Synthesis of Unsymmetrical Mono- and Bissquaramides with (3-Amino­propyl)triethoxysilane (APTES) or Dopamine Moieties

Abstract

A simple and efficient synthesis of unsymmetrical mono- and bissquaramides derivatives and their corresponding methyltrialkyl ammonium salts was achieved in moderate yields from diethyl squarate via sequencial reactions.

Key words

squaramides - bissquaramides - modular synthesis - ammonium iodide salt - receptors

• References and Notes

• 1a Cohen S, Cohen SG. J. Am. Chem. Soc. 1966; 88: 1533
• 1b Schmidt AH, Ried W. Synthesis 1978; 869
• 1c Liu H, Tomooka CS, Moore HW. Synth. Commun. 1997; 27: 2177
• 1d Seio K, Miyashita T, Sato K, Sekine M. Eur. J. Org. Chem. 2005; 51: 63
• 1e Storer RI, Aciro C, Jones LH. Chem. Soc. Rev. 2011; 40: 2330
• 2a Quiñonero D, Prohens R, Garau C, Frontera A, Ballester P, Costa A, Deyà PM. Chem. Phys. Lett. 2002; 351: 115
• 2b Prohens R, Tomas S, Morey J, Deyà PM, Ballester P, Costa A. Tetrahedron Lett. 1998; 39: 1063
• 2c Tomas S, Prohens R, Vega M, Rotger MC, Deyà PM, Ballester P, Costa A. J. Org. Chem. 1996; 61: 9394 ; and references therein.
• 2d Quiñonero D, Frontera A, Suñer GA, Morey J, Costa A, Ballester P, Deyà PM. Chem. Phys. Lett. 2000; 326: 247 ; and references cited therein
• 2e Quiñonero D, Frontera A, Ballester P, Deyà PM. Tetrahedron Lett. 2000; 41: 2001
• 3 Rotger C, Soberats B, Quiñonero D, Frontera A, Ballester P, Benet-Buchholz J, Deyà PM, Costa A. Eur. J. Org. Chem. 2008; 1864 ; and references cited therein.
• 4a Frontera A, Morey J, Oliver A, Piña MN, Quiñonero D, Costa A, Ballester P, Deyà PM, Anslyn EV. J. Org. Chem. 2006; 71: 7185
• 4b Quiñonero D, López KA, Deyà PM, Piña MN, Morey J. Eur. J. Org. Chem. 2011; 6187
• 5a Rajh T, Chen LX, Lukas K, Liu T, Thurnauer MC, Tiede DM. J. Phys. Chem. B 2002; 106: 10543
• 5b Xu C, Xu K, Gu H, Zheng R, Liu H, Zhang X, Guo Z, Xu B. J. Am. Chem. Soc. 2004; 126: 9938
• 6 Piña MN, Rotger MC, Soberats B, Ballester P, Deyà PM, Costa A. Chem. Commun. 2007; 9: 963
• 7a Dopamine, like catecholamines, can be oxidized in the presence of either oxygen at a high pH value or other oxidants to the corresponding ortho-quinones, see: Hawley MD, Tatawawadi SV, Piekarski S, Adams RN. J. Am. Chem. Soc. 1967; 89: 447
• 7b Smith MB, March J In March’s Advanced Organic Chemistry. Reactions, Mechanisms, and Structure . 5th ed. John Wiley and Sons; New York: 2001: 1517-1518
• 8 Morey J, Saá JM. Tetrahedron 1993; 49: 105
• 9 Caravajal GS, Leyden DE, Quinting GR, Maciel GE. Anal. Chem. 1988; 60: 1776
• 10 Delgado E, Rotger MC, Costa A, Piña MN, Jiménez HR, Alarcón J, García-España G. Chem. Commun. 2012; 48: 2609
• 11 MeI is volatile and reported to be a potent carcinogen.
• 12 Piña MN, Rotger MC, Costa A, Ballester P, Deyà PM. Tetrahedron Lett. 2004; 45: 3749
• 13 Caution: This compound has been found, in some individuals, to be irritating upon contact with the skin.
• 14 Typical Procedure for the Synthesis of Unsymmetrical Bissquaramide�Reaction of Diethyl Squarate 1b with 1,6-DiaminehexaneA solution of 1,6-diaminehexane (0.35 g, 3 mmol) in ethanol (50 mL) was added drop-wise to a stirred solution of 1b (1.5 g, 8.8 mmol) in ethanol (10 mL). The reaction mixture was stirred overnight at room temperature under an atmosphere of argon. The resulting white solid 15 was isolated by centrifugation after decanting the supernatant and washed with ether (3 × 10 mL) and cold ethanol (3 × 10 mL). Finally, the precipitate 15 was dried under vacuum; yield: 0.99 g (91%). m.p. = 163–164 °C. 1H NMR (300 MHz, DMSO-d6) δ = 8.81 (br, J = 5.6 Hz, NH), 8.60 (br, J = 5.6 Hz, NH), 4.65 (q, J = 7 Hz, 4 H), 3.45 (q, J = 6.1 Hz, 2 H), 3.27 (q, J = 6.6 Hz, 2 H), 1.50 (m, J = 6.3 Hz, 4 H), 1.36 (t, J = 6.3 Hz, 6 H), 1.28 (m, 4 H) ppm. 13C NMR (75 MHz, DMSO-d6): δ = 190.32, 182.99, 177.90, 177.35, 173.58, 173.20, 69.69, 44.63, 44.30, 31.20, 30.69, 26.24, 16.57 ppm. IR (KBr): 3284, 2944, 1804, 1703, 1598, 1517, 1461, 1388, 1340, 1288, 1106, 1043, 1009, 817 cm–1. HRMS–ES(+): m/z calcd for C18H24N2O6Na: 387.1533; found: 387.1532.�Reaction of 15 with 3-(Dimethylamine)-1-propylamine: A solution of 3-(dimethylamine)-1-propylamine (115 μL, 0.9 mmol) in ethanol (50 mL) was added dropwise to a stirred solution of 15 (0.5 g, 1.37 mmol) in a mixture of ethanol (10 mL) and acetonitrile (5 mL). The reaction mixture was stirred overnight at room temperature under an atmosphere of argon. After this period, a white precipitated was collected from the reaction mixture by centrifugation, washed with ether (3 × 5 mL) and with cold acetonitrile (3 × 5 mL) to give 16; yield: 24 mg (63%). m.p. = 183–185 °C. 1H NMR (300 MHz, DMSO-d6): δ = 8.79 (br, J = 5.6 Hz, 1 H), 8.58 (br, J = 5.6 Hz, 1 H), 7.32 (br, 1 H), 4.63 (q, J = 6.9 Hz, 2 H), 3.47 (t, J = 6.1 Hz, 4 H), 3.32 (t, J = 6.9 Hz, 2 H), 2.25 (t, J = 6.9 Hz, 2 H), 2.12 (s, 6 H), 1.65 (m, J = 7.5 Hz, 2 H), 1.51 (m, 4 H), 1.36 (t, J = 6.9 Hz, 3 H), 1.27 (m, 4 H) ppm. 13C NMR (75 MHz, DMSO-d6): δ = 189.85, 182.96, 182.53, 177.51, 176.89, 173.05, 172.67, 168.33, 69.20, 56.40, 45.36, 44.22, 43.88, 43.63, 42.00, 31.19, 30.73, 30.38, 28.85, 25.65, 16.30 ppm. IR (KBr): 3171, 2942, 1803, 1703, 1639, 1584, 1518, 1432, 1357 cm–1. HRMS–ES(+): m/z calcd for C21H32N4O5Na: 443.2270; found: 443.2276.Reaction of 16 with Dopamine: To a mixture of