Palladium Catalyzed Decarboxylative Addition of Allyl
carbonates and Allyl acetoacetate to Isatin
1. Introduction
Palladium, the 46th element in the periodic table, has significantly changed and improved
the art of organic synthesis over the last four decades. The interconversion between the two stable
oxidation states of palladium, Pd (0) and Pd (II) is responsible for the versatile reactivity of
palladium in organic synthesis. The discovery of palladium catalyzed carbon-carbon bond
forming reactions via cross coupling between organometallic reagents and organic electrophiles
is a milestone in organic chemistry. Negishi, Suzuki, Stille and Sonagashira reactions represent
the most widely used palladium-catalyzed cross coupling reactions.
2. π-Allylpalladium chemistry
2.1 Palladium catalyzed allylation
The carbon-carbon bond forming reaction is one of the most powerful tools for making
new compounds and for developing creative synthetic methodologies. Such a reaction, in general
is most useful and efficient when performed catalytically. Among the complexes of a variety of
transition metals for carbon-carbon bond formation employed previously, palladium complexes
have been most often used because they display wide reactivity and higher selectivity than other
transition-metal complexes.1,2 Particularly, reactive π-allylpalladium complexes 1 are useful
reaction intermediates for the above mentioned purposes. In general, π-allylpalladium complexes
1 are electrophilic and react with various nucleophiles such as malonates,3 β-keto esters,4 and
amines5 to form carbon-carbon or carbon-heteroatom bonds under neutral or basic conditions.
Figure 1. -allylpalladium complex
It is widely accepted that -allylpalladium complexes 1, which are intermediates for the
Tsuji-Trost reaction, have an electrophilic character and react with nucleophiles to afford the
corresponding allylation products (Scheme 1).6
1
Scheme 1
Tsuji and and saegusa almost simultaneously reported the decarboxylative allylation of
-ketoallyl esters.7 In this method the loss of CO2 replaces the need to selectively prepare
preformed enolate equivalents. Another potential benefit of the decarboxylative allylation is the
ability to generate both nucleophile and electrophile in situ.
Scheme 2
2.2 Interceptive Decarboxylative Allylations (IDcA)
Decarboxylative allylation reactions which performed in the presence of an
electrophile is termed as Inteceptive Decarboxylative Allylations (IDcA). Treatment of allyl
esters with transition metal catalyst affords the electrophilic and nucleophilic species. These
intermediates can be intercepted with externally added electrophile before their combination to
form DcA products (Scheme 3).
Scheme 3. Representation of DcA and IDcA
2
2.3 Intramolecular Interceptive DcA
In 1989, Tsuji and co-workers reported palladium catalyzed intramolecular aldol
reaction of aldehydes with ketone enolate generated by the allyl-β-keto ester 11 under neutral
conditions.8 The reaction proceeds through the formation of (π-allyl) palladium enolates A.
Scheme 4. Intramolecular Decarboxylative Aldol reaction
2.4 Intermolecular Interceptive DcA
Nearly a decade after Tsuji's seminal report, Yamamoto and co-workers reported the
intermolecular β-acetonation-allylation of activated olefins with allyl acetoacetate.9 The
intermolecular IDcA proceeded in the presence of a catalytic amount of Pd(PPh3)4 in THF.
Scheme 5. β-acetonation-allylation of activated olefins
Schaus and co-workers developed a mild and selective hetero bimetallic-catalyzed
intermolecular decarboxylative aldol reaction. The reaction is promoted by Pd(0)-and Yb(III)DIOP complexes and involves the in situ formation of a ketone enolate from allyl -keto
esters followed by addition of the enolate to aldehydes.10
Scheme 6
3
2.5 Asymmetric Interceptive DcA
The asymmetric decarboxylative addition of cyclic β-keto ester with activated olefins
was reported by Stoltz and co-workers.11 Both electron-deficient arylidene malononitriles and
benzylidene Meldrum’s acid derivatives were used as electrophiles. Cyclic β-ketoesters and
arylidene malononitriles smoothly underwent the interceptive DcA in the presence of the
PHOX-ligated palladium catalyst, allowing generation of adjacent quaternary and tertiary
carbon stereocenters with high enantioselectivity and diastereoselectivity.
Scheme 7. Asymmetric IDcA of cyclic β-keto ester
2.6 Interceptive DcA of Diphenylglycinate Esters
Chruma et al. reported palladium catalyzed interceptive decarboxylative allylation of
allyl diphenylglycinate ester with benzylidene malononitrile.12 The reaction is proceeded
through the formation of 2-aza-allyl anion A which is generated by the ionization of allyl ester
followed by decarboxylation in presence of catalytic amount of palladium catalyst. The
formed intermediate A is intercepted by the benzylidene malononitrile to form B. The
resultant anion then reacts with the π-allyl palladium intermediate to give allylated imine.
Scheme 8. IDcA of diphenylglycinate imines
4
2.7
Interceptive
Decarboxylative
Michael
Addition-Allylation
using
Allylcarbonates:
Yamamoto and co-workers reported the palladium catalyzed decarboxylative alkoxyallylation of activated olefins.13 Both electron deficient and electron withdrawing substituted
arylidene malononitrile underwent interceptive DcA with allyl ethyl carbonate in high yield.
Scheme 9. Decarboxylative alkoxy-allylation of activated olefin
2.8 Interceptive DcA of Cyclic Carbamates
Building on investigations of palladium catalyzed reactions of allylic carbamate by
Tsuji, Tunge and Wang developed a similar palladium catalyzed interceptive DcA of vinyl
oxazinones with Michael acceptors to form 4-vinylpiperidines. Treatment of racemic vinyl
oxazinones with 1 equiv of benzylidene malononitrile and 5 mol % Pd(PPh3)4 in CH2Cl2
furnished vinyl piperidine. 14
Scheme 10. Diastereoselective Cycloadditions of vinyl Oxazinones
2.9 Interceptive DcA of N-Phenyl carbamats
Yamamoto and co-workers developed a palladium-catalyzed, highly stereo-selective,
tandem -allylation -amination of activated olefins via interceptive decarboxylative azaMichael addition–allylation cascade.15 In the case of a carbamate bearing a methyl group on
5
the nitrogen, the reaction did not proceed. The introduction of an alkoxycarbonyl group on the
amine would lead to the formation of amino-allylation product. The reactions of carbamates
bearing an alkoxycarbonyl group proceeded smoothly with 5 mol% Pd(PPh3)4 in THF at room
temperature giving the products as a single diastereomer.
Scheme 11. Decarboxylative Amino-allylation of Activated Olefins
3. Background to the present investigation
Our group developed a viable route for the efficient bis-functionalization of
isatilidenes by utilizing decarboxylative allylation reaction and amphiphilic bis-π-allyl
palladium complex.16
Scheme 12
Later in 2011, we have studied 1,8-conjugate addition in heptafulvenes by utilizing
bis-π-allyl palladium complex . Also the interceptive decarboxylative allylation of allyl
catbonates and allyl acetoacetate with dicyanoheptafulvenes in presence of Pd(PPh3)4 resulted
in the formation of 1,8-conjugate addition product. 17
6
Scheme 13
Recently, we have reported the bis-functionalization of 1,3-diene by utilizing π-allyl
palladium chemistry.18 The functionalized 1,3-diene undergo interceptive 1,4-addition by both
bis-π-allyl palladium complex and diallyl carbonate.
Scheme 14
Isatins have been widely used as precursors of spiro-oxindoles and many natural
products. The most fascinating application of isatins in organic synthesis is undoubtedly due
to the highly reactive C-3 carbonyl group. The reactions of the C-3 carbonyl group of isatins,
mostly by nucleophilic additions or spiroannulation, transform it into 2-oxindole derivatives.
2-Oxindoles, especially those which are spiro-fused to other cyclic frameworks, have drawn
tremendous interest of researchers in the area of synthetic organic chemistry and medicinal
chemistry worldwide because they occur in many natural products such as spirotryprostatins,
horsfiline, gelsemine, gelseverine, rhynchophylline, and elacomine, etc. (figure 2). 19
Figure 2. Spiro-oxindole containing Natural products
7
Spiro-oxindoles have been reported to have various types of bioactivity such as
progesterone receptor modulators,20 anti-HIV,21 anticancer,22 antimalarial23 and
MDM2
inhibitor.24 Some of the compounds possessing the potent activities are shown in figure 3.
Figure 3
As a continuation of palladium catalyzed allylation reaction and because of the
biological significance of isatins, we undertook an investigation of Pd- catalyzed 1,2- addition
reaction of C-3 carbonyl group of isatin with π-allyl palladium complex.
4. Results and Discussion
4.1 Palladium catalyzed Decarboxylative 1,2-addition of C-3 carbonyl group of Nsubstituted isatin with allyl carbonates:
Interceptive decarboxylative 1,2-addition was carried out in N-substituted isatin with
allyl carbonates. In an initial attempt, we carried out the reaction of 1-ethyl isatin 41 with
diallyl carbonate 25a in presence of 5 mol % Pd(PPh3)4 in THF at room temperature. The C-3
carbonyl group underwent smooth allylation-oxyallylation to afford 3,3-bis(allyloxy)-1ethylindolin-2-one 42a in 57% yield (Scheme 15).
8
Scheme 15
The structure of the product 42a was elucidated by various spectroscopic techniques.
The IR spectrum of the product 42a showed characteristic carbonyl stretching at 1729 cm-1.
Figure 4. IR Spectrum of 42a
In the 1H NMR spectrum of compound 42a, proton at C-14 and C-18 appeared as
multiplet at δ 5.93 ppm. The sp3 –CH2 protons at C-13 and C-17 protons were observed as two
separate multiplets at δ 4.46 and 4.32 ppm. The methylene protons at C-10 resonated as
quartet at δ 3.72 ppm and the methyl protons at C-11 visible at δ 1.27 ppm.
9
Figure 5. 1H NMR Spectrum of 42a
In the
13
C NMR spectrum, the carbonyl carbon at C-2 resonated at δ 170.1 ppm. The
quaternary carbon at C-3 was located at δ 96.5 ppm. The sp3 carbons C-13 and C-17 were seen
at δ 64.2 ppm.
10
Figure 6. 13C NMR Spectrum of 42a
The structure was further supported by high resolution mass spectral analysis which
showed a molecular ion peak [M+Na]+ at m/z=296.12634.
Figure 7. HRMS-ESI spectrum of 42a
11
The scope of the reaction was substantially expanded by utilizing different allyl
carbonates such as diallyl carbonate, allyl methyl carbonate and dimethallyl carbonate (25a-c).
All the reactions proceeded smoothly at room temperature to produce the desired ketals 42a42c in moderate yields. The results are shown in table 1.
Table 1. Decarboxylative interceptive 1,2-Addition of Allyl Carbonates with isatins
Mechanistic considerations:
Based on the results, we propose a plausible mechanism as illustrated in Scheme 16.
The catalytic cycle is initiated by the oxidative addition of Pd(0) to allyl carbonate 25
followed by decarboxylation to generate π- allylpalladium complex B. The alkoxy anion
undergo 1,4-addition with isatin 41 to give cationic π- allylpalladium complex C having
12
oxyanion of isatin as the counter ion. Reductive elimination of C results in the formation of
allylated product 42 and regenerates the catalyst.
Scheme 16
4.2 Synthesis of dioxepine fused spiro-oxindole
Synthetic utility of this chemistry is highlighted by the synthesis of spiro-dioxepine
fused 2-oxindole. Ring-closing metathesis of 42a using Grubbs' first generation catalyst
afforded dioxepine fused spiro-oxindole 43 in 76% yields.
Scheme 17
The structure of the compound 43 was elucidated from spectroscopic data. In the IR
spectrum, the peak visible at 1727 cm-1 showed the presence of carbonyl group. In the 1H
NMR spectrum (Figure 8), the olefenic protons were resonated as singlet at  5.81 ppm. The
13
methylene protons attached to oxygen atom resonated as two separate doublets at  5.03 and
4.56 ppm. All other protons were in accordance with the expected structure.
Figure 8. 1H NMR Spectrum of 43
In the 13C NMR spectrum (Figure 9) the characteristic carbonyl peak was observed at 
171.4 ppm. The peak corresponding to the spiro-carbon appeared at  96.8 ppm. The peaks
observed at  63.7 corresponding methylene carbons attached to two oxygen atom.
14
Figure 9. 13C NMR Spectrum of 43
Mass spectra clearly showed molecular ion peak at 268.09503 ([M+Na]+), which
further supported the assigned structure.
The architecture of a spiro-cyclic framework has always been a challenging endeavor
for synthetic organic chemists because it often requires synthetic design based on specific
strategies.
It
is
noteworthy that
spiro-cyclic
oxindole
compounds
are
valuable
pharmaceuticals. Spiro-oxindoles have been reported to possess a wide range of biological
activities.
4.3 Palladium catalyzed Decarboxylative addition of Allyl acetoacetate to C-3
carbonyl group of isatin
Encouraged by the decarboxylative 1,2-interceptive addition of allyl
carbonates, we were interested to study the reactivity of allyl acetoacetate with N-substituted
isatins. In an initial attempt, we have tried the reaction of 1-ethyl isatin 41 with allyl
acetoacetate 13 and to our delight the reaction afforded 1-ethyl-3-hydroxy-3-(2oxopropyl)indolin-2-one 44, an important structural motif in medicinal chemistry in 72 %
yield.
15
Scheme 18
The structure of the product 44 was established by spectroscopic analysis. In the IR
spectrum, the characteristic O-H stretching was found at 3381cm-1 and carbonyl stretching at
1694 cm-1. In the 1H NMR spectrum, a broad singlet at δ 4.30 ppm was assigned to the proton
of hydroxyl group attached to C-3 carbon. The methylene proton connected to C-3 carbon
resonated as doublets at δ3.19 and 2.97 ppm and the methyl protons bonded to C-5 carbonyl
group was observed at δ 2.15 ppm.
Figure 10. 1H NMR Spectrum of 44
In
13
C NMR spectrum, the characteristic peak 206.5 corresponds to carbonyl carbon
and peak observed at δ 175.9 ppm corresponds to carbonyl carbon of amide functionality. The
quaternary carbon bearing hydroxyl group was located at δ 49.24 pm. All other signals of 1H
NMR and 13C NMR were agreement with the proposed structure.
16
Figure 11. 13C NMR Spectrum of 44
Further structure of the product was unambiguously confirmed by single crystal X-ray
analysis.
Figure 12. ORTEP Diagram of compound 44
The generality of the reaction was examined by reacting different N-substituted isatins
with allyl acetoacetate 13 under identical conditions and the products were obtained in good
yields. The results are shown in table 2.
17
Table 2. Decarboxylative addition of allyl acetoacetate with isatin
The synthesized compounds, 3-hydroxy-3-substituted oxindoles, are important
structural motifs in medicinal chemistry.25 Some of the biologically significant hydroxyl
substituted 2-oxindoles are shown in figure 13.
Figure 13. Bioactive 3-hydroxy-3-substituted oxindoles
4.4 Reductive Cyclization of 3-hydroxy oxindoles
To demonstrate the utility of the present method in synthetic chemistry, further
transformations of the obtained oxindoles were then investigated. The treatment of compound
18
45 with lithium aluminum hydride (LAH) in THF under 0oC led to product 47 as diastereomer
(dr ratio = 1: 0.7) in 80% yield (Scheme 19).
Scheme 19
The structure of product 47 was assigned on the basis of spectral data. The compound
showed characteristic O-H stretching at 3390 cm-1 in the IR spectrum. In the 1H NMR spectrum
of compound 47 the ring junction proton which is attached to both oxygen and nitrogen was
observed as a singlet at 5.19 ppm. The hydroxyl proton was discernible as a singlet at 4.76
ppm. The proton attached to oxygen atom in the furan ring was observed as a multiplet at δ 4.394.32 ppm. In the 13C NMR spectrum, the methyl carbon was seen at 20.4 ppm. All other signals
in the 1H and 13C NMR spectra were in agreement with the proposed structure. The mass spectral
analysis showed a peak at m/z 282.14932 ([M+1]+), which also supported the proposed structure.
The synthesized furoindoline skeleton was found in indole alkaloid physovenine26 and it
also analogue to the half fragment of natural products madindoline A and B.27
Figure 14
19
5. Conclusion
In summary, we have developed a palladium catalyzed interceptive decarboxylative
1,2-addition of allyl carbonates to N-substituted isatins. The ring-closing metathesis of bisallyloxy oxindole derivatives furnished the corresponding spiro-dioxepine fused 2-oxindoles.
Similarly, the palladium catalyzed decarboxylative addition of allyl acetoacetate to isatins
afforded the 3-hydroxy oxindoles. Furthermore, the synthesized hydroxyl oxindole derivatives
could be transformed into biologically important hydroxyl furoindoline skeleton.
6. Experimental Section
All the chemicals were of the best grade commercially available and were used without
further purification. All the solvents were purified according to standard procedures; dry
solvents were obtained according to the literature methods and stored over molecular sieves.
All reactions were monitored by TLC (silica gel 60 F254, 0.25mm, Merck), visualization was
effected with UV and/or by staining with Enholm yellow solution. Gravity column
chromatography was performed using 60-120 or 100-200 mesh silica gel, mixtures of hexaneethyl acetate were used for elution. Melting point was determined on a Buchi melting point
apparatus and is uncorrected. Proton nuclear magnetic resonance spectra (1H NMR) were
recorded on Bruker AV 500 spectrophotometers (CDCl3 as solvent). Chemical shifts for 1H
NMR spectra are reported as δ in units of parts per million (ppm) downfield from SiMe4 (δ
0.0) and relative to the signal of chloroform-d (δ 7.25, singlet). Multiplicities were given as: s
(singlet); d (doublet); t (triplet); q (quartet); quin (quintet); dd (double doublet); m (multiplet).
Coupling constants are reported as J value in Hz. Carbon nuclear magnetic resonance spectra
(13C NMR) are reported as δ in units of parts per million (ppm) downfield from SiMe4 (δ 0.0)
and relative to the signal of chloroform-d (δ 77.03, triplet). Mass spectra were recorded under
ESI/HRMS at 61800 resolution using Thermo Scientific Exactive mass spectrometer. IR
spectra were recorded on Bruker Alpha FT-IR spectrometer.
General Procedure for the palladium-catalyzed Decarboxylative addition of allyl
carbonates to isatin:
N-substituted isatin (1 equiv.) and Pd(PPh3)4 (5 mol %) were taken in a Schlenk tube,
degassed and diallyl carbonate 25a (2 equiv.) was added followed by 2 mL THF. Argon gas is
purged into the reaction mixture and stirred at room temperature for 12h. The reaction was
monitored by TLC. The solvent was removed under reduced pressure and the residue on silica
20
gel (100-200 mesh) column chromatography using ethyl acetate/hexane mixture as eluent to
afford the product.
General Procedure for the palladium-catalyzed Decarboxylative addition of Allyl
acetoacetate to isatins:
N-protected isatin (1 equiv.) and Pd(PPh3)4 (5 mol %) were taken in a Schlenk tube,
degassed and allyl acetoacetate (2 equiv) was added followed by 2 mL THF. Argon gas is
purged into the reaction mixture and stirred at room temperature for 12h. The reaction was
monitored by TLC. The solvent was removed under reduced pressure and the residue on silica
gel (100-200 mesh) column chromatography using ethyl acetate/hexane mixture as eluent to
afford the product.
3,3-bis(allyloxy)-1-ethylindolin-2-one (42a):
Following the general experimental procedure, N-ethyl isatin 41 (100 mg, 0.57 mmol),
diallyl carbonate (142 mg, 1.14 mmol), Pd(PPh3)4 (33 mg, 0.028 mmol) in 2 mL THF at
room temperature under argon atmosphere for 12 h gave the product 42a as a pale yellow
viscous liquid (89 mg, 57 % yield) after column chromatography (5% Ethylacetate-Hexane).
Rf = 0.78 (3:7 EtOAc: hexane).
IR (neat) max: 3077, 2979, 2933, 2875, 1729, 1613, 1465, 1366,
1264, 1212, 1159, 1117, 1048, 927, 754 cm-1.
1H
NMR (500 MHz, CDCl3): δ 7.41 (d, J = 7.0 Hz, 1H), 7.33 (t,
J = 8.0 Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H),
5.95-5.89 (m, 2H), 5.31-5.26 (m, 4H), 5.15-5.13 (m, 2H), 4.474.43 (m, 2H), 4.33-4.29 (m, 2H), 1.27 (t, J = 7.0 Hz, 3H).
13C
NMR (125 MHz, CDCl3): δ 170.1, 142.4, 134.1, 130.5,
125.6, 124.9, 122.4, 116.8, 108.7, 96.5, 64.2, 34.4, 12.5.
HRMS (ESI): m/z Calcd for C16H19O3NNa [M+Na]+: 296.12626;
Found: 296.12634.
21
3-(allyloxy)-1-ethyl-3-methoxyindolin-2-one (42b):
Following the general experimental procedure, N-ethyl isatin 41 (100 mg, 0.57 mmol),
allylmethyl carbonate (133 mg, 1.14 mmol), Pd(PPh3)4 (33 mg, 0.028 mmol) in 2 mL THF at
room temperature under argon atmosphere for 12 h gave the product 42b as a pale yellow
viscous liquid (71 mg, 50 % yield) after column chromatography (10% Ethylacetate-Hexane).
Rf = 0.39 (3:7 EtOAc: hexane).
IR (neat) max: 3061, 2980, 2940, 1729, 1614, 1489, 1466, 1371,
1288, 1263, 1213, 1155, 1121, 1050, 931, 756 cm-1.
1H
NMR (500 MHz, CDCl3): δ 7.43 (d, J = 7.0 Hz, 1H), 7.35 (t, J
= 8.0 Hz, 1H), 7.08 (t, J = 7.5 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H),
5.99-5.91 (m, 1H), 5.32-5.15 (m, 2H), 4.49-4.46 (m, 1H), 4.364.33 (m, 1H), 3.72 (q, J = 7.5 Hz, 2H), 3.55 (s, 3H), 1.26 (t, J =
7.5 Hz, 3H).
13C
NMR (125 MHz, CDCl3): δ 170.3, 142.4, 134.1, 130.6,
125.3, 124.9, 122.5, 116.9, 108.9, 96.8, 64.2, 50.9, 34.4, 12.5.
HRMS (ESI): m/z Calcd for C14H17O3NNa [M+Na]+: 270.11061;
Found: 270.11057.
1-Ethyl-3,3-bis(2-methylallyloxy)indolin-2-one (42c):
Following the general experimental procedure, N-ethyl isatin 41 (100 mg, 0.57 mmol),
dimethallyl carbonate (194 mg, 1.14 mmol), Pd(PPh3)4 (33 mg, 0.028 mmol) in 2 mL THF at
room temperature under argon atmosphere for 12 gave the product 42c as a pale yellow
viscous liquid (82 mg, 48 % yield) after column chromatography (10% Ethylacetate-Hexane).
Rf = 0.57 (3:7 EtOAc: hexane).
IR (neat) max: 3074, 2975, 2927, 2867, 1729, 1654, 1613, 1463,
1368, 1212, 1119, 1043, 901, 752 cm-1.
1H
NMR (500 MHz, CDCl3): δ 7.42 (d, J = 7.5 Hz, 1H), 7.33 (t, J
= 7.5 Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H),
4.98 (s, 2H), 4.83 (s, 2H), 4.34-4.18 (m, 4H), 3.72 (q, J = 7.0 Hz,
22
2H), 1.75 (s, 6H), 1.27 (t, J = 7.0 Hz, 3H).
13C
NMR (125 MHz, CDCl3): δ 170.2, 142.4, 141.5, 130.4, 125.8,
124.9, 122.4, 111.8, 108.6, 96.5, 66.8, 34.4, 19.7, 12.5.
HRMS (ESI): m/z Calcd for C18H23O3NNa [M+Na]+: 324.15756;
Found: 324.15765.
1'-ethyl-4,7-dihydrospiro[[1,3]dioxepine-2,3'-indolin]-2'-one (43):
Bis-allyloxy 2-oxindole 42a (25 mg, 0.092 mmol) was dissolved in 4 mL
dichloromethane. To this Grubbs’ first generation catalyst (4 mg, 0.0046 mmol) was added
and stirred at room temperature for 3 hours. The reaction was monitored by Thin Layer
Chromatography. The solvent was removed under reduced pressure and the residue was
purified b silica gel (100-200 mesh) column chromatography using 10% ethyl acetate/hexane
mixture as eluent to afford the product 43 as a pale yellow viscous liquid ( 17 mg, 76% yield).
Rf = 0.48 (3:7 EtOAc: hexane).
IR (neat) max: 3031, 29708, 2936, 2873, 1727, 1613, 1489, 1467,
1371, 1259, 1213, 1123, 1084, 1051, 1024, 754 cm-1.
1H
NMR (500 MHz, CDCl3): δ 7.49(d, J = 7.5 Hz, 1H), 7.34(t, J =
8.0 Hz, 1H), 7.04(t, J = 8.0 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H),
5.81(s, 2H), 5.03(d, J = 14.5 Hz, 2H), 4.56(d, J = 15.0 Hz, 2H),
3.72(q, J = 7. 5 Hz, 2H), 1.28(t, J = 7.5 Hz, 3H).
13C
NMR (125 MHz, CDCl3): δ 171.4, 142.3, 130.6, 129.3, 126.7,
124.3, 122.5, 108.8, 96.8, 63.7, 34.4, 12.4.
HRMS (ESI): m/z Calcd for C14H15NNaO3 [M+Na]+: 268.09496;
Found: 268.09503.
1-ethyl-3-hydroxy-3-(2-oxopropyl)indolin-2-one (44):
Following the general experimental procedure, N-ethyl isatin 41 (50 mg, 0.285 mmol),
allyl acetoacetate (81 mg, 0.57 mmol), Pd(PPh3)4 (16 mg, 0.014 mmol), in 3 mL DCM at
room temperature under argon atmosphere for 12 h gave the product 44 as a colourless
23
crystals (48 mg, 72% yield) after column chromatography (35% Ethylacetate-Hexane). Rf =
0.39 (8:2 EtOAc: hexane). Mp. 144-148 0C.
IR (neat) max: 3381, 2924, 2821, 1694, 1615, 1546, 1492, 1466,
1419, 1376, 1359, 1205, 1102, 1080, 755 cm-1.
1H
NMR (500 MHz, CDCl3): 7.34 (d, J = 7.5 Hz, 1H), 7.29 (t, J =
7.5 Hz, 1H), 7.04 (t, J = 7.5 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H),
4.30 (s, 1H), 3.82-3.67 (m, 2H), 3,19 (d, J = 17.0 Hz, 1H), 2.97 (d,
J = 17.0 Hz, 1H), 2.15 (s, 3H), 1.29(t, J = 7.5 Hz, 3H).
13C
NMR (125 MHz, CDCl3): 206.5, 175.9, 142.7, 130.0, 129.8,
123.9, 122.8, 108.6, 73.9, 49.2, 34.8, 31.1, 12.3.
HRMS (ESI): m/z Calcd for C13H15NO3Na [M+Na]+: 256.09496;
Found: 256.09497.
1-benzyl-3-hydroxy-3-(2-oxopropyl)indolin-2-one (45):
Following the general experimental procedure, N-benzyl isatin (50 mg, 0.21 mmol),
allyl acetoacetate (61 mg, 0.42 mmol), Pd(PPh3)4 (12 mg, 0.011 mmol), in 2 mL DCM at
room temperature under argon atmosphere for 12 h gave the product 45 as a colourless
crystals (41 mg, 66% yield) after column chromatography (35% Ethylacetate-Hexane). Rf =
0.48 (8:2 EtOAc: hexane). Mp. 148-152 0C.
IR (neat) max: 3359, 2956, 2922, 2853, 1707, 1612, 1490, 1466,
1359, 1173, 1075, 966, 751, 696 cm-1.
1H
NMR (500 MHz, CDCl3): 7.38-7.32 (m, 5H), 7.29-7.27 (m,
1H), 7.20 (t, J = 7.5 Hz, 1H), 7.03(t, J = 7.5 Hz, 1H), 6.71 (d, J =
8.0 Hz, 1H), 4.96 (d, J = 15.5Hz, 1H ), 4.85 (d, J = 16.0 Hz, 1H),
4,47(s, 1H), 3.27(d, J = 17.0 Hz, 1H), 3.06(d, J = 17.0 Hz, 1H),
2.19(s, 3H).
13C
NMR (125 MHz, CDCl3): 207.3, 176.4, 142.7, 135.4, 129.9,
129.7, 128.8, 127.7, 127.2, 123.8, 123.2, 109.7, 74.2, 48.9, 43.9,
31.3.
24
HRMS (ESI): m/z Calcd for C18H17NO3Na [M+Na]+: 318.11061;
Found: 318.11111.
3-hydroxy-1-methyl-3-(2-oxopropyl)indolin-2-one (46):
Following the general experimental procedure, N-methyl isatin (50 mg, 0.31 mmol),
allyl acetoacetate (88 mg, 0.62 mmol), Pd(PPh3)4 (18 mg, 0.015 mmol), in 2 mL DCM at
room temperature under argon atmosphere for 12 h gave the product 46 as a pale yellow
crystals (52 mg, 76% yield) after column chromatography (40% Ethylacetate-Hexane). Rf =
0.34 (8:2 EtOAc: hexane). Mp. 134-138 0C.
IR (neat) max: 3302, 2919, 2850, 1696, 1612, 1493, 1468, 1422,
1356, 1258, 1222, 1172, 1094, 1020, 963, 754 cm-1.
1H
NMR (500 MHz, CDCl3): δ 7.35-7.28 (m, 2H), 7.05 (t, J = 7.5
Hz, 1H), 6.82 (d, J = 7.5 Hz, 1H), 4.62 (s, 1H), 3.22-3.18 (m, 4H),
2.99 (d, J = 17.0 Hz, 1H), 2.14 (s, 3H).
13C
NMR (125 MHz, CDCl3): δ 206.6, 176.4, 143.6, 129.9, 129.8,
123.8, 123.1, 108.5, 74.0, 49.2, 31.2, 26.3.
HRMS (ESI): m/z Calcd for C12H13NO3Na [M+Na]+: 242.07931;
Found: 242.07967.
(3aR,8aS)-8-benzyl-2-methyl-3,3a,8,8a-tetrahydro-2H-furo[2,3-b]indol-3a-ol (47):
To the stirred solution of 3-hydroxy 2-oxindole 45 (160 mg, 0.54 mmol) in dry THF
was added LiAlH4 (41 mg, 1.08 mmol) at 0oC under nitrogen. The resulting mixture was
stirred at 0oc for 4h. Then the reaction was quenched by the addition of 5 mL water and the
resulting mixture was stirred at room temperature until the generation of gas ceased. The
reaction mixture was filtered through a plug of celite with ethyl acetate. Then the filtrate was
extracted with ethyl acetate. The combined organic layer dried over Na2SO4 and concentrated
under vaccum. Product 47 obtained as a brown coloured solid (122 mg, 80% yield) after
purified by column chromatography (silica gel 100-200 mesh) using 15%
acetate/hexane mixture as eluent. Rf: 0.41 (3:7 EtOAc: Hexane). Mp. 98 0C.
25
ethyl
IR (neat) max: 3390, 2965, 2923, 1609, 1468, 1453, 1355, 1260,
1125, 1021, 947, 742, 696 cm-1.
1H
NMR (500 MHz, Acetone-d6): δ 7.41 (d, J = 7.5 Hz, 2H), 7.37
(d, J = 7.5 Hz, 1.4H), 7.31 (t, J = 7.5 Hz, 3H), 7.25-7.22 (m,3H),
7.06-7.01 (m, 2H), 6.67-6.62 (m, 2H), 6.37 (d, J = 8.0 Hz, 1H),
6.32 (d, J = 8.0 Hz, 0.7 H), 5.31 (s, 0.7 H), 5.19 (s, 1H), 4.81 (s,
0.7H), 4.76 (s, 1H), 4.58-4.52 (m, 2H), 4.47-4.36 (m, 2H), 4.394.32 (m, 1H), 3.90-3.84 (m, 0.7H), 2.53 (dd, J1 = 12.5 Hz, J2 = 5.5
Hz, 1H), 2.39 (dd, J1 = 12.0 Hz, J2 = 4.5 Hz, 0.7H), 2.05- 2.04 (m,
0.7H), 1.86-1.81 (m, 1H), 1.24 (d, J = 6.0 Hz, 2.2 H), 1.12 (d, J =
6.0 Hz, 3H).
13C
NMR (125 MHz, Acetone-d6): δ 150.6, 149.1, 139.0, 138.8,
133.0, 131.7, 129.4, 129.1, 128.3, 128.2, 127.5, 127.3, 126.8,
126.8, 126.7, 123.8, 123.4, 117.5, 117.3, 106.6, 105.5, 105.0,
103.8, 87.7, 87.5, 74.3, 74.2, 49.7, 49.1, 48.6, 48.3, 20.4, 19.2.
HRMS (ESI): m/z Calcd for C18H20NO2 [M+1]+ : 282.14940,
Found: 282.14932
26
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