One-pot synthesis of quinoline-fused [1,4]thiazepines via the tandem Ugi/post-Ugi reactions

Article abstract of DOI:10.1007/s13738-018-1511-z

A one-pot strategy has been developed for the synthesis of novel tetrahydro-[1,4]thiazepino[7,6-b]quinoline-5-carboxamide derivatives. These reactions presumably proceed by the combination of a Ugi 4CR and three intramolecular S_N2 aliphatic, an alkaline hydrolysis and an intramolecular cyclization S_NAr nucleophilic substitution processes in moderate to good yields. Unambiguous assignment of the molecular structures was carried out by single-crystal X-ray diffraction.

Full text of DOI:10.1007/s13738-018-1511-z

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-018-1511-z
ORIGINAL PAPER
One-pot synthesis of quinoline-fused [1,4]thiazepines via the tandem
Ugi/post-Ugi reactions
Mehdi Ghandi1 · Irene Efteghar1 · Alireza Abbasi1
Received: 20 May 2018 / Accepted: 27 September 2018
© Iranian Chemical Society 2018
Abstract
A one-pot strategy has been developed for the synthesis of novel tetrahydro-[1,4]thiazepino[7,6-b]quinoline-5-carboxamide
derivatives. These reactions presumably proceed by the combination of a Ugi 4CR and three intramolecular SN2 aliphatic, an
alkaline hydrolysis and an intramolecular cyclization SNAr nucleophilic substitution processes in moderate to good yields.
Unambiguous assignment of the molecular structures was carried out by single-crystal X-ray diffraction.
Keywords Pyrrolidine-2-ones · Ugi reaction · Piperazines
Introduction
Example includes metabolic [21], CNS [22], neuromus-
cular [23], cardiovascular [24], oncological [25] and anti-
viral [26] indications. On the other hand, quinoline-con-
taining compounds have been extensively used in medicinal
chemistry because of various biological activities, such as
anti-inflammatory [27] antimalarial [28], anticancer [29],
analgesic [30], and antifungal [31]. As such, obtaining novel
fused biheterocycles encompassing bioactive [1,4]thiazepine
and quinoline motifs seemed to be interesting due to their
individual widespread known biological activities and uses.
Several years ago, Marcaccini and co-workers reported
the synthesis of 4,5-dihydro-1,4-benzothiazepin-3(2H)-ones
via post-condensation modifications of the Ugi reaction [32].
Although the reported procedure is interesting, utilization of
2-chloro-5-nitrobenzaldehyde as the only bifunctional alde-
hyde limits the synthesized scaffolds to 7-nitrobenzo [1,4]
thiazepines. On the other hand, doing reaction in two step
could be a drawback of this method. Therefore, we became
interested to extend this methodology in using 2-chloroqui-
noline-3-carbaldehyde for a one-pot synthesis of quinoline-
fused [1,4]thiazepine derivatives.
Multicomponent reactions (MCRs) are defined as one-pot
processes in which the desired compounds are synthesized
using at least three or more different simple substrates
[1–3]. As attractive procedures, these reactions frequently
occur by several sequential steps [4]. Advantages including
simplicity, rather high efficiency, and atom economy with
generation of complex heterocyclic compounds similar to
“drug-like” compounds in one-pot transformation can be
mentioned for these reactions [5–7]. One may regard these
reactions as diversity-oriented syntheses which are extend-
able to combinatorial strategies [8–14].
The isocyanide-based multicomponent reactions (IMCRs)
in which isocyanide as the key starting material undergoes
reaction with other desired materials are one of the sub-
classes of MCRs [15]. Recall that the pioneering work in this
area is the Ugi IMCR in which synthesis of an N-substituted
acyl aminoamide containing four independently varying
groups is carried out using four carboxylic acids, a primary
amine, an aldehyde, and an isocyanide in an one-pot reaction
[16]. Thereafter, new developments for the synthesis of more
complex structures have been reported via the tandem Ugi/
post-Ugi reactions [17–20].
