HETEROCYCLES

Short Paper | Regular issue | Vol. 87, No. 8, 2013, pp. 1749-1764
Received, 22nd May, 2013, Accepted, 25th June, 2013, Published online, 4th July, 2013.
DOI: 10.3987/COM-13-12747

■ Efficient Synthesis of N-Methylamides and Amines via 4-(Alkylamino)benzyl-N-methylamine as a New Protecting Group

Sang-Hak Lee, Yu Mu, Gun-Woo Kim, Jin-Seok Kim, Seok-Hwi Park, Tian Jin, Kee-Young Lee, and Won-Hun Ham*

School of Pharmacy, Sungkyunkwan University, 2066, Seobu-Ro, Jangan-Gu, Suwon-Si, Gyeong gi-Do 440-746, Korea

Abstract

4-(Alkylamino)benzyl-N-methylamine is a good protecting group for the synthesis of N-methylamides and amines. The N-debenzylation of N-methylamides and amines can be carried out selectively and efficiently under condition using trifluoroacetic acid (TFA).

Amines are important functionalities in various natural products. Due to its unique biological properties, the amine moiety plays a central role in important pharmacophores.1 Considering their numerous applications in the fields of pharmacology, biology and organic chemistry, there are continuous needs for efficient synthetic methods for their derivatives.1,2 Especially the synthesis of N-methylamine is of great interest in organic chemistry. General synthetic methods for the preparation of N-methylamines include direct N-methylation,3 N-methylation of carbamate derivatives,4 the use of N-methylbenzylamine5 or reductive amination protocol.6 N-Methylation of amide and amine is usually carried out by the treatment of an amine with a methyl halide in the presence of a base. However, selective synthesis of N-methylation is often complex due to the difficulty of preventing the formation of the corresponding N,N-dimethylation.3 So it is general that the N-methyl functionality of N-methylamide and amine is introduced from N-methylbenzylamine and the benzyl group is removed afterward. N-Methylbenzylamine is used for the synthesis of selectively monomethylated products.5 Unfortunately, the use of N-benzyl groups has problems because their removal is often difficult.7 There are numerous procedures in the literature which describe a variety of cleavage and N-deprotection methods for amine and amide synthesized with the N-benzyl groups strategy. The most common method of removal is the use of hydrogenolysis with catalytic Pd/C,8 or strongly reductive conditions, such as Na/NH3(l)9 or Li.10 These conditions can limit the use of N-benzyl protecting groups for unstable compounds. Many studies have been conducted to develop more efficient N-debenzylation conditions and N-protecting groups.

We report the use of 4-(alkylamino)benzylamines as convenient and effective protecting groups. The application of these reagents is summarized in Table 1. A series of six 4-(alkylamino)benzylamides were synthesized by the reaction of the corresponding carboxylic acids with 4-(alkylamino)benzylamines in the presence of O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluorophosphate (HBTU) at ambient temperature with good yields produced.11 The N-debenzylation method was used with TFA. This reaction condition produced an efficient and selective deprotection of 4-(alkylamino)benzylamides. The results are summarized in Table 1.

As shown in entries 1, 4 and 5, the N-debenzylation reaction gave corresponding N-methylamines in good yields. None of the established methods was useful for entries 2, 3 and 6, and product formation was not observed even after prolonged reaction (20 h). In entry 2, it is well known that the electron-donating methyl can increase the negative charge population on the nitrogen atom in amine molecules (i.e. NH is less reactive than NHMe). The N-debenzylation of N-methylamide and amide can be carried out selectively. In entries 3 and 6, it is difficult for electrons to move through a benzene ring because of the heteroatom, which prevents deprotection. 4-(Alkylamino)benzylamides are expected to undergo N-debenzylation with TFA through the initial protonation of nitrogen atom of the weakly basic amide (Scheme 1).

4-(Alkylamino)benzyl groups can be cleaved with TFA in CH2Cl2 at ambient temperature and also produce good protecting groups for amide. Among them, 4-(dimethylamino)benzyl-N-methylamine was selected as the protecting group of other amides and arylamines due to its convenience and low cost. We hope to investigate the possibility of applying 4-(dimethyl-amino)benzyl-N-methylamine to other amides and amines.
A series of nine 4-(dimethylamino)benzyl-N-methylamides (3a-i) were synthesized by the reaction of the corresponding carboxylic acids with 4-(dimethylamino)benzyl-N-methylamines in the presence of HBTU at ambient temperature, producing good yields. The N-debenzylation method was used with TFA. In case of amides and amines except indoleamides, the reaction was not progressed at rt. So, we carried out the reaction of amides and amines except indoleamides in MeCN-H2O at 80~100 oC because of the reactivity. The N-debenzylation results are shown in Table 2. As shown in entries 1-9, the debenzylation reactions were rapid and produced N-methylamines (4a-i) in good yields. A variety of amides were applicable to the reaction condition.

As shown in entries 1-5, 4-(dimethylamino)benzyl-N-methylarylamines (5a-e) were synthesized by the reaction of addition-elimination with 4-(dimethylamino)benzyl-N-methylamine, with good yields. As shown in entries 6-8, 4-(dimethylamino)benzyl-N-methyl aliphatic amines (5f-h) were synthesized by the reaction of 4-(dimethylamino)benzyl-N-methylamine and aliphatic halides, with good yields.
The N-debenzylation reaction of 4-(dimethylamino)benzyl-N-methylarylamines and aliphatic amines was examined by the use of TFA / MeCN / H2O at 80~120 oC, and the results are shown in Table 3. The yields of N-debenzylation reaction (6a-h) were good as shown in entries 1-8.

