DBU-Mediated Diastereoselective Aldol-Type Cyanomethylation of Isatins

Article abstract of DOI:10.1021/acs.joc.7b00512

An efficient, metal-free approach to 3-substituted 3-hydroxyoxindole by DBU-mediated highly diastereoselective addition of aryl acetonitrile to N-protected isatin under mild conditions has been developed. The reaction proceeds smoothly to produce respecti

Full text of DOI:10.1021/acs.joc.7b00512

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DBU-mediated Diastereoselective Aldol-type Cyanomethylation of Isatins
V. U. Bhaskara Rao, Krishna Kumar, Tamal Das, Kumar Vanka, and Ravi P Singh
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00512 • Publication Date (Web): 30 Mar 2017
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The Journal of Organic Chemistry
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DBU-mediated Diastereoselective Aldol-type Cyanomethylation
of Isatins
V. U. Bhaskara Rao†, Krishna Kumar†, Tamal Das‡, Kumar Vanka‡ and Ravi P. Singh*†
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†
Department of Chemistry, Indian Institute of Technology, Delhi, Hauz Khas, New Delhiꢀ110016, India.
‡
Physical Chemistry Division, National Chemical Laboratory, Dr. Homi Bhabha Road, Puneꢀ411008, India.
Supporting Information Placeholder
TOC GRAFIC & ABSTRACT:
An efficient, metal free approach to 3ꢀsubstituted 3ꢀhydroxy oxindole by DBU mediated highly diastereoselective
addition of aryl acetonitrile to Nꢀprotected isatin under mild condition has been developed. The reaction proceeds
smoothly to produce respective cyanomethylated adducts in good yield and excellent diastereoselectivity. Further
transformation of the cyanide group allowed the synthesis of an advance intermediate of corresponding (+/ꢀ) CPC
analogue. The mechanistic insight towards the aldol type cyanomethylation of Nꢀtrityl isatin with benzyl cyanide
was obtained by DFT calculation.
Cyanoalkyls, an ubiquitous nitrogenꢀcontaining compounds, found in many molecular scaffolds of natural products and
pharmaceuticals,1 provides an easy access to many bioactive functionalities.2 For instance, γꢀamino alcohols, a functional
group present in a number of neuronal uptake inhibitors,3 can be easily synthesized through βꢀhydroxy cyanoalkyls.
Considering its wide application, significant work has been done towards the synthesis of functional cyanoalkyls.
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Specifically stereochemical addition of nitrile enolates to aldehydes has been well investigated.4 Although addition of
nitrile enolates on ketones remains relatively less explored. In case where such additions have been attempted, the reaction
has been low yielding due to its reversible nature. In such transformations, the position of the equilibrium is greatly
influenced by the structure of methylated nitriles as well as the carbonyl compounds.
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Few decades ago, Kaiser and Hauser demonstrated that the reaction of hindered carbonyl compound with hindered αꢀalkali
nitriles proceeded with a strained alkoxide intermediate and delivered lower yield of βꢀhydroxy nitrile.5 Interestingly, it was
found that addition of chelating metal such as Mg and Al cations, were helpful in shifting the equilibrium towards the product
and resulted in higher yield of beta hydroxyl nitriles than those of the corresponding lithio acetonitrile. In 1998, Timberlake and
coꢀworkers showed that CeCl3ꢀmediated aldol reaction of αꢀlithiated nitrile with alkyl and aryl ketones gave good yield of the
corresponding βꢀhydroxy nitriles.6 Later, Fleming and coworkers used the in situ generated βꢀhydroxy nitriles obtained from the
reaction of αꢀlithiated nitriles and various unsymmetrical ketone, to transform it into corresponding α, βꢀunsaturated nitrile in
presence of MgBr2 and MeMgCl.7 In a more recent report, Sarvanan and coworkers have reported a large scale procedure for the
addition of 4ꢀmethoxy phenyl acetonitrile to symmetrical ketone, cyclohexanone, in presence of a high amount of base.8
However, there is no report till date about diasterioselective phenyl acetonitrile addition to ketones due to poor steric control of
the substrate. Difficulties associated mainly with the catalytic generation of active species, eg. αꢀcyano carbanions on metal ions,
hampers the use of alkylnitriles as proꢀnucleophile in selective CꢀC bond forming reaction. We hypothesize that use of soft bases
such as metal free organocatalysts for the generation of αꢀcyano carbanions can help in dramatically shifting the equilibrium
towards alkoxides as it might stabilize the intermediate generated via hydrogen bonding (Fig 1).
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Figure 1. Strategies for cyanomethylation of ketones and natural products with 3ꢀhydroxyꢀ2ꢀoxindole core.
Organocatalyst with high reactivity, have gathered attention being an environmentally green and economically viable alternative
to metal catalyst. Organocatalyst such as tertiary amine DBU, have been shown to produce corresponding adducts in high yield
for aldol reaction between reactive ketone derived enolates as donor and unsymmetrical ketones as acceptors.9 The catalyst
worked equally well for the homoꢀaldol reaction of 2ꢀoxocarboxylic esters.10 Recently, aryl and trifluromethyl substituted tertiary
alcohols were synthesized by the aldol reaction of ketones as donor and aryl trifluoromethyl ketone as acceptor in presence of
DBU as catalyst.11 Recently, our group as well as others have demonstrated the cyanomethylation by using TMSAN (trimethyl
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The Journal of Organic Chemistry
silyl acetonitrile) as cyanomethylating agents.12 Here we report, DBU mediated direct alkylnitrile addition to isatins, a facile
access to 3ꢀhydroxyꢀ3ꢀcyanomethyl oxindoles.
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Table 1. Optimization of Cyanomethylation reaction of isatins 1 with Benzylcyanide 2aa,d
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aUnless noted all reactions were performed under argon with 0.1 mmol of 1 and 0.12 mmol of 2a in 1.0 mL of solvent with
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0.12 mmol of base. Isolated combined yield based on 1. Ratios determined by H NMR analysis of crude mixtures.
dReactions (9ꢀ16) performed under argon with 0.1 mmol of 1 and 0.12 mmol of 2a in 1.0 mL of solvent and 0.18 mmol of
base.
We initiated the optimization of the reaction conditions on Nꢀprotected isatin core due to its importance in natural and
bioactive molecules.13 We first explored the cyanomethylation reaction of 1 equivalent of Nꢀmethyl isatin (entry 1, table 1)
with 1.2 equivalent of phenyl acetonitrile and 1.2 equivalent of DBU as a base at room temperature in dichloromethane as
a solvent. The desired βꢀhydroxy nitrile 3a was obtained in moderate yield of 54% with lower diastereoselectivity of
72:28. Encouraged by the initial yield and selectivity, the cyanomethylation reactions of different Nꢀsubstituted isatins
were screened (table 1, entry 2ꢀ4). It was observed that the reaction on Nꢀbenzyl isatin, yielded the corresponding cyanoꢀ
methylated product (57%, entry 2, table 1) in moderate yield and diastereoselectivity, whereas NꢀPMB isatin pro duced
comparatively lower yield and slightly improved selectivity (32%, dr 79:21 entry 3, table 1). The use of bulkier Nꢀ
protecting group such as Nꢀtritylisatin resulted in an enhanced reactivity as well as improved stereocontrol (65%, dr 82:18,
entry 4, table 1). To further improve the reactivity and selectivity, we screened various organic bases such as DMAP,
DABCO, CH3ONa and PhONa for the reaction of Nꢀtritylisatin with benzylcyanide in dichloromethane (entry 5ꢀ8, table
1). Surprisingly, none of the base showed better reactivity than DBU. We then decided to explore the impact of the base
amount on the selectivity and reactivity. Increasing the amount of DBU to 1.8 equivalent at room temperature resulted in
good yield (75%) and increased selectivity (83:17) of desired product (entry 9, table 1). We then screened various solvents
such as THF, Et2O, MTBE and toluene for the cyanomethylation reaction of Nꢀtrityl isatin at room temperature (table 1,
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entries 10ꢀ13). Surprisingly, Et2O turned out to be very effective (2h 15 min) with quantitative yield (>98%, entry 11) and
excellent diastereo selectivity (97:3). The other etherial solvent, MTBE, also provided quantitative yield with good
diastereoselectivity (98%, dr 93:7, entry 12, table 2), while solvents such as THF and Toluene showed no effect on
reactivity. After optimizing Et2O as the most efficient solvent, we reꢀexamined the reactivity of NꢀMe, Bn, PMB protected
isatins in Et2O. No significant improvement in yield and selectivity for various Nꢀprotected isatins was observed (table 1,
entry 14ꢀ16).
