Synthesis and structural properties of 2-([2.2]paracyclophanyl)-2,3-dihydroquinazolines by cyclocondensation of 2-aminoaryl-benzimidamides with 4-formyl[2.2]paracyclophane catalyzed efficiently by iodine

Technical iodine was found to catalyze the condensation between 2-aminoarylbenzimidamide derivatives ( 1a-i ) and 4-formyl[2.2]paracyclophane ( 2 ) in absolute ethanol under mild conditions to afford 2-([2.2]paracyclophanyl)-4-arylamino-2,3-dihydroquinazoline derivatives ( 3a-i ) in good yields and with high diastereoselectivity. The obtained products were oxidized easily by KMnO 4 to yield the corresponding 2-([2.2]paracyclophanyl)-4-arylaminoquinazoline derivatives ( 6a-g ). The structure of 3b was conformed by X-ray crystallography.


Introduction
The quinazoline skeleton is an important part of many alkaloids and has been isolated from some plants, especially of the Rutacea family. 1,2Quinazoline moieties are considered to be pharmacophores because they show many types of pharmacological properties 3,4 especially as antiinflamatory, 5 antiallergic 6 and antimalarial agents 7 and in cancer treatment. 8Some quinazolines possess inhibiting properties for tyrosine kinase, 9 which is useful in inhibiting tumour growth.Thus quinazolines are considered to be a privileged structure for drug development.Quinazolines have been synthesized from the reaction of 2-aminobenzonitrile with Grignard reagents in presence of acyl halides, or by treating 2-aminobenzonitrile with Grignard reagent in presence of aldehydes or ketones or by heating 2-aminobenzonitrile with phenylisocyanate or lactic acid. 10,11They have also been synthesized by using low-valent titanium compounds as catalysts, 12 by using a tandem Aza-Wittig reaction, 13 or by heating 2aminobenzamide with aldehydes 14 or, very recently, by reacting 2-aminoarylbenzimidamides with tetracyanoethylene. 15

