One-pot three-component synthesis of functionalized spirooxindoles in gluconic acid aqueous solution

Article abstract of DOI:10.1016/j.tet.2012.12.081

A general, efficient, and green method for one-pot synthesis of functionalized spirooxindoles through three-component condensation reaction of isatins, cyclohexane-1,3-diones, and barbituric acids is described employing gluconic acid aqueous solution (GAAS) as a novel reaction medium and catalyst. The reaction medium could be recycled and reused several times without significant loss of its efficiency.

Full text of DOI:10.1016/j.tet.2012.12.081

Tetrahedron 69 (2013) 2056e2061
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
One-pot three-component synthesis of functionalized
spirooxindoles in gluconic acid aqueous solution
,
Rui-Yun Guo a, Ping Wang b, Guo-Dong Wang a, Li-Ping Mo a, Zhan-Hui Zhang a
*
a College of Chemistry & Material Science, Hebei Normal University, Shijiazhuang 050024, China
b Department of Chemical and Environmental Engineering, Hebei Chemical and Pharmaceutical Vocational Technology College, Shijiazhuang 050026, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A general, efficient, and green method for one-pot synthesis of functionalized spirooxindoles through
three-component condensation reaction of isatins, cyclohexane-1,3-diones, and barbituric acids is de-
scribed employing gluconic acid aqueous solution (GAAS) as a novel reaction medium and catalyst. The
reaction medium could be recycled and reused several times without significant loss of its efficiency.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 28 September 2012
Received in revised form 7 December 2012
Accepted 14 December 2012
Available online 9 January 2013
Keywords:
Spirooxindoles
Multicomponent reaction
One-pot
Gluconic acid aqueous solution
1. Introduction
growth of both MCRs and green solvents toward ideal organic
synthesis.7
With ever-increasing environmental consciousness in chemical
research and industry, there has been a growing interest in the
development of efficient, practical, and environmentally friendly
synthetic methods. In this regard, to address the problem of pol-
lution of traditional volatile organic solvents (VOCs) used in many
synthetic organic processes, tremendous efforts have been devoted
toward sustainable reaction media. Although a variety of un-
conventional solvents, such as water,1 ionic liquids,2 fluorous me-
dia,3 supercritical fluids,4 and polyethylene glycol5 have been
extensively studied and fascinating results have been reported, the
use of these solvents is still subject to strict limitations, such as the
instability of reactive reagents or substrates in water, high prices
and lack of data about the toxicity and bio-compatibility for ionic
liquids, the demand of sophisticated equipment for supercritical
fluids. Therefore, the search of new reaction media is thus gaining
prominence. Meanwhile, multicomponent reactions (MCRs) offer
significant advantages over conventional linear-type synthesis,
such as high atom economy and bond-forming efficiency, reducing
labor time, energy input and waste.6 The combination of multi-
component reactions and benign reaction media has become
a promising frontier field of research, which enables simultaneous
Recently, the use of bio-based materials as alternatives to con-
ventional organic solvents has grabbed considerable interest
among synthetic community. Many naturally available products,
such as glycerol,8 ethyl lactate,9 -valerolactone,10 2-methyl-tetra-
g
hydrofuran,11 carbohydrates-based low melting mixtures12 have
been proposed as safer, sustainable, renewable, and biodegradable
solvents for catalysis and organic chemistry. However, the number
of bio-based solvents is still limited at this stage. More recently, Gu
et al. introduced gluconic acid aqueous solution (GAAS, 50 wt %) as
a promoting medium and catalyst for organic transformations.13
Gluconic acid is an organic compound with molecular formula
C6H12O7 and it is abundantly available in plants, fruits, and other
foodstuffs, such as rice, meat, dairy products, wine, honey, and
vinegar. In particular, the low toxicity of gluconic acid also allows its
use in the formulation of food, pharmaceutical and hygienic
products. It is normally available as an aqueous solution of gluconic
acid, which is composed of equilibrium between the free acid and
the two lactones. GAAS is a noncorrosive, nonvolatile, stable, in-
expensive industrial product and largely available in the market. It
is a weakly acidic aqueous solution and can promote some organic
reactions that need the assistance of a week acid. Thus, such media
may constitute alternative solvents for the development of sus-
tainable chemistry.
It is well known that spirooxindole system is important core
structure of many natural and synthetic molecules with a wide
range of utilities in medicinal chemistry. Spirooxindoles, especially
* Corresponding author. Fax: þ86 311 80787431; e-mail addresses: zhanhui@
mail.nankai.edu.cn, zhanhui@126.com (Z.-H. Zhang).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.12.081

R.-Y. Guo et al. / Tetrahedron 69 (2013) 2056e2061
2057
those spiroannulated with heterocycles at the 3-position, have
shown good biological activities.14 Owing to their important, there
is a need to augment a simple and novel method to generate
structurally varied spirooxindoles with a variety of substituents.
As part of an ongoing program geared toward the design and
development of novel and environmental benign synthetic meth-
odologies,15 we report herein a straightforward one-pot three-
component method for the synthesis of functionalized spiroox-
indoles by multiple covalent bond. To the best of our knowledge,
this is the first report for the synthesis of spirooxindole-
pyrimidines using GAAS an efficient and reusable promoting me-
dium and catalyst (Scheme 1).
