Electrophilically Activated Nitroalkanes in Synthesis of 3,4-Dihydroquinozalines

Nitroalkanes activated with polyphosphoric acid serve as efficient electrophiles in reactions with various nucleophilic amines. Strategically placed second functionality allows for the design of annulation reactions enabling preparation of various heterocycles. This strategy was employed to develop an innovative synthetic approach towards 3,4-dihydroquinazolines from readily available 2-(aminomethyl)anilines.


Introduction
3,4-Dihydroquinazolines belong to privileged scaffolds widely used in drug design, with their importance in medicinal chemistry being difficult to overstate. This structural fragment is found in thousands of natural products and synthetic medicinal agents, including many alkaloids with valuable biological activities. Among them are cytotoxic alkaloid chaetominine isolated from endophytic fungi of the Chaetomium genus [1] and 3-hydroxyfumiquinazoline A isolated from the fungus Aspergillus fumigatus, which has demonstrated promising antifungal and insecticidal activities [2] (Figure 1). Additionally, a family of trigonoliimine alkaloids were isolated from the leaves of tropical plants from the genus Trigonostemon [3]. Due to their highly unusual polycyclic scaffolds and newly discovered anti-cancer and antiviral activities, these trigoliimines are in focus of multiple synthetic exercises [4][5][6][7][8]. Still, elaboration of novel synthetic methods allowing for the efficient assembly of the 3,4-dihydroquinazoline core is exceedingly desired. Herein, we wish to disclose an account of our recent progress towards preparation of these important heterocycles via annulation involving electrophilically activated nitroalkanes.

Introduction
3,4-Dihydroquinazolines belong to privileged scaffolds widely used in drug design, with their importance in medicinal chemistry being difficult to overstate. This structural fragment is found in thousands of natural products and synthetic medicinal agents, including many alkaloids with valuable biological activities. Among them are cytotoxic alkaloid chaetominine isolated from endophytic fungi of the Chaetomium genus [1] and 3hydroxyfumiquinazoline A isolated from the fungus Aspergillus fumigatus, which has demonstrated promising antifungal and insecticidal activities [2] (Figure 1). Additionally, a family of trigonoliimine alkaloids were isolated from the leaves of tropical plants from the genus Trigonostemon [3]. Due to their highly unusual polycyclic scaffolds and newly discovered anti-cancer and antiviral activities, these trigoliimines are in focus of multiple synthetic exercises [4][5][6][7][8]. Still, elaboration of novel synthetic methods allowing for the efficient assembly of the 3,4-dihydroquinazoline core is exceedingly desired. Herein, we wish to disclose an account of our recent progress towards preparation of these important heterocycles via annulation involving electrophilically activated nitroalkanes.

