Novel polycyclic Diels-Alder adducts from ring distorted 3-aza[5] and 3-aza[6] (1,7) naphthalenophanes

Ring distorted 3-aza[5] and 3-aza[6](1,7)naphthalenophanes have been shown to undergo ready Diels-Alder cycloaddition reactions with 4-phenyl-1,2,4-triazoline-3,5-dione, tetracyanoethylene, 1,1-dicyanoethylene and 1,1-diethyl methylenemalonate to form new functionalized polycyclic heterocyclic derivatives. Addition was shown to occur selectively in each case in the less substituted aromatic ring of the naphthalene moiety.


Introduction
2][3][4][5] If the planarity of the naphthalene is partially disrupted by bulky substituents or by incorporating the naphthalene moiety in a short-bridged cyclophane, then the feasibility of this reaction is likely to be increased. 6Such a ring distortion occurs in the [5]-or [6]-aza-1,7-naphthalenophane systems.Diels-Alder reactions of these systems were of interest mechanistically to assess the effects of ring strain on reactivity.Also, synthetically, the cycloaddition afforded the possibility of facile access to compact and rigid polycyclic heterocyclic systems of potential interest as drug scaffolds.The results of some aspects of this work are now reported in this paper.
The structural assignments of the adducts 2a-c were supported by analytical and spectroscopic data.Microanalysis of 2a indicated an empirical formula of C 25 H 23 N 5 O 4 and this was shown to be the molecular formula from high-resolution mass spectrometry.The infrared spectrum showed a strong absorption band at 2204 cm -1 , consistent with the presence of cyanamide functionality 10 and a sharp doublet at 1770 and 1712 cm -1 , characteristic of the fivemembered cyclic imide component. 11The 1 H NMR spectrum of the adduct 2a showed broadened peaks at 25 o C due to conformational interconversion of the bridging aza-methylene ring.As the temperature was increased sharpened signals were observed.At 50 o C in the 1 H NMR spectrum of 2a, a one-proton singlet at δ 6.44 and another one-proton singlet at δ 6.08 was ascribed to the aromatic proton H-7 and the bridgehead proton H-15a respectively, while a one-proton doublet at δ 6.54 (J = 5.7 Hz) was assigned to the olefinic proton H-16.The other bridgehead proton H-10 appeared as a doublet at δ 6.20 (J = 5.7 Hz).
In the 1 H NMR spectrum of the adduct 2b, a one-proton singlet at δ 6.51 was attributed to the aromatic proton H-8.A doublet of doublets centred at δ 6.55 (J = 5.9, 1.6 Hz) and two oneproton doublets at δ 6.01 (J = 1.6 Hz) and at δ 6.23 (J = 5.9 Hz) were assigned to the olefinic proton H-17 and the bridgehead proton H-16a and H-11 respectively.
In the 1 H NMR spectrum of the adduct 2c in tetradeuteriomethanol, the corresponding aromatic proton H-8, the olefinic proton H-17 and the two bridgehead protons H-16a and H-11 appeared as a singlet at δ 7.01 and as broad singlets at δ 6.04, 5.19 and 5.99 respectively.The presence of a three-proton singlet resonance at δ 2.67 confirmed the incorporation of a methyl group attached to nitrogen.
In the 13 C NMR spectrum of the adduct 2b, resonance signals for the two carbonyl carbons appeared at δ 156.5 and 156.4.A quaternary carbon at δ 116.9 was attributed to the cyanamide carbon while two methine carbon at δ 52.0 and 55.9 were assigned to the two bridgehead carbons.In the 13 C NMR spectrum of the adduct 2c, the corresponding carbonyl carbons both appeared at δ 157.3 and the two bridgehead carbons appeared at δ 47.5 and 67.3.The remainder of the spectra of the adducts 2b-c were consistent with the proposed structures.
3][14] In all such adducts, only the endo adducts have been observed in X-ray crystallographic studies, with the exception of the adduct of 4-methyl-1,2,4-triazoline-3,5-dione with 11-cyano-1,6-methano [10]annulene; the endo and exo adducts were isolated in this case and their configurations were confirmed by X-ray crystal structure analysis. 14t is of interest that the dienophile adds exclusively onto the less-substituted ring at the 5,8 positions in 1a-c; no addition on the dimethoxy-substituted ring at the 1,4-positions was observed.This may be a result of the steric crowding by the bridging substituent at position 1 and the 4-methoxy group.Diels-Alder cycloaddition at other positions is excluded on the basis of no aromatic ring stabilization in the products that would result; the 1 H NMR spectra were also not in accord with such products.
Reaction of the 3-aza [5](1,7)naphthalenophane (1a) and 3-aza [6](1,7)naphthalenophanes (1b) and (1d) with tetracyanoethylene also proceeded smoothly under mild conditions, giving the 1:1 adducts (3a), (3b) and (3c) respectively in high yields (Scheme 2 and Table 2 Structural assignments of the adducts (3a-c) were supported by spectroscopic and analytical data.The molecular formula of the adducts 3a and 3c were determined from high-resolution mass spectrometry and, in each case, were reinforced by elemental analysis.In the case of the adduct 3b, the mass spectrum had an identical fragmentation pattern to that of the starting 3aza [6](1,7)naphthalenophane (1b) due to a thermal retro Diels-Alder reaction of the adduct 3b in the mass spectrometer and no molecular ion was observed, as was the case with the adduct 2b.A satisfactory elemental analysis on the adduct 3b was obtained.
