Domino Aza-Michael-SNAr-Heteroaromatization Route to C5-Substituted 1-Alkyl-1H-Indole-3-Carboxylic Esters

A new synthesis of C5-substituted 1-alkyl-1H-indole-3-carboxylic esters is reported. A series of methyl 2-arylacrylate aza-Michael acceptors were prepared with aromatic substitution to activate them towards SNAr reaction. Subsequent reaction with a series of primary amines generated the title compounds. Initially, the sequence was expected to produce indoline products, but oxidative heteroaromatization intervened to generate the indoles. The reaction proceeded under anhydrous conditions in DMF at 23–90 °C using equimolar quantities of the acrylate and the amine with 2 equiv. of K2CO3 to give 61–92% of the indole products. The reaction involves an aza-Michael addition, followed by SNAr ring closure and heteroaromatization. Since the reactions were run under nitrogen, the final oxidation to the indole likely results from reaction with dissolved oxygen in the DMF. Substrates incorporating a 2-arylacrylonitrile proved too reactive to prepare using our protocol. The synthesis of the reaction substrates, their relative reactivities, and mechanistic details of the conversion are discussed.


Introduction
Indoles are among the most widely distributed heterocycles in nature and many have critical functions in living organisms. Due to their potent biological profiles, numerous natural and synthetic indoles have been prepared and studied by chemists to mitigate the effects of various diseases [1,2]. To date, numerous synthetic approaches have been developed and this family of compounds remains a highly active area of research in organic and medicinal chemistry.
The current study sought to develop a new synthetic approach to these systems through a domino aza-Michael-S N Ar-heteroaromatization sequence from acrylate esters substituted at C2 by an aromatic system substituted to promote nucleophilic aromatic substitution by an addition-elimination (S N Ar) mechanism. Previously, indole derivatives have been prepared by a domino-reduction-reductive amination reaction from 2-nitrophenylacetone [16] and a domino reduction-aza-Michael-elimination process from ethyl 2-(2-nitrophenyl)-b-ketoesters [17]. These procedures differ from the current route in aromatizing via elimination of water from the initial adduct. The present study involves (1) aza-Michael addition to a polarized 2-arylacrylate double bond, (2) ring formation by S N Ar of the added nitrogen to the electron-deficient aromatic ring, and (3) aromatization by reaction with molecular oxygen which is either dissolved in the reaction solvent or admitted to the flask during removal of TLC samples. The conversion is clean and provides the indoles in high yield.
Indoles are prevalent in many drug compounds showing a wide range of activities. Filtering for compounds that possess similar structural features to the compounds prepared here-an alkylated nitrogen at position 1 and an acyl group at C3-revealed a number of structures that are pictured in Figure 1. Pravadoline (1) has potent analgesic properties via binding to the cannabinoid CB 1 /CB 2 receptors [18] and is closely related to neuroprotective compounds that inhibit inflammation caused by b-amyloid proteins involved in Alzheimer's disease [19]. The iodinated naphthoylindole 2 is a strong analgesic as it also binds to the CB 1 /CB 2 receptors [20]. Arbidol (Umifenovir, 3) is a potent antiviral [21], used primarily in Russia and China, against influenza A [22]. Finally, 3-indolyl-5-amino-2phenyl-1,2,3-triazine 4 has shown highly promising antimicrobial activity towards both Gram positive and Gram negative bacteria [23]. aromatizing via elimination of water from the initial adduct. The present study involves (1) aza-Michael addition to a polarized 2-arylacrylate double bond, (2) ring formation by SNAr of the added nitrogen to the electron-deficient aromatic ring, and (3) aromatization by reaction with molecular oxygen which is either dissolved in the reaction solvent or admitted to the flask during removal of TLC samples. The conversion is clean and provides the indoles in high yield. Indoles are prevalent in many drug compounds showing a wide range of activities. Filtering for compounds that possess similar structural features to the compounds prepared here-an alkylated nitrogen at position 1 and an acyl group at C3-revealed a number of structures that are pictured in Figure 1. Pravadoline (1) has potent analgesic properties via binding to the cannabinoid CB1/CB2 receptors [18] and is closely related to neuroprotective compounds that inhibit inflammation caused by b-amyloid proteins involved in Alzheimer's disease [19]. The iodinated naphthoylindole 2 is a strong analgesic as it also binds to the CB1/CB2 receptors [20]. Arbidol (Umifenovir, 3) is a potent antiviral [21], used primarily in Russia and China, against influenza A [22]. Finally, 3-indolyl-5-amino-2-phenyl-1,2,3-triazine 4 has shown highly promising antimicrobial activity towards both Gram positive and Gram negative bacteria [23].