Scheme 3. Mechanistic rationale of the featured annulation.
With this idea in mind, we attempted to carry out reactions between 2-(1-aminoethyl)aniline (1a) and 1-nitropropane (4c) in a molar ratio of 1:2. In the initial experiment, a mixture of these reagents was heated in 86% orthophosphoric acid at 110 °C (Table 1, entry 1) or 120 °C (entry 2). However, the reaction did not proceed under these conditions. Next, a mixture of 86% orthophosphoric acid and 87% polyphosphoric acids (approximately corresponding to anhydrous H3PO4) or molten 87% polyphosphoric acid (PPA) were employed as the media for the reactions carried out at 120 °C. Again, the reactions did not proceed, and the starting amine 1a remained intact in both cases (entries 3, 4). As it was shown in our previous report [25] that addition of phosphorous acid to the reaction medium could enable stubborn steric-restricted annulations, we also decided to attempt to stimulate the reactivity using this trick. To this end, the reaction of 1a and 4c was carried out in a mixture of H3PO3 and 87% PPA (1:1 m/m) at 130 °C. Formation of product 3ac was detected, albeit in a low yield (entry 5). To improve the reaction performance, we attempted to increase the temperature. At 150 °C, the reaction outcome still remained quite marginal (entry 6). However, at 160 °C, a synthetically meaningful result was obtained (entry 7). We also tested the reaction in pure phosphorous acid without addition of PPA. This reaction was accompanied with partial thermal decomposition of the medium, which complicated the isolation and rendered notably lower yield (entry 8).
With optimized conditions in hand, we then proceeded to investigate the scope of the featured transformation. The results presented in Scheme 4 demonstrate that 3,4-dihydroquinazolines substituted with alkyl groups at C-2, C-4, or C-6 can be routinely obtained via this method in good to excellent yields. It should be pointed out that alkyl substituents at these positions as well as the length of the alkyl chain in the nitroalkane reagent do not seem to affect the efficiency of the featured transformation. Aromatic halide substituent in substrate 1d was also well tolerated, allowing for efficient preparation of brominated product 3cd (Scheme 4).
An attempt to use ethyl 2-nitroacetate as an electrophilic component in the described transformation proved unfruitful. The reaction with 1a produced complex mixtures of unidentified products, and none of them was isolated in a meaningful yield. More interesting results were obtained in reactions employing α-nitroacetophenone (4g). The products of these reactions, 3ag and 3cg, were identified as 3,4-dihydroquinozalines bearing With this idea in mind, we attempted to carry out reactions between 2-(1-amino ethyl)aniline (1a) and 1-nitropropane (4c) in a molar ratio of 1:2. In the initial experiment, a mixture of these reagents was heated in 86% orthophosphoric acid at 110 • C ( Table 1, entry 1) or 120 • C (entry 2). However, the reaction did not proceed under these conditions. Next, a mixture of 86% orthophosphoric acid and 87% polyphosphoric acids (approximately corresponding to anhydrous H 3 PO 4 ) or molten 87% polyphosphoric acid (PPA) were employed as the media for the reactions carried out at 120 • C. Again, the reactions did not proceed, and the starting amine 1a remained intact in both cases (entries 3, 4). As it was shown in our previous report [25] that addition of phosphorous acid to the reaction medium could enable stubborn steric-restricted annulations, we also decided to attempt to stimulate the reactivity using this trick. To this end, the reaction of 1a and 4c was carried out in a mixture of H 3 PO 3 and 87% PPA (1:1 m/m) at 130 • C. Formation of product 3ac was detected, albeit in a low yield (entry 5). To improve the reaction performance, we attempted to increase the temperature. At 150 • C, the reaction outcome still remained quite marginal (entry 6). However, at 160 • C, a synthetically meaningful result was obtained (entry 7). We also tested the reaction in pure phosphorous acid without addition of PPA. This reaction was accompanied with partial thermal decomposition of the medium, which complicated the isolation and rendered notably lower yield (entry 8).
With optimized conditions in hand, we then proceeded to investigate the scope of the featured transformation. The results presented in Scheme 4 demonstrate that 3,4dihydroquinazolines substituted with alkyl groups at C-2, C-4, or C-6 can be routinely obtained via this method in good to excellent yields. It should be pointed out that alkyl substituents at these positions as well as the length of the alkyl chain in the nitroalkane reagent do not seem to affect the efficiency of the featured transformation. Aromatic halide substituent in substrate 1d was also well tolerated, allowing for efficient preparation of brominated product 3cd (Scheme 4).
phenyl substituents at C-2 (Schemes 4 and 5). It is believed that the mechanism of this transformation involves initial formation of imine 19 via condensation of ketone 4g with one of the available amino groups. Subsequent 6-endo-trig nucleophilic cyclization took place, providing cyclic aminal 20, which underwent further elimination of nitromethane moiety to afford the observed products (Scheme 5).

Materials and Methods
General. 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). 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). Signals in 13 C NMR spectra marked with an asterisk (*) were assigned based on 2D 1 H-13 C HMBC and 1 H-13 C HSQC experiments. HRMS spectra were measured on a Bruker maXis impact (electrospray ionization, in MeCN solutions, employing HCO2Na-HCO2H for calibration). IR spectra were measured on an FT-IR spectrometer Shimadzu IRAffinity-1S equipped with an ATR sampling module. The reaction progress, the purity of isolated compounds, and the Rf values were monitored with TLC on Silufol UV-254 plates. Column chromatography was performed on silica gel (32-63 μm, 60 Å pore size). Melting points were measured with a Stuart SMP30 apparatus. Polyphosphoric acid (87%) was prepared by dissolving a precisely measured amount of P2O5 in 85% orthophosphoric acid. All the reagents and solvents were purchased from commercial venders and used as received. An attempt to use ethyl 2-nitroacetate as an electrophilic component in the described transformation proved unfruitful. The reaction with 1a produced complex mixtures of unidentified products, and none of them was isolated in a meaningful yield. More interesting results were obtained in reactions employing α-nitroacetophenone (4g). The products of these reactions, 3ag and 3cg, were identified as 3,4-dihydroquinozalines bearing phenyl substituents at C-2 (Schemes 4 and 5). It is believed that the mechanism of this transformation involves initial formation of imine 19 via condensation of ketone 4g with one of the available amino groups. Subsequent 6-endo-trig nucleophilic cyclization took place, providing cyclic aminal 20, which underwent further elimination of nitromethane moiety to afford the observed products (Scheme 5).

Materials and Methods
General. 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). 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). Signals in 13 C NMR spectra marked with an asterisk (*) were assigned based on 2D 1 H-13 C HMBC and 1 H-13 C HSQC experiments. HRMS spectra were measured on a Bruker maXis impact (electrospray ionization, in MeCN solutions, employing HCO 2 Na-HCO 2 H for calibration). IR spectra were measured on an FT-IR spectrometer Shimadzu IRAffinity-1S equipped with an ATR sampling module. The reaction progress, the purity of isolated compounds, and the R f values were monitored with TLC on Silufol UV-254 plates. Column chromatography was performed on silica gel (32-63 µm, 60 Å pore size). Melting points were measured with a Stuart SMP30 apparatus. Polyphosphoric acid (87%) was prepared by dissolving a precisely measured amount of P 2 O 5 in 85% orthophosphoric acid. All the reagents and solvents were purchased from commercial venders and used as received.

