Isothioureas, Ureas, and Their N-Methyl Amides from 2-Aminobenzothiazole and Chiral Amino Acids

Abstract

In this investigation, the reaction of 2-dithiomethylcarboimidatebenzothiazole with a series of six chiral amino-acids was studied. The reaction proceeds through the isolable sodium salt of SMe-isothiourea carboxylates as intermediates, whose reaction with methyl iodide in stirring DMF as solvent affords SMe-isothiourea methyl esters. The presence of water in the reaction leads to the corresponding urea carboxylates as isolable intermediates, whose methyl esters were obtained. Finally, the urea N-methyl amide derivatives were isolated when SMe-isothiourea or urea methyl esters were reacted with methylamine in the presence of water. The structures of synthesized compounds were established by ¹H and ¹³C nuclear magnetic resonance and the structures of SMe-isothiourea methyl esters derived from (l)-glycine, (l)-alanine, (l)-phenylglycine, and (l)-leucine, by X-ray diffraction analysis. This methodology allows to functionalize 2-aminobenzothiazole with SMe-isothiourea, urea, and methylamide groups derived from chiral amino acids to get benzothiazole derivatives containing coordination sites and hydrogen bonding groups. Further research on the biological activities of some of these derivatives is ongoing.

Keywords: 2-aminobenzothiazole; 2-dithiomethylcarboimidatebenzothiazole; S-methyl-isothioureas; urea-carboxylate methyl esters and urea N-methyl amides; α-amino-acids.

Scheme 1

Dithiomethylcarboimidatebenzothiazole 2, SMe-isothioureas 3 and guanidines 4 starting from 2-aminobenzothiazole 1.

Scheme 2

Generation of sodium carboxylates C from neutral amino acids A.

Scheme 3

Synthesis of SMe-isothiourea carboxylates 5a–f, isourea-carboxylates 6a–f, their corresponding methyl esters 8a–f, 9e,f, 10a–f, and 12e,f, isourea-amides 11a–f and urea-amides 13e,f derived from benzothiazole and amino acids.

Scheme 4

Sygmatropic rearrangement of compound 2. The numbers on the atoms are the ¹H and ¹³C chemical shifts in CDCl₃.

Figure 1

¹H and ¹³C NMR data in CDCl₃ of compounds 9e, 9f, and 9f HI.

Figure 2

¹H and ¹³C NMR data in CDCl₃ of urea carboxylate methyl esters 12e, 12f, and their corresponding urea NMe amides 13e, 13f.

Figure 3

X-ray diffraction structure of compound 8a. Bond lengths (Å): S(1)–C(2) 1.7624(1), S(1)–C(8) 1.7342(1), S(23)–C(11) 1.7599(1), S(23)–C(24) 1.7927(1), N(3)–C(2) 1.3115(1), N(3)–C(9) 1.3855(1), N(10)–C(2) 1.3621(1), N(10)–C(11) 1.3104(1), N(12)–C(11) 1.3308(1), N(12)–C(13) 1.4402(1), O(14)–C(14) 1.1936(1), O(15)–C(14) 1.3291(1), O(15)–C(16) 1.4530(1). Bond angles (Deg.): C(2)–S(1)–C(8) 89.25(1), C(11)–S(23)–C(24) 1102.17(1).Torsion angles (Deg.): S(23)–C(11)–N(10)–C(2) 179.34(1), N(10)–C(11)–S(23)–C(24) −6.18(1), N(10)–C(11)–N(12)–C(13) 178.17(1), N(12)–C(13)–C(14)–O(14) 2.25(1), N(12)–C(13)–C(14)–O(15) −177.67(1), O(14)–C(14)–O(15)–C(16) 0.25(1).