Results and Discussion
The 2-arylacrylate indole precursors 7, 10 and 13 were prepared using standard techniques (Scheme 1). Methyl 2-fluorophenylacetate (5) was converted to methyl 2-(2-fluoro-5-nitrophenyl)acrylate (6) by nitration using NaNO 3 in H 2 SO 4 at 0-23 • C for 2 h [24]. Installation of the acrylate double bond to give 7 was accomplished by aldol condensation with formaldehyde (37% aq. formaldehyde (formalin), K 2 CO 3 , DMF, 23 • C) [25]. The 2-(5-cyano-2-fluorophenyl)acrylate substrate (10) was prepared from the aforementioned intermediate nitration product 6. Reduction of the nitro group to give aniline 8 (Fe/NH 4 Cl, aq. EtOH, 70 • C) [26] was followed by diazotization (HONO) and Sandmeyer replacement of nitrogen by cyanide (CuCN) [27,28] to afford 9. Final conversion to acrylate 10 was accomplished as above. Finally, the diester substituted substrate 13 was prepared from 5-cyano-2-fluorobenzaldehyde (11). Reduction of the aldehyde to the benzyl alcohol (NaBH 4 , EtOH, 23 o C), conversion to the bromide (PBr 3 , Et 2 O, 0-23 • C) [29], S N 2 displacement of bromide by cyanide (KCN, aq. EtOH) and methanolysis of the dicyano compound (25% H 2 SO 4 in MeOH, 90 • C) generated diester 12. Aldol condensation with formaldehyde then led to 13. Yields were reasonable for all steps and each synthesis was performed on a multigram scale. It should be noted that attempts to install the aza-Michael accepting double bond in 2-(2-fluoro-5-nitrophenyl)acetonitrile (15), generated from 2-fluoro-5-nitrobenzyl bromide (14) [30], yielded polymeric material under the aldol conditions used and 1-fluoro-4-nitro-2-((phenylsulfonyl)methyl)benzene ( 16), prepared from this same bromide [31], failed to aldolize under the conditions used. Our cyclization results are summarized in Table 1. The reaction was carried out in anhydrous DMF using 1 mmol of the acrylate, 1 mmol of the RNH2 and 2 mmol of K2CO3. Primary amines incorporating a primary, secondary or tertiary alkyl group were all successful in the reaction but anilines failed to initiate the sequence due to their diminished reactivity. We also found that hydrazine reacted with nitro activated substrate 7 but not the cyano and ester activated substrates 10 and 13, respectively [32]. Despite the a-effect which increases the nucleophilicity of hydrazine [33], the less SNAr active substrates 10 and 13 primarily afforded products resulting from reaction at the pendant ester and cyano groups. As expected, the five-membered ring was entropically favored over the six-membered ring in the reaction of hydrazine with 7. Additionally, the five-membered ring also benefited from stabilization gained via heteroaromatization. Our cyclization results are summarized in Table 1. The reaction was carried out in anhydrous DMF using 1 mmol of the acrylate, 1 mmol of the RNH 2 and 2 mmol of K 2 CO 3 . Primary amines incorporating a primary, secondary or tertiary alkyl group were all successful in the reaction but anilines failed to initiate the sequence due to their diminished reactivity. We also found that hydrazine reacted with nitro activated substrate 7 but not the cyano and ester activated substrates 10 and 13, respectively [32]. Despite the a-effect which increases the nucleophilicity of hydrazine [33], the less S N Ar active substrates 10 and 13 primarily afforded products resulting from reaction at the pendant ester and cyano groups. As expected, the five-membered ring was entropically favored over the six-membered ring in the reaction of hydrazine with 7. Additionally, the five-membered ring also benefited from stabilization gained via heteroaromatization.
