Synthesis of novel hexahydroquinolines and 6-amino-2-oxopyridine-3,5-dicarbonitriles incorporating sulfamethoxazole via [3?+?3] annulation

Article abstract of DOI:10.1002/jhet.3737

Cyclic enaminone and cyanoacetamide derivative with incorporated sulfamethoxazole moiety were prepared. Their reactions with arylidenemalononitrile derivatives in ethanol or pyridine/piperidine at reflux yielded the corresponding hexahydroquinoline and 6-amino-2-oxopyridine-3,5-dicarbonitrile derivatives incorporating sulfamethoxazole. The mechanism and structural elucidation of products were discussed.

Full text of DOI:10.1002/jhet.3737

Received: 11 May 2019
DOI: 10.1002/jhet.3737
Revised: 13 August 2019
Accepted: 27 August 2019
A R T I C L E
Synthesis of novel hexahydroquinolines and 6‐amino‐2‐
oxopyridine‐3,5‐dicarbonitriles incorporating
sulfamethoxazole via [3 + 3] annulation
Amr M. Abdelmoniem
| Mohamed Gamal Mohamed Abdelrahman |
Said Ahmed Soliman Ghozlan | Ismail A. Abdelhamid
Department of Chemistry, Faculty of
Abstract
Science, Cairo University, Giza, Egypt
Cyclic enaminone and cyanoacetamide derivative with incorporated sulfa-
Correspondence
methoxazole moiety were prepared. Their reactions with arylidenema-
lononitrile derivatives in ethanol or pyridine/piperidine at reflux yielded the
Ismail A. Abdelhamid, Department of
Chemistry, Faculty of Science, Cairo
University, PO 12613 Giza, Egypt.
Email: ismail_shafy@yahoo.com
corresponding
hexahydroquinoline
and
6‐amino‐2‐oxopyridine‐3,5‐
dicarbonitrile derivatives incorporating sulfamethoxazole. The mechanism
and structural elucidation of products were discussed.
1 | INTRODUCTION
as well as one of the most common therapeutic agents for
the treatment of cardiovascular diseases, including
Sulfamethoxazole is a chemotherapeutic drug that exhibits
a wide range of pharmacological and biological activities
that include antimicrobial[1–5] and anticancer agents.[6,7]
Also, it is used in the treatment of urinary tract infec-
tions.[1,8] In addition, pyridine derivatives have attracted
a particular interest over the past years due to their various
biological activities, including antiviral,[9] antihista-
hypertension.[29,30]
2 | RESULTS AND DISCUSSION
In continuation to our interest in the C─C bond forma-
tion reactions,[31–45] the possibility of [3 + 3] atom combi-
nation reaction of the cyclic enamine incorporating
sulfamethoxazole with α,β‐unsaturated nitriles through
Michael addition reaction was studied. First, the cyclic
enamine 3 was prepared via the reaction of dimedone 1
with sulfamethoxazole 2 according to the procedure
reported in the literature by us[33–35,44–46] and by
others[47] (Scheme 1). The Michael addition reaction of
the cyclic enamine 3 with arylidenemalononitriles 4a‐e
was then investigated. In principle, for this type of reac-
tion, there are two possible isomeric structures for the
product. The product is either 4‐aminohexahy-
droquinoline‐3‐carbonitrile 6 that results from initial
addition of NH to the activated double bond in com-
pound 4 to give 5 that readily cyclizes to 6 (pathway A)
minic,[10]
antihypertensive,[11]
anti‐inflammatory
agents,[12] and antitumors.[13] Furthermore, quinolines
are unique fused six‐membered heterogeneous pharmaco-
logical compounds that offered a wide range of activities
such as antibacterial, antitumor, anti‐inflammatory, anti‐
asthmatic, antimalarial, antituberculosis, and antihyper-
tensive properties.[14–19] On the other hand, due to the
excellent mechanical characteristics of quinolines, they
have found significant use in electronics, optoelectronics,
and polymer chemistry.[20,21] Self‐hierarchical assembly
of quinoline copolymers into meso‐ and nano‐structures
enhanced greatly their photonic and electronic features.[22]
Hexahydroquinolines exhibited potent and promising
cytotoxic, antibacterial, myorelaxant, calcium channel
modulatory, and neuroprotective activities.[23–28] 1,4‐
Dihydropridines have emerged as important derivatives
that selectively prohibit L‐type calcium channels and act
or 2‐aminohexahydroquinoline‐3‐carbonitrile
8
that
results from the initial addition of enamine CH to the
activated double bond in compound 4 to yield 7 that
J Heterocyclic Chem. 2019;1–9.
wileyonlinelibrary.com/journal/jhet
© 2019 Wiley Periodicals, Inc.
