaacetate (2 g, 5.1 mmol) treat as toxic
2-Bromoethanol (distilled from CaO, 0.45 ml, 6.3 mmol) treat as toxic
Dichloromethane (9 ml distilled from CaH2) highly flammable, harmful
Dichloromethane (15 ml × 3) risk of irreversible effects
BF3·OEt2 (3.3 ml, 26.0 mmol) flammable, corrosive
Ice water (15 ml × 2) no risk
Water (15 ml) no hazard
Sodium hydrogencarbonate solution (aq., saturated, 15 ml) assume toxic
Magnesium sulfate irritant
Ethyl acetate for chromatography flammable irritant
Hexane for chromatography toxic, flammable, irritant
Iso-octane for recrystallization toxic, flammable, irritant

Equipment.

Round bottomed flask (25 ml)

Syringe (5 ml) and needle

Nitrogen source/balloon and bubbler head/septum

Ice bath

Conical flask (100 ml × 2)

Separatory funnel (250 ml)

Filtration equipment

Rotary evaporator

Flash chromatography equipment

Special precautions.

Safety glasses and gloves should be worn during this experiment and work should be carried out in a fume hood: BF3OEt2, in particular, is corrosive. Take care not to add the BF3·OEt2 too rapidly—the ‘hot spots’ formed in the solution result in decomposition and lower yields. Do not prolong the reaction time unnecessarily as this leads to the deacetylation of the product 2-bromoethyl glucoside.

Procedure.

Dissolve the d-glucose pentaacetate (2 g, 5.1 mmol) and 2-bromoethanol (0.45 ml, 6.3 mmol) in DCM (9 ml) under nitrogen and cool to 0 °C using the ice bath. Add the freshly distilled BF3·OEt2 (3.3 ml, 26.0 mmol) dropwise using the syringe and needle over the course of 15 min. After 1.5 h allow the solution to warm to room temperature. After 20 h pour the reaction solution into ice water (15 ml) and extract with DCM three times (15 ml × 3). Combine these organic extracts, wash with water (15 ml), sat. NaHCO3 solution (aq., 15 ml), water again (15 ml) and then dry over magnesium sulfate. Filter the dried solution and remove the solvent on the rotary evaporator. Purify the resulting residue by flash chromatography (EtOAc/hexane, 1:3) to give 2-bromoethyl 2,3,4,6-tetra-O-acetyl-β-d-glucopyranoside (1.42 g, 61%) as a white solid, which can be recrystallised from ethyl acetate/iso-octane; mp 118–120 °C (lit. [12] mp 117.3 °C (EtOH)); [α]22D = – 11.9 (c 1.65, CHCl3) (lit. [77]: [α]22D= – 12.3 (c 0.2, CHCl3)); 1HNMR (200 MHz, CDCl3) 2.00, 2.02, 2.07, 2.09 (s × 4, 3H × 4, Ac × 4), 3.42–3.51 (m, 2H), 3.67–3.87 (m, 2H), 4.10–4.31 (m, 3H), 4.57 (d, J1,2 = 8 Hz, 1H, H-1), 4.97–5.27 (m, 3H).

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Thiiranes and Thiirenes

D.C. Dittmer, in Comprehensive Heterocyclic Chemistry, 1984

5.06.3.3.3 Lewis acids

The most important reaction with Lewis acids such as boron trifluoride etherate is polymerization (Scheme 30) 〈72MI50601〉. Other Lewis acids have been used: SnCl4, Bui2AlCl, Bui3Al, Et2Zn, SO3, PF5, TiCl4, AlCl3, Pd(II) and Pt(II) salts. Trialkylaluminum, dialkylzinc and other alkyl metal initiators may partially hydrolyze to catalyze the polymerization by an anionic mechanism rather than the cationic one illustrated in Scheme 30. Cyclic dimers and trimers are often products of cationic polymerization reactions, and desulfurization of the monomer may occur. Polymerization of optically active thiiranes yields optically active polymers 〈75MI50600〉.

Scheme 30.

