HETEROCYCLES

Paper | Special issue | Vol. 88, No. 2, 2014, pp. 1149-1161
Received, 30th June, 2013, Accepted, 17th September, 2013, Published online, 26th September, 2013.
DOI: 10.3987/COM-13-S(S)73

■ Aminophenylpyrrole Synthesis and Application to Pyrrolo[1,2-c]quinazolinone Synthesis

Aurélie A. Dörr and William D. Lubell*

Department of Chemistry, University of Montreal, CP 6128, Succursale-Centre-Ville
Montreal, Quebec, H3C 3J7, Canada

Abstract

Aminophenylpyrroles have been synthesized by a three-step route from methyl N-(Boc)anthranilate (2). Amine protection of commercially available methyl anthranilate (1) gave Boc-protected methyl ester 2, which reacted with vinylmagnesium bromide in the presence of a catalytic amount of copper (I) cyanide to yield 1-[2-N-(Boc)aminophenyl]pent-4-en-1-one (3) in 43% yield. Oxidation of homoallylic ketone 3 using either a mixture of OsO4•NaIO4 and 2,6-lutidine, or PdCl2-CuCl under oxygen atmosphere gave respectively aldehyde 4 and ketone 5. Treatment of 1,4-dicarbonyl compounds 4 and 5 with ammonium formate as well as primary amines under Paal-Knorr conditions afforded a set of eight 2-[2-N-(Boc)aminophenyl]pyrroles 6a-d and 7a-d. In addition, treatment of 2-[2-N-(Boc)aminophenyl]-1H-pyrrole 6a with NaH provided a novel entry to pyrrolo[1,2-c]quinazolin-5(6H)-one 8.

INTRODUCTION
Pyrrole derivatives have considerable synthetic importance due to their abundance in natural products and extensive applications in materials science and drug discovery.1 Pyrroles containing a 2-aminophenyl unit are present in a variety of molecules exhibiting interesting biological activity, including nitric oxide synthase (NOS) inhibitors,2 and α1 adrenergic receptor agonists,3 as well as antifungal,4,5 antibacterial,5 and antimicrobial agents.5 Furthermore, the 2-(2-aminophenyl)pyrrole skeleton is an integral component of various biologically active heterocycles: pyrrolo[1,2-d][1,4]benzodiazepin-6-ones,6 which exhibit antiviral activity against HIV-1; pyrrolo[1,2-e][1,5]benzodiazocin-7-ones,7 which have CNS activity; pyrrolo[3,2-c]cinnolines,8 which show anti-germinative properties; pyrrolo-[3,2-c]quinolines,9-11 which have antitumor, hypotensive and anti-inflamatory activities; and pyrrolo[1,2-c]quinazolines,12,13 which have anti-hypertensive, antiviral, antimalarial, and antibacterial activity (Figure 1). Although the 2-(2-aminophenyl)pyrrole unit may appear to be a useful building block for making such interesting targets, to the best of our knowledge, all approaches to date have employed the corresponding 2-(2-nitrophenyl)pyrrole analogs, which are subsequently reduced to afford the 2-(2-aminophenyl)pyrrole counterpart. Procedures involving the 2-(2-nitrophenyl)pyrrole precursors have entailed multiple steps employing cyclisations2a,9,10,13-15 and condensations6-8,11 onto the pyrrole ring. For example, a one-pot gold-catalyzed nitro-Mannich/hydroamination cascade reaction provided moderate yields of 2-(2-nitrophenyl)pyrrole analogs.16 Pyrrole arylation with nitroaromatic derivatives has also been achieved using Pd-catalyzed cross-coupling reactions in alkaline, super-basic and ionic liquid media to afford 2-(2-nitrophenyl)pyrroles.3,17-22

Considering the utility of an approach which introduces the amino group at a lower oxidation state, we describe the synthesis of 2-(2-aminophenyl)pyrroles from relatively inexpensive methyl anthranilate (1). Employing N-(Boc)anthranilate 2 in a copper-catalyzed cascade addition of vinyl Grignard reagent, followed by olefin oxidation, this route affords 1,4-diketone 4 and 1,4-ketoaldehyde 5 precursors, which were found suitable for Paal-Knorr condensations to deliver a variety 2-(2-aminophenyl)pyrrole analogs.