sodium carbonate (400 mg, 3.6 mmol) and sodium dithionite (200 mg, 0.59 mmol) was added methanol (10 mL). A solution of dopamine hydrochloride (0.17 g, 0.88 mmol) in methanol (5 mL) was added drop-wise to the stirred mixture. Immediately, a solution of 16 (0.25 g, 0.59 mmol) in methanol (55 mL) and DMSO (10 mL) was added into the above solution drop-wise too. The pH of the mixture was adjusted to 7 by adding 2 drops of 1 M NaOH. The reaction mixture was stirred for 2 h at room temperature under an atmosphere of argon and in the absence of light. After this period, the solution was filtered and the resulting solution was stirred overnight in the same conditions. The product was obtained by evaporating the solvent under vacuum. The white solid 17 was washed with cold methanol (5 × 10 mL) and acetone (2 × 10 mL); yield: 0.24 g (77%). m.p. = 243–245 °C. 1H NMR (300 MHz, DMSO-d6): δ = 8.79 (br, J = 5.6 Hz, 1 H), 8.70 (br, J = 5.6 Hz, 1 H), 7.70 (br, 2 NH), 7.38 (br, 2 NH), 6.64 (dd, J = 8.2, 4.2 Hz, 2 H), 6.48 (d, J = 7.9 Hz, 1 H), 3.49 (t, J = 6.6 Hz, 8 H), 2.67 (t, J = 6.7 Hz, 2 H), 2.49 (t, J = 7.2 Hz, 2 H), 2.26 (s, 6 H), 1.72 (m, J = 5.9 Hz, 2 H), 1.52 (m, 4 H), 1.31 (m, 4 H) ppm. 13C NMR (75 MHz, DMSO-d6): δ = 183.45, 168.84, 146.10, 144.66, 130.21, 120.36, 117.10, 116.49, 56.11, 45.82, 44.88, 44.06, 37.43, 31.51, 28.66, 26.30 ppm. IR (KBr): 3170, 2931, 1799, 1641, 1582, 1432, 1357 cm–1. MALDI–TOF/TOF(+): m/z calcd for C27H37N5O6Na: 550.2636; found: 550.2646.�Reaction of 17 with MeI: Methyl Iodide (0.24 mL, 3.80 mmol) was added via syringe to a solution of 17 (0.50 g, 0.95 mmol) in DMF (7 mL). The mixture was heated under reflux at 153 °C for 12 h, after which it was cooled to room temperature. 30 mL of acetone were added and the solution was placed in an ice-cold water bath to obtain the product. The resulting brown solid was isolated by centrifugation after decanting the supernatant and purified by washing with cold methanol (3 × 10 mL) and cold acetone (3 × 10 mL). Finally, the precipitate 18 was dried under vacuum; yield: 0.19 g (30%). m.p.= 229–231 ºC. 1H NMR (300 MHz, DMSO-d6): δ = 8.77 (br, 1 H), 8.68 (br, 1 H), 7.41 (br, 4 NH), 6.63 (dd, J = 7.9, 3.5 Hz, 2 H), 6.47 (d, J = 8.1 Hz,1 H), 3.64 (t, 2 H), 3.47 (m, 6 H), 3.10 (s, 9 H), 2.65 (t, J = 7.1 Hz, 2 H), 1.97 (m, 1 H), 1.82 (m, 1 H), 1.50 (m, 4 H), 1.30 (m, 4 H) ppm. 13C NMR (75 MHz, DMSO-d6): δ = 182.21, 167.79, 145.08, 143.74, 129.31, 119.33, 116.06, 115.48, 54.38, 54.19, 44.86, 43.17, 36.41, 30.65, 25.41 ppm. IR (KBr): 3171, 1800, 1645, 1583, 1434, 1384, 1357, 1284, 1116, 617 cm–1. MALDI–TOF/TOF(+): m/z calcd for C28H40N5O6: 542.2973; found: 542.3003.��