Beirut Reaction

The Beirut reaction involves the condensation of benzofurazan oxide (BFO) 1 with an enamine 2 or an enolate anion 3 in an alcohol solvent to give the corresponding quinoxaline-1,4-dioxide 4.  

In 1965, Haddadin and Issidorides, at the American University of Beirut, observed that combining 1 with morpholinocyclohexene 5 in methanol afforded quinoxaline-1,4-dioxide 6 in 48% yield. Shortly thereafter, the same authors reported that 1 also reacts with 1,3-dicarbonyl compound 7 in the presence of triethylamine to give the quinoxaline-1,4-dioxide 8 in 38% yield. This reaction has been referred to in the chemical literature as the Beirut reaction to acknowledge the city in which it was discovered. 

Substituted benzofurazan oxides 9 and 11 have been studied by NMR at low temperature and were observed as a mixture of tautomers, presumably interconverting via the ortho-dinitroso intermediate 10. When R = Cl, MeO, or AcO, tautomer 9 is the more stable 

There is some debate in the literature as to the actual mechanism of the Beirut reaction. It is not clear which of the electrophilic nitrogens of BFO is the site of nucleophilic attack or if the reactive species is the dinitroso compound 10. In the case of the unsubstituted benzofurazan oxide (R = H), the product is the same regardless of which nitrogen undergoes the initial condensation step. When R 7 H, the nucleophilic addition step determines the structure of the product and, in fact, isomeric mixtures of quinoxaline-1,4-dioxides are often observed. One report suggests that N-3 of the more stable tautomer is the site of nucleophilic attack in accord with observed reaction products. However, a later study concludes that the product distribution can be best rationalized by invoking the ortho-dinitrosobenzene form 10 as the reactive intermediate. 

In the case of unsubstituted BFO 1 reacting with an enamine, the following mechanism is generally accepted in the literature. The first step is nucleophilic addition of an enamine 2 to electrophilic BFO 1 to form the intermediate 12. Ring closure occurs via condensation of the imino-oxide onto the iminium functionality to give 13. Finally, P-elimination of the dialkyl amine produces the quinoxaline-1,4-dioxide 4. 

Synthesis of quinoxaline-1,4-dioxides from benzofurazan oxide. 

Haddadin, M. J. Issidorides, C. H. Heterocycles 1976, 4, 767. The authors named the reaction after the city where it was discovered, Beirut, the capital of Lebanon. 

Tinsley, J. M. Beirut reaction in Name Reactions in Heterocyclic Chemistry, Li, J. J. Corey, E. J. Eds. Wiley Sons Hoboken, NJ, 2005, 504—509. (Review). 

Final deprotonation of the carboxylic acid drives the reaction forward. 

Tanaka, K. Kagawa, Y. Sakaino, Y. Chem. Lett. 1990, 373. 

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Quinoxaline and phenazine di-fV-oxides are also directly available by the Beirut reaction (see Section 2.14.3.2). 

Perhaps one of the most exciting developments in the chemistry of quinoxalines and phenazines in recent years originates from the American University of Beirut in Lebanon, where Haddadin and Issidorides first made the observation that benzofuroxans undergo reaction with a variety of alkenic substrates to produce quinoxaline di-AT-oxides in a one-pot reaction which has subsequently become known as the Beirut reaction . Many new reactions tend to fall by the wayside by virtue of the fact that they are experimentally complex or require starting materials which are inaccessible however, in this instance the experimental conditions are straightforward and the starting benzofuroxans are conveniently prepared by hypochlorite oxidation of the corresponding o-nitroanilines or by pyrolysis of o-nitrophenyl azides. 

In spite of the usefulness of the Beirut reaction, mechanistically it is not well understood. It has been suggested that the first step involves the nucleophilic attack by the enolate or the enamine at N-3 of the benzofuroxan to yield an intermediate iV-oxide (Scheme 50) which subsequently undergoes tautomerism to an hydroxylamino derivative. This intermediate then cyclizes to the dihydroquinoxaline 1,4-dioxide. This suggestion has not been proven, and indeed there is evidence that benzofuroxan is in equilibrium with 1,2-dinitrosobenzene... 

The more traditional methods of phenazine synthesis falling into the type A synthesis are altogether less satisfactory than the application of the Beirut reaction. Traditionally, Ris prepared phenazine in low yield by heating o-phenylenediamine and catechol in a sealed tube at 200 °C (1886CB2206) however, the method appears to be unsatisfactory at best and gives, in addition to phenazine, 5,10-dihydrophenazine in varying amounts (Scheme 53). Several variants of this procedure exist o-benzoquinone has been used in condensation with 0-phenylenediamine and yields as high as 35% have been reported, and 1,2,3,4-tetrahydrophenazine has been prepared by condensation of o-phenylenediamine with cyclohexane- 1,2-dione. 

BAY 94337 — see l,2,4rTriazin-5-one, 4-amino-6-t-butyl-3-methylthio- Bay region epoxides, 7, 189 Beckmann rearrangement, 7, 34 Beirut reaction, 3, 181-184 6, 407, 425 Bemegride... 

HAOOAOIN-ISSIOORIOES Ouinoxaline synthesis Synthesis ot quinoxaiine dioxides trom benzoiurazan oxide and ketone enoiates or enamines (also known as Beirut reaction). 

The generation of other heteroq cles from Bfx and Fx has been the subject of exhaustive investigation. The most important transformation of Bfx to other heterocycles has been described by Haddadin and Issidorides, and is known as the Beirut reaction . This reaction involves a condensation between adequate substituted Bfx and alkene-type substructure synthons, particularly enamine and enolate nucleophiles. The Beirut reaction has been employed to prepare quinoxaline 1,4-dioxides [41], phenazine 5,10-dioxides (see Chap. Quinoxahne 1,4-dioxide and Phenazine 5,10-dioxide. Chemistry and Biology ), 1-hydroxybenzimidazole 3-oxides or benzimidazole 1,3-dioxides, when nitroalkanes have been used as enolate-producer reagent [42], and benzo[e] [ 1,2,4]triazine 1,4-dioxides when Bfx reacts with sodium cyan-amide [43-46] (Fig. 4). 

Fig. 4 Transformation of Bfx to different heterocycles using the Beirut reaction...

Another one-step method of similarly limited value for the synthesis of multiply substituted phenazines 84 is the Beirut reaction [80]. It involves the transformation of the easily accessible benzofuroxans 85 together with, in... 

A simple, efficient, one-step synthesis of quinoxaline 1,4-dioxides from the reaction of benzofurazan oxide 179 with activated alkenes such as enamines was named the Beirut reaction in honor of the city of its discovery. Developments up to 1993 were surveyed by Haddadin and Issidorides <1993H(35)1503>, who first demonstrated this reaction. The benzofurazan oxide 179 (Scheme 52) also condenses with 1,3-diketones <1995M1217, 1996JHC1057, 1999CHE459, 2003EJM791, 2005H(65)1589>, /3-keto acid derivatives <1995H(41)2203,... 

Many quinoxaline 1,4-dioxides have been prepared by the Beirut reaction (Section 8.03.10). Phenazine 5,10-dioxides are prepared by the Beirut reaction using hydroquinone (Section 8.03.10), and they can be also synthesized by treatment of o-nitroanilines with dihydroxybenzenes (Equation 32) <1995M1217>. 

Haddadin and Issidorides first reported an elegant method for the synthesis of quinoxaline 1,4-dioxides (47) from the reaction of benzofurazan 1-oxide (46) and an enamine or an active methylene compound, such as a /J-diketone or a /J-ketoester, in the presence of base.46 47 Quinoxaline 1,4-dioxide formation formally involves loss of secondary amine in the enamine reaction and loss of water when an active methylene compound of the type R CH2CORJ is used. This reaction is now commonly referred to as the Beirut reaction. The isolation of the dihydroquinoxaline 1,4-dioxide 48 from the reaction of 46 and NJV-dimethylisobutenylamine (Me2C=CHNMe2), which is unable to aromatize by amine loss, suggests that 2,3-dihydroquinoxalines are likely intermediates in all these reactions.48... 

There are many patents on the Beirut reaction thus 2-carbamoyl,57 2-amino-3-amidino-,58 2-methyl-3-carbamoyl-,59 2-amino-3-carbamoyl-,60 2-halomethyl-3-carboxy,61 2-mercapto-,62 and 2-trifluoromethyl63 quinoxaline 1,4-dioxides are just a few examples among the many quinoxaline derivatives prepared by this method. In a... 

Makhluf J. Haddadin was born in Main, Jordan. He holds B.S. and M.S. degrees (Professor C. H. Issidorides) from the American University of Beirut and a Ph.D. degree from the University of Colorado, USA (Professor A. Hassner). He was a research fellow at Harvard University (Professor L. F. Fieser). The art of heterocyclic chemistry has been his main hobby as he worked on heterocyclic steroids, isobenzofurans, isoindoles, quinoxaline 1,4-dioxides (the Beirut reaction), pyridazines, tetrazines, 277-indazoles, and other heterocycles. He rejoined his alma mater in 1964 and currently serves as professor of chemistry. He was vice-president for academic affairs (1987-99). 

The main synthetic approaches for the preparation of QDO and PDO until the middle of the 20th century [7] had been associated with the oxidation of the parent heterocycles, Qx and Pz, respectively. However, since the description of the Beirut reaction, by Haddadin and Issidorides [8], the most important preparation procedure of both heterocycle systems is the expansion of ben-zofuroxans (Bfxs) with adequate synthons that introduces carbons 2 and 3 for QDO or carbons l-4a and 10a in the case of PDO. Some other synthetic procedures have also been depicted, which are described in the next sections. 

Mechanistically, the Beirut reaction is a heterocycle expansion-process where the nucleophile attack conducts, after atomic rearrangements, to a new diazine system. In general, a further elimination—i.e., of H2O, amines, acetate—aromatizes the new heterocycle. 

The Beirut process as a method for preparing QDO and PDO is sometimes inconvenient. One of the main problems has been evidenced when substituted Bfxs were used as a reagent for the Beirut reaction. In this case, a mixture of positional isomers, in general non-separable by ordinary chromatographic techniques, of QDO or PDO have been obtained. This finding is the result of the well-known tautomerism that affects the Bfx reactants at room temperature (see example in Scheme 2) [41,42], In general, the tautomeric equilibrium energy barrier is very low at room temperature and therefore... 

Fig. 4 Different isomeric 2-amino-7/8-substituted PDO obtained through the Beirut reaction, relationship with electronic substituent characteristics...

Another recognized inconvenience of the Beirut reaction involves the 4/7-mono and disubstituted Bfx that reacts significantly slower or does not react at all in producing the corresponding 5/8-mono or disubstituted QDO and 1/4-mono or disubstituted PDO. This is explained by the repulsive effect of the substituent and the N-oxidc in the forming product [44],... 

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