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yielding a yellow oil (300 mg, 84%): RP-HPLC: 100%, (tR =5.94, k=
1.31). H NMR (300 MHz, CD3OD, tri-trifluoroacetate) δ 8.81 (d, J=
1.3 Hz, 1H), 7.35 (s, 1H), 3.30–3.23 (m, 4H), 3.01 (t, J=7.4 Hz, 2H),
2.81 (t, J=7.3 Hz, 2H), 1.96 (m, 4H). 13C NMR (75 MHz, CD3OD, tri-
trifluoroacetate) δ 157.66, 134.92, 134.54, 116.99, 41.68, 39.61,
38.13, 28.75, 28.02, 22.55. HRMS (ESI-MS): m/z [M+H+] calculated
for C10H21N6+: 225.1822, found 225.1822; C10H20N6 x 3 TFA. (566.38).
General Procedure for the Guanidinylation reaction of 93–109
1
2
3
4
5
1
To a suspension of the pertinent amine 5, 6, or 7 (1 equiv), the
pertinent N’-Boc-S-methylisothiourea 77–87 (1 equiv) and HgCl2
(1 equiv) in DCM, NEt3 (3 equiv) was added. The mixture was stirred
overnight at rt. A possible excess of HgCl2 was quenched with 7 N
NH3 in MeOH (3-5 mL). The resulting suspension was filtered over
Celite and the crude product was purified with column chromatog-
raphy (DCM/MeOH/7N NH3 in MeOH 98/1/1 – 95/3/2 v/v/v).
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7
8
Synthesis of the SK&F 91486analogues 141–145
9
2-tert-Butoxycarbonyl-1-(N-tert-butoxycarbonylaminopropany-
l)-3-[3-(1-trityl-1H-imidazol-4-yl)propyl]guanidine (93)
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11
12
13
14
15
16
17
18
19
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22
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24
25
26
27
28
29
30
31
32
33
34
35
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39
40
41
42
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44
45
46
47
48
49
50
51
52
N-{[3-(1-Trityl-1H-imidazol-4-yl)propyl]thiocarbamoyl}
benzamide (137)
Compound 93 was prepared from 5 (500 mg, 1.36 mmol), 77
(473 mg, 1.36 mmol), HgCl2 (369 mg, 1.36 mmol) and NEt3 (0.57 mL,
4.08 mmol) in DCM (20 mL) conforming to the general procedure
yielding a yellow foamlike solid (420 mg, 46%): Rf =0.30 (DCM/
MeOH/NH3 98:2:0.1); 1H NMR (300 MHz, CDCl3) δ 9.05 (bs, 1H) 7.42–
7.27 (m, 10H), 7.15–7.07 (m, 6H), 6.56 (d, J=0.8 Hz, 1H), 5.91 (bs,
1H), 3.55–3.16 (m, 4H), 3.09 (q, J=5.6 Hz, 2H), 2.56 (t, J=6.3 Hz, 2H),
1.87 (p, J=6.7 Hz, 2H), 1.67–1.48 (m, 2H), 1.44 (s, 9H), 1.41 (s, 9H).
13C NMR (75 MHz, CDCl3) δ 164.20, 160.89, 156.55, 142.34, 140.46,
138.02, 129.72, 128.12, 128.10, 118.31, 78.74, 75.26, 75.24, 40.23,
40.20, 36.93, 33.15, 30.58, 29.16, 28.57, 28.51. HRMS (ESI-MS): m/z
[M+H+] calculated for C39H51N6O4+: 667.3966, found 667.3970;
C39H50N6O4 (666.87).
Compound 137 was prepared according to the general procedure
described in 4.2.5. using 5 (4.80 g, 13.06 mmol) and 28 (1.76 mL,
13.06 mmol) in 100 mL DCM. After column chromatography
(EtOAc/PE 1/2 – 1/1 v/v) the product was obtained as a yellow solid
(4.60 g, 66%): Rf =0.55 (EtOAc/Hex 1:1); mp 139.4 C. 1H NMR
°
(300 MHz, CDCl3) δ 10.76 (bs, 1H), 9.09 (bs, 1H), 7.85–7.74 (m, 2H),
7.63–7.54 (m, 1H), 7.52–7.42 (m, 2H), 7.37 (d, J=1.3 Hz, 1H), 7.39–
7.25 (m, 9H), 7.20–7.05 (m, 6H), 6.60 (s, 1H), 3.72 (q, J=6.9 Hz, 2H),
2.66 (t, J=7.3 Hz, 2H), 2.05 (p, J=7.3 Hz, 2H). 13C NMR (75 MHz,
CDCl3) δ 179.69, 166.76, 142.53, 140.22, 138.62, 133.46, 131.89,
129.80, 129.08, 128.05, 127.99, 127.49, 118.26, 75.14, 45.35, 27.72,
25.73. HRMS (ESI-MS): m/z [M+H+] calculated for C33H31N4OS+:
531.2213, found 531.2218; C33H30N4OS (530.69).
General Procedure for the Guanidinylation Reaction of 110–114
1-[3-(1-Trityl-1H-imidazol-4-yl)propyl]thiourea (140)
To a suspension of the amine 5 (2 equiv), the pertinent N’-Boc-S-
methylisothiourea 88–92 (1 equiv) and HgCl2 (4 equiv) in DCM, NEt3
(6 equiv) was added. The mixture was stirred overnight at rt. A
possible excess of HgCl2 was quenched with 7 N NH3 in MeOH (3–
5 mL). The resulting suspension was filtered over Celite and the
crude product was purified with column chromatography (DCM/
MeOH/7 N NH3 in MeOH 98/1/1 – 95/3/2 v/v/v).