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Table 2. Cyanomethylation reaction of various isatins 1 and benzylcyanide 2a a,b,c
aUnless noted reactions were performed under argon with 0.1 mmol of 1d-1o and 0.12 mmol of 2a in 1.0 mL of solvent
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with 0.18 mmol of base. Isolated yield of 3d-3o. Ratios determined by H NMR analysis of crude mixtures. Xꢀray
crystal structure of adduct 3d (see SI).
The optimized conditions were then used to explore the generality of the reaction with various substituents on the aromatic
ring of Nꢀtritylisatins. All reactions reached completion at rt in about 2.25 h. Generally good yield and excellent
selectivities were obtained in presence of almost all kinds of substituents including electronꢀdonating groups (3e), halogen
substituents at various positions (3f, 3g , 3k and 3o) and other electronꢀwithdrawing groups (3h-3i), (Table 2) on the
aromatic ring of oxindole 1. In almost all cases we observed quantitative yield and excellent streocontrol. We achieved
good yield and excellent diastereoselectivity (99:1) with 5ꢀphenyl and 4ꢀhalo substituted isatin (table 2, entry 3j, 3k and
3l), whereas the 6ꢀhalo and 7ꢀhalo substitution resulted in very high yield and excellent diastereocontrol (entry 3m-3o).
The relative configuration of the Aldol adduct was determined by Xꢀray crystal structure analysis of 3d and the relative
configuration of the major stereoisomer was established to be anti.
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The Journal of Organic Chemistry
We also investigated the reaction with various substituted benzylcyanides (2b-2g, Table 3). Substitution at 4ꢀ position of
benzyl cyanide afforded very high selectivity in all the cases. Selectivity for reactions of 4ꢀchloro, 2ꢀnaphthyl acetonitrile
and 3, 5ꢀbis trifluoromethyl benzyl acetonitriles was very high with dr up to 99:1 (4c, 4e and 4f). Since,
trifluoromethylated compounds are commonly used in drug discovery; we tried an alternative access to these compounds
by addition of 4ꢀtrifluorometyl benzyl cyanide to 5ꢀF, 5ꢀBr, 5ꢀPh substituted tritylisatins. For
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Table 3. Cyanomethylation reaction of various isatins with substituted benzylcyanides 2 a,b,c
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aUnless noted reactions were performed under argon with 0.1 mmol of 1 and 0.12mmol of 2 in 1.0 mL of solvent with 0.18
mmol of base. bIsolated combined yield 4a-4i. cRatios determined by 1H NMR analysis of crude mixtures.
Scheme 1. Scaleꢀup and Transformation of cyanomethyl adduct 3d.
all three, good yield with high diastereoselectivity (4g-4i, table 3) was observed. Further, to demonstrate the synthetic
utility of the cyanomethyl adduct 3d, a simple 1 mmol scaleꢀup of the reaction was performed, gave corresponding adduct
3d in excellent yield with very high diastereoselectivity under standard reaction condition. The 3d was also transformed to
an advance intermediate of (±) CPC 1 analogue (scheme 1).14
In order to understand the mechanism and formation of the syn (VI) and the anti (IX) products, full quantum chemical
calculations were done with density functional theory (DFT) at the PBE/TZVP level of theory. [for computational method
details please see Supporting Information (SI)]. The reaction can proceed via two pathways: the syn pathway and the anti
pathway (Figure 2) In the observed highly selective base catalyzed cyanomethylation the reactant complex (RC) consisting
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of DBU, benzyl cyanide and Nꢀtritylisatins goes through the transition state II, where DBU abstracts a proton from benzyl
cyanide to make intermediate III, which is 8.8 kcal/mol (ꢁG) higher in energy than the RC.
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Figure 2. Density functional theory calculations comparing the free energy profiles: red (syn product pathway) and blue (anti
product pathway).
The activation energy barrier corresponding to the first transition state is found to be 10.6 kcal/mol. Subsequent to this
step, intermediate III can reorient itself and form intermediates VII and IV, which are more stable by 9.0 kcal/mol and 9.6
kcal/mol respectively than intermediate III. Intermediate IV would lead to the syn pathway, while VII leads to the anti
pathway. As there are two possibilities of nucleophilic attack by the carbanion of benzyl cyanide to the carbonyl carbon of
Nꢀtritylisatin, followed by deprotonation from DBUH+, leading to the formation of the syn (VI) and the anti (IX)
cyanomethylated products. The syn product pathway (shown in red, Figure 2) is seen to have a barrier of 4.3 kcal/mol,
passing through the transition state V en route to forming the final syn product VI, which was seen to be more stable in
comparison to RC, by 7.3 kcal/mol. However, the more facile pathway is the one shown in blue, having a barrier of only
0.8 kcal/mol, corresponding to the formation of the anti product (see Figure. 2). Hence, the calculations indicate that the
major diastereoselective product formed that would be the anti product, which corroborates the experimental results. Thus,
the reaction pathway and the eventual outcome is governed by the kinetics of the two reactions: the major product being
the one with the lower barrier, i.e. the anti product here. This product is preferred because of the less sterically hindered
transition state in the anti case in comparison to the syn (Figure S3 in the Supporting Information file).
In conclusion, we have demonstrated a direct DBU mediated alkyl nitrile addition to various isatins, which can be
further exploited to directly access quaternary 3ꢀhydroxyꢀ3ꢀcyanomethyl oxindoles. The versatility of the cyanomethylation
reaction is also demonstrated by converting the direct cyanomethyl adduct to an advance intermediate of a natural product
analogue in simple steps.
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The Journal of Organic Chemistry
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EXPERIMENTAL SECTION
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General Information. Bruker AVꢀ300 instrument (300 MHz and 75 MHz, respectively) was used to record H and 13C NMR
spectra in deuterated solvents with residual protonated solvent signals as internal reference.1H NMR’s data is reported as follows:
chemical shift (δ, ppm), multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), integration, coupling constant (Hz).
13C NMR’s data is recorded in terms of chemical shift (δ, ppm). FTꢀIR Spectrometer was used to record infrared spectra and are
reported in frequency of absorption. MSꢀTOF mass spectrometer and ESI mass spectrometer were used to record low resolution
and high resolution mass spectra. Column chromatographic separations were carried out on silica gel (100–200 mesh).
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1. General reaction procedure for Cyanomethylation Reaction.
To a solution of Nꢀprotected isatin 1 (0.1 mmol) in solvent (specified below) (1 ml) was added Phenyl acetonitrile (0.12 mmol) at
room temperature under N2. The resulting mixture was stirred for 1 min at the same temperature and then DBU (0.18 mmol) was
added drop wise. The resulting mixture was stirred for 2.25h at room temperature. The progress of the reaction was monitored by
thin layer chromatography. Once the reaction completed it was quenched by addition of 1M HCl (1.0 mL) solution. The resulting
mixture was extracted with ethyl acetate (5 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and
concentrated under reduced pressure to provide an oily residue that was purified by flash chromatography on silica gel (eluent:
EtOAc/PE = 1/3, v/v). The ratio of diastereomers was determined by 1H NMR.
2-(3-hydroxy-2-oxo-1-tritylindolin-3-yl)-2-phenylacetonitrile (3d): DBU mediated (0.18 mmol) reaction of Nꢀtrityl isatin 1d
(0.1 mmol) and Phenyl acetonitrile (0.12 mmol) in Et2O (1 ml) was run at room temperature for 2.25h under N2. The reaction
mixture was quenched according to the general procedure. The anti/syn ratio (97:3) was determined by 1H NMR analysis of the
crude product (δ major: 4.29 ppm, δ minor: 4.38 ppm). The crude mixture was purified by flash chromatography (silica gel, ethyl
acetate/petroleum ether = 5/95 to 30/70) to give the inseparable mixture of diastereomers as white solid (50 mg, 98% yield,
anti/syn = 97:3), MP 198ꢀ199 oC. Rf = 0.4 (ethyl acetate/petroleum ether = 1/2); 1H-NMR (300 MHz, CDCl3) δ 4.29 (s, 1H), 5.28
(d, J = 8.1 Hz, 1H), 6.80ꢀ6.86 (m, 7H), 6.97ꢀ7.05 (m, 2H), 7.07ꢀ7.09 (m, 9H), 7.18 (s, 1H), 7.24ꢀ7.29 (m, 2H), 7.33ꢀ7.38 (m, 1H),
7.86 (d, J = 7.16 Hz, 1H); 13C-NMR (75 MHz, CDCl3) δ 47.1, 75.1, 76.3, 116.8, 118.4, 123.1, 124.3, 125.5, 127.1, 127.5, 127.6,
128.7, 129.3, 129.4, 129.6, 140.7, 143.6, 176.6; FTIR (KBr) cmꢀ1, 3379, 2361, 1736, 1489, 1124, 749; HRMS ESI: [M+Na]+,
Calcd for C35H26O2N2Na 529.1886 ; found 529.1871.
2-(3-hydroxy-5-methyl-2-oxo-1-tritylindolin-3-yl)-2-phenylacetonitrile (3e): DBU mediated (0.18 mmol) reaction of Nꢀtrityl
isatin 1e (0.1 mmol) and Phenyl acetonitrile (0.12 mmol) in Et2O (1 ml) was run at room temperature for 2.25h under N2. The
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reaction mixture was quenched according to the general procedure. The anti/syn ratio (87:13) was determined by H NMR
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analysis of the crude product (δ major: 4.36 ppm, δ minor: 4.45 ppm). The crude mixture was purified by flash chromatography
(silica gel, ethyl acetate/petroleum ether = 5/95 to 30/70) to give the inseparable mixture of diastereomers as white solid (50.3
mg, 83% yield, anti/syn = 87:13), MP 193ꢀ194 oC. Rf = 0.4 (ethyl acetate/petroleum ether = 1/2); 1H-NMR (300 MHz, CDCl3) δ
2.32 (s, 3H), 4.36 (s, 1H), 5.95 (d, J = 8.29 Hz, 1H), 6.70 (d, J = 8.29 Hz, 1H), 6.94 (bs, 5H), 7.17ꢀ7.22 (m, 11H), 7.36ꢀ7.42 (m,
4H), 7.75 (s, 1H); 13C-NMR (75 MHz, CDCl3) δ 20.8, 47.0, 75.0, 76.4, 116.5, 118.5, 124.8, 125.5, 127.0, 127.4, 127.6, 128.7,
129.3, 129.4, 129.6, 129.8, 132.9, 140.8, 141.2, 176.6; FTIR (KBr) cmꢀ1, 3419, 2923, 2856, 1703, 1488, 1260, 1093, 745;
HRMS ESI: [M+Na]+, Calcd for C36H28O2N2Na 543.2042; found 543.2027.
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2-(5-chloro-3-hydroxy-2-oxo-1-tritylindolin-3-yl)-2-phenylacetonitrile (3f): DBU mediated (0.18 mmol) reaction of Nꢀtrityl
isatin 1f (0.1 mmol) and Phenyl acetonitrile (0.12 mmol) in Et2O (1 ml) was run at room temperature for 2.25h under N2. The
1
reaction mixture was quenched according to the general procedure. The anti/syn ratio (88:12) was determined by H NMR
analysis of the crude product (δ major: 4.37 ppm, δ minor: 4.46 ppm). The crude mixture was purified by flash chromatography
(silica gel, ethyl acetate/petroleum ether = 5/95 to 30/70) to give the inseparable mixture of diastereomers as white solid (48mg,
89% yield, anti/syn = 88:12), MP 182ꢀ183 oC. Rf = 0.4 (ethyl acetate/petroleum ether = 1/2); 1H-NMR (300 MHz, CDCl3) δ 4.37
(s, 1H), 6.00 (d, J = 8.67 Hz, 1H), 6.90ꢀ6.92 (m, 6H), 7.17ꢀ7.23 (m, 12H), 7.39ꢀ7.47 (m, 3H), 7.92 (s, 1H); 13C-NMR (75 MHz,
CDCl3) δ 47.0, 75.4, 76.3, 117.8, 118.0, 124.7, 127.3, 127.6, 127.8, 128.6, 128.9, 129.3, 129.4, 129.6, 129.8, 140.4, 140.8, 142.2,
176.3; FTIR (KBr) cmꢀ1, 3400, 2924, 2854, 1720, 1460, 1097, 1606, 804; HRMS ESI: [M+Na]+, Calcd for C35H25O2N2Cl1Na
563.1496; found 563.1468.
.
2-(5-bromo-3-hydroxy-2-oxo-1-tritylindolin-3-yl)-2-phenylacetonitrile (3g): DBU mediated (0.18 mmol) reaction of Nꢀtrityl
isatin 1g (0.1 mmol) and Phenyl acetonitrile (0.12 mmol) in Et2O (1 ml) was run at room temperature for 2.25h under N2. The
reaction mixture was quenched according to the general procedure. The anti/syn ratio (93:7) was determined by 1H NMR analysis
of the crude product (δ major: 4.45 ppm, δ minor: 4.52 ppm). The crude mixture was purified by flash chromatography (silica
gel, ethyl acetate/petroleum ether = 5/95 to 30/70) to give the inseparable mixture of diastereomers as white solid (51 mg, 87%
o
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yield, anti/syn = 93:7), MP 196ꢀ197 C. Rf = 0.4 (ethyl acetate/petroleum ether = 1/2); H-NMR (300 MHz, CDCl3) δ 3.40 (s,
1H), 4.45 (s,1H), 6.03 (d, J = 8.67 Hz, 1H), 6.98ꢀ7.01 (m, 6H), 7.10 (dd, J1 = 1.88 Hz, J2 = 8.67 Hz, 1H), 7.22ꢀ7.25 (m, 5H),
7.32ꢀ7.35 (m, 5H), 7.45ꢀ7.58 (m, 4H), 8.13 (d, J = 1.70 Hz, 1H); 13C-NMR (75 MHz, CDCl3) δ; 47.0, 75.4, 76.1, 116.3, 118.0,
118.2, 127.3, 127.4, 127.5, 127.6, 128.9, 129.2, 129.4, 129.6, 129.6, 132.3, 140.4, 142.8, 176.1; FTIR (KBr) cmꢀ1, 3422, 2895,
2382, 1639,1057, 898; HRMS ESI: [M+Na]+, Calcd for C35H25O2N2Br1Na 607.0991; found 607.0977.
2-(3-hydroxy-5-nitro-2-oxo-1-tritylindolin-3-yl)-2-phenylacetonitrile (3h): DBU mediated (0.18 mmol) reaction of Nꢀtrityl
isatin 1h (0.1 mmol) and Phenyl acetonitrile (0.12 mmol) in Et2O (1 ml) was run at room temperature for 2.25h under N2. The
reaction mixture was quenched according to the general procedure. The anti/syn ratio (93:7) was determined by 1H NMR analysis
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of the crude product (δ major: 4.35ppm, δ minor: 4.43 ppm). The crude mixture was purified by flash chromatography (silica gel,
ethyl acetate/petroleum ether = 5/95 to 30/70) to give the inseparable mixture of diastereomers as white solid (27 mg, 49% yield,
anti/syn = 93:7), 175ꢀ176 oC. Rf = 0.4 (ethyl acetate/petroleum ether = 1/2); 1H-NMR (300 MHz, CDCl3) δ 3.63 (bs, 1H), 4.35 (s,
1H), 6.14 (d, J = 9.04 Hz, 1H), 6.84ꢀ6.86 (m, 6H), 7.05ꢀ7.09 (m, 2H), 7.11ꢀ7.13 (m, 6H), 7.17ꢀ7.19 (m, 3H), 7.29ꢀ7.33(m, 2H),
7.38ꢀ7.40 (m, 1H), 7.75 (dd, J1 = 2.07 Hz, J2 = 9.04 Hz, 1H), 8.67 (d, J = 2.07 Hz, 1H); 13C-NMR (75 MHz, CDCl3) δ 47.0, 75.8,
76.0, 116.6, 117.5, 120.0, 125.5, 126.7, 127.6, 127.8, 128.7, 129.1, 129.3, 129.5, 129.9, 139.9, 143.5, 149.4, 176.7; FTIR (KBr)
cmꢀ1, 3363, 2923, 2358, 1760, 1721, 1486, 1195, 746; HRMS ESI: [M+Na]+, Calcd for C35H25O4N3Na 574.1737; found
574.1720.
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2-(3-hydroxy-2-oxo-5-(trifluoromethoxy)-1-tritylindolin-3-yl)-2-phenylacetonitrile (3i): DBU mediated (0.18 mmol) reaction
of Nꢀtrityl isatin 1i (0.1 mmol) and Phenyl acetonitrile (0.12 mmol) in Et2O (1 ml) was run at room temperature for 2.25h under
N2. The reaction mixture was quenched according to the general procedure. The anti/syn ratio (97:3) was determined by 1H NMR
analysis of the crude product (δ major: 4.38 ppm, δ minor: 4.43 ppm). The crude mixture was purified by flash chromatography
(silica gel, ethyl acetate/petroleum ether = 5/95 to 30/70) to give the inseparable mixture of diastereomers as white solid (53.3
o
1
mg, 90% yield, anti/syn = 97:3), MP 187ꢀ188 C. Rf = 0.4 (ethyl acetate/petroleum ether = 1/2); H-NMR (300 MHz, CDCl3) δ
3.32 (bs, 1H), 4.38 (s, 1H), 6.07 (d, J = 8.85 Hz, 1H), 6.77 (d, J = 7.54 Hz, 1H), 6.91ꢀ6.93 (m, 6H), 7.11ꢀ7.23 (m, 11H), 7.35ꢀ
7.40 (m, 2H), 7.44ꢀ7.49 (m, 1H), 7.83 (s, 1H); 13C-NMR (75 MHz, CDCl3) δ 47.1, 75.5, 76.1, 117.5, 117.9, 122.0, 127.1, 127.3,
127.7, 127.8, 128.9, 129.1, 129.2, 129.4, 129.5, 129.6, 140.3, 142.2, 144.8 (q, J1 = 2.19 Hz, J2 = 3.84 Hz), 176.5; FTIR (KBr)
cmꢀ1, 3837, 3406, 2724, 2311, 1717, 1219, 896; HRMS ESI: [M+Na]+, Calcd for C36H25O3N2F3Na 613.1709; found 613.1741.
2-(3-hydroxy-2-oxo-5-phenyl-1-tritylindolin-3-yl)-2-phenylacetonitrile (3j): DBU mediated (0.18 mmol) reaction of Nꢀtrityl
isatin 1j (0.1 mmol) and Phenyl acetonitrile (0.12 mmol) in Et2O (1 ml) was run at room temperature for 2.25h under N2. The
reaction mixture was quenched according to the general procedure. The anti/syn ratio (99:1) was determined by 1H NMR analysis
of the crude product (δ major: 4.35 ppm, δ minor: 4.42 ppm). The crude mixture was purified by flash chromatography (silica
gel, ethyl acetate/petroleum ether = 5/95 to 30/70) to give the inseparable mixture of diastereomers as white solid (57.1 mg, 98%
yield, anti/syn = 99:1), 202ꢀ203 oC. Rf = 0.4 (ethyl acetate/petroleum ether = 1/2); 1H-NMR (300 MHz, CDCl3) δ 3.55 (bs, 1H),
4.35 (s, 1H), 6.06 (d, J = 7.72 Hz, 1H), 6.87 (bs, 6H), 7.09ꢀ7.16 (m, 12H), 7.28ꢀ7.34 (m, 6H), 7.50 (m, 2H), 8.14 (s, 1H); 13C-
NMR (75 MHz, CDCl3) δ 47.0, 75.2, 77.2, 117.0, 118.4, 122.7, 126.1, 126.1, 126.6, 127.1, 127.3, 127.5, 127.8, 128.8, 129.4,
129.4, 129.5, 129.6, 136.1, 139.5, 140.7, 142.8, 176.7; FTIR (KBr) cmꢀ1, 3408, 2954, 2590, 1727, 1053, 768; HRMS ESI:
[M+Na]+, Calcd for C41H30O2N2Na 605.2199; found 605.2172.
2-(4-chloro-3-hydroxy-2-oxo-1-tritylindolin-3-yl)-2-phenylacetonitrile (3k): DBU mediated (0.18 mmol) reaction of Nꢀtrityl
isatin 1k (0.1 mmol) and Phenyl acetonitrile (0.12 mmol) in Et2O (1 ml) was run at room temperature for 2.25h under N2. The
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reaction mixture was quenched according to the general procedure. The anti/syn ratio (99:1) was determined by 1H NMR analysis
of the crude product ((δ major: 4.27 ppm, δ minor: 4.34 ppm). The crude mixture was purified by flash chromatography (silica
gel, ethyl acetate/petroleum ether = 5/95 to 30/70) to give the inseparable mixture of diastereomers as white solid (45 mg, 83%
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yield, anti/syn = 99:1), MP 194ꢀ195 C. Rf = 0.4 (ethyl acetate/petroleum ether = 1/2); H-NMR (300 MHz, CDCl3) δ 3.21 (bs,
1H), 4.27 (s, 1H), 5.97 (s, 1H), 6.83 (bs, 6H), 6.97ꢀ7.04 (m, 3H), 7.11ꢀ7.18 (m, 9H), 7.30ꢀ7.38 (m, 3H), 7.76 (d, J = 7.72 Hz, 1H)
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13C-NMR (75 MHz, CDCl3) δ 47.05, 75.5, 76.0, 117.2, 118.2, 123.3, 123.9, 125.2, 127.3, 127.6, 127.8, 128.9, 129.3, 129.5,
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129.6, 135.2, 140.3, 144.9, 176.5; FTIR (KBr) cmꢀ1, 3373, 2924, 2360, 1743, 1453, 1089, 809; HRMS ESI: [M+Na]+, Calcd for
C35H25O2N2 Cl1Na 563.1496; found 563.1494.
.
2-(4-bromo-3-hydroxy-2-oxo-1-tritylindolin-3-yl)-2-phenylacetonitrile (3l):
DBU mediated (0.18 mmol) reaction of Nꢀtrityl isatin 1l (0.1 mmol) and Phenyl acetonitrile (0.12 mmol) in Et2O (1 ml) was run
at room temperature for 2.25h under N2. The reaction mixture was quenched according to the general procedure. The anti/syn
1
ratio (99:1) was determined by H NMR analysis of the crude product (δ major: 5.32 ppm, δ minor: 5.55 ppm). The crude
mixture was purified by flash chromatography (silica gel, ethyl acetate/petroleum ether = 5/95 to 30/70) to give the inseparable
mixture of diastereomers as white solid (55.1 mg, 94% yield, anti/syn = 99:1), MP 192ꢀ193 oC. Rf = 0.4 (ethyl acetate/petroleum
ether = 1/2); 1H-NMR (300 MHz, CDCl3) δ 3.54 (bs, 1H), 5.32 (s, 1H), 5.92 (d, J = 8.10 Hz, 1H), 6.63 (t, J = 8.10 Hz, 1H), 6.80ꢀ
6.82 (m, 6H), 7.04ꢀ7.17 (m, 12H), 7.29 (t, J = 7.16 Hz, 2H), 7.36 (d, J = 7.16 Hz, 1H); 13C-NMR (75 MHz, CDCl3) δ 43.4, 75.4,
77.2, 115.9, 116.6, 118.7, 124.0, 127.0, 127.2, 127.6, 128.8, 129.1, 129.3, 130.2, 140.5, 146.0, 175.2; FTIR (KBr) cmꢀ1, 3372,
3032, 2205, 1632, 997; HRMS ESI: [M+Na]+, Calcd for C35H25O2N2Br1Na 607.0992 ; found 607.0981.
2-(6-chloro-3-hydroxy-2-oxo-1-tritylindolin-3-yl)-2-phenylacetonitrile (3m): DBU mediated (0.18 mmol) reaction of Nꢀtrityl
isatin 1m (0.1 mmol) and Phenyl acetonitrile (0.12 mmol) in Et2O (1 ml) was run at room temperature for 2.25h under N2. The
reaction mixture was quenched according to the general procedure. The anti/syn ratio (97:3) was determined by 1H NMR analysis
of the crude product (δ major: 4.37 ppm, δ minor: 4.43 ppm). The crude mixture was purified by flash chromatography (silica
gel, ethyl acetate/petroleum ether = 5/95 to 30/70) to give the inseparable mixture of diastereomers as white solid (50.5 mg, 93%
o
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yield, anti/syn = 97:3), MP 202ꢀ203 C. Rf = 0.4 (ethyl acetate/petroleum ether = 1/2); H-NMR (300 MHz, CDCl3) δ 4.37 (s,
1H), 6.07 (s, 1H), 6.91ꢀ6.93 (m, 6H), 7.06ꢀ7.15 (m,3H), 7.18ꢀ7.24 (m, 9H), 7.36ꢀ7.41 (m, 2H), 7.45ꢀ7.50 (m, 1H), 7.85 (d, J =
8.10 Hz, 1H); 13C-NMR (75 MHz, CDCl3) δ 47.0, 75.5, 76.0, 117.2, 118.2, 123.3, 124.0, 125.2, 127.3, 127.6, 128.9, 129.3,
129.3, 129.5, 129.6, 135.2, 140.3, 144.9, 176.5; FTIR (KBr) cmꢀ1, 3353, 2923, 2070, 1738, 1184, 828; HRMS ESI: [M+Na]+,
Calcd for C35H25O2N2Cl1Na 563.1496; found 563.1486.
2-(6-bromo-3-hydroxy-2-oxo-1-tritylindolin-3-yl)-2-phenylacetonitrile (3n): DBU mediated (0.18 mmol) reaction of Nꢀtrityl
isatin 1n (0.1 mmol) and Phenyl acetonitrile (0.12 mmol) in Et2O (1 ml) was run at room temperature for 2.25h under N2. The
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reaction mixture was quenched according to the general procedure. The anti/syn ratio (93:7) was determined by 1H NMR analysis
of the crude product (δ major: 4.36 ppm, δ minor: 4.42 ppm). The crude mixture was purified by flash chromatography (silica
gel, ethyl acetate/petroleum ether = 5/95 to 30/70) to give the inseparable mixture of diastereomers as white solid (55 mg, 94%
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yield, anti/syn = 93:7), MP 206ꢀ207 C. Rf = 0.4 (ethyl acetate/petroleum ether = 1/2); H-NMR (300 MHz, CDCl3) δ 4.36 (s,
1H), 6.21 (s, 1H), 6.90ꢀ6.92 (m, 6H), 7.10ꢀ7.13 (m, 2H), 7.18ꢀ7.25 (m, 10H), 7.37ꢀ7.42 (m, 2H), 7.45ꢀ7.47 (m, 1H), 7.79 (d, J =
7.91 Hz, 1H); 13C-NMR (75 MHz, CDCl3) δ 46.9, 75.5, 76.0, 118.1, 120.0, 123.2, 124.5, 125.5, 126.2, 127.3, 127.6, 128.9,
129.2, 129.3, 129.5, 129.6, 140.3, 144.9, 176.4; FTIR (KBr) cmꢀ1, 3367, 2902, 2330, 1926, 1601, 1051, 802; HRMS ESI:
[M+Na]+, Calcd for C35H25O2N2Br1Na 607.0991; found 607.0966.
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2-(7-fluoro-3-hydroxy-2-oxo-1-tritylindolin-3-yl)-2-phenylacetonitrile (3o):
DBU mediated (0.18 mmol) reaction of Nꢀtrityl isatin 1o (0.1 mmol) and Phenyl acetonitrile (0.12 mmol) in Et2O (1 ml) was run
at room temperature for 2.25h under N2. The reaction mixture was quenched according to the general procedure. The anti/syn
1
ratio (94:6) was determined by H NMR analysis of the crude product (δ major: 4.37 ppm, δ minor: 4.47 ppm). The crude
mixture was purified by flash chromatography (silica gel, ethyl acetate/petroleum ether = 5/95 to 30/70) to give the inseparable
o
mixture of diastereomers as white solid (48 mg, 92% yield, anti/syn = 94:6), MP 182ꢀ183 C. Rf = 0.4 (ethyl acetate/petroleum
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ether = 1/2); H-NMR (300 MHz, CDCl3) δ 3.27 (bs, 1H), 4.37 (s, 1H), 6.71ꢀ6.77 (m, 1H), 6.88ꢀ6.91 (m, 6H), 7.09ꢀ7.21 (m,
12H), 7.34ꢀ7.39 (t, J = 7.35 Hz, 2H), 7.45ꢀ7.49 (m, 1H), 7.87 (d, J = 7.35 Hz, 1H); 13C-NMR (75 MHz, CDCl3) δ 47.3, 76.1,
77.2, 118.2, 120.0 (d, J = 23.60 Hz), 120.8 (d, J = 3.29 Hz), 125.3 (d, J = 7.14 Hz), 127.0, 127.3, 128.3, 128.9, 129.0, 129.1,
129.5, 129.7, 130.7 (d, J = 8.23 Hz), 142.3 (d, J = 2.20 Hz), 144.9 (d, J = 251.93 Hz), 176.2; FTIR (KBr) cmꢀ1, 3690, 3501,
3088, 2315, 1740, 1448, 968; HRMS ESI: [M+Na]+, Calcd for C35H25O2N2F1Na 547.1792; found 547.1799.
2-(3-hydroxy-2-oxo-1-tritylindolin-3-yl)-2-p-tolylacetonitrile (4a): DBU mediated (0.18 mmol) reaction of Nꢀtrityl isatin 1d
(0.1 mmol) and Phenyl acetonitrile 2b (0.12 mmol) in Et2O (1 ml) was run at room temperature for 2.25h under N2. The reaction
mixture was quenched according to the general procedure. The anti/syn ratio (88:12) was determined by 1H NMR analysis of the
crude product (δ major: 4.36 ppm, δ minor: 4.44 ppm). The crude mixture was purified by flash chromatography (silica gel, ethyl
acetate/petroleum ether = 5/95 to 30/70) to give the inseparable mixture of diastereomers as white solid (50.2 mg, 97% yield,
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anti/syn = 88:12), MP 205ꢀ206 C. Rf = 0.4 (ethyl acetate/petroleum ether = 1/2); H-NMR (300 MHz, CDCl3) δ 2.40 (s, 3H),
3.38 (bs, 1H), 4.36 (s, 1H), 6.08 (d, J = 8.10 Hz, 1H), 6.89ꢀ7.01 (m, 8H), 7.06ꢀ7.08 (m, 1H), 7.16ꢀ7.27 (m, 12H), 7.94 (d, J = 7.16
Hz, 1H); 13C-NMR (75 MHz, CDCl3) δ 21.3, 46.7, 75.2, 76.4, 116.8, 118.5, 123.1, 124.3, 125.6, 126.6, 127.1, 127.4, 127.6,
129.2, 129.4, 129.5, 139.4, 140.8, 143.7, 176.7; FTIR (KBr) cmꢀ1, 3575, 2813, 2329, 1716, 1330, 1060, 811; HRMS ESI:
[M+Na]+, Calcd for C36H28O2N2Na 543.2042; found 543.2047.
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2-(3-hydroxy-2-oxo-1-tritylindolin-3-yl)-2-(4-methoxyphenyl)acetonitrile (4b):
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DBU mediated (0.18 mmol) reaction of Nꢀtrityl isatin 1d (0.1 mmol) and Phenyl acetonitrile 2c (0.12 mmol) in Et2O (1 ml) was
run at room temperature for 2.25h under N2. The reaction mixture was quenched according to the general procedure. The anti/syn
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ratio (93:7) was determined by H NMR analysis of the crude product (δ major: 4.32 ppm, δ minor: 4.42 ppm). The crude
mixture was purified by flash chromatography (silica gel, ethyl acetate/petroleum ether = 5/95 to 30/70) to give the inseparable
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mixture of diastereomers as white solid (35.5 mg, 66% yield, anti/syn = 93:7), MP187ꢀ188 C. Rf = 0.4 (ethyl acetate/petroleum
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ether = 1/2); H-NMR (300 MHz, CDCl3) δ 3.80 (s, 3H), 4.32 (s, 1H), 6.07 (d, J = 8.10 Hz, 1H), 6.82ꢀ6.85 (m, 2H), 6.89ꢀ7.02
(m, 9H), 7.06ꢀ7.11 (m, 1H), 7.16ꢀ7.23 (m, 9H), 7.92 (d, J = 7.16 Hz, 1H); 13C-NMR (75 MHz, CDCl3) δ 46.4, 55.3, 75.1, 76.4,
114.1, 116.8, 118.6, 121.4, 123.1, 124.3, 125.5, 127.1, 127.4, 129.3, 129.5, 130.8, 140.8, 143.8, 160.5, 176.7; FTIR (KBr) cmꢀ1,
3406, 2925, 2311, 1717, 1261, 1023, 820; HRMS ESI: [M+Na]+, Calcd for C36H28O3N2Na 559.1992; found 559.1977.
2-(4-chlorophenyl)-2-(3-hydroxy-2-oxo-1-tritylindolin-3-yl)acetonitrile (4c):
DBU mediated (0.18 mmol) reaction of Nꢀtrityl isatin 1d (0.1 mmol) and Phenyl acetonitrile 2d (0.12 mmol) in Et2O (1 ml) was
run at room temperature for 2.25h under N2. The reaction mixture was quenched according to the general procedure. The anti/syn
1
ratio (99:1) was determined by H NMR analysis of the crude product (δ major: 4.78 ppm, δ minor: 5.02 ppm). The crude
mixture was purified by flash chromatography (silica gel, ethyl acetate/petroleum ether = 5/95 to 30/70) to give the inseparable
o
mixture of diastereomers as white solid (51 mg, 96% yield, anti/syn = 99:1), MP 201ꢀ202 C. Rf = 0.4 (ethyl acetate/petroleum
ether = 1/2); 1H-NMR (300 MHz, dmsoꢀd6) δ 4.78 (s, 1H), 6.02 (d, J = 7.91 Hz, 1H), 6.91ꢀ6.93 (m, 5H), 7.00ꢀ7.02 (m, 2H), 7.06ꢀ
7.14 (m, 2H), 7.18ꢀ7.20 (m, 10H), 7.42ꢀ7.52 (m, 2H), 7.69 (d, J = 7.16 Hz, 1H); 13C-NMR (75 MHz, dmsoꢀd6) δ 44.6, 74.0, 75.4,
79.1, 115.9, 119.1, 122.3, 123.9, 126.7, 126.9, 127.4, 128.7, 128.9, 129.1, 131.2, 134.3, 141.0, 142.9, 175.6; FTIR (KBr) cmꢀ1,
3353, 2923, 2667, 2070, 1738, 1609, 1490, 1035, 828; HRMS ESI: [M+Na]+, Calcd for C35H25O2N2Cl1Na 563.1496; found
563.1498.
2-(3-hydroxy-2-oxo-1-tritylindolin-3-yl)-2-(4-(trifluoromethyl)phenyl)acetonitrile (4d):
DBU mediated (0.18 mmol) reaction of Nꢀtrityl isatin 1d (0.1 mmol) and Phenyl acetonitrile 2e (0.12 mmol) in Et2O (1 ml) was
run at room temperature for 2.25h under N2. The reaction mixture was quenched according to the general procedure. The anti/syn
1
ratio (86:14) was determined by H NMR analysis of the crude product (δ major: 4.49 ppm, δ minor: 4.46 ppm). The crude
mixture was purified by flash chromatography (silica gel, ethyl acetate/petroleum ether = 5/95 to 30/70) to give the inseparable
o
mixture of diastereomers as white solid (52 mg, 91% yield, anti/syn = 86:14), MP 194ꢀ195 C. Rf = 0.4 (ethyl acetate/petroleum
ether = 1/2); 1H-NMR (300 MHz, CDCl3) δ 4.49 (s, 1H), 6.10 (d, J = 8.29 Hz, 1H), 6.95ꢀ6.97 (m, 6H), 7.07ꢀ7.26 (m, 11H), 7.35ꢀ
7.46 (m, 2H), 7.57ꢀ7.66 (m, 2H), 7.93 (d, J = 7.35 Hz, 1H); 13C-NMR (75 MHz, CDCl3) δ 46.4, 75.3, 76.2, 117.0, 117.8, 123.4
(d, J = 74.65 Hz), 125.2, 125.6 (q, J1 = 3.29 Hz, J2 = 6.59 Hz), 127.2, 127.5, 127.7, 129.3, 129.6, 130.1, 130.5, 133.6, 140.7,
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141.1, 143.6, 176.2; FTIR (KBr) cmꢀ1, 3471, 3232, 2813, 2329, 1716, 1331, 1060, 896; HRMS ESI: [M+Na]+, Calcd for
C36H25O2N2F3Na 597.1760; found 597.1761.
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2-(3-hydroxy-2-oxo-1-tritylindolin-3-yl)-2-(naphthalen-1-yl)acetonitrile (4e): DBU mediated (0.18 mmol) reaction of Nꢀtrityl
isatin 1d (0.1 mmol) and Phenyl acetonitrile 2f (0.12 mmol) in Et2O (1 ml) was run at room temperature for 2.25h under N2. The
reaction mixture was quenched according to the general procedure. The anti/syn ratio (99:1) was determined by 1H NMR analysis
of the crude product (δ major: 5.32 ppm, δ minor: 5.41 ppm). The crude mixture was purified by flash chromatography (silica
gel, ethyl acetate/petroleum ether = 5/95 to 30/70) to give the inseparable mixture of diastereomers as white solid (33 mg, 59%
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yield, anti/syn = 99:1), MP 198ꢀ199 C. Rf = 0.4 (ethyl acetate/petroleum ether = 1/2); H-NMR (300 MHz, CDCl3) δ 5.32 (s,
1H), 6.05 (d, J = 7.91 Hz, 1H), 6.53ꢀ6.55 (m, 6H), 6.92ꢀ7.00 (m, 7H), 7.06ꢀ7.16 (m, 5H), 7.36ꢀ7.42 (m, 1H), 7.56ꢀ7.64 (m, 2H),
7.88 (d, J = 6.59 Hz, 1H), 7.96 (d, J = 8.10 Hz, 1H), 8.04 (t, J = 7.91 Hz, 2H); 13C-NMR (75 MHz, CDCl3) δ 41.9, 75.1, 77.2,
116.9, 119.1, 123.2, 124.5, 124.7, 125.9, 126.1, 126.3, 126.8, 127.3, 127.4, 127.7, 128.2, 129.0, 129.2, 129.3, 130.1, 130.7, 133.9,
140.8, 143.7, 176.8; FTIR (KBr) cmꢀ1, 3803, 3365, 2931, 1641, 896; HRMS ESI: [M+Na]+, Calcd for C39H28O2N2Na 579.2042;
found 579.2042.
2-(3,5-bis(trifluoromethyl)phenyl)-2-(3-hydroxy-2-oxo-1-tritylindolin-3-yl)acetonitrile (4f):
DBU mediated (0.18 mmol) reaction of Nꢀtrityl isatin 1d (0.1 mmol) and Phenyl acetonitrile 2g (0.12 mmol) in Et2O (1 ml) was
run at room temperature for 2.25h under N2. The reaction mixture was quenched according to the general procedure. The anti/syn
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ratio (99:1) was determined by H NMR analysis of the crude product (δ major: 4.51 ppm, δ minor: 4.55 ppm). The crude
mixture was purified by flash chromatography (silica gel, ethyl acetate/petroleum ether = 5/95 to 30/70) to give the inseparable
mixture of diastereomers as white solid (42.6 mg, 66% yield, anti/syn = 99:1), MP 139ꢀ140 oC. Rf = 0.4 (ethyl acetate/petroleum
ether = 1/2); 1H-NMR (300 MHz, CDCl3) δ 4.51 (s, 1H), 6.14 (d, J = 8.29 Hz, 1H), 6.89ꢀ6.91 (m, 5H), 6.99 (t, J = 7.72 Hz, 1H),
7.16ꢀ7.27 (m, 11H), 7.55 (s, 2H), 7.94ꢀ7.97 (m, 2H); 13C-NMR (75 MHz, CDCl3) δ 46.3, 75.7, 76.2, 117.1, 117.4, 120.8, 123.4
(q, J1 = 3.29 Hz, J2 = 7.14 Hz), 123.7, 124.2, 124.4 (d, J = 4.39 Hz), 127.4, 127.6, 129.2, 129.8 (d, J = 2.75 Hz), 130.0, 132.0,
132.5, 140.5, 143.5, 175.9; FTIR (KBr) cmꢀ1, 3347, 3059, 2923, 1719, 1608, 1278, 1137, 1035, 899; HRMS ESI: [M+Na]+,
Calcd for C37H24O2N2F6Na 665.1634; found 665.1610.
2-(5-fluoro-3-hydroxy-2-oxo-1-tritylindolin-3-yl)-2-(4-(trifluoromethyl)phenyl)acetonitrile (4g): DBU mediated (0.18
mmol) reaction of Nꢀtrityl isatin 1p (0.1 mmol) and Phenyl acetonitrile 2e (0.12 mmol) in Et2O (1 ml) was run at room
temperature for 2.25h under N2. The reaction mixture was quenched according to the general procedure. The anti/syn ratio
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(85:15) was determined by H NMR analysis of the crude product (δ major: 6.05 ppm, δ minor: 6.29 ppm). The crude mixture
was purified by flash chromatography (silica gel, ethyl acetate/petroleum ether = 5/95 to 30/70) to give the inseparable mixture of
o
diastereomers as white solid (39.3 mg, 66% yield, anti/syn = 85:15), 192ꢀ193 C. Rf = 0.4 (ethyl acetate/petroleum ether = 1/2);
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1H-NMR (300 MHz, CDCl3) δ 4.47 (s, 1H), 6.05 (dd, J1 = 3.96 Hz, J2 = 8.85 Hz, 1H), 6.63 (t, J = 8.67Hz, 1H), 6.94ꢀ6.95 (m,
5H), 7.18ꢀ7.31 (m, 12H), 7.62ꢀ7.69 (m, 3H); 13C-NMR (75 MHz, CDCl3) δ 46.4, 75.5, 76.2, 112.0 (d, J = 24.70 Hz), 116.3 (d, J
= 23.05 Hz), 117.4, 118.0 (d, J = 7.68 Hz), 125.8 (q, J1 = 2.75 Hz, J2 = 6.59 Hz), 127.4, 127.6, 127.8, 129.1, 129.2, 130.0, 130.4,
131.6 (d, J = 32.93 Hz), 133.2, 139.4 (d, J = 2.20 Hz), 140.3, 140.8, 157.3 (d, J = 245.35 Hz), 176.2; FTIR (KBr) cmꢀ1, 3584,
3410, 2913, 2373, 2202, 1614, 1497,1328, 1054,807; HRMS ESI: [M+Na]+, Calcd for C36H24O2N2F4Na 615.1666; found
615.1650.
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2-(5-bromo-3-hydroxy-2-oxo-1-tritylindolin-3-yl)-2-(4-(trifluoromethyl)phenyl)acetonitrile (4h): DBU mediated (0.18
mmol) reaction of Nꢀtrityl isatin 1g (0.1 mmol) and Phenyl acetonitrile 2e (0.12 mmol) in Et2O (1 ml) was run at room
temperature for 2.25h under N2. The reaction mixture was quenched according to the general procedure. The anti/syn ratio
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(85:15) was determined by H NMR analysis of the crude product (δ major: 6.03 ppm, δ minor: 6.27 ppm). The crude mixture
was purified by flash chromatography (silica gel, ethyl acetate/petroleum ether = 5/95 to 30/70) to give the inseparable mixture of
diastereomers as white solid (63 mg, 97% yield, anti/syn = 85:15), MP 189ꢀ190 oC. Rf = 0.4 (ethyl acetate/petroleum ether = 1/2);
1H-NMR (300 MHz, CDCl3) δ 4.54 (s, 1H), 6.03 (d, J = 8.67 Hz, 1H), 6.97ꢀ6.99 (m, 4H), 7.09ꢀ7.14 (m, 1H), 7.21ꢀ7.35 (m,
12H), 7.47 (d, J = 8.10 Hz, 1H), 7.67ꢀ7.75 (m, 2H), 8.08 (s, 1H); 13C-NMR (75 MHz, CDCl3) δ 46.2, 75.5, 76.0, 115.9, 116.5,
117.4, 118.4, 125.7 (q, J1 = 3.29 Hz, J2 = 7.14 Hz), 127.2, 127.4, 127.4, 127.7, 127.8, 129.1, 129.2, 130.1, 130.4, 132.6, 133.1,
140.2, 140.7 (d, J = 144.90 Hz), 175.8; FTIR (KBr) cmꢀ1, 3382, 2739, 2104, 1602, 964, 832; HRMS ESI: [M+Na]+, Calcd for
C36H24O2N2F3Br1Na 675.0865; found 675.0899.
2-(3-hydroxy-2-oxo-5-phenyl-1-tritylindolin-3-yl)-2-(4-(trifluoromethyl)phenyl)acetonitrile (4i): DBU mediated (0.18
mmol) reaction of Nꢀtrityl isatin 1j (0.1 mmol) and Phenyl acetonitrile 2e (0.12 mmol) in Et2O (1 ml) was run at room
temperature for 2.25h under N2. The reaction mixture was quenched according to the general procedure. The anti/syn ratio (99:1)
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was determined by H NMR analysis of the crude product (δ major: 4.52 ppm, δ minor: 4.75 ppm). The crude mixture was
purified by flash chromatography (silica gel, ethyl acetate/petroleum ether = 5/95 to 30/70) to give the inseparable mixture of
diastereomers as white solid (32 mg, 49% yield, anti/syn = 99:1), 199ꢀ200 oC. Rf = 0.4 (ethyl acetate/petroleum ether = 1/2); 1H-
NMR (300 MHz, CDCl3) δ 3.62 (bs, 1H), 4.52 (s, 1H), 6.18 (d, J = 8.48 Hz, 1H), 6.99ꢀ7.01 (m, 6H), 7.19ꢀ7.21 (m, 9H), 7.27ꢀ
7.37 (m, 4H), 7.41ꢀ7.46 (m, 2H), 7.58ꢀ7.64 (m, 4H), 8.19 (s, 1H); 13C-NMR (75 MHz, CDCl3) δ 46.5, 75.4, 76.2, 117.2, 117.8,
122.6, 125.3, 125.7 (q, J = 4.39 Hz), 126.7, 127.3, 127.5, 127.6, 127.8, 128.2, 128.8, 128.9, 129.3, 130.1, 131.5, 131.9, 133.5,
136.4, 139.3, 140.6, 142.8, 176.2; FTIR (KBr) cmꢀ1, 3478, 3282, 2894, 2362, 1718, 1602, 964, 866; HRMS ESI: [M+Na]+,
Calcd for C42H29O2N2F3Na 673.2073; found 673.2106.
2-(3-hydroxy-2-oxoindolin-3-yl)-2-phenylacetonitrile (5): To a solution of compound 3d (101 mg, 0.2 mmol) in DCM (2 ml),
trifluoroacetic acid (28.17 mmol, 2 ml) was dropwise added at room temperature. The resulting reaction mixture was run at same
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temperature for next 12 h. The progress of the reaction was monitored by TLC. Once the reaction was completed, the reaction
mixture was evaporated off under reduced pressure. The organic residue was purified by flash chromatography (silica gel, ethyl
acetate/petroleum ether = 5/95 to 80/20) to give the inseparable mixture of diastereomers as white solid (52.3 mg, yield = 99%).
Rf = 0.4 (ethyl acetate/petroleum ether = 1/2); 1H-NMR (300 MHz, CD3OD) δ 4.52 (s, 1H), 6.60 (d, J = 7.72 Hz, 1H), 6.95 (d, J
= 7.35 Hz, 2H), 7.09 (m, 3H), 7.18ꢀ7.29 (m, 2H), 7.77 (d, J = 7.35 Hz, 1H); 13C-NMR (75 MHz, CD3OD) δ 46.7, 78.6, 111.4,
120.1, 123.7, 126.3, 128.6, 129.4, 129.8, 130.3, 131.2, 131.8, 143.2, 178.7; FTIR (KBr) cmꢀ1, 3741, 3414, 2487, 2355, 1702,
1616, 1482, 1362, 1026; HRMS ESI: [M+Na]+, Calcd for C16H12O2N2Na 287.0790; found 287.0777.
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2-(3-hydroxy-1-methyl-2-oxoindolin-3-yl)-2-phenylacetonitrile (3a): To a solution of compound of 5 (53 mg, 0.2 mmol) in dry
DMF (1.0 mL), Cs2CO3 (65.2 mg, 0.2 mmol) was added at 0 °C. The resulting mixture was stirred for 10 minutes at same
temperature, then methyl iodide (0.22 mmol, 13.8 ꢂL) was added to it. Subsequently, the reaction mixture was warmed to room
temperature and stirred for next 12 h. The progress of the reaction was monitored by TLC. Once the reaction completed, it was
quenched with water. The biphasic mixture was transferred to the separating funnel with help of EtOAc (2.0 mL). The organic
layer was separated and washed with water (2.0 mLx3). The combined aqueous layer was extracted with EtOAc (2.0 mL). The
combined organic layer was washed with brine, dried over Na2SO4 and evaporated under reduced pressure. The organic residue
was purified by flash chromatography (silica gel, ethyl acetate/petroleum ether = 5/95 to 80/20) to give the inseparable mixture of
diastereomers as white solid (33 mg, yield = 59%), MP 174ꢀ175 oC. Rf = 0.4 (ethyl acetate/petroleum ether = 1/2); 1H-NMR (300
MHz, CDCl3) δ 2.81 (s, 3H), 4.21 (s, 1H), 4.55 (s, 1H), 6.55 (d, J = 7.72 Hz, 1H), 6.84 (d, J = 7.35 Hz, 2H), 7.05 (d, J = 7.35 Hz,
2H), 7.14ꢀ7.23 (m, 2H), 7.29ꢀ7.35 (m, 1H), 7.92 (d, J = 7.35 Hz, 1H); 13C-NMR (75 MHz, CDCl3) δ 25.9, 46.4, 77.5, 108.5,
118.1, 123.5, 124.9, 125.8, 128.1, 128.6, 128.9, 129.5, 130.8, 143.1, 174.9; FTIR (KBr) cmꢀ1, 3737, 3404, 2931, 2360, 1712,
1614, 1462, 1113, 1023, 932; HRMS ESI: [M+Na]+, Calcd for C17H14O2N2Na 301.0947; found 301.0951.
1,8-dimethyl-3-phenyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-3a-ol (6)15
:
A solution of 3a (55.6 mg, 0.2 mmol) in THF (4.0 mL) was cooled to 0 °C and LiAlH4(31 mg, 0.8 mmol) was added in portions.
The reaction was stirred for 4 hours at room temperature, quenched with water, and the suspension obtained was filtered over
celite (washings with EtOAc). The crude product is subjected to next step, Formaldehyde ( 0.11 ml 1.38 mmol 37% in water )
was added to a solution of crude product in MeOH (2 ml), the reaction mixture was stirred at RT for 3h, then the reaction
o
mixture cooled to 0 C and NaBH3CN (86.7 mg, 1.38 mmol) was added. After stirred at room temperature 1hour, the reaction
quenched with water and filtered over celite (washing with EtOAc ). The biphasic mixture was transferred to the separating
funnel with help of EtOAc (2.0 mL). The organic layer was separated and washed with water (2.0 mLx3). The combined aqueous
layer was extracted with EtOAc (2.0 mL). The combined organic layer was washed with brine, dried over Na2SO4 and evaporated
under reduced pressure. The organic residue was purified by flash chromatography (silica gel, ethyl acetate/petroleum ether =
5/95 to 60/40) to give a pale yellow sticky solid 6 (10 mg, yield = 18%). Rf = 0.4 (ethyl acetate/petroleum ether = 1/2); 1H-NMR
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(300 MHz, CDCl3) δ 3.15 (s, 3H), 3.21 (s, 3H), 3.41ꢀ3.52 (m, 1H), 3.62 (dd, J1 = 6.03 Hz, J2 = 10.55 Hz, 1H), 4.01 (dd, J1 = 6.03
Hz, J2 = 13.38 Hz, 1H), 4.59 (s, 1H), 6.65 (d, J = 8.10 Hz, 1H), 6.77 (td, J1 = 0.75 Hz, J2 = 7.35 Hz, 1H), 6.97 (dd, J1 = 0.75 Hz,
J2 = 7.54 Hz, 1H), 7.31ꢀ7.33 (m, 1H), 7.41ꢀ7.49 (m, 5H); 13C-NMR (75 MHz, CD3OD) δ 36.5, 50.7, 52.0, 64.0, 86.5, 104.6,
108.2, 119.2, 121.8, 128.5, 128.8, 130.0, 130.7, 130.9, 132.6, 150.8; FTIR (KBr) cmꢀ1, 3743, 3388, 2928, 2326, 1677, 1469,
1140; HRMS ESI: [M+H]+, Calcd for C18H21O1N2 281.1648; found 281.1638.
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2. Details of DFT calculations
All the calculations in this study have been performed with density functional theory (DFT), with the aid of the Turbomole 6.4
suite of programs, using the PBE functional. The TZVP basis set has been employed. The resolution of identity (RI), along with
the multipole accelerated resolution of identity (marij) approximations have been employed for an accurate and efficient
treatment of the electronic Coulomb term in the DFT calculations. Solvent correction were incorporated with optimization
calculations using the COSMO model, with diethyl ether (ε = 4.33) as the solvent. The values reported are ꢁG values, with zero
point energy corrections, internal energy and entropic contributions included through frequency calculations on the optimized
minima with the temperature taken to be 298.15 K. Harmonic frequency calculations were performed for all stationary points to
confirm them as a local minima or transition state structures (for details see SI).
ASSOCIATED CONTENT
Supporting Information
Experimental procedures and characterization of compounds (1H, 13C NMR) including Xꢀray data (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Email: ravips@chemistry.iitd.ac.in
Present Addresses
†Department of Chemistry, Indian Institute of Technology, Delhi, Hauz Khas, New Delhi, India 110016.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We are grateful for the generous financial support from DSTꢀIndia (SR/S1/OCꢀ83/2012) CSIRꢀOSDD and CSIR
[02(0254)/16/EMRꢀII]. VUBR thank CSIRꢀNew Delhi for the award of a Senior Research Fellowship. KK thanks UGC for the
Senior Research Fellowship. We thank Kushboo Kaim for the initial optimisation of these reactions. We thank Dr. Rajesh
Gonnade (Center for Materials Characterization, CSIRꢀNCL, Pune) for Xꢀray analysis.
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REFERENCES
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(1) (a) Powell, R. G.; Mikolajczak, K. L.; Zilkowski, B. W.; B. W.; Lu, H. S. M.; Mantus, E. K.; Clardy, J. Experkntia
1991,47, 304. (b) Fleming, F. F. Nat. Prod. Rep. 1999, 16, 597. (C) Mesa, R. A.; Yasothan, U.; Kirkpatrick, P. Nature
Reviews Drug Discovery 2012, 11, 103. (d) Ki, K. S.; Pal, G.; Haider, H.; Singh, M.; Kothari, J. S.; Agarwal, V. K. WO
Patent 2007/054963.
5
6
7
8
9
10
11
12
13
14
15
16
17
18
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21
22
23
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48
49
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52
53
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55
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59
60
(2) (a) Koenig, T. M.; Mitchell, D. Tetrahedron Lett. 1994, 35, 1339. (b) Carlier, P. R.; Lo, K. M.; Lo, M. M.ꢀC.; Lo, P. C.ꢀ
K.; Lo, C.W.ꢀS. J. Org. Chem. 1997, 62, 6316. (c) Kamal, A.; Khanna, G. B. R.; Ramu, R. Tetrahedron: Asymmetry 2002,
13, 2039. (d) Alcaide, B.; Almendros, P.; Cabrero, G.; Ruiz, M. P. J. Org. Chem. 2007, 72, 7980. (e) Ankati, H.; Zhu, D.;
Yang, Y.; Biehl, E. R.; Hua, L. J. Org. Chem. 2009, 74, 1658.
(3) (a) Yardley, J. P.; Husbands, G. E. M.; Stack, G.; Butch, J.; Bicksler, J.; Moyer, J. A.; Muth, E. A.; Andree, T.; Fletcher,
H.; James, M. N. G.; Sielecki, A. R. J. Med. Chem. 1990, 33, 2899. (b) Carlier, P. R.; Lo, M. M.ꢀC.; Lo, P. C.ꢀK.;
Richelson, E.; Tatsumi, M.; Reynolds, I. J.; Sharma, T. A. Bioorg. Med. Chem. Lett. 1998, 8, 487.
(4) (a) Carlier, P. R.; Lam, W. W.ꢀF.; Wan, N. C.; Williams, I. D. Angew. Chem. Int. Ed. 1998, 37, 2252. (b) Carlier, P. R.;
Lo, C. W.ꢀS. ; Lo, M. M.ꢀC.; Wan, N. C.; Williams, I. D. Org. Lett., 2000, 2,2443. (c) Denmark, S. E.; Wilson, T. W.;
Angew. Chem. Int. Ed. 2012, 51, 9980. (d) Long, S.; Panunzio, M.; Qin, W.; Bongini, A.; Monari. M. Eur. J. Org. Chem.
2013, 5127. (e) Denmark, S. E.; Wilson, T. W.; T. Burk, M. T. Chem. Eur. J. 2014, 20, 9268. (f) Qin, W.; Long, S.;
Bongini, A.; Panunzio, M. Eur. J. Org. Chem. 2015, 3495.
(5) Kaiser, E. M.; Hauser, C. R. J. Am. Chem. Soc. 1967, 89, 4566.
(6) Xiao, Z.; Timberlake, J. W. Tetrahedron 1998, 54, 4211.
(7) Fleming, F. F.; Shook, B. C. J. Org. Chem. 2002, 67, 3668.
(8) Saravanan, M.; Satyanarayana, B.; Reddy, P. P. Org. Process Res. Dev. 2011, 15, 1392.
(9) (a) Shi, M.; Zhang, W. Tetrahedron 2005, 61, 11887. (b) Zhang, D.; Johnson, S.; Cui, HꢀL.; Tanaka, F. Asian J. Org.
Chem. 2014, 3, 391.
(10) (a) Sun, Y.; Chen, H.; Li, Z.; Wang, Q.; Tao, F. Synthesis 2008, 4, 589. (b) Chen, H.; Ma, X.; Li, Z.; Wang, Q.; Tao, F.
Arkivoc 2009, 87.
(11) Zhang, D.; Tanaka, F. Adv. Synth. Catal. 2015, 357, 3458.
(12) (a) Suto, Y.; Kumagai, N.; Matsunaga, S.; Kanai, M.; Shibasaki, M. Org. Lett., 2003, 5, 3147. (b) Kawano, Y.;
Kaneko, N.; Mukaiyama, T. Chem. Lett., 2005, 34, 1508. (c) Wadhwa, K.; Verkade, J. G. J. Org. Chem., 2009, 74, 5683.
(d) Jinzaki, T.; Arakawa, M.; Kinoshita, H.; Ichikawa, J.; Miura, K. Org. Lett., 2013, 15, 3750. (e) Rao, V. U. B.; Kumar,
K.; Singh, R. P. Org. Biomol. Chem., 2015, 13, 9755.
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(13) (a) Liu, Y.ꢀL.; Wang, B.ꢀL.; Cao, J.ꢀJ.; Chen, L.; Zhang, Y.ꢀX.; Wang, C.; Zhou, J. J. Am. Chem. Soc., 2010, 132,
15176. (b) Chen,M.; Gan, L.; Lin, S.; Wang, X.; Li, L.; Li, Y.; Zhu, C.; Wang, Y.; Jiang, B.; Jiang, J.; Yang, Y.; Shi, J. J.
Nat. Prod., 2012, 75, 1167. (c) Kumar, A.; Chimni, S. S. RSC Adv., 2012, 2, 9748. (d) Deng, T.; Wang, H.; Cai, C. Eur. J.
Org. Chem., 2014, 7259.
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(14) Wang, G.ꢀW.; Zhou, A.ꢀX.; Wang, J.ꢀJ.; Hu, R.ꢀB.; Yang, S.ꢀD. Org. Lett., 2013, 15, 5270.
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(15) Retini, M.; Bergonzinia, G.; Melchiorre, P. Chem. Commun., 2012, 48, 3336.
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