Synthesis of C-2 arylated tryptophan amino acids and related compounds through palladium-catalyzed C-H Activation

Article abstract of DOI:10.1021/jo400961x

Tryptophan (Trp) and tryptophan derivatives are C2-arylated. A C-H activation process allows the preparation of both protected and unprotected arylated-Trp amino acids, directly from the amino acid precursor and aryl iodides. The obtained compounds are suitable for standard solid-phase peptide synthesis.

Full text of DOI:10.1021/jo400961x

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Note
Synthesis of C-2 Arylated Tryptophan Amino Acids and Related
Compounds through Palladium Catalyzed C-H Activation
Sara Preciado, Lorena Mendive-Tapia, Fernando Albericio, and Rodolfo Lavilla
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo400961x • Publication Date (Web): 18 Jul 2013
Downloaded from http://pubs.acs.org on July 21, 2013
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Synthesis of C-2 Arylated Tryptophan Amino Acids and Related
Compounds through Palladium Catalyzed C-H Activation
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Sara Preciado,±,† Lorena Mendive-Tapia,±,‡,§ Fernando
Albericio,‡,§,║,£,* and Rodolfo Lavilla†,¶,*
†- Barcelona Science Park, Baldiri Reixac 10-12, 08028 Barcelona, Spain.
‡- Institute for Research in Biomedicine, Barcelona Science Park, Baldiri Reixac 10-12,
08028 Barcelona, Spain.
§-Department of Organic Chemistry, University of Barcelona, Martí i Franqués 1-11, 08028
Barcelona, Spain.
║-CIBER-BBN, Networking Centre on Bioengineering Biomaterials and Nanomedicine,
Barcelona Science Park, Baldiri Reixac 10, 08028 Barcelona, Spain.
£- School of Chemistry,University of KwaZulu-Natal, 4001-Durban, South Africa.
¶- Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, Avda.
Joan XXII s.n. 08028 Barcelona, Spain.
rlavilla@pcb.ub.es
± Both researchers have contributed equally to this work.
ABSTRACT
Tryptophan (Trp) and tryptophan derivatives are C2-arylated. A C-H activation process
allows the preparation of both protected and unprotected arylated-Trp amino acids, directly
from the amino acid precursor and aryl iodides. The obtained compounds are suitable for
standard solid-phase peptide synthesis.
Although Tryptophan (Trp) shows a low relative abundance in peptide and protein
sequences (around 1% of the overall amino acids), its presence is of crucial importance for the
activity of these molecules. Furthermore, Trp is a common precursor to a wide range of
biologically active compounds (natural products and drugs), and its structural, chemical and
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biological roles make it an ideal site for selective chemical modifications. The access to
modified Trp peptides would provide novel and useful applications in organic chemistry, drug
discovery and medicinal chemistry.1 Furthermore, it would open the possibility of preparing
new chemically modified peptides that are potentially useful in chemical biology. Right now,
this goal is only achievable through de novo synthesis of the non natural amino acid, by
means of long stepwise syntheses,2 with the exception of C- and N- allylations which have
been reported through Pd-catalyzed transformations.3
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Indole, the heterocyclic residue of Trp, is probably one of the most abundant heterocycles in
nature. Owing to the great structural diversity of biologically active indoles, it is not
surprising that this ring system has become an important structural component in many
pharmaceutical agents. Substituted indoles have been referred to as “privileged substructures”
since they appear in many scaffolds capable of binding a variety of different receptors with
high affinity. 4 Incidentally, the 2-arylindole moiety has gained relevance in medicinal
chemistry and is considered a common scaffold.5 Interestingly, the synthetic access to related
drugs relays on its previous preparation. For well over a hundred years, the synthesis and
functionalization of indoles has been a major area of focus for synthetic organic chemists, and
numerous methods for the preparation of indoles have been described.6
Thus, the development of new synthetic methodologies for the selective chemical
modification of Trp is of major importance. Particularly, the introduction of aromatic moieties
into the indole ring of the Trp to modulate the structure and bioactivity of the selected
biomolecules might be a challenging issue. Recently, the metal-catalyzed C-C coupling
through direct C-H activation7 for the functionalization of indoles has been extensively
studied.8
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Particularly relevant to our research was Larrosa’s methodology for indole arylation using
Pd(OAc)2, Ag2O and o-nitrobenzoic acid (2-NO2BzOH) in DMF.8c In this context, we
described C-2 arylation of indoles in Trp derivatives and peptides through a Pd-catalyzed C-H
activation protocol, allowing the preparation of a variety of peptide sequences with modified
Trp moieties (Figure 1, a).9,10 In this work, it was determined that unprotected Trp was not
reactive under the original conditions, and only the Nα-acetyl tryptophan methyl ester (Ac-
Trp-OMe) could be properly arylated, using high temperature microwave (W) activation.11
As the Ac is not a friendly group to mask the amino function, applicability of that
methodology for the preparation of some peptides containing modified Trp units was
restricted, and therefore prompted us to tackle this problem (Figure 1, b). Thus, a more
convenient N-protecting group was tested next, and the Nα-trifluoroacetyl (Tfa) Trp 1a could
be successfully arylated (Table 1, entry 1). Although this group can be hydrolytically removed
in solution, it was reluctant to standard deprotection methods in solid-phase,12 which is the
method of choice for the preparation of peptides.
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Figure 1. Arylation of indole in Trp derivatives
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As a starting point, we analyzed the reaction of native Trp 1b using our standard conditions
(2-NO2BzOH, 150 ºC, MW) but the arylated product was obtained just in traces in a complex
mixture (Table 1, entry 2). Satisfactorily, the use of TFA alone (1 equiv) afforded 75% in 20
minutes (Table 1, entry 3). This result encouraged us to optimize the process using this acid,
which apparently removes the incompatibility of a free amino group. In this regard, TFA is
more convenient than other carboxylic acids, as it is water soluble, has a low boiling point and
therefore can be conveniently removed, not hampering the stability and purification of the
final products. Although traces of the acid could remain in the crude residue after standard
evaporation, the use of TFA constitutes a practical improvement for this transformation, as it
does not require chromatographic methods for the removal of the acid input. Also, it is
evident that working at temperatures well below 150 ºC is essential to keep the integrity of the
Trp amino acids. Working at 90 ºC under the same conditions, allowed us to reduce the
amount of aryl iodide while slightly increasing the conversion (87%, Table 1, entry 4).
However, a slighltly higher temperature (100 ºC) resulted in a less efficient transformation
(Table 1, entry 5), probably fixing the practical limit of this reaction. Interestingly, the
absence of an external acidic source still allowed the arylation process, although in lower
conversion (Table 1, entry 6). Interestingly, a key parameter was the amount of Ag+ salt
present. Thus, using an excess of the Ag+ salt (Table 1, entry 7) gave a practically quantitative
reaction. Next, the Fmoc-Trp-OH derivative 1c, which can be used directly in a solid-phase
peptide synthesis, was assayed to be arylated (Table 1, entry 8), and again the use of 2 equiv
of AgBF4 afforded a quantitative transformation.13 Incidentally, this optimized conditions lead
to a total conversion of Tfa-Trp-OH derivative 1a into 3 (Table 1, entry 9). Excess of TFA (up
to 4 equiv) did not improve the yields, whereas the use of Ag2CO3 or different Pd sources
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[Pd(TFA)2] was not beneficial. On the other hand, the presence of additives (LiCl, Cs2CO3,
K2CO3) was detrimental to the reaction, leading to lower conversions.
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Table 1. Selected optimization results for the arylation of tryptophans (1) under microwave
irradiationa
entry
R
T
(ºC)
time
(min)
5
15
20
20
20
20
20
acidb
AgBF4
(eq)
1.0
1.0
1.0
1.0
1.0
1.0
2.0
I-Ar
(eq)
4.0
4.0
3.0
1.5
1.5
1.5
1.5
1.5
1.5
conv
(%)c
76
<5
75
87
78
49
1
2
3
4e
5
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9
Tfad 150
2-NO2BzOH
2-NO2BzOH
TFA
H
H
H
H
H
H
150
80
90
100
100
90
TFA
TFA
—
TFA
TFA
TFA
>99
>99
>99
Fmoc 90
Tfa 90
20
20
2.0
2.0
a
Unless otherwise noted, all reactions were carried out using 5 mol % Pd(OAc)2 and 1.0 equiv of Trp in a
0.2M solution. b 1.5 equiv of 2-NO2BzOH (entries 1-2) and 1.0 equiv of TFA were used. c Conversion measured
by HPLC. Tfa = trifluoroacetyl. e These reactions were also tested using PBS:DMF (1:1) as a solvent, and
d
other silver salts, without any relevant improvement.