1

2
ABDELMONIEM ET AL.
SCHEME 1 Synthesis of cyclic enamine
incorporating sulfamethoxazole 3.
SCHEME 2 The Michael addition reaction of the cyclic enamine 3 with arylidenemalononitriles 4a‐e.
readily cyclizes to 8 (pathway B) (Scheme 2). Although
the 1H and 13C‐NMR cannot simply differentiate between
the two isomers, we indubitably solved this problem and
assumed that compound 8 to be the correct structure
based on previous chemical elucidation[33,44,45] and
heteronuclear multiple bond correlation (HMBC) spectral
analysis[35] of some related compounds. In addition, we
managed to confirm the structure through HMBC spec-
trum of compound 8c. The HMBC spectrum revealed
cross‐correlation peaks between quinoline H4 at δ
4.41 ppm and carbonyl group at δ 195.3 ppm which is
copatible with the proposed structure (Figure 1). The
mass spectrum of 8c showed a molecular ion peak at
m/z 543 [M+]. The IR spectrum revealed broad absorp-
tion bands at νmax 3399, 3324, and 3223 cm−1 for the
NH and NH2 groups. In addition, it indicated a character-
istic band at νmax 2183 cm−1 for the cyano group and a
strong stretching band at νmax 1648 cm−1 for the carbonyl
group. The 1H NMR displayed a singlet at δ 4.41 ppm for
isoxazole‐H4. It also featured a singlet at δ 5.28 ppm for
the amino group. The aromatic protons appeared as
multiplets at δ 7.13 to 7.14 ppm. The broad signal at δ
8.49 ppm was assigned to the NH group.
It is worth mentioning that the delocalization of nitro-
gen lone pair in enamine 3 develops a negative charge on
the β‐carbon (intermediate 3(II)). Michael addition reac-
tion of 3(II) to the delocalized double bond in arylidene
derivatives 4 in the presence of a basic catalyst (acts as
a carrier for the labile hydrogen) leads to the formation
of the Michael adduct 9. Intermediate 9 abstracts the pro-
ton again from the catalyst, leading to the formation of
the intermediate 10 which tautomerizes into 7. Nucleo-
philic addition of NH to the cyano group affords the
cyclic intermediate 11. Which tautomerizes into com-
pound 8 (Scheme 3).
In an extension to this work, the 2‐cyanoacetamide
incorporating sulfamethoxazole group 13 was chosen as a
key starting material in Michael addition reaction for syn-
thesis of a variety of novel cyanopyridone derivatives. It is
quinoline‐H4 and
a singlet at δ 5.86 ppm for

ABDELMONIEM ET AL.
3
FIGURE 1 The heteronuclear multiple bond correlation (HMBC) spectrum of compound 8c [Color figure can be viewed at
wileyonlinelibrary.com]
SCHEME 3 A plausible mechanism of the reaction of enamine 3 with arylidenemalononitriile derivatives 4.

4
ABDELMONIEM ET AL.
prepared via the cyanoacylation of the sulfamethoxazole
bands at νmax 3366, 3315, and 3208 cm−1 for the NH and
NH2 groups. It showed characteristic bands at νmax 2215
and 1634 cm−1 for the cyano and carbonyl groups, respec-
2
with 3‐(3,5‐dimethyl‐1H‐pyrazol‐1‐yl)‐3‐oxopropane-
nitrile 12 in toluene at reflux according to our recently
reported procedure[48,49] (Scheme 4). The Michael addition
reaction of 2‐cyanoacetamide 13 with unsaturated nitriles
4 was then explored. Thus, the reaction of compound 13
with arylidenemalononitriles 4a‐f can generally lead to
the formation of either 4‐aminopyridine‐3,5‐dicarbonitrile
15 (pathway A) or its isomeric structure 6‐aminopyridine‐
3,5‐dicarbonitrile 17 (pathway B) through the intermedi-
acy of 14 or 16, respectively (Scheme 5). The constitution
of pyridine derivatives 17 was unambiguously confirmed
through careful comparison with spectral data of some
similar reported structures.[49–51] For instance, the mass
spectrum of compound 17c displayed a molecular ion peak
at m/z 486. The IR spectrum exhibited three absorption
1
tively. Moreover, the H NMR spectrum of 17c indicated
the signals of aromatic protons at δ 7.37 to 8.06 ppm,
together with a broad peak centered at δ 8.04 ppm for the
amino group. Additionally, it featured a broad singlet for
the NH at δ 11.65 ppm.
