Annulation of Perimidines with 5-Alkynylpyrimidines en Route to 7-Formyl-1,3-Diazopyrenes

Unusual rearrangements were shown to accompany Brønsted acid-assisted peri-annulations of 1H-perimidines with 5-alkynylpyrimidines. These transformations take different routes depending on the nature of acetylene precursor, and lead to the formation of 7-formyl-1,3-diazopyrenes.


Introduction
Due to their unique physicochemical properties, pyrene derivatives have emerged as some of the most privileged structures in the design of organic fluorescent materials. Pyrene motifs attract attention of many research groups studying photochemistry and molecular electronics. Examples demonstrating utilization of pyrenes in the manufacturing of organic light-emitting diodes (OLED) [1-3], organic filed-effect transistors (OFET) [2,[4][5][6], organic photo-voltaic devises (OPVs) [2,7,8], hole-conductive materials for solar cells [9], and other photoconductive covalent organic building blocks are omnipresent in literature [10]. Major advances were made in the development of pyrene-based fluorescent probes [11] for the analytical detection of copper [12,13] and other heavy metals [13], as well as picric acid [14]. These versatile synthons also possess a great intercalating ability to selectively bind to DNA in cellular nuclei [15,16]. The undisputed advantages of pyrene derivatives are outweighed by one significant drawback-their low solubility in common organic solvents-which complicates synthesis of advanced synthetic precursors for the manufacturing of photosensors and electronic devices. Another problem is associated with high carcinogenicity of these compounds and their slow metabolism, which severely limits their application in medicinal and pharmaceutical chemistry. Both issues could be addressed by incorporation of nitrogen atoms in the pyrene structure, simultaneously providing a powerful tool for the fine-tuning of photochemical and electrochemical properties of the resulting products. Our research group has a pioneering expertise in the development of synthetic methods for peri-annulation of carbo-and azacyclic compounds [17][18][19][20]. 1H-Perimidines 1 are typically employed as model substrates in these investigations, since they are characterized by increased electron density in the peri-position, making them excellent nucleophilic synthons. Reactions of 1H-perimidines with chalcones 2 [21] and pyrimidines 4 [19], which proceed in acidic media and afford derivatives of 1,3-diazapyrenes 3, deserve a special note as an expeditious one-step route to 1,3-diazopyrenes (Scheme 1). Herein, we disclose an alternative approach to 1,3-diazopyrenes 6 or 7 via annulation of 1H-perimidines 1 with 5-alkynylpyrimidines 5 (Scheme 1). This reaction allows for selective installation of the formyl group at C-7 amenable for further synthetic modifications. allows for selective installation of the formyl group at C-7 amenable for further synthetic modifications.
To evaluate this idea, we carried out a reaction between 2-phenyl-1H-perimidine (1a) with 5-(hept-1-yn-1-yl)pyrimidine (5a) in methanesulfonic acid at room temperature. Contrary to our expectations, the reaction did not afford product 15. Instead, 1,3-diazapyrene 16a possessing a n-hexyl substituent at C-6 and an aldehyde moiety at C-7 was obtained as a sole isolable product in modest yield (Scheme 4). The reaction proceeded to completion consuming both starting materials 1a and 5a, but a significant amount of product decomposed, as indicated by the formation of notable amounts of polymeric tars. The same outcome was observed in the reaction of alkyne 5a with other perimidines (1b-g) affording a series of 7-formyl-1,3-diazapyrenes in low to moderate yield (Scheme 4).  To evaluate this idea, we carried out a reaction between 2-phenyl-1H-perimidine (1a) with 5-(hept-1-yn-1-yl)pyrimidine (5a) in methanesulfonic acid at room temperature. Contrary to our expectations, the reaction did not afford product 15. Instead, 1,3-diazapyrene 16a possessing a n-hexyl substituent at C-6 and an aldehyde moiety at C-7 was obtained as a sole isolable product in modest yield (Scheme 4). The reaction proceeded to completion consuming both starting materials 1a and 5a, but a significant amount of product decomposed, as indicated by the formation of notable amounts of polymeric tars. The same outcome was observed in the reaction of alkyne 5a with other perimidines (1b-g) affording a series of 7-formyl-1,3-diazapyrenes in low to moderate yield (Scheme 4).
Next, we explored the possibility to perform this reaction with perimidine 1a using 5-(phenylethynyl)pyrimidine (5b) as the electrophilic component. Interestingly, the reaction took a different route leading to the formation of 1,3-diazopyrene 17a bearing a benzylamine moiety at C-6 (Scheme 4). Similarly to the example above, this reaction was rather general with respect to a variety of perimidines 1a-f,g affording the corresponding 1,3-diazopyrenes 17a-f,g as sole isolable products in moderate yield. The material balance in both of these reactions was far from perfect due to significant polymerization of the products. However, in all cases, the polymers were easily separated via a simple filtration through a short path silica gel column.
It was rationalized that formation of 7-formyl-1,3-diazapyrenes 16 and 17 may occur via two related cascade transformations depicted in Scheme 5. The initially produced dihydroquinazolino [6,7,8-gh]perimidines 15 (Scheme 3) are unstable under strongly acidic conditions, but their further reactivity is strongly dependent on the nature of the substituent at C-10a. n-Hexyl-substituted derivative 15a undergoes electrocyclic cleavage of the dehydropyrimidine ring to establish aromaticity of 1,3-diazapyrene core (Scheme 5). The resulting intermediate 18 bearing a masked aldehyde functionality in a form of acyclic formamidine moiety is highly susceptible to acidic hydrolysis. The removal of this protecting group should afford 7-formyl-1,3-diazapyrene 16 (Scheme 5). Benzyl-substituted analog 15b reacts via an alternative mechanistic pathway due to a much greater migratory aptitude of the benzyl group. Since 15b has four nitrogen atoms with nearly identical basicity, it can form several protonated species coexisting in a dynamic equilibrium in the strongly acidic reaction medium. One of such forms (19) is an intermediate in tautomerization of 10,10a-dihydro-(15) into 1,10a-dihydroquinazolino [6,7,8-gh]perimidine 20 (Scheme 5). Protonation of the latter triggers 1,2-migration of the benzyl moiety to N-10a to furnish 21. A significant energy release accompanying aromatization of 1,3-diazopyrene serves as a strong driving force for this transformation. Furthermore, formation of a more basic sp 3 -hybridized nitrogen atom should be favored in an acidic medium. The non-aromatic heterocyclic ring in 21 is essentially a (methyleneamino)methanamine, which collapses under acidic hydrolysis conditions to furnish the benzylamine substituent at C-6 and an aldehyde group at C-7 in product 17. Next, we explored the possibility to perform this reaction with perimidine 1a using 5-(phenylethynyl)pyrimidine (5b) as the electrophilic component. Interestingly, the reaction took a different route leading to the formation of 1,3-diazopyrene 17a bearing a benzylamine moiety at C-6 (Scheme 4). Similarly to the example above, this reaction was rather general with respect to a variety of perimidines 1a-f,g affording the corresponding 1,3-diazopyrenes 17a-f,g as sole isolable products in moderate yield. The material balance in both of these reactions was far from perfect due to significant polymerization of the products. However, in all cases, the polymers were easily separated via a simple filtration through a short path silica gel column.

General
The NMR spectra, 1 H, and 13 C were measured in solutions of CDCl3 or DMSO-d6 on a Bruker AVANCE-III HD instrument (at 400.40 or 100.61 MHz, respectively). The residual solvent signals were used as internal standards in DMSO-d6 (2.50 ppm for 1 H, and 40.45 ppm for 13 C nuclei) or in CDCl3 (7.26 ppm for 1 H, and 77.16 ppm for 13 C nuclei). The high-resolution mass spectra were registered with a Bruker Maxis spectrometer (electrospray ionization, in MeCN solution, using HCO2Na-HCO2H for calibration). See Supplementary Materials for NMR (Figures S1-S32) and HRMS ( Figures S33-S48) spectral charts. The IR spectra were measured on FT-IR spectrometer Shimadzu IR Affinity-1S equipped with an ATR sampling module. The melting points were measured with a Stuart SMP30 apparatus. The reaction progress and purity of isolated compounds were controlled by TLC on ALUGRAM Xtra SIL G UV 254 plates. The column chromatography was performed with Macherey Nagel Silica gel 60 (particle size: 0.063-0.2 mm). The pyrimidines were synthesized by published methods [22,23] and the synthesis of 5-

General
The NMR spectra, 1 H, and 13 C were measured in solutions of CDCl 3 or DMSO-d 6 on a Bruker AVANCE-III HD instrument (at 400.40 or 100.61 MHz, respectively). The residual solvent signals were used as internal standards in DMSO-d 6 (2.50 ppm for 1 H, and 40.45 ppm for 13 C nuclei) or in CDCl 3 (7.26 ppm for 1 H, and 77.16 ppm for 13 C nuclei). The high-resolution mass spectra were registered with a Bruker Maxis spectrometer (electrospray ionization, in MeCN solution, using HCO 2 Na-HCO 2 H for calibration). See Supplementary Materials for NMR (Figures S1-S32) and HRMS (Figures S33-S48) spectral charts. The IR spectra were measured on FT-IR spectrometer Shimadzu IR Affinity-1S equipped with an ATR sampling module. The melting points were measured with a Stuart SMP30 apparatus. The reaction progress and purity of isolated compounds were controlled by TLC on ALUGRAM Xtra SIL G UV 254 plates. The column chromatography was performed with Macherey Nagel Silica gel 60 (particle size: 0.063-0.2 mm). The pyrimidines were synthesized by published methods [22,23] and the synthesis of 5-ethynylpyrimidines is described in our recent report [24]. All other reagents and solvents were purchased from commercial vendors and used as received.