Spiro[4H-pyran-3,3′-oxindoles] Derived from 1,2,3,4-Tetrahydroquinoline

Article abstract of DOI:10.1002/jhet.2237

Three-component reactions of 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1,2-dione with malononitrile, or ethyl cyanoacetate, and cyclic six-membered or a five-membered 1,3-diketone, produce spiro[4H-pyran-3,3′-oxindoles].

Full text of DOI:10.1002/jhet.2237

Month 2014 Spiro[4H-pyran-3,3′-oxindoles] Derived from 1,2,3,4-Tetrahydroquinoline
a
a
a
b
*
Hosein Vahedi, Mehdi M. Baradarani, Ahmad Rashidi, and John A. Joule
aDepartment of Organic Chemistry, Faculty of Chemistry, University of Urmia, Urmia 57153-165, Iran
bThe School of Chemistry, The University of Manchester, M13 9PL, UK
*
E-mail: mmbaradarani@yahoo.com
Received December 7, 2013
DOI 10.1002/jhet.2237
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
Three-component reactions of 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1,2-dione with malononitrile, or
ethyl cyanoacetate, and cyclic six-membered or a five-membered 1,3-diketone, produce spiro[4H-pyran-
3,3′-oxindoles].
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
of the eight products, yields, and times of reaction are
shown in Table 1.
The cyclocondensation reaction between a ketone,
malononitrile (or a cyanoacetate), and a 1,3-diketone, gener-
ating a 2-amino-4H-pyran-3-carbonitrile (or 3-carboxylate)
has been often exemplified. In the context of our continuing
studies of various aspects of indole chemistry [1–4], we noted
that this 4H-pyran-constructing sequence has in particular
been applied several times to isatin (1H-indole-2,3-dione)
in which the 3-carbonyl group plays the role of the ketone
in the three-component process. Scheme 1 shows the dom-
ino-Knoevenagel-Michael sequence of events using isatin,
malononitrile, and a generalized 1,3-diketone (the initial
Knovenagel condensation can be conducted separately
before interaction with the 1,3-diketone). In three recent isatin
examples, nanocrystalline MgO, [5] indium(III) chloride, [6],
and a chiral organocatalyst [7] were employed as catalysts.
However, no previous work has employed the tricyclic
oxindole, 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1,2-
dione (3). We decided to examine whether, in this some-
what more strained isatin, the 4H-pyran-forming process
would take place.
None of the solid products could be induced to crystallize
in a form suitable for X-ray crystallographic examination;
however, all the spectroscopic evidence, and in particular
the strong analogy with previous work, for example, refer-
ences 5–7, make the structures secure. Thus, each of the
nitriles, 6a, 6c, 6e, and 6f, showed nitrile and carbonyl
stretches in the ranges 2190–2196 and 1626–1686 cmÀ1
.
1
In the H-NMR spectra of each of the ethyl esters, 6b, 6d,
6f, and 6h, the methyl triplet was present in the range
δ 0.70–0.87 and the carbonyl stretches in the range
1606–1686 cmÀ1. All products demonstrated a broad
two-hydrogen 1H-NMR signal for the NH2 group between
δ 4.76 and δ 8.10, but mostly around δ 8.00.
There is some doubt over the structures deriving from
4,4-dimethylcyclohexane-1,3-dione 5c concerning the
orientation in which the unsymmetrical dione reacts. We
base our tentative assignment (Figure 1) of the structures 6e
and 6f by analogy with the only two reports [9,10] in which
this dione has been used in comparable three-component
pyran-forming sequences. These are shown in Scheme 4,
though the evidence for structures 7 in both reports is far
from strong.
RESULTS AND DISCUSSION
5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1,2-dione (3)
was prepared following a literature procedure [8] in which
1,2,3,4-tetrahydroquinoline (1) was reacted with oxalyl
chloride and the resulting amide-acid chloride (2) cyclised
by treatment with aluminum chloride (Scheme 2).
CONCLUSIONS
It seems that the extra strain present in the tricyclic isatin
1 does not preclude its reaction in this pyran-forming
sequence, in a manner completely analogous to that of
simpler, bicyclic isatins. We intend to make further use
of the reactivity inherent in this interesting keto-lactam in
future studies.
Reaction of amido-ketone
3 with malononitrile
(or ethyl cyanoacetate) and each of four cyclic 1,3-
diketones (Scheme 3) proceeded smoothly in the presence
of triethylamine, in refluxing ethanol. The structures
© 2014 HeteroCorporation

H. Vahedi, M. M. Baradarani, A. Rashidi, and J. A. Joule
Vol 000
Scheme 1
Scheme 2
Scheme 3
EXPERIMENTAL
Table 1
Synthesis of spiro[4H-pyran-3,3′-oxindoles] 6.
