Palladium(II)/N-Heterocyclic Carbene Catalyzed One-Pot Sequential α-Arylation/Alkylation: Access to 3,3-Disubstituted Oxindoles

Article abstract of DOI:10.1021/acs.joc.8b00264

Rationally designed fluorene-based mono- and bimetallic Pd-PEPPSI complexes were synthesized and demonstrated to be effective for the one-pot sequential α-arylation/alkylation of oxindoles. This streamlined approach offers efficient access to functionalized 3,3-disubstituted oxindoles in excellent yields (up to 89%) under mild reaction conditions.

Full text of DOI:10.1021/acs.joc.8b00264

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Article
Palladium(II)/N-Heterocyclic Carbene catalyzed one-pot sequential
alpha arylation/alkylation: Access to 3,3-disubstituted oxindoles
Pradeep Kumar Reddy Panyam, Bharat Ugale, and Thirumanavelan Gandhi
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00264 • Publication Date (Web): 08 Jun 2018
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Palladium(II)/NꢀHeterocyclic Carbene catalyzed oneꢀpot
sequential alpha arylation/alkylation: Access to 3,3ꢀ
disubstituted oxindoles
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Pradeep Kumar Reddy Panyam,§ Bharat Ugale,† and Thirumanavelan
Gandhi,*,§
§ Department of Chemistry, School of Advanced Sciences, VIT University, Vellore
632014, India
† Department of Chemistry, Indian Institute of Technology Ropar, Punjab 140001, India
Eꢀmail: velan.g@vit.ac.in
ABSTRACT
Rationally designed fluoreneꢀbased monoꢀ and bimetallic PdꢀPEPPSI complexes
were synthesized and demonstrated to be effective for the oneꢀpot sequential αꢀ
arylation/alkylation of oxindoles. This streamlined approach offers efficient access to
functionalized 3,3ꢀdisubstituted oxindoles in excellent yields (up to 89%) under mild
reaction conditions.
INTRODUCTION
Oxindoles are privileged structural motif prevalent in natural products,
pharmaceuticals, agrochemicals, and bioactive compounds (Figure 1).1 Of these, 3,3ꢀ
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disubstituted oxindoles have attracted much interest from synthetic chemists in light of its
challenging tertiary carbon at Cꢀ3 and complementary bioactivity manifestation.
Although plethora of reports on the chemistries of spiroindoles has been published,2
studies on 3ꢀalkylꢀ3ꢀaryloxindoles are limited.
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Figure 1. Biologically relevant molecules with 3,3ꢀdisubstituted oxindoles.
Traditionally, 3,3ꢀdisubstituted oxindoles were synthesized by double
electrophilic aromatic substitution of isatin involving strong acids via 3ꢀhydroxylꢀ3ꢀ
aryloxindoles.3 Additionally, isatin undergoes nucleophilic addition4 to form desired
products in the presence of transition metal catalysts. Pioneering studies by Miura,5
Buchwald,6 and Hartwig7 on αꢀarylation started off intramolecular αꢀarylation of amides,8
and later applied to the synthesis of oxindoles.6c, 6d, 9 Furthermore, careful selection of
cyclization precursors leads to an access to 3,3ꢀdisubstituted oxindoles either by direct
oxidative αꢀarylation of amides10 or upon intramolecular Heck reactions.8c,
3,3ꢀ
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disubstituted oxindoles were also generated by simple direct functionalization of 3ꢀ
substituted oxindoles.12 Thus far, great progress has been witnessed in synthesizing 3,3ꢀ
disubstituted oxindoles.13 Notwithstanding, most of these approaches rely on preꢀ
functionalized amides, multistep synthesis and harsh reaction conditions (pyrophoric
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bases, expensive ligands and fewer diversifications), demands definite improvement in
the synthesis of 3,3ꢀdisubstituted oxindoles.
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Over the past decade, NHCs emerged as an upꢀandꢀcoming ancillary ligand, and
its versatility and suitability in homogenous catalysis have been well realised. Its
popularity in catalysis is substantiated as it forms stable complexes with transition metal
salts and participates in various catalytic organic transformations. Strong σꢀdonating and
weaker πꢀaccepting abilities of NHCs make them unique and robust and outsmart the
phosphine ligands.14 Recently, we have reported the straightforward, convenient, and
oneꢀpot synthesis of 2ꢀalkenylindoles catalyzed by PdꢀNHCs (appended with
naphthalimide or bisnaphthalimide) from oꢀhaloanilines and tertiary propargyl alcohols.15
This appealing report inspired us to design and develop new PdꢀNHCs catalysts. Herein,
we report an unambiguous and oneꢀpot synthesis of 3ꢀalkylꢀ3ꢀaryloxindoles catalyzed by
newly synthesized fluoreneꢀbased PdꢀNHC complexes. In addition, this protocol
proceeds with excellent substrate scope and yields under moderate reaction conditions.
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RESULTS AND DISCUSSION
The ligand systems were synthesized by copper mediated Nꢀarylation of
imidazoles by 2ꢀbromoꢀ9,9ꢀdibutylꢀ9Hꢀfluorene 1 followed by reacting with various alkyl
bromides to give corresponding azolium salts 3aꢀ3c. Likewise, 7aꢀ7c were synthesized
by choosing 2,7ꢀdibromoꢀ9,9ꢀdibutylꢀ9Hꢀfluorene 5 as the arylating partner (Scheme 1).
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Imidazole(1.1 equiv)
4
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6
Cu2O (5 mol %)
Dipivaloylmethane (10 mol %)
Cs2CO3 (2 equiv)
RX (3 equiv)
7
8
Acetonitrile
80 °C, 24 h
DMSO. 120 °C, 12 h
9
N
N
Br
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1
N
N
R
2; 81%
X
3a; 92%
X = Br
Br
R = Et
n-Bu
3b
3c
; 95%
; 87%
Br
Benzyl
R
N
X
N
N
Br
Imidazole (2.2 equiv)
Cu2O (10 mol %)
Dipivaloylmethane (20 mol %)
Cs2CO3 (4 equiv)
N
RX (6 equiv)
Acetonitrile
80 °C, 36 h
DMSO. 120 °C, 12 h
N
N
Br
N
5
N
R
6
; 72%
X
7a
; 89%
7b
X = Br
Br
R = Et
n-Bu
; 93%
Br 7c; 90%
Benzyl
Scheme 1. Synthesis of fluorene based mono and bisimidazolium salts.
Treatment of the azolium salt 3aꢀ3c, at 80 °C, with 1.05 equiv of PdCl2, 5 equiv of
K2CO3, 3 equiv of KBr in pyridine (5 mL) for 16 h resulted in PEPPSI (Pyridineꢀ
Enhanced Precatalyst Preparation Stabilization
and Initiation)
type
trans-
(NHC)PdBr2(py) complexes 4aꢀ4c (Yield range 71ꢀ73%). Complexes 8aꢀ8c (Yield range
52ꢀ61%) were prepared by adapting the aforementioned procedure by doubling the
stoichiometric quantities of PdCl2 (2.1 equiv), K2CO3 (10 equiv) & KBr (6 equiv) to 7aꢀ
7c (Scheme 2). The crude complexes were purified over a shortꢀpad of silica and they
were isolated as yellow solids. These yellow solids were freely soluble in DCM and
CH3CN and airꢀstable. The synthesized complexes 4aꢀ4c & 8aꢀ8c were identified by
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multinuclear NMR and ESIꢀMS. The absence of imidazolium NC(H)N proton resonances
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and the presence of pyridine proton resonances in the H NMR spectra of 4aꢀ4c & 8aꢀ8c
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exemplifies that the imidazolium moieties were deprotonated and coordinated to Pd with
pyridine as an ancillary ligand. PdꢀC carbene signals appear within a range of δ 148.21
to 149.87 in the 13C NMR spectrum.
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Scheme 2. Synthesis of monoꢀ and bisꢀpalladiumꢀPEPPSI complexes.
The molecular structure of monometallic 4c and bimetallic 8a were unequivocally
established by single crystal Xꢀray analysis.16 Pale yellow coloured crystals of 4c and 8a
were grown by slow evaporation of saturated dichloromethane solution at ambient
conditions. Comparatively, both 4c and 8a exhibit squareꢀplanar geometry around the
palladium metal center with the carbene and pyridine oriented trans to one another.
ORTEP representations at 50% probability for 4c and 8a are shown in the Figure 2. The
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PdꢀC carbene bond length in 4c is 1.963(3) Å and the PdꢀC carbene bond lengths in 8a
for Pd1 and Pd2 are 1.968(5) Å, which are quite analogous to those of structurally related
complexes.15
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Figure 2. Crystal structures of PdꢀNHC complexes 4c and 8a. (Thermal ellipsoids are
shown at 50% probability level)
The applicability of Pd salts in the synthesis of 3,3ꢀdisubstituted oxindoles has
been extensively studied. However, it incurred with downside involving expensive
phosphine ligands and employment of strong bases. To circumvent this hurdle, we
utilized the synthesized PdꢀNHCs 4aꢀ4c and 8aꢀ8c to synthesize 3ꢀalkylꢀ3ꢀaryloxindoles.