2-(1-Aminoethyl)aniline (1a):
This compound was obtained via transformation of acetophenone into the corresponding oxime and its subsequent reduction with either sodium borohydride in the presence of TiCl 4 in dimethoxyethane (DME) (method A), or with zinc dust in hydrochloric acid (method B).
The oxime was subsequently reduced via one of the following procedures: Method A: A solution of 1-(2-nitrophenyl)ethan-1-one oxime (1.80 g, 10.0 mmol) in anhydrous DME was added slowly under argon atmosphere to a stirred and chilled in ice-bath mixture of sodium borohydride (1.59 g, 42 mmol) and titanium (IV) chloride (3.99 g, 21 mmol) in anhydrous DME (40 mL), and the mixture was stirred at room temperature for 20 h [41]. Then, the reaction mixture was carefully poured into ice-cold water (100 mL), neutralized with aqueous ammonia (25%), and concentrated in vacuum. The residual solid was extracted in a Soxhlet apparatus for 8 h into isopropyl alcohol (230 mL). The extract was concentrated in vacuum to obtain crude 2-(1-aminoethyl)aniline chlorohydride as off-white powder, mp 172-179 • C (Literature data: mp 187 • C (decomp) [42]. Yield: 1.58 g (9.1 mmol, 91%). For isolation of 2-(1-aminoethyl)aniline as free base, the salt was dissolved in water, washed with ethyl acetate, basified with aqueous NaOH (20%), and extracted with ethyl acetate. Combine organic extracts were washed with brine, dried with sodium sulphate, and concentrated in vacuum.

Method B:
To a solution of 1-(2-nitrophenyl)ethan-1-one oxime (2.07 g, 11.5 mmol) in a mixture of ethanol (45 mL), water (12 mL) and concentrated HCl (24 mL) stirred at 0 • C zinc duct was added in small portions over 30 min (9.03 g, 138.1 mmol) [43]. The reaction mixture was stirred at 50 • C for 1.5 h (the reaction progress was monitored with TLC), then cooled down to room temperature, and filtered. The filtrate was concentrated in vacuum, and the residue was basified with aqueous ammonia (25%) to pH 9 and extracted with ethyl acetate (3 × 50 mL). Combined organic extracts were dried with sodium sulphate and concentrated in vacuum. The residual amber-colored oil was dissolved in diluted aqueous HCl (70 mL, pH of resulting solution c.a. [4][5], and washed with ethyl acetate (3 × 25 mL). The aqueous phase was basified with ammonia (25%) to pH 9 and extracted with ethyl acetate (3 × 25 mL). Combined organic phases were washed with brine, dried with sodium sulphate, and concentrated.

2-(Aminomethyl)aniline (1c):
This compound was obtained analogously to diamine 1a from 2-nitrobenzaldehyde via its conversion to the corresponding oxime and subsequent reduction either with sodium borohydride in DME in the presence of TiCl 4 (method A), or with zinc dust in hydrochloric acid (method B).
Transformation of this hydrochloride into free amine was performed by dissolving the salt in water, washing the solution with ethyl acetate, basification of the aqueous phase with aqueous ammonia to pH 9, and extraction with ethyl acetate in the same manner as described above for material 1a. Combined organic extracts were dried and concentrated in vacuum to afford free titled amine.

Conclusions
In conclusion, a new protocol was developed, allowing for the assembly of 3,4dihydroquinazolines from readily available 2-(aminomethyl)anilines and electrophilically activated nitroalkanes. Typically, reactions proceeding via nucleophilic attacks of nitronates with nucleophilic aniline moieties can be performed routinely. However, the featured transformation, involving the reaction of aliphatic amine groups, required careful optimization of the reaction conditions. It was found that switching to a mixture of 87% PPA and H 3 PO 3 as a reaction medium allowed the transformation to be carried out efficiently, obtaining adequate to high yields of 3,4-dihydroquinazolines from a range of linear nitroalkanes (from nitromethane to 1-nitrohexane). Reaction with α-nitroacetophenone allowed for efficient preparation of phenyl-substituted derivatives. Evidently, the described method largely depends on availability and stability of the corresponding starting materials. Since nitroalkanes are activated at quite high temperatures and are used in the reaction as surrogates for much more available and reactive carboxylic acid derivatives, it is hard to expect that the method as is would be strongly competitive. This reaction might become invaluable, however, as a part of multi-step cascade transformations involving PPA as an "intelligent" reaction medium, which are being developed lately in our laboratories.  Institutional Review Board Statement: Not applicable. This study did not involve human or animal subject.
Informed Consent Statement: Not applicable. This study did not involve human or animal subject.
Data Availability Statement: Supporting Information data include NMR spectral charts and are available.

Conflicts of Interest:
The authors declare no conflict of interest.
Sample Availability: Not applicable.