An hypothetical mechanism for this C-H activation may proceed through a catalytic cycle
involving Pd(II)/Pd(IV) species, taking into account the intramolecular coordination of the
carboxylic acid moiety and the facilitated formation of the putative palladacycle (Scheme
1).7a,14 However, alternative Pd(0)/Pd(II) pathways could also be considered in this context,
starting with the Pd insertion into the C-I bond, the C-H activation taking place upon the
metallated intermediate.7c, 8c The role of silver salts and carboxylic acids seems to be critical
for the fate of the catalytic cycle. Firstly, coordination of Trp derivative 1 to the PdII species
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may evolve through indole palladation, presumably by a concerted metallation deprotonation
mechanism15 to generate PdII complex I. Insertion of this intermediate upon the C-I bond of
the aryl halide by oxidative addition yields the palladium (IV) complex II, and then silver
cation (I) acts as halide scavenger, removing the iodide and setting up the reductive
elimination to release the arylated products 3-5 and regenerate the Pd(II) catalyst. 16
Additionally, TFA is acidic enough (pKa 0.23) to protonate the amino group of the
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unprotected Trp, avoiding in this way an unproductive amino acid coordination.
Furthermore, trifluoroacetate anion can also coordinate with the metal to render it more
electrophilic and also take part in the deprotonation and proton transfer steps. DMF seems to
be very suitable for this process as it dissolves all the reactants involved and is also a ligand,
capable to stabilize palladium intermediates as well.
Scheme 1. Proposed mechanism for the reaction of Trp amino acid with aryl iodides
We next examined the scope of the reaction with a variety of differently substituted aryl
iodides. As shown in Table 2, excellent yields are obtained in the reaction of Fmoc-Trp-OH
with several aryl iodides. Both electron withdrawing (5b-f) and electron-donating
substitutents (5g-h) are suitable groups for this transformation. Furthermore, a rather hindered
pyrenyl fluorophore was introduced (5i), which would allow the synthesis of labelled Trp-
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containing peptides.18 With respect to heterocyclic iodides, although an -thienyl resiue can
be attached to the Trp-2 position, the reactivity was low and purification problems precluded
the isolation of the corresponding adduct (Table 2, entry 11). In this way an array of arylated
Fmoc-Trp derivatives were prepared in a direct manner with useful yields (Table 2) in
scalable procedures (up to 500 mg of the Fmoc-Trp-OH were successfully arylated).
Interestingly, the mild conditions allowed to preserve the stereochemical integrity of the
parent amino acid. Thus, the S and R enantiomers of the Fmoc-Trp-OH were separatedly
subjected to the arylation reaction to yield compounds 5a and 5a’ respectively (entries 1 and
2, Table 2), whose chromatographic behavior (chiral HPLC, see SI) confirmed the
conservation of the initial absolute stereochemistry.19
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Table 2. C-2 Arylation of Fmoc-Trp-OH Amino Acid 1c
entry
I-Ar
compound yield (%)a
1
2b
3
4
5
6
7
8
9
C6H5-
C6H5-
5a
5a’
5b
5c
5d
5e
5f
5g
5h
5i
56
51
91
68
62
59
77
81
63
66
p-NO2-C6H4-
p-MeO2C-C6H4-
p-Br-C6H4-
m-CF3-C6H4-
o-F-C6H4-
p-Me-C6H4-
p-MeO-C6H4-
1-pyrenyl
10
c
11
2-thienyl
-
-
a Yields are of the isolated pure material.b Opposite absolute stereochemistry (R). c Conversion lower than 15%,
the thienyl-Trp was detected (1H NMR, HPLC-MS) but not purified.
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To prove the suitability for standard solid-phase peptide synthesis of the arylated-Trp amino
acids, two peptide sequences were chosen as proof of principle (Table 3). The syntheses were
performed using Fmoc-based SPPS on a 2-chlorotrityl chloride resin and standard coupling
protocol. N-terminal peptide chain elongation was carried out by anchoring the Na-Fmoc
protected amino acids with DIC/OxymaPure followed by Fmoc-deprotection in an iterative
manner. Finally, sequences 6-7 were cleaved from the resin with 5% TFA in DCM affording
the corresponding peptides in high yield and purity (more than 99%), as determined by
integration of the chromatographic peak areas of RP-HPLC-ESMS. The direct introduction of
the Fmoc-arylated amino acid 5f on solid-phase is very efficient and also overcomes the
limitation encountered in previous studies regarding sequences containing sulfur-amino acids
(Met or Cys). It also allows the selective preparation of arylated Trp peptides in sequences
with multiple Trp units.9
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Table 3. Solid-phase synthesis of peptide sequences containing arylated-Trp amino acids.
entry
peptide
compound
1
2
H-Met-Gly-Trp(C2-p-methylphenyl)-Ala-OH
H-Trp-Gly-Trp(C2-p-methylphenyl)-Ala-OH
6
7
As the carboxylic acid moiety in Trp seems to actively promote the arylation by
coordination with the palladium species, we extended this methodology to a series of indole-
carboxylic acids having the CO2H linked to the heteroaromatic ring by spacers of different
length (1 to 4 bonds, Table 4). In this way, the corresponding arylated compounds 8-12 were
obtained in high yields but, remarkably, the indole 3-carboxylic acid was not reactive under
this conditions, and the expected adduct was not detected. Incidentally, indoleacetic acid is a
natural plant hormone involved in growth and development, and indolebutyric acid is a
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synthetic and metabolically more stable analog.20 Taking into account the potential bioactivity
of derivatives 8-10, it is relevant to note the easy access to these compounds. Furthermore,
compound 10 is also a patented IL-8 receptor antagonist,21,22 whereas the other two phenyl-
indole carboxylic acids 8 and 9 also showed interesting biological properties.23 Interestingly,
their preparation is reported through long stepwise synthetic sequences. Using our
methodology, a more direct synthetic approach to this family of compounds can be feasible
using cheap common indole precursors and a variety of commercially available aryl iodides in
just one step.
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Table 4. C-2 arylation of indole-carboxylic acids and tryptamines
entry
R
compound
yield (%)a
1
2
3
4
5
6
CO2H
CH2CO2H
CH2CH2CO2H
CH2CH2CH2CO2H
CH2CH2NH2
CH2CH2NHAc
—
8
9
10
11
12
—
79
75
74
48b
73
a Yields are of the isolated pure material.b The reaction was carried out using two MW cycles,
without adding TFA.
Analogously, tryptamine was arylated under this acidic conditions (1 equiv TFA) to yield
compound 11, as expected in a low conversion (16%). However, when operating in the
absence of TFA, an improved transformation (48%, Table 4, entry 5) was determined,
suggesting that in this case the aminopalladacycle was an intermediate en route of the final
compound.24 In agreement with previous results,9 the N-acetyltryptamine was satisfactorily
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arylated to yield derivative 12 (73%). This compound was prepared in higher yields and under
much milder conditions than previously reported in a distinct C-H activation protocol.25
Overall, the process is effective upon Trp, indole carboxylic acids, indole amines and amides.
It has to be stated that although different coordination modes are feasible depending on the
substrate, TFA-protonation allows the arylation of the free amino acids, which was not
possible in the previous protocol.9 Presumably, the formation of palladium–amino acid
complexes is inhibited in these conditions, leading to productive catalytic cycles.
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In conclusion, we have developed a synthetic methodology to α-arylated indoles in Trp,
tryptamines and β-substituted indole carboxylic acids which is simple, high-yielding, versatile
and mild enough to allow the efficient transformation of biomolecules. Remarkably, the
intramolecular ligand effect of the carboxylic acid seems to facilitate the process, as the
conditions are milder than many C-H arylations previously reported upon 3-substituted
indoles. Application of the newly synthesized amino acid derivatives to the preparation of
modified Trp-containing peptides through solid-phase methodology has shown to be efficient.
