Substitution at carbon

An enantioselective alkylation of pyrrole with enones has been reported 05JA4154 . For example, treatment of V-methylpyrrole 59 with enone 60 in the presence of a catalytic amount (10 mol%) of bis(oxazoline) catalyst 61 provided chiral adduct 62. Different additives including iodine 05T11751 and an aluminum surfactant 05CC789 have been utilized to mediate the Michael addition of pyrroles to p-nitrostyrenes. 

Fused heterocyclic 1,2,3,4,5-pentathiepins have been prepared by treatment of p3nroles and related heterocycles with disulfur dichloride in the presence of diazabicyclooctane (DABCO) 05OBC3496 . Thus, pentathiepin 64 was prepared from 2,5-dimethylp3UTole 63 using this 

The snbstitntion chemistry of 3,5-dichloro-2,4-p3Troledicarboxaldehydes has been investigated with different amine nncleophiles 05T5831 . Secondary amines preferentially form addncts with the formyl gronps, while primary amines replace the 5-chloro group. 

New electrophilic substitution reaction methods for the preparation of dipyrromethanes have been reported. The condensation of IV-methylpyrrole with benzaldehyde leading to the corresponding dipyrromethane was promoted by the addition of the organic catalyst, pyrrolidinium tetrafluoroborate 06T12375 . The reaction between pyrrole and N-tosyl imines promoted by metal triflates gave dipyrromethanes whereas tripyrromethane byproducts were not observed 06T10130 . 

A Nazarov-type cyclization was exploited to prepare annelated pyrroles 06OL163 . Acylation of iV-tosylpyrrole 65 with carboxylic acid 66 promoted by trifluoroacetic anhydride gave intermediate 2-ketopyrrole 67 which underwent a Nazarov-type cyclization to give cyclopenta[fc pyrrolc 68. Another route to cyclopenta[fc]pyrroles involved a novel cyclization involving pyrrole-substituted enones and isocyanides 06OL3975 . 

A gallium metal-mediated allylation of pyrrole led selectively to the formation of the 3-substituted pyrroles 06TL3535 . In contrast, a palladium-catalyzed allylation of pyrrole with allylic alcohols performed in the presence of triethylborane led to 2-substituted pyrroles 06H(67)535 . 

The Heck cyclization of bromopyrrole 77 and the corresponding oxidative Heck cyclization of desbromopyrrole 78 was studied 06SL3081 . While the Heck cyclization of 77 led to a mixture of [3.3.l]bicycle 79 and [3.2.2]bicycle 80 under a variety of conditions, the oxidative Heck cyclization of 78 led solely to the desired building block 79. The latter has previously been utilized in a total synthesis of dragmacidin F. 

An enantiospecific, gold-catalyzed pyrrole annelation reaction was utilized in a total synthesis of rhazinilam 95 06JACS10352 . Specifically, treatment of allene 81 with gold triflate - triphenylphosphine led to the formation of annelated pyrrole 82, which was subsequently converted into 95. A gold-catalyzed direct coupling of pyrroles with 1,3-dicarbonyls led to the formation (3-(pyrrol-2-yl)enones 06ASC331 . 

In most cases, electrophilic substitution of pyridines occurs very much less readily than for the correspondingly substituted benzene. The main reason is that the electrophilic reagent, or a proton in the reaction medium, adds first to the pyridine nitrogen, generating a pyridinium cation, which is naturally very resistant to attack by an electrophile. When it does occur, electrophilic substitution at carbon must involve either highly unfavoured attack on a pyridinium cation or a relatively easier attack, but on a very low equilibrium concentration of uncharged free pyridine base. 

Some of the typical benzene electrophihc substitution reactions do not occur at all Friedel-Crafts alkylation and acylation fail because pyridines form complexes with the Lewis-acid catalyst required, involving donation of the nitrogen lone pair to the metal centre. Milder electrophilic species, such as Mannich cations, diazonium ions or nitrous acid, which in any case require activated benzenes for success, naturally fail with pyridines. 

Electrophilic C-substitution in pyridines carrying strongly activating substituents (nitrogen and oxygen) is discussed in Sections 8.9.3.1 and 8.9.2.I. 

H-D exchange via an electrophilic substitution process, such as will operate for benzene, does not take place with pyridine. A special mechanism allows selective exchange at the two a-positions in DCI-D2O, or even in water at 200 °C, the key species being an ylide formed by 2/6-deprotonation of the 1//-pyridinium cation (see also 8.11). Efficient exchange at aU positions can be achieved at 110 °C in D2O in the presence of hydrogen and paUadium-on-carbon (a method which also works for other heterocycles, including indoles).  

Pyridine itself can be converted into 3-nitropyridine only inefficiently by direct nitration, even with extremely vigorons conditions, however a couple of ring methyl groups facihtate electrophilic substitution snfficiently to allow nitration both collidine (2,4,6-trimethylpyridine) and its M-methyl quaternary salt are nitrated at similar rates under the same conditions, showing that the former reacts via its A -protonic salt. Steric or/and inductive inhibition of M-nitration allows C-3-substitution using nitronium tetrafluo-roborate an example is the nitration of 2,6-dichloropyridine or of 2,6-difluoropyridine using tetramethyl-ammoninm nitrate with trifluoromethansulfonic anhydride.  