We commenced our investigations on the αꢀarylation of Nꢀmethyl oxindole 1a using
bromobenzene 2a as a coupling partner, 4a as a catalyst and KOtꢀBu as a base in toluene
at 80 °C for 6 h. Subsequently, the addition of nꢀbutyl bromide to the reaction mixture
and stirring for 2 h resulted in 3ꢀbutylꢀ3ꢀphenyloxindoles 3aa in 54% yield (Table 1,
entry 1). Switching the solvent from toluene to THF displayed enhancement in the yield
of 3aa to 76% (entry 5). Screening of various bases was found to be ineffective (entry 6 ꢀ
12). Bases such as K2CO3, Cs2CO3, triethylamine, DBU and sodium acetate (entry 6ꢀ7 &
10ꢀ12) were not successful indicating the importance of metal enolate formation as
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reported earlier by Willis and coworkers. However, strong bases such as NaOH and KOH
in combination with our PdꢀNHC delivered only trace amounts of 3aa.
Table 1. Optimization of the catalyst system.[a,b]
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Yields (%)
Entry
[Pd]
Base
Solvent
3aa
54
1
2
KOtꢀBu
KOtꢀBu
KOtꢀBu
KOtꢀBu
KOtꢀBu
K2CO3
Toluene
DMSO
NMP
1,4ꢀdioxane
THF
4a
27
4a
3
57
71
4a
4
4a
5
76[c], 59[d]
21
4a
6
THF
4a
7
Cs2CO3
THF
36
4a
8
KOH
THF
16
4a
9
NaOH
THF
11
4a
10
11
12
13
14
15
16
17
18
19
20
Triethylamine
DBU
THF
23
4a
THF
<5
4a
Sodium acetate
KOtꢀBu
KOtꢀBu
KOtꢀBu
KOtꢀBu
KOtꢀBu
KOtꢀBu[f]
KOtꢀBu
KOtꢀBu
THF
ꢀ
4a
THF
83[c], 61[d]
81[c], 60[d]
79[c], 80[d]
84[c,d]
89[c,d]
71
4b
THF
4c
8a
THF
THF
8b
8c
THF
THF
8c
ꢀ
THF
ꢀ[g]
<5[e,g]
Pd(OAc)2/PPh3
Pd(OAc)2/1,10ꢀ
phenathroline
Pd(PPh3)2Cl2
Pd(PPh3)4
5%ꢀ Pd/C
10%ꢀ Pd/C
THF
21
KOtꢀBu
THF
<5 [e,g]
22
23
24
25
KOtꢀBu
KOtꢀBu
KOtꢀBu
KOtꢀBu
THF
THF
THF
THF
11[c,g]
<5[c,g]
ꢀ[c,g]
ꢀ[c,g]
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PdCl2
KOtꢀBu
KOtꢀBu
KOtꢀBu
KOtꢀBu
THF
THF
THF
THF
<5[c,g]
52[e]
87
PdCl2/ 7c
PEPPSIꢀIPr
8c
84[h]
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[a] Unless otherwise mentioned all the reactions are carried out using 1a (1 equiv), 2a (2 equiv) at 80ºC for
6 h. [b] GC yields determined using nꢀdecane as internal standard [c] 5 mol % loading of Pd catalyst. [d] 3
mol % of Pd catalyst. [e] 5 mol % of Pd catalyst and 10 mol % of ligand. [f] 2 equivalents of KOtꢀBu. [g]
3,3ꢀdibutyloxindole is observed as major product. [h] Optimized conditions with a drop of mercury.
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Next, we screened the efficacy of the remaining PdꢀNHCs 4bꢀ4c & 8aꢀ8c (entry
13ꢀ17). Astonishingly, a profound increment in the yield of 3aa (89%, entry 17) was
achieved, when 8c was employed as a catalyst. Notably, bispalladium catalyst outsmarts
the monopalladium even at lower loading. Predictably, in the absence of palladium
source, undesired product 3,3ꢀdibutyloxindole was identified in lieu of 3aa (entry 19). In
comparison, wellꢀestablished palladium catalytic systems such as Pd(OAc)2/PPh3 and
Pd(OAc)2/1,10ꢀphen were proved ineffective (entry 20ꢀ21).
In continuation,
commercially available palladium salts led to either decreased or no reactivity (entry 22ꢀ
26). As a final attempt, a combination of PdCl2 and 7c (NHC ligand) afforded a low
yield of 3aa (entry 27). The activity of the synthesized PdꢀPEPPSI catalysts were equally
active compared with the commercially available PEPPSIꢀIpr (entry 28). The formation
of palladium nanoparticle clusters has been ruled out from the preliminary mercury drop
test (entry 29). Consequently, the best reaction condition was identified: 1.0 equiv of Nꢀ
methyloxindole 1a, 1.1 equiv of bromobenzene 2a, 3 mol % of 8c as a catalyst and 2.2
equiv of KOtꢀBu as a base in 1 mL of THF at 80 °C for 6 h.
With the efficient optimized conditions in hand, we examined the scope of
intermolecular sequential αꢀarylation/alkylation of oxindoles with arylꢀ and alkyl halides.
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Initially, various halobenzenes were evaluated (Table 2) and fluorobenzene was
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nonreactive unlike iodo, bromo and chlorobenzenes (3aa; 81ꢀ89%).
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Table 2. Scope of arylhalides & Nꢀsubstituted oxindoles.[a]
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[a] Reaction conditions i) 1a (1 mmol), 2 (1.1 mmol), 8c (0.03 mmol), KOtꢀBu (2.2 mmol), tetrahydrofuran
(1 mL) 80 °C, 6 h, ii) nꢀbutyl bromide (1.2 mmol) 80 °C 2 h, isolated yields. [b] 8c (5 mol %), KOtꢀBu (2.5
mmol), 100 °C, 12 h, [c] 8c (5 mol %), KOtꢀBu (3 mmol), 120 °C, 12 h. [d] Gramꢀscale reaction. [e] 3,3ꢀ
dibutyl oxindole observed as major product.
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Furthermore, arylation of 1a with 2a was carried out on a gram scale, furnishing the
product 3aa in 83% yield (1.57 g). This oneꢀpot reaction is tested with various aryl
bromides bearing 4ꢀMe (2b), 4ꢀOMe (2c) and 4ꢀEt (2d). Gratifyingly, it was found to be
facile adjudged by the excellent yields (3abꢀ3ad, 82ꢀ86%). Aryl halides with –Me and –
OMe groups at the C3 position were equally reactive to afford desired products in good
yields (3aeꢀ3af, 72ꢀ79%). However, no desired products were observed under the
optimized conditions when substitutions at 2nd position of aryl bromides were tested,
which probably can be attributed to the steric influence. Surprisingly, sterically
encumbered 3ꢀbutylꢀ3ꢀ(2ꢀnaphthyl)oxindoles (3ag) were successfully synthesized using
this protocol. It is worth mentioning that 2ꢀbromothiophene (2h) and 2ꢀbromopyridine
(2i) are well tolerated yielding 3ah & 3ai respectively in 65ꢀ71% yields. Electronꢀ
withdrawing substituents such as cyano (2j) and nitro (2k) on bromobenzenes were
problematic, resulting in undesired product 3,3ꢀdibutyloxindole.
As is evident from Table 2, a variety of substituted oxindoles 1b–1k smoothly
underwent the desired oneꢀpot arylation & alkylation in moderate to good yields (3ba–
3ka, 3bb & 3jb; 62ꢀ86%). This furnishes a possibility for further elaboration on the final
products. Significant electronic perturbation at 5 & 7ꢀ position on oxindole moiety were
tolerated yielding desired products in good to moderate yields (3ba – 3ia & 3bb; 71ꢀ
84%). Remarkably, potentially reactive chlorides were also successfully tolerated,
providing a handle for derivatization of 3ea & 3ia (71ꢀ77%). It was also important that
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the nature of the amide appears to play only a negligible role, with Nꢀbutyl 1j and Nꢀ
benzylic 1k amides successfully undergoing oneꢀpot arylation & alkylation furnishing
desired products in good yields (3ja – 3jb & 3ka; 62ꢀ86%).
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Table 3. Scope of alkylhalides.[a]
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[a] Reaction conditions are similar to table 1.
Of note, a wide array of alkyl bromides (Table 3) was as well compatible with the
reaction conditions affording 4aa–15aa respectively (65ꢀ82%). Even the alkyl groups
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bearing heteroatoms were also well tolerated yielding desired products in good yields
(9aaꢀ14aa).
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A plausible mechanism based on the literature 9g, 17 has been proposed (Scheme 3).
Oxidative addition of Pd(0) to the aryl bromide leads to formation of Pd(II)
organometallic intermediate A which then undergoes substitution of bromide by
potassium enolate of oxindole moiety leading to the formation of intermediate B.