EXPERIMENTAL SECTION
Reactions were monitored by RP-HPLC-ESMS at 220 nm and thin layer chromatography
using Merck silica gel 60 F254 TLC glass plates and visualized with UV at 254 nm.
Chromatographic purification was performed with flash chromatography on silica 60A, 35-70
nm from SDS. Yields refer to chromatographically pure compounds. NMR spectra were
recorded on a 400 spectrometer, operating at 400 MHz for 1H, 100 MHz for 13C and 376 MHz
for 19F. Chemical shifts (δ) are reported in ppm. Multiplicities are referred by the following
abbreviations: s = singlet, d = doublet, t = triplet, dd = double doublet, dt = double triplet, q =
quartet, p = pentuplet and m = multiplet. IR spectra were obtained with an FTIR spectrometer
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and are reported in cm–1. HRMS (ESI positive) were obtained with a linear ion trap mass
analyzer. Optical rotation was performed using MeOH as solvent. All microwave reactions
were carried out in 10 mL sealed glass tubes in a focused mono-mode microwave oven
("Discover" by CEM Corporation) featured with a surface sensor for internal temperature
determination. Cooling was provided by compressed air ventilating the microwave chamber
S3 during the reaction. The chiral chromatography was performed in a linear gradient of
CH3CN (+0.1 % TFA) into H2O (+0.1 % TFA) from 50 to 90 % CH3CN, and a chiral HPLC
column (Chiralpak ia, Amylose tris-(3,5-dimetylphenylcarbamate) immobilized on 5 μm
silica gel, 250 x 2 mm).
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Preparation of (S)-3-(1H-Indol-3-yl)-2-(2,2,2 trifluoroacetamido)propanoic acid (1a).26
Compound 1a was prepared using amino acid 1b (1.0 g, 5.0 mmol). The system was purged
with N2 and the amino acid was dissolved in anhydrous MeOH (4.5 mL). With stirring, NEt3
(696.5 μL, 5.0 mmol) was added, followed by ethyl trifluoroacetate (1.5 mL, 12.8 mmol) after
5 minutes. The reaction was left under vigorous agitation at r.t for 24 h. The solvent was
removed under vacuum and the crude product was dissolved in H2O (46 mL) and acidified
with of concentrated HCl (1 mL). The precipitate was filtered by filter plate, leaving 1a as a
white solid (1.22 g, 81 %). 1H-NMR (400 MHz, DMSO): δ 10.84 (d, J = 2.5 Hz, 1H), 9.74 (d,
J = 8.1 Hz, 1H), 7.53 (d, J = 7.8 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.12 (d, J = 2.3 Hz, 1H),
7.08 – 7.02 (m, 1H), 6.97 (t, J = 7.4 Hz, 1H), 4.49 (ddd, J = 10.3, 7.9, 4.3 Hz, 1H), 3.30 (dd, J
13
= 14.8, 4.4 Hz, 3H), 3.14 (dd, J = 14.8, 10.3 Hz, 1H) ppm. C-NMR (100 MHz, DMSO): δ
172.2, 157.3-156.6 (m), 136.5, 127.4, 124.0, 121.5, 120.5, 118.9, 118.4, 117.6, 114.8, 111.9,
110.1, 110.0, 54.1, 26.4 ppm.
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Preparation of 1-iodopyrene (2b).27 Compound 2b was prepared using 1-Aminopyrene
(973 mg, 4.47 mmol) which was suspended in aqueous HCl solution (3M, 25 mL) with
vigorous stirring at 0 °C. A solution of NaNO2 (308.4 mg, 4.47 mmol) in H2O (1.5 mL) was
added in small portions. After 5 min, a solution of KI (742.4 mg, 4.47 mmol) in H2O (3 mL)
was added to the reaction mixture. The ice bath was removed, the reaction mixture was stirred
for 2 h at r.t and then heated to 60 ºC for 1 h. The crude product was separated by filtration,
dissolved in ether and washed with a concentrated solution of Na2SO3. The ether solution was
dried with MgSO4 and concentrated under vacuum. The resulting product was purified by
flash chromatography on silica gel (hexane/ethyl acetate) to obtain 1-Iodopyrene 2b as a
white yellowish solid (598.8 mg, 41 %). 1H-NMR (400 MHz, CDCl3): δ 8.37 (d, J = 8.1 Hz,
1H), 8.16 (d, J = 9.2 Hz, 1H), 8.11 – 8.06 (m, 2H), 8.01 – 7.94 (m, 2H), 7.93 – 7.85 (m, 2H),
7.72 (d, J = 8.1 Hz, 1H) ppm.
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General procedure for the C2 arylation of Trp amino acids (3-5). Unless stated otherwise,
Trp amino acid (1a-c) (0.117 mmol, 1 equiv), aryl iodide (1.5 equiv), AgBF4 (2 equiv), TFA
(1.0 equiv) and Pd(OAc)2 (5 % mol) were placed in a microwave reactor vessel in dry DMF
(600 µL). The mixture was heated under microwave irradiation (250 W) at 90 °C for 20 min.
Ethyl acetate (20 mL) was added and the resulting suspension was filtered through Celite and
the solvent was removed under vacuum. Unless otherwise quoted, the crude extract was
purified by flash chromatography on silica gel (hexane/ethyl acetate) to obtain 3-5 as a pure
product. Fractions containing the arylated tryptophans were collected and the solvent was
removed under reduced pressure, the residue was dissolved in CH3CN/H2O and lyophilized
for 24 h to yield the pure product.
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(S)-3-(2-(p-Tolyl)-1H-indol-3-yl)-2-(2,2,2 trifluoroacetamido)propanoic acid (3).
Starting from amino acid 1a (100 mg, 0.333 mmol) and 4-iodotoluene (110 mg, 0.500 mmol).
Pale oil (65.9 mg, 51 %). 1H-NMR (400 MHz, DMSO): δ 11.16 (s, 1H), 9.77 (d, J = 8.2 Hz,
1H), 7.62 (d, J = 8.0 Hz, 1H), 7.54 – 7.51 (m, 2H), 7.30 (td, J = 7.9, 0.9 Hz, 3H), 7.06 (ddd, J
= 8.1, 7.0, 1.1 Hz, 1H), 6.96 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 4.51 (td, J = 8.7, 5.1 Hz, 1H),
3.47 (dd, J = 14.7, 5.1 Hz, 1H), 3.32 – 3.23 (m, 1H), 2.35 (s, 3H) ppm. 13C -NMR (100 MHz,
DMSO): δ 171.3, 156.0, 155.7, 136.6, 135.5, 135.1, 129.6, 129.0, 128.6, 127.6, 121.1, 118.5,
118.4, 116.9, 114.0, 110.8, 106.7, 53.8, 25.8, 20.6 ppm. IR (Film, cm-1) ν = 3378.65, 3301.78,
2930.25, 1693.95 cm-1. HRMS (ESI) m/z calcd 391.12640 (C20H18F3N2O3) found 391.12592
(M+H)+.
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(S)-2-Amino-3-(2-(p-tolyl)-1H-indol-3-yl)propanoic acid (4). Starting from amino acid
1b (50.0 mg, 0.245 mmol) and 4-iodotoluene (80.2 mg, 0.368 mmol). The crude product was
purified by flash chromatography on silica using hexane/ethyl acetate and then DCM/EtOH.
Pale oil (39.9 mg, 56 %). 1H-NMR (400 MHz, DMSO): δ 11.20 (s, 1H), 7.62 (d, J = 7.8 Hz,
1H), 7.55 (d, J = 7.8 Hz, 2H), 7.34 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 7.8 Hz, 2H), 7.08 (t, J =
7.5 Hz, 1H), 6.99 (t, J = 7.4 Hz, 1H), 3.68 (t, J = 7.2 Hz, 1H), 3.44 (dd, J = 14.9, 6.2 Hz, 1H),
13
3.10 (dd, J = 14.8, 8.4 Hz, 1H), 2.34 (s, 3H) ppm. C -NMR (100 MHz, DMSO): δ 170.9,
137.2, 136.4, 136.1, 130.2, 129.6, 129.1, 128.5, 121.8, 119.2, 119.0, 111.5, 106.5, 54.7, 27.5,
21.3 ppm. IR (Film, cm-1) ν = 3404.27, 3231.32, 3051.96, 2962.28, 2923.84, 1706.76 cm-1.
HRMS (ESI) m/z calcd 295.14410 (C18H19N2O2) found 295.14381 (M+H)+.
(S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-phenyl-1H-indol-3-
yl)propanoic acid (5a). Starting from amino acid 1c (50.0 mg, 0.117 mmol) and iodobenzene
(26.2 μL, 0.234 mmol). Pale oil (32.9 mg, 56 %). Scale-up: Starting from amino acid 1c (0.5
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g, 1.17 mmol) and iodobenzene (200 μL, 1.75 mmol) in dry DMF (2 mL). The general
microwave process was performed six times, all the reaction mixtures were collected
altogether and the resulting crude was treated according to the general procedure. Pale oil
(1.98 g, 56 %). 1H-NMR (400 MHz, DMSO): δ 12.62 (s, 1H), 11.20 (s, 1H), 7.88 – 7.84 (m,
2H), 7.78 (d, J = 8.6 Hz, 1H), 7.72 – 7.60 (m, 5H), 7.47 (t, J = 7.7 Hz, 2H), 7.41 – 7.32 (m,
4H), 7.28 (td, J = 7.4, 1.1 Hz, 1H), 7.23 (td, J = 7.5, 1.1 Hz, 1H), 7.10 – 7.05 (m, 1H), 6.97
(ddd, J = 8.0, 6.9, 1.0 Hz, 1H), 4.31 (td, J = 8.6, 5.8 Hz, 1H), 4.15 – 4.06 (m, 3H), 3.40 – 3.34
(m, 1H), 3.18 (dd, J = 14.6, 8.7 Hz, 1H) ppm. IR (Film, cm-1) ν = 3372.24, 3321.00, 3051.96,
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-1
+
ꢀ ꢂꢄꢅ
2955.87, 1693.95 cm . RP-HPLC-ESMS: m/z (%): 503.22 (M+H) . ꢁ
-5.9 (c 0.48,
ꢃ
MeOH).
(R)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-phenyl-1H-indol-3-
yl)propanoic acid (5a’). Starting from amino acid 1c (50.0 mg, 0.117 mmol) and
iodobenzene (26.2 μL, 0.234 mmol). Pale oil (29.9 mg, 51 %). 1H-NMR (400 MHz, DMSO):
δ 12.64 (s, 1H), 11.20 (s, 1H), 7.86 (d, J = 7.6 Hz, 2H), 7.78 (d, J = 8.6 Hz, 1H), 7.72 – 7.60
(m, 5H), 7.47 (t, J = 7.7 Hz, 2H), 7.41 – 7.32 (m, 4H), 7.28 (td, J = 7.5, 1.2 Hz, 1H), 7.23 (td,
J = 7.5, 1.2 Hz, 1H), 7.10 – 7.05 (m, 1H), 6.98 (t, J = 7.4 Hz, 1H), 4.31 (td, J = 8.5, 5.7 Hz,
1H), 4.15 – 4.06 (m, 3H), 3.37 (dd, J = 14.5, 5.8 Hz, 1H), 3.19 (dd, J = 14.6, 8.7 Hz, 1H)
ppm. 13C -NMR (100 MHz, DMSO): δ 174.0, 156.3, 144.2, 144.12, 141.07, 136.3, 135.6,
133.2, 129.4, 129.1, 128.4, 128.05, 128.03, 127.8, 127.5, 125.8, 121.9, 120.5, 119.5, 119.2,
111.5, 108.4, 66.2, 55.7, 47.0, 27.4 ppm. IR (Film, cm-1) ν = 3372.24, 3321.00, 3051.96,
2955.87, 1693.95 cm-1. HRMS (ESI) m/z calcd 503.19653 (C32H26N2O4), found 503.19761
+
ꢀ ꢂꢄꢅ
(M+H) . ꢁ
+13.2 (c 0.27, MeOH).
ꢃ
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(S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(4-nitrophenyl)-1H-indol-3-
yl)propanoic acid (5b). Starting from amino acid 1c (100 mg, 0.234 mmol) and 1-iodo-4-
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nitrobenzene (89.4 mg, 0.352 mmol). Pale oil (116.7 mg, 91 %). H-NMR (400 MHz,
DMSO-d6): δ 11.50 (s, 1H), 8.31 – 8.26 (m, 2H), 7.96 – 7.92 (m, 2H), 7.86 (d, J = 7.6 Hz,
2H), 7.79 (d, J = 8.8 Hz, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.60 (dd, J = 7.5, 4.5 Hz, 2H), 7.41 –
7.36 (m, 3H), 7.29 – 7.20 (m, 2H), 7.19 – 7.13 (m, 1H), 7.03 (t, J = 7.5 Hz, 1H), 4.31 (td, J =
8.8, 5.3 Hz, 1H), 4.17 – 4.00 (m, 3H), 3.51 – 3.39 (m, 2H) ppm. 13C-NMR (100 MHz,
DMSO-d6): δ 173.31, 155.87, 145.92, 143.76, 143.65, 140.65, 139.32, 136.56, 132.78,
128.85, 128.52, 127.62, 127.01, 125.28, 123.87, 122.81, 120.07, 119.52, 119.34, 111.48,
111.10, 65.73, 54.99, 46.50, 26.92 ppm. IR (Film, cm-1): ν = 3404.27, 3327.40, 3058.36,
2943.06, 2917.44, 1700.36, 1508.19, 1348.04, 848.40, 733.10 cm-1. RP-HPLC-ESMS: m/z
+
ꢀ ꢂꢄꢅ
(%): calcd 548,1816 (C32H26N3O6), found 548.18268 (M+H) . ꢁ
-21.8 (c 0.50, MeOH).
ꢃ
(S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(4-(methoxycarbonyl)phenyl)
-1H-indol-3-yl)propanoic acid (5c). Starting from amino acid 1c (50 mg, 0.117 mmol) and
1
methyl 4-iodobenzoate (46.1 mg, 0.176 mmol). Pale oil (44.8 mg, 68 %). H-NMR (400
MHz, CDCl3): δ 8.00 (s, 1H), 7.63 (dd, J = 33.5, 7.4 Hz, 3H), 7.43 – 7.28 (m, 7H), 7.23 –
7.17 (m, 2H), 7.16 – 7.11 (m, 1H), 7.10 – 7.05 (m, 1H), 6.88 – 6.83 (m, 2H), 5.04 (d, J = 7.9
Hz, 1H), 4.55 (q, J = 6.8 Hz, 1H), 4.18 – 4.07 (m, 2H), 4.01 (t, J = 7.3 Hz, 1H), 3.70 (s, 3H),
3.43 (qd, J = 14.9, 6.3 Hz, 2H) ppm. 13C -NMR (100 MHz, CDCl3): δ 175.9, 166.8, 159.5,
143.8, 143.79, 143.72, 141.2, 136.0, 135.5, 135.0, 130.2, 129.7, 129.3, 128.1, 127.7, 127.0,
125.1, 123.2, 122.3, 120.5, 120.2, 119.91, 119.89, 119.2, 114.5, 111.1, 110.9, 108.2, 106.1,
67.1, 55.3, 54.4, 52.3, 47.0 ppm. IR (Film, cm-1) ν = 3410.68, 3340.21, 3058.36, 2949.47,
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1713.17, 1693.95 cm-1. HRMS (ESI) m/z calcd 561.20201 (C34H28N2O6) found 561.20365
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ꢀ ꢂꢄꢅ
(M+H) . ꢁ
-15.9 (c 0.51, MeOH).
ꢃ
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(S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(4-bromophenyl)-1H-indol-3-
yl)propanoic acid (5d). Starting from amino acid 1c (50.0 mg, 0.117 mmol) and 1-bromo-4-
iodobenzene (50.8 mg, 0.176 mmol). Pale oil (42.5 mg, 62 %). 1H-NMR (400 MHz, CDCl3):
δ 8.02 (s, 1H), 7.72 – 7.65 (m, 2H), 7.64 – 7.57 (m, 1H), 7.44 – 7.36 (m, 4H), 7.37 – 7.27 (m,
2H), 7.29 – 7.21 (m, 3H), 7.26 – 7.17 (m, 2H), 7.16 (d, J = 7.9 Hz, 1H), 7.09 (t, J = 7.4 Hz,
1H), 5.04 (d, J = 8.0 Hz, 1H), 4.57 (q, J = 6.5 Hz, 1H), 4.22 – 4.00 (m, 3H), 3.45 (qd, J =
14.9, 6.0 Hz, 2H) ppm. 13C -NMR (100 MHz, CDCl3): δ 176.1, 155.7, 143.73, 143.67,
141.25, 141.23, 135.7, 135.2, 132.2, 131.6, 129.9, 129.0, 127.7, 127.0, 125.2, 122.9, 122.3,
120.4, 119.9, 119.0, 111.1, 107.2, 67.1, 54.3, 46.9, 26.8 ppm. IR (Film, cm-1) ν = 3378.65,
3314.59, 3058.36, 2949.47, 1687.54 cm-1. HRMS (ESI) m/z calcd 581.10705
+
ꢀ ꢂꢄꢅ
(C32H25BrN2O4), found 581.10888 (M+H) . ꢁ
-8.1 (c 0.50, MeOH).
ꢃ
(S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(3-(trifluoromethyl)phenyl)-
1H-indol-3-yl)propanoic acid (5e). Starting from amino acid 1c (50.0 mg, 0.117 mmol) and
1-iodo-3-trifluoromethylbenzene (25.9 μL, 0.176 mmol). Pale oil (39.4 mg, 59 %). 1H-NMR
(400 MHz, DMSO): δ 12.67 (s, 1H), 11.39 (s, 1H), 8.01 – 7.95 (m, 2H), 7.89 – 7.79 (m, 3H),
7.74 (d, J = 8.1 Hz, 1H), 7.72 – 7.69 (m, 2H), 7.61 (dd, J = 11.1, 7.5 Hz, 2H), 7.41 – 7.35 (m,
3H), 7.30 – 7.20 (m, 2H), 7.12 (t, J = 7.8 Hz, 1H), 7.00 (t, J = 7.5 Hz, 1H), 4.30 (td, J = 8.6,
5.6 Hz, 1H), 4.15 – 4.04 (m, 3H), 3.40 (dd, J = 14.6, 5.7 Hz, 2H), 3.23 (dd, J = 14.7, 8.7 Hz,
1H) ppm. 19F -NMR (376 MHz, DMSO): δ -61.07 ppm. 13C -NMR (100 MHz, DMSO): δ
173.8, 156.3, 144.2, 144.1, 141.1, 136.5, 134.1, 133.7, 132.2, 130.22, 130.16, 129.3, 128.05,
128.03, 127.5, 125.7, 124.60, 124.56, 124.3, 122.5, 120.5, 119.8, 119.5, 111.7, 109.7, 66.2,
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55.5, 46.9, 27.3 ppm. IR (Film, cm-1) ν = 3391.46, 3314.59, 3064.77, 2949.47, 1706.76 cm-1.
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+
ꢀ ꢂꢄꢅ
HRMS (ESI) m/z calcd 571.18392 (C33H25F3N2O4), found 571.18559 (M+H) . ꢁ
-12.1 (c
ꢃ
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0.50, MeOH).
(S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(2-fluorophenyl)-1H-indol-3-
yl)propanoic acid (5f). Starting from amino acid 1c (100 mg, 0.234 mmol) and 2-
1
fluoroiodobenzene (41.4 μL, 0.351 mmol). Pale oil (121.8 mg, 77 %). H-NMR (400 MHz,
CDCl3): δ 8.16 (s, 1H), 7.68 (d, J = 7.6 Hz, 2H), 7.62 (d, J = 7.9 Hz, 1H), 7.44 – 7.25 (m,
8H), 7.24 – 7.20 (m, 1H), 7.17 – 7.04 (m, 4H), 5.07 (d, J = 8.1 Hz, 1H), 4.63 – 4.53 (m, 1H),
4.21 – 4.06 (m, 2H), 4.03 (t, J = 7.4 Hz, 1H), 3.48 – 3.30 (m, 2H) ppm. 19F-NMR (376 MHz,
CDCl3): δ -114.0 – -114.2 (m) ppm. 13C -NMR (100 MHz, CDCl3): δ 175.8, 158.7, 155.9,
144.0, 141.4, 136.1, 131.5, 130.6, 130.5, 130.3, 127.8, 127.2, 125.3, 124.84, 124.81, 123.1,
120.4, 120.1, 119.1, 116.6, 116.4, 111.2, 108.9, 67.3, 54.3, 47.1, 27.2. IR (Film, cm-1) ν =
3415.92, 3334.19, 3062.16, 2924.47, 1715.77 cm-1. HRMS (ESI) m/z calcd 521.18711
+
ꢀ ꢂꢄꢅ
(C32H25FN2O4), found 521.18728 (M+H) . ꢁ
-2.9 (c 0.50, MeOH).
ꢃ
(S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(p-tolyl)-1H-indol-3-
yl)propanoic acid (5g). Starting from amino acid 1c (100 mg, 0.234 mmol) and 4-
iodotoluene (76.7 mg, 0.351 mmol). Pale oil (97.4 mg, 81 %). 1H-NMR (400 MHz, CDCl3): δ
8.03 (s, 1H), 7.69 – 7.65 (m, 2H), 7.59 (d, J = 7.9 Hz, 1H), 7.41 – 7.27 (m, 8H), 7.21 – 7.19
(m, 1H), 7.16 – 7.08 (m, 3H), 7.09 – 7.05 (m, 1H), 5.02 (d, J = 7.9 Hz, 1H), 4.54 (q, J = 6.9
Hz, 1H), 4.16 – 4.05 (m, 2H), 4.00 (t, J = 7.2 Hz, 1H), 3.54 – 3.35 (m, 2H), 2.26 (s, 3H) ppm.
13C -NMR (100 MHz, CDCl3): δ 175.8, 155.8, 143.8, 143.7, 141.2, 138.2, 136.64, 135.60,
129.7, 129.6, 129.0, 128.3, 127.7, 127.6, 127.1, 127.0, 125.2, 122.5, 120.2, 120.0, 119.9,
118.7, 110.9, 106.4, 67.1, 54.5, 47.0, 26.8, 21.2 ppm. IR (Film, cm-1) ν = 3385.05, 3314.59,
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3051.96, 2949.47, 1693.95 cm-1. HRMS (ESI) m/z calcd 517.21218 (C33H28N2O4), found
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+
ꢀ ꢂꢄꢅ
517.21356 (M+H) . ꢁ
-9.9 (c 0.50, MeOH).
ꢃ
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(S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(4-methoxyphenyl)-1H-indol-
3-yl)propanoic acid (5h). Starting from amino acid 1c (50.0 mg, 0.117 mmol) and 4-
iodoanisole (41.2 mg, 0.176 mmol). Pale oil (39.0 mg, 63 %). 1H-NMR (400 MHz, CDCl3): δ
8.18 (s, 1H), 7.98 – 7.94 (m, 2H), 7.71 – 7.61 (m, 3H), 7.48 (d, J = 8.3 Hz, 2H), 7.42 – 7.28
(m, 5H), 7.23 – 7.16 (m, 3H), 7.09 (t, J = 7.5 Hz, 1H), 5.15 (d, J = 8.4 Hz, 1H), 4.60 (q, J =
6.6, 6.1 Hz, 1H), 4.18 – 4.07 (m, 2H), 3.99 (t, J = 7.3 Hz, 1H), 3.80 (s, 3H), 3.59 – 3.42 (m,
2H) ppm. 13C -NMR (100 MHz, CDCl3): δ 175.2, 158.5, 154.8, 142.8, 142.7, 140.19, 140.17,
134.5, 129.2, 128.7, 127.1, 126.6, 126.0, 124.2, 123.9, 121.3, 119.1, 118.90, 118.87, 117.6,
113.5, 109.9, 107.1, 105.1, 66.1, 54.2, 53.5, 51.2, 46.0 ppm. IR (Film, cm-1) ν = 3365.84,
3308.19, 3051.96, 2923.84, 1693.95 cm-1. HRMS (ESI) m/z calcd 533.20710 (C33H28N2O5),
+
ꢀ ꢂꢄꢅ
found 533.20867 (M+H) . ꢁ
-9.8 (c 0.45, MeOH).