It is also noteworthy that the reaction of aldehyde 18
with cyanoacetamide 13 afforded the cyanoacrylamide
19. The subsequent reaction with malononitrile 20
resulted in the formation of the target product 17. In sup-
port of this viewpoint, we managed to isolate the
Knoevenagel condensation in some cases 19a,b[51] and
were found in agreement with the reported literature
(Scheme 6).
SCHEME 4 Synthesis of 2‐cyanoacetamide incorporating sulfamethoxazole group 13.
SCHEME 5 The Michael addition reaction of 2‐cyanoacetamide 13 with unsaturated nitriles 4.
SCHEME 6 An alternative synthesis of 17 employing Knoevenagel adducts 19a‐f and malononitrile 20

ABDELMONIEM ET AL.
5
2 mmol) for 3 hours. The excess solvent was evaporated
under reduced pressure and the collected crude product
was purified by crystallization from EtOH/dioxane
(5 mL, 3:1, v/v).
3 | CONCLUSIONS
Cyclic enaminones and 2‐cyanoacetamide were used as
versatile precursors for the synthesis of a novel series of
the respective hexahydroquinoline and 6‐amino‐2‐
oxopyridine‐3,5‐dicarbonitrile derivatives incorporating
sulfamethoxazole derivatives.
4.3 | 4‐(2‐Amino‐3‐cyano‐7,7‐dimethyl‐5‐
oxo‐4‐phenyl‐5,6,7,8‐tetrahydroquinolin‐
1(4H)‐yl)‐N‐(5‐methylisoxazol‐3‐yl)
benzenesulfonamide (8a)
4 | EXPERIMENTAL
Melting points were measured with a Stuart melting
point apparatus and are uncorrected. The IR spectra
were recorded using a Fourier‐transform infrared (FTIR)
Bruker‐vector 22 spectrophotometer as KBr pellets. The
1H and 13C NMR spectra were recorded in DMSO–d6
as solvent on Varian Gemini NMR spectrometer at 300
and 75 MHz, respectively, using tetramethylsilane
(TMS) as internal standard. Chemical shifts are reported
as δ values in ppm. Mass spectra were recorded with a
Shimadzu GCMS‐QP 1000 EX mass spectrometer in
EI (70 eV) model. The elemental analyses were
performed at the Micro Analytical Center, Cairo
University.
Off‐white crystals (344 mg, 65%). Mp 117°C to 120°C. IR
(KBr): νmax/cm−1 3401, 3330, 3226 (NH and NH2), 2183
(C≡N), 1649 (CO), 1374, 1134 (SO2). 1H NMR
(400 MHz, DMSO‐d6): δ/ppm 0.73 (s, 3H, CH3), 0.88 (s,
3H, CH3), 1.64 to 1.70 (m, 2H, CH2), 1.97 to 2.21 (m,
2H, CH2), 2.17 (s, 3H, isoxazole‐CH3), 4.45 (s, 1H,
quinoline‐H4), 5.92 (s, 1H, isoxazole‐H), 6.55 (s, 2H,
NH2), 7.21 to 7.88 (m, 9H, ArH), 8.41 (br, 1H, NH). MS
(EI, 70 eV): m/z 529 [M]+. Anal. Calcd. for C28H27N5O4S:
C, 63.50; H, 5.14; N, 13.22. Found: C, 63.14; H, 5.38;
N, 12.95.
