Pyrrolo[1,2-a ]quinazolines. Synthesis and biological properties

Pyrrolo[1,2-a ]quinazolines have raised some interest as bioactive scaffolds but their synthetic strategies based mainly on the anthranilic acid route have been rather limited. The last two decades have brought new approaches to the synthesis of pyrrolo[1,2-a ]quinazoline framework and thus their potential could be valued in the obtaining of new lead compounds from the important class of quinazolines. Herein we present the synthetic strategies towards compounds containing the pyrrolo[1,2-a ]quinazoline scaffold and their biological properties

Quinazolines are known to possess important biological properties 1 and thus their pyrrolofused derivatives are good candidates for the discovery of new lead compounds in medicinal chemistry.The main focus was on their linear pyrrolo-condensed natural products (i.e vasicinone) and consequently on their synthetic analogs. 2 However, the angular tricyclic system of pyrrolo[1,2-a]quinazoline has been rather seldom investigated regarding its biological properties and studies of its synthesis are quite limited prior to the last two decades.Nevertheless, new reports presented herein give reason to expect that efficient synthetic pathways could renew interest in this class of pyrrolo [1,2-a]quinazolines.
A review on syntheses and properties of these and related compounds was published in 1986, 3 and a short chapter focused on heterocycles containing the pyrimidine moiety was reported in 1991. 4This paper presents an up-to-date classification of the synthetic strategies, reviews the biological properties of pyrrolo [1,2-a]quinazoline, and covers all the relevant literature available.

The Synthesis of Pyrrolo[1,2-a]quinazolines
There are three known strategies for the synthesis of pyrrolo[1,2-a]quinazolines: syntheses starting from substituted quinazolines, synthetic routes starting from substituted N-arylpyrroles, and syntheses by double cyclisation of different starting reagents.

2.1
Syntheses starting from quinazoline and its derivatives 2.1.1From quinazolinium N-ylides.6][7] The N-ylide approach to pyrrolo[1,2-a]quinazolines is versatile in providing series of compounds by simple procedures.In the literature are known three main routes to these compounds via quinazolinium N-ylides, starting either from dichloroquinazolinium ylide (2) or the unsubstituted (3) or a monosubstituted quinazolinium N-ylide (4).The pyrrolo[1,2-a]quinazoline 5 (Scheme 1) was obtained by Khlebnikov et al. 8 in mixture with other two isomers from the corresponding dichloroquinazolinium N-ylide 2. Their synthetic strategy in obtaining pyrrolo-fused compounds was the 1,3-dipolar cycloaddition of the quinazolinium dichloromethanides generated in situ by the reaction of the quinazoline with dichlorocarbenes, in presence of different dipolarophiles such as dimethyl maleate.The result of the reaction was a mixture of isomeric pyrroloquinazolines, as the dichlorocarbene could also react at the N3 of the quinazoline generating the corresponding N-ylide.In some cases the fully aromatic compounds were obtained by using an oxidizing agent.Azouz et al. 9 obtained the tetrahydropyrrolo[1,2-a]quinazolines 6 and 7 starting with carbanion-unsubstituted quinazolinium N1-ylides using activated olefinic dipolarophiles (Scheme 2).The yields however were not high.When they employed dimethyl acetylenedicarboxylate (DMAD) as dipolarophile, an in situ ring-opening of the pyrroloquinazoline was observed with the formation of the corresponding N-arylpyrrole, but no further studies were performed in this direction. 9Recently, during the investigation on the cycloaddition reaction between monosubstituted quinazolinium ylides and symmetrical or unsymmetrical acetylenic dipolarophiles with the aim of obtaining pyrrolo[1,2-a]quinazolines, 10 the formation of substituted N-arylpyrroles 10,11 was observed.The dihydropyrrolo[1,2-a]quinazoline 8 was obtained however by using triethylamine as base in ethanol as solvent, and was characterized by NMR (Scheme 3).The pyrrolo[1,2-a]quinazoline derivatives 9 were observed in mixtures with the pyrroles only in the case when dimethyl acetylenedicarboxylate was used as dipolarophile (R = E = COOMe) and were isolated in two cases with moderate yields.2.1.2From substituted quinazolines.][15][16][17][18][19][20] By intramolecular cyclisation of the 1,2-dihydroquinazolinepropionitrile 3-oxides in alkaline media (Scheme 4) the corresponding 1-iminotetrahydropyrrolo[1,2-a]quinazoline-4-oxides 10 were obtained. 13

Scheme 10
There is also a report that on flash vacuum pyrolysis (FVP) of the pyrrole oxime 25 the parent pyrrolo[1,2-a]quinazoline (26) is obtained (Scheme 11) as the major product in a mixture with the pyrrole 27. 27The author also presents a study on the reaction mechanism leading to the pyrrolo[1,2a]quinazoline and extends his work on the reactivity of this parent heterocycle.

Synthesis by the tert-amino effect
By the cyclisation of the ortho substituted anilines of type 35, also known as tert-amino effect, the compounds 36 were obtained in medium yields. 35Recently, using the tert-amino effect Akyiama et al. 36

Syntheses by double cyclisation reactions
Various substituted quinazolines were obtained in two step reactions involving in the first step the formation of the bicyclic quinazoline or a N-arylpyrrole system followed in the second step by intramolecular cyclisation to the desired tricyclic pyrrolo[1,2-a]quinazoline system.2.4.1.Double cyclisation starting from anthranilic acid and its derivatives.The anthranilic acid route is one of the most facile synthetic route to quinazolines. 37Pyrrolo[1,2-a]quinazolines derivatives were obtained  starting from suitable anthranilic acid derivatives by reaction with aliphatic acids, esters or acid halides containing keto groups, followed by intramolecular cyclisation of the corresponding intermediates. Recen reports [67][68][69][70] state that starting with substituted anthranilic acid or its derivatives the pyrrolo[1,2-a]quinazolines 37 are obtained by cyclisation with substituted 3-oxo-4-halobutanenitriles.(Scheme 15) Most probably the reaction goes via a N-arylpyrrole intermediate.

Scheme 16
∆ Starting from the anthranilic acid amides 39 the pyrrolo[1,2-a]quinazolinones 40 were obtained by a gold-catalyzed cascade reaction with suitable alkynoic acids (Scheme 17). 74,75There were also obtained more complex structures containing the pyrrolo[1,2-a]quinazoline framework. 75Earlier studies by Patil et al. 76 showed that from alkynes tethered with hydroxyl groups, by double hydroamination with various substituted 2-aminobenzamides in presence of PtCl 4 , compounds similar to 40 were obtained.

Scheme 19
An interesting application of rhodium catalyzed hydroformylation of compounds of type 45, obtained starting from anthranilamides, was reported by Campi et al. 82,83 The reaction led to the reduced pyrrolo[1,2-a]quinazolines 46 (Scheme 20).

Scheme 25
By condensating 3-(4-chlorobenzoyl)propionic acid 58 with the amine 59 the hydrogenated pyrrolo[1,2-a]quinazoline 60 was obtained (Scheme 26). 94,95Studies were made in order to obtain specific stereoisomers of 60 starting from specific stereoisomers of the amine 59.Some studies regarding the fragmentation of such compounds by mass spectrometry should be mentioned. 96

Scheme 29
By the same strategy of metal reduction-condensative cyclization strategy Bunce and Nammalwar obtained similar compounds using Fe as metal catalyst and starting from the unsubstituted 2-nitrobenzamide in reaction with linear keto bearing compounds. 102ecently a synthesis 103 starting from different substituted anilic esters 66 was reported to yield pyrrolo [1,2-a]quinazolines 67a,b.The reaction goes through an isolable cyclic imide.

Biological Properties of the Pyrrolo[1,2-a]quinazolines
The biological properties of the pyrrolo[1,2-a]quinazoline system have not been much investigated, perhaps because of the scarcity of preparative routes to such compounds.However, there are some reports and patents claiming potentially bioactive pyrrolo [1,2-a]quinazolines and these will be presented briefly in this chapter.

Antibiotic activity
Compounds 54 (Scheme 24) are reported as antibiotics, 91 but the author did not mention the specific antibiotic activity.

Analgesic, anti-inflammatory and antipyretic activity
Compounds of structure 68 are known to possess analgesic, anti-inflammatory and antipyretic properties.The patent contains also the pharmaceutical formulation of the active ingredients as capsules or tablets. 52 Compounds of type 69 are reported as anti-edema agents.The tests were carried out on mice which are subjected to strong inflammatory response induced by carrageenin with 25-100 mg doses of compounds of type 69. 56

Cardiovascular potential activity
Compounds of type 24 (Scheme 10) present antihypotensive activity and thus possess potential as cardiovascular therapeutics. 25,26ompounds of quinazoline class are hypotensive and bronchodilatators. 104,105Formula 70 presents some compounds with antiarrhythmic properties being therapeutics in treatment of atrial or ventricular arrhythmias.The pyrrolo[1,2-a]quinazolines 71 are claimed to possess hypotensive activity by regulating the blood pressure. 40The authors propose also pharmaceutical formulations for the compounds.Compounds similar to 71 substituted at N4 or possessing a carbonyl at C-1 are also claimed to possess antihypertensive properties. 48The inventors also present possible formulations as tablets for orally administration.The mechanism of action is not clearly defined; thus the compounds could have CNS depressant action also.

Bioactive compounds acting on the respiratory system
Compounds with general formula 72 were tested on guinea pigs and found to possess bronchodilatator properties. 106The patent includes a pharmacological formulation and possible administration methods.These compounds are claimed to be suited to the treatment of bronchial asthma.

Central nervous system activity
Compounds with general formula 73 were tested as CNS depressants.The tests on mice showed decreased motor-activity, respiration and sedative-ataxic effects. 47The compounds 71 with similar structure were also claimed to possess CNS depressant activity. 40The same authors present some pyrrolo[1,2-a]quinazolines with potential tranquilizant activity, 90 but the patent lacks details on how this activity was tested and measured.Compounds of formula 10 are reported only as intermediates in obtaining open cycle compounds as CNS depressants. 13The authors don't seem to provide biological data on the compounds 10 included in the patent.
The pyrrolo[1,2-a]quinazoline 74 was tested together with other quinazoline structure related compounds as sedatives, having potentiating barbiturate properties and are thus claimed to be useful as adjuvants in the treatment of convulsions, insomnia or mental disorders. 53This work is a continuation of a previous report by the same authors. 46The patent could refer to other analogs of the general formula 75.Pyrrolo[1,2-a]quinazolines with anticonvulsant properties are also reported in a German patent. 64ompounds 54 (Scheme 23) are also claimed to possess CNS depressant activity, mydriasis being one of the effects. 91

Conclusions
Pyrrolo[1,2-a]quinazolines are tricyclic compounds with great potential and combine the quinazoline substructure, a privileged structure in the medicinal chemistry, with a pyrrole.The synthetic methods are rather scarce but the past ten years have brought efficient new synthetic strategies which could lead to an increased interest in pyrrolo [1,2-a]quinazolines in the near future, mainly for their potential applications in medicinal chemistry.
a]quinazoline 1 is a pyrrolo-fused quinazoline N-bridgehead aromatic tricyclic system.The structure and numbering of the atoms in the pyrrolo[1,2-a]quinazoline skeleton are presented in formula 1.