Experiment
General information
* Mehdi Ghandi
All commercially available chemicals and reagents were pur-
chased from Merck Chemical Company and used without
further purification. Melting points were determined with an
ghandi@khayam.ut.ac.ir
1
School of Chemistry, College of Science, University
of Tehran, P.O. Box 14155 6455, Tehran, Iran
Vol.:(0123456789)
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Journal of the Iranian Chemical Society
Electrothermal model 9100 apparatus and are uncorrected. IR
spectra were recorded on a Bomem B100 series spectropho-
tometer, in cm−1. 1H and 13C NMR spectra were recorded on
a Bruker DRX-300-ADVANCE spectrometer at 500 (1H) and
125 MHz (13C). Mass spectra of the products were obtained
with an HP (Agilent Technologies) 5937 Mass Selective
Detector. Elemental analyses were carried out by a CHN-
Rapid Heraeus elemental analyzer (Wellesley, MA).
(500 MHz, DMSO-d6): δH = 1.20 (s, 9H, 3CH3), 3.60 (d,
J=14.7 Hz, 1H, CHS), 4.19 (d, J=14.7 Hz, 1H, CHS), 4.65
(d, J=14.9 Hz, 1H, CHPh), 4.89 (d, J=14.9 Hz, 1H, CHPh),
5.49 (s, 1H, CHN), 6.77 (s, 1H, Ar), 7.05 (t, J =7.5 Hz, 1H,
Ar), 7.13 (t, J=7.5 Hz, 2H, Ar), 7.28 (d, J=7.5 Hz, 2H, Ar),
7.49–7.66 (m, 1H, Ar), 7.72–7.77 (m, 3H, Ar), 8.05 (s, 1H,
NH); 13C NMR (125 MHz, DMSO-d6): δ 28.5, 32.2, 51.7,
51.9, 65.8, 125.4, 126.4, 126.7, 127.2, 127.7, 128.2, 128.6,
128.7, 131.0, 137.9, 139.7, 146.6, 158.6, 168.3, 169.0;
EI-MS: m/z (%): 419 (1, M+), 319 (37), 229 (25), 186 (38),
91 (100). Anal. Calcd for C24H25N3O2S (419.17): C 68.71,
H 6.01, N 10.02, S 7.64%. Found: C 68.91, H 6.39, N 9.73,
S 7.27%.
General procedure for the preparation of 6a–i
To a stirring solution of aldehydes 3a–c (1 mmol) in MeOH
(5 mL), amines 4a–d (1 mmol), 2-chloroacetic acid (9.4 mg,
1 mmol), and isocyanides 5a–c (1 mmol) were added, and
the reaction mixture was stirred at room temperature for
24 h. After completion of this step as indicated by TLC,
the solvent was removed under reduced pressure, and then
acetone (5 mL) and thiourea (7.6 mg, 1 mmol) were added
to the residue. The reaction mixture was stirred at room tem-
perature for 24 h. The progress of the reaction was monitored
by TLC. Upon completion, the solvent was removed under
reduced pressure. EtOH (8 mL) and KOH (112 mg, 2 mmol)
were then added and the mixture was heated at reflux for 2 h.
After removal of the solvent, the residue was extracted with
ethyl acetate (3×20 mL). The combined extracts were dried
over Na2SO4 and removal of solvent gave a residue which
was recrystallized from ethanol to afford 7a–i.
