Furan positional selectivity

The positional selectivity on formation of the cydoadducts from 221 is less pronounced than that of the isobenzene 162, but it is the conjugated double of the allene moiety as well that predominantly undergoes the reaction. As demonstrated by the thermolysis of several products, these are formed from 221 under kinetic control. For example, on heating, the styrene adduct 240 and the furan adduct 231 rearranged virtually completely to 241 and 232, which are formally the cycloadducts to the non-conjugated double bond of the allene subunit of 221 [92, 137]. The cause of the selectivity may be the spin-density distribution in the phenylallyl radical entity of the diradical intermediates. 

Hence the positional selectivity is different from that of the furan additions to 417 (Scheme 6.90). Assuming diradical intermediates for these reactions [9], the different types of products are not caused by the nature of the allene double bonds of 417 and 450 but by the properties of the allyl radical subunits in the six-membered rings of the intermediates. Also N-tert-butoxycarbonylpyrrole intercepted 450 in a [4 + 2]-cycloaddition and brought about 455 in 29% yield. Pyrrole itself and N-methylpyr-role furnished their substituted derivatives of type 456 in 69 and 79% yield [155, 171b]. Possibly, these processes are electrophilic aromatic substitutions with 450 acting as electrophile, as has been suggested for the conversion of 417 into 442 by pyrrole (Scheme 6.90). 

L. I. Belen kii, I. A. Suslov, N. D. Chuvylkin, Substrate and Positional Selectivity in Electrophilic Substitution Reactions of Pyrrole, Furan, Thiophene, and Selenophene Derivatives, Chem. Heterocycl. Compd. 2003, 39, 36- 8. 

Quantum chemical study of positional selectivities in reactions of furan, thiophene, selenophene, N-unsubstituted pyrrole and related benzannulated systems with electrophiles... 

Electrophilic substitution is an important type of reactions for five-membered heterocycles with one heteroatom and enables compounds with various substituents to be obtained. The present work is devoted to certain features of substrate and positional selectivities in electrophilic substitution reactions of derivatives of pyrrole, furan, thiophene and selenophene, and also the corresponding benzannulated systems, which had not been explained until recently. In a recent review (05RKZ(6)59), these problems were mainly discussed for thiophenes, while in a previous review (94H(37)2029) only monocyclic pyrrole, furan and thiophene derivatives were considered. 

POSITIONAL SELECTIVITY IN REACTIONS OF FURAN, THIOPHENE, SELENOPHENE, PYRROLE AND THEIR DERIVATIVES WITH ELECTROPHILES... 

The data considered confirm the reactivity sequence pyrrole furan > selenophene > thiophene for substrate selectivity on electrophilic substitution (71 AHC(13)235) and show that the positional selectivity is reduced in the series furan > selenophene > thiophene > pyrrole, which correlate with that for the relative stability of the onium states of the elements (O < Se < S " < N" ") in agreement with the hypothesis proposed previously (79MI2,80KGS1587), not including selenophene and its derivatives. 

We undertook a quantum chemical study of the protonation of monocyclic and benzannulated five-membered heterocyclic systems with one heteroatom (03KGS38). The initial calculations, carried out by the semi-empirical CNDO/2 method (81ZOR1129), gave values for the differences in energy of the cations formed on protonation of the a- and yS-positions iAEa-p) that corresponded with the available experimental data on the sequence of change in positional selectivity furan > thiophene > pyrrole. However, the place of selenophene between thiophene and pyrrole in this series predicted by these calculations was contradicted by the experimental results obtained later (95JHC53). The results of calculations by the MNDO and PM3 methods also did not fit the experimental data, possibly linked with poor parametrization for selenium atom (97M12). 

Structural changes affect seriously an electrophilic substitution orientation in pyrroles owing to their low positional selectivity in reactions with electrophiles. Thus, in contrast to thiophene, selenophene, and, especially, furan analogues, even a relatively weak type 11 substituent in position 2 of the pyrrole ring is capable of overcoming the a-oiienting effect of the heteroatom and directs an electrophile preferably to the position 4 (68JCS(B)392). N-(p-Nitrophenyl)pyrrole-2-carbaldehyde... 