In conclusion, we report 4-(alkylamino)benzylamines as convenient and effective protecting groups. The N-debenzylation of N-methylamides and amines were carried out selectively and efficiently with the use of TFA. This procedure is very useful for synthesizing a wide variety of nitrogen-containing amides and arylamines, and can be applied to a variety of functional groups. The application of this methodology can afford high chemical yields.

EXPERIMENTAL
General: Commercially available reagents were used without additional purification, unless otherwise stated. All reactions were performed under an inert atmosphere of nitrogen. Nuclear magnetic resonance spectra (1H and 13C NMR) were recorded on a Bruker Unity 400 MHz spectrometer for CDCl3 solutions and chemical shifts are reported as parts per million (ppm) relative to, respectively, residual CHCl3 δ H (7.26 ppm) and CDCl3 δ C (77.0 ppm) as internal standards. Resonance patterns are reported with the notations s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublet), td (triplet of doublet), and m (multiplet). In addition, the notation br is used to indicate a broad signal. Coupling constants (J) are reported in hertz (Hz). IR spectra were recorded on a Bruker Vector IFS-66. Infrared spectrophotometer is reported as cm-1. Thin layer chromatography was carried out using plates coated with Kieselgel 60F254 (Merck). For flash column chromatography, E. Merck Kieselgel 60 (230-400 mesh) was used. HPLC-Mass spectra (LC/MS) were recorded on a Waters 2767 LC/MS System. High-resolution mass spectra (HRMS) were recorded on a JEOL, JMS-700 spectrometer.