General. Melting points were recorded on Electrothermal
1
Engineering LTD 16218. H-NMR and 13C-NMR spectra were
Time
Yield
(%)
recorded on a Bruker Avance AQS (300 and 400 MHz)
spectrometer, at (300, 400 MHz and 75, 100 MHz), respectively.
Chemical shifts δ are in parts per million (ppm) measured in
CDCl3 and DMSO-d6 as solvent and relative to TMS as the
Entry
Product
X
Compound 5
(h)
1
2
3
4
5
6
7
8
6a
6b
6c
6d
6e
6f
CN
CO2Et
CN
CO2Et
CN
CO2Et
CN
a
a
b
b
c
c
d
d
4
5
3
3.5
4.5
5
6
7
80
80
85
85
75
75
70
70
internal standard. Infrared spectra were recorded on
Thermonicolet-Nexus 670 Fourier transform infrared instrument.
Mass spectra were recorded using Varian MAT 311
a
a
spectrometer operating at an ionizing voltage of 70 eV. For thin-
layer chromatography, silica-coated aluminum plates (Merck
Kieselgel F254) were used.
6g
6h
CO2Et
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Spiro[4H-pyran-3,3′-oxindoles] Derived from 1,2,3,4-Tetrahydroquinoline
3.80–3.94 (m, 3H), 6.61 (s, 2H, NH2), 6.78–6.82 (m, 2H),
6.95 (d, 1H, J = 6.6 Hz); δC (75 MHz, CDCl3): 13.96, 21.12,
24.65, 27.24, 28.82, 31.81, 39.03, 41.18, 47.81, 51.20,
59.57, 113.90, 118.79, 120.16, 121.32, 126.66, 133.15, 141,
158.96, 162.39, 168.35, 177.62, 195.30; MS, m/z (%): 422
(M+, 68), 349 (100), 338 (61), 321 (20), 83 (43), 55 (36)
Found: [M]+ 422.1844, C24H26N2O5 requires [M]+ 422.1842.
2-Amino-2′,5-dioxo-2′,4′,5,5′,6,6′,7,8-octahydrospiro[chromene-
4,1′-pyrrolo[3,2,1-ij]quinoline]-3-carbonitrile (6c). White powder
(0.295 g, 85%), mp 279–281°C; νmax (KBr) 3381, 3290, 2946,
2190, 1671, 1630, 1350cmÀ1; δH (400MHz, CDCl3): 2.03–2.15
(m, 4H), 2.3–2.38 (m, 2H), 2.67–2.7 (m, 2H), 2.83 (t, 2H,
J = 6 Hz), 3.78–3.87 (m, 2H), 4.76 (bs, 2H, NH2), 6.88–6.95 (m,
2H, ArH), 7.05 (d, 1H, ArH, J = 7.2 Hz); δC (100 MHz, CDCl3):
19.96, 21.14, 24.64, 27.59, 37.49, 39.08, 47.99, 53.48, 59.58,
114.98, 118.79, 120.35, 121.39, 126.65, 133.32, 140.98, 158.96,
168.43, 177.99, 195.53; MS, m/z (%): 347 (M+, 42), 291 (85),
187 (100), 69 (50), 55 (69). Found: [M]+ 347.1271, C20H17N3O3
requires [M]+ 347.1270.
Ethyl 2-amino-2′,5-dioxo-2′,4′,5,5′,6,6′,7,8-octahydrospiro
[chromene-4,1′-pyrrolo[3,2,1-ij]quinoline]-3-carboxylate (6d).
White powder (0.335g, 85%). mp 269–271°C; νmax (KBr) 3356,
3257, 2941, 1685, 1626, 1356 cmÀ1; δH (400 MHz, DMSO-d6):
0.74 (t, 3H, J = 7.2 Hz), 1.82–1.9 (m, 4H), 2.1–2.25 (m, 2H),
2.65 (m, 2H), 2.7–2.78 (m, 2H), 3.48–3.54 (m, 1H), 3.62–3.79
(m, 3H), 6.7–6.75 (m, 2H, ArH), 6.92 (dd, 1H, J = 6, 2 Hz), 7.9
(bs, 2H, NH2); δC (100 MHz, DMSO-d6): 14.22, 20, 20.99,
24.41, 27.33, 37.47, 47.73, 59.31, 76.16, 114.32, 119.96, 120.38,
121.50, 126.67, 133.80, 141.17, 159.51, 165.23, 168.10, 177.87,
196; MS, m/z (%): 394 (M+ ,24), 338 (30), 321 (71), 307 (66),
187 (51), 73 (100). Found: [M]+ 394.1528, C22H22N2O5 requires
[M]+ 394.1529.
2-Amino-8,8-dimethyl-2′,5-dioxo-2′,4′,5,5′,6,6′,7,8-octahydro
spiro[chromene-4,1′-pyrrolo[3,2,1-ij]quinoline]-3-carbonitrile (6e).