Figure 4

X-ray diffraction structure of compound 8c. Bond length (Å): S(1)–C(2) 1.753(2), N(3)–C(2) 1.301(3), N(10)–C(2) 1.372(3), N(10)–C(11) 1.306(3), N(12)–C(11) 1.338(3), N(12)–C(13) 1.452(3), S(23)–C(11) 1.770(2). Bond angles (Deg.): S(1)–C(2)–N(10) 115.55(16), N(3)–C(2)–N(10) 129.2 (2), C(2)–N(10)–C(11) 120.36(17), N(10)–C(11)–N(12) 126.08(18). Torsion angles (Deg.): N(3)–C(2)–N(10)–C(11) −1.25, C(24)–S(23)–C(11)–N(10) 1.41(19), C(24)–S(23)–C(11)–N(12) −179.90(17), N(12)–C(13)–C(14)–O(14) 6.2(3), C(16)–O(15)–C(14)–O(14) −0.1(4).

Figure 5

X-ray diffraction structure of compound 8b. Bond Lengths (Å): S(1)–C(2) 1.7618(1), S(1)–C(8) 1.7300(1), S(23)–C(11) 1.7667(1), S(23)–C(24) 1.7919(1), O(14)–C(14) 1.1870(1), O(15)–C(14) 1.3134(1), O(15)–C(16) 1.4522(1), N(3)–C(2) 1.2954(1), N(3)–C(9) 1.3912(1), N(10)–C(2) 1.3592(1), N(10)–C(11) 1.3043(1), N(12)–C(11) 1.3295(1), N(12)–C(13) 1.4527(1). Bond Angles (Deg.): C(2)–S(1)–C(8) 89.62(1), C(11)–S(23)–C(24) 101.25(1). Torsion angles (Deg.): N(3)–C(2)–S(1)–C(8) –0.35(1), N(10)–C(2)–S(1)–C(8) 179.59(1), S(1)–C(2)–N(3)–C(9) 0.18(1), N(10)–C(2)–N(3)–C(9) −179.74(1), S(1)–C(2)–N(10)–C(11) −177.17(1), N(3)–C(2)–N(10)–C(11) 2.75(1), N(10)–C(11)–S(23)–C(24) 5.19(1), N(12)–C(11)–S(23)–C(24) −173.79(1), S(23)–C(11)–N(10)–C(2) 179.27(1), N(12)–C(11)–N(10)–C(2) −1.88(1), S(23)–C(11)–N(12)–C(13) 0.16(1), N(10)–C(11)–N(12)–C(13) −178.71(1), C(14)–C(13)–N(12)–C(11) −85.82(1), C(17)–C(13)–N(12)–C(11) 147.32(1), C(17)–C(13)–C(14)–O(14) 140.21(1).

Figure 6

X-ray diffraction structure of compound 9f. Bond Lengths (Å). S1–C2 1.757(5), S1–C8 1.748(5), S12–C11 1.766(5), S12–C13 1.790(5), O16–C16 1.200(7), O17–C16 1.336(6), O17–C18 1.457(8), N3–C2 1.360(5), N3–C9 1.388(6), N3–C23 1.463(6), N10–C2 1.309(6), N10–C11 1.369(5), N14–C11 1.283(6), N14–C15 1.461(6), C4–C5 1.374(8). Torsion angles (Deg.): N3–C2–S1–C8 −2.4(4), N10–C2–S1–C8 175.6(5), S1–C2–N3–C9 2.3(5), S1–C2–N3–C23 −178.2(4), N10–C2–N3–C9 −175.8(4), N10–C2–N3–C23 3.6(7), S1–C2–N10–C11 2.1(7), N3–C2–N10–C11 179.9(4), N10–C11–S12–C13 −5.6(4), N14–C11–S12–C13 175.1(4), S12–C11–N10–C2 −169.8(4), N14–C11–N10–C2 9.6(7), S12–C11–N14–C15 −2.3(6), N10–C11–N14–C15 178.5(4), C16–C15–N14–C11 −70.1(5), C19–C15–N14–C11 169.6(4), N14–C15–C19–C20 −66.1(6).