4.4 | 4‐(2‐Amino‐4‐(4‐chlorophenyl)‐3‐
cyano‐7,7‐dimethyl‐5‐oxo‐5,6,7,8‐
tetrahydroquinolin‐1(4H)‐yl)‐N‐(5‐
methylisoxazol‐3‐yl)benzenesulfonamide
(8b)
4.1 | 4‐((5,5‐Dimethyl‐3‐oxocyclohex‐1‐en‐
1‐yl)amino)‐N‐(5‐methylisoxazol‐3‐yl)
benzenesulfonamide (3)
A mixture of dimedone 1 (1000 mg, 7.13 mmol) and
sulfamethaxazole 2 (1804 mg, 7.13 mmol) and trichloro-
acetic acid (250 mg, 153 mmol) was heated in an oil bath
at 140°C for 15 minutes. The crude product was isolated
and then purified by crystallization from ethanol (15 mL)
to yield the pure compound 3 as orange crystals (338 mg,
90%). Mp 118°C to 120°C. IR (KBr): νmax/cm−1 3333,
3379, (2NH), 1523 (CO), 1405, 1161 (SO2). 1H NMR
(DMSO‐d6): δ/ppm 1.02 (s, 6H, 2CH3), 2.10 (s, 2H,
CH2), 2.30 (s, 3H, isoxazole‐CH3), 2.40 (s, 2H, CH2),
5.55 (s, 1H, isoxazole‐H), 6.12 (s, 1H, enamine‐CH),
7.33–7.36 (d, J = 8.8 Hz, 2H, ArH), 7.78–7.82 (d,
J = 8.8 Hz, 2H, ArH), 9.09 (s, 1H, NH), 11.35 (br, 1H,
NH). MS (EI, 70 eV): m/z 375 [M]+. Anal. Calcd. for
C18H21N3O4S: C, 57.58; H, 5.64; N, 11.19. Found: C,
57.84; H, 5.45; N, 11.51.
Off‐white crystals (394 mg, 70%). Mp 238°C to 242°C; IR
(KBr): νmax/cm−1 3398, 3322, 3222 (NH and NH2), 2183
(C≡N), 1648 (CO), 1375, 1131 (SO2). H NMR (DMSO‐
1
d6): δ/ppm 0.72 (s, 3H, CH3), 0.88 (s, 3H, CH3), 1.55 to
1.63 (m, 2H, CH2), 2.02 to 2.20 (m, 2H, CH2), 2.14 (s,
3H, isoxazole‐CH3), 4.46 (s, H, quinoline‐H4), 5.38 (s,
2H, NH2), 5.87 (s, 1H, isoxazole‐H), 7.27 to 7.85 (m,
8H, ArH), 8.61 (br, 1H, NH). MS (EI, 70 eV): m/z 563
[M]+. Anal. Calcd. for C28H26ClN5O4S: C, 59.62; H,
4.65; Cl, 6.28; N, 12.42. Found: C, 59.41; H, 4.80; Cl,
6.64; N, 12.15.
4.5 | 4‐(2‐Amino‐3‐cyano‐7,7‐dimethyl‐5‐
oxo‐4‐(p‐tolyl)‐5,6,7,8‐tetrahydroquinolin‐
1(4H)‐yl)‐N‐(5‐methylisoxazol‐3‐yl)
benzenesulfonamide (8c)
Pale yellow crystals (380 mg, 70%). Mp 237°C to 239°C. IR
4.2 | General procedure for synthesis of
compounds (8a‐e)
(KBr): νmax/cm−1 3399, 3324, 3223 (NH and NH2), 2183
1
(C≡N), 1648 (CO), 1375, 1131 (SO2). H NMR (DMSO‐
A mixture of β‐enaminone 3 (375 mg, 1 mmol) and
arylidene malononitrile 4a‐e (1 mmol) was heated at
reflux in ethanol (20 mL) containing piperidine (0.2 mL,
d6): δ/ppm 0.73 (s, 3H, CH3), 0.88 (s, 3H, CH3), 1.56 to
1.65 (m, 2H, CH2), 2.00 to 2.20 (s, 2H, CH2), 2.14 (s, 3H,
isoxazole‐CH3), 2.26 (s, 3H, p‐tolyl‐CH3), 4.41 (s, H,

6
ABDELMONIEM ET AL.