White powder (0.281 g, 75%). mp 266–268°C; νmax (KBr) 3398,
3299, 2931, 2193, 1669, 1627, 1355 cmÀ1; δH (400 MHz, DMSO-
d6): 0.88 (s, 3H), 0.92 (s, 3H), 1.8 (t, 2H, J=6.4Hz), 1.87–1.98
(m, 2H), 2.6–2.68 (m, 1H), 2.71–2.77 (m, 3H), 3.54–3.62 (m,
2H), 6.83–6.89 (m, 2H, ArH), 7.01 (d, 1H, ArH, J = 6.4 Hz),
7.26 (bs, 2H, NH2); δC (100 MHz, DMSO-d6): 21.36, 24.01,
24.27, 24.42, 33.23, 48.20, 57.35, 79.66, 110.26, 117.82,
119.89, 120.78, 122.18, 127.57, 132.69, 139.72, 159.13,
164.38, 175.79, 200.03; MS, m/z (%): 375 (M+, 44), 349 (16),
291 (94), 83 (100), 65 (41). Found: [M]+ 375.1585,
C22H21N3O3 requires [M]+ 375.1583.
Ethyl 2-amino-8,8-dimethyl-2′,5-dioxo-2′,4′,5,5′,6,6′,7,8-
octahydrospiro[chromene-4,1′-pyrrolo[3,2,1-ij]quinoline]-3-
carboxylate (6f). White powder (0.317 g, 75%). mp 254–256°C;
νmax (KBr) 3364, 3242, 2967, 1686, 1626, 1358 cmÀ1; δH
(400 MHz, DMSO-d6): 0.73 (t, 3H, J = 7.2 Hz), 0.82 (s, 3H), 0.9
(s, 3H), 1.73–1.76 (m, 2H), 1.95–2.00 (m, 2H), 2.58–2.8 (m,
4H), 3.48–3.5 (m, 1H), 3.65–3.68 (m, 1H), 3.71–3.75 (m, 2H),
6.71–6.75 (m, 2H, ArH), 6.91 (dd, 1H, J = 6.4, 2 Hz), 7.92 (bs,
2H, NH2); δC (100 MHz, DMSO-d6): 14.35, 21.15, 24.06, 24.48,
Figure 1. Proposed structures of 6e and 6f.
2-(1,2,3,4-Tetrahydroquinolin-1-yl)-2-oxoacetyl chloride
(2).
Oxalyl chloride (5.5 mmol, 0.7 g) was added dropwise
to a solution of 1,2,3,4-tetrahydroquinoline (2.7 mmol) in PhH
(10 mL) at 5°C. The mixture was stirred for 2 h at RT, then
the PhH was evaporated leaving the acid chloride as a solid.
The crude product was used without further purification.
5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1,2-dione (3).
Sublimed AlCl3 (3.1 mmol, 0.4 g) was added slowly to a
solution of 2-(1,2,3,4-tetrahydroquinolin-1-yl)-2-oxoacetyl
chloride (1.2 mmol) in CH2Cl2 (20 mL). The reaction mixture
was stirred overnight at RT, then aq HCl (2 M, 30 mL) was
added. The organic layer was separated, washed with aq
KHCO3 (2 M, 20 mL) then H2O (20 mL). Finally, the CH2Cl2
was evaporated using a rotary evaporator. The residue was
recrystallized from ethanol, mp 197°C (lit [9] 195–197°C).
General procedure for the synthesis of compounds 6.
5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1,2-dione (3) (0.187g,
1 mmol), malononitrile/ethyl cyanoacetate (4) (1 mmol), and
diketone 5 (1 mmol) were dissolved in EtOH (5 mL) with
heating, and Et3N (0.3 mL) was then added. The reaction
mixture was then heated at reflux for the indicated time
(Table 1) and cooled to 4°C overnight. The solid that
separated was filtered off, washed three times with EtOH, and
dried at 60–70°C.
2-Amino-7,7-dimethyl-2′,5-dioxo-2′,4′,5,5′,6,6′,7,8-octahydro
spiro[chromene-4,1′-pyrrolo[3,2,1-ij]quinoline]-3-carbonitrile
(6a). White powder (0.3 g, 80%). mp 284–286°C; νmax (KBr)
3357, 3304, 2959, 2196, 1676, 1633, 1352 cmÀ1; δH (300 MHz,
CDCl3): 1.07 (s, 3H), 1.12 (s, 3H), 2.06–2.20 (m, 4H), 2.47 (d,
1H, J = 18 Hz), 2.58 (d, 1H, J = 18 Hz), 2.81 (t, 2H, J = 5.7 Hz),
3.76–3.82 (m, 2H), 4.96 (s, 2H, NH2), 6.84–6.94 (m, 2H), 7.03
(d, 1H, J = 7.5 Hz); δC (75 MHz, CDCl3): 21.17, 24.51, 27.65,
28.51, 32.24, 39.26, 40.91, 50.54, 61.97, 111.85, 116.27,
120.46, 120.56, 122.45, 127.99, 131.09, 139.47, 158.27,
163.60, 175.38, 195.04; MS, m/z (%): 375(M+, 75), 349
(50), 291 (100), 83 (69), 55 (65). Found: [M]+ 375.1585,
C22H21N3O3 requires [M]+ 375.1583.
