Reaction of Aromatic Azides with Strong Acids : Formation of Fused Nitrogen Heterocycles and Arylamines

Descrevemos neste trabalho a ação de ácido trifluoroacético, ácido trifluorometanossulfônico e cloreto de alumínio sobre aril azidas orto-substituídas para formar indóis, azepinas e arilaminas com bons rendimentos. As azidas protonadas perdem nitrogênio para formar íons arilnitrênios intermediários que sofrem N-substituição aromática intramolecular. A decomposição ácida de aril azidas é comparada com resultados de termólise tomados da literatura.


Introduction
Nitrenium ions are reactive intermediates that have been the subject of much recent attention 1 .One reason for this is the proposal that arylnitrenium ions are intermediates in the reactions whereby various chemical carcinogens damage DNA 2 .The target of this reaction appears to be guanine bases in the DNA molecule 3 .Studies have confirmed that arylnitrenium ions, alleged to be involved in the carcinogenic pathways, do in fact react very rapidly with the critical DNA components 4 .Moreover, it has become increasingly clear that various ions have microsecond or longer lifetimes in water 5 .
In this paper, we report the reaction of various orthosubstituted aryl azides with strong acids like trifluoroacetic acid, trifluoromethanesulfonic acid and aluminum chloride to form nitrenium ion intermediates that collapse to a nitrogen five and seven-membered ring.Also we compare these results with thermal decomposition of the same azides in which a nitrene is the reactive intermediate.

Results and Discussion
trans-2-Azidostilbene 1, prepared by the procedure of Sundberg 12 , was treated in dichloromethane at 0 °C with trifluoromethanesulfonic acid (triflic acid) or trifluoroacetic acid.The temperature was allowed to reach the ambient and after neutralization, the crude material was purified by thick layer chromatography on silica gel to give 2-phenyl-1H-indole 3, mp 187-188 °C13 , in 85% yield.This cyclization suggests that protonated azide, a nitrenium like ion or a nitrenium ion, resulting from the protonated azide by loss of nitrogen 7a,9a , is responsible for the formation of the five membered ring (Scheme 1).Since Takeuchi reported formation of arylnitrenium ion (or a nitrenium-AlCl 3 complex) from decomposition of azides in presence of AlCl 3 , we treated 1 under the same conditions 9c .After the evolution of nitrogen stopped, the excess AlCl 3 was destroyed by 10% NaOH and after purification on silica gel plates, we isolated trans-2-aminostilbene, mp 101-103 °C13 , (formed by triplet nitrenium ion hydrogen atom abstraction) in 45% yield and only traces of 3. Thermolysis of 1 in ethylene glycol (reflux for 4 h) also furnished the 2-phenyl-1H-indole in 87% yield but in this case the intermediate is a nitrene 12 .Decomposition of 1, either in acidic conditions or by thermolysis, gave 2-phenyl-1H-indole 3 with comparable yields.
Ethyl E-2-azido-3-phenylpropenoate 7 (prepared by the procedure of Hermtsberger 15 with the Rees modification 16 ) with triflic acid in dicloromethane at 0 °C gave the 1H-indole 4 in 45% yield, mp 124-125 °C, while the TFA-catalyzed reaction under the same conditions gave 4 in 52% yield.Decomposition with AlCl 3 gave the 1H-indole 4 in 29% yield.Both reactions gave tarry material from which the 1H-indole 4 was isolated with difficulty.Thermolysis of 7 in xylene was reported to give 4 in high yield via a nitrene intermediate 17 and again this procedure gave a superior yield to the acid decomposition.cis-2-Azidostilbene 8 was prepared by the procedure of Staub 18a with the modifications of Detar and Chu 18b as an oil with IR and NMR identical to those reported by Smith et al. 19 Decomposition of 8 in dichloromethane solution with triflic acid gave 5H-dibenz[b,f]azepine 10, mp 198-199 °C20 , in 58% yield together with cis-2-aminostilbene 12, mp 63-64 °C17b , formed by reduction of the intermediate arylnitrenium in 17% yield.Very similar results were obtained with TFA, 10 was formed in 62% yield and 12 in 19% yield.Since Smith 19 observed that thermolysis of 8 in 7  4 cumene gave 2-phenyl-1H-indole 3 in only 18% yield and an intractable tar, we repeated the thermal decomposition of azide 8 in xylene reflux and we obtained the same results.
In order to explain the isolation of 3 Smith explained that when the phenyl and o-azidophenyl groups are cis, "there is steric interference with rotation of the o-nitrenophenyl group, making it difficult for it to engage the β carbon.As a result, there is time for intersystem crossing to the triplet nitrene to take place, and formation of the observed tars results" 19 .By comparison, the decomposition of cis-o-azidostilbene in acidic medium only gave 5Hdibenzo[b,f]azepine in reasonable yield in our experiments.
Treatment of 2-(2-phenylethyl)phenylazide 9 21 with triflic acid in dichloromethane gave an intractable dark material.However, with AlCl 3 we isolated 10,11-dihydro-5H-dibenz[b,f]azepine 11, mp 107-108 °C22 , in 20% yield, ortho-aminodihydrostilbene 13 in 12% yield 23 and 2'-amino-5'-dichlorodihydrostilbene 14 in low yield (detected in the mass spectrum).The geometry of 9 is not as favorable for intramolecular cyclization as the other two preceding examples and gave 11 in low yield.This less favorable geometry for cyclization leads the intermediate nitrenium ion to abstract hydrogen (via triplet species) forming 13 (together with tarry polymers) and to be intermolecularly intercepted by chloride ion giving 14.Thermal decomposition of 9 in xylene reflux also gave an intractable tar.Tomioka et al. studied the photolysis of the azide of 9 in cyclohexane that afforded 2-phenyl-1H-indoline exclusively in low yield 24 .
We observed that with TFA the yields of the cyclized compounds are identical or greater than those with TFSA.A possible explanation is based on the rationalization proposed by Okamoto for the acid-based catalysed reaction of N-arylhydroxylamines with the same acids that we have used.In TFA, the reaction center is the nitrogen atom and intramolecular nucleophilic attack probably proceeds at the nitrogen atom with some anilenium character 27 .In TFSA, Okamoto proposed a very reactive dicationic intermediate, the imine-benzenium ion, which takes part in the reaction and can be intercepted by a nucleophile at the ring.Using the same rationalization, one can propose a different behavior between TFA and TFSA for the acid decomposition of azides.We observed nucleophilic attack of the weak counter-ion at the ring only for the strong TFSA (H o = -14) 28 catalyzed reaction (Scheme 2, path b), while with Vol. 10, No. 5, 1999  Aromatic Azides with Strong Acids 417 ) which is better regarded as a 6-iminocyclohexadienyl carbocation 29 .
In conclusion, ortho-arylazides decompose in Lewis acids and strong protonic acids to give nitrenium ion intermediates which by an intramolecular electrophilic attack upon an ortho-aromatic nucleus regiospecificly form fiveand seven-membered nitrogen rings.It is not possible to predict a priori which acid will give cyclic products since it depends on the substituents of the aromatic starting material.When the geometry is favorable, the nitrenium ion is very efficient for the formation of a cyclized product and in this case the less acidic TFA gives a better yield than TFSA.Considering that the nitrenium ion is a very reactive species, an unfavorable geometry leads the intermediate to be intercepted by any nucleophilic species present in the reaction medium and even a weak nucleophile like trifluoromethanesulfonate ion can react.To avoid this intermolecular reaction, we propose that it is necessary to use a less acidic medium or to block the para and ortho positions in relation to the azide to allow the intramolecular electrophilic attack of the nitrenium ion upon an ortho-aromatic nucleus; further studies are in course to prove this assertion.Another possible pathway is via the initial singlet nitrenium ion with an extended lifetime which is transformed into a triplet nitrenium ion that may abstract hydrogen atoms 30 from the medium to produce amines or tarry polymers 9c .Thermal decomposition of the same azides gave compara-ble results in some cases and better or worse than acid decomposition in other cases.This is not unexpected since different intermediates should be involved, nitrenium ion or nitrenium-like ion in the acid medium and nitrene species in the thermolysis.