Substrates incorporating nitro and cyano activation on the S N Ar acceptor ring proceeded at room temperature while the ester-bearing substrate required heating up to 90 • C. This observation likely reflects the relative activating ability of the different groups in the S N Ar process. In all cases, the work-up required adding the crude reaction mixture to aq. NH 4 Cl, extracting with ether, and washing the combined organic layers with aq. NaCl. The ether layers were dried and concentrated to give a crude product that was purified by column chromatography. All products exhibited spectral and analytical data in accord with the assigned structures (see Supplementary Materials).  The exact chronology of events in the reaction sequence is unknown, but a plausible sequence is outlined for substrate 7 in Scheme 2. Due to the low temperatures employed, the initiating step was assumed to involve aza-Michael addition of the amine to the unhindered 2-arylacrylate double bond followed by loss of a proton to give amine adduct A. The nitrogen in this intermediate is positioned to add to the activated aromatic ring by a S N Ar reaction via Meisenheimer intermediate B to give indoline C. The heteroaromatization process likely occurs due to exposure of the compound to dissolved oxygen in the DMF [34] or oxygen introduced during removal of TLC samples. Since indoline C has a highly activated benzylic C-H substituted by an ester group, insertion of oxygen at this site to form a peroxide intermediate D should be facile. This process often requires a radical initiator [32], but it is unclear what could perform this function in the current reaction. Once oxygen inserts into the activated C-H bond, elimination under the basic conditions would install the double bond to afford the indole 17 (Scheme 2). In no case was indoline C detected during the reaction or in the final product. A similar process was hypothesized for the formation of quinolones in an earlier study [35].
sequence is outlined for substrate 7 in Scheme 2. Due to the low temperatures employed, the initiating step was assumed to involve aza-Michael addition of the amine to the unhindered 2-arylacrylate double bond followed by loss of a proton to give amine adduct A. The nitrogen in this intermediate is positioned to add to the activated aromatic ring by a SNAr reaction via Meisenheimer intermediate B to give indoline C. The heteroaromatization process likely occurs due to exposure of the compound to dissolved oxygen in the DMF [34] or oxygen introduced during removal of TLC samples. Since indoline C has a highly activated benzylic C-H substituted by an ester group, insertion of oxygen at this site to form a peroxide intermediate D should be facile. This process often requires a radical initiator [35], but it is unclear what could perform this function in the current reaction. Once oxygen inserts into the activated C-H bond, elimination under the basic conditions would install the double bond to afford the indole 17 (Scheme 2). In no case was indoline C detected during the reaction or in the final product. A similar process was hypothesized for the formation of quinolones in an earlier study [36].