Treatment of tetrafluorothiirane with aluminum chloride gave a 64% yield of 2,4-bis(pentafluoroethylthio)-2,4-bis(trifluoromethyl)-1,3-dithietane, the dimer of pentafluoroethyl dithiotrifluoroacetate formed by rearrangement of the thiirane via trifluorothioacetyl fluoride 〈65JOC4188〉. Thiiranes form complexes with manganese, cobalt, nickel, mercury, silver, gold, palladium and platinum salts; with cadmium, zinc and magnesium porphyrins; and with diethylzinc and diethylcadmium. The complex of 2-methylthiirane with diethylzinc is less stable than the corresponding complex with 2-methyloxirane. The metal ions may catalyze nucleophilic attack on the ring carbon atoms.

Tungsten hexachloride and molybdenum pentafluoride desulfurize 2-methylthiirane to propene 〈72DOK(207)899〉 and a ruthenium(II) complex desulfurizes thiirane 〈73JA4758〉.

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Iodosylbenzene

A. Varvoglis, in Hypervalent Iodine in Organic Synthesis, 1997

5.2.2 Silyl enol ethers

Silyl enol ethers are quite reactive towards IOB-boron trifluoride (or tetrafluoroboric acid) and can be considered as valuable starting materials for several reactions of synthetic importance. Of special interest is their use for carbon–carbon bond formation: 1,4-diketones and unsaturated ketones are the products of such reactions; further, they can be transformed to α-hydroxy, methoxy or trifyloxy ketones. With tetrafluoroboric acid IOB forms a yellow solution containing the highly electrophilic PhI+ OH BF4, stable up to 0 °C. This species reacts readily with silyl ethers of several ketones, notably acetophenones, at –78 °C, forming an unstable iodonium ion (ArCOCH2I+ Ph) which with another silyl ether affords 1,4-diketones.

Butane-1,4-diones [23]

To a stirred suspension of IOB (220 mg, 1 mmol) in dichloromethane (5 ml) was added tetrafluoroboric acid in dimethyl ether (0.2 ml) at –50 °C. The mixture was warmed to 0 °C until formation of a yellow solution and then cooled to –78 °C. To this the first silyl enol ether (1 mmol) was added with stirring. The cold reaction mixture was then added to a stirred solution of the second silyl enol ether (1 mmol) in dichloromethane (5 ml) at room temperature. After 10 min stirring, the reaction mixture was poured into water (50 ml) and extracted with dichloromethane (2 x 10 ml). The organic extract, after drying and concentration, yielded the crude diketone which was purified by column chromatography on silica gel (hexanes-ethyl acetate). When a silyl enol ether was treated with IOB.BF3 in the ratio 1:2, then the symmetrical butane- 1,4-diones were formed in good yields. Diketones obtained by these methods are shown in Table 5.2. Some of these products were also obtained using other hypervalent iodine reagents in better yield (sections 6.4.3 and 12.3sections 6.4.312.3).

Table 5.2. Butane-1,4-diones and γ,δ-unsaturated ketones from Sily1 enol ethers upon reaction with IOB/HBF4 and a carbon nucleophile

Precursors Product Yield (%) Ref.
a. For symmetrical 1,4-diones
ArC(OSiMe3) = CH2 (ArCOCH2)2 43-62 [23]
ButC(OSiMe3) = CH2 (ButCOCH2)2 55 [23]
50-56 [24]
63 [24]
b. For unsymmetrical 1,4-diones
50 [25]
30-75 [25]
ArC(OSiMe3) = CH2 + Ar'C(OSiMe3) = CH2 ArCOCH2CH2COAr' 27-51 [25]
c. For unsaturated ketones
90 [25]
PhC(OSiMe3) = CH2 + PhC(Me) = CH2
59 [25]
PhC(OSiMe3) = CH2 + Me3SiCH2CH = CH2 CH2 = CHCH2CH2COPh 63 [25]

The iodonium ion formed on reaction of the silyl enol ether of acetophenone also reacted with alkenes or allylsilanes, providing a good approach for the preparation of γ,δ-unsaturated ketones as exemplified in Table 5.2. An interesting deviation from this reactivity occurred with 2,3-dimethyl-2-butene which afforded a dihydrofuran derivative [25]. Another group of useful α-functionalization of carbonyl compounds effected through their silyl enol ethers involved carbon–oxygen bond formation. Water, methanol, and trimethylsilyl triflate served as nucleophiles in order to convert the iodonium intermediates (RCOCH2I+Ph) into, respectively, α-hydroxy-, α-methoxy- or α-trifyloxyketones. Not only α-hydroxyacetophenones but also several other α-hydroxyketones (ketols) were obtained in this way, as illustrated in Table 5.3, which also contains examples of α-methoxy- and α- trifyloxyketones.