4‑Benzyl‑N‑cyclohexyl‑3‑oxo‑2,3,4,5‑tetrahy‑
dro‑[1,4]thiazepino[7,6‑b]quinoline‑5‑carboxamide
(7c)
White solid, yield: 272 mg (61%), mp 255–257 °C. IR
(KBr) (νmax, cm−1): 3316, 2926, 2853, 1640, 1588; 1H NMR
(500 MHz, DMSO-d6): δH =1.02–1.68 (m, 10H, cy), 3.49
(d, J=14.7 Hz, 1H, CHS), 3.60 (brs, 1H, CHNH), 4.13 (d,
J = 14.7 Hz, 1H, CHS), 4.41 (d, J = 14.9 Hz, 1H, CHPh),
5.11 (d, J=14.9 Hz, 1H, CHPh), 5.53 (s, 1H, CHN), 6.97
(t, J=7.3 Hz, 1H, Ar), 7.05 (t, J=7.5 Hz, 2H, Ar), 7.19 (d,
J = 7.5 Hz, 2H, Ar), 7.45 (t, J = 7.4 Hz, 1H, Ar), 7.58 (d,
J = 8.0 Hz, 1H, Ar), 7.57–7.75 (m, 3H, Ar), 7.93 (s, 1H,
NH); 13C NMR (125 MHz, DMSO-d6): δC =25.2, 25.3, 25.6,
32.1, 32.2, 32.3, 49.2, 52.4, 65.8, 125.5, 126.3, 126.6, 127.2,
127.5, 128.2, 128.3, 128.5, 130.9, 137.8, 140.0, 146.7,
158.4, 168.2, 169.0; EI-MS m/z (%) : 445 (1, M+), 319 (32),
229 (13), 186 (34), 91 (100). Anal. Calcd for C26H27N3O2S
(445.18): C 70.09, H 6.11, N 9.43, S 7.20%. Found: C 69.80,
H 6.40, N 9.18, S 6.92%.
N‑(tert‑Butyl)‑4‑butyl‑3‑oxo‑2,3,4,5‑tetrahydro‑[1,4]
thiazepino[7,6‑b]quinoline‑5‑carboxamide (7a)
White solid, yield: 0.20 g (52%), mp 245–247 °C. IR (KBr)
1
(νmax, cm−1): 3310, 2961, 2869, 1646, 1583 : H NMR
(500 MHz, DMSO-d6): δH =0.66 (t, J=7.3 Hz, 3H, CH3),
1.00-1.13 (m, 2H, CH2), 1.29 (s, 9H, 3CH3), 1.31–1.35 (m,
2H, CH2), 3.31–3.38 (m, 1H, CHCH2), 3.50 (d, J=14.8 Hz,
1H, CHS), 3.78–3.85 (m, 1H, CHCH2), 4.15 (d, J=14.8 Hz,
1H, CHS), 5.51 (s, 1H, CHN), 7.09 (s, 1H, Ar), 7.51 (t,
J = 7.5 Hz, 1H, Ar), 7.71 (t, J = 7.6 Hz, 1H, Ar), 7.81 (d,
J = 8.4 Hz, 1H, Ar), 7.87 (d, J = 8.2 Hz, 1H, Ar), 8.36 (s,
1H, NH);13C NMR (125 MHz, DMSO-d6): δc=14.0, 19.6,
28.6, 30.3, 32.4, 48.6, 51.8, 65.5, 125.6, 126.4, 127.2, 127.6,
128.3, 131.1, 139.5, 146.8, 159.0, 168.6, 168.7; EI-MS: m/z
(%): 385 (15, M+), 285 (97), 227 (100), 186 (96), 57 (49).
Anal. Calcd for C21H27N3O2S (385.18): C 65.43, H 7.06, N
10.90, S 8.32%. Found: C 65.45, H 7.24, N 10.63, S, 8.22%.