General Methods
Unless otherwise indicated, all reactions were performed under dry N2 in oven-dried glassware. All reagents and solvents were used as received. All wash solutions in workup procedures were aqueous. Reactions were monitored by thin layer chromatography on Analtech No 21521 silica gel GF plates (Newark, DE, USA). Preparative separations were performed by flash chromatography on silica gel (Davisil ® , grade 62, 60-200 mesh) containing 0.5% of UV-05 UV-active phosphor (both from Sorbent Technologies, Scheme 2. Plausible mechanism for the domino aza-Michael-S N Ar-heteroaromatization of 7.

General Methods
Unless otherwise indicated, all reactions were performed under dry N 2 in oven-dried glassware. All reagents and solvents were used as received. All wash solutions in workup procedures were aqueous. Reactions were monitored by thin layer chromatography on Analtech No 21521 silica gel GF plates (Newark, DE, USA). Preparative separations were performed by flash chromatography on silica gel (Davisil ® , grade 62, 60-200 mesh) containing 0.5% of UV-05 UV-active phosphor (both from Sorbent Technologies, Norcross, GA, USA) slurry packed into quartz columns. Band elution for all chromatographic separations was monitored using a hand-held UV lamp (Fisher Scientific, Pittsburgh, PA, USA). Melting points were obtained using a MEL-TEMP apparatus (Cambridge, MA, USA) and are uncorrected. FT-IR spectra (0.09 cm −1 resolution between 4000-500 cm −1 ) were run as thin films on NaCl disks using a Nicolet iS50 spectrophotometer (Madison, WI, USA). 1 H-and 13 C-NMR spectra were measured using a Bruker Avance 400 system (Billerica, MA, USA) at 400 MHz and 101 MHz, respectively, in the indicated solvents containing 0.05% (CH 3 ) 4 Si as the internal standard; coupling constants (J) are given in Hz. Low-resolution mass spectra were obtained using a Hewlett-Packard Model 1800A GCD GC-MS system (Palo Alto, CA, USA). Elemental analyses (±0.4%) were determined by Atlantic Microlabs (Norcross, GA, USA).

Methyl 2-(5-Cyano-2-fluorophenyl)acetate (9)
The general procedure of Clarke and Read was used [27]. All water and aqueous solutions in this procedure used deionized H 2 O. CuCl was prepared from CuSO 4 ·5H 2 O (3.42 g, 13.7 mmol), NaCl (0.90 g, 15.5 mmol) and Na 2 SO 3 (from 0.72 g of NaHSO 3 /Na 2 S 2 O 5 and 0.48 g (18 mmol) of NaOH) in H 2 O (14 mL) as described by Marvel and McElvain [28]. The CuCl was purified by decantation and suspended in H 2 O (10 mL). To the magnetically stirred suspension, a solution of NaCN (1.82 g, 37.1 mmol) in H 2 O (5 mL) was added drop-wise over 10 min and the CuCl dissolved with the generation of heat.
Aminoester 8 (2.00 g, 10.9 mmol) was mixed with crushed ice (ca 5 g) and 28% HCl (3 mL) was added. The flask was surrounded by an ice bath to maintain the temperature at 0-5 • C and a solution of NaNO 2 (0.84 g, 12.1 mmol) in H 2 O (3 mL) was added with stirring over 15 min. This mixture was neutralized to pH 7 by slow addition of solid anhydrous Na 2 CO 3 to give a solution of the diazonium salt.
The above CuCN solution was cooled to 0-5 • C, toluene (4 mL) was added and vigorous stirring was initiated. To this was added drop-wise the cold solution of the diazonium salt during 15-20 min keeping the temperature at 0-5 • C. N 2 was evolved during the addition. The mixture was warmed to 23 • C over 2 h and then heated to 50 • C for 5 min. The heat was removed and the reaction was allowed to return to 23 • C over 1 h. The crude reaction mixture was transferred to a separatory funnel and the mixture was extracted with EtOAc (3 × 25 mL). The combined organic extracts were washed with saturated NaCl (3 × 50 mL), dried (Na 2 SO 4 ), and concentrated under vacuum. The product from two runs at the above scale was purified by silica gel column chromatography (50 cm × 2.

Methyl (4-Carbomethoxy-2-fluorophenyl)acetate (12)
To a solution of the 5-cyano-2-fluorobenzaldehyde (11, 10.0 g, 67.1 mmol) in absolute ethanol (80 mL) at 0 • C (ice-water bath), NaBH 4 (1.27 g, 33.5 mmol) was added portionwise with stirring during 10-15 min. The cooling bath was removed and the reaction was allowed to warm to room temperature for 1 h. The reaction was quenched by addition to saturated NaCl (250 mL) and extracted with ether (3 × 50 mL). The combined ether layers were washed with saturated NaCl (3 × 50 mL) and dried (Na 2 SO 4 ). Filtration and concentration under vacuum gave the alcohols as off-white solids that were purified by trituration with 2% ether in pentane to give (5-cyano-2-fluorophenyl)methanol (9. A solution of concentrated sulfuric acid in methanol (100 mL, 25% v/v) was prepared at 0 • C. The benzylic nitrile was added slowly and the mixture was heated to boiling for 16 h (bath temperature 90 • C). After cooling, the reaction was quenched by addition to saturated NaCl (250 mL) and extracted with ether (3 × 50 mL). The combined ether layers were washed with saturated NaCl (3 × 50 mL) and dried (Na 2 SO 4 ).

