A. Wallace-Povirk et al.
Bioorganic & Medicinal Chemistry 37 (2021) 116093
1.65(m, 4H, 2CH2), 2.64(m, J = 7.6 Hz,2H, CH2), 3.67(t, J = 6.5 Hz ,2H,
CH2), 3.89(s, 3H, CH3), 7.17(d, 1.4 Hz, 1H, CH, Ar),7.65 (d, 1.4 Hz, 1H,
CH, Ar).
Methyl 5-(6-oxohexyl)thiophene-3-carboxylate (14g). Using the
general procedure, 14g was obtained as a light-yellow liquid (1.42 g,
71%); TLC Rf 0.71 (Hexane/Ethyl Acetate = 1:1). 1H NMR (400 MHz,
Chloroform-d): δ 1.42 (m, 2H, CH2), 1.71 (m, 4H, 2CH2), 2.47(m, 2H,
CH2), 2.83 (m, 2H, CH2), 3.86 (s, 3H, CH3), 7.21 (d, J = 1.3 Hz 1H, CH),
7.91(d, J = 1.3 Hz, H, CH), 9.79 (t, J = 1.7 Hz ,1H, CHO).
Methyl 5-(5-hydroxypentyl)thiophene-3-carboxylate (13f).
Using the general procedure, 13f was obtained from 12f as a light-
yellow liquid (1.58 g, 86%); TLC Rf 0.36 (Hexane/Ethyl Acetate =
1:1). 1H NMR (400 MHz, Chloroform-d): δ 1.47(m, 2H, CH2), 1.78 – 1.69
(m, 4H, 2CH2), 2.84(m, 2H, CH2), 3.67 (t, 2H, CH2), 3.87 (s, 3H, CH3),
7.22 (d, J = 1.2 Hz, 1H, CH, Ar), 7.91 (d, J = 1.2 Hz, 1H, CH, Ar).
6.2.5. General procedures for the synthesis of 15.
To a 20 mL microwave vial was added a solution of aldehyde 14
(6.18 mmol) with a mixture of sulfur (300 mg, 9.3 mmol), ethyl cya-
noacetate (700 mg, 6.18 mmol), ethanol (15 mL) and triethylamine (68
mg, 0.62 mmol); the vial was sealed and subjected to microwave irra-
diation at 80 ◦C for 30 min. Unreacted sulfur was removed by filtration,
and the filtrate was concentrated under reduced pressure to afford an
orange liquid. The residue was loaded on a silica gel column and eluted
with 10% ethyl acetate in hexane. Fractions were pooled and evaporated
to afford the desired products.
Methyl
5-(6-hydroxyhexyl)thiophene-3-carboxylate
(13g).
Using the general procedure, 13g was obtained from 12g as a light-
yellow liquid (1.76 g, 96%); TLC Rf 0.37 (Hexane / Ethyl Acetate =
1:1). 1H NMR (400 MHz, Chloroform-d): δ 1.42 (m, 4H, CH2), 1.60 (m,
2H, CH2), 1.72 (m, 2H, CH2), 2.82 (m, 2H, CH2), 3.67 (t, 2H, CH2), 3.87
(s, 3H, CH3), 7.21(d, J = 1.2 Hz ,1H, CH, Ar), 7.91 (d, J = 1.2 Hz ,1H,
CH, Ar).
6.2.4. General procedures for the synthesis of 14.
Methyl 5-(3-(5-amino-4-(ethoxycarbonyl)thiophen-2-yl)propyl)
thiophene-2-carboxylate (15a). Using the general procedure, 15a was
obtained from 14a (1.49 g, 6.18 mmol) as a yellow liquid (1.58 g, 70%);
TLC Rf 0.73 (Hexane/Ethyl Acetate = 1:1). 1H NMR (400 MHz, Chlo-
roform-d): δ1.43 (t, 3H, CH3), 1.61 (m, 2H, CH2), 2.81 (m, 2H, CH2),
3.18 (m, 2H, CH2), 4.27–4.37 (m, 5H, CH2 and CH3), 5.83 (s, 2H, NH2-
exchange), 6.68 (d, 1H, CH, Ar), 6.81–6.82 (d, J = 3.7 Hz, 1H, CH, Ar),
7.65–7.66 (d, J = 3.7 Hz, H, CH, Ar).
To a solution of compound 13 (1.5 g, 6.4 mmol) in anhydrous
dichloromethane (10 mL) in a round bottom flask cooled in an ice bath
was added a stirred solution of Dess-Martin periodinane (DMP) (2.96 g,
6.9 mmol) in dichloromethane (8 mL) at 0˚C, and the mixture was
allowed to warm from 0 ˚C to rt. After 3 h, when the TLC showed the
disappearance of 13, 10 mL of 1 N sodium hydroxide solution was added
to deactivate the remaining DMP, followed by extraction with ethyl
acetate (3 × 30 mL). Fractions that showed the desired product (TLC) 14
were pooled and evaporated to dryness; this afforded 14 as a yellow
liquid.
Methyl 5-(4-(5-amino-4-(ethoxycarbonyl)thiophen-2-yl)butyl)
thiophene-2-carboxylate (15b). Using the general procedure, 15b was
obtained from 14b (1.40 g, 6.18 mmol) as a yellow liquid (1.55 g, 71%);
TLC Rf 0.74 (Hexane/Ethyl Acetate = 1:1). 1H NMR (400 MHz,
DMSO‑d6): δ 1.20–1.24 (t, 3H, CH3), 1.49–1.56 (m, 2H, CH2), 1.60–1.67
(m, 2H, CH2), 2.52–2.56 (m, 2H, CH2), 2.83–2.86 (t, 2H, CH2), 3.77 (s,
3H, CH3), 4.10–4.15 (q, 2H, CH2), 6.49(s, 1H, CH, Ar), 6.94–6.95(s, 1H,
CH, Ar), 7.10 (s, 2H, NH2-exchange), 7.65–7.66 (d, 1H, CH, Ar).
Methyl 5-(4-[5-amino-4-(ethoxycarbonyl)thiophen-2-yl]butyl}
furan-2-carboxylate (15c). Using the general procedure, 15c was ob-
tained from 14c (1.58 g, 6.18 mmol) as a yellow liquid (0.78 g, 41%);
TLC Rf 0.34 (hexane/Ethyl Acetate = 3:1). 1H NMR (DMSO‑d6)
1.20–1.24 (t, 3H, J = 6.8 Hz, OCH2CH3), 1.49–1.63 (m, 4H), 2.57–2.60
(t, 2H, J = 7.2 Hz), 2.68–2.70 (t, 2H, J = 7.2 Hz), 3.76 (s, 3H, OCH3),
4.09–4.15 (q, 2H, J = 6.8 Hz, OCH2CH3), 6.33–6.34 (d, 1H, J = 3.2 Hz),
6.49 (s, 1H), 7.01 (s, 2H, 2-NH2 exch), 7.19–7.20 (d, 1H, J = 3.2 Hz).
Methyl 4-(3-(5-amino-4-(ethoxycarbonyl)thiophen-2-yl)propyl)
thiophene-2-carboxylate (15d). Using the general procedure, 15d was
obtained from 14d (1.58 g, 6.18 mmol) as a yellow liquid (1.30 g, 69%);
TLC Rf 0.75 (Hexane/Ethyl Acetate = 1:1). 1H NMR (400 MHz, Chlo-
roform-d): δ 1.36 (t,3H, CH3) δ 1.93 (m, 2H, CH2), 2.63 (t, J = 7.0 Hz,
2H, CH2), 2.68 (m, 2H, CH2), 4.31 – 4.25 (m, 2H, CH2), 5.83 (s, 2H, NH2-
exchange), 6.68 (d, 1H, CH), 6.81–6.82 (d, J = 1.5 Hz ,1H,CH, Ar),
7.65–7.66 (d, J = 1.5 Hz ,1H,CH, Ar).
Methyl 5-(5-oxopentyl)thiophene-2-carboxylate (14a). Using the
general procedure, 14a was obtained as a light-yellow liquid (1.53 g,
83%); TLC Rf 0.70 (Hexane/Ethyl Acetate = 1:1). 1H NMR (400 MHz,
Chloroform-d): δ 1.78–1.70 (m, 2H, CH2), 2.50 (td, J = 6.7, 2H, CH2),
2.88 (t, J = 7.1 Hz, CH2), (d, J = 1.0 Hz, 2H), 3.88 (s, 3H, CH3), 6.81 (d,
J = 3.7 Hz 1H, CH), 7.65 (d, J = 3.7 Hz ,H, CH), 9.79 (t, J = 1.5 Hz, 1H,
CHO).
Methyl 5-(6-oxohexyl)thiophene-2-carboxylate (14b). Using the
general procedure, 14b was obtained as a light-yellow liquid (1.81 g,
91%); TLC Rf 0.68 (Hexane/Ethyl Acetate = 1:1). 1H NMR (400 MHz,
Chloroform-d): δ 1.27–1.32 (m, 2H, CH2), 1.49–1.53 (t, 2H, CH2),
1.59–1.65 (t, J = 7.1 Hz, CH2), 2.39–2.43 (t, 2H, CH2), 3.77 (s, 3H, CH3),
6.94 (d, J = 3.7 Hz, 1H, CH, Ar), 7.63(d, J = 3.7 Hz ,H, CH, Ar), 9.63(t, J
= 1.5 Hz, 1H, CHO).