ꢃ
(S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(pyren-1-yl)-1H-indol-3-
yl)propanoic acid (5i). Starting from amino acid 1c (100 mg, 0.234 mmol) and 1-iodopyrene
2b (115 mg, 0.352 mmol). Pale oil (94.2 mg, 66 %). 1H-NMR (400 MHz, DMSO): δ 12.36 (s,
1H), 11.46 (s, 1H), 8.36 – 8.21 (m, 6H), 8.17 – 8.07 (m, 4H), 7.95 (d, J = 9.2 Hz, 1H), 7.86
(d, J = 7.6 Hz, 2H), 7.79 (d, J = 7.9 Hz, 1H), 7.52 (t, J = 7.1 Hz, 2H), 7.44 – 7.35 (m, 4H),
7.27 – 7.15 (m, 3H), 7.09 (t, J = 7.4 Hz, 1H), 4.13 (q, J = 7.8 Hz, 1H), 4.01 – 3.78 (m, 3H),
3.12 (s, 2H) ppm. 13C -NMR (100 MHz, DMSO): δ 173.2, 155.5, 143.7, 140.6, 136.2, 134.8,
130.8, 130.7, 130.4, 129.4, 128.8, 128.2, 128.0, 127.8, 127.7, 127.5, 127.3, 127.0, 126.4,
125.4, 125.3, 125.2, 124.5, 124.0, 123.8, 121.3, 120.0, 118.89, 118.86, 111.1, 109.8, 65.5,
54.8, 46.4, 26.8 ppm. IR (Film, cm-1) ν = 3417.33, 3308.19, 3043.35, 2923.54, 1714.91 cm-1.
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+
ꢀ ꢂꢄꢅ
HRMS (ESI) m/z calcd 627.22783 (C42H30N2O4), found 627.23025 (M+H) . ꢁ
+7.6 (c
ꢃ
8
9
0.13, MeOH).
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2-(2-Phenyl-1H-indol-3-yl)acetic acid (8).28 Starting from 2-(1H-indol-3-yl)acetic acid
(42.0 mg, 0.240 mmol) and iodobenzene (40.3 μL, 0.360 mmol). Pale oil (47.8 mg, 79 %).
1H-NMR (400 MHz, CDCl3): δ 8.10 (s, 1H), 7.60 (ddt, J = 7.8, 1.5, 0.7 Hz, 1H), 7.57 – 7.54
(m, 2H), 7.46 – 7.36 (m, 2H), 7.35 – 7.30 (m, 2H), 7.21 – 7.12 (m, 1H), 7.14 – 7.05 (m, 1H),
3.80 (s, 2H) ppm. HRMS (ESI) m/z calcd 252.10191 (C16H13NO2), found 252.10168 (M+H)+.
3-(2-Phenyl-1H-indol-3-yl)propanoic acid (9).29 Starting from 3-(1H-indol-3-yl)propanoic
acid (45.4 mg, 0.240 mmol) and iodobenzene (41.1 μL, 0.360 mmol). Pale oil (47.6 mg, 75
1
%). H-NMR (400 MHz, CDCl3): δ 7.96 (s, 1H), 7.58 – 7.55 (m, 1H), 7.48 – 7.45 (m, 2H),
7.43 – 7.38 (m, 2H), 7.33 – 7.28 (m, 2H), 7.15 (ddd, J = 8.1, 7.1, 1.2 Hz, 1H), 7.08 (ddd, J =
8.1, 7.1, 1.1 Hz, 1H), 3.21 – 3.16 (m, 2H), 2.68 – 2.63 (m, 2H) ppm. HRMS (ESI) m/z calcd
266.11756 (C17H15NO2), found 266.11729 (M+H)+.
4-(2-Phenyl-1H-indol-3-yl)butanoic acid (10).30 Starting from 4-(1H-indol-3-yl)butanoic
acid (83.7 mg, 0.412 mmol) and iodobenzene (69.2 μL, 0.618 mmol). Pale oil (84.8 mg, 74
1
%). H-NMR (400 MHz, CDCl3): δ 7.97 (s, 1H), 7.57 (ddt, J = 7.8, 1.2, 0.7 Hz, 1H), 7.49 –
7.46 (m, 2H), 7.41 – 7.35 (m, 2H), 7.31 – 7.25 (m, 2H), 7.16 – 7.10 (m, 1H), 7.07 (ddt, J =
7.9, 6.9, 0.7 Hz, 1H), 2.91 – 2.87 (m, 2H), 2.33 (t, J = 7.3 Hz, 2H), 2.03 – 1.94 (m, 2H) ppm.
HRMS (ESI) m/z calcd 280.13321 (C18H17NO2), found 280.13287 (M+H)+.
31
2-(2-Phenyl-1H-indol-3-yl)ethanamine (11).
Tryptamine (76.9 mg, 0.480 mmol),
iodobenzene (80.6 µL, 0.720 mmol), AgBF4 (186.9 mg, 0.960 mmol) and Pd(OAc)2 (5.4 mg,
0.024 mmol) were placed in a microwave reactor vessel in dry DMF (2.4 mL). The mixture
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was heated under microwave irradiation (250 W) at 90 °C for 20 min. HPLC/MS analysis
showed a 29 % of compound 11. Incidentally, iodobenzene (80.6 µL, 0.720 mmol) and
Pd(OAc)2 (5.4 mg, 0.024 mmol) were added and a second irradiation cycle was performed
(250 W) at 90 °C for 20 min, thus increasing the conversion up to 89 %, as shown in the
HPLC/MS. Ethyl acetate (30 mL) was added and the resulting suspension was filtered
through Celite and the solvent was removed under vacuum. The crude product was purified
by flash chromatography on silica using hexane/ethyl acetate and then DCM/MeOH to obtain
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11 as an oil (54.4 mg, 48 %). H-NMR (400 MHz, DMSO): δ 11.30 (s, 1H), 7.79 (s, 2H),
7.63 – 7.59 (m, 3H), 7.52 (t, J = 7.6 Hz, 2H), 7.44 – 7.35 (m, 2H), 7.15 – 7.10 (m, 1H), 7.08 –
7.02 (m, 1H), 3.15 – 3.09 (m, 2H), 3.09 – 2.98 (m, 2H) ppm. RP-HPLC-ESMS: m/z (%):
237.12 (M+H)+.
N-(2-(2-phenyl-1H-indol-3-yl)ethyl)acetamide (12). 32 Starting from N-(2-(1H-indol-3-
yl)ethyl)acetamide (98.0 mg, 0.485 mmol) and iodobenzene (80.6 μL, 0.720 mmol). Yellow
solid (103.1 mg, 73 %). 1H-NMR (400 MHz, CDCl3): δ 8.28 (s, 1H), 7.56 (d, J = 7.9 Hz, 1H),
7.52 – 7.45 (m, 2H), 7.38 (t, J = 7.7 Hz, 2H), 7.33 – 7.26 (m, 2H), 7.17 – 7.12 (m, 1H), 7.09 –
7.05 (m, 1H), 5.41 (s, 1H), 3.46 (q, J = 6.5 Hz, 2H), 3.04 (t, J = 6.8 Hz, 2H), 1.67 (s, 3H)
ppm. RP-HPLC-ESMS: 279.12 (M+H)+.
General procedure for SPPS. All peptides were manually synthesized in polystyrene
syringes fitted with a polyethylene porous disc. The synthesis of the peptides were performed
using Fmoc-based SPPS on a 2-chlorotrityl chloride resin. Solvents and soluble reagents were
removed by suction. The Fmoc group was removed with piperidine-DMF (1:4, v/v) (1 × 1
min, 2 × 5 min). Peptide synthesis transformations and washes were performed at r.t.
