Lewis Acid-Catalyzed Nucleophilic Addition of Indoles to in Situ-Generated 2-Amidoallyl Cations

Article abstract of DOI:10.1021/acs.joc.7b00791

We report herein the first Lewis acid-catalyzed generation of 2-amidoallyl cations through ring-opening of 4-benzylidene-2-oxazolines with Sc(OTf)₃. Upon nucleophilic addition of indoles, indolylenamides were obtained with yields of 60-99% and excellent (Z)-selectivity. In addition, the novel strategy was also successfully applied to pyrroles and naphthols as -nucleophiles. A Br?nsted acid-catalyzed process using TfOH formed in situ was ruled out by control experiments.

Full text of DOI:10.1021/acs.joc.7b00791

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Note
Lewis Acid-Catalyzed Nucleophilic Addition of
Indoles to in situ Generated 2-Amidoallyl Cations
Marcel Schlegel, and Christoph Schneider
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 12 May 2017
Downloaded from http://pubs.acs.org on May 12, 2017
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Lewis AcidꢀCatalyzed Nucleophilic Addition of
Indoles to in situ Generated 2ꢀAmidoallyl Cations
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Marcel Schlegel and Christoph Schneider*
Institut für Organische Chemie, University of Leipzig, Johannisallee 29, Dꢀ04103 Leipzig,
Germany
*Email: schneider@chemie.uniꢀleipzig.de
ABSTRACT: We report herein the first Lewis acidꢀcatalyzed generation of 2ꢀamidoallyl
cations through ringꢀopening of 4ꢀbenzylideneꢀ2ꢀoxazolines with Sc(OTf)3. Upon
nucleophilic addition of indoles indolylenamides were obtained with yields of 60 to 99% and
excellent (Z)ꢀselectivity. In addition, the novel strategy was also successfully applied to
pyrroles and naphtholes as πꢀnucleophiles. A Brønsted acidꢀcatalyzed process using TfOH
formed in situ was ruled out by control experiments.
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Oxyallyl cations have emerged as highly reactive intermediates in CꢀCꢀbond forming
processes due to their unique electrophilic character. These species are known to undergo
(4+3)1ꢀ and (3+2)ꢀcycloadditions2 easily and therefore many synthetic applications have been
developed for the construction of complex molecules. More recently, the nucleophilic capture
of oxyallyl cations has become a versatile method in synthesizing highly functionalized
ketones which are otherwise not accessible by classical strategies.3−10 For example, Kartika et
al. demonstrated the first Brønstedꢀacid catalyzed, regioselective addition of πꢀ and
σꢀnucleophiles to introduce αꢀquaternary centers in ketoneꢀderived compounds.3 Moreover,
the group of MacMillan has very recently developed the first enantioselective, nucleophilic
addition of Nꢀprotected indoles to oxyallyl cations generated in situ using a Jørgensenꢀ
Hayashi type catalyst.10
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Despite of their enormous potential as templates in organic synthesis, 2ꢀaminoꢀ and
2ꢀamidoallyl cations are less wellꢀstudied because methods for their generation are limited.
Typical procedures comprise ionization of rather unstable αꢀchloroenamines or
αꢀchloroimines with stoichiometric amounts of silver(I) salts as Lewis acids followed by
(4+3)ꢀcycloaddition with furan or dienes.11 Shipman and coꢀworkers reported a BF3ꢁOEt2ꢀ
promoted or Sc(OTf)3ꢀcatalyzed intramolecular (4+3) cycloaddition of 2ꢀaminoallyl cations
which are formed in situ by the release of ring strain from 2ꢀmethyleneaziridines.12,13 Blakey
and Stoll developed a Rhꢀcatalyzed allene amination which affords cyclopropaneimines via
2ꢀamidoallyl cation species.14 These intermediates were also described in (4+3)ꢀ,15 (3+3)ꢀ,16
and (3+2)ꢀcycloadditions14 as well as addition reactions with nucleophiles.17
We envisioned 4ꢀalkylidene substituted 2ꢀoxazolines as suitable precursors in the generation
of 2ꢀamidoallyl cations. Although 2ꢀoxazolines are particularly known to undergo cationic
polymerization reactions by Lewis acidꢀcatalyzed ring opening,18 the addition of
πꢀnucleophiles to trap the resulting cations has never been achieved in an effective and
catalytic manner.19 Hence, we decided to install the 4ꢀalkylidene group to stabilize the cation
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more efficiently by resonance effects which would allow the attack of a nucleophile under
mild conditions. We now report our results on the first Lewisꢀacid catalyzed nucleophilic
capture of in situ generated 2ꢀamidoallyl cations with indole.
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Commercially available αꢀacetamidocinnamic acid 1 was converted into 4ꢀbenzylideneꢀ2ꢀ
oxazoline 2 in a 5ꢀstep prodecure. Esterification of the carboxylic acid and reduction with
LiAlH4 afforded the allyl alcohol as a single double bond isomer. Selective oxidation was
achieved with high yields by treating with MnO2. The addition of phenyl magnesium bromide
delivered the secondary alcohol which was then dehydrated through methanesulfonyl chloride
and NEt3 to give rise to oxazoline 2. The resulting (Z)ꢀ and (E)ꢀisomers of 2 were separated
by column chromatography and their relative configuration was determined by NOEꢀ
experiments (Scheme 1).
Scheme 1. Synthesis of Oxazoline 2.
We initially started our investigations with the Brønstedꢀacid catalyzed activation of (Z)ꢀ2
with diphenylphosphate (DPP) followed by the reaction with indole. It turned out that
conventional solvents (CH2Cl2, CH3CN, THF, toluene) failed to yield the desired addition
product, even under refluxing conditions. Based upon procedures in which oxyallyl cations
were generally formed in protic solvents,5–9 we decided to employ trifluoroethanol (TFE),
which successfully gave rise to the formation of indolylenamide 3a with 91% yield and high
(Z)ꢀselectivity (Scheme 2, eq. 1). The (Z)ꢀconfiguration of the enamide double bond, which
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was rigorously determined by Xꢀray crystal structure analysis (see Supporting Information,
Figure S1), is favored to minimize 1,3ꢀallylic strain. No reaction was observed without DPP
in TFE.
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In addition to Brønsted acidꢀcatalysis, we decided to study the ringꢀopening of oxazoline 2
with Lewis acids in nonꢀprotic organic solvents mainly for two reasons: 1) During our
investigations we occasionally observed the addition of TFE to the intermediate 2ꢀamidoallyl
cations in competition to other nucleophiles, a side reaction that is also described in the
nucleophilic capture of oxyallyl cations.5,9 2) We wanted to exclude the potential hydrolysis
of the enamide moiety in the presence of the Brønsted acid and the protic solvent. After
extensive optimization studies (see Supporting Information, Table S1) we eventually settled
on 5 mol% of Sc(OTf)3 providing 3a in 95% yield for the subsequent investigations (Scheme
2, eq. 2).
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Scheme 2. Synthesis of 3a with DPP and Sc(OTf)3 under optimized conditions.