General Procedure for Conversion of the 2-Arylacetate Esters to Acrylates
The basic procedure of Selvakumar and co-workers was used [25]. To a mixture of the methyl 2-arylacetate (8.0 mmol) in formalin (37%, 18 mL) was added a suspension of anhydrous K 2 CO 3 (1.66 g, 12.0 mmol) in DMF (5 mL). The resulting mixture was heated to 60 • C for 2 h and then cooled to 23 • C. The crude reaction mixture was quenched with water (75 mL) and extracted with ether (3 × 50 mL). The combined ether extracts were washed with saturated NaCl (3 × 50 mL) and dried (Na 2 SO 4 ). Filtration and concentration under vacuum gave the crude product as a light yellow oil. Purification by silica gel column chromatography (25 cm × 2.5 cm) eluted with increasing concentrations of ether in hexanes afforded the pure acrylate esters, which solidified on standing.

General Procedure for Preparing C5-Substituted Methyl 1-Alkyl-1H-indole-3-carboxylates
A solution of the C5-substituted 2-arylacrylate (1 mmol) and the primary amine (1 mmol) in DMF (4 mL) was treated with anhydrous K 2 CO 3 (276 mg, 2 mmol) and stirred for 12 h at 23 • C. At this time, TLC indicated that the reaction was complete. The crude reaction mixture was added to saturated NH 4 Cl (50 mL) and extracted with ether (3 × 25 mL). The combined organic extracts were washed with saturated NaCl (50 mL), dried (Na 2 SO 4 ), filtered, and concentrated under vacuum. The crude product was purified by passing through a short silica gel column (25 × 2.5 cm) eluted with increasing concentrations of ether in hexanes. The compounds prepared are summarized below. Notes: (1) When 3-nitrobenzylamine hydrochloride was used as the amine, 3 equiv of K 2 CO 3 were used. (2) When the substrate incorporated an ester activating group on the S N Ar acceptor ring, the reaction was stirred for 12 h at 50-90 • C as indicated in Table 1.

Conclusions
A method has been developed for the efficient synthesis of 1-alkyl-1H-indole-3carboxylic esters that uses a domino aza-Michael-S N Ar-heteroaromatization sequence. Following synthesis of the substrates, the reaction was performed using an equimolar mixture of the acrylate and the amine in the presence of 2 equiv of K 2 CO 3 in anhydrous DMF. The reaction proceeded at room temperature for substrates with nitro and cyano activated S N Ar acceptor rings and at 50-90 • C for rings activated by an ester. The amines were all primary alkylamines with no restriction on the structure of the alkyl group. Anilines did not undergo the ring formation due to their reduced nucleophilicity. The entire process occurred in a single reaction flask to give the aromatized product. The anticipated indoline products were not produced, but instead, oxidation to the aromatic indoles was observed. The heteroaromatization is believed to be promoted by oxygen dissolved in the DMF solvent or introduced during removal of samples for TLC analysis. In no case was an indoline observed or isolated from the reaction. Hydrazine reacted with the nitro activated substrate, but failed for substrates with less active S N Ar acceptor rings, giving products resulting from reaction with the cyano and ester substituents. The corresponding 2-arylacrylonitrile substrate polymerized under the aldol conditions with formalin while the phenylsulfonyl precursor to the vinyl sulfone failed to undergo aldol condensation with formaldehyde using K 2 CO 3 as the base.