quinoline‐H4), 5.28 (s, 2H, NH2), 5.86 (s, 1H, isoxazole‐H),
7.13 to 7.14 (m, 4H, ArH), 7.35 to 7.37 (d, J = 8.8 Hz, 2H,
ArH), 7.82–7.85 (d, J = 8.8 Hz, 2H, ArH), 8.49 (br, 1H,
NH). 13C NMR (100 MHz, DMSO‐d6): δ 12.7, 21.1, 22.7,
26.7, 29.4, 32.4, 36.3, 49.8, 61.4, 97.4, 112.6, 121.9, 127.1,
127.9, 129.4, 130.3, 135.7, 137.5, 143.9, 148.8, 150.3, 151.5,
166.2, 166.7, 195.3. MS (EI, 70 eV): m/z 543 [M]+. Anal.
Calcd. for C29H29N5O4S: C, 64.07; H, 5.38; N, 12.88. Found:
C, 63.84; H, 5.52; N, 12.65.
4.8 | 2‐Cyano‐N‐(4‐{[(5‐methylisoxazol‐3‐
yl)amino]sulfonyl}phenyl)acetamide (13)
A mixture of sulphamethaxazole (2533 mg, 10 mmol) 2
and 3‐(3,5‐dimethyl‐1H‐pyrazol‐1‐yl)‐3‐oxopropanenitrile
12 (1630 mg, 10 mmol) in dry toluene (20 mL) was
heated at reflux for 3 hours. The crude isolated product
was purified by crystallization with ethanol (10 ml) to
give white crystals (2880 mg, 90%). Mp 216°C to
218°C. IR (KBr): νmax/cm−1 3331, 3279 (2NH), 2264
(C≡N), 1690 (C=O), 1397, 1167 (SO2). 1H NMR
(400 MHz, DMSO‐d6): δ/ppm 2.30 (s, 3H, CH3), 3.96
(s, 2H, CH2), 6.13 (s, 1H, isoxazole‐CH), 7.73 to 7.75
(d, J = 8.8 Hz, 2H, ArH), 7.82 to 7.85 (d, J = 8.8 Hz,
2H, ArH), 10.71 (s, 1H, CONH), 11.37 (br, 1H, SO2NH).
13C NMR (100 MHz, DMSO‐d6): δ/ppm 12.5, 27.5, 95.9,
116.1, 119.6, 128.7, 134.4, 143.1, 158.0, 162.5, 170.9. MS
(EI, 70 eV): 320 [M+], Anal. Calcd. for C13H12N4O4S:
C, 48.75; H, 3.78; N, 17.49. Found C, 48.46; H, 3.53;
N, 17.28;
4.6 | 4‐(2‐Amino‐3‐cyano‐4‐(4‐
methoxyphenyl)‐7,7‐dimethyl‐5‐oxo‐5,6,7,8‐
tetrahydroquinolin‐1(4H)‐yl)‐N‐(5‐
methylisoxazol‐3‐yl)benzenesulfonamide
(8d)
Yellow crystals (447 mg, 80%). Mp 228°C to 230°C. IR
(KBr): νmax/cm−1 3405, 3331, (NH and NH2), 2182
1
(C≡N), 1650 (CO), 1378, 1129 (SO2). H NMR (DMSO‐
d6): δ/ppm 0.73 (s, 3H, CH3), 0.88 (s, 3H, CH3), 1.50 to
1.64 (m, 2H, CH2), 1.98 to 2.21 (m, 2H, CH2), 2.14 (s,
3H, isoxazole‐CH3), 3.73 (s, 3H, OCH3), 4.4 (s, H,
quinoline‐H), 5.28 (s, 2H, NH2), 5.87 (s, 1H,
isoxazole‐H), 6.86 to 6.89 (d, J = 8.8 Hz, 2H, ArH), 7.16
to 7.19 (d, J = 8.8 Hz, 2H, ArH), 7.35 to 7.38 (d,
J = 8.8 Hz, 2H, ArH), 7.82 to 7.85 (d, J = 8.8 Hz, 2H,
ArH), 8.72 (br, 1H, NH). MS (EI, 70 eV): m/z 559 [M]+.
Anal. Calcd. for C29H29N5O5S: C, 62.24; H, 5.22; N,
12.51. Found: C, 61.92; H, 5.51; N, 12.83.
4.9 | General procedure for the synthesis
of compounds (17a‐f)
Equimolar amounts of 13 (320 mg, 1 mmol) and the
appropriate arylidene malononitrile 4 (1 mmol) was dis-
solved in pyridine (5 mL). Piperidine (0.2 mL, 2 mmol)
was added and the reaction mixture was heated at reflux
for 3 hours. Then the resulting solution was poured
onto ice‐cold HCl (10 N, 30 mL). The crude isolated
product was crystallized from EtOH/dioxane (5 mL,
1:1, v/v).
4.7 | 4‐(2‐Amino‐4‐(benzo[d][1,3]dioxol‐5‐
yl)‐3‐cyano‐7,7‐dimethyl‐5‐oxo‐5,6,7,8‐
tetrahydroquinolin‐1(4H)‐yl)‐N‐(5‐
methylisoxazol‐3‐yl)benzenesulfonamide
(8e)
4.10 | 4‐(6‐Amino‐3,5‐dicyano‐2‐oxo‐4‐
phenylpyridin‐1(2H)‐yl)‐N‐(5‐
methylisoxazol‐3‐yl)benzenesulfonamide
(17a)
Off‐white crystals (459 mg, 80%). Mp 234°C to 236°C. IR
(KBr): νmax/cm−1 3391, 3322, 3217 (NH and NH2), 2183
1
(C≡N), 1649 (CO), 1383, 1134 (SO2). H NMR (DMSO‐
Gray crystals (330 mg, 70%). Mp. > 300°C. IR (KBr): νmax/
d6): δ/ppm 0.75 (s, 3H, CH3), 0.88 (s, 3H, CH3), 1.59 to
1.63 (m, 2H, CH2), 1.99 to 2.19 (m, 2H, CH2), 2.14 (s,
3H, isoxazole‐CH3), 4.39 (s, 1H, quinoline‐H4), 5.30 (s,
2H, NH2), 5.86 (s, 2H, OCH2O), 5.98 (s, H,
isoxazole‐H), 6.72 to 6.75 (d, J = 8.8 Hz, 2H, ArH), 6.76
(s, 1H, ArH), 6.83 to 6.85 (d, J = 8.8 Hz, 1H, ArH), 7.33
to 7.36 (d, J = 8.8 Hz, 2H, ArH), 7.82 to 7.85 (d,
J = 8.8 Hz, 2H, ArH), 8.57 (br, 1H, NH). MS (EI,
70 eV): m/z 573 [M]+. Anal. Calcd. for C29H27N5O6S: C,
60.79; H, 4.74; N, 12.21. Found: C, 61.04; H, 4.37;
N, 12.45.
cm−1 3363, 3317, 3213 (NH and NH2), 2219 (C≡N), 1631
(CO), 1408, 1169 (SO2). 1H NMR (400 MHz, DMSO‐d6): δ/
ppm 2.34 (s, 3H, CH3), 6.25 (s, 1H, CH), 7.53 (s, 2H, NH2),
7.55 to 7.60 (m, 5H, ArH), 7.67 to 7.69 (d, J = 8.8 Hz, 2H,
ArH), 8.05 to 8.07 (br d, J = 8.8 Hz, 4H, ArH and NH2),
11.66 (br, 1H, NH). 13C NMR (100 MHz, DMSO‐d6): δ
12.6, 76.0, 95.9, 116.1, 116.6, 128.4, 129.2, 129.35, 130.63,
130.87, 135.1, 138.68, 141.52, 157.39, 157.87, 159.89,
162.05, 170.94. MS (EI, 70 eV): 472.1 [M+]. Anal. Calcd.
for C23H16N6O4S: C, 58.47; H, 3.41; N, 17.79. Found: C,
58.68; H, 3.53; N, 17.54.

ABDELMONIEM ET AL.
7
8.07 (br d, J = 8.8 Hz, 4H, ArH and NH2), 11.65 (br,
1H, NH). 13C NMR (100 MHz, DMSO‐d6): δ/ppm 12.6,
55.8, 76.0, 95.9, 114.5, 116.4, 116.9, 127.0, 129.3, 130.3,
130.6, 138.7, 141.5, 157.4, 157.8, 160.0, 161.3, 161.7,
171.0. MS (EI, 70 eV): 502 [M+], Anal. Calcd. for
C24H18N6O5S: C, 57.37; H, 3.61; N, 16.72. Found: C,
57.11; H, 3.83; N, 16.43.
4.11 | 4‐(6‐Amino‐4‐(4‐chlorophenyl)‐3,5‐
dicyano‐2‐oxopyridin‐1(2H)‐yl)‐N‐(5‐
methylisoxazol‐3‐yl)benzenesulfonamide
(17b)
Yellow crystals (405 mg, 80%). Mp 291°C to 293°C. IR
(KBr): νmax/cm−1 3330, 3317, 3204 (NH and NH2), 2219
1
(C≡N), 1637 (CO), 1408, 1169 (SO2). H NMR (400 MHz,
DMSO‐d6): δ/ppm 2.34 (s, 3H, CH3), 6.24 (s, 1H, CH),
7.57 to 7.59 (d, J = 8.8 Hz, 2H, ArH), 7.65 to 7.67 (d,
J = 8.8 Hz, 2H, ArH), 7.67 to 7.69 (d, J = 8.8 Hz, 2H,
ArH), 8.06 (d, J = 8.8 Hz, 2H, ArH), 8.05 to 8.07 (d, 2H,
ArH), 8.14 (br, 2H, NH2), 11.66 (br, 1H, NH). 13C NMR
(100 MHz, DMSO‐d6): δ/ppm 12.6, 76.0, 95.9, 116.0,
116.5, 129.4, 129.5, 130.4, 130.6, 133.9, 135.7, 138.6,
141.5, 157.4, 157.8, 159.8, 160.9, 171.0. MS (EI, 70 eV):
506 [M+], Anal. Calcd. for C23H15ClN6O4S: C, 54.50; H,
2.98; Cl, 6.99; N, 16.58. Found: C, 54.75; H, 3.20; Cl,
6.72; N, 16.39.
4.14 | 4‐(6‐Amino‐4‐(benzo[d][1,3]dioxol‐5‐
yl)‐3,5‐dicyano‐2‐oxopyridin‐1(2H)‐yl)‐N‐(5‐
methylisoxazol‐3‐yl)benzenesulfonamide
(17e)
Yellow crystals (413 mg, 80%). Mp > 300°C. IR (KBr):
ν
max/cm−1 3363, 3315, 3206 (NH and NH2), 2219 (C≡N),
1628 (CO), 1339, 1169 (SO2). 1H NMR (400 MHz,
DMSO‐d6): δ/ppm 2.33 (s, 3H, CH3), 6.16 (s, 1H, CH),
6.22 (s, 2H, OCH2O), 7.02 to 7.13 (m, 3H, ArH), 7.63 to
7.66 (d, J = 8.8 Hz, 1H, ArH), 8.05 (br d, J = 8.8 Hz,
4H, ArH and NH2), 11.62 (s, 1H, NH). 13C NMR
(100 MHz, DMSO‐d6): δ/ppm 12.1, 75.4, 95.5, 101.9,
108.5, 115.2, 115.7, 120.8, 122.6, 124.0, 128.0, 129.7,
138.0, 138.2, 148.6, 149.0, 156.9, 157.4, 159.2, 159.6,
170.5. MS (EI, 70 eV): 516 [M+]. Anal. Calcd. for
C24H16N6O6S: C, 55.81; H, 3.12; N, 16.27. Found: C,
55.57; H, 3.37; N, 16.56.
