An Efficient Approach to Aromatic Aminomethylation Using Dichloromethane as Methylene Source

Ultrasound-promoted N-aminomethylation of indoles can be achieved in basic medium using sodium hydride and dichloromethane (DCM) as C1 donor source. This innovative amino methylation protocol results in good to excellent yields of multifunctional indole derivatives. The procedure is also applicable to other aza-heterocyclic compounds and, interestingly, affords direct access to aminomethyl-substituted aryl alcohols.

CHART 1 | Aminomethylation of N-1 indole position. Mastalir et al. (2017) obtained an N1 derivative in basic medium by reaction of indole with a secondary amine using a manganesebased catalyst and methanol as C1 donor source. However, all these methods require highly controlled conditions or the presence of specific catalysts.

General Informations
Reagents, starting materials, and solvents were purchased from Sigma-Aldrich (Milan, Italy) and used as received. Reactions were carried out with magnetic stirring in 25 mL roundbottomed or in falcon tubes (10 mL). Ultrasonication was performed in a Bandelin Sonorex Digital 10P ultrasonic bath with a frequency of 60 Hz and power of 240 W. Microwave assisted closed vessel reactions were performed in a Biotage Initiator + reactor, using 10 mL vials type and external temperature sensor. Analytical thin layer chromatography (TLC) was performed on pre-coated glass silica gel plates 60 (F254, 0.25 mm, VWR International). UHPLC analyses were performed on a Nexera UHPLC system (Shimadzu, Kyoto, Japan) consisting of a CBM-20A controller, two LC-30AD dual-plunger parallel-flow pumps, a DGU-20 AR5 degasser, an SPD-M20A photo diode array detector (equipped with a 2.5 µL detector flow cell volume), a CTO-20A column oven, a SIL-30AC autosampler. The chromatographic profile was obtained on a Kinetex TM C18 150 × 2.1 mm × 2.6 µm (100 Å) column (Phenomenex, Bologna, Italy). The optimal mobile phase consisted of 0.1% TFA/H 2 O v/v (A) and 0.1% TFA/ACN v/v (B). Analysis was performed in gradient elution as follows: 0-13.00 min, 5-65% B; 13-14.00 min, 65-95% B; 14-15.00 min, isocratic to 95% B; 15-15.01 min, 95-5% B; then 3 min for column re-equilibration. Flow rate was 0.5 mL min −1 . Column oven temperature was set to 45 • C. Injection volume was 2 µL of sample. The following PDA parameters were applied: sampling rate, 12.5 Hz; detector time constant, 0.160 s; cell temperature, 40 • C. Data acquisition was set in the range 190-800 nm and chromatograms were monitored at 254 nm. For the quantification of main chromatographic peaks, indole was selected as external standard. Stock solution (1 mg mL −1 ) was prepared in methanol, the calibration curve was obtained in a concentration range of 250-10.0 µg mL −1 with six concentration levels and triplicate injection of each level were run. Peak areas of indole derivatives were plotted against corresponding concentrations (µg mL −1 ) and the linear regression was used to generate calibration curve (y = 0.00024x−1.39094) with R2 values was ≥ 0.9999. Purifications were conducted on the Biotage Isolera One flash purification system, using prepacked KP-sil columns (Biotage, Uppsala, Sweden). 1D and 2D NMR spectra were recorded with Bruker Avance (400 MHz) spectrometer, at room temperature. Spectra were referenced to residual chloroform (7.24 ppm, 1H; 77.23 ppm, 13C) or methanol (3.31 ppm, 1H; 49.15 ppm, 13C). Chemical shifts are reported in δ values (ppm) relative to internal Me 4 Si, and J values are reported in hertz (Hz). The following abbreviations are used to describe peaks: s (singlet), d (doublet), dd (double doublet), t (triplet), bs (broad singlet), and m (multiplet). HR-MS experiments were performed by an LTQ-Orbitrap-XL-ETD mass spectrometer (Thermo Scientific, Bremen, Germany), using electrospray ionization. Elemental analysis was performed by the FlashSmart Elemental Analyzer (Thermo Fisher Scientific, Waltham, MA USA).

Method Optimization
Indole (1 mmol), base (2 mmol), piperidine (1.5 mmol) were mixed in different solvents (5 mL) under the conditions reported in Table 1. After the time indicated in Table 1, the reaction was quenched with 5 mL of a 10% citric acid solution and the organic solvents were evaporated in vacuo. The crude was dissolved in DCM (20 mL) and extracted with water (3 × 20 mL). Compounds 2, 3, and 4 were obtained after flash chromatography, using 1/4 ethyl acetate/n-hexane as eluent mixture.

Application of the Optimized Procedure
Substrates (1 mmol) were dissolved in acetonitrile (5 mL) in a falcon tubes (10 mL) and sodium hydride (2 mmol), amines (1.5 mmol), and dichloromethane (3 mmol) were added. The mixture was introduced in an ultrasonic bath setting the temperature at 50 • C and irradiating for 120 min. Then, the work up of the reaction and the purification of final compounds were performed as described above. The NMR spectra of synthesized compounds are depicted in Figures S1-S60.  (14) Obtained from tert-butyl ((1H-indol-5-yl)methyl)carbamate and piperidine. Rf = 0.35 (dichlorometane/acetate 9/

RESULTS AND DISCUSSION
When we performed N-methylation reactions of non-substituted indole using CH 3 I in sodium hydride/DCM/DMF solution assisted by ultrasound irradiation (US), we observed the almost exclusive formation of 1-diindolylmethane (86% of yield), which suggested that DCM is a bridging agent in the formation of this N-aminomethylated compound (Mills et al., 1987(Mills et al., , 2009Matsumoto et al., 1993;Souquet et al., 2006;Rudine et al., 2010;Zhou et al., 2011). In an attempt to capitalize on DCM behavior, we introduced a secondary amine, specifically piperidine, in SCHEME 1 | Reaction of 1 with piperidine in the presence of CHCl 3 .
Frontiers in Chemistry | www.frontiersin.org the reaction. In this case, we observed the formation of 1diindolylmethane 2 and -(piperidin-1-ylmethyl)-1H-indole 3, which were isolated in yields of 40 and 51%, respectively. Here we describe an efficient approach to the synthesis of 1-indolyl methanamines, starting from different indole substrates and amines under basic conditions.
As shown in Table 2 (entries 2-10), the substitution of NaH by different bases (entries 2-5, 9, and 10) resulted in a strong decrease of 3 yields, while acetonitrile was the solvent of choice (entries 6 and 7). Interestingly, the absence of NaH in CH 3 CN (entry 8) resulted in the aminomethylation of N-1 in a yield of 16%, while Cs 2 CO 3 did not improve the reaction performance in terms of either CH 3 CN or acetone (entries 9 and 10).
The formation of these products can be explained considering the dichlorocarbene generated from chloroform in basic conditions as electrophilic species (Hine et al., 1953;Saunders and Murray, 1960;Kirmse et al., 1990;Wynberg and Meijer, 2005). The addition of the dichlorocarbene to positions 2 and 3 of indole leads to the well-known Reimer-Tiemann (Wynberg and Meijer, 2005) formylated derivative 5, while, according to literature (Hine et al., 1953;Saunders and Murray, 1960;Kirmse et al., 1990), compound 6 could be obtained from a halogenated alkyl adduct, which quickly undergoes β-elimination leading to a reactive chloromethylene indolinium intermediate, as shown in Scheme S1. Addition of a nucleophile and regeneration of the indolium species followed by a second nucleophilic attack leads to the major compound 6.
Besides these results confirm the halogenated solvents as appropriate C1 sources, the low yields obtained using CHCl 3 discouraged further investigations. Therefore, we next explored the scope of the reaction using DCM as C1 source under the optimized reaction conditions (entry 7, Table 2), by varying the amine partners, using alkyl, and aryl amines as the second reaction component. Given the incidence of nitrogen heterocycles in chemistry and pharmaceuticals (Vitaku et al., 2014;Blakemore et al., 2018), we used various substituted indoles and other N-heterocycles in combination with piperidine (Chart 2). The reactions of indole with another secondary amine, morpholine, or with primary alkyl and aryl amines such as benzyl and phenylethyl amines resulted in N-((1H-indol-1-yl)methyl) derivatives 7-9 in high yields (68-71%, Chart 2). However, the reaction with anilines can only be performed with anilines containing an electron donor group. Therefore, using 4-methoxy aniline, we obtained the amino methylene derivative 10 in a yield of 42%. Biologically relevant 3-or 5-substituted indoles (Bertamino et al., 2016;Musella et al., 2016) reacted with piperidine to provide the N-aminomethyl derivatives 11-15 in a yield range of 59-75% and high selectivity, especially in the case of indoles substituted with electron donor groups ( Table 3).
Compounds 14 and 15 containing a Boc-protecting group are stable under classical acid deprotection conditions, thus becoming effective intermediates in the synthesis of more complex derivatives. Using 2-methyl indole as starting material, we also obtained the aminomhetylated product (16) in 22% of yield, and its related dimeric compound (17) in 31% of yield. Next, the reaction of piperidine with pyrrole and carbazole generated a high yield of the corresponding aminomethyl derivatives 18 (74%) and 19 (89%), which were also obtained with high selectivity (Table 3). However, benzoimidazole yielded only bis-benzoimidazolylmethane (20, 38%) while pyridine and pyridinol derivatives did not react in our conditions (Mastalir et al., 2017).
Given the chemist community's interest in the chemistry of phenol and its derivatives, in particular for the activation of C-H bonds to generate new C-C bonds (Nair et al., 1994;Joshi et al., 2004;Roman, 2015;Dai et al., 2017;Mastalir et al., 2017), we applied the above described methodology to phenols as well as to other heterocycles namely, 1-and 2-napthol, 5-hydroxyisoquinoline, thiophene, and thiophenol, again using piperidine and DCM as the other two reaction components (Chart 2).

CONCLUSIONS
In conclusion, we have developed a practical and sustainable three-component aminomethylation method using different Nheterocycles in combination with a wide range of amines and DCM as C1 source. Thanks to the full N-vs. C-regioselectivity observed in this reaction, this method is an attractive alternative approach to the synthesis of 1-aminomethyl indole derivatives, a class of compounds hitherto poorly accessible. This atomefficient reaction exploits the potential of ultrasound waves to provide new highly functionalized indoles that are stable both over time and in common synthetic transformations thereby increasing the molecular diversity of this important template.
The methodology may also be suitable for other aza-heterocycles, phenols, and some of its derivatives as aryl alcohols, which suggests its potential in the chemistry of materials and medicines, as well as in the life sciences.

DATA AVAILABILITY
The raw data supporting the conclusions of this manuscript will be made available by the authors, without undue reservation, to any qualified researcher.