Typical procedure for the syntheses of 4-(alkylamino)benzylamides.
To a solution of carboxylic acid (0.285 mmol) in anhydrous DMF (1 mL) were added HBTU (130 mg, 0.342 mmol) and DIPEA (0.119 mL, 0.684 mmol) at 25 oC. The reaction mixture was stirred at 25 oC for 30 min and then 4-(alkylamino)benzylamine (0.342 mmol) was added at 25 oC. The reaction mixture was stirred at 80 oC for 8 h and then cooled to 25 oC. The reaction mixture was treated with water (50 mL) and the product extracted into Et2O (50 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuum. The residue was purified by column chromatography (n-hexane / CH2Cl2 = 10 / 90).
N-(4-(Dimethylamino)benzyl)-N,1-dimethyl-1H-indole-3-carboxamide (1a); Yield 85%; as a yellow oil; IR (KBr) νmax 3358, 2947, 2833, 1665, 1452, 1115, 1032, 658 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.0 Hz, 1H), 7.18~7.36 (m, 6H), 6.73 (d, J = 8.4 Hz, 2H), 4.72 (s, 2H), 3.78 (s, 3H), 3.08 (s, 3H), 2.95 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 167.5, 150.0, 136.5, 130.5, 129.2, 128.6, 127.0, 125.2, 122.4, 121.4, 120.9, 112.8, 112.7, 109.5, 40.7, 33.1; HRMS (EI+) Calcd for C20H23N3O [M]+ 321.1837, found 321.1841.
N-(4-(Dimethylamino)benzyl)-1-methyl-1H-indole-3-carboxamide (1b); Yield 75%; as a white solid; mp 156 oC; IR (KBr) νmax 3358, 2946, 2833, 1665, 1452, 1115, 1032, 694 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 7.6 Hz, 1H), 7.65 (s, 1H), 7.18~7.36 (m, 5H), 6.72 (d, J = 8.8 Hz, 2H), 6.05 (br, 1H), 4.60 (d, J = 5.2 Hz, 2H), 3.81 (s, 3H), 2.95 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 164.9, 137.6, 132.3, 129.1, 125.4, 122.5, 121.4, 120.2, 112.9, 111.0, 43.3, 40.7, 33.3; HRMS (EI+) Calcd for C19H21N3O [M]+ 307.1682, found 307.1685.
N-((6-(Dimethylamino)pyridin-3-yl)methyl)-N,1-dimethyl-1H-indole-3-carboxamide (1c); Yield 80%; as a yellow oil; IR (KBr) νmax 3358, 2946, 2833, 1665, 1452, 1115, 1032, 748 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.48 (m, 1H), 7.38 (s, 1H), 7.18~7.35 (m, 3H), 6.51 (d, J = 8.8 Hz, 1H), 3.81 (s, 3H), 4.65 (s, 2H), 3.09 (s, 6H), 3.03 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 167.5, 136.5, 130.8, 126.7, 122.5, 121.2, 120.9, 110.6, 109.6, 106.1, 38.2, 33.2; HRMS (EI+) Calcd for C19H22N4O [M]+ 322.1795, found 322.1794.
N,1-Dimethyl-N-((4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)methyl)-1H-indole-3-carboxamide(1d); Yield 81%; as a yellow oil; IR (KBr) νmax 3380, 2947, 2833, 1660, 1453, 1116, 1032, 659 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.0 Hz, 1H), 7.18~7.36 (m, 4H), 6.78 (d, J = 8.0 Hz, 1H), 6.70 (s, 1H), 6.66 (d, J = 8.4 Hz, 1H), 4.65 (s, 2H), 4.30 (t, J = 4.4 Hz, 2H), 3.77 (s, 3H), 3.25 (t, J = 4.4 Hz, 2H), 3.04 (s, 3H), 2.88 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 167.6, 144.5, 136.5, 135.9, 130.6, 127.4, 127.0, 122.4, 121.4, 120.9, 112.7, 109.5, 65.0, 50.9, 49.2, 38.9, 33.1; HRMS (EI+) Calcd for C21H23N3O2 [M]+ 349.1792, found 349.1790.
N,1-Dimethyl-N-(4-morpholinobenzyl)-1H-indole-3-carboxamide (1e); Yield 80%; as a yellow oil; IR (KBr) νmax 3359, 2946, 2833, 1665, 1452, 1115, 1032, 659 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 8.0 Hz, 1H), 7.18~7.36 (m, 6H), 6.92 (d, J = 8.4 Hz, 2H), 4.72 (s, 2H), 3.87 (t, J = 4.8 Hz, 4H), 3.78 (s, 3H), 3.17 (t, J = 4.8 Hz, 4H), 3.04 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 167.7, 163.6, 140.5, 136.9, 136.7, 130.9, 129.0, 126.7, 124.7, 122.6, 121.2, 121.1, 110.1, 109.7, 61.0, 53.5, 49.4, 30.9; HRMS (EI+) Calcd for C22H25N3O2 [M]+ 363.1947, found 363.1947.
N,1-Dimethyl-N-((2-morpholinopyrimidin-5-yl)methyl)-1H-indole-3-carboxamide (1f); Yield 77%; as a yellow oil; IR (KBr) νmax 3358, 2946, 2833, 1665, 1452, 1116, 1032, 677 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.35 (s, 2H), 7.79 (d, J = 8.0 Hz, 1H), 7.39 (s, 1H), 7.18~7.35 (m, 3H), 4.60 (s, 2H), 3.75~3.85 (m, 11H), 3.08 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 167.5, 161.5, 158.0, 136.5, 131.1, 122.6, 121.1, 121.1, 119.1, 110.3, 109.7, 66.8, 44.3, 33.2; HRMS (EI+) Calcd for C20H23N5O2 [M]+ 365.1855, found 365.1852.
N-(4-(Dimethylamino)benzyl)-N-methylbenzamide (3a); Yield 97%; as a yellow oil; IR (KBr) νmax 2921, 2801, 1633, 1523, 1399, 1349, 1072, 1011, 836, 755 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.47~7.43 (m, 5H), 7.21 (m, 1H), 7.02 (d, J = 7.7 Hz, 1H), 6.65 (dd, J = 18.9, 7.7 Hz, 2H), 4.75 (s, 1H), 4.52 (s, 1H), 3.00 (s, 1.5H), 2.94 (s, 6H), 2.81 (s, 1.5H); 13C NMR (100 MHz, CDCl3) δ 172.1, 171.4, 150.1, 136.4, 129.4, 128.4, 127.9, 126.8, 124.7, 123.9, 122.6, 112.6, 54.6, 50.2, 40.5, 36.7, 32.8; HRMS (EI+) Calcd for C17H20N2O [M]+ 268.1576, found 268.1577.