N‑Cyclohexyl‑3‑oxo‑4‑(1‑phenylethyl)‑2,3,4,5
‑tetrahydro‑[1,4] thiazepino[7,6‑b]quinoline‑5‑car‑
boxamide (7d)
White solid, yield: 208 mg (45%), mp 244–246 °C. IR
1
(KBr) (νmax, cm−1): 3337, 2931, 2852, 1635, 1588; H
NMR (500 MHz, DMSO-d6): δH = 0.97–1.08 (m, 1H,
cy), 1.17–1.32 (m, 4H, cy), 1.51 (d, J = 13.2 Hz, 1H, cy),
1.61–1.69 (m, 4H, cy overlapped with a doublet, J=7.1 Hz,
3H, Me), 3.38 (d, J=14.9 Hz, 1H, CHS), 3.62–3.69 (m, 1H,
CH-cy), 4.14 (d, J=14.9 Hz, 1H, CHS), 5.12 (s, 1H, CHN),
5.96 (q, J=7.1 Hz, 1H, CHMe), 6.77 (t, J=7.4 Hz, 1H, Ar),
6.88 (t, J=7.6 Hz, 2H, Ar), 7.11 (d, J=7.6 Hz, 2H, Ar), 7.21
(brs, 1H, Ar), 7.38–7.50 (m, 3H, Ar), 7.61 (t, J = 7.9 Hz,
1H, Ar), 7.70 (d, J=8.3 Hz, 1H, NH); 13C NMR (125 MHz,
acetone-d6): δC = 14.8, 24.9, 25.0, 25.2, 31.9, 32.2, 32.6,
49.6, 51.9, 61.8, 125.3, 125.5, 126.0, 127.0, 127.3, 127.6,
127.7, 127.8, 130.2, 139.7, 140.1, 146.7, 158.1, 168.1,
4‑Benzyl‑N‑(tert‑Butyl)‑3‑oxo‑2,3,4,5‑tetrahy‑
dro‑[1,4]thiazepino[7,6‑b]quinoline‑5‑carboxamide
(7b)
White solid, yield: 248 mg (59%), mp 250–252 °C. IR (KBr)
1
(νmax, cm−1): 3314, 2968, 1642, 1518; 50:50; H NMR
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Journal of the Iranian Chemical Society
168.7; EI-MS m/z (%) : 459 (1, M+), 333 (1), 229 (92), 187
(50), 105 (100). Anal. Calcd for C27H29N3O2S (459.20): C
70.56, H 6.36, N 9.14, S 6.98%. Found: C 70.81, H 6.37, N
9.00, S 6.63%.
1591; H NMR (500 MHz, DMSO-d6): δH = 1.16–1.26
1
(m, 4H, cy), 1.55 (d, J = 12.35 Hz, 1H, cy), 1.61–1.70
(m, 4H, cy), 3.45–3.52 (m, 1H, cy), 3.56–3.65 (m, 1H,
cy), 3.85 (s, 3H, CH3), 4.10 (d, J = 14.5 Hz, 1H, CHS),
4.34 (d, J = 14.5 Hz, 1H, CHS), 4.44 (d, J = 15.1 Hz, 1H,
CHPh), 5.08 (d, J = 15.1 Hz, 1H, CHPh), 5.51 (s, 1H,
CHN), 6.99–7.15 (m, 6H, Ar), 7.31–7.34 (t, J = 2.8 Hz,
1H, Ar), 7.53 (d, J = 8.1 Hz, 1H, Ar), 7.68 (d, J = 9.2 Hz,
1H, Ar), 7.87 (s, 1H, NH);13C NMR (125 MHz, DMSO-
d6): δC = 19.0, 25.2, 25.3, 25.6, 32.1, 32.2, 32.3, 49.2,
56.0, 56.5, 106.1, 123.2, 126.5, 126.8, 127.5, 128.2, 128.5,
128.7, 137.9, 139.0, 142.9, 155.0, 157.2, 168.1, 169.2;
EI-MS m/z (%) 475 (8,M+), 349 (29), 259 (10), 216 (33),
91 (100). Anal. Calcd for C27H29N3O3S (475.19): C 68.19,
H 6.15, N 8.84, S 6.74%. Found: C 68.26, H 6.44, N 7.31,
S 6.34%.
