Benzyne with furans

The reaction of benzyne with furan was the first example of a Diels-Alder reaction of benzyne to be studied b. No authenticated examples of arynes are known which fail to give cyclo-adducts with furan i38>. The tetrahalogenobenzynes all form the expected adducts 103, X = F 6), Cl 57>i39)j gr 59) or i 59)). d0 other highly fluorinated arynes i40,i4i>. The isomeric adducts (104) and (105) have been detected by 19F n.m.r. spectroscopy when the dilithio-compound (12) was allowed to decompose in the presence of furan 28 103). 

Deoxygenation of naphthalene-1,4-endoxides. A new method for conversion of these Diels-Alder adducts of benzynes with furanes to naphthalenes consists in reduction with sodium borohydride in trifluoroacetic acid.5 Excess acid is used when the substrate bears methyl groups at the bridgeheads. Substrates lacking such groups tend to undergo acid-catalyzed rearrangement to naphthols, but are reduced satisfactorily with THF as solvent and a limited amount of acid. 

Benzyne in solution reacts as a dienophile Wittig (1957) first demonstrated this in the reaction of benzyne with furan. Corbett and Porter (1965) obtained further supporting evidence by isolating 1,4-addition products from benzyne with 1-vinylnaphthalene and 3-vinylbenzo[b]-thiophene Dilling (1966) did the same with styrene. 

Wolthuis employed chloranil in refluxing xylene to effect nearly quantitative dehydrogenation of 1,4-dihydroanthracene derivatives such as (11) obtained by a synthesis starting with (9), the adduct of benzyne with furane. Functioning as an... 

Deoxygenation of 1,4-epoxy-1,4-dihydronaphthalenes. The Diels—Alder adducts of benzynes with furanes can be aromatized by this radical anion in... 

When benzyne is generated in the absence of another reactive molecule it dimerizes to biphenylene.132 In the presence of dienes, benzyne is a very reactive dienophile and [4+2] cycloaddition products are formed. The adducts with furans can be converted to polycyclic aromatic compounds by elimination of water. Similarly, cyclopentadienones can give a new aromatic ring by loss of carbon monoxide. Pyrones give adducts that can aromatize by loss of C02, as illustrated by Entry 7 in Scheme 11.9. 

The AuCl-catalysed 4 + 2-cycloaddition of benzyne with o-alkynyl(oxo)benzenes produced anthracene derivatives having a ketone in the 9-position, in good to high yields under mild conditions.118 Hypervalent iodine compounds, [5-acyl-2-(trimethyl-silyl)]iodonium triflates, readily yielded acylbenzynes which could be trapped with furan.119 Both DMAD and benzyne reacted with borabenzene to yield substituted borabarrelenes and borabenzobarrelenes, respectively.120... 

Benzyne is a good dienophile. For example, reaction of 2-bromofluorobenzene with lithium metal or decomposition of benzenedi-azonium-2-carboxylate both generate benzyne, which can be trapped with furan to give a naphthalene endoxide (Scheme 4.10). 

The high efficiency of the present precursor 2 is demonstrated by comparison with a similar precursor, 2-(trimethylsilyl)phenyl triflat (4), which generates benzyne under mild conditions (room temperature and neutral).7 Benzyne precursor 2 gives the adduct, 1,4-epoxy-1,4-dihydronaphthalene 3, quantitatively in the reaction with furan, while the reaction of benzyne precursor 4 under the same conditions leads to a lower yield of adduct 3 and needs longer reaction time. 

Benzynes are readily formed when we have a leaving group ortho to a lithium atom. Thus when ortho-bromo(1 uorobenzene 143 is reacted with butyl lithium, the intermediate formed is ortho-lithiofluorobenzene 144. Lithium fluoride can eliminate from this to yield benzyne 145. Benzynes are reactive species and do not hang about. Here, ort/to-bromofluorobenzene is treated with butyl lithium in the presence of furan. When the benzyne forms it rapidly reacts with furan in a cycloaddition reaction to form the adduct 146 in a 68% yield. 

Although benzyne is too unstable to be isolated, evidence that it is formed can be obtained by a trapping experiment. When furan is added to a reaction that forms a benzyne intermediate, furan traps the benzyne intermediate by reacting with it in a Diels-Alder reaction (Section 8.8). The product of the Diels-Alder reaction can be isolated. 

Dieh-Alder reactions with benzyne. Shepard has recently demonstrated that benzyne generated from chlorobenzene and LiTMP undergoes expected Diels-Alder cycloadditions with reactive dienes. The reaction with furane itself fails because of a base-promoted side reaction. 

A new cathodic cyclodimerisation of 4-pyrones yields either (90) or (91) depending on conditions,88 2-Benzopyran-3-one has been isolated at low temperature and intercepted by NPM as the adduct (92) 88 high-pressure cycloaddition reactions of 2H-pyran-3-ones with a variety of dienophiles have been recorded.88 Cycloaddition reactions of furans and isobenzofurans continue to dominate this section. Dienophiles whose reactions with furan have been studied recently include phenylsulphonylpropadiene (giving predominantly the endo-adduct (93) 8b. benzynes (derived from aryloxazoli nesJ.8 and... 