Experimental
Chemicals were purchased from Aldrich Chemical Co. or prepared following literature procedures 3 .Melting points were obtained on a Fisher-Johns melting point apparatus and are uncorrected.Infrared spectra were taken on a Jasco A-202 spectrophotometer.The 1 H-NMR spectra were recorded with a Bruker AW-80 spectrometer using tetramethylsilane as an internal standard.Mass spectra were obtained on a Varian Mat 311 A instrument at 70 eV using a direct insertion probe.Preparative thick layer chromatography was carried out on plates coated with silica gel PF 254 (Merck) and column chromatography was run on silica gel 60 (Merck).

General procedure for azide decompositions with trifluoroacetic or trifluoromethanesulfonic acids
Trifluoromethanesulfonic acid (or trifluoroacetic acid) (1.2 mmol) 31 was added dropwise to a solution of the azide (1 mmol) in dichloromethane (10 mL) in a water-ice bath under nitrogen atmosphere and magnetic stirring.After the nitrogen evolution ceased, the reaction was neutralized with saturated solution of sodium bicarbonate, extracted with dichloromethane, dried with magnesium sulfate and the solvent evaporated.The crude residue was chromatographed on preparative plates using silica gel.

General procedure for azide decompositions with aluminum chloride
Anhydrous dichloromethane (10 mL) was added to anhydrous aluminum chloride (1.2 mmol) and the appropriate azide (1 mmol) was added dropwise with stirring.After the evolution of nitrogen gas ceased, aqueous sodium hydroxide solution (10%) was added and extracted with dichloromethane, dried over anhydrous magnesium sulfate and the solvent evaporated.The crude residue was chromatographed on preparative silica gel plate.