Reductive elimination from the intermediate B leads to the formation of C which then
undergoes alkylation in the presence of nꢀbutyl bromide leading to the formation of the
desired 3,3ꢀdisubstituted oxindole 3aa.
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NHC
Br Pd Br
Py
KOt-Bu
Ar
Butyl
O
(NHC)Pd(0)Py
N
Br
3aa
Py
n-butyl bromide
Br
(II)
Pd
NHC
Ar
A
O
N
Ar
Pd
(II)
C
Py
NHC
O
OK
N
N
KBr
B
KOt-Bu
O
N
Scheme 3. Plausible Mechanism
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CONCLUSIONS
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In conclusion, we have synthesized monoꢀ and bimetallic palladium catalyst
system for the oneꢀpot sequential αꢀarylation/alkylation process to deliver a series of 3,3ꢀ
disubstituted oxindole products. The present protocol provides high step economy and
tolerates a wide range of functional groups, offering the desired products in moderate to
good yields. Currently, our studies are focused on developing efficient asymmetric
catalyst and their application towards enantioselective reactions.
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EXPERIMENTAL SECTION:
General Information: Unless otherwise mentioned, all the reactions were carried out in
screw cap reaction tubes and all the chemicals were purchased commercially and used
without purification. Different palladium salts and the reagents were purchased at the
highest commercial quality and used without purification. Flash chromatographic
technique on silica gel (100ꢀ200 or 230ꢀ400 mesh) was used for the purification of the
products. 0.25mm silica plates (60F254) were used for thin layer chromatography and
1
visualized by exposure to UV light (254 nm). H NMR spectra were recorded on Bruker
spectrometer (400 MHz) and are reported in units ppm (parts per million) relative to the
signals for residual chloroform (7.26 ppm) and DMSO (2.54 ppm) in the deuterated
solvent. 13C NMR spectra were recorded on Bruker spectrometer (100 MHz) and are
reported in ppm relative to deuterated chloroform (77.23 ppm) and DMSO (39.52 ppm).
Coupling constants (J) are reported in Hz; splitting patterns are assigned s = singlet, d =
doublet, t = triplet, q = quartet, td = triplet of doublets. Highꢀresolution mass spectra
(HRMS) and ESI mass were performed on TOFꢀQ analyser.
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Synthesis of 1ꢀ(9,9ꢀdibutylꢀ9Hꢀfluorenꢀ2ꢀyl)ꢀ1Hꢀimidazole 2:
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A mixture of 2ꢀbromoꢀ9,9ꢀdibutylꢀ9Hꢀfluorene 1 (1 equiv), imidazole (1.1 equiv),
copper oxide (5 mol%), dipivaloylmethane (10 mol%) and cesium carbonate (2 equiv)
were suspended in DMSO and heated at 120 °C for 12 h. On completion of reaction
(TLC monitoring), the mass was cooled to room temperature and added into ice cold
water to form solids which were filtered and dried. The crude product was purified by
column chromatography using 3% MeOH in DCM as eluent to yield desired product 2
(81% yield).
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Typical procedure for the synthesis of NHC (3a–3c):
A solution of 2 (1 equiv) and alkyl halide (3 equiv) were heated to reflux in
acetonitrile until the consumption of 2 (monitored by TLC with 98:2 CH2Cl2/MeOH).
After completion of the reaction, the solvent was removed under reduced pressure and the
residue was stirred in diethyl ether. The solids were filtered and dried to obtain the
desired product (3aꢀ3c; 87ꢀ95%).
1ꢀ(9,9ꢀDibutylꢀ9Hꢀfluorenꢀ2ꢀyl)ꢀ3ꢀethylꢀ1Hꢀimidazolꢀ3ꢀium bromide (3a): 605 mg
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(92%) from 500 mg (1.451 mmol) of 2. H NMR (400 MHz, CDCl3) δ 11.26(s, 1H),
7.86 (d, J = 7.12 Hz, 1H), 7.81 (s, 1H), 7.74 – 7.72 (m, 2H), 7.66 (s, 1H), 7.59 (s, 1H),
7.38 (m, 3H), 4.72 (m, 2H), 2.15 – 1.99 (m, 4H), 1.69 (m, 3H),
1.14 – 1.02 (m, 4H),
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0.67 – 0.63 (t, J = 7.30 Hz, 6H), 0.59 – 0.51 (m, 4H); C NMR (100 MHz, CDCl3)
153.8, 151.2, 143.4, 139.2, 136.1, 133.3, 128.5, 127.3, 123.2, 122.6, 121.4, 120.8, 120.7,
120.5, 116.5, 56.0, 45.9, 40.1, 26.1, 23.0, 16.0, 13.9; HRMS (ESI) m/z: [M – Br]+ Calcd
for C26H33N2 373.2638; Found, 373.2641.
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3ꢀButylꢀ1ꢀ(9,9ꢀdibutylꢀ9Hꢀfluorenꢀ2ꢀyl)ꢀ1Hꢀimidazolꢀ3ꢀium bromide (3b): 660 mg
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(95%) from 500 mg (1.451 mmol) of 2. H NMR (400 MHz, CDCl3) δ 11.31 (s, 1H),
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7.86 (d, J = 8.12 Hz, 1H), 7.82 (d, J = 1.88 Hz, 1H), 7.76 – 7.72 (m, 2H), 7.65 (s, 1H),
7.50 (s, 1H), 7.38 – 7.37 (m, 3H), 4.66 – 4.63 (t, J = 7.42 Hz, 2H), 2.15 – 1.97 (m, 6H),
1.53 – 1.44 (m, 2H), 1.16 – 1.04 (m, 4H), 1.02 – 0.98 (t, J = 7.34 Hz, 3H), 0.67 – 0.63 (t,
J = 7.34 Hz, 6H), 0.61 – 0.51 (m, 4H); 13C NMR (100 MHz, CDCl3) 153.8, 151.2,
143.4, 139.2, 136.4, 133.3, 128.5, 127.3, 123.2, 122.9, 121.4, 1207, 120.6, 120.5, 116.3,
56.0, 50.4, 40.1, 32.5, 26.1, 23.0, 19.7, 13.9, 13.7; HRMS (ESI) m/z: [M – Br]+ Calcd
for C28H37N2 401.2951; Found, 401.2940.
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3ꢀBenzylꢀ1ꢀ(9,9ꢀdibutylꢀ9Hꢀfluorenꢀ2ꢀyl)ꢀ1Hꢀimidazolꢀ3ꢀium bromide (3c): 650 mg
(87%) from 500 mg (1.451 mmol) of 2. 1H NMR (400 MHz, DMSOꢀd6) δ 10.15 (s, 1H),
8.45 – 8.44 (m, 1H), 8.09 – 8.06 (m, 2H), 7.99 – 7.98 (m, 1H), 7.94 – 7.92 (m, 1H), 7.81
– 7.78 (m, 1H), 7.58 (m, 2H), 7.51 – 7.38 (m, 6H), 5.55 (s, 2H), 2.08 – 2.04 (t, J = 8.2
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Hz, 4H), 1.08 – 0.99 (m, 4H), 0.63 – 0.59 (t, J = 7.32 Hz, 6H), 0.55 – 0.41 (m, 4H); C
NMR (100 MHz, DMSOꢀd6) 152.8, 150.9, 142.4, 139.5, 135.9, 135.0, 134.2, 129.5,
129.3, 129.0, 128.7, 127.7, 123.6, 123.6, 122.2, 121.6, 121.1, 116.8, 55.7, 52.8, 39.4,
26.2, 22.9, 14.2; HRMS (ESI) m/z: [M – Br]+ Calcd for C31H35N2 435.2795; Found,
435.2784.
Synthesis of 1,1'ꢀ(9,9ꢀdibutylꢀ9Hꢀfluoreneꢀ2,7ꢀdiyl)bis(1Hꢀimidazole) 6:
A mixture of 2,7ꢀdibromoꢀ9,9ꢀdibutylꢀ9Hꢀfluorene 5 (1 equiv), imidazole (2.2
equiv), copper oxide (10 mol%), dipivaloylmethane (20 mol%) and cesium carbonate (4
equiv) were suspended in DMSO and heated at 120 °C for 12 h. On completion of
reaction (TLC monitoring), the reaction mass was cooled to room temperature and added
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into ice cold water to form solids which were filtered and dried. The crude product was
purified by column chromatography using 5% MeOH in DCM as eluent to yield desired
product 6 (72% yield).
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Typical procedure for the synthesis of NHC (7a–7c):
A solution of 6 (1 equiv) and alkyl halide (6 equiv) were heated to reflux in
acetonitrile until 6 gets totally consumed (monitored by TLC with 95:5 CH2Cl2/MeOH).
After completion of the reaction, the solvent was removed under reduced pressure and the
residue was stirred in diethyl ether. The solids were filtered and dried to obtain the
desired product.
1,1'ꢀ(9,9ꢀDibutylꢀ9Hꢀfluoreneꢀ2,7ꢀdiyl)bis(3ꢀethylꢀ1Hꢀimidazolꢀ3ꢀium)bromide (7a):
680 mg (89%) from 500 mg (1.217 mmol) of 6. 1H NMR (400 MHz, DMSO d6) δ 10.08
(d, J = 6.32 Hz, 2H), 8.48 (s, 2H), 8.23 (d, J = 8.24 Hz, 2H), 8.13 (d, J = 9.04 Hz, 4H),
7.89 – 7.87 (dd, J = 1.6, 8.2 Hz, 2H), 4.36 – 4.31 (q, J = 7.30 Hz, 4H), 2.18 – 2.14 (t, J =
7.94 Hz, 4H), 1.57 – 1.53 (t, J = 7.28 Hz, 6H), 1.10 – 1.01 (m, 4H), 0.64 – 0.60 (t, J =
7.24 Hz, 6H), 0.49 (m, 4H); 13C NMR (100 MHz, DMSO d6) 153.2, 140.7, 135.6, 134.9,
123.4, 122.5, 121.5, 121.2, 116.9, 56.4, 45.3, 39.4, 26.2, 22.8, 15.4, 14.2; HRMS (ESI)
m/z: [Mꢀ2Br]+2 Calcd for C31H40N4 234.1621; Found, 234.1640.
1,1'ꢀ(9,9ꢀDibutylꢀ9Hꢀfluoreneꢀ2,7ꢀdiyl)bis(3ꢀbutylꢀ1Hꢀimidazolꢀ3ꢀium)bromide (7b):
775 mg (93%) from 500 mg (1.217 mmol) of 6. 1H NMR (400 MHz, DMSO d6) δ
10.03 (s, 2H), 8.47 (s, 2H), 8.24 (d, J = 8.24 Hz, 2H), 8.11 (s, 2H), 8.08 (s, 2H), 7.89 –
7.86 (dd, J = 1.88, 8.24 Hz, 2H), 4.32 – 4.28 (t, J = 7.26 Hz, 4H), 2.18 – 2.14 (m, 4H),
1.99 – 1.89 (m, 4H), 1.43 – 1.34 (m, 4H), 1.12 – 1.03 (m, 4H), 0.98 – 0.95 (t, J = 7.36
Hz, 6H), 0.65 – 0.62 (t, J = 7.32 Hz, 6H), 0.55 – 0.51 (m, 4H); 13C NMR (100 MHz,
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DMSO d6) 153.1, 140.7, 135.8, 134.9, 123.8, 122.5, 121.6, 121.3, 116.9, 56.4, 49.6, 39.4,
31.7, 26.1, 22.9, 19.4, 14.2, 13.9; HRMS (ESI) m/z: [Mꢀ2Br]+2 Calcd for C35H48N4
262.1934; Found, 262.1955.
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1,1'ꢀ(9,9ꢀDibutylꢀ9Hꢀfluoreneꢀ2,7ꢀdiyl)bis(3ꢀbenzylꢀ1Hꢀimidazolꢀ3ꢀium)bromide
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(7c): 825 mg (90%) from 500 mg (1.217 mmol) of 6. H NMR (400 MHz, DMSO d6) δ
10.28 (s, 2H), 8.50 (s, 2H), 8.25 (d, J = 8.24 Hz, 2H), 8.10 (s, 4H), 7.90 – 7.88 (dd, J =
1.92, 8.20 Hz, 2H), 7.60 (d, J = 6.88 Hz, 4H), 7.49 – 7.43 (m, 6H), 5.58 (s, 4H), 2.18 –
2.14 (t, J = 7.94 Hz, 4H), 1.08 – 1.04 (m, 4H), 0.65 – 0.61 (t, J = 7.32 Hz, 6H), 0.55 –
0.47 (m, 4H); 13C NMR (100 MHz, DMSO d6) 153.2, 140.8, 136.1, 135.0, 134.9, 129.5,
129.3, 129.1, 123.7, 122.5, 122.2, 121.5, 117.0, 56.4, 52.8, 39.4, 26.1, 22.9, 14.2; HRMS
(ESI) m/z: [Mꢀ2Br]+2 Calcd for C41H44N4 296.1778; Found, 296.1808
General Procedure for the synthesis of PdꢀPEPPSIꢀNHC (4a–4c)
An ovenꢀdried vial equipped with a magnetic stir bar was charged with mono
imidazolium salt 3a–3c (1 equiv), PdCl2 (1.05 equiv), potassium carbonate (5 equiv),
potassium bromide (3 equiv) and pyridine (5 mL). The vial was sealed and the solution
was allowed to stir at 80 °C for 16 h. The reaction mass was then cooled to room
temperature, diluted with DCM and filtered through a short plug of celite and the solvent
was removed under reduced pressure. The crude was purified by column chromatography
using dichloromethane/methanol to yield yellow coloured solids.
Complex 4a: Purified by column chromatography on silica gel (DCM/Methanol = 98/2).
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Yellow solid, 110 mg (71%) from 100 mg (0.220 mmol) of 3a; Mp: 172ꢀ174 °C; H
NMR (400 MHz, CDCl3) δ 8.91 (d, J = 5.12 Hz, 2H), 8.11 (s, 1H), 7.86 (d, J = 8.04 Hz,
1H), 7.81 – 7.79 (dd, J = 1.2, 8 Hz, 1H), 7.76 (d, J = 7.28 Hz, 1H), 7.69 – 7.65 (t, J =
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(q, J = 7.32 Hz, 2H), 2.09 – 1.96 (m, 4H), 1.73 – 1.69 (t, J = 7.34 Hz, 3H), 1.03 – 0.94
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(m, 4H), 0.83 – 0.63 (m, 4H), 0.60 – 0.57 (t, J = 7.34 Hz, 6H); C NMR (100 MHz,
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CDCl3) 152.7, 152.0, 151.4, 148.2, 141.5, 140.3, 138.6, 137.7, 127.6, 127.1, 125.0,
124.4, 123.8, 123.1, 121.8, 121.3, 120.2, 120.2, 55.6, 46.7, 40.2, 26.2, 23.1, 15.7, 13.9;
HRMS (ESI) m/z: [M – Br ꢀ Py]+ Calcd for C26H32BrN2Pd 559.0782; Found, 559.0798.
Complex 4b: Purified by column chromatography on silica gel (DCM/Methanol = 99/1).
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Yellow solid, 120 mg (77%) from 100 mg (0.208 mmol) of 3b; Mp: 150ꢀ152 °C; H
NMR (400 MHz, CDCl3) δ 8.90 (d, J = 5.32 Hz, 2H), 8.11 (s, 1H), 7.85 (d, J = 8 Hz,
1H), 7.81 (d, J = 8.08 Hz, 1H), 7.76 (d, J = 7.12 Hz, 1H), 7.68 – 7.65 (t, J = 7.60 Hz,
1H), 7.38 – 7.32 (m, 3H), 7.24 – 7.20 (m, 3H), 7.11 (s, 1H), 4.68 – 4.64 (t, J = 7.68 Hz,
2H), 2.20 – 2.12 (m, 2H), 2.09 – 1.96 (m, 4H), 1.62 – 1.56 (m, 2H), 1.09 – 1.06 (t, J =
7.32 Hz, 3H), 1.03 – 0.94 (m, 4H), 0.83 – 0.64 (m, 4H), 0.60 – 0.57 (t, J = 7.32 Hz, 6H);
13C NMR (100 MHz, CDCl3) 152.7, 152.0, 151.4, 148.4, 141.5, 140.3, 138.7, 137.7,
127.6, 127.0, 125.0, 124.4, 123.6, 123.1, 122.0, 121.8, 120.2, 120.1, 55.6, 51.6, 40.2,
32.2, 26.1, 23.1, 20.2, 14.0, 13.9; HRMS (ESI) Exact mass: [M+H]+ Calcd for
C33H42Br2N3Pd 744.0775; Found, 744.0787.
Complex 4c: Purified by column chromatography on silica gel (DCM/Methanol = 98/2).
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Yellow solid, 110 mg (73%) from 100 mg (0.194 mmol) of 3c; Mp: 168ꢀ170 °C; H
NMR (400 MHz, CDCl3) δ 8.91 – 8.89 (m, 2H), 8.16 (d, J = 1.48 Hz, 1H), 7.87 – 7.81
(m, 2H), 7.77 – 7.75 (m, 1H), 7.69 – 7.62 (m, 3H), 7.45 – 7.32 (m, 6H), 7.24 – 7.20 (m,
3H), 6.86 (d, J = 2.04 Hz, 1H), 5.94 (s, 2H), 2.11 – 1.97 (m, 4H), 1.04 – 0.96 (m, 4H),
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0.84 – 0.73 (m, 2H), 0.61 – 0.57 (m, 8H); C NMR (100 MHz, CDCl3) 152.7, 152.1,
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151.3, 149.4, 141.6, 140.3, 138.5, 137.8, 135.1, 129.6, 129.1, 128.8, 127.7, 127.1, 125.0,
124.5, 123.9, 123.1, 121.7, 121.6, 120.2, 120.2, 55.6, 55.5, 40.2, 26.1, 23.1, 13.9; HRMS
(ESI) m/z: [M – 2Br – Py + CH3CN]+2 Calcd for C33H36N3Pd+2 580.1944; Found,
580.1980.
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General Procedure for the synthesis of PdꢀPEPPSIꢀNHC (8a–8c)
8aꢀ8c were obtained by following the aforementioned procedure using bis
imidazolium salt 7a–7c (1 equiv), PdCl2 (2.1 equiv), potassium carbonate (10 equiv),
potassium bromide (6 equiv) and pyridine (8 mL).
Complex 8a: Purified by column chromatography on silica gel (DCM/Methanol = 96/4).
Yellow solid, 96 mg (52%) from 100 mg (0.160 mmol) of 7a; Mp: 252ꢀ254 °C; 1H NMR
(400 MHz, CDCl3) δ 8.91 – 8.89 (m, 4H), 8.11 (s, 2H), 7.91 (s, 4H), 7.69 – 7.65 (t, J =
7.6 Hz, 2H), 7.27 (d, J = 1.92 Hz, 2H), 7.25 – 7.21 (m, 4H), 7.15 (d, J = 1.96 Hz, 2H),
4.79 – 4.74 (q, J = 7.32 Hz, 4H), 2.11 – 2.06 (t, J = 8.08 Hz, 4H), 1.73 – 1.69 (t, J = 7.34
Hz, 6H), 0.95 – 0.86 (m, 4H), 0.81 – 0.74 (m, 4H), 0.52 – 0.49 (t, J = 7.22 Hz, 6H); 13C
NMR (100 MHz, CDCl3) 152.6, 152.5, 148.3, 140.5, 138.9, 137.6, 125.1, 124.4, 123.6,
121.7, 121.3, 120.5, 56.0, 46.7, 40.0, 26.1, 23.0, 15.6, 13.8; HRMS (ESI) m/z: [M – Br ꢀ
Py]+1 Calcd for C36H43Br3N5Pd2 997.9116; Found, 997.9138.
Complex 8b: Purified by column chromatography on silica gel (DCM/Methanol = 97/3).
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Yellow solid, 110 mg (61%) from 100 mg (0.146 mmol) of 7b; Mp: 228ꢀ230 °C; H
NMR (400 MHz, CDCl3) δ 8.92 – 8.90 (m, 4H), 8.14 (s, 2H), 7.92 (s, 4H), 7.71 – 7.66
(m, 2H), 7.36 – 7.33 (m, 1H), 7.28 – 7.27 (m, 2H), 7.25 – 7.23 (m, 3H), 7.15 (d, J = 1.96
Hz, 2H), 4.70 – 4.66 (t, J = 7.70 Hz, 4H), 2.22 – 2.14 (m, 4H), 2.13 – 2.09 (m, 4H), 1.61
– 1.56 (m, 4H), 1.11 – 1.07 (t, J = 7.36 Hz, 6H), 0.96 – 0.88 (m, 4H), 0.84 – 0.78 (m,
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4H), 0.54 – 0.50 (t, J = 7.22 Hz, 6H); 13C NMR (100 MHz, CDCl3) 154.3, 152.6, 148.5,
140.4, 139.0, 138.4, 137.6, 125.1, 125.0, 124.4, 123.3, 122.0, 121.7, 120.5, 56.0, 51.5,
40.0, 32.1, 26.1, 23.0, 20.1, 13.9, 13.8; HRMS (ESI) m/z: [M – Br ꢀ Py]+1 Calcd for
C40H51Br3N5Pd2 1053.9742; Found, 1053.9768.
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Complex 8c: Purified by column chromatography on silica gel (DCM/Methanol = 95/5).
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Yellow solid, 102 mg (60%) from 100 mg (0.133 mmol) of 7c; Mp: 236ꢀ238 °C; H
NMR (400 MHz, CDCl3) δ 8.85 – 8.83 (m, 4H), 8.10 (s, 2H), 7.86 (m, 4H), 7.62 – 7.57
(m, 2H), 7.56 – 7.54 (m, 4H), 7.37 – 7.31 (m, 6H), 7.17 – 7.14 (m, 6H), 6.80 (d, J = 2.08
Hz, 2H), 5.87 (s, 4H), 2.06 – 2.02 (t, J = 8.06 Hz, 4H), 0.88 – 0.81 (m, 4H), 0.76 – 0.69
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(m, 4H), 0.46 – 0.42 (t, J = 7.20 Hz, 6H); C NMR (100 MHz, CDCl3) 154.3, 152.6,
152.5, 149.9, 149.5, 140.5, 138.9, 138.4, 137.7, 136.0, 134.9, 129.5, 129.0, 128.7, 125.1,
125.0, 124.4, 123.7, 123.7, 121.7, 121.6, 120.5, 56.0, 55.5, 40.0, 26.1, 23.0, 13.8; HRMS
(ESI) m/z: [M – Br ꢀ 2Py]+1 Calcd for C41H42Br3N4Pd2 1042.9007; Found, 1042.9040.
General procedure for oneꢀpot synthesis of 3,3ꢀdisubstituted Nꢀalkyloxindoles
An ovenꢀdried reaction vial equipped with a stir bar was charged with Nꢀ
alkyloxindole 1 (1 mmol), 8c (3 mol %), potassium tertiary butoxide (2.2 mmol),
halobenzene 2 (1.1 mmol) and anhydrous THF (1 mL). The reaction mixture was stirred
at 80 °C for 6 h and nꢀbutyl bromide (1.2 equiv) was added and further heated for another
2 h. The reaction mass was then diluted with ethyl acetate and filtered over celite. The
filtrate was then washed with water twice and the solvent was concentrated under
reduced pressure. The crude material was then purified by column chromatography using
ethyl acetate/hexane as eluents.
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silica gel (hexane/ethyl acetate = 95/5). 242 mg (87%), White coloured solid; H NMR
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(400 MHz, CDCl3) δ: 7.37 – 7.36 (m, 2H), 7.33 – 7.31 (dd, J = 1.2, 7.68 Hz, 1H), 7.30 –
7.28 (m, 2H), 7.24 – 7.22 (m, 2H), 7.14 – 7.10 (td, J = 0.84, 7.56 Hz, 1H), 6.92 (d, J =
7.76 Hz, 1H), 3.23 (s, 3H), 2.40 – 2.33 (td, J = 4.52, 13.04 Hz, 1H), 2.22 – 2.15 (td, J =
4.24, 12.72 Hz, 1H), 1.32 – 1.28 (m, 2H), 1.10 – 1.05 (m, 1H), 0.90 – 0.83 (m, 1H), 0.82
– 0.78 (t, J = 7.34 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 178.8, 144.0, 140.4, 132.5,
128.5, 128.1, 127.2, 126.9, 124.8, 122.6, 108.2, 56.7, 37.8, 26.7, 26.4, 22.9, 13.8;
HRMS: C19H22NO [M+H]+ calcd: 280.1701, found: 280.1703.
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on silica gel (hexane/ethyl acetate = 95/5). 250 mg (86%), colourless oil; H NMR (400
MHz, CDCl3) δ: 7.34 – 7.30 (td, J = 1.2, 7.72 Hz, 1H), 7.25 – 7.20 (m, 3H), 7.13 – 7.08
(m, 3H), 6.91 (d, J = 7.76 Hz, 1H), 3.22 (s, 3H), 2.38 – 2.31 (td, J = 4.52, 12.96 Hz, 1H),
2.29 (s, 3H), 2.20 – 2.12 (td, J = 4.2, 12.76 Hz, 1H), 1.19 – 1.02 (m, 2H), 0.91 – 0.84 (m,
2H), 0.81 – 0.78 (t, J = 7.34 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 179.0, 144.1,
137.6, 137.0, 132.8, 129.3, 128.1, 126.9, 124.9, 122.7, 108.3, 56.6, 37.8, 26.8, 26.5, 23.0,
21.1, 14.0; HRMS: C20H24NO [M+H]+ calcd: 294.1858, found: 294.1860.
3ꢀButylꢀ3ꢀ(4ꢀmethoxyphenyl)ꢀ1ꢀmethylindolinꢀ2ꢀone (3ac): Purified by column
chromatography on silica gel (hexane/ethyl acetate = 92/8). 252 mg (82%), light yellow
coloured liquid; 1H NMR (400 MHz, CDCl3) δ: 7.35 – 7.31 (td, J = 1.28, 7.68 Hz, 1H),
7.79 – 7.28 (m, 1H), 7.27 – 7.26 (m, 1H), 7.23 – 7.21 (dd, J = 0.72, 7.36 Hz, 1H), 7.14 –
7.10 (td, J = 0.92, 7.52 Hz, 1H), 6.91 (d, J = 7.76 Hz, 1H), 6.83 – 6.82 (m, 1H), 6.81 –
6.79 (m, 1H), 3.76 (s, 3H), 3.21 (s, 3H), 2.36 – 2.29 (td, J = 4.52, 13.04 Hz, 1H), 2.18 –
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2.10 (td, J = 4.24, 12.72 Hz, 1H), 1.12 – 1.02 (m, 2H), 0.90 – 0.82 (m, 2H), 0.81 – 0.78
(t, J = 7.34 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 179.0, 158.7, 144.0, 132.6, 132.5,
128.0, 124.7, 122.5, 113.8, 108.2, 56.0, 55.3, 37.9, 26.7, 26.3, 22.9, 13.8; HRMS:
C20H24NO2 [M+H]+ calcd: 310.1807, found: 310.1806.
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3ꢀButylꢀ3ꢀ(4ꢀethylphenyl)ꢀ1ꢀmethylindolinꢀ2ꢀone (3ad): Purified by column
chromatography on silica gel (hexane/ethyl acetate = 95/5). 255 mg (83%), light yellow
coloured liquid; 1H NMR (400 MHz, CDCl3) δ: 7.33 – 7.29 (td, J = 1.24, 7.68 Hz, 1H),
7.25 – 7.23 (m, 2H), 7.22 – 7.20 (dd, J = 0.76, 7.36 Hz, 1H), 7.12 – 7.08 (m, 3H), 6.89 (d,
J = 7.76 Hz, 1H), 3.20 (s, 3H), 2.60 – 2.55 (q, J = 7.6 Hz, 2H), 2.38 – 2.31 (td, J = 4.52,
13.04 Hz, 1H), 2.19 – 2.11 (td, J = 4.20 Hz, 12.68 Hz, 1H), 1.22 – 1.20 (m, 2H), 1.19 –
1.15 (t, J = 7.6 Hz, 3H), 1.11 – 0.98 (m, 1H), 0.89 – 0.82 (m, 1H), 0.80 – 0.76 (t, J =
7.34 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 179.1, 144.1, 143.3, 137.8, 132.8, 128.1,
126.9, 124.9, 122.6, 108.3, 56.6, 37.9, 28.5, 26.8, 26.5, 23.0, 15.6, 13.9; HRMS:
C21H26NO [M+H]+ calcd: 308.2014, found: 308.2015.
3ꢀButylꢀ1ꢀmethylꢀ3ꢀ(mꢀtolyl)indolinꢀ2ꢀone (3ae): Purified by column chromatography
on silica gel (hexane/ethyl acetate = 94/6). 230 mg (79%), light yellow coloured liquid;
1H NMR (400 MHz, CDCl3) δ: 7.35 – 7.31 (td, J = 1.12, 7.68 Hz, 1H), 7.23 (d, J = 7.32
Hz, 1H), 7.19 – 7.10 (m, 4H), 7.05 (d, J = 7.08 Hz, 1H), 6.92 (d, J = 7.76 Hz, 1H), 3.23
(s, 3H), 2.40 – 2.33 (td, J = 4.48, 12.76 Hz, 1H), 2.31 (s, 3H), 2.21 – 2.14 (td, J = 4.2,
12.72 Hz, 1H), 1.25 – 1.19 (m, 2H), 1.12 – 1.01 (m, 1H), 0.90 – 0.84 (m, 1H), 0.82 – 0.78
(t, J = 7.34 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 179.0, 144.1, 140.5, 138.2, 132.8,
128.5, 128.1, 128.1, 127.6, 124.8, 124.0, 122.7, 108.3, 56.8, 37.8, 26.8, 26.5, 23.0, 21.7,
14.0; HRMS: C20H24NO [M+H]+ calcd: 294.1858, found: 294.1860.
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3ꢀButylꢀ3ꢀ(3ꢀmethoxyphenyl)ꢀ1ꢀmethylindolinꢀ2ꢀone (3af): Purified by column
chromatography on silica gel (hexane/ethyl acetate = 92/8). 220 mg (72%), light yellow
coloured liquid; 1H NMR (400 MHz, CDCl3) δ: 7.34 – 7.30 (t, J = 7.70 Hz, 1H), 7.24 –
7.18 (m, 2H), 7.13 – 7.09 (t, J = 7.50 Hz, 1H), 6.96 – 6.94 (m, 2H), 6.91 (d, J = 7.80 Hz,
1H), 6.78 – 6.76 (m, 1H), 3.76 (s, 3H), 3.22 (s, 3H), 2.39 – 2.31 (td, J = 4.48, 12.92 Hz,
1H), 2.21 – 2.14 (td, J = 4.16, 12.80 Hz, 1H), 1.30 – 1.28 (m, 1H), 1.24 – 1.20 (m, 1H),
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1.13 – 1.02 (m, 1H), 0.90 – 0.87 (m, 1H), 0.82 – 0.78 (t, J = 7.32 Hz, 3H); C NMR
(100 MHz, CDCl3) δ: 178.6, 159.6, 143.9, 142.0, 132.4, 129.4, 128.1, 124.8, 122.6,
119.3, 113.5, 112.0, 108.2, 56.7, 55.2, 37.7, 26.7, 26.4, 22.9, 13.8; HRMS: C20H24NO2
[M+H]+ calcd: 310.1807, found: 310.1806.
3ꢀButylꢀ1ꢀmethylꢀ3ꢀ(naphthalenꢀ2ꢀyl)indolinꢀ2ꢀone (3ag): Purified by column
chromatography on silica gel (hexane/ethyl acetate = 95/5). 265 mg (81%), Yellow
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coloured thick syrup; H NMR (400 MHz, CDCl3) δ: 7.78 – 7.74 (m, 4H), 7.52 – 7.49
(dd, J = 1.8, 8.68 Hz, 1H), 7.45 – 7.41 (m, 2H), 7.39 – 7.35 (td, J = 1.24, 7.72 Hz, 1H),
7.29 – 7.27 (dd, J = 0.68, 7.36 Hz, 1H), 7.17 – 7.13 (td, J = 0.92, 7.52 Hz, 1H), 6.96 –
6.94 (d, J = 7.8 Hz, 1H), 3.26 (s, 3H), 2.52 – 2.45 (td, J = 4.52, 12.92 Hz, 1H), 2.34 –
2.26 (td , J = 4.24, 12.68 Hz, 1H), 1.38 – 1.29 (m, 2H), 1.20 ꢀ 1.09 (m, 1H), 0.97 – 0.86
(m, 1H)0.84 – 0.81 (t, J = 7.32 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 178.9, 144.2,
137.9, 133.4, 132.69, 132.66, 128.4, 128.30, 128.26, 127.5, 126.13, 126.07, 125.8, 125.3,
125.0, 122.8, 108.4, 57.0, 37.7, 26.8, 26.5, 23.1, 14.0; HRMS: C23H24NO [M+H]+ calcd:
330.1858, found: 330.1858.
3ꢀButylꢀ1ꢀmethylꢀ3ꢀ(thiophenꢀ2ꢀyl)indolinꢀ2ꢀone (3ah): Purified by column
chromatography on silica gel (hexane/ethyl acetate = 90/10). 200 mg (71%), Yellow
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coloured liquid; H NMR (400 MHz, CDCl3) δ: 7.35 – 7.29 (m, 2H), 7.15 – 7.14 (t, J =
3.24 Hz, 1H), 7.12 – 7.08 (t, J = 7.48 Hz, 1H), 6.88 – 6.84 (m, 3H), 3.18 (s, 3H), 2.33 –
2.25 (td, J = 4.56, 12.92 Hz, 1H), 2.18 – 2.11 (td, J = 4.2, 12.8 Hz, 1H), 1.19 – 1.13 (m,
2H), 0.91 – 0.78 (m, 2H), 0.77 – 0.73 (t, J = 7.32 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ: 177.6, 144.6, 143.9, 132.0, 128.7, 126.7, 124.82, 124.78, 124.7, 122.8, 108.4, 54.7,
40.1, 26.8, 26.6, 22.8, 13.9; HRMS: C17H20NOS [M+H]+ calcd: 286.1266, found:
286.1265.
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3ꢀButylꢀ1ꢀmethylꢀ3ꢀ(pyridinꢀ2ꢀyl)indolinꢀ2ꢀone
(3ai):
Purified
by
column
chromatography on silica gel (hexane/ethyl acetate = 88/12). 182 mg (65%), brown
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coloured liquid; H NMR (400 MHz, CDCl3) δ: 8.50 (m, 1H), 7.51 – 7.47 (td, J = 1.72,
7.84 Hz, 1H), 7.26 (d, J = 7.36 Hz, 1H), 7.20 (s, 1H), 7.18 – 7.17 (d, J = 3.16 Hz, 1H),
7.06 – 7.03 (m, 1H), 7.00 – 6.96 (t, J = 7.54 Hz, 1H), 6.81 (d, J = 7.76 Hz, 1H), 3.22 (s,
3H), 2.40 – 2.27 (m, 2H), 1.15 – 1.11 (m, 1H), 1.03 – 0.92 (m, 1H), 0.84 – 0.74 (m, 2H),
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0.73 – 0.69 (t, J = 7.32 Hz, 3H); C NMR (100 MHz, CDCl3) δ: 178.3, 159.8, 149.6,
143.8, 136.7, 132.7, 128.1, 124.7, 122.8, 122.2, 121.3, 108.1, 59.6, 37.2, 26.5, 26.5, 23.0,
14.0; HRMS: C18H21N2O [M+H]+ calcd: 281.1654, found: 281.1655.
3ꢀButylꢀ1,5ꢀdimethylꢀ3ꢀphenylindolinꢀ2ꢀone
(3ba):
Purified
by
column
chromatography on silica gel (hexane/ethyl acetate = 95/5). 245 mg (84%), pale yellow
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coloured liquid; H NMR (400 MHz, CDCl3) δ: 7.30 – 7.27 (m, 2H), 7.24 – 7.19 (m,
2H), 7.17 – 7.13 (m, 1H), 7.06 – 7.04 (dd, J = 0.76, 7.88 Hz, 1H), 6.96 (m, 1H), 6.73 (d, J
= 7.88 Hz, 1H), 3.14 (s, 3H), 2.33 – 2.26 (m, 1H), 2.30 (s, 3H), 2.13 – 2.06 (dd, J = 4.24,
12.72 Hz, 1H), 1.24 – 1.20 (m, 2H), 1.07 – 0.95 (m, 1H), 0.87 – 0.78 (m, 1H), 0.76 – 0.72
(t, J = 7.34 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 178.9, 141.7, 140.8, 132.8, 132.2,
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C20H24NO [M+H]+ calcd: 294.1858, found: 294.1860
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(3bb):
Purified
by
column
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chromatography on silica gel (hexane/ethyl acetate = 94/6). 255 mg (83%), pale yellow
coloured liquid; 1H NMR (400 MHz, CDCl3) δ: 7.16 (d, J = 7.76 Hz, 2H), 7.05 – 7.01 (t,
J = 8.22 Hz, 3H), 6.93 (s, 1H), 6.72 (d, J = 7.84 Hz, 1H), 3.12 (s, 3H), 2.28 (s, 3H), 2.26
– 2.24 (m, 1H), 2.21 (s, 3H), 2.10 – 2.03 (td, J = 4.00, 12.68 Hz, 1H), 1.16 – 1.10 (m,
2H), 1.06 – 0.89 (m, 1H), 0.83 – 0.78 (m, 1H), 0.75 – 0.71 (t, J = 7.32 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ: 179.0, 141.7, 137.8, 136.9, 132.9, 132.2, 129.3, 128.3,
126.9, 125.5, 108.0, 56.6, 37.6, 26.7, 26.5, 23.0, 21.4, 21.1, 14.0; HRMS: C21H26NO
[M+H]+ calcd: 308.2014, found: 308.2015
3,5ꢀDibutylꢀ1ꢀmethylꢀ3ꢀphenylindolinꢀ2ꢀone
(3ca):
Purified
by
column
chromatography on silica gel (hexane/ethyl acetate = 95/5). 281 mg (84%), pale yellow
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coloured liquid; H NMR (400 MHz, CDCl3) δ: 7.33 (d, J = 7.68 Hz, 2H), 7.24 – 7.22
(m, 2H), 7.20 – 7.16 (m, 1H), 7.10 (d, J = 7.88 Hz, 1H), 7.00 (s, 1H), 6.78 (d, J = 7.92
Hz, 1H), 3.16 (s, 3H), 2.60 – 2.56 (t, J = 7.7 Hz, 2H), 2.36 – 2.28 (td, J = 4.48, 12.84 Hz,
1H), 2.17 – 2.09 (td, J = 4.16, 12.72 Hz, 1H), 1.38 – 1.24 (m, 4H), 1.17 – 0.98 (m, 2H),
0.90 – 0.86 (t, J = 7.34 Hz, 3H), 0.84 – 0.79 (m, 2H), 0.78 – 0.74 (t, J = 7.32 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ: 178.9, 141.9, 140.8, 137.5, 132.5, 128.6, 127.8, 127.2,
127.1, 125.1, 108.0, 56.9, 37.8, 35.5, 34.2, 26.8, 26.5, 23.0, 22.4, 14.1, 14.0; HRMS:
C23H30NO [M+H]+ calcd: 336.2327, found: 336.2326
3ꢀButylꢀ5ꢀfluoroꢀ1ꢀmethylꢀ3ꢀphenylindolinꢀ2ꢀone (3da): Purified by column
chromatography on silica gel (hexane/ethyl acetate = 96/4). 235 mg (79%), yellow
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coloured liquid; H NMR (400 MHz, CDCl3) δ: 7.27 – 7.20 (m, 4H), 7.18 – 7.16 (m,
1H), 6.98 – 6.93 (td, J = 2.56, 9.04 Hz, 1H), 6.91 – 6.89 (dd, J = 2.52, 8.04 Hz, 1H), 6.76
– 6.73 (m, 1H), 3.14 (s, 3H), 2.34 – 2.27 (td, J = 4.44, 13.04 Hz, 1H), 2.12 – 2.05 (td, J =
4.12, 12.92 Hz, 1H), 1.26 – 1.20 (m, 2H), 1.05 – 0.94 (m, 1H), 0.83 – 0.77 (m, 1H), 0.76
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– 0.72 (t, J = 7.32 Hz, 3H); C NMR (100 MHz, CDCl3) δ: 178.6, 160.6, 158.3, 140.0
(d, J = 8.06 Hz), 134.4 (d, J = 7.86 Hz), 128.7, 127.5, 126.9, 114.6 (d, J = 23.33 Hz),
113.0 (d, J = 24.6 Hz), 108.8 (d, J = 8.26 Hz), 57.3, 37.7, 26.7, 26.6, 23.0, 13.9; 19F
NMR (376 MHz; proton coupled; CDCl3) δ ꢀ120.4; HRMS: C19H21FNO [M+H]+
calcd: 298.1607, found: 298.1608
3ꢀButylꢀ5ꢀchloroꢀ1ꢀmethylꢀ3ꢀphenylindolinꢀ2ꢀone (3ea): Purified by column
chromatography on silica gel (hexane/ethyl acetate = 96/4). 240 mg (77%), yellow
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coloured liquid; H NMR (400 MHz, CDCl3) δ: 7.32 – 7.29 (m, 3H), 7.28 (s, 1H), 7.25
– 7.20 (m, 2H), 7.17 (d, J = 2.08 Hz, 1H), 6.82 – 6.79 (d, J = 8.28 Hz, 1H), 3.20 (s, 3H),
2.39 – 2.31 (td, J = 4.48, 13Hz, 1H), 2.17 – 2.10 (td, J = 4.2, 12.76 Hz, 1H), 1.29 ꢀ 1.26
(m, 2H), 1.09 – 0.98 (m, 1H), 0.90 – 0.83 (m, 1H), 0.81 – 0.78 (t, J = 7.34 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ: 178.4, 142.7, 139.9, 134.5, 128.8, 128.2, 128.2, 127.6,
126.9, 125.2, 109.2, 57.1, 37.7, 26.7, 26.6, 23.0, 13.9; HRMS: C19H21ClNO [M+H]+
calcd: 314.1312, found: 314.1310
3ꢀButylꢀ1,7ꢀdimethylꢀ3ꢀphenylindolinꢀ2ꢀone (3fa): Purified by column chromatography
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on silica gel (hexane/ethyl acetate = 94/6). 237 mg (81%), colourless liquid; H NMR
(400 MHz, CDCl3) δ: 7.29 – 7.27 (m, 2H), 7.22 – 7.20 (m, 2H), 7.18 – 7.11 (m, 1H),
7.00 – 6.91 (m, 3H), 3.46 (s, 3H), 2.57 (s, 3H), 2.38 – 2.30 (td, J = 4.44, 12.72 Hz, 1H),
2.13 – 2.05 (td, J = 4.12, 12.72 Hz, 1H), 1.18 – 1.13 (m, 2H), 1.05 – 0.96 (m, 1H), 0.85
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(m, 1H), 0.76 – 0.74 (t, J = 7.34 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 179.7, 141.9,
141.1, 133.3, 131.9, 128.6, 127.2, 127.0, 122.8, 122.6, 119.9, 56.2, 37.9, 29.9, 26.8, 23.0,
19.4, 14.0; HRMS: C20H24NO [M+H]+ calcd: 294.1858, found: 294.1860
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3ꢀButylꢀ7ꢀethylꢀ1ꢀmethylꢀ3ꢀphenylindolinꢀ2ꢀone (3ga):
Purified
by column
chromatography on silica gel (hexane/ethyl acetate = 94/6). 240 mg (78%), pale yellow
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coloured liquid; H NMR (400 MHz, CDCl3) δ: 7.30 – 7.27 (m, 2H), 7.24 – 7.21 (m,
2H), 7.19 – 7.14 (m, 1H), 7.08 – 7.04 (m, 1H), 7.01 – 6.97 (m, 2H), 3.46 (s, 3H), 2.99 –
2.84 (m, 2H), 2.38 – 2.31 (td, J = 4.48, 12.76 Hz, 1H), 2.13 – 2.06 (td, J = 4.16, 12.72
Hz, 1H), 1.28 – 1.24 (t, J = 7.54 Hz, 3H), 1.21 – 1.20 (m, 2H), 1.07 – 0.96 (m, 1H), 0.86
– 0.85 (m, 1H), 0.78 ꢀ 0.74 (t, J = 7.34 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 179.8,
141.2, 141.1, 133.6, 130.2, 128.6, 127.2, 127.1, 126.6, 122.7, 122.7, 56.1, 38.0, 29.7,
26.7, 25.1, 23.0, 17.0, 13.9; HRMS: C21H26NO [M+H]+ calcd: 308.2014, found:
308.2015
3ꢀButylꢀ7ꢀfluoroꢀ1ꢀmethylꢀ3ꢀphenylindolinꢀ2ꢀone (3ha): Purified by column
chromatography on silica gel (hexane/ethyl acetate = 96/4). 214 mg (72%), yellow
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coloured liquid; H NMR (400 MHz, CDCl3) δ: 7.30 – 7.29 (m, 2H), 7.25 (s, 1H), 7.23
– 7.18 (m, 2H), 7.04 – 6.98 (m, 2H), 6.96 – 6.94 (m, 1H), 3.40 (d, J = 2.76 Hz, 3H), 2.39
– 2.31 (td, J = 4.44, 12.8 Hz, 1H), 2.16 – 2.08 (td, J = 4.2, 12.72 Hz, 1H), 1.29 – 1.23 (m,
2H), 1.09 – 0.98 (m, 1H), 0.86 – 0.80 (m, 1H), 0.79 – 0.75 (t, J = 7.34 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ: 178.5, 146.8, 140.2, 135.6 (d, J = 2.95 Hz), 130.8 (d, J =
7.92 Hz), 128.7, 127.5, 126.9, 123.2 (d, J = 6.15 Hz), 120.7 (d, J = 3.29 Hz), 116.2 (d, J
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= 19.03), 57.2 (d, J = 1.51 Hz), 37.9, 29.0 (d, J = 5.92 Hz), 26.8, 23.0, 13.9; F NMR
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(376 MHz; proton coupled; CDCl3) δ – 137.2; HRMS: C19H21FNO [M+H]+ calcd:
298.1607, found: 298.1607
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3ꢀButylꢀ7ꢀchloroꢀ1ꢀmethylꢀ3ꢀphenylindolinꢀ2ꢀone (3ia): Purified by column
chromatography on silica gel (hexane/ethyl acetate = 96/4). 220 mg (71%), yellow
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coloured liquid; H NMR (400 MHz, CDCl3) δ: 7.33 – 7.30 (m, 4H), 7.27 (s, 1H), 7.25
(m, 1H), 7.09 – 7.07 (m, 1H), 7.04 – 7.00 (t, J = 7.61 Hz, 1H), 3.61 (s, 3H), 2.46 – 2.39
(td, J = 4.44, 12.88 Hz, 1H), 2.19 – 2.12 (td, J = 4.12, 12.8 Hz, 1H), 1.34 – 1.28 (m, 2H),
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1.12 – 1.01 (m, 1H), 0.98 – 0.86 (m, 1H), 0.84 – 0.81 (t, J = 7.32 Hz, 3H); C NMR
(100 MHz, CDCl3) δ: 179.1, 140.3, 140.0, 135.6, 130.5, 128.7, 127.5, 126.9, 123.5,
123.3, 115.8, 56.6, 37.8, 29.9, 26.7, 23.0, 13.9; HRMS: C19H21ClNO [M+H]+ calcd:
314.1312, found: 314.1311
1,3ꢀDibutylꢀ3ꢀphenylindolinꢀ2ꢀone (3ja): Purified by column chromatography on silica
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gel (hexane/ethyl acetate = 97/3). 275 mg (86%), pale yellow coloured syrup; H NMR
(400 MHz, CDCl3) δ: 7.30 (d, J = 8.24 Hz, 2H), 7.25 – 7.23 (m, 2H), 7.21 (s, 1H), 7.19 –
7.15 (m, 2H), 7.06 – 7.02 (t, J = 7.50 Hz, 1H), 6.87 (d, J = 7.8 Hz, 1H), 3.72 – 3.60 (m,
2H), 2.36 – 2.28 (td, J = 4.4, 12.6 Hz, 1H), 2.16 – 2.09 (td, J = 4.12, 12.68 Hz, 1H), 1.64
– 1.59 (m, 2H), 1.36 – 1.25 (m, 2H), 1.17 – 0.98 (m, 2H), 0.90 – 0.87 (t, J = 7.28 Hz,
3H), 0.84 – 0.78 (m, 2H), 0.76 – 0.73 (t, J = 7.28 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ: 178.7, 143.6, 140.8, 132.9, 128.6, 128.1, 127.2, 127.0, 125.0, 122.4, 108.6, 56.7, 40.0,
37.7, 29.7, 26.7, 23.0, 20.3, 14.0, 13.9; HRMS: C22H28NO [M+H]+ calcd: 322.2171,
found: 322.2170
1,3ꢀDibutylꢀ3ꢀ(pꢀtolyl)indolinꢀ2ꢀone (3jb): Purified by column chromatography on
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silica gel (hexane/ethyl acetate = 96/4). 280 mg (83%), pale yellow coloured syrup; H
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NMR (400 MHz, CDCl3) δ: 7.25 – 7.22 (t, J = 7.68 Hz, 1H), 7.16 – 7.12 (t, J = 8.20 Hz,
3H), 7.03 – 7.00 (m, 3H), 6.85 (d, J = 7.8 Hz, 1H), 3.70 – 3.58 (m, 2H), 2.32 – 2.25 (td, J
= 4.44, 12.84 Hz, 1H), 2.22 (s, 3H), 2.13 – 2.05 (td, J = 4.04, 12.8 Hz, 1H), 1.65 – 1.59
(m, 2H), 1.35 – 1.25 (m, 2H), 1.07 – 0.96 (m, 2H), 0.89 – 0.85 (t, J = 7.34 Hz, 3H), 0.83
– 0.76 (m, 2H), 0.75 – 0.71 (t, J = 7.32 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 178.9,
143.6, 137.8, 136.9, 133.1, 129.3, 128.0, 126.8, 124.9, 122.4, 108.5, 56.4, 40.0, 37.7,
29.7, 26.7, 23.0, 21.1, 20.3, 14.0, 13.9; HRMS: C23H30NO [M+H]+ calcd: 336.2327,
found: 336.2329
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1ꢀBenzylꢀ3ꢀbutylꢀ3ꢀphenylindolinꢀ2ꢀone (3ka): Purified by column chromatography on
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silica gel (hexane/ethyl acetate = 93/7). 220 mg (62%), pale yellow coloured liquid; H
NMR (400 MHz, CDCl3) δ: 7.31 – 7.28 (m, 2H), 7.20 – 7.18 (m, 6H), 7.16 – 7.10 (m,
3H), 7.04 – 6.99 (m, 1H), 6.96 – 6.94 (m, 1H), 6.70 (d, J = 7.8 Hz, 1H), 4.84 (d, J = 7.04
Hz, 2H), 2.40 – 2.33 (m, 1H), 2.19 – 2.11 (m, 1H), 1.23 – 1.13 (m, 2H), 0.87 – 0.76 (m,
2H), 0.73 – 0.70 (t, J = 7.26 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 178.9, 143.1,
140.6, 136.1, 132.6, 130.2, 128.8, 128.6, 128.0, 127.6, 127.4, 127.3, 127.0, 124.8, 122.7,
109.3, 56.7, 43.9, 37.8, 26.9, 23.0, 13.9; HRMS: C25H26NO [M+H]+ calcd: 356.2014,
found: 356.2015
1,3ꢀDimethylꢀ3ꢀphenylindolinꢀ2ꢀone (4aa): Purified by column chromatography on
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silica gel (hexane/ethyl acetate = 93/7). 190 mg (81%), colourless liquid; H NMR (400
MHz, CDCl3) δ: 7.24 – 7.18 (m, 5H), 7.17 – 7.14 (m, 1H), 7.12 (d, J = 6.96 Hz, 1H),
7.03 – 7.00 (m, 1H), 6.84 (d, J = 7.76 Hz, 1H), 3.15 (s, 3H), 1.71 (s, 3H); 13C NMR (100
MHz, CDCl3) δ: 179.5, 143.3, 140.8, 134.9, 128.6, 128.1, 127.2, 126.7, 124.2, 122.8,
108.3, 52.2, 26.5, 23.8; HRMS: C16H16NO [M+H]+ calcd: 238.1232, found: 238.1235.
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