Ethyl 2-amino-7,7-dimethyl-2′,5-dioxo-2′,4′,5,5′,6,6′,7,8-
octahydrospiro[chromene-4,1′-pyrrolo[3,2,1-ij]quinoline]-3-
carboxylate (6b). White powder (0.338 g, 80%). mp 277°C;
νmax (KBr) 3368, 3265, 2954, 1686, 1627, 1353 cmÀ1; δH
(300 MHz, CDCl3): 0.87 (t, 3H, J = 7.2 Hz), 0.99 (s, 3H), 1.01
(s, 3H), 2.05–2.23 (m, 4H), 2.38 (d, 1H, J = 17.7 Hz), 2.52
(d, 1H, J = 17.7 Hz), 2.70–2.83 (m, 2H), 3.60–3.68 (m, 1H),
Scheme 4
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

H. Vahedi, M. M. Baradarani, A. Rashidi, and J. A. Joule
Vol 000
24.52, 32.93, 47.93, 59.03, 76.18, 112.59, 118.43, 120.25, 121.10,
126.57, 133.92, 141.54, 159.56, 159.62, 162.36, 168.14, 177.45,
199.91; MS, m/z (%): 422 (M+, 34.6), 349 (100), 338 (42), 154
(35), 69 (47), 55 (86). Found: [M]+ 422.1845 C24H26N2O5
requires [M]+ 422.1842.
m/z (%): 380 (M+, 60), 307 (100), 279 (38), 153 (33), 55 (51).
Found: [M]+ 380.1370, C21H20N2O5 requires [M]+ 380.1372.
Acknowledgment. The authors are grateful to the University of
Urmia for financial support of this work.
2-Amino-2′,5-dioxo-2′,4′,5′,6,6′,7-hexahydro-5H-spiro[cyclopenta
[b]pyran-4,1′-pyrrolo[3,2,1-ij]quinoline]-3-carbonitrile (6g).
Yellow powder (0.233 g, 70%). mp 247°C; νmax (KBr) 3299,
3148, 2945, 2195, 1664, 1636, 1343cmÀ1; δH (400 MHz,
DMSO-d6): 1.86–1.99 (m, 2H), 2.36–2.38 (m, 2H), 2.78
(m, 2H), 2.82–2.85 (m, 2H), 3.55–3.66 (m, 2H), 6.89–6.96
(m, 2H, ArH), 7.09 (d, 1H, J = 6.8 Hz), 7.56 (bs, 2H, NH2); δC
(100 MHz, DMSO-d6): 21.33, 24.27, 25.33, 33.67, 47.72,
56.37, 115.21, 117.97, 120.35, 122.01, 122.56, 129.26,
130.22, 139.65, 161.11, 161.15, 174.17, 179.05, 200.2; MS,
m/z (%): 333 (M+, 100), 305 (84), 290 (61), 268 (63), 249
(63), 55 (63). Found: [M]+ 333.1113, C19H15N3O3 requires
[M]+ 333.1113.
Ethyl 2-amino-2′,5-dioxo-2′,4′,5′,6,6′,7-hexahydro-5H-spiro
[cyclopenta[b]pyran-4,1′-pyrrolo[3,2,1-ij]quinoline]-3-carboxylate
(6h). White powder (0.266 g, 70%). mp 245°C; νmax (KBr) 3344,
3264, 2934, 1685, 1627, 1356 cmÀ1; δH (400 MHz, DMSO-d6): 0.7
(t, 3H, J= 6.8 Hz), 1.96 (t, 2H, J=5.2Hz), 2.3–2.32 (m, 2H), 2.7–2.8
(m, 4H), 3.5–3.54 (m, 1H), 3.65–3.72 (m, 3H), 6.75–6.8 (m, 2H,
ArH), 6.97–6.99 (dd, 1H, ArH, J= 6.4, 2.4 Hz), 8.1 (bs, 2H, NH2);
δC (100 MHz, DMSO-d6): 14.14, 21.22, 24.46, 24.84, 33.62,
47.44, 59.23, 74.83, 117.34, 119.09, 120.68, 121.62, 126.90,
132.70, 140.59, 161.50, 168.15, 175.84, 176.29, 200.06; MS,
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet