Regioorientation in the Addition Reaction of α-Substituted Cinnamonitrile to Enamines Utilizing Chitosan as a Green Catalyst: Unambiguous Structural Characterization Using 2D-HMBC NMR Spectroscopy

Article abstract of DOI:10.1002/jhet.2341

Hexahydroquinolines and their fused derivatives are obtained in good to excellent yields by proceeding through a simple, mild, and efficient procedure including the reaction of enamines with substituted cinnamonitriles using DABCO, piperidine, or chitosan

Full text of DOI:10.1002/jhet.2341

May 2016
Regioorientation in the Addition Reaction of α-Substituted Cinnamonitrile
to Enamines Utilizing Chitosan as a Green Catalyst: Unambiguous
Structural Characterization Using 2D-HMBC NMR Spectroscopy
817
Said A. S. Ghozlan,a Ahmed Gamal Ahmed,a and Ismail Abdelshafy Abdelhamida,b
*
aDepartment of Chemistry, Faculty of Science, Cairo University, 12613 Giza, A. R., Egypt
bInstitut für Organische Chemie, Leibniz Universität Hannover, Schneiderberg 1B, D-30167 Hannover, Germany
*
E-mail: ismail_shafy@yahoo.com; ismail.abdelhamid@oci.uni-hannover.de
Received June 17, 2014
DOI 10.1002/jhet.2341
Published online 11 June 2015 in Wiley Online Library (wileyonlinelibrary.com).
Hexahydroquinolines and their fused derivatives are obtained in good to excellent yields by proceeding
through a simple, mild, and efficient procedure including the reaction of enamines with substituted
cinnamonitriles using DABCO, piperidine, or chitosan as catalysts. The regioorientation of Michael addition
was established with no doubt using the 2D-HMBC spectroscopy.
J. Heterocyclic Chem., 53, 817 (2016).
INTRODUCTION
RESULTS AND DISCUSSIONS
Enamines are versatile reagents, and the nucleophilic
character of C-2 has found extensive applications in
synthetic organic chemistry [1,2]. Also, it is known that
quinoline derivatives are an important class of heterocycles
of considerable interest, which have been the subject of
extensive research, particularly in the pharmaceutical field,
including antibacterial [3–5] and anticancer [6–12]
activities, so their synthesis and applications have been
comprehensively reviewed [3–7]. Despite the biological
importance of quinolones and their fused derivatives, stud-
ies on their synthesis are rather limited, which include two-
[8a,b], three- [8c], and four-component reactions [8d,e].
This contribution describes the full details of our investiga-
tion on the synthesis of hexahydroquinolines and their
fused derivatives through the two-component reactions of
the cyclic enaminones with the arylidenemalononitrile
derivatives.
Although the synthesis of biologically interesting
hexahydroquinoline derivatives has been investigated in
the past [13–20], there is still demand for more concise
and efficient elucidation of molecular structure especially
using 2D-NMR spectroscopy. In conjunction of this work,
we report here the results of our investigations aimed at ex-
ploring synthetic potentials of the functionally substituted
enamines 1, 7, 11, 14, and 17, which were prepared ac-
cording to the procedure originally reported by Karimi-
Jaberi et al. [21]. Thus, the Michael addition reaction of
the cyclic enaminone 1 toward α,β-unsaturated nitriles
was investigated. The reaction of the cyclic enaminone 1
with arylidenemalononitriles 2a–d affords products for
which several isomeric structures seemed possible. The
reaction product is either 4-aminohexahydroquinoline-
3-carbonitrile 4 that results from initial addition of NH
to the activated double bond in 2 (pathway A) or
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S. A. S. Ghozlan, A. G. Ahmed, and I. A. Abdelhamid
Vol 53
2-aminohexahydroquinoline-3-carbonitrile 6 that results
from initial addition of enamine CH to activated double
bond in 2 to yield 5 that readily cyclizes into 6 (pathway
B). However, 1H and 13C-NMR simply cannot differentiate
the two isomers. In the present study, HMBC experiments
unambiguously solved this problem as the decisive differ-
ence between the alternative structures 4 and 6 in the
HMBC measurement of compound 6d is due to the fact
that in case of compound 6d, quinoline hydrogen-H4 at
δ= 4.42 ppm shows a cross peak which indicates a 3J
coupling to CO at δ= 195.5 ppm. (Fig. 1; Scheme 1).