Methyl 5-(6-oxohexyl)furan-2-carboxylate (14c). Using the gen-
eral procedure, 14c was obtained as a light-yellow liquid (1.99 g, 95%);
TLC Rf 0.72 (hexane/Ethyl Acetate = 1:1). 1H NMR (400 MHz,
DMSO‑d6) δ 1.24 (m, 2H), 1.60 (m, 4H), 2.43 (t, 2H), 2.68 (t, 2H), 3.68
(s, 3H, CH3), 6.34–6.35 (d, 1H, J = 3.6 Hz), 7.20–7.21 (d, 1H, J = 3.6
Hz), 9.63–9.65 (t, 1 CHO).
Methyl 4-(5-oxopentyl)thiophene-2-carboxylate (14d). Using the
general procedure, 14d was obtained as a light-yellow liquid (1.76 g,
88%); TLC Rf 0.67 (Hexane/Ethyl Acetate = 1:1). 1H NMR (400 MHz,
DMSO‑d6): δ 1.54 (m, 4H, 2CH2), 2.46 (t, J = 7.0, 1.4 Hz, 2H,CH2), 2.60
(t, J = 7.1 Hz 2H, CH2), 3.80 (s, 3H, CH3), 7.58 (d, J = 1.5 Hz 1H, CH,
Ar), 7.68 (d, J = 1.5 Hz H, CH, Ar), 9.66 (t, J = 1.5 Hz 1H, CHO).
Methyl 4-(5-oxopentyl)thiophene-2-carboxylate (14e). Using the
general procedure, 14e was obtained as a light-yellow liquid (1.74 g,
87%); TLC Rf 0.68 (Hexane/Ethyl Acetate = 1:1). 1H NMR (400 MHz,
Chloroform-d): δ 1.54 (m, 4H, 2CH2), 1.72–1.60 (m, 4H, 2CH2), 2.60 (m,
2H, CH2), 3.80 (s, 3H, CH3), 7.58 (d, J = 1.5 Hz, 1H, CH, Ar), 7.68(d, J =
1.5 Hz, 1H, CH, Ar), 9.66 (t, J = 1.7 Hz ,1H, CHO).
Methyl 4-(4-(5-amino-4-(ethoxycarbonyl)thiophen-2-yl)butyl)
thiophene-2-carboxylate (15e). Using the general procedure, 15e was
obtained from 14e (1.40 g, 6.18 mmol) as a yellow liquid (1.18 g,
55.12%); TLC Rf 0.73 (Hexane/Ethyl Acetate = 1:1). 1H NMR (500 MHz,
Chloroform-d): δ 1.28 (t, J = 7.2 Hz, 3H, CH3), 1.67 (m, 4H, 2CH2),
2.6–2.8 (m, 4H, 2CH2), 3.89 (s, 3H, CH3), 4.14 (q, J = 7.2 Hz, 2H, CH2),
5.81 (s, 2H, NH2-exchange), 6.63(s,1H, CH, Ar), 7.17 (d, J = 1.4 Hz, 1H,
Ar), 7.64 (d, J = 1.6 Hz, 1H, Ar).
Methyl 5-(3-(5-amino-4-(ethoxycarbonyl)thiophen-2-yl)propyl)
thiophene-3-carboxylate (15f). Using the general procedure, 15f was
obtained from 14f (1.58 g, 6.18 mmol) as a yellow liquid (1.33 g, 61%);
TLC Rf 0.74 (Hexane/Ethyl Acetate = 1:1). 1H NMR (400 MHz, Chlo-
roform-d): δ1.36 (td, J = 7.1, 3.0 Hz, 3H, CH3), 2.04–1.93 (m, 2H, CH2),
2.67(t, J = 7.0 Hz ,2H, CH2), 2.86 (t, J = 7.5 Hz, 2H, CH2), 3.87 (s, 3H,
CH3), 4.29 (m, 2H, CH2), 5.832 (s, 2H, NH2-exchange), 6.68 (d, 1H, CH,
Ar), 7.23 (d, J = 1.4 Hz 1H, CH, Ar), 7.93 (d, J = 1.4 Hz 1H, CH, Ar).
Ethyl 2-amino-5-(4-(4-(methoxycarbonyl)thiophen-2-yl)butyl)
Methyl 5-(5-oxopentyl)thiophene-3-carboxylate (14f). Using the
general procedure, 14f was obtained as a light-yellow liquid (1.82 g,
92%); TLC Rf 0.69 (Hexane/Ethyl Acetate = 1:1). 1H NMR (400 MHz,
Chloroform-d): δ 1.74(m, 4H, 2CH2), 2.50(m, 2H, CH2), 2.85 (m, 2H,
CH2), 3.87(s, 3H, CH3), 7.22(d, J = 1.4 Hz ,1H, CH, Ar), 7.92(d, H, CH,
Ar), 9.79 (t, J = 1.6 Hz ,1H, CHO).
13