Lanthanum(III)-Catalyzed Three-Component Reaction of Coumarin-3-carboxylates for the Synthesis of Indolylmalonamides and Analysis of Their Photophysical Properties

Article abstract of DOI:10.1021/acs.joc.6b00541

New methodology has been developed for the Lewis acid catalyzed synthesis of malonamides. First, the scandium(III)-catalyzed addition of diverse nucleophiles (e.g., indoles, N,N-dimethyl-m-anisidine, 2-ethylpyrrole, and 2-methylallylsilane) to coumarin-3-carboxylates has been developed to afford chromanone-3-carboxylates in high yields as a single diastereomer. Upon investigating a subsequent lanthanum(III)-catalyzed amidation reaction, a new multicomponent reaction was designed by bringing together coumarin-3-carboxylates with indoles and amines to afford indolylmalonamides, which were identified to exhibit fluorescent properties. The photophysical properties for selected compounds have been analyzed, including quantum yield, molar absorptivity, and Stokes shift. Synthetic studies of several reaction byproducts involved in the network of reaction equilibria for the three-component reaction provide mechanistic insight for the development of this methodology.

Full text of DOI:10.1021/acs.joc.6b00541

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Article
Lanthanum(III)-catalyzed three-component reaction
of coumarin-3-carboxylates for the synthesis of
indolylmalonamides and analysis of their photophysical properties
Julia J. Jennings, Chinmay P. Bhatt, and Annaliese K. Franz
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00541 • Publication Date (Web): 15 Jun 2016
Downloaded from http://pubs.acs.org on June 20, 2016
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Lanthanum(III)-catalyzed three-component reaction of coumarin-3-carboxylates for the synthesis
of indolylmalonamides and analysis of their photophysical properties
Julia J. Jennings, Chinmay P. Bhatt‡ and Annaliese K. Franz*
9
Department of Chemistry, University of California, One Shields Avenue, Davis, California 95616, United
States
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Dedicated to Professor Stuart L. Schreiber on the occasion of his 60th Birthday
ABSTRACT:
Multi-component reaction
New methodology has been developed for the Lewis acid-
O
O
X
O
NHR2
NHR2
CO2Me
catalyzed synthesis of malonamides. First, the scandium(III)-
catalyzed addition of diverse nucleophiles (e.g. indoles, N,N-
dimethyl-m-anisidine, 2-ethylpyrrole and 2-methylallylsilane)
X
La(OTf)3
R2 NH2
O
R
OH
Y
N
Y
R1
10 examples
up to 90% yield
Fluorescent Products
R
N
R1
to coumarin-3-carboxylates has been developed to afford chromanone-3-carboxylates in high yields as a
single diastereomer. Upon investigating a subsequent lanthanum(III)-catalyzed amidation reaction, a new
multi-component reaction was designed by bringing together coumarin-3-carboxylates with indoles and
amines to afford indolylmalonamides, which were identified to exhibit fluorescent properties. The
photophysical properties for selected compounds have been analyzed, including quantum yield, molar
absorptivity and Stoke’s shift. Synthetic studies of several reaction byproducts involved in the network of
reaction equilibria for the three-component reaction provide mechanistic insight for the development of
this methodology.
INTRODUCTION
Multi-component reactions (MCRs) are an efficient and powerful tool for organic synthesis.1-4
MCRs combine three or more building blocks in a single operation for the synthesis of structurally
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diverse molecules with applications for the discovery of new pharmaceutical leads, agrochemicals, and
other useful organic compounds.5-7 These processes have the advantages of being operationally simple,
atom economical, and can reduce waste and energy consumption compared to stepwise syntheses. The
challenge to develop a successful MCR requires orchestrating a series of reactions that channel into a
major product without formation of significant side products.8 While thermal processes have dominated
the history of MCRs, many recent discoveries have been enabled using catalysts to activate new
substrates for MCRs and provide high selectivity under mild reaction conditions.9-15 Examples of catalysts
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used for MCRs include rare earth salts such as La(OTf)3, CAN, and Yb(OTf)3.16
A. Multicomponent Synthesis of Malonamides (this work)
O
O
O
NHR3
NHR3
X
10 mol %
La(OTf)3
X
CO2Me
O
R
OH
Y
R
CH2Cl2, rt
R3 NH2
N
R1
N
Y
R1
• Lanthanum catalyst
• Simple purification via filtration
• Multiple sites for modularity
• Fluorescent products
B. Examples of Malonamides with Medicinal or Industrial Applications
H3C
O
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O
O
O
Ph
N
R
R
N
N
Ph
N
N
R1 R2 R1
H
Me
N
R
N
O
Ph
Opioid κ agonist
κKi = 0.27 nM
ligands for Cu,
La, U, and Pu
Triflubazam R = CF3
Clobazam R = Cl
OH
Figure 1. A. Multi-component synthesis of malonamides. B. Examples of
malonamides with medicinal or industrial applications.
Here we describe the development of a Sc(III)-catalyzed addition of nucleophiles to coumarin-3-
carboxylates where we recognized the opportunity to design a La(III)-catalyzed three-component reaction
(3CR) involving indoles, amines and coumarin-3-carboxylates for the synthesis of indolylmalonamides
(Figure 1A). Many traditional MCRs utilize imine or isocyanide substrates;16 however, MCRs
incorporating indoles are desirable because these important heterocycles are found in many natural
products and medicinally relevant compounds.17-19 The malonamide motif is also useful for various
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applications in medicinal and industrial chemistry (Figure 1B). Malonamides have been identified as
ligands for copper20 and lanthanides,21-23 actinide chelators for nuclear waste sequestration,24-26 and
medicinal compounds such as opioid κ agonists27 and as 1,5-benzodiazepinedione derivatives such as
clobazam and triflubazam.28-29 In addition to these applications, our results presented here also
demonstrate the fluorescence properties of indolylmalonamides.
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Coumarin-3-carboxylates such as 1 are useful 1,3-dicarbonyl electrophiles, however, they are also
challenging substrates that often require longer reaction times and afford products in lower yields
compared to related dicarbonyl substrates investigated in methodology development.30-33 We have
previously reported examples of oxazole cyclizations and an allylsilane carboannulation using coumarin-
3-carboxylates with Ti(IV) and Sc(III) Lewis acids.31-32 Two examples of an indole addition to ethyl
coumarin-3-carboxylate have been achieved previously, initially using a urea palladacycle catalyst30 and
more recently with Sc(OTf)3/sodium dodecyl sulfate (SDS) in water.33 Indolylchromanones and other
indolylmalonates can be accessed via the three-component Yonemitsu reaction34-35 of aldehydes, indoles
and Meldrum’s acid.36 Recently, catalyst-free tandem Michael addition/decarboxylation of coumarin-3-
carboxylic acid and thiocoumarin-3-carboxylic acid with indole has also been reported.37 In our studies to
expand the utility of coumarin-3-carboxylates, we sought to develop general methodology for the Sc(III)-
catalyzed addition of indoles, methallyltrimethylsilane and N,N-dimethyl-m-anisidine to coumarin-3-
carboxylates and also demonstrate that both esters can be utilized in further transformations that are
desirable for medicinal compounds.
RESULTS AND DISCUSSION
In our initial studies for the Sc(III)-catalyzed addition of indoles to methyl coumarin-3-
carboxylate, we obtained indolylchomanone 3a as the thermodynamically-favored trans38 diastereomer in
88% yield using dichloromethane with 10 mol % of Sc(OTf)3 as a catalyst (Table 1, entry 1). Solvent,
concentration and temperature were investigated (Table 1, entries 1-4) and conditions with increased
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concentration and heating to 50 °C improved the reaction rate significantly (54 vs 12 h). Conditions using
toluene were selected to accommodate a substrate scope with a wide range of solubilities and melting
points. The reaction was effectively catalyzed with other scandium salts (ScCl3) with excellent
diastereoselectivity maintained (Table 1, entry 5). The reaction was also catalyzed by other rare earth
salts, such as Y(OTf)3. A decrease in product formation was observed within a series of lanthanide
catalysts, i.e. Sc > Y > La, correlating with decreasing Lewis acidity39 (Table 1, entry 2 vs entries 6 and
7). Using TiCl4 resulted in low conversion (Table 1, entry 8). No product was observed in the absence of
Lewis acid (Table 1, entry 9). In general, three equivalents of indole was optimal for higher yields and
lower reaction times. Using either two or one equivalents of indole afforded 83% and 65% yields,
respectively. The trans-chromanone product was observed as a single diastereomer under all reaction
conditions.
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Table 1. Reaction optimization for the addition of indole to methyl coumarin-3-carboxylatea
entry
conditions
yield (%)b,c
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8
9
Sc(OTf)3, CH2Cl2, rt, 54 hd
Sc(OTf)3, PhMe, 50 ˚C, 12 h
Sc(OTf)3, neat, rt, 24 h
88e
85e
60
81
63
38
6
Sc(OTf)3, neat, 50 ˚C, 12 h
ScCl3, PhMe, 50 ˚C, 12 h
Y(OTf)3, PhMe, 50 ˚C, 12 h
La(OTf)3, PhMe, 50 ˚C, 12 h
TiCl4, PhMe, 50 ˚C, 12 h
no catalyst, PhMe, 50 ˚C, 12 h
77
0
a Reactions performed under argon with 0.1 mmol of coumarin 1a, 0.3 mmol of
indole 2a, and 0.1 mL of PhMe unless otherwise indicated. Molecular sieves
were not necessary when the vial was dried and purged with argon. b Determined
1
c
using H NMR spectroscopy, see experimentals for details. Only the trans-
diastereomer is observed for all reaction conditions. d Performed in 0.5 mL
CH2Cl2. e Isolated yield.
