Iron(III)-Catalyzed (4 + 2)-Cycloannulation of 2-Hydroxy Ketoxime Ethers with Indol-2-ylamides: Synthesis of Indole-Fused 2-Piperidinones

Article abstract of DOI:10.1021/acs.joc.9b00261

A highly regio- and diastereoselective (4 + 2)-cycloannulation process of indanone-derived 2-hydroxy ketoxime ethers with 1,4-bisnucleophilic indol-2-ylamides has been developed. In the presence of 5 mol % FeCl₃, densely functionalized 2-piperidinones containing two new σ-bonds and two vicinal quaternary stereogenic centers were formed under mild reaction conditions in a one-pot operation. Moreover, most of the products directly precipitated out of the solution and were isolated by simple filtration without purification by column chromatography.

Full text of DOI:10.1021/acs.joc.9b00261

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Note
Iron(III)-Catalyzed (4+2)-Cycloannulation of 2-Hydroxy Ketoxime Ethers
with Indol-2-ylamides: Synthesis of Indole-Fused 2-Piperidinones
Marcel Schlegel, and Christoph Schneider
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00261 • Publication Date (Web): 27 Mar 2019
Downloaded from http://pubs.acs.org on March 27, 2019
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Iron(III)-Catalyzed (4+2)-Cycloannulation of
2-Hydroxy Ketoxime Ethers with Indol-2-ylamides:
Synthesis of Indole-Fused 2-Piperidinones
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Marcel Schlegel and Christoph Schneider*
Institut für Organische Chemie, Universität Leipzig, Johannisallee 29, D-04103 Leipzig,
Germany
*Email: schneider@chemie.uni-leipzig.de
ABSTRACT:
A highly regio- and diastereoselective (4+2)-cycloannulation process of indanone-derived
2-hydroxy ketoxime ethers with 1,4-bisnucleophilic indol-2-ylamides has been developed. In
the presence of 5 mol-% FeCl3, densely functionalized 2-piperidinones containing two new -
bonds and two vicinal quaternary stereogenic centers were formed under mild reaction
conditions in a one-pot operation. Moreover, most of the products directly precipitated out of
the solution and were isolated by simple filtration without purification by column
chromatography.
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The indole skeleton represents one of the most abundant structural motifs in natural products
and pharmaceutically relevant compounds.1 In particular, indole-fused 2-piperidinones are not
only important synthetic precursors for drug discovery2 but also exhibit interesting biological
activities themselves (Figure 1).3‒8 For example, several substituted tetrahydro-1H-pyrido[3,4-
b]indol-1-ones 1 were identified as metabotropic receptor (mGluR1) antagonists,3 protein
kinase D (PKD) inhibitors4 or MAP kinase-actived protein kinase 2 (MK2) inhibitors.5
Moreover, rhetsinine (2), isolated from Evodia rutaecarpa, appears promising for the
treatment of diabetic complications due to its aldose reductase inhibitory effect.6 The alkaloid
bauerine A (3) exhibits significant cytotoxic and antiviral activities7 and alosetron (4) is an
important serotonin receptor antagonist.8
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Figure 1. Biologically Active Indole-Fused 2-Piperidinones.
We have recently established various Lewis acid-catalyzed transformations of 2-hydroxy
ketoxime ethers 5 including highly versatile Friedel-Crafts reactions (FCRs)9 as well as
multicomponent reactions toward complex 2-pyrrolines.10,11 We proposed that these reactions
proceeded through putative 1-azaallyl cations and provided computational evidence for their
intermediacy.10 Based upon these studies we envisioned novel (4+2)-cycloannulation
reactions when 1,4-bisnucleophiles were employed to capture the intermediate 1-azaallyl
cations. Regioselective addition of Nu1 would form addition product A followed by
cyclization via Nu2 onto the ketoxime ether to generate the six-membered cycloannulation
product B (Scheme 1).
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Scheme 1. Conceptual Design.
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As heteroarenes proved to be suitable nucleophiles for FeCl3-catalyzed FCRs12 in our
previous work,9 we initially investigated different bisnucleophilic indoles for the envisioned
(4+2)-cycloannulation of 2-hydroxy ketoxime ether 5a under the established reaction
conditions (Scheme 2). It turned out that treatment of 5a with N-methoxy indol-2-ylamide 6a
and 5 mol-% FeCl3 in CH2Cl2 at 40 °C furnished a colorless precipitate within just 10
minutes. After filtration, the indole-fused 2-piperidinone 7a was obtained in excellent yield of
92% and as a single diastereomer.13 As neither secondary indol-2-ylamins (8) nor N-alkyl
indol-2-ylamides (9)14 enabled access to the corresponding N-heterocycles, we settled on N-
alkoxy indol-2-ylamides 6 for the (4+2)-cycloannulation.
Scheme 2. Optimization of the 1,4-Bisnucleophile.
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With a suitable 1,4-bisnucleophile in hand, we next focused on the substrate scope of this
reaction (Scheme 3). 2-Hydroxy ketoxime ethers 5 with electron-rich aryl groups (R3)
delivered 7b‒d in typically excellent yields within 20 minutes. Compounds 7b and 7d with
substituents in meta-position of the phenyl ring were isolated in quantitative yields by column
chromatography as no precipitation in the reaction medium occurred. The para-chlorophenyl
substituted product 7e was obtained in 75% yield after 2 hours due to higher dilution of the
reaction medium.15 Furthermore, alcohol 5f with a strongly electron-withdrawing para-
(trifluoromethyl)phenyl residue (R3) was tolerated likewise and provided 7f in good yield.
The aryl groups (R3) could also be replaced by a methyl group to form N-heterocycle 7g
which was isolated by column chromatography. Alcohols 5h-i with a modified indanone
backbone (R1 = Br, R2 = Me, R3 = Ph) or a O-TBS-protecting group (R1 = H, R2 = TBS, R3 =
Ph) furnished products 7h and 7i, respectively, in high yields after filtration. For the latter
compound, column chromatography of the residual filtrate gave rise to another 19% of
product totaling up to 89% overall yield.16 2-Hydroxy ketoxime ethers with 1-tetralone- or
cyclopentanone-derived scaffolds were no feasible substrates for the (4+2)-cycloannulation as
rapid decomposition of the corresponding products was observed under the established
reaction conditions.
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Another six products 7j-o were synthesized from 2-hydroxy ketoxime ether 5a and different
N-alkoxy indol-2-ylamides 6. The N-methoxy group of 6 (R5 = Me) was apparently crucial for
the high insolubility of 7 as N-benzyloxy lactam 7j was completely dissolved in the reaction
medium. Thus, isolation of 7j was achieved by column chromatography followed by
recrystallization in 85% yield. Finally, variation of the indole scaffold of 7 gave rise to the
products 7k‒o in good yields directly after filtration (Scheme 3).17
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Scheme 3. Substrate Scope of the (4+2)-Cycloannulation.
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Reaction conditions: 5 (0.22 mmol), indol-2-ylamide 6 (0.20 mmol), FeCl3 (10 µmol) in CH2Cl2 (0.6 mL), 40
°C. Yields of 7 after filtration of the crude reaction mixture. [a] Isolated yield after column chromatography. [b]
CH2Cl2 (1.5 mL). [c] Isolated yield after column chromatography followed by recrystallization
(EtOAc/hexanes).
The reactivity of the resulting aminal moiety of compound 7j was further investigated by a
subsequent transformation (Scheme 4). Under Lewis acidic activation we observed the
substitution of methoxyamine by external nucleophiles as demonstrated by the reduction of 7j
with Et3SiH and BF3•OEt2 generating 2-piperidinone 10 with high diastereoselectivity.
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Scheme 4. Reduction of the Aminal.
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In summary, we have established a novel (4+2)-cycloannulation reaction of 2-hydroxy
ketoxime ethers 5 and N-alkoxy indol-2-ylamides 6 for the rapid assembly of multiply
substituted indole-fused 2-piperidinones 7 in high yields and with excellent regio- and
diastereoselectivity. The present methodology benefits from readily accessible starting
materials, inexpensive FeCl3-catalysis, operational simplicity, short reaction times and, in
particular, the straightforward isolation of most of the products by simple filtration. Moreover,
its synthetic value was further demonstrated by a nucleophilic substitution reaction of the
aminal moiety. The investigation of other 1,4-bisnucleophiles for respective transformations
is currently ongoing in our laboratory.
EXPERIMENTAL SECTION
General methods. All reactions to the final products were carried out in oven dried glassware
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and in dry solvents under ambient atmosphere. H- and C{1H}-NMR spectra were recorded
in DMSO-d6 or CDCl3 at 26 °C using a Mercury plus 300 MHz and a Bruker Avance DRX
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400 MHz spectrometer. The spectra were referenced to residual DMSO-d6 (2.50 ppm, H;
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39.52 ppm, 13C{1H}) or CDCl3 (7.26 ppm, H; 77.16 ppm, 13C{1H}). Chemical shifts are
reported in ppm, multiplicities are indicated by s (singlet), br s (broad singlet), d (doublet), t
(triplet), q (quartet), p (pentet), m (multiplet), and related permutations. Coupling constants, J,
are reported in Hertz. All high-resolution mass spectra (HRMS) were recorded on a Bruker
Daltonics Apex II FT-ICR with a TOF mass analyzer. Melting points were determined
uncorrected on a Boetius measurement device. Dichloromethane was dried using a MBraun
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Solvent Purification System (SPS) 800. Solvents for aqueous work-up and column
chromatography were of technical grade and distilled from the indicated drying reagents:
dichloromethane (CaH2), diethyl ether (KOH), methyl-tert-butyl ether (KOH), ethyl acetate
(CaCl2) and hexane (KOH). Flash column chromatography was performed by using silica gel
(Fluka, 60 Å, 230 –400 mesh size). Analytical thin-layer chromatography (TLC) was
performed on Macherey-Nagel pre-coated TLC-sheets AlugramXtra SIL G/UV254.
Visualization of the spots was achieved by UV-light and treatment with a vanillin staining
solution.
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2-Hydroxy ketoxime ethers 5a-i were synthesized according to procedures by Schneider et
al.9,11 Indol-2-ylamine 8 and N-alkyl indol-2-ylamide 9 were synthesized according to
literature procedures.18 The structures of all starting materials are displayed in Figure S1 of
the SI.
General Procedure for the Synthesis of N-Alkoxy Indol-2-ylamides 6
According to a procedure by Zhao et al.,19 indol-2-carboxylic acids (1.00 equiv) were
suspended in abs. CH2Cl2 (0.33 M) and cooled down to 0 °C. Oxalyl chloride (1.20 equiv) was
added dropwise followed by 2-3 droplets of abs. DMF. The reaction mixture was stirred at
room temperature for 2 h. After complete reaction, the solvent was removed under reduced
pressure and the crude mixture was dissolved in EtOAc (2.5 mL/mmol of carboxylic acid).
In a separate flask, K2CO3 (2.00 equiv) was dissolved in a 2:1-mixture of EtOAc and water
(0.17 M) and treated with methoxyamine hydrochloride (1.20 equiv) portionwise at 0 °C.
After stirring for 5 min at the same temperature, the solution of crude acid chloride was added
dropwise and the mixture was stirred at room temperature overnight. The organic phase was
separated and the aqueous one was extracted twice with EtOAc. The combined organic phases
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were dried over Na2SO4, filtered and the solvent was removed under reduced pressure. If not
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otherwise stated, the products 6 were directly used without further purification.
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N-Methoxy-1H-indol-2-ylamide 6a was obtained from 1H-indole-2-carboxylic acid (1.61 g,
10.0 mmol, 1.00 equiv), oxalyl chloride (1.03 mL, 12.0 mmol, 1.20 equiv) and 2-3 droplets
DMF in 30 mL CH2Cl2 followed by treatment with K2CO3 (2.77 g, 20.0 mmol, 2.00 equiv)
and MeONH2•HCl (1.00 g, 12.0 mmol, 1.20 equiv) in 60 mL EtOAc/H2O (2:1). Compound
6a was obtained as a colorless solid (1.88 g, 99%). The analytical data are in agreement with
literature.19
N-Benzyloxy-1H-indol-2-ylamide 6b was obtained from 1H-indole-2-carboxylic acid (1.61
g, 10.0 mmol, 1.00 equiv), oxalyl chloride (1.03 mL, 12.0 mmol, 1.20 equiv) and 2-3 droplets
DMF in 30 mL CH2Cl2 followed by treatment with K2CO3 (2.77 g, 20.0 mmol, 2.00 equiv)
and BnONH2•HCl (1.92 g, 12.0 mmol, 1.20 equiv) in 60 mL EtOAc/H2O (2:1). Compound 6b
was obtained after recrystallization from EtOAc/hexane as a colorless solid (2.42 g, 91%). Mp
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138-139 °C; H NMR (300 MHz, DMSO-d6) δ 11.83 (bs, 1H), 11.73 (bs, 1H), 7.62 (d,
J = 8.0 Hz, 1H), 7.51-7.46 (m, 3H), 7.44-7.34 (m, 3H), 7.21 (ddd, J = 8.0 7.0, 1.0 Hz, 1H),
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7.08-7.03 (m, 2H), 4.99 (s, 2H); C{1H} NMR (75 MHz, DMSO-d6) δ 159.9, 136.6, 135.9,
128.9, 128.8, 128.4 (3x), 127.0, 123.6, 121.6, 119.9, 112.3, 102.8, 77.4; IR (KBr) ṽ 3347,
3229, 3089, 3059, 3032, 1644, 1531, 1497, 1486, 1454, 1417, 1342, 1312, 1260, 1127, 1038,
808, 743, 699; HR-MS (ESI+) m/z: [M+Na]+ Calcd. for C16H14N2O2Na 289.0948; Found:
289.0945.
N-Methoxy-1H-indol-2-ylamide 6c was obtained from 5-methyl-1H-indole-2-carboxylic
acid (350 mg, 2.00 mmol, 1.00 equiv), oxalyl chloride (210 µL, 2.40 mmol, 1.20 equiv) and
2-3 droplets DMF in 6.0 mL CH2Cl2 followed by treatment with K2CO3 (554 mg, 4.00 mmol,
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2.00 equiv) and MeONH2•HCl (200 mg, 2.40 mmol, 1.20 equiv) in 12 mL EtOAc/H2O (2:1).
Compound 6c was obtained as a yellowish solid (284 mg, 70%).
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Mp 141-143 °C; H NMR (300 MHz, DMSO-d6) δ 11.70 (bs, 1H), 11.55 (bs, 1H), 7.37 (s,
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1H), 7.31 (d, J = 8.5 Hz, 1H), 7.02 (d, J = 8.5 Hz, 1H), 6.90 (s, 1H), 3.73 (s, 3H), 2.36 (s, 3H);
13C{1H} NMR (100 MHz, DMSO-d6) δ 159.6, 134.9, 128.7, 128.4, 127.2, 125.4, 120.8,
112.0, 102.1, 63.6, 21.1; IR (KBr) ṽ 3327, 3202, 2980, 1618, 1563, 1537, 1443, 1324, 1120,
1048, 798; HR-MS (ESI+) m/z: [M+Na]+ Calcd. for C11H12N2O2Na 227.0791; Found:
227.0796.
N-Methoxy-1H-indol-2-ylamide 6d was obtained from 5-methoxy-1H-indole-2-carboxylic
acid (382 mg, 2.00 mmol, 1.00 equiv), oxalyl chloride (210 µL, 2.40 mmol, 1.20 equiv) and
2-3 droplets DMF in 6.0 mL CH2Cl2 followed by treatment with K2CO3 (554 mg, 4.00 mmol,
2.00 equiv) and MeONH2•HCl (200 mg, 2.40 mmol, 1.20 equiv) in 12 mL EtOAc/H2O (2:1).
Compound 6d was obtained as a yellowish solid (433 mg, 98%). Mp 203-205 °C
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(decomposition); H NMR (400 MHz, DMSO-d6) δ 11.72 (bs, 1H), 11.55 (bs, 1H), 7.32 (d,
J = 9.0 Hz, 1H), 7.08 (d, J = 2.5 Hz. 1H), 6.93 (d, J = 2.0 Hz, 1H), 6.85 (dd, J = 9.0, 2.5 Hz,
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1H), 3.75 (s, 3H), 3.74 (s, 3H); C{1H} NMR (100 MHz, DMSO-d6) δ 159.6, 153.9, 131.8,
129.1, 127.3, 114.8, 113.1, 102.3, 102.3, 63.6, 55.2; IR (KBr) ṽ 3289, 3170, 2989, 2959,
2940, 1640, 1533, 1480, 1453, 1435, 1425, 1257, 1236, 1199, 1164, 1122, 1058, 1027, 932,
844, 816, 804, 760, 753, 731, 725; HR-MS (ESI+) m/z: [M+Na]+ Calcd. for C11H12N2O3Na
243.0740; Found: 243.0737.
N-Methoxy-1H-indol-2-ylamide 6e was obtained from 5,6-dimethoxy-1H-indole-2-
carboxylic acid (442 mg, 2.00 mmol, 1.00 equiv), oxalyl chloride (210 µL, 2.40 mmol, 1.20
equiv) and 2-3 droplets DMF in 6.0 mL CH2Cl2 followed by treatment with K2CO3 (554 mg,
4.00 mmol, 2.00 equiv) and MeONH2•HCl (200 mg, 2.40 mmol, 1.20 equiv) in 12 mL
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EtOAc/H2O (2:1). Compound 6e was obtained as a brown solid (482 mg, 96%). Mp 168-169
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°C; H NMR (400 MHz, DMSO-d6) δ 11.56 (bs, 1H), 11.39 (bs, 1H), 7.07 (s, 1H), 6.88 (m,
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2H), 3.77 (s, 3H), 3.75 (s, 3H), 3.72 (s, 3H); C{1H} NMR (100 MHz, DMSO-d6) δ 159.9,
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148.5, 145.4, 131.6, 126.9, 119.7, 102.9, 102.6, 94.5, 63.6, 55.7, 55.4; IR (KBr) ṽ 3303, 2981,
2937, 1645, 1529, 1499, 1466, 1439, 1409, 1286, 1253, 1224, 1203, 1148, 1121, 1052, 1007,
847; HR-MS (ESI+) m/z: [M+Na]+ Calcd. for C12H14N2O4Na 273.0846; Found: 273.0848.
N-Methoxy-1H-indol-2-ylamide 6f was obtained from 5-chloro-1H-indole-2-carboxylic acid
(391 mg, 2.00 mmol, 1.00 equiv), oxalyl chloride (210 µL, 2.40 mmol, 1.20 equiv) and 2-3
droplets DMF in 6.0 mL CH2Cl2 followed by treatment with K2CO3 (554 mg, 4.00 mmol,
2.00 equiv) and MeONH2•HCl (200 mg, 2.40 mmol, 1.20 equiv) in 12 mL EtOAc/H2O (2:1).
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Compound 6f was obtained as a orange solid (439 mg, 98%). Mp 158-159 °C; H NMR
(400 MHz, DMSO-d6) δ 11.91 (bs, 1H), 11.86 (bs, 1H), 7.70 (d, J = 2.0 Hz, 1H), 7.43 (d,
J = 8.5 Hz, 1H), 7.19 (dd, J = 8.5, 2.0 Hz, 1H), 6.98 (d, J = 2.0 Hz, 1H), 3.74 (s, 3H); 13C{1H}
NMR (100 MHz, DMSO-d6) δ 159.0, 134.9, 130.3, 128.0, 124.4, 123.6, 120.6, 113.9, 102.1,
63.6; IR (KBr) ṽ 3368, 3251, 2988, 2940, 1643, 1532, 1499, 1439, 1421, 1329, 1421, 1329,
1263, 1132, 1052, 917, 870, 797, 761, 582; HR-MS (ESI+) m/z: [M+Na]+ Calcd. for
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C10H9 ClN2O2Na 247.0245; Found: 247.0240.
N-Methoxy-1H-indol-2-ylamide 6g was obtained from 5-fluoro-1H-indole-2-carboxylic acid
(358 mg, 2.00 mmol, 1.00 equiv), oxalyl chloride (210 µL, 2.40 mmol, 1.20 equiv) and 2-3
droplets DMF in 6.0 mL CH2Cl2 followed by treatment with K2CO3 (554 mg, 4.00 mmol,
2.00 equiv) and MeONH2•HCl (200 mg, 2.40 mmol, 1.20 equiv) in 12 mL EtOAc/H2O (2:1).
Compound 6g was obtained as a yellowish solid (416 mg, >99%). Mp 188-190 °C
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(decomposition); H NMR (400 MHz, DMSO-d6) δ 11.82 (bs, 2H), 7.44-7.38 (m, 2H), 7.05
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(td, J = 9.0, 2.5 Hz, 1H), 6.98 (s, 1H), 3.74 (s, 3H); C{1H} NMR (100 MHz, DMSO-d6) δ
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159.1, 157.2, (d, J = 233.0 Hz), 133.3, 130.5, 127.0 (d, J = 10.5 Hz), 113.5 (d, J = 10.0 Hz),
112.3 (d, J = 26.5 Hz), 105.8 (d, J = 23.0 Hz), 102.5, 63.6; IR (KBr) ṽ 3366, 3216, 2987,
1635, 1538, 1506, 1483, 1446, 1426, 1337, 1267, 1228, 1161, 1120, 1112, 1052, 954, 935,
864, 795, 759, 595, 546, 519; HR-MS (ESI+) m/z: [M+Na]+ Calcd. for C10H9FN2O2Na
231.0540; Found: 231.0544.
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General Procedure for the (4+2)-Cycloannulation
2-Hydroxy ketoxime ether 5 (0.22 mmol, 1.1 equiv), indol-2-ylamide 6 (0.20 mmol,
1.0 equiv) and FeCl3 (10 µmol, 5.0 mol-%) were dissolved in 0.6 mL CH2Cl2. The reaction
mixture was stirred at 40 °C for the indicated time. After complete reaction, 5.0 mL Et2O
were added and the mixture was stirred at 40 °C for 10 minutes. The resulting precipitation of
7 was filtered and washed twice with 2.0 mL Et2O. In case of no precipitation, the solvent of
the reaction mixture was removed under reduced pressure and the crude product was purified
by flash column chromatography (70% MTBE/hexane → MTBE). The products 7 were dried
in vacuo (ca. 5 mbar) at 60 °C for 2 hours.
Tetrahydropyrido[3,4-b]indol-1-one 7a was obtained from 2-hydroxy ketoxime ether 5a (56
mg, 0.22 mmol, 1.1 equiv), indol-2-ylamide 6a (38 mg, 0.20 mmol, 1.0 equiv) and FeCl3 (1.6
mg, 10 µmol, 5.0 mol-%) after 10 min (filtration) as a colorless solid (78 mg, 92%). Mp 240-
242 °C (decomposition); 1H NMR (300 MHz, DMSO-d6) δ 11.88 (bs, 1H), 7.46-7.42 (m, 2H),
7.32-7.12 (m, 6H), 6.89-6.82 (m, 2H), 6.68 (bs, 1H), 6.51 (d, J = 8.0 Hz, 1H), 3.70 (s, 3H),
1
3.33 (d, J = 16.5 Hz, 1H), 3.19 (s, 3H), 2.82 (d, J = 16.5 Hz, 1H), two H-signals are very
broad and could not be clearly detected; 13C{1H} NMR (100 MHz, DMSO-d6) δ 160.6, 146.0,
139.2, 138.7, 137.5, 127.8, 127.6, 127.5, 127.3, 125.9, 124.4, 124.1, 124.0, 123.7, 121.3,
120.3, 119.8, 112.7, 97.2, 63.3, 60.54, 60.48, 36.0, one 13C{1H}-signal is very broad and
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could not be clearly detected; IR (KBr) ṽ 3421, 3251, 1668, 1618, 1476, 1331, 1024, 746;
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HR-MS (ESI+) m/z: [M+Na]+ Calcd. for C26H23N3O3Na 448.1632; Found 448.1623.
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Tetrahydropyrido[3,4-b]indol-1-one 7b was obtained from 2-hydroxy ketoxime ether 5b
(59 mg, 0.22 mmol, 1.1 equiv), indol-2-ylamide 6a (38 mg, 0.20 mmol, 1.0 equiv) and FeCl3
(1.6 mg, 10 µmol, 5.0 mol-%) after 20 min (column chromatography) as a colorless solid (88
mg, >99%). Compound 7b contained ca. 15% of opened product 7b’. The spectroscopic data
1
are displayed for 7b. Rf (70% MTBE/hexane) 0.26; mp 138-140 °C; H NMR (400 MHz,
DMSO-d6) δ 11.87 (bs, 1H), 7.44-7.42 (m, 2H), 7.28 (m, 1H), 7.20-7.08 (m, 5H), 6.89-6.81
(m, 2H), 6.69 (bs, 1H), 6.55 (d, J = 8.0 Hz, 1H), 6.18 (m, 1H), 3.70 (s, 3H), 3.32 (d,
J = 16.5 Hz, 1H), 3.19 (s, 3H), 2.82 (d, J = 16.5 Hz, 1H), 2.14 (s, 3H); 13C{1H} NMR
(100 MHz, DMSO-d6) δ 160.6, 146.2, 139.2, 138.9, 137.5, 136.3, 128.0, 127.9, 127.6, 127.4,
125.9, 124.5, 124.1, 123.8, 121.4, 120.5, 119.8, 112.8, 97.3, 63.4, 60.5, 60.4, 36.1, 21.3, two
13C{1H}-signals are very broad and could not be clearly detected; IR (KBr) ṽ 3395, 3255,
2976, 2936, 2905, 1670, 1475, 1459, 1331, 1030, 744; HR-MS (ESI+) m/z: [M+H]+ Calcd.
for C27H26N3O3 440.1969; Found 440.1979.
Tetrahydropyrido[3,4-b]indol-1-one 7c was obtained from 2-hydroxy ketoxime ether 5c (68
mg, 0.22 mmol, 1.1 equiv), indol-2-ylamide 6a (38 mg, 0.20 mmol, 1.0 equiv) and FeCl3 (1.6
mg, 10 µmol, 5.0 mol-%) after 10 min (filtration) as a colorless solid (82 mg, 85%). Mp 138-
140 °C (decomposition); 1H NMR (400 MHz, DMSO-d6) δ 11.85 (bs, 1H), 7.44-7.42 (m, 2H),
7.30-7.25 (m, 3H), 7.19-7.11 (m, 2H), 6.88-6.81 (m, 2H), 6.61 (bs, 1H), 6.51 (d, J = 8.0 Hz,
1H), 3.69 (s, 3H), 3.34-3.29 (m, 1H), 3.20 (s, 3H), 2.82 (d, J = 16.5 Hz, 1H), 1.26 (s, 9H), two
1H-signals are very broad and could not be clearly detected; 13C{1H} NMR (75 MHz, DMSO-
d6) δ 160.7, 149.6, 146.3, 138.7, 137.5, 136.1, 127.8, 127.5, 125.9, 124.5, 124.3, 124.1 (2x),
13
123.7 121.3, 120.5, 119.8, 112.7, 97.2, 63.4, 60.6, 60.3, 36.1, 34.2, 31.2, one C{1H}-signal
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is very broad and could not be clearly detected; IR (KBr) ṽ 3444, 2962, 1670, 1331, 1024,
5
6
745; HR-MS (ESI+) m/z: [M+Na]+ Calcd. for C30H31N3O3Na 504.2258; Found 504.2248.
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Tetrahydropyrido[3,4-b]indol-1-one 7d was obtained from 2-hydroxy ketoxime ether 5d
(62 mg, 0.22 mmol, 1.1 equiv), indol-2-ylamide 6a (38 mg, 0.20 mmol, 1.0 equiv) and FeCl3
(1.6 mg, 10 µmol, 5.0 mol-%) after 20 min (column chromatography) as a colorless solid (91
1
mg, >99%). Rf (70% MTBE/hexane) 0.24; mp 147-149°C (decomposition); H NMR
(300 MHz, DMSO-d6) δ 11.87 (bs, 1H), 7.45-7.42 (m, 2H), 7.28 (td, J = 7.5, 1.0 Hz, 1H),
7.26-7.11 (m, 3H), 6.91-6.81 (m, 3H), 6.69 (bs, 1H), 6.59 (d, J = 8.0 Hz, 1H), 3.69 (s, 3H),
3.56 (s, 3H), 3.33 (d, J = 16.5 Hz, 1H), 3.21 (s, 3H), 2.83 (d, J = 16.5 Hz, 1H); two 1H-signals
are very broad and could not be clearly detected; 13C{1H} NMR (100 MHz, DMSO-d6) δ
160.6, 158.7, 146.0, 140.8, 138.7, 137.5, 128.5, 127.9, 127.6, 125.9, 124.5, 124.1, 123.8,
13
121.3, 120.3, 119.9, 112.8, 97.3, 63.4, 60.7, 60.6, 54.8, 36.1, three C{1H}-signals are very
broad and could not be clearly detected; IR (KBr) ṽ 3417, 3257, 2937, 1669, 1599, 1584,
1476, 1461, 1331, 1290, 1257, 1027, 746; HR-MS (ESI+) m/z: [M+Na]+ Calcd. for
C27H25N3O4Na 478.1737; Found 478.1718.
Tetrahydropyrido[3,4-b]indol-1-one 7e was obtained from 2-hydroxy ketoxime ether 5e (63
mg, 0.22 mmol, 1.1 equiv), indol-2-ylamide 6a (38 mg, 0.20 mmol, 1.0 equiv) and FeCl3 (1.6
mg, 10 µmol, 5.0 mol-%) in 1.5 mL CH2Cl2 after 2 h (filtration) as a colorless solid (69 mg,
1
75%). Mp 214-217 °C (decomposition); H NMR (400 MHz, DMSO-d6) δ 11.94 (bs, 1H),
7.46-7.44 (m, 2H), 7.34-7.28 (m, 3H), 7.21-7.13 (m, 2H), 6.92 (t, J = 7.5 Hz, 1H), 6.85 (m,
2H), 6.58 (d, J = 8.0 Hz, 1H), 3.69 (s, 3H), 3.34 (d, J = 16.5 Hz, 1H), 3.18 (s, 3H), 2.82 (d,
1
J = 16.5 Hz, 1H), two H-signals are very broad and could not be clearly detected; 13C{1H}
NMR (75 MHz, DMSO-d6) δ 160.6, 145.7, 138.7, 137.4, 137.6, 132.1, 128.1, 127.8, 127.6,
126.0, 124.29, 124.25, 124.0, 123.9, 123.7, 121.1, 120.1, 119.8, 112.9, 97.2, 63.4, 60.6, 60.2,
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36.0; IR (KBr) ṽ 3418, 3259, 2938, 1672, 1488, 1476, 1332, 1025, 1016, 931, 757, 746; HR-
5
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MS (ESI+) m/z: [M+Na]+ Calcd. for C26H2235ClN3O3Na 482.1242; Found 482.1257.
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Tetrahydropyrido[3,4-b]indol-1-one 7f was obtained from 2-hydroxy ketoxime ether 5f (71
mg, 0.22 mmol, 1.1 equiv), indol-2-ylamide 6a (38 mg, 0.20 mmol, 1.0 equiv) and FeCl3 (1.6
mg, 10 µmol, 5.0 mol-%) after 90 min (filtration) as a colorless solid (70 mg, 71%). Mp 205-
207 °C; 1H NMR (300 MHz, DMSO-d6) δ 11.98 (bs, 1H), 7.64 (d‘, J = 8.0 Hz, 2H), 7.49-7.45
(m, 2H), 7.31 (t, J = 7.5 Hz, 1H), 7.22-7.13 (m, 2H), 6.93-6.86 (m, 3H), 6.52 (d, J = 8.0 Hz),
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3.71 (s, 3H), 3.40-3.33 (m, 1H), 3.17 (s, 3H), 2.85 (d, J = 16.5 Hz, 1H), two H-signals are
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very broad and could not be clearly detected; C{1H} NMR (100 MHz, DMSO-d6) δ 160.6,
145.4, 144.2, 138.9, 137.6, 128.2, 127.91 (q, J = 32.0 Hz), 127.86, 126.1, 124.5 (m), 124.4,
124.3 (q, J = 275.0 Hz), 124.2, 124.1, 123.9, 121.0, 120.2, 119.4, 113.0, 97.2, 63.5, 60.6,
13
60.5, 36.1, one C{1H}-signal is very broad and could not be clearly detected; IR (KBr) ṽ
3405, 3257, 2939, 1674, 1618, 1477, 1326, 1169, 1124, 1070, 1020, 756, 745; HR-MS (ESI+)
m/z: [M+H]+ Calcd. for C27H23F3N3O3 494.1686; Found 494.1668.
Tetrahydropyrido[3,4-b]indol-1-one 7g was obtained from 2-hydroxy ketoxime ether 5g (42
mg, 0.22 mmol, 1.1 equiv), indol-2-ylamide 6a (38 mg, 0.20 mmol, 1.0 equiv) and FeCl3 (1.6
mg, 10 µmol, 5.0 mol-%) after 10 min (column chromatography) as a colorless solid (60 mg,
1
83%). Rf (70% MTBE/hexane) 0.20; mp 161-163 °C (decomposition); H NMR (400 MHz,
DMSO-d6) δ 11.75 (bs, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.47-7.45 (m, 2H), 7.31-7.26 (m, 2H),
7.18-7.14 (m, 2H), 7.10 (m, 1H), 7.02 (m, 1H), 3.69 (s, 3H), 3.36 (d, J = 16.5 Hz, 1H), 3.22
(s, 3H), 3.11 (d, J = 16.5 Hz, 1H), 1.84 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 160.8,
148.9, 137.7, 136.7, 127.2, 124.6, 124.5, 124.3, 123.8, 122.6, 121.6, 120.4, 120.1, 112.9, 96.4,
63.4, 60.4, 52.0, 35.9, 23.2; IR (KBr) ṽ 3410, 3242, 2936, 1668, 1477, 1332, 1057, 740; HR-
MS (ESI+) m/z: [M+Na]+ Calcd. for C21H21N3O3Na 386.1475; Found 386.1459.
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Tetrahydropyrido[3,4-b]indol-1-one 7h was obtained from 2-hydroxy ketoxime ether 5h
(73 mg, 0.22 mmol, 1.1 equiv), indol-2-ylamide 6a (38 mg, 0.20 mmol, 1.0 equiv) and FeCl3
(1.6 mg, 10 µmol, 5.0 mol-%) after 10 min (filtration) as a colorless solid (91 mg, 90%). Mp
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204-206 °C; H NMR (400 MHz, DMSO-d6) δ 11.94 (bs, 1H), 7.71 (s, 1H), 7.44 (d,
J = 8.5 Hz, 1H), 7.36-7.25 (m, 4H), 7.18 (t, J = 8.0 Hz, 1H), 6.86 (t, J = 7.5 Hz, 1H), 6.75 (m,
2H), 6.48 (d, J = 8.0 Hz, 1H), 3.71 (s, 3H), 3.38-3.34 (m, 1H), 3.18 (s, 3H), 2.83 (d,
J = 16.5 Hz, 1H), two H-signals are very broad and could not be clearly detected; C{1H}
NMR (100 MHz, DMSO-d6) δ 160.6, 145.5, 141.6, 138.7, 137.6, 130.7, 127.6, 127.5, 127.2,
126.1, 126.0, 124.3, 123.9, 121.1, 120.7, 119.9, 119.8, 112.8, 97.2, 63.5, 60.5, 60.2, 35.9, one
13C{1H}-signal is very broad and could not be clearly detected; IR (KBr) ṽ 3434, 3258, 2938,
1673, 1332, 753, 746; HR-MS (ESI+) m/z: [M+Na]+ Calcd. for C26H2279BrN3O3Na 526.0737;
Found 526.0733.
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Tetrahydropyrido[3,4-b]indol-1-one 7i was obtained from 2-hydroxy ketoxime ether 5i (78
mg, 0.22 mmol, 1.1 equiv), indol-2-ylamide 6a (38 mg, 0.20 mmol, 1.0 equiv) and FeCl3 (1.6
mg, 10 µmol, 5.0 mol-%) after 10 min (filtration) as a colorless solid (74 mg, 70%). Mp 167-
169 °C (decomposition); 1H NMR (400 MHz, DMSO-d6) δ 11.91 (bs, 1H), 7.44-7.41 (m, 3H),
7.30-7.12 (m, 6H), 6.85-6.81 (m, 2H), 6.50 (d, J = 8.0 Hz, 1H), 6.40 (bs, 1H), 5.87 (bs, 1H),
3.64 (s, 3H), 3.38-3.33 (m, 1H), 2.89 (d, J = 16.5 Hz, 1H), 0.64 (s, 9H), 0.00 (s, 3H), −0.12 (s,
3H); C{1H} NMR (100 MHz, DMSO-d6) δ 160.6, 146.0, 138.9, 138.5, 137.4, 127.8, 127.6,
13
126.4, 124.3, 124.02, 123.97, 123.4, 121.1, 120.0, 119.6, 112.7, 98.1, 63.3, 60.8, 36.7, 25.6,
17.2, −5.65, −5.69, two C{1H}-signals are very broad and could not be clearly detected; IR
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(KBr) ṽ 3242, 2952, 2928, 2855, 1671, 1473, 1460, 1388, 1331, 1283, 1252, 1072, 1023, 907,
883, 835, 784, 744, 704, 693; HR-MS (ESI+) m/z: [M+Na]+ Calcd. for C31H35N3O3SiNa
548.2340; Found 548.2335.
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Tetrahydropyrido[3,4-b]indol-1-one 7j was obtained from 2-hydroxy ketoxime ether 5a (56
mg, 0.22 mmol, 1.1 equiv), indol-2-ylamide 6b (53 mg, 0.20 mmol, 1.0 equiv) and FeCl3 (1.6
mg, 10 µmol, 5.0 mol-%) after 10 min (column chromatography (20% → 30% → 40%
MTBE/hexane) and recrystallization from EtOAc/hexane) as a colorless solid (85 mg, 85%);
Rf (40% MTBE/hexane) 0.27; mp 185-187 °C; 1H NMR (300 MHz, CDCl3) δ 10.12 (bs, 1H),
7.57-7.52 (m, 3H), 7.42-7.37 (m, 3H), 7.35-7.13 (m, 7H), 7.06 (d, J = 7.5 Hz, 1H), 6.94 (ddd,
J = 8.0, 7.0, 1.0 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H), 5.85 (bs, 1H), 5.37 (d, J = 10.0 Hz, 1H),
4.74 (d, J = 10.0 Hz, 1H), 3.48 (d, J = 16.0 Hz, 1H), 3.37 (s, 3H), 2.90 (d, J = 16.0 Hz, 1H),
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two H-signals are very broad and could not be clearly detected; 13C{1H} NMR (100 MHz,
CDCl3) δ 162.5, 146.1, 138.9, 138.3, 137.9, 135.5, 129.5 127.8, 128.7, 128.2 (3x), 128.0,
126.2, 125.4, 125.2, 124.7, 124.0, 122.4, 121.6, 120.5, 112.9, 98.0, 78.5, 62.0, 61.6, 37.0, one
13C{1H}-signal is very broad and could not be clearly detected; IR (KBr) ṽ 3433, 3251, 3061,
2936, 1666, 1476, 1331, 1012, 747, 700; HR-MS (ESI+) m/z: [M+Na]+ Calcd. for
C32H27N3O3Na 524.1945; Found 524.1926.
Tetrahydropyrido[3,4-b]indol-1-one 7k was obtained from 2-hydroxy ketoxime ether 5a
(56 mg, 0.22 mmol, 1.1 equiv), indol-2-ylamide 6c (41 mg, 0.20 mmol, 1.0 equiv) and FeCl3
(1.6 mg, 10 µmol, 5.0 mol-%) after 3 min (filtration) as a colorless solid (85 mg, 96%). Mp
214-216 °C (decomposition); 1H NMR (400 MHz, DMSO-d6) δ 11.75 (bs, 1H), 7.45-7.43 (m,
1H), 7.34-7.25 (m, 5H), 7.15 (t, J = 7.5 Hz, 1H), 7.01 (d, J = 8.5 Hz, 1H), 6.85 (d, J = 7.5 Hz,
1H), 6.66 (bs, 1H), 6.29 (s, 1H), 3.69 (s, 3H), 3.33-3.30 (m, 1H), 3.19 (s, 3H), 2.81 (d,
1
J = 16.5 Hz, 1H), 2.13 (s, 3H), two H-signals are very broad and could not be clearly
detected; 13C{1H} NMR (100 MHz, DMSO-d6) δ 160.7, 146.2, 139.2, 138.8, 136.0, 128.3,
127.9, 127.7, 127.6, 127.3, 126.0, 125.7, 124.7, 124.2, 124.1, 120.6, 119.9, 112.5, 97.2, 63.4,
60.6, 60.5, 36.1, 21.3, one 13C{1H}-signal is very broad and could not be clearly detected; IR
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(KBr) ṽ 3429, 3244, 2936, 1668, 1325, 1025, 754; HR-MS (ESI+) m/z: [M+H]+ Calcd. for
5
6
C27H26N3O3 440.1969; Found 440.1957.
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Tetrahydropyrido[3,4-b]indol-1-one 7l was obtained from 2-hydroxy ketoxime ether 5a (56
mg, 0.22 mmol, 1.1 equiv), indol-2-ylamide 6d (44 mg, 0.20 mmol, 1.0 equiv) and FeCl3 (1.6
mg, 10 µmol, 5.0 mol-%) after 10 min (filtration) as a colorless solid (76 mg, 83%). Mp 186-
190°C (decomposition); 1H NMR (400 MHz, DMSO-d6) δ 11.73 (bs, 1H), 7.45-7.43 (m, 1H),
7.34-7.26 (m, 5H), 7.16 (m, 1H), 6.87-6.84 (m, 2H), 6.71 (bs, 1H), 5.84 (d, J = 2.5 Hz, 1H),
1
3.69 (s, 3H), 3.42-3.35 (m, 4H), 3.20 (s, 3H), 2.82 (d, J = 16.5 Hz, 1H), two H-signals are
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very broad and could not be clearly detected; C{1H} NMR (100 MHz, DMSO-d6) δ 160.6,
153.3, 146.2, 139.1, 138.7, 132.9, 127.8, 127.7, 127.6, 127.3, 126.4, 124.7, 124.1 (2x), 120.1,
114.4, 113.5, 102.2, 97.2, 63.3, 60.54, 60.48, 54.7, 36.1, one 13C{1H}-signal is very broad and
could not be clearly detected; IR (KBr) ṽ 3412, 3259, 3220, 2937, 1667, 1488, 1444, 1436,
1264, 1215, 1035, 1025, 754; HR-MS (ESI+) m/z: [M+Na]+ Calcd. for C27H25N3O4Na
478.1737; Found 478.1714.
Tetrahydropyrido[3,4-b]indol-1-one 7m was obtained from 2-hydroxy ketoxime ether 5a
(56 mg, 0.22 mmol, 1.1 equiv), indol-2-ylamide 6e (50 mg, 0.20 mmol, 1.0 equiv) and FeCl3
(1.6 mg, 10 µmol, 5.0 mol-%) after 20 min (filtration) as a colorless solid (72 mg, 74%). Mp
206-209 °C (decomposition); 1H NMR (400 MHz, DMSO-d6) δ 11.58 (bs, 1H), 7.44-7.42 (m,
1H), 7.31-7.25 (m, 4H), 7.15 (t, J = 7.5 Hz, 1H), 6.87-6.85 (m, 2H), 6.68 (bs, 1H), 5.79 (s,
1H), 3.78 (s, 3H), 3.68 (s, 3H), 3.36-3.29 (m, 4H), 3.20 (s, 3H), 2.81 (d, J = 16.0 Hz, 1H), two
1H-signals are very broad and could not be clearly detected; 13C{1H} NMR (100 MHz,
DMSO-d6) δ 160.6, 148.7, 146.2, 144.8, 139.2, 138.7, 132.7, 127.7, 127.6, 127.4, 127.2,
124.2, 124.1, 124.0, 120.8, 117.0, 102.2, 97.1, 94.8, 63.3, 60.46, 60.42, 55.5, 55.1, 36.2, one
13C{1H}-signal is very broad and could not be clearly detected; IR (KBr) ṽ 3415, 3225, 3209,
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2936, 2902, 1665, 1630, 1489, 1461, 1447, 1309, 1276, 1216, 1034, 1024, 748, 731; HR-MS
(ESI+) m/z: [M+Na]+ Calcd. for C28H27N3O5Na 508.1843; Found 508.1823.
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Tetrahydropyrido[3,4-b]indol-1-one 7n was obtained from 2-hydroxy ketoxime ether 5a
(56 mg, 0.22 mmol, 1.1 equiv), indol-2-ylamide 6f (45 mg, 0.20 mmol, 1.0 equiv) and FeCl3
(1.6 mg, 10 µmol, 5.0 mol-%) after 30 min (filtration) as a colorless solid (77 mg, 83%).
Compound 7n contained ca. 20% of opened product 7n’. The spectroscopic data are displayed
for 7n. Mp 224-226 °C; 1H NMR (400 MHz, DMSO-d6) δ 12.15 (bs, 1H), 7.47-7.45 (m, 2H),
7.33-7.25 (m, 4H), 7.21-7.16 (m, 2H), 6.80-6.76 (m, 2H), 6.39 (d, J = 2.0 Hz, 1H), 3.69 (s,
3H), 3.36-3.33 (m, 1H), 3.20 (s, 3H), 2.82 (d, J = 16.5 Hz, 1H), two 1H-signals are very broad
and could not be clearly detected; 13C{1H} NMR (100 MHz, DMSO-d6) δ 160.2, 145.7,
138.8, 138.7, 135.9, 128.0, 127.8, 127.7, 127.6, 127.5, 125.4, 124.3, 124.2, 123.9, 120.0,
13
119.9, 114.5, 97.4, 63.4, 60.6, 60.4, 36.0, one C{1H}-signal is very broad and could not be
clearly detected; IR (KBr) ṽ 3434, 3234, 1670, 1654, 1458, 1300, 1057, 754, 705; HR-MS
(ESI+) m/z: [M+Na]+ Calcd. for C26H2235ClN3O3Na 482.1242; Found 482.1227.
Tetrahydropyrido[3,4-b]indol-1-one 7o was obtained from 2-hydroxy ketoxime ether 5a (56
mg, 0.22 mmol, 1.1 equiv), indol-2-ylamide 6g (56 mg, 0.20 mmol, 1.0 equiv) and FeCl3 (1.6
mg, 10 µmol, 5.0 mol-%) after 20 min (filtration) as a colorless solid (82 mg, 92%).
Compound 7o contained ca. 25% of opened product 7o’. The spectroscopic data are displayed
1
for 7o. Mp 219-220 °C (decomposition); H NMR (400 MHz, DMSO-d6) δ 12.04 (bs, 1H),
7.48-7.45 (m, 2H), 7.33-7.25 (m, 4H), 7.19-7.16 (m, 1H), 7.15-7.05 (m, 1H), 6.83 (d,
J = 7.5 Hz, 1H), 6.76 (bs, 1H), 6.39 (dd, J = 10.0, 2.5 Hz, 1H), 3.70 (s, 3H), 3.37-3.33 (m,
1
1H), 3.21 (s, 3H), 2.83 (d, J = 16.5 Hz, 1H), two H-signals are very broad and could not be
clearly detected; 13C{1H} NMR (100 MHz, DMSO-d6) δ 160.3, 156.7 (d, J = 233.5 Hz),
145.9, 138.8, 138.7, 134.3, 128.0, 127.8, 127.74, 127.71, 127.5, 124.4 (d, J = 10.0 Hz), 124.2,
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124.0, 120.4 (d, J = 5.0 Hz), 114.2 (d, J = 9.5 Hz), 112.0 (d, J = 26.5 Hz), 105.2 (d,
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J = 23.0 Hz), 97.4, 63.4, 60.6, 60.4, 36.0, one C{1H}-signal is very broad and could not be
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clearly detected; IR (KBr) ṽ 3426, 3239, 2939, 1670, 1656, 1487, 1305, 752, 707; HR-MS
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(ESI+) m/z: [M+Na]+ Calcd. for C26H22FN3O3Na 466.1537; Found 466.1534.
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Tetrahydropyrido[3,4-b]indol-1-one 10
Compound 7j (50 mg, 0.10 mmol, 1.0 equiv) was dissolved in 1.0 mL CH2Cl2 and Et3SiH (32
µL, 0.20 mmol, 2.0 equiv) followed by BF3•OEt2 (19 µL, 0.15 mmol, 1.5 equiv) was added
dropwise. The reaction mixture was stirred at room temperature for 24 h and then quenched
with water (2.0 mL). The aqueous phase was separated and extracted twice with CH2Cl2. The
combined organic phases were dried over Na2SO4, filtered and the solvent was removed under
reduced pressure. Product 10 was obtained after column chromatography (20%
EtOAc/hexane) as a colorless solid (30 mg, 65%). Rf (30% EtOAc/hexane) 0.52; Mp 114-116
°C; 1H NMR (400 MHz, CDCl3) δ 9.88 (bs, 1H), 7.52 (d, J = 8.5 Hz, 1H), 7.38-7.33 (m, 2H),
7.33-7.19 (m, 12H), 7.00-6.95 (m, 3H), 4.93 (d, J = 11.0 Hz, 1H), 4.89 (d, J = 11.0 Hz, 1H),
4.49 (t, J = 6.5 Hz, 1H), 3.42 (dd, J = 15.5, 6.5 Hz, 1H), 3.25 (dd, J = 15.5, 7.0 Hz, 1H);
13C{1H} NMR (100 MHz, CDCl3) δ 160.8, 145.5, 143.6, 140.9, 138.5, 135.3, 129.4, 128.64,
128.55, 128.5, 128.2, 127.8, 127.4, 127.3, 126.4, 126.0, 125.3, 125.2, 124.9, 122.0, 120.8,
118.4, 112.8, 77.8, 76.6, 58.0, 36.3; IR (KBr) ṽ 3444, 3243, 1662, 1475, 741, 699; HR-MS
(ESI+) m/z: [M+Na]+ Calcd. for C31H24N2O2Na 479.1730; Found 479.1731.
ASSOCIATED CONTENT
High-temperature-NMR studies, 1H and 13C NMR spectra for all new compounds (PDF).
ACKNOWLEDGEMENTS
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This work was generously supported by the European Social Fund through a predoctoral
fellowship awarded to M. S. We thank BASF and Evonik for the generous donation of
chemicals.
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(14) N-benzyl indol-2-ylmide 9 was highly unsoluble resulting in the failed reaction.
(15) Fast precipitation and incomplete conversion of starting material was observed in 0.6
mL dichloromethane.
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(16) Another 7-24% yield of product was obtained after column chromatography of the
filtrates of the other substrates 7.
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measured in DMSO-d6. For example, compound 7o contained ca. 25% of opened
compound 7o’ at room temperature which was identified by high-temperature-NMR
studies (see Figure S2 in the SI for more details). The use of the polar solvent DMSO-d6
might result in the partial opening of 7 to form traces of 7’ in solution.
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