Table 5.3. α-Functionalized ketones from silyl enol ethersa

α-Hydroxy ketones α-Methoxy ketones α-Ketotriflates
ArCOCH2OH
(65-70%)
ArCOCH2OMe
(68-78%)
ArCOCH2OTf
(53-77%)
PhCOCH(OH)Me
(74%)
PhCOCH(OMe)Me
(75%)
ButCOCH2OH
(83%)
ButCOCH2OMe
(85%)
PBM
PhCOCH2OEt
(80%)
PhCOCH2OPri
(45%)
a
References: for a α-hydroxy ketones [26,27] ; for α-methoxy ketones [28] ; and for α-ketotriflates [29].

A catalytic route using a manganese (III) complex has been developed for α- hydroxylation of ketones avoiding the use of water or a protic solvent; mixtures of α- hydroxyketones and their silyl derivatives were formed in excellent yield. By using a chiral pyrrolidine-based manganese (III) complex as catalyst, asymmetric oxidation was effected, with enantiomeric excess varying from 14 to 62% [30]. Another kind of α-functionalized ketones resulted from silyl enol ethers which after the addition of IOB.BF3 were treated with triethyl phosphite; α-ketophosphonates were obtained in this way [31]:

2-(Trimethylsilyloxy)furan may be considered as a special silyl enol ether; in its reaction with IOB.BF3, followed by addition of ethanol, γ-functionalization occurred, with formation of 5-ethoxy-2(5H)-furanone [32]:

Similar functionalization was noted by using acetic acid or p-toluenesulphonic acid instead of ethanol. Also, 2-(trimethylsilyloxy)benzofuran, on treatment with IOB and these acids, followed by boron trifluoride etherate, afforded 3-acetoxy-(and 3-tosyloxy)-2-coumaranone. 1 -Trimethylsilyloxy-2-oxa-bicyclo[3.1.0]hexane although not an enol ether, upon treatment with IOB and tetrabutylammonium fluoride afforded its ring homologated α,β-unsaturated lactone [22]:

Similar behaviour was shown by some analogues which instead of the 5-membered ring had a 6-, 7- or 14-membered ring. The unsaturated lactones were obtained in good yield, in reactions involving β-functionalization and concomitant elimination.

Overall, α-, β- and γ-functionalization is possible with the various silyl substrates reported in this section. In a formal sense, the relevant reactions discussed correspond to an umpolung of reactivity of the enolic or cyclopropyl systems, as depicted schematically below [22]:

These synthetic equivalents of α-, β- and γ-carbonyl cations might also be useful in other reactions.

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Three-membered Rings, with all Fused Systems containing Three-membered Rings

Kuriya Madavu Lokanatha Rai, Alfred Hassner, in Comprehensive Heterocyclic Chemistry II, 1996

1.02.5.1 Reactions

Reaction of activated aziridines with acetonitrile in the presence of boron trifluoride etherate takes place via ring expansion leading to imidazolines 〈92RTC59〉. Treatment of zwitterionic aziridine-2-carboxylic acid prepared from the ester, with triethylborane in hexane gave boraxazolidones 〈92RTC211〉 via 1,3-dipolar cycloaddition. Aziridine-2-carboxylates react with 2-methyl-β-nitro-styrene to yield substituted pyrrole derivatives 〈89BSF409〉. 2-Pyrrolidone is the product in the reaction with dimethyl malonate anion 〈91JHC1757〉. On thermolysis aziridine (91) undergoes intramolecular cycloaddition via an intermediate azomethine ylide to yield metacyclophane (Equation (32)) 〈86TL4003〉. Alkylation of a triazole with an aziridine using boron trifluoride etherate as catalyst gave a bicyclic amino ester 〈92TA51〉. Studies show that N-methylindole reacts at the C-3 position of aziridine-2-carboxylates (92) and reacts exclusively at the C-2 position of aziridine-2-lactone (93). This unexpected regioselectivity can moreover be rationalized by consideration of the LUMO coefficients of the reaction centers of the substrates 〈94JOC434〉.

