Bischler-Napieralski Reaction Bischler-Napieralski Cyclization

For the cyclization, an activated arene is needed to effect ring closure at reflux temperature if the solvent is toluene. Alternatively, xylene can be used, and microwave-assisted chemistry in superheated solvents is also a viable solution.

The Bischler-Napieralski Reaction allows the synthesis of 3,4dihydroisoquinolines from the -ethylamides of electron-rich arenes using condensation reagents such as P2O5, POCl3 or ZnCl2.

One of the most important side reactions is the retro-Ritter reaction forming styrenes, which is also evidence for nitrilium salts as intermediates:

Mechanism of the Bischler-Napieralski Reaction According to detailed studies by Fodor and Nagubandi (Tetrahedron 1980, 36, 1279. DOI), the Bischler-Napieralski Reaction involves an initial dehydration step of the amide followed by a cyclization. Fodor was able to prepare stable imidoyl salts at room temperature that formed nitrilium salts upon mild heating, whereas the Bischler-Napieralski Reaction required elevated temperatures to form dihydroisoquinolines. A mechanism that includes nitrilium salts also accounts the In this example, the formation of a conjugated system favors the retro-Ritter reaction. A possible solution is the use of the corresponding nitrile as solvent, occurrence of styrenes as side products as will be explained later. which shifts the equilibrium to the left side, but some nitriles (R' Me) can be expensive. Another solution was recently presented by Larsen using oxalyl In the dehydration, reagents such as PCl5, POCl3, SOCl2, ZnCl2 can be used to chloride to form an N-acyliminium intermediate, so that elimination of the amide promote loss of the carbonyl oxygen. Use of POCl3 leads first to formation of group as the nitrile is avoided. imidoyl phosphates in which phosphate is a good leaving group. Use of P2O5 or addition of P2O5 to a reaction with POCl3 leads to pyrophosphates, which are even better leaving groups.

R. D. Larsen, R. A. Reamer, E. G. Corley, P. Davis, E. J. J. Grabowski, P. J. Reider, I. Shinkai, J. Org. Chem., 1991, 56, 6034-6038.

In the following recently published procedure by Movassaghi, Tf2O is used in the presence of 2-chloropyridine to provide a mild cyclodehydration reaction. Here the authors suggest that electrophilic activation of N-alkylamides may lead to a transient highly electrophilic nitrilium ion (or pyridinium adduct) that is trapped by the arene ring. Microwave-assisted Bischler-Napieralski or Pictet-Spengler reactions allowed the production of substituted isoquinoline libraries. The generated dihydroisoquinolines and tetrahydroisoquinolines could be oxidized to their corresponding isoquinoline analogues. A more practical and efficient route to C1and C4-substituted isoquinolines involves the preparation and activation of isoquinolin-1(2H)-ones. E. Awuah, A. Capretta, J. Org. Chem., 2010, 75, 5627-5634. M. Movassaghi, M. D. Hill, Org. Lett., 2008, 10, 3485-3488. The two-step procedure reported by Larsen and the method described by Movassaghi allow the transformation of a broad range of substrates into 3,4dihydroisoquinolines and the use of milder conditions. Some more procedures can A modified Bischler-Napieralski procedure for the synthesis of 3-aryl-3,4be found in the Recent Literature section. dihydroisoquinolines R. D. Larsen, R. A. Reamer, E. G. Corley, P. Davis, E. J. J. Grabowski, P. J. Recent Literature Reider, I. Shinkai, J. Org. Chem., 1991, 56, 6034-6038.

A Versatile Cyclodehydration Reaction for the Synthesis of Isoquinoline and Carboline Derivatives M. Movassaghi, M. D. Hill, Org. Lett., 2008, 10, 3485-3488.

The first Bischler-Napieralski cyclization in a room temperature ionic liquid

A Very Mild Access to 3,4-Dihydroisoquinolines Using Triphenyl PhosphiteBromine-Mediated Bischler-Napieralski-Type Cyclization D. Vaccari, P. Davoli, C. Ori, A. Spaggiari, F. Prati, Synlett, 2008, 2803-2806.

Vicarious Nucleophilic Substitution (VNS)

Vicarious Nucleophilic Substitution allows the nucleophilic replacement of hydrogen in nitroaromatics and heteroaromatics by using carbanions that bear leaving groups at the nucleophilic center.

Mechanism of the Vicarious Nucleophilic Substitution

It was well known that polynitroarenes form stable adducts with various nucleophiles (Meisenheimer complexes) and that bond formation to carbon atoms bearing hydrogen is faster than to those bearing other substituents, including halogens. However, no general nucleophilic replacement of hydrogen was known until the end of the 1970s, when Mieczysaw Makosza began elaborating the direct nucleophilic replacement of hydrogen in electrophilic arenes. He hypothesized that -adducts formed from carbanions that contain leaving groups at the carbanionic center proceed to lose the leaving group. This was first proven by treatment of nitrobenzene with chloromethyl phenyl sulfone.

As the chloride in this case acts vicariously as a leaving group, the reaction was named "vicarious nucleophilic substitution of hydrogen" (VNS). In typical vicarious nucleophilic substitutions, nitroarenes react with carbanions that are usually generated from active methylenes by reaction with a base that is also consumed in a later elimination step. Thus, the reaction runs best with more VNS reactions have been reported between chloromethyl sulfone and heterocycles than two equivalents of a strong base. The proper choice of solvent and base assures a fast deprotonation of the active methylenes and a fast -elimination from such as 2- and 3-nitrothiophenes, 2-nitrofurans, 2-, 3- and 4-nitropyridines and many others. the -adducts. The nitrobenzylic carbanions that form are highly colored (blue, red, etc.), which offers some diagnostic value. Acidic work-up leads to the products.

For nitropyrroles, replacement of the acidic N-H by an alkyl group is necessary because the nitropyrrole anion itself does not undergo VNS. For carbanions stabilized with sulfonyl groups or phosphorus-containing substituents, chloride is a convenient leaving group. For -cyanoalkylation, though, (thio-)phenoxy nitriles (leaving group: PhO or PhS) often assure better yields, because the chloronitriles are frequently unstable in basic media or undergo fast self-condensation. For -carboalkoxyalkylation, carbanions of esters that contain PhS are of general use, although ethyl -chloropropionate and chlorobutyrate also afford VNS products, often in good yields. The following are some examples of suitable nucleophiles:

For VNS of substituted nitroarenes: 4-substituted nitroarenes give only one product (VNS ortho to nitro group), whereas 2- and 3-substituted nitroarenes normally lead to mixtures of isomeric products (VNS ortho and para to nitro group). In halonitroarenes, VNS is normally faster than aromatic nucleophilic substitution of halogen, except for 2- or 4-F-substituted nitroarenes where fluoride is a superior leaving group. Nucleophilic substitution is disfavored by direct conjugation of anions, such as in the case of nitrophenolates. As the nitrobenzylic carbanions themselves do not add nucleophiles, the reaction is very selective for monosubstitution. However, a second or third nitro group substituent compensates the negative charge, although here the rates of introduction of the substituents are very different.

As both the addition and elimination step are sensitive to steric effects, tertiary carbanions (R: Me, Ph,...) react preferably at the para position. A general overview of VNS, including detailed mechanistic discussions and examples dealing with the synthesis of heterocycles in which VNS is used for ring closure, can be found in a review written by Makosza and Winiarski (Acc. Chem. Res. 1987, 20, 282. DOI). For recent applications of VNS, including protocols for amination and hydroxylation, please also refer to the recent literature section in this site.

Recent Literature

The conversion of aryl amines to aryl fluorides via diazotisation and subsequent thermal decomposition of the derived tetrafluoroborates or hexafluorophosphates. The decomposition may also be induced photochemically.

Mechanism of the Balz-Schiemann Reaction para-Formylation of nitroarenes via vicarious nucleophilic substitution of hydrogen with tris(benzotriazol-1-yl)methane A. R. Katritzky, L. Xie, Tetrahedron Lett., 1996, 37, 347-350. see Diazotisation. The mechanism of the Balz-Schiemann reaction remains obscure. A possible pathway is shown below:

1,1,1-Trimethylhydrazinium Iodide: A Novel, Highly Reactive Reagent for Aromatic Amination via Vicarious Nucleophilic Substitution of Hydrogen P. F. Pagoria, A. R. Mitchell, R. D. Schmidt, J. Org. Chem., 1996, 61, 2934-2935.

Hydroxylation of Nitroarenes with Alkyl Hydroperoxide Anions via Vicarious Nucleophilic Substitution of Hydrogen M. Makosza, K. Sienkiewicz, J. Org. Chem., 1998, 63, 4199-4208. Schiemann Reaction