4‑Benzyl‑N‑(tert‑Butyl)‑8‑methyl‑3‑oxo‑2,3,4,5‑tet‑
rahydro‑[1,4] thiazepino[7,6‑b]quinoline‑5‑carbox‑
amide (7e)
White solid, yield: 204 mg (47%), mp 231–233 °C; IR
(KBr) (νmax, cm−1): 3319, 3063, 2959, 2924, 1645, 1589;
1H NMR (500 MHz, DMSO-d6): δH =1.20 (s, 9H, 3CH3),
2.43 (s, 3H, CH3), 3.59 (d, J=14.9 Hz, 1H, CHS), 4.19 (d,
J=14.9 Hz, 1H), 4.64 (d, J=14.8 Hz, 1H, CHPh), 4.89 (d,
J = 14.8 Hz, 1H, CHPh), 5.48 (s, 1H, CHN), 6.76 (s, 1H,
Ar), 7.07 (t, J=7.3 Hz, 1H, Ar), 7.14 (t, J=7.5 Hz, 2H, Ar),
7.27 (d, J=7.4 Hz, 2H, Ar), 7.49–7.53 (m, 2H, Ar), 7.67 (d,
J=8.4 Hz, 1H, Ar), 7.96 (s, 1H, NH); 13C NMR (125 MHz,
DMSO-d6): δC = 21.4, 28.5, 32.2, 51.6, 51.9, 65.8, 125.4,
126.6, 126.8, 127.0, 127.7, 128.5, 128.7, 133.1, 135.9,
138.0, 139.1, 145.3, 157.3, 168.3, 169.2; EI-MS m/z (%)
433 (1, M+), 333 (36), 243 (11), 200 (37), 91(100). Anal.
Calcd for C25H27N3O2S (433.18): C 69.26, H 6.28, N 9.69,
S 7.39%. Found: C 69.57, H 6.75, N 9.64, S 7.16%.
8‑Methoxy‑4‑(4‑methylbenzyl)‑3‑oxo‑N‑(2,4,4‑tri‑
methylpentan‑2‑yl)‑2,3,4,5‑tetrahydro‑[1,4]
thiazepino[7,6‑b]quinoline‑5‑carboxamide (7h)
White solid, yield: 232 mg (46%), mp 193–195 °C. IR (KBr)
(νmax, cm−1): 3312, 2960, 1645, 1589 ; 1H NMR (500 MHz,
DMSO-d6): δH =0.80 (s, 9H, 3CH3), 1.22 (s, 3H, CH3), 1.25
(s, 3H, CH3), 1.35 (d, J=14.7 Hz, 1H, CHCMe3), 1.69 (d,
J=14.7 Hz, 1H, CHCMe3), 2.13 (s, 3H, CH3), 3.54 (brs, 1H,
CHS), 3.86 (s, 3H, CH3), 4.21 (d, J=14.9 Hz, 1H, CHS),
4.62 (d, J=14.6 Hz, 1H, CHPh), 4.77 (d, J=14.6 Hz, 1H,
CHPh), 5.28 (s, 1H, CHN), 6.21 (s, 1H, Ar), 6.21 (s, 1H,
Ar), 7.02 (d, J = 7.7 Hz, 2H, Ar), 7.17 (d, J = 2.8 Hz, 1H,
Ar), 7.24 (d, J = 7.7 Hz, 2H, Ar), 7.33–7.45 (m, 1H, Ar),
7.71 (d, J = 9.2 Hz, 1H, Ar), 7.97 (s, 1H, NH); 13C NMR
(125 MHz, DMSO-d6): δC = 19.0, 21.0, 28.3, 28.9, 31.5,
31.6, 32.2, 51.4, 55.6, 56.0, 56.5, 66.3, 106.0, 123.4, 126.4,
126.5, 128.7, 128.8, 129.6, 134.9, 137.2, 139.0, 142.9,
155.1, 157.4, 167.8, 169.2; EI-MS m/z (%) 519 (1, M+),
363 (28), 259 (19), 217 (18), 105 (100). Anal. Calcd for
C30H37N3O3S (519.26): C 69.33, H 7.18, N 8.09, S 6.17%.
Found: C 69.25, H 7.31, N 7.62, S 6.06%.