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Six-membered Rings with Two or More Heteroatoms and Fused Carbocyclic Derivatives

Philip C. Bulman Page, Andrew Lund, in Comprehensive Heterocyclic Chemistry II, 1996

6.08.8.3.3 Miscellaneous reactions

The reaction of propargylic esters with aldehydes and hydrogen sulfide in the presence of boron trifluoride etherate leads to 1,3-dithiins (86) (Equation (56)) 〈71T5753〉. Dieckmann cyclization of suitably substituted acyclic 1,3-dithioacetals gives rise to 1,3-dithian-5-ones (87) (Equation (57)) 〈59LA(624)79, 63LA(661)84〉.

(56)
(57)

In an interesting process, the prochiral 2-substituted 5-methylidene-1,3-dioxane (88) was isomerized to give a mixture of the enantiomeric dioxins using a chiral ruthenium catalyst. Enantiomeric excesses ranged from 13 to 38% (Equation (58)) 〈94SL517〉.

(58)
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Four-membered Rings, with all Fused Systems containing Four-membered Rings

Chantu R. Saha-MöllerWaldemar Adam, in Comprehensive Heterocyclic Chemistry II, 1996

1.33.5.2 Electrophilic Attack at Ring Heteroatoms

Very few reactions of dioxetanes with electrophiles are known. The electrophilic attack of boron trifluoride, a strong Lewis acid, at the peroxide oxygen atom of the tetramethyl-1,2-dioxetane (1a) leads to pinacolone and the 1,2,4,5-tetroxane (Scheme 28) 〈77JA1890〉. Brønsted acids such as CF3CO2H catalyze rearrangement of the dioxetanes to allylic hydroperoxides (Scheme 29), but this transformation is limited to the easily opened benzofuran dioxetanes 〈91JA8005〉. Under Lewis or Brønsted catalysis, aldehydes add to dioxetanes with α-alkoxy or aryloxyl substituents to give 1,2,4-trioxanes (Scheme 30) 〈83HCA2615, 85T2081〉. The latter transformation has been utilized extensively for the preparation of model compounds for the natural product Artemisinin, a Chinese folk medicine to treat malaria 〈94ACR211〉.

Scheme 28.

Scheme 29.

Scheme 30.

The reaction of divalent transition metals such as copper, nickel, cobalt, zinc, manganese, and cadmium with dioxetanes leads to catalytic decomposition into carbonyl fragments (Scheme 31). An electron-transfer mechanism has been proposed for this dark decomposition route 〈74JA5557〉. In contrast, univalent rhodium and iridium complexes react with dioxetanes by insertion of the metal into the peroxide bond and subsequent cleavage of the metallacycle releases the carboxyl fragments and the metal complex (Scheme 32) 〈77JA5334〉.

Scheme 31.

Scheme 32.

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Five- and Six-membered Fused Systems with Bridgehead (Ring Junction) Heteroatoms concluded: 6-6 Bicyclic with One or Two N or Other Heteroatoms; Polycyclic; Spirocyclic

R.L. Riggs, D.M. Smith, in Comprehensive Heterocyclic Chemistry III, 2008

12.17.4.2.2(ii) Fused pyridopyrimidines

Reaction of the benzotriazole-linked aminopyridine 503 with 2,3-dihydrofuran and boron trifluoride etherate results in cyclization to the furopyridopyrimidinium salt 504 with loss of benzotriazole (Equation 221) <1998S704>.

(221)

Several routes to thienopyridopyrimidines, starting from the thiophenes, are shown in Equations (222) <1996CHE315>, (223) <2001HAC168> and (224) <2001RCB2428>, and Scheme 110 <2002M1443>. Various methods starting from the appropriate five-membered heterocycle are applicable to the synthesis of the furo, pyrrolo, thiazolo, or pyrazolo analogues (Equations (224) <2001RCB2428>, (225) <2004IJB909, 1999IJB452>, (226) <2001H(55)365>, and (227) <2003EJC487>).

(222)
(223)

Scheme 110.

(224)
(225)
(226)
(227)

Synthesis of these fused systems by formation of the five-membered ring is exemplified by the reaction of the pyridopyrimidine 505 with an arylacetyl chloride (Equation 228) <1999JPR332>.

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