Synthesis of Indolines by a Zn-Mediated Mannich Reaction/Pd-Catalyzed Amination Sequence

Article abstract of DOI:10.1021/acs.joc.7b00013

1,2-Disubstituted indolines have been prepared in fair to good yields by a Zn-mediated organometallic Mannich reaction, followed by an intramolecular Pd-catalyzed aromatic amination. The reactions are easy to set up and compatible with a large variety of simple or commercially available reagents. The method was further extended to the preparation of a 1,2,3-trisubstituted indoline.

Full text of DOI:10.1021/acs.joc.7b00013

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Note
Synthesis of indolines by a Zn-mediated Mannich
reaction / Pd-catalyzed amination sequence
Marc Presset, Antoine Pignon, Jérôme Paul, Erwan Le Gall, Eric Leonel, and Thierry Martens
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00013 • Publication Date (Web): 24 Feb 2017
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Synthesis of indolines by a Znꢀmediated Mannich reaction / Pdꢀcatalyzed amination sequence
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Marc Presset, Antoine Pignon, Jérôme Paul, Erwan Le Gall,* Eric Léonel, Thierry Martens
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Électrochimie et Synthèse Organique, Université Paris Est, ICMPE (UMR 7182), CNRS, UPEC,
2ꢀ8 rue Henri Dunant, Fꢀ94320 Thiais, France
legall@icmpe.cnrs.fr
Abstract
1,2ꢀDisubstituted indolines have been prepared in fair to good yields by a Znꢀmediated
organometallic Mannich reaction followed by an intramolecular Pdꢀcatalyzed aromatic amination.
The reactions are easy to set up and compatible with a large variety of simple or commerciallyꢀ
available reagents. The method was further extended to the preparation of a 1,2,3ꢀtrisubstituted
indoline.
The indoline scaffold is an important structural motif for medicinal chemists as it can be found in
numerous naturally occurring alkaloids such as strychnine or oleracein A–D and in other bioactive
compounds such as pentopril (Figure 1).1,2,3 These attractive properties have made indolines
relevant targets for the organic chemists' community.4 Apart from the hydrogenation of indoles,
main synthetic strategies towards indolines are based on the construction of the pyrrolidine ring
system. For instance, the Pdꢀcatalyzed heteroannulation of dienes with oꢀiodoanilines has been
introduced by Larock in 1990.5 This method has been recently improved by Jamison through
extension to terminal alkenes using dual Ni/photoredox catalysis,6 while Glorius developed the use
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of alkenes in Rh(III)ꢀcatalyzed C–H activation/alkene insertion reactions.7 A more general route has
been pioneered by Buchwald, using a Pdꢀcatalyzed intramolecular amination reaction between an
aryl halide and an amine.8,9,10 The main advantages of this strategy are the use of mild reaction
conditions and a great functional group tolerance. However, it requires the preparation of orthoꢀ
halogenated βꢀarylethylamines bearing both reactive sites, usually by means of a multipleꢀstep
linear synthesis.
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Although few of the usual synthetic methods could approach the high degree of modularity reached
by multicomponent reactions (MCRs),11 exploitation of this class of reactions for the preparation of
indolines precursors has not been exploited so far. Based on our experience in MCRs involving
organometallic species,12,13 we anticipated that orthoꢀhalogenated βꢀarylethylamines required for
the preparation of indolines could be prepared by an organometallic Mannich reaction involving an
orthoꢀbrominated benzyl bromide.14,15,16 Therefore, we describe herein a general twoꢀstep sequence
involving a Znꢀmediated Mannich reaction and a Pdꢀcatalyzed intramolecular amination for the
synthesis of 1,2ꢀdiꢀ and even 1,2,3ꢀtrisubstituted indolines.
Figure 1. Selected bioactive indolines
We began our study with the optimization of the organometallic Mannich reaction between
commercial or easily accessible orthoꢀbrominated benzyl bromides 1, primary amines 2 and
aldehydes 3. Based on previous studies,17,18,19 we turned our attention to Znꢀmediated
transformations as this metal proved efficient for the metalation of benzylic carbonꢀhalogen bonds.
A preliminary experiment using 2ꢀbromobenzyl bromide 1a (2.0 equiv), aniline 2a (1.0 mmol) and
4ꢀtolualdehyde 3a (1.0 equiv) in the presence of zinc dust (2.0 equiv) in acetonitrile at ambient
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temperature afforded the expected compound 4a in 68%. This result revealed that 1a was
chemoselectively activated at the benzylic position without alteration of the aromatic C–Br bond.
This information was consistent with previous reports by Gosmini indicating that zincation of
aromatic carbonꢀhalogen bonds requires the use of an additional cobalt catalyst.20 We next found
the addition of TFA to activate Zn was beneficial for the reaction with an increased yield of 90%
whereas the use of THF as the solvent or Mn as the reductant were deleterious (59% yield and no
reaction, respectively). The requirement of an excess (> 2.0 equiv) of the organozinc reagent to
obtain the desired orthoꢀhalogenated βꢀarylethylamine 4 in useful yields was confirmed by the
decreased yield (58%) observed when the reaction was performed with only 1.5 equiv of 1a.21 We
then turned our attention to the scope of the reaction and the results are reported in Table 1.
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The Znꢀmediated organometallic Mannich reaction proved general for the preparation of orthoꢀ
brominated βꢀarylamines 4.22 Using commercially available 2ꢀbromobenzyl bromide (1a) as a
starting material, a large variety of primary amines underwent the reaction even if small amines
such as allylamine and nꢀpropylamine afforded lower yields of coupling products (4c and 4d),
presumably due to their volatility under such exothermic conditions. The reaction also tolerated
various aldehydes including aromatic (products 4aꢀf, 4i and 4oꢀp), heteroaromatic (product 4g) or
aliphatic aldehydes (product 4h) in moderate to decent yields. However, the expected reaction was
not observed with primary amides, ketones, pivaldehyde or methyl pyruvate. Substitution at the
aromatic ring of the dibromide 1 with electronꢀneutral or electronꢀwithdrawing groups was also
possible (products 4i and 4j), but the introduction of an electronꢀdonating group led only to traces
of the desired product. Importantly, the present protocol was also compatible with the use of ethyl
glyoxylate (3f) as the aldehyde partner, affording the corresponding αꢀaminoester derivatives in
useful yields (products 4jꢀm). The diastereoselectivity of the multicomponent reaction was also
evaluated using commercial chiral substrates. Therefore, when (–)ꢀmenthyl glyoxylate (3g) was
used, the expected product 4n was obtained but only with moderate stereoinduction (dr=1.7:1). On
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the other hand, when (R)ꢀαꢀmethylbenzylamine (2f) was used, the secondary βꢀarylethylamine 4o
was obtained in 65% yield with a fair diastereoselectivity (dr=3.8:1). The importance of the chiral
group linked to the amine function was confirmed by the reaction performed with (S)ꢀ1ꢀ(1ꢀ
naphthyl)ethylamine (2g) which displayed a slightly higher diastereoselectivity (dr=4.3:1).
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Table 1. Multicomponent synthesis of orthoꢀbrominated βꢀarylethylaminea
a Yields of isolated products. Reaction conditions: 1 (2.5 equiv), 2 (2.5 mmol), 3 (1.1 equiv), Zn
b
(3.75 equiv), TFA (25 mol%), CH3CN (C=0.5 M), 1 h; Reaction conditions: 1 (2.0 equiv), 2
c
(1.0 mmol), 3 (1.0 equiv), Zn (2.0 equiv), TFA (10 mol%), CH3CN (C=0.5 M), 16 h; Reaction
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performed under conditions b with 3a (3.0 equiv) and Zn (3.0 equiv); Diastereoisomeric ratio,
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determined by 1H NMR analysis.
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The cyclization of these βꢀarylethylamines 4 was undertaken by intramolecular aromatic amination.
After a screening of diverse catalysts under varied conditions, the use of 5 mol% of PdCl2(PPh3)2
with 2.0 equiv of potassium tertꢀbutylate in refluxing toluene was identified as a very efficient
catalytic system. The conversion of precursors 4 into the corresponding indolines was thus
performed under such conditions and the results are reported in Table 2. These conditions proved to
be general and afforded the desired indolines 5 in fair to good yields (products 5aꢀi), regardless of
the nature of the substituent of the pyrrolidine ring. However, although this set of conditions proved
to efficiently deliver most of the target indolines, phenylalanine derivatives 4jꢀn showed no
conversion under standard conditions. Considering the presence of an enolizable ester group on the
starting substrate, the base was thus changed to the less alkaline cesium carbonate and the solvent
was switched from toluene to tetrahydrofuran. These modifications proved relevant, as the
corresponding cyclization products 5jꢀn were thus obtained in decent to good yields. Importantly,
none of these conditions provoked either aromatization or erosion of diastereoisomeric ratios
observed during the Mannich step (products 5nꢀp).
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Table 2. Pdꢀcatalyzed cyclization of βꢀarylethylaminesa
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a Yields of isolated products. Reaction conditions: 4 (0.5 mmol), PdCl2(PPh3)2 (5 mol%), tꢀBuOK
(2.0 equiv), toluene (C=0.2 M), 110 °C, 14 h; b The free indoline resulting from hydrodeallylation is
c
concomitantly obtained in 19% yield; Reactions performed using Cs2CO3 in THF at 80 °C for
24 h; d Diastereoisomeric ratio determined by 1H NMR analysis.
Extension of this twoꢀstep strategy to the preparation of a 1,2,3ꢀtrisubstituted indoline required
additional investigations. Indeed, the use of the aboveꢀmentioned conditions for the preparation of
indolines precursors starting from secondary benzyl bromide 1d only led to traces of the desired
product together with major amounts of dimeric sideꢀproducts. It was noticed that a decrease of the
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reaction temperature to 0 °C and dropwise addition of the dihalogenated starting material favors the
desired multicomponent coupling. Under such conditions, the reaction between substrate 1d,
benzylamine (2b) and 4ꢀtolualdehyde (3a) afforded a correct 50% isolated yield of 4q with a
moderate diastereoselectivity (Scheme 1).23 The following intramolecular amination step, which
was realized under the same aboveꢀmentioned conditions, led to the corresponding 1,2,3ꢀ
trisubstituted indoline 5q in very good yield (86%), without modification of the diastereoisomeric
ratio.
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Scheme 1. Synthesis of a 1,2,3ꢀtrisubstituted indoline
To ascertain that this method can represent a reliable route to substituted indoles, a tentative
oxidation of indolinic αꢀamino ester 5k to the corresponding indole 6 was undertaken using
manganese oxide. The oxidized compound was obtained in an excellent 90% yield after 4 days in
refluxing toluene (Scheme 2).
Scheme 2. Oxidation of indoline 5k to indole 6
CO2Et
MnO2 (4.0 equiv)
CO2Et
N
N
toluene, 110 °C, 96 h
Ph
Ph
6, 90%
5k
In conclusion, we present herein a straightforward twoꢀstep procedure for the generation of
diversely substituted indolines starting from commercial or easily accessible substrates. The tolerant
and modular character of the method is ensured by an organometallic Mannich reaction followed by
an intramolecular amination that allows the facile synthesis of 1,2ꢀdisubstituted indolines. The
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present methodology was also demonstrated efficient for the preparation of indolinic αꢀamino esters
and of a 1,2,3ꢀtrisubstituted indoline.
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Experimental Section
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General considerations: All commercially available reagents were used as received. In particular,
zinc dust (<10 ꢁm) was purchased from SigmaꢀAldrich and 2ꢀbromobenzyl bromide 1a from Alfaꢀ
Aesar. Compound 1b was prepared by NaBH4 reduction and Appel’s bromation of 2ꢀbromoꢀ4ꢀ
methylbenzaldehyde. Compounds 1c and 1d were prepared by radical bromination of the
corresponding toluene derivatives using NBS in the presence of a catalytic amount of AIBN. All 2ꢀ
bromobenzyl bromides 1 are strong lachrymators and should be used under a wellꢀventilated fume
hood. Acetonitrile (over calcium hydride) and THF (over sodium/benzophenone) were distilled
prior to use. Unless other precision, reactions were performed under an argon atmosphere under
magnetic stirring. Diastereomeric ratios were determined by 1H NMR analysis of the crude mixture.
Analytical thinꢀlayer chromatography (TLC) was performed on TLC silica gel plates (0.25 mm)
precoated with a fluorescent indicator. Flash chromatography (FC) was performed on 40–63 ꢁm
silica gel with mixtures of ethyl acetate (EtOAc) and petroleum ether (PE), following Still’s
method. Visualization was effected with ultraviolet light and ethanolic KMnO4. Melting point (mp)
are uncorrected and were measured on a Büchi Bꢀ545 apparatus. NMR spectra were recorded on a
1
Bruker 300 or 400 MHz spectrometer. H NMR chemical shifts were referenced to the residual
solvent signal; 13C NMR chemical shifts were referenced to the deuterated solvent signal.
Multiplicity was defined by DEPT 135 analysis. Data are presented as follows: chemical shift δ
(ppm), multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet, br = broad), coupling constant
J (Hz), integration. HighꢀResolution Mass Spectra were obtained at the ICOA of the Université of
Orléans by electrospray ionization using a QꢀTOF analyzer.
Preparation of orthoꢀbromo βꢀarylethylamines 4:
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General procedure A: In air, a flameꢀdried 25 mL roundꢀbottom flask equipped with a stir bar was
charged with Zn (613 mg, 9.4 mmol, 3.75 equiv), closed with a septum and flushed with Ar.
CH3CN (5 mL, C=0.5 M), oꢀbromobenzyl bromide 1 (6.25 mmol, 2.5 equiv), aldehyde 3 (2.75
mmol, 1.1 equiv), amine 2 (2.5 mmol, 1.0 equiv) and TFA (48 ꢁL, 0.62 mmol, 25 mol%) were
successively added, and the reaction was stirred at rt for 1 h. Then, the reaction mixture was poured
into sat aq NH4Cl (50 mL) and the solution was extracted with EtOAc (2x25 mL). The combined
organic layers were washed with brine (50 mL), dried (Na2SO4) and evaporated. The crude material
was purified either by FC or by an acid/base workꢀup: the residue was solubilized in Et2O (50 mL)
and concentrated H2SO4 (0.14 mL, 2.5 mmol, 1.0 equiv) was added dropwise under stirring. After
5 min, the ammonium salt was collected by gravity filtration on a fritted funnel and washed with
Et2O (2x20 mL). Then, the solid was poured into 50% aq NaOH (50 mL) and the solution was
extracted with DCM (2x50 mL). The combined organic layers were dried (MgSO4) and evaporated
to afford the desired product 4.
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General procedure B: In air, a flameꢀdried 25 mL roundꢀbottom flask equipped with a stir bar was
charged with Zn (131 mg, 2.0 mmol, 2.0 equiv), closed with a septum and flushed with Ar. CH3CN
(2 mL, C=0.5 M), oꢀbromobenzyl bromide 1 (2.0 mmol, 2.0 equiv), aldehyde 3 (1.0 mmol,
1.0 equiv), amine 2 (1.0 mmol, 1.0 equiv) and TFA (8 ꢁL, 0.10 mmol, 10 mol%) were successively
added, and the reaction was stirred at rt for 16 h. Then, the reaction mixture was poured into sat aq
NH4Cl (20 mL) and the solution was extracted with EtOAc (2x10 mL). The combined organic
layers were washed with brine (20 mL), dried (Na2SO4) and evaporated. The crude material was
purified by FC to afford the desired product 4.
Compound 4a: Following the general procedure B, the reaction performed with 2ꢀbromobenzyl
bromide 1a (500 mg, 2.0 mmol, 2.0 equiv), aniline 2a (91 ꢁL, 1.0 mmol, 1.0 equiv) and 4ꢀ
tolualdehyde 3a (118 ꢁL, 1.0 mmol, 1.0 equiv) afforded, after purification by FC (50 mL SiO2,
PE/EtOAc:99/1 then 97/3), the desired product 4a (332 mg, 90%) as a yellow oil. Rf
(PE/EtOAc:95/5, UV+KMnO4): 0.39. HRMS (ESI): m/z calcd for C21H21BrN (M+H)+ 366.0851,
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found 366.0849. H NMR (400 MHz, CDCl3): δ 7.61 (dd, J=7.9, 1.1 Hz, 1H), 7.34 (d, J=8.0 Hz,
2H), 7.23 (dd, J=7.3, 1.2 Hz, 1H), 7.19–7.14 (m, 3H), 7.12–7.058 (m, 3H), 6.66 (t, J=7.3 Hz, 1H),
6.53 (dd, J=8.6, 1.0 Hz, 2H), 4.74 (dd, J=8.4, 5.9 Hz, 1H), 4.31 (br s, 1H), 3.27–3.17 (m, 2H), 2.38
(s, 3H). 13C NMR{1H} (100 MHz, CDCl3): δ 147.4 (C), 140.5 (C), 137.8 (C), 136.8 (C), 133.1
(CH), 131.4 (CH), 129.4 (2 CH), 129.1 (2 CH), 128.5 (CH), 127.6 (CH), 126.3 (2 CH), 125.1 (C),
117.4 (CH), 113.6 (2 CH), 57.9 (CH), 45.4 (CH2), 21.2 (CH3).
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Compound 4b: Following the general procedure A, the reaction performed with 2ꢀbromobenzyl
bromide 1a (1.6 g, 6.25 mmol, 2.5 equiv), benzylamine 2b (0.27 mL, 2.5 mmol, 1.0 equiv) and 4ꢀ
tolualdehyde 3a (0.32 mL, 2.75 mmol, 1.1 equiv) afforded, after purification by FC (100 mL SiO2,
PE/Et2O:95/5 then 90/10), the desired product 4b (666 mg, 70%) as a yellow oil. Rf
(PE/Et2O:90/10, UV+KMnO4): 0.17. HRMS (ESI): m/z calcd for C22H23BrN (M+H)+ 380.1008,
found 380.1011.
1H NMR (400 MHz, CDCl3): δ 7.41 (dd, J=7.9, 1.2 Hz, 1H), 7.16–7.12 (m, 4H), 7.10–7.08 (m,
1H), 7.04–7.02 (m, 4H), 7.00 (dd, J=7.4, 1.3 Hz, 1H), 6.92 (td, J=7.6, 1.8 Hz, 1H), 6.88 (dd, J=7.4,
1.7 Hz, 1H), 3.90 (dd, J=7.9–6.1 Hz, 1H), 3.58 (d, J=13.5 Hz, 1H), 3.39 (d, J=13.5 Hz, 1H), 3.01–
2.90 (m, 2H), 3.07 (s, 3H), 1.67 (br s, 1H). 13C NMR{1H} (100 MHz, CDCl3): δ 140.6 (C), 140.5
(C), 138.5 (C), 136.8 (C), 132.9 (CH), 131.8 (CH), 129.2 (2 CH), 128.3 (2 CH), 128.1 (CH), 127.9
(2 CH), 127.3 (2 CH), 127.2 (CH), 126.8 (CH), 125.0 (C), 61.5 (CH), 51.4 (CH2), 45.4 (CH2), 21.3
(CH3).
Compound 4c: Following the general procedure A, the reaction performed with 2ꢀbromobenzyl
bromide 1a (1.6 g, 6.25 mmol, 2.5 equiv), allylamine 2c (0.19 mL, 2.5 mmol, 1.0 equiv) and 4ꢀ
tolualdehyde 3a (0.32 mL, 2.75 mmol, 1.1 equiv) afforded, after purification by FC (100 mL SiO2,
CH/EtOAc:97.5/2.5 then 95/5), the desired product 4c (217 mg, 26%) as a pale yellow oil. Rf
(CH/EtOAc:95/5, UV+KMnO4): 0.08. HRMS (ESI): m/z calcd for C18H21BrN (M+H)+ 330.0851,
1
found 330.0850. H NMR (400 MHz, CDCl3): δ 7.56 (dd, J=7.9, 1.2 Hz, 1H), 7.23 (d, J=8.1 Hz,
2H), 7.17–7.12 (m, 3H), 7.08–7.01 (m, 2H), 5.82 (dddd, J=16.9, 10.3, 6.4, 5.3, 1H), 5.08–5.02 (m,
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2H), 4.04 (dd, J = 7.5, 6.5 Hz, 1H), 3.18–3.10 (m, 2H), 3.07–3.00 (m, 2H), 2.35 (s, 3H) [NH not
detected]. 13C NMR{1H} (100 MHz, CDCl3): δ 140.2 (C), 138.4 (C), 136.8 (CH), 136.8 (C), 133.0
(CH), 131.8 (CH), 129.1 (2 CH), 128.1 (CH), 127.3 (2 CH), 127.2 (CH), 125.0 (C), 115.7 (CH2),
61.5 (CH), 50.0 (CH2), 45.2 (CH2), 21.2 (CH3).
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Compound 4d: Following the general procedure B, the reaction performed with 2ꢀbromobenzyl
bromide 1a (1.0 g, 4.0 mmol, 2.0 equiv), propylamine 2d (0.16 mL, 2.0 mmol, 1.0 equiv) and 4ꢀ
tolualdehyde 3a (0.24 mL, 2.0 mmol, 1.0 equiv) afforded, after purification by FC (50 mL SiO2,
PE/EtOAc:9/1 then 8/2), the desired product 4d (287 mg, 43%) as a yellow oil. Rf (PE/EtOAc:8/2,
UV+KMnO4): 0.31. HRMS (ESI): m/z calcd for C18H23BrN (M+H)+ 332.1008, found 332.1005.
1H NMR (400 MHz, CDCl3): δ 7.42 (dd, J=7.9, 1.2 Hz, 1H), 7.10 (d, J=8.0 Hz, 2H), 7.02–6.98 (m,
3H), 6.93–6.86 (m, 2H), 3.87–3.84 (m, 1H), 2.97 (dd, J=13.4, 7.7 Hz, 1H), 2.89 (dd, J=13.4, 6.3
Hz, 1H), 2.33–2.23 (m, 2H), 2.21 (s, 3H), 1.46 (br s, 1H), 1.35–1.24 (m, 2H), 0.68 (t, J=7.4 Hz,
3H). 13C NMR {1H}(100 MHz, CDCl3): δ 140.7 (C), 138.5 (C), 136.5 (C), 132.9 (CH), 131.8
(CH), 129.0 (2 CH), 128.0 (CH), 127.2 (2 CH), 127.1 (CH), 124.9 (C), 62.2 (CH), 49.6 (CH2), 45.4
(CH2), 23.2 (CH2), 21.2 (CH3), 11.7 (CH3).
Compound 4e: Following the general procedure A, the reaction performed with 2ꢀbromobenzyl
bromide 1a (1.6 g, 6.25 mmol, 2.5 equiv), pꢀanisidine 2e (308 mg, 2.5 mmol, 1.0 equiv) and
benzaldehyde 3b (0.28 mL, 2.75 mmol, 1.1 equiv) afforded, after purification by FC (100 mL SiO2,
PE/Et2O:95/5 then 90/10), the desired product 4e (620 mg, 65%) as a brown oil. Rf
(PE/Et2O:90/10, UV+KMnO4): 0.26. HRMS (ESI): m/z calcd for C21H21BrNO (M+H)+ 382.0801,
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found 382.0799. H NMR (400 MHz, CDCl3): δ 7.62 (dd, J=8.1, 1.2 Hz, 1H), 7.46–7.44 (m, 2H),
7.39–7.35 (m, 2H), 7.32–7.28 (m, 1H), 7.26–7.22 (m, 1H), 7.15–7.11 (m, 2H), 6.71 (d, J=9.0 Hz,
2H), 6.50 (d, J=8.9 Hz, 2H), 4.71 (t, J=7.1 Hz, 1H), 4.08 (br s, 1H), 3.72 (s, 3H), 3.24–3.22 (m,
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2H). C NMR{1H} (100 MHz, CDCl3): δ 152.1 (C), 143.7 (C), 141.5 (C), 137.8 (C), 133.1 (CH),
131.4 (CH), 128.7 (2 CH), 128.5 (CH), 127.5 (CH), 127.2 (CH), 126.5 (2 CH), 125.1 (CH), 114.9
(2 CH), 114.7 (2 CH), 58.9 (CH), 55.8 (CH3), 45.4 (CH2).
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Compound 4f: Following the general procedure B, the reaction performed with 2ꢀbromobenzyl
bromide 1a (500 g, 2.0 mmol, 2.0 equiv), aniline 2a (91 ꢁL, 1.0 mmol, 1.0 equiv) and 2ꢀ
tolualdehyde 3c (116 ꢁL, 1.0 mmol, 1.0 equiv) afforded, after purification by FC (50 mL SiO2,
PE/Et2O:99/1 then 97.5/2.5), the desired product 4f (323 mg, 88%) as a colorless oil. Rf
(PE/Et2O:95/5, UV+KMnO4): 0.50. HRMS (ESI): m/z calcd for C21H21BrN (M+H)+ 366.0852,
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found 366.0853. H NMR (300 MHz, CDCl3): δ 7.73ꢀ7.69 (m, 2H), 7.38ꢀ7.29 (m, 4H), 7.25ꢀ7.19
(m, 4H), 6.80 (t, J=7.3 Hz, 1H), 6.61 (d, J=7.7 Hz, 2H), 5.13 (dd, J=8.5, 5.8 Hz, 1H), 4.45 (br s,
1H), 3.41 (dd, J=14.1, 8.5 Hz, 1H), 3.29 (dd, J=14.1, 5.8 Hz, 1H), 2.55 (s, 3H). 13C NMR{1H} (100
MHz, CDCl3): δ 147.2 (C), 141.2 (C), 137.5 (C), 135.1 (C), 133.0 (CH), 131.3 (CH), 130.6 (CH),
129.1 (2 CH), 128.5 (CH), 127.5 (CH), 127.0 (CH), 126.7 (CH), 125.6 (CH), 125.1 (C), 117.4
(CH), 113.3 (2 CH), 54.3 (CH), 43.6 (CH2), 19.3 (CH3).
Compound 4g: Following the general procedure A, the reaction performed with 2ꢀbromobenzyl
bromide 1a (1.6 g, 6.25 mmol, 2.5 equiv), pꢀanisidine 2e (308 mg, 2.5 mmol, 1.0 equiv) and 2ꢀ
thiophenecarboxaldehyde 3d (0.26 mL, 2.75 mmol, 1.1 equiv) afforded, after purification by FC
(100 mL SiO2, PE/EtOAc:97.5/2.5 then 95/5), the desired product 4g (532 mg, 55%) as an orange
oil. Rf (PE/EtOAc:95/5, UV+KMnO4): 0.19. HRMS (ESI): m/z calcd for C19H19BrNOS (M+H)+
388.0365, found 388.0353. 1H NMR (400 MHz, CDCl3): δ 7.61 (dd, J=7.8, 1.0 Hz, 1H), 7.25–7.21
(m, 2H), 7.16–7.13 (m, 2H), 6.98–6.92 (m, 2H), 6.75 (d, J=9.0 Hz, 2H), 6.60 (d, J=9.0 Hz, 2H),
5.01 (t, J=6.8 Hz, 1H), 4.03 (br s, 1H), 3.74 (s, 3H), 3.36–3.34 (m, 2H). 13C NMR{1H} (100 MHz,
CDCl3): δ 152.5 (C), 148.9 (C), 141.1 (C), 137.3 (C), 133.0 (CH), 131.5 (CH), 128.5 (CH), 127.5
(CH), 126.8 (CH), 125.0 (C), 123.9 (CH), 123.7 (CH), 115.2 (2 CH), 114.7 (2 CH), 55.7 (CH3),
55.3 (CH), 45.6 (CH2).
Compound 4h: Following the general procedure B, the reaction performed with 2ꢀbromobenzyl
bromide 1a (1.0 g, 4.0 mmol, 2.0 equiv), aniline 2a (0.18 mL, 2.0 mmol, 1.0 equiv) and isoꢀ
butyraldehyde 3e (0.18 mL, 2.0 mmol, 1.0 equiv) afforded, after purification by FC (50 mL SiO2,
PE/Et2O:99/1 then 97.5/2.5), the desired product 4h (246 mg, 38%) as a pale yellow oil. Rf
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(PE/Et2O:97.5/2.5, UV+KMnO4): 0.43. HRMS (ESI): m/z calcd for C17H21BrN (M+H)+
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318.0852, found 318.0854. H NMR (400 MHz, CDCl3): δ 7.38 (dd, J=8.0, 1.2 Hz, 1H), 7.10 (dd,
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J=7.6, 1.8 Hz, 1H), 7.03 (td, J=7.5, 1.3 Hz, 1H), 6.96–6.94 (m, 2H), 6.90–6.86 (m, 1H), 6.47 (tt,
J=7.4, 1.0 Hz, 1H), 6.39–6.37 (m, 2H), 3.59–3.54 (m, 2H), 2.89 (dd, J=14.0, 4.6 Hz, 1H), 2.67 (dd,
J=14.0, 9.3 Hz, 1H), 1.90–1.86 (m, 1H), 0.96 (d, J=6.9 Hz, 3H), 0.88 (d, J=6.8 Hz, 3H). 13C
NMR{1H} (100 MHz, CDCl3): δ 148.2 (C), 139.1 (C), 132.8 (CH), 131.4 (CH), 129.2 (2 CH),
127.9 (CH), 127.4 (CH), 124.9 (C), 116.7 (CH), 113.0 (2 CH), 58.5 (CH), 38.2 (CH2), 31.2 (CH),
18.6 (CH3), 18.1 (CH3).
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Compound 4i: Following the general procedure B, the reaction performed with αꢀbromobenzyl
bromide 1b (437 mg, 2.0 mmol, 2.0 equiv), aniline 2a (91 ꢁL, 1.0 mmol, 1.0 equiv) and 4ꢀ
tolualdehyde 3a (118 ꢁL, 1.0 mmol, 1.0 equiv) afforded, after purification by FC (50 mL SiO2,
PE/Et2O:97.5/2.5 then 95/5), the desired product 4i (197 mg, 52%) as a brown solid. Rf
(PE/Et2O:95/5, UV+KMnO4): 0.43. mp: 75–78 °C. HRMS (ESI): m/z calcd for C22H23BrN
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(M+H)+ 380.1008, found 380.1010. H NMR (400 MHz, CDCl3): δ 7.53 (s, 1H), 7.44 (d, J=8.0
Hz, 2H), 7.29–7.26 (m, 2H), 7.21–7.27 (m, 2H), 7.13–7.12 (2H), 6.76 (t, J=7.3 Hz, 1H),6.63 (dd,
J=8.6, 0.9 Hz, 2H), 4.81 (dd, J=8.8, 5.4 Hz, 1H), 4.40 (br s, 1H),3.33–3.22 (m, 2H), 2.47 (s, 3H),
2.41 (s, 3H). 13C NMR {1H}(100 MHz, CDCl3): δ 147.4 (C), 140.6 (C), 138.5 (C), 136.6 (C),
134.6 (C), 133.5 (CH), 131.0 (CH), 129.4 (2 CH), 129.0 (2 CH), 128.3 (CH), 126.3 (2 CH), 124.7
(C), 117.3 (CH), 113.6 (2 CH), 58.0 (CH), 44.9 (CH2), 21.2 (CH3), 20.7 (CH3).
Compound 4j: Following the general procedure B, the reaction performed with αꢀbromobenzyl
bromide 1c (1.2 g, purity=50%, 2.0 mmol, 2.0 equiv), aniline 2a (91 ꢁL, 1.0 mmol, 1.0 equiv) and
ethyl glyoxylate 3f (0.24 mL, 50% in toluene, 1.0 mmol, 1.0 equiv) afforded, after purification by
FC (100 mL SiO2, PE/Et2O:8/2 then 6/4), the desired product 4j (240 mg, 59%) as a brown solid.
Rf (PE/Et2O:8/2, UV+KMnO4): 0.23. mp: 75–78 °C. HRMS (ESI): m/z calcd for C19H21BrNO4
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(M+H)+ 406.0648, found 406.0647. H NMR (400 MHz, CDCl3): δ 7.91 (d, J=2.1 Hz, 1H), 7.75
(dd, J=8.3, 2.1 Hz, 1H), 7.64 (d, J=8.3 Hz, 1H), 7.15 (dd, J=8.6, 7.4 Hz, 2H), 6.73 (t, J=7.3 Hz,
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(s, 3H), 3.32 (dd, J=13.7, 7.4 Hz, 1H), 3.25 ꢀ(dd, J=13.7, 7.0 Hz, 1H), 1.14 (t, J=7.1 Hz, 3H). C
NMR{1H} (100 MHz, CDCl3): δ 173.0 (C), 166.3 (C), 146.4 (C), 137.1 (C), 133.2 (CH), 132.5
(CH), 130.3 (C), 129.6 (C), 129.5 (CH), 129.4 (2 CH), 118.7 (CH), 113.8 (2 CH), 61.4 (CH2), 56.8
(CH), 52.4 (CH3), 39.4 (CH2), 14.1 (CH2).
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Compound 4k: Following the general procedure A, the reaction performed with 2ꢀbromobenzyl
bromide 1a (1.6 g, 6.25 mmol, 2.5 equiv), benzylamine 2b (0.27 mL, 2.5 mmol, 1.0 equiv) and
ethyl glyoxylate 3f (0.56 mL, 50% in toluene, 2.75 mmol, 1.1 equiv) afforded, after purification by
FC (100 mL SiO2, PE/Et2O:9/1 then 8/2), the desired product 4k (625 mg, 69%) as a yellow oil. Rf
(PE/Et2O:8/2, UV+KMnO4): 0.23. HRMS (ESI): m/z calcd for C18H21BrNO2 (M+H)+ 362.0750,
found 362.0747. 1H NMR (400 MHz, CDCl3): δ 7.57 (d, J=8.2 Hz, 1H), 7.31–7.24 (m, 7H), 7.14–
7.10 (m, 1H), 4.14 (q, J=7.1 Hz, 2H), 3.87 (d, J=13.2 Hz, 1H), 3.72–3.68 (m, 2H), 3.17 (dd, J=13.6,
7.5 Hz, 1H), 3.10 (dd, J=13.6, 7.4 Hz, 1H), 2.01 (br s, 1H), 1.19 (t, J=7.1 Hz, 3H). 13C NMR{1H}
(100 MHz, CDCl3): δ 174.6 (C), 139.6 (C), 137.2 (C), 132.7 (CH), 131.5 (CH), 128.3 (2 CH),
128.3 (CH), 128.0 (2 CH), 127.1 (CH), 126.9 (CH), 124.9 (C), 60.6 (CH2), 60.4 (CH), 51.9 (CH2),
40.0 (CH2), 14.1 (CH3).
Compound 4l: Following the general procedure A, the reaction performed with 2ꢀbromobenzyl
bromide 1a (1.6 g, 6.25 mmol, 2.5 equiv), aniline 2a (0.28 mL, 2.5 mmol, 1.0 equiv) and ethyl
glyoxylate 3f (0.56 mL, 50% in toluene, 2.75 mmol, 1.1 equiv) afforded, after purification by FC
(100 mL SiO2, PE/Et2O:9/1 then 8/2), the desired product 4l (365 mg, 42%) as a yellow paste. Rf
(PE/Et2O:8/2, UV+KMnO4): 0.29. HRMS (ESI): m/z calcd for C17H19BrNO2 (M+H)+ 348.0593,
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found 348.0592. H NMR (400 MHz, CDCl3): δ 7.46 (dd, J=7.6, 0.9 Hz, 1H), 7.13–7.11 (m, 2H),
7.06 (dd, J=8.6, 7.4 Hz, 2H), 7.02–6.97 (m, 1H), 6.63 (tt, J=7.4, 1.0 Hz, 1H), 6.53 (dd, J=8.6, 1.0
Hz, 2H), 4.36 (t, J=7.3 Hz, 1H), 4.18 (br s, 1H), 4.03–3.94 (m, 2H), 3.20 (dd, J=13.6, 7.4 Hz, 1H),
3.08 (dd, J=13.6, 7.1 Hz, 1H), 1.01 (t, J=7.1 Hz, 3H). 13C NMR{1H} (100 MHz, CDCl3): δ 173.4
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(C), 146.5 (C), 136.5 (C), 133.0 (CH), 131.5 (CH), 129.4 (2 CH), 128.7 (CH), 127.5 (CH), 124.9
(C), 118.5 (CH), 113.7 (2 CH), 61.2 (CH2), 56.8 (CH), 39.5 (CH2), 14.1 (CH3).
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Compound 4m: Following the general procedure B, the reaction performed with 2ꢀbromobenzyl
bromide 1a (1.0 g, 4.0 mmol, 2.0 equiv), pꢀanisidine 2e (246 mg, 2.0 mmol, 1.0 equiv) and ethyl
glyoxylate 3f (0.48 mL, 50% in toluene, 2.0 mmol, 1.0 equiv) afforded, after purification by FC
(100 mL SiO2, PE/Et2O:9/1 then 8/2), the desired product 4m (363 mg, 48%) as a yellow oil. Rf
(PE/Et2O:8/2, UV+KMnO4): 0.16. HRMS (ESI): m/z calcd for C18H20BrNNaO3 (M+Na)+
400.0519, found 400.0518. 1H NMR (400 MHz, CDCl3): δ 7.56 (dd, J=7.6, 0.8 Hz, 1H), 7.24–7.22
(m, 2H), 7.12–7.08 (m, 1H), 6.75 (d, J=9.0 Hz, 2H), 6.61 (d, J=9.0 Hz, 2H), 4.37 (t, J=7.3 Hz, 1H),
4.12–4.03 (m, 2H), 3.72 (s, 3H), 3.28 (dd, J=13.6, 7.4 Hz, 1H), 3.16 (dd, J=13.6, 7.2 Hz, 1H), 1.11
(t, J=7.1 Hz, 3H) [NH not detected]. 13C NMR{1H} (100 MHz, CDCl3): δ 173.7 (C), 152.9 (C),
140.6 (C), 136.6 (C), 133.0 (CH), 131.5 (CH), 128.6 (CH), 127.5 (CH), 124.9 (C), 115.4 (2 CH),
114.9 (2 CH), 61.1 (CH2), 58.0 (CH), 55.7 (CH3), 39.7 (CH2), 14.1 (CH3).
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Compound 4n: Following the general procedure B, the reaction performed with 2ꢀbromobenzyl
bromide 1a (0.75 g, 3.0 mmol, 3.0 equiv), aniline 2a (91 ꢁL, 1.0 mmol, 1.0 equiv) and (–)ꢀmenthyl
glyoxylate monohydrate 3g (230 mg, 1.0 mmol, 1.0 equiv) with Zn (196 mg, 3.0 mmol, 3.0 equiv)
afforded, after purification by FC (50 mL SiO2, PE/Et2O:97.5/2.5 then 95/5), the desired product 4n
(220 mg, dr=1.7:1, 48%) as a yellow oil. Rf (PE/Et2O:95/5, UV+KMnO4): 0.27. HRMS (ESI):
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diasteromers) δ 7.47 (dd, J=8.0, 1.2 Hz, 2H), 7.20–7.09 (m, 4H), 7.06–6.98 (m, 6H), 6.65–6.59 (m,
2H), 6.56–6.51 (m, 4H), 4.57–4.50 (m, 2H), 4.39–4.36 (m, 2H), 4.14 (br s, 2H), 3.22–3.06 (m, 4H),
1.87–1.81 (m, 1H), 1.72–1.50 (m, 7H), 1.34–1.18 (m, 5H), 0.93–0.85 (m, 4H), 0.80–0.73 (m, 9H),
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0.63 (d, J=6.9 Hz, 3H), 0.54 (d, J=7.0 Hz, 3H), 0.45 (d, J=6.8 Hz, 3H). C NMR{1H} (100 MHz,
CDCl3): (2 diastereomers) δ 173.2 (C), 173.0 (C), 146.8 (C), 146.7 (C), 136.5 (C), 136.5 (C), 133.0
(CH), 133.0 (CH), 131.7 (CH), 131.5 (CH), 129.3 (2 CH), 129.2 (2 CH), 128.7 (CH), 128.7 (CH),
127.6 (CH), 127.6 (CH), 125.0 (C), 124.9 (C), 118.7 (CH), 118.6 (CH), 114.0 (2 CH), 113.8 (2
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CH), 75.5 (CH), 75.2 (CH), 57.4 (CH), 57.0 (CH), 46.8 (CH), 46.8 (CH), 40.8 (CH2), 40.4 (CH2),
39.7 (CH2), 39.6 (CH2), 34.2 (CH2), 34.1 (CH2), 31.4 (CH), 31.3 (CH), 26.1 (CH), 25.5 (CH), 23.2
(CH2), 23.0 (CH2), 22.0 (CH3), 22.0 (CH3), 20.9 (CH3), 20.9 (CH3), 16.0 (CH3), 15.9 (CH3).
Compound 4o: Following the general procedure A, the reaction performed with 2ꢀbromobenzyl
bromide 1a (1.6 g, 6.25 mmol, 2.5 equiv), (R)ꢀαꢀmethylbenzylamine 2f (0.32 mL, 2.5 mmol, 1.0
equiv) and 4ꢀtolualdehyde 3a (0.32 mL, 2.75 mmol, 1.1 equiv) afforded, after purification by FC
(100 mL SiO2, PE/Et2O:95/5 then 90/10), the desired product 4o (641 mg, dr=3.8:1, 65%) as a
yellow paste. Rf (PE/Et2O:9/1, UV+KMnO4): 0.18. HRMS (ESI): m/z calcd for C23H25BrN
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(M+H)+ 394.1165, found 394.1164. H NMR (400 MHz, CDCl3): (major diasteromer) δ 7.40 (dd,
J=7.9, 1.3 Hz, 1H), 7.19–7.07 (m, 5H), 7.04–6.95 (m, 5H), 6.93–6.88 (m, 1H), 6.82–6.76 (m, 1H),
3.96 (t, J=7.0 Hz, 1H), 3.61 (q, J=6.5 Hz, 1H), 3.09 (dd, J=13.3, 7.0 Hz, 1H), 2.89 (dd, J=13.3, 7.1
Hz, 1H), 2.22 (s, 3H), 1.61 (br s, 1H), 1.15 (d, J=6.5 Hz, 3H). 13C NMR{1H} (100 MHz, CDCl3):
(major diasteromer) δ 146.3 (C), 140.7 (C), 138.7 (C), 136.6 (C), 132.8 (CH), 131.9 (CH), 129.1 (2
CH), 128.4 (2 CH), 127.9 (CH), 127.2 (2 CH), 127.0 (CH), 126.8 (CH), 126.7 (2 CH), 125.0 (C),
59.5 (CH), 54.8 (CH), 45.0 (CH2), 22.6 (CH3), 21.2 (CH3).
Compound 4p: Following the general procedure B, the reaction performed with 2ꢀbromobenzyl
bromide 1a (500 mg, 2.0 mmol, 2.0 equiv), (S)ꢀ1ꢀ(1ꢀnaphthyl)ethylamine 2g (160 ꢁL, 1.0 mmol,
1.0 equiv) and 4ꢀtolualdehyde 3a (118 ꢁL, 1.0 mmol, 1.0 equiv) afforded, after purification by FC
(50 mL SiO2, PE/Et2O:90/10 then 80/20), the desired product 4p (162 mg, dr=4.3:1, 36%) as a pale
yellow oil. Rf (PE/Et2O:80/20, UV+KMnO4): 0.42. HRMS (ESI): m/z calcd for C27H27BrN
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(M+H)+ 444.1321, found 444.1326. H NMR (300 MHz, CDCl3): (major diasteromer) δ 7.93 (d,
J=8.3 Hz, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.78 (d, J=8.1 Hz, 1H), 7.59–7.52 (m, 2H), 7.50–7.41 (m,
3H), 7.25–7.14 (m, 4H), 7.12–6.98 (m, 3H), 4,61 (q, J=6.5 Hz, 1H), 4.23 (dd, J=7.1, 6.9 Hz, 1H),
3.27 (dd, J=13.3, 7.1 Hz, 1H), 3.10 (dd, J=13.3, 6.9 Hz, 1H), 2.41 (s, 3H), 1.90 (br s, 1H), 1.46 (d,
J=6.5 Hz, 3H). 13C NMR{1H} (75 MHz, CDCl3): (major diasteromer) δ 142.0 (C), 140.7 (C),
138.8 (C), 136.7 (C), 134.0 (C), 132.8 (CH), 132.0 (CH), 131.2 (C), 129.2 (2 CH), 128.9 (2 CH),
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127.9 (CH), 127.3 (2 CH), 127.0 (CH), 125.7 (2 CH), 125.4 (CH), 125.0 (C), 123.6 (CH), 123.0
(CH), 59.7 (CH), 50.5 (CH), 45.1 (CH2), 22.1 (CH3), 21.3 (CH3).
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Preparation of indolines 5:
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General procedure A: In air, a flameꢀdried 25 mL Schlenk flask equipped with a stir bar was
charged with βꢀarylethylamine 4 (0.5 mmol, 1.0 equiv) and toluene (2.5 mL, C=0.2 M). The
solution was degassed by Ar bubbling for 5 min. tꢀBuOK (112 mg, 1.0 mmol, 2.0 equiv) and
PdCl2(PPh3)2 (18 mg, 0.025 mmol, 5 mol%) were successively added under an Ar flow and the
flask was sealed (glass stopper). The reaction was heated at 110 °C overnight (14 h). Then, the
reaction mixture was filtered through a pad of Celite (10 mL), thoroughly rinsed with EtOAc (ca. 50
mL), and the filtrate was evaporated. The crude material was purified by FC to afford the desired
product 5.
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General procedure B (glyoxylate derivatives): In air, a flameꢀdried 25 mL Schlenk flask
equipped with a stir bar was charged with βꢀarylethylamine 4 (0.5 mmol, 1.0 equiv) and THF (2.5
mL, C=0.2 M). The solution was degazed by Ar bubbling for 5 min. Cs2CO3 (326 mg, 1.0 mmol,
2.0 equiv) and PdCl2(PPh3)2 (18 mg, 0.025 mmol, 5 mol%) were successively added under an Ar
flow and the flask was sealed (glass stopper). The reaction was heated at 80 °C for 24 h. Then, the
reaction mixture was filtered through a pad of Celite (10 mL), thoroughly rinsed with EtOAc (ca. 50
mL), and the filtrate was evaporated. The crude material was purified by FC to afford the desired
product 5.
Compound 5a: Following the general procedure A, the reaction performed with 4a (183 mg, 0.5
mmol, 1.0 equiv) afforded, after purification by FC (50 mL SiO2, PE then PE/EtOAc:95/5), the
desired product 5a (114 mg, 80%) as a yellow solid. Rf (PE/EtOAc:95/5, UV+KMnO4): 0.90. mp:
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113–115 °C. HRMS (ESI): m/z calcd for C21H20N (M+H)+ 286.1590, found 286.1589. H NMR
(400 MHz, CDCl3): δ 7.11–7.04 (m, 6H), 7.01–6.95 (m, 5H), 6.79 (t, J=7.1 Hz, 1H), 6.69–6.65 (m,
1H), 5.10 (dd, J=9.4, 6.3 Hz, 1H), 3.52 (dd, 15.6, 9.6 Hz, 1H), 2.84 (dd, J=15.6, 6.2 Hz, 1H), 2.17
(s, 3H). 13C NMR{1H} (100 MHz, CDCl3): δ 148.1 (C), 143.7 (C), 140.6 (C), 136.9 (C), 129.5 (2
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CH), 129.3 (C), 129.1 (2 CH), 127.4 (CH), 126.2 (2 CH), 125.2 (CH), 121.8 (CH), 119.4 (2 CH),
108.8 (2 CH), 67.8 (CH), 39.8 (CH2), 21.2 (CH3).
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Compound 5b: Following the general procedure A, the reaction performed with 4b (190 mg, 0.5
mmol, 1.0 equiv) afforded, after purification by FC (50 mL SiO2, PE then PE/EtOAc:95/5), the
desired product 5b (149 mg, 99%) as a yellow oil. Rf (PE, UV+KMnO4): 0.29. HRMS (ESI): m/z
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calcd for C22H22N (M+H)+ 300.1747, found 300.1747. H NMR (400 MHz, CDCl3): δ 7.22 (d,
J=8.0 Hz, 2H), 7.15–7.09 (m, 5H), 7.04 (d, J=7.8 Hz, 2H), 6.96–6.90 (m, 2H), 6.57 (t, J=7.3 Hz,
1H), 6.28 (d, J=7.8 Hz, 1H), 4.49 (t, J=9.7 Hz, 1H), 4.25 (d, J=15.8 Hz, 1H), 3.82 (d, J=15.8 Hz,
1H), 3.24 (dd, J=15.7, 9.0 Hz, 1H), 2.90 (dd, J=15.7, 10.4 Hz, 1H), 2.23 (s, 3H). 13C NMR{1H}
(100 MHz, CDCl3): δ 152.5 (C), 139.5 (C), 138.5 (C), 137.4 (C), 129.4 (2 CH), 128.6 (C), 128.5 (2
CH), 127.7 (3 CH), 127.6 (2 CH), 126.9 (CH), 124.2 (CH), 117.9 (CH), 107.5 (CH), 69.2 (CH),
50.9 (CH2), 39.6 (CH2), 21.3 (CH3).
Compound 5c: Following the general procedure A, the reaction performed with 4c (165 mg, 0.5
mmol, 1.0 equiv) afforded, after purification by FC (50 mL SiO2, PE/EtOAc:97.5/2.5 then 95/5),
the desired product 5c (44 mg, 34%) as a yellow oil. Rf (PE/EtOAc:95/5, UV+KMnO4): 0.72.
HRMS (ESI): m/z calcd for C18H20N (M+H)+ 250.1590, found 250.1585. H NMR (400 MHz,
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CDCl3): δ 7.36 (d, J=7.9 Hz, 2H), 7.20 (d, J=7.9 Hz, 2H), 7.15–7.07 (m, 2H), 6.72 (td, J=7.4, 0.9
Hz, 1H), 6.57 (d, J=7.8 Hz, 1H), 5.82 (dddd, J=17.2, 10.3, 7.0, 4.5 Hz, 1H), 5.22–5.16 (m, 2H),
4.65 (dd, J=10.8, 9.0 Hz, 1H), 3.84–3.78 (m, 1H), 3.47–3.40 (m, 1H), 3.35 (dd, J=15.6, 8.9 Hz,
1H), 2.96 (dd, J=15.6, 10.9 Hz, 1H), 2.39 (s, 3H). C NMR{1H} (100 MHz, CDCl3): δ 152.2 (C),
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139.7 (C), 137.4 (C), 133.6 (CH), 129.4 (2 CH), 128.7 (C), 127.7 (CH), 127.6 (2 CH), 124.2 (CH),
117.9 (CH), 117.4 (CH2), 107.4 (CH), 68.7 (CH), 49.2 (CH2), 39.6 (CH2), 21.3 (CH3).
Compound 5d: Following the general procedure A, the reaction performed with 4d (166 mg, 0.5
mmol, 1.0 equiv) afforded, after purification by FC (50 mL SiO2, PE/EtOAc:97.5/2.5 then 95/5),
the desired product 5d (98 mg, 78%) as a pale yellow oil. Rf (PE/EtOAc:95/5, UV+KMnO4):
0.69. HRMS (ESI): m/z calcd for C18H22N (M+H)+ 252.1747, found 252.1747. H NMR (400
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MHz, CDCl3): δ 7.43 (d, J=7.9 Hz, 2H), 7.28 (d, J=7.9 Hz, 2H), 7.23 (t, J=7.7 Hz, 1H), 7.15 (d,
J=7.1 Hz, 1H), 6.77 (td, J=7.5, 0.8 Hz, 1H), 6.59 (d, J=7.8 Hz, 1H), 4.74 (t, J=9.6 Hz, 1H), 3.45
(dd, J=15.7, 9.1 Hz, 1H), 3.15 (ddd, J=14.5, 8.6, 7.1 Hz, 1H), 3.07–2.95 (m, 2H), 2.48 (s, 3H),
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1.63–1.57 (m, 2H), 0.94 (t, J=7.4 Hz, 3H). C NMR{1H} (100 MHz, CDCl3): δ 152.5 (C), 140.2
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(C), 137.2 (C), 129.3 (2 CH), 128.3 (C), 127.7 (CH), 127.4 (2 CH), 124.1 (CH), 117.1 (CH), 106.3
(CH), 68.8 (CH), 48.5 (CH2), 39.8 (CH2), 21.2 (CH3), 19.6 (CH2), 11.8 (CH3).
Compound 5e: Following the general procedure A, the reaction performed with 4e (191 mg, 0.5
mmol, 1.0 equiv) afforded, after purification by FC (50 mL SiO2, PE/EtOAc:95/5 then 90/10), the
desired product 5e (122 mg, 81%) as a yellow oil. Rf (PE/EtOAc:90/10, UV+KMnO4): 0.50.
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HRMS (ESI): m/z calcd for C21H20NO (M+H)+ 302.1539, found 302.1538. H NMR (400 MHz,
CDCl3): δ 7.27 (d, J=7.1 Hz, 2H), 7.20–7.16 (m, 2H), 7.13 (d, J=7.2 Hz, 1H), 7.02–6.96 (m, 4H),
6.69–6.64 (m, 4H), 5.06 (t, J=8.9 Hz, 1H), 3.63 (s, 3H), 3.49 (dd, J=15.7, 9.5 Hz, 1H), 2.93 (dd,
J=15.7, 8.4 Hz, 1H). 13C NMR {1H} (100 MHz, CDCl3): δ 155.7 (C), 150.2 (C), 143.4 (C), 137.1
(C), 128.7 (2 CH), 128.6 (C), 127.5 (CH), 127.4 (CH), 126.9 (2 CH), 124.8 (CH), 123.5 (2 CH),
118.8 (CH), 114.5 (2 CH), 108.0 (CH), 69.4 (CH), 55.5 (CH3), 39.8 (CH2).
Compound 5f: Following the general procedure A, the reaction performed with 4f (183 mg, 0.5
mmol, 1.0 equiv) afforded, after purification by FC (50 mL SiO2, PE then PE/Et2O:97.5/2.5), the
desired product 5f (117 mg, 82%) as a yellow oil. Rf (PE/Et2O:95/5, UV+KMnO4): 0.61. HRMS
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(ESI): m/z calcd for C21H20N (M+H)+ 286.1590, found 286.1588. H NMR (300 MHz, CDCl3): δ
7.37 (d, J=7.3 Hz, 1H), 7.32–7.25 (m, 4H), 7.22–7.11 (m, 6H), 6.98 (t, J=7.2 Hz, 1H), 6.87 (t, J=7.3
Hz, 1H), 5.50 (dd, J=9.9, 5.3 Hz, 1H), 3.82 (dd, J=15.5, 9.9 Hz, 1H), 2.92 (dd, J=15.5, 5.3 Hz, 1H),
2.50 (s, 3H). 13C NMR{1H} (75 MHz, CDCl3): δ 147.6 (C), 143.9 (C), 141.4 (C), 134.1 (C), 130.9
(CH), 129.4 (C), 129.2 (2 CH), 127.4 (CH), 127.1 (CH), 126.5 (CH), 125.8 (CH), 125.5 (CH),
121.4 (CH), 119.6 (CH), 118.3 (2 CH), 109.4 (CH), 65.1 (CH), 37.9 (CH2), 19.4 (CH3).
Compound 5g: Following the general procedure A, the reaction performed with 4g (194 mg, 0.5
mmol, 1.0 equiv) afforded, after purification by FC (50 mL SiO2, PE/EtOAc:97.5/2.5 then 95/5),
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the desired product 5g (105 mg, 68%) as a yellow solid. Rf (PE/EtOAc:95/5, UV+KMnO4): 0.27.
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mp: 120–125 °C. HRMS (ESI): m/z calcd for C19H18NOS (M+H)+ 308.1104, found 308.1099. H
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NMR (400 MHz, CDCl3): δ 7.21–7.15 (m, 4H), 7.11 (t, J=7.7 Hz, 1H), 6.95 (dd, J=3.4, 0.7 Hz,
1H), 6.92–6.86 (m, 3H), 6.83–6.79 (m, 1H), 6.66 (d, J=7.9 Hz, 1H), 5.41 (t, J=9.0 Hz, 1H), 3.80 (s,
3H), 3.63 (dd, J=15.6, 9.0 Hz, 1H), 3.24 (dd, J=15.6, 9.0 Hz, 1H). 13C NMR{1H} (100 MHz,
CDCl3): δ 156.5 (C), 150.2 (C), 147.1 (C), 136.9 (C), 128.2 (C), 127.6 (CH), 126.5 (CH), 125.3
(CH), 125.1 (2 CH), 124.7 (CH), 124.6 (CH), 119.0 (CH), 114.5 (2 CH), 108.4 (CH), 65.8 (CH),
55.4 (CH3), 40.3 (CH2).
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Compound 5h: Following the general procedure A, the reaction performed with 4h (159 mg, 0.5
mmol, 1.0 equiv) afforded, after purification by FC (50 mL SiO2, PE/Et2O:95/5), the desired
product 5h (105 mg, 89%) as a yellow oil. Rf (PE/Et2O:95/5, UV+KMnO4): 0.88. HRMS (ESI):
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m/z calcd for C17H20N (M+H)+ 238.1590, found 238.1590. H NMR (400 MHz, CDCl3): δ 7.45
(dd, J=8.5, 7.3 Hz, 2H), 7.35 (dd, J=8.5, 1.2 Hz, 2H), 7.20 (dd, J=7.2, 0.8 Hz, 1H), 7.16 (ddd,
J=7.5, 4.2, 1.2 Hz, 1H), 7.08 (ddd, J=8.0, 1.2, 0.6 Hz, 1H), 6.83 (d, J=7.8 Hz, 1H), 6.78 (td, J=7.3,
0.9 Hz, 1H), 4.44 (ddd, J=9.6, 8.6, 3.9 Hz, 1H), 3.13 (dd, J=16.0, 9.6 Hz, 1H), 3.04 (dd, J=16.0, 8.6
Hz, 1H), 2.28–2.24 (m, 1H), 1.02 (d, J=7.0 Hz, 3H), 0.90 (d, J=6.8 Hz, 3H). 13C NMR{1H} (100
MHz, CDCl3): δ 150.0 (C), 143.6 (C), 129.5 (C), 129.3 (2 CH), 127.1 (CH), 124.8 (CH), 123.3
(CH), 122.9 (2 CH), 118.4 (CH), 107.4 (CH), 68.3 (CH), 28.7 (CH2), 28.4 (CH), 19.1 (CH3), 15.0
(CH3).
Compound 5i: Following the general procedure A, the reaction performed with 4i (190 mg, 0.5
mmol, 1.0 equiv) afforded, after purification by FC (50 mL SiO2, PE/EtOAc:97.5/2.5 then 95/5),
the desired product 5i (108 mg, 72%) as a colorless oil. Rf (PE/EtOAc:95/5, UV+KMnO4): 0.39.
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HRMS (ESI): m/z calcd for C22H20N (M–H)+ 298.1590, found 298.1593. H NMR (400 MHz,
CDCl3): δ 7.40 (s, 1H), 7.30 (d, J=8.0 Hz, 2H), 7.14 (d, J=7.8 Hz, 2H), 7.05 (dd, J=8.5, 7.3 Hz,
2H), 7.01 (s, 2H), 6.62 (t, J=7.3 Hz, 1H), 6.48 (t, J=7.7 Hz, 2H), 4.66 (dd, J=8.9, 5.4 Hz, 1H), 3.17
(dd, J=14.2, 5.3 Hz, 1H), 3.11 (dd, J=14.2, 9.0 Hz, 1H), 2.34 (s, 3H), 2.30 (s, 3H). 13C NMR{1H}
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(100 MHz, CDCl3): δ 147.4 (C), 140.6 (C), 138.5 (C), 136.8 (C), 134.6 (C), 133.6 (CH), 131.1
(CH), 129.4 (3 CH), 129.1 (3 CH), 128.4 (CH), 126.3 (2 CH), 124.8 (C), 113.7 (CH), 58.1 (CH),
45.0 (CH2), 21.2 (CH3), 20.7 (CH3).
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Compound 5j: Following the general procedure B, the reaction performed with 4j (203 mg, 0.5
mmol, 1.0 equiv) afforded, after purification by FC (50 mL SiO2, PE/EtOAc:90/10 then 80/20), the
desired product 5j (76 mg, 47%) as a yellow oil. Rf (PE/EtOAc:90/10, UV+KMnO4): 0.26.
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HRMS (ESI): m/z calcd for C19H20NO4 (M+H)+ 326.1387, found 326.1385. H NMR (400 MHz,
CDCl3): δ 7.74 (d, J=8.4 Hz, 1H), 7.71 (s, 1H), 7.31–7.27 (m, 2H), 7.18 (d, J=7.6 Hz, 2H), 7.03 (t,
J=7.4 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 4.82 (dd, J=10.7, 5.9 Hz, 1H), 4.12–4.02 (m, 2H), 3.78 (s,
3H), 3.50 (dd, J=16.1, 10.7 Hz, 1H), 3.16 (dd, J=16.1, 5.9 Hz, 1H), 1.09 (t, J=7.1 Hz, 3H). 13C
NMR{1H} (100 MHz, CDCl3): δ 172.1 (C), 167.2 (C), 151.8 (C), 141.9 (C), 131.0 (CH), 129.5 (2
CH), 128.1 (C), 126.3 (CH), 124.1 (CH), 120.9 (2 CH), 120.8 (C), 107.4 (CH), 65.9 (CH), 61.6
(CH2), 51.8 (CH3), 33.2 (CH2), 14.1 (CH3).
Compound 5k:24 Following the general procedure B, the reaction performed with 4k (181 mg, 0.5
mmol, 1.0 equiv) afforded, after purification by FC (50 mL SiO2, PE/EtOAc:97.5/2.5 then 95/5),
the desired product 5k (103 mg, 73%) as a pale yellow solid. Rf (PE/EtOAc:95/5, UV+KMnO4):
0.27. mp: 56–58 °C. HRMS (ESI): m/z calcd for C18H20NO2 (M+H)+ 282.1489, found 282.1490.
1H NMR (400 MHz, CDCl3): δ 7.41–7.39 (m, 2H), 7.38–7.34 (m, 2H), 7.31–7.29 (m, 1H), 7.11–
7.06 (m, 2H), 6.72 (ddd, J=7.5, 0.9 Hz, 1H), 6.48 (d, J=7.8 Hz, 1H), 4.56 (d, J=15.6 Hz, 1H), 4.36
(d, J=15.6 Hz, 1H), 4.29 (dd, J=10.3, 8.3 Hz, 1H), 4.21–4.13 (m, 2H), 3.42 (dd, J=15.9, 10.3 Hz,
1H), 3.24 (dd, J=15.9, 8.3 Hz, 1H), 1.26 (t, J=7.1 Hz, 3H). 13C NMR{1H} (100 MHz, CDCl3): δ
172.9 (C), 151.5 (C), 138.0 (C), 128.6 (2 CH), 127.9 (2 CH), 127.8 (CH), 127.3 (CH), 127.0 (C),
124.2 (CH), 118.2 (CH), 107.3 (CH), 65.6 (CH), 61.1 (CH2), 52.3 (CH2), 33.6 (CH2), 14.2 (CH3).
Compound 5l:23 Following the general procedure B, the reaction performed with 4l (174 mg, 0.5
mmol, 1.0 equiv) afforded, after purification by FC (50 mL SiO2, PE/EtOAc:97.5/2.5 then 95/5),
the desired product 5l (127 mg, 95%) as a yellow solid. Rf (PE/EtOAc:95/5, UV+KMnO4): 0.64.
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mp: 55–57 °C. HRMS (ESI): m/z calcd for C17H18NO2 (M+H)+ 268.1332, found 268.1327. H
NMR (400 MHz, CDCl3): δ 7.26–7.22 (m, 2H), 7.16–7.14 (m, 2H), 7.04 (d, J=7.3 Hz, 1H), 6.99
(d, J=7.3 Hz, 1H), 6.96–6.91 (m, 2H), 6.68 (td, J=7.2, 1.0 Hz, 1H), 4.71 (dd, J=10.5, 5.8 Hz, 1H),
4.12–4.02 (m, 2H), 3.47 (dd, J=15.9, 10.5 Hz, 1H), 3.12 (dd, J=15.9, 5.8 Hz, 1H), 1.09 (t, J=7.1 Hz,
3H). 13C NMR {1H}(100 MHz, CDCl3): δ 172.8 (C), 147.3 (C), 143.4 (C), 129.3 (2 CH), 128.3
(C), 127.5 (CH), 124.9 (CH), 122.5 (CH), 119.5 (CH), 119.4 (2 CH), 109.2 (CH), 65.6 (CH), 61.3
(CH2), 33.8 (CH2), 14.2 (CH3).
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Compound 5m: Following the general procedure B, the reaction performed with 4m (189 mg, 0.5
mmol, 1.0 equiv) afforded, after purification by FC (50 mL SiO2, PE/Et2O:90/10 then 80/20), the
desired product 5m (109 mg, 73%) as a pale yellow paste. Rf (PE/EtOAc:80/20, UV+KMnO4):
0.43. HRMS (ESI): m/z calcd for C18H20NO3 (M+H)+ 298.1438, found 2981436. H NMR (400
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MHz, CDCl3): δ 7.28 (d, J=9.1 Hz, 2H), 7.16 (ddd, J=7.2, 1.2, 0.5, 1H), 7.11–7.07 (m, 1H), 6.95
(d, J=9.1 Hz, 2H), 6.79–6.75 (m, 2H), 4.77 (dd, J=10.4, 7.4 Hz, 1H), 4.26–4.16 (m, 2H), 3.85 (s,
3H), 3.58 (dd, J=15.9, 10.4 Hz, 1H), 3.28 (dd, J=15.9, 7.4 Hz, 1H), 1.24 (t, J=7.1 Hz, 3H). 13C
NMR{1H} (100 MHz, CDCl3): δ 172.8 (C), 156.3 (C), 149.3 (C), 136.9 (C), 127.6 (CH), 127.5
(C), 124.6 (CH), 123.8 (2 CH), 118.9 (CH), 114.7 (2 CH), 108.3 (CH), 66.8 (CH), 61.2 (CH2), 55.5
(CH3), 33.9 (CH2), 14.2 (CH3).
Compound 5n: Following the general procedure B, the reaction performed with 4n (236 mg, 0.5
mmol, 1.0 equiv) afforded, after purification by FC (50 mL SiO2, PE/Et2O:97.5/2.5 then 95/5), the
desired product 5n (125 mg, 66%, dr=1.7:1) as a white solid. Rf (PE/Et2O:95/5, UV+KMnO4):
0.47. mp: 48–58 °C. HRMS (ESI): m/z calcd for C25H31NNaO2 (M+Na)+ 400.2247, found
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400.2248. H NMR (400 MHz, CDCl3): (2 diastereomers) δ 7.25–7.21 (m, 4H), 7.15–7.11 (m,
4H), 7.05–7.03 (m, 2H), 6.99–6.96 (m, 4H), 6.93–6.89 (m, 2H), 6.69–6.65 (m, 2H), 4.81 (dd,
J=10.3, 7.6 Hz, 1H), 4.68 (dd, J=10.4, 5.5 Hz, 1H), 4.60–4.52 (m, 2H), 3.49–3.38 (m, 2H), 3.15–
3.04 (m, 2H), 1.83–1.78 (m, 2H), 1.56–1.48 (m, 6H), 1.40–1.20 (m, 4H), 1.22–1.12 (m, 2H), 0.94–
0.84 (m, 4H), 0.79 (d, J=6.6 Hz, 3H), 0.77 (d, J=6.6 Hz, 3H), 0.68 (d, J=7.0 Hz, 3H), 0.63 (d, J=7.0
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Hz, 3H), 0.55 (d, J=7.0 Hz, 3H), 0.44 (d, J=6.9 Hz, 3H). 13C NMR {1H} (100 MHz, CDCl3): (2
diastereomers) δ 172.6 (C), 172.3 (C), 147.4 (C), 147.2 (C), 143.2 (C), 143.1 (C), 129.3 (2 CH),
129.3 (2 CH), 128.4 (C), 128.2 (C), 127.6 (CH), 127.5 (CH), 124.8 (2 CH), 122.4 (CH), 122.2
(CH), 119.4 (CH), 119.4 (CH), 119.3 (2 CH), 119.0 (2 CH), 108.8 (CH), 108.4 (CH), 75.3 (CH),
75.3 (CH), 65.7 (CH), 65.6 (CH), 46.9 (CH), 46.8 (CH), 40.5 (CH2), 40.4 (CH2), 34.2 (2 CH2), 34.1
(CH2), 33.8 (CH2), 31.4 (CH), 31.4 (CH), 26.0 (CH), 25.5 (CH), 23.2 (CH2), 23.0 (CH2), 22.1
(CH3), 22.0 (CH3), 20.9 (CH3), 20.8 (CH3), 16.0 (CH3), 15.7 (CH3).
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Compound 5o: Following the general procedure A, the reaction performed with 4o (197 mg, 0.5
mmol, 1.0 equiv) afforded, after purification by FC (50 mL SiO2, PE then PE/EtOAc:95/5), the
desired product 5o (92 mg, 59%, dr=3.8:1) as a pale yellow solid. Rf (PE/EtOAc:90/10,
UV+KMnO4): 0.95. mp: 110–112 °C. HRMS (ESI): m/z calcd for C23H24N (M+H)+ 314.1903,
found 314.1903. 1H NMR (400 MHz, CDCl3): (major diastereomer) δ 7.35 (d, J=8.1 Hz, 2H), 7.32
(d, J=8.0 Hz, 2H), 7.21 (t, J=7.6 Hz, 2H), 7.14–7.08 (m, 1H), 7.07 (d, J=6.1 Hz, 2H), 6.94 (d, J=7.3
Hz, 1H), 6.77 (t, J=7.7 Hz, 1H), 6.54 (t, J=7.3 Hz, 1H), 5.99 (d, J=7.9 Hz, 1H), 4.62 (dd, J=10.6,
9.0 Hz, 1H), 4.33–4.25 (m, 1H), 3.28 (dd, J=15.6, 9.0 Hz, 1H), 2.91 (dd, J=15.6, 10.6 Hz, 1H), 2.24
(s, 3H), 1.37 (d, J=6.9 Hz, 3H). 13C NMR{1H} (100 MHz, CDCl3): (major diastereomer) δ 149.9
(C), 142.7 (C), 140.6 (C), 137.4 (C), 129.4 (2 CH), 129.3 (C), 128.4 (2 CH), 127.6 (2 CH), 127.1
(CH), 126.9 (2 CH), 126.7 (CH), 124.2 (CH), 117.8 (CH), 109.7 (CH), 67.9 (CH), 53.7 (CH), 39.8
(CH2), 21.3 (CH3), 12.8 (CH3).
Compound 5p: Following the general procedure A, the reaction performed with 4p (110 mg, 0.25
mmol, 1.0 equiv) afforded, after purification by FC (50 mL SiO2, PE/Et2O:99/1 then 97.5/2.5), the
desired product 5p (74 mg, 82%, dr=4.3:1) as a colorless oil. Rf (PE/Et2O:95/5, UV+KMnO4):
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0.74. HRMS (ESI): m/z calcd for C27H26N (M+H)+ 364.2060, found 364.2055. H NMR (300
MHz, CDCl3): (major diastereomer) δ 7.95–7.84 (m, 3H), 7.53–7.38 (m, 4H), 7.14–7.01 (m, 6H),
6.71 (t, J=7.7 Hz, 1H), 6.51 (d, J=7.8 Hz, 1H), 5.39 (q, J=6.8 Hz, 1H), 4.42 (dd, J=10.1, 5.6 Hz,
1H), 3.45 (dd, J=15.9, 10.1 Hz, 1H), 2.91 (dd, J=15.9, 5.6 Hz, 1H), 2.40 (s, 3H), 1.55 (d, J=6.8 Hz,
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3H). 13C NMR{1H} (75 MHz, CDCl3): (major diastereomer) δ 151.0 (C), 142.6 (C), 137.1 (C),
137.0 (C), 133.8 (C), 132.0 (C), 129.1 (2 CH), 128.9 (CH), 128.2 (C), 128.1 (CH), 127.6 (CH),
126.8 (2 CH), 126.4 (CH), 125.6 (CH), 125.2 (CH), 124.8 (CH), 124.4 (CH), 123.8 (CH), 116.7
(CH), 105.8 (CH), 64.9 (CH), 51.4 (CH), 39.5 (CH2), 21.3 (CH3), 17.9 (CH3).
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Synthesis of 1,2,3ꢀtrisubstituted indoline 5q:
Compound 4q: In air, a flameꢀdried 25 mL roundꢀbottom flask equipped with a stir bar was charged
with Zn (368 mg, 5.6 mmol, 3.75 equiv), closed with a septum and flushed with Ar. CH3CN (1 mL)
and TFA (29 ꢁL, 0.37 mmol, 25 mol%) were successively added and the mixture was stirred at
room temperature for 5 min. The mixture was cooled down to 0 °C (ice/water bath) and 4ꢀ
tolualdehyde 3a (0.2 mL, 1.65 mmol, 1.1 equiv) and benzylamine 2b (163 ꢁL, 1.5 mmol, 1.0 equiv)
were added in one portion. oꢀbromobenzyl bromide 1d (1.0 g, 3.75 mmol, 2.5 equiv) in solution in
CH3CN (2 mL, C=0.5 M) was added dropwise (1 drop/s) at 0 °C, and the reaction was stirred for 1
h at 0 °C. Then, the reaction mixture was poured into sat aq NH4Cl (50 mL) and the solution was
extracted with EtOAc (2x25 mL). The combined organic layers were washed with brine (50 mL),
dried (Na2SO4) and evaporated. The crude material was purified by FC (100 mL SiO2,
PE/EtOAc:97.5/2.5 then 95/5) to afford the desired product 4q (296 mg, 50%, dr=2:1) as a pale
yellow oil. Rf (PE/EtOAc:90/10, UV+KMnO4): 0.52 & 0.57. HRMS (ESI): m/z calcd for
C23H25BrN (M+H)+ 394.1165, found 394.1164. H NMR (400 MHz, CDCl3): (2 diastereomers) δ
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7.70 (dd, J=7.9, 1.1 Hz, 1H), 7.60 (dd, J=8.0, 1.0 Hz, 1H), 7.43–7.29 (m, 18H), 7.25–7.23 (m, 2H),
7.20–7.14 (m, 4H), 4.09 (d, J=5.5 Hz, 1H), 3.83–3.80 (m, 2H), 3.76–3.73 (m, 5H), 3.52–3.46 (m,
2H), 2.50 (s, 3H), 2.44 (s, 3H), 1.86 (br s, 2H), 1.40 (d, J=7.1 Hz, 3H), 1.04 (d, J=6.8 Hz, 3H). 13C
NMR{1H} (100 MHz, CDCl3): (2 diastereomers) δ 144.0 (C), 143.7 (C), 140.8 (C), 140.5 (C),
139.2 (C), 138.9 (C), 136.9 (C), 136.3 (C), 133.0 (CH), 133.0 (CH), 129.0 (3 CH), 128.9 (CH),
128.8 (2 CH), 128.5 (2 CH), 128.3 (CH), 128.2 (4 CH), 128.2 (4 CH), 127.9 (CH), 127.8 (2 CH),
127.7 (2 CH), 127.2 (CH), 126.7 (CH), 125.8 (C), 125.1 (C), 66.5 (CH), 64.6 (CH), 51.5 (CH2),
51.0 (CH2), 44.8 (CH), 44.6 (CH), 21.3 (CH3), 21.2 (CH3), 18.7 (CH3), 15.1 (CH3).
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Compound 5q: In air, a flameꢀdried 25 mL Schlenk flask equipped with a stir bar was charged with
βꢀarylethylamine 4q (192 mg, 0.5 mmol, 1.0 equiv) and toluene (2.5 mL, C=0.2 M). The solution
was degazed by Ar bubbling for 5 min. tꢀBuOK (112 mg, 1.0 mmol, 2.0 equiv) and PdCl2(PPh3)2
(18 mg, 0.025 mmol, 5 mol%) were successively added under an Ar flow and the flask was sealed
(glass stopper). The reaction was heated at 110 °C overnight (14 h). Then, the reaction mixture was
filtered through a pad of Celite (10 mL), thoroughly rinsed with EtOAc (ca. 50 mL), and the filtrate
was evaporated. The crude material was purified by FC (50 mL SiO2, PE/EtOAc:97.5/2.5 then 95/5)
to afford the desired product 5q (131 mg, 86%, dr=2:1) as a pale yellow solid. Rf (PE/EtOAc:95/5,
UV+KMnO4): 0.70 & 0.80. mp: 68–70 °C. HRMS (ESI): m/z calcd for C23H24N (M+H)+
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314.1903, found 314.1900. H NMR (400 MHz, CDCl3): (2 diastereomers) δ 7.55 (d, J=8.0 Hz,
2H), 7.45–7.42 (m, 8H), 7.38–7.27 (m, 8H), 7.24–7.19 (m, 4H), 6.93–6.88 (m, 2H), 6.61–6.57 (m,
2H), 4.89 (d, J=8.9 Hz, 1H), 4.60 (d, J=15.8 Hz, 1H), 4.50 (d, J=15.7 Hz, 1H), 4.22 (d, J=10.4 Hz,
1H), 4.14–4.10 (m, 2H), 3.70–3.63 (m, 1H), 3.43–3.39 (dq, J=13.4, 6.7 Hz, 1H), 2.52 (s, 3H), 2.50
(s, 3H), 1.48 (d, J=6.7 Hz, 3H), 1.03 (d, J=7.2 Hz, 3H). 13C NMR {1H}(100 MHz, CDCl3): (2
diastereomers) δ 152.0 (C), 151.9 (C), 138.6 (2 C), 138.5 (2 C), 137.5 (C), 137.0 (C), 135.1 (C),
134.6 (C), 133.5 (CH), 130.5 (CH), 129.4 (2 CH), 129.0 (2 CH), 128.5 (2 CH), 128.4 (2 CH), 128.0
(2 CH), 127.7 (2 CH), 127.6 (2 CH), 127.6 (2 CH), 126.9 (CH), 126.9 (CH), 123.7 (CH), 122.7
(CH), 118.2 (CH), 118.0 (CH), 107.9 (CH), 107.4 (CH), 78.4 (CH), 72.4 (CH), 51.4 (CH2), 50.7
(CH2), 45.8 (CH), 40.7 (CH), 21.3 (CH3), 21.0 (CH3), 16.7 (CH3), 16.5 (CH3).
Oxidation of indoline 5k to indole 6:25 In air, a flameꢀdried 25 mL roundꢀbottom flask equipped
with a stir bar was charged with 5k (100 mg, 0.35 mmol, 1.0 equiv), toluene (4 mL, C=0.1 M) and
MnO2 (124 mg, 1.4 mmol, 4.0 equiv). The flask was equipped with a condenser closed by a septum
opened to air by a needle. The reaction was heated at reflux for 96 h. Then, the reaction mixture was
filtered through a pad of Celite (10 mL), thoroughly rinsed with CH2Cl2 (ca. 50 mL), and the filtrate
was evaporated. The crude material was purified by FC (50 mL SiO2, PE/Et2O:95/5 then 90/10) to
afford the desired product 6 (90 mg, 90%) as a white solid. Rf (PE/Et2O:90/10, UV+KMnO4):
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0.43. mp: 57–58 °C (litt. 55–56 °C). HRMS (ESI): m/z calcd for C18H18NO2 (M+H)+ 280.1332,
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found 280.1332. H NMR (400 MHz, CDCl3): δ 7.59 (d, J=8.0 Hz, 1H), 7.29 (d, J=0.7 Hz, 1H),
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7.22 (dd, J=8.4, 0.7 Hz, 1H), 7.18 (dd, J=6.8, 1.2 Hz, 1H), 7.15–7.02 (m, 4H), 6.93 (d, J=6.8 Hz,
2H), 5.72 (s, 2H), 4.20 (q, J=7.1 Hz, 2H), 1.23 (t, J=7.1 Hz, 3H). 13C NMR{1H} (100 MHz,
CDCl3): δ 162.0 (C), 139.6 (C), 138.4 (C), 128.6 (2 CH), 127.8 (C), 127.2 (CH), 126.3 (2 CH),
126.2 (C), 125.3 (CH), 122.7 (CH), 120.9 (CH), 111.1 (CH), 110.9 (CH), 60.7 (CH2), 47.9 (CH2),
14.4 (CH3).
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Acknowledgments
The financial support of this work by the CNRS and the University ParisꢀEst (PhD grants to A. P.
and J. P.) is gratefully acknowledged.
Supporting Information
Copies of NMR spectra for all compounds.
References
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21 One equivalent of the organometallic reagent is required to trap the water generated by the imine formation.
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When the reaction was performed on a larger scale (2.5 mmol), increased amounts of 1 (2.5 equiv) and Zn (3.75
equiv) were necessary to balance the dimerization of the organozinc reagent.
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Other attempts carried out by changing the nature of halogen atom (benzylic chloride in spite of bromide) or the
reducing metal (Mn in spite of Zn) gave only lower amounts of the expected product. Moreover, the introduction of a
phenyl substituent in the benzylic position has also been evaluated but this modification resulted in almost exclusive
dimerization of this starting material.
24 Hlasta, D. J.; Luttinger, D.; Perrone, M. H.; Silbernagel, M. J.; Ward, S. J.; Haubrich, D. R. J. Med. Chem. 1987, 30,
1555–1562.
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Sechi, M.; Derudas, M.; Dallocchio, R. Dessì, A.; Bacchi, A.; Sannia, L.; Carta, F.; Palomba, M.; Ragab, O.; Chan,
C.; Shoemaker, R.; Sei, S.; Dayam, R.; Neamati, N. J. Med. Chem. 2004, 47, 5298–5310.
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