4‑Benzyl‑8‑methyl‑3‑oxo‑N‑(2,4,4‑trimethylpen‑
tan‑2‑yl)‑2,3,4,5‑tetrahydro‑[1,4] thiazepino[7,6‑b]
quinoline‑5‑carboxamide (7f)
White solid, Yield: 210 mg (43%), mp 170–172 °C; IR (KBr)
(νmax, cm−1): 3326, 2956, 1645, 1589; 1H NMR (500 MHz,
DMSO-d6): δH =0.82 (s, 9H, 3CH3), 1.25 (s, 3H, CH3), 1.26
(s, 3H, CH3), 1.41 (d, J=14.7 Hz, 1H, CHCMe3), 1.67 (d,
J=14.7 Hz, 1H, CHCMe3), 2.44 (s, 3H, CH3), 3.58 (brs, 1H,
CHS), 4.28 (d, J=14.8 Hz, 1H, CHS), 4.70 (d, J=14.8 Hz,
1H, CHPh), 4.81 (d, J=14.8 Hz, 1H, CHPh), 5.41 (s, 1H,
CHN), 6.44 (s, 1H, Ar), 7.11(t, J=7.3 Hz, 1H, Ar), 7.18(t,
J=7.5 Hz, 2H, Ar), 7.30 (d, J=7.2 Hz, 2H, Ar), 7.50–7.53
(m, 2H, Ar), 7.69 (d, J=9.1 Hz, 1H, Ar), 7.99 (s, 1H, NH);
13C NMR (125 MHz, DMSO-d6): δC =21.5, 28.3, 28.9, 31.5,
31.6, 32.3, 51.5, 55.6, 125.4, 126.3, 126.8, 127.0, 127.8,
128.5, 128.8, 133.3, 136.0, 137.9, 139.2, 145.4, 157.3,
167.8, 169.3; EI-MS m/z (%) 489 (1, M+), 333 (48), 243
(15), 200 (35), 91 (100). Anal. Calcd for C29H35N3O2S
(489.24): C 71.13, H 7.20, N 8.58, S 6.55%. Found: C 71.33,
H 7.54, N 8.45, S 6.41%.
N‑Cyclohexyl‑8‑methoxy‑4‑(4‑methylbenzyl)‑3‑ox
o‑2,3,4,5‑tetrahydro‑[1,4] thiazepino[7,6‑b]quino‑
line‑5‑carboxamide (7i)
White solid, yield: 201 mg (41%), mp 280–283 °C. IR
1
(KBr) (νmax, cm−1): 3326, 2931, 2854, 1646, 1593; H
NMR (500 MHz, DMSO-d6): δH = 1.01–1.09 (m, 1H,
cy), 1.18–1.27 (m, 4H, cy), 1.55 (d, J = 11.6 Hz, 1H, cy),
1.61–1.69 (m, 4H, cy), 2.03 (s, 3H, CH3), 3.42–3.50 (m,
1H, cy), 3.59 (brs, 1H, CHS), 3.86 (s, 3H, CH3), 4.09 (d,
J = 14.4 Hz, 1H, CHS), 4.40 (d, J = 14.6 Hz, 1H, CHPh),
5.02 (d, J=14.6 Hz, 1H, CHPh), 5.43 (s, 1H, CHN), 6.87
(d, J=7.6, 2H, Ar), 7.06–7.10 (m, 3H, Ar), 7.31–7.34 (m,
4‑Benzyl‑N‑cyclohexyl‑8‑methoxy‑3‑oxo‑2,3,4,5‑tet‑
rahydro‑[1,4] thiazepino[7,6‑b]quinoline‑5‑carbox‑
amide (7g)
White solid, yield: 148 mg (31%), mp 218–220 °C; IR
(KBr) (νmax, cm−1): 3327, 3259, 3003, 2923, 2851, 1645,
1 3

Journal of the Iranian Chemical Society
1H, Ar), 7.47 (d, J = 6.6 Hz, 1H, Ar), 7.68 (d, J = 9.2 Hz,
1H, Ar), 7.81 (s, 1H, NH); 13C NMR (125 MHz, acetone-
d6): δC =20.9, 25.2, 25.3, 25.6, 32.1, 32.2, 32.3, 49.1, 52.0,
56.0, 65.8, 106.0, 123.2, 126.5, 126.8, 128.4, 128.7, 129.1,
134.9, 136.7, 139.1, 142.8, 155.0, 157.2, 168.2, 169.0;
EI-MS m/z (%) 489 (9, M+), 363 (30), 259 (15), 217 (24),
105 (100). Anal. Calcd for C28H31N3O3S (489.21): C 68.69,
H 6.38, N 8.58, S 6.55%. Found: C 68.22, H 6.65, N 8.23,
S 6.33%.