4.12 | 4‐(6‐Amino‐3,5‐dicyano‐2‐oxo‐4‐(p‐
tolyl)pyridin‐1(2H)‐yl)‐N‐(5‐
methylisoxazol‐3‐yl)benzenesulfonamide
(17c)
Pale yellow crystals (413.2 mg, 85%). Mp > 300°C. IR
(KBr): νmax/cm−1 3366, 3315, 3208 (NH and NH2),
2215 (C≡N), 1634 (CO), 1343, 1167 (SO2). 1H NMR
(400 MHz, DMSO‐d6): δ/ppm 2.33 (s, 3H, isoxazole‐
CH3), 2.41 (s, 3H, p‐tolyl‐CH3), 6.23 (s, 1H, CH), 7.37
to 7.45 (m, 4H, J = 8.8 Hz, ArH), 7.65 to 7.68 (d,
J = 8.8 Hz, 2H, ArH), 8.03 to 8.06 (br d, J = 8.8 Hz,
4H, ArH and NH2), 11.65 (br, 1H, NH). 13C NMR
(100 MHz, DMSO‐d6): δ/ppm 12.1, 21.0, 75.5, 95.5,
115.7, 116.3, 127.9, 128.9, 129.2, 130.2, 131.7, 138.2,
140.3, 141.1, 156.9, 157.4, 159.5, 161.6, 170.5. MS (EI,
70 eV): 486 [M+], Anal. Calcd. for C24H18N6O4S: C,
59.25; H, 3.73; N, 17.27. Found: C, 58.98; H, 3.48;
N, 17.56.
4.15 | 4‐(6‐Amino‐3,5‐dicyano‐4‐(4‐
nitrophenyl)‐2‐oxopyridin‐1(2H)‐yl)‐N‐(5‐
methylisoxazol‐3‐yl)benzenesulfonamide
(17f)
Brown crystals (362 mg, 70%). Mp > 300°C. IR (KBr):
ν
max/cm−1 3430, 3363, 3317 (NH and NH2), 2220 (C≡N),
1642 (CO), 1348, 1173 (SO2). 1H NMR (400 MHz,
DMSO‐d6): δ/ppm 2.33 (s, 3H, CH3), 6.23 (s, 1H, CH),
7.64 to 7.67 (d, J = 8.8 Hz, 2H, ArH), 7.83 to 7.85 (d,
J = 8.8 Hz, 2H, ArH), 8.05 to 8.08 (d, J = 8.8 Hz, 2H,
ArH), 8.22 (br., 2H, NH2), 8.42 to 8.45 (d, J = 8.8 Hz,
2H, ArH), 11.61 (s, 1H, NH). 13C NMR (100 MHz,
DMSO‐d6): δ/ppm 12.1, 75.4, 95.5, 115.1, 115.7, 123.9,
129.0, 129.6, 130.0, 138.0, 140.9, 141.2, 148.6, 156.9,
157.3, 159.1, 159.6, 170.4. MS (EI, 70 ev): 517 [M+]. Anal.
Calcd. for C23H15N7O8S: C, 53.38; H, 2.92; N, 18.95.
Found: C, 53.09; H, 2.59; N, 19.16.
4.13 | 4‐(6‐Amino‐3,5‐dicyano‐4‐(4‐
methoxyphenyl)‐2‐oxopyridin‐1(2H)‐yl)‐N‐
(5‐methylisoxazol‐3‐yl)benzenesulfonamide
(17d)
Light yellow crystals (376.5 mg, 75%). Mp 285°C to
287°C. IR (KBr): νmax/cm−1 3400, 3317, 3315 (NH and
NH2), 2213 (C≡N), 1606 (CO), 1410, 1174 (SO2). 1H
NMR (400 MHz, DMSO‐d6): δ/ppm 2.34 (s, 3H, CH3),
3.87 (S, 3H, OCH3), 6.25 (s, 1H, CH), 7.13 to 7.15 (d,
J = 8.8 Hz, 2H, ArH), 7.51 to 7.53 (d, J = 8.8 Hz, 2H,
ArH), 7.66 to 7.68 (d, J = 8.8 Hz, 2H, ArH), 8.04 to
ACKNOWLEDGMENTS
Ismail A. Abdelhamid and Amr M. Abdelmoniem
acknowledge Alexander von Humboldt foundation for
research fellowships.

8
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How to cite this article: Abdelmoniem AM,
Abdelrahman MGM, Ghozlan SAS, Abdelhamid
IA. Synthesis of novel hexahydroquinolines and 6‐
amino‐2‐oxopyridine‐3,5‐dicarbonitriles
incorporating sulfamethoxazole via [3 + 3]
annulation. J Heterocyclic Chem. 2019;1–9. https://
doi.org/10.1002/jhet.3737
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M. Elwahy, J. Heterocyclic Chem. 2017, 54, 2670.
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SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of the
article.