In order to provide chemical evidence for the proposed
structure, we investigated the Michael addition reaction
of enamine 7 with methyl carboxylate ester on ortho posi-
tion, where only further cyclization occurred in the case of
2-aminohexahydroquinoline-3-carbonitrile, whereas in the
case of 4-aminohexahydroquinoline-3-carbonitrile, no fur-
ther cyclization occurred. Thus, the reaction results in the
formation of product of cyclization with methanol elimina-
tion to give compounds 10.
The structure of compound 10a was confirmed based on
the spectroscopic data that revealed the absence of
methoxy group. The mass spectrum of 10a revealed molec-
ular ion peak as a base peak at m/z 395 corresponding to
1
the loss of methanol. H NMR also revealed the absence
of OMe protons in the area 3.6–4.0 ppm. In addition, it in-
dicated the presence of a broad singlet signal at 11.69ppm
corresponding to the NH group (cf. Scheme 2).
In a similar manner, the reaction of enamine 11 [22] with
2 has resulted in the formation of compounds 13. Struc-
ture 13 was readily established based on IR and 13C
NMR that revealed the presence of one CN band and
signal. We also managed to establish the structure of the
product with certainty through 2D-HMBC measurements
of compound 13a, which revealed H-8 at δ= 4.67 ppm that
3
shows a cross-peak that indicates a J coupling to CO at
δ =195.8 ppm (Fig. 2; Scheme 3).
Encouraged by the results acquired from enamines 1, 7,
and 11, we attempted to expand the scope of this reaction
to prepare pentacyclic structures. Thus, enamines incorpo-
rating a tetrahydrothiophene moiety 14 and 17 were pre-
pared. The reaction of enamine 14 with 2 results in the
formation of product of cyclization with ethanol elimina-
tion to give the benzothienopyrimidoquinoline derivatives
16. The formation of such pentacyclic product 16 supports
our suggestion that the reaction proceeds via initial addition
of the enamine CH in compound 14 to the activated double
bond in 2 followed by cyclization rather than initial addition
of NH in 14 to the double bond in 2. The structure of
compound 16 was established through inspection of their
spectroscopic data. The mass spectrum of 16d revealed
molecular ion peak as a base peak at m/z 499. 1H NMR re-
vealed the disappearance of OEt group and the appearance
of NH as a broad singlet at 11.26 ppm. In addition, it re-
vealed a singlet signal at 4.57 ppm corresponding to H-5.
Figure 1. 2D-HMBC NMR spectrum of compound 6d.
Scheme 1
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Enamines: Unambiguous Structural Characterization Using 2D-HMBC NMR Spectroscopy
Scheme 2
In an extension of this reaction, the cyclic enamine 17
carrying CN group on the thiophene ring was prepared.
The reaction of enamine 17 with 2 leads to the formation
of the pentacyclic structures 19. The structure of 19a was
established based on spectral data. The 1H NMR spectrum
of 19a indicated two singlet signals at δ=0.96 and 1.1ppm
for the two methyl groups. It also featured characteristic set
of multiplets at δ= 1.84 and 2.64 for the methylene pro-
tons. It indicated a singlet signal at δ= 4.4 ppm assigned
for H-5. In addition, it indicated a broad singlet at
δ= 6.17 ppm for NH2. It also revealed aromatic protons
as multiplets at δ= 7.07 and 7.32. Furthermore, full assign-
ment of the 13 C-NMR data confirmed the structure of 19a,
where the key signal at δ= 36.6 was assigned to C-5 and
signal at 195.8ppm assigned to CO group.
In this study, different catalysts were used including
piperidine and DABCO. Also, in conjunction with our
interest in the utility of green benign approaches in organic
synthesis [23,24], we used the green heterogeneous basic
catalyst chitosan. The percentage yields were compared
in each case, and it was found that chitosan and DABCO
were highly effective in most cases (the percentage yields
are cited in Table 1; Scheme 5).
Figure 2. 2D-HMBC NMR spectrum of compound 13a.
13C NMR was found also to be in agreement with the
proposed structure where it showed amidic carbonyl at
157ppm in addition to the ketonic carbonyl at 195.8 ppm.
All other carbon signals appeared at their expected posi-
tions (cf. Scheme 4).
Scheme 3
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S. A. S. Ghozlan, A. G. Ahmed, and I. A. Abdelhamid
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Scheme 4
Table 1
Comparison of percentage yield of products obtained from piperidine, chitosan, and DABCO.
% Yields
DABCO
% Yields
Entry
Piperidine
Chitosan
Entry
Piperidine
DABCO
Chitosan
6a [25,26]
6b
6c [26]
6d
10a [27]
10b
10c
10d
13a
13b
88
90
85
82
78
70
68
69
76
68
90
90
93
89
92
93
90
92
95
94
95
94
96
94
82
80
78
83
82
76
13c
13d
16a
16b
16c
16d
19a
19b
19c
19d
74
72
75
80
69
72
73
72
75
80
92
96
90
88
85
86
93
91
88
93
83
81
78
80
78
82
88
86
82
84
Scheme 5
EXPERIMENTAL
CONCLUSION
Melting points were determined on a Stuart melting point ap-
paratus and are uncorrected. The IR spectra were recorded as
KBr pellets using a Bruker-vector 22 spectrophotometer FTIR.
The 1H and 13C NMR spectra were recorded in DMSO-d6 as sol-
vent at 300 and 75 MHz, respectively, on Varian Gemini NMR
spectrometer using TMS as internal standard. Chemical shifts
are reported in δ units (ppm). Mass spectra were measured on a
Shimadzu GMSS-QP-1000 EX mass spectrometer at 70 eV.
In conclusion, the synthesis of hexahydroquinoline and
fused quinolines via reactions of different substituted
cyclic enamines with unsaturated nitriles are very efficient.
Moreover, DABCO and chitosan were found to be the best
catalysts for this type of reactions. Furthermore, 2D-
HMBC spectroscopy can be utilized effectively to estab-
lish, with certainty, the structures of the reaction products.
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Enamines: Unambiguous Structural Characterization Using 2D-HMBC NMR Spectroscopy
The enaminoketones 1 [21], 7 [21], 11 [22], 14 [28], and 17
[28] were prepared from the corresponding cyclohexa-1,
3-diones and amines according to procedures described in the
literature.
Anal. Calcd for C25H20N4O4 (440.45): C, 68.17; H, 4.58; N,
12.72. Found: C, 68.35; H, 4.72; N, 12.93.
8-(4-Methoxyphenyl)-11,11-dimethyl-5,9-dioxo-6,8,9,10,11,
12-hexahydro-5H-quinolino[1,2-a]quinazoline-7-carbonitrile
(10c). This compound was obtained as yellow solid (ethanol-
dioxane), mp 292–294°C; ir: 3381 (NH), 2193 (CN), 1690 and
General procedures for compounds 6a-d, 10a-d, 13a-d,
16a-d and 19a-d.
1
1655 (2CO) cmÀ1; H nmr (400 MHz, DMSO-d6): δ, ppm: 0.91,
Method A. A mixture of 3-arylamino-5,5-dimethylcyclohex-
2-enone 1, 7, 11, 14, or 17 (10 mM), and benzylidene derivatives
2a-d was refluxed in dioxan (20 mL) in the presence of
piperidine (0.5 mL) or DABCO (0.5 mL) for 6 h. The solvent
was evaporated under vacuum, and the crude product was
collected and crystallized from ethanol or ethanol/dioxan.
Method B. A mixture of 3-arylamino-5,5-dimethylcyclohex-
2-enone 1, 7, 11, 14, 17 (10 mM), and benzylidene derivatives
2a-d was refluxed in dioxan (20 mL) in the presence of chitosan
(0.2 g) for 6 h. The solvent was evaporated under vacuum, and
the crude product was collected and crystallized from ethanol or
ethanol/dioxan. The catalyst, chitosan, is removed by filtration
prior or during the crystallization process.
1.08 (2 s, 6H, 2CH3), 2.06–2.27 (m, 4H, 2CH2), 3.67 (s, 3H,
OCH3), 4.61 (s, 1H, CH), 6.80–7.98 (m, 8H, Ar–H), 11.67
(s, 1H, NH, D2O exchangeable); 13C nmr (100 MHz,
DMSO-d6): δ, ppm: 25.7, 32.2, 35.5, 35.9, 50.6, 55.5, 70.3,
114.1, 114.7, 118.3, 119.9, 120.5, 120.8, 125.6, 127.9,
134.4, 134.7, 137.8, 146.1, 150.8, 158.8, 159.6, 195.8; MS (EI):
m/z (%) = 425 (M+).
Anal. Calcd for C26H23N3O3 (425.48): C, 73.39; H, 5.45; N,
9.88. Found: C, 73.53; H, 5.66; N, 9.69.
8-(Benzo[d][1,3]dioxol-5-yl)-11,11-dimethyl-5,9-dioxo-6,8,9,10,
11,12-hexahydro-5H-quinolino[1,2-a]quinazoline-7-carbonitrile
(10d). This compound was obtained as yellowish green solid
(ethanol-dioxane), mp 293–295°C; ir: 3328 (NH), 2195 (CN),
2-Amino-7,7-dimethyl-4-(4-nitrophenyl)-5-oxo-1-phenyl-1,4,5,
6,7,8-hexahydroquinoline-3-carbonitrile (6b). This compound
was obtained as yellow solid (ethanol), mp 264–266°C; ir:
1
1681 and 1650 (2CO) cmÀ1; H nmr (400 MHz, DMSO-d6): δ,
ppm: 0.90, 1.08 (2 s, 6H, 2CH3), 2.12–2.57 (m, 4H, 2CH2), 4.60
(s, 1H, CH), 5.93 (s, 2H, –OCH2O–), 6.67–7.98 (m, 7H, Ar–H),
11.65 (s, 1H, NH, D2O exchangeable); MS (EI): m/z (%) = 439 (M+).
Anal. Calcd for C26H21N3O4 (439.46): C, 71.06; H, 4.82; N,
9.56. Found: C, 71.17; H, 4.67; N, 9.73.
3459, 3320 (NH2), 2179 (CN) and 1645 (CO) cmÀ1 1H nmr
;
(400 MHz, DMSO-d6): δ, ppm: 0.73, 0.89 (2 s, 6H, 2CH3),
1.71–2.20 (m, 4H, 2CH2), 4.63 (s, 1H, CH), 5.50 (s, 2H, NH2,
D2O exchangeable), 7.45–8.24 (m, 9H, Ar–H); MS (EI): m/z (%)
= 414 (M+).
Anal. Calcd for C24H22N4O3 (414.46): C, 69.55; H, 5.35; N,
13.52. Found: C, 69.36; H, 5.45; N, 13.73.
5-Amino-11,11-dimethyl-9-oxo-8-phenyl-9,10,11,12-tetrahydro-
8H-quinolino[1,2-a]quinazoline-7-carbonitrile (13a). This
compound was obtained as yellowish green solid (ethanol-
dioxane), mp > 300°C; ir: 3414, 3335 (NH2), 2190 (CN) and
2-Amino-4-(benzo[d][1,3]dioxol-5-yl)-7,7-dimethyl-5-oxo-1-
phenyl-1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile (6d).
This compound was obtained as yellow solid (ethanol), mp
258–260°C; ir: 3448, 3324 (NH2), 2180 (CN) and 1655
1
1610 (CO) cmÀ1; H nmr (400 MHz, DMSO-d6): δ, ppm: 0.89,
1.09 (2s, 6H, 2CH3), 2.08–2.25 (m, 2H, CH2), 3.16–3.34 (m, 2H,
CH2), 4.67 (s, 1H, CH), 7.12–8.07 (m, 11H, Ar–H and NH2); 13
C
(CO) cmÀ1
;
1H nmr (400 MHz, DMSO-d6): δ, ppm: 0.76,
nmr (100MHz, DMSO-d6): δ, ppm: 25.5, 30.0, 35.6, 36.7, 49.1,
50.7, 73.9, 116.0, 120.0, 120.1, 121.7, 124.8, 125.4, 126.7, 127.1,
129.1, 133.4, 137.7, 143.7, 151.0, 153.4, 156.6, 195.8; MS (EI):
m/z (%) = 394 (M+).
Anal. Calcd for C25H22N4O (394.47): C, 76.12; H, 5.62; N,
14.20. Found: C, 76.45; H, 5.83; N, 14.05.
0.89 (2 s, 6H, 2CH3), 1.69–2.21 (m, 4H, 2CH2), 4.42 (s, 1H, CH),
5.32 (s, 2H, NH2, D2O exchangeable), 6.0 (s, 2H, –OCH2O–),
6.74–7.62 (m, 8H, Ar–H); 13C nmr (100 MHz, DMSO-d6): δ, ppm:
26.8, 29.5, 32.4, 36.6, 41.4, 49.8, 61.0, 101.3, 107.6, 108.7, 120.2,
121.9, 130.2, 130.4, 130.7, 136.7, 141.2, 146.1, 147.7, 150.5,
151.5, 195.5; MS (EI): m/z (%) = 413 (M+).