(d, J = 14.9 Hz, 1H), 4.19 (d, J = 14.9 Hz, 1H), 4.64 (d,
J = 14.8 Hz, 1H), 4.89 (d, J = 14.8 Hz, 1H), 5.48 (s, 1H)
and 7.96 (s, 1H) due to CHS, CHS, CHPh, CHPh, CHN
and NH, respectively. The 1H-decoupled 13C NMR spec-
trum of 7e showed 21 distinct signals, including char-
acteristic signals at δC 168.3 and 169.2 due to two C=O
group, in agreement with the proposed structure. Unam-
biguous evidence for the proposed structures of 7e was
finally obtained by single crystal X-ray-diffraction analy-
sis (Fig. 1) [34].
The suggested mechanism for the formation of 7a is
shown in Scheme 3. It has been postulated that the Ugi
reaction involved a sequence of imine formation followed
by protonation of the imine I by an acid thus strongly
increasing the electrophilicity of the C=N bond, leading
to intermediate II. Subsequent addition of isocyanide to the
electrophilic iminium cation with concomitant nucleophilic
attack of carboxylate anion on isocyanide affords III. Then,
it undergoes the intramolecular acyl-transfer or Mumm’s
rearrangement to IV and Ugi product V (Scheme 3). The
formation of sulfur bridge in two steps to VI and VII with
subsequent intramolecular SNAr reaction finally affords the
3-oxo-2,3,4,5-tetrahydro-[1,4] thiazepino[7,6-b]quinoline-
5-carboxamide 7a as the desired product.
Results and discussion
Initially, 2-chloroquinoline-3-carbaldehydes 3a–c
were prepared using the previously reported procedure
(Scheme 1) [33]. Subsequently, four-component reac-
tions employing 2-chloroquinoline-3-carbaldehydes
3a–c, amines 4a–d, isocyanides 5a–c, and chloroacetic
acid in methanol at ambient temperature afforded 6a–i
within 24 h (Scheme 2, path 1). Compounds 6a–i with-
out characterizations were used in the second step sim-
ply by removing the solvent under reduced pressure and
resolving in acetone containing an equivalent amount
of thiourea (Scheme 2, path 2). After stirring the mix-
ture at room temperature for 16 h, acetone was removed
under reduced pressure and the residue was hydrolyzed
in ethanolic KOH under reflux condition for 2 h. 3-Oxo-
2,3,4,5-tetrahydro-[1,4]thiazepino[7,6-b]quinoline-
5-carboxamides 7a–i were obtained in satisfactory yields
(Scheme 2, path 3, Table 1). The structures of 7a–i were
Interestingly, whereas reaction of unsubstituted alde-
hyde 3a with aliphatic amines gives the corresponding
products 7a–c in satisfactory yields (entries 1–3, Table 1),
7d–i are produced in lower yields perhaps due to increase
in amine steric effect (entry 4, Table 1) or using substi-
tuted aldehydes 2b and 2c with electron-donating groups
(entries 5–9, Table 1).
