2
S. Alnabulsi et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
Fig. 1. Structures of the non-symmetrical furan-amidine 1, the symmetrical 3,4-dimethylfuran-amidine 2 and the proposed 4-methylfuran-amidine 3.
the reaction between the 1,4-diketone 203 and Lawesson’s reagent.
The conversion of the nitrile group of 21 to the amidine 19 was via
the amidoxime intermediate 22. Reduction of the amidoxime 22 to
the amidine 19 was attempted by heating at reflux in acetic acid in
the presence of ammonium formate and Pd. Only starting material
22 was recovered, which was attributed to poisoning of the Pd cat-
alyst by the thiophene. The reduction of 22 to amidine 19 was
therefore achieved using triethylsilane as hydrogen donor in the
presence of palladium (II) chloride catalyst (Scheme 4).14
To address the high basicity of the amidine group, several less
basic isosteres of 1 were synthesized in which the amidine group
was replaced with methyl imidate 23, amidoxime 24, N-aryl amidi-
nes (reversed amidines) 25–26 and N-aryl amide 27–29. pKa and
clogS are given in Table 1 and clogP and solubilities (mg/ml) are
given in SI for the key compounds, with the non-amidine ana-
logues being less basic, potentially enhancing passive permeability.
The syntheses of these analogues are illustrated in Schemes 5 and
6. It was anticipated that heating of ethyl benzimidate hydrochlo-
ride 30 (prepared by reaction of nitrile 31 with ethanol)3 at reflux
with ammonium chloride methanol/water would give the furan-
amidine 1, however the isolated product was the methyl imidate
2315 (Scheme 5). The methyl imidate group is a much less basic
isostere (pKa 6.2)15 than the highly basic amidine group (pKa
11.8).16
Scheme 1. Synthesis of 4-(4-phenyl-1H-imidazol-2-yl)benzamidine acetate 4;
Reagents and conditions: (i) NH4OAc, MeOH, rt. (ii) NH2OHꢁHCl, t-BuOK, dry DMSO,
0 °C – rt; (iii) HCO2NH4, Pd/C, AcOH, reflux; (iv) HCl(g), abs. EtOH, CHCl3, 0 °C – rt; (v)
NH4OAc, Abs. EtOH, rt, 12 h.
An isosteric analogue of the asymmetric furan-amidine 1 with
an amidoxime group 24 was synthesized as a less basic isostere
(pKa 5–6) for the furan amidine.17 In addition, the amidoxime
group is a known prodrug for the amidine group and can enhance
oral bioavailability of amidine-containing drugs4,5 which is acti-
vated through reduction of the amidoxime group by human liver
microsomes.18 N-Hydroxy-4-(5-phenylfuran-2-yl)benzamidine 24
was synthesized by the reaction of nitrile 31 with hydroxylamine
(Scheme 5).
The first step in the syntheses of the reverse amidine and amide
analogues 25–29 was the preparation of the key 1,4-diketone
intermediates 32 and 333 (Scheme 6). The cyclization of the 1,4-
diketones 32, 33 into furans 34, 35 and thiophenes 36, 37 were
catalysed by dry hydrogen chloride gas and Lawesson’s reagent,
respectively. The nitro-groups in the intermediates 34–37 were
reduced to amines 38–41 using sodium borohydride in the pres-
ence of catalytic copper sulfate.19 The reduction of the nitro-groups
into amines was confirmed by upfield shift of the protons on the
aromatic ring: The peaks of the H-20, H-40, H-50 and H-60 protons
of 34 were shifted up-field from 8.57, 8.12, 7.59 and 8.05 ppm to
6.87, 6.52, 7.08 and 6.94 ppm in 38, respectively (Fig. S2). The N-
aryl amidines 25 and 26 were synthesized from the reaction of
the amines 39 and 41, respectively, with S-2-naphthylmethyl
thioacetimidate hydrobromide (Scheme 6).20–22 The furan N-aryl
amides 27 and 28 and N-(3-(5-phenylthiophen-2-yl)phenyl)ac-
etamide 29 were synthesized from the reaction of acetyl chloride
with amines 38, 39 and 40, respectively (Scheme 6).
Scheme 2. Synthetic pathway for 4-(1-methyl-4-phenyl-1H-imidazol-2-yl)benza-
midine 9; Reagents and conditions: (i) CH3I, KOH, acetone, rt. (ii) NH2OHꢁHCl, t-
BuOK, dry DMSO, 0 °C – rt; (iii) HCO2NH4, Pd/C, AcOH, reflux.
possibility of the formation of two regioisomers 10 or 11. The
NOESY spectrum confirmed the formation of the least hindered
regioisomer 10 (see Fig. S1) which showed a long-range interaction
between the N-methyl protons and H-50. 4-(1-Methyl-4-phenyl-
1H-imidazol-2-yl)benzamidine 9 was synthesized from 10 through
the formation of amidoxime 12 (Scheme 2).
The oxazole-amidine 13 (clogS ꢀ1.30, 13.3 mg/ml7) was syn-
thesized as shown in Scheme 3. The key precursor 4-cyano-N-(2-
oxo-2-phenylethyl)benzamide 16 was prepared from the coupling
between 4-cyanobenzoyl chloride 14 and 2-amino-1-phenyletha-
none hydrochloride 15, in the presence of sodium bicarbonate.11
In the presence of acetic anhydride/conc. sulfuric acid, the benza-
mide 16 readily cyclised to give 4-(5-phenyloxazol-2-yl)benzoni-
trile 1712,13, which was converted to the oxazole-amidine 13
through the formation of the amidoxime intermediate 18
(Scheme 3).
The synthesis of the 3-methylfuran-amidine analogue 3 was
attempted as shown in Scheme 7, however coupling of 4-cyano-
The thiophene-amidine 19 (clogS ꢀ2.25, 1.57 mg/ml9) was also
synthesized (Scheme 4) as a more lipophilic isostere of the furan-
amidine 1 (clogS ꢀ1.81, 4.03 mg/ml9). The synthesis of 19 first
required the Paal-Knorr synthesis of 2,5-diarylthiophene 21 from
phenyl methyl ketone 42 and
a-bromomethyl phenyl ketone 43
failed to give the diaryl mono-methyl 1,4-diketone 44. Diketone
44 would have cyclised to give furan 45, a precursor for amidine
3. Instead, the condensation of 42 and 43 led to the formation of