The infrared spectra of the adduct 3a-b showed characteristic absorption bands at 2216 cm -1 for 3a and 2208 cm -1 for 3b indicating the presence of the cyanamide moiety, while a strong absorption band at 1698 cm -1 ascribed to the N-carboxylate group was observed in the infrared spectrum of the adduct 3c.
The characteristic features of the 1 H NMR spectra of the adducts 3a-c were two one-proton doublets at δ values ranging from 5.45 to 5.79 (J = 1.2-1.5 Hz) and at δ values ranging from 5.33 to 5.64 (J = 6.2-6.3Hz) which were ascribed, respectively, to the bridgehead protons H-6a, H-9 in 3a and H-7a, H-10 in 3b-c.A one proton singlet at δ values ranging from 6.79 to 7.16 and a one-proton doublet of doublets centred at δ 6.68, 6.89 and 6.76 (J = 6.2-6.3 and 1.2-1.5 Hz) were assigned to the aromatic proton H-12 in 3a, H-13 in 3b-c and the olefinic proton H-13 in 3a, H-14 in 3b-c.
In the 13 C NMR spectrum of the adduct 3b, two methine signals appeared at δ 45.0 and 52.4 which were assigned to the two bridgehead carbons.Four quaternary carbon resonances at δ values ranging from δ 113.9 to 113.2 were assigned to the cyanide carbons.The resonance at δ 117.5 was ascribed to the cyanamide carbon.
In the 13 C NMR spectrum of the adduct 3c, the bridgehead carbons appeared at δ 44.9 and 51.1 while four cyanide carbon resonances at δ values ranging from 113.9 to 113.8 and an Ncarboxylate carbonyl carbon resonance at δ 158.8 were observed.The remainder of the spectra of the adducts 3b-c were in accord with the structures proposed.
The reduced yields of the adducts 4b and 5b compared with those of the analogous adducts 4a and 5a, may be attributed to their slower rate of formation; indeed, a substantial amount of starting naphthalenophane (1d) was recovered from the reaction of 1d with 1,1-dicyanoethylene.
The structural assignment of the adducts 4 and 5 rested on analytical and spectroscopic evidence.Microanalyses of the adducts 4a and 5a indicated an empirical formula of C 22 H 22 N 4 O 2 and this was shown to be the molecular formula for both regioisomeric adducts from highresolution mass spectrometry.A strong absorption band at 2208 cm -1 , indicative of cyanamide functionality, together with a weak absorption band at 2248 cm -1 attributed to the nitrile group, were present in the infrared spectra of both adducts.
In the 1 H NMR spectrum of 4a, a one-proton triplet of doublets centred at δ 4.35 (J t = 3.0 Hz, J d = 1.6 Hz) and a one-proton singlet at δ 6.52 were assigned to the bridgehead proton H-7a and the aromatic proton H-13 respectively while the bridgehead proton H-10 and the aromatic proton H-14 appeared at δ 4.97 (d, J = 6.1 Hz) and at δ 6.26 (br.d,J = 6.1 Hz) respectively.The methylene protons H-8 adjacent to the bridgehead carbon C-7a appeared as an AB quartet of doublets centred at δ 2.43 and δ 2.32 indicating geminal coupling (J = 13.2Hz) and vicinal coupling (J = 3.0 Hz).The remainder of the spectrum was consistent with the proposed structure.
In the 1 H NMR spectrum of the adduct 5a, a one-proton doublet of triplets centred at δ 4.64 (J d =6.4 Hz, J t = 2.6 Hz) and a one-proton singlet at δ 6.51 were ascribed to the bridgehead proton H-10 and the aromatic proton H-13 respectively, while the bridgehead proton H-7a and the olefinic proton H-14 appeared as a doublet at δ 4.80 (J = 1.5 Hz) and a broad doublet at δ 6.47 (J = 6.4 Hz) respectively.The methylene proton H-9 adjacent to the bridgehead carbon C-10 appeared as an AB quartet of doublets centred at δ 2.48 and 2.28 indicating geminal coupling (J = 13.0Hz) and vicinal coupling (J = 2.6 Hz).
The 13 C NMR spectrum of the adduct 4a was also in accord with the proposed structure.The methylene carbon (C-8) adjacent to the bridgehead (C-7a) appeared at δ 41.1 and two bridgehead carbons (C-7a) and (C-10) appeared at δ 43.1 and 42.8, respectively.
In the case of the adducts 4b and 5b, the molecular formula, C 23 H 25 N 3 O 5 , for both compounds was again established from high-resolution mass spectrometry and this was supported by elemental analyses.A strong absorption band at 1698 cm -1 for 4b and at 1700 cm -1 for 5b in the infrared spectra confirmed the presence of the N-carboxylate carbonyl group.
In the 1 H NMR spectrum of the adduct 4b, a one-proton triplet of doublets centred at δ 4.20 (J t =2.6 Hz, J d = 1.5 Hz) and a one-proton doublet at δ 4.92 (J = 6.1 Hz) were assigned to the bridgehead proton H-7a and H-10 respectively, while the aromatic proton H-13 and the olefinic proton H-14 appeared as a singlet at δ 6.51 and a broad doublet at δ 6.18 (J = 5.9 Hz) respectively.The methylene protons H-8 adjacent to the bridgehead carbon C-7a appeared as an AB quartet of doublets centred at δ 2.38 and 2.26 indicative of geminal coupling (J = 12.9 Hz) and vicinal coupling (J = 2.6 Hz).
In the 1 H NMR spectrum of the adduct 5b, a one-proton doublet of triplets centred at δ 4.46 (J d = 6.3 Hz, J t = 2.6 Hz) and a one-proton doublet at δ 4.69 (J = 1.5 Hz) were assigned to the bridgehead proton H-7a and H-10 respectively, while the aromatic proton H-13 and the olefinic proton H-14 appeared as a singlet at δ 6.51 and a broad doublet at δ 6.41 (J = 6.2 Hz) respectively.The methylene protons H-9 adjacent to the bridgehead carbon C-10 appeared as an AB quartet of doublets centred at δ 2.47 and 2.32 indicative of geminal coupling (J = 12.8 Hz) and vicinal coupling (J = 2.6 Hz).
Analogous product patterns were observed with 1a and the diester 1,1-diethyl methylene malonate, affording the polycyclic adducts 4c and 5c with ester functionality.