Metal triflates and other Lewis acids are known to release traces of protons that might act as
the active catalyst.20,21 We carried out some control experiments to exclude this type of
“hidden Brønsted acid” catalysis in the Sc(OTf)3ꢀcatalyzed process (see Supporting
Information, Table S2). In the presence of 2,6ꢀdiꢀtertꢀbutylpyridine (DTBP), which is known
to be a nonꢀcoordinating and selective proton scavenger,20,22 no difference in reaction time and
yield was obtained in comparison to the result without the base. Moreover, we performed the
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same reaction with 10 mol% TfOH, which gave rise to 3a in 87% yield within one day.
Addition of DTBP to the TfOHꢀcatalyzed reaction significantly decreased the conversion of
starting material and furnished the product with less than 10% yield after 3 days. These
experiments strongly indicated that Sc(OTf)3 itself was the active catalyst but traces of TfOH
generated in situ can also assist in this transformation.
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We next studied the influence of different substituted indoles on the nucleophilic attack to
oxazolines (Z)ꢀ and (E)ꢀ2. It turned out that electronꢀdonating as well as electronꢀwithdrawing
groups were well tolerated, leading to the corresponding products with good to excellent
yields and high (Z)ꢀselectivities (Table 1). Reactions that started from the (E)ꢀisomer of
oxazoline 2 afforded the products 3 within generally longer reactions times but with similar
yields as indicated by comparing entries 1 and 2. The lower reactivity of (E)ꢀ2 likely resulted
from the enhanced 1,3ꢀallylic strain between the two phenyl groups. This led to double bond
isomerization into the more reactive (Z)ꢀconfigured oxazoline 2, which was observed by TLC
monitoring of the reaction mixtures. Indoles with electronꢀdonating substituents typically
furnished the products with very high yields and in most cases exclusively as (Z)ꢀisomers
(entries 3ꢀ10). NꢀMethylated as well as 2ꢀmethyl indole were suitable nucleophiles but
required longer reaction times (entries 3ꢀ4). However, placing a phenyl group at the 2ꢀposition
of indole provided the corresponding product in quantitative yield within one day (entry 10).
Cꢀ4 Substituted indoles showed slower conversion of starting material and a slight decrease of
product yield because of steric hindrance to the nucleophilic center (entries 9 and 11). The 4ꢀ
bromoindole substituted product 3j was the only case in which a significantly lower Z/E ratio
was observed (entry 11). Other functional groups like halides (entries 12ꢀ13) or esters (entries
14ꢀ15) also delivered the corresponding products 3kꢀ3n with excellent yields. Indoles
carrying strongly electronꢀwithdrawing cyano or nitro groups showed a significant decrease in
reactivity with oxazoline (Z)ꢀ2. After column chromatography, 3o and 3p were isolated in
62% and 60% yield, respectively, and high (Z)ꢀselectivities (entries 16ꢀ17).
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Table 1. Substrate Scope with Indoles toward Indolylenamides 3.[a]
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entry
1
product
3a
2
R
time [h]
15
yield [%][b]
Z/E[c]
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
94:6
Z
E
E
E
Z
Z
E
E
Z
Z
Z
E
Z
Z
Z
Z
Z
H
95
91
82
72
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89
80
72
99
82
93
90
95
92
62
60
2
H
39
3a
3
1ꢀCH3
2ꢀCH3
5ꢀCH3
7ꢀCH3
5ꢀOCH3
7ꢀOCH3
4,5ꢀ(OCH2)2
2ꢀPh
96
3b
3c
4
96[d,e]
21
5
3d
3e
6
20
7
22
3f
8
69[d]
44
>95:5
94:6
3g
9
3h
3i
10
11
12
13
14
15
16
17
15
>95:5
85:15
94:6
4ꢀBr
96[d,e]
64
3j
6ꢀCl
3k
3l
5ꢀF
18
92:8
5ꢀCO2Me
6ꢀCO2Me
5ꢀCN
5ꢀNO2
48[d]
69[d]
96[d,f]
96[d,f]
>95:5
>95:5
>95:5
>95:5
3m
3n
3o
3p
[a] Reaction conditions: oxazoline 2 (0.20 mmol), indole (0.24 mmol), Sc(OTf)3 (5 mol%) in
0.5 mL CHCl3 at 60 °C. [b] Isolated yield after column chromatography. [c] Z/E ratio was
determined by 1H NMR spectroscopy after column chromatography. [d] Catalyst loading was
increased to 10 mol% Sc(OTf)3 after 40 h. [e] 0.8 additional equivalents of the corresponding
indole were added after 40 h. [f] Incomplete conversion of starting material.
We also investigated other πꢀ as well as σꢀnucleophiles to extend the substrate scope of our
established protocol. When oxazolines (Z)ꢀ and (E)ꢀ2 were treated with pyrrole and 10 mol%
Sc(OTf)3 in CHCl3 at 60 °C, E/Zꢀmixtures of pyrrolylenamide 4 were obtained with good
overall yields and high Z/E ratios after 17 h and 64 h, respectively. Both isomers could be
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separated by column chromatography. Under identical conditions, the nucleophilic addition of
1ꢀnaphthol to (Z)ꢀ2 resulted in a separable mixture of orthoꢀproduct 5 and paraꢀproduct 6 in a
ratio of 62:38 after 17 h. Both isomers were isolated in moderate yields and excellent (Z)-
selectivities (Scheme 3). Other potential πꢀnucleophiles such as βꢀdiketones, enol ethers, and
enamines did not furnish any product, but exclusively gave rise to decomposition of starting
material.
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Scheme 3. Addition Products of 2 with Pyrrole and 1ꢀNaphthol.
Mechanistically, we propose that the Lewis acid will first coordinate to the basic nitrogen
atom of oxazolines (Z)ꢀ and (E)ꢀ2 resulting in ringꢀopening of the heterocycle and formation
of 2ꢀamidoallyl cation 7. This symmetrical and highly reactive intermediate can exist in 3
different conformations. The Wꢀform 7a is generally preferred over the sickle form 7b and the
Uꢀform 7c due to minimized 1,3ꢀallylic strain between the two Phꢀgroups. However, in
analogy to reported Lewisꢀacid catalyzed formations of 2ꢀaminoallyl cations, the Wꢀform 7a
might be less favored compared to the sickle form 7b because of additional 1,3ꢀallylic strain
between one Phꢀgroup and the bulky, coordinating Lewis acid.12,13 Intramolecular attack of
the acetyl group to 7 regenerates the oxazoline 2. The addition of indole finally forms the
product 3a in an irreversible step (Scheme 4). It is unclear whether the (Z)ꢀconfiguration of 3a
is directly related to the 2ꢀamidoallyl cation intermediate 7 or whether double bond
isomerization of a potential (E)ꢀ3aꢀisomer had taken place in the reaction medium. Although
a possible SN2 or SN2’ mechanism cannot be fully ruled out in this reaction, we rather assume
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a SN1ꢀtype mechanism due to a high resonance stabilization of intermediate 7. Moreover, our
successful experiments with DPP in TFE underline a unimolecular mechanism based on
stabilization of 7 by the protic solvent (see Scheme 2, eq. 1).
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Scheme 4: Proposed Mechanism in the Formation of Indolylenamide 3a.
CONCLUSION
In summary, we have reported a novel strategy to form 2ꢀamidoallyl cations by Sc(OTf)3ꢀ
catalyzed ringꢀopening of 4ꢀalkylidene substituted oxazolines. A broad range of indoles as
well as pyrrole and 1ꢀnaphthol proved to be suitable πꢀnucleophiles to give rise to highly
αꢀsubstituted enamides with good to excellent yields and (Z)ꢀselectivities. We could prove
that Sc(OTf)3 itself acts as the active catalytic species. Furthermore, we were able to run the
same reaction under mild Brønsted acidic conditions using catalytic amounts of
diphenylphosphate in trifluoroethanol providing addition product 3a with high yield and
(Z)ꢀselectivity.
EXPERIMENTAL SECTION
General methods. Unless otherwise noted, all reactions were carried out in oven dried
1
glassware and in dry solvents under an argon atmosphere. Hꢀ and 13CꢀNMR spectra were
recorded in DMSOꢀd6 or CDCl3 at 26 °C using a Mercury plus 300 MHz and a Bruker
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Avance DRX 400 MHz spectrometer. The spectra were referenced to residual DMSO (2.50
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5
1
13
1
13
ppm, H; 39.52 ppm, C) or CHCl3 (7.26 ppm, H; 77.16 ppm, C), respectively. 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 highꢀresolution mass spectra (HRMS) were recorded
on a Bruker Daltonics Apex II FTꢀICR. Melting points were determined uncorrected on a
Boetius measurement device. The used solvents dichloromethane and tetrahydrofuran (THF)
were dried using a MBraun Solvent Purification System (SPS) 800. Dry chloroform and
methanol were purchased from Acros Organics and stored over molecular sieve. Acetonitrile
was technical grade. Solvents for column chromatography were of technical grade and
distilled from the indicated drying reagents: dichloromethane (CaH2), diethyl ether (KOH),
methylꢀtertꢀbutyl ether (KOH), ethyl acetate (CaCl2) and nꢀhexane (KOH). Methanol was
technical grade. Triethylamine was distilled freshly prior to use. Flash column
chromatography was performed by using silica gel (Fluka, 60 Å, 230 – 400 mesh size).
Analytical thinꢀlayer chromatography (TLC) was performed on MachereyꢀNagel preꢀcoated
TLCꢀsheets AlugramXtra SIL G/UV254. Visualization of the spots was achieved by UVꢀlight
and treatment with a vanillin staining solution.
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Synthesis of Oxazoline 2
Methyl αꢀacetamidocinnamate was synthesized from αꢀacetamidocinnamic acid 1 according
to known literature.23
A solution of methyl αꢀacetamidocinnamate (17.5 g, 80.0 mmol, 1.00 equiv) in 150 mL dry
THF was added dropwise to a suspension of LiAlH4 (10.6 g, 280 mmol, 3.50 equiv) in 400
mL dry THF over 30 min at 0 °C. The reaction mixture was stirred at 0 °C for 1 h and then
transferred into 300 mL iceꢀcold EtOAc. It was filtered over Celite and the residue was
washed with EtOAc and MeOH. The filtrate was treated with sat. NH4Cl solution. The
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organic phase was separated and the aqueous phase was extracted twice with EtOAc. The
combined organic phases were dried over Na2SO4, filtered and the solvent was removed under
reduced pressure. After purification by flash column chromatography (30% EtOAc/nꢀhexane
→ EtOAc) Nꢀ(3ꢀhydroxyꢀ1ꢀphenylpropꢀ1ꢀenꢀ2ꢀyl)acetamide was isolated as a white solid
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1
(9.65 g, 63%). Rf (EtOAc) 0.42; mp 80 °C; H NMR (400 MHz, DMSOꢀd6) δ 9.14 (bs, 1H),
7.40 (m, 2H), 7.32 (m, 2H), 7.21 (m, 1H), 6.27 (s, 1H), 5.12 (t, 1H, J = 6.0 Hz), 4.13 (d, 2H,
J = 6.0 Hz), 1.95 (s, 3H); 13C{1H} NMR (100 MHz, DMSOꢀd6) δ 169.0, 137.6, 135.6, 128.3,
126.7, 118.3, 62.3, 22.9; IR (KBr) ṽ 3239, 3172, 3062, 3049, 3021, 2940, 2919, 1646, 1556,
1489, 1437, 1373, 1348, 1310, 1183, 1037, 850, 755, 692, 526 cm−1; HRMS (ESI+) m/z:
[M+Na]+ Calcd for C11H13NO2Na 214.0838; Found 214.0835.
To a solution of Nꢀ(3ꢀhydroxyꢀ1ꢀphenylpropꢀ1ꢀenꢀ2ꢀyl)acetamide (9.65 g, 50.5 mmol, 1.00
equiv) in 200 mL CH3CN was added activated MnO2 (88% w/w, 40.0 g, 404 mmol, 8.00
equiv) and the mixture was stirred at rt for 15 h. It was filtered over Celite and the residue was
washed with EtOAc. The filtrate was concentrated in vacuo and the crude product was
purified by flash column chromatography (30% EtOAc/nꢀhexane → EtOAc). Nꢀ(3ꢀOxoꢀ1ꢀ
phenylpropꢀ1ꢀenꢀ2ꢀyl)acetamide was isolated as a white solid (8.36 g, 88%). Rf (80%
EtOAc/nꢀhexane) 0.50; mp 104ꢀ105 °C; 1H NMR (400 MHz, DMSOꢀd6) δ 9.55 (bs, 1H), 9.45
(s, 1H), 7.69 (m, 2H), 7.48ꢀ7.43 (m, 3H), 7.32 (s, 1H), 2.05 (s, 3H); 13C{1H} NMR (100 MHz,
DMSOꢀd6) δ 190.8, 168.9, 139.7, 134.7, 133.4, 130.2, 128.7, 22.6; IR (KBr) ṽ 3464, 3250,
3016, 2847, 1698, 1687, 1659, 1634, 1490, 1419, 1382, 1372, 1321, 1277, 1189, 980, 764,
746, 684, 536, 438 cm−1; HRMS (ESI+) m/z: [M+Na]+ Calcd for C11H11NO2Na 212.0682;
Found 212.0681.
Bromobenzene (13.4 mL, 128 mmol, 3.50 equiv) was added dropwise to a mixture of
activated magnesium turnings (3.20 g, 132 mmol, 3.60 equiv) in 80 mL dry THF over 20 min.
After complete addition, the resulting black suspension was heated under reflux in an oil bath
for 90 min and then cooled down to 0 °C. Nꢀ(3ꢀOxoꢀ1ꢀphenylpropꢀ1ꢀenꢀ2ꢀyl)acetamide (6.79
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g, 36.6 mmol, 1.0 equiv) was dissolved in 80 mL dry THF and added dropwise to the
Grignard reagent at 0 °C. The reaction mixture was stirred at 0 °C for 1 h and then quenched
with 200 mL sat. NH4Cl solution. The organic phase was separated and the aqueous phase
was extracted twice with EtOAc. The combined organic phases were dried over Na2SO4,
filtered and the solvent was removed under reduced pressure. After purification by flash
column chromatography (10% EtOAc/nꢀhexane → EtOAc) Nꢀ(3ꢀhydroxyꢀ1,3ꢀdiphenylpropꢀ
1ꢀenꢀ2ꢀyl)acetamide was isolated as a yellowish solid (9.31 g, 95%). Rf (70% Et2O/nꢀhexane)
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0.22; mp 115ꢀ117 °C; H NMR (300 MHz, DMSOꢀd6) δ 9.01 (bs, 1H), 7.43ꢀ7.40 (m, 2H),
7.35ꢀ7.28 (m, 6H), 7.27ꢀ7.17 (m, 2H), 6.58 (s, 1H), 5.92 (d, 1H, J = 5.0 Hz), 5.48 (d, 1H, J =
5.0 Hz), 1.85 (s, 3H); 13C{1H} NMR (75 MHz, DMSOꢀd6) δ 169.0, 143.3, 139.2, 135.6,
128.4, 128.2, 127.9, 127.0, 126.8, 126.7, 119.3, 72.8, 22.8; IR (KBr) ṽ 3396, 3246, 3166,
3054, 3021, 1660, 1645, 1540, 1489, 1447, 1410, 1375, 1319, 1305, 1276, 1179, 1041, 1014,
756, 712, 696 cm−1; HRMS (ESI+) m/z: [M+Na]+ Calcd for C17H17NO2Na 290.1151; Found
290.1148.
To a solution of Nꢀ(3ꢀhydroxyꢀ1,3ꢀdiphenylpropꢀ1ꢀenꢀ2ꢀyl)acetamide (3.00 g, 11.2 mmol,
1.00 equiv) in 50 mL dry CH2Cl2, triethylamine (6.20 mL, 44.8 mmol, 4.00 equiv) was added
dropwise at 0 °C followed by methanesulfonyl chloride (1.30 mL, 16.8 mmol, 1.50 equiv).
After 10 min stirring the reaction mixture was quenched with sat. NaHCO3 solution. The
organic phase was separated and the aqueous phase was extracted twice with CH2Cl2. The
combined organic phases were dried over Na2SO4, filtered and the solvent was removed under
reduced pressure. After purification by flash column chromatography (10% → 50% Et2O/nꢀ
hexane), oxazoline (Z)ꢀ2 was isolated as a white solid (1.23 g, 44%). In another fraction,
oxazoline (E)ꢀ2 was obtained as a white solid (1.23 g, 44%). (Z)ꢀIsomer: Rf (70% Et2O/nꢀ
hexane) 0.85; mp 85 °C; 1H NMR (400 MHz, CDCl3) δ 7.81 (m, 2H), 7.45ꢀ7.37 (m, 5H), 7.33
(m, 2H), 7.18 (m, 1H), 6.01 (d, 1H, J = 2.5 Hz), 5.58 (d, 1H, J = 2.5 Hz), 2.31 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 172.2, 152.9, 138.8, 136.4, 129.2, 129.0, 128.6, 128.4,
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127.7, 126.4, 112.1, 85.8, 15.2; IR (KBr) ṽ 3083, 3063, 3039, 3029, 3019, 1613, 1593, 1492,
1387, 1307, 1295, 1273, 1248, 1205, 977, 926, 755, 695 cm−1; HRMS (ESI+) m/z: [M+H]+
Calcd for C17H16NO 250.1226; Found 250.1223. (E)ꢀIsomer: Rf (70% Et2O/nꢀhexane) 0.41;
mp 80 °C; 1H NMR (400 MHz, CDCl3) δ 7.39ꢀ7.37 (m, 2H), 7.34ꢀ7.31 (m, 3H), 7.15ꢀ7.11 (m,
2H), 7.07ꢀ7.01 (m, 3H), 6.74 (d, 1H, J = 2.5 Hz), 6.34 (d, 1H, J = 2.5 Hz), 2.17 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 169.4, 152.3, 136.1, 135.6, 129.3, 129.1, 128.4, 128.3,
127.7, 126.4, 116.3, 84.5, 14.7; IR (KBr) ṽ 3433, 3086, 3063, 3046, 3026, 1665, 1607, 1589,
1572, 1492, 1446, 1422, 1387, 1318, 1308, 1387, 1230, 1187, 1141, 960, 917, 909, 870, 765,
759, 712, 692, 621, 605, 513 cm−1; HRMS (ESI+) m/z: [M+H]+ Calcd for C17H16NO
250.1226; Found 250.1228.
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General Procedure for the Synthesis of Indolylenamides 3
Oxazoline (Z)ꢀ2 or (E)ꢀ2 (50 mg, 0.20 mmol, 1.00 equiv), Sc(OTf)3 (4.9 mg, 10 µmol, 0.05
equiv) and indole (1.20 equiv) were dissolved in dry CHCl3 (0.5 mL) and stirred at 60 °C in
an oil bath for the indicated time. The reaction mixture was quenched with sat. NaHCO3
solution. The organic phase was separated and the aqueous phase was extracted twice with
CH2Cl2. The combined organic phases were dried over Na2SO4, filtered and the solvent was
removed under reduced pressure. The crude products were purified by flash column
chromatography (CH2Cl2 → 1% MeOH/CH2Cl2) and dried under high vacuum (0.1 mbar) at
60 °C overnight.
Indolylenamide 3a was obtained from oxazoline (Z)ꢀ2 and indole (28 mg, 0.24 mmol) after
16 h as a white solid (69 mg, 95%, Z/E >95:5). Rf (1% MeOH/CH2Cl2) 0.28; mp 175ꢀ177 °C;
1H NMR (400 MHz, DMSOꢀd6) δ 10.90 (bs, 1H), 9.22 (bs, 1H), 7.62 (d, 1H, J = 8.0 Hz),
7.34ꢀ7.24 (m, 10H), 7.19ꢀ7.14 (m, 1H), 7.05 (t, 1H, J = 7.5 Hz), 6.92 (t, 1H, J = 7.5 Hz) 6.73
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(s, 1H), 5.84 (s, 1H), 5.62 (s, 1H), 1.86 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ 168.9,
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142.1, 139.4, 136.6, 135.8, 128.8, 128.2, 128.1, 126.8, 126.6, 126.4, 124.2, 122.5, 121.1,
119.7, 118.3, 116.1, 111.4, 47.3, 23.0; IR (KBr) ṽ 3413, 3056, 3024, 2924, 2853, 1655, 1491,
1455, 1267, 745, 698 cm−1; HRMS (ESI+) m/z: [M+Na]+ Calcd for C25H22N2ONa 389.1624;
Found 389.1626.
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Indolylenamide 3b was obtained from oxazoline (E)ꢀ2 and 1ꢀmethylindole (31 µL, 0.24
mmol) after 96 h as a white solid (62 mg, 82%, Z/E >95:5). Rf (1% MeOH/CH2Cl2) 0.44; mp
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154ꢀ157 °C; H NMR (400 MHz, DMSOꢀd6) δ 9.22 (bs, 1H), 7.69 (d, 1H, J = 8.0 Hz), 7.39ꢀ
7.35 (m, 5H), 7.30ꢀ7.24 (m, 5H), 7.19ꢀ7.14 (m, 1H), 7.13 (t, 1H, J = 7.5 Hz), 6.97 (t, 1H,
J = 7.5 Hz), 6.71 (s, 1H), 5.88 (s, 1H), 5.64 (s, 1H), 3.71 (s, 3H), 1.86 (s, 3H); 13C{1H} NMR
(100 MHz, DMSOꢀd6) δ 169.0, 142.0, 139.4, 137.1, 135.7, 128.7, 128.5, 128.3, 128.3, 128.1,
127.1, 126.7, 126.4, 122.6, 121.2, 120.0, 118.5, 115.5, 109.5, 47.2, 32.3, 23.0; IR (KBr) ṽ
3406, 3055, 3023, 2930, 1655, 1614, 1490, 1449, 1371, 1330, 1273, 743, 700 cm−1; HRMS
(ESI+) m/z: [M+Na]+ Calcd for C26H24N2ONa 403.1781; Found 403.1782.
Indolylenamide 3c was obtained from oxazoline (E)ꢀ2, 2ꢀmethylindole (53 mg, 0.40 mmol,
2.00 equiv) and Sc(OTf)3 (9.8 mg, 20 µmol, 0.10 equiv) after 96 h as a brown solid (55 mg,
72%, Z/E >95:5). Rf (1% MeOH/CH2Cl2) 0.21; mp 103ꢀ108 °C; 1H NMR (400 MHz, DMSOꢀ
d6) δ 10.87 (bs, 1H), 9.18 (bs, 1H), 7.33ꢀ7.23 (m, 10H) 7.20ꢀ7.15 (m, 2H), 6.94 (t, 1H,
J = 7.5 Hz) 6.82 (t, 1H, J = 7.5 Hz), 5.91 (s, 1H), 5.81 (s, 1H), 2.26 (s, 3H), 1.81 (s, 3H);
13C{1H} NMR (100 MHz, DMSOꢀd6) δ 168.7, 142.3, 139.3, 135.8, 135.3, 133.2, 128.9,
128.2, 128.1, 128.0, 126.6, 125.9, 122.5, 119.7, 118.7, 118.2, 110.5, 110.0, 46.0, 23.0, 11.8;
IR (KBr) ṽ 3399, 3056, 3023, 1660, 1621, 1490, 1458, 746, 698 cm−1; HRMS (ESI+) m/z:
[M+Na]+ Calcd for C26H24N2ONa 403.1781; Found 403.1780.
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Indolylenamide 3d was obtained from oxazoline (Z)ꢀ2 and 5ꢀmethylindole (32 mg, 0.24
mmol) after 21 h as a white solid (70 mg, 92%, Z/E >95:5). Rf (1% MeOH/CH2Cl2) 0.45; mp
88ꢀ95 °C; 1H NMR (400 MHz, DMSOꢀd6) δ 10.79 (bs, 1H), 9.23 (bs, 1H), 7.40 (s, 1H), 7.34ꢀ
7.33 (m, 4H), 7.31ꢀ7.24 (m, 6H), 7.18ꢀ7.14 (m, 1H), 6.89 (dd, 1H, J = 8.5, 1.5 Hz, 1H), 6.72
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(d, 1H, J = 2.0 Hz) 5.84 (s, 1H), 5.64 (s, 1H), 2.31 (s, 3H), 1.87 (s, 3H); C{1H} NMR (100
MHz, DMSOꢀd6) δ 168.8, 142.3, 139.6, 135.9, 135.0, 128.8, 128.2, 128.1, 127.1, 126.7,
126.6, 126.3, 124.3, 122.7, 122.4, 119.1, 115.5, 111.1, 47.1, 23.0, 21.4; IR (KBr) ṽ 3407,
3296, 3055, 3023, 1661, 1599, 1491, 1448, 1424, 1369, 796, 753, 699 cm−1; HRMS (ESI+)
m/z: [M+Na]+ Calcd for C26H24N2ONa 403.1781; Found 403.1777.
Indolylenamide 3e was obtained from oxazoline (Z)ꢀ2 and 7ꢀmethylindole (32 mg, 0.24
mmol) after 20 h as a white solid (74 mg, 97%, Z/E >95:5). Rf (1% MeOH/CH2Cl2) 0.36; mp
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95ꢀ98 °C; H NMR (400 MHz, DMSOꢀd6) δ 10.87 (bs, 1H), 9.24 (bs, 1H), 7.46 (dd, 1H,
J = 7.0, 2.0 Hz), 7.35ꢀ7.23 (m, 9H), 7.17ꢀ7.14 (m, 1H), 6.87ꢀ6.82 (m, 2H), 6.75 (d, 1H,
J = 2.0 Hz), 5.86 (s, 1H), 5.65 (s, 1H), 2.46 (s, 3H), 1.88 (s, 3H); C{1H} NMR (100 MHz,
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DMSOꢀd6) δ 168.9, 142.2, 139.5, 136.2, 135.9, 128.8, 128.2, 128.1, 126.6, 126.5, 126.4,
123.9, 122.6, 121.6, 120.4, 118.6, 117.3, 116.6, 47.4, 23.0, 16.8; IR (KBr) ṽ 3420, 3054,
3024, 1655, 1492, 1448, 749, 699 cm−1; HRMS (ESI+) m/z: [M+Na]+ Calcd for
C26H24N2ONa 403.1781; Found 403.1777.
Indolylenamide 3f was obtained from oxazoline (E)ꢀ2 and 5ꢀmethoxyindole (35 mg, 0.24
mmol) after 15 h as a white solid (70 mg, 89%, Z/E 94:6). Rf (1% MeOH/CH2Cl2) 0.22; mp
86ꢀ90 °C; 1H NMR (400 MHz, DMSOꢀd6) δ 10.70 (bs, 1H), 9.20 (bs, 1H), 7.36ꢀ7.35 (m, 4H),
7.28ꢀ7.22 (m, 7H), 7.18ꢀ7.14 (m, 1H), 6.71 (dd, 1H, J = 8.5, 2.5 Hz), 6.63 (d, 1H, J = 2.0 Hz),
5.69 (s, 1H), 5.51 (s, 1H), 3.66 (s, 3H), 1.87 (s, 3H); 13C{1H} NMR (100 MHz, DMSOꢀd6) δ
169.1, 152.8, 142.0, 139.3, 135.9, 131.8, 128.8, 128.2, 128.0, 127.2, 126.7, 126.4, 124.8,
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122.9, 116.1, 111.9, 111.0, 102.0, 55.2, 47.6, 22.9; IR (KBr) ṽ 3411, 3056, 3024, 2936, 2829,
1656, 1626, 1485, 1451, 1209, 1171, 699 cm−1; HRMS (ESI+) m/z: [M+Na]+ Calcd for
C26H24N2O2Na 419.1730; Found 419.1729.
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Indolylenamide 3g was obtained from oxazoline (E)ꢀ2, 7ꢀmethoxyindole (35 mg, 0.24 mmol)
and Sc(OTf)3 (9.8 mg, 20 µmol, 0.10 equiv) after 69 h as a white solid (63 mg, 80%, Z/E
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>95:5). Rf (1% MeOH/CH2Cl2) 0.29; mp 94ꢀ98 °C; H NMR (400 MHz, DMSOꢀd6) δ 10.97
(bs, 1H), 9.21 (bs, 1H), 7.34ꢀ7.33 (m, 4H), 7.27ꢀ7.20 (m, 6H), 7.17ꢀ7.14 (m, 1H), 6.85 (t, 1H,
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J = 8.0 Hz), 6.63ꢀ6.61 (m, 2H), 5.83 (s, 1H), 5.60 (s, 1H), 3.89 (s, 3H), 1.86 (s, 3H); C{1H}
NMR (100 MHz, DMSOꢀd6) δ 168.9, 146.0, 142.2, 139.4, 135.8, 128.8, 128.3, 128.2, 128.1,
126.7, 126.6, 126.4, 123.8, 122.5, 118.9, 116.7, 112.6, 101.6, 55.0, 47.3, 23.0; IR (KBr) ṽ
3422, 3055, 3024, 2934, 1655, 1578, 1494, 1465, 1448, 1370, 1261, 1232, 1091, 1046, 782,
752, 731, 716, 700 cm−1; HRMS (ESI+) m/z: [M+Na]+ Calcd for C26H24N2O2Na 419.1730;
Found 419.1729.
Indolylenamide 3h was obtained from oxazoline (Z)ꢀ2 and 4,5ꢀethylenedioxyindole (42 mg,
0.24 mmol) after 44 h as a white solid (61 mg, 72%, Z/E 94:6). Rf (1% MeOH/CH2Cl2) 0.18;
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mp 104ꢀ109 °C; H NMR (400 MHz, DMSOꢀd6) δ 10.77 (bs, 1H), 9.13 (bs, 1H), 7.31ꢀ6.57
(m, 10H), 6.81ꢀ6.77 (m, 2H), 6.58 (d, 1H, J = 8.5 Hz), 5.77 (s, 1H), 5.64 (s, 1H), 4.12ꢀ4.08
(m, 3H) 4.02ꢀ3.98 (m, 1H), 1.80 (s, 3H); 13C{1H} NMR (100 MHz, DMSOꢀd6) δ 167.8,
143.6, 140.0, 136.5, 136.3, 134.9, 134.9, 128.9, 128.0, 127.8, 127.7, 126.3, 125.8, 123.7,
122.2, 117.1, 114.8, 112.3, 104.0, 64.0, 63.7, 48.4, 23.1; IR (KBr) ṽ 3417,3055, 3023, 2926,
2870, 1668, 1503, 1446, 1368, 1338, 1274, 1257, 1222, 1085, 962, 714, 699 cm−1; HRMS
(ESI+) m/z: [M+Na]+ Calcd for C27H24N2O3Na 447.1679; Found 447.1680.
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Indolylenamide 3i was obtained from oxazoline (Z)ꢀ2 and 2ꢀphenylindole (46 mg, 0.24
mmol) after 15 h as a white solid (87 mg, 99%, Z/E >95:5). Rf (1% MeOH/CH2Cl2) 0.24; mp
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107ꢀ112 °C; H NMR (400 MHz, DMSOꢀd6) δ 11.34 (bs, 1H), 9.14 (bs, 1H), 7.59 (m, 2H),
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J = 7.5 Hz), 6.90 (t, 1H, J = 7.5 Hz), 6.10 (s, 1H), 5.84 (s, 1H), 1.70 (s, 3H); C{1H} NMR
(100 MHz, DMSOꢀd6) δ 168.5, 142.4, 139.0, 136.5, 135.8, 132.6, 128.9, 128.6, 128.5, 128.2,
128.1, 128.0, 127.7, 126.7, 125.9, 123.4, 121.1, 120.5, 118.8, 111.5, 110.6, 46.8, 22.8; IR
(KBr) ṽ 3397, 3281, 3056, 3023, 1668, 1600, 1490, 1449, 1426, 764, 746, 699 cm−1; HRMS
(ESI+) m/z: [M+Na]+ Calcd for C31H26N2ONa 465.1937; Found 465.1941.
Indolylenamide 3j was obtained from oxazoline (Z)ꢀ2, 4ꢀbromoindole (50 µL, 0.40 mmol,
2.00 equiv) and Sc(OTf)3 (9.8 mg, 20 µmol, 0.10 equiv) after 96 h as a white solid (73 mg,
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82%, Z/E 85:15). (Z)ꢀisomer: Rf (1% MeOH/CH2Cl2) 0.26; mp 93ꢀ95 °C; H NMR (400
MHz, DMSOꢀd6) δ 11.41 (bs, 1H), 9.22 (bs, 1H), 7.40 (d, 1H, J = 8.0 Hz), 7.08ꢀ7.31 (m,
11H) 7.01 (d, 1H, J = 2.0 Hz), 6.95 (t, 1H, J = 8.0 Hz), 6.16 (s, 1H), 5.52 (s, 1H), 1.79 (s,
3H); 13C{1H} NMR (100 MHz, DMSOꢀd6) δ 167.8, 143.1, 139.9, 138.2, 136.4, 129.2, 128.0,
127.9, 126.4, 126.0, 124.5, 122.9, 122.7, 122.2, 115.5, 113.1, 111.3, 47.3, 23.2; IR (KBr) ṽ
3419, 3056, 3024, 1669, 1652, 1491, 1335, 1184, 746, 699 cm−1; HRMS (ESI+) m/z:
[M+Na]+ Calcd for C25H2179BrN2ONa 467.0730; Found 467.0726.
Indolylenamide 3k was obtained from oxazoline (E)ꢀ2 and 6ꢀchloroindole (36 mg, 0.24
mmol) after 64 h as a white solid (74 mg, 93%, Z/E 94:6). Rf (1% MeOH/CH2Cl2) 0.33; mp
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205ꢀ206 °C; H NMR (400 MHz, DMSOꢀd6) δ 11.05 (bs, 1H), 9.24 (bs, 1H), 7.66 (d, 1H,
J = 8.5 Hz), 7.40 (d, 1H, J = 1.5 Hz), 7.36ꢀ7.33 (m, 4H), 7.29ꢀ7.24 (m, 5H), 7.18ꢀ7.15 (m,
1H), 6.95 (dd, 1H, J = 8.5, 1.5 Hz), 6.74 (d, 1H, J = 1.5 Hz), 5.83 (s, 1H), 5.59 (s, 1H), 1.87
(s, 3H); 13C{1H} NMR (100 MHz, DMSOꢀd6) δ 169.1, 141.7, 139.3, 137.0, 135.7, 128.8,
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128.3, 128.2, 128.1, 126.7, 126.5, 125.9, 125.6, 125.4, 122.8, 121.1, 118.7, 116.6, 111.0, 47.2,
22.9; IR (KBr) ṽ 3420, 3223, 3057, 3022, 1649, 1518, 1491, 1450, 907, 812, 749, 716, 700
cm−1; HRMS (ESI+) m/z: [M+Na]+ Calcd for C25H2135ClN2ONa 423.1235; Found 423.1231.
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Indolylenamide 3l was obtained from oxazoline (Z)ꢀ2 and 5ꢀfluoroindole (32 mg, 0.24
mmol) after 18 h as a white solid (69 mg, 90%, Z/E 92:8). Rf (1% MeOH/CH2Cl2) 0.29; mp
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84ꢀ89 °C; H NMR (400 MHz, DMSOꢀd6) δ 10.97 (bs, 1H), 9.25 (bs, 1H), 7.46 (dd, 1H,
J = 10.0, 2.5 Hz), 7.38ꢀ7.24 (m, 10H), 7.20ꢀ7.16 (m, 1H), 6.90 (td, 1H, J = 9.0, 2.5 Hz), 6.76
(d, 1H, J = 2.5 Hz), 5.88 (s, 1H), 5.54 (s, 1H), 1.89 (s, 3H); 13C{1H} NMR (100 MHz,
DMSOꢀd6) δ 169.2, 156.5 (d, J = 231.0 Hz), 141.7, 139.2, 135.7, 133.3, 128.8, 128.3, 128.2,
128.1, 127.0 (d, J = 10.0 Hz), 126.8, 126.6, 126.3, 122.8, 116.7 (d, J = 4.5 Hz), 112.4 (d,
J = 10.0 Hz), 109.3 (d, J = 26.0 Hz), 104.5 (d, J = 23.5 Hz), 47.4, 22.9; IR (KBr) ṽ 3417,
3383, 3283, 3056, 3024, 2922, 1661, 1582, 1486, 1451, 1369, 1263, 1166, 940, 798, 751, 699
cm−1; HRMS (ESI+) m/z: [M+Na]+ Calcd for C25H21FN2ONa 407.1530; Found 407.1533.
Indolylenamide 3m was obtained from oxazoline (Z)ꢀ2, methyl indoleꢀ5ꢀcarboxylate (42 mg,
0.24 mmol) and Sc(OTf)3 (9.8 mg, 20 µmol, 0.10 equiv) after 48 h as a white solid (81 mg,
95%, Z/E >95:5). Rf (1% MeOH/CH2Cl2) 0.11; mp 199ꢀ201 °C; 1H NMR (400 MHz, DMSOꢀ
d6) δ 11.37 (bs, 1H), 9.26 (bs, 1H), 8.32 (s, 1H), 7.71 (d, 1H, J = 8.5 Hz), 7.44 (d, 1H,
J = 8.5 Hz), 7.35ꢀ7.24 (m, 9H), 7.18ꢀ7.14 (m, 1H), 6.94 (d, 1H, J = 2.5 Hz), 5.81 (s, 1H), 5.74
(s, 1H), 3.79 (s, 3H), 1.86 (s, 3H); 13C{1H} NMR (100 MHz, DMSOꢀd6) δ 168.8, 167.2,
141.9, 139.3, 139.2, 135.7, 128.7, 128.3, 128.2, 128.1, 126.7, 126.5, 126.4, 126.2, 122.5,
122.2, 122.1, 120.1, 117.4, 111.5, 51.6, 46.8, 23.0; IR (KBr) ṽ 3420, 3023, 2949, 1691, 1654,
1617, 1491, 1436, 1279, 1244, 1109, 754, 699 cm−1; HRMS (ESI+) m/z: [M+Na]+ Calcd for
C27H24N2O3Na 447.1679; Found 447.1680.
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Indolylenamide 3n was obtained from oxazoline (Z)ꢀ2, methyl indoleꢀ6ꢀcarboxylate (42 mg,
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0.24 mmol) and Sc(OTf)3 (9.8 mg, 20 µmol, 0.10 equiv) after 69 h as a white solid (78 mg,
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92%, Z/E >95:5). Rf (1% MeOH/CH2Cl2) 0.19; mp 99ꢀ104 °C; H NMR (400 MHz, DMSOꢀ
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d6) δ 11.32 (bs, 1H), 9.25 (bs, 1H), 8.05 (s, 1H), 7.73 (d, 1H, J = 8.5 Hz), 7.44 (d, 1H,
J = 8.5 Hz), 7.36ꢀ7.35 (m, 4H), 7.29ꢀ7.25 (m, 5H), 7.18ꢀ7.14 (m, 1H), 7.01 (d, 1H,
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J = 2.0 Hz), 5.84 (s, 1H), 5.67 (s, 1H), 3.83 (s, 3H), 1.87 (s, 3H); C{1H} NMR (100 MHz,
DMSOꢀd6) δ 169.0, 167.2, 141.1, 139.2, 135.9, 135.7, 130.3, 128.8, 128.3, 128.2, 128.1,
126.8, 126.6, 122.8, 122.2, 119.5, 119.1, 116.8, 113.5, 51.7, 47.1, 23.0; IR (KBr) ṽ 3411,
3323, 3057, 3024, 2949, 1694, 1665, 1623, 1492, 1455, 1435, 1320, 1276, 1218, 1086, 776,
749, 699 cm−1; HRMS (ESI+) m/z: [M+Na]+ Calcd for C27H24N2O3Na 447.1679; Found
447.1677.
Indolylenamide 3o was obtained from oxazoline (Z)ꢀ2, 5ꢀcyanoindole (34 mg, 0.24 mmol)
and Sc(OTf)3 (9.8 mg, 20 µmol, 0.10 equiv) after 96 h as a pink solid (48 mg, 62%, Z/E
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>95:5). Rf (1% MeOH/CH2Cl2) 0.18; mp 107ꢀ110 °C; H NMR (400 MHz, DMSOꢀd6) δ
11.47 (bs, 1H), 9.30 (bs, 1H), 8.26 (s, 1H), 7.53 (d, 1H, J = 8.5 Hz), 7.42 (d, 1H, J = 8.5 Hz),
7.39ꢀ7.35 (m, 4H), 7.32ꢀ7.25 (m, 5H), 7.20ꢀ7.16 (m, 1H), 6.87 (d, 1H, J = 2.5 Hz), 5.87 (s,
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1H), 5.60 (s, 1H), 1.90 (s, 3H); C{1H} NMR (100 MHz, DMSOꢀd6) δ 169.4, 141.2, 139.2,
138.4, 135.5, 128.8, 128.4, 128.3, 128.1, 126.9, 126.8, 126.6, 125.5, 123.9, 123.2, 120.9,
117.8, 112.8, 100.5, 47.2, 22.9; IR (KBr) ṽ 3387, 3296, 3057, 3025, 2220, 1656, 1617, 1492,
1473, 1448, 1368, 807, 753, 699 cm−1; HRMS (ESI+) m/z: [M+Na]+ Calcd for C26H21N3ONa
414.1577; Found 414.1578.
Indolylenamide 3p was obtained from oxazoline (Z)ꢀ2, 5ꢀnitroindole (39 mg, 0.24 mmol)
and Sc(OTf)3 (9.8 mg, 20 µmol, 0.10 equiv) after 96 h as a yellow solid (49 mg, 60%, Z/E
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>95:5). Rf (1% MeOH/CH2Cl2) 0.20; mp 109ꢀ114 °C; H NMR (400 MHz, DMSOꢀd6) δ
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11.32 (bs, 1H), 9.30 (bs, 1H), 8.76 (d, 1H, J = 2.0 Hz), 7.98 (dd, 1H, J = 9.0, 2.0 Hz), 7.53 (d,
1H, J = 9.0 Hz), 7.38ꢀ7.36 (m, 4H), 7.31ꢀ7.25 (m, 5H), 7.19ꢀ7.15 (m, 1H), 6.97 (s, 1H), 5.87
(s, 1H), 5.71 (s, 1H), 1.90 (s, 3H); 13C{1H} NMR (100 MHz, DMSOꢀd6) δ 169.3, 141.3,
140.4, 139.8, 139.1, 135.5, 128.8, 128.5, 128.2, 128.1, 126.9, 126.8, 126.1, 123.0, 119.2,
117.0, 116.7, 112.0, 47.0, 22.9; IR (KBr) ṽ 3408, 3058, 3025, 1654, 1624, 1518, 1492, 1472,
1332, 1100, 700 cm−1; HRMS (ESI+) m/z: [M+Na]+ Calcd for C25H21N3O3Na 434.1475;
Found 434.1472.
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Pyrrolylenamides 4. Oxazoline (Z)ꢀ2 (50 mg, 0.20 mmol, 1.00 equiv), Sc(OTf)3 (9.8 mg, 20
µmol, 0.10 equiv) and pyrrole (28 µL, 0.40 mmol, 2.00 equiv) were dissolved in dry CHCl3
(0.5 mL) and stirred at 60 °C in an oil bath for 17 h. The reaction mixture was quenched with
sat. NaHCO3 solution. The organic phase was separated and the aqueous phase was extracted
twice with CH2Cl2. The combined organic phases were dried over Na2SO4, filtered and the
solvent was removed under reduced pressure. The crude products were purified by flash
column chromatography (20% → 50% MTBE/nꢀhexane) and dried under high vacuum (0.1
mbar) at 60 °C overnight. Compound (Z)ꢀ4 was obtained as an orange solid (38 mg, 59%). Rf
(50% MTBE/nꢀhexane) 0.25; mp 49ꢀ52 °C; 1H NMR (300 MHz, DMSOꢀd6) δ 10.61 (bs, 1H),
9.21 (bs, 1H), 7.33ꢀ7.16 (m, 10H), 6.67ꢀ6.64 (m, 1H), 5.97ꢀ5.94 (m, 1H), 5.78ꢀ5.75 (m, 2H),
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5.46 (s, 1H), 1.83 (s, 3H); C{1H} NMR (75 MHz, DMSOꢀd6) δ 168.8, 142.2, 139.5, 135.7,
131.2, 128.7, 128.21, 128.15, 128.07, 126.7, 126.3, 122.6, 117.3, 107.1, 106.9, 48.8, 23.0; IR
(KBr) ṽ 3419, 3372, 3269, 3057, 3024, 2924, 2853, 1656, 1516, 1492, 1369, 1276, 1075,
1028, 751, 711, 698 cm−1; HRMS (ESI+) m/z: [M+Na]+ Calcd for C21H20N2ONa 339.1468;
Found 339.1466; Compound (E)ꢀ4 was obtained as an orange solid (5 mg, 7%). Rf (50%
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MTBE/nꢀhexane) 0.40; mp 102ꢀ105 °C; H NMR (400 MHz, DMSOꢀd6) δ 10.74 (bs, 1H),
7.81 (bs, 1H), 7.50 (s, 1H), 7.35ꢀ7.18 (m, 8H), 7.10 (m, 2H), 6.75ꢀ6.73 (m, 1H), 6.03ꢀ6.01 (m,
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1H), 5.91ꢀ5.89 (m, 1H), 5.45 (s, 1H), 1.92 (s, 3H); C{1H} NMR (100 MHz, DMSOꢀd6) δ
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169.1, 140.6, 136.7, 135.4, 129.4, 128.5, 128.4, 127.8, 126.7, 126.3, 118.0, 117.3, 107.6,
107.4, 44.0, 24.2; IR (KBr) ṽ 3410, 3344, 3024, 2924, 1675, 1647, 1517, 1494, 1267, 734,
700 cm−1; HRMS (ESI+) m/z: [M+Na]+ Calcd for C21H20N2ONa 339.1468; Found 339.1466.
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1-Hydroxynaphthalenylenamides 5 and 6. Oxazoline (Z)ꢀ2 (50 mg, 0.20 mmol, 1.00 equiv),
Sc(OTf)3 (9.8 mg, 20 µmol, 0.10 equiv), and 1ꢀnaphthol (35 mg, 0.24 mmol, 1.20 equiv) were
dissolved in dry CHCl3 (0.5 mL) and stirred at 60 °C in an oil bath for 17 h. The reaction
mixture was quenched with sat. NaHCO3 solution. The organic phase was separated and the
aqueous phase was extracted twice with CH2Cl2. The combined organic phases were dried
over Na2SO4, filtered and the solvent was removed under reduced pressure. The crude
products were purified by flash column chromatography (10% → 70% MTBE/nꢀhexane) and
dried under high vacuum (0.1 mbar) at 60 °C overnight. Compound 5 was obtained as a white
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solid (28 mg, 36%, Z/E >95:5). Rf (30% MTBE/nꢀhexane) 0.26; mp 210ꢀ212 °C; H NMR
(400 MHz, DMSOꢀd6) δ 10.30 (bs, 1H), 10.00 (bs, 1H), 8.23ꢀ8.21 (m, 1H), 7.78ꢀ7.76 (m,
1H), 7.46ꢀ7.40 (m, 4H), 7.37ꢀ7.26 (m, 8H), 7.23ꢀ7.20 (m, 1H), 6.80 (d, 1H, J = 8.5 Hz), 5.94
(s, 1H), 5.65 (s, 1H), 2.03 (s, 3H); 13C{1H} NMR (100 MHz, DMSOꢀd6) δ 171.9, 150.1,
139.9, 138.2, 134.7, 133.2, 129.4, 128.6, 128.4, 128.2, 127.4, 127.2, 127.0, 126.8, 125.8,
125.6, 124.83, 124.77, 122.2, 121.3, 118.2, 49.9, 22.3; IR (KBr) ṽ 3407, 3250, 3056, 3025,
2925, 1654, 1569, 1508, 1492, 1383, 1279, 752, 698 cm−1; HRMS (ESI+) m/z: [M+Na]+
Calcd for C27H23NO2Na 416.1621; Found 416.1611; Compound 6 was obtained as a white
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solid (17 mg, 22%, Z/E >95:5). Rf (70% MTBE/nꢀhexane) 0.56; mp 127ꢀ133 °C; H NMR
(400 MHz, DMSOꢀd6) δ 10.05 (bs, 1H), 9.30 (bs, 1H), 8.36 (d, 1H J = 8.5 Hz), 8.16 (dd, 1H,
J = 8.0, 1.5 Hz), 7.48ꢀ7.39 (m, 2H), 7.36ꢀ7.32 (m, 2H), 7.25ꢀ7.23 (m, 7H), 7.18ꢀ7.13 (m, 1H),
6.89 (d, 1H, J = 8.0 Hz), 6.80 (d, 1H, J = 8.0 Hz), 6.26 (s, 1H), 5.53 (s, 1H), 1.82 (s, 3H);
13C{1H} NMR (100 MHz, DMSOꢀd6) δ 169.0, 152.2, 141.9, 139.6, 135.6, 132.9, 129.4,
128.4, 128.2, 128.1, 127.9, 127.1, 126.8, 126.5, 126.2, 125.1, 124.6, 124.2, 123.5, 122.3,
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107.3, 50.6, 23.0; IR (KBr) ṽ 3384, 3058, 3025, 2925, 1656, 1625, 1598, 1586, 1516, 1491,
1378, 1271, 765, 754, 700 cm−1; HRMS (ESI+) m/z: [M+Na]+ Calcd for C27H23NO2Na
416.1621; Found 416.1626.
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ASSOCIATED CONTENT
13
1H and C NMR spectra for all new compounds and crystallographic data for compound 3a
(deposition numbers: CCDC 1541861) (PDF).
Crystal data and structure refinement for indolylenamide 3a (CIF).
ACKNOWLEDGEMENTS
This work was generously supported by the European Social Fund through a predoctoral
fellowship awarded to M. S. and by BASF and Evonik through the generous donation of
chemicals. We thank Peter Coburger (University of Leipzig) for obtaining the Xꢀray structure
of 3a and Caroline Dorsch (University of Leipzig) for her support in the synthesis of
oxazoline 2.
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