Results and Discussion
Because of the increasing importance of 2-substituted quinazolines, and as part of our program designed to expand the chemistry of 4-formyl [2.2]paracyclophane and other chiral phanes, a simpler approach to synthesize these heterocyclics was thought to be of value.Quinazolinophane and related compounds constitute an essentially unexplored area and this encouraged us to initiate a study of the chemistry of these compounds.Among the various catalysts that have been applied to cyclocondensation reactions, molecular iodine was found to be the best. 16-Aminoarylbenzimidamides 15 serve as convenient building blocks for the formation of heterocyclic moieties with two nitrogen atoms.The heterocyclization proceeds with the involvement of the N-C-C=C-N fragment of benzimidamide derivatives.Thus the condensation of the latter class of compounds with carbonyl compounds affords the 2,3-dihydroquinazoline system (3a-i).In the present study, we investigated the heterocyclization of 2-aminoarylbenzimidamides (1a-i) with 4-formyl [2.2]paracyclophane (2) in presence of a catalytic amount of commercial iodine.As shown in Scheme 1 this led to the formation of the title compounds in good yields.Since the products 3 have two elements of chirality (a center and a plane) one would expect the formation of diastereomeric mixtures.However, according to TLC analysis (one spot only) and NMR spectra (no sign of line doubling in the 13 C NMR spectra) only one diastereoisomer appears to be formed: (Z)-aryl-N-(2-(R)-[2.2]paracyclophanyl-2,3-dihydroquinazolin-4(1H)-ylidne)aniline.This means that the formation of the products 3 takes place with very high diastereoselectivity.
The single crystal X-ray structure of the selected example 3b (see below) supports this observation of very high diastereoselectivity.
The formation of the products (3a-i) may be rationalized according to the pathway shown in Scheme Possible mechanism for the formation of compounds (3a-i).
The reaction begins by attack of the nucleophiles 1a-i on the carbonyl group of 2. We have previously shown that the oxygen atoms of several [2.2]paracyclophanes carrying a keto function in 4-position point towards the ethano bridge. 17Furthermore, we postulate that the bulky reagents 1 approach 2 only from the "outside" then the intermediate 4a-i would result in the first step.It is easily conceivable that the intramolecular ring closure of 4a-i could take place from the sterically less shielded outside also, resulting in the formation of the intermediate zwitterions 5ai.This, ultimately, will stabilize itself by a (formal) 1,3-proton transfer to the isolated products 3.
The structures of the synthesized 2-([2.2]paracyclophanyl)-2,3-dihydroquinazolinederivatives (3a-i) were deduced from their IR and NMR spectra as well as their mass spectrometric properties.The IR spectra displayed (NH) absorption peaks at ν = 3490-3300 cm -1 , in addition to the (C=N) absorption peaks at ν = 1640-1600 cm -1 .Taking 3g as an example and with the help of 2D-NMR data we found that, its 1 H NMR spectrum showed in addition to the aliphatic protons of the bridge of the [2.2]paracyclophane unit which appeared as two multiplets at δ = 3.08-2.86and at δ = 3.51-3.43ppm characteristic for (H-14,15,20,21a) and (H-21b), respectively.However, the aromatic protons of the first paracyclophane ring resonated as two doublets at δ = 5.90, 6.39 ppm with a coupling constant of 7.92 Hz for the protons H-23 and H-24, respectively.The protons of the second paracyclophanyl ring protons (H-17,18,25,26) resonated as a multiplet at δ = 6.49-6.44 ppm.Furthermore, the 1 H NMR spectrum revealed a doublet of doublets at δ = 5.63-5.61ppm with coupling constants (J = 1.67, 3.31 Hz) corresponding to the quinazoline C-2 carbon atom.The quinazoline C-2 carbon atom resonates in the 13 C NMR spectrum at δ = 62.36 ppm as expected.Moreover, the two NH protons absorb in the 1 H NMR spectrum at δ = 6.30, 6.54 ppm as a doublet and a singlet, respectively.While the protons of the 2,5-dichloroaniline moiety were registered in the 1 H NMR spectrum as two doublets at δ = 7.26, 7.60 (J = 2.50, J = 8.54 Hz) and a doublet of doublets at δ = 7.14-7.11ppm related to H-28,31 and H-30, respectively.The carbon atoms of this aromatic ring moiety resonated in the 13 C NMR spectrum at δ = 123.14,131.20 ppm and the aromatic protons of the quinazoline substrate resonate in the 1 H NMR spectrum as a multiplet at δ = 6.67-6.58ppm for H-7,8 and a multiplet at δ = 7.14-7.11ppm backs to H-9.Whereas, the quinazoline proton (H-6) resonated as a doublet of doublets at δ = 7.91-7.88ppm with coupling constants (J = 1.46, 7.81 Hz).Finally, the mass spectra show the molecular ion peaks in accordance with the products 3a-i.The intensities of the molecular ion peaks of compounds 3a-i varied between 100 % (compound 3a) and 12 % (compound 3f); in other cases it lay between 60 % in compound 3d and 80 % in compound 3g depending on the aromatic moiety in the quinazoline C-4.Electron withdrawing sunbstituents gave higher molecular ion peaks than electron donating substituents.
It has previously been claimed that of 2,4-diaryl-2,3-dihydroquinazoline derivatives are unstable 14a and change directly during silica-gel chromatography to the corresponding 2,4diarylquinazolines.In our case, we found that the reaction was highly stereoselective leading to only one stereoisomer.Our product structures were confirmed by the representative single crystal X-ray structures of compound 3b (Figure 1).The packing of compound 3b in the crystal lattice is as shown in Figure 2. It involves chains of molecules parallel to the z axis, linked by the hydrogen bond N1-HΛN2.The structures of the 2-([2.2]paracyclophanyl)quinazolinederivatives 6a-g were elucidated by the usual spectral analyses (IR, NMR and MS).The IR spectrum shows an absorption maximum at ν = 3420-3300 cm -1 characteristic of NH groups.The NH protons resonated in the 1 H NMR as a singlet at δ = 8.29-7.27ppm depending on both the deuterated solvents that were used for measuring the NMR spectrum and the nature of the substituent at the quinazoline C-4 atom.The 1 H NMR spectrum of 6g as an example revealed the paracyclophane bridge protons as five multiplets at δ = 2.70-2.60,3.11-2.98,3.26-3.18,3.39-3.29,4.61-4.52ppm corresponding to the protons H-21b, H-21a,20, H-14, H-15a, H-15b, respectively.The carbon atoms of these bridge protons resonated in the 13 C NMR spectrum at δ = 36.13, 35.43, 35.41, 35.19 ppm.
Whereas the ring protons of 2,5-dichloroaniline appeared in the 1 H NMR spectrum as two doublets at δ = 9.54 and 7.42 ppm with J = 2.49 and 8.55 Hz related to H-28 and H-31, respectively.In addition to a doublet of doublets at δ = 7.14-7.09ppm with coupling constants J = 2.51 and 8.52 Hz related to H-30.The molecular ion peaks obtained from mass spectrometry were in accordance with the molecular weight of the products 6a-g (see experimental section).