Anal. Calcd for C25H23N3O3 (413.47): C, 72.62; H, 5.61; N,
10.16. Found: C, 72.58; H, 5.86; N, 10.39.
11,11-Dimethyl-5,9-dioxo-8-phenyl-6,8,9,10,11,12-hexahydro-
5-Amino-11,11-dimethyl-8-(4-nitrophenyl)-9-oxo-9,10,11,
12-tetrahydro-8H-quinolino[1,2-a]quinazoline-7-carbonitrile (13b).
This compound was obtained as yellow solid (ethanol-dioxane),
mp > 300°C; ir: 3456, 3323 (NH2), 2183 (CN) and 1652 (CO) cmÀ1
;
1H nmr (400 MHz, DMSO-d6): δ, ppm: 0.78, 0.89 (2 s, 6H, 2CH3),
1.79–2.27 (m, 4H, 2 CH2), 4.64 (s, 1H, CH), 7.58–8.22 (m, 10H,
Ar–H+NH2); 13C nmr (100MHz, DMSO-d6): δ, ppm: 26.0, 32.2,
37.9, 41.3, 49.5, 60.2, 111.2, 114.1, 116.6, 121.3, 123.8, 129.1,
131.4, 132.8, 135.0, 135.7, 138.4, 146.6, 150.3, 150.5, 151.1,
154.2, 195.2; MS (EI): m/z (%) = 439 (M+).
5H-quinolino[1,2-a]quinazoline-7-carbonitrile (10a).
This
compound was obtained as white solid (ethanol-dioxane), mp
290–292°C; ir: 3396 (NH), 2195 (CN), 1714 and 1652 (2CO)
cmÀ1 1H nmr (400 MHz, DMSO-d6): δ, ppm: 0.91, 1.08
;
(2 s, 6H, 2CH3), 2.14–2.25 (m, 4H, 2CH2), 4.68 (s, 1H, CH),
7.19–7.98 (m, 9H, Ar–H), 11.69 (s, 1H, NH, D2O exchangeable);
MS (EI): m/z (%) = 395 (M+).
Anal. Calcd for C25H21N3O2 (395.45): C, 75.93; H, 5.35; N,
10.63. Found: C, 76.11; H, 5.46; N, 10.96.
11,11-Dimethyl-8-(4-nitrophenyl)-5,9-dioxo-6,8,9,10,11,
12-hexahydro-5H-quinolino[1,2-a]quinazoline-7-carbonitrile (10b).
This compound was obtained as yellow solid (ethanol-dioxane), mp
288–290°C; ir: 3438 (NH), 2198 (CN), 1696 and 1656 (2CO)
cmÀ1; 1H nmr (400 MHz, DMSO-d6): δ, ppm: 0.91, 1.08 (2 s, 6H,
2CH3), 2.15–2.26 (m, 4H, 2CH2), 4.85 (s, 1H, CH), 7.38–8.1
(m, 8H, Ar–H), 11.79 (s, 1H, NH, D2O exchangeable); MS (EI):
m/z (%) = 440 (M+).
Anal. Calcd for C25H21N5O3 (439.47): C, 68.33; H, 4.82; N,
15.94. Found: C, 68.59; H, 4.65; N, 15.67.
5-Amino-8-(4-methoxyphenyl)-11,11-dimethyl-9-oxo-9,10,11,
12-tetrahydro-8H-quinolino[1,2-a]quinazoline-7-carbonitrile
(13c). This compound was obtained as yellow solid (ethanol-
dioxane), mp > 300°C; ir: 3458, 3326 (NH2), 2181 (CN) and
1644 (CO) cmÀ1 1H nmr (400 MHz, DMSO-d6): δ, ppm:
;
0.76, 1.03 (2 s, 6H, 2CH3), 1.81–2.22 (m, 4H, 2CH2), 3.71
(s, 3H, OCH3), 4.41 (s, 1H, CH), 6.76–8.12 (m, 10H, Ar–H
+ NH2); 13C nmr (100 MHz, DMSO-d6): δ, ppm: 26.0, 35.5,
36.9, 41.8, 49.7, 55.4, 61.5, 111.2, 113.7, 114.3, 116.3, 120.5,
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127.7, 129.1, 131.2, 132.8, 135.7, 138.7, 139.2, 150.7, 153.3,
22.8, 24.1, 25.3, 25.4, 30.3, 32.6, 35.3, 36.3, 49.9, 60.8, 69.2,
101.5, 107.3, 108.8, 117.9, 118.7, 120.1, 129.5, 132.1, 136.7,
144.5, 146.8, 148.0, 148.6, 157.0, 195.8; MS (EI): m/z (%)
= 499 (M+).
158.5, 195.8; MS (EI): m/z (%) = 424 (M+).
Anal. Calcd for C26H24N4O2 (424.49): C, 73.56; H, 5.70; N,
13.20. Found: C, 73.49; H, 5.95; N, 13.12.
5-Amino-8-(benzo[d][1,3]dioxol-5-yl)-11,11-dimethyl-9-oxo-9,
10,11,12-tetrahydro-8H-quinolino[1,2-a]quinazoline-7-carbonitrile
(13d). This compound was obtained as yellow solid (ethanol-
dioxane), mp > 300°C; ir: 3446, 3335 (NH2), 2178 (CN) and
Anal. Calcd for C28H25N3O4S (499.16): C, 67.32; H, 5.04; N,
8.41; S, 6.42. Found: C, 67.18; H, 5.17; N, 8.62; S, 6.64.
8-Amino-2,2-dimethyl-4-oxo-5-phenyl-2,3,4,5,9,10,11,12-
octahydro-1H-benzo[4′,5′]thieno[3′,2′:5,6]pyrimido[1,2-a]
quinoline-6-carbonitrile (19a). This compound was obtained as
yellow solid (ethanol-dioxane), mp >300°C; ir: 3466 (NH), 2183
(CN), 1647 and 1579 (2CO) cmÀ1; 1H nmr (400MHz, DMSO-d6):
δ, ppm: 0.96 and 1.1 (2 s, 6H, 2CH3), 1.84–2.32 (m, 6H,
3CH2), 2.64–2.78 (m, 6H, 3CH2), 4.4 (s, 1H, CH), 6.17 (br s.,
2H, NH2), 7.07–7.32 (m, 5H, Ar–H); 13C nmr (100 MHz,
DMSO-d6): δ, ppm: 21.8, 22.8, 24.3, 25.1, 26.9, 32.5, 36.6,
49.7, 114.8, 118.5, 121.2, 126.6, 127.0, 127.7, 128.6, 128.9,
129.1, 144.3, 148.5, 149.9, 150.0, 153.3, 154.8, 195.8; MS
(EI): m/z (%) = 454 (M+).
1652 (CO) cmÀ1 1H nmr (400 MHz, DMSO-d6): δ, ppm:
;
0.79, 0.90 (2 s, 6H, 2CH3), 2.02–2.21 (m, 4H, 2 CH2), 4.41
(s, 1H, CH), 5.9 (s, 2H, –OCH2O–), 6.73–8.12 (m, 9H,
Ar–H + NH2).; 13C nmr (100 MHz, DMSO-d6): δ, ppm: 26.1,
32.3, 37.5, 41.3, 49.7, 62.1, 101.1, 108.0, 108.5, 112.1, 114.3,
116.4, 121.2, 121.6, 131.3, 132.7, 134.9, 135.6, 138.6, 141.1,
146.1, 147.6, 149.3, 150.4, 195.2; MS (EI): m/z (%) = 438 (M+).
Anal. Calcd for C26H22N4O3 (438.48): C, 71.22; H, 5.06; N,
12.78. Found: C, 71.37; H, 5.19; N, 12.96.
2,2-Dimethyl-4,8-dioxo-5-phenyl-2,3,4,5,7,8,9,10,11,12-decahydro-
1H-benzo[4′,5′]thieno[3′,2′:5,6]pyrimido[1,2-a]quinoline-6-
carbonitrile (16a). This compound was obtained as yellow solid
(ethanol-dioxane), mp >300°C; ir: 3429 (NH), 2185 (CN), 1707
Anal. Calcd for C27H26N4OS (454.59): C, 71.34; H, 5.76; N,
12.32; S, 7.05. Found: C, 71.52; H, 5.92; N, 12.11; S, 7.35.
8-Amino-2,2-dimethyl-5-(4-nitrophenyl)-4-oxo-2,3,4,5,9,10,11,
12-octahydro-1H-benzo[4′,5′]thieno[3′,2′:5,6]pyrimido[1,2-a]
quinoline-6-carbonitrile (19b). This compound was obtained
as yellow solid (ethanol-dioxane), mp >300°C; ir: 3461, 3366
1
and 1652 (2CO) cmÀ1; H nmr (400 MHz, DMSO-d6): δ, ppm:
0.81, 1.11 (2 s, 6H, 2CH3), 1.74–2.10 (m, 6H, 3CH2), 2.60–2.81
(m, 6H, 3CH2), 4.64 (s, 1H, CH), 7.44–8.22 (m, 5H, Ar–H),
11.40 (br s., 1H, NH); MS (EI): m/z (%) = 455 (M+).
(NH2), 2191 (CN) and 1657 (CO) cmÀ1 1H nmr (400 MHz,
;
DMSO-d6DMSO-d6): δ, ppm: 0.81 and 0.98 (2 s, 6H, 2CH3),
1.84–2.32 (m, 8H, 4CH2), 2.64–2.78 (m, 4H, 2CH2), 4.6
(s, 1H, CH), 6.3 (br s., 2H, NH2), 7.44–7.60 (dd, 2H, Ar–H,
J = 8.0 Hz), 8.11–8.23 (dd, 2H, Ar–H, J = 8.0 Hz); 13C nmr
(100 MHz, DMSO-d6): δ, ppm: 21.8, 22.7, 24.9, 26.2, 32.6,
37.4, 49.5, 60.4, 113.6, 113.7, 120.8, 123.9, 124.4, 128.4,
128.8, 134.9, 135.7, 142.2, 146.7, 150.7, 150.9, 151.6, 153.8,
195.4; MS (EI): m/z (%) = 499 (M+).
Anal. Calcd for C27H25N3O2S (455.57): C, 71.18; H, 5.53; N,
9.22; S, 7.04. Found: C, 71.44; H, 5.75; N, 9.32; S, 7.11.
2,2-Dimethyl-5-(4-nitrophenyl)-4,8-dioxo-2,3,4,5,7,8,9,10,11,
12-decahydro-1H-benzo[4′,5′]thieno[3′,2′:5,6]pyrimido[1,2-a]
quinoline-6-carbonitrile (16b). This compound was obtained
as yellow solid (ethanol-dioxane), mp 280–282°C; ir: 3403 (NH),
2185 (CN), 1705 and 1649 (2CO) cmÀ1 1H nmr (400 MHz,
;
DMSO-d6): δ, ppm: 0.81, 0.92 (2 s, 6H, 2CH3), 1.20–1.27
(m, 2H, CH2), 1.80–1.81 (m, 4H, 2CH2), 2.09–2.16 (m, 2H,
CH2), 2.78–2.81 (m, 4H, 2CH2), 4.59 (s, 1H, CH),
7.44–7.66 (dd, 2H, Ar–H, J = 8.4 Hz), 8.16–8.22 (dd, 2H,
Ar–H, J = 8.4 Hz), 11.53 (br s., 1H, NH); MS (EI): m/z (%)
= 500 (M+).
Anal. Calcd for C27H25N5O3S (499.58): C, 64.91; H, 5.04; N,
14.02; S, 6.42. Found: C, 65.11; H, 5.23; N, 14.35; S, 6.77.
8-Amino-5-(4-methoxyphenyl)-2,2-dimethyl-4-oxo-2,3,4,5,9,10,
11,12-octahydro-1H-benzo[4′,5′]thieno[3′,2′:5,6]pyrimido[1,2-a]
quinoline-6-carbonitrile (19c). This compound was obtained as
yellow solid (ethanol-dioxane), mp 275–278°C; ir: 3449, 3355
Anal. Calcd for C27H24N4O4S (500.57): C, 64.78; H, 4.83; N,
11.19; S, 12.78. Found: C, 64.67; H, 4.91; N, 11.32; S, 12.67.
5-(4-Methoxyphenyl)-2,2-dimethyl-4,8-dioxo-2,3,4,5,7,8,9,10,
11,12-decahydro-1H-benzo[4′,5′]thieno[3′,2′:5,6]pyrimido[1,2-a]
quinoline-6-carbonitrile (16c). This compound was obtained as
yellow solid (ethanol-dioxane), mp 290–292°C; ir: 3434 (NH),
(NH2), 2185 (CN) and 1657 (CO) cmÀ1 1H nmr (400 MHz,
;
DMSO-d6): δ, ppm: 0.81 and 0.97 (2 s, 6H, 2CH3), 1.84–2.31
(m, 8H, 4CH2), 2.64–2.78 (m, 4H, 2CH2), 3.72 (s, 3H, OCH3),
4.35 (s, 1H, CH), 6.13 (br s., 2H, NH2), 6.80–6.96 (dd, 2H, Ar–H,
J = 8.0 Hz), 7.04–7.23 (dd, 2H, Ar–H, J =8.0Hz); 13C nmr
(100 MHz, DMSO-d6): δ, ppm: 21.7, 22.8, 24.4, 24.8, 27.2, 32.6,
36.4, 49.7, 55.5, 59.0, 113.4, 114.1, 115.2, 121.3, 128.0, 128.7,
135.6, 137.3, 138.2, 142.6, 149.5, 150.9, 158.9, 162.6, 195.3; MS
(EI): m/z (%) = 484 (M+).