(entries 8e12). The reaction conducted in glycerol also occurred to
give the corresponding product in 56% isolated yields (entry 13). It
has previously been reported in the literature that this three-
component reaction was usually carried out in the presence of
acid catalysts, such as p-toluenesulfonic acid,17 alum,18 magnetic
nanoparticle supported dodecyl benzenesulfonic acid,19 and
montmorillonite K-1020 in water or ionic liquid media. This
prompted us to investigate acidic solvent to improve the reaction.
Acetic acid was examined and displayed less efficiency (entry 14).
When the reaction proceeded in low melting mixtures, such as
citric acid-dimethylurea (DMU) and
L-(þ)-tartaric acid-choline
chloride, slightly improved yields were obtained (entries 15 and
16). To our great delight, the yield of 4a was enhanced to 95% when
GAAS was used as the solvent (entry 18). Further tests with low-
ering of the reaction temperature (entries 19e20), inferior results
in terms of reaction time and yield were observed.
This interesting finding promised a bright prospect and made us
start to investigate the substrate scope and generality of this three-
component reaction and the results are summarized in Table 2.
Various isatins bearing electron-donating and electron-withdrawing
substituents underwent the reactionwith 5,5-dimethylcyclohexane-
1,3-dione and barbituric acid to afford the desired spirooxindole-
pyrimidines (4) in high yields (Table 2, entries 1e10). This system
was tolerant to a number of functional groups. Generally, isatins
possessing electron-withdrawing showed better reactivity and
needed shorter reaction time than those with electron-donating
groups. Furthermore, the nitrogen protected isatin substrates were
also consistent with the optimized conditions (entries 11e15). In
addition, 7-substituted isatin reacted smoothly to give the corre-
sponding product 4f in 94% yield (entry 6). To our disappointment,
when the more sterically substrate, such as 4-bromoistain was sub-
jected to the reaction system, no reaction was observed.
Additionally, the substrate scope of cyclic 1,3-dicarbobonyl
compounds was further investigated. When cyclohexane-1,3-
dione was subjected to the reaction system, similar results were
observed. Other cyclic 1,3-dicarbobonyl compounds, such as
cyclopentane-1,3-dione and 2H-indene-1,3-dione, were used under
the same conditions, however, TLC and 1H NMR spectra of the re-
action mixture showed a combination of starting materials and
numerous by-products and the yield of the desired product was
very poor. Different barbituric acids, such as 1,3-dimethylbarbituric
acid and thiobarbituric acid were also tested. As revealed in Table 2,
these barbituric acids also worked well and furnished the desired
products in high yields.
Scheme 1. Synthesis of functionalized spirooxindole in GAAS.
2. Results and discussion
Initially, we conducted the model reaction of isatin, 5,5-
dimethylcyclohexane-1,3-dione and barbituric acid in different
solvents under catalyst-free conditions and the results are listed in
Table 1. Only a trace amount of products were detected in aceto-
nitrile, dimethyl sulfoxide, tetrahydrofuran, ethanol, polyethylene
glycol 400, or in neat conditions (Table 1, entries 1e6). When the
reaction was performed in deep eutectic solvents (DES),16 such as
choline chloride-urea, the desired product was obtained in 12%
yield (entry 7). Low melting sugar-urea-salt mixtures also moder-
ately promoted the reaction, and gave the product in 35e51% yields
Table 1
Reaction of isatin, 5,5-dimethylcyclohexane-1,3-dione and barbituric acid in differ-
ent solventsa
Compounds 4 are stable solids and their structures were
established by IR, 1H NMR and 13C NMR spectra, and elemental
analysis. The structure of 4ak was further confirmed by X-ray dif-
fraction analysis (Fig. 1).21
Entry Solvent
Temperature (ꢀC) Time (h) Yield (%)
1
No
100
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
Trace
Trace
Trace
Trace
Trace
Trace
12
39
36
51
35
2
CH3CN
Reflux
Reflux
Reflux
Reflux
100
Although the detailed mechanism of this three-component re-
action remains to be fully clarified, the condensation of isatin, 5,5-
dimethylcyclohexane-1,3-dione, and barbituric acid, which ratio-
nalizes the formation of product 4a, could be explained by the re-
action sequence via two plausible pathways (Scheme 2). Isatin may
react with 5,5-dimethylcyclohexane-1,3-dione to afford the aldol
adduct I, which may be subsequently attacked by barbituric acid to
furnish intermediate II. Alternatively, the reaction may be initiated
by aldol reaction of isatin with barbituric acid to give III, followed
by nucleophilic attack of 5,5-dimethylcyclohexane-1,3-dione, to
provide intermediate II. Finally, the hydroxyl group of intermediate
II attacks the adjacent carbonyl group, followed by dehydration, to
produce the expected product 4a. Only a trace amount of self-
condensation product 5 was detected. Although by-product 6
seems to be a reasonable candidate, it was not observed in the
reaction.
3
DMSO
4
THF
5
EtOH
6
PEG 400
7
Choline chlorideeurea (55:45)
100
8
9
MaltoseeDMUeNH4Cl (50:40:10) 100
-(ꢁ)-FructoseeDMU (70:30) 100
D
10
11
12
13
14
15
16
L-(þ)-Tartaric acideDMU (30:70) 100
LactoseeDMUeNH4Cl (50:40:10) 100
MannoseeDMUeNH4Cl (50:40:10) 100
Glycerol
Acetic acid
Citric acideDMU (40:60)
41
56
15
58
100
100
100
100
L
-(þ)-Tartaric acidecholine
78
chloride (50:50)
H2O
17
18
19
20
Reflux
100
60
10
1
5
38
95
21
48
GAAS
GAAS
GAAS
80
5
a
In addition, we investigated the reusability of GAAS using the
model reaction of isatin and 5-dimethylcyclohexane-1,3-dione
Reaction condition: 5,5-dimethyl-cyclohexane-dione (1 mmol), barbituric
(1 mmol), isatin (1 mmol), solvent (3 ml).

2058
R.-Y. Guo et al. / Tetrahedron 69 (2013) 2056e2061
Table 2
One-pot synthesis of functionalized spirooxindoles
Entry
R1
R2
R3
R4
R5
X
Product
Time (min)
Yielda (%)
Mp (ꢀC)
1
2
3
4
5
6
7
8
H
H
H
H
H
H
F
H
H
H
H
H
H
H
H
H
H
Me
Et
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
4t
4u
4v
4w
4x
4y
4z
4aa
4ab
4ac
4ad
4ae
4af
4ag
4ah
4ai
4aj
4ak
4al
4am
4an
4ao
4ap
4aq
4ar
4as
4at
4au
4av
4aw
4ax
4ay
4az
4ba
4bb
4bc
4bd
60
180
30
120
30
40
45
50
60
20
60
60
120
60
120
70
180
25
140
70
50
95
81
93
85
94
90
93
93
92
96
90
91
90
92
90
90
82
93
83
90
92
91
90
92
90
90
83
85
90
91
92
93
89
90
85
89
93
92
94
88
82
93
84
85
89
92
90
91
93
93
92
93
91
89
91
90
>30017
>300
267e269
293e294 (290)17
>30019
OMe
OCF3
Me
F
H
Cl
Br
I
NO2
H
H
H
H
H
H
OMe
OCF3
Me
F
>300
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
>30019
>30018
9
>30019
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
293e295 (292)18
>30018
254e256 (253e255)18
211e212
259e260 (258e259)18
>300
CH2CH2CH2CH3
Bz
CH2CH]CH2
H
H
H
H
H
>30017
>300
281e282
>30019
>30019
Cl
H
H
H
>30019
Br
NO2
H
H
H
H
Me
F
55
50
>30019
>300 (298)17
187e188
209e210
232e233
>30019
CH2CH2CH2CH3
Bz
CH2CH]CH2
H
H
H
H
H
H
Me
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
Me
H
H
H
H
H
Me
110
130
120
70
150
40
45
45
30
70
60
120
40
45
50
35
60
200
25
180
75
70
35
50
80
80
170
60
50
50
>30019
>30018
Cl
>30019
Br
NO2
H
H
Me
F
245e247 (242e245)18
282e284 (280e281)18
>30018
>30019
>30019
>30019
Cl
>30019
Br
NO2
H
OMe
OCF3
Me
F
290e291 (2888e289)19
>30017
H
293e295 (292e293)19
>300
Me
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
H
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
>300
>30019
>30019
Cl
>30019
Br
NO2
H
H
Me
F
Cl
Br
H
H
H
285 (282e283)19
>30017
>30019
>30019
>30019
>30019
>30019
>30019
H
H
H
H
H
H
60
100
140
>30019
CH2CH2CH2CH3
Bz
201e202
223e235
a
Isolated yield.
with barbituric acid. After the reaction was completed, the reaction
mixture was cooled to room temperature, the product was isolated
by simple filtration. The recovered gluconic acid aqueous solution
could be reused three additional times in subsequent reactions
without significant loss of its activity.
the addition of any additive or organic co-solvent. The notable ad-
vantages of this methodology are operational simplicity, wide sub-
strate scope, excellent functional group tolerance, environmentally
benign, inexpensive reaction medium, short reaction time, high
yield of products, and easy-handing. Further investigations on the
applications of gluconic acid aqueous solution on other catalytically
synthetic reactions are under progress in our group.
3. Conclusion
In conclusion, we have developed a novel, high efficient, green,
and sustainable protocol for synthesis of functionalized spiroox-
indoles through one-pot, three-component condensation reaction
of isatins, cyclohexane-1,3-diones, and barbituric acids using glu-
conic acid aqueous solution as an inexpensive, biodegradable,
commercially available and reusable promoting medium without
4. Experimental
4.1. General information
All solvents and chemicals were obtained commercially and
were used as received without further purification. Melting points

R.-Y. Guo et al. / Tetrahedron 69 (2013) 2056e2061
2059
were determined on an X-4 digital melting point apparatus without
correction. IR spectra were taken as KBr discs using a Bruker-
TENSOR 27 spectrometer instrument. 1H NMR and 13C NMR spec-
tra were recorded on Bruker DRX-500 spectrometer at 500 MHz
and 125 MHz, respectively, using DMSO-d6 as the solvent and TMS
as an internal standard. Elemental analyses were determined on
a Vario EL III CHNOS elemental analyzer.
4.2. Typical procedure for the synthesis of functionalized
spirooxindoles 4a
A mixture of isatin (0.15 g, 1 mmol), 5,5-dimethylcyclohexane-
dione (0.14 g, 1 mmol), barbituric (0.13 g, 1 mmol) in gluconic acid
aqueous solution (3 ml) was stirred at 100 ꢀC. The reaction progress
was monitored by thin-layer chromatography. After completion of
the reaction, the reaction mixture was cooled to room temperature.
Then, the precipitated product was filtered and washed with water.
The crude product was crystallized from ethanol to give 4a.
4.3. Characterization data
Fig. 1. Crystal structure of compound 4ak.
4.3.1. 50-Methoxy-8,8-dimethyl-8,9-dihydrospiro[chromeno[2,3-d]
pyrimidine-5,30-indoline]-2,20,4,6(1H,3H,7H)-tetraone (4b). White
crystals, mp>300 ꢀC; IR (KBr): 3340, 2960, 1685, 1624, 1538, 1521,
1482, 1436, 1363, 1332, 1307, 1209, 1151, 1026, 873, 794, 696 cmꢁ1
;
1H NMR (DMSO-d6, 500 MHz)
d: 0.97 (s, 3H, CH3), 1.02 (s, 3H, CH3),
2.07 and 2.18 (AB system, JAB¼16.0 Hz, 2H, CH2), 2.54 and 2.63 (AB
system, JAB¼17.5 Hz, 2H, CH2), 3.60 (s, 3H, OCH3), 6.61e6.64 (m, 3H,
ArH), 10.18 (s, 1H, NH), 10.99 (s, 1H, NH) ppm; 13C NMR (DMSO-d6,
125 MHz) d: 27.2, 28.2, 32.2, 46.0, 50.9, 55.8, 89.5, 109.1, 110.8, 112.6,
113.5, 135.3, 137.7, 149.6, 153.6, 155.0, 161.9, 163.7, 178.2, 195.4 ppm;
Anal. Calcd for C21H19N3O6: C, 61.61; H, 4.68; N, 10.26. Found: C,
61.45; H, 4.80; N, 10.08.
4.3.2. 8,8-Dimethyl-50-(trifluoromethoxy)-8,9-dihydrospiro-[chro-
meno[2,3-d]pyrimidine-5,30-indoline]-2,20,4,6(1H,3H,7H)-tetraone
(4c). White crystals, mp 267e269 ꢀC; IR (KBr): 3310, 2966, 1627,
1533, 1489, 1421, 1363, 1332, 1240, 1176, 1165, 1074, 1003, 885,
771 cmꢁ1; 1H NMR (DMSO-d6, 500 MHz)
d: 0.97 (s, 3H, CH3), 1.04 (s,
3H, CH3), 2.07 and 2.23 (AB system, JAB¼16.0 Hz, 2H, CH2), 2.54 and
2.77 (AB system, JAB¼17.5 Hz, 2H, CH2), 6.77 (d, J¼8.5 Hz), 7.09 (d,
J¼8.5 Hz, 1H, ArH), 7.16 (s, 1H, ArH), 10.58 (s, 1H, NH), 11.06 (s, 1H,
NH), 12.25 (s, 1H, NH) ppm; 13C NMR (DMSO-d6, 125 MHz)
d: 26.7,
28.3, 32.2, 45.9, 50.7, 88.9, 109.3, 113.0, 117.5, 119.6, 121.4, 121.6,
135.6, 143.2, 143.5, 149.5, 153.8, 162.0, 164.1, 178.4, 195.6 ppm; Anal.
Calcd for C21H16F3N3O6: C, 54.43; H, 3.48; N, 9.07. Found: C, 54.24;
H, 3.66; N, 9.25.
4.3.3. 70-Fluoro-8,8-dimethyl-8,9-dihydrospiro[chromeno[2,3-d]py-
rimidine-5,30-indoline]-2,20,4,6(1H,3H,7H)-tetraone (4f). Light yellow
solid, mp>300 ꢀC; IR (KBr): 3340, 2958, 2821, 1685, 1624,1521, 1490,
1471,1419,1307,1236,1195,1178,1155,1089,1001, 852, 734 cmꢁ1; 1H
NMR (DMSO-d6, 500 MHz) d: 0.94 (s, 3H, CH3), 1.00 (s, 3H, CH3), 2.06
and 2.18 (AB system, JAB¼16.0 Hz, 2H, CH2), 2.54 and 2.63 (AB system,
JAB¼17.5 Hz, 2H, CH2), 6.77e6.81 (m, 1H, ArH), 6.84 (d, J¼7.5 Hz, 1H,
ArH), 6.98 (d, J¼9.0 Hz, 1H, ArH), 10.85 (s, 1H, NH), 11.05 (s, 1H, NH)
ppm; 13C NMR (DMSO-d6, 125 MHz)
d: 27.2, 28.1, 32.2, 45.8, 50.7,
89.2, 113.2, 115.6 (d, 2JCF¼17.4 Hz), 119.4, 122.1 (d, 3JCF¼5.4 Hz), 131.2,
4
131.3, 136.8 (d, JCF¼3.8 Hz), 145.4, 147.3, 149.5, 153.6, 163.1 (d,
1JCF¼249.6 Hz), 178.1, 195.6 ppm; Anal. Calcd for C20H16FN3O5: C,
60.45; H, 4.06; N, 10.57. Found: C, 60.61; H, 3.89; N, 10.38.
4.3.4. 10-Butyl-8,8-dimethyl-8,9-dihydrospiro[chromeno[2,3-d]pyrim-
idine-5,30-indoline]-2,20,4,6(1H,3H,7H)-tetraone (4m). White crys-
tals, mp 211e212 ꢀC; IR (KBr): 3414, 2954, 1627, 1521, 1480, 1465,
1425, 1361, 1338, 1230, 1168, 1083, 923, 754 cmꢁ1; 1H NMR (DMSO-
Scheme 2. Plausible reaction mechanism.

2060
R.-Y. Guo et al. / Tetrahedron 69 (2013) 2056e2061
d6, 500 MHz)
d
: 0.91 (t, J¼7.5 Hz, 3H, CH3), 0.96 (s, 3H, CH3), 1.03 (s,
152.5, 159.9, 163.6, 176.6, 195.4 ppm; Anal. Calcd for C26H29N3O5: C,
67.37; H, 6.31; N, 9.07. Found: C, 67.18; H, 6.50; N, 8.91.
3H, CH3),1.43 (sext, J¼7.5 Hz, 2H, CH2),1.63 (quin, J¼7.5 Hz, 2H, CH2),
2.05 and 2.19 (AB system, JAB¼16.0 Hz, 2H, CH2), 2.56 and 2.67 (AB
system, JAB¼17.5 Hz, 2H, CH2), 3.56e3.67 (m, 2H, CH2), 6.85 (t,
J¼7.5 Hz, 1H, ArH), 6.90 (d, J¼7.5 Hz, 1H, ArH), 7.03 (d, J¼7.5 Hz, 1H,
ArH), 7.16 (t, J¼7.5 Hz, 1H, ArH), 11.01 (s, 1H, NH), 12.22 (s, 1H, NH)
4.3.9. 10-Benzyl-1,3,8,8-tetramethyl-8,9-dihydrospiro [chromeno[2,3-
d]pyrimidine-5,30-indoline]-2,20,4,6(1H,3H,7H)-tetraone (4y). White
crystals, mp 209e210 ꢀC; IR (KBr): 3032, 2955, 1654, 1629, 1608,
ppm; 13C NMR (DMSO-d6, 125 MHz)
d:14.4, 20.2, 27.1, 28.2, 29.3,
1489, 1458, 1371, 1356, 1317, 1273, 1230, 1178, 1101, 964, 754 cmꢁ1
;
32.2, 45.0, 50.7, 89.5, 107.9, 113.5, 121.7, 123.2, 128.5, 133.3, 145.3,
149.5, 153.6, 161.9, 163.8, 176.5, 195.3 ppm; Anal. Calcd for
C24H25N3O5: C, 66.19; H, 5.79; N, 9.65. Found: C, 65.99; H, 5.98; N,
9.56.
1H NMR (DMSO-d6, 500 MHz)
d: 1.01 (s, 3H, CH3), 1.08 (s, 3H, CH3),
2.15 and 2.28 (AB system, JAB¼16.0 Hz, 2H, CH2), 2.70 and 2.80 (AB
system, JAB¼17.5 Hz, 2H, CH2), 3.05 (s, 3H, NeCH3), 3.43 (s, 3H,
NeCH3), 4.85 and 4.97 (AB system, JAB¼16.0 Hz, 2H, PhCH2), 6.55 (d,
J¼7.5 Hz, 1H, ArH), 6.87 (t, J¼7.5 Hz, 1H, ArH), 7.06e7.10 (m, 2H,
ArH), 7.28 (t, J¼7.5 Hz, 1H, ArH), 7.35 (t, J¼7.5 Hz, 2H, ArH), 7.64 (d,
4.3.5. 1’-Allyl-8,8-dimethyl-8,9-dihydrospiro[chromeno[2,3-d]pyrim-
idine-5,30-indoline]-2,20,4,6(1H,3H,7H)-tetraone (4o). White crys-
tals, mp>300 ꢀC; IR (KBr): 3414, 2928, 1568, 1525, 1504, 1435, 1263,
1186,1166,1136,1097,1082, 993, 871, 758 cmꢁ1; 1H NMR (DMSO-d6,
J¼7.5 Hz, 2H, ArH) ppm; 13C NMR (DMSO-d6, 125 MHz)
d: 27.2, 28.2,
29.8, 32.3, 44.7, 45.9, 50.8, 89.9, 108.7, 113.4, 122.2, 123.5, 127.4,
127.7, 128.6, 128.8, 133.0, 137.2, 145.0, 150.0, 152.5, 160.0, 163.9,
177.2, 195.6 ppm; Anal. Calcd for C29H27N3O5: C, C, 70.01; H, 5.47; N,
8.45. Found: C, 69.82; H, 5.66; N, 8.23.
500 MHz) d: 0.98 (s, 3H, CH3), 1.03 (s, 3H, CH3), 2.07 and 2.21 (AB
system, JAB¼16.0 Hz, 2H, CH2), 2.56 and 2.69 (AB system,
JAB¼17.5 Hz, 2H, CH2), 4.23e4.34 (m, 2H, NeCH2), 5.17 (dd, J¼10.5,
1.5 Hz, 1H, ]CH2), 5.61 (dd, J¼17.0, 1.5 Hz, 1H, ]CH2), 5.87e5.94
(m, 1H, ]CH), 6.79 (d, J¼7.5 Hz, 1H, ArH), 6.88 (t, J¼7.5 Hz, 1H, ArH),
7.07 (d, J¼7.5 Hz, 1H, ArH), 7.16 (t, J¼7.5 Hz, 1H, ArH), 11.06 (s, 1H,
4.3.10. 10-Allyl-1,3,8,8-tetramethyl-8,9-dihydrospiro [chromeno[2,3-
d]pyrimidine-5,30-indoline]-2,20,4,6(1H,3H,7H)-tetraone (4z). White
crystals, mp 232e233 ꢀC; IR (KBr): 2958, 2872, 1541, 1425, 1286,
NH), 12.28 (s, 1H, NH) ppm; 13C NMR (DMSO-d6, 125 MHz)
d: 27.1,
1278, 1259, 1230, 1134, 1099, 1049, 1028, 1003, 925, 761 cmꢁ1
;
1H
28.2, 32.3, 42.9, 45.1, 50.7, 55.4, 89.4, 108.6, 113.5, 117.2, 122.0, 123.2,
128.4, 132.8, 133.1, 144.9, 149.5, 153.6, 161.9, 163.9, 176.6, 195.4 ppm;
Anal. Calcd for C23H21N3O5: C, 65.86; H, 5.05; N, 10.02. Found: C,
66.05; H, 4.90; N, 9.83.
NMR (DMSO-d6, 500 MHz) d: 1.00 (s, 3H, CH3), 1.06 (s, 3H, CH3), 2.12
and 2.23 (AB system, JAB¼16.0 Hz, 2H, CH2), 2.68 and 2.77 (AB
system, JAB¼17.5 Hz, 2H, CH2), 3.02 (s, 3H, NeCH3), 3.42 (s,
3H, NeCH3), 4.26e4.37 (m, 2H, NeCH2), 5.21 (dd, J¼10.0,
2.0 Hz, 1H, ]CH2), 5.63 (dd, J¼17.5, 2.0 Hz, 1H, ]CH2), 5.90e5.97
(m, 1H, ]CH), 6.81 (d, J¼7.5 Hz, 1H, ArH), 6.88 (t, J¼7.5 Hz, 1H, ArH),
7.07 (d, J¼7.5 Hz, 1H, ArH), 7.17 (t, J¼7.5 Hz, 1H, ArH) ppm; 13C NMR
4.3.6. 50-Methoxy-1,3,8,8-tetramethyl-8,9-dihydrospiro [chromeno
[2,3-d]pyrimidine-5,30-indoline]-2,20,4,6(1H,3H,7H)-tetraone
(4q). White crystals, mp>300 ꢀC; IR (KBr): 3356, 2956, 1627, 1458,
(DMSO-d6, 125 MHz) d: 27.2, 28.2, 29.8, 32.3, 43.0, 45.8, 50.8, 89.8,
1371, 1354, 1316, 1298, 1265, 1215, 1184, 1165, 1084, 1031, 785 cmꢁ1
;
108.6, 113.5, 117.5, 122.0, 123.3, 128.6, 132.9, 133.0, 144.9, 150.0,
152.5, 160.0, 163.7, 176.6, 195.4 ppm; Anal. Calcd for C25H25N3O5: C,
67.10; H, 5.63; N, 9.39. Found: C, 66.92; H, 5.48; N, 9.21.
1H NMR (DMSO-d6, 500 MHz)
d: 1.00 (s, 3H, CH3), 1.05 (s, 3H, CH3),
2.12 and 2.21 (AB system, JAB¼16.0 Hz, 2H, CH2), 2.65 and 2.73 (AB
system, JAB¼17.5 Hz, 2H, CH2), 3.03 (s, 3H, CH3), 3.40 (s, 3H, CH3),
3.61 (s, 3H, OCH3), 6.63e6.68 (m, 3H, ArH), 10.22 (s, 1H, NH) ppm;
4.3.11. 50-Methoxy-8,8-dimethyl-2-thioxo-2,3,8,9-tetrahydrospiro
[chromeno[2,3-d]pyrimidine-5,30-indoline]-20,4,6(1H,7H)-trione
(4ao). White crystals, mp>300 ꢀC; IR (KBr): 3357, 2928, 1670, 1610,
1490, 1334, 1303, 1203, 1190, 1176, 1203, 1157, 1105, 1037, 956,
13C NMR (DMSO-d6, 125 MHz)
d: 27.2, 28.09, 28.1, 29.7, 32.2, 46.8,
51.0, 55.7, 89.9, 109.1, 111.1, 112.5, 113.5, 135.2, 137.8, 150.1, 152.4,
155.0, 159.9, 163.5, 178.2, 195.4 ppm; Anal. Calcd for C23H23N3O6: C,
63.15; H, 5.30; N, 9.61. Found: C, 59.96; H, 5.12; N, 9.80.
786 cmꢁ1; 1H NMR (DMSO-d6, 500 MHz)
d: 0.97 (s, 3H, CH3), 1.01 (s,
3H, CH3), 2.07 and 2.18 (AB system, JAB¼16.0 Hz, 2H, CH2), 2.53 and
2.63 (AB system, JAB¼17.5 Hz, 2H, CH2), 3.59 (s, 3H, OCH3), 6.59 (d,
J¼8.5 Hz, 1H, ArH), 6.63 (dd, J¼8.5, 2.0 Hz, 1H, ArH), 6.71 (d,
J¼2.0 Hz,1H, ArH),10.22 (s,1H, NH),12.37 (s,1H, NH) ppm; 13C NMR
4.3.7. 1,3,8,8-Tetramethyl-50-(trifluoromethoxy)-8,9-dihydrospiro
[chromeno[2,3-d]pyrimidine-5,30-indoline]-2,20,4,6(1H,3H,7H)-tet-
raone (4r). White crystals, mp 281e282 ꢀC; IR (KBr): 3227, 2962,
1423, 1082, 1057, 1039, 989, 966, 831, 680 cmꢁ1; 1H NMR (DMSO-d6,
(DMSO-d6, 125 MHz) d: 27.2, 28.1, 32.2, 46.0, 49.1, 50.8, 55.8, 94.2,
500 MHz)
d
: 0.98 (s, 3H, CH3), 1.06 (s, 3H, CH3), 2.10 and 2.26 (AB
109.2, 111.0, 112.9, 113.3, 134.7, 137.8, 152.9, 155.1, 159.6, 163.6, 174.0,
177.6, 195.3 ppm; Anal. Calcd for C21H19N3O5S: C, 59.28; H, 4.50; N,
9.88. Found: C, 59.10; H, 4.68; N, 10.06.
system, JAB¼16.0 Hz, 2H, CH2), 2.64 and 2.78 (AB system, JAB¼17.5 Hz,
2H, CH2), 3.04 (s, 3H, NeCH3), 3.41 (s, 3H, NeCH3), 6.79 (d, J¼8.5 Hz),
7.09 (d, J¼8.5 Hz, 1H, ArH), 7.10 (s, 1H, ArH), 10.61 (s, 1H, NH) ppm;
13C NMR (DMSO-d6,125 MHz)
d: 26.6, 28.1, 28.3, 29.7, 32.2, 46.6, 50.8,
4.3.12. 8,8-Dimethyl-2-thioxo-50-(trifluoromethoxy)-2,3,8,9-
tetrahydrospiro[chromeno[2,3-d]pyrimidine-5,30-indoline]-
20,4,6(1H,7H)-trione (4ap). White crystals, mp>300 ꢀC; IR (KBr):
3360, 2960, 1624, 1489, 1456, 1396, 1363, 1136, 1093, 1068, 1043,
89.3, 109.4, 113.1, 117.5, 119.6, 121.6, 135.4, 143.2, 143.6, 150.0, 152.6,
160.0, 163.9, 178.3, 195.5 ppm; Anal. Calcd for C23H20F3N3O6: C,
56.21; H, 4.10; N, 8.55. Found: C, 56.03; H, 3.92; N, 8.71.
831, 686 cmꢁ1 1H NMR (DMSO-d6, 500 MHz)
; d: 0.97 (s, 3H, CH3),
4.3.8. 10-Butyl-1,3,8,8-tetramethyl-8,9-dihydrospiro [chromeno[2,3-d]
1.04 (s, 3H, CH3), 2.07 and 2.23 (AB system, JAB¼16.0 Hz, 2H, CH2),
2.54 and 2.70 (AB system, JAB¼17.5 Hz, 2H, CH2), 6.79 (d, J¼8.5 Hz),
7.09 (d, J¼8.5 Hz, 1H, ArH), 7.25 (s, 1H, ArH), 10.63 (s, 1H, NH), 12.44
pyrimidine-5,30-indoline]-2,20,4,6(1H,3H,7H)-tetraone
(4x). White
crystals, mp 187e188 ꢀC; IR (KBr): 3423, 2960, 1626, 1313,1211, 1180,
1155, 1139, 1091, 1049, 1031, 958, 893, 752 cmꢁ1; 1H NMR (DMSO-d6,
(s, 1H, NH), 12.25 (s, 1H, NH) ppm; 13C NMR (DMSO-d6, 125 MHz)
d:
500 MHz)
d
: 0.94 (t, J¼7.5 Hz, 3H, CH3), 0.99 (s, 3H, CH3), 1.05 (s, 3H,
26.7, 28.3, 32.2, 45.9, 50.7, 93.6, 109.4, 112.8, 117.8, 121.6, 135.0,
143.3, 143.5, 153.3, 159.7, 164.2, 174.1, 177.9, 199.5 ppm; Anal. Calcd
for C21H16F3N3O5S: C, 52.61; H, 3.36; N, 8.76. Found: C, 52.80; H,
3.55; N, 8.60.
CH3),1.45 (sext, J¼7.5 Hz, 2H, CH2),1.67 (quin, J¼7.5 Hz, 2H, CH2), 2.08
and 2.22 (AB system, JAB¼16.0 Hz, 2H, CH2), 2.67 and 2.76 (AB system,
JAB¼17.5 Hz, 2H, CH2), 3.01 (s, 3H, NeCH3), 3.42 (s, 3H, NeCH3),
3.58e3.70 (m, 2H, CH2), 6.86 (t, J¼7.5 Hz, 1H, ArH), 6.92 (d, J¼7.5 Hz,
1H, ArH), 7.03 (d, J¼7.5 Hz, 1H, ArH), 7.18 (t, J¼7.5 Hz, 1H, ArH) ppm;
4.3.13. 10-Butyl-8,8-dimethyl-2-thioxo-2,3,8,9-tetrahydrospiro[chro-
meno[2,3-d]pyrimidine-5,30-indoline]-20,4,6(1H,7H)-trione
(4bc). White crystals, mp 201e202 ꢀC; IR (KBr): 2958, 2872, 1662,
13C NMR (DMSO-d6,125 MHz)
d: 14.3, 20.2, 27.2, 28.2, 29.3, 29.8, 32.2,
45.8, 50.8, 89.8, 107.9, 113.5, 121.8, 123.4, 128.7, 133.1, 145.2, 150.0,

R.-Y. Guo et al. / Tetrahedron 69 (2013) 2056e2061
2061
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1610, 1554, 1491, 1465, 1452, 1406, 1363, 1340, 1309, 1203, 1165,
1039 cmꢁ1 1H NMR (DMSO-d6, 500 MHz)
;
d: 0.92 (t, J¼7.5 Hz, 3H,
CH3), 0.98 (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.43 (sext, J¼7.5 Hz, 2H,
CH2), 1.64 (quin, J¼7.5 Hz, 2H, CH2), 2.07 and 2.21 (AB system,
JAB¼16.0 Hz, 2H, CH2), 2.57 and 2.69 (AB system, JAB¼17.5 Hz, 2H,
CH2), 3.60e3.65 (m, 2H, CH2), 6.87 (t, J¼7.5 Hz, 1H, ArH), 6.92 (d,
J¼7.5 Hz, 1H, ArH), 7.10 (d, J¼7.5 Hz, 1H, ArH), 7.19 (t, J¼7.5 Hz, 1H,
ArH), 12.38 (s, 1H, NH), 13.74 (s, 1H, NH) ppm; 13C NMR (DMSO-d6,
125 MHz) d: 14.3, 20.2, 27.1, 28.2, 29.3, 32.2, 45.0, 50.7, 94.1, 108.0,
113.3, 121.8, 123.5, 128.7, 132.7, 145.3, 153.0, 159.5, 163.8, 174.1, 176.0,
195.3 ppm; Anal. Calcd for C24H25N3O4S: C, 63.84; H, 5.58; N, 9.31.
Found: C, 64.01; H, 5.76; N, 9.12.
7. Gu, Y. Green Chem. 2012, 14, 2091e2128.
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meno[2,3-d]pyrimidine-5,30-indoline]-20,4,6(1H,7H)-trione
(4bd). White crystals, mp 223e225 ꢀC; IR (KBr): 3444, 2926, 1610,
1556, 1489, 1465, 1456, 1361, 1311, 1203, 1163, 1074, 1041, 1010, 923,
750 cmꢁ1; 1H NMR (DMSO-d6, 500 MHz)
d: 1.00 (s, 3H, CH3), 1.06 (s,
3H, CH3), 2.13 and 2.26 (AB system, JAB¼16.0 Hz, 2H, CH2), 2.60 and
2.72 (AB system, JAB¼17.5 Hz, 2H, CH2), 4.89 (s, 2H, CH2), 6.55 (d,
J¼7.5 Hz, 1H, ArH), 6.88 (t, J¼7.5 Hz, 1H, ArH), 7.09 (t, J¼7.5 Hz, 1H,
ArH), 7.16 (d, J¼7.5 Hz, 1H, ArH), 7.27 (t, J¼7.5 Hz, 1H, ArH), 7.33 (t,
J¼7.5 Hz, 2H, ArH), 7.61 (d, J¼7.5 Hz, 2H, ArH),12.50 (s,1H, NH) ppm;
11. Pace, V.; Hoyos, P.; Castoldi, L.; de Maria, P. D.; Alcantara, A. R. ChemSusChem
2012, 5, 1369e1379.
€
12. (a) Imperato, G.; Vasold, R.; Konig, B. Adv. Synth. Catal. 2006, 348, 2243e2247;
€
(b) Imperato, G.; Eibler, E.; Niedermaier, J.; Konig, B. Chem. Commun. 2005,
1170e1172; (c) Imperato, G.; Hoger, S.; Lenoir, D.; Konig, B. Green Chem. 2006, 8,
€
1051e1055; (d) Zhang, Z. H.; Zhang, X. N.; Mo, L. P.; Li, Y. X.; Ma, F. P. Green
13C NMR (DMSO-d6, 125 MHz)
d: 27.1, 28.2, 32.3, 44.6, 45.2, 50.7,
Chem. 2012, 14, 1502e1506; (e) Gore, S.; Baskaran, S.; Koenig, B. Green Chem.
€
2011, 13, 1009e1013; (f) Ilgen, F.; Konig, B. Green Chem. 2009, 11, 848e854; (g)
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159.8, 164.1, 174.1, 176.8, 195.6 ppm; Anal. Calcd for C27H23N3O4S: C,
66.79; H, 4.77; N, 8.65. Found: C, 66.96; H, 4.59; N, 8.83.
€
Ilgen, F.; Ott, D.; Kralisch, D.; Reil, C.; Palmberger, A.; Konig, B. Green Chem.
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Acknowledgements
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We gratefully acknowledge financial support from the National
Natural Science Foundation of China (21272053, 21072042 and
20872025) and Nature Science Foundation of Hebei Province
(B2011205031).
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