N-(4-(Dimethylamino)benzyl)-N-methyl-4-nitrobenzamide (3b); Yield 90%; as a yellow oil; IR (KBr) νmax 3332, 2939, 2865, 2843, 2354, 1648, 1512, 1054, 1033, 1016, 617 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.27 (t, J = 8.8 Hz, 2H), 7.61 (dd, J = 13.2, 8.4 Hz, 2H), 7.25 (d, J = 9.2 Hz, 1H), 6.98 (d, J = 8.0 Hz, 1H), 6.71 (dd, J = 11.6, 8.4 Hz, 2H), 4.66 (s, 1H), 4.34 (s, 1H), 3.06 (s, 1.5H), 2.96 (s, 6H), 2.80 (s, 1.5H); 13C NMR (100 MHz, CDCl3) δ 169.8, 169.1, 150.3, 148.2, 142.8, 142.7, 129.6, 127.9, 127.6, 123.9, 122.8, 112.6, 54.5, 50.3, 40.5, 36.4, 33.1; HRMS (EI+) Calcd for C17H19N3O3 [M]+ 313.1426, found 313.1426.
4-Bromo-N-(4-(dimethylamino)benzyl)-N-methylbenzamide (3c); Yield 98%; as a yellow oil; IR (KBr) νmax 2923, 2802, 1685, 1631, 1523, 1446, 1355, 1264, 1064, 844 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.51~7.50 (m, 2H), 7.37~7.34 (m, 2H), 7.24~7.22 (m, 1H), 7.00 (d, J = 7.5 Hz, 1H), 6.71~6.69 (m, 2H), 4.63 (s, 1H), 4.38 (s, 1H), 3.03 (s, 1.5H), 2.95 (s, 6H), 2.81 (s, 1.5H); 13C NMR (100 MHz, CDCl3) δ 171.1, 170.2, 150.1, 135.3, 131.6, 129.5, 128.6, 127.7, 124.4, 123.8, 112.8, 54.6, 50.3, 40.5, 36.6, 33.0; HRMS (EI+) Calcd for C17H19BrN2O [M]+ 346.0681, found 346.0678.
4-Acetyl-N-(4-(dimethylamino)benzyl)-N-methylbenzamide (3d); Yield 88%; as a yellow oil; IR (KBr) νmax 2924, 1658, 1633, 1522, 1447, 1315, 1067, 925, 703 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.99~7.96 (m, 2H), 7.56 (d, J = 8.2 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.73 (d, J = 8.4 Hz, 1H), 6.70 (d, J = 8.4 Hz, 1H), 4.66 (s, 1H), 4.36 (s, 1H), 3.02 (s, 1.5H), 2.93 (s, 6H), 2.80 (s, 1.5H), 2.62 (d, J = 12.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 197.42, 170.99, 170.28, 150.15, 140.91, 137.56, 129.56, 128.50, 127.79, 127.08, 124.29, 123.30, 112.65, 54.51, 50.19, 40.52, 36.45, 32.85, 26.70; HRMS (EI+) Calcd for C19H22N2O2 [M]+ 310.1681, found 310.1682.
4-Benzoyl-N-(4-(dimethylamino)benzyl)-N-methylbenzamide (3e); Yield 73%; as a yellow oil; IR (KBr) νmax 3730, 3626, 2923, 2354, 1636, 1523, 1351, 1067, 863, 807, 724 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.86~7.79 (m, 4H), 7.60~7.47 (m, 5H), 7.27~7.26 (m, 1H), 7.03 (d, J = 8.6 Hz, 1H), 6.74 (d, J = 8.2 Hz, 1H), 6.71(d, J = 8.4 Hz, 1H), 4.68 (s, 1H), 4.41 (s, 1H), 3.04 (s, 1.5H), 2.96 (s, J = 9.0 Hz, 6H), 2.84 (s, 1.5H); 13C NMR (100 MHz, CDCl3) δ 196.08, 171.08, 170.36, 162.24, 150.15, 140.24, 138.33, 137.14, 132.85, 130.15, 129.56, 128.39, 127.81, 126.67, 124.32, 123.35, 122.60, 112.63, 54.58, 50.21, 40.52, 36.64, 32.89; HRMS (EI+) Calcd for C24H24N2O2 [M]+ 372.1838, found 372.1837.
N-(4-(Dimethylamino)benzyl)-3,4-dimethoxy-N-methylbenzamide (3f); Yield 88%; as a yellow oil; IR (KBr) νmax 3332, 2940, 2834, 1635, 1510, 1351, 1270, 1233, 1132, 1032, 768, 630 cm-1; 1H NMR (400 MHz, CD3OD) δ 7.22 (br, 1H), 7.05~6.95 (m, 4H), 6.77 (d, J = 8.4 Hz, 2H), 6.98 (d, J = 8.0 Hz, 1H), 6.71 (dd, J = 11.6, 8.4 Hz, 2H), 4.66~4.33 (m, 2H), 3.85 (s, 3H), 3.72 (s, 1.5H), 2.97 (s, 1.5H), 2.91 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 150.1, 148.8, 129.4, 128.8, 127.7, 124.5, 120.0, 112.7, 110.8, 110.5, 60.4, 55.9, 40.6, 38.6; HRMS (EI+) Calcd for C19H24N2O3 [M]+ 328.1787, found 328.1790.
N-(4-(Dimethylamino)benzyl)-N-methyl-2-phenylacetamide (3g); Yield 85%; as a yellow oil; IR (KBr) νmax 3466, 2924, 1645, 1522, 1455, 1398, 1348, 1164, 1105, 946, 809, 727, 697, 571 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.24~7.34 (m, 5H), 7.12 (d, J = 8.4 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 6.68 (t, J = 8.0 Hz, 2H), 4.46 (dd, J = 33.6 Hz, 2H), 3.77 (dd, J = 12.8 Hz, 3H), 2.94 (dd, J = 6.4 Hz, 6H), 2.89 (dd, J = 19.6 Hz, 3H); 13C NMR (400 MHz, CDCl3) δ 171.1, 150.1, 135.3, 129.4, 128.8, 128.6, 127.6, 126.7, 125.1, 123.9, 112.7, 53.2, 50.3, 41.3, 41.0, 40.6, 34.9, 33.7; HRMS (EI+) Calcd for C18H22N2O [M]+ 282.1732, found 282.1725.
N-(4-(Dimethylamino)benzyl)-N-methyldecanamide (3h); Yield 75%; as a colorless oil; IR (KBr) νmax 3466, 2924, 1652, 1521, 1456, 1399, 1348, 1226, 1163, 947, 802 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.13 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H), 6.67~6.72 (m, 2H), 4.46 (dd, J = 23.6 Hz, 2H), 2.94 (d, J = 6 Hz, 6H), 2.89 (dd, J = 9.6 Hz, 3H), 2.31~2.41 (m, 2H), 1.26 (br, 14H), 0.88 (t, J = 4.4 Hz, 3H); 13C NMR (400 MHz, CDCl3) δ 173.5, 173.1, 150.1, 129.3, 127.4, 125.5, 124.2, 112.7, 52.9, 50.1, 40.6, 34.5, 33.7, 33.5, 33.2, 31.9, 29.4, 25.6, 25.2, 22.7, 14.1; HRMS (EI+) Calcd for C20H34N2O [M]+ 318.2671, found 318.2670.
N-(4-(Dimethylamino)benzyl)-N-methylacetamide (3i); Yield 80%; as a yellow oil; IR (KBr) νmax 3465, 2926, 1645, 1521, 1404, 1348, 1239, 1118, 809 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.14 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.68~6.73 (m, 2H), 4.45 (dd, J = 24.8 Hz, 2H), 2.94 (dd, J = 6.0 Hz, 6H), 2.89 (dd, J = 9.2 Hz, 3H), 2.15 (dd, J = 20.8 Hz, 3H); 13C NMR (400 MHz, CDCl3) δ 170.9, 170.5, 150.1, 129.3, 127.5, 125.2, 124.0, 112.7, 53.8, 50.0, 40.6, 35.2, 33.4, 22.0, 21.5; HRMS (EI+) Calcd for C12H18N2O [M]+ 206.1419, found 206.1420.

Typical procedure for debenzylation of 4-(alkylamino)benzylamides.
To a solution of debenzylation of 4-(alkylamino)benzylamide (0.093 mmol) in CH2Cl2 (1 mL) was added TFA (1 mL) at 25 oC. The reaction mixture was stirred at 25 oC for 8 h and concentrated in vacuum. Then, saturated solution of sodium bicarbonate was slowly added (50 mL) and the reaction mixture extracted with EtOAc (50 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuum. The residue was purified by column chromatography (CH2Cl2 / EtOAc = 90 / 10).
N,1-Dimethyl-1H-indole-3-carboxamide (2); Yield 80%; as a yellow solid; mp 153 oC; IR (KBr) νmax 3425, 2928, 1594, 1525, 1290, 1191, 763 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 7.2 Hz, 1H), 7.65 (s, 1H), 7.18~7.36 (m, 3H), 5.98 (br, 1H), 3.80 (s, 3H), 3.04 (d, J = 4.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.9, 137.2, 132.2, 125.3, 122.5, 121.4, 120.1, 111.0, 110.1, 33.3, 26.4; HRMS (EI+) Calcd for C11H12N2O [M]+ 188.0950, found 188.0950.

Typical procedure for the synthesis of 4-(dimethylamino)benzyl-N-methylarylamines.
To a solution of aryl halide (1.26 mmol) in 2-methoxyethanol (5 mL) was added DIPEA (0.45 mL, 2.52 mmol) and N,N-dimethyl-4-((methylamino)methyl)aniline (309 mg, 1.89 mmol) at 25 oC in a 10 mL seal tube. The reaction mixture was heated to 80 oC for 8 h. Then, saturated solution of sodium bicarbonate (50 mL) was slowly added and the reaction mixture extracted with EtOAc (50 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuum. The residue was purified by column chromatography (CH2Cl2 / EtOAc = 90 / 10).
N-(4-(Dimethylamino)benzyl)-N-methyl-5-nitropyridin-2-amine (5a); Yield 71%; as a yellow solid; mp 175 oC; IR (KBr) νmax 3442, 3219, 3055, 2864, 1598, 1329, 1291, 1191, 768 cm-1; 1H NMR (400 MHz, CDCl3) δ 9.09 (d, J = 2.8 Hz, 1H), 8.18 (dd, J = 9.6, 2.8 Hz, 1H), 7.11 (d, J = 8.4 Hz, 2H), 6.68 (d, J = 8.4 Hz, 2H), 6.47 (d, J = 9.6 Hz, 1H), 4.80 (s, 2H), 3.16 (s, 3H), 2.29 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 160.8, 150.2, 146.7, 134.8, 132.8, 128.3, 112.7, 104.3, 53.2, 40.6, 36.5; HRMS (EI+) Calcd for C15H18N4O2 [M]+ 286.1426, found 286.1430.
N-(4-(Dimethylamino)benzyl)-N-methyl-4-nitroaniline (5b); Yield 98%; as a yellow solid; mp 171 oC; IR (KBr) νmax 3382, 2940, 2831, 2524, 2354, 2051, 1454, 1310, 1052, 1033, 1018, 618 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 10.5 Hz, 2H), 7.04 (d, J = 10.5 Hz, 2H), 6.70 (m, 4H), 4.57 (s, 2H), 3.15 (s, 3H), 2.93 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 154.3, 150.3, 127.7, 126.4, 124.2, 113.1, 111.3, 110.8, 55.8, 40.8, 38.9; HRMS (FAB-MS) Calcd for C16H19N3O2 [M]+ 285.1476 found 285.1477.
N-(4-(Dimethylamino)benzyl)-N-methyl-2,4-dinitroaniline (5c); Yield 83%; as a yellow solid; mp 169 oC; IR (KBr) νmax 3357, 2939, 2865, 2843, 2354, 1621, 1454, 1111, 1053, 1053, 1033, 1017, 617 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.71 (d, J = 2.4 Hz, 1H), 8.16 (dd, J = 2.4, 12.3 1H), 7.11 (m, 3H), 6.79 (m, 2H), 4.51 (s, 2H), 2.95 (s, 3H), 2.90 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 150.3, 149.2, 128.3, 128.1, 127.6, 124.1, 121.9, 118.0, 112.7, 57.5, 40.5, 40.4; HRMS (EI+) Calcd for C16H18N4O4 [M]+ 330.1330, found 330.1328.
6-((4-(Dimethylamino)benzyl)(methyl)amino)nicotinamide (5d); Yield 68%; as a brown solid; mp 183 oC; IR (KBr) νmax 2920, 2802, 1631, 1523, 1399, 1349, 1068, 807, 701 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.61(dd, J = 2.4, 0.4 Hz, 1H), 7.90 (dd, J = 9.2, 2.4 Hz, 1H), 7.10 (d, J = 8.8 Hz, 2H), 6.69 (dd, J = 6.8, 2.0 Hz, 2H), 6.52 (dd, J = 9.2, 0.4 Hz, 1H), 4.75 (s, 2H), 3.10 (s, 3H), 2.94 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 168.1, 160.4, 150.0, 148.2, 136.9, 128.1, 125.2, 116.4, 112.7, 52.7, 40.7, 36.1; HRMS (EI+) Calcd for C16H20N4O [M]+ 284.1636, found 284.1637.
Methyl 6-((4-(dimethylamino)benzyl)(methyl)amino)nicotinate (5e); Yield 70%; as an ivory solid; mp 90.5 oC; IR (KBr) νmax 3382, 2947, 2831, 2519, 2354, 2048, 1712, 1603, 1519, 1277, 1118, 1033, 690 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.82 (d, J = 2.4, 1H), 7.97 (dd, J = 8.8, 2.4 Hz, 1H), 7.10 (d, J = 8.8 Hz, 2H), 6.68 (d, J = 8.4 Hz, 2H), 6.48 (d, J = 8.8 Hz, 1H), 4.76 (s, 2H), 3.86 (s, 3H), 3.10 (s, 3H), 2.92 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 166.8, 160.8, 151.3, 150.0, 138.2, 128.2, 125.2, 113.7, 112.7, 104.6, 52.7, 51.5, 40.7, 36.1; HRMS (EI+) Calcd for C17H21N3O2 [M]+ 299.1632, found 299.1634.

Typical procedure for the synthesis of 4-(dimethylamino)benzyl-N-methylaliphaticamines.
To a solution of aliphatic halide (0.285 mmol) in anhydrous THF (1 mL) were added DIPEA (0.119 mL, 0.684 mmol) and 4-(dimethylamino)benzyl-N-methylamine (0.342 mmol) at 25 oC. The reaction mixture was stirred at 25 oC for 8 h. The reaction mixture was treated with 1N NaOH (50 mL) and the product extracted into EtOAc (50 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuum. The residue was purified by amine column chromatography (n-hexane/CH2Cl2=70/30).
4-((Benzyl(methyl)amino)methyl)-N,N-dimethylaniline (5f); Yield 80%; as a yellow oil; IR (KBr) νmax 2784, 1614, 1521, 1452, 1345, 1163, 1023, 802, 698 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.20~7.36 (m, 7H), 6.71 (d, J = 8.4 Hz, 2H), 3.46 (dd, J = 17.2 Hz, 1H), 2.93 (s, 6H), 2.16 (s, 3H); 13C NMR (400 MHz, CDCl3) δ 149.9, 139.6, 129.9, 129.0, 128.2, 127.1, 126.8, 112.6, 61.5, 42.1, 40.8, 31.6, 22.7, 14.2; HRMS (EI+) Calcd for C17H22N2 [M]+ 254.1783, found 254.1781.
4-((Decyl(methyl)amino)methyl)-N,N-dimethylaniline (5g); Yield 80%; as a colorless oil; IR (KBr) νmax 2926, 1743, 1467, 1239, 1042, 721 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.16 (d, J = 8.4 Hz, 2H), 7.70 (dd, J = 8.4 Hz, 6H), 3.39 (s, 2H), 2.93 (s, 6H), 2.32 (t, J = 7.6 Hz, 2H), 2.16 (s, 3H), 1.50 (t, J = 6.4 Hz, 2H), 1.26 (br, 14H), 0.88 (t, J = 6.4 Hz, 3H); 13C NMR (400 MHz, CDCl3) δ 149.8, 130.1, 112.5, 61.7, 57.4, 42.1, 40.8, 31.9, 29.7, 29.4, 27.6, 27.4, 22.7, 14.1; HRMS (EI+) Calcd for C20H36N2 [M]+ 304.2878, found 304.2879.
N,N-Dimethyl-4-((methyl(phenethyl)amino)methyl)aniline (5h); Yield 77%; as a colorless oil; IR (KBr) νmax 2943, 2788, 1614, 1521, 1347, 1163, 947, 947, 801, 699 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.14~7.29 (m, 7H), 6.70 (d, J = 8.8 Hz, 2H), 3.48 (s, 2H), 2.93 (s, 6H), 2.80~2.84 (m, 2H), 2.61~2.65 (m, 2H), 2.26 (s, 3H); 13C NMR (400 MHz, CDCl3) δ 149.8, 140.7, 130.128.8, 128.3, 126.7, 125.9, 112.6, 61.6, 59.0, 42.0, 40.8, 33.9; HRMS (EI+) Calcd for C18H24N2 [M]+ 268,1939, found 268.1938.

Typical procedure for debenzylation of 4-(dimethylamino)benzyl-N-methylamide and amine.
To a solution of debenzylation of 4-(dimethylamino)benzyl-N-methylamide and amine (0.093 mmol) in MeCN / H2O(1 mL /1 mL) was added TFA (1 mL) at 25 oC in a 10 mL seal tube. The reaction mixture was heated to 80~120 oC for 2~5 h and concentrated in vacuum. Then, saturated solution of sodium bicarbonate (50 mL) was slowly added and the reaction mixture extracted with EtOAc (50 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuum. The residue was purified by column chromatography (CH2Cl2 / EtOAc = 50 / 50).
N-Methylbenzamide (4a); Yield 72%; as a white solid; mp 75.4 oC; IR (KBr) νmax 3332, 2940, 2831, 2354, 2643, 1552, 1452, 1412, 1311, 1033, 696 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.77~7.76 (m, 2H), 7.49 (t, J = 7.0 Hz, 1H), 7.43 (t, J = 7.0 Hz, 2H), 6.20 (br, 1H), 3.02 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.26, 134.64, 131.36, 128.57, 126.81, 26.84; HRMS (EI+) Calcd for C8H9NO [M]+ 135.0684, found 135.0682.
N-Methyl-4-nitrobenzamide (4b); Yield 80%; as a yellow solid; mp 207 oC; IR (KBr) νmax 3382, 2968, 2865, 2354, 1695, 1611, 1055, 1033, 1016 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.30 (dd, J = 9.2, 2.0 Hz, 2H), 7.93 (dd, J = 7.2, 2.0 Hz, 2H), 6.18 (br, 1H), 3.07 (d, J = 4.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.9, 166.1, 149.6, 140.2, 128.0, 123.9, 29.7, 27.1; HRMS (EI+) Calcd for C8H8N2O3 [M]+ 180.0535, found 180.0534.
4-Bromo-N-methylbenzamide (4c); Yield 72%; as a white solid; mp 150 oC; IR (KBr) νmax 3343, 2940, 2831, 2519, 2354, 2049, 1642, 1554, 1484, 1032, 839, 750, 623 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 8.6 Hz, 2H), 7.56 (d, J = 8.6 Hz, 2H), 6.16 (br, 1H), 3.01 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 167.24, 133.43, 131.80, 128.46, 126.03, 26.91; HRMS (EI+) Calcd for C8H8BrNO [M]+ 212.9789, found 212.9787.
4-Acetyl-N-methylbenzamide (4d); Yield 75%; as a white solid; mp 128 oC; IR (KBr) νmax 3383, 2939, 2831, 2354, 1731, 1683, 1648, 1413, 1267, 1032, 857, 614 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.6 Hz, 2H), 7.85 (d, J = 8.6 Hz, 2H), 6.28 (br, 1H), 3.04 (d, J = 4.9 Hz, 3H), 2.63 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 197.47, 167.22, 139.10, 138.51, 128.55, 127.17, 26.97, 26.82; HRMS (EI+) Calcd for C10H11NO2 [M]+ 177.0790, found 177.0788.
4-Benzoyl-N-methylbenzamide (4e); Yield 70%; as a white solid; mp 127 oC; IR (KBr) νmax 3382, 2939, 2831, 1650, 1453, 1278, 1033, 699 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.86 (dd, J = 13.4, 8.5 Hz, 4H), 7.80 (d, J = 7.1 Hz, 2H), 7.62 (t, J = 7.5 Hz, 1H), 7.51 (t, J = 7.7 Hz, 2H), 6.20 (br, 1H), 3.06 (d, J = 4.7 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 195.98, 167.33, 140.02, 137.88, 137.05, 132.88, 130.18, 130.09, 128.46, 126.82, 27.00; HRMS (EI+) Calcd for C15H13NO2 [M]+ 239.0946, found 239.0947.
3,4-Dimethoxy-N-methylbenzamide (4f); Yield 75%; as a yellow solid; mp 127 oC; IR (KBr) νmax 3381, 2947, 2831, 1649, 1454, 1052, 1033, 617 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 2.0 Hz, 1H), 7.26 (dd, J = 8.4, 2.0 Hz, 1H ), 6.86 (d, J = 8.4 Hz, 1H), 6.11 (br, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 3.01 (d, J = 4.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 167.8, 151.6, 149.0, 127.4, 119.1, 110.6, 110.3, 56.0, 26.9; HRMS (EI+) Calcd for C10H13NO3 [M]+ 195.0895, found 195.0896.
N-Methyl-2-phenylacetamide (4g); Yield 88%; as a yellow oil; IR (KBr) νmax 3306, 1652, 1558, 1413, 1205, 1133, 724, 697 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.25~7.38 (m, 5H), 5.36 (br, 1H), 3.58 (s, 2H), 2.76 (d, J = 4.8, 7.7 Hz, 3H); 13C NMR (400 MHz, CDCl3) δ 171.7, 134.9, 129.6, 129.1, 127.4, 43.8, 26.5; HRMS (EI+) Calcd for C9H11NO [M]+ 149.0841, found 149.0798.
N-Methyldecanamide (4h); Yield 76%; as a yellow oil; IR (KBr) νmax 3299, 2919, 1634, 1566, 1465, 1205, 1163, 722, 597 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.41 (br, 1H), 2.81(d, J = 4.8 Hz, 3H), 2.16 (t, J = 7.6 Hz, 2H), 1.27 (br, 14H), 0.88 (t, J = 6.4 Hz, 3H); 13C NMR (400 MHz, CDCl3) δ 173.8, 36.8, 31.9, 29.4, 25.8, 22.7, 14.1; HRMS (EI+) Calcd for C11H23NO [M]+ 185.1780, found 185.1786.
N-Methylacetamide (4i); Yield 65%; as a yellow oil; IR (KBr) νmax 3305, 1645, 1567, 1415, 1162, 600 cm-1; 1H NMR (400 MHz, CDCl3) δ 6.15 (br, 1H), 2.79 (d, J = 4.8 Hz, 3H), 1.98 (s, 3H); 13C NMR (400 MHz, CDCl3) δ 171.0, 26.4, 23.0; HRMS (EI+) Calcd for C3H7NO [M]+ 73.0528, found 73.0336.
N-Methyl-5-nitropyridin-2-amine (6a); Yield 75%; as a yellow solid; mp 180 oC; IR (KBr) νmax 3561, 3493, 1633, 1570, 1333, 1205, 842 cm-1; 1H NMR (400 MHz, DMSO) δ 8.91 (s, 1H), 8.08 (br, 2H), 6.54 (d, J = 9.2 Hz, 1H), 2.89 (s, 3H); 13C NMR (100 MHz, DMSO) δ 161.9, 146.9, 134.1, 131.5, 108.5, 27.8; HRMS (EI+) Calcd for C6H7N3O2 [M]+ 153.0540, found 153.0538.
N-Methyl-4-nitroaniline (6b); Yield 91%; as a yellow solid; mp 168 oC; IR (KBr) νmax 3373, 2939, 2831, 2354, 1745, 1455, 1306, 1111, 1052, 1033, 618 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.10 (m, 2H), 6.54 (m, 2H), 4.55 (br, 1H), 2.94 (d, J = 5.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) 154.3, 138.4, 126.6, 110.9, 29.9; HRMS (FAB-MS) Calcd for C7H8N2O2 [M]+ 152.0587, found 152.0586.
N-Methyl-2,4-dinitroaniline (6c); Yield 67%; as a yellow solid; mp 173 oC; IR (KBr) νmax 3355, 2940, 2831, 1740, 1454, 1368, 1216, 1051, 1033, 618 cm-1; 1H NMR (400 MHz, CDCl3) δ 9.16 (d, J = 2.66 Hz, 1H), 8.58 (br, 1H), 8.32 (m, 1H), 6.93 (d, J = 9.52, 1H), 3.15 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 149.1, 136.2, 130.5, 124.3, 113.5, 30.3; HRMS (EI+) Calcd for C7H7N3O4 [M]+ 197.0436, found 197.0437.
6-(Methylamino)nicotinamide (6d); Yield 71%; as a white solid; mp 164 oC; IR (KBr) νmax 3382, 2941, 2831, 1740, 1668, 1616, 1375, 1206, 1120, 1052, 1033, 1018, 617 cm-1; 1H NMR (400 MHz, DMSO) δ 8.53 (d, J = 2 Hz, 1H), 7.87 (dd, J = 8.8, 2.4 Hz, 1H), 6.51 (d, J = 8.8 Hz, 1H), 2.91 (s, 3H); 13C NMR (100 MHz, DMSO) δ 171.1, 162.7, 149.7, 137.6, 118.3, 108.5, 28.6; HRMS (EI+) Calcd for C7H9N3O [M]+ 151.0746, found 151.0744.
Methyl 6-(methylamino)nicotinate (6e); Yield 80%; as a white solid; mp 92 oC; IR (KBr) νmax 3382, 2948, 2864, 2831, 1713, 1614, 1537, 1434, 1284, 1053, 1033, 1017, 779, 618 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.75 (d, J = 2 Hz, 1H), 8.01 (dd, J = 8.8, 2.4 Hz, 1H), 6.36 (d, J = 8.8 Hz, 1H), 5.06 (br, 1H), 3.87 (s, 3H), 2.99 (d, J = 2 Hz, 3H); 13C NMR (100 MHz, DMSO) δ 166.5, 161.6, 151.6, 138.6, 115.1, 104.9, 51.7, 29.0; HRMS (EI+) Calcd for C8H10N2O2 [M]+ 166.0743, found 166.0742.
N-Methyl-1-phenylmethanamine (6f); Yield 70%; as a yellow oil; IR (KBr) νmax 3320, 2932, 1645, 1521, 1454, 1353, 739, 699 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.29 (m, 5H), 3.73 (s, 2H), 2.44 (s, 3H), 1.42 (br, 1H); 13C NMR (400 MHz, CDCl3) δ 140.2, 128.4, 128.2, 127.0, 55.1, 36.1; HRMS (EI+) Calcd for C8H11N [M]+ 121.0891, found 121.0899.
N-Methyldecan-1-amine (6g); Yield 82%; as a yellow oil; IR (KBr) νmax 2926, 1744, 1467, 1239, 1041, 721 cm-1; 1H NMR (400 MHz, CDCl3) δ 2.62 (br, 2H), 2.47 (s, 3H), 1.58~1.63 (m, 5H), 1.27 (br, 6H), 0.86~0.89 (m, 8H); 13C NMR (400 MHz, CDCl3) δ 31.9, 29.5, 29.3, 28.6, 27.2, 25.9, 22.7; HRMS (EI+) Calcd for C11H25N [M]+ 171.1987, found 171.1980.
N-Methyl-2-phenylethan-1-amine (6h); Yield 75%; as a colorless oil; IR (KBr) νmax 3314, 2938, 1549, 1455, 1384, 1306, 1110, 748, 700 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.31~7.20 (m, 5H), 2.85~2.76 (m, 4H), 2.43 (s, 3H); 13C NMR (400 MHz, CDCl3) δ 140.1, 128.7, 128.4, 161.1, 53.3, 36.4, 36.3; HRMS (EI+) Calcd for C9H13N [M]+ 135.1048, found 135.1039.

ACKNOWLEDGEMENTS
This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education, Science and Technology (2010-0022900), (2011-0029199) and Yonsung Fine Chemicals Co., Ltd. The Global Ph.D. Fellowship grants to S.H.P. are gratefully acknowledged.

References

1. A. B. Reits, D. J. Bennett, P. S. Blum, E. E. Codd, C. A. Maryanoff, M. E. Ortegon, M. J. Renzi, M. K. Ascott, R. P. Shank, and J. L. Vaught, J. Med. Chem., 1994, 37, 1060; CrossRef D. A. Horton, G. T. Bourne, and M. L. Smythe, Chem. Rev., 2003, 103, 901. CrossRef
2. S. Fletcher and P. T. Gunning, Tetrahedron. Lett., 2008, 49, 4817. CrossRef
3. A. R. Karitzky, O. Meth-Cohn, and C. W. Rees, ‘Comprehensive Organic Functional Group Transformation,’ Vol. 2, Pergamon Press, Inc., New York, 1995; X. Li, E. A. Mintz, X. R. Bu, O. Zehender, C. Bosshard, and P. Gunter, Tetrahedron, 2000, 56, 5785. CrossRef
4. J. E. Christopher, K. Katherine, and C. P. Steven, J. Chem. Soc., Chem. Commun., 1991, 1475.
5. G. Bringmann, R. M. Pfeifer, P. Schreiber, K. Hartner, N. Kocher, R. Brun, K. Peters, E. M. Peters, and M. Breuning, Tetrahedron, 2004, 60, 6335. CrossRef
6. M. L. Moore, Org. React., 1949, 5, 301; W. S. Emerson, Org. React., 1948, 4, 174; E. W. Baxter and A. B. Reitz, Org. React., 2002, 59, 1.
7. S. D. Bull, S. G. Davies, G. Fenton, A. W. Mulvaney, R. S. Prasad, and A. D. Smith, J. Chem. Soc., Perkin Trans. 1, 2000, 3765. CrossRef
8. R. Gigg and R. Conant, Carbohydr. Res., 1982, 100, C5. CrossRef
9. T. Ohgi and S. M. Hecht, J. Org. Chem., 1981, 46, 1232; CrossRef F. X. Webster, J. G. Millar, and R. M. Silverstein, Tetrahedron Lett., 1986, 27, 4941. CrossRef
10. E. Alonso, D. J. Ramon, and M. Yus, Tetrahedron, 1997, 53, 14355. CrossRef
11. V. Dourtoglou, J.-C. Ziegler, and B. Gross, Tetrahedron Lett., 1978, 19, 1269; CrossRef V. Dourtoglou, J.-C. Ziegler, and B. Gross, Synthesis, 1984, 572. CrossRef