Bismuth(iii)-catalyzed regioselective alkylation of tetrahydroquinolines and indolines towards the synthesis of bioactive core-biaryl oxindoles and CYP19 inhibitors

Article abstract of DOI:10.1039/d0ob02385j

Bismuth(iii)-catalyzed regioselective functionalization at the C-6 position of tetrahydroquinolines and the C-5 position of indolines has been demonstrated. For the first time, one pot symmetrical and unsymmetrical arylation of isatins with tetrahydroquinolines was accomplished giving a completely new product skeleton in good to excellent yields. Most importantly, this protocol leads to the formation of a highly strained quaternary carbon stereogenic center, which is a challenging task. Benzhydryl and 1-phenylethyl trichloroacetimidates have been used as the alkylating partners to functionalize the C-6 and C-5 positions of tetrahydroquinolines and indolines, respectively. The scope of the developed methodology has been extended for the synthesis of the bioactive CYP19-inhibitor and its analogue.

Full text of DOI:10.1039/d0ob02385j

Organic &
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Bismuth(III)-catalyzed regioselective alkylation of
tetrahydroquinolines and indolines towards the
synthesis of bioactive core-biaryl oxindoles and
CYP19 inhibitors†
Cite this: Org. Biomol. Chem., 2021,
19, 891
Namrata Prusty, Lakshmana K. Kinthada, Rohit Meena, Rajesh Chebolu and
Ponneri Chandrababu Ravikumar
*
Bismuth(III)-catalyzed regioselective functionalization at the C-6 position of tetrahydroquinolines and the
C-5 position of indolines has been demonstrated. For the first time, one pot symmetrical and unsymme-
trical arylation of isatins with tetrahydroquinolines was accomplished giving a completely new product
skeleton in good to excellent yields. Most importantly, this protocol leads to the formation of a highly
strained quaternary carbon stereogenic center, which is a challenging task. Benzhydryl and 1-phenylethyl
trichloroacetimidates have been used as the alkylating partners to functionalize the C-6 and C-5 positions
of tetrahydroquinolines and indolines, respectively. The scope of the developed methodology has been
extended for the synthesis of the bioactive CYP19-inhibitor and its analogue.
Received 30th November 2020,
Accepted 16th December 2020
DOI: 10.1039/d0ob02385j
rsc.li/obc
demonstrated elegant strategies to deliver meta functionali-
zation of cyclic amines (indolines and tetrahydroquinolines)
1. Introduction
Tetrahydroquinoline and indoline skeletons are the common by utilizing a U-shaped template.13 However, template assisted
structural motifs present in a wide range of pharmaceuticals para-functionalization of cyclic amines is still underdeveloped
and bioactive natural products.1 As substituted tetrahydroqui- as it is associated with certain limitations such as regio-
nolines and indolines show significant effects on biological selectivity (ortho and para products) (Fig. 2a), chemoselectivity
metabolism2 and they show pharmaceutical activity towards and reactivity (mono- and di-alkylation) (Fig. 2b).14,15
Alzheimer’s disease, obesity, asthma, epilepsy, antitumor, anti- Consequently, the development of efficient synthetic method-
biotic, bradykinin antagonist, schistosomicidal, and anti-pro- ology to access those molecules overcoming the regio- and
liferative activities, the synthesis and functionalization of tetra- chemo-selectivity issues is a challenging task.
hydroquinolines and indolines are of immense interest
(Fig. 1).
Considering the significance of selective functionalization,
we have explored the selective C-5 and C-6 alkylation of indo-
In this context, development of new methodology for the lines and tetrahydroquinolines, respectively, through Lewis
selective C–H functionalization of these molecules can give acid assisted alkylation reaction. The developed alkylation
access to medicinally important scaffolds.3 Significant efforts reaction works efficiently in a regioselective manner under
have been made over the last decade to develop efficient and transition metal free conditions.
practical strategies for the regioselective alkylation on the ben-
zenoid nucleus of indolines4–7 and tetrahydroquinolines.8–10
In this regard, the directing group assisted transition metal
(Rh, Ru, Pd, Ir, and Co)-catalyzed activation of the proximal
sp2 C–H bond, i.e. C-7 of indolines,11 and C-8 of tetrahydroqui-
nolines,12 are well documented. Recently, the Yu group has
School of Chemical Sciences, National Institute of Science Education and Research
(NISER) HBNI, Bhubaneswar, Odisha 752050, India. E-mail: pcr@niser.ac.in
†Electronic supplementary information (ESI) available. CCDC 2041963 and
2041964. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/d0ob02385j
Fig. 1 Selected examples of natural products and bioactive analogs
bearing substituted indoline and substituted tetrahydroquinoline
scaffolds.
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yield of 3aa, 79%. So, we kept DCE as the optimised solvent
and varied other parameters for further optimization. When
we screened other Lewis acids such as ZnCl2, AlCl3 and Bi
(OTf)3, the yield of 3aa was improved to 83% with Bi(OTf)3
(Table 1, entries 7–9). Interestingly, further improvement of
the product yield to 96% was observed on increasing the reac-
tion time to 8 h (Table 1, entry 10). Then we reduced the cata-
lyst loading from 10 mol% to 5 mol%, but the yield of 3aa
decreased to 55% (Table 1, entry 11). Therefore, we fixed the
catalyst loading to 10 mol% and varied the temperature.
However, at reduced or increased temperature such as 60 °C,
100 °C and room temperature (Table 1, entries 12–14) the
yields of 3aa dropped to 79%, 48% and 11%, respectively.
Moreover, to understand the influence of the number of
equivalents of quinolines, we tested the reaction with 2 and
2.8 equivalents of 2a (for more details see the ESI†) and
observed a decrease in the yield of 3aa (Table 1, entries 15 &
16) in both cases. This indicates that 2.5 equivalents of 2a are
essential for this reaction. Thus, 10 mol% of Bi(OTf)3, with
DCE as the solvent at 80 °C for 8 h were found to be the opti-
mized conditions (Table 1, entry 10).
Fig. 2 Regio- and chemo-selectivity challenges between C-6 and C-8
functionalization of tetrahydroquinoline.
2. Results and discussion
We decided to try a new substrate combination which has
never been explored before. Hence, we chose 5-methoxyisatin
1a and tetrahydroquinoline 2a (Table 1) as the model sub-
strates to test the hypothesis. Accordingly, the reaction of 1a
with 2a was tested under Lewis acid conditions.
Gratifyingly, under the influence of the catalytic quantity of
In(OTf)3 in 1,4-dioxane, at 80 °C for 6 h, the selective C-6
functionalization of tetrahydroquinoline occurred smoothly
resulting in the desired product 3aa in 55% isolated yield
(Table 1, entry 1). Next, a series of solvents such as DMSO,
DMF, MeOH, DCM and DCE were tested using In(OTf)3
(Table 1, entries 2–6). Among them, DCE produced a better
With the optimized reaction conditions in hand, the viabi-
lity of the C-6 functionalization of quinoline derivatives 2 was
tested with various substituted and unsubstituted isatins 1 in
both protected and unprotected forms (Scheme 1).
The C-6 functionalization of 2a with N–H isatin 1b gave a
69% isolated yield of the arylated product (Scheme 1, 3ba).
When C5-trifluoromethoxy isatin was used, the yield of the
product 3ca increases to 72%. Then C5-halo substituted oxi-
ndoles were used, and 65%, 70% and 59% yields of the
respective products were observed (Scheme 1, 3da, 3ea & 3fa).
Upon taking the dihalo substituted isatin, good yield of the
product 3ga (62%) was obtained, but when C7-methyl isatin
was taken as the substrate, the yield of the product 3ha
decreased to 41%.
Table 1 Optimization of the reaction conditionsa
Then we decided to check the effect of N-protection on
isatin. Interestingly, the yield (67%) did not change much with
N-acetyl isatin (Scheme 1, 3ia). However, the yields (77% &
75%) of the arylated adduct improved with both N-benzyl and
N-methyl isatins (Scheme 1, 3ja & 3ka). Next, we tested the
effect of a halo group on N-methyl isatin that led to further
improvement of yield, 80% (Scheme 1, 3la). From the above set
of experiments, it can be concluded that the reaction works
well irrespective of the nature of the substituent present on the
benzenoid ring of isatin. Subsequently, the effect of
N-protection on tetrahydroquinolines was explored while
keeping the nitrogen atom of the isatin molecule unprotected.
The reaction of 2b with 1e and 1a produced very good yields
(91% & 83%) of their respective products (Scheme 1, 3eb &
3ab). Furthermore, we have screened the effect of N-protection
on both tetrahydroquinoline and isatin derivatives.
2a
Yieldb
Time (%)
Entry (equiv.) Lewis acid Solvent
Temp
1
2
3
4
5
6
7
8
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
ZnCl2
1,4-Dioxane 80 °C
6 h
6 h
6 h
6 h
6 h
6 h
6 h
6 h
6 h
8 h
8 h
6 h
59 (55)c
Nr
56
67
64
79
58
39
DMSO
DMF
MeOH
DCM
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
60 °C
AlCl3
9
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
83
10
11d
12
13
14
15
16
96 (92)c
55
79 (73)
48
100 °C 6 h
rt
80 °C
80 °C
6 h
8 h
8 h
11
68
75
In these cases, we obtained good to excellent yields 60–97%
of the products (Scheme 1, 3kc, 3kb, 3jc, 3jb & 3lc). Overall,
this reaction worked well with a broad range of substrates.
Then we applied our developed protocol to other cyclic amine
substrates such as aniline and indoline. The N-protected
2.8
a Reaction conditions: 1a (0.1 mmol), 2a (2.5 equiv.), Lewis acid
(10 mol%), and solvent (0.25 M), rt to 80 °C, 6–8 h. b NMR yield.
c Isolated yields. d Bi(OTf)3 ( 5 mol%).
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Scheme 2 Scope of the isatins and tetrahydroquinolines in a three-
component system and its oxidized product. Reaction conditions for
products 3jac–3lac: (a) 1 (0.1 mmol), 2a (1.2 equiv.), 2c (1.2 equiv.), Bi
(OTf)3 (10 mol%), and DCE (0.25 M), 80 °C, 8 h; Reaction conditions for
products 4jac–4lac: (b) 3 (0.1 mmol), CuI (10 mol%), DMAP (20 mol%),
DIAD (10 mol%), and MeCN (0.1 M), rt, 12 h.
reported in the literature.17 A reasonable yield of the respective
oxidized products was obtained (Scheme 2, 4jac, 4kac & 4lac).
Synthesis of molecules containing all carbon quaternary
centers is always a challenging task in organic synthesis.
Indeed, the generation of a quaternary carbon stereo center is
even more challenging. Herein, we have successfully syn-
thesized the compounds bearing a quaternary stereo center.18
In addition, our protocol provides an opportunity to synthesize
various analogs of biologically important symmetrical and
unsymmetrical 3,3′-bis-heteroaryl-2-oxindoles, which were not
accessed before.
Scheme 1 Scope of the isatins and tetrahydroquinolines in a two-com-
ponent system. Reaction conditions: 1 (0.1 mmol), 2 (2.5 equiv.), Bi(OTf)3
(10 mol%), and DCE (0.25 M), 80 °C, 8 h.
Based on the above experiments and literature precedence19
a plausible mechanism is depicted in Scheme 3. Coordination
of bismuth to the keto-carbonyl group of isatin 1 increases the
electrophilicity so much so that the C-6 position of tetrahydro-
quinoline 2 undergoes electrophilic attack by carbonyl carbon
aniline with 5-methoxy isatin gave the product 3b′ with 42%
yield and indoline with isatin gave the product 3b″ in a trace
amount. So the above study reveals the broader scope of this
developed methodology.
Having successfully demonstrated the utility of this proto-
col for the synthesis of a variety of symmetrically arylated pro-
ducts, we were interested in examining the scope of this proto-
col for the synthesis of an unsymmetrically arylated product as
well.16 Accordingly, we tested this protocol with two different
tetra-hydroquinolines (2a and 2c) with N-benzylisatin. To our
delight, we obtained a 37% yield of an unsymmetrically ary-
lated product (Scheme 2, 3jac) along with the symmetrical pro-
ducts 3ja (13%) and 3jc (14%). Also, with N-methylisatin and
5-chloro-N-methylisatin, 38% and 33% of respective yields of
the unsymmetrically arylated products were obtained
(Scheme 2, 3kac & 3lac) along with symmetrical products 3ka
(18%), 3kc (22%), 3la (17%), 3lc (19%). To further enhance the
scope of the products through this methodology, we oxidized
Scheme 3 Plausible mechanism for regioselective C-6 functionali-
the unsymmetrically arylated products following a procedure zation of tetrahydroquinoline.
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of isatin and forms intermediate A. Even though the C-8 posi- (82% & 93%) of their respective alkylated products (Scheme 4a,
tion of tetrahydroquinoline is also capable of undergoing a 6fa & 6ga). Additionally, when the alkylating agent was
similar electrophilic attack, we did not observe any product changed to 1-phenylethyltrichloroacetimidate, the reaction
derived from this mode of attack, possibly due to steric worked efficiently affording 55% and 88% yields of the respect-
reasons as shown below (intermediate D). Deprotonation and ive alkylated products (Scheme 4a, 6db & 6fb).
elimination of hydroxide from intermediate A lead to a
To test the robustness of this methodology we designed a
quinoid type of intermediate B (detected by HRMS; see the substrate, which could potentially undergo intramolecular
ESI†) which reacts with another molecule of tetrahydroquino- Friedel–Crafts alkylation in addition to intermolecular alkyl-
line at the C-6 position and forms Sigma complex C which ation. When compound 2h was allowed to react with 5a and 5b
then undergoes deprotonation to regain aromaticity giving rise under the standard conditions, to our delight, it underwent
to biarylated product 3.
chemoselective alkylation furnishing good yields 67% & 61%
We intended to further demonstrate the scope of this meth- of their respective intermolecular alkylation products
odology for the synthesis of another biologically important (Scheme 4a, 6ha & 6hb).
class of molecules such as 5-substituted indoline and 6-substi-
In order to diversify the product library, products 6 were
tuted tetrahydroquinoline derivatives 6 (Scheme 4a) for which oxidized using DDQ. Interestingly, in all cases triarylmethine
trichloroacetimidate 5 was taken as the alkylating agent.20 carbon was oxidized to tertiary alcohol (Scheme 4b, 7da, 7ea,
Hence, 2c and 5a were subjected to the optimized reaction 7fa & 7ga) and in indoline cases, we obtained both hydroxy-
conditions. As expected, we obtained the C-6 alkylated product lation and aromatization products (Scheme 4b, 7fa′ & 7ga′)
in a very good yield of 85% (Scheme 4a, 6ca).
with 2 equivalents of DDQ. Apparently, it is clear that the
Also, with N-tosyl and N-mesyl tetrahydroquinolines 2d and hydroxylation step seems to be faster as compared to the aro-
2e the respective alkylated products were obtained in excellent matization of indoline to indole.
yields of 90% and 91% (Scheme 4a, 6da & 6ea). Similarly,
To show the efficiency of our protocol, we performed gram
N-protected indolines 2f and 2g also resulted in good yields scale reaction for the synthesis of the biaryl oxindole and
distal C–H functionalized product of tetrahydroquinoline and
Scheme 5 Application of this methodology. Reaction conditions: (A)
1 g scale reaction for biaryloxindole synthesis; (B) 1 g scale reaction for
Scheme 4 Scope of remote C–H functionalization of cyclic amines &
DDQ oxidation. Reaction conditions for products 6ca–6hb: (a)
(0.1 mmol), 5 (1.5 equiv.), Bi(OTf)3 (10 mol%), and DCE (0.25 M), 80 °C,
8 h; Reaction conditions for products 7da–7ga’: (b) 6 (0.1 mmol), DDQ
(2 equiv.), and 1,4-dioxane (0.1 M), 120 °C, 12–14 h.
the synthesis of C-5 substituted indoline; (C) 1st step = 8h (0.1 mmol), 5a
(1.5 equiv.), Bi(OTf)3 (10 mol%), and DCE (0.25 M), 80 °C, 8 h; 2nd step =
9ha (0.1 mmol), DDQ (2 equiv.), and 1,4-dioxane (0.1 M), 120 °C, 8 h; (D)
8h (0.1 mmol), 5c (1.5 equiv.), Bi(OTf)3 (10 mol%), DCE (0.25 M),
80–140 °C, 8–24 h.
2
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indoline. When 1 g 5-methoxy isatin 1a was reacted with 2a, it = 77.36 for 13C NMR). Data for 1H NMR spectra are reported as
gave the product 3aa with 81% yield (1.95 g) (Scheme 5a). The follows: chemical shift (multiplicity, coupling constants, and
N-tosyl indoline 2f (1 g) on reaction with 5b gave the product number of hydrogen). Abbreviations are as follows: s (singlet),
6fb with 66% yield (911 mg) (Scheme 5b). Hence the method- d (doublet), t (triplet), q (quartet), quint (quintet), m (multi-
ology is very much efficient in a large scale. Then to show plet), dd (double doublet), br (broad signal), and J (coupling
more applications of this methodology we have synthesized constants) in Hz (hertz). High-resolution mass spectrometry
molecules with close similarity to potent drug candidates such (HRMS) data were recorded using a micro-TOF Q-II mass
as the CYP19 inhibitor. Intramolecular alkylation of 2h in the spectrometer using methanol as solvent. IR spectra were
presence of AlCl3 at 140 °C gave the intramolecular alkylation recorded on a FTIR system and values are reported in fre-
product 8h, which under the standard conditions along with quency of absorption (cm−1). Digital melting point apparatus
5a resulted in the C-5 alkylated product in 98% yield is used to record the melting points. Reagents and starting
(Scheme 5c, 9ha). The molecule 9ha is analogous to the drug materials were purchased from Sigma Aldrich, Alfa Aesar, TCI,
candidate, CYP19 inhibitor. Oxidation of 9ha with 2 equiva- Avra, Spectrochem and other commercially available sources
lents of DDQ led to the formation of two products (Scheme 5c, and were used without further purification unless otherwise
10ha & 10ha′). With further interest, we tried to synthesize the noted.
CYP19 inhibitor molecule by reacting pyridin-4-yl(m-tolyl)
methyl 2,2,2-trichloroacetimidate 5c with 8h, where a trace
4.2 Experimental procedures
amount of product was found which was detected by HRMS.
General procedure for the synthesis of N-acetyl isatin (1i). 1-
Acetylindoline-2,3-dione was prepared according to a pre-
viously reported procedure.29 Isatin (1.7 mmol) was suspended
in acetic anhydride (10 mL) in a round bottom flask with a stir
bar. Then 1 drop of H2SO4 was added to it and the reaction
3. Conclusions
In summary, we have developed bismuth catalyzed regio- mixture was heated at reflux for 5 minutes at 140 °C. After the
selective C-6 alkylation of tetrahydroquinolines with isatin completion of reaction determined by TLC analysis, the reac-
derivatives. Both symmetrical and unsymmetrically arylated tion mixture was diluted with H2O and saturated aqueous
product of isatin derivatives were prepared in good to excellent NaHCO3 and worked up with EtOAc and the organic layer was
yields. Bismuth is found to be the best catalyst choice because washed with brine solution and dried over Na2SO4 and evapor-
it is less toxic, works under low catalyst loading and allows ated. Column chromatography gave the pure product as a
hydrocompatibility (substrates with free OH/NH bonds). We yellow solid (82% yield).
have also developed C-6 and C-5 alkylation of tetrahydroquino-
General procedure for the synthesis of N-alkyl isatin (1j–1l).
lines and indolines, respectively, using trichloroacetimidates N-Protected isatins were prepared according to a previously
for the first time, where we attempted to synthesize the CYP-19 reported procedure.22–28 Isatin (1 equiv., 3.4 mmol) was dis-
inhibitor and its analogues. We have demonstrated numerous solved in DMF (5 mL) solvent under a N2 atmosphere and the
applications of this methodology for the synthesis of drug-like mixture was taken in an oven-dried round-bottom flask
molecules.
equipped with a magnetic stir bar at room temperature. To
this reaction mixture NaH (1.2 equiv., 4.1 mmol) was added
portion-wise at 0 °C. Then alkyl halide (1.2 equiv., 4.1 mmol)
was added to the solution in a dropwise manner through a
syringe. The reaction mixture was allowed to stir for 2 h at 0 °C
and then it was stirred at rt for 12 h. After the completion of
4. Experimental section
4.1 General information
Reactions were performed using oven dried Borosil seal-tube reaction as monitored by TLC analysis, the reaction mixture
glass vials with Teflon-coated magnetic stirring bars under a was quenched with slow addition of water and then diluted
N2 atmosphere. A syringe was used to transfer the solvents and with 10 mL of DCM. The organic layer was separated, dried
liquid reagents. Dioxane, DMF, MeOH, DCM, DCE, and over anhydrous Na2SO4 and concentrated in a rotary evapor-
CH3CN were distilled and dried over calcium hydride. All other ator under vacuum. The crude products were purified by flash
solvents such as hexane, EtOAc, DMSO, THF, diethyl ether, chromatography on silica gel (30% EtOAc/petroleum ether) to
and acetone was used as received. Column chromatography afford the desired product.
was performed by using 100–200 and 230–400 mesh size silica
General procedure for the synthesis of N-alkyl tetrahydro-
gel from Acme Synthetic Chemicals Company. A gradient quinolines (2b and 2c). N-Protected tetrahydroquinolines were
elution was performed by using distilled petroleum ether and prepared according to a previously reported procedure.30
ethyl acetate. TLC plates were detected under UV light at Tetrahydroquinoline (1 equiv., 7.5 mmol) was dissolved in
254 nm. 1H NMR and 13CNMR spectra were recorded on THF (10 mL) solvent under a N2 atmosphere and the mixture
Bruker AV 400 and 700 MHz spectrometers and a JEOL was taken in an oven-dried round-bottom flask equipped with
400 MHz spectrometer using CDCl3 as the deuterated a magnetic stir bar at rt. To the reaction mixture, NaH (1.2
solvent.21 Chemical shifts (δ) are reported in ppm relative to equiv., 9.0 mmol) was added portion-wise at 0 °C. Then alkyl
the residual solvent (CHCl3) signal (δ = 7.26 for 1H NMR and δ halide (1.2 equiv., 9.0 mmol) was added to the solution in a
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dropwise manner through a syringe. The reaction mixture was present in NaH and then hexane was decanted through a
allowed to stir for 16 h at rt. It was quenched with slow syringe. Then indoline (1 equiv.) in diethyl ether (5 mL) was
addition of water and then diluted with 10 mL of EtOAc upon added slowly after the addition of dry ether (3 mL) (under ice
completion of reaction. The organic layer was separated, dried cold conditions). Then it was washed with 2 mL dry ether and
over anhydrous Na2SO4 and concentrated in the rotary evapor- left for stirring for 30 minutes. Then methane sulfonyl chlor-
ator under vacuum. The crude products were purified by ide in diethyl ether was added to it and washed with 5 mL
column chromatography to give the pure product as a colorless ether under ice cold conditions. After being stirred at room
liquid.
temperature for 14 h, the reaction was quenched with satu-
General procedure for the synthesis of N-tosyl tetrahydroqui- rated aqueous NH4Cl (10 mL), and extracted with DCM (3 ×
noline (2d). N-Tosyl tetrahydroquinoline was prepared accord- 10 mL). The combined organic phases were washed with brine
ing to a previously reported procedure.31 To a solution of tetra- (10 mL), dried over anhydrous Na2SO4 and concentrated under
hydroquinoline (1 equiv.) in pyridine was added TsCl (1.2 reduced pressure. Purification by column chromatography on
equiv.). It was stirred at rt for 2 h. When the reaction was com- silica gel (hexane : ethyl acetate = 3 : 1) afforded the pure
plete as monitored by TLC, the pyridine was evaporated under product (67% yield) as a light brown solid, Rf = 0.3 (20% EtOAc
reduced pressure. To the obtained crude product, H2O was in hexane).
added followed by DCM solvent. After the separation of the
General procedure for N-acylation of indoline (2h). 3-Chloro-
organic layer, the water layer was extracted with 30 mL DCM. dihydro-indolyl propanone was prepared according to a pre-
The combined organic layer was dried over anhydrous Na2SO4, viously reported procedure.35 To a solution of indoline (4.0 g,
filtered, evaporated and the evaporation residue was purified 0.03 mol) in acetone (100 mL) in a round bottomed flask was
via column chromatography on silica gel (eluent: petroleum added 3-chloro-propionyl chloride (4.7 g, 0.04 mol). After
ether/ethyl acetate) to give the desired product as a white solid heating the mixture at 70 °C in an oil bath for 3 h, the solvent
(84% yield).
was removed under vacuum. The resulting residue was dis-
General procedure for the synthesis of N-mesyl tetrahydro- solved in DCM and washed with water and brine. The organic
quinoline (2e). N-Mesyl tetrahydroquinoline was prepared layer was dried over Na2SO4, filtered, and concentrated to give
according
Tetrahydroquinoline (1000 mg, 7.5 mmol) was dissolved in
5 mL dry pyridine and methanesulfonyl chloride (1.2 equiv., (8h). Tetrahydropyrroloquinolinone was prepared according to
9.0 mmol) was dropped in 2 portions under N2. The reaction molten mixture of
previously reported procedure.36
to
a
previously
reported
procedure.32 the product as a brown solid (7.0 g, 99% yield).
General procedure for the synthesis of pyrroloquinolinone
a
A
mixture was stirred for 2 h at room temperature and an 3-chloro-dihydro-indolyl propanone (44.5 g, 212 mmol) and
intense red colour developed. When the reaction was complete AlCl3 (149 g, 1.12 mol) was taken in a round bottom flask and
as determined by TLC, the crude reaction mixture was poured refluxed at 140 °C in a preheated oil bath for 4 h. Upon com-
into 100 mL of cold 0.5 M HCl and extracted twice with 50 mL pletion of reaction, it was cooled to 0 °C and then a mixture of
DCM. The organic phase was evaporated and the evaporation water/ice (500 g) was added to decompose excess AlCl3. The
residue was purified by passing through a silica plug. The resulting solution was extracted with EtOAc (3 × 200 ml), fol-
product eluted in 7/3 PE/EtOAc, while all of the pink polar by- lowed by drying over MgSO4. Removal of the solvent gave a
product was retained on silica. The product was obtained as a yellow solid, which was purified by flash chromatography
brown solid (85% yield).
(EtOAc : hexane = 2 : 5, Rf = 0.15) to give the product as a white
General procedure for the synthesis of N-tosyl indoline (2f). solid (25.7 g, 70% yield).
N-Tosyl indoline was prepared according to a previously
General procedure for the synthesis of trichloroacetimidate
reported procedure.33 To a solution of the indoline (1.0 (5). Trichloroacetimidate was prepared according to a pre-
equiv.) in DCM (0.1 M) were added pyridine (3.0 equiv.) and viously reported procedure.37 Acetophenol or benzophenol (1
p-toluenesulfonyl chloride (1.1 equiv.) and the resulting solu- equiv.) was taken in a round bottom flask with a stir bar and
tion was stirred at room temperature for 16 h. Upon com- to that DCM (0.32 M) was added through a syringe. Then DBU
pletion of reaction confirmed by TLC check, H2O was added. (0.02 equiv.) was added to the reaction mixture and kept at
The phases were separated and the aqueous layer was 0 °C by putting ice. After stirring for 5 min, trichloroacetoni-
extracted with DCM (3 × 10 mL). The combined organic trile (10 equiv.) was added to the reaction mixture slowly and
layers were washed with 1 M HCl and brine. Then the left to stir for 10 min under cold conditions. Then after bring-
organic solvent was dried over anhydrous Na2SO4 and filtered ing it to room temperature, it was allowed to stir for 16 h. After
and evaporated under reduced pressure. The evaporation the reaction completion, the reaction mixture was rota-evapor-
residue was purified on silica gel to give the product as a ated and column chromatography (5% basified with Et3N)
white solid (76% yield).
gave the pure product.
General procedure for the synthesis of N-mesyl indoline
General procedure A for the synthesis of biaryl oxindole via
(2g). N-Mesyl indoline was prepared according to a previously 2-component reaction (3). Isatin derivative
1 (1 equiv.,
reported procedure.34 In a 100 mL two-neck round bottom 0.3 mmol) was dissolved in DCE (0.25 M) solvent under a
flask, NaH (1.3 equiv.) was taken under a N2-atmosphere and N2 atmosphere in an oven-dried sealed tube equipped with
to it dry hexane was added, so that it dissolved the grease a magnetic stir bar at room temperature. A catalytic amount
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of Bi(OTf)3 (10 mol%) was added to the reaction mixture fol- The reaction mixture was then passed through Celite and the
lowed by the addition of tetrahydroquinoline derivative 2 (2.5 solvent was evaporated. The crude products were purified by
equiv., 0.6 mmol). The reaction mixture was allowed to stir at column chromatography (200–400 mesh silica) to give the pure
80 °C in a pre-heated aluminum block until the reaction com- product 6.
pleted. The reaction mixture was quenched with and diluted
General procedure D for oxidation of 6 to 7. The oxidized
with EtOAc after the completion of reaction (monitored by product of 6 was prepared according to a previously reported
TLC). The reaction mixture was then passed through Celite procedure.39 The compound 6 (1 equiv.) was dissolved in
and evaporated. The evaporation residue was purified by dioxane (0.1 M) solvent under a N2 atmosphere and the
column chromatography (200–400 mesh silica, basified with mixture was taken in an oven-dried sealed tube flask equipped
5% Et3N) to give the pure product 3.
with a magnetic stir bar at room temperature. Then a catalytic
Procedure for the synthesis of biaryl oxindole via 3-com- amount of DDQ (2 equiv.) was added to the solution of the
ponent reaction (3jac–3lac). Isatin derivative 1 (1 equiv., starting material and then the reaction mixture was allowed to
0.3 mmol) was dissolved in DCE (1 mL) solvent under a N2 stir at 120 °C in a pre-heated aluminum block until the reac-
atmosphere in an oven-dried sealed tube flask equipped with a tion completed. The reaction mixture was quenched and
magnetic stir bar at room temperature. A catalytic amount of diluted with EtOAc after the completion of reaction (monitored
Bi(OTf)3 (10 mol%) was added to the solution of the starting by TLC). The reaction mixture was then passed through Celite
material and then tetrahydroquinoline 2a (1.2 equiv., and the solvent was evaporated. The crude products were puri-
0.34 mmol) and another derivative of tetrahydroquinoline 2c fied by column chromatography (200–400 mesh silica) to give
(1.2 equiv., 0.34 mmol) were added to the reaction mixture. the pure product 7.
The reaction mixture was allowed to stir at 80 °C in a pre-
heated aluminum block until the reaction completed. It was
4.3 Mechanistic studies
quenched and diluted with EtOAc after the completion of reac-
Synthesis of 3aa in the presence of BHT. 5-Methoxy isatin
tion (monitored by TLC). The reaction mixture was then (1a, 30 mg, 1 equiv.), tetrahydroquinoline (2a, 2.5 equiv.), Bi
passed through Celite and the solvent was evaporated. The (OTf)3 (10 mol%), BHT (1 equiv.) and DCE (0.25 M) were
evaporation residue was purified by column chromatography charged into a Schlenk tube. The reaction mixture was allowed
(200–400 mesh silica, basified with 5% Et3N) to give the pure to stir at 80 °C in a pre-heated aluminum block for 8 h. After
product.
the completion of reaction as monitored by TLC, the crude
General procedure B for the synthesis of oxidized product 4. reaction mixture was passed through a Celite pad. The solvent
The oxidised product of biaryl oxindole 3 was prepared accord- was removed under reduced pressure and the residue was puri-
ing to a previously reported procedure.38 Biaryl oxindole fied by silica gel chromatography using a hexane/ethyl acetate
derivative 3 (1 equiv., 0.1 mmol) was dissolved in CH3CN (4 : 6) solvent system to afford compound 3aa in 92% isolated
(1.5 mL) solvent under an O2 atmosphere and the mixture was yield.
taken in an oven-dried round bottom flask equipped with a
Synthesis of 3aa in the presence of TEMPO. 5-Methoxy isatin
magnetic stir bar at room temperature. Then copper iodide (1a, 30 mg, 1 equiv.), tetrahydroquinoline (2a, 2.5 equiv.), Bi
(0.1 equiv., 0.01 mmol) and DIAD (0.1 equiv., 0.01 mmol) were (OTf)3 (10 mol%), TEMPO (1 equiv.) and DCE (0.25 M) were
added followed by the addition of DMAP (20 mol%) to this charged into a Schlenk tube. The reaction mixture was allowed
reaction mixture. The reaction mixture was allowed to stir at to stir at 80 °C in a pre-heated aluminum block for 8 h. After
room temperature until the reaction completed. The reaction the completion of reaction as monitored by TLC, the crude
mixture was quenched and diluted with EtOAc after the com- reaction mixture was passed through a Celite pad. The solvent
pletion of reaction (monitored by TLC). The reaction mixture was removed under reduced pressure and the residue was puri-
was then passed through Celite and the solvent was evapor- fied by silica gel chromatography using a hexane/ethyl acetate
ated. The crude mixture was purified by column chromato- (4 : 6) solvent system to afford compound 3aa in 78% isolated
graphy (200–400 mesh silica, basified by 5% Et3N) to give the yield.
pure product 4.
General procedure C for the synthesis of the remote C–H
4.4 Application
functionalized product of tetrahydroquinolines & indolines
General procedure for the synthesis of the CYP19 inhibitor
(6). The compound 2 (1 equiv., 0.43 mmol) was dissolved in (9hc) & its analogue (9ha). Tetrahydropyrroloquinolinone (8h,
DCE (0.2 M) solvent under a N2 atmosphere in an oven-dried 40 mg, 0.23 mmol) was dissolved in DCE (0.25 M) under a N2
sealed tube flask equipped with a magnetic stir bar at room atmosphere in an oven-dried sealed tube equipped with a mag-
temperature. Then a catalytic amount of Bi(OTf)3 (10 mol%) netic stir bar at room temperature. An amidate derivative (1.5
was added to the solution of the starting material and then tri- equiv., 0.35 mmol) was added to the reaction mixture followed
chloroacetimidate derivative 5 (1.2 equiv.) was added to this by the addition of a catalytic amount of Bi(OTf)3 (10 mol%).
reaction mixture. The reaction mixture was allowed to stir at The reaction mixture was allowed to stir at 80 °C in a pre-
80 °C in a pre-heated aluminum block until the reaction com- heated aluminum block until the reaction completed. The
pleted. The reaction mixture was quenched and diluted with reaction mixture was quenched and diluted with EtOAc after
EtOAc after the completion of reaction (monitored by TLC). the completion of reaction (monitored by TLC) and then it was
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passed through Celite and evaporated. The crude products
3,3-Bis(1,2,3,4-tetrahydroquinolin-6-yl)-5-(trifluoromethoxy)
were purified by column chromatography (200–400 mesh indolin-2-one (3ca) was prepared according to general pro-
silica) to give the pure product. cedure A. The crude reaction mixture was purified by
General procedure for the synthesis of 10ha & 10ha′. The column chromatography using silica gel (230–400 mesh)
product 9ha (50 mg, 0.15 mmol) was taken in an oven-dried giving 3ca (75 mg for 0.22 mmol scale) in 72% yield.
sealed tube equipped with a magnetic stir bar and subjected to Physical state: white solid. M.p.: 157–162 °C. Rf-Value: 0.5
DDQ (2 equiv., 0.3 mmol) in dioxane solvent (0.1 M). The reac- (30% EtOAc/hexane).
tion mixture was allowed to stir at 120 °C in a pre-heated alumi-
1H NMR (400 MHz, CDCl3): δ 9.42 (s, 1H), 7.04–7.01 (m,
num block for 8 h and it was quenched and diluted with EtOAc 2H), 6.84–6.81 (m, 5H), 6.37 (d, J = 8.4 Hz, 2H), 3.24 (t, J = 5.6
after the completion of reaction (monitored by TLC) and then it Hz, 4H), 2.65 (t, J = 6.4 Hz, 4H), 1.87 (quint, J = 6.4 Hz, 4H).
was passed through Celite and evaporated. The crude products 13C NMR (100 MHz, CDCl3): δ 182.1, 144.8, 144.3, 139.4, 137.0,
were purified by column chromatography (200–400 mesh silica) 129.5, 127.1, 122.1, 121.5, 120.45, 119.6, 114.4, 111.0, 62.5,
to give the pure products 10ha as a white solid (27 mg, 52% 42.2, 27.3, 22.3.
yield) and 10ha′ as a brown solid (20 mg, 40% yield).
IR (KBr, cm−1): 3390, 2930, 2843, 1716, 1699, 1615, 1510,
1218, 823. HRMS (ESI) m/z: [M + H]+ Calcd for C27H25F3N3O2:
480.1893; Found: 480.1896.
5-Fluoro-3,3-bis(1,2,3,4-tetrahydroquinolin-6-yl)indolin-2-one
(3da) was prepared according to general procedure A. The
crude reaction mixture was purified by column chromato-
graphy using silica gel (100–200 mesh) giving 3da (49 mg for
0.18 mmol scale) in 65% yield. Physical state: pale yellow
solid. M.p.: 110–120 °C. Rf-Value: 0.3 (50% EtOAc/hexane). 1H
NMR (400 MHz, CDCl3): δ 9.16 (s, 1H), 6.91–6.78 (m, 7H),
6.38–6.36 (m, 2H), 3.25 (t, J = 5.6 Hz, 4H), 2.66 (t, J = 6.4 Hz,
4H), 1.87 (quint, J = 6.4 Hz, 4H). 13C NMR (100 MHz, CDCl3):
δ 181.9, 159.3 (d, JC–F = 239.0 Hz), 144.3, 137.1 (d, JC–F = 8
Hz), 136.4 (d, JC–F = 2 Hz), 129.8, 129.5, 127.2, 121.6, 114.4,
5. Experimental characterization data
for the starting materials, products
and post-functionalized adducts
Staring materials used in this study:
Starting materials 1i,29 1j–1k,25,26 1l,25,27 2b–2c,30 2d,32
2e,31 2f,33 2g,34 2h,35 5a–5c,37 and 8h 36 were synthesized
according to previously reported procedures and the spectro-
scopic data were identical to those reported.
5.1 Experimental characterization data for the products 3
114.3 (d, JC–F = 23 Hz), 114.0 (d, JC–F = 25 Hz), 110.9 (d, JC–F
=
5-Methoxy-3,3-bis(1,2,3,4-tetrahydroquinolin-6-yl)indolin-2-one
8 Hz), 62.6, 42.2, 27.3, 22.3. IR (KBr, cm−1): 3402, 2926, 2841,
(3aa) was prepared according to general procedure A. The 1702, 1510, 1485, 793. HRMS (ESI) m/z: [M + H]+ Calcd for
crude reaction mixture was purified by column chromato-
C
26H25FN3O: 414.1976; Found: 414.2010.
graphy using silica gel (230–400 mesh) giving 3aa (44.2 mg for
5-Chloro-3,3-bis(1,2,3,4-tetrahydroquinolin-6-yl)indolin-2-one
0.11 mmol scale) in 92% yield. Physical state: white solid. M. (3ea) was prepared according to general procedure A. The
p.: 118–120 °C. Rf-Value: 0.3 (50% EtOAc/hexane). 1H NMR crude reaction mixture was purified by column chromato-
(400 MHz, CDCl3): δ 8.03 (s, 1H), 6.86–6.79 (m, 6H), 6.71 (dd, graphy using silica gel (230–400 mesh) giving 3ea (33 mg for
J1 = 8.4 Hz, J2 = 2.4 Hz, 1H), 6.38 (d, J = 8.8 Hz, 2H), 3.73 (s, 0.11 mmol scale) in 70% yield. Physical state: light yellow
1
3H), 3.26 (t, J = 5.2 Hz, 4H), 2.67 (t, J = 6.0 Hz, 4H), 1.88 (quint, solid. M.p.: 138–140 °C. Rf-Value: 0.2 (40% EtOAc/hexane). H
J = 6 Hz, 4H). 13C NMR (100 MHz, CDCl3): δ 181.1, 156.1, NMR (400 MHz, CDCl3): δ 8.70 (s, 1H), 7.13 (s, 2H), 6.82–6.81
144.1, 136.9, 133.8, 130.5, 129.7, 127.3, 121.6, 114.4, 113.6, (m, 5H), 6.37 (d, J = 8.8 Hz, 2H), 3.26–3.25 (m, 4H), 2.68–2.66
112.5, 110.4, 62.5, 56.1, 42.3, 27.4, 22.4. IR (KBr, cm−1): 3384, (m, 4H), 1.88–1.87 (m, 4H). 13C NMR (100 MHz, CDCl3): δ
3157, 2925, 1698, 1611, 1508, 1302. HRMS (ESI) m/z: [M + H]+ 181.1, 144.4, 139.0, 137.3, 129.7, 129.6, 128.1, 128.0, 127.2,
Calcd for C27H28N3O2: 426.2176; Found: 426.2173.
126.8, 121.6, 114.4, 111.2, 62.3, 42.3, 27.4, 22.4. IR (KBr,
3,3-Bis(1,2,3,4-tetrahydroquinolin-6-yl)indolin-2-one (3ba) was cm−1): 3401, 3158, 2925, 1700, 1612, 1508, 732. HRMS (ESI)
prepared according to general procedure A. The crude reaction m/z: [M + H]+ Calcd for C26H25ClN3O: 430.1681; Found:
mixture was purified by column chromatography using silica 430.1701.
gel (230–400 mesh) giving 3ba (37 mg for 0.14 mmol scale) in
5-Bromo-3,3-bis(1,2,3,4-tetrahydroquinolin-6-yl)indolin-2-one
69% yield. Physical state: light yellow solid. M.p.: 190–197 °C. (3fa) was prepared according to general procedure A. The
1
Rf-Value: 0.2 (50% EtOAc/hexane). H NMR (400 MHz, CDCl3): crude reaction mixture was purified by column chromato-
δ 8.21 (s, 1H), 7.19–7.16 (m, 2H), 7.01 (t, J = 7.6 Hz, 1H), graphy using silica gel (230–400 mesh) giving 3fa (62 mg for
6.91–6.84 (m, 5H), 6.38–6.36 (m, 2H), 3.25 (t, J = 5.6 Hz, 4H), 0.22 mmol scale) in 59% yield. Physical state: yellow solid. M.
2.66 (t, J = 6.4 Hz, 4H), 1.88 (quint, J = 6.0 Hz, 4H). 13C NMR p.: 140–145 °C. Rf-Value: 0.2 (40% EtOAc/hexane). 1H NMR
(100 MHz, CDCl3): δ 181.2, 144.0, 140.3, 135.5, 130.5, 129.7, (400 MHz, CDCl3): δ 8.46 (s, 1H), 7.31–7.27 (m, 2H), 6.82–6.77
127.9, 127.3, 126.5, 122.9, 121.6, 114.4, 110.1, 62.0, 42.3, 27.3, (m, 5H), 6.39–6.37 (m, 2H), 3.26 (t, J = 5.6 Hz, 4H), 2.67 (t, J =
22.4. IR (KBr, cm−1): 3402, 3022, 2836, 1703, 1653, 1510. 6.4 Hz, 4H), 1.89 (quint, J = 6.4 Hz, 4H). 13C NMR (100 MHz,
HRMS (ESI) m/z: [M + H]+ Calcd for C26H26N3O: 396.2070; CDCl3): δ 181.0, 144.4, 139.4, 137.6, 130.8, 129.6, 129.56,
Found: 396.2084.
129.5, 127.2, 121.6, 115.5, 114.4, 111.7, 62.3, 42.3, 27.4, 22.4.
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IR (KBr, cm−1): 3380, 3105, 2809, 1704, 1580, 1509, 738. 1.89–1.88 (m, 4H). 13C NMR (100 MHz, CDCl3): δ 179.1, 144.1,
HRMS (ESI) m/z: [M + H]+ Calcd for C26H25BrN3O: 474.1176; 142.3, 136.5, 134.9, 130.8, 129.7, 129.0, 127.73, 127.72, 127.6,
Found: 474.1148.
127.2, 126.1, 122.9, 121.5, 114.3, 109.5, 61.6, 44.2, 42.3, 27.4,
5,6-Difluoro-3,3-bis(1,2,3,4-tetrahydroquinolin-6-yl)indolin-2- 22.4. IR (KBr, cm−1): 3389, 2924, 2838, 1701, 1608, 1509.
one (3ga) was prepared according to general procedure A. The HRMS (ESI) m/z: [M + H]+ Calcd for C33H32N3O: 486.2540;
crude reaction mixture was purified by column chromato- Found: 486.2533.
graphy using silica gel (230–400 mesh) giving 3ga (71 mg for
1-Methyl-3,3-bis(1,2,3,4-tetrahydroquinolin-6-yl)indolin-2-one
0.27 mmol scale) in 62% yield. Physical state: yellow solid. M. (3ka) was prepared according to general procedure A. The
p.: 175–180 °C. Rf-Value: 0.1 (30% EtOAc/hexane). 1H NMR crude reaction mixture was purified by column chromato-
(400 MHz, CDCl3): δ 8.77 (s, 1H), 6.985 (dd, J1 = 9.6 Hz, J2 = graphy using silica gel (230–400 mesh) giving 3ka (38 mg for
7.6 Hz, 1H), 6.82–6.79 (m, 4H), 6.73 (dd, J1 = 9.6 Hz, J2 = 6.4 0.12 mmol scale) in 75% yield. Physical state: pale solid. M.p.:
Hz, 1H), 6.38 (d, J = 8.0 Hz, 2H), 3.26 (t, J = 5.6 Hz, 4H), 2.67 278–280 °C. Rf-Value: 0.13 (30% EtOAc/hexane). 1H NMR
(t, J = 6.4 Hz, 4H), 1.89 (quint, J = 6.4 Hz, 4H). 13C NMR (400 MHz, CDCl3): δ 7.26–7.21 (m, 2H), 7.04 (t, J = 7.2 Hz, 1H),
(100 MHz, CDCl3): δ 182.3, 171.6, 150.1, 146.9, 144.4, 136.6, 6.87–6.81 (m, 5H), 6.35–6.33 (m, 2H), 3.76 (br, 2H), 3.25–3.22
131.0, 129.5, 129.4, 127.1, 121.6, 115.4, 114.4, 100.6, 62.3, (m, 7H), 2.65 (t, J = 6.4 Hz, 4H), 1.87 (p, J1 = 5.6 Hz, 4H). 13C
42.2, 27.3, 22.2, (60.7, 21.4, 14.5 = EtOAc peaks). IR (KBr, NMR (100 MHz, CDCl3): δ 179.1, 144.1, 143.3, 134.8, 130.7,
cm−1): 3399, 2929, 2841, 1716, 1630, 1612, 1503, 1184, 798. 129.6, 127.9, 127.2, 126.2, 122.8, 121.4, 114.2, 108.4, 61.5,
HRMS (ESI) m/z: [M + H]+ Calcd for C26H24F2N3O: 432.1882; 42.3, 27.4, 26.9, 22.4. IR (KBr, cm−1): 3409, 2839, 2925, 1703,
Found: 432.1812.
1606, 1511, 1275. HRMS (ESI) m/z: [M + H]+ Calcd for
7-Methyl-3,3-bis(1,2,3,4-tetrahydroquinolin-6-yl)indolin-2-one
(3ha) was prepared according to general procedure A. The
C
27H28N3O: 410.2227; Found: 410.2246.
5-Chloro-1-methyl-3,3-bis(1,2,3,4-tetrahydroquinolin-6-yl)
crude reaction mixture was purified by column chromato- indolin-2-one (3la) was prepared according to general pro-
graphy using silica gel (230–400 mesh) giving 3ha (52 mg for cedure A. The crude reaction mixture was purified by column
0.31 mmol scale) in 41% yield. Physical state: yellow solid. M. chromatography using silica gel (230–400 mesh) giving 3la
p.: 240–245 °C. Rf-Value: 0.2 (30% EtOAc/hexane). 1H NMR (36 mg for 0.10 mmol scale) in 80% yield. Physical state: pink
1
(400 MHz, CDCl3): δ 8.50 (s, 1H), 7.03–6.98 (m, 2H), 6.94–6.90 solid. M.p.: 195–200 °C. Rf-Value: 0.3 (40% EtOAc/hexane). H
(m, 1H), 6.86–6.84 (m, 4H), 6.36 (d, J = 8.8 Hz, 2H), 3.25 (t, J = NMR (400 MHz, CDCl3): δ 7.23 (dd, J1 = 8.0 Hz, J2 = 2.0 Hz,
5.6 Hz, 4H), 2.66 (t, J = 6.4 Hz, 4H), 2.25 (s, 3H), 1.88 (quint, 1H), 7.18 (d, J = 2.0 Hz, 1H), 6.79–6.77 (m, 5H), 6.37–6.35 (m,
J = 6.4 Hz, 4H). 13C NMR (100 MHz, CDCl3): δ 182.0, 144.0, 2H), 3.27–3.24 (m, 7H), 2.67 (t, J = 6.4 Hz, 4H), 1.89 (quint, J =
139.2, 135.0, 130.6, 129.7, 129.1, 127.3, 123.9, 122.6, 121.4, 5.6 Hz, 4H). 13C NMR (100 MHz, CDCl3): δ 178.7, 144.3, 141.9,
119.6, 114.3, 62.4, 42.3, 27.3, 22.4, 16.9. IR (KBr, cm−1): 2957, 136.5, 130.0, 129.5, 128.2, 127.9, 127.2, 126.5, 121.5, 114.3,
2856, 1699, 1611, 1508, 1464, 1301, 810, 732. HRMS (ESI) m/z: 109.4, 61.8, 42.3, 27.4, 27.0, 22.4. IR (KBr, cm−1): 3365, 2923,
[M + H]+ Calcd for C27H28N3O: 410.2227; Found: 410.2169.
2836, 1706, 1610, 1514, 811. HRMS (ESI) m/z: [M + H]+ Calcd
1-Acetyl-3,3-bis(1,2,3,4-tetrahydroquinolin-6-yl)indolin-2-one for C27H27ClN3O: 444.1837; Found: 444.1780.
(3ia) was prepared according to general procedure A. The
3,3-Bis(1-benzyl-1,2,3,4-tetrahydroquinolin-6-yl)-5-chloro-
crude reaction mixture was purified by column chromato- indolin-2-one (3eb) was prepared according to general pro-
graphy using silica gel (230–400 mesh) giving 3ia (31 mg for cedure A. The crude reaction mixture was purified by column
0.11 mmol scale) in 67% yield. Physical state: colourless chromatography using silica gel (230–400 mesh) giving 3eb
1
liquid. Rf-Value: 0.2 (30% EtOAc/hexane). H NMR (400 MHz, (61 mg for 0.11 mmol scale) in 91% yield. Physical state: pale
CDCl3): δ 8.29 (d, J = 8.4 Hz, 1H), 7.32–7.28 (m, 1H), 7.18 (d, J green solid. M.p.: 110–120 °C. Rf-Value: 0.5 (30% EtOAc/
= 4.4 Hz, 2H), 6.80–6.75 (m, 4H), 6.36 (d, J = 8.4 Hz, 2H), 3.26 hexane). 1H NMR (400 MHz, CDCl3): δ 9.48–9.40 (m, 1H),
(t, J = 5.6 Hz, 4H), 2.69–2.64 (m, 7H), 1.89 (quint, J = 6.0 Hz, 7.33–7.18 (m, 10H), 7.10 (s, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.87
4H). 13C NMR (100 MHz, CDCl3): δ 180.1, 171.8, 144.4, 139.5, (s, 2H), 6.81–6.80 (m, 2H), 6.72 (d, J = 8.4 Hz, 1H), 6.39 (d, J =
134.0, 130.1, 129.7, 128.2, 127.4, 126.1, 125.5, 121.4, 116.9, 8.4 Hz, 2H), 4.39 (s, 4H), 3.28 (br, 4H), 2.70–2.69 (m, 4H),
114.2, 62.1, 42.2, 27.4, 27.2, 22.3. IR (KBr, cm−1): 3405, 3126, 1.93–1.92 (m, 4H). 13C NMR (100 MHz, CDCl3): δ 181.9, 145.2,
2928, 1709, 1611, 1511. HRMS (ESI) m/z: [M + H]+ Calcd for 139.2, 137.4, 129.1, 128.9, 128.4, 127.9, 127.8, 127.5, 127.1,
C
28H28N3O2: 438.2176; Found: 438.2166.
127.0, 126.6, 122.5, 111.6, 111.5, 111.1, 62.3, 55.6, 50.1, 28.5,
1-Benzyl-3,3-bis(1,2,3,4-tetrahydroquinolin-6-yl)indolin-2-one 22.6. IR (KBr, cm−1): 3366, 2923, 2838, 1707, 1610, 1509, 732.
(3ja) was prepared according to general procedure A. The HRMS (ESI) m/z: [M + H]+ Calcd for C40H37ClN3O: 610.2620;
crude reaction mixture was purified by column chromato- Found: 610.2616.
graphy using silica gel (230–400 mesh) giving 3ja (31.5 mg for
3,3-Bis(1-benzyl-1,2,3,4-tetrahydroquinolin-6-yl)-5-methoxy
0.08 mmol scale) in 77% yield. Physical state: yellow solid. M. indolin-2-one (3ab) was prepared according to general pro-
p.: 82–88 °C. Rf-Value: 0.4 (50% EtOAc/hexane). 1H NMR cedure A. The crude reaction mixture was purified by column
(400 MHz, CDCl3): δ 7.28–7.22 (m, 6H), 7.11–7.09 (m, 1H), chromatography using silica gel (230–400 mesh) giving 3ab
7.01–6.97 (m, 1H), 6.84 (s, 4H), 6.73–6.71 (m, 1H), 6.36 (d, J = (57 mg for 0.11 mmol scale) in 83% yield. Physical state:
7.2 Hz, 2H), 4.96 (s, 2H), 3.25 (br, 4H), 2.66 (br, 4H), brown solid. M.p.: 125–130 °C. Rf-Value: 0.5 (30% EtOAc/
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hexane). H NMR (400 MHz, CDCl3): δ 8.47 (s, 1H), 7.29 (t, J =
Organic & Biomolecular Chemistry
1
1-Methyl-3,3-bis(1-methyl-1,2,3,4-tetrahydroquinolin-6-yl) indolin-
7.2 Hz, 4H), 7.24–7.19 (m, 6H), 6.90 (d, J = 2 Hz, 2H), 6.84 (d, J 2-one (3kc) was prepared according to general procedure A. The
= 2 Hz, 1H), 6.82 (d, J = 2.4 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), crude reaction mixture was purified by column chromatography
6.76 (d, J = 2.8 Hz, 1H), 6.68 (dd, J1 = 8.4 Hz, J2 = 2.4 Hz, 2H), using silica gel (230–400 mesh) giving 3kc (32.5 mg for
6.40 (d, J = 8.8 Hz, 2H), 4.41 (s, 4H), 3.71 (s, 3H), 3.30 (t, J = 5.6 0.12 mmol scale) in 60% yield. Physical state: brown solid. M.p.:
Hz, 4H), 2.72 (t, J = 6.4 Hz, 4H), 1.95 (quint, J = 6.4 Hz, 4H). 150–165 °C. Rf-Value: 0.6 (30% EtOAc/hexane). 1H NMR
13C NMR (100 MHz, CDCl3): δ 182.0, 155.9, 145.0, 139.3, 137.0, (700 MHz, CDCl3): δ 7.18–7.16 (m, 2H), 6.96 (t, J = 7.7 Hz, 1H),
134.1, 129.2, 129.1, 128.8, 127.5, 127.0, 126.9, 122.3, 113.5, 6.84 (d, J = 8.4 Hz, 2H), 6.79–6.77 (m, 3H), 6.39 (d, J = 8.4 Hz,
112.3, 111.0, 110.6, 62.4, 56.0, 55.6, 50.1, 28.5, 22.6. IR (KBr, 2H), 3.18 (s, 3H), 3.09 (t, J = 5.6 Hz, 4H), 2.75 (s, 6H), 2.59 (t, J = 7
cm−1): 3433, 3053, 2985, 1635, 1421, 1247. HRMS (ESI) m/z: Hz, 4H), 1.84 (quint, J = 6.3 Hz, 4H). 13C NMR (175 MHz, CDCl3):
[M + H]+ Calcd for C41H40N3O2: 606.3115; Found: 606.3118.
δ 179.1, 146.0, 143.3, 134.9, 129.8, 129.0, 127.8, 127.4, 126.2,
1-Benzyl-3,3-bis(1-benzyl-1,2,3,4-tetrahydroquinolin-6-yl) indolin- 122.9, 122.8, 110.8, 108.4, 61.4, 51.5, 39.4, 28.2, 26.9, 22.7. IR
2-one (3jb) was prepared according to general procedure A. The (KBr, cm−1): 3130, 2927, 1709, 1606, 1510. HRMS (ESI) m/z: [M +
crude reaction mixture was purified by column chromato- H]+ Calcd for C29H32N3O: 438.2540; Found: 438.2511.
graphy using silica gel (230–400 mesh) giving 3jb (52 mg for
5-Chloro-1-methyl-3,3-bis(1-methyl-1,2,3,4 tetrahydroquinolin-
0.08 mmol scale) in 92% yield. Physical state: maroon solid. 6-yl)indolin-2-one (3lc) was prepared according to general pro-
1
M.p.: 105–115 °C. Rf-Value: 0.6 (30% EtOAc/hexane). H NMR cedure A. The crude reaction mixture was purified by column
(400 MHz, CDCl3): δ 7.29–7.23 (m, 16H), 7.10–7.07 (m, 1H), chromatography using silica gel (230–400 mesh) giving 3lc
6.98–6.95 (m, 1H), 6.90 (s, 2H), 6.83 (d, J = 8.4 Hz, 2H), 6.69 (d, (47 mg for 0.10 mmol scale) in 97% yield. Physical state: white
1
J = 7.2 Hz, 1H), 6.39 (d, J = 8.0 Hz, 2H), 4.94 (s, 2H), 4.41 (s, solid. M.p.: 110–112 °C. Rf-Value: 0.2 (50% EtOAc/hexane). H
4H), 3.30 (br, 4H), 2.71 (br, 4H), 1.95 (br, 4H). 13C NMR NMR (400 MHz, CDCl3): δ 7.23–7.19 (m, 2H), 6.89–6.86 (m,
(100 MHz, CDCl3): δ 179.2, 145.0, 142.3, 139.4, 136.5, 135.0, 2H), 6.81–6.76 (m, 3H), 6.46 (d, J = 8.4 Hz, 2H), 3.23 (s, 3H),
129.4, 129.3, 129.1, 129.0, 128.8, 127.7, 127.6, 127.5, 127.1, 3.18 (t, J = 6.0 Hz, 4H), 2.84 (s, 6H), 2.67 (t, J = 6.4 Hz, 4H),
127.0, 126.2, 122.8, 122.3, 110.9, 109.5, 61.4, 55.6, 50.2, 44.2, 1.92 (quint, J = 6.0 Hz, 4H). 13C NMR (100 MHz, CDCl3): δ
28.6, 22.6. IR (KBr, cm−1): 3028, 2925, 1710, 1608, 1510. HRMS 178.7, 146.2, 141.9, 136.5, 129.0, 128.9, 128.1, 127.9, 127.3,
(ESI) m/z: [M + H]+ Calcd for C47H44N3O: 666.3479; Found: 126.5, 123.0, 110.8, 109.3, 61.6, 51.5, 39.3, 28.2, 27.0, 22.7. IR
666.3480.
3,3-Bis(1-benzyl-1,2,3,4-tetrahydroquinolin-6-yl)-1-methyl indolin- z: [M + H]+ Calcd for C29H31ClN3O: 472.2150; Found: 472.2167.
2-one (3kb) was prepared according to general procedure A. The 3,3-Bis(4-(dimethylamino)phenyl)-5-methoxyindolin-2-one
(KBr, cm−1): 2928, 2817, 1717, 1608, 1510, 806. HRMS (ESI) m/
crude reaction mixture was purified by column chromatography (3b′) was prepared according to general procedure A. The
using silica gel (230–400 mesh) giving 3kb (50 mg for 0.12 mmol crude reaction mixture was purified by column chromato-
scale) in 68% yield. Physical state: brown solid. M.p.: 120–130 °C. graphy using silica gel (230–400 mesh) giving 3b′ (17 mg for
1
Rf-Value: 0.5 (30% EtOAc/hexane). H NMR (400 MHz, CDCl3): δ 0.10 mmol scale) in 42% yield. Physical state: yellow solid. M.
7.26–7.21 (m, 12H), 7.00 (s, 1H), 6.88–6.79 (m, 5H), 6.36 (d, J = p.: 247–250 °C. Rf-Value: 0.4 (40% EtOAc/hexane). 1H NMR
7.2 Hz, 2H), 4.38 (S, 4H), 3.28–3.22 (m, 7H), 2.70 (br, 4H), 1.92 (400 MHz, CDCl3): δ 8.90 (s, 1H), 7.15 (d, J = 8.8 Hz, 4H), 6.82
(br, 4H). 13C NMR (100 MHz, CDCl3): δ 179.2, 144.9, 143.2, 139.3, (d, J = 8.4 Hz, 1H), 6.79 (d, J = 2.4 Hz, 1H), 6.70 (dd, J1 = 8.4
134.8, 129.3, 129.1, 128.8, 127.8, 127.4, 127.0, 126.9, 126.2, 122.7, Hz, J2 = 2.4 Hz, 1H), 6.65 (J = 8.8 Hz, 4H), 3.78 (s, 3H), 2.90 (s,
122.2, 110.8, 108.3, 61.2, 55.5, 50.1, 28.5, 26.8, 22.6. IR (KBr, 12H). 13C NMR (100 MHz, CDCl3): δ 181.5, 156.0, 149.9, 136.6,
cm−1): 3142, 2924, 2851, 1709, 1607, 1509. HRMS (ESI) m/z: [M + 134.1, 130.0, 129.4, 113.4, 112.7, 112.67, 110.7, 62.4, 56.0, 40.9.
H]+ Calcd for C41H40N3O: 590.3166; Found: 590.3161.
IR (KBr, cm−1): 2922, 2850, 1717, 1516, 1489, 1288, 1246, 1030.
1-Benzyl-3,3-bis(1-methyl-1,2,3,4-tetrahydroquinolin-6-yl) indolin- HRMS (ESI) m/z: [M + H]+ Calcd for C25H28N3O2: 402.2176;
2-one (3jc) was prepared according to general procedure A. The Found: 402.2171.
crude reaction mixture was purified by column chromatography
2,2″,3,3″-Tetrahydro-1H,1″H-[5,3′:3′,5″-terbenzo[b]pyrrol]-
using silica gel (230–400 mesh) giving 3jc (82 mg for 0.21 mmol 2′(1′H)-one (3b″) was prepared according to general procedure
scale) in 76% yield. Physical state: white solid. M.p.: 117–122 °C. A. The crude reaction mixture was subjected to HRMS and a
1
Rf-Value: 0.5 (20% EtOAc/hexane). H NMR (400 MHz, CDCl3): δ trace amount of the product 3b″ was observed. HRMS (ESI)
7.28–7.24 (m, 6H), 7.11 (dt, J1 = 7.6 Hz, J2 = 1.2 Hz, 1H), 7.00 (dd, m/z: [M + H]+ Calcd for C24H22N3O: 368.1757; Found: 368.1728.
J1 = 7.6 Hz, J2 = 1.2 Hz, 1H), 6.95 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 2H),
5.2 Experimental characterization data for the three-
component products 3jac–3lac
6.87 (d, J = 2.4 Hz, 2H), 6.71 (d, J = 7.6 Hz, 1H), 6.48 (d, J = 8.4
Hz, 2H), 4.96 (s, 2H), 3.17 (t, J = 6 Hz, 4H), 2.84 (s, 6H), 2.67 (t, J
= 6.4 Hz, 4H), 1.92 (quint, J = 6.4 Hz, 4H). 13C NMR (100 MHz, 1-Benzyl-3-(1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-3-(1,2,3,4-
CDCl3): δ 179.1, 146.0, 142.4, 136.6, 135.0, 129.9, 129.1, 129.0, tetrahydroquinolin-6-yl)indolin-2-one (3jac) was prepared
127.7, 127.6, 127.4, 126.2, 122.9, 122.88, 110.9, 109.5, 61.4, 51.5, according to general procedure A. The crude reaction mixture
44.2, 39.4, 28.2, 22.7. IR (KBr, cm−1): 2927, 2855, 1713, 1608, was purified by column chromatography using silica gel
1506, 1323, 1207. HRMS (ESI) m/z: [M + H]+ Calcd for C35H36N3O: (230–400 mesh) giving 3jac (78 mg for 0.42 mmol scale) in
514.2818; Found: 514.2853.
37% yield along with the formation of two 2-component pro-
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ducts 3ja (13% yield) & 3jc (14% yield). Physical state: pale giving 4jac (13.5 mg for 0.06 mmol scale) in 45% yield.
yellow solid. M.p.: 150–160 °C. Rf-Value: 0.2 (40% EtOAc/ Physical state: pale yellow solid. M.p.: 110–117 °C. Rf-Value:
hexane). 1H NMR (400 MHz, CDCl3): δ 7.28–7.23 (m, 6H), 0.4 (30% EtOAc/hexane). 1H NMR (400 MHz, CDCl3): δ 8.87
7.13–7.09 (m, 1H), 7.01–6.94 (m, 2H), 6.86 (d, J = 6.4 Hz, 3H), (dd, J1 = 4.0 Hz, J2 = 1.2 Hz, 1H), 8.04 (d, J = 8.8 Hz, 2H), 7.74
6.72 (d, J = 8.0 Hz, 1H), 6.48 (d, J = 8.8 Hz, 1H), 6.38–6.36 (m, (dd, J1 = 8.8 Hz, J2 = 2.0 Hz, 1H), 7.70 (d, J = 1.6 Hz, 1H),
1H), 4.96 (s, 2H), 3.25 (t, J = 5.6 Hz, 2H), 3.17 (t, J = 5.6 Hz, 7.37–7.25 (m, 7H), 7.19 (t, J = 7.6 Hz, 1H), 7.06 (t, J = 7.6 Hz,
2H), 2.84 (s, 3H), 2.66 (t, J = 5.6 Hz, 4H), 1.95–1.85 (m, 4H). 13
C
1H), 6.95–6.93 (m, 1H), 6.86–6.81 (m, 2H), 6.50 (d, J = 8.8 Hz,
NMR (100 MHz, CDCl3): δ 179.1, 146.0, 144.1, 142.4, 136.6, 1H), 5.02 (d, J = 2.8 Hz, 2H), 3.20 (t, J = 5.6 Hz, 2H), 2.86 (s,
135.0, 130.8, 129.9, 129.7, 129.1, 129.0, 128.7, 127.7, 127.6, 3H), 2.66 (t, J = 6.4 Hz, 2H), 1.93 (quint, J = 6.4 Hz, 2H). 13C
127.4, 127.3, 126.2, 122.93, 122.9, 121.5, 114.3, 110.9, 109.5, NMR (100 MHz, CDCl3): δ 178.2, 150.7, 147.8, 146.4, 142.5,
61.5, 51.5, 44.2, 42.3, 39.4, 28.2, 27.4, 22.7, 22.5. IR (KBr, 141.1, 136.7, 136.3, 133.6, 131.0, 129.9, 129.12, 129.1, 128.7,
cm−1): 3380, 2924, 2836, 1706, 1608, 1511. HRMS (ESI) m/z: [M 128.4, 128.2, 127.9, 127.6, 127.4, 127.0, 126.3, 123.23, 123.2,
+ H]+ Calcd for C34H34N3O: 500.2696; Found: 500.2667.
121.5, 111.0, 109.9, 62.0, 51.5, 44.4, 39.3, 28.2, 22.6. IR (KBr,
1-Methyl-3-(1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-3-(1,2,3,4- cm−1): 3133, 2924, 1709, 1607, 1511, 1401. HRMS (ESI) m/z:
tetrahydroquinolin-6-yl)indolin-2-one (3kac) was prepared [M + H]+ Calcd for C34H30N3O: 496.2383; Found: 496.2387.
according to general procedure A. The crude reaction mixture
1-Methyl-3-(1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-3-(quino-
was purified by column chromatography using silica gel lin-6-yl)indolin-2-one (4kac) was prepared according to general
(230–400 mesh) giving 3kac (30 mg for 0.19 mmol scale) in procedure B. The crude reaction mixture was purified by
38% yield along with the formation of two 2-component pro- column chromatography using silica gel (230–400 mesh)
ducts 3ka (18% yield) & 3kc (22% yield). Physical state: pale giving 4kac (20 mg for 0.09 mmol scale) in 51% yield. Physical
yellow solid. M.p.: 119–120 °C. Rf-Value: 0.3 (30% EtOAc/ state: pale yellow solid. M.p.: 105–110 °C. Rf-Value: 0.2 (50%
1
hexane). H NMR (400 MHz, CDCl3): δ 7.27–7.22 (m, 2H), 7.04 EtOAc/hexane). 1H NMR (400 MHz, CDCl3): δ 8.86 (d, J = 2.8
(t, J = 7.6 Hz, 1H), 6.91 (dd, J1 = 8.4 Hz, J2 = 2.4 Hz, 1H), Hz, 1H), 8.07–8.01 (m, 2H), 7.72–7.67 (m, 2H), 7.36–7.31 (m,
6.87–6.81 (m, 4H), 6.46 (d, J = 8.4 Hz, 1H), 6.36–6.34 (m, 1H), 3H), 7.10 (t, J = 8.0 Hz, 1H), 6.95–6.90 (m, 2H), 6.84 (d, J = 1.6
3.25–3.23 (m, 5H), 3.16 (t, J = 6.0 Hz, 2H), 2.83 (s, 3H), 2.66 (t, J Hz, 1H), 6.48 (d, J = 8.4 Hz, 1H), 3.32 (s, 3H), 3.19 (t, J = 5.6 Hz,
= 6.4 Hz, 4H), 1.95–1.84 (m, 4H). 13C NMR (100 MHz, CDCl3): δ 2H), 2.85 (s, 3H), 2.66 (t, J = 6.4 Hz, 2H), 1.93 (quint, J = 6.0 Hz,
179.1, 146.0, 144.0, 143.3, 134.8, 130.8, 129.8, 129.6, 129.0, 2H). 13C NMR (100 MHz, CDCl3): δ 178.2, 150.7, 147.8, 146.4,
127.8, 127.4, 127.2, 126.2, 122.9, 122.8, 121.4, 114.3, 110.8, 143.4, 141.1, 136.7, 133.5, 130.9, 129.8, 129.0, 128.6, 128.5,
108.4, 61.4, 51.5, 42.3, 39.4, 28.2, 27.3, 26.9, 22.7, 22.4. IR 128.2, 127.4, 127.0, 126.3, 123.2, 123.1, 121.5, 110.9, 108.9,
(KBr, cm−1): 2925, 2835, 1707, 1607, 1510. HRMS (ESI) m/z: [M 64.0, 51.5, 39.3, 28.2, 27.0, 22.6. IR (KBr, cm−1): 3160, 2927,
+ H]+ Calcd for C28H30N3O: 424.2383; Found: 424.2376.
1686, 1608, 1511, 1401. HRMS (ESI) m/z: [M + H]+ Calcd for
5-Chloro-1-methyl-3-(1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)- C28H26N3O: 420.2070; Found: 420.2092.
3-(1,2,3,4-tetrahydroquinolin-6-yl)indolin-2-one (3lac) was pre-
5-Chloro-1-methyl-3-(1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-
pared according to general procedure A. The crude reaction 3-(quinolin-6-yl)indolin-2-one (4lac) was prepared according to
mixture was purified by column chromatography using silica general procedure B. The crude reaction mixture was purified
gel (230–400 mesh) giving 3lac (16 mg for 0.10 mmol scale) in by column chromatography using silica gel (230–400 mesh)
33% yield along with the formation of two 2-component pro- giving 4lac (7 mg for 0.04 mmol scale) in 35% yield. Physical
ducts 3la (17% yield) & 3lc (19% yield). Physical state: pale state: light orange solid. M.p.: 122–130 °C. Rf-Value: 0.4 (40%
yellow solid. M.p.: 118–120 °C. Rf-Value: 0.4 (30% EtOAc/ EtOAc/hexane). 1H NMR (400 MHz, CDCl3): δ 8.89–8.88 (m,
1
hexane). H NMR (400 MHz, CDCl3): δ 7.22 (dd, J1 = 8.4 Hz, J2 1H), 8.08–8.03 (m, 2H), 7.68–7.64 (m, 2H), 7.38–7.35 (m, 1H),
= 2.0 Hz, 1H), 7.18 (d, J = 2.0 Hz, 1H), 6.87 (dd, J1 = 8.4 Hz, J2 = 7.31–7.27 (m, 2H), 6.89–6.85 (m, 2H), 6.80 (d, J = 1.6 Hz, 1H),
2.4 Hz, 1H), 6.81–6.77 (m, 4H), 6.46 (d, J = 8.4 Hz, 1H), 6.49 (d, J = 8.4 Hz, 1H), 3.30 (s, 3H), 3.21 (t, J = 6.0 Hz, 2H),
6.36–6.34 (m, 1H), 3.26–3.23 (m, 5H), 3.18 (t, J = 5.6 Hz, 2H), 2.86 (s, 3H), 2.67 (t, J = 6.4 Hz, 2H), 1.94 (quint, J = 6 Hz, 2H).
2.83 (s, 3H), 2.67 (t, J = 6.4 Hz, 4H), 1.95–1.85 (m, 4H). 13C 13C NMR (100 MHz, CDCl3): δ 177.8, 150.9, 147.9, 146.5, 142.0,
NMR (100 MHz, CDCl3): δ 178.7, 146.2, 144.3, 141.9, 136.5, 140.3, 136.7, 135.2, 130.7, 130.1, 128.9, 128.6, 128.5, 128.2,
129.9, 129.5, 128.94, 128.9, 128.1, 127.9, 127.3, 127.1, 126.5, 127.8, 127.3, 127.0, 126.7, 123.3, 121.6, 110.9, 109.8, 62.2, 51.4,
123.0, 121.5, 114.3, 110.8, 109.3, 61.6, 51.5, 42.2, 39.3, 28.2, 39.3, 28.2, 27.2, 22.6. IR (KBr, cm−1): 3133, 1716, 1607, 1401,
27.4, 27.0, 22.6, 22.4. IR (KBr, cm−1): 3132, 1714, 1638, 1401, 809. HRMS (ESI) m/z: [M + H]+ Calcd for C28H25ClN3O:
811. HRMS (ESI) m/z: [M + H]+ Calcd for C28H29ClN3O: 454.168; Found: 454.1660.
458.1994; Found: 458.1998.
5.4 Experimental characterization data for the products 5c & 6
5.3 Experimental characterization data for the products 4
Pyridin-4-yl(m-tolyl)methyl 2,2,2-trichloroacetimidate (5c) was
1-Benzyl-3-(1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-3-(quinolin- prepared according to a previously reported procedure. The
6-yl)indolin-2-one (4jac) was prepared according to general crude reaction mixture was purified by column chromato-
procedure B. The crude reaction mixture was purified by graphy using silica gel (100–200 mesh) giving 5c (82 mg for
column chromatography using silica gel (230–400 mesh) 0.25 mmol scale) in 95% yield. Physical state: yellow liquid. Rf-
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Value: 0.4 (30% EtOAc/hexane). H NMR (400 MHz, CDCl3): δ 4H), 7.21 (t, J = 7.6 Hz, 2H), 7.11 (d, J = 7.2 Hz, 4H), 6.94–6.91
8.60–8.58 (m, 2H), 8.49 (s, 1H), 7.35–7.34 (m, 2H), 7.28–7.21 (m, 1H), 6.88 (s, 1H), 5.46 (s, 1H), 3.81–3.78 (m, 2H), 2.90 (s,
(m, 3H), 7.15–7.13 (m, 1H), 6.86 (s, 1H), 2.34 (s, 3H). 13C NMR 3H), 2.76 (t, J = 6.8 Hz, 2H), 1.97 (quint, J = 6.8 Hz, 2H). 13C
(100 MHz, CDCl3): δ 161.3, 150.2, 149.0, 138.8, 138.4, 129.8, NMR (100 MHz, CDCl3): δ 143.9, 140.3, 135.4, 130.8, 129.6,
128.9, 128.1, 124.5, 121.5, 91.5, 80.2, 21.7. IR (KBr, cm−1): 129.1, 128.6, 128.1, 126.6, 122.6, 56.4, 46.7, 38.9, 27.4, 22.5. IR
3028, 2922, 1688, 1599, 1412, 1289, 1068, 795. HRMS (ESI) m/z: (KBr, cm−1): 1491, 1344, 1155, 975, 753. HRMS (ESI) m/z: [M +
[M + H]+ Calcd for C15H14Cl3N2O: 343.0166; Found: 343.0160.
Na]+ Calcd for C23H23NO2SNa: 400.1342; Found: 400.1331.
6-Benzhydryl-1-methyl-1,2,3,4-tetrahydroquinoline (6ca) was
5-Benzhydryl-1-tosylindoline (6fa) was prepared according to
prepared according to general procedure C. The crude reaction general procedure C. The crude reaction mixture was purified
mixture was purified by column chromatography using silica by column chromatography using silica gel (230–400 mesh)
gel (230–400 mesh) giving 6ca (36 mg for 0.14 mmol scale) in giving 6fa (40 mg for 0.11 mmol scale) in 82% yield. Physical
85% yield. Physical state: colourless solid. M.p.: 108–111 °C. state: brown solid. M.p.: 106–112 °C. Rf-Value: 0.2 (20% EtOAc/
1
1
Rf-Value: 0.2 (5% EtOAc/hexane). H NMR (400 MHz, CDCl3): δ hexane). H NMR (400 MHz, CDCl3): δ 7.65 (d, J = 8.0 Hz, 2H),
7.27–7.22 (m, 4H), 7.19–7.11 (m, 6H), 6.76 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.27–7.17 (m, 8H), 7.06 (d, J = 7.2 Hz,
6.71 (s, 1H), 6.50 (d, J = 8.4 Hz, 1H), 5.40 (s, 1H), 3.17 (t, J = 5.6 4H), 6.94 (d, J = 8.4 Hz, 1H), 6.80 (s, 1H), 5.45 (s, 1H), 3.87 (t, J
Hz, 2H), 2.84 (s, 3H), 2.67 (t, J = 6.4 Hz, 2H), 1.94 (quint, J = 6.4 = 8.4 Hz, 2H), 2.77 (t, J = 8.4 Hz, 2H), 2.36 (s, 3H). 13C NMR
Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 145.5, 145.1, 131.9, (100 MHz, CDCl3): δ 144.3, 144.1, 140.6, 139.9, 134.3, 132.3,
130.2, 129.8, 128.5, 128.2, 126.3, 123.0, 111.0, 56.4, 51.6, 39.5, 129.9, 129.6, 129.1, 128.6, 127.6, 126.6, 126.3, 114.9, 56.5, 50.4,
28.1, 22.8. IR (KBr, cm−1): 3134, 1636, 1510, 1401. HRMS (ESI) 28.1, 21.8. IR (KBr, cm−1): 3164, 1596, 1484, 1401, 1354, 1164,
m/z: [M + H]+ Calcd for C23H24N: 314.1903; Found: 314.1901.
1029. HRMS (ESI) m/z: [M + H]+ Calcd for C28H26NO2S:
6-Benzhydryl-1-tosyl-1,2,3,4-tetrahydroquinoline (6da) was 440.1679; Found: 440.1685.
prepared according to general procedure C. The crude reaction
5-(1-Phenylethyl)-1-tosylindoline (6fb) was prepared accord-
mixture was purified by column chromatography using silica ing to general procedure C. The crude reaction mixture was
gel (230–400 mesh) giving 6da (71 mg for 0.17 mmol scale) in purified by column chromatography using silica gel
90% yield. Physical state: white solid. M.p.: 150–160 °C. Rf- (230–400 mesh) giving 6fb (36 mg for 0.11 mmol scale) in 88%
1
Value: 0.2 (20% EtOAc/hexane). H NMR (400 MHz, CDCl3): δ yield. Physical state: white solid. M.p.: 101–104 °C. Rf-Value:
1
7.59 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 8.4 Hz, 2H), 7.21–7.17 (m, 0.3 (20% EtOAc/hexane). H NMR (400 MHz, CDCl3): δ 7.65 (d,
4H), 7.13–7.07 (m, 4H), 7.00 (d, J = 7.2 Hz, 4H), 6.83 (dd, J1 = J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 1H), 7.26 (t, J = 7.6 Hz, 2H),
8.8 Hz, J2 = 1.6 Hz, 1H), 6.66 (s, 1H), 5.38 (s, 1H), 3.68 (t, J = 6.0 7.21–7.15 (m, 5H), 7.06 (dd, J1 = 8.0 Hz, J2 = 0.8 Hz, 1H), 6.90
Hz, 2H), 2.28–2.25 (m, 5H), 1.52 (quint, J = 6.4 Hz, 2H). 13C (s, 1H), 4.06 (q, J = 7.2 Hz, 1H), 3.87 (t, J = 8.4 Hz, 2H), 2.80 (t, J
NMR (100 MHz, CDCl3): δ 144.1, 143.7, 140.7, 137.2, 135.5, = 8.4 Hz, 2H), 2.35 (s, 3H), 1.57 (d, J = 7.2 Hz, 3H). 13C NMR
130.7, 130.2, 129.8, 129.7, 128.6, 127.8, 127.4, 126.6, 124.8, (100 MHz, CDCl3): δ 146.7, 144.3, 142.4, 140.4, 134.3, 132.3,
56.6, 46.9, 27.0, 21.9, 21.8. IR (KBr, cm−1): 3019, 2922, 1595, 129.9, 128.7, 127.8, 127.6, 127.2, 126.4, 124.6, 115.0, 50.4, 44.6,
1489, 1357, 1186. HRMS (ESI) m/z: [M + H]+ Calcd for 28.2, 22.3, 21.8. IR (KBr, cm−1): 3133, 1636, 1401, 1165, 1106.
C29H28NO2S: 454.1835; Found: 454.1837.
6-(1-Phenylethyl)-1-tosyl-1,2,3,4-tetrahydroquinoline (6db) was found: 378.1525.
HRMS (ESI) m/z: [M + H]+ Calcd for C23H24NO2S: 378.1522;
prepared according to general procedure C. The crude reaction
5-Benzhydryl-1-(methylsulfonyl)indoline (6ga) was prepared
mixture was purified by column chromatography using silica according to general procedure C. The crude reaction mixture
gel (230–400 mesh) giving 6db (15 mg for 0.07 mmol scale) in was purified by column chromatography using silica gel
55% yield. Physical state: white solid. M.p.: 120–130 °C. Rf- (230–400 mesh) giving 6ga (47 mg for 0.14 mmol scale) in 93%
1
Value: 0.3 (20% EtOAc/hexane). H NMR (400 MHz, CDCl3): δ yield. Physical state: colourless white solid. M.p.: 98–102 °C.
1
7.67 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.31–7.27 (m, Rf-Value: 0.2 (20% EtOAc/hexane). H NMR (400 MHz, CDCl3):
2H), 7.20–7.16 (m, 5H), 7.06–7.04 (m, 1H), 6.83 (s, 1H), 4.07 (q, δ 7.30 (m, 5H), 7.24–7.19 (m, 2H), 7.10 (d, J = 7.6 Hz, 4H),
J = 7.2 Hz, 1H), 3.78–3.75 (m, 2H), 2.41–2.37 (m, 5H), 1.61–1.56 6.96–6.94 (m, 2H), 5.49 (s, 1H), 3.95 (t, J = 8.4 Hz, 2H), 3.07 (t, J
(m, 5H). 13C NMR (100 MHz, CDCl3): δ 146.7, 143.7, 143.2, = 8.4 Hz, 2H), 2.85 (s, 3H). 13C NMR (100 MHz, CDCl3): δ
137.3, 135.2, 130.7, 129.9, 128.7, 128.5, 127.9, 127.4, 126.4, 144.1, 140.7, 140.0, 131.7, 129.7, 129.5, 128.7, 126.7, 126.6,
126.1, 125.0, 46.8, 44.5, 27.0, 22.2, 21.92, 21.9. IR (KBr, cm−1): 113.7, 56.6, 50.9, 34.8, 28.3. IR (KBr, cm−1): 3371, 3023, 2927,
3025, 2920, 2872, 1598, 1493, 1341, 1163. HRMS (ESI) m/z: 1696, 1485, 1347, 1160. HRMS (ESI) m/z: [M + Na]+ Calcd for
[M + Na]+ Calcd for C24H25NO2SNa: 414.1498; found: 414.1488. C22H21NO2SNa: 386.1185; Found: 386.1185.
6-Benzhydryl-1-(methylsulfonyl)-1,2,3,4-tetrahydroquinoline
1-(5-Benzhydrylindolin-1-yl)-3-chloropropan-1-one (6ha) was
(6ea) was prepared according to general procedure C. The prepared according to general procedure C. The crude reaction
crude reaction mixture was purified by column chromato- mixture was purified by column chromatography using silica
graphy using silica gel (230–400 mesh) giving 6ea (44 mg for gel (230–400 mesh) giving 6ha (36 mg for 0.14 mmol scale) in
0.13 mmol scale) in 91% yield. Physical state: yellow solid. M. 67% yield. Physical state: brown solid. M.p.: 168–172 °C. Rf-
p.: 94–96 °C. Rf-Value: 0.4 (20% EtOAc/hexane). 1H NMR Value: 0.4 (20% EtOAc/hexane). 1H NMR (700 MHz, CDCl3):
(400 MHz, CDCl3): δ 7.60 (d, J = 8.8 Hz, 1H), 7.29 (t, J = 7.6 Hz, δ 8.05 (d, J = 8.4 Hz, 1H), 7.21–7.17 (m, 4H), 7.14–7.12 (m,
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2H),7.02 (d, J = 7.7 Hz, 4H), 6.89 (d, J = 8.4 Hz, 1H), 6.85 (s, (230–400 mesh) giving 7fa (10 mg for 0.04 mmol scale) in 51%
1H), 5.43 (s, 1H), 3.96 (t, J = 8.4 Hz, 2H), 3.81 (t, J = 7.0 Hz, yield. Physical state: white solid. M.p.: 120–130 °C. Rf-Value:
1
2H), 3.05 (t, J = 8.4 Hz, 2H), 2.80 (t, J = 7.0 Hz, 2H). 13C NMR 0.3 (30% EtOAc/hexane). H NMR (400 MHz, CDCl3): δ 7.67 (d,
(175 MHz, CDCl3): δ 167.9, 144.3, 141.4, 140.2, 131.7, 129.7, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 1H), 7.32–7.21 (m, 12H),
129.1, 128.6, 126.6, 125.8, 117.1, 56.7, 48.5, 39.7, 39.0, 28.3. IR 7.05 (dd, J1 = 8.4 Hz, J2 = 2.0 Hz, 1H), 7.01 (s, 1H), 3.89 (t, J =
(KBr, cm−1): 3131, 1661, 1487, 1401, 1115. HRMS (ESI) m/z: [M 8.4 Hz, 2H), 2.85 (br, 1H), 2.83 (t, J = 8.4 Hz, 2H), 2.39 (s, 3H).
+ H]+ Calcd for C24H23ClNO: 376.1463; Found: 376.1464.
13C NMR (100 MHz, CDCl3): δ 147.1, 144.4, 142.8, 141.4, 134.2,
3-Chloro-1-(5-(1-phenylethyl)indolin-1-yl)propan-1-one (6hb) 131.9, 130.0, 128.3, 128.1, 128.0, 127.7, 127.6, 125.1, 114.1,
was prepared according to general procedure C. The crude 82.1, 50.4, 28.1, 21.9. IR (KBr, cm−1): 3511, 3135, 1482, 1401,
reaction mixture was purified by column chromatography 1345, 1161. HRMS (ESI) m/z: [M
using silica gel (230–400 mesh) giving 6hb (18 mg for C28H25NO3SNa: 478.1447; Found: 478.1457.
0.09 mmol scale) in 61% yield. Physical state: light yellow Diphenyl(1-tosyl-1H-indol-5-yl)methanol (7fa′) was prepared
+
Na]+ Calcd for
1
solid. M.p.: 152–156 °C. Rf-Value: 0.3 (20% EtOAc/hexane). H according to general procedure D. The crude reaction mixture
NMR (400 MHz, CDCl3): δ 8.13 (d, J = 8.4 Hz, 1H), 7.29–7.28 was purified by column chromatography using silica gel
(m, 2H), 7.21–7.17 (m, 3H), 7.09 (d, J = 8.4 Hz, 1H), 7.01 (s, (230–400 mesh) giving 7fa′ (9 mg for 0.04 mmol scale) in 43%
1H), 4.14–4.10 (m, 1H), 4.05 (t, J = 8.4 Hz, 2H), 3.90 (t, J = 6.8 yield. Physical state: light yellow solid. M.p.: 130–133 °C. Rf-
1
Hz, 2H), 3.16 (t, J = 8.4 Hz, 2H), 2.89 (t, J = 6.8 Hz, 2H), 1.61 (d, Value: 0.4 (30% EtOAc/hexane). H NMR (400 MHz, CDCl3): δ
J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 167.8, 156.1, 7.90 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 3.6
146.8, 142.8, 131.7, 128.7, 127.9, 127.1, 126.4, 124.2, 117.2, Hz, 1H), 7.37 (d, J = 1.6 Hz, 1H), 7.30–7.22 (m, 13H), 6.56 (d,
48.5, 44.7, 39.8, 39.0, 28.3, 22.3. IR (KBr, cm−1): 3133, 1650, J = 4.0 Hz, 1H), 2.86 (s, 1H), 2.35 (s, 3H). 13C NMR (100 MHz,
1490, 1402, 1287, 1114. HRMS (ESI) m/z: [M + Na]+ Calcd for CDCl3): δ 147.3, 145.3, 142.5, 135.6, 134.1, 130.5, 130.3, 128.3,
C19H20ClNONa: 336.1126; Found: 336.1117.
128.2, 127.6, 127.2, 127.0, 125.3, 121.2, 113.2, 109.5, 82.4, 21.9.
IR (KBr, cm−1): 3543, 3161, 1401, 1364, 1170, 1122. HRMS (ESI)
m/z: [M + Na]+ Calcd for C28H23NO3SNa: 476.1291; Found:
5.5 Experimental characterization data for the products 7
Diphenyl(1-tosyl-1,2,3,4-tetrahydroquinolin-6-yl)methanol (7da) 476.1281.
was prepared according to general procedure D. The crude
(1-(Methylsulfonyl)indolin-5-yl)diphenylmethanol (7ga) was
reaction mixture was purified by column chromatography prepared according to general procedure D. The crude reaction
using silica gel (230–400 mesh) giving 7da (13 mg for mixture was purified by column chromatography using silica
0.04 mmol scale) in 62% yield. Physical state: white solid. M. gel (230–400 mesh) giving 7ga (15 mg for 0.08 mmol scale) in
p.: 172–178 °C. Rf-Value: 0.3 (20% EtOAc/hexane). 1H NMR 49% yield. Physical state: white solid. M.p.: 155–160 °C. Rf-
1
(400 MHz, CDCl3): δ 7.61–7.59 (m, 1H), 7.42 (d, J = 8.4 Hz, 2H), Value: 0.2 (30% EtOAc/hexane). H NMR (400 MHz, CDCl3): δ
7.25–7.16 (m, 10H), 7.11 (d, J = 8.0 Hz, 2H), 6.92–6.91 (m, 2H), 7.27–7.18 (m, 11H), 7.10 (s, 1H), 7.00 (d, J = 8.4 Hz, 1H), 3.90
3.71 (t, J = 6.0 Hz, 2H), 2.79 (br, 1H), 2.34–2.30 (m, 5H), 1.56 (t, J = 8.4 Hz, 2H), 3.02 (t, J = 8.4 Hz, 2H), 2.80 (s, 3H). 13C
(quint, J = 6.0 Hz, 2H). 13C NMR (175 MHz, CDCl3): δ 147.0, NMR (100 MHz, CDCl3): δ 147.1, 143.0, 141.4, 131.3, 128.32,
143.9, 143.4, 137.1, 136.3, 130.1, 129.9, 128.7, 128.3, 128.2, 128.3, 128.1, 127.7, 125.4, 113.0, 82.1, 50.9, 34.9, 28.3. IR (KBr,
127.6, 127.4, 126.6, 124.0, 82.0, 46.9, 27.2, 21.9, 21.87. IR (KBr, cm−1): 3500, 1483, 1443, 1338, 1242, 1151. HRMS (ESI) m/z:
cm−1): 3547, 3133, 1493, 1401, 1345, 1160, 1025. HRMS (ESI) [M + Na]+ Calcd for C22H21NO3SNa: 402.1134; Found: 402.1131.
m/z: [M + H]+ Calcd for C29H28NO3S: 470.1784; Found:
(1-(Methylsulfonyl)-1H-indol-5-yl)diphenylmethanol (7ga′) was
470.1774.
prepared according to general procedure D. The crude reaction
(1-(Methylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)diphenyl mixture was purified by column chromatography using silica
methanol (7ea) was prepared according to general procedure gel (230–400 mesh) giving 7ga′ (13 mg for 0.08 mmol scale) in
D. The crude reaction mixture was purified by column chrom- 42% yield. Physical state: light yellow solid. M.p.: 90–93 °C. Rf-
atography using silica gel (230–400 mesh) giving 7ea (16 mg Value: 0.4 (30%
1
for 0.05 mmol scale) in 78% yield. Physical state: white solid.
EtOAc/hexane). H NMR (400 MHz, CDCl3): δ 7.75 (d, J = 8.8
Hz, 1H), 7.43 (d, J = 1.2 Hz, 1H), 7.35 (d, J = 3.6 Hz, 1H),
M.p.: 150–160 °C. Rf-Value: 0.2 (30% EtOAc/hexane).
1H NMR (400 MHz, CDCl3): δ 7.53 (d, J = 8.8 Hz, 1H), 7.28–7.18 (m, 11H), 6.55 (d, J = 3.6 Hz, 1H), 3.02 (s, 3H). 13C
7.26–7.18 (m, 10H), 7.04 (d, J = 1.2 Hz, 1H), 6.94 (dd, J1 = 8.8 NMR (175 MHz, CDCl3): δ 147.3, 142.9, 134.2, 130.5, 128.33,
Hz, J2 = 2.0 Hz, 1H), 3.72 (t, J = 6.0 Hz, 2H), 2.83 (s, 3H), 2.71 128.3, 127.7, 126.8, 125.6, 121.3, 112.7, 109.5, 82.4, 41.2. IR (KBr,
(t, J = 6.4 Hz, 2H), 1.93–1.87 (m, 2H). 13C NMR (175 MHz, cm−1): 3516, 3150, 1401, 1360, 1164, 1141. HRMS (ESI) m/z: [M +
CDCl3): δ 147.0, 143.1, 136.2, 129.3, 128.6, 128.3, 128.1, 127.7, Na]+ Calcd for C22H19NO3SNa: 400.0978; Found: 400.0810.
127.0, 121.9, 81.9, 46.8, 39.0, 27.7, 22.5. IR (KBr, cm−1): 3134,
5.6 Experimental characterization data for the products 9ha,
9hc, 10ha, and 10ha′
1636, 1492, 1401, 1338, 1151. HRMS (ESI) m/z: [M + Na]+ Calcd
for C23H23NO3SNa: 416.1291; Found: 416.1294.
Diphenyl(1-tosylindolin-5-yl)methanol (7fa) was prepared 8-Benzhydryl-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinolin-4(2H)-one
according to general procedure D. The crude reaction mixture (9ha) was prepared according to general procedure C. The
was purified by column chromatography using silica gel crude reaction mixture was purified by column chromato-
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graphy using silica gel (230–400 mesh) giving 9ha (76 mg for DMF
Dimethyl formamide
0.23 mmol scale) in 98% yield. Physical state: light yellow Et2O
solid. M.p.: 105–110 °C. Rf-Value: 0.5 (30% EtOAc/hexane). H EtOAc
Diethyl ether
Ethyl acetate
1
NMR (400 MHz, CDCl3): δ 7.28 (t, J = 7.6 Hz, 4H), 7.23–7.18 (m, ETOH
2H), 7.11 (d, J = 7.6 Hz, 4H), 6.82 (s, 1H), 6.75 (s, 1H), 5.48 (s, MeOH
1H), 4.04 (t, J = 8.8 Hz, 2H), 3.09 (t, J = 8.4 Hz, 2H), 2.86 (t, J = tBuOH
7.6 Hz, 2H), 2.63 (t, J = 7.6 Hz, 2H). 13C NMR (100 MHz, TFE
CDCl3): δ 167.8, 144.3, 140.0, 139.8, 129.6, 129.2, 128.6, 126.9, AcOH
126.6, 124.6, 120.1, 56.9, 45.6, 31.9, 28.0, 24.7. IR (KBr, cm−1): Ac2O
3056, 2928, 1615, 1490, 1382, 1154. HRMS (ESI) m/z: [M + H]+ Et3N
Ethanol
Methanol
tert-Butanol
2,2,2-trifluoroethanol
Acetic acid
Acetic anhydride
Triethylamine
Calcd for C24H22NO: 340.1696; Found: 340.1711.
DIAD
Diisopropyl azodicarboxylate
4-Dimethylaminopyridine,
Butylated hydroxytoluene
Diazabicycloundecene
8-(Pyridin-3-yl(m-tolyl)methyl)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]- DMAP
quinolin-4(2H)-one (9hc) was prepared according to general pro- BHT
cedure C. The crude reaction mixture was subected to HRMS DBU
and a trace amount the product 9hc was observed. HRMS (ESI) CCl3CN Trichloroacetonitrile
m/z: [M + H]+ Calcd for C24H23N2O: 355.1805; Found: 355.1780. NaH
Sodium hydride
8-(Hydroxydiphenylmethyl)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]- Bi(OTf)3 Bismuth triflate
quinolin-4(2H)-one (10ha) was prepared according to general In(OTf)3 Indium triflate
procedure D. The crude reaction mixture was purified by ZnCl2
Zinc chloride
column chromatography using silica gel (230–400 mesh) AlCl3
Aluminium chloride
giving 10ha (27 mg for 0.15 mmol scale) in 52% yield. Physical NaHCO3 Sodium bicarbonate
state: white solid. M.p.: 140–145 °C. Rf-Value: 0.3 (70% EtOAc/ Na2SO4
hexane). 1H NMR (400 MHz, CDCl3): δ 7.35–7.27 (m, 10H), 6.97 OTf
(s, 1H), 6.93 (s, 1H), 4.07 (t, J = 8.8 Hz, 2H), 3.13 (t, J = 8.8 Hz, Ts
2H), 2.90 (t, J = 7.6 Hz, 2H), 2.77 (s, 1H), 2.66 (t, J = 7.6 Hz, Ms
2H). 13C NMR (100 MHz, CDCl3): δ 168.0, 147.4, 143.0, 140.9, Bn
128.8, 128.4, 128.2, 127.7, 125.7, 123.5, 119.7, 82.4, 45.8, 32.0, rt
28.1, 24.9. IR (KBr, cm−1): 3134, 1645, 1494, 1400. HRMS (ESI)
m/z: [M + H]+ Calcd for C24H22NO2: 356.1645; Found: 356.1661.
8-(Hydroxydiphenylmethyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]-
Sodium sulfate
Trifluoromethanesulfonate
Tosyl
Mesyl
Benzyl
Room temperature
Conflicts of interest
quinolin-4-one (10ha′) was prepared according to general pro-
cedure D. The crude reaction mixture was purified by column The authors declare no conflict of interest.
chromatography using silica gel (230–400 mesh) giving 10ha′
(20 mg for 0.15 mmol scale) in 40% yield. Physical state: brown
1
Acknowledgements
solid. M.p.: 138–142 °C. Rf-Value: 0.1 (70% EtOAc/hexane). H
NMR (400 MHz, CDCl3): δ 7.67 (d, J = 3.2 Hz, 1H), 7.35–7.27 (m,
We are thankful to the NISER, Department of Atomic Energy
11H), 7.16 (s, 1H), 6.61 (d, J = 3.6 Hz, 1H), 3.21 (t, J = 7.6 Hz,
2H), 2.99 (t, J = 7.6 Hz, 2H), 2.87 (s, 1H). 13C NMR (100 MHz,
CDCl3): δ 166.9, 147.5, 143.5, 134.9, 129.0, 128.5, 128.3, 127.6,
122.3, 122.1, 120.0, 119.2, 110.6, 82.7, 32.9, 24.7. IR (KBr, cm−1):
3406, 3141, 2919, 2850, 1685, 1467, 1399. HRMS (ESI) m/z: [M +
Na]+ Calcd for C24H19NO2Na: 376.1308; Found: 376.1314.
(DAE), Council for Scientific and Industrial Research (CSIR),
New Delhi (Grant 02(0256)/16/EMR II), and Science and
Engineering Research Board (SERB), New Delhi (Grant EMRII/
2017/001475) for financial support. Namrata Prusty, Lakshmana
Kumar Kinthada and Rohit Meena thank DAE for fellowship.
Rajesh Chebolu thanks the CSIR for the fellowship. We are
thankful to Shyam Kumar Banjare, Asit Ghosh, and Smruti
Ranjan Mohanty, NISER Bhubaneswar for helpful discussions.
5.7 Crystallographic studies
Details of the single crystal X-ray structures have been de-
posited in the form of crystallographic information files with
the Cambridge Crystallographic Data Centre (see Schemes 1 &
4 for specific CCDC numbers) where copies of the data can be
downloaded free-of-charge.
Notes and references
1 (a) J. L. McCormick, T. C. McKee, J. H. Cardellina and
M. R. Boyd, J. Nat. Prod., 1996, 59, 469–471; (b) W. Gul and
M. T. Hamann, Life Sci., 2005, 78, 442–453; (c) P. Ruiz-
Sanchis, S. A. Savina, F. Albericio and M. Álvarez, Chem. –
Eur. J., 2011, 17, 1388–1408; (d) Y. Garg, S. Gahalawat and
S. K. Pandey, RSC Adv., 2015, 5, 38846–38850;
(e) I. Muthukrishnan, V. Sridharan and J. C. Menendez,
Chem. Rev., 2019, 119, 5057–5191.
Abbreviation
CH3CN
DCE
DCM
Acetonitrile
Dichloroethane
Dichloromethane
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