In regard to transformation of the benzyne cycloadduct product between benzyne and furan into benzo[c]furan, the direct transformation by elimination of acetylene will not occur because computed activation barriers for this reaction were to high. The AMI computed activation barrier for acetylene elimination was 57.0 kcal/mol, while the activation barriers for the addition of a-pyrone (30.4 kcal/mol) and the elimination of carbon dioxides and benzene (29.9 kcal/mol) were much more energetically favorable (Scheme 1). These computational results are in full agreement with experimental evidence [38]. 

Benzyne formation and their reactions are not limited to simple benzene derivatives. Heterocyclic mole-ules can also be used for benzene reactions. One important use of benzyne derivatives is in the Diels-Alder caction (see sec. 11.4.A). When 3-bromo-2-methoxypyridine (394) was treated with EDA at -78°C, for. ample, lithium-hydrogen exchange occurred to give 395. Loss of LiBr led to benzyne (396), which reacted with furan to give the Diels-Alder product (397) in 74% yield. ... 

Benzyne is formed when 1-chlorobenzvalene 118 is treated with -BuLi at -105 °C, as shown by trapping with furans or BuLi. Apparently 1,6-dehydrobenzvalene 119, a presumed intermediate, is unstable with respect to benzyne even at that low temperature. 2,3-Naphthyne was similarly formed from the benzo analog of 118. 

Aryne cycloadditions to furans have been employed in the synthesis of bio-related molecules. For example, adduct 272 served as the starting point for the preparation of the aromatic segment of rifamycin W (an antibiotic). Previously unreported benzyne 274 (its precursor 273 was prepared in several steps from piperonal) readily gave cycloadduct 275 with furan, but unfortunately for a proposed route to podophyllotoxin, did not undergo... 

Recently, we developed a second route to 55a and 56a (Scheme 14) [41]. Bromocyclophane II was treated with a strong base to generate a benzyne intermediate, which was trapped with furan or isobenzofuran to afford [4 + 2] adducts 57 (two isomers 6 1 ratio) and 58 (two isomers 2 1 ratio), respectively. Deoxygenation of 57 and 58 with a low valent titanium reagent prepared from TiCU, LiAlH4, and triethylamine gave 55a and 56a, respectively. 

Arynes with their reactive triple bond would be expected to participate readily in cycloaddition reactions. However, as demonstrated in the previous section, the addition of nucleophiles is extremely facile, and therefore reactions with non-nucleophilic reagents cannot usually be observed unless the aryne is generated in the absence of nucleophiles. In practice this usually means that routes involving the treatment of aryl halides with nucleophilic bases cannot be used. The first cycloaddition reaction of ortho-benzyne, the Diels-Alder reaction with furan was observed in 1955 by Wittig and used 2-fluorobromobenzene as the precursor. The cycloadduct was obtained in almost 90% yield, and the reaction has formed the basis for numerous synthetically useful Diels-Alder cycloadditions involving arynes. Tetrabromobenzene reacts with butyllithium to give the diaryne intermediate with furan to form a tetrahydroanthracene. The mixture of syn and anti conformers can be separated based on differences in methanol solubility (Scheme 7.26). 

Furan has generally been observed to be a good diene in Diels-Alder reactions with arynes, and has been widely used in trapping aryne intermediates. Upon treatment with one equivalent of lanthanum, l-halo-2-iodobenzenes effectively generate benzynes, which are trapped with furan to afford the Diels-Alder product 99 (Equation 12.35) [58]. 

While preparing benzonorbornadienes by the Diels-Alder cycloaddition of substituted benzyne intermediates with furan. Caster and coworkers discovered significantly differentregiochemistries be tween bromobenzene 121 and chlorobenzene 124 in the n-BuIi induced metallation step (Schemes 12.40 and 12.41) [72]. In the case of bromobenzene 121, benzyne intermediate 122 was generated via bromine-Uthium exchange, followed by elimination of UF trapping by furan then afforded 6-fluoro-9-oxabenzonorbornadiene (123). In contrast, aryne 125 was produced... 

Besides furan, the Diels-Alder reaction between other heteroaromatics and arynes is also known. The [A+2] cycloaddition of benzyne with 3,4-dimethylphos-phole pentacarbonylmolybdenum complexes 133 has recently been reported by Mathey (Equation 12.37) [75]. The cycloaddition mainly takes place on the less-hindered side of the phosphole ring, affording 2,3-benzo-7-phosphanorbornadiene complexes 134 in moderate yields. 

With selected aryne precursors it has been possible to demonstrate the intermediacy of free arynes in cyclojaddition reactions by other methods. The most convincing of these is the previously mentioned spectroscopic detection of benzyne (1) from the photolysis of phthaloyl peroxide (72) in an argon matrix at 8 K and its subsequent reaction with furan (146a) upon warming to give the adduct 148a. A conceptually similar technique is pseudodilution, in which... 

Kitamura and coworkers reported that treatment of (phenyl)[2-(trimethylsilyl) phenyl]iodonium triflate with TBAF results in the formation of benzyne, which can be trapped with furan and other dienes in cycloaddition reactimis [35, 267, 268]. This feature was recently utilized with an iodonium salt containing an ort/io-(pyridyldiisopropyl)silyl group [269]. Diaryliodonium salts are also useful in covalent grafting of carbon surfaces useful in materials chemistry [270-273]. 

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