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Resin loading. Fmoc-XX-OH (1 equiv.) was attached to the resin (1 equiv.) with DIPEA (3
equiv.) in DCM at r.t for 10 min and then DIPEA (7 equiv.) for 40 min. The remaining trityl
groups were capped adding 0.8 μL MeOH/mg resin for 10 minutes. After that, the resin was
filtered and washed with DCM (4 x 1 min), DMF (4 x 1 min). The loading of the resin was
determined by titration of the Fmoc group.33
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Peptide elongation. After the Fmoc group was eliminated, the resin was washed with DMF
(4 x 1 min), DCM (3 x 1 min), DMF (4 x 1 min). Amino acid coupling. Fmoc-XX-OH (3
equiv.) were incorporated with a 5-min pre-activation with DIPCDI (3 equiv.) and
OxymaPure (3 equiv.) in DMF for 1h. The completion of the coupling was monitored with the
ninhydrin test (free amine group).34 Then, the resin was filtered and washed with DCM (4 x 1
min) and DMF (4 x 1 min) and the Fmoc group was eliminated.
Final cleavage. The resin bound peptide was treated with 5 % TFA in DCM (5 x 1 min).
The resin was washed with DCM and the combined eluates were evaporated under vacuum.
Then, the residue was dissolved in ACN:H2O and liophilized furnishing the corresponding
peptide.
H-Met-Gly-Trp(C2-p-methylphenyl)-Ala-OH (6). Starting from 150 mg of 2-chlorotrityl
1
resin (0.92 mmol/g). Pale solid (purity  99%, HPLC). H-NMR (400 MHz, DMSO d6): δ
12.51 (s, 1H), 11.09 (s, 1H), 8.53 (t, J = 5.6 Hz, 1H), 8.20 – 8.07 (m, 5H), 7.74 (d, J = 7.9 Hz,
1H), 7.58 (d, J = 8.0 Hz, 2H), 7.31 – 7.28 (m, 2H), 7.10 – 7.02 (m, 1H), 6.97 (t, J = 7.5 Hz,
1H), 4.76 (q, J = 7.6 Hz, 1H), 4.13 (p, J = 7.2 Hz, 1H), 3.85 (m, 1H), 3.78 (dd, J = 16.8, 5.4
Hz, 1H), 3.60 (dd, J = 16.8, 5.7 Hz, 1H), 3.26 (dd, J = 14.5, 5.7 Hz, 1H), 3.05 (dd, J = 14.5,
7.9 Hz, 1H), 2.48 (m, 2H), 2.37 (s, 3H), 2.03 (s, 3H), 1.99 – 1.88 (m, 2H), 1.22 (d, J = 7.2 Hz,
13
3H) ppm. C -NMR (100 MHz, DMSO): δ 173.6, 170.7, 168.2, 167.5, 136.6, 135.8, 135.5,
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129.9, 129.2, 129.0, 128.1, 121.2, 119.2, 118.5, 110.9, 107.0, 53.7, 51.5, 47.5, 41.6, 30.9,
28.3, 28.0, 20.8, 17.3, 14.4 ppm. HRMS (ESI) m/z calcd 554.2432 (C28H35N5O5S), found
554.2429 (M+H)+.
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H-Trp-Gly-Trp(C2-p-methylphenyl)-Ala-OH (7). Starting from 150 mg of 2-chlorotrityl
1
resin (0.92 mmol/g). Pale solid (purity  99%, HPLC). H-NMR (400 MHz, DMSO d6): δ
11.10 (s, 1H), 10.98 (d, J = 2.5 Hz, 1H), 8.72 (t, J = 5.5 Hz, 1H), 8.16 (dd, J = 8.0, 5.8 Hz,
2H), 7.97 (m, 3H), 7.75 (d, J = 7.9 Hz, 1H), 7.68 – 7.63 (m, 1H), 7.60 – 7.54 (m, 2H), 7.36 (d,
J = 8.1, 1H), 7.29 (d, J = 7.8 Hz, 2H), 7.19 (m, 1H), 7.08 (dddd, J = 8.1, 6.9, 5.8, 1.2 Hz, 2H),
6.98 (dddd, J = 8.0, 7.0, 4.4, 1.1 Hz, 2H), 4.79 (td, J = 8.3, 5.6 Hz, 1H), 4.14 (p, J = 7.2 Hz,
1H), 4.00 (m, 1H), 3.90 (dd, J = 16.9, 5.9 Hz, 1H), 3.45 (dd, J = 16.9, 5.0 Hz, 1H), 3.23 (ddd,
J = 35.5, 14.7, 5.2 Hz, 2H), 3.04 (m, 2H), 2.36 (s, 3H), 1.22 (d, J = 7.3 Hz, 3H) ppm. 13C -
NMR (100 MHz, DMSO): δ 173.6, 170.8, 168.6, 167.5, 136.6, 136.3, 135.8, 135.6, 130.0,
129.2, 129.0, 128.1, 127.0, 125.0, 121.2, 119.2, 118.5, 118.4, 111.5, 110.9, 107.0, 106.8, 53.6,
52.5, 47.6, 41.8, 27.52 (2 C), 20.8, 17.3 ppm. HRMS (ESI) m/z calcd 609.2820
(C34H36N6O5), found 609.2820 (M+H)+.
Acknowledgment
This work was supported by DGICYT – Spain (project BQU-CTQ2012-30930) and
Generalitat de Catalunya (project 2009SGR 1024).
Supporting Information Available
1
Spectral and analytical data: copies of the H, 13C and 19F NMR spectra for all new
compounds, chiral HPLC profiles of 5a and 5a’. This material is available free of charge via
the Internet at http://pubs.acs.org
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1 (a) Yukl, E. T.; Wilmot, C. M. Curr. Opin. Chem. Biol. 2012, 16(1-2), 54-59. (b) Abu, T.,
N.; Jensen, L. M. R.; Yukl, E. T.; Geng, J.; Liu, A.; Wilmot, C. M.; Davidson, V. L. Proc.
Natl. Acad. Sci. U. S. A. 2011, 108(41), 16956-16961.
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2 For the synthesis of a C2-arylated Trp derivative through a multistep sequence, see: Wang,
W.; Cai, M.; Xiong, C.; Zhang, J.; Trivedi D.; Hruby, V. J. Tetrahedron, 2002, 58, 7365-
7374.
3
For Pd-catalyzed allylations on Trp-derivatives, see: (a) Yokoyama, Y.; Hikawa, H.;
Mitsuhashi, M.; Uyama, A.; Hiroki, Y.; Murakami, Y. Eur. J. Org. Chem. 2004, 1244-1253.
(b) Hikawa, H.; Yokoyama, Y. Org. Biomol. Chem., 2011, 4044–4050.
4 (a) Rodrigues de Sa Alves, F.; Barreiro, E. J.; Fraga, C. A. M. Mini-Rev. Med. Chem.,
2009, 9, 782-793. (b) Zhao, H.; Donnelly, A. C.; Kusuma, B. R.; Brandt, G. E. L.; Brown, D.;
Rajewski, R, A.; Vielhauer, G.; Holzbeierlein, J.; Cohen, M. S.;. Blagg. B. S. J. J. Med.
Chem., 2011, 54, 3839–3853. (c) Painter, T. O.; Wang, L.; Majumder, S.; Xie X-Q.;
Brummond, K. M. ACS Comb. Sci., 2011, 13, 166-174.
5 (a) Johansson, H.; Jorgensen, T. B.; Gloriam, D. E.; Braeuner-Osborne, H.; Pedersen, D.
S. RSC Adv. 2013, 3(3), 945-960. (b) Gloriam, D. E.; Wellendorph, P.; Johansen, L. D.;
Thomsen, A. R. B.; Phonekeo, K.; Pedersen, D. S.; Braeuner-Osborne, H. Chem. & Biol.
(Cambridge, MA, United States), 2011, 18(11), 1489-1498.
6 Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875-2911.
7
For selected reviews, see: (a) Ackermann, L. Chem. Rev. 2011, 111, 1315-1345. (b)
McMurray, L.; O’Hara, F. O.; Gaunt, M. Chem. Soc. Rev. 2011, 40, 1885-1898. (c) Wencel-
Delord, J.; Dröge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev. 2011, 40, 4740-4761. (d) Chen, X.;
Engle, K. M.; Wang D.-H.; Yu, J.-Q. Angew. Chem. Int. Ed., 2009, 48, 5094-5115. (e)
Alberico, D.; Scott M. E.; Lautens, M.; Chem. Rev. 2007, 107, 174-238. (f) Mendoza P.;
Echavarren A. In Modern Arylation Methods; Ackermann, L. Ed.; Wiley-VCH, Weinheim,
2009; 363-399.
8 For C-H arylation of indoles, see: (a) Beck, E. M.; Gaunt, M. J. In C-H Activation; Yu, J.-
Q.; Shi, Z.; Eds., Topics in Current Chemistry 292, Springer-Verlag, Heidelberg, 2010, 87–
121. (b) Lebrasseur, N.; Larrosa, I. Adv. Heterocycl. Chem. 2012, 105, 309-351. (c)
Lebrasseur, N.; Larrosa, I. J. Am. Chem. Soc. 2008, 130, 2926-2927.
9 Ruiz-Rodríguez, J.; Albericio, F.; Lavilla, R. Chem. Eur. J. 2010, 16, 1124-1127.
10 For a recent peptide macrocyclization via Pd-catalyzed C-H arylation of the side-chains
of Trp with iodo-containing amino acids, see: Dong, H.; Limberakis, C.; Liras, S.; Priceb, D.;
James, K. Chem. Commun. 2012, 48, 11644-11646.
11 Sharma, A.; Vacchani, D.; Van der Eycken, E. Chem. Eur. J. 2013, 19, 1158-1168.
12 Hughes, A.B. ed. Amino Acids, Peptides and Proteins in Organic Chemistry. Vol.3 –
Building Blocks, Catalysis and Coupling Chemistry Wiley-VCH Verlag GmbH & Co. KGaA,
Weinheim (Germany), (2011).
13 For previous stepwise syntheses of racemic 2-aryltrptophans, see: (a) Majchrzak, M. W.;
Zobel, J. N.; Obradovich, D. J. Synth. Commun. 1997, 27(18), 3201-3211. (b) Balsamini, C.;
Diamantini, G.; Duranti, A.; Spadoni, G.; Tontini, A. Synthesis 1995, (4), 370-2.
14 (a) Chiong, H. A.; Pham, Q.-N.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 9879-9884.
(b) Thirunavukkarasu, V. S.; Parthasarathy, K.; Cheng, C.-H. Angew. Chem. Int. Ed. 2008, 47,
9462-9465.
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15 (a) Garcia-Cuadrado, D.; de Mendoza, P.; Braga, A. A. C.; Maseras, F.; Echavarren, A.
M. J. Am. Chem. Soc. 2007, 129, 6880-6886. (b) Gorelsky, S. I.; Lapointe, D.; Fagnou, K. J.
Am. Chem. Soc. 2008, 130, 10848-10849, and references cited therein.
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16 Weibel, J.-M.; Blanc, A.; Pale, P. Chem. Rev. 2008, 108, 3149-3173.
17 The Trp free amino acid may form stable Pd complexes that quench the reaction. For
instance, see: Beck, W. Pure Appl. Chem. 1988, 60, 1357-1362.
18 (a) For a fluoresent Trp surrogate, see: Moroz, Y. S.; Binder, W.; Nygren, P.; Caputod, G.
A.; Korendovych, I. V. Chem. Commun., 2013, 49, 490-492. (b) The pyrenyl group is
commonly used as a protein fluorophore, attached to cystein: Kouyama, T.; Mihashi, K. Eur.
J. Biochem. 1981, 114, 33-38.
19 Although the HPLC profiles are slightly overlapped and a low level of racemization can
not be excluded, the incorporation of these amino acids into peptides through SPPS (see
below) does not show evidence of diastereomer formation, therefore indicating that the
racemization in the Pd-catalyzed reaction, if any, should be minimal.
20 (a) Strader L. C; Bartel B. Molecular plant, 2011, 4(3), 477-86. (b) Labavitch, J. M. Proc.
Plant Growth Regul. Soc. Am., 1999, 26th, 13-14.
21 Paquet, J.-L.; Barth, M.; Pruneau, D.; Dodey, P. PCT Int. Appl. 2001, WO 2001038305 A2
20010531.
22
2-Arylated indole butyric acids are also found in other applications: (a) Slade, R.;
Klimova, Y.; Halter, Robert J.; Yungai, A. J.; Weiner, W. S.; Walton, R. J.; Willardsen, J. A.;
Anderson, M. B.; Zavitz, K. U.S. Pat. Appl. Publ. 2008, US 20080249135 A1 20081009. (b)
Rolland, C.; Gozalbes, R.; Nicolaie, E.; Paugam, M.-F.; Coussy, L.; Barbosa, F.; Horvath, D.;
Revah, F. J. Med. Chem. 2005, 48(21), 6563-6574.
23 For some relevant examples: (a) Arisawa, M.; Kasaya, Yayoi; O., Tohru; S., Takuma; I.,
Mika; A., Hiroshi; I., Yoshihiro; Y., Akihito; S., S. ACS Med. Chem. Lett. 2011, 2(5), 353-
357. (b) Girisha, M.; Badiger, J.; Purohit, M. G.; Thippeswamy, B. S.; Patil, B. M. Indian J.
Heterocycl. Chem. 2008, 17(3), 275-276. (c) Yang, Z.; Reiling, S.; Nieduzak, T. R.; Mathew,
R. M.; Jackson, S.; Harris, K. J. PCT Int. Appl. 2008, WO 2008014186 A1 20080131.
24 For instance, see: Vicente, J.; Saura-Llamas, I.; García- López, J.-A. Organometallics,
2009, 28, 448-464.
25 Wang, X.; Gribkov, D. V.; Sames, D. J. Org. Chem. 2007, 72, 1476-1479.
26 Chambers, J. J.; Kurrasch-Orbaugh, D. M.; Parker, M. A.; Nichols, D. E. J. Med. Chem.
2001, 44, 1003-1010.
27
Rivera, E.; Belletete, M.; Zhu, X. X.; Durocher, G.; Giasson, R. Polymer,
2002, 43(19), 5059-5068.
28 Arisawa, M.; Kasaya, Y.; Obata, T.; Sasaki, T.; Nakamura, T.; Araki, T.; Yamamoto, K.;
Sasaki, A.; Yamano, A.; Ito, M.; Abe, H.; Ito, Y.; Shuto, S. J. Med. Chem. 2012, 55,
8152−8163.
29 Jennings, L. D.; Foreman, K. W.; Rush, T. S. III; Tsao, D. H. H.; Mosyak, L.; Kincaid, S.
L.; Sukhdeo, M. N.; Sutherland, A. G.; Ding, W.; Kenny, C. H.; Sabus, C. L.; Liu, H.;
Dushin, E. G.; Moghazeh, S. L.; Labthavikul, P.; Petersen, P. J.; Tuckmand, M.; Ruzind, A.
V. Bioorg. Med. Chem. 2004, 12, 5115–5131.
30 Saleha, S.; Khan, N. H.; Siddiqui, A. A.; Kidwai, M. M.; Indian J. Chem., Sect. B. 1978,
16B, 1122-1124.
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Page 25 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
31 C. A. Bunders, M. J. Minvielle, R. J. Worthington, M. Ortiz, J. Cavanagh, C. Melander. J.
Am. Chem. Soc. 2011, 133, 20160–20163.
32 Wang, X.; Gribkov, D. V.; Sames, D. J. Org. Chem. 2007, 72, 1476-1479.
33 W. Chan, P. D. White, Fmoc Solid Phase Peptide Synthesis, Oxford University Press,
New York, 2000.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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34
35
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37
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
34 E. Kaiser, R. L. Colescott, C. D. Bossinger, P. I. Cook, Anal. Biochem. 1970, 34, 595-
598.
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