Compound 140 was prepared according to the general procedure
described in 4.2.6. using 137 (1.50 g, 2.83 mmol) and K2CO3
(781 mg, 5.65 mmol) in 30 mL MeOH/H2O (7/3 v/v). The product
was obtained as a beige solid (920 mg, 76%): Rf =0.20 (DCM/MeOH
1
°
95:5); mp 196.1 C. H NMR (400 MHz, CD3OD) δ 7.45–7.28 (m, 10H),
7.22–7.08 (m, 6H), 6.71 (s, 1H), 3.48+3.13 (2 bs, 1.2H+0.8H,
(thione-thiol tautomerism)), 2.56 (t, J=7.3 Hz, 2H), 1.84 (p, J=
7.3 Hz, 2H). 13C NMR (101 MHz, CD3OD) δ 179.77, 143.76, 141.40,
139.35, 130.88, 129.28, 129.24, 119.92, 76.77, 45.09, 29.93, 26.03.
HRMS (ESI-MS): m/z [M+H+] calculated for C26H27N4S+: 427.1951,
found 427.1955; C26H26N4S (426.58).
2-tert-Butoxycarbonyl-1-(N’-tert-butoxycarbonylcarbodiimidopr-
opyl)-3-[3-(1-trityl-1H-imidazol-4-yl)propyl]guanidine (110)
Compound 110 was prepared from 5 (1.0 g, 2.72 mmol), 88
(572 mg, 1.36 mmol), HgCl2 (1.48 g, 5.44 mmol) and NEt3 (1.13 mL,
8.16 mmol) in DCM (20 mL) conforming to the general procedure
yielding a yellow oil (430 mg, 46%): Rf =0.44 (DCM/MeOH/NH3
N-{[3-(1H-Imidazol-4-yl)propyl]thiocarbamoyl}benzamide (141)
1
The title compound was prepared from 137 (1.0 g, 1.88 mmol), TFA
(4 mL) and DCM (16 mL) according to the general procedure (cf.
4.2.11). The crude product was purified by column chromatography
(DCM/MeOH/7 M NH3 in MeOH 95/3/2 v/v/v) yielding 141 as free
98:2:0.1); H NMR (300 MHz, CDCl3) δ 9.75 (bs, 1H), 7.34–7.21 (m,
10H), 7.14–7.03 (m, 6H), 6.51 (s, 1H), 3.52–3.08 (m, 6H), 2.68–2.46
(m, 2H), 1.99–1.71 (m, 4H), 1.41 (s, 9H), 1.39 (s, 9H). 13C NMR
(75 MHz, CDCl3) δ 164.45, 160.71, 158.01, 156.00, 142.52, 140.58,
138.41, 129.73, 128.00, 127.94, 117.91, 85.50, 78.63, 75.02, 53.52,
45.56, 43.58, 28.54, 28.26, 27.93, 25.78, 21.06. MS (LC–MS, ESI): m/z
692.39 [M+H+]; C40H49N7O4 (691.88).
base and yellow solid (350 mg, 64%): Rf =0.12 (DCM/MeOH 95:5);
1
°
mp 139.8 C. H NMR (300 MHz, CD3OD) δ 8.01–7.84 (m, 2H), 7.71–
7.62 (m, 1H), 7.61 (s, 1H), 7.57–7.46 (m, 2H), 6.88 (s, 1H), 3.72 (t, J=
7.0 Hz, 2H), 2.70 (t, J=7.5 Hz, 2H), 2.04 (p, J=7.3 Hz, 2H). 13C NMR
(75 MHz, CD3OD) δ 182.06, 169.56, 137.51, 135.97, 134.24, 133.95,
129.88, 129.19, 117.78, 45.70, 29.01, 25.07. HRMS (ESI-MS): m/z [M+
H+] calculated for C14H17N4OS+: 289.1118, found 289.1120;
C14H16N4OS (288.37); Anal. calculated for C14H16N4OS: C 58.31, H
5.59, N 19.43, found: C 58.32, H 5.66, N 19.16.
General Procedure for the Preparation of the Title Compounds
115–136
The general procedure for the synthesis of 115–136 is described in
the literature (cf. 4.2.7.).[40] All compounds were obtained as tri-
trifluoroacetates.
N-[3-(1H-Imidazol-4-yl)propyl]-S-methylisothiourea (143)
To an ice-cold suspension of 140 (500 mg, 1.17 mmol) in EtOH
(20 mL) an aqueous solution of HI (66%, 5 mL) was added dropwise.
The resulted yellow precipitate (142 x HI) was filtrated and washed
with Et2O. Subsequently, 142 x HI was dissolved in MeOH (5 mL),
treated with methyl iodide (0.08 mL, 1.29 mmol) and refluxed for
53 1-(3-Aminopropyl)-3-[3-(1H-imidazol-4-yl)propyl]guanidine
(115)
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55
56
57
The title compound was prepared from 93 (420 mg, 0.63 mmol),
TFA (4 mL) and DCM (16 mL) according to the general procedure,
ChemistryOpen 2019, 8, 285–297
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