RESULTS AND DISCUSSION
Methyl anthranilate (1) was converted into 1,4-diketone 4 and 1,4-ketoaldehyde 5 by a common route featuring N-protection, copper-catalyzed cascade addition of vinylmagnesium bromide to the ester and olefin oxidation (Scheme 1). Heating anthranilate 1 and excess di-tert-butyl dicarbonate (Boc2O) in ethanol at 50 °C for 9 days afforded methyl N-(Boc)anthranilate (2) in 98% yield, after destruction of excess of Boc2O with imidazole, and chromatography.23,24 Treatment of methyl ester 2 with vinyl- magnesium bromide (400 mol%) in the presence of a catalytic amount of CuCN (60 ml%) in THF at –45 °C followed by stirring at room temperature for 16 h gave the desired homoallylic ketone 3 contaminated with starting material in a 1:1 ratio as determined by 1H NMR spectroscopy by comparison of the integrations of the methyl singlet of 2 at 3.92 ppm and the vinyl multiplet of 3 in CDCl3 at 5.91 ppm.25 Augmenting the amount of Grignard reagent to 500 mol% and the reaction time to 36 h gave an improved 4:1 ratio favoring homoallylic ketone 3. Although ketone 3 and ester 2 were inseparable by chromatography, oxidation of the terminal olefin could be performed on the crude mixture and the ester could be recovered thereafter. For example, oxidation of olefin 3 [ratio 4:1] using a mixture of OsO4•NaIO4 and 2,6-lutidine in dioxane/water gave 4-ketoaldehyde 4 in 49% yield over two steps along with 15% recovered 2.26 On the other hand, Tsuji-Wacker oxidation of olefin 3 [ratio 1:1] using PdCl2 and CuCl in a DMF/water mixture under oxygen atmosphere afforded 1,4-diketone 5 in 35% over two steps with 44% recovered ester 2.27 Finally, by augmenting the amount of Grignard reagent to 600 mol% and the reaction time to 52 h, only the desired homoallylic ketone 3 was obtained in 43% yield after purification. Subsequent oxidations of pure 3 as described above gave respectively 4-ketoaldehyde 4 and 1,4-diketone 5 in 76% and 79% yields.

To demonstrate the utility of 1,4-dicarbonyl compounds 4 and 5, a set of pyrrole targets were prepared employing diverse Paal-Knorr reaction conditions using ammonia and three different primary amines: ethylamine, β-alanine methyl ester and benzylamine (Scheme 2).

First, ketoaldehyde 4 was respectively treated with ammonium formate and ethylamine hydrochloride (500 mol%) with NaOAc/AcOH (1 equiv w/w) in acetonitrile at 65 °C for 5-6 h, which afforded pyrroles 6a and 6b in 39% and 19% yields. On the other hand, no pyrrole 6c was obtained from β-alanine methyl ester hydrochloride (300 mol%) under the same conditions for 2 days; instead, degradation of starting ketoaldehyde 4 was observed.25a,28 Employing 1,4-diketone 5 under the same conditions, pyrroles 7a-c were obtained in 51-66% yields after 3-5 days. Improved yields (74-84%) of pyrroles 7a-d were obtained by increasing the reaction temperature to 80 °C, which shortened reaction times, and which gave 86-100% crude purities as determined by reversed-phase HPLC at 280 nM.
Attempting to improve pyrrole yields from ketoaldehyde 4, a biphasic mixture of 1,2-dichloroethane and AcOH/H2O (1:1) at 85 °C was employed using ammonium formate, β-alanine methyl ester hydrochloride and benzylamine (500 mol%).28 Only N-benzylpyrrole 6d was however isolated in 44%. Analysis of the other reactions by thin layer chromatography indicated trace amounts of pyrrole 6a and no pyrrole 6c contaminated with many impurities from degradation of starting ketoaldehyde 4.
Pyrrole 6a was isolated in 80% yield by chromatography of the condensation product (93% crude HPLC purity) of ketoaldehyde 4 and ammonium formate (500 mol%) using NaOAc/AcOH (2 equiv w/w) in a mixture of MeCN/H2O (1:1) at 80 °C for 6 h. Similarly, better yields (51%) of pyrroles 6b and 6c were obtained from purification of condensation products (88 and 78% crude HPLC purities) of ketoaldehyde 4 respectively with ethylamine hydrochloride and β-alanine methyl ester hydrochloride for 10 h and 7 h. On the contrary, N-benzylpyrrole 6d was obtained in lower quality (58% crude purity) from the MeCN/H2O (1:1) conditions, which led to an insoluble product and degradation as observed by TLC. Employing benzylamine in the Paal-Knorr conditions using a biphasic mixture of 1,2-dichloroethane and H2O (1:1) for 5 h gave N-benzylpyrrole 6d in 55% yield (90% crude HPLC purity). On the other hand, attempts to synthesize pyrroles 7 using a mixture of MeCN/H2O (1:1) with NaOAc/AcOH (2 equiv w/w) at 80 °C afforded only recovered starting diketone 5 after 3 days.
To further demonstrate the utility of the 2-aminophenylpyrrole structure, pyrrolo[1,2-c]quinazolinone 8 was prepared in 96% yield by treatment of 2-[2-N-(Boc)aminophenyl]-1H-pyrrole 6a with NaH in THF at 65 °C overnight (Scheme 3). In spite of growing interest in this tricyclic system because of medicinally relevant biological activity,12 few pyrrolo[1,2-c]quinazolinone syntheses have been reported to date.12,13,17,29