Conclusions
The 3-aza [5](1,7)naphthalenophane 1a showed facile and selective dienophilic reactivity in the Diels-Alder reaction with electron deficient dienophiles.The 3-aza [6](1,7)naphthalenophanes 1b-d reacted similarly but were not as diene-like consistent with less naphthalene ring distortion with the longer bridging chain.The Diels-Alder reaction in these systems provided ready access to new rigid polycyclic heterocyclic systems with a range of functionalities which should be capable of further manipulation.

Experimental Section
General Procedures.Elemental analyses were performed by the Canadian Microanalytical Service Ltd, Vancouver, Canada.Melting points were determined on a Yanagimoto Seisakusho micro-melting point apparatus, and are uncorrected.
Mass spectra were determined on VG MM 7070F mass spectrometer operating at 70eV, with source temperature of 200 o C (direct insertion); peak intensities, in parentheses, are expressed as a percentage of the base peak. 1 H nuclear magnetic resonance spectra were determined at 300 MHz with a Bruker AM-300 spectrometer, tetramethylsilane being used as internal standard. 13C NMR spectra were recorded at 75.5 MHz with a Bruker AM-300 spectrometer; assignments indicated by superscript letters may be interchanged for carbon atoms within each group defined by these letters.NMR spectra were determined in CDCl 3 as solvent unless otherwise stated.Infrared spectra were recorded on a Hitachi 270-30 infrared spectrophotometer.
R f values refer to thin-layer chromatography on Merck silica gel 60 F 254 .Preparative thinlayer chromatography and column chromatography were performed on Camag silica gel.

Table 3 .
Diels-Alder reaction of the 3-aza[6](1,7)naphthalenophanes (1b) and (1d) with 1,1dicyanoethylene In this table and in others given in this paper, the percentage yield refers to the mole percentage yield of that product.