1
deduced by elemental analysis, MS, IR, H NMR, and
13C NMR spectroscopy. For example, part of the 1H NMR
Since 7a–i have been generated from apparently four
synthetic Ugi/post-Ugi cyclization processes, obtaining
spectrum of 7e exhibited characteristic signals at δH 3.59
R1
Scheme 1 Preparation of
R1
CHO
Cl
R
O
2-chloroquinoline-3-carbalde-
DMF, POCl3
80 °C
CH3COCl
hydes 3a–c
N
NH2
N
K2CO3, acetone
30 °C
H
1a-c
2a-c
3a-c
O
R3HNOC
R2
R1
R3HNOC
R2
R2 NH2
R1
H
(2)
(3)
N
R1
N
(1)
4a-d
+
O
S
N
Cl
O
KOH, EtOH
NH2
MeOH
CO2H
N
Cl
3a-c
N
S
Cl
H2N
Cl
R3 NC
7a-i
6a-i
5a-c
R1 : H, Me, OMe
Scheme 2 Synthesis of quinoline-fused [1,4]thiazepine derivatives 7a–i
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Journal of the Iranian Chemical Society
Table 1 Results obtained for the synthesis of quinoline-based-[1,4]thiazepines
Yielda
(%)
Entry
Aldehyde
Amine
Isocyanide
Product
O
HN
O
N
H
H
H2N
1
O
52
59
NC
N
Cl
N
S
7a
3a
4a
4b
5a
O
O
HN
Ph
N
H2N
2
O
N
Cl
NC
N
S
3a
5a
7b
O
O
HN
N
Ph
N
H
H2N
3
O
61
45
47
NC
N
Cl
S
3a
4b
5b
7c
O
O
HN
N
Ph
N
H
H2N
4
O
NC
N
Cl
S
3a
4c
4c
5b
7d
O
HN
O
Ph
N
H2N
H
O
5
NC
N
Cl
N
S
5a
3b
7e
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Journal of the Iranian Chemical Society
Table 1 (continued)
Yielda
Entry
Aldehyde
Amine
Isocyanide
Product
(%)
O
HN
O
Ph
N
H
NC
H2N
H2N
H2N
6
O
43
N
Cl
N
S
4b
5c
7f
3b
O
O
HN
O
Ph
H
O
N
7
31
O
N
Cl
NC
NC
N
S
4b
4d
4d
5b
5c
5b
7g
3c
O
HN
O
O
O
N
H
8
46
41
O
N
N
Cl
S
7h
3c
O
HN
N
O
9
O
O
N
H2N
H
NC
O
N
Cl
S
7i
3c
aIsolated yield
overall yields ranging from 31 to 61% (Table 1) reveals
that the described method seems to be successful. As such,
it can be concluded that the reactions have proceeded with
excellent yields in each step.
Conclusion
In conclusion, a number of 3-oxo-2,3,4,5-tetrahydro-[1,4]
thiazepino[7,6-b]quinoline-5-carboxamides 7a–i were
synthesized using a sequential Ugi-4CR followed by three
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Journal of the Iranian Chemical Society
post-Ugi processes of a substitution nucleophilic dis-
placement, an alkaline hydrolysis and an intramolecular
cyclization SNAr reaction. The synthesized products will
be rather difficult to obtain using other methods. Gratify-
ingly, the results indicated in this presentation proves once
more that combining Ugi reaction with other processes
implemented in one-pot tandem sequences is an efficient
strategy for the synthesis of more complex heterocyclic
compounds. These new structures broaden the quinoline-
fused [1,4]thiazepines that are accessible through Ugi/post-
Ugi reactions, and many of them may represent interesting
pharmacophores.
Fig. 1 ORTEP diagram of 7e
O
N
C
Cl
2a
Cl
O
O
N
H
N
O
N
Cl
O
II
N
H
Cl
OH
N
Cl
III
Mumm
rearrangement
N
N
Cl
I
O
N
Cl
O
N
H
N
N
Cl
CHO
O
IV
+
NH2
H
N
Cl
N
3a
1a
O
N
7a
S
H
N
O
O
OH-/H2O
SNAr
-HCl
CO2 + NH4OH
H2N
NH2
N
N
Cl
O
H
N
V
O
Cl
S
SN2
N
H
N
H2N
NH2
O
N
Cl
O
VII
NH2
S
N
NH
O
H
N
Cl
O
NH2
VI
S
NH2
Cl
Scheme 3 Proposed mechanism for the formation of 9a
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Journal of the Iranian Chemical Society
Acknowledgements The authors acknowledge the University of Tehran
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for financial support of this research.
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20. X.H.T. Wehrens, S.E. Lehnart, S.R. Reiken, S.-X. Deng, J.A. Vest,
D. Cervantes, J. Coromilas, D.W. Landry, A.R. Marks, Science
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