Eight 2-(2-N-(Boc)aminophenyl)pyrroles were synthesized from methyl N-(Boc)anthranilate (2) using a three-step protocol featuring the copper-catalyzed cascade addition of vinyl Grignard reagent to the ester, olefin oxidation of the resulting γ,δ-unsaturated ketone and Paal-Knorr condensation. From the Paal-Knorr reaction of ketoaldehyde 4 with ammonium formate and primary amines (500 mol%), pyrroles 6a-d were isolated in 51-80% yields using NaOAc/AcOH (2 equiv w/w) in MeCN/H2O (1:1) or 1.2-dichloroethane/H2O (1:1) at 80 °C. On the other hand, 5-methylpyrroles 7a-d were prepared in 74-84% yields from treatment of 1,4-diketone 5 with ammomium formate and primary amines (500 mol%) using NaOAc/AcOH (1 equiv w/w) in MeCN at 80 °C. In addition, the parent pyrrolo[1,2-c]quinazolinone skeleton has been assembled from exposure of 2-[2-N-(Boc)aminophenyl]-1H-pyrrole 6a to sodium hydride. Effective access to aminophenylpyrroles and potential for constructing various heterocycle systems from common building blocks makes this practical approach useful for the synthesis of pyrrole analogs for multiple applications.

EXPERIMENTAL
Anhydrous conditions refer to reactions performed in flame-dried glassware under a positive pressure of argon using dry solvent transferred by syringe. Anhydrous solvents (THF and MeCN) were obtained by passage through solvent filtration systems (GlassContour, Irvine, CA). Final isolated compounds, all were purified by flash column chromatography on silica gel (230-400 mesh).30 TLC was performed on glass-backed silica gel plates. Silica gel was pre-treated with 1% Et3N in hexane before purification of pyrroles 6 and 7, and with 1% Et3N in chloroform before purification of pyrroloquinazolinone 8 respectively. 1H NMR spectra were measured in CDCl3, acetone-d6 and DMSO-d6 at 400 MHz and referenced to CDCl3 (7.26 ppm), acetone-d6 (2.05 ppm) and DMSO-d6 (2.50 ppm). 13C NMR spectra were measured in CDCl3, acetone-d6 and DMSO-d6 at 100 MHz and referenced to CDCl3 (77.2 ppm), acetone-d6 (29.9 ppm) and DMSO-d6 (39.5 ppm). HRMS measurements were made on a LC-MSD TOF (Agilent) mass analyzer. HPLC analyses were performed on a Gemini Analytical C18 reverse-phase analytical column (Prevail column from Phenomenex, 5µm, 4.6 x 150 mm, Part No. 00F-4435-E0). Analytical elution was performed using a flow rate of 0.5 mL/min and gradients from 60:40 to 90:10 A/B over 20 min (method A), and 70:30 to 90:10 A/B over 20 min (method B), in which A = CH3OH (0.1% formic acid) and B = H2O (0.1% formic acid). Retention times (Rt) are reported in minutes followed by elution conditions.
Starting Materials. Vinylmagnesium bromide was freshly prepared or purchased from Aldrich and titrated before use. All commercially available chemicals were employed without further purification.
Methyl 2-N-(Boc)anthranilate (2). A solution of methyl anthranilate (1, 5 g, 33.07 mmol) in dry EtOH (60 mL) was treated with (Boc)2O (21.75 g, 99.65 mmol) stirred for 9 days at 50 °C, cooled to rt, and treated with imidazole (9 g, 132.3 mmol) to destroy excess (Boc)2O. After 30 min, the volatiles were evaporated, the residue was dissolved in CHCl3 (150 mL), washed with 1% HCl (2 × 300 mL, 0 °C), dried (MgSO4), and evaporated to give an oil, that was purified by column chromatography on silica gel (10-20% EtOAc in hexane). Evaporation of the collected fractions gave 2-N-(Boc)anthranilate 2 (8.19 g, 98%) as white crystalline solid; mp 77-79 °C; Rf 0.65 (20:80 EtOAc/hexane); 1H NMR (400 MHz, CDCl3) δ 1.54 (s, 9H), 3.92 (s, 3H), 7.97-7.03 (m, 1H), 7.47-7.54 (m, 1H), 7.99 (dd, J = 8.0, 1.6 Hz, 1H), 8.44 (d, J = 8.4 Hz, 1H), 10.28 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ 28.5, 52.4, 80.7, 114.5, 119.0, 121.3, 131.1, 134.7, 142.6, 153.1, 168.8; HRMS (ESI) Calcd m/z for C13H17NNaO4 [(M + Na)+] 274.1050, found 274.1059.
1-[2-N-(Boc)Aminophenyl]pent-4-en-1-one (3). A flask containing CuCN (1.60 g, 18 mmol, 60 mol%), was briefly flame-dried under a stream of argon and filled with dry THF (36 mL; 2.0 mL per 1 mmol of CuCN). The suspension was cooled to –45 °C under argon atmosphere and treated via syringe with a commercially available solution of 1.3 M vinylmagnesium bromide in THF (139 mL, 180 mmol, 600 mol%). The slurry was stirred for 2 h at –45 °C then treated dropwise with a solution of methyl ester 2 (7.53 g, 30 mmol, 100 mol%) in dry THF (60 mL; 2.0 mL per 1 mmol of methyl ester). The resultant mixture was stirred for 1 h at –45 °C. The cold bath was replaced with an ice bath, stirring was maintained for 1 h at 0 °C, and the ice bath was removed. The reaction mixture was allowed to stir and warm to room temperature for 52 h, cooled to 0 °C, quenched on treatment with 1M aqueous NaH2PO4 solution (500 mL, 200% v/v based on total reaction volume) and diluted with Et2O (500 mL). The biphasic solution was vigorously stirred at 0 °C. When a white precipitate had formed, the layers were separated. The aqueous phase was extracted with Et2O (2 × 500 mL). The combined organic layers were washed with saturated aqueous NaHCO3 solution (1 × 500 mL), brine (1 × 500 mL), dried (MgSO4), filtered, and evaporated to a residue, which was purified by column chromatography on silica gel (5-10% EtOAc in hexane). Evaporation of the collected fractions gave homoallylic ketone 3 (3.56 g, 43%) as pale yellow oil; Rf 0.43 (EtOAc-hexane 10:90); 1H NMR (400 MHz, CDCl3) δ 1.53 (s, 9H), 2.45-2.53 (m, 2H), 3.13 (t, J = 7.4 Hz, 2H), 5.02-5.06 (ddd, J = 10.2, 3.0, 1.4 Hz, 1H), 5.07-5.14 (ddd, J = 17.2, 3.2, 1.6 Hz, 1H), 5.85-5.97 (m, 1H), 7.00-7.06 (m, 1H), 7.48-7.55 (m, 1H), 7.90 (dd, J = 8.0, 1.6 Hz, 1H), 8.49 (dd, J = 8.4, 1.2 Hz, 1H), 10.95 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ 28.6, 39.2 (2C), 80.7, 115.7, 119.6, 121.2, 121.3, 130.9, 144.0, 137.3, 142.1, 153.4, 203.6; HRMS (ESI) Calcd m/z for C16H21NNaO3 [M + Na]+ 298.1414, found 298.1413.
1-[2-N-(Boc)Aminophenyl]-4-oxobutanal (4). A solution of homoallylic ketone 3 (1.68 g, 6.10 mmol) in 3:1 dioxane/H2O (60 mL) was treated with 2,6-lutidine (1.50 mL, 12.65 mmol), OsO4 (4% in H2O, 0.80 mL, 12.65 × 10-2 mmol) and NaIO4 (5.41 g, 25.31 mmol), stirred at room temperature overnight, and partitioned between H2O (60 mL) and CH2Cl2 (150 mL). The aqueous phase was extracted with CH2Cl2 (3 × 75 mL). The combined organic layers were washed with brine (150 mL), dried (Na2SO4), filtered and evaporated to a residue, which was purified by column chromatography on silica gel (20-80% EtOAc in hexane). Evaporation of the collected fractions gave ketoaldehyde 4 (1.29 g, 76%) as pale-grey crystalline solid: mp 98-100 °C; Rf 0.37 (30:70 EtOAc-hexane); 1H NMR (400 MHz, CDCl3) δ 1.53 (s, 9H), 2.91 (t, J = 6.3 Hz, 2H), 3.39 (t, J = 6.2 Hz, 2H), 7.02-7.08 (m, 1H), 7.50-7.57 (m, 1H), 7.95 (dd, J = 8.2, 1.4 Hz, 1H), 8.50 (dd, J = 8.6, 1.0 Hz, 1H), 9.92 (s, 1H), 10.83 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ 28.6, 32.5, 37.8, 80.8, 119.5, 120.9, 121.2, 130.9, 135.3, 142.2, 153.3, 200.7, 201.5; HRMS (ESI) Calcd m/z for C15H19NNaO4 [M + Na]+ 300.1206, found 300.1206.
1-[2-N-(Boc)Aminophenyl]pentane-1,4-dione (5). In a two-necked flask fitted with a septum and a three-way stopcock connected to an oxygen-filled rubber balloon, PdCl2 (228 mg, 1.29 mmol) and CuCl (638 mg, 6.44 mmol) were placed in 7:1 DMF/H2O (10 mL). The flask was evacuated and flushed with oxygen three times, during which the initial black solution turned gradually to green. After stirring 40 min at room temperature, the mixture was treated via syringe with a solution of homoallylic ketone 3 (1.77 g, 6.44 mmol) in 7:1 dioxane/H2O (22 mL). The reaction mixture was stirred vigorously at room temperature under oxygen overnight, poured into cold 1 M aqueous KHSO4 (150 mL) and extracted with EtOAc (4 × 100 mL). The combined organic layers were washed with saturated aqueous NaHCO3 solution (1 × 200 mL) and brine (1 × 200 mL), dried (MgSO4), filtered and evaporated to a residue, which was purified by column chromatography on silica gel (15% EtOAc in hexane) to give diketone 5 (1.47 g, 79%) as viscous pale-yellow oil: Rf 0.38 (EtOAc-hexane 30:70); 1H NMR (400 MHz, CDCl3) δ 1.53 (s, 9H), 2.28 (s, 3H), 2.87 (t, J = 6 Hz, 2H), 3.34 (t, J = 6 Hz, 2H), 7.00-7.07 (m, 1H), 7.48-7.55 (m, 1H), 7.96 (dd, J = 8.2, 1.4 Hz, 1H), 8.48 (d, J = 7.6 Hz, 1H), 10.85 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ 28.5, 30.3, 33.7, 37.3, 80.7, 119.4, 121.1, 121.2, 131.0, 135.1, 142.1, 153.3, 202.2, 207.3; HRMS (ESI) Calcd m/z for C16H21NNaO4 [M + Na]+ 314.1363, found 314.1363.
1-[2-N-(Boc)Aminophenyl]-4-oxobutanal (4) from methyl 2-N-(Boc)anthranilate (2). Methyl ester 2 (4.62 g, 18.37 mmol) was treated with a solution of freshly prepared 1.25 M vinylmagnesium bromide (74 mL, 92.50 mmol, 500 mol%) and CuCN (981 mg, 11.02 mmol, 60 mol%) in THF for 36 h at room temperature as described above to give after work-up, 4.95 g of a 4:1 mixture of homoallylic ketone 3 and starting 2, as measured by 1H NMR spectroscopy and integration of the methyl singlet of 2 at 3.92 ppm and the vinyl multiplet of 3 at 5.91 ppm. Without further purification, 1.25 g of the mixture in 3:1 dioxane/H2O (40 mL) was treated with 2,6-lutidine (0.85 mL, 7.26 mmol), OsO4 (4% in H2O, 440 µL, 7.26 10-2 mmol) and NaIO4 (3.11 g, 14.52 mmol), stirred at room temperature overnight, and partitioned between H2O (75 mL) and CH2Cl2 (150 mL). The aqueous phase was extracted with CH2Cl2 (3 × 75 mL). The combined organic layers were washed with brine (150 mL), dried (Na2SO4), filtered and evaporated to a residue, which was purified by column chromatography on silica gel (10-20% EtOAc in hexane). First to elute was 2 (517 mg, 15%) followed by ketoaldehyde 4 (637 mg, 49% over 2 steps).
1-[2-N-(Boc)Aminophenyl]pentane-1,4-dione (5) from methyl-2-N-(Boc)-anthranilate (2). Methyl ester 2 (1.5 g, 5.98 mmol) was treated with a solution of freshly prepared 1.3 M vinylmagnesium bromide (18.5 mL, 24.05 mmol, 400 mol%) and CuCN (320 mg, 3.59 mmol, 60 mol%) in THF for 16 h at room temperature as described above to give after work-up, 1.21 g of a 1:1 mixture homoallylic ketone 3 and starting 2. Without further purification, 604 mg of the mixture in 7:1 dioxane/H2O (5 mL) was added to a two-necked flask fitted with a septum and a three-way stopcock connected to an oxygen-filled rubber balloon, in which PdCl2 (39 mg, 0.22 mmol) and CuCl (109 mg, 1.10 mmol) in 7:1 DMF/H2O (2 mL) had been pre-treated with oxygen for 1h at room temperature. After stirring vigorously at room temperature under oxygen overnight, the mixture was poured into cold 1 M aqueous KHSO4 (25 mL) and extracted with EtOAc (4 × 25 mL). The combined organic layers were washed with saturated aqueous NaHCO3 solution (1 × 25 mL), brine (1 × 25 mL), dried (MgSO4), filtered and evaporated to a residue, which was purified by column chromatography on silica gel (10-20 AcOEt in hexane). First to elute was ester 2 (331 mg, 44%) followed by diketone 5 (305 mg, 35% over 2 steps).