Experimental Section
General Procedures.All reagents were purchased from Alfa Aesar, Fluka and Aldrich companies and were used without further purification.2-Aminoarylbenzimidamide derivatives 1a-i were prepared according to ref 15 and 4-formyl[2.2]paracyclophane(2) was synthesized according to ref 18 .The m.p.s were measured in capillary tubes without corrections using a Büchi 530 melting point apparatus.IR spectra were run as KBr discs using a Bruker Tensor 27 instrument.The NMR spectra were recorded on a Bruker AM400 MHz spectrometer with TMS as internal standard; the coupling constants are given in Hz.The mass spectra (EI, 70 eV) were performed using a Finnigan MAT 8430 spectrometer.

Reactions of 2-aminoarylbenzimidamides (1a-i) with 4-formyl[2.2]paracyclophane (2). General procedures
In a three necked-flask fitted with reflux condenser a solution of 0.25 mmol of 2aminoarylbenzimidamides (1a-i) dissolved in 15 mL of absolute ethanol was added dropwise under nitrogen, to a solution of 4-formyl[2.2]paracyclophane(2) (59 mg, 0.25 mmol) dissolved in 20 mL of absolute ethanol at room temperature.A catalytic amount of commercial iodine (32 mg, 0.126 mmol) was added.The reaction mixture was heated under gentle reflux for 3-5 h.The progress of the reaction was monitored by TLC, and after completion the mixture was cooled to room temperature and sodium thiosulfate was added.The organic product was extracted by CH 2 Cl 2 .The aqueous phase was washed with CH 2 Cl 2 and the combined organic layers were dried over MgSO 4 .The solvent was removed and the residue was purified by silica gel chromatography using CH 2 Cl 2 as the eluent to give the desired products (3a-i) in 70-82% yield.

Oxidation of (Z)-aryl-N-(2-[2.2]paracyclophanyl-2,3-dihydroquinazolin-4(1H)-ylidene)aniline (3a-g) by KMnO 4 . General procedures
To a stirred solution of 0.25 mmol of (Z)-aryl-N-(2-[2.2]paracyclophanyl-2,3-dihydroquinazolin-4(1H)-ylidene)aniline(3a-g) dissolved in 15 mL of dry acetone and placed in a three-necked flask fitted with a dropping funnel, a solution of (53 mg, 0.30 mmol) of KMnO 4 dissolved in 15 mL of dry acetone was added dropwise.After complete addition, the reaction mixture was stirred at room temperature for 9-12 h.After completion of the reaction (monitored by TLC) it was poured onto ice-H 2 O and 20 mL of saturated solution of sodium sulfite was added to reduce the permanganate.The product was extracted by CH 2 Cl 2 , the organic layer was dried over MgSO 4 .The solvent was removed and the products were purified by silica gel chromatography using CH 2 Cl 2 .The products were obtained in yields of 65-77 %.

Figure 2 .Scheme 3 . 4 .
Figure 2. Packing diagram of 3b viewed perpendicular to the yz plane in the region x ≈ 0.