Anal. Calcd for C28H28N4O2S (484.61): C, 69.40; H, 5.82; N,
11.56; S, 6.62. Found: C, 69.53; H, 5.63; N, 11.56; S, 6.74.
8-Amino-5-(benzo[d][1,3]dioxol-5-yl)-2,2-dimethyl-4-oxo-2,3,4,
5,9,10,11,12-octahydro-1H-benzo[4′,5′]thieno[3′,2′:5,6]pyrimido
2200 (CN), 1704 and 1657 (2CO) cmÀ1 1H nmr (400 MHz,
;
DMSO-d6): δ, ppm: 0.94, 1.11 (2s, 6H, 2CH3), 1.76–2.18
(m, 6H, 3CH2), 2.63–2.81 (m, 6H, 3CH2), 3.68 (s, 3H,
OCH3), 4.57 (s, 1H, CH), 6.82 (d, 2H, Ar–H, J = 8.0 Hz), 7.06
(d, 2H, Ar–H, J = 8.0 Hz), 11.23 (br s., 1H, NH); MS (EI): m/z
(%) = 484 (M+).
Anal. Calcd for C28H27N3O3S (485.60): C, 69.25; H, 5.60; N,
8.65; S, 6.60. Found: C, 69.43; H, 5.71; N, 8.76; S, 6.71.
5-(Benzo[d][1,3]dioxol-5-yl)-2,2-dimethyl-4,8-dioxo-2,3,4,5,7,
8,9,10,11,12-decahydro-1H-benzo[4′,5′]thieno[3′,2′:5,6]pyrimido
[1,2-a]quinoline-6-carbonitrile (19d).
This compound was
obtained as yellow solid (ethanol-dioxane), mp >300°C; ir: 3585,
3352 (NH2), 2189 (CN) and 1650 (CO) cmÀ1; 1H nmr (400MHz,
DMSO-d6): δ, ppm: 0.83 and 0.96 (2 s, 6H, 2CH3), 1.84–2.24
(m, 8H, 4CH2), 2.65–2.78 (m, 4H, 2CH2), 4.34 (s, 1H, CH), 5.96
(s, 2H, –OCH2O–), 6.10 (br s., 2H, NH2), 6.66–6.78 (m, 3H,
Ar–H); MS (EI): m/z (%) = 498 (M+).
[1,2-a]quinoline-6-carbonitrile (16d).
This compound was
obtained as yellow solid (ethanol-dioxane), mp >300°C; ir: 3424
(NH), 2188 (CN), 1704 and 1650 (2CO) cmÀ1; 1H nmr (400 MHz,
DMSO-d6): δ, ppm: 0.94, 1.11 (2 s, 6H, 2CH3), 1.73–2.17
(m, 6H, 3CH2), 2.62–2.80 (m, 6H, 3CH2), 4.57 (s, 1H, CH),
5.9 (s, 2H, –OCH2O–), 6.62–6.82 (m, 3H, Ar–H), 11.26
(br s., 1H, NH); 13C nmr (100 MHz, DMSO-d6): δ, ppm: 22.0,
Anal. Calcd for C28H26N4O3S (498.60): C, 67.45; H, 5.26; N,
11.24; S, 6.43. Found: C, 67.67; H, 5.12; N, 11.13; S, 6.79.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Regioorientation in the Addition Reaction of α-Substituted-Cinnamonitrile to
May 2016
823
Enamines: Unambiguous Structural Characterization Using 2D-HMBC NMR Spectroscopy
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Acknowledgments. Ismail A. Abdelhamid is deeply indebted to
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him a postdoctoral fellowship. He is also very thankful to Prof.
Dr Holger Butenschön, Institut für Organische Chemie, Leibniz
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet