NHC-catalyzed oxidative γ-addition of α,β-unsaturated aldehydes to isatins: A high-efficiency synthesis of spirocyclic oxindole-dihydropyranones

Article abstract of DOI:10.1039/c3ob42008f

This manuscript discloses an efficient construction of the spirocyclic oxindole-dihydropyranone scaffold via the N-heterocyclic carbene (NHC)-catalyzed oxidative γ-functionalization of α,β-unsaturated aldehydes bearing γ-H with isatin derivatives. The ready availability of the starting materials, easy work-up, mild reaction conditions and the potential utilization value of the products make this strategy attractive.

Full text of DOI:10.1039/c3ob42008f

Organic &
Biomolecular Chemistry
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NHC-catalyzed oxidative γ-addition of
α,β-unsaturated aldehydes to isatins:
a high-efficiency synthesis of spirocyclic
oxindole-dihydropyranones
Cite this: Org. Biomol. Chem., 2014,
12, 1885
Rui Liu,a Chenxia Yu,a Zhaoxin Xiao,a Tuanjie Li,a Xiangshan Wang,a Yuanwei Xiea and
Changsheng Yao*b
Received 5th October 2013,
Accepted 30th December 2013
This manuscript discloses an efficient construction of the spirocyclic oxindole-dihydropyranone scaffold
via the N-heterocyclic carbene (NHC)-catalyzed oxidative γ-functionalization of α,β-unsaturated alde-
hydes bearing γ-H with isatin derivatives. The ready availability of the starting materials, easy work-up,
mild reaction conditions and the potential utilization value of the products make this strategy attractive.
DOI: 10.1039/c3ob42008f
www.rsc.org/obc
Introduction
Spirooxindole alkaloid scaffolds are frequently found in
natural products and biologically active compounds.1 Their
derivatives with wide therapeutic potential have aroused great
research interest for developing facile approaches to the gen-
eration of multi-functionalized spirooxindoles and natural
product-like derivatives from readily available and inexpensive
raw materials.2–5 In past decades, much effort has been
devoted to the efficient assembly of diversely structured spiro-
oxindoles bearing a tetrasubstituted all-carbon or nitrogen-
containing stereocenter at the C3 position, such as in a spiro-
cycloalkane-oxindole framework and a spirocyclic oxindole
piperidine (or pyrrolidine) motif.6 However, to the best of our
knowledge, strategies were not well explored for the fabrication
of the medicinally important oxa-spirooxindole scaffold
(Fig. 1),7–9 an attractive combination of pharmacologically sig-
nificant pyran and oxindole units.10
In 2012, Cassani et al. and Xie et al. put forward aminocata-
lyst-promoted construction of oxa-spirooxindole scaffolds
independently.11,12 Metal-mediated multi-step transformations
could give rise to the oxa-spirooxindole derivatives success-
fully.10,13,14 These biologically significant skeletons could also
be assembled through Prins-type cyclization.15,16 In addition,
some one-pot syntheses were developed to construct functiona-
lized oxa-spirooxindole frameworks.17,18 These works could
Fig. 1 Some oxa-spirocyclic oxindole scaffolds present in natural pro-
ducts and pharmaceutical applications.
provide effective strategies to prepare the oxa-spirooxindoles.
However, the use of a precious metal catalyst, the complexity
of the starting material and the multi-step procedure associ-
ated with these approaches means that there is an urgent need
to devise a new alternative method to synthesize these spiro
compounds with bioactive potential.
Recently, the N-heterocyclic carbene (NHC)-catalyzed um-
polung reaction of aldehydes, e.g., the benzoin reaction and the
Stetter reaction, paved new avenues to structurally and stereo-
chemically densely functionalized molecules.19 Ye et al. and
our group developed the cascade assembly of the oxa-spiroox-
indole scaffold through the NHC-bound vinyl enolate A (or B)
generated from a ketene or α-bromoenal in the presence
of NHC (Scheme 1).20,21 Lately, Chi et al. have disclosed an
elegant way to yield the same intermediate A from the catalytic
oxidation of an enal bearing a γ-H by NHC (Scheme 2).22 Thus
we envisaged that NHC-catalyzed oxidative reaction of an enal
bearing a γ-H and isatin would afford spirocyclic oxindole-
dihydropyranone derivatives readily (Scheme 3). In connection
with our current research interest in the preparation of biologi-
cally relevant cyclic compounds through NHC-catalyzed
cascade reactions,21,23 we shall herein report our recent results
aSchool of Chemistry and Chemical Engineering, Jiangsu Key Laboratory of Green
Synthetic Chemistry for Functional Materials, Jiangsu Normal University,
Xuzhou 221116, P. R. China
bSchool of Chemistry and Chemical Engineering, Key Laboratory of Biotechnology for
Medicinal Plant, Jiangsu Normal University, Xuzhou, 221116, P. R. China.
E-mail: csyao@jsnu.edu.cn
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Table 1 Optimization of the reaction conditions
Scheme 1 Assembly of the oxa-spirooxindole scaffold through NHC-
bound vinyl enolate.
Scheme 2 Oxidation of γ-functionalization of enals to afford NHC-
bound vinyl enolate.
Precat.
Entry (mol%) Sol.
Base
(mol%)
T
Yieldb
Oxidanta [°C] [%]
1
2
3
4
5
6
7
8
4a (15)
4b (15)
4c (15)
4d (15)
4e (15)
4c (10)
4c (20)
4c (15)
4c (15)
4c (15)
4c (15)
4c (15)
4c (15)
4c (15)
4c (15)
4c (15)
4c (15)
4c (15)
4c (15)
4c (15)
4c (15)
4c (15)
4c (15)
THF
THF
THF
THF
THF
THF
THF
NaH (115)
NaH (115)
NaH (115)
NaH (115)
NaH (115)
NaH (115)
NaH (115)
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
30
20
25
25
25
25
25
25
n.r.
23.
51
n.r.
Trace
42.
48.
n.r.
23
49
n.r.
45
72
55
69
59
43
51
Trace
n.r.
n.r.
n.r.
n.r.
Toluene NaH (115)
Scheme 3 An envisaged pathway to give spirocyclic oxindole-dihydro-
pyranone derivatives.
9
CH2Cl2
CH3OH
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
NaH (115)
NaH (115)
tBuOK (115)
K2CO3 (115)
10
11
12
13
14
15
16
17
18
19
20
21
22
Cs2CO3 (115) 5a
Cs2CO3 (110) 5a
Cs2CO3 (120) 5a
Cs2CO3 (115) 5a
Cs2CO3 (115) 5a
Cs2CO3 (115) 5b
Cs2CO3 (115) 5c
Cs2CO3 (115) 5d
Cs2CO3 (115) 5e
Cs2CO3 (115) 5f
Cs2CO3 (115) 5g
Scheme 4 An NHC-catalyzed oxidative synthesis of spirocyclic oxi- 23
ndole-dihydropyranone derivatives.
a 100 mol% oxidants were used. b Isolated yield; n.r. = no reaction.
on oxidative γ-functionalization of enals under NHC catalysis
to give spirocyclic oxindole-dihydropyranones (Scheme 4).
to optimize the reaction conditions. As shown in Table 1, we
screened precatalysts using different thiazole, imidazolium
salts 4a–4e and the desired result was obtained when the reac-
tion was conducted in the presence of 4c for the synthesis of
product 3a. Subsequently, we surveyed several readily available
solvents and the results revealed THF should be optimal in
terms of yield. When the reaction was performed in toluene or
CH2Cl2, the yield dropped sharply. After that, we found that
Cs2CO3 was the best one among several bases that were
studied (K2CO3, NaH and t-BuOK) (Table 1, entries 3, 11–13). A
loading of Cs2CO3 of 115 mol% was found to be preferable,
Results and discussion
To test our hypothesis, a detailed investigation was done on
the conditions of the formal [4 + 2] reaction of 3-methylbut-
2-enal 1a with 1-methylindoline-2,3-dione 2a (Table 1). We first
selected quinone 5a, previously explored in NHC-catalyzed
oxidations in numerous studies,24 as a starting oxidant. Then,
the influences of NHCs, bases and solvents were investigated
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Table 2 Synthesis of spirocyclic oxindole dihydropyranones
Scheme 5 Asymmetric annulation catalyzed by chiral precatalysts.
Entry
R1
R2
R3
R4
Product
Yielda (%)
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
Me
Et
Allyl
Bn
Me
Et
Allyl
Bn
Me
Et
Bn
Me
Me
Me
Me
H
H
H
H
H
Me
Me
Me
Me
OMe
OMe
OMe
F
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
72
77
73
76
71
75
72
77
80
68
69
79
75
78
81
69
9
10
11
12
13
14
15
16
Cl
Me
H
Ph
Me
H
a Isolated yield
leading to a high yield at 25 °C (Table 1, entry 13). However,
increasing the concentration provided a lower yield, while
reducing the amount of base below 115 mol% resulted in an
incomplete reaction (Table 1, entries 14 and 15). Then, several
typical oxidants including MnO2,25 H2O2, PCC, mCPBA, Dess–
Martin periodinane and phenazine 5b26 were examined.
However, no expected products were obtained. Thus quinone
5a was chosen as the ideal oxidant to explore the scope of this
NHC-catalyzed oxidation.
Scheme 6 A proposed reaction mechanism.
enantioselectivity. Recent results concerning co-catalyzation of
Lewis acids and NHC promoted us to investigate this reaction
employing a NHC–Lewis acid approach instead of modifying
the NHC catalysts to enhance the enantioselectivity.22,29 Dis-
appointingly, the combination of chiral triazolium salt 4f with
Yb(OTf)3 as a Lewis acid co-catalyst led to formation of 3a in
the highest enantioselectivity (33% ee, Scheme 5). It is clear
that the level of chiral induction is not ideal yet. We are
currently designing new catalysts to perfect this reaction from
the standpoint of enantioselectivity.
An envisioned and detailed mechanism of the above
mentioned transformation can be rationalized as shown in
Scheme 6. Homoenolate intermediate C, generated from the
reaction of enal with the NHC, was transformed into D
through a3→d3 umpolung. The vinyl enolate intermediate B
likely came from γ-deprotonation of the oxidatively generated
unsaturated acylazolium ion D. The vinyl enolate B then
underwent a formal [4 + 2] reaction with isatin 2a to eventually
afford product 3a and regenerated NHC 4c for the next cataly-
tic cycle.
Having established an optimal protocol for the reaction, the
scope and generality of the enal and isatin substrates were
examined under the optimised conditions. We first examined
the scope of the reaction towards α,β-unsaturated aldehydes
(Table 2). Aryl and aliphatic enals were well applied in this
transformation, leading to the desired spirocyclic oxindole-
dihydropyranones in excellent yields. Then, the scope of isatin
substrate was investigated. Methyl and methoxy groups on the
aromatic ring of the isatin were compatible with the reaction
conditions. Moreover, different protecting groups on the nitro-
gen of the isatin backbone were also examined. Various pro-
tecting groups, such as methyl, ethyl, allyl and benzyl groups,
were tolerated effectively, affording the products with good
yields. It should be mentionable that isatin without any pro-
tecting groups attached also worked well and gave the desired
product successfully (Table 2, entry 16), which highlighted the
wide application scope of this NHC-catalyzed oxidative cyclization.
Intrigued by the prospect of developing an enantioselective
entry to these attractive products, we screened known chiral
triazolium salts as catalysts. Several chiral NHCs that have suc-
ceeded in the generation of asymmetric homoenolate,27
Conclusions
enolate,28 and acyl anion19o,p were used to catalyze this In summary, we have presented a new method to synthesize
reaction. However, the reaction proceeded in poor spirocyclic oxindole-dihydropyranones via the oxidatively
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generated vinyl enolate from enals catalyzed by NHC. More 7.6 Hz, 1H, ArH), 6.06 (s, 1H, CHv), 5.83–5.80 (m, 1H, CHv),
importantly, this study not only provides an efficient approach 5.26 (d, J = 13.6 Hz, 2H, CH2v), 4.31 (d, J = 1.2 Hz, 2H, CH2),
of NHC-mediated γ-functionalization of enals with the help of 2.88 (d, J = 18.0 Hz, 1H, HCH), 2.62 (d, J = 18.4 Hz, 1H, HCH),
external oxidation to synthesize spirocyclic oxindole-dihydro- 2.06 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ 172.4, 162.7,
pyranones, but also expands on the applications of NHC- 154.2, 142.3, 130.9, 130.6, 127.9, 123.9, 123.4, 118.2, 116.6,
catalyzed reactions. Explorations of mechanistic studies, 109.8, 79.6, 42.6, 35.3, 23.2; IR (potassium bromide) (v, cm−1):
functionalization of less reactive sites of common substrates 2985, 2919, 1727, 1646, 1612, 1467, 1378, 1243, 1086, 760;
and further applications of NHC toward synthesis of other new HRMS (ESI) m/z: Calcd for [M + Na]+ C16H15NNaO3: 292.0950,
pharmaceutical importance are underway in our laboratory.
found: 292.0927.
1-Benzyl-4′-methylspiro[indoline-3,2′-pyran]-2,6′(3′H)-dione
1
3d. White solid; M.P: 136–138 °C; H NMR (400 MHz, CDCl3)
δ 7.45 (dd, J1 = 7.2 Hz, J2 = 0.4 Hz, 1H, ArH), 7.36–7.25 (m, 6H,
ArH), 7.05 (td, J1 = 8.4 Hz, J2 = 0.8 Hz, 1H, ArH), 6.75 (d, J =
7.6 Hz, 1H, ArH), 6.11 (dd, J1 = 2.8 Hz, J2 = 1.2 Hz, 1H, CHv),
4.90 (s, 2H, Ar-CH2), 2.97 (dd, J1 = 18.0 Hz, J2 = 0.4 Hz, HCH),
Experimental section
Typical procedure for the NHC-catalyzed reaction of
α,β-unsaturated aldehydes with isatin derivatives
Into an oven-dried 25 mL vial were weighed precatalyst 4c 2.67 (d, J = 18.0 Hz, 1H, HCH), 2.10 (s, 3H, CH3); 13C NMR
(25.5 mg, 15 mol%) and Cs2CO3 (186.9 mg, 115 mol%). THF (100 MHz, CDCl3) δ 172.9, 162.8, 154.5, 142.2, 135.0, 130.9,
(5 mL) was added to the mixture. The resulting mixture was 129.0, 128.0, 127.9, 127.3, 124.0, 123.5, 116.5, 110.0, 79.7, 43.9,
stirred at room temperature for 5 min followed by the addition 35.3, 23.2; IR (potassium bromide) (v, cm−1): 3677, 3650, 2888,
of a solution of 3-methylbut-2-enal 1a (0.5 mmol), isatin 2 1734, 1610, 1489, 1348, 1249, 1073, 820, 859; HRMS (ESI) m/z:
(0.5 mmol) and 3,3′,5,5′-tetra-tert-butyldiphenoquinone Calcd for [M + Na]+ C20H17NNaO3: 342.1106, found: 342.1092.
(203 mg), in THF (3 mL). The mixture was stirred at room
1,4′,5-Trimethylspiro[indoline-3,2′-pyran]-2,6′(3′H)-dione 3e.
temperature until completion (monitored by TLC). After White solid; M.P: 170–172 °C (reported 173–176 °C21); 1H
removal of the solvent under reduced pressure, the crude NMR (400 MHz, CDCl3) δ 7.22 (s, 1H, ArH), 7.17 (d, J = 8.0 Hz,
product was purified by column chromatography (silica gel, 1H, ArH), 6.74 (d, J = 8.0 Hz, 1H, ArH), 6.05 (d, J = 1.2 Hz, 1H,
mixtures of ethyl acetate–petroleum ether, 1 : 3, v/v).
1,4′-Dimethylspiro[indoline-3,2′-pyran]-2,6′(3′H)-dione
CHv), 3.17 (s, 3H, CH3), 2.86 (d, J = 18.0 Hz, 1H, HCH), 2.60
3a. (d, J = 18.4 Hz, 1H, HCH), 2.31 (s, 3H, CH3), 2.05 (s, 3H, CH3);
White solid; M.P: 178–179 °C (reported 178–180 °C21); 1H 13C NMR (100 MHz, CDCl3) δ 172.6, 162.8, 154.3, 140.7,
NMR (400 MHz, CDCl3) δ 7.42 (dd, J1 = 7.6 Hz, J2 = 0.6 Hz, 1H, 133.1, 131.2, 128.0, 124.6, 116.5, 108.7, 79.8, 35.2, 26.4,
ArH), 7.39 (td, J1 = 8.0 Hz, J2 = 1.2 Hz, 1H, ArH), 7.07 (td, J1 = 23.2, 21.0; IR (potassium bromide) (v, cm−1): 2914, 1718,
7.6 Hz, J2 = 0.8 Hz, 1H, ArH), 6.88 (d, J = 8.0 Hz, 1H, ArH), 6.06 1627, 1607, 1505, 1470, 1352, 1256, 1101, 811; HRMS (ESI)
(q, J = 1.6 Hz, 1H, CHv), 3.20 (s, 3H, NCH3), 2.87 (ddd, J1 = m/z: Calcd for [M + Na]+ C15H15NNaO3: 280.0950, found:
18.0 Hz, J2 = 1.6 Hz, J3 = 0.8 Hz, 1H, HCH), 2.63 (d, J = 18.4 Hz, 280.0944.
1H, HCH), 2.08 (d, J = 1.2 Hz, 3H, CH3); 13C NMR (100 MHz,
1-Ethyl-4′,5-dimethylspiro[indoline-3,2′-pyran]-2,6′(3′H)-dione
CDCl3) δ 172.7, 162.7, 154.2, 143.2, 131.0, 127.9, 123.9, 123.4, 3f. White solid; M.P: 101–102 °C (reported 101–104 °C21); H
116.5, 108.9, 79.6, 35.1, 26.4, 23.2; IR (potassium bromide) NMR (400 MHz, CDCl3) δ 7.22 (s, 1H, ArH), 7.16 (d, J = 7.6 Hz,
(v, cm−1): 1725, 1616, 1472, 1420, 1374, 1349, 1255, 1133, 1H, ArH), 6.76 (d, J = 8.0 Hz, 1H, ArH), 6.05 (s, 1H, CHv),
1092, 1005, 752; HRMS (ESI) m/z: Calcd for [M + Na]+ 3.75–3.68 (m, 2H, CH2), 2.87 (d, J = 18.0 Hz, 1H, HCH), 2.58 (d,
1
C14H13NNaO3: 266.0793; found: 266.0750.
J = 18.4 Hz, 1H, HCH), 2.31 (s, 3H, CH3), 2.06 (s, 3H, CH3),
1-Ethyl-4′-methylspiro[indoline-3,2′-pyran]-2,6′(3′H)-dione 3b. 1.26 (t, J = 6.8 Hz, 3H, CH2CH3); 13C NMR (100 MHz, CDCl3) δ
White solid; M.P: 84–86 °C (reported 84–86 °C21); 1H NMR 172.2, 162.9, 154.4, 139.8, 132.9, 131.1, 128.2, 124.8, 116.5,
(400 MHz, CDCl3) δ 7.42 (d, J = 7.2 Hz, 1H, ArH), 7.35 (td, J1 = 108.8, 79.8, 35.2, 35.0, 23.2, 21.0, 12.4; IR (potassium
7.6 Hz, J2 = 0.8 Hz, 1H, ArH), 7.05 (t, J = 7.6 Hz, 1H, ArH), 6.87 bromide) (v, cm−1): 2983, 2946, 1713, 1623, 1605, 1496, 1375,
(d, J = 7.6 Hz, 1H, ArH), 6.05 (d, J = 1.2 Hz, 1H, CHv), 1252, 847, 689; HRMS (ESI) m/z: Calcd for [M + Na]+
3.77–3.70 (m, 2H, NCH2), 2.88 (d, J = 18.4 Hz, 1H, HCH), 2.59 C16H17NNaO3: 294.1106, found: 294.1092.
(d, J = 18.0 Hz, 1H, HCH), 2.05 (s, 3H, CH3), 1.28 (t, J = 7.2 Hz,
1-Allyl-4′,5-dimethylspiro[indoline-3,2′-pyran]-2,6′(3′H)-dione
3H, CH2CH3); 13C NMR (100 MHz, CDCl3) δ 172.2, 162.8, 3g. White solid; M.P: 108–110 °C (reported 108–110 °C21); H
154.3, 142.2, 131.0, 128.2, 124.1, 123.2, 116.5, 109.0, 79.6, 35.2, NMR (400 MHz, CDCl3) δ 7.23 (s, 1H, ArH), 7.13 (d, J = 8.0 Hz,
35.0, 23.2, 12.4; IR (potassium bromide) (v, cm−1): 1721, 1611, 1H, ArH), 6.74 (d, J = 8.0 Hz, 1H, ArH), 6.07 (s, 1H, CHv), 5.26
1490, 1469, 1377, 1353, 1227, 1138, 1081, 1017, 844, 757, 595; (d, J = 1.2 Hz, CHv), 5.23 (dd, J1 = 2.8 Hz, J2= 0.8 Hz, 1H,
HRMS (ESI) m/z: Calcd for [M + Na]+ C15H15NNaO3: 280.0950, CHv), 4.29 (d, J = 4.0 Hz, 2H, NCH2), 2.89 (d, J = 18.4 Hz, 1H,
1
found: 280.0930.
HCH), 2.61 (d, J = 18.4 Hz, 1H, HCH), 2.30 (s, 3H, CH3), 2.06 (s,
1-Allyl-4′-methylspiro[indoline-3,2′-pyran]-2,6′(3′H)-dione 3c. 3H, CH3); 13C NMR (100 MHz, CDCl3) δ 172.4, 162.8, 154.3,
White solid; M.P: 93–95 °C (reported 98–99 °C21); 1H NMR 139.9, 133.1, 131.1, 130.7, 128.0, 124.7, 118.1, 116.5, 109.6,
(400 MHz, CDCl3) δ 7.42 (d, J = 7.2 Hz, 1H, ArH), 7.34 (t, J = 79.7, 42.5, 35.3, 23.2, 21.0; IR (potassium bromide) (v, cm−1):
7.6 Hz, 1H, ArH), 7.06 (t, J = 7.2 Hz, 1H, ArH), 6.85 (d, J = 2982, 2917, 1731, 1645, 1618, 1493, 1373, 1249, 1170, 996, 926,
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825; HRMS (ESI) m/z: Calcd for [M + Na]+ C17H17NNaO3: 3.21 (s, 3H, NCH3), 2.90 (d, J = 18.0 Hz, 1H, HCH), 2.60 (d, J =
306.1106, found: 306.1088.
18.4 Hz, 1H, HCH), 2.08 (s, 3H, CH3); 13C NMR (100 MHz,
1-Benzyl-4′,5-dimethylspiro[indoline-3,2′-pyran]-2,6′(3′H)-dione CDCl3) δ 172.3, 159.2 (JC–F = 241.5 Hz), 162.2, 154.1, 139.1
1
3h. White solid; M.P: 179–180 °C (reported 179–181 °C21); H (JC–F = 2.2 Hz), 129.1 (JC–F = 7.8 Hz), 117.2 (JC–F = 23.4 Hz),
NMR (400 MHz, CDCl3) δ 7.34–7.22 (m, 6H, ArH), 7.03 (d, J = 116.5, 112.2 (JC–F = 25.3 Hz), 109.6 (JC–F = 7.9 Hz), 79.5,
8.0 Hz, 1H, ArH), 6.61 (d, J = 8.0 Hz, 1H, ArH), 6.08 (d, J = 35.0, 26.6, 23.2; IR (potassium bromide) (v, cm−1): 2948, 1652,
1.6 Hz, 1H, CHv), 4.86 (s, 2H, CH2), 2.93 (d, J = 18.4 Hz, 1H, 1557, 1494, 1470, 1421, 1411, 1382, 806, 757, 690; HRMS (ESI)
HCH), 2.63 (d, J = 18.0 Hz, 1H, HCH), 2.27 (s, 3H, CH3), 2.07 (s, m/z: Calcd for [M + Na]+ C14H12FNNaO3: 284.0699, found:
3H, CH3); 13C NMR (100 MHz, CDCl3) δ 172.8, 162.8, 154.3, 284.0699.
139.8, 135.0, 133.2, 131.1, 128.9, 128.0, 127.9, 127.2, 124.7,
5-Chloro-1,4′-dimethylspiro[indoline-3,2′-pyran]-2,6′(3′H)-
116.6, 109.8, 79.8, 44.0, 35.4, 23.3, 21.0; IR (potassium dione 3m. White solid; M.P: 190–192 °C (reported
bromide) (v, cm−1): 1716, 1619, 1494, 1377, 1252, 1083, 999, 190–193 °C21); 1H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 2.0 Hz,
819, 721; HRMS (ESI) m/z: Calcd for [M + Na]+ C21H19NNaO3: 1H, ArH), 7.36 (dd, J1= 8.4 Hz, J2 = 2.4 Hz, 1H, ArH), 6.80 (d, J =
356.1263, found: 356.1245.
8.4 Hz, 1H, ArH), 6.08 (dd, J1= 2.8 Hz, J2 = 1.2 Hz, 1H, CHv),
5-Methoxy-1,4′-dimethylspiro[indoline-3,2′-pyran]-2,6′(3′H)- 3.19 (s, 3H, CH3), 2.87 (d, J = 18.0 Hz, 1H, HCH), 2.59 (d, J =
dione 3i. White solid; M.P: 174–176 °C (reported 18.4 Hz, 1H, HCH), 2.06 (d, J = 0.8 Hz, 3H, CH3); 13C NMR
175–178 °C21); 1H NMR (400 MHz, CDCl3) δ 7.02 (d, J = 2.4 Hz, (100 MHz, CDCl3) δ 172.2, 162.2, 154.1, 141.7, 130.9, 129.4,
1H, ArH), 6.88 (dd, J1 = 8.4 Hz, J2 = 2.4 Hz, 1H, ArH), 6.76 (d, 128.8, 124.5, 116.5, 110.0, 79.4, 34.9, 26.6, 23.3; IR (potassium
J = 8.4 Hz, 1H, ArH), 6.05 (s, 1H, CHv), 3.78 (s, 3H, OCH3), bromide) (v, cm−1): 3630, 2888, 1734, 1610, 1489, 1472, 1348,
3.17 (s, 3H, NCH3), 2.85 (d, J = 18.4 Hz, 1H, HCH), 2.60 (d, J = 1249, 1089, 1073, 859, 820, 547; HRMS (ESI) m/z: Calcd for
18.0 Hz, 1H, HCH), 2.05 (s, 3H, CH3); 13C NMR (100 MHz, [M + Na]+ C14H12ClNNaO3: 300.0403, found: 300.0397.
CDCl3) δ 172.4, 162.7, 156.4, 154.3, 136.4, 129.0, 116.5, 114.9,
1,5-Dimethyl-4′-phenylspiro[indoline-3,2′-pyran]-2,6′(3′H)-
111.6, 109.4, 79.9, 55.9, 35.2, 26.5, 23.2; IR (potassium dione 3n. White solid; M.P: 191–194 °C (reported
1
bromide) (v, cm−1): 3410, 3015, 2944, 2842, 1715, 1613, 1151, 198–199 °C21); H NMR (400 MHz, CDCl3) δ 7.56–7.54 (m, 2H,
1472, 1433, 1362, 1255, 1131, 1027, 810, 690; HRMS (ESI) m/z: ArH), 7.46–7.42 (m, 3H, ArH), 7.27 (s, 1H, ArH), 7.18 (d, J =
Calcd for [M + Na]+ C15H15NNaO4: 296.0899, found: 296.0865.
7.6 Hz, 1H, ArH), 6.76 (d, J = 7.6 Hz, 1H, ArH), 6.59 (s, 1H,
1-Ethyl-5-methoxy-4′-methylspiro[indoline-3,2′-pyran]-2,6′(3′H)- CHv), 3.34 (dd, J1 = 17.6 Hz, J2 = 1.6 Hz, 1H, HCH), 3.20
dione 3j. White solid; M.P: 119–121 °C (reported (s, 3H, CH3), 3.09 (dd, J1 = 17.6 Hz, J2 = 0.8 Hz, 1H, HCH), 2.29
1
115–118 °C21); H NMR (400 MHz, CDCl3) δ 7.03 (s, 1H, ArH), (s, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ 167.3, 158.1, 146.7,
6.88 (d, J = 8.0 Hz, 1H, ArH), 6.78 (d, J = 8.4 Hz, 1H, ArH), 6.04 135.5, 130.8, 128.0, 126.1, 125.7, 123.9, 122.6, 120.9, 119.6,
(s, 1H, CHv), 3.77 (s, 3H, OCH3), 3.74–3.67 (m, 2H, CH2CH3), 109.5, 103.5, 74.7, 27.3, 21.3, 15.8; IR (potassium bromide)
2.87 (d, J = 18.4 Hz, 1H, HCH), 2.58 (d, J = 18.4 Hz, 1H, HCH), (v, cm−1): 1731, 1715, 1619, 1496, 1363, 1269, 1077,760, 682;
2.05 (s, 3H, CH3), 1.26 (t, J = 6.4 Hz, 3H, CH2CH3); 13C NMR HRMS (ESI) m/z: Calcd for [M − H]− C20H16NO3: 318.1130,
(100 MHz, CDCl3) δ 172.0, 162.7, 156.2, 154.3, 135.4, 129.3, found: 318.1139.
116.5, 114.9, 111.7, 109.5, 79.9, 55.9, 35.2, 35.1, 23.2, 12.4; IR
1,3′-Dimethyl-4′-phenylspiro[indoline-3,2′-pyran]-2,6′(3′H)-
(potassium bromide) (v, cm−1): 3067, 2984, 2935, 2838, 1718, dione 3o. White solid; M.P: 167–170 °C; 1H NMR (400 MHz,
1604, 1499, 1461, 1212, 1026, 860, 809; HRMS (ESI) m/z: Calcd CDCl3) δ 7.48–7.37 (m, 7H, ArH), 7.03 (t, J = 8.0 Hz, 1H, ArH),
for [M + Na]+ C16H17NNaO4: 310.1055, found: 310.1030.
6.88 (d, J = 8.0 Hz, 1H, ArH), 6.39 (s, 1H, CHv), 3.40 (q, J =
1-Benzyl-5-methoxy-4′-methylspiro[indoline-3,2′-pyran]-2,6′(3′H)- 8.0 Hz, 1H, CH3CH), 3.23 (s, 3H, NCH3), 1.25 (d, J = 4.0 Hz,
dione 3k.21 White solid; M.P: 144–145 °C (reported 3H, CH3CH); 13C NMR (100 MHz, CDCl3) δ 171.4, 163.1, 159.0,
1
147–149 °C21); H NMR (400 MHz, CDCl3) δ 7.33–7.26 (m, 5H, 143.5, 136.1, 131.0, 130.3, 129.0, 128.0, 126.6, 124.0, 123.3,
ArH), 7.02 (d, J = 2.4 Hz, 1H, ArH), 6.75 (dd, J1 = 8.8 Hz, J2 = 115.5, 108.8, 82.6, 37.4, 26.4, 14.6; IR (potassium bromide)
2.4 Hz, 1H, ArH), 6.62 (d, J = 8.8 Hz, 1H, ArH), 6.07 (d , J = (v, cm−1): 1732, 1447, 1491, 1372, 1254, 1164,1098, 691; HRMS
1.2 Hz, 1H, CHv), 4.85 (s, 2H, CH2), 3.73 (s, 3H, OCH3), (ESI) m/z: Calcd for [M + H]+ C20H18NO3: 320.1287, found:
2.93 (d, J = 18.0 Hz, 1H, HCH), 2.64 (d, J = 18.0 Hz, 1H, HCH), 320.1277.
2.07 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ 172.6,
4′-Methylspiro[indoline-3,2′-pyran]-2,6′(3′H)-dione 3p. White
1
162.7, 156.4, 154.2, 135.4, 135.0, 129.1, 128.9, 127.9, 127.3, solid; M.P: 217–219 °C; H NMR (400 MHz, DMSO-d6) δ 10.72
116.6, 114.9, 111.5, 110.5, 79.9, 55.9, 44.1, 35.4, 23.3; IR (s, 1H, NH), 7.45 (d, J = 8.0 Hz, 1H, ArH), 7.34 (td, J1 = 8.0 Hz,
(potassium bromide) (v, cm−1): 3056, 2943, 1721, 1608, 1499, J2 = 1.2 Hz, 1H, ArH), 7.03 (td, J1= 7.8 Hz, J2 = 0.8 Hz, 1H, ArH),
1435, 1345, 1244, 1172, 1029, 848, 699; HRMS (ESI) m/z: Calcd 6.90 (d, J = 8.0 Hz, 1H, ArH), 5.99 (d, J = 1.2 Hz, 1H, CHv),
for [M + H]+ C21H20NO4: 350.1392, found: 350.1381.
2.87 (d, J = 20.0 Hz, 1H, HCH), 2.78 (d, J = 20.0 Hz, 1H, HCH),
5-Fluoro-1,4′-dimethylspiro[indoline-3,2′-pyran]-2,6′(3′H)- 1.99 (s, 3H, CH3); 13C NMR (100 MHz, DMSO-d6) δ 174.6,
dione 3l. White solid; M.P: 195–196 °C; 1H NMR (400 MHz, 163.1, 156.7, 142.0, 131.3, 128.7, 124.7, 122.9, 115.5, 110.9,
CDCl3) δ 7.19 (dd, J1 = 7.6 Hz, J2 = 2.8 Hz, 1H, ArH), 7.11 (td, 80.3, 34.5, 23.1; IR (potassium bromide) (v, cm−1): 3190, 3093,
J1 = 8.8 Hz, J2 = 2.8 Hz, 1H, ArH), 6.82 (dd, J1 = 4.0 Hz, J2
=
2978, 1717, 1621, 1205, 1239, 1100, 840, 769; HRMS (ESI) m/z:
8.8 Hz, 1H, ArH), 6.08 (dd, J1 = 8.8 Hz, J2 = 4.0 Hz, 1H, CHv), Calcd for [M + H]+ C13H12NO3: 230.0817, found: 230.0811.
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Organic & Biomolecular Chemistry
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Acknowledgements
We are grateful for financial support by National Natural
Science Foundation of China (no. 21242014 and 21372101),
A Project Funded by the Priority Academic Program Develop-
ment of Jiangsu Higher Education Institutions, the Major
Basic Research Project of the Natural Science Foundation of
the Jiangsu Higher Education Institutions (09KJA430003).
The authors appreciated the help from Prof. Changsheng
Cao in Jiangsu Normal University, China, on the synthesis of
precatalysts.
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