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The scope of coumarin-3-carboxylate 1 and nucleophile was examined (Figure 2). The reaction
proceeds in good yield with both electron-withdrawing and donating groups on either coumarin-3-
carboxylate (Figure 2, 3g and 3h) or indole substrates (Figure 2, 3e and 3d). Both N-H and N-methyl
indoles were effective nucleophiles (Figure 2, 3a vs 3c and 3b vs 3f). The reaction of tert-butyl coumarin-
3-carboxylate also proceeds with no loss of the tert-butyl group or decarboxylation observed under the
reaction conditions (Figure 2, 3i). The reactivity observed for indole also applies to other nucleophiles40
such as 2-methyl-allyltrimethylsilane, N,N-dimethyl-m-anisidine and 2-ethylpyrrole, yielding substituted
chromanones 4, 5, and 6, respectively (eqs 1-3). In the case of the methallylsilane, the reaction proceeds
rapidly with 93% yield achieved within 3 hours.
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Figure 2. Scope of indole additions to coumarin-3-carboxylates
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We planned to elaborate the chromane scaffold by transformation of the methyl carboxylate, but
instead discovered a novel route to malonamides 7 using La(III)-catalyzed amidation conditions
developed by Ohshima and coworkers.41 Although amidation of the external methyl carboxylate was
initially expected to afford chromane-3-carboxamide 8, we observed amidation of both the exocyclic ester
and the chromane ring to afford malonamide 7a in 61% yield (eq 4). No product resulting from single
amidation (e.g. 8 or 9) was observed (eq 4). Various amines, including ethanolamine, are effective in the
amidation reaction to afford highly functionalized malonamides 7 with good yields (Figure 3).
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Figure 3. Scope of La(OTf)3-catalyzed amidation to form malonamides
With the effective amidation of indolylchomanones, we recognized the opportunity to design a
new one-pot, three-component process for malonamide synthesis because rare earth catalysts are used for
both reactions. Initial investigations using scandium salts as catalysts afforded < 5% of the malonamide
product and only starting materials were observed (Table 2, entry 1), attributed to the amine inhibiting the
catalytic ability of the scandium Lewis acid in the indole addition to coumarin-3-carboxylate.41 However,
we identified that La(OTf)3 was effective at catalyzing both the indole addition and the amidation in a
one-pot, multi-component reaction to afford the desired indolylmalonamides (Table 2, entries 2 and 3)
with minimal side products observed. Amides 8 and 9 were not observed under any conditions; however,
the formation of small amounts (<5%) of the coumarin carboxamide (13) and imine (14) was observed
using H NMR spectroscopy.42 A decreased yield was observed for other Lewis acids, such as Y(OTf)3
1
and TiCl4 (Table 2, entries 4 and 5).
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Table 2. Optimization and solvent effects for the malonamide 3CRa
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entry
R
Me
H
Me
Me
Me
Me
Me
Me
Me
catalyst
Sc(OTf)3
La(OTf)3
La(OTf)3
Y(OTf)3
TiCl4
La(OTf)3
La(OTf)3
La(OTf)3
La(OTf)3
solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
PhMe
iPrOH
CH3CN
THF
yield (%)b
1
2
3
4
5
6
7
8
9
<5
64
90
38
39
90
77
74
70
aAll reactions performed under argon with 0.1 mmol of coumarin 1a, 0.3
mmol of indole, 0.3 mmol of amine, 10 mol % of Lewis acid and 0.1 M
solvent for 24 h. Yield determined using H NMR spectroscopy of the
unpurified reaction mixture with phenylTMS as an internal standard.
b
1
The indolylmalonamide product precipitates in dichloromethane, allowing the product to be
collected using simple filtration, which we expect is a key feature in driving the reaction forward. A
solvent screen was performed to analyze solvent effects on product yield (Table 2, entries 6-10). The 3CR
proceeds in toluene with comparable yield (Table 2, entry 6) and only slight reductions in yield observed
for acetonitrile, tetrahydrofuran and isopropanol (Table 2, entries 7-9). Due to the precipitation of the
malonamide product in CH2Cl2 and favorable solubility of any side products and starting materials, the
highest yield and purity was observed when the product is isolated from CH2Cl2.
The 3CR tolerates variation on the coumarin and indole components and both aromatic and alkyl
amines could be utilized. The 3CR proceeds in good yields ranging from 47-85% with aromatic amines,
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electron-rich indoles and coumarin-3-carboxylates (Figure 4). The use of electron-rich indoles favors
product formation and increases yield by reducing the amount of byproducts observed. Electron-neutral or
electron-poor coumarin-3-carboxylates proceeds to give the highest yields, but electron-rich coumarin-3-
carboxylates were tolerated (7i vs 7b and 7f). The highest yields for the 3CR were observed while using
aromatic amines such as p-anisidine and aniline due to a favorable balance of nucleophilicity (7c and 7h,
Figure 4). The 3CR also proceeds with secondary cyclic amines such as pyrrolidine and morpholine (7j
and 7k, Figure 4). In these cases, heating to 50 °C was required to attain significant amounts of the
desired malonamide. When a primary amine such as benzylamine was employed, malonamide product 7l
was observed, albeit with a lower yield of 27% because significant amounts of benzyl carboxamide 15
and benzyl imine 16 were also formed in the 3CR (eq 5). Dibenzylamine was also tested as a reactant in
the 3CR as a comparison, however malonamide product was observed even with heating to 50 °C (not
shown). This amidation reactivity matches the previous report from the Oshima group, who observed that
the lanthanum(III)-catalyzed amidation of esters is sensitive to sterics. When other nucleophiles were
investigated in the 3CR, the reaction favored formation of amidation by-products 13 and 14, even with
very active nucleophiles such as 2-methyl-allylTMS.
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Figure 4. Scope in the multi-component synthesis of malonamides aReactions were performed in toluene
at 50 °C.
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The success of the La(OTf)3 as a catalyst for this MCR is unexpected based on the fact that this
metal salt showed no catalytic activity for the indole conjugate addition (Table 1, 6% with La vs 85%
with Sc). The success of lanthanum as a catalyst for this 3CR can be potentially attributed to the
importance of atomic radii and coordination number where increasing substrate coordination can enhance
catalytic activity.43 We also hypothesized that there are reaction components, such as the malonamide
product or a byproduct (e.g. 13 and 14) formed during the progress of reaction that may serve as a ligand
to enhance the activity of the lanthanum salt. Coumarin-3-carboxamide 13 and imine 14 were both
independently synthesized44 and investigated as additives to enhance the activity of the lanthanum catalyst
for the indole conjugate addition reaction. These investigations revealed that addition of 10 mol % of
imine 14 to the reaction increases the yield of the indole conjugate addition (6% vs 35%), providing
support for the hypothesis that a component formed in reaction mixture may be acting as a ligand to
activate the lanthanum catalyst (Table 3, entry 1 vs 2). The addition of amide 13 or an indolylmalonamide
such as 7b did not increase the yield for the conjugate addition reaction, and combinations with imine 14
did not provide any further increases (Table 3, entries 3-6).45
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Table 3. Effect of additives on yield of 3
entry additive time (h) yield (%)b
1
2
3
4
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6
-
14
13
12
12
12
24
24
24
6
35
4
41
7
13 + 14
7b
14 + 7b
31
aAll reactions performed under argon with 0.1 mmol of coumarin 1a, 0.3 mmol
b
1
of indole, 10 mol % of La(OTf)3 and 0.1 M PhMe. Yield determined using H
NMR spectroscopy for analysis of the unpurified reaction mixture with
hexamethylcyclotrisiloxane as an internal standard.
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The mechanistic details leading to selective formation of malonamides in the 3CR were
investigated. Coumarin-3-carboxamide 13 was independently synthesized and tested as a substrate for the
indole addition (eqs 6 and 7). In the absence of indole, the lanthanum-catalyzed amidation of 1a proceeds
to afford carboxamide 13 in 60 % yield, with a significant amount (33 % yield) of imine 14 also observed
(eq 6). The addition of indole was investigated directly with carboxamide 13 and no reaction was
observed using either scandium or lanthanum catalysts (eq 7). In order to understand the factors leading to
the favorable formation of indolylmalonamides over coumarin-3-carboxamide in the 3CR, a competition
experiment was performed (eq 8). If both coumarin-3-carboxylate 1a and indolylchromanone 3a are
present, the amidation of the indolylchromanone is favored over formation of 13 and 14. This result helps
indicate why the 3CR product is observed in much higher yields than 13 and 14.
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The catalytic cycle shown in Figure 5 describes the mechanism for the La(III)-catalyzed synthesis
of indolylmalonamides and summarizes the network of competing side pathways for the reactants in the
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3CR. The proposed mechanism is initiated by activation of the lanthanum salt upon complexation under
the reaction conditions, e.g. with a ligand such as imine 14. The activation of coumarin-3-carboxylate 1a
occurs upon coordination of La(OTf)2·L to the 1,3-dicarbonyl. Indole addition must proceed faster than
amidation because limited quantities of coumarin-3-carboxamide 13 are observed. In the case of less
reactive indoles, the yield of malonamide decreases (vide supra) as the amidation reaction begins to
compete more effectively with the indole addition pathway. Upon formation of indolylchromane 3,
consecutive amidation reactions occur consecutively at the chromane ring and exocyclic ester to afford
malonamide 7a. Here amidation favors formation of malonamide products over formation of 13 and 14.
The 3CR requires balance between the relative nucleophilcities of the indole and the amine, where the
indole must be sufficiently nucleophilic to out-compete the amidation of the coumarin-3-carboxylate to
favor formation of indolylchromanone first. In the case of non-aromatic primary amines with enhanced
nucleophilicity, the amidation of 1a can out-compete the indole addition and a low yield of malonamide is
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observed. Using 19F and H NMR spectroscopy to monitor the reaction shows early product formation
with no accumulation of ester 3 or amide 9. Peaks associated with coumarin carboxylate 1 are observed to
shift and broaden upon addition of catalyst, indicating that complexation and consumption of 1a occurs
immediately. Formation of imine 14 was also observed, albeit as a very broad NMR signal attributed to
chelation with the lanthanum salt.
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Figure 5. Proposed catalytic cycle and mechanism for the malonamide 3CR
During our studies, we observed that indolylmalonamide products such as 7 have notable
fluorescence when exposed to longwave UV light (366 nm) (Figure 7A). We have performed initial
studies to evaluate and compare the photophysical properties of chromanone 3a and malonamides 7b and
7g. The excitation and emission spectra show maximum absorbance in the range of 262 to 284 nm and
maximum emission in the range of 341 to 376 nm, with Stokes' shifts corresponding to a range of 79-94
(Figure 7B, Table 4).56 A large Stokes’ shift is often desirable for fluorophores because it can reduce the
reabsorption of photons which decrease fluorescence.57 Favorable molar absorptivities (ε, M-1 cm-1) were
measured for all compounds. Although the compounds were observed to be fluorescent, the
indolylmalonamides exhibited low quantum yields, which we attribute in part to the quenching of the
indole fluorescence by adjacent amides.58 No significant difference in quantum yield was observed
during initial investigations of solvent effects (7b, DMSO vs MeOH, Table 4).
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Figure 6. A. Samples of 3b and 7b dissolved in DMSO fluorescing under long-wave UV light (366 nm).
B. Absorption (dashed) and emission (solid) spectra of 3a, 7b (in DMSO) and 7g measured in DMSO or
MeOH (see table 4). Spectra are normalized to the same height at the maximum.
Table 4. Photophysical properties of selected compoundsa
compound #
solvent
DMSO
DMSO
MeOH
DMSO
H2O
λabsmax (nm)
284
λemmax (nm)
376
stokes shift (nm)
εb (M-1 cm-1)
2.7 x 103
3.1 x 104
3.5 x 104
4.1 x 104
3.4 x 103
6.4 x 103
Φ
3a
7b
7b
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94
92
79
74
85
0.0094
0.013
0.0094
0.018
0.14
266
258
262
278
360
350
341
352
7g
(L)-Trpc
indolec
H2O
270
355
0.47
aAbsorption intensities and molar absorptivity (ε, M-1 cm-1) were measured using UV-Vis spectroscopy in
the solvent indicated at µM concentrations. Emission intensities and quantum yields (Φ) were determined
using a spectrophotometer in the solvent indicated at µM concentrations using (L)-tryptophan in water (Φ
= 0.14) as a reference standard.49 b Molar absorptivity (ε, M-1 cm-1) was calculated at λabsmax. Literature
c
values included for comparison.50, 49
In addition to indole fluorescence, the aryl malonamide component may contribute to the
fluorescent properties, and we hypothesized that small quantities of a tautomer,51 may provide extended
conjugation to enhance fluorescence. To assess this hypothesis, N1,N3-bis(4-methoxyphenyl)malonamide
was synthesized and also observed to be fluorescent under long-wave UV (366 nm). However, we have
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not observed any evidence that would support formation of the enol tautomer.52 Using H NMR
spectroscopy, only the diketo tautomer has been observed for N1,N3-bis(4-methoxyphenyl)malonamide
and malonamides such as 7. While the observed fluorescence of N1,N3-bis(4-methoxyphenyl)malonamide
supports an initial hypothesis for the source of fluorescence, further studies are needed to confirm the
structural features that dictate fluorescence.
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In conclusion, we have designed a novel lanthanum(III)-catalyzed three-component reaction for
the efficient synthesis of indolylmalonamides that demonstrate interesting photophysical properties. The
opportunity to develop this 3CR was recognized during the development of step-wise methodology for
the scandium-catalyzed addition of nucleophiles to coumarin-3-carboxylates based on the coupling of two
rare earth metal-catalyzed reactions. Both the 3CR and the step-wise processes proceed with consecutive
amidation of the exocyclic ester and ring-opening amidation of the chromane for rapid assembly of highly
functionalized malonamides. Synthetic studies suggest that an imine byproduct may enhance catalytic
activity of the lanthanum salt in the 3CR. The mechanistic studies and minimal formation of side products
showcase the role of catalysts to orchestrate a series of reactions to discover new MCRs. Selected
compounds were analyzed for their photophysical properties including quantum yields (Φ) and molar
absorptivity (ε). These compounds exhibit a large Stokes’ shift and high molar absorptivity which may
lend them to useful applications. Enabled by this synthetic methodology, a more detailed study of the
structural features responsible for the fluorescent properties of indolylmalonamides is currently underway.
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EXPERIMENTAL SECTION
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General Information. Commercially-available reagents were obtained from commercial sources
and used without further purification unless indicated. p-Anisidine was recrystallized from aqueous
ethanol and then dried under vacuum at 40 °C for 2 days; other amines were distilled over CaH; 2-
methylindole was recrystallized from toluene. Indole starting materials were stored in amber bottles or
wrapped in foil. Anhydrous CH2Cl2 and PhMe solvents were dispensed from a solvent purification system
that passes solvent through two columns of anhydrous neutral alumina. Except for coumarin-3-
carboxylate 1b, all coumarin-3-carboxylate reagents were synthesized according to literature
procedures.53 Lanthanum(III) triflate [La(OTf)3], min. 97% and Scandium(III) chloride [ScCl3] were
purchased from Strem Chemicals, Inc. Scandium(III) triflate [Sc(OTf)3], min 97%, was purchased from
Strem Chemicals, Inc. or Thermo Fisher Scientific, Inc. ScCl3(THF)3 was synthesized according to
literature procedure.54 The following abbreviations are used throughout: toluene (PhMe), ethyl acetate
(EtOAc), dimethylsulfoxide (DMSO), diastereomeric ratio (dr), melting point (mp). All reactions were
performed in vacuum and heat or flame-dried and Ar-purged glassware (including 8- and 4-mL vials
fitted with PTFE closure) unless noted otherwise. 4Å molecular sieves < 50 µm were activated under high
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1
vacuum and heating with a heat gun under vacuum for 15 minutes. All H and 13C NMR spectra were
recorded at ambient temperature at 600 mHz and 150 mHz respectively. The 1H spectral data are reported
as follows: chemical shift in ppm downfield from tetramethylsilane internal standard, or downfield from
tetramethylsilane with the solvent reference employed as the internal standard from DMSO-d6,
multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; s, septet; m, multiplet; dd, doublet of doublets, dt
13
doublets of triplets, td triplet of doublets, and b, broadened), coupling constant (Hz), and integration. C
NMR chemical shifts are reported in ppm from tetramethylsilane with the solvent reference employed as
the internal standard (deuterochloroform (CDCl3) at 77.16 ppm or deuterodimethylsulfoxide (DMSO-d6)
at 39.5 ppm). Infrared spectra were recorded neat on an ATI-FTIR spectrometer.
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Compounds were analyzed for HRMS on an orbitrap spectrometer using electrospray ionization
in the positive ion mode at >60,000 resolution and using typical ESI source values. These settings result
in mass accuracies <5 ppm. Samples were analyzed via flow injection analysis by injecting 5 µL samples
into a stream of 50% acetonitrile and 50% aqueous solution of 0.1% formic acid, flowing at 200
µL/minute. When indicated, the progress of reactions was monitored by analytical thin layer
chromatography using glass or aluminum plates pre-coated with silica gel 60 F254 and visualized with
UV light. Flash chromatography was performed either using silica gel 60 Å (0.035-0.070 mm), or silica
gel 150 Å grade 62 (60-200 mesh). Melting points were recorded using an automated melting point
apparatus with digital image processing technology (ramp rate of 1 ˚C/min and melt range of 100-300
˚C). Samples were prepared in 1.5-1.8 x 90mm capillary tubes. The melting points provided are the final
melting points recorded by the instrument.
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General procedure for synthesis of methyl coumarin-3-carboxylates. Coumarin-3-
carboxylates 1 were synthesized according to literature proceedure.1 Salicylaldehyde (1.0 equiv, 5.0
mmol), malonate (1.0 equiv, 5.0 mmol), 4-methylpiperidine (0.13 equiv, 0.63 mmol,) and acetic acid (1
drop) were combined with 2.5 mL toluene in a 25-mL round bottom flask. The solution was heated to
reflux with stirring for 12 h. The solution was then cooled to room temperature, allowing the product to
crystallize out of solution. The crystalline product was collected by vacuum filtration and washed with 3 x
5 mL of diethyl ether to yield the coumarin-3-carboxylate product; no further purification was required.
methyl 6-fluoro-2-oxo-2H-chromene-3-carboxylate (1b). Prepared from 5-fluorosalicylaldehyde
(0.70 g), dimethyl malonate (0.63 mL), 4-methylpiperidine (74 µL) and acetic acid (1 drop) to yield
1
colorless square crystals, mp = 147-149 ˚C (0.60 g, 54 % yield). H NMR (600 MHz, CDCl3) δ 8.49 (s,
13
1H), 7.40 – 7.33 (m, 2H), 7.30 (dd, J = 7.5, 2.7 Hz, 1H), 3.96 (s, 3H). C NMR (150 MHz, CDCl3) δ
163.3, 158.7 (d, J1CF = 245.9 Hz), 156.2, 151.3 (d, J4CF = 1.7 Hz), 147.9 (d, J4CF = 2.9 Hz), 122.0 (d, J2
=
CF
24.5 Hz), 119.1, 118.5 (d, J3 = 8.2 Hz), 118.4 (d, J3 = 9.1 Hz), 114.1 (d, J2 = 23.8 Hz), 53.0. IR
CF
CF
CF
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(neat, selected peaks): 3060, 2952, 1733, 1706 cm-1. Exact mass calculated for C11H8FO4 [M + H]+,
223.0401. Found 223.0410.
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General procedure for the Sc(III)-catalyzed synthesis of indolylchromanones. Coumarin-3-
carboxylate 1 (1.0 equiv, 0.20 mmol), indole 2 (3.0 equiv, 0.60 mmol), and 0.2 mL of anhydrous toluene
were added to a flame-dried 4 mL vial, followed by the addition scandium triflate (0.10 equiv, 0.020
mmol). The vial was then charged with Ar and wrapped with parafilm. The mixture was stirred at 50 °C
until complete as judged by TLC (1% EtOAc/CH2Cl2). Upon completion, the reaction mixture was passed
through a plug of silica gel and the eluent was concentrated in vacuo. The diastereomeric ratio (dr) was
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determined by H NMR spectroscopic analysis of the unpurified material. The resulting residue was
purified via flash column chromatography (gradient of 0% to 2% EtOAc/CH2Cl2) to yield the product (3)
as a colorless foam. Indolylchromanone products change in product appearance (from colorless to red in
clear vials) but no degradation was observed after 1 year of storage at ambient temperature.
methyl 4-(1H-indol-3-yl)-2-oxochromane-3-carboxylate (3a). Prepared from methyl coumarin-3-
carboxylate (66 mg), indole (0.11 g), scandium triflate (15 mg) and 0.3 mL of dry PhMe for 12 h. The
1
product was isolated as a colorless foam, mp = 180-184 ˚C (88 mg, 85% yield, >95:5 dr). H NMR (600
MHz, CDCl3) δ 8.20 (s, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.1 Hz, 1H), 7.32 (dd, J = 7.4 Hz, 1H),
7.23 (dd, J = 7.6 Hz, 1H), 7.17 (d, J = 8.1 Hz, 1H), 7.15 – 7.06 (m, 3H), 6.81 (d, J = 2.5 Hz, 1H), 5.06 (d,
J = 7.2 Hz, 1H), 4.23 (d, J = 7.2 Hz, 1H), 3.65 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 167.8, 164.9,
150.7, 136.9, 128.9, 128.7, 125.2, 125.1, 123.8, 123.5, 122.3, 119.6, 118.5, 116.8, 112.2, 111.8, 53.0,
52.9, 36.4. IR (neat, selected peaks): 3389, 2950, 1754, 1731 cm-1. Exact mass calculated for C19H16NO4
[M + H]+, 322.1074. Found 322.1074.
methyl 4-(2-methyl-1H-indol-3-yl)-2-oxochromane-3-carboxylate (3b). Prepared from methyl
coumarin-3-carboxylate (62 mg), 2-methylindole (0.12 g) and scandium triflate (18 mg) for 12 h. The
product was isolated as a colorless foam, mp = 176-181 ˚C with decomposition (87 mg, 86% yield, >95:5
dr). 1H NMR (600 MHz, CDCl3) δ 8.00 (s, 1H), 7.33 – 7.27 (m, 2H), 7.17 (dd, J = 8.1, 1.2 Hz, 1H), 7.11
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(ddd, J = 8.1, 6.6, 1.6 Hz, 1H), 7.01 – 6.92 (m, 4H), 6.89 (d, J = 7.8 Hz, 1H), 5.02 (d, J = 12.9 Hz, 1H),
4.23 (d, J = 12.9 Hz, 1H), 3.59 (s, 3H), 2.39 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 168.0, 165.3, 150.9,
135.7, 134.4, 128.8, 128.6, 126.0, 124.9, 123.9, 121.4, 119.6, 118.9, 116.8, 110.8, 106.1, 52.7, 51.9, 35.2,
9
+
11.9. IR (neat, selected peaks): 3390, 2948, 1756, 1732 cm-1. Exact mass calculated for C20H17NNaO4 [M
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+ Na]+, 358.1055, found 358.1060.
methyl 4-(1-methyl-1H-indol-3-yl)-2-oxochromane-3-carboxylate (3c). Prepared from methyl
coumarin-3-carboxylate (65 mg), 1-methylindole (0.12 mL), scandium triflate (15 mg) and 0.3 mL of dry
PhMe for 12 h. The product was isolated as a yellow solid, mp = 163-165˚C (0.10 g, 98% yield, >95:5
dr). 1H NMR (600 MHz, CDCl3) δ 7.50 (d, J = 8.0 Hz, 1H), 7.35 – 7.29 (m, 2H), 7.25 (d, J = 7.7 Hz, 1H),
7.19 – 7.06 (m, 4H), 6.64 (s, 1H), 5.04 (d, J = 6.7 Hz, 1H), 4.21 (d, J = 6.7 Hz, 1H), 3.68 (s, 3H), 3.64 (s,
3H). 13C NMR (150 MHz, CDCl3) δ 167.7, 164.5, 151.0, 137.6, 129.1, 128.9, 127.6, 125.9, 125.2, 124.0,
122.3, 119.7, 118.8, 117.1, 111.6, 109.9, 53.3, 53.1, 36.5, 32.9. IR (neat, selected peaks): 2951, 1763,
1741, 1585 cm-1. Exact mass calculated for C20H18NO4 [M + H]+, 336.1230. Found 336.1227.
+
methyl 4-(5-bromo-1-methyl-1H-indol-3-yl)-2-oxochromane-3-carboxylate (3d). Prepared from
methyl coumarin-3-carboxylate (62 mg), 5-bromo-1-methylindole (0.17 g), scandium triflate (20 mg) and
0.3 mL of dry PhMe for 12 h. The product was isolated as a red solid, mp = 137-137 ˚C (96 mg, 82%
1
yield, >95:5 dr). H NMR (600 MHz, CDCl3) δ 7.61 (s, 1H), 7.34 – 7.29 (m, 2H), 7.16 (d, J = 8.8, 1H),
7.15 (d, J = 8.1, 1H), 7.12 – 7.07 (m, 2H), 6.64 (s, 1H), 4.96 (d, J = 6.8 Hz, 1H), 4.14 (d, J = 6.8 Hz, 1H),
13
3.64 (m, 6H, NMe and CO2Me overlapping). C NMR (150 MHz, CDCl3) δ 167.4, 164.3, 150.9, 136.2,
129.3, 128.8, 128.7, 127.5, 125.24, 125.20, 123.5, 121.2, 117.1, 113.1, 111.4, 111.2, 53.2, 53.1, 36.2,
33.0. IR (neat, selected peaks): 2918, 1760, 1740, 1558 cm-1. Exact mass calculated for C20H16BrNNaO4
[M + Na]+, 436.0160, found 436.0162.
methyl 4-(5-methoxy-1H-indol-3-yl)-2-oxochromane-3-carboxylate (3e). Prepared from methyl
coumarin-3-carboxylate (63 mg), 5-methoxyindole (0.14 g), scandium triflate (15 mg) and 0.3 mL of dry
PhMe for 14 h. The product was isolated as a colorless solid, mp = 167-168 ˚C (87 mg, 81% yield, >95:5
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dr). 1H NMR (600 MHz, CDCl3) δ 8.03 (s, 1H), 7.32 (dd, J = 7.8 Hz, 1H), 7.28 (d, J = 9.5 Hz, 1H), 7.16
(d, J = 8.2 Hz, 1H), 7.14 (d, J = 7.5 Hz, 1H), 7.10 (dd, J = 7.5 Hz, 1H), 6.92 – 6.87 (m, 2H), 6.79 (d, J =
2.5 Hz, 1H), 5.01 (d, J = 7.2 Hz, 1H), 4.19 (d, J = 7.2 Hz, 1H), 3.81 (s, 3H), 3.66 (s, 3H). 13C NMR (150
MHz, CDCl3) δ 167.8, 164.7, 154.4, 151.0, 131.9, 129.2, 128.9, 126.0, 125.2, 123.9, 117.1, 112.8, 112.7,
112.6, 100.9, 56.1, 53.1, 53.0, 36.5. IR (neat, selected peaks): 3375, 2954, 1736, 1585 cm-1. Exact mass
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+
calculated for C20H18NO5 [M + H]+, 352.1179. Found 352.1177.
methyl 4-(1,2-dimethyl-1H-indol-3-yl)-2-oxochromane-3-carboxylate (3f). Prepared from methyl
coumarin-3-carboxylate (1.0 equiv, 0.20 mmol, 41 mg), 1,2-dimethylindole (3.0 equiv, 0.60 mmol, 92
mg), scandium triflate (0.10 equiv, 0.020 mmol, 10 mg) and 0.2 mL of dry PhMe for 14 h. To the crude
reaction mixture, 2 ml methanol was added and the product crashed out of solution. The product was then
collected via vacuum filtration to yield 3f as a colorless crystalline solid, mp = 206 - 207 ˚C (62 mg, 89%
1
yield, >95:5 dr). H NMR (600 MHz, DMSO-d6) δ 7.41 (d, J = 8.4 Hz, 1H), 7.31 (dd, J = 7.7 Hz, 1H),
7.20 (dd, J = 8.1, 0.8 Hz, 1H), 7.08 – 7.03 (m, 2H), 6.98 (ddd, J = 7.6, 0.8 Hz, 1H), 6.82 (dd, J = 7.5 Hz,
1H), 6.64 (d, J = 7.6 Hz, 1H), 5.06 (d, J = 13.3 Hz, 1H), 4.64 (d, J = 13.3 Hz, 1H), 3.70 (s, 3H), 3.50 (s,
3H), 2.36 (s, 3H). 13C NMR (150 MHz, DMSO-d6) δ 167.9, 165.4, 150.7, 136.9, 136.5, 128.5, 127.8,
124.8, 124.7, 124.4, 120.3, 118.9, 118.5, 116.4, 109.5, 104.7, 52.2, 51.4, 34.6, 29.5, 10.0. IR (neat,
selected peaks): 2958, 1760, 1742, 1610 cm-1. Exact mass calculated for C21H20NO4 [M + H]+, 350.1387.
Found 350.1382.
methyl 6-fluoro-4-(1H-indol-3-yl)-2-oxochromane-3-carboxylate (3g). Prepared from methyl 6-
fluoro-coumarin-3-carboxylate (68 mg), indole (0.11 g), scandium triflate (19 mg) and 0.3 mL dry PhMe
for 18 h. The product was isolated as a colorless foam, mp = 151-152 ˚C (85 mg, 82% yield, >95:5 dr). 1H
NMR (600 MHz, CDCl3) δ 8.24 (s, 1H), 7.45 (dd, J = 8.0, 0.7 Hz, 1H), 7.37 (d, J = 8.2 Hz, 1H), 7.23
(ddd, J = 8.2, 7.2, 1.0 Hz, 1H), 7.14 – 7.10 (m, 2H), 7.00 (ddd, J = 8.4, 3.0 Hz, 1H), 6.84 – 6.79 (m, 2H),
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5.01 (d, J = 7.7 Hz, 1H), 4.20 (d, J = 7.7 Hz, 1H), 3.64 (s, 3H). C NMR (150 MHz, CDCl3) δ 167.5,
164.4, 159.5 (d, J1 = 244.7 Hz), 146.9 (d, J J4 = 2.6 Hz), 136.8, 125.2, 123.3, 122.9, 120.3, 118.7,
CF
CF
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112.1, 111.9, 53.2, 52.7, 36.5. IR (neat, selected peaks): 3413, 2952, 1758, 1732 cm-1. Exact mass
calculated for C19H15FNO4 [M + H]+, 340.0980. Found 340.0982.
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methyl 4-(1H-indol-3-yl)-8-methoxy-2-oxochromane-3-carboxylate (3h). Prepared from methyl 8-
methoxy-coumarin-3-carboxylate (73 mg), indole (0.13 mg), scandium triflate (16 mg) and 0.3 mL dry
PhMe for 18 h. The product was isolated as a colorless solid, mp = 197-200 ˚C (97 mg, 85% yield, >95:5
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dr). H NMR (600 MHz, CDCl3-d) δ 8.16 (s, 1H), 7.29 (d, J = 8.1 Hz, 1H), 7.09 (dd, J = 7.5 Hz, 1H),
6.98 (d, J = 7.8 Hz, 1H), 6.95 – 6.87 (m, 3H), 6.45 (d, J = 7.1 Hz, 1H), 5.00 (d, J = 12.9 Hz, 1H), 4.24 (d,
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J = 12.9 Hz, 1H), 3.92 (s, 3H), 3.54 (s, 3H), 2.36 (s, 3H). C NMR (150 MHz, CDCl3) δ 168.0, 164.4,
147.5, 140.1, 135.7, 134.4, 126.1, 125.2, 124.6, 121.3, 119.9, 119.5, 118.8, 111.5, 110.8, 106.2, 56.2,
52.6, 51.7, 35.3, 11.9. IR (neat, selected peaks): 3342, 2953, 1762, 1745 cm-1. Exact mass calculated for
C21H20NO5 [M + H]+, 366.1336. Found 366.1341.
tert-butyl 4-(1-methyl-1H-indol-3-yl)-2-oxochromane-3-carboxylate (3i). Prepared from tert-butyl
coumarin-3-carboxylate (76 mg), 1-methylindole (0.12 mL), scandium triflate (16 mg) and 0.3 mL of dry
PhMe for 12 h. The product was isolated as a white solid, mp = 130 – 131 ˚C (96 mg, 83% yield, >95:5
dr). 1H NMR (600 MHz, CDCl3) δ 7.58 (d, J = 7.9 Hz, 1H), 7.31 (dd, J = 7.7 Hz, 1H), 7.28 (d, J = 8.2 Hz,
1H), 7.24 (dd, J = 7.5 Hz, 1H), 7.20 (d, J = 7.4 Hz, 1H), 7.18 – 7.11 (m, 2H), 7.09 (dd, J = 7.4 Hz, 1H),
6.56 (s, 1H), 4.95 (d, J = 5.2 Hz, 1H), 4.10 (d, J = 5.2 Hz, 1H), 3.62 (s, 3H), 1.22 (s, 9H). 13C NMR (150
MHz, CDCl3) δ 166.1, 165.0, 151.4, 137.5, 129.0, 128.8, 127.3, 126.0, 124.9, 124.3, 122.3, 119.6, 118.7,
116.9, 111.9, 109.8, 83.2, 54.5, 37.3, 32.8, 27.6. IR (neat, selected peaks): 2940, 1772, 1759, 1719 cm-1.
HRMS (ESI) mass calculated for C23H24NO4 [M + H]+, 378.1700. Found 378.1693.
methyl 4-(2-methylallyl)-2-oxochromane-3-carboxylate (4). Prepared from coumarin-3-
carboxylate (41 mg), methallyltrimethylsilane (0.10 mL), scandium triflate (10 mg), 0.3 mL of dry PhMe
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for 3 h. The product was isolated as a white solid, mp = 146-150 ˚C (49 mg, 93% yield, > 95:5 dr). H
NMR (600 MHz, CDCl3) δ 7.26 (ddd, J = 8.2, 7.7, 1.2 Hz, 1H), 7.19 (dd, J = 7.7, 1.2 Hz, 1H), 7.11 (ddd,
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J = 7.7 1.1 Hz, 1H), 7.06 (d, J = 8.2 Hz, 1H), 4.92 (s, 1H), 4.72 (s, 1H), 3.87 (d, J = 1.8 Hz, 1H), 3.60 (s,
3H), 3.56 (ddd, J = 10.4, 5.9, 1.8 Hz, 1H), 2.31 (dd, J = 14.1, 5.9 Hz, 1H), 2.19 (dd, J = 14.1, 10.4 Hz,
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1H), 1.78 (s, 3H). C NMR (151 MHz, CDCl3) δ 167.9, 164.0, 150.7, 140.6, 129.0, 128.5, 125.0, 124.1,
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117.1, 115.2, 53.2, 50.4, 43.3, 37.8, 22.1. IR (neat, selected peaks): 2961, 2912, 1772, 1734 cm-1. Exact
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mass calculated for C15H17O4 [M + H] + 261.1121, found 261.1120.
methyl 4-(4-(dimethylamino)-2-methoxyphenyl)-2-oxochromane-3-carboxylate (5). Prepared from
coumarin-3-carboxylate 1a (65 mg), N,N-dimethyl-m-anisidine (0.13 mL), scandium triflate (18 mg) 0.3
mL of dry PhMe for 24 h. The product was isolated as a white solid, mp = 158-160 ˚C (87 mg, 77% yield,
1
>95:5 dr). H NMR (600 MHz, CDCl3) δ 7.27 (ddd, J = 7.9, 6.9, 1.6 Hz, 1H), 7.11 (dd, J = 8.2, 1.0 Hz,
1H), 7.07 (ddd, J = 7.5, 1.1 Hz, 1H), 7.02 (dd, J = 7.6, 1.2 Hz, 1H), 6.64 (d, J = 8.5 Hz, 1H), 6.24 (d, J =
2.4 Hz, 1H), 6.18 (dd, J = 8.5, 2.4 Hz, 1H), 4.88 (d, J = 5.9 Hz, 1H), 4.19 (d, J = 5.9 Hz, 1H), 3.81 (s,
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3H), 3.65 (s, 3H), 2.93 (s, 6H). C NMR (150 MHz, CDCl3) δ 167.8, 164.8, 157.7, 151.6, 151.1, 129.3,
128.6, 128.5, 124.8, 124.1, 116.6, 113.8, 104.5, 96.0, 55.0, 52.8, 52.0, 40.4, 39.4. IR (neat, selected
peaks): 2953, 2933, 1765, 1739 cm-1. Exact mass calculated for C20H22NO4 [M + H] + 356.1492, found
+
356.1495.
methyl 4-(5-ethyl-1H-pyrrol-2-yl)-2-oxochromane-3-carboxylate (6). Prepared from methyl
coumarin-3-carboxylate (59.3 mg), 2-ethylpyrrole (95 mg), scandium triflate (15 mg) 0.3 mL of dry
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PhMe for 12 h. The product was isolated as a brown oil, (74.6 mg, 73% yield, >95:5 dr). H NMR (600
MHz, CDCl3) δ 7.75 (s, 1H), 7.31 (ddd, J = 8.0, 1.7 Hz, 1H), 7.18 (dd, J = 7.6, 1.3 Hz, 1H), 7.14 (dd, J =
7.4, 1.0 Hz, 1H), 7.11 (dd, J = 8.0, 0.8 Hz, 3H), 5.85 (dd, J = 3.0 Hz, 1H), 5.81 (dd, J = 3.0 Hz, 1H), 4.71
(d, J = 6.9 Hz, 1H), 4.03 (d, J = 6.9 Hz, 1H), 3.66 (s, 3H), 2.54 (q, J = 7.6 Hz, 2H), 1.19 (t, J = 7.6 Hz,
3H). 13C NMR (150 MHz, CDCl3) δ 167.5, 164.2, 150.8, 135.2, 129.4, 128.5, 126.0, 125.3, 123.3, 117.3,
107.1, 105.1, 53.2, 53.0, 38.2, 20.9, 13.5. IR (neat, selected peaks): 3457, 2948, 1763 1742 cm-1. Exact
mass calculated for C17H18NO4 [M + H]+ 300.1230, found 300.1240.
+
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General procedure for the preparation of indolylmalonamides from Indolylchromanones.
Indolylchromanone 3 (1.0 equiv), amine (3.0 equiv) and CH2Cl2 (1.0 M) were added to a flame-dried 4mL
vial, followed by the addition of lanthanum triflate (0.10 equiv). The vial was then charged with Ar and
wrapped in parafilm. The mixture stirred at room temperature until the indolylchromanone 3 was judged
to be consumed according to TLC (1% EtOAc/CH2Cl2). The solids were collected via vacuum filtration
on grade 1 Whatman filter paper and washed with 3 x 2 mL of CH2Cl2 to isolate the indolylmalonamide 7
as a colorless solid; no further purification was typically required.
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N1,N3-bis(2-hydroxyethyl)-2-((2-hydroxyphenyl)(1H-indol-3-yl)methyl)malonamide
(10).
Prepared from 3a (1.0 equiv, 0.22 mmol, 50 mg), ethanolamine (3.0 equiv, 0.66 mmol, 9.6 µL),
lanthanum triflate (0.050 equiv, 0.010 mmol, 5.1 mg) and 0.2 mL CH2Cl2. After 49 h, the product was
1
isolated as a colorless solid, mp = 200-206 ˚C with decomposition (38 mg, 57% yield). H NMR (600
MHz, DMSO-d6) δ 10.72 (s, 1H), 9.31 (s, 1H), 8.05 (t, J = 5.5 Hz, 1H), 7.62 – 7.56 (m, 2H), 7.31 (s, 1H),
7.24 (d, J = 8.1 Hz, 1H), 7.18 (d, J = 7.8 Hz, 1H), 6.98 (dd, J = 7.5 Hz, 1H), 6.91 – 6.84 (m, 2H), 6.71 (d,
J = 8.1 Hz, 1H), 6.63 (dd, J = 7.5 Hz, 1H), 5.23 (d, J = 12.3 Hz, 1H), 4.63 (t, J = 5.5 Hz, 1H), 4.27 (d, J =
12.3 Hz, 1H), 3.40 (s, 1H), 3.27 – 2.91 (m, 8H).13C NMR (150 MHz, DMSO-d6) δ 169.3, 168.7, 154.8,
136.2, 129.5, 127.4, 127.0, 122.1, 121.1, 119.5, 119.1, 118.4, 116.9, 115.7, 111.4, 60.1, 59.9, 58.5, 41.9,
41.7, 36.0. IR (neat, selected peaks): 3332, 3266, 2878, 1653, 1580 cm-1. Exact mass calculated for
+
C22H26N3O5 [M + H]+, 412.1867. Found 412.1867.
N1,N3-diallyl-2-((2-hydroxyphenyl)(1H-indol-3-yl)methyl)malonamide (11). Prepared from 3a
(1.0 equiv, 0.42 mmol, 0.13 g), allylamine (3.0 equiv, 1.3 mmol, 72 mg), lanthanum triflate (0.010 equiv,
0.021 mmol, 12 mg) and CH2Cl2 (0.5 mL). After 26 h, the reaction mixture was purified via flash column
chromatography (gradient of 20% to 75% EtOAc/CH2Cl2, followed by a gradient of 0% to 10%
1
MeOH/CH2Cl2) to yield 11 as a pink chalky solid, mp = 183-184˚C (0.14 g, 88% yield). H NMR (600
MHz, DMSO-d6) δ ) δ 10.74 (s, 1H), 9.37 (s, 1H), 8.11 (t, J = 5.8 Hz, 1H), 7.64 (t, J = 5.8 Hz, 1H), 7.59
(d, J = 7.8 Hz, 1H), 7.32 (d, J = 2.4 Hz, 1H), 7.24 (d, J = 8.1 Hz, 1H), 7.20 (dd, J = 7.6, 1.0 Hz, 1H), 6.98
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(ddd, J = 8.1, 7.1, 1.1 Hz, 1H), 6.90 – 6.85 (m, 2H), 6.70 (dd, J = 8.0, 1.0 Hz, 1H), 6.63 (ddd, J = 7.5, 1.1
Hz, 1H), 5.65 – 5.50 (m, 2H), 5.28 (d, J = 12.3 Hz, 1H), 4.92 – 4.87 (m, 3H), 4.84 (dq, J = 17.2, 1.8 Hz,
1H), 4.35 (d, J = 12.3 Hz, 1H), 3.62 – 3.55 (m, 3H), 3.51 (dtt, J = 16.3, 5.4, 1.8 Hz, 2H). 13C NMR (150
MHz, DMSO-d6) δ 168.6, 168.1, 154.4, 135.9, 134.9, 134.8, 129.2, 129.1, 126.9, 126.6, 121.7, 120.8,
119.1, 118.8, 118.0, 116.5, 115.5, 114.7, 111.1, 58.4, 40.89, 40.86, 35.2. IR (neat, selected peaks): 3695,
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2947, 1737, 1610 cm-1. Exact mass calculated for C24H25N3NaO3 [M + Na] + 426.1794, found 426.1792
2-((4-(dimethylamino)-2-methoxyphenyl)(2-hydroxyphenyl)methyl)-N1,N3-bis(4-
methoxyphenyl)malonamide (12). Prepared from 5 (1.0 equiv, 0.14 mmol, 51 mg), p-anisidine (3.0 equiv,
0.43 mmol, 54 mg), lanthanum triflate (0.010 equiv, 0.014 mmol, 8.2 mg) and CH2Cl2 (0.15 mL). After
24 h, the reaction mixture was purified via flash column chromatography (gradient of 10% to 75%
EtOAc/CH2Cl2 with 0.1% triethylamine) to yield 12 a colorless chalky solid, mp = 165-167 ˚C (40 mg,
1
49% yield). H NMR (600 MHz, DMSO-d6) δ 9.67 (s, 1H), 9.63 (s, 1H), 9.18 (s, 1H), 7.39 (d, 2H), 7.36
(dd, J = 8.0, 1.4 Hz, 1H), 7.33 (d, J = 9.0 Hz, 2H), 7.31 (d, J = 3.8 Hz, 1H), 6.88 (ddd, J = 7.8, 1.5 Hz,
1H), 6.86 – 6.78 (m, 4H), 6.68 – 6.62 (m, 2H), 6.18 (dd, J = 8.6, 2.3 Hz, 1H), 6.15 (s, 1H), 5.25 (d, J =
13
12.3 Hz, 1H), 4.75 (d, J = 12.3 Hz, 1H), 3.71 (s, 3H), 3.68 (s, 3H), 3.67 (s, 3H), 2.80 (s, 6H). C NMR
(150 MHz, DMSO-d6) δ 166.5, 166.3, 157.8, 155.4, 155.3, 155.0, 150.2, 150.1, 132.0, 131.8, 129.6,
129.4, 129.3, 128.3, 126.6, 121.0, 120.7, 120.6, 118.3, 117.8, 115.3, 113.9, 113.82, 113.80, 104.1, 96.6,
58.1, 55.3, 55.2, 40.3, 39.0. IR (neat, selected peaks): 3298, 3240, 1677, 1646 cm-1. Exact mass calculated
+
for C33H36N3O6 [M + H]+, 570.2599. Found 570.2597.
General procedure for the La(OTf)3-catalyzed 3CR synthesis of indolylmalonamides
Coumarin-3-carboxylate 1 (1.0 equiv, 0.20 mmol), indole 2 (3.0 equiv, 0.60 mmol), amine (3.0 equiv,
0.60 mmol) and CH2Cl2 (0.2 mL) were added to a flame-dried 4 mL vial, followed by the addition of
lanthanum triflate (0.10 equiv, 0.020 mmol). The vial was then charged with Ar and the mixture stirred at
room temperature until the coumarin-3-carboxylate was consumed by TLC (1% EtOAc/CH2Cl2). The
solids were collected via vacuum filtration on grade 1 Whatman filter paper and washed with 3 x 2 mL of
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CH2Cl2 to isolate the indolylmalonamide 7 as a colorless solid; no further purification was typically
required.
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2-((2-Hydroxyphenyl)(1H-indol-3-yl)methyl)-N1,N3-bis(4-methoxyphenyl) malonamide (7a).
Prepared from methyl coumarin-3-carboxylate (41 mg), indole (74 mg), p-anisidine (75 mg), lanthanum
triflate (12 mg) and 0.2 mL CH2Cl2. After 63 h the product was isolated as a colorless solid, mp = 184-
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191 °C with decomposition (65 mg, 61% yield). H NMR (600 MHz, DMSO-d6) δ 10.74 (s, 1H), 10.06
(s, 1H), 9.52 (s, 1H), 9.35 (s, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.42 (d, J = 2.2 Hz, 1H), 7.39 (ddd, J = 9.8,
2.6 Hz, 2H), 7.32 – 7.28 (m, 3H), 7.22 (d, J = 8.1 Hz, 1H), 6.97 (dd, J = 7.5 Hz, 1H), 6.90 – 6.83 (m, 2H),
6.81 (d, J = 5.5 Hz, 2H), 6.79 (d, J = 5.5 Hz, 2H), 6.68 (d, J = 7.6 Hz, 1H), 6.64 (dd, J = 7.4 Hz, 1H), 5.45
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(d, J = 12.3 Hz, 1H), 4.62 (d, J = 12.3 Hz, 1H), 3.67 (s, 3H), 3.65 (s, 3H). C NMR (150 MHz, DMSO-
d6) δ 166.9, 166.1, 155.5, 155.4, 154.6, 135.9, 131.9, 131.6, 129.4, 128.6, 128.9, 126.9, 121.7, 121.3,
120.9, 120.8, 119.0, 118.9, 118.2, 116.2, 115.5, 113.83, 113.79, 111.2, 59.9, 55.19, 55.17, 36.1. IR (neat,
+
selected peaks): 3404, 3359, 2952, 1542 cm-1. Exact mass calculated for C32H29N3NaO5 [M + Na] +
558.2005, found 558.1996.
2-((2-hydroxyphenyl)(2-methyl-1H-indol-3-yl)methyl)-N1,N3-bis(4-methoxyphenyl)malonamide
(7b). Prepared from methyl coumarin-3-carboxylate (41 mg), 2-methylindole (79 mg) and p-anisidine (75
mg), lanthanum triflate (12 mg) and 0.2 mL CH2Cl2. After 63 h, the product was isolated as a pink solid,
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mp = 170-172 ˚C with decomposition (0.10 g, 90% yield). H NMR (600 MHz, DMSO-d6) δ 10.61 (s,
1H), 10.11 (s, 1H), 9.38 (s, 1H), 9.33 (s, 1H), 7.79 (d, J = 6.7 Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.45 (d, J
= 8.8 Hz, 2H), 7.29 (d, J = 8.8 Hz, 2H), 7.16 (d, J = 8.2 Hz, 1H), 6.96 – 6.84 (m, 5H), 6.80 (d, J = 8.9 Hz,
2H), 6.75 (dd, J = 7.5 Hz, 1H), 6.69 (d, J = 7.9 Hz, 1H), 5.38 (d, J = 12.5 Hz, 1H), 4.91 (d, J = 12.5 Hz,
1H), 3.69 (s, 3H), 3.66 (s, 3H), 2.54 (s, 3H). 13C NMR (150 MHz, DMSO-d6) δ 166.6, 166.0, 155.4,
155.3, 155.0, 135.2, 133.1, 131.9, 131.6, 128.7, 127.1, 126.4, 120.9, 120.7, 119.2, 118.8, 118.2, 117.7,
115.1, 113.9, 113.8, 113.7, 110.4, 109.5, 57.7, 55.2, 55.1, 55.1, 35.8, 12.1. IR (neat, selected peaks):
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3326, 3392, 1656, 1628 cm-1. Exact mass calculated for C33H32N3O5 [M + H]+, 550.2336. Found
550.2362.
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2-((2-hydroxyphenyl)(2-methyl-1H-indol-3-yl)methyl)-N1,N3-diphenylmalonamide (7c). Prepared
from methyl coumarin-3-carboxylate (41 mg), 2-methylindole (79 mg), aniline (56 mL), lanthanum
triflate (12 mg) and 0.2 mL CH2Cl2. After 48 h, the product was isolated as a colorless solid, mp = 188-
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190 °C with decomposition (61 mg, 80% yield). H NMR (600 MHz, DMSO-d6) δ 10.59 (s, 1H), 10.21
(s, 1H), 9.50 (s, 1H), 9.33 (s, 1H), 7.82 – 7.72 (m, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.52 (d, J = 8.0 Hz, 2H),
7.37 (d, J = 8.0 Hz, 2H), 7.29 (dd, J = 7.8 Hz, 2H), 7.21 (dd, J = 7.8 Hz, 2H), 7.16 – 7.10 (m, 1H), 7.04
(dd, J = 7.4 Hz, 1H), 6.98 (dd, J = 7.3 Hz, 1H), 6.94 – 6.80 (m, 3H), 6.72 (dd, J = 7.4 Hz, 1H), 6.66 (d, J
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= 7.9 Hz, 1H), 5.38 (d, J = 12.4 Hz, 1H), 4.98 (d, J = 12.4 Hz, 1H), 2.52 (s, 3H). C NMR (150 MHz,
DMSO-d6) δ 166.8, 166.2, 155.0, 138.7, 138.4, 135.2, 133.2, 128.8, 128.69, 128.67, 127.1, 126.4, 123.6,
123.5, 119.4, 119.24, 119.19, 118.8, 118.3, 117.8, 115.2, 113.9, 110.4, 109.4, 57.9, 35.7, 12.2. IR (neat,
selected peaks): 3412, 3369, 1667, 1637 cm-1. Exact mass calculated for C31H28N3O3 [M + H]+, 490.2125.
Found 490.2160.
2-((1,2-dimethyl-1H-indol-3-yl)(2-hydroxyphenyl)methyl)-N1,N3-bis(4-
methoxyphenyl)malonamide (7d). Prepared from methyl coumarin-3-carboxylate (1.0 equiv, 0.30 mmol,
63 mg), 1,2-dimethylindole (6.0 equiv, 0.90 mmol, 0.13 g) p-anisidine (3.0 equiv, 0.90 mmol, 0.12 g),
lanthanum triflate (22 mg) and 0.3 mL CH2Cl2. After 45 h, the product was isolated as a colorless solid,
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mp = 169-170 °C with decomposition (0.13 g, 75% yield). H NMR (600 MHz, DMSO-d6) δ 10.09 (s,
1H), 9.38 (s, 1H), 9.30 (s, 1H), 7.80 (d, J = 7.9 Hz, 1H), 7.66 (d, J = 7.5 Hz, 1H), 7.41 (d, J = 9.0 Hz,
2H), 7.26 (d, J = 9.0 Hz, 2H), 7.24 (d, J = 8.1 Hz, 1H), 6.96 (dd, J = 7.5 Hz, 1H), 6.92 (dd, J = 7.5 Hz,
1H), 6.88 – 6.83 (m, 3H), 6.78 (d, J = 9.0 Hz, 2H), 6.70 (dd, J = 7.5 Hz, 1H), 6.63 (d, J = 7.9 Hz, 1H),
5.38 (d, J = 12.5 Hz, 1H), 4.89 (d, J = 12.5 Hz, 1H), 3.69 (s, 3H), 3.66 (s, 3H), 3.54 (s, 3H), 2.51 (s, 3H).
13C NMR (150 MHz, DMSO-d6) δ 167.0, 166.3, 155.9, 155.7, 155.4, 136.7, 135.1, 132.3, 132.0, 129.1,
127.5, 126.9, 121.4, 121.2, 121.1, 119.8, 119.5, 118.6, 118.4, 115.6, 114.4, 114.2, 110.0, 109.4, 58.2,
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55.6, 55.5, 36.5, 29.7, 11.1. IR (neat, selected peaks): 3312, 3268, 2950, 1672 cm-1. Exact mass calculated
for C34H34N3O5 [M + H]+, 564.2493. Found 564.2511.
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2-((5-fluoro-2-hydroxyphenyl)(1H-indol-3-yl)methyl)-N1,N3-bis(4-methoxyphenyl)malonamide
(7e). Prepared from methyl 6-fluoro coumarin-3-carboxylate (44 mg), indole (70 mg), p-anisidine (74
mg), lanthanum triflate (11 mg) and 0.2 mL CH2Cl2. After 42 h, the product was isolated as a colorless
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solid, mp = 185-188˚C (69 mg, 63 % yield). H NMR (600 MHz, DMSO-d6) δ 10.80 (s, 1H), 10.09 (s,
1H), 9.57 (s, 1H), 9.48 (s, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.49 (d, J = 2.1 Hz, 1H), 7.43 (d, J = 9.0 Hz,
2H), 7.36 (d, J = 8.9 Hz, 2H), 7.28 (d, J = 8.1 Hz, 1H), 7.16 (d, J = 8.1 Hz, 1H), 7.02 (dd, J = 7.5 Hz,
1H), 6.95 (dd, J = 7.5 Hz, 1H), 6.85 (d, J = 9.0 Hz, 2H), 6.83 (d, J = 9.0 Hz, 2H), 6.76 – 6.68 (m, 2H),
5.50 (d, J = 12.2 Hz, 1H), 4.65 (d, J = 12.2 Hz, 1H), 3.69 (s, 3H), 3.67 (s, 3H). 13C NMR (150 MHz,
DMSO-d6) δ 166.6, 165.9, 155.6, 155.5, 155.3 (d, J1 = 233.5 Hz), 151.0, 135.9, 131.9, 131.5, 130.3 (d,
CF
J3 = 6.3 Hz), 126.8, 121.9, 121.4, 121.0, 120.9, 118.9, 118.3, 116.2 (d, J3 = 8.0 Hz), 115.4 (d, J2
=
CF
CF
CF
20.5 Hz), 114.6, 113.81, 113.80, 113.2 (d, J2 = 22.4 Hz), 111.3, 59.6, 55.20, 55.18, 36.1. IR (neat,
CF
selected peaks): 3346, 3194, 1670, 1644 cm-1. Exact mass calculated for C32H29FN3O5 [M + H]+,
554.2086. Found 554.2097.
2-((5-fluoro-2-hydroxyphenyl)(2-methyl-1H-indol-3-yl)methyl)-N1,N3-bis(4-
methoxyphenyl)malonamide (7f). Prepared from methyl 6-fluoro coumarin-3-carboxylate 1 (1.0 equiv, 0.5
mmol, 0.11 g), 2-methylindole (3.0 equiv, 1.5 mmol, 0.20 g) and p-anisidine (3.0 equiv, 1.5 mmol, 0.19
g), lanthanum triflate (0.1 equiv, 0.050 mmol, 29 mg) and 0.5 mL CH2Cl2. After 46 h, the product was
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isolated as a colorless solid, mp = 192-198 ˚C with decomposition (0.24 g, 85% yield). H NMR (600
MHz, DMSO-d6) δ 10.66 (s, 1H), 10.16 (s, 1H), 9.38 (s, 2H), 7.77 (d, J = 5.5 Hz, 1H), 7.50 (d, J = 10.2
Hz, 1H), 7.44 (dd, J = 9.1, 2.4 Hz, 2H), 7.28 (dd, J = 9.0, 2.2 Hz, 2H), 7.17 (dd, J = 5.0, 2.3 Hz, 1H), 6.93
(dd, J = 6.2, 2.6 Hz, 2H), 6.89 (d, J = 8.5 Hz, 2H), 6.79 (d, J = 8.6 Hz, 2H), 6.73 (ddd, J = 8.7, 5.6, 2.5
Hz, 1H), 6.64 (ddd, J = 7.9, 5.0, 2.8 Hz, 1H), 5.36 (d, J = 12.4 Hz, 1H), 4.84 (d, J = 12.4 Hz, 1H), 3.70 (s,
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3H), 3.66 (s, 3H), 2.52 (s, 3H). C NMR (150 MHz, DMSO-d6) δ 166.5, 165.7, 155.6, 155.4, 155.0 (d,
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J1 = 232.9 Hz), 151.3 (d, J4 = 1.3 Hz), 135.2, 133.5 (d, J3 = 6.4 Hz), 131.8, 131.6, 130.4, 127.0,
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CF
CF
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121.1, 120.9, 119.4, 118.6, 117.9, 115.6 (d, J3CF = 8.1 Hz), 114.0, 113.8 (d, J2CF = 23.3 Hz), 112.4 (d, J2
CF
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= 22.3 Hz), 110.5, 108.8, 57.6, 55.2, 55.1, 36.2, 12.1. IR (neat, selected peaks): 3435, 3324, 3305, 1659,
1627 cm-1. Exact mass calculated for C33H31FN3O5 [M + H]+, 568.2242. Found 568.2251.
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2-((5-fluoro-2-hydroxyphenyl)(5-methoxy-1H-indol-3-yl)methyl)-N1,N3-bis(4-
methoxyphenyl)malonamide (7g). Prepared from methyl 6-fluoro-coumarin-3-carboxylate (1.0 equiv, 0.30
mmol, 66 mg), 5-methoxyindole (3.0 equiv, 0.90 mmol, 0.14 g), p-anisidine (3.0 equiv, 0.9 mmol, 0.12
g), lanthanum triflate (0.1 equiv, 0.030 mmol, 20 mg) and 0.3 mL CH2Cl2. After 48 h, the product was
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isolated as a colorless solid, mp = 174-176 ˚C (0.11 g, 63 % yield). H NMR (600 MHz, DMSO-d6) δ
10.63 (s, 1H), 10.04 (s, 1H), 9.57 (s, 1H), 9.42 (s, 1H), 7.42 – 7.36 (m, 3H), 7.31 (d, J = 8.9 Hz, 2H), 7.18
(d, J = 2.5 Hz, 1H), 7.12 (d, J = 8.6 Hz, 1H), 7.08 (d, J = 9.4 Hz, 1H), 6.81 (m, 4H), 6.73 – 6.61 (m, 3H),
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5.41 (d, J = 12.3 Hz, 1H), 4.54 (d, J = 12.3 Hz, 1H), 3.70 (s, 3H), 3.68 (s, 3H), 3.66 (s, 3H). C NMR
(150 MHz, DMSO-d6) δ 166.5, 165.9, 155.6, 155.4, 155.3 (d, J1CF = 233.6 Hz), 152.8, 150.9 (d, J4CF = 1.4
Hz), 131.8, 131.4, 131.0, 130.3 (d, J3 = 6.3 Hz), 127.2, 122.4, 121.4, 120.9, 116.1 (d, J3 = 7.9 Hz),
CF
CF
115.5, 115.3 (d, J2CF = 23.2 Hz), 115.0, 114.5, 113.8, 113.1 (d, J2CF = 22.4 Hz), 111.8, 110.8, 101.2, 59.6,
55.3, 55.18, 55.16. IR (neat, selected peaks): 3368, 3318, 1667, 1603 cm-1. Exact mass calculated for
C33H30FN3NaO6 [M + Na] + 606.2016, Found 606.2036.
2-((1,2-dimethyl-1H-indol-3-yl)(5-fluoro-2-hydroxyphenyl)methyl)-N1,N3-diphenylmalonamide
(7h). Prepared from methyl 6-fluoro-coumarin-3-carboxylate (1.0 equiv, 0.18 mmol, 40 mg), 1,2-
dimethylindole (3.0 equiv, 0.54 mmol, 78 mg), aniline (3.0 equiv, 0.54 mmol, 50 mg), lanthanum triflate
(0.10 equiv, 0.018 mmol, 11 mg) and 0.2 mL of dry CH2Cl2. After 72 h, the product was isolated as a
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colorless solid, mp = 163-165 ˚C (68 mg, 72% yield). H NMR (300 MHz, DMSO-d6) δ 10.28 (s, 1H),
9.56 (s, 1H), 9.40 (s, 1H), 7.82 (d, J = 6.8 Hz, 1H), 7.53 (d, J = 8.3 Hz, 2H), 7.46 (dd, J = 10.1, 2.6 Hz,
1H), 7.38 (d, J = 8.3 Hz, 2H), 7.30 (dd, J = 7.7 Hz, 2H), 7.26 (d, J = 7.3 Hz, 1H), 7.21 (dd, J = 7.7 Hz,
2H), 7.06 (dd, J = 7.4 Hz, 1H), 7.02 – 6.95 (m, 3H), 6.71 (ddd, J = 8.4, 2.9 Hz, 1H), 6.63 (dd, J = 8.7, 5.1
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