2-[2-N-(Boc)Aminophenyl]-1H-pyrrole (6a). A mixture of ketoaldehyde 4 (200 mg, 0.73 mmol), ammonium formate (229 mg, 3.63 mmol) and NaOAc/AcOH (prepared by mixing equimolar quantities of NaOAc and AcOH; 2 eq w/w, 400 mg) in MeCN/H2O (1:1, 10 mL) was heated to 80 °C with rapid stirring for 6 h, when complete consumption of the starting material was observed by TLC (30:70 EtOAc/hexane). After cooling to room temperature, the reaction mixture was partitioned between 2:1 Et2O/CH2Cl2 (25 mL) and 5 % aqueous Na2CO3 (25 mL). The layers were separated, and the aqueous phase was extracted with Et2O/CH2Cl2 (2:1, 2 × 20 mL). The combined organic phases were washed with pH 6.8 phosphate buffer (25 mL) and brine (25 mL), dried (MgSO4), filtered, evaporated and purified by column chromatography on silica gel (10% EtOAc in hexane). Evaporation of the collected fractions yielded pyrrole 6a (151 mg, 80%) as colorless oil: Rf 0.58 (30:70 EtOAc/hexane); 1H NMR (400 MHz, acetone-d6) δ 1.47 (s, 9H), 6.23-6.27 (m, 1H), 6.31-6.35 (m, 1H), 6.93-6.97 (m, 1H), 7.07 (td, J = 7.6, 1.2 Hz, 1H), 7.21-7.27 (m, 1H), 7.35 (dd, J = 7.6, 1.6 Hz, 1H), 7.46 (br s, 1H), 8.01 (br d, J = 8.0 Hz, 1H), 10.36 (br s, 1H); 13C NMR (100 MHz, acetone-d6) δ 28.6, 80.5, 108.7, 110.1, 120.3, 121.4, 124.0, 125.2, 128.2, 128.7, 129.6, 136.5, 153.8; HRMS (ESI) Calcd m/z for C15H19N2O2 [MH]+ 259.1441, found 259.1443; HPLC Rt 12.6 (method A).
1-Ethyl-2-[2-N-(Boc)aminophenyl]pyrrole (6b). Prepared using the procedure described for the synthesis of 6a from ketoaldehyde 4 (20.9 mg, 7.54 × 10-2 mmol), ethylamine hydrochloride (31 mg, 3.77 × 10-1 mmol) and NaOAc/AcOH (42 mg) in MeCN/H2O (1:1, 2 mL) for 10 h, pyrrole 6b (11 mg, 51%) was isolated by chromatography on silica gel (10% EtOAc in hexane) as colorless oil: Rf 0.74 (30:70 EtOAc/hexane); 1H NMR (400 MHz, acetone-d6) δ 1.19 (t, J = 7.2 Hz, 3H), 1.44 (s, 9H), 3.75 (q, J = 7.2 Hz, 2H), 6.07 (dd, J = 3.6, 2.0 Hz, 1H), 6.20 (dd, J = 3.6, 2.8 Hz, 1H), 6.91-7.00 (br s at 6.96 partially overlaped with dd, J = 2.8, 1.6 Hz, 2H), 7.09 (td, J = 7.6, 1,2 Hz, 1H), 7.20 (ddd, J = 7.6, 1.6, 0.4 Hz, 1H), 7.33-7.40 (m, 1H), 8.16 (br d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, acetone-d6) δ 17.0, 28.5, 42.2, 80.7, 109.1, 110.1, 119.8, 122.5, 123.2, 123.5, 128.6, 129.7, 132.2, 138.9, 153.3; HRMS (ESI) Calcd m/z for C17H22N2NaO2 [M + Na]+ 309.1574, found 309.1571; HPLC Rt 12.2 (method B).
Methyl 3-{2-[2-N-(Boc)aminophenyl]-1H-pyrrolyl}propanoate (6c). Prepared using the procedure described for the synthesis of 6a from ketoaldehyde (4) (20.4 mg, 7.34 × 10-2 mmol), β-alanine methyl ester hydrochloride (51 mg, 3.67 × 10-1 mmol) and NaOAc/AcOH (40 mg) in MeCN/H2O (1:1, 2 mL) for 7 h, pyrrole 6c (13 mg, 51%) was isolated by chromatography on silica gel (10% EtOAc in hexane) as colorless gum: Rf 0.66 (30:70 EtOAc/hexane); 1H NMR (400 MHz, acetone-d6) δ 1.45 (s, 9H), 2.59 (t, J = 7 Hz, 2H), 3.55 (s, 3H), 4.05 (t, J = 7 Hz, 2H), 6.09 (dd, J = 3.6, 1.6 Hz, 1H), 6.18 (dd, J = 3.6, 2.8 Hz, 1H), 6.93 (dd, J = 2.8, 1.6 Hz, 1H), 7.02 (br s, 1H), 7.10 (td, J = 7.6, 1.2 Hz, 1H), 7,23 (dd, J = 7.6, 1.6 Hz, 1H), 7.34-7.40 (m, 1H), 8.16 (br d, 8.0 Hz, 1H); 13C NMR (100 MHz, acetone-d6) δ 28.5, 51.3, 80.6, 109.3, 110.7, 119.6, 123.0 (C2), 124.1, 127.7, 128.2, 129.3, 129.4, 129.8, 132.3, 139.0, 139.6, 153.1; HRMS (ESI) Calcd m/z for C22H25N2O2 [MH]+ 349.1911, found 349.1901; HPLC Rt 13.6 (method B).13C NMR (100 MHz, acetone-d6) δ 28.5, 36.2, 43.3, 52.0, 80.6, 109.2, 110.5, 120.1, 123.2, 123.3, 128.9, 129.8, 132.3, 139.0, 153.4, 171.8; HRMS (ESI) Calcd m/z for C19H25N2O4 [MH]+ 345.1809, found 345.1808; HPLC Rt 14.2 (method A).