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The reactivities of the substrate and the nucleophilic reagent change vyhen fluorine atoms are introduced into their structures This perturbation becomes more impor tant when the number of atoms of this element increases A striking example is the reactivity of alkyl halides S l and mechanisms operate when few fluorine atoms are incorporated in the aliphatic chain, but perfluoroalkyl halides are usually resistant to these classical processes However, formal substitution at carbon can arise from other mecharasms For example nucleophilic attack at chlorine, bromine, or iodine (halogenophilic reaction, occurring either by a direct electron-pair transfer or by two successive one-electron transfers) gives carbanions These intermediates can then decompose to carbenes or olefins, which react further (see equations 15 and 47) Single-electron transfer (SET) from the nucleophile to the halide can produce intermediate radicals that react by an SrnI process (see equation 57) When these chain mechanisms can occur, they allow reactions that were previously unknown Perfluoroalkylation, which used to be very rare, can now be accomplished by new methods (see for example equations 48-56, 65-70, 79, 107-108, 110, 113-135, 138-141, and 145-146)... 

Does this imply that steric effects will be amplified it the transition state, and that the rates of Sn2 reactions wil decrease with increased substitution at carbon ... 

Next, examine the Sn2 transition states as space-filling models. Are you able to identify unfavorable nonbondec (steric) interactions that are not present in the reactants If so, which Sn2 reaction is likely to be most affected b] steric interactions Least affected Rationalize you observations. Hint Compare CBr bond distances in thf Sn2 transition states. How do these change with increasec substitution at carbon What effect, if any, does this havf on crowding ... 

A. Reactions of the Fully Aromatic Carbolines i. Substitutions at Carbon... 

The reaction of tetraphenylcyclopentadienone (tetracyclone) with dialkyl phosphites has invoked further interest. Miller has shown that reactions at 20 °C in the presence of sodium bicarbonate lead to products (35) and (36), with phosphorus substituted at carbon rather than oxygen. Quite different products (37) and (38) are obtained at 160 °C, although whether (38) is obtained from initial attack at oxygen or carbon is still unresolved. 

Phosphate esters have a variety of mechanistic paths for hydrolysis. Both C-O and P-0 cleavage are possible depending on the situation. A phosphate monoanion is a reasonable leaving group for nucleophilic substitution at carbon and so 8 2 or SnI reactions of neutral phosphate esters are well known. PO cleavage can occur by associative (by way of a pentacoordinate intermediate), dissociative (by way of a metaphosphate species), or concerted (avoiding both of these intermediates) mechanisms. 

In contrast to the ease of reaction of ring nitrogen atoms in 77-deficient six-membered heterocycles with electrophiles, electrophilic heteroaromatic substitution at carbon of the unsubstituted compounds proceeds only under very drastic conditions and yields of products are usually very poor. This is also true with pyridinium, pyrylium and thiopyrylium salts,... 

For general review on electrophilic substitution at carbon atom see (88BSB573 92H(33)1129 93AHC(57)291, 96KGS1535). 

The [(NH3)5CoOP(OMe)3]3+ ion has recently been shown292 to react with SCN, I or S2032-to produce (NH3)5Co02P(OMe)2]2+ and respectively MeSCN, Mel or MeS203. The reactions are believed to occur by SN2 substitution at carbon. This establishes a new mode of reaction for a coordinated phosphate ester. The rate enhancement on coordination is ca. 150. 

Bimolecular Electrophilic Substitutions at Carbon-Hydrogen Bonds... 

As in substitution at carbon, stereochemical and kinetic data provide the means of differentiating between these two possibilities. The stereochemical data are examined first. Substitution at silicon leads to both retention and inversion of configuration and the stereochemical outcome depends upon the nature of the leaving group, the nucleophile, solvent, complexing agents and whether or not the silicon is part of a ring. 

The mechanism shown in (25) can be described as an SN2 substitution at tin, or as an SE1 substitution at carbon catalysed by the ion OY, i.e. as mechanism Se1-OY-. A similar mechanism to that of (25) has also been postulated27 for the base-catalysed cleavage of 3-phenallyl derivatives of silicon, germanium, and tin these cleavages are more fully discussed in Chapter 10, Section 1 (p. 195). 

A. Schiavelli, M. D. Hughey, M. R. Bimolecu-lar substitution at carbon in neopentyl-like silylcarbinyl sulfonates. J. Am. Chem. Soc. 

Electrophilic substitutions at carbon, for example the reaction of an organometal-lic reagent with an electrophile, can occur either with retention [236, 238, 274, 275, 525, 529] or inversion [234, 471] at the nucleophilic carbon atom [57, 189, 522, 531, 532],... 

Apart from overcoming coulombic repulsions, 8 2 reactions also proceed with inversion in the face of steric hindrance. By comparison, the stereochemical result of unimolecular nucleophilic substitution SN1 is variable. In fact, nucleophilic substitutions at carbon with retention invariably follow other than SN2 paths. In its broad outlines, the Hughes-Ingold approach swept away the confusions of the period 1895-1933 and has not ceased to stimulate and provoke ideas in the area of substitution reactions. Surprisingly enough, the theoretical foundations of the SN2 process require reexamination and modification, as we shall see. 

No attempt will be made to test all of the predictions of Table 7 on the substitutions at carbon, silicon, and phosphorus. These have been reviewed repeatedly. Only a few examples have been chosen to illustrate certain points. 

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