Fig. 34. Positional selectivity of gaseous CH3FCH3 and f-C4Hj ions toward furan and thiophene [82JA7091 83JCS(P2)1491].

These substitutions are facilitated by electron release from the heteroatom pyrroles are more reactive than furans, which are in turn more reactive than thiophenes. Quantitative comparisons of the relative reactivities of the three heterocycles vary from electrophile to electrophile, but for trifluoroacetylation, for example, the pyrrole furan thiophene ratio is 5 x 10 1.5 x 10 I " in formylation, furan is 12 times more reactive than thiophene, and for acetylation, the value is 9.3. In hydrogen exchange (deuteriodeproton-ation), the partial rate factors for the a and p positions of A-methylpyrrole are 3.9 x 10 ° and 2.0 x 10 ° respectively for this same process, the values for furan are 1.6 x 10 and 3.2 x l(f and for thiophene, 3.9 X 10 and 1.0 x 10 respectively, and in a study of thiophene, a P ratios ranging from 100 1 to 1000 1 were found for different electrophiles. Relative substrate reactivity parallels positional selectivity i.e. the a P ratio decreases in the order furan > thiophene > pyrrole. ° Nice illustrations of these relative reactivities are found in acylations of compounds containing two different systems linked together. ... 

Kinetic studies of acylation reactions are somewhat limited by the insolubility of the acyl halide-Lewis acid complexes in many of the solvent systems that are used. However, useful results have been obtained and, as far as we are concerned, relative rates of reactions are of greater importance than absolute values. In any case it is not possible to distinguish between the two mechanistic extremes on the basis of the observed kinetics." Friedel-Crafts acylations are generally characterized by high substrate selectivity and frequently by high positional selectivity. Relative rate data show, as expected, that toluene is more reactive than benzene and that /n-xylene is the most reactive of the dimethylbenzenes. Values, relative to benzene, for benzoylation catalyzed by aluminum chloride were r-butylbenzene (72), toluene (1.1 X 10 ), p-xylene (1.4 x 10 ), o-xylene (1.12 x 10 ), and m-xylene (3.94 x 10- ). Competition data for the trifluoroacetylation of a number of heterocycles using trifluoroacetic anhydride at 75 "C gave the relative rates thiophene (1.0), furan (1.4 x lO ), 2-methylfuran (1.2 x 10 ) and pyrrole (5.3 x 10 ). ... 

Electrophilic reactions on the electron-rich, aromatic thiophene nucleus continue to provide a powerful route to substituted derivatives. Comparison of positional selectivity of the heteroarenium ions derived from furan. pyrrole or thiophene suggest that ease of P-substitution correlates with the relative stabilities <94H2029>. Freidel-Crafts reaction of 2,5-... 

The reactivity of thiophen has also been compared with that of seleno-phen and the relative reactivities in five electrophilic substitutions have been determined by kinetic or competitive procedures. The results have been compared with those available in the literature for furan. In all the reactions examined, selenophen exhibited a reactivity intermediate between those of furan and thiophen. p-Constants for electrophilic substitution of substituted thiophens are usually smaller than in the benzene series. A comparison of the trifluoroacetylation of a series of substituted thiophens and furans yielded p-values of — 7.4 and — 10.7 respectively. The observed order of substrate selectivity in the trifluoroacetylation (furan > thiophen) thus parallels the positional selectivity in electrophilic substitution, the oi ratio always being larger in furans than in thiophens. The relative importance of primary steric effects in benzene and thiophen has been investigated by determination of the isomer distributions in the acetylations of 2- and 3-methylthiophen, 2- and 3-t-butylthiophen, and toluene and t-butylbenzene. Steric hindrance is less significant in the thiophen series owing to the more favourable geometry. - ... 

As in the above chemistry with alkynes, the palladium-bound products of this cydoisomerization (e.g., 15, Scheme 6.23) can also be trapped with the addition of external reagents prior to the elimination step. This typically involves the oxidative addition of R—X substrates (e.g., aryl or vinyl halides, allylic substrates, etc.) to a palladium(O) catalyst to create the palladium( 11) complex needed for cydoisomerization, followed by reductive elimination of the substituted furan product. As illustrated with the example in Scheme 6.25, this provides a route to selectively install substituents into the 3-furan position a derivatization difficult via more traditional electrophilic aromatic substitution routes [35]. 

Benzoic acid and naphthoic acid are formed by the oxidative carbonylation by use of Pd(OAc)2 in AcOH. t-Bu02H and allyl chloride are used as reoxidants. Addition of phenanthroline gives a favorable effect[360], Furan and thiophene are also carbonylated selectively at the 2-position[361,362]. fndole-3-carboxylic acid is prepared by the carboxylation of 1-acetylindole using Pd(OAc)2 and peroxodisulfate (Na2S208)[362aj. Benzoic acid derivatives are obtained by the reaction of benzene derivatives with sodium palladium mal-onate in refluxing AcOH[363]. 

A different procedure provides access to 2,3,5-trisubstituted furans. Deslongchamps discovered that simply heating a mixture of glyceraldehyde (41) and methyl acetoacetate (42) in DMF provides a high yield of furan 43. Subsequent transformations enable selective substitution at the 2-position of the product. 

The construction of the five contiguous stereocenters required for a synthesis of compound 3 is now complete you will note that all of the substituents in compound 5 are positioned correctly with respect to the carbon backbone. From intermediate 5, the completion of the synthesis of the left-wing sector 3 requires only a few functional group manipulations. Selective protection of the primary hydroxyl group in 5 as the corresponding methoxymethyl (MOM) ether, followed by benzylation of the remaining secondary hydroxyl, provides intermediate 30 in 68 % overall yield. It was anticipated all along that the furan nucleus could serve as a stable substi-... 

A series of inhibitors containing an electrophilic keto-l,3,4-oxadiazole moiety as the warhead has been reported in which the substituent at the 5-position was varied resulting in the identification of furan as the optimal prime side substituent. Exploration of P3 substituents led to the identification of 10 with a K, of 1 nM against Cat K with > 700-fold selectivity over off-target cathepsins (Cat B Ki = 730 nM Cat L Rj = 960 nM Cat S Rj = 700 nM) [54], The potency of this compound was shifted in a functional bone resorption assay (Cat K IC50= 132 nM). 

Halopyrimidines also couple with stannanes of heterocycles such as furans [41], azaindoles [42], pyridines [43-46], thiazoles, pyrroles [46] and thiophenes [47], A representative example is the coupling of 3-tributylstannyl-7-azaindole 72 with 5-bromopyrimidine to furnish heterobiaryl 73 after acidic hydrolysis [42]. Moreover, a selective substitution at the 5-position was achieved when 4-chloro-5-iodopyrimidine 74 was allowed to react with 2-thienylstannane to provide thienylpyrimidine 75 [47]. 

The silylation of heteroarenes was also reported [96]. Silylation of thiophene or furan with 11 occurs selectively at the ot-position in the presence of [Ir(COD) (OMe)]2/2-ferf-butyl-l,10-phenanthroline (tbphen, 17). Silylation of pyrrole or indole under the same conditions was unsuccessful presumably due to the presence of the acidic N-H bond. Accordingly, N-substituted pyrrole and indole undergo silylation with 11, to selectively give 3-substituted products (Scheme 7). 

The scope of allylic electrophiles that react with amines was shown to encompass electron-neutral and electron-rich ciimamyl methyl carbonates, as well as furan-2-yl and alkyl-substituted allylic methyl carbonates. An ort/io-substituted cinnamyl carbonate was found to react with lower enantioselectivity, a trend that has been observed in later studies of reactions with other nucleophiles. The electron-poor p-nitrocinnamyl carbonate also reacted, but with reduced enantioselectivity. Allylic amination of dienyl carbonates also occur in some cases with high selectivity for formation of the product with the amino group at the y-position over the s-position of the pentadienyl unit [66]. Arylamines did not react with allylic carbonates under these conditions. However, they have been shown to react in the presence of the metalacyclic iridium-phosphoramidite catalysts that are discussed in Sect. 4. 

The aromatic silylation of five-membered heteroarenes under the same conditions (catalyst, temperature, solvent) also proceeded in regioselective fashion. Both, thiophene and furane derivatives are exclusively silylated at the a-position, but 1-triisopropylsily 1-pyrrole and -indole each produce selectively ]3-silyl products (Equations 14.9 and 14.10). 

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