1-Benzyl-2-[2-N-(Boc)aminophenyl]pyrrole (6d). Prepared using a modification of the procedure described for the synthesis of 6a from ketoaldehyde (4) (20.8 mg, 7.50 10-2 mmol), benzylamine (42 µL, 3.75 10-1 mmol) and NaOAc/AcOH (42 mg) in 1,2-dichloroethane/H2O (1:1, 2 mL) for 5 h. pyrrole 6d (14.4 mg, 55%) was isolated by chromatography on silica gel (10% EtOAc in hexane) as pale yellow gum: Rf 0.72 (30:70 EtOAc-hexane); 1H NMR (400 MHz, acetone-d6) δ 1.44 (s, 9H), 4.97 (s, 2H), 6.16 (dd, J = 3.4, 1.8 Hz, 1H), 6.25 (dd, J = 3.4, 3.2 Hz, 1H), 6.87 (br s, 1H), 6.88-6.92 (m, 2H), 6.97-7.00 (m, 1H), 7.00-7.04 (dd, J = 7.2, 1.2 Hz, 1H), 7.11-7.16 (ddd, J = 7.7, 1.9, 0.5 Hz, 1H), 7.17-7.26 (m, 3H), 7.29-7.36 (m, 1H), 8.40 (br d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, acetone-d6) δ 28.5, 51.3, 80.6, 109.3, 110.7, 119.6, 123.0 (C2), 124.1, 127.7, 128.2, 129.3, 129.4, 129.8, 132.3, 139.0, 139.6, 153.1; HRMS (ESI) Calcd m/z for C22H25N2O2 [MH]+ 349.1911, found 349.1901; HPLC Rt 13.6 (method B).
2-[2-N-(Boc)Aminophenyl]-5-methyl-1H-pyrrole (7a). A mixture of diketone 5 (200 mg, 0.68 mmol), ammonium formate (218 mg. 3.46 mmol), and NaOAc/AcOH (prepared by mixing equimolar quantities of NaoAc and AcOH; 1 eq w/w, 210 mg) in MeCN (10 mL) was heated at 80 °C with rapid stirring for 94 h, when complete consumption of the starting material was observed by TLC (30:70 EtOAc/hexane). After cooling to room temperature, the reaction mixture was partitioned between 2:1 Et2O/CH2Cl2 (30 mL) and a mixture of pH 6.8 phosphate buffer solution (30 mL) and brine (10 mL). The layers were separated. The organic phase was washed with a mixture of pH 6.8 phosphate buffer (10 mL) and brine (5 mL). The combined aqueous phase was extracted with Et2O/CH2Cl2 (2:1, 3 × 30 mL). The combined organic phases were washed with brine (1 × 30 mL), dried (Na2SO4), filtered, and evaporated to a residue, which was purified by column chromatography on silica gel (10% EtOAc in hexane) to yield pyrrole 7a (142 mg, 76%) as pale yellow crystalline solid: mp 125-126 °C; Rf 0.72 (30:70 EtOAc/hexane); 1H NMR (400 MHz, acetone-d6) δ 1.48 (s, 9H), 2.29 (d, J = 0.8 Hz, 3H), 5.89-5.94 (m, 1H), 6.19 (t, J = 3 Hz, 1H), 7.04 (td, J = 7.5, 1.0 Hz, 1H), 7.20 (td, J = 7.8, 1.1 Hz, 1H), 7.32, (dd, J = 7.8, 1.4 Hz, 1H), 7.52 (br s, 1H), 8.00 (br d, J = 8.0 Hz, 1H), 10.06 (br s, 1H); 13C NMR (100 MHz, acetone-d6) δ 13.0, 28.6, 80.4, 108.2, 108.8, 121.2, 123.9, 125.3, 127.2, 127.7, 129.1, 130.3, 136.1, 153.8; HRMS (ESI) Calcd m/z for C16H20N2NaO2 [M + Na]+ 295.1417, found 295.1417; HPLC Rt 10.6 (method B).
1-Ethyl-2-[2-N-(Boc)aminophenyl]-5-methylpyrrole (7b). Prepared by the same protocol as described for the synthesis of 7a from diketone 5 (200 mg, 0.68 mmol), ethylamine hydrochloride (282 mg, 3.45 mmol) and NaOAc/AcOH (216 mg) in MeCN (10 mL) for 29 h, pyrrole 7b (152 mg, 74%) was isolated by column chromatography (10% EtOAc in hexane) as viscous colorless oil: Rf 0.71 (30:70 EtOAc/hexane); 1H NMR (400 MHz, acetone-d6) δ 1.03, (t, J = 7.2 Hz, 3H), 1.44 (s, 9H), 2.29 (d, J = 0.4 Hz, 3H), 3.72 (q, J = 7.2 Hz, 2H), 5.92-5.95 (dd, J = .2, 0.8 Hz, 1H), 5.95-5.99 (d, J = 3.2 Hz, 1H), 7.01 (br s, 1H), 7.07 (td, J = 7.4, 1.2 Hz, 1H), 7.19 (dd, J = 7.6, 1.6 Hz, 1H), 7.32-7.40 (m, 1H), 8.18 (br d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, acetone-d6) δ 12.6, 16.5, 28.5, 39.3, 80.7, 108.0, 109.2, 119.4, 123.0, 123.9, 127.5, 129.6, 130.3, 132.4, 139.0, 153.3; HRMS (ESI) Calcd m/z for C18H25N2O2 [MH]+ 301.1911, found 301.1907; HPLC Rt 13.1 (method B).
Methyl 3-{2-[2-N-(Boc)aminophenyl]-5-methyl-1H-pyrrolyl}propanoate (7c). Prepared by the same protocol as described for the synthesis of 7a from diketone 5 (200 mg, 0.68 mmol), β-alanine methyl ester hydrochloride (482 mg, 3.45 mmol) and NaOAc/AcOH (211 mg) in MeCN (10 mL) for 19 h, pyrrole 7c (190 mg, 77%) was isolated by column chromatography (10% EtOAc in hexane) as viscous pale yellow oil: Rf 0.60 (30:70 EtOAc/hexane); 1H NMR (400 MHz, acetone-d6) δ 1.45 (s, 9H), 2.30 (d, J = 0.8 Hz, 3H), 2.41 (t, J = 7.6 Hz, 2H), 3.51 (s, 3H), 4.04 (t, J = 7.6 Hz, 2H), 5.92-5.95 (dd, J = 3.6, 0.8 Hz, 1H), 5.98-6.01 (d, J = 3.2 Hz, 1H), 7.05-7.13 (br s totally overlapped with td, J = 7.4, 1.2, 2H), 7.20 (dd, J = 7.6, 1.6 Hz, 1H), 7.32-7.39 (m, 1H), 8.18 (br d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, acetone-d6) δ 12.6, 28.5, 35.7, 40.4, 51.9, 80.6, 108.2, 109.9, 119.7, 123.2, 123.7, 127.8, 129.7, 130.9, 132.2, 139.0, 153.4, 171.6; HRMS (ESI) Calcd m/z for C20H26N2NaO4 [M + Na]+ 381.1785, found 381.1788; HPLC Rt 11.8 (method B).
1-Benzyl-2-[2-N-(Boc)aminophenyl]-5-methyl-pyrrole (7d). Prepared by the same protocol as described for the synthesis of 7a from diketone 5 (200 mg, 0.68 mmol), benzylamine (375 µL, 3.43 mmol) and NaOAc/AcOH (209 mg) in MeCN (10 mL) for 24 h, pyrrole 7d (208 mg, 84%) was isolated by column chromatography (10% EtOAc in hexane) as yellow solid: mp 76-78 °C; Rf 0.71 (30:70 EtOAc/hexane); 1H NMR (400 MHz, acetone-d6) δ 1.45 (s, 9H), 2.18 (d, J = 0.4 Hz, 3H), 4.98 (s, 2H), 6.04-6.07 (dd, J = 3.2, 0.8 Hz, 1H), 6.09-6.13 (d, J = 3.2 Hz, 1H), 6.79 (br d, J = 6.8 Hz, 2H), 6.96 (td, J = 7.4, 1.2 Hz, 1H), 7.07 (br s, 1H), 7.11 (dd, J. = 7.6, 1.6 Hz, 1H), 7.15-7.31 (m, 4H), 8.11 (br d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, acetone-d6) δ 12.8, 28.5, 48.0, 80.6, 108.4, 109.7, 119.4, 122.9, 123.4, 126.7, 127.9, 128.8, 129.4, 129.6, 131.4, 132.2, 138.9, 139.8, 153.1; HRMS (ESI) Calcd m/z for C23H26N2NaO2 [M + Na]+ 385.1886, found 385.1890; HPLC Rt 14.5 (method B).
Pyrrolo[1,2-c]quinazolin-5(6H)-one (8). Sodium hydride (60% dispersion in mineral oil, 8.7 mg, 21.75 × 10-2 mmol) was added to a solution of pyrrole 6a (46.7 mg, 18.08 × 10-2 mmol) in THF (3 mL) under an argon atmosphere. The mixture was stirred at 65 °C overnight, and partitioned between H2O (10 mL) and CHCl3 (20 mL). The aqueous phase was extracted with CHCl3 (2 × 10 mL). The combined organic layers were washed with brine (10 mL), dried (Na2SO4), filtered and evaporated to a crude residue, which was purified by crystallisation from MeOH to give pyrroloquinazolinone 8 (32.1 mg, 96%) as white solid: mp 264-265 °C; Rf 0.32 (30:70 EtOAc/hexane); 1H NMR (400 MHz, DMSO-d6) δ 6.67 (t, J = 3.2 Hz, 1H), 7.00 (dd, J = 3.4, 1.4 Hz, 1H), 7.17-7.22 (m, 1H), 7.23-7.26 (dd, J = 8.0, 0.8, 1H), 7.30-7.35 (m, 1H), 7.59 (dd, J = 3.2, 1.6, 1H), 7.92 (br d, J = 8.0 Hz, 1H), 11.48 (br s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 104.4, 113.8, 114.3, 115.5 (2C), 122.2, 123.1, 127.5, 129.2, 132.5, 145.5; HRMS (ESI) Calcd m/z for C11H9N2O [MH]+ 185.0709, found 185.0715.

ACKNOWLEDGEMENTS
The authors would like to thank the Natural Sciences and Engineering Research Council (NSERC) of Canada as well as the Fond Québecois de Recherche sur la Nature et les Technologies for their financial support. We thank Dr. Alexandra Fürtös of the Université de Montréal Mass Spectrometry facility for mass spectral analyses.

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