One-pot reductive cyclization to antitumor quinazoline precursors

A highly efficient and versatile synthetic approach to the central core of anti-cancer quinazolinone derivatives is reported. Intermolecular reductive N -heterocyclizations of various 2-nitrobenzoic acid derivatives with formamide were catalyzed by indium(III) or bismuth(III) salts to yield the title compounds in high yields and excellent purities. In the present one-pot sequence, the arylnitro group is apparently reduced by formamide decomposition product carbon monoxide and the resultant anthranilic acid derivative proceeds to Niementowski cyclocondensation to form quinazolinones. The transformation is robust for diverse substituents on the aryl group and In(III) counterions, and is also compatible with N -alkyl formamides but not dimethylformamide.


Introduction
6][7] Among other pharmacological activities, quinazoline derivatives show remarkable antimicrobial properties against microorganisms associated with death in patients carrying immunocompromised diseases. 8We recently embarked on a program to synthesize anilinoquinazoline analogs as experimental cancer therapeutics.0] Here, we describe a streamlined and highly efficacious entry into the quinazolinone derivatives via a novel reductive heterocyclization mediated by indium(III) and bismuth(III) acetates.The syntheses of quinazolinone derivatives has been accomplished by cyclocondensation of formamide with anthranilic acid derivatives (Scheme 1, route a) or the less common Friedel-Crafts annulation of aminoaryl substrates (Scheme 1, route b). 11Variations of the former transformation typically proceed via a two-step sequence [11][12] beginning with reduction of 2nitrobenzoate to the amino analog followed by conventional Niementowski 11a cyclization with formamide to elaborate the quinazolinone framework.The overall yield of this route is reduced by the modest efficiencies of the reduction (Zn/acetic acid, SnCl 2 /HCl, or catalytic hydrogenation) and cyclocondensation steps, and the purifications required after each stage.In the present report, the reduction and Niementowski cyclization steps occur in a single pot without added reducing agents to provide quinazolinone products in excellent yields and purities.
Cognizant that a diverse set of substituted quinazolinone analogs have been employed in medicinal studies, a preliminary examination of the generality of this sequence was undertaken.6][7] For example, 2b is the precursor to cancer drugs ZD6474 (Vandetanib, developed by AstraZeneca under the trade name Zactima®) 15 and ZD4190 (currently under clinical trials; AstraZeneca), 16 while 2c is the precursor for the potent lung cancer drug ZD1839 (Gefitinib, developed by AstraZeneca under the trade name Iressa®). 17A comparison of the yields of this streamlined sequence with reported cyclocondensations (from anthranilic acids) are presented in the Table 1 (reported yields do not include the nitro group reductions as they are not typically reported).a All reactions were performed in the presence of 100 mol% catalyst at 150 °C and were completed within 5 hours according to TLC and 1H-NMR analyses.b See Scheme 2 for the positions of R 1 , R 2 , and R 3 on substrates and products.c Isolated yields after silica gel filtration and crystallization.d The yields reported are for Niementowski cyclization only.e Reference 14.
f Yield of the reaction with 100 mol% Bi(OAc) 3 in place of In(OAc) 3 .g Yields we obtained after following the procedure in Reference 13. h These compounds were previously reported without melting points (reference 13).i Yield from microwave assisted reaction (reference 12b).j Reference 12b.

Table 2. Reactions of carboxylic acid and formamide derivatives
The transformation was compatible with indium(III) chloride and triflate salts, as well as bismuth(III) acetate but did not occur with the acetates of Zn +2 , Fe +3 , Sc +3 , Yb +3 , and Ni +2 .A full equivalent of In(III) or Bi(III) salt was required for the complete conversion.The transformation did not proceed in the absence of salt even after extended heating.Only a small amount of 2a was formed when methyl 2-nitrobenzoate and formamide were reacted with 20 mol% of In(OAc) 3 or InCl 3 (150 °C), even after 5 days.
Several observations and experiments yielded mechanistic insights for this transformation.The reaction is likely to proceed via nitro group reduction followed by typical Niementowski cyclocondensation (Scheme 3), however the reagents used in this transformation include no obvious reductant.Carbon monoxide has been previously employed in transition metal complex 18 or selenium 19 catalyzed arylnitro group reductions to anilines and is also a known byproduct of formamide thermal decomposition 20 at 197 °C20a or at 230 °C.20b To test for the decomposition of formamide under the present conditions, methyl benzoate was heated with formamide (150 °C, 5 h) in the presence and absence of In(OAc) 3 .The observation of the quantitative formation of benzamide in the In(III) containing preparation and the lack of benzamide in the reaction not containing In(III) indicates that the metal salt catalyzes the formamide decomposition at these lower temperatures.Also, the nitro group reduction under these conditions was further examined by exposing nitrobenzene to In(III) salts (chloride or acetate, N-methylformamide, 150 °C, 10 h).The quantitative formation of aniline was observed ( 1 H NMR), indicating the reductive potential of these conditions.In all In(III)-and Bi(III)promoted transformations a brown, organic-insoluble solid was also recovered in place of the original white salt.An experiment in which metal salts InCl 3 , In(OAc) 3 , and Bi(OAc) 3 were independently heated in formamide (150 °C, 10 h) also induced the conversion of the white metal salts to dark materials (dark gray beads in the case of the bismuth salt), which suggests that CO reduces the metal(III) cation concurrently in this transformation.This was confirmed by the observation that the beads obtained from Bi(OAc) 3 were capable of conducting electric current.Several experiments examined the possibility that a reduced amount of formamide might selectively reduce the arylnitro group without effecting metal cation reduction, which would enable the development of a conversion using a catalytic quantity of metal salt.Preparations with reduced amounts of formamide (3 or 6 equiv; 1.0 equiv InCl 3 ) generated dark salts and trace amounts of quinazoline, indicating that the metal cation and arylnitro groups are reduced at similar rates.

Scheme 3. Reductive cyclization by formamide.
In the present reactions metal salts promote formamide decomposition and arylnitro group conversion to arylamines, but are reduced in the reaction leading to the requirement for a full equivalent of metal salt.The metal cation might also participate in catalyzing the subsequent cyclization step, but this issue has yet to be addressed.We are continuing to search for conditions under which metal salts are preserved in this reaction, which would permit the use of metal salts in catalytic quantities to promote the preparation of quinazoline products.

Conclusions
Intermolecular reductive N-heterocyclization of 2-nitrobenzoic acid and its acid derivatives with formamide was catalyzed by indium(III) or bismuth(III) salts to yield 4(3H)-quinazolinones in one-pot.Product purities preclude the need for chromatographic isolation, which contrasts sharply with the purifications required in the two-step sequence.A notable feature of this transformation is the role of formamide as reductant, cyclocondensate, and solvent.These studies also establish the precedent for employing formamide/metal salts as surrogates for CO.Studies are continuing on the syntheses of quinazolinones and on mechanistic issues related to this reaction.

Experimental Section
General Procedures.Proton NMR and 13 C NMR spectra were recorded at 500 MHz and 75 MHz (Varian Inova), respectively in DMSO-d 6 at 25°C.Chemical shift values are reported in ppm with TMS as reference.The coupling constant J values are given in Hz.The IR spectra were recorded on a BRUKER VECTOR 22 FT-IR spectrometer.Kieselgel 60F 254 silica gel TLC plates were used for monitoring reaction progress.Column chromatography was performed using silica gel-60 (TSI Scientific, 230-400 mesh) with ethyl acetate (Optima®, Fisher Scientific) as solvent.All necessary chemicals were purchased from either Sigma-Aldrich (St. Louis, MO) or Acros (Geel, Belgium) Chemical Companies